Cardiovascular Medicine

Cardiovascular Medicine
Risk Factors and Primary Prevention of Coronary Artery Disease

Coronary artery disease is the major health problem in the United States and other industrialized countries. In the developing world, the prevalence has been increasing and is predicted to continue to do so over the next 20 years. In conjunction with cerebrovascular disease, coronary artery disease is projected to soon become the leading cause of death worldwide.
Epidemiology
It is estimated that 60 million persons in the United States (about one fifth of the population) have coronary artery disease. More than 1 million acute myocardial infarctions occur yearly, of which one third are recurrent and 20% to 30% cause sudden death. Coronary artery disease is the most common cause of out-of-hospital death in the United States. Most coronary events occur in persons older than 65 years of age. Although mortality rates from coronary artery disease have been decreasing in the United States and other western countries over the past 30 years, the total burden of coronary artery disease is not decreasing because the number of older persons continues to increase. Long-term results of the Framingham Heart Study predict the lifetime risk for coronary artery disease at 40 years of age to be 49% in men and 32% in women. At 70 years of age, the lifetime risk is 35% for men and 24% for women (Lloyd-Jones et al.). Risk factors have been identified that are directly linked to the development of coronary artery disease (Table 1) and that may predispose to coronary artery disease. In addition, several potential risk factors remain the subject of clinical investigation and ongoing epidemiologic research. Emerging important factors in the pathogenesis of atherosclerosis include inflammation, insulin resistance, and various nonlow-density lipoprotein cholesterol lipid moieties. Nevertheless, the classic coronary artery disease risk factors contribute to the increased incidence and prevalence of coronary artery disease, and prediction algorithms have repeatedly confirmed the usefulness of identifying and treating these traditional risk factors. For most of the definite risk factors, such as dyslipidemia, effective treatment is associated with a decrease in morbidity and mortality from coronary artery disease (Shepherd et al.; Downs et al.). Evolving and new developments in primary prevention include: 1. Increasing evidence that dyslipidemia is a crucial factor in coronary artery disease and that lipid lowering is beneficial in healthy persons at increased risk for vascular disease; 2. Because diabetes mellitus is an important and particularly dangerous risk factor for both coronary artery disease and stroke, patients with diabetes should receive aggressive primary prevention measures directed toward reducing their coronary artery disease risk; 3. Contrary to prior belief, female hormone replacement therapy does not reduce the risk of vascular disease; 4. Demonstration of the lack of efficacy for antioxidant therapy with vitamin E, vitamin C, and -carotene.
Lloyd-Jones DM, Larson MG, Beiser A, Levy D. Lifetime risk of developing coronary heart disease. Lancet. 1999;353:89-92. PMID: 10023892 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;333:1301-7. PMID: 7566020 Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Trial. JAMA. 1998;279:1615-22. PMID: 9613910
KEYPOINTS
The current estimated lifetime risk for coronary artery disease at age 40 years is 49% for men and 32% for women; at 70 years, the lifetime risk is 35% for men and 24% for women. Newly recognized factors in the pathogenesis of atherosclerosis include inflammation, insulin resistance, and various nonlow-density lipoprotein cholesterol moieties.
Major Risk Factors and Risk Assessment
TA B L E 1 Risk Factors for Coronary Artery Disease
Major risk factors Hypertension

KEYPOINTS
An elevated plasma triglyceride concentration is an independent risk factor for coronary artery disease and should be treated; the desirable concentration is less than 150 mg/dL. In patients who are at high risk for coronary artery disease, hypertension should be treated with an angiotensinconverting enzyme inhibitor or angiotensin receptor blocker. However, in black patients, a diuretic should be considered as first-line therapy. Type 2 diabetes mellitus is now considered a coronary artery disease equivalent, and risk factor targets for patients with diabetes are the same as those in patients with established coronary artery disease. Calculation of non-HDL cholesterol is recommended in patients with a plasma triglyceride concentration greater than 200 mg/dL and an LDL cholesterol concentration that is normal or at target level. The metabolic syndrome is defined as any three of the following: abdominal obesity, plasma triglyceride level greater than 150 mg/dL, HDL cholesterol level less than 40 mg/dL in men and less than 50 mg/dL in women, and a fasting plasma glucose level of 110 mg/dL or greater; the syndrome confers a major cardiovascular risk, and affected patients should be aggressively treated. Measurement of markers of inflammation (such as inflammatory cytokines, C-reactive protein, and adhesion molecules) is not recommended for population screening; however, measurement of highly sensitive C-reactive protein may be useful to detect enhanced absolute risk in patients with intermediate risk according to the Framingham criteria.
Diabetes Dyslipidemia (elevated LDL cholesterol, low HDL cholesterol) Family history of premature vascular disease Cigarette smoking Associated predisposing risk factors Obesity Metabolic syndrome Sedentary life style High-fat diet Other positive risk factors Lipoprotein abnormalities (small dense [pattern B] LDL cholesterol, increased lipoprotein(a), increased postprandial VLDL and IDL) Elevated homocysteine Impaired glucose tolerance Chronic infections Vascular inflammation Increased oxidative stress Renal insufficiency
HDL = high-density lipoprotein; IDL = intermediate-density lipoprotein; LDL = low-density lipoprotein; VLDL = very-lowdensity lipoprotein

Is the concentration of plasma triglycerides an independent risk factor for coronary artery disease? What is the first-line therapy for hypertension in patients at high risk for coronary artery disease? What are the treatment goals for modifiable coronary artery disease risk factors in patients with diabetes mellitus? In which patients is calculation of nonhigh-density lipoprotein cholesterol recommended? What are the defining clinical characteristics of the metabolic syndrome? Is measurement of newly defined risk factors such as inflammatory mediators (for example, C-reactive protein), lipid subfractions, and homocysteine indicated in primary prevention of coronary artery disease? What is the role of hormone replacement therapy in primary prevention of coronary artery disease?
Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97. PMID: 11368702
An aggressive approach toward primary prevention of coronary artery disease has been described by the most recent update of the National Cholesterol Educational Program Adult Treatment Panel III (NCEP ATP III). The panel adopted the Framingham Risk Scoring System to assign categories of risk based on the low-density lipoprotein (LDL) cholesterol level and major risk factors, including age, sex, family history, smoking, hypertension, and low plasma highdensity lipoprotein (HDL) cholesterol level (Table 2, Table 3). Patients with diabetes mellitus are considered to have the same risk as those with overt vascular disease. A high plasma HDL cholesterol level is considered a negative risk factor. With this risk stratification system, goals are set for initiating treatment for hyperlipidemia and specific goals are set for decreasing the LDL cholesterol level.
TA B L E 2 Estimate of 10-Year Risk for Men (Framingham Point Scores)
Age (y) 2034 3539 4044 4549 5054 5559 6064 6569 7074 7579 HDL Cholesterol Level (mg/dL) 60 5059 4049 <40
Total Cholesterol Points at Age Points at Age Points at Age Points at Age Points at Age Points Level (mg/dL) 2039 Years 4049 Years 50-59 Years 6069 Years 7079 Years 9 4 0 3 6 8 10 11 12 13 Systolic BP Points (mm Hg) 1 0 1 2 <120 120129 130139 140159 160 Point Total <0 0 1 2 3 4 5 6 7 8 9 10 10-Year Risk (%) <1 1 1 1 1 1 2 2 3 4 5 6 <160 160199 200239 240279 280 0 4 7 9 11 0 3 5 6 8 0 2 3 4 5 0 1 1 2 3 0 0 0 1 1
Nonsmoker Smoker
0 8
0 5
0 3
0 1
0 1
If Untreated 0 0 1 1 2 Point Total 11 12 13 14 15 16 17
If Treated 0 1 2 2 3 10-Year Risk (%) 8 10 12 16 20 25 30
BP = blood pressure; HDL = high-density lipoprotein
On the basis of recent data, an elevated fasting triglyceride level is now an accepted independent risk factor and warrants treatment. The NCEP ATP III has decreased the desirable range of triglyceride from less than 200 to less than 150 mg/dL and emphasizes that a high triglyceride level may be a risk marker in association with other atherogenic lipid moieties. However, if the LDL cholesterol level is also increased, it should be the initial target of therapy. Many studies indicate that patients are often not prescribed appropriate drugs, or they are given the appropriate drug but not at a recommended dosage. Furthermore, therapy is commonly not maintained for more than 1 year. Through professional organizations, concerted efforts are being made to close this gap between guidelines and practice.
Cigarette Smoking
Cigarette smoking remains the most common preventable cause of illness in the United States. Twenty-five percent of Americans smoke. Rates are highest 3
TA B L E 3 10-Year Risk Estimates for Women (Framingham Point Scores)
Age (y) 2034 3539 4044 4549 5054 5559 6064 6569 7074 7579 HDL Cholesterol Level (mg/dL) 60 5059 4049 <40
Total Points Cholesterol 7 3 0 3 6 8 10 12 14 16 Systolic BP Points (mm Hg) 1 0 1 2 <120 120129 130139 140159 160 Point Total <9 9 10 11 12 13 14 15 16 17 18 19 <160 160199 200239 240279 280
Points at Age Points at Age Points at Age Points at Age Points at Age 2039 Years 4049 Years 5059 Years 6069 Years 7079 Years 0 4 8 11 13 0 3 6 8 10 0 2 4 5 7 0 1 2 3 4 0 0 1 2 2
Nonsmoker Smoker
0 9
0 7
0 4
0 2
0 1
If Untreated 0 1 2 3 4 10-Year Risk (%) <1 1 1 1 1 2 2 3 4 5 6 8 Point Total 20 21 22 23 24 25
If Treated 0 3 4 5 6 10-Year Risk (%) 11 14 17 22 27 30
BP = blood pressure; HDL = high-density lipoprotein
Ferry LH, Grissino LM, Runfola PS. Tobacco dependence curricula in US undergraduate medical education. JAMA. 1999;282:825-9. PMID: 10478687 Solberg LI, Boyle RG, Davidson G, Magnan SJ, Carlson CL. Patient satisfaction and discussion of smoking cessation during office visits. Mayo Clin Proc. 2001;76:138-43. PMID: 11213301
among women and young adults; however, recent data confirm that rates of smoking among youth have decreased. Passive exposure to tobacco smoke has been shown to have adverse effects. Physical addiction to nicotine and psychological dependence are the primary reasons for continuing to smoke. Smoking induces up-regulation of nicotine receptors that do not immediately return to baseline after cessation. Effective therapy to promote smoking cessation and counter nicotine addiction begins with an inquiry about smoking and includes counseling and pharmacologic therapy with nicotine replacement or bupropion. Most smokers make several attempts at smoking cessation before they are successful. A survey of U.S. medical schools found that only 21% of practicing physicians reported that they received adequate training to help their patients in smoking cessation (Ferry et al.). Another study reported that only 15% of smokers who saw physicians were offered assistance in smoking cessation (Solberg et al.). Detailed validated tools to aid smoking cessation as well as state and national smoking cessation resources are available from the National Cancer
Institute (http://smokefree.gov), the Centers for Disease Control and Prevention (www://cdc.gov/tobacco), and the office of the U.S. Surgeon General (www://surgeongeneral.gov/tobacco).
Hypertension
Hypertension is discussed in detail in the Nephrology and Hypertension book of MKSAP 13, and only issues relevant to primary prevention of cardiovascular disease will be discussed here. Three important recent concepts merit emphasis:
A 10 Cumulative Incidence (%) 8 6 4 2 0
Women High normal
Normal
Optimal
10
12
14
Time (yr) No. at Risk Optimal 1875 Normal 1126 High normal 891 1867 1115 874 1851 1097 859 1839 1084 840 1821 1061 812 1734 974 722 887 649 520
B 14 Cumulative Incidence (%) 12 10 8 6 4 2 0
Men High normal Normal

FIGURE 1. Cumulative incidence of cardiovascular events in women (Panel A) and men (Panel B) without hypertension, according to blood pressure category at baseline examination. Vertical bars indicate 95% confidence intervals. Optimal blood pressure is a systolic pressure of less than 120 mm Hg and a diastolic pressure of less than 80 mm Hg. Normal blood pressure is a systolic pressure of 120 to 129 mm Hg or a diastolic pressure of 80 to 84 mm Hg. Highnormal blood pressure is a systolic pressure of 130 to 139 mm Hg or a diastolic pressure of 85 to 89 mm Hg. If the systolic and diastolic pressure readings for a subject were in different categories, the higher of the two categories was used.
Reproduced with permission from: Vasan RS, Larson MG, Leip EP, Evans JC, ODonnell CJ, Kannel WB, Levy D. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl Med. 2001;345:1291-7.
Optimal
10
12
14
Time (yr) No. at Risk Optimal 1005 Normal 1059 High normal 903
995 1039 879
973 1012 857
962 982 819
934 952 795
892 892 726
454 520 441
Vasan RS, Larson MG, Leip EP, Evans JC, ODonnell CJ, Kannel WB, Levy D. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med. 2001;345:1291-7. PMID: 11794147 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-72. PMID: 12748199 Vollmer WM, Sacks FM, Ard J, Appel LJ, Bray GA, Simons-Morton DG, et al. Effects of diet and sodium intake on blood pressure: subgroup analysis of the DASHsodium trial. Ann Intern Med 2001;135:1019-28. PMID: 11747380 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359: 1004-10. PMID: 11937179
in general, the lower the blood pressure, the better; the choice of antihypertensive drug class may have substantial impact on clinical outcomes; and elevated systolic pressure is as an important target for therapy, particularly in elderly persons. Evidence suggests that hypertension is not adequately controlled in the majority of Americans receiving treatment. The Framingham Offspring Study, which followed 6859 participants over 10 years, demonstrated that adverse clinical events are related to blood pressure cut-points even within the normal range (Figure 1), with the lowest event rate in persons with blood pressure less than 120/80 mm Hg and the highest in persons with blood pressure values considered high-normal (Vasan et al.). In participants older than 65 years, high-normal blood pressure was associated with an annual cardiovascular event rate greater than 2% in men and a similar rate in women. Furthermore, previous data from the Hypertension Optimal Treatment (HOT) study, the Systolic Hypertension in the Elderly Program (SHEP) study, and the United Kingdom Prospective Diabetes Study (UKPDS) confirm that persons who achieve lower on-treatment blood pressure fare better than those with higher on-treatment blood pressure. The target or optimal blood pressure for healthy persons is less than 120 to 125 mm Hg systolic and 80 to 85 mm Hg diastolic. Even lower goals may be appropriate for high-risk patients with hypertension, such as AfricanAmericans, those with diabetes, overt proteinuria or an elevated creatinine concentration, or with documented coronary, vascular, or peripheral vascular disease. Much recent data confirm that an elevated pulse pressure or systolic pressure is more predictive of adverse outcomes than a high diastolic pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, released in May 2003, reaffirmed these precepts of hypertension therapy (Chobanian et al.). Lifestyle modifications play an important role in treatment of hypertension. These include weight loss, exercise, moderation of alcohol intake, and reduction of sodium intake. Maintenance of adequate potassium intake is important, particularly in persons taking diuretics. The Dietary Approaches to Stop Hypertension sodium substudy confirmed the benefit of a low-sodium diet plus the DASH diet of fresh fruit, vegetables, low-fat dairy products, whole grains, poultry, and fish (Vollmer et al.). Large trials published since the Sixth Joint National Committee examined the relative benefits of specific classes of antihypertensive agents with respect to cardiovascular outcomes. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared the rate of cardiovascular events in severely hypertensive patients with echocardiographic evidence of left ventricular hypertrophy treated with losartan or atenolol over a mean of 4.8 years. Despite similar decreases in blood pressure with the two agents (Figure 2), the rate of combined end point was lower in the losartan group primarily due to a 24% reduction in stroke. In the LIFE diabetic substudy, the advantages of treatment with this angiotensin receptor blocker were even more impressive (Lindholm et al.). The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) randomized approximately 45,000 patients to a diuretic (chlorthalidone), calcium channel blocker (amlodipine), an angiotensin-converting enzyme inhibitor (lisinopril), and an -blocker (doxazosin). The doxazosin arm was prematurely terminated due to an excess of heart failure. Monotherapy controlled blood pressure in approximately two thirds of patients in each of the three remaining arms, but the treated blood pressure was slightly higher in the lisinopril group. Among the three arms, no difference was seen in the primary outcome of coronary heart disease mortality and nonfatal myocardial infarction. However, there was a slightly higher inci-
dence of heart failure with amlodipine compared with chlorthalidone. There was a higher incidence of combined cardiovascular outcomes, stroke, and heart failure when lisinopril was compared with chlorthalidone. The latter effect was limited to the subgroup of black patients. It seems reasonable to treat hypertension with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker in all high-risk patients with hypertension, such as those with diabetes, left ventricular hypertrophy, proteinuria, azotemia, or clinical or subclinical atherosclerotic vascular disease. However, black patients should probably receive a diuretic as first-line therapy. Diuretics are recommended to be a part of all multi-drug regimens.
Type 2 Diabetes
It is estimated that 6% to 8% of the U.S. population has recognized diabetes, and millions of other persons are unaware that they have diabetes or will become diabetic. Approximately 95% of diabetic persons have type 2 disease. Diabetes confers a risk for a major coronary event similar to known coronary artery (Haffner et al.), and most diabetics will die of cardiovascular disease. Because of the high incidence of adverse cardiovascular outcomes, the American Diabetes Association, American Heart Association, and NCEP ATP III have categorized type 2 diabetes as a major risk factor for coronary artery disease and a risk equivalent for coronary artery disease. Treatment goals for modifiable risk factors should be identical to those in patients with established cardiovascular disease.
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339:229-34. PMID: 9673301
16 Proportion of patients with first event (%) 14 12 10 8 6 4 2 0 0 Number at risk
Primary composite endpoint Atenolol Losartan
Adjusted risk reduction: 13 0%, p=0 021 Unadjusted risk reduction: 14 6%, p=0 009

12
18
24
30
36
42
48
54
60 66
FIGURE 2. Kaplan-Meier curves for primary composite endpoint.
Reproduced with permission from: Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, deFaire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.
Time (months)
90 87 6
46
45
44
43
43
42
41
41
40
38
45
44
44
43
42
42
41
40
39
38
18
Atenolol
88
94
14
49
89
05
35
66
92
21
54
18
Losartan
05
24
60
92
12
47
89
12
47
97
89
Hypertriglyceridemia
Calculation of non-HDL cholesterol content is recommended by the NCEP ATP III for patients with high triglyceride levels (>200 mg/dL) and an LDL cholesterol level that is normal or at the target value. Non-HDL cholesterol is computed by subtracting the HDL cholesterol level from the total cholesterol level. The treatment goal for nonHDL cholesterol is a value no more than 30 mg/dL above the patients LDL cholesterol target value according to NCEP ATP III. Some consider nonHDL cholesterol to be a better predictor of coronary artery disease than is LDL cholesterol. In addition to LDL cholesterol, non-HDL cholesterol accounts for atherogenic lipid particles, such as intermediate-density lipoprotein, very-low-density lipoprotein remnants, triglycerides, and lipoprotein(a).
Obesity
An estimated 50% to 60% of the U.S. population is overweight, of whom 23% are obese. The specific definition of overweight is a body mass index of 25 to 30 kg/m2. Obesity is diagnosed when the body mass index is greater than 30 kg/m2. Overweight and obesity are a particular problem in ethnic minority groups. Young obese men (but apparently not women) experience early atherosclerosis in proportion to their obesity status. Being overweight in early childhood or adolescence predicts adult obesity. The reasons for increasing body weight in the United States are not entirely clear, but the phenomenon is probably related to both increased energy intake and decreased total energy expenditure. Overweight and obese persons are at substantially increased risk for cardiovascular disease, including coronary artery disease, stroke, and heart failure. Recent data from the Framingham Heart Study confirm that obesity is associated with premature death and significantly decreased life expectancy (Peeters et al.). The combination of obesity and smoking results in even worse survival outcomes. In addition, other risk factors for coronary artery disease, such as hypertension, dyslipidemia, insulin resistance, and diabetes, tend to cluster in overweight persons. Overweight and obese persons are at high risk for having the metabolic syndrome.
Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003;138:24-32. PMID: 12513041 Wagner A, Simon C, Evans A, Ferrieres J, Montaye M, Ducimetiere P, Arveiler D. Physical activity and coronary event incidence in Northern Ireland and France: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 2002;105:2247-52. PMID: 12010905 Albert CM, Mittleman MA, Chae CU, Lee IM, Hennekens CH, Manson JE. Triggering of sudden death from cardiac causes by vigorous exertion. N Engl J Med. 2000;343:1355-61. PMID: 11070099 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. PMID: 11832527
Physical Inactivity
Regular moderate exercise has been shown to decrease risk for coronary artery disease and improve the coronary artery disease risk factor profile. The Prospective Epidemiological Study of Myocardial Infarction 5-year observational study in 9800 men demonstrated that greater leisure time and physical activity are associated with fewer coronary artery disease events (Wagner et al.). Although a small proportion of sudden deaths occur during vigorous exercise, the incidence of sudden death is inversely related to the degree of exercise participation (Albert et al.). One component of the benefit of exercise is based on its effect on risk factor modification. Physical activity is an important component of reducing and maintaining a desirable body weight. The Diabetes Prevention Program trial demonstrated that the incidence of new-onset diabetes is inversely related to regular exercise as well as weight loss (Knowler et al.). (Recommendations for maintenance exercise programs are discussed in the Primary Care Medicine book of MKSAP 13.)
The Metabolic Syndrome

The metabolic syndrome (also known as the dysmetabolic syndrome, Reavens syndrome, and syndrome X) is a variable complex of clinical and metabolic features that imparts an increased likelihood for coronary artery disease events 8
(Laaka et al.; Isomaa et al.). It occurs in at least 20% of the U.S. population. Among persons older than 60 years, the prevalence may be as high as 40%. Hispanic and African American persons are particularly at risk for the metabolic syndrome (Grundy). The NCEP ATP III defines the metabolic syndrome as any three of the following factors: abdominal obesity (waist circumference at the iliac crest >40 inches in men and >35 inches in women), a triglyceride level greater than 150 mg/dL, a low HDL cholesterol level (<40 mg/dL in men and <50 mg/dL in women), and a fasting glucose level of 110 mg/dL or greater (Table 4).
Newer Risk Factors for Coronary Artery Disease

The list of putative coronary artery disease risk factors is constantly increasing (Table 1). None of these have yet been conclusively proven to cause coronary artery disease or its progression. Their measurement is not currently recommended for routine screening in a primary prevention setting. However, focus on these risk factors may shift with mounting evidence of their importance.
Laaka HM, Laaksonen DE, Laaka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, et al. The metabolic syndrome and total and cardiovascular disease mortality in middleaged men. JAMA. 2002;288:2709-16. PMID: 12460094 Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care. 2001;24:683-9. PMID: 11315831 Grundy SM. Obesity, metabolic syndrome, and coronary atherosclerosis. Circulation. 2002;105:2696-8. PMID: 12057978
TA B L E 4 Clinical Identification of
the Metabolic Syndrome Risk Factor Abdominal obesity Men Women Triglyceride level HDL cholesterol Men Women Blood pressure Fasting glucose Defining Level Waist circumferance >102 cm (>40 in) >88 cm (>35 in) 150 mg/dL <40 md/dL <50 mg/dL 130/85 mm Hg 110 mg/dL
Inflammation and C-Reactive Protein

It has been fairly well established that inflammation plays a role in atherosclerotic disease. C-reactive protein is an acute-phase reactant that is produced by the liver in response to other inflammatory stimuli. Recent studies confirm that blood levels of C-reactive protein are related to the likelihood of myocardial infarction, stroke, and peripheral vascular disease in healthy men and women (Ridker et al.). Other inflammatory markers, such as serum amyloid A, fibrinogen, and interleukin-6, are also associated with coronary artery disease. It has not been established whether these reactants are actual risk factors that contribute to the pathogenesis of the disease or risk markers that are associated with the disease, but do not contribute to its pathogenesis. While current data do not support use of these markers of inflammation for widespread screening, highly sensitive C-reactive protein assays may help guide primary prevention therapy. A recent AHA/CDC Scientific Statement includes the following recommendations (Pearson et al.). Among the assays for inflammatory markers, the one for highly sensitive C-reactive protein is the most reliable and well studied. The average of two separate values, ideally obtained 2 weeks apart, should be used for risk stratification by using the following risk tertiles: low risk, less than 1.0 mg/dL; moderate risk, 1.0 to 3.0 mg/dL; and high risk, greater than 3.0 mg/dL. In patients with a highly sensitive C-reactive protein level greater than 10 mg/dL, another cause of inflammation should be sought and treated before the value is remeasured. The expert panel concluded that traditional risk assessment should be performed according to the Framingham criteria. Determination of highly sensitive C-reactive protein levels has merit as an optional test for persons with an intermediate risk of coronary heart disease (10year risk, 10% to 20%) to guide preventive therapy, such as a statin and aspirin. The panel also concluded that an elevated highly sensitive C-reactive protein level could provide additional incentive for patients to adhere to lifestyle modification regimens. Persons at very low risk (10-year risk <10%) and those at high risk (10-year risk >20%), as well as those with established coronary, peripheral, or cerebrovascular disease, do not need C-reactive protein testing because the role of risk factor modification is well established. At this time, there is no evidence from randomized controlled trials that decreasing C-reactive protein levels reduces ischemic events or disease severity or increases survival.
HDL = high-density lipoprotein Reproduced from: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. National Instiitutes of Health. NIH Publication No. 02-5215. September 2002. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm.
Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959-65. PMID: 11430324 Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO III, Criqui M, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: A statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003;107:499-511. PMID: 12551878
Sniderman AD, Furberg CD, Keech A, Roeters van Lennep JE, Frohlich J, Jungner I, Walldius G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment. Lancet. 2003;361:777-80. PMID: 12620753
Lipid Subfractions
Lipid subfractions, such as lipoprotein(a), and low-density lipoprotein particle size are being studied and appear to have additive value for risk assessment (Sniderman et al.). Lipoprotein(a) is a lipid particle with structural similarity to plasminogen. It has long been suspected to enhance thrombotic activity. Although routine assessment for primary prevention is not yet recommended, measurement of lipoprotein(a) may be warranted in patients with premature vascular disease or a strong family history. Niacin is the most effective drug to decrease lipoprotein(a) levels. The value of determining LDL particle size is controversial. Data suggest that larger, more buoyant LDL particles (pattern A) are less atherogenic, whereas smaller LDL particles (pattern B) are more atherogenic and have a greater oxidation potential. Patients with an elevated triglyceride level are most likely to have a preponderance of small LDL particles. Specific therapy to alter the size distribution of LDL particles is not available. Therefore, the goal in patients with established pattern B should be to decrease LDL cholesterol concentration to as low a level as possible. Postprandial measurements of triglycerides, intermediate-density lipoprotein, and very-low-density lipoprotein have been studied as predictors of vascular disease but cannot be recommended in routine clinical practice.
Homocysteine
Epidemiologic data from casecontrol and cross-sectional studies suggested a direct relationship between homocysteine levels and coronary vascular disease. However, not all prospective studies have provided convincing evidence of this relationship (Christen et al.). Although endothelial dysfunction and a proatherogenic state result from increased homocysteine levels, in patients with vascular disease, elevated homocysteine levels may represent an acute-phase reaction. Until ongoing randomized trials conclusively resolve the question of whether intervention with folic acid and B vitamins is beneficial, there is no consensus as to the need for routine measurement of plasma homocysteine or for treatment of homocysteinemia. Nevertheless, the apparent absence of an adverse effect of therapy makes it reasonable to administer folic acid with B vitamins in selected high-risk patients, especially those with premature coronary artery disease or elderly patients.
Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med. 2000;160:422-34. PMID: 10695683 Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med. 2001;134:629-36. PMID: 11304102 Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-9. PMID: 11565518
Renal Disease
Renal disease has a strong relationship to cardiovascular risk. Patients with endstage renal disease have an annual mortality rate from coronary artery disease of 20% to 25%. Mild renal insufficiency, as defined by a serum creatinine concentration greater than 1.5 mg/dL in women and greater than 2.0 mg/dL in men or a creatinine clearance of less than 70 mL/min, is present in 5% to 10% of the population and may be associated with increased risk for coronary artery disease. Diabetic persons represent 40% of those with mild renal insufficiency, and hypertensive persons account for approximately 30%. Whether efforts to preserve renal function will result in reduced cardiovascular mortality is still unproven. For example, recent studies examining tight glycemic control in diabetic patients showed a reduction in the incidence of nephropathy but no significant decrease in the incidence of myocardial infarction. On the other hand, trials have shown that angiotensin-converting enzyme inhibitors or angiotension receptor blockers reduce the risk of cardiovascular events in patients with renal abnormalities (Mann et al.; Brenner et al.).
10
Therapies in Primary Prevention
Infection
Although many reports suggest a relationship between the prevalence of coronary artery disease and previous viral or bacterial infection, available data do not support use of antibiotics to prevent or slow the progression of coronary artery disease. Current data are conflicting, and several large randomized clinical trials of antibiotics are under way.
Oxidative Stress
The role of oxidation due to free radical anions in the vasculature has been extensively investigated. Many atherogenic processes are activated or enhanced in the presence of oxidative stress. Nitric oxide availability is reduced and oxidation of LDL cholesterol is increased. Much basic and animal research data suggest that suppression of oxidative stress should help to slow, reverse, or even prevent atherothrombotic processes. The oxidative hypothesis resulted in numerous trials of antioxidant agents, particularly vitamins E and C. However, no difference was seen between placebo and antioxidative regimens, including vitamin E, in at least four major trials encompassing 46,000 persons with vascular disease or at high risk for cardiovascular events (Heart Protection Study). Therefore, therapy with antioxidants, such as vitamin E or C or -carotene, is currently not recommended for primary or secondary prevention of coronary artery disease.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22. PMID: 12114036
KEYPOINTS

What lipid levels indicate the need for initiation of pharmacotherapy for primary prevention of coronary artery disease? What are the target lipid levels for treatment in the primary prevention of coronary artery disease? Is combination lipid-lowering pharmacotherapy indicated in patients with the metabolic syndrome? What is the role of antiplatelet therapy in primary prevention of coronary artery disease? Are there any indications for hormone replacement therapy for primary prevention of coronary artery disease?
Case 1 A 46-year-old man requests consultation for high cholesterol. Recent laboratory values include a serum total cholesterol of 268 mg/dL, LDL cholesterol of 179 mg/dL, HDL cholesterol of 28 mg/dL, triglycerides of 320 mg/dL, and fasting plasma glucose of 120 mg/dL. He smokes 1 pack of cigarettes per day and is sedentary. He is moderately overweight with abdominal obesity; his body mass index is 27 kg/m2. Blood pressure is 150/95 mm Hg. The NCEP ATP III guidelines assigns the level of risk based on the Framingham score and sets goals for LDL cholesterol lowering based on the level of risk (Table 5).
Pharmacotherapy should be considered in a patient with coronary artery disease or a risk equivalent or those with two or more risk factors and a plasma LDL cholesterol concentration of 130 mg/dL or greater. The LDL goal for therapy is less than 100 mg/dL in those with coronary heart disease or a risk equivalent and less than 130 mg/dL in those with two or more risk factors. Combination pharmacotherapy may be required in patients with the metabolic syndrome to treat the dyslipidemia and the glucose intolerance. Low-dose aspirin (100 mg/d) is safer than higher doses and as effective for primary prevention; aspirin should be considered in patients at intermediate risk or high risk for cardiovascular events (10-year likelihood 10%); patients at low risk for cardiovascular events should not be advised to take aspirin as primary prevention. Hormone replacement therapy is not recommended for primary prevention of coronary artery disease.
Lipid Lowering
Treatment begins with lifestyle modifications including a diet low in saturated fat (<7% daily caloric intake); decreased cholesterol intake (<200 mg/d); and increased intake of soluble fiber, plant stanols, and sterols. Weight control and regular physical activity are important for all persons at risk. Lipid-modifying drug therapy is initiated if target LDL cholesterol goals are not reached with 11
TA B L E 5 Drug Therapy Considerations and Goals of Therapy for Primary Prevention
LDL Cholesterol Risk Category Multiple (2) risk factors 10-Year Risk for CAD >20% (includes all CAD risk equivalents*) 10%20% <10% 0 or 1 risk factor <10% Level to Consider Therapy (mg/dL) >100 130 160 190 Primary Goal of Therapy (mg/dL) <100 <130 <130 <160
CAD = coronary artery disease; LDL = low-density lipoprotein *Most patients with coronary artery disease risk equivalents have multiple risk factors and a 10-year risk >20%. They include patients with noncoronary forms of clinical atherosclerosis, diabetes, and multiple (2) risk factors with a 10-year risk >20% by Framingham scoring. When LDL cholesterol is 130 mg/dL, a cholesterol-lowering drug can be started concomitantly with therapeutic lifestyle changes. If baseline LDL cholesterol is 100 to 129 mg/dL, therapeutic lifestyle changes should be started immediately. Concomitant use of drugs is optional; several options for drug therapy are available (statins, bile-acid sequestrants, fibrates, nicotinic acid). When LDL cholesterol is in the range of 130 to 159 mg/dL, drug therapy can be used if necessary to reach the LDL cholesterol goal of <130 mg/dL, after an adequate trial of therapeutic lifestyle changes. When LDL cholesterol is in the range of 160 to 189 mg/dL, use of cholesterol-lowering drugs is optional, depending on response to therapeutic lifestyle changes. Reproduced from: Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Final Report. National Instiitutes of Health. NIH Publication No. 02-5215. September 2002. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm.
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999;341:410-8. PMID: 10438259
standard lifestyle changes. Statins, fibrates, bile acid sequestrants, or nicotinic acid can be used to decrease levels of low-density lipoprotein C. The choice of agent is determined by the lipid profile and the target lipid goals. Results from recent trials may suggest an even more aggressive approach than that recommended in NCEP ATP III. The recommended LDL cholesterol cut-points for initiation of pharmacologic therapy are more restrictive than those used in AFCAPS-TexCAPS or the Heart Protection Study. In the Heart Protection Study, many patients had a baseline LDL cholesterol level less than 130 mg/dL and some had levels less than 100 mg/dL. These patients experienced the same reduction in relative risk as did those with an LDL cholesterol level of 130 mg/dL or greater, although their actual risk for an event risk was smaller (Figure 3). Therefore, the results of the Heart Protection Study suggest that a statin should be considered in all diabetic patients or those with treated hypertension who are older than 55 years of age, regardless of baseline LDL cholesterol levels. Patients with the metabolic syndrome may require more than one class of lipid-lowering drugs. Fibrates are peroxisome proliferatoractivated receptor- activators used to treat the dyslipidemia seen the metabolic syndrome, which is characterized by a low HDL cholesterol level and a high triglyceride level (Rubins et al.). Niacin should be considered for low HDL cholesterol and high triglyceride levels but must be used with caution because it may worsen glucose tolerance. The patient in Case 1 has a significant burden of cardiovascular risk, with a Framingham 10-year risk score of 11% and an LDL cholesterol level greater than 130 mg/dL. He meets criteria for the metabolic syndrome and NCEP ATP III identifies his LDL cholesterol target goal of less than 130 mg/dL. Although appropriate therapeutic lifestyle changes, diet, and an exercise program is recommended, these measures may not adequately control his dyslipidemia. Therapy with a statin will lower his LDL cholesterol to target, but HDL cholesterol may not increase. Niacin would be an appropriate choice, with or without a statin, but it could precipitate overt diabetes in this patient with impaired glucose tolerance. A fibrate is unlikely to completely normalize the lipid profile. Consideration of aspirin therapy is appropriate. Chlorthalidone is
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a low-cost initial choice for treatment of his hypertension. Vigorous effects at smoking cessation are indicated.
Aspirin and Other Antiplatelet Agents

The widespread administration of aspirin in primary prevention of coronary artery disease remains controversial for several reasons. The optimal dose of aspirin has not been established, although recent studies and a recent metaanalysis conclude that low doses (100 mg) are safer and as effective as higher doses. Minor bleeding, mostly gastrointestinal, and a nonsignificant increase in hemorrhagic stroke are adverse effects of regular aspirin administration. Other unresolved matters include aspirin resistance and a possible adverse interaction between aspirin and angiotensin-converting enzyme inhibitors (Lauer). Recent recommendations are all based on the Framingham risk score but vary among the different organizations that have formulated guidelines. There is general agreement that intermediate- to high-risk patients (10-year risk of
Lauer MS. Clinical practice: aspirin for primary prevention of coronary events. N Engl J Med. 2002;346:1468-74. PMID: 12000818
Cause of death
Simvastatinallocated (10 269) 587 (57%) 194 (19%) 781 (76%)
Placeboallocated (10 267) 707 (69%) 230 (22%) 937 (91%)
Death rate ratio (95% Cl)
Vascular causes Coronary Other vascular Subtotal: any vascular Non-vascular causes Neoplastic Respiratory Other medical Non-medical Subtotal: any non-vascular ANY DEATH
083 (075091) p<0-0001
359 (35%) 90 (0 9%)
345 (34%) 114 (11%) 90 (09%) 21 (02%) 570 (56%) 1507 (147%) 095 (085107) p=04 087 (081094) p=0.0003 06 08 10 12 14
82 (08%) 16 (02%) 547 (5 3%)
1328 (129%)
0 4
Simvastatin better
Placebo better
FIGURE 3. Effects of simvastatin therapy on cause-specific mortality. Rate ratios (RR) are plotted (black squares with area proportional to the amount of statistical information in each subdivision) comparing outcome among participants allocated simvastatin to that among those allocated placebo, along with 95% confidence intervals (horizontal lines; ending with arrow when CI extends beyond scale). For particular subtotals and totals, the result and its 95% CI are represented by a diamond, with the RR (95% CI) and its statistical significance given alongside. Squares or diamonds to the left of the solid vertical line indicate benefit with simvastatin, but this is conventionally significant (P <0.05) only if the horizontal line or diamond does not overlap the solid vertical line. A broken vertical line indicates the overall RR for a particular subtotal or total.
Reproduced with permission from: MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
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Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286:954-9. PMID: 11509060 Catella-Lawson F, Reilly MP, Kapoor SC, Cucchiara AJ, DeMarco S, Tournier B, et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Engl J Med. 2001;345:1809-17. PMID: 11752357
cardiovascular event 15%) without overt vascular disease should receive lowdose (<100 mg/d) aspirin. Those at low annual risk for cardiovascular events should not be advised to take aspirin, but the level assigned to low risk varies from less than 6% to less than 10% risk over 10 years. When the estimated 10year risk is 10% to 15%, the decision to take low-dose aspirin can be left to the patient after careful discussion of the riskbenefit ratio. Independent of the Framingham risk score, the American Diabetic Association has recommended aspirin administration in all diabetic patients who have one additional risk factor for cardiovascular disease. Clopidogrel is an effective antiplatelet agent that should be considered for primary prevention only in high-risk patients who are allergic to or intolerant of aspirin. Aspirin resistance is a reduced antiplatelet effect of aspirin administration and may explain the absence of a protective effect in some patients. In the future, better ways to identify patients with aspirin resistance may lead to the use of alternative antiplatelet drugs, such as clopidogrel. Cyclooxygenase-2 inhibitors, which are nonsteroidal anti-inflammatory drugs selective for the cyclooxygenase-2 pathway, are widely prescribed for musculoskeletal pain. Recently, an analysis of data from the Vioxx Gastrointestinal Outcomes Research (VIGOR) study demonstrated a higher incidence of myocardial infarction in patients treated with the cyclooxygenase-2 inhibitor refocoxib compared to those treated with naproxen (Mukherjee et al.). Although the study was not designed to test the end point of cardiovascular outcomes, one possible inference from the VIGOR study is that this new class of agents provides less potent antiplatelet protection than the nonselective cyclooxygenase inhibitor. Others have argued the VIGOR results can be explained by antiplatelet effect specific to naproxen that are not seen with other NSAIDS, such as ibuprofen. Not all available data confirm the results of the VIGOR study, and this issue remains unresolved. However, it is recommended, that patients at high risk for coronary artery disease who are receiving a cyclooxygenase 2 inhibitor also receive low-dose aspirin. It is also recommended that aspirin be administered 2 hours before administration of ibuprofen, but not refocoxib and diclofenac, because of its potential for diminishing the antiplatelet effect of aspirin when given in reverse order (Catella-Lawson et al.).
Hormone Replacement Therapy

Estrogen has several favorable effects on vascular physiology: The hormone promotes endothelial-dependent vasodilation and inhibits inflammation, platelet aggregation, and smooth-muscle hyperplasia. On the basis of results of large observational studies, the beneficial role of hormone replacement therapy in preventing or slowing the onset of cardiovascular disease was widely accepted. This assumption was first challenged by two trials of secondary prevention. The Heart and Estrogen/progestin Replacement Study (HERS) studied the effect of hormone replacement therapy in older postmenopausal women with established coronary artery disease and demonstrated an adverse clinical outcome in the estrogenprogestin arm during the first 2 years of the trial (Grady et al.), and the ERA trial in a similar sample found no benefit (Herrington et al.). The Womens Health Initiative, a randomized controlled trial of estrogen and progesterone, was designed to test the role of hormone replacement therapy in the primary prevention of cardiovascular disease, stroke, breast cancer, and osteoporosis. In July 2002, the arm studying continuous estrogenprogestin therapy versus placebo was abruptly terminated because of an increased risk for invasive breast cancer and a composite index of several conditions (including stroke, pulmonary embolus, and total cardiovascular disease)
Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002;288:49-57. PMID: 12090862 Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, et al. Effects of estrogen replacement on the progression of coronaryartery atherosclerosis. N Engl J Med. 2000;343:522-9. PMID: 10954759
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(Rossouw et al.). This arm of the study included 16,608 healthy postmenopausal women 50 to 79 years old who were followed for a mean of 5.2 years (planned duration of 8 years). The arm of the study examining the role of unopposed estrogen in women with prior hysterectomy was continued because no adverse effect was demonstrated at this time point. Therefore, hormone replacement therapy can no longer be recommended for primary or secondary prevention of coronary artery disease. It is appropriate only to treat intolerable postmenopausal symptoms.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. JAMA. 2002;288:321-33. PMID: 12117397
Acute Coronary Syndromes

Each year in the United States, there are over 5 million visits to emergency departments for evaluation of chest pain. There are roughly 1.7 million hospitalizations each year for unstable angina and the closely related condition nonST-segment elevation myocardial infarction. In the United States alone, ST-segment elevation myocardial infarction occurs in roughly 1.5 million persons and accounts for roughly 0.6 million deaths each year. Data from the Framingham Study indicate that 45% of persons with myocardial infarction (MI) are younger than 65 years of age and 5% are younger than 40 years of age. With advances in the rapid diagnosis and management of acute ischemic heart disease, the mortality rate from coronary heart disease has decreased by 50% over the past three decades. Although the incidence of MI has decreased only slightly, the case fatality rate for patients with MI has decreased dramatically. In-hospital and out-of-hospital mortality rates for both men and women with MI have steadily decreased over the past several decades. The term acute coronary syndrome (ACS) refers to any component of the constellation of clinical syndromes caused by acute myocardial ischemia. It encompasses the spectrum from unstable angina to nonST-segment elevation MI to ST-segment elevation MI (Figure 4).
Acute Coronary Syndrome
No ST Elevation
ST Elevation
FIGURE 4. Nomenclature of acute coronary syndrome (ACS). The spectrum of clinical conditions ranging from UA to NQMI to QwMI is referred to as ACS.
NQMI = nonQ-wave myocardial infarction; NSTEMI = nonST-segment elevation myocardial infarction; QwMI = Q-wave myocardial infarction; UA = unstable angina Reproduced with permission from: Braunwald E. Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/unstable/unstable.pdf
NSTEMI
Myocardial Infarction Unstable Angina NQMI QwMI
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Unstable Angina and NonST-Segment Elevation Myocardial Infarction
ST-segment elevation MI is diagnosed in patients with a clinical presentation consistent with acute MI and electrocardiographic evidence of ST-segment elevation. The majority of patients with ST-segment elevation MI ultimately develop a Q-wave acute MI, while a minority develop nonQ-wave acute MI on subsequent electrocardiography. Patients who present with ischemic chest pain (termed possible ACS) but no ST-segment elevation are categorized as having unstable angina or nonSTsegment elevation MI. These two conditions are closely related and have similar pathophysiology and clinical presentations, but they differ in the severity of the myocardial ischemia. In nonST-segment elevation MI, ischemia is severe and results in a detectable release of biomarkers of myocardial injury, most commonly cardiac troponin I, troponin T, or the MB isoenzyme of creatine phosphokinase (creatine phosphokinase). In unstable angina, there is no detectable increase in these enzymes. Biomarkers of myocardial injury may be detected in the bloodstream hours after the onset of ischemic chest pain. However, at time of initial presentation, unstable angina and nonST-segment elevation MI may be indistinguishable, and principles of risk stratification and management apply to both entities. In most patients with nonST-segment elevation MI, a Q wave does not evolve on repeated electrocardiography, and disease is subsequently diagnosed as nonQ-wave acute MI; only a minority of patients with nonSTsegment elevation MI develop a Q wave. Acute coronary syndrome is characterized by an imbalance between myocardial oxygen supply and demand. This syndrome typically is caused by atherosclerotic coronary artery disease. The pathophysiology of ACS is characterized by atherosclerotic plaque rupture, formation of platelet and fibrin thrombi, and release of locally active vasoactive substances. Unstable angina and nonST-segment elevation MI are most commonly caused by a nonocclusive thrombus that develops on a disrupted atherosclerotic coronary artery plaque, resulting in reduced myocardial perfusion. Less commonly, unstable angina and nonST-segment elevation MI may be caused by severe coronary artery narrowing without thrombus. This may occur in patients with restenosis after percutaneous coronary intervention or those with progressive atherosclerosis. Rare causes of unstable angina and nonST-segment elevation MI include dynamic obstruction from intense coronary vasospasm of an epicardial coronary artery (termed Prinzmetals angina) and secondary unstable angina, in which the precipitating condition is extrinsic to the coronary arteries (that is, hypotension, hypoxemia, anemia, tachycardia, or thyrotoxicosis). The most common cause of ST-segment elevation MI is an occlusive thrombus that develops on a dissected or ulcerated atherosclerotic plaque, resulting in complete epicardial coronary artery occlusion.

What is the appropriate treatment of patients with unstable angina or nonSTsegment elevation MI? What are the roles of low-molecular-weight heparin and glycoprotein IIb/IIIa receptor inhibitors? What adjunctive therapies should be considered for management of unstable angina or nonST-segment elevation MI? When should early invasive coronary angiography be recommended for patients with unstable angina or nonST-segment elevation MI?
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Case 2 A 68-year-old postmenopausal woman with history of current smoking has had stable angina for 2 years. She takes aspirin daily and sublingual nitroglycerin on occasion. Over the past day, she has had three episodes of substernal chest discomfort with associated dyspnea at rest. The first two episodes were relieved with one sublingual nitroglycerin tablet, but the most recent episode was not relieved after three nitroglycerin tablets. She comes to the emergency department with decreased but continued chest discomfort. Electrocardiography shows 1-mm ST-segment depression in leads V2 to 5. Her troponin I level is mildly elevated at 2.2 ng/mL.
KEYPOINTS
Risk Stratification
Patients with unstable angina or nonST-segment elevation MI most frequently present with rest angina but may also describe patterns of new-onset or increasing angina (Table 6). Early risk stratification for patients with chest discomfort focuses on anginal symptoms, physical findings, 12-lead electrocardiography, and biomarkers of cardiac injury. The following clinical features, which are available from history and physical examination, increase the likelihood that a patients chest discomfort represents ACS: chest or left arm pain or discomfort, age 65 years or older, male sex, history of coronary artery disease or diabetes, pulmonary edema, and findings of noncardiac vascular disease. The following electrocardiographic and cardiac biomarker findings increase the risk of adverse cardiac events in patients with unstable angina or nonST-segment elevation MI: ST-segment deviation of 0.5 mm or greater or T-wave inversions with symptoms, and elevated levels of troponin I, troponin T, or creatine phosphokinase (Table 7). Recent studies reported that serologic markers of inflammation (C-reactive protein) and left ventricular dysfunction (B-type natriuretic peptide) provide unique prognostic information in addition to these clinical features and cardiac biomarkers (Sabatine et al.; de Lemos et al.). Although C-reactive protein and B-type natriuretic peptide may identify patients with inflammation or left ventricular dysfunction, respectively, these tests are still not indicated in the routine evaluation of patients with ACS. A simple seven-point risk estimation score has been established for patients with unstable angina or nonST-segment elevation MI. The Thrombolysis in Myocardial Infarction (TIMI) risk score is defined as the sum of seven individual prognostic variables (Table 8) (Antman et al.). Patients may be categorized as low (TIMI risk score, 0 to 2), intermediate (score, 3 or 4), or high risk (score, 5 to 7) according to the number of variables they fulfill. As the TIMI risk score increases, more aggressive therapies offer progressively greater benefit; these include low-molecular-weight heparin, glycoprotein IIb/IIIa receptor inhibitors, and an invasive management strategy (Figure 5).
TA B L E 6 Principal Presentations of Unstable Angina
Aspirin, heparin, nitrates, and -blockers are the foundation of management of acute coronary syndromes. Low-molecular-weight heparin (enoxaparin) is a suitable alternative to heparin for patients with acute coronary syndrome or ST-segment elevation myocardial infarction and those undergoing early percutaneous coronary intervention. Glycoprotein IIb/IIIa receptor inhibitors are indicated for high-risk patients with acute coronary syndrome (particularly ST-segment depression or an elevated cardiac troponin level) and those undergoing percutaneous coronary intervention. New evidence from randomized trials supports the addition of clopidogrel and statins, beginning early in the management of acute coronary syndromes. Intermediate- and high-risk patients with unstable angina or nonST-segment elevation myocardial infarction (STsegment depression, elevated cardiac biomarkers, or Thrombolysis in Myocardial Infarction risk score 3) benefit from an early invasive approach with coronary angiography rather than a conservative approach with noninvasive stress testing to assess risk.
Sabatine MS, Morrow DA, de Lemos JA, Gibson CM, Murphy SA, Rifai N, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105:1760-3. PMID: 11956114 de Lemos JA, Morrow DA, Bentley JH, Omland T, Sabatine MS, McCabe CH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med. 2001;345:1014-21. PMID: 11586953 Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/ non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835-42. PMID: 10938172
Rest angina New-onset angina Increasing angina
Angina occurring at rest, usually >20 minutes New-onset angina which markedly affects ordinary daily activity Previously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold
Adapted from: Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). 2002. Available at: http://www.acc.org/clinical/guidelines/ unstable/unstable.pdf.
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TA B L E 7 Early Indicators of High-Risk among Patients with Unstable Angina and NonST-Segment Elevation Myocardial Infarction
Clinical presentation
Rest angina Age 65 years Diabetes mellitus History of CAD, with coronary artery diameter stenosis 50% Need for intravenous nitroglycerin Hypotension Diaphoresis Pulmonary edema, S3 gallop
Physical examination
12-lead ECG Cardiac biomarkers Additional markers Angiographic findings Noninvasive testing
Transient mitral regurgitation ST-segment depression or transient elevation T-wave inversions with chest pain Elevated level of troponin I, troponin T, or creatine kinase-MB C-reactive protein, B-type natriuretic peptide Intracoronary thrombus High-grade atherosclerotic CAD Wall-motion abnormalities at rest or stress echocardiography Reversible perfusion defects on nuclear imaging
CAD = coronary artery disease; ECG = electrocardiography
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E. Outcome at 1 year after an invasive compared with a noninvasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial. FRISC II Investigators. Fast revascularisation during instability in coronary artery disease. Lancet. 2000;356:9-16. PMID: 10892758 Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344:1879-87. PMID: 11419424
Recent randomized trials have established that higher-risk patients with unstable angina or nonST-segment elevation MI benefit from a strategy of early invasive coronary angiography compared with a more conservative approach involving risk stratification with predischarge noninvasive stress testing (Wallentin et al.; Cannon et al.). The benefits of early coronary angiography include identification of left main or three-vessel coronary disease, assessment of coronary thrombus or plaque ulceration, measurement of left ventricular function, and facilitation of early coronary revascularization if indicated. In the modern era of interventional cardiology using coronary stenting and glycoprotein IIb/IIIa receptor inhibitors, patients with a TIMI risk score of 3 or greater, ST-segment depression, or elevated cardiac biomarkers seem to benefit from early coronary angiography and revascularization (Figure 6). For the patient in Case 2, the TIMI risk score is 5, identifying her as a high-risk patient who would probably benefit from an early invasive approach (Table 8). Her coronary angiograms (Figure 7 A and B) show a high-grade stenosis in the
35 30 25 20 15 10 5 0 Low (0-2) Intermediate (3-4) TIMI Risk Score High (5-7) 11.8 12.8 20.3 16.1 19.5 Conservative Invasive
FIGURE 5. Impact of the Thrombolysis In Myocardial Infarction (TIMI) risk score on 6-month adverse cardiac events (death, myocardial infarction, acute coronary syndrome rehospitalization) among patients randomized to conservative or invasive management in the TACTICS* TIMI-18 trial.
*TACTICS = Treat angina with Aggrastat and determine Cost of Therapy with an Invasive Conservative Strategy Adapted with permission from: Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis G, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284:835-42.
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6-Month Death/MI/ACS Rehosp (%)
30.6
TA B L E 8 The TIMI Risk Score for Patients with Unstable Angina
Prognostic Variables Age 65 years 3 CAD traditional risk factors Documented coronary disease with 50% coronary artery diameter stenosis ST-segment deviation 2 anginal episodes in the past 24 hours Aspirin use in the past week Elevated cardiac biomarkers (creatine kinase-MB or troponin) Risk Low Intermediate High Score* 02 34 57 Recommended Management Conservative or invasive Invasive Invasive
CAD = coronary artery disease; TIMI = Thrombolysis in Myocardial Infarction *The sum of the prognostic variables. Adapted from: Antman EM, Louwerenburg HW, Baars HF, Wesdorp JC, Hamer B, Bassand JP, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation. 2002;105:1642-9.
Aspirin -blockers Nitrates UFH or LMWH Monitoring (telemetry and daily ECGs)
Early invasive strategy: TIMI risk scores 3 ST-segment deviation Positive CK-MG or troponin
Early conservative strategy: TIMI risk scores <3 No ischemia on ECG Negative biomarkers
Add GP IIb/IIIa inhibitor Coronary angiography Recurrent symptoms Heart failure Serious arrhythmia Patient stabilizes
Stress test
Not Low risk LVEF .40
Low risk LVEF >.40
Follow on medical therapy
FIGURE 6. Algorithm for the management of patients admitted with unstable angina or nonSTsegment elevation myocardial infarction.
CK-MB = creatine kinase-MB; ECG = electrocardiography; GP = glycoprotein; LMWH = low-molecular-weight heparin; LVEF = left ventricular ejection fraction; TIMI = Thrombolysis in Myocardial Infarction; UFH = unfractionated heparin
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FIGURES 7A AND 7B. Coronary angiography in the patient in Case 2. Coronary angiography shows a high-grade stenosis (arrow) in the mid-portion of the left anterior descending (LAD) coronary artery, with mildly diminished filling of the distal vessel. There were no other significant coronary stenoses. Left ventriculography showed mild anteroapical hypokinesis with an ejection fraction of 45%. B. The patient underwent successful stenting (arrow) of the LAD, with restoration of normal flow in the distal vessel.
mid-left anterior descending coronary artery, which was treated with stenting with adjunctive glycoprotein IIb/IIIa receptor inhibition. Low-risk patients may undergo noninvasive exercise or pharmacologic stress testing with echocardiographic or nuclear imaging; if testing is positive, coronary angiography should be performed before hospital discharge.
Antman EM, Cohen M, McCabe C, Goodman SG, Murphy SA, Braunwald E. Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE. Eur Heart J. 2002;23:308-14. PMID: 11812067 Young JJ, Kereiakes DJ. Low-molecularweight heparin in percutaneous coronary intervention: ready for prime time? ACC Curr J Rev. 2002;11:59-64. ORourke RA, Hochman JS, Cohen MC, Lucore CL, Popma JJ, Cannon CP. New approaches to diagnosis and management of unstable angina and non-ST-segment elevation myocardial infarction. Arch Intern Med. 2001;161:674-82. PMID: 11231699 Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). 2002. Available at: http://www.acc.org/clinical/ guidelines/unstable/unstable.pdf.
Management
For the patient in Case 2, the goal of initial therapy should be control of chest pain with nitrates and narcotic analgesics, if necessary, and control of heart rate and blood pressure with a -blocker, given intravenously and then orally. She should receive a chewable aspirin in the emergency department. Oxygen and anxiolytics should be administered as needed. Anemia and acute infection should be excluded as contributing or precipitating factors. Twelve-lead electrocardiography should be performed and repeated at least daily if the character or intensity of the chest pain changes. Baseline cardiac biomarkers (troponin or creatine phosphokinase) should be measured on admission and then remeasured at least once more within 6 to 12 hours. While the patient is still in the emergency department, initiation of additional antithrombotic and antiplatelet therapy should be considered. Unfractionated heparin is beneficial in the management of unstable angina and nonST-segment elevation MI. Recent data from randomized clinical trials support the safety and efficacy of the low-molecular-weight heparin enoxaparin compared with unfractionated heparin (Antman et al., 2002). Compared with intravenous unfractionated heparin, the weight-based dosing of enoxaparin (1 mg/kg subcutaneously every 12 hours) has more predictable absorption owing to a low degree of protein binding, offers a more predictable anticoagulant effect, obviates the need to monitor partial thromboplastin time, has a higher activity against factor Xa, and has a lower incidence of thrombocytopenia. Enoxaparin should not be given to patients with severe obesity (>150 kg), thrombocytopenia, or a creatinine clearance less than 30 mL/min. Algorithms have been developed for the seamless integration of care for patients with unstable angina and nonST-segment elevation MI who require percutaneous coronary intervention while receiving treatment with low-molecular-weight heparin
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ST-Segment Elevation Myocardial Infarction
(Young and Kereiakes). Not all low-molecular-weight heparins have performed well in clinical trials of ACS; other agents, such as dalteparin, have not been shown to be superior to unfractionated heparin. High-risk patients with unstable angina or nonST-segment elevation MI should be considered for treatment with a glycoprotein IIb/IIIa receptor inhibitor (ORourke et al.). The small-molecule agents, such as tirofiban and eptifibatide, have been shown to provide benefit compared with heparin alone. Patients who present with ST-segment depression or elevated troponin or creatine phosphokinase levels, and those with a TIMI score of 3 or greater, should be considered for glycoprotein IIb/IIIa receptor inhibitor treatment (Braunwald et al.). Recent studies have shown that low-molecular-weight heparin and glycoprotein IIb/IIIa receptor inhibitors can be combined safely in patients with unstable angina or nonST-segment elevation MI (Goodman et al.). In addition to aspirin (81 to 325 mg/d, given orally), low-molecularweight heparin, and glycoprotein IIb/IIIa receptor inhibitors, the antiplatelet agent clopidogrel appears to offer further benefit to patients with unstable angina or nonST-segment elevation MI. Clopidogrel (300-mg loading dose, followed by 75 mg/d orally) reduced both early (48 hours) and late (1 year) refractory ischemia, MI, and stroke (Yusuf et al.). In the Clopidogrel in Unstable Angina to prevent Recurrent Events study, patients with unstable angina or nonST-segment elevation MI received clopidogrel for 9 months. A recent randomized trial demonstrated that atorvastatin, 80 mg/d, significantly reduced recurrent ischemia (Schwartz et al.). Administration of this high-dose statin early in the management of unstable angina or nonST-segment elevation MI appeared to have a beneficial effect in terms of plaque stabilization. The incidence of stroke was also significantly reduced over the 4-month study period. It is still unclear whether other statins or lower doses of atorvastatin offer a similar benefit. However, a recent study showed that atorvastatin may decrease with the antiplatelet effect of clopidogrel. Simvastatin and lovastatin also may have a similar drug interaction due to P450 hepatic metabolism. Pravastatin, which does not have this interference, is a reasonable substitute for combination therapy with clopidogrel and a statin (Lau et al.).
Goodman SG, Fitchett D, Armstrong PW, Langer A. The Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial. INTERACT Trial Investigators. In: Program and Abstracts of the American College of Cardiology 51st Annual Meeting, March 1720, 2002, Atlanta, Georgia. Abstract 405-5. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. N Engl J Med. 2001;345: 494-502. PMID: 11519503 Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285:1711-8. PMID: 11277825 Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp SA, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation. 2003;107:32-7. PMID: 12515739
KEYPOINTS

What clinical factors identify patients with ST-segment elevation MI who are at high-risk for adverse events? What is the best approach to the management of ST-segment elevation MI? What adjunctive measures should be used? When should coronary angiography be considered for patients who have received thrombolytic agents for management of ST-segment elevation MI?
Case 3 A 52-year-old man with a history of hyperlipidemia, obesity, and adult-onset diabetes mellitus was brought to the emergency department by ambulance within 60 minutes of onset of severe substernal chest pain with associated dyspnea and diaphoresis. Blood pressure is 100/80 mmHg, with a heart rate of 80/min. His lung fields are clear to auscultation. Electrocardiography shows 3-mm ST-segment elevation in leads II, III, and aVF, with no Q waves.
Advancing age, anterior-wall myocardial infarction (MI), and evidence of heart failure are the three most important clinical factors that identify high-risk patients with ST-segment elevation MI. Immediate reperfusion therapy with either percutaneous coronary intervention or thrombolysis should be performed as soon as possible after identification of ST-segment elevation. An oral angiotensin-converting enzyme inhibitor should be started within 24 hours in patients with anterior MI, signs or symptoms of congestive heart failure, or reduced left ventricular ejection fraction. An angiotensin-converting enzyme inhibitor generally should not be prescribed for patients with hypotension or hyperkalemia, those with severe renal insufficiency (creatinine level 3.0 mg/dL) who are not dialysis dependent, or those with bilateral renal artery stenosis. Coronary angiography should be performed after thrombolysis in patients with evidence of failure to reperfuse, recurrent angina, congestive heart failure, or residual myocardial ischemia on noninvasive stress testing.
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Early Risk Stratification

The initial history and physical examination performed in the emergency department provides important information for immediate risk stratification of patients with ST-segment elevation MI. The most important predictors of mortality identified at presentation include age, clinically evident heart failure, diabetes mellitus, renal failure, and previous MI. The time of presentation is also important: Patients who present more than 12 hours after the onset of symptoms are less likely to have successful reperfusion and have a worse prognosis. The initial 12-lead electrocardiogram can identify patients at higher risk for adverse events. Patients with anterior-wall MI, right ventricular MI, and advanced atrioventricular block are at increased risk. The TIMI risk score in patients with ST-segment elevation MI is also useful for estimating prognosis by using variables readily available in the emergency department (Table 9) (Morrow et al.). The 14-point risk score is based on advancing age, evidence of heart failure, anterior wall infarction, and late time to reperfusion therapy. As the score increases, the 30-day risk for death in patients with ST-segment elevation MI increases from 0.8% (risk score of 0) to 36% (risk score >8).
Morrow DA, Antman EM, Giugliano RP, Cairns R, Charlesworth A, Murphy SA, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet. 2001;358:1571-5. PMID: 11716882 Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996;28:1328-428. PMID: 8890834
Management
Patients with ST-segment elevation MI should promptly be treated with aspirin, narcotic analgesics, intravenous nitroglycerin, and intravenous -blockers (Ryan et al.). Suitable candidates should receive immediate reperfusion therapy with thrombolysis or percutaneous coronary intervention. The advantages of thrombolysis include its ease of use, whereas the advantages of primary percutaneous coronary intervention include higher vessel patency rates, lower reinfarction and stroke rates, and immediate risk stratification. Treatment outcomes are closely related to achievement of early, complete, and sustained reperfusion. Thrombolysis should be started within 30 minutes of entry to the emergency department; for percutaneous coronary intervention, the infarct-related artery should be recanalized within 90 minutes. There are four subgroups in which
TA B L E 9 The TIMI Risk Score for Patients with ST-Segment Elevation Myocardial Infarction
Prognostic Variables Historical Age 75 years Age 6574 years Diabetes, hypertension, or angina Physical Examination Systolic blood pressure <100 mm Hg Heart rate >100/min Killip class IIIV Weight <67 kg (150 lb) Presentation Anterior ST-segment elevation or left bundle-branch block Time to reperfusion therapy >4 hours Risk score = total points (014)
TIMI = Thrombolysis in Myocardial Infarction *The total of the prognostic variables.
Points
Risk Score*
30-Day Mortality Rate (%)
3 2 1
0 1 2 3 4 5 6 7 8 >8
0.8 1.6 2.2 4.4 7.3 12 16 23 27 36
3 2 2 1
1 1
Adapted from: Morrow DA, Antman EM, Giugliano RP, Cairns R, Charlesworth A, Murphy SA, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet. 2001;358:1571-5.
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percutaneous coronary intervention is preferred because of concerns about the safety or efficacy of thrombolysis: patients in whom thrombolysis is contraindicated (Table 10), those presenting more than 12 hours since the onset of chest pain and who have continued chest pain or ST-segment elevation, those with a history of coronary artery bypass graft surgery, and those with cardiogenic shock (pulmonary edema and systolic blood pressure less than 100 mm Hg). The most important risk of thrombolysis is bleeding, particularly intracranial hemorrhage. This complication is more common in patients with a history of chronic severe hypertension, those who present with severe hypertension, and elderly persons. Contraindications to and cautions about thrombolytic agents are listed in Table 10. Evidence of successful thrombolysis involves resolution of both chest pain and ST-segment elevation. The rapidity with which these resolve is directly related to early patency of the infarct-related artery. Reperfusion arrhythmias, typically manifested as a transient accelerated idioventricular arrhythmia, usually do not require additional antiarrhythmic therapy. In the past 5 years, significant advances have been made in thrombolytic and primary percutaneous coronary intervention strategies. Tissue plasminogen activator achieves normal coronary flow in the infarct-related artery at 60 minutes in 50% to 55% of cases. Newer thrombolytic agents, such as tenecteplase and reteplase, are administered as a single or double bolus, respectively. Pilot coronary angiographic studies showed that patency rates were improved by combining full-dose glycoprotein IIb/IIIa receptor inhibitors with half-dose thrombolytic agents. In large clinical trials, this combination therapy reduced reinfarction rates but had no significant effect on mortality (Topol; ASSENT-3 Investigators). Diabetic patients and older patients had higher rates of adverse
TA B L E 1 0 Absolute and Relative Contraindications for the Use of Thrombolytic Agents To Treat ST-Segment Elevation Myocardial Infarction
Topol EJ. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. The GUSTO V Investigators. Lancet. 2001; 357:1905-14. PMID: 11425410 Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet. 2001;358:605-13. PMID: 11530146
Absolute Contraindications Any hemorrhagic stroke Nonhemorrhagic stroke or cerebrovascular events within the past year Known intracranial neoplasm Active internal bleeding, or active peptic ulcer disease (does not include menses) Suspected aortic dissection Blood pressure >180/110 mm Hg despite antihypertensive medication Relative Contraindications Blood pressure >180/110 mm Hg initially at presentation, but lower with medication History of chronic severe hypertension History of intracerebral pathologic condition History of proliferative diabetic retinopathy Current uses of anticoagulants in therapeutic doses (INR 2.0); known bleeding diathesis Recent trauma or major surgery (within 4 weeks), or prolonged CPR (>10 minutes) Recent internal bleeding (within 4 weeks) Noncompressible vascular punctures Pregnancy For streptokinase or anistreplase: previous exposure (within 2 years) or previous allergic reaction
INR = international normalized ratio; CPR = cardiopulmonary resuscitation Adapted from: Ryan TJ, Anderson JL, Antman EM, Braniff BA, Brooks NH, Califf RM, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1996;28:1328-428.
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Antman EM, Louwerenburg HW, Baars HF, Wesdorp JC, Hamer B, Bassand JP, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation. 2002;105:1642-9. PMID: 11940541 Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med. 2001;344:1895-903. PMID: 11419426 Stone GW, Grines CL, Cox DA, Garcia E, Tcheng JE, Griffin JJ, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med. 2002;346:957-66. PMID: 11919304 Aversano T, Aversano LT, Passamani E, Knatterud GL, Terrin ML, Williams DO, Forman SA. Thrombolytic therapy vs primary percutaneous coronary intervention for myocardial infarction in patients presenting to hospitals without on-site cardiac surgery: a randomized controlled trial. JAMA. 2002;287:1943-51. PMID: 11960536 Andersen HR. The Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction. DANAMI-2 Study Group. Program and Abstracts of the American College of Cardiology 51st Annual Meeting, March 17-20, 2002, Atlanta, Georgia. Abstract 421.4
events with combination therapy. Use of low-molecular-weight heparin instead of unfractionated heparin with newer thrombolytic strategies not only improves ease of administration but also is associated with lower rates of recurrent ischemic complications (Antman et al.). The strategy of primary percutaneous coronary intervention has evolved into facilitated percutaneous coronary intervention, which includes the use of half-dose thrombolytics and/or glycoprotein IIb/IIIa receptor inhibitors before planned immediate percutaneous coronary intervention (Montalescot et al.; Stone et al.). At this time, coronary stenting with adjunctive glycoprotein IIb/IIIa receptor inhibitors appears to be the optimal immediate reperfusion strategy if access to cardiac catheterization facilities is readily available. The patient in Case 3 underwent immediate percutaneous coronary intervention. Coronary angiography (Figure 8 A and B) shows thrombotic occlusion of the mid right coronary artery, which was treated successfully with coronary stenting and adjunctive glycoprotein IIb/IIIa inhibition. Several recent trials have randomized thrombolytic-eligible patients with ST-segment elevation MI to receive thrombolysis with front-loaded tissue plasminogen activator or primary percutaneous coronary intervention. Both the Atlantic Cardiovascular Patient Outcomes Research Team (CPORT) trial (Aversano et al.) and the Danish Trial in Acute Myocardial Infarction 2 (DANAMI) (Andersen et al.) demonstrated the superiority of percutaneous coronary intervention over thrombolysis. In the CPORT trial, percutaneous coronary intervention was performed at U.S. hospitals without on-site cardiac surgery. In the DANAMI study, patients randomized to percutaneous coronary intervention were transported by ambulance to a hospital with cardiac catheterization facilities. Despite these limitations and delays in patient transport, those assigned to the percutaneous coronary intervention group had significantly improved clinical outcomes and shorter hospital stays. Current standard of care recommendations for immediate reperfusion therapy for patients with ST-segment elevation MI would favor primary percutaneous coronary intervention over thrombolysis if transfer to an experienced cardiac catheterization center is feasible within 90 minutes of presentation. Intravenous glycoprotein IIb/IIIa inhibitors may be started in the emergency department before transfer for percutaneous coronary intervention.
Mechanical Complications after Myocardial Infarction

Mechanical complications occur in roughly 0.1% of patients with acute MI, typically around 2 to 7 days after the event. These complications include ventricular septal defect, papillary muscle rupture leading to acute mitral regurgitation, and left ventricular free wall rupture leading to tamponade. Ventricular septal defect and papillary muscle rupture usually lead to abrupt pulmonary edema or hypotension. Papillary muscle dysfunction without rupture can also cause severe mitral regurgitation after acute MI. Early diagnosis is critical because the survival rate 24 hours after a large ventricular septal defect or papillary muscle rupture is roughly 25% with medical therapy. Emergent echocardiography is indicated to help with the early diagnosis. Hemodynamic monitoring with a pulmonary artery catheter is usually necessary. Increased oxygen saturation between the right atrium and ventricle is seen with left-to-right shunting through a ventricular septal defect. Both ventricular septal defect and papillary muscle rupture may be associated with prominent V waves on the pulmonary capillary wedge tracing. For both disorders, rapid treatment involves nitroprusside or intra-aortic balloon pump (or both). Emergent surgical repair is usually considered for definitive therapy; however, the survival rate is still only 50% after repair.
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Pericardial tamponade from rupture of the left ventricular free wall usually leads to sudden hypotension and death. After heart failure, free-wall rupture represents the second most common cause of death for patients who in die in hospitals after an MI. Predisposing factors include advanced age as well as first MI, probably due to lack of coronary collaterals. Ventricular free-wall rupture is most commonly seen 1 to 4 days after acute MI but in rare cases occurs up to 3 weeks after MI. The free-wall rupture typically occurs in the junction of the infarction with normal myocardium and less often within the center of the infarct. Patients usually present with cardiovascular collapse, tamponade, or pulseless electrical activity. Right-heart catheterization would demonstrate diastolic elevation and equalization of pressures from the right atrium, right ventricle, and pulmonary capillary wedge with reduced cardiac output.
Post-MI Risk Stratification

Mortality rates from trials enrolling patients with ST-segment elevation MI patients differ according to the type of reperfusion therapy (percutaneous coronary intervention versus thrombolysis) and the presence of cardiogenic shock. In the CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial, in which patients were randomized to primary angioplasty or stenting, the 30-day mortality rate was 1.0% to 1.6%. In the GUSTO V (Global Use of Strategies To Open Coronary Arteries V) thrombolytic trial that randomized patients to tissue plasminogen activator alone or half-dose tissue plasminogen activator plus abciximab, the 30-day mortality rate was 5.5% to 6.0%. The 30-day mortality rate was 5% for those who received thrombolytic therapy within 4 hours of chest pain and increased to 11% for those treated more than 6 hours after the onset of chest pain. The 7-day reinfarction rate was 3%. In the SHOCK (SHould we use emergently revascularize Occluded Coronaries in cardiogenic shocK?) trial, patients were randomized patients with acute MI with cardiogenic shock to maximal medical therapy (including pressors, intra-aortic balloon pump, and thrombolysis) or emergent coronary revascularization; the 30-day mortality rate was 50% (Hochman et al.). The TIMI risk score is a helpful index to gauge the risk for early mortality in patients presenting with ST-segment elevation MI (Table 9). In summary, postMI mortality rates are generally low for stable patients who present early for reperfusion therapy but remain high for patients admitted in cardiogenic shock. After initial reperfusion therapy, additional risk stratification involves assessment of left ventricular function, residual myocardial ischemia, and risk of ventricular arrhythmias. All survivors of MI should have left ventricular systolic function measured. Patients with depressed left ventricular function are at increased risk for adverse events, and they should be treated aggressively with -blockers (if heart failure is compensated) and oral angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors should be used in patients with anterior-wall MI, clinical evidence of heart failure, or an fraction of 40% or less. In light of the results of the HOPE (Heart Outcomes Prevention Evaluation) trial, it is reasonable to consider angiotensin-converting enzyme inhibitor therapy for any patient after MI. Patients who undergo primary percutaneous coronary intervention for STsegment elevation MI already have immediate risk stratification for nonculprit coronary disease. Further noninvasive stress testing is indicated only if intermediate-severity stenosis is present in a nonculprit coronary artery or if myocardial viability testing is required before further coronary revascularization. Once a patient has undergone successful thrombolysis, further evaluation is required to assess for residual myocardial ischemia. Patients with the following features should undergo invasive coronary angiography: recurrent myocardial ischemia,
FIGURES 8A AND 8B. Coronary angiography in the patient in Case 3. Coronary angiography shows thrombotic occlusion of the mid-right coronary artery (RCA). There were no other significant coronary stenoses. Left ventriculography showed inferior hypokinesis with an ejection fraction of 40%. B. The patient underwent successful stenting of the RCA with adjunctive glycoprotein IIb/IIIa receptor inhibitor use.
Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD,et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341:625-34. PMID: 10460813
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Diagnosis of Coronary Artery Disease
Scanlon PJ, Faxon DP, Audet AM, Carabello B, Dehmer GJ, Eagle KA, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol. 1999;33:1756-824. PMID: 10334456
hemodynamic instability, ventricular tachycardia, clinical heart failure, ejection fraction of 40% or less, or post-MI mechanical complications (Scanlon et al.). Low-risk patients with an uncomplicated MI course who do not have these indications for coronary angiography may undergo predischarge noninvasive symptom-limited stress testing. The approaches are identical to those described in the section on chronic coronary artery disease. Patients with depressed left ventricular systolic function are at higher risk for subsequent ventricular tachyarrhythmias. The occurrence of asymptomatic nonsustained ventricular tachycardia within 48 hours of MI should not change usual management consisting of aspirin, -blockers, ACE inhibitors, and statins. If antiarrhythmic drug therapy is considered for patients after MI, amiodarone is generally the preferred agent. The finding of asymptomatic nonsustained ventricular tachycardia more than 48 hours after MI or symptomatic ventricular arrhythmias, particularly in patients with an ejection fraction of 35% or less, generally prompts electrophysiologic testing or implantation of an implantable cardioverter-defibrillator. Such studies as Multicenter Automatic Defibrillator Implantation Trial-I (MADIT-I) and MADIT-II have consistently shown that high-risk patients who have had MI typically do better with implantable cardioverter-defibrillator therapy compared to antiarrhythmic therapy. Patient selection for electrophysiologic testing and implantable cardioverter-defibrillator after MI is described in the section on arrhythmia.
Coronary Artery Disease and Chronic Stable Coronary Artery Disease

In this discussion, coronary artery disease (CAD) refers to atherosclerotic disease of the major epicardial coronary arteries. The first step in the diagnosis of CAD is to estimate its likelihood by taking into account the patients risk factors for CAD and symptoms. The pretest probability of CAD is estimated as low, intermediate, or high and is important for choosing the right diagnostic approach.

Which stress test is best for the diagnosis of coronary artery disease? Is electron-beam computed tomography useful for the diagnosis of coronary artery disease?
Most noninvasive tests for detecting CAD perform best when pretest probability is intermediate. In patients with low pretest probability, a positive test result is more likely to be falsely so. In patients with a high pretest probability of disease, a negative test result is most likely to be false. Thus, in patients with a high pretest probability of disease, a test such as coronary angiography is preferable to noninvasive stress testing. In patients with a low pretest probability of disease, a test such as electron-beam computed tomography (CT) for coronary calcification may be more appropriate (Greenland et al.; Newman et al.).
Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation. 2001;104:1863-7. PMID: 11591627 Newman AB, Naydeck BL, SuttonTyrrell K, Feldman A, Edmundowicz D, Kuller LH. Coronary artery calcification in older adults to age 99: prevalence and risk factors. Circulation. 2001;104:2679-84. PMID: 11723018
Case 4 A 40-year-old man presents because during a heated argument with his wife, he noted mild anterior chest tightness. He has a family history of premature CAD and a low-density lipoprotein cholesterol level of 160 mg/dL. He rarely exercises and has a body mass index of 28 kg/m2. He does not have diabetes and is a nonsmoker. Physical examination was remarkable for blood pressure of 150/90 mm Hg, pulse rate 90/min and regular, and a grade II/VI early systolic murmur at the base. A treadmill stress echocardiographic study was normal.
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For patients with an intermediate likelihood of CAD, stress testing is the preferred approach (Shavelle et al.). Various techniques are available for stressing the cardiovascular system (Table 11); exercise is the preferred method. Most patients prefer treadmill exercise to bicycle and consequently achieve higher workloads with treadmill exercise. For patients who cannot exercise, pharmacologic stress testing can be performed by using with agents that mimic the catecholamine increases of exercise, such as dobutamine, or agents that cause coronary artery vasodilation, such as dipyridamole. A method of detecting myocardial ischemia is used in conjunction with stress testing to establish the diagnosis of CAD. The traditional technique for detecting ischemia is electrocardiographic monitoring. Currently, however, many patients undergo cardiac imaging studies, such as echocardiography or myocardial perfusion scintigraphy, during stress testing. The determination of which stress and which ischemia detection method to use is often a source of confusion for the generalist. Regardless of the technical merits of the various stress testing procedures, access, availability, cost, and perceived quality often simplify the decision in some clinical settings. Risk to the patient is similar with all stress testing methods. The overall risk of a serious cardiac event, such as myocardial infarction or death, is approximately 1 in 10,000 stress tests. With careful patient selection and the availability of highly trained staff to supervise the stress test, this risk can often be decreased to almost zero. Although individual factors at particular clinical locations may modify test selection, the following is a general approach based on the strengths and weaknesses of the various tests relative to pretest probability of disease. First, exercise, especially treadmill exercise, is the preferred mode of stress testing as long as the patient can perform well. The patient must be able to exercise sufficiently to increase the heart rate to 85% or more of the maximum predicted value. Although most patients believe that they can exercise to this level, relatively few are actually able to do so. Second, the resting electrocardiogram must be considered. If it is normal and the patient can exercise well, the overall accuracy of exercise electrocardiography is about 85%. However, if the patient does not exercise well or has abnormalities on the resting electrocardiogram, the accuracy decreases to about 50%, rendering the test diagnostically worthless. Thus, in patients who can exercise well and have a normal resting electrocardiogram, treadmill electrocardiography testing is still an efficacious and low-cost initial approach. In patients with an abnormal resting electrocardiogram, cardiac imaging methods must be used. For practical purposes, there are two methods of imaging: echocardiography and myocardial perfusion scintigraphy. Although in individual clinical settings one of these methods may be superior to the other, in general echocardiography has a lower sensitivity but higher specificity than radionuclide perfusion imaging. Radionuclide perfusion imaging, on the other hand, has high sensitivity (approaching 95% in some studies) but a somewhat lower specificity than echocardiography. The sensitivity and specificity of both techniques also depend on the number of diseased vessels, increasing with more extensive disease. Radionuclide perfusion imaging is superior for localizing which coronary distribution is probably causing the ischemia because on
TA B L E 1 1 Stress Testing Possibilities To Diagnose Coronary Artery Disease
Shavelle DM, Budoff MJ, LaMont DH, Shavelle RM, Kennedy JM, Brundage BH. Exercise testing and electron beam computed tomography in the evaluation of coronary artery disease. J Am Coll Cardiol. 2000; 36:32-8. PMID: 10898409
Cardiac Stressor Exercise Dobutamine Dipyridamole/adenosine
Ischemia Detector Electrocardiography Echocardiography Radionuclide perfusion
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Keelan PC, Bielak LF, Ashai K, Jamjoum LS, Denktas AE, Rumberger JA, et al. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation. 2001;104:412-7. PMID: 11468202 Bielak LF, Rumberger JA, Sheedy PF 2nd, Schwartz RS, Peyser PA. Probabilistic model for prediction of angiographically defined obstructive coronary artery disease using electron beam computed tomography calcium score strata. Circulation. 2000;102:380-5. PMID: 10908208 Haberl R, Becker A, Leber A, Knez A, Becker C, Lang C, et al. Correlation of coronary calcification and angiographically documented stenoses in patients with suspected coronary artery disease: results of 1,764 patients. J Am Coll Cardiol. 2001;37:451-7. PMID: 11216962 ORourke RA, Brundage BH, Froelicher VF, Greenland P, Grundy SM, Hachamovitch R, et al. American College of Cardiology/American Heart Association Expert Consensus document on electronbeam computed tomography for the diagnosis and prognosis of coronary artery disease. Circulation. 2000;102:126-40. PMID: 10880426
echocardiography, abnormal wall motion in one area may affect adjacent areas. Finally, both tests have significant technological limitations. Echocardiography with stress testing is challenging and requires highly skilled technicians and experienced physician readers. In general, the proportion of patients with poor echocardiographic images from stress testing is about 5%. This rate can be decreased to almost zero if contrast echocardiography is used. Radionuclide imaging suffers from photon attenuation due to chest-wall structures, such as breasts. Unless special attention is paid to attenuation, false-positive studies often result. In addition, since radionuclide imaging depends on a difference in perfusion between areas of the heart, the scan can appear normal in patients with severe three-vessel CAD in which all three coronary vessels are equally diseased. This unusual circumstance reinforces the idea that if clinical information indicates CAD, further invasive testing may be appropriate even if results of noninvasive testing are normal. In head-to-head comparison studies, the relative strengths and weaknesses of the two imaging techniques tend to cancel out, and the overall accuracy in the clinical arena is similar. Therefore, test selection often depends on patient factors, physician preference, and institutional factors. For example, in Case 5, stress echocardiography was chosen because the patient had a systolic heart murmur. Some evidence indicates that stress testing is less accurate in women and that imaging must always be used in women; however, these studies suffered from selection bias, and the evidence is not sufficiently strong to opt for an expensive imaging test as the first choice in all women. However, women have a higher likelihood of not being able to exercise adequately, which must be considered in test ordering. If electrocardiographic abnormalities are present, imaging must be substituted for electrocardiography with exercise stress testing. Autopsy studies have shown a direct relationship between calcium in the walls of coronary arteries and underlying coronary atherosclerosis. This principle was used in conjunction with electron-beam CT to develop a coronary artery calcium score, which identifies the risk of subsequent cardiac events (Keelan et al.). A higher coronary artery calcium score is associated with an increased risk of coronary artery disease regardless of the number of conventional risk factors present. However, the coronary calcium score does not correlate well with coronary angiographic results because of coronary artery remodeling in the setting of plaque deposition (Bielak et al.). Coronary arteries can increase their lumen size to compensate for plaque development. Although this measurement can be useful, calcium scores derived from electron-beam CT do not correlate exactly with clinical events in an individual patient. For example, a patient may have a very low score yet have cholesterol deposits in the coronary arteries, increasing the risk for rupture and acute myocardial infarction. Or a patient may have heavily calcified coronary arteries yet stable plaques, and myocardial infarction does not ensue. Overall accuracy is about 70%, mainly owing to low specificity (Haberl et al.). The precise role of electron-beam CT calcium scores is still being defined (ORourke et al.). In patients with a low probability of CAD on the basis of traditional risk factors but who are concerned because of a family history of premature CAD, electrom-beam CT may be useful, especially if negative, to reassure the patient. However, it is likely to be more accurate when positive in an elderly asymptomatic patient. Patients with symptoms suggestive of CAD and risk factor profiles that make the presence of disease almost certain do not benefit from a calcium score because it will not affect their management. In addition, there is insufficient evidence to recommend using calcium scores to assess the response of CAD to treatment.
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Treatment of Coronary Artery Disease
Case 5 A 66-year-old man had had multivessel coronary artery bypass graft surgery for severe angina 5 years ago. In the past month, he has experienced dyspnea on exertion. Since this symptom may indicate an angina equivalent, further evaluation was warranted. Dipyridamole radionuclide perfusion imaging is done because the patients ability to exercise fully was in doubt. No angina or ischemic electrocardiographic changes were found. The perfusion scintigraphy showed a small area of ischemia in the inferoapical region. The right coronary artery was bypassed, but distal posterior descending disease was noted on the preoperative coronary angiogram. It was decided that this was a low-risk situation that was not causing the patients symptoms and did not warrant coronary angiography. Other causes for dyspnea were pursued. If the patient cannot exercise, pharmacologic stress with myocardial imaging must be used. Pharmacologic stress does not reliably produce electrocardiographic changes even in patients in whom imaging shows evidence of myocardial ischemia. Thus, pharmacologic electrocardiographic testing is not recommended. Dobutamine echocardiography and dipyridamole or adenosine nuclear perfusion imaging both have similar accuracy in general clinical settings (Smart et al.). Some believe that dipyridamole nuclear perfusion imaging is superior to dobutamine echocardiography in patients with left bundle-branch block on resting electrocardiography, although head-to-head data on this topic are sparse. Compared to echocardiography or myocardial perfusion imaging, exercise radionuclide ventriculography does not perform as well and has largely been abandoned. Although stress magnetic resonance imaging has been tested, it has not been sufficiently developed to the point where it is a clinical reality.
Smart SC, Bhatia A, Hellman R, Stoiber T, Krasnow A, Collier BD, Sagar KB. Dobutamine-atropine stress echocardiography and dipyridamole sestamibi scintigraphy for the detection of coronary artery disease: limitations and concordance. J Am Coll Cardiol. 2000;36:1265-73. PMID: 11028482
KEYPOINTS
An electron-beam computed tomography coronary calcium score is most useful for refining the assessment of risk for coronary artery disease in elderly asymptomatic patients. If the diagnosis of coronary artery disease is in question after history, physical examination, resting electrocardiography, and chest radiography, exercise electrocardiography is the next step in most patients. The initial stress test should use cardiac imaging if the resting electrocardiogram is abnormal, adequate exercise performance is unlikely, or prior revascularization or known coronary artery disease is present.

Are calcium antagonists contraindicated for the treatment of angina? Is coronary artery bypass graft surgery ever superior to angioplasty?
The treatment of chronic stable CAD begins with lifestyle modification to control risk factors. A low-fat, low-cholesterol diet, regular exercise, and smoking cessation have all been shown to improve outcomes in patients with CAD. Secondary prevention involves use of aspirin, statin drugs in patients whose lipid level cannot be adequately controlled by diet and exercise, and angiotensin-converting enzyme or receptor blocking drugs in patients with hypertension (Table 12). All three of these approaches have been shown to reduce events in patients with known CAD (Dagenais et al.; White et al.). Aggressive risk factor control, including use of statin drugs, may obviate the need for revascularization in patients with CAD (MRC/BHF Heart Protection Study). Symptoms of CAD should also be treated. The most common symptom is angina pectoris, for which three major classes of drugs are useful prophylactically: long-acting nitrates, -blockers, and calcium antagonists. All three classes of drugs have been shown in double-blind studies to decrease the number of angina attacks and increase exercise tolerance. -Blockers prevent angina pectoris largely by decreasing heart rate and reducing blood pressure, thereby reducing myocardial energy consumption. -Blockers have a definite role after myocardial infarction, in hypertensive patients, and in patients with reduced left ventricular performance. -Blocker use is encouraged because they have proven
Dagenais GR, Yusuf S, Bourassa MG, Yi Q, Bosch J, Lonn EM, et al. Effects of ramipril on coronary events in high-risk persons: results of the Heart Outcomes Prevention Evaluation Study. Circulation. 2001;104:522-6. PMID: 11479247 White CW, Gobel FL, Campeau L, Knatterud GL, Forman SA, Forrester JS, et al. Effect of an aggressive lipid-lowering strategy on progression of atherosclerosis in the left main coronary artery from patients in the post coronary artery bypass graft trial. Circulation. 2001;104:2660-5. PMID: 11723015 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22. PMID: 12114036
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TA B L E 1 2 Proven Secondary
Prevention Interventions for Patients with Coronary Artery Disease Aspirin and angiotensin-converting enzyme inhibitors -Blockers and blood pressure control Cholesterol lowering and smoking cessation Diet and diabetes control Exercise
Gibbons RJ, Miller DD, Liu P, Guo P, Brooks MM, Schwaiger M. Similarity of ventricular function in patients alive 5 years after randomization to surgery or angioplasty in the BARI trial. Circulation. 2001;103: 1076-82. PMID: 11222469
Seven-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI) by treatment and diabetic status. J Am Coll Cardiol. 2000;35:1122-9. PMID: 10758950 Leavitt BJ, OConnor GT, Olmstead EM, Morton JR, Maloney CT, Dacey LJ, et al. Use of the internal mammary artery graft and in-hospital mortality and other adverse outcomes associated with coronary artery bypass surgery. Circulation. 2001;103: 507-12. PMID: 11157714
efficacy and relatively few patients are intolerant of them or have contraindications to their use. Nitrates and calcium antagonists work largely by dilating the coronary arteries and increasing myocardial blood flow to the ischemic areas. Although nitrates are effective, patients may develop tolerance to them, and special dosing regimens are required. To avoid tolerance, patients should spend at least 8 hours daily (usually overnight) free of nitrates. Calcium antagonists have fewer side effects than do -blockers and nitrates and are well tolerated by most patients. The most common side effect of calcium antagonists is peripheral edema due to changes in capillary hydrostatic pressure rather than to induction of heart failure. The newer dihydroperidine calcium antagonists have few negative inotropic effects and can be used in patients with reduced left ventricular performance. However, observational studies have raised concerns about the long term safety of calcium channel blockers, especially the short-acting preparations. In addition, these agents do little to arrest the progression of disease and have not been shown to increase longevity. Patients with angina pectoris that is refractory to medical therapy; those with high-risk coronary anatomy, such as left main stenosis; and those with significant coronary lesions and reduced left ventricular performance benefit from revascularization. Studies have shown that revascularization is excellent for eliminating angina pectoris, increasing longevity in patients with certain anatomic features, and improving left ventricular performance in appropriately selected patients (Gibbons et al.). For patients with discrete single- or double-vessel CAD, a percutaneous intervention is often preferred because it avoids the morbidity and mortality of bypass surgery. The main limitation of percutaneous intervention is restenosis, which with plain balloon angioplasty occurs in 30% to 40% of patients. The advent of stents has decreased the incidence of restenosis to 15% to 20%, which explains why almost all patients currently undergoing percutaneous intervention receive a stent. Stent technology is evolving rapidly, and stents coated with antineoplastic agents are now available. These agents inhibit the neointimal hyperplasia that causes in-stent restenosis. Data from the initial studies with 6 months to 1 year of follow-up has shown restenosis rates in the range of 5% to 10%. If very low rates of restenosis continue with coated stents in the long term, less severe lesions will be stented more often. In patients with severe multivessel disease, especially diabetic patients or patients with reduced left ventricular ejection fraction, coronary artery bypass graft (CABG) surgery is the preferred revascularization technique. In appropriately selected patients, such surgery has a 30-day mortality rate in the range of 1% to 3% range. Other comorbid conditions, especially renal failure, can increase the mortality rate. Although diabetic patients with multi-vessel disease have better outcomes with CABG surgery than with percutaneous intervention, they perioperative rates of mortality and morbidity rates are somewhat higher (The BARI Investigators). For example, the incidence of postoperative wound infection is higher in diabetic patients. The average vein graft lasts about 8 years. Patients who carefully control their risk factors after surgery can extend the life of the graft to to 12 years or more. Arterial grafts last much longer than vein grafts and are preferred if technically feasible. The internal thoracic arteries are the preferred conduits, either as pedical grafts or as freestanding grafts (Leavitt et al.). Other arteries, such as the radial, the gastroepiploic, and splenic, have been also used. Some centers believe that a total arterial CABG is the preferred technique. Minimally invasive techniques have been developed for CABG that allow revascularization through small intercostal incisions by using specially designed
30
Management of Coronary Artery Disease
equipment and by using the femoral vessels for cardiopulmonary bypass. However, these techniques lend themselves best to simple operations on the proximal anterior coronary vessels and are more difficult to perform on posterior vessels or on multiple vessels (Mehran et al.). Use of several intercostal incisions, although small and cosmetically more appealing than a mid-sternal vertical incision, frequently results in much greater postoperative pain. Given the limited access to the heart, the postoperative pain associated with these minimally invasive techniques, and the increased success of percutaneous intervention, these procedures have waned in popularity. The reported incidence of demonstrable cognitive problems after CABG is 10% to 15%; frank neurologic defects occurred in half of the patients, and minimal cognitive dysfunction occurred in the other half. Concern about this complication led to the development of off-pump revascularization techniques, because the effect of the heartlung pump on coagulation elements in the blood is thought to be a major reason for these neurologic defects. Off-pump revascularization has become more feasible with technologic advances in coronary revascularization techniques, such as a sutureless attachment device that allows rapid insertion of bypass grafts on the beating heart. Despite the theoretic attractiveness of these off-pump techniques, they do not completely prevent neurologic events. This is probably because disruption of aortic debris from the proximal anastomosis procedure accounts for a significant proportion of central nervous system events. Currently, aorta manipulation during bypass graft insertion cannot be completely avoided, unless only arterial pedicle grafts are used. A few patients have angina that is refractory to maximum medical therapy and are not good candidates for revascularization, usually because the risk outweighs the potential benefit. Few options are available for such patients. Although heart transplantation can be done, these patients are often not good candidates for this surgery. Long-term use of narcotic analgesics is not optimal but is often the only option. Recently, some success with enhanced external counterpulsation was reported. This procedure involves foot-to-buttock sequential inflation of compressive cuffs during diastole, with rapid deflation in early systole. Like intra-aortic balloon pumping, external counterpulsation increases diastolic aortic or coronary perfusion pressure and reduces afterload, augmenting cardiac output. Studies have shown that after brief periods of counterpulsation, angina is relieved, exercise tolerance is increased, and ischemia is reduced for prolonged periods (Urano et al.).
Mehran R, Dangas G, Stamou SC, Pfister AJ, Dullum MK, Leon MB, Corso PJ. One-year clinical outcome after minimally invasive direct coronary artery bypass. Circulation. 2000;102:2799-802. PMID: 11104735
KEYPOINTS
Proven secondary prevention strategies in patients with coronary artery disease include aspirin, angiotensin-converting enzyme inhibitors, -blockers, decreasing lipid levels, blood pressure control, smoking cessation, and exercise. Calcium antagonists are potent antianginal drugs that have few adverse effects compared with nitrates and -blockers, but they do not increase longevity in patients with coronary artery disease. Coronary revascularization is excellent for relieving angina, increasing longevity in patients with certain highrisk anatomic feature, and improving left ventricular function in selected patients. Randomized studies have shown similar benefits of percutaneous intervention and coronary artery bypass graft surgery, except in diabetic patients, who do better with coronary artery bypass graft surgery.
Management of Coronary Artery Disease

Are routine stress tests after revascularization advisable?
Follow-up of patients after revascularization is often shared by the surgeon or cardiologist and the primary care physician until the periprocedure period is over and the surgeon or cardiologist feels comfortable releasing the patient to the care of the primary care physician. At 3 months after any stressful procedure, stress-related neurohormonal changes have usually abated. At this time, cholesterol measurements are again accurate, as are determinations of blood pressure and heart rate. This is a good time to assess and treat risk factors to prevent future events. In addition to providing secondary prevention of atherosclerosis, the physician must assess the patient for evidence of restenosis or graft failure. This can usually be accomplished by assessment of the patients symptoms, especially if he or she had symptoms before revascularization.
Urano H, Ikeda H, Ueno T, Matsumoto T, Murohara T, Imaizumi T. Enhanced external counterpulsation improves exercise tolerance, reduces exercise-induced myocardial ischemia and improves left ventricular diastolic filling in patients with coronary artery disease. J Am Coll Cardiol. 2001;37:93-9. PMID: 11153780
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Epidemiology
Zellweger MJ, Lewin HC, Lai S, Dubois EA, Friedman JD, Germano G, et al. When to stress patients after coronary artery bypass surgery? Risk stratification in patients early and late post-CABG using stress myocardial perfusion SPECT: implications of appropriate clinical strategies J Am Coll Cardiol. 2001;37:144-52. PMID: 11153729
KEYPOINTS
Routine stress testing after revascularization in asymptomatic patients is not recommended in the first 5 years.
The use of routine exercise testing, especially in the first 5 years after revascularization, is controversial (Zellweger et al.). There is little scientific evidence that routine stress testing in the absence of symptoms or other indications provides any definite benefit for its cost early after revascularization. Nonetheless, some physicians perform a yearly stress test in all patients, perhaps to provide the patient a psychological boost and incentive to continue their secondary prevention measures. Physicians who do not advocate routine testing often have a low threshold for doing repeated stress testing. Patients with successfully treated CAD should have follow-up visits every 4 to 12 months, depending on how recently successful treatment was accomplished.
Heart Failure
Heart failure is a major worldwide public health problem. In the United States, heart failure affects nearly 5 million persons (about 2% of the population). Greater understanding of the pathophysiology of heart failure has improved prevention and treatment protocols. Heart failure is a clinical syndrome of cardiac pump dysfunction that manifests as systolic or diastolic abnormalities, along with myocardial remodeling (ventricular hypertrophy, chamber dilation, and interstitial fibrosis). Hormonal, cytokine, and neural regulatory function is disturbed, with subsequent circulatory insufficiency. Patients with heart failure may be asymptomatic or experience fatigue, dyspnea, or fluid retention of fluctuating severity.
Epidemiology
The prevalence of heart failure is increasing (Table 13). The condition is newly diagnosed in almost 500,000 patients annually. Almost 300,000 patients per year die of heart failure, and this figure is increasing. The annual mortality rate in severely decompensated patients is 80% to 90%. Heart failure is associated with aging. It is estimated that 10% of persons older than 65 years have heart failure and that approximately 80% of patients hospitalized for decompensated heart failure are older than 65 years of age.
TA B L E 1 3 The Burden of Heart Failure in North America
Economic, Morbidity, and Mortality Burden 5 million patients diagnosed with symptomatic heart failure 500,000 new cases of symptomatic heart failure diagnosed annually 15 million visits for heart failure annually 6.5 million heart failure hospital days annually Almost 1 million hospitalizations for heart failure annually 2.6 million patients hospitalized with heart failure as a second-degree diagnosis annually 2% prevalence of heart failure in population 10% of patients older than 65 years with heart failure 80% of hospitalized patients with heart failure older than 65 years of age 33% of patients with heart failure as discharge diagnosis readmitted within 90 days Heart failure most common Medicare diagnosis-related group 24 billion dollars spent annually on heart failure in United States 5-10% annual mortality rate in mildly symptomatic heart failure 30-40% annual mortality rate in more symptomatic heart failure 20-25% mortality rate at 180 days after heart failure hospitalization
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Epidemiology
Heart failure is the most common Medicare diagnosis-related group categorization, and more Medicare dollars are spent for diagnosis and treatment of heart failure than for any other single diagnosis.
TA B L E 1 4 World Health Organization: Classification of Heart Failure
Etiologies Dilated cardiomyopathy Idiopathic Hypertrophic cardiomyopathy Idiopathic hypertrophic subaortic stenosis Hypertrophic obliterative cardiomyopathy Hypertrophic nonobstructive cardiomyopathy Restrictive cardiomyopathy Specific infiltrating diseases Idiopathic Arrhythmogenic right ventricular cardiomyopathy Idiopathic right ventricular outflow tract tachycardia Arrhythmogenic right ventricular dysplasia Unclassifiable cardiomyopathies Atypical presentation: fibroelastosis, systolic dysfunction without dilation, mitochondrial cardiomyopathy Mixed presentation (dilated/hypertrophic/restrictive): amyloidosis, hypertension Specific cardiomyopathies Ischemic Valvular obstruction/insufficiency Hypertensive Inflammatory: myocarditis (lymphocytic, giant cell, autoimmune) Infectious: Chagas disease, HIV, Enterovirus, adenovirus cytomegalovirus Bacterial and fungal endocarditis Metabolic Endocrine: thyrotoxicosis, hypothyroidism, adrenal cortical insufficiency, pheochromocytoma, acromegaly, diabetes mellitus Familial storage disease/infiltration: hemochromatosis, glycogen storage disease, Hurlers syndrome, Refsums disease, NiemannPick disease, Hand-Schuler-Christian disease, FabryAnderson disease, MorquioUllrich disease Electrolyte deficiency syndromes: potassium metabolism disturbances (hypokalemia), magnesium deficiency Nutritional disorders: kwashiorkor, anemia, beriberi, selenium deficiency, nonspecific malabsorption, starvation Amyloid (primary, secondary, familial, hereditary, senile) Familial Mediterranean fever General system disease Rheumatologic disorders: systemic lupus erythematosus, polyarteritis nodosa, rheumatoid arthritis, scleroderma, dermatomyositis Nonspecific infiltrations and granulomas: sarcoidosis Leukemia Muscular dystrophies: Duchennes, Beckers, myotonic Neuromuscular disorders: Friedreichs ataxia, Noonans syndrome, lentiginosis Sensitivity and toxic reactions: alcohol, catecholamines (endogenous or exogenous), anthracyclines, irradiation Peripartum cardiomyopathy (a heterogeneous group)
Information from: 1995 Report World Health Organization/International Society and Federation of Cardiology Task Force on the Definition of Cardiomyopathies. Circulation. 1996;93:8412.
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Etiology
Etiology
The causes of heart failure are varied. Table 14 summarizes the current World Health Organization categorization of diseases that cause heart failure. Structural heart lesions are commonly diagnosed, and arrhythmias are frequent. Specific cardiomyopathies include ischemic heart disease, valvular obstruction and insufficiency causing heart failure, hypertensive heart disease with heart failure, and various inflammatory cardiomyopathies. Often, combinations of diseases contribute to underlying heart failure. Idiopathic dilated cardiomyopathy is diagnosed when heart failure with systolic dysfunction is discovered and no other disease is apparent. A detailed family history is critical because specific genetic disorders are associated with heart failure. Dilated cardiomyopathy is familial in approximately 20% to 25% of patients. Hypertrophic cardiomyopathies, usually associated with heart failure due to diastolic dysfunction are a distinct entity that are genetic in origin and have well-defined heritable characteristics and gene mutations. Arrhythmogenic right-ventricular cardiomyopathy is uncommon but lifethreatening because of unstable ventricular arrhythmias that arise in the right ventricular outflow tract. Fibrotic infiltration of the outflow tract and generalized right ventricular dysplasia account for substantial right-sided congestive heart failure in many patients. Metabolic abnormalities that can cause cardiomyopathy include endocrinopathies, such as thyrotoxicosis and hypothyroidism; pheochromocytoma; acromegaly; diabetes mellitus; and Addisons disease. General systemic illnesses also precipitate heart failure and include a large group of rheumatologic disorders such as systemic lupus erythematosus (see Table 14). Systemic muscular dystrophies, in particular, Duchennes, Beckers, and myotonic dystrophy are also associated with cardiomyopathy. Toxic injury to the heart can result from alcohol, anthracyclines, and irradiation, as well as states in which endogenous catecholamines are chronically elevated.
KEYPOINTS
Coronary artery disease and hypertension are the most common causes of heart failure. Primary myocardial injury results in ventricular remodeling (hypertrophy, chamber dilation, and interstitial fibrosis), which perpetuates the syndrome.
Pathophysiology of Heart Failure

After primary heart injury, a series of molecular biodynamic, cellular membrane, subcellular signaling, and other compensatory events occur that lead to cardiac dysfunction and circulatory inadequacy (Figure 9). Even after elimination of the initiating events, the latter forces perpetuate dysfunction and failure. Remodeling of the heart, resulting in abnormal myocyte contraction and relaxation, causes cardiac dysfunction, resulting in circulatory perturbation (generally decreased vital organ perfusion). Circulatory perturbation results in physiologic responses that initially preserve organ perfusion but ultimately produce the clinical manifestations of heart failure. The clinical presentation of heart failure can primarily be categorized into low cardiac output states (which manifest as weakness, fatigue, malaise, and organ dysfunction) and congestive conditions (which manifest as systemic volume overload with peripheral, central organ, and pulmonary edema). Although some congestive conditions may be designated as congestive heart failure, not all patients with heart failure have a congestive state. The molecular biodynamics of heart failure result primarily from production of more contractile proteins by cardiac myocytes and from the signaling schemes of various membranes and submembranes after an initial injury. These mechanisms would restore contractile function in normal circumstances. However, this response in heart failure results in production of a fetal type of myocyte contractile protein and less normal interstitial matrix matter, such that
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Pathophysiology of Heart Failure
cardiac remodeling with cardiac hypertrophy, chamber enlargement, and worsening interstitial fibrosis ensues. The anatomic and morphologic responses to cardiac injury are primarily myocyte hypertrophy, cardiac chamber dilation, and varying degrees of interstitial fibrosis. Cardiomegaly ensues, in which chamber volumes, cardiac mass, and sphericity of the ventricles and atria are increased. Cellular responses include adrenoreceptor abnormalities, such as down-regulation of myocyte surface -adrenergic receptors. Circulatory abnormalities manifest as baroreceptor dysfunction; decreased systemic flow; and activation of peripheral venous and arterial autoregulatory actions, in which changes in nitric oxide, prostacyclin, and endothelin expression produce local vasoconstriction and vasodilation. Other physiologic responses include sympathetic nervous system up-regulation, with increased blood levels of epinephrine and norepinephrine and activation of the reninangiotensinaldosterone systems. The inflammation seen in heart failure involves release of interleukins and tumor necrosis factor, which subsequently contribute further to abnormal cardiac cell function, apoptosis, and interstitial fibrosis. All of these complicated interactions produce the setting for cardiac dysfunction, and many faces of clinical heart failure subsequently emerge. Heart failure may occur with normal left ventricular systolic function. This state is commonly called diastolic dysfunction heart failure or heart failure with preserved systolic function. These patients have impaired ventricular filling and elevated left-sided filling pressures that increase during exercise, leading to exertional dyspnea. The ventricular volume is usually reduced and the ventricular walls are thick, either because of hypertrophy or an infiltrative process, such as amyloid. The atrial volumes are often increased. Neurohormonal and other biochemical responses are less marked.
Circulatory Perturbation Physiologic Responses
Cardiac Dysfunction
Anatomic/ Morphologic (Remodeling) Cellular Responses
The Heart Failure Milieu Chronic Congestive Heart Failure
Clinical Manifestations
Asymptomatic Acute Pulmonary Edema/ Shock
Molecular Biodynamic
Injury/Induction
Failure is the inability to measure up to certain normal standards Websters Dictionary

FIGURE 9. The facets of heart failure: complexity of the syndrome.
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Diagnosis of Heart Failure

Diagnosis algorithms for heart failure have been based largely on experience gained through large clinical trials (Table 15). These algorithms have been incorporated into practice guidelines that contain several common factors specific to diagnosis of the syndrome (Table 16). Early diagnosis is stressed because therapy has greater benefit when, for example, asymptomatic left ventricular systolic dysfunction is discovered and treated. Furthermore, heart failure is not the primary problem in all patients with dyspnea and edema. Therefore, measurement of systolic and diastolic left ventricular function in patients at risk and in symptomatic patients is critical. Identification of specific cardiac structural abnormalities and determination of the primary cause of cardiac dysfunction are of major importance. The European Society of Cardiology Guidelines for the Diagnosis and Treatment of Chronic Heart Failure focus attention on the diagnosis of heart failure (Remme and Swedberg). Figure 10 summarizes the recommended approach in persons in whom heart failure is suspected on the basis of certain symptoms and signs. Symptoms associated with heart failure (such as dyspnea) or physical findings in heart failure (such as peripheral edema) trigger this diagnostic algorithm. Mild symptoms and early signs should be investigated to identify disease at an early stage. Electrocardiography or chest radiography should be used to assess for cardiac disease. If heart failure is suspected on the basis of initial assessment, cardiac imaging should be done. Echocardiography should be done first because it is widely available; its cost is reasonable; and it can characterize systolic and diastolic ventricular function, wall-motion abnormalities, ventricular hypertrophy, valvular
Remme WJ, Swedberg K. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure: task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail 2002;4:11-22. PMID: 11812661
TA B L E 1 5 Clinical Heart Failure Guidelines
Guideline Clinical Practice Guideline No. 11. Rockville, MD: U.S. Department of Health and Human Services, Agency for Healthcare Policy and Research; 1994. Publication 94-0612. American College of Cardiology/American Heart Association Guidelines for the Evaluation and Management of Heart Failure. Circulation. 1995;92:2764. Revised in Circulation. 2001;104:1996. World Health Organization Heart Failure Guidelines. J Card Failure. 1996;2:153. European Society of Heart Failure Guidelines. Eur Heart J. 1997;18:736. Revised in Eur J Heart Failure. 2002;4:11. ACTION Heart Failure Treatment Guidelines. Am J Cardiol. 1999;83(2A):1. Heart Failure Society of America Guidelines for the Management of Heart Failure. J Card Failure. 1999;5:358.
TA B L E 1 6 Common Themes of Heart Failure Guidelines: Diagnosis
of the Syndrome Diagnostic Themes Diagnose syndrome early Measure left ventricular function (systolic vs. diastolic dysfunction) Identify specific cardiac structural abnormalities Determine cause of cardiac dysfunction Determine whether ischemic heart disease, hypertension, valvular heart disease, arrhythmias, or a metabolic disturbance (e.g., diabetes mellitus or thyroid function disorders) are contributing to the problem
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abnormalities, cardiac hemodynamics, and anatomic relationships. Radionuclide angiography can be used to measure ejection fraction but does not provide additional information about structural heart disease. Magnetic resonance imaging and computed tomography of the heart may be helpful in selected patients. A normal echocardiogram (no evidence of systolic dysfunction, diastolic dysfunction, or valvular dysfunction) in the setting of test abnormalities rules out significant heart failure with great certainty. As Figure 10 suggests, if the echocardiogram is abnormal, various ancillary tests should be done to determine the etiology, severity, and precipitating factors of the heart failure and the type of cardiac dysfunction. Laboratory testing may reveal conditions that can lead to or exacerbate heart failure. The initial evaluation of patients with heart failure should include complete blood count, urinalysis, serum electrolytes, and lipid levels, as well as tests of renal and hepatic function, chest radiography, and 12-lead electrocardiography. Thyroid function tests should be performed because hyperthyroidism and hypothyroidism can be primary or contributory causes of heart failure. The serum ferritin level and transferrin saturation may help to detect hemochromatosis. Assays for connective tissue diseases and pheochromocytoma should be performed if these diagnoses are suspected. Coronary angiography should be considered in patients in whom atherosclerotic cardiovascular disease is suspected as a cause of heart fail-
Suspected heart failure because of symptoms and signs
Assess presence of cardiac disease by ECG, radiograph, or natriuretic peptide levels (where available)
Normal: heart failure unlikely
Test abnormal
Image by echocardiography (nuclear angiography or MRI where available)
Normal: heart failure unlikely
Test abnormal
Assess etiology, degree, precipitating factors, and type of cardiac dysfunction
Additional diagnostic tests when appropriate (e.g., coronary angiography)
Choose therapy
FIGURE 10. European Society of Cardiology guidelines for the diagnosis and treatment of chronic heart failure.
ECG = electrocardiography; MRI = magnetic resonance imaging Peproduced with permission from: Remme WJ, Swedberg K; European Society of Cardiology. Comprehensive guidelines for the diagnosis and treatment of chronic heart failure. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Eur J Heart Fail. 2002;4:11-22.
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Staging Heart Failure
KEYPOINTS
In patients with symptoms or signs that may be related to heart failure, electrocardiography, chest radiography, echocardiography, and serum and blood levels of B-type natriuretic peptide are important diagnostic and prognostic tools. Measurement of left ventricular ejection fraction is recommended in all patients with heart failure.
ure. Information from the history, physical examination, and diagnostic tests will guide best therapies. Natriuretic peptide levels are now recognized as useful for distinguishing dyspnea due to a pulmonary or central process from heart failure. B-type natriuretic peptide is a 32amino acid peptide released predominantly from the ventricles in response to stretch and increased volume. The specific role for B-type natriuretic peptide in screening for heart failure is still being defined. However, if the diagnosis of heart failure is uncertain on the basis of the history and physical examination, use of the B-type natriuretic peptide assay can be considered. If the B-type natriuretic peptide level is less than 100 pg/mL, heart failure is less likely.
Staging Heart Failure

What are the clinical stages of heart failure?
Case 6 A 54-year-old woman with a 10-year history of hypertension presents for routine follow-up. She has no symptoms and reports that her blood pressure is well controlled. The medical history is notable for hypertension and mild osteoarthritis. The family history is notable for breast cancer. She does not smoke or drink alcohol. She takes amlodipine, 10 mg/d; aspirin, 81 mg/d; and vitamin E. On physical examination, the blood pressure is 130/85 mm Hg, heart rate was 82/min, respiratory rate is 14/min, and body mass index was 26 kg/m2. Electrocardiography shows left ventricular hypertrophy. Her physician did not alter her medication regimen. On a return visit, she had had symptoms of bronchitis for 3 days. Chest radiography shows cardiomegaly. Echocardiography shows a left ventricular ejection fraction of 40%, left ventricular end-diastolic dimension of 66 mm, mild mitral regurgitation, and mild tricuspid regurgitation. Amlodipine therapy is discontinued, and treatment is started with the angiotensin-converting enzyme inhibitor ramipril, 5 mg/d, and the -blocker metoprolol CR/XL, 50 mg/d. The angiotensin-converting enzyme inhibitor and -blocker therapy is titrated over time. She remains free of heart failure symptoms over the next 5 years.
TA B L E 1 7 American Heart Association/American College of Cardiology Heart Failure Guidelines: Stages of Heart Failure
Stage A
Description Patients at high risk of developing heart failure because conditions associated with heart failure are present, but with no overt structural/functional abnormalities of the heart and no heart failure symptoms or signs Patients with overt heart disease that is strongly associated with developing heart failure but who have never shown signs or symptoms of heart failure Patients with prior or current symptoms of heart failure associated with structural heart disease Patients with advanced structural heart disease and marked symptoms of heart failure at rest despite maximal treatment and require specialized interventions
Examples Hypertension, diabetes mellitus, coronary heart disease, cardiotoxin exposure, family history of DCM, past rheumatic fever, hemochromatosis Ventricular hypertrophy, cardiac chamber dilation, asymptomatic valve disease, prior MI or angina Dyspnea, fatigue, fluid retention or other signs and symptoms due to cardiac dysfunction Frequent CHF hospitalizations, hospital bound on inotropes, heart transplant candidate, hospice patient
C D
CHF=congestive heart failure; DCM=dilated cardiomyopathy; MI=myocardial infarction
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Medical Treatment of Heart Failure Due to Systolic Dysfunction
Table 17 presents the new and broader classification scheme for staging heart failure from the American College of Cardiology (ACC) and the American Heart Association (AHA). Four clinical stages of heart failure (stage A through D) were defined to reflect the fact that patients can present at different points in the course of their illness. This scheme is not intended to replace the New York Heart Association functional classification, which grossly quantitates the severity of symptoms (class I to IV) in patients with stage C or D disease. Stage A includes persons at high risk for heart failure because of associated conditions (hypertension, ischemic heart disease, diabetes, or family history of cardiomyopathy), who have no overt structural or functional heart abnormalities and no symptoms of heart failure. Stage B includes patients who have overt structural heart disease but do not have signs or symptoms of heart failure. Stage C includes patients with prior or current symptoms of heart failure with structural heart disease, and stage D includes patients with advanced structural heart disease and marked symptoms of heart failure despite maximal and aggressive therapies. The patient described in Case 6 progressed from stage A or B to stage C heart failure. There is no way of knowing whether she already had structural heart disease at the time of her first visit when she was asymptomatic. Even with adequate blood pressure control, patients with hypertension are at higher risk for heart failure. Angiotensin-converting enzyme inhibitors and -blockers would have decreased the likelihood of progression to symptomatic heart failure and death. No consensus has been reached on the best screening method for identifying asymptomatic persons who would be characterized as having stage B disease.
KEYPOINTS
Patients who have diseases associated with heart failure but no symptoms or identifiable structural abnormalities (stage A) and those who have structural or functional abnormalities but no symptoms or obvious clinical findings (stage B) must be identified. Appropriate intervention can often prevent progression to symptomatic (stage C) or advanced or refractory (stage D) disease.

Can heart failure be prevented? What are the core therapies and adjunctive treatments of heart failure?
Figure 11 summarizes the ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult and links therapeutic intervention to the four stages of heart failure (Hunt et al.). Core treatments for heart failure include diuretics to achieve euvolemia, angiotensin-converting enzyme inhibitors in all tolerant patients with left-ventricular systolic dysfunction, and selected -blockers in patients with stable compensated heart failure (who also have depressed left ventricular ejection fraction). Adjunctive medical therapies include electrolyte supplements, digitalis, and aldosterone blockade with spironolactone in certain circumstances (Hood et al.; Rathore et al.). Preventive measures, including control of systolic and diastolic hypertension and treatment of lipid disorders, are key for patients with stage A disease. Education about avoidance of high-risk behaviors (cigarette smoking, excessive alcohol consumption, illicit drug use, and cardiovascular deconditioning) is essential. New evidence from clinical trials suggests that all patients with a history of arteriosclerotic disease, diabetes mellitus, or hypertension (Arnold et al.) and associated risk factors who can tolerate an angiotensin-converting enzyme inhibitor should receive these agents. Other important considerations are control of heart rate in patients with supraventricular tachyarrhythmias, treatment of manifest thyroid disorders, and periodic evaluation for signs and symptoms of congestive heart failure (progression to stage C).
Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldman AM, Francis GS, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). Circulation 2001;104: 2996-3007. PMID: 11739319 Hood WB, Dans A, Guyatt GH, Jaeschke R, McMurray JV. Digitalis for treatment of congestive heart failure in patients in sinus rhythm. Cochrane Database Syst Rev 2001. Rathore SS, Wang Y, Krumholz HM. Sex-based differences in the effect of digoxin for the treatment of heart failure. N Engl J Med 2002;347:1403-11. PMID: 12409542 Arnold JM, Yusuf S, Young J, Mathew J, Johnstone D, Avezum A, et al. Prevention of heart failure in patients in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2003 Mar 11;107(9):1284-90. PMID: 12628949
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Screening patients at high risk for heart failure (stage A) for the development of asymptomatic left ventricular dysfunction (stage B) is desirable, but routine echocardiography would be cost prohibitive. Recently, the B-type natriuretic peptide blood test has been demonstrated to identify patients with Stage B disease and may be cost-effective, but further study is needed. Recommendations for patients with asymptomatic left ventricular systolic dysfunction (stage B disease) include use of angiotensin-converting enzyme inhibitors and -blockers. All patients with prior myocardial infarction should receive these agents even if the ejection fraction is normal. Furthermore, angiotensin-converting enzyme inhibitors and -blockers should be used in patients with reduced left ventricular ejection fraction regardless of whether they have experienced prior myocardial infarction. In patients with reduced ejection fraction, three -blockers have been well studied in clinical trials and demonstrate incontrovertible evidence of efficacy: bisoprolol, carvedilol, and metoprolol CR/XL. Currently, only metoprolol CR/XL and carvedilol are approved by the U.S. Food and Drug Administration for use in heart failure. One of the agents recommended in the heart failure guidelines should be prescribed, as it is not clear that other -blockers provide similar benefits in patients with reduced ejection fraction and target doses have not been defined. Regular evaluation for the development of signs and symptoms of heart failure is important,
Stage A At high risk for HF but without structural heart disease or symptoms of HF e.g., Patients with: Hypertension Diabetes mellitus Using cardiotoxins With family history of cardiomyopathy
Stage B Structural heart disease but without symptoms of HF
Stage C Structural heart disease with prior or current symptoms of HF
Stage D Refractory HF requiring specialized interventions
Structural Heart Disease
e.g., Patients with: Previous MI LV systolic dysfunction Asymptomatic valvular disease
e.g., Patients with: Known structural Symptoms heart disease of HF Shortness of develop breath and fatigue, reduced exercise tolerance
Refractory symptoms of HF at rest
e.g., Patients who have symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from hospital without specialized interventions)
Therapy
Therapy
Therapy
Therapy
Treat hypertension Encourage smoking cessation Treat lipid disorders Encourage regular exercise Discourage alcohol intake, illicit drug use ACE inhibition in appropriate patients
All measures under stage A ACE inhibitors in appropriate patients -blockers in appropriate patients
All measures under stage A Drugs for routine use: - Diuretics - ACE inhibitors - -blockers - Digitalis Dietary salt restriction
All measures under stages A, B, and C Mechanical assist devices Heart transplantation Continuous (not intermittent) IV inotropic infusions for palliation Hospice care
FIGURE 11. American College of Cardiology/American Heart Association guidelines for the diagnosis and treatment of heart failure.
ACE = angiotensin-converting enzyme; HF = heart failure; IV = intravenous; LV = left ventricular; MI = myocardial infarction Reproduced with permission from: Hunt SA, Baker DW, Chin MH, Cinquegrani MP, Feldmanmd AM, Francis GS, et al. ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the International Society for Heart and Lung Transplantation; Endorsed by the Heart Failure Society of America. Circulation. 2001;104:2996-3007.
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as is implementing all measures discussed for patients with stage A disease. Digoxin is not recommended in patients with stage B disease who are in sinus rhythm. Case 7 A 65-year-old man with a history of myocardial infarction and left ventricular ejection fraction of 20% presents with 2 weeks of worsening shortness of breath at rest and lower-extremity edema despite an increase in his furosemide dose. He has no chest pain but notes orthopnea requiring three pillows and weight gain of 2.3 kg (5 lb). The medical history is notable for coronary artery bypass grafting surgery 10 years ago and myocardial infarction 5 years ago and 2 years ago. He has had symptoms of heart failure for the past 2 years and has been hospitalized for heart failure twice in the past 6 months. At baseline, he can walk only across the room before becoming short of breath. His medical regimen was furosemide 120 mg twice daily; digoxin, 0.125 mg/d; benazepril, 5 mg/d. On physical examination, blood pressure is 95/43 mm Hg, heart rate is 90/min, and respiratory rate is 24/min. The jugulovenous pressure is estimated to be 16 cm, and the lungs are clear. Cardiac examination reveals a regular rate and rhythm, normal S1, physiologically split S2, grade III/IV holosystolic murmur, and an S3. Abdominal examination showed hepatomegaly, and the extremities showed 3+ pitting edema. The patient is admitted. Chest radiography shows cardiomegaly and pulmonary vascular redistribution. The creatinine concentration is 1.6 mg/dL and the sodium concentration is 132 meq/L. Treatment with intravenous furosemide and nesiritide is started. Over the next few hours, shortness of breath resolves. More than 2 L is diuresed in the first 24 hours of hospitalization. The dose of angiotensin-converting enzyme inhibitor is increased to 10 mg/d. After 48 hours, nesiritide therapy is discontinued. Treatment with oral furosemide and spironolactone, 12.5 mg/d, is begun. A 2-g sodium diet and monitoring of body weight daily is prescribed. Treatment with aspirin, 81 mg/d, and simvastatin, 40 mg/d, is started. Since the patient is no longer volume overloaded, -blocker therapy with carvedilol, 3.125 mg/twice daily, is begun. An implantable cardioverter-defibrillator is inserted, and he is discharged to home 1 day later. Over a few weeks, the patients condition improves, and he is able to walk two blocks. The medication regimen is adjusted to benazepril, 40 mg/d; aspirin, 81 mg/d; carvedilol, 25 mg twice daily; simvastatin, 40 mg/d; furosemide, 80 mg/d; and spironolactone, 25 mg/d. He continues to do well. On cardiopulmonary exercise testing, his peak oxygen consumption is 18.4 mg/kg/min. During an argument with his wife, he passes out and his implantable cardioverter-defibrillator fires. On device interrogation, he is found to have had a successfully cardioverted episode of ventricular tachycardia. Over the next year, the patients condition improves enough that he returns to work as a college professor. In patients with left ventricular dysfunction and current or prior symptoms of heart failure (stage C disease), measures discussed for patients with stage A or B
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disease should be implemented. Immunization against influenza and pneumococcal pneumonia are important, and patients should be encouraged to perform moderate aerobic physical activity except during periods of acute decompensation. Table 18 lists the core drugs used to treat chronic heart failure, initial dosing recommendations, and maximum or target doses. Generally, patients with symptomatic left ventricular systolic dysfunction will be managed with a diuretic, an angiotensin-converting enzyme inhibitor, a -blocker, and digoxin. Generally, patients with evidence of fluid retention on physical examination are given diuretics until a euvolemic state is reached. Diuretic therapy should probably be continued in most of these patients to prevent recurrence of sodium and water retention. Of note, diuretics do not beneficially affect mortality, and they may create a metabolic milieu that leads to increased rates of adverse events. With salt and fluid restriction, patients can often discontinue diuretic therapy. Even if patients respond favorably to diuresis, treatment with angiotensin-converting enzyme inhibitors and -blockers should be initiated and maintained, perhaps indefinitely, in all patients who tolerate them. The patient in Case 7 was stabilized with medications. During his hospitalization, he was initially treated with nesiritide, an intravenous preparation of B-type natriuetic peptide, that was recently approved for treatment of acutely decompensated heart failure. In a decompensated patient who has already been taking high-dose diuretics, such as this patient, an intravenous infusion of nesiritide is often helpful. This agent has been shown to lower pulmonary capillary
TA B L E 1 8 Drugs Used to Treat Chronic Heart Failure
Agent Loop diuretics*
Initial Dose
Maximum/Target Dose 10 mg 400 mg 200 mg
Bumetanide Furosemide Torsemide Angiotensin-converting enzyme inhibitors Captopril Enalapril Fosinopril Lisinopril Quinapril Ramipril -Blockers Bisoprolol Carvedilol Metoprolol tartrate (CR/XL-extended release) Digitalis Digoxin
0.5-1.0 mg qd or bid 20-40 mg qd or bid 10-20 mg qd or bid
6.25 mg tid 2.5 mg bid 5 mg qd 2.5 mg qd 10 mg bid 1.25 mg qd 1.25 mg qd 3.125 mg bid 6.25 mg bid
50 mg tid 10 mg bid 40 mg qd 20 mg qd 40 mg bid 10 mg qd 10 mg qd 25 mg bid 75 mg bid
0.125 mg qd
0.25 mg qd
bid = twice daily; qd = once daily; tid = three times daily

*Diuretics
should be titrated up or down with respect to dose to achieve dry weight. Thiazide agents may be appropriate in mild heart failure, for associated hypertension, or as a second diuretic with loop agents in severe congestive states (loop diureticresistant patients). Maximum dose dose
Target
From: American College of Cardiology/American Heart Association Guidelines for the Evaluation and Management of Heart Failure. Circulation. 2001;104:1996.
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wedge pressure. The most common side effect is hypotension which usually resolves with discontinuation of the drug and restarting it at a lower dose. In an open-label trial comparing nesiritide to dobutamine, there were fewer serious arrhythmias and a trend toward lower readmission rates and mortality (Burger et al.; Silver et al.). Once the patient was stable and euvolemic, -blocker therapy was indicated. With appropriate adjustment of his heart failure regimen, the patient was able to take target doses in the evidence-based regimen of angiotensinconverting enzyme inhibitors and -blockers. Because he had coronary artery disease it was important to use therapies that decrease the risk for atherosclerotic events (including aspirin and lipid-lowering medication adjusted to achieve a low-density lipoprotein cholesterol level <100 mg/dL, a high-density lipoprotein cholesterol level >40 mg/dL, and a triglyceride level <150 mg/dL). Several additional pharmacologic strategies have been shown in controlled clinical trials to be useful in selected patients with heart failure. In the Randomized Aldactone Evaluation Study (RALES), spironolactone was shown to decrease morbidity and mortality in patients older than 65 years of age with New York Heart Association class III or IV (ACC/AHA stage C or D) chronic congestive heart failure (Pitt et al.). Low doses of spironolactone are recommended (12.5 mg/d to 25 mg/d) and serum potassium should be monitored closely. The drug should be used with caution in patients with a serum creatinine concentration greater than 2.5 mg/dL. In patients with intolerance to angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers should be administered. One large clinical trial and several smaller ones have suggested that angiotensin receptor blockers are at least equivalent to angiotensin-converting enzyme inhibitors in patients with heart failure who cannot tolerate the latter agents (Lindholm et al.). Use of an angiotensin receptor blocker when a patient is already receiving an angiotensinconverting enzyme inhibitor and a -blocker may be associated with adverse outcome, but is being studied in several ongoing clinical trials. Another option in patients who cannot tolerate angiotensin-converting enzyme inhibitors is the combination of hydralazine and isosorbide dinitrate. When prescribing diuretics, the clinician should choose a dose that will relieve congestion, whereas with angiotensin-converting enzyme inhibitors and -blockers, the target dose defined by clinical trials should be attempted. Withdrawal of treatment with drugs known to adversely affect the clinical outcome of patients (such as nonsteroidal anti-inflammatory drugs, most antiarrhythmic agents, most calcium channel blocking agents, and the glitazone insulin-sensitizing agents) is often sufficient to restabilize a significantly congested patient. Therapeutic interventions for which there is little evidence of efficacy and possible evidence of harm include long-term intermittent infusion of a positive inotropic drug, use of an angiotensin receptor blocker instead of an angiotensin-converting enzyme inhibitor in patients with heart failure who can tolerate an angiotensin-converting enzyme inhibitor, addition of an angiotensin receptor blocker before a -blocker in patients with heart failure who are taking an angiotensin-converting enzyme inhibitor, and use of a calcium channel blocking drug as a primary treatment for heart failure. Nutritional supplements (such as multivitamins, coenzyme Q10, carnitine, taurine, selenium) and hormonal therapies (growth hormone or thyroid hormone in the absence of deficiency states) have no proven efficacy. Patients with stage D disease involving refractory end-stage heart failure are more challenging to treat. These patients generally have profound fatigue, weakness, and dyspnea with associated fluid retention, which preclude even the minimal exertion required for activities of daily living. Patients with advanced
Burger AJ, Elkayam U, Neibaur MT, Haught H, Ghali J, Horton DP, et al. Comparison of the occurrence of ventricular arrhythmias in patients with acutely decompensated congestive heart failure receiving dobutamine versus nesiritide therapy. Am J Cardiol. 2001;88:35-9. PMID: 11423055 Silver MA, Horton DP, Ghali JK, Elkayam U. Effect of nesiritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure. J Am Coll Cardiol. 2002;39: 798-803. PMID: 11869844 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341:709-17. PMID: 10471456 Lindholm LH, Ibsen H, Dahlof B, Devereux RB, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359: 1004-10. PMID: 11937179
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Medical Treatment of Heart Failure with Preserved Systolic Dysfunction
KEYPOINTS
Tailored therapeutic protocols important for heart failure include multiple different drug classes, and are based on the progression from insidious (stage A or B) to symptomatic (stage C) or advanced or refractory disease (stage D). Therapy for heart failure aims to prevent as well as treat cardiac dysfunction and its manifestations. Detecting and eliminating treatable diseases, such as ischemic heart disease, hypertension, and valvular heart disease, are critical to improving symptoms and attenuating morbidity and mortality. Diuretics should be used to create a euvolemic state and relieve symptoms associated with congestion, but they do not favorably effect mortality. When left-ventricular systolic dysfunction is present, angiotensin-converting enzyme (ACE) inhibitors in all tolerant patients and certain -blockers in stable patients with mild to moderate to severe symptoms reduce mortality and morbidity. Ancillary medications include digitalis preparations in patients with symptomatic congestive heart failure and spironolactone in selected patients. The digoxin level should be measured and the dose adjusted to maintain a level less than 0.7 ng/mL. Angiotensin-receptor blocking drugs are effective when an ACE inhibitor cannot be tolerated, but these drugs should not be substituted in patients who tolerate ACE inhibitors. They should not be added to therapy with ACE inhibitors, particularly in conjunction with a -blocker. Therapy for heart failure with potentially detrimental drugs or those of questionable benefit should be stopped.
heart failure often deteriorate because of salt and water retention resulting from dietary or medication noncompliance. These patients should be treated with aggressive salt and fluid restriction and all of the measures listed for patients in stages A, B, and C heart failure. -Blockers may worsen the congestive state in patients with stage D disease. Nonetheless, recent evidence supports use of these agents to reduce morbidity and mortality when advanced heart failure is present, but the patients who are most likely to benefit from upward titration are generally not significantly congested. Another potentially beneficial therapeutic strategy is inpatient titration of medication directed by invasive hemodynamic monitoring. Although routine intermittent infusion of positive inotropic agents is not recommended, continuous infusion of these agents may be required for palliation of symptoms in patients with severe end-stage disease. Nesiritide (B-type natriuretic peptide) in the outpatient setting is being evaluated in clinical trials. Eventually, patients may require referral for cardiac transplantation evaluation or for other procedures. Table 19 summarizes when to consider referral to a heart failure specialist or heart transplantation center.
Medical Treatment of Heart Failure with Preserved Systolic Dysfunction

Treatment of patients with symptoms of congestive heart failure but ejection fractions that are considered normal or near-normal are often said to have heart failure due to diastolic dysfunction. The best management strategies for these patients have not yet been defined. Most experts, however, stress the importance of controlling systolic and diastolic hypertension in accordance with published guidelines. In patients with atrial fibrillation, control of the ventricular rate should be a goal. Diuretics should be used to control pulmonary congestion and peripheral edema. Patients with heart failure due to diastolic dysfunction and ischemic heart disease also benefit greatly from coronary revascularization. Some emphasize restoration of normal sinus rhythm in patients with atrial fibrillation, even though this was not associated with improved outcomes in patients in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. Although use of digitalis was generally discouraged in patients with diastolic dysfunction, a subset of patients in the Digitalis Investigation Group trial with normal systolic function were treated and heart failure hospitalizations were reduced (Digitalis Investigation Group). Thus, digoxin therapy should be considered when moderate symptoms of congestive heart failure are present.
TA B L E 1 9 When to Refer Patients to Heart Failure Specialists or for Heart
Transplant Consideration Consider Patient Referral Frequent hospital or emergency department admissions for heart failure decompensation Difficulty in determining patients volume or systemic organ perfusion status Complex heart failure with renal insufficiency, hepatic congestion, severe pulmonary hypertension, systemic hypoperfusion, or congenital abnormalities Problems emerge with up-titration of complex polypharmacy therapeutic protocols Biventricular pacing or defibrillator insertion being considered Patient is severely ill from heart failure but is of reasonable age with adequate preservation of systemic organ function such that heart transplantation might be feasible and acceptable
The effect of digoxin on mortality and morbidity in patients with heart failure. Digitalis Investigation Group. N Engl J Med 1997;336:525-33. PMID: 9036306
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Other Therapeutic Considerations
Randomized clinical trials of angiotensin-converting enzyme inhibitors, -blockers, and calcium channel blockers have not been performed in patients with heart failure and preserved systolic function. Recommendations are based on observational studies and expert opinion and should thus be considered a bit tenuous (Table 20). Because patients with diastolic dysfunction frequently have hypertension, coronary artery disease, or diabetes, use of angiotensinconverting enzyme inhibitors is recommended. Data from observational studies show that use of angiotensin-converting enzyme inhibitors is associated with reduced mortality. Use of -blockers has also been associated with improved outcomes. Calcium channel blockers have not been studied in this setting and do not improve outcome in systolic dysfunction heart failure; thus, their use should be reserved for patients with hypertension that is not controlled with angiotensin-converting enzyme inhibitors and -blockers. Angiotensin receptor antagonists are being studied in this patient population.
TA B L E 2 0 Treating Heart Failure Due to Diastolic Dysfunction
KEYPOINTS
In symptomatic congestive heart failure with preserved or relatively preserved systolic left ventricular function (socalled diastolic heart failure), treatment guidelines are less well established. There is general agreement on aggressive blood pressure control, diuretics to create a euvolemic state, and use of ACE inhibitors and -blockers.
Considerations Control systolic and diastolic hypertension and consider use of -blockers and angiotensin-converting enzyme inhibitors Prescribe diuretics and digoxin to minimize symptoms Consider coronary revascularization in patients with symptomatic or demonstrable ischemia that is thought to have an adverse effect on diastolic function Control ventricular rate in patients with atrial fibrillation and consider restoration of sinus rhythm
Other Therapeutic Considerations

Patients with chronic heart failure are at increased risk of thromboembolic events due to stasis of blood in dilated hypokinetic cardiac chambers and peripheral blood vessels as well as increased activity of procoagulant factors. The risk of thromboembolization in clinically stable patients has been low (1% to 3% per year), even in patients with very depressed ejection fraction and echocardiographic evidence of intracardiac thrombi. In the absence of definitive trials, it is not clear that anticoagulants should be prescribed to patients with heart failure who are in sinus rhythm unless they have experienced embolic events. In the absence of contraindications, anticoagulation is recommended in patients with heart failure and paroxysmal or sustained atrial fibrillation. Although atrial fibrillation increases the risk of embolic events, the outcome associated with restoring and maintaining sinus rhythm was uncertain until recently. It was long recognized that class I antiarrhythmic agents can have cardiodepressant and proarrhythmic effects in patients with heart failure, increasing the risk of sudden death. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial showed that the strategy of rate control and anticoagulation was similar to rhythm control in patients with atrial fibrillation (although this trial included relatively few patients with moderate or severe heart failure) (Wyse et al.). When an antiarrhythmic agent is indicated, amiodarone is usually well tolerated and has a low incidence of proarrhythmic events despite prolongation of the QT interval. Patients with heart failure who are treated with this agent should be monitored for excessive bradycardia, especially in association with use of a -blocker, and for thyroid and hepatic toxicity (which are well-known side effects).
Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-33. PMID: 12466506
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Nonpharmacologic Therapies for Heart Failure
Nonpharmacologic Therapies for Heart Failure

Standard approaches to heart failure should also include recommendations for routine nonpharmacologic interventions. Appropriate dietary recommendations include salt and fluid restriction in patients with volume overload and a diet low in animal fat in patients with arteriosclerosis. Elimination of alcohol seems appropriate in patients with cardiomyopathy but normal coronary arteries. Aerobic exercise is increasing in importance as part of treatment of patients with heart failure, but its effect on mortality remains undetermined. Surgical or procedural therapies to consider include coronary revascularization (coronary artery bypass graft surgery or percutaneous interventions), repair or replacement of faulty heart valves, ventricular remodeling after myocardial infarction, biventricular pacing, and implantation of cardioverterdefibrillators. Ventricular assist devices and heart transplantation can be considered in highly selected patients (Goldstein et al.; Hosenpud et al.). Novel surgical approaches to patients with heart failure are becoming increasingly important. Revascularization strategies in patients with symptomatic or demonstrable ischemia should be considered in the presence of documented viable myocardium, although the effect on survival is not yet fully defined. The choice between percutaneous coronary intervention (angioplasty with or without stenting) and coronary bypass surgery is largely based on technical and anatomic considerations. An emerging surgical approach combines coronary artery bypass surgery with infarct exclusion. Removing the scarred tissue from a failing left ventricle and favorably reshaping the heart, addresses ischemia and may improve the mechanical abnormalities associated with detrimental heart remodeling. Patients with significant mitral or tricuspid regurgitation may benefit from valve repair or replacement that eliminates the associated volume overload. Consensus on these approaches is beginning to emerge. Randomized controlled trials of these surgical interventions are probably not feasible, but accumulated experience provide more definitive information on which patients are likely to benefit from them. Approximately 20% of patients with heart failure have a wide QRS complex (>120 ms) due to an interventricular conduction delay, most commonly a left bundle-branch block. This condition leads to a dyssynchronous contraction pattern within the left ventricle and has been associated with worse prognosis in patients with heart failure. Simultaneous activation of the right and left ventricles with biventricular pacing in patients with marked QRS prolongation has been shown to improve quality of life, symptoms of heart failure, and exercise variables and is associated with remodeling of the heart (decreased cardiac volume and increased ejection fraction). Biventricular pacing systems have been approved for use in patients who have refractory symptoms of heart failure despite optimized medical therapy (ACC/AHA stage C or D disease and New York Heart Association functional class III or IV), with an ejection fraction less than 35% and a QRS duration greater than 120 ms. Implantation of these devices requires an experienced electrophysiologist, as the success of the procedure is sometimes compromised by constraints posed by the coronary sinus and left lateral coronary venous anatomy. The effect of cardiac resynchronization with biventricular pacing on mortality is being evaluated (Abraham). Malignant ventricular arrhythmias are common in the setting of heart failure. Prevention of sudden cardiac death in patients with heart failure is important. Most antiarrhythmic drugs are contraindicated in heart failure, and use of amiodarone alone for prevention of sudden death is controversial; therefore, an implantable cardioverter-defibrillator, alone or in combination with amiodarone therapy, is recommended for patients with heart failure who have a history of
Goldstein DJ, Oz MC, Rose EA. Implantable left ventricular assist devices. N Engl J Med 1998;339:1522-33. PMID: 9819452 Hosenpud JD, Bennett LE, Keck BM, Boucek MM, Novick RJ. The Registry of the International Society for Heart and Lung Transplantation: seventeenth official report2000. J Heart Lung Transplant 2000;19:909-31. PMID: 11044685
Abraham WT. Rationale and design of a randomized clinical trial to assess the safety and efficacy of cardiac resynchronization therapy in patients with advanced heart failure: the Multicenter InSync Randomized Clinical Evaluation (MIRACLE). J Card Fail. 2000;6:369-80. PMID: 11145762
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Prognosis
ventricular fibrillation or hemodynamically destabilizing ventricular tachycardia. Data from the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) suggest that mortality rate can be significantly reduced in patients who have had myocardial infarction and have an ejection fraction less than or equal to 30% despite presence or absence of arrhythmias (Moss et al.). The ACC/AHA guidelines recommend prophylactic placement of an implantable cardioverter-defibrillator in patients with ischemic cardiomyopathy and left ventricular ejection fraction less than or equal to 30%, as long as they do not have stage D heart failure or medical illness that would otherwise greatly limit survival.
Moss AJ, Daubert J, Zareba W. MADIT-II: clinical implications. Card Electrophysiol Rev. 2002;6:463-5. PMID: 12438829
KEYPOINTS
Prognosis
Much information has been accrued to predict adverse outcomes in patients with heart failure. The presence and persistence of jugular venous distension and S3 gallop carry a poor prognosis. Adverse electrocardiographic findings include wide QRS complexes; low limb-lead voltage; extensive Q-wave formation; and arrhythmias, including atrial fibrillation and ventricular tachycardia. Radiographic evidence of severe cardiomegaly and persistent pulmonary venous congestion despite medical therapy are ominous signs. Laboratory findings associated with poor prognosis include hyponatremia, azotemia, and hepatic function abnormalities and prolonged prothrombin time in the absence of anticoagulation. Levels of B-type natriuretic peptide have prognostic value in patients with heart failure. The following ranges for B-type natriuretic peptide levels have been generally associated with the following heart failure syndromes: less than 100 pg/mL, no significant heart failure; 100 to 250 pg/mL, significant left ventricular dysfunction but compensated congestion; 250 to 500 pg/mL, congestive heart failure with both diastolic and systolic dysfunction; 500 to 1000 pg/mL, decompensated congestive state; greater than 1000 pg/mL, high-risk patients with substantial congestive heart failure. Pilot trials suggest that adjustment of medical therapy for heart failure on the basis of B-type natriuretic peptide levels plus clinical assessment produced superior outcomes compared to therapy guided by clinical assessment alone (Maisel). Echocardiographic variables that suggest an adverse outcome include low ejection fraction (particularly <20%). Large ventricular volumes and significant diastolic dysfunction are also associated with adverse outcome. Cardiopulmonary exercise testing, which provides an objective measurement of peak oxygen consumption during exercise, is the most useful tool for defining heart failure disability and determining prognosis and is recommended in patients being considered for heart transplantation. In the ACC/AHA guidelines, this test receives a class IIa recommendation to determine whether heart failure is the cause of a patients exercise limitation. Patients who do not reach anaerobic threshold (a respiratory exchange ratio <1.0) are probably limited by factors in addition to cardiac abnormalities; these factors may include pulmonary disease, anemia, obesity, and cardiovascular deconditioning. Peak VO2 is determined by using formulas based on age and sex. Some heart failure specialists believe that a peak VO2 in the setting of a respiratory exchange ratio greater than 1.10 and less than 14 mL O2/kg/min is associated with such a poor prognosis the findng characterizes patients best referred for cardiac transplantation.
Surgical therapies in carefully selected patients can dramatically relieve symptoms. Patients with coronary or valvular heart disease amenable to operative intervention should be referred for appropriate surgeries. Ancillary electrophysiologic and surgical treatment strategies for heart failure are available.
Maisel A. B-type natriuretic peptide in the diagnosis and management of congestive heart failure. Cardiol Clin. 2001;19:557-71. PMID: 11715177
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When To Consider Cardiac Transplantation and Use of Ventricular Assist Devices
When To Consider Cardiac Transplantation and Use of Ventricular Assist Devices

Cardiac transplantation can be lifesaving in selected patients with end-stage heart failure. Donor organ availability limits to the number of transplants to approximately 2500 yearly in the U.S. Therefore, alternative strategies and proper patient selection are important. Even in patients with severe systolic left ventricular dysfunction, the 3- to 5-year survival rate with optimal medical therapy is about 80%. With contemporary immunosuppressive therapies, the halflife of a transplanted heart is about 10 years. Thus, even after a patient is accepted and listed for transplantation, every attempt should be made to optimize therapy. Age is only a relative contraindication, and patients in their 60s and early 70s have substantially benefited from heart transplantation. Diabetes was once thought to be a contraindication to heart transplantation but is no longer considered absolutely exclusionary, as long as renal function is preserved and the patient does not have substantial retinopathy, neuropathy, or peripheral vascular disease. Determination of candidacy for cardiac transplantation is best made by an experienced heart transplantation center. Left ventricular assist devices have improved dramatically over the past two decades. They are primarily used to bridge patients with cardiogenic shock to transplantation while awaiting a suitable donor organ. The greatest challenge in selecting patients for ventricular assist device stems from the need to ensure reversibility of renal failure, hepatic insufficiency, and severe pulmonary hypertension after device insertion. Several intracorporeal pulsatile and extracorporeal pulsatile devices are available. The device is selected on the basis of the size of the patient and acuity of the situation. General contraindications to ventricular assist device insertion include septicemia and profound coagulopathy. Once renal or hepatic failure and pulmonary hypertension are irreversible, device placement may be futile. A recent clinical trial in patients with end-stage heart failure who were not eligible for transplantation demonstrated that an implantable pulsatile left ventricular assist device system increased days alive out of the hospital compared with maximal medical therapy with chronic continuous infusion of an inotrope. The morbidity rate associated with the device was high, primarily related to infection and neurologic events. Mechanical reliability of the device was also problematic. With technological improvements, left ventricular assist devices may become a reasonable alternative to transplantation in carefully selected patients. In patients with very advanced heart failure who are not candidates for transplantation, end-of-life care issues must be considered. It is important to educate the patient and family or other caregivers about reasonable expectations regarding morbidity and mortality in advanced heart failure. Hospice services have proven helpful in patients dying of heart failure. Compassionate care of patients with advanced heart failure may require frequent administration of parenteral agents, such as diuretics, and positive inotropic drugs as well as judicious use of anxiolytics, soporifics, and potent analgesics.
Arrhythmias
Significant advances have occurred in the recognition and management of supraventricular arrhythmias and acute management of atrial fibrillation and stroke prevention. Indications for pacemaker implantation for bradyarrhythmias and new guidelines for acute treatment of cardiac arrest have also been developed and published.
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Supraventricular Arrhythmias
How do supraventricular arrhythmias manifest? What are the common supraventricular arrhythmias? What is the mechanism of atrioventricular nodal reentrant tachycardia and atrioventricular reentrant tachycardia? Which drugs are useful in the management of supraventricular arrhythmias? Which patients should be offered catheter ablation?
KEYPOINTS
By definition, supraventricular arrhythmias are any abnormal rhythm arising from above the ventricle. They can occur as sustained, intermittent, or paroxysmal arrhythmias.
Premature Atrial Contractions

Premature atrial contractions are a common form of benign supraventricular arrhythmia and usually does not require treatment. They are estimated to occur in 78% of healthy male aviators (Folarin et al.). Typically, they occur sporadically and may be present for hours at a time. Often, people will experience a symptomatic period, are symptom-free for months or years, and then experience a recurrence. Evaluation of the patient with frequent premature atrial contractions should focus on excluding an underlying pathologic cause for the ectopy. Causes may include any lesion that results in atrial enlargement or pressure elevation, such as hypertension or valvular heart disease. Endogenous (for example, stress) or exogenous (for example, caffeine) stimulants may lead to frequent premature atrial contractions. In some patients, premature atrial contractions may trigger atrial fibrillation. Treatment may include management of underlying pathology. If patients remain symptomatic despite reassurance and desire therapy, -blockers and calcium channel blockers can be used. It is rarely necessary to use antiarrhythmics to treat premature atrial contractions. Patients who have noted an association between palpitations and exogenous stimulants, such as caffeine, should be advised to avoid these agents.
Paroxysmal Reentrant Supraventricular Tachycardia

Case 8 A 32-year-old woman presents to the emergency department with palpitations, dizziness, and feeling as though she might faint. She states that this is the first time she has experienced such symptoms. In her efforts to make a work deadline, she has been drinking five to seven cups of coffee daily. Her symptoms began abruptly as she bent to tie her shoes. Physical examination shows a blood pressure of 100/65 mm Hg and a pulse rate of 180/min. Electrocardiography shows a narrow complex rhythm without apparent P waves. Paroxysmal reentrant supraventricular arrhythmias are characterized by abrupt onset and regularity. Offset may appear to be gradual because the patient may convert from the arrhythmia to sinus tachycardia, which then gradually slows. For reentry to occur, these arrhythmias require two tissues that have discrepant conduction velocities and refractory periods. One pathway must block in one direction while the impulse can progress through the other. Both pathways must have conductive properties that permit the rhythm to persist. The most common paroxysmal reentrant supraventricular arrhythmia is atrioventricular nodal reentrant tachycardia (AVNRT), which involves reentry within atrioventricular nodal tissue. AVNRT is usually a regular, narrow com-
Premature atrial contractions are common, benign, and usually do not require treatment. Evaluation of the patient with frequent premature atrial contractions should focus on excluding an underlying pathologic cause for the ectopy; causes may include any lesion that results in atrial enlargement or pressure elevation, stress, or ingestion of stimulants. Paroxysmal reentrant supraventricular arrhythmias are characterized by abrupt onset and regularity; the most common paroxysmal reentrant supraventricular arrhythmia is atrioventricular nodal reentrant tachycardia (AVNRT). Vagal maneuvers can terminate tachycardia; medical therapy may be appropriate in patients with recurrent episodes who cannot interrupt their tachycardia by vagal maneuvers. In the Wolff-Parkinson-White syndrome, atrial fibrillation can be treated with drugs that block conduction in the accessory pathway; useful oral drugs include class Ia, Ic, and III agents. Curative catheter ablation is recommended in patients with WolffParkinson-White syndrome when symptomatic tachycardia is drug resistant or when the patient is drug intolerant or does not desire long-term drug therapy. Atrial tachycardia can manifest as an intermittent or persistent arrhythmia; the mechanism can be reentry, triggered, or automatic. Reentry is the most common mechanism of arrhythmia. Persistent atrial tachycardia can cause a tachycardia-mediated cardiomyopathy.
Folarin VA, Fitzsimmons PJ, Kruyer WB. Holter monitor findings in asymptomatic male military aviators without structural heart disease. Aviat Space Environ Med. 2001;72:836-8. PMID: 11565820
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Zipes DP, DiMarco JP, Gillette PC, Jackman WM, Myerburg RJ, Rahimtoola SH, et al. Guidelines for clinical intracardiac electrophysiological and catheter ablation procedures. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Clinical Intracardiac Electrophysiologic and Catheter Ablation Procedures), developed in collaboration with the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol. 1995;26:555-73. PMID: 7608464 Goudevenos JA, Katsouras CS, Graekas G, Argiri O, Giogiakas V, Sideris DA. Ventricular pre-excitation in the general population: a study on the mode of presentation and clinical course. Heart. 2000;83:29-34. PMID: 10618331 Munger TM, Packer DL, Hammill SC, Feldman BJ, Bailey KR, Ballard DJ, et al. A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989. Circulation. 1993;87:866-73. PMID: 8443907
plex tachycardia of 160 to 180 beats/min. The retrograde P wave is typically buried within the QRS complex but may occur shortly before or after it. In the absence of structural heart disease, AVNRT is a benign arrhythmia. Typical presenting symptoms are palpitations and shortness of breath. Infrequently syncope occurs. Case 8 describes a typical first onset of AVNRT. Vagal maneuvers, such as a Valsalva maneuver, immersion of the face or forearm in ice water, or carotid massage, can terminate tachycardia. Acute pharmacologic termination of tachycardia can usually be achieved with adenosine. Medical therapy may be appropriate in patients with recurrent episodes who cannot interrupt their tachycardia by vagal maneuvers. Atrioventricular nodal blocking agents, such as -blockers and calcium channel blockers, are often effective in preventing recurrence of AVNRT. Antiarrhythmics, including class IC and III agents, can be effective in preventing AVNRT. However, their utility is limited by side effects and potential for proarrhythmia. Patients with refractory AVNRT or those who do not tolerate or do not wish to take medication should be offered curative catheter ablation (Zipes et al.). Conservative management would be most appropriate for the patient described in Case 8. After treatment of the initial episode, further medical or ablative therapy should be intiated only if the arrhythmia recurs.
Preexcitation Syndromes
Preexcitation is related to the presence of an accessory pathway that can conduct the impulse from the atrium to the ventricle by a route that bypasses the atrioventricular node. Accessory pathways straddle the atrioventricular groove on the mitral or tricuspid annuli. Most patients with an accessory pathway will have manifest preexcitation (a short PR interval and delta waves on electrocardiography), making the diagnosis of Wolff-Parkinson-White syndrome readily apparent. However, a smaller percentage have a concealed pathway capable of only retrograde conduction (from ventricle to atrium). In this case, the surface electrocardiogram is normal. The most common arrhythmia in the Wolff-Parkinson-White syndrome is atrioventricular reentrant tachycardia, in which the pathway serves as one limb and the atrioventricular node as the second. Most atrioventricular reentrant tachycardia is narrow complex, since antegrade conduction is through the atrioventricular node and retrograde through the accessory pathway (orthodromic reentry). In some, the circuit is reversed (antidromic), with antegrade conduction through the accessory pathway and retrograde through the atrioventricular node. In these, the tachycardia is wide complex. The exact percentage of patients with Wolff-Parkinson-White syndrome who have atrial fibrillation is hard to determine but has been estimated to be as high as 8% (Goudevenos et al.). Atrial fibrillation becomes concerning in patients whose accessory pathway is capable of rapid anterograde conduction, which can degenerate to ventricular fibrillation. The overall incidence of sudden death in patients with the Wolff-Parkinson-White syndrome is estimated to be 0.15%, and most cases are probably related to degeneration of rapid atrial fibrillation (Munger et al.). In some patients with the Wolff-Parkinson-White syndrome and atrial fibrillation, the ventricular response rate is slower and the electrocardiogram shows QRS morphologies that vary in width. This phenomenon is due to varying degrees of fusion as the impulse conducts simultaneously through the atrioventricular node and the accessory pathway. Patients in this category generally have a better prognosis. The acute management of arrhythmias in Wolff-Parkinson-White syndrome depends on the mechanism. Adenosine is effective in terminating the narrow complex orthodromic reentry. However, drugs that block the atrioven-
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tricular node should be avoided in patients whose arrhythmia is wide complex (that is, preexcited). Atrioventricular node blocking agents will not block the accessory pathway and may enhance conduction via the bypass track, potentially rendering the arrhythmia unstable. Any unstable patient should be acutely cardioverted regardless the mechanism of the arrhythmia. In the setting of Wolff-Parkinson-White syndrome, atrial fibrillation can be treated with drugs that block conduction in the accessory pathway; such agents include ibutilide, procainamide, propafenone, flecainide, and amiodarone. Patients rarely present with sustained antidromic AVNRT (down the accessory pathway and up the atrioventricular node). This rhythm will appear wide, and the morphology the QRS complex will be fully preexcited. These patients should be handled the same way as the patient with atrial fibrillation. Atrioventricular nodal blocking agents should be avoided. Oral agents useful in treatment of Wolff-Parkinson-White syndrome includes class Ia, Ic and III agents. For patients with orthodromic AVNRT (narrow complex), an antiarrhythmic agent plus a -blocker can be used. No longterm studies of drug efficacy have been done. However, the class Ic drug flecainide has been reported to have a success rate of over 80% in the acute setting. For patients with Wolff-Parkinson-White syndrome who present with stable atrial fibrillation, management guidelines are similar to those in other groups. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend curative catheter ablation in patients with Wolff-Parkinson-White syndrome when symptomatic tachycardia is drug resistant or when the patient is drug intolerant or does not desire long-term drug therapy. This recommendation is independent of the type of associated arrhythmia (atrial fibrillation or atrioventricular reentry) or the mode of conduction (orthodromic or antidromic). Given the benign nature of asymptomatic Wolff-Parkinson-White syndrome, patients who are incidentally discovered to have preexcitation should not undergo electrophysiologic testing or receive treatment.
Atrial Tachycardia
Atrial tachycardia can manifest as an intermittent or persistent arrhythmia. The mechanism of atrial tachycardia can be reentry, triggered, or automatic. Triggered arrhythmias are dependent on the occurrence of the previous beat and arise from afterdepolarizations (oscillations in membrane potential after an action potential). If the afterdepolarizations reach adequate amplitude, abnormal beats occur. Automatic rhythms are generally associated with altered membrane function, which permits spontaneous depolarizations. Reentry is the most common mechanism of arrhythmia. Atrial tachycardia can arise from almost any region of the right or left atrium. Atrial tachycardias are more common in children than in adults. If atrial tachycardia persists for long enough, a tachycardia-mediated cardiomyopathy can occur. This is a reversible cause of heart failure, but ventricular function may take several months to normalize after cessation of the arrhythmia. Atrial tachycardias are in general resistant to drug treatment (Kowey). Control of heart rate may be achieved with atrioventricular node blocking agents. However, patients with atrial tachycardia that is drug resistant and patients who are drug intolerant or do not desire long-term drug therapy should be considered for ablation of the atrial focus. In addition to the atrioventricular node blocking agents, such as calcium channel blockers and -blockers, type Ia, Ic, and II antiarrhythmics can be used to attempt suppression of atrial tachycardias. The long-term efficacy of drugs in suppression of atrial tachycardia is probably no more than 50%.
Kowey PR. Pharmacological effects of antiarrhythmic drugs. Review and update. Arch Intern Med. 1998;158:325-32. PMID: 9487229
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Atrial Fibrillation and Atrial Flutter
KEYPOINTS

What are the incidence and prevalence of atrial fibrillation? What are the major sequelae of atrial fibrillation? What are the risk factors for stroke in atrial fibrillation? What are the treatment options for patients with atrial fibrillation?
The term lone atrial fibrillation generally applies to people younger than 60 years of age without clinical or echocardiographic evidence of cardiopulmonary disease and hypertension. Persistent atrial fibrillation may become permanent if cardioversion or drug therapy is not attempted. Because excessive thyroid hormone replacement can result in atrial fibrillation, it is important to measure thyroidstimulating hormone in elderly patients who present with atrial fibrillation but have no other signs of hyperthyroidism. Risk factors for stroke in patients with atrial fibrillation include a history of prior stroke, history of myocardial infarction, history of hypertension, age over 65 years, and diabetes. After restoration of sinus rhythm, in patients with atrial fibrillation, longterm antiarrhythmic therapy may not be needed, but short-term therapy may prevent early recurrences. If recurrences of paroxysmal atrial fibrillation are brief or minimally symptomatic, avoidance of long-term therapy with antiarrhythmic drugs is reasonable. Atrial or atrioventricular synchronous pacing may reduce the incidence of atrial fibrillation in patients with bradycardia-dependent or vagally mediated atrial fibrillation. The criteria for patient selection for catheter-based radiofrequency ablation are not yet well established and pulmonary venous obstruction is a reported complication.
Furberg CD, Psaty BM, Manolio TA, Gardin JM, Smith VE, Rautaharju PM. Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study). Am J Cardiol. 1994;74:236-41. PMID: 8037127 Fuster V, Ryden LE, Asinger RW, Cannom DS, Crijns HJ, Frye RL, et al. ACC/AHA/ESC guidelines for the management of patients with atrial fibrillation: executive summary. A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation): developed in Collaboration With the North American Society of Pacing and Electrophysiology. J Am Coll Cardiol. 2001;38:1231-66. PMID: 11583910
Incidence and Classification

Atrial fibrillation is the most common sustained atrial arrhythmia. Atrial fibrillation is associated with a loss of sinus node function as the primary pacemaker of the heart. There is uncoordinated atrial activation, which results in deterioration of atrial mechanical function. The electrocardiogram is characterized by loss of sinus P waves, and gross irregularity of the ventricular response is usually present. The fibrillatory waves may be of variable amplitude and are often seen on electrocardiography. Atrial flutter is sometimes seen with atrial fibrillation, particularly in patients taking drug therapy. It is characterized by more regular atrial activity. Typical atrial flutter creates a saw-tooth pattern on electrocardiography. A large macro reentrant counterclockwise circuit contained largely in the right atrium creates this pattern. The ventricular response in flutter is generally more regular than in atrial fibrillation owing to a 2:1, 3:1, or greater atrial-to-ventricular conductive pattern. In terms of risk assessment and anticoagulation, patients with flutter should be handled the same as those with atrial fibrillation. Sustained atrial flutter is less common than atrial fibrillation, and the former will typically over time give way to the latter. The prevalence of atrial fibrillation increases with age, affecting less than 1% of people younger than 60 years of age and greater than 6% of those older than 80 years of age (Furberg et al.). The age-adjusted prevalence is higher in men than in women and higher in white persons than in black persons. Atrial fibrillation is commonly associated with cardiovascular disease; an identifiable structural lesion is absent in less than 12% of all patients with atrial fibrillation. The term lone atrial fibrillation generally applies to people younger than 60 years of age who do not have clinical or echocardiographic evidence of cardiopulmonary disease and who do not have hypertension. Subclinical hyperthyroidism is a concern in elderly patients with atrial fibrillation. Similarly, excessive thyroid hormone replacement can result in atrial fibrillation. It is therefore important to measure thyroid-stimulating hormone in elderly patients who present with atrial fibrillation but have no other signs of hyperthyroidism. Various classifications for atrial fibrillation have been proposed. The scheme recommended in the ACC/AHA/ESC Guidelines is as follows (Fuster et al.). The first episode of atrial fibrillation should be evaluated to determine if this was the correct diagnosis, whether the episode was symptomatic, and whether it was self-limited. By definition, if a patient has had two or more episodes, atrial fibrillation is considered recurrent. If the abnormal rhythm terminates spontaneously, recurrent atrial fibrillation is paroxysmal. If the recurrent arrhythmia is sustained, atrial fibrillation is designated persistent. Persistent atrial fibrillation may become permanent if cardioversion or drug therapy is not attempted.
Stroke Risk and Mortality

Case 9 A 78-year-old man presents for a routine annual physical examination. He notes mild dyspnea on exertion over the past several months but has continued his usual activities. He has a history
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of hypertension that is well controlled with a diuretic alone. Physical examination and electrocardiography are consistent with atrial fibrillation, with a ventricular rate of 110/min. There are no other changes on electrocardiography, and echocardiography shows an ejection fraction of 50% with left atrial enlargement and mild aortic sclerosis. He has no history of stroke or ulcer disease. The major concern in atrial fibrillation is the potential for thromboembolism, in particular, stroke. The stroke rate in patients with nonrheumatic atrial fibrillation is about 5% per year (Wolf et al.). This rate is two to seven times that of people without atrial fibrillation. In the Manitoba Follow-up Study (Krahn et al.), atrial fibrillation doubled the risk of stroke. Risk factors for stroke in patients with atrial fibrillation include a history of stroke, myocardial infarction, hypertension, age over 65 years, and diabetes. Echocardiographic evidence of left ventricular dysfunction and left atrial enlargement have also been shown to be risk factors for stroke (Echocardiographic predictors of stroke.). Use of warfarin can significantly mitigate the risk for stroke. The patient in Case 9 has multiple risk factors for stroke and should be anticoagulated. Aspirin (325 mg/d) alone can be used in patients younger than 60 years of age who have lone atrial fibrillation or underlying heart disease, as long as there is no heart failure or hypertension and the left ventricular ejection fraction is greater than 35%. For patients 60 years of age or older without risk factors, aspirin therapy (325 mg/d) is adequate. In all other patients with atrial fibrillation, warfarin therapy should be initiated unless there is a specific contraindication. The target international normalized ratio for most patients is 2.0 to 3.0. However, if the patient has rheumatic heart disease, a prosthetic valve, prior thromboembolism, or persistent intra-atrial thrombus on transesophogeal echocardiography, a target international normalized ratio of 2.5 to 3.5 may be appropriate. Another concern in atrial fibrillation is the potential for rate-related cardiomyopathy. Maintaining rate control can obviate this (Shinbane et al.). In the Atrial Fibrillation Follow-up Investigation in Rhythm Management (AFFIRM) trial, rate control was defined as a resting pulse rate 80/min or less and 110/min or less after a 6-minute walk. These guidelines are appropriate for clinical use. Although studies have shown that the mortality rate of patients with atrial fibrillation is about double that of patients in normal sinus rhythm, this is largely due to the presence of underlying heart disease. The AFFIRM trial did not report causes of death.
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983-8. PMID: 1866765 Krahn AD, Manfreda J, Tate RB, Mathewson FA, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am J Med. 1995;98: 476-84. PMID: 7733127 Echocardiographic predictors of stroke in patients with atrial fibrillation: a prospective study of 1066 patients from 3 clinical trials. Arch Intern Med. 1998;158:1316-20. PMID: 9645825 Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: a review of animal models and clinical studies. J Am Coll Cardiol. 1997;29:709-15. PMID: 9091514
Acute Management of Atrial Fibrillation

The acute management of patients presenting with either atrial flutter or atrial fibrillation depends on associated symptoms, hemodynamic stability, and the accuracy with which onset can be determined. The risk of thromboembolism warrants anticoagulation if atrial fibrillation has been present for more than 48 hours or if the time of onset is uncertain. It may not be clear when the episode began or whether it is the patients first episode of atrial fibrillation, since some patients have minimal or no symptoms of the arrhythmia. A hemodynamically unstable patient with a rapid rate who does not respond to initial therapies with rate control and other supportive measures must be acutely cardioverted even before anticoagulation is established, In the hemodynamically stable patient, there is time to decide whether the primary approach will be rate control or rhythm control.
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After controlling the heart rate with an atrioventricular node blocker, a period of observation is warranted, as many episodes are self-limited. In these patients, antiarrhythmic drugs to prevent atrial fibrillation are generally not needed unless the patient experiences or has experienced severe symptoms (such as hypotension, myocardial ischemia, or heart failure). The decision regarding long-term anticoagulation depends on the risk assessment for stroke. In patients with persistent atrial fibrillation, one may attempt to restore sinus rhythm with or without pretreatment with an antiarrhythmic agent. The sooner this is done, the greater the likelihood of success. If cardioversion is to be attempted in these patients, waiting days rather than weeks or months is appropriate. However, the risk of thromboembolism must be minimized. Studies using transesophageal echocardiography in patients with atrial fibrillation of more than 48 hours duration showed that the incidence of thrombus in the left atrial appendage is approximately 15%. The Assessment of Cardioversion Using Transesophageal Echocardiography (ACUTE) trial investigators randomized more than 1200 patients to either a transesophageal echocardiography-guided approach (immediate anticoagulation with heparin followed by transesophageal echocardiography and cardioversion and 4 weeks of warfarin therapy) or a conventional approach (3 weeks of therapeutic anticoagulation followed by cardioversion and 4 weeks of warfarin therapy). The groups did not differ in the rate of embolic events. However, the patients randomized to transesopahgeal echocardiography had a shorter duration of atrial fibrillation, a higher success rate of cardioversion, and a lower rate of bleeding episodes. This trial suggests that this approach is reasonable and safe. After restoration of sinus rhythm, long-term antiarrhythmic therapy may not be needed, but short-term therapy may prevent early recurrences. In patients with atrial fibrillation for longer than 3 months, early recurrence is common after cardioversion. In these patients, antiarrhythmic medication can be started before cardioversion and after adequate anticoagulation to reduce the likelihood of recurrence. The antiarrhythmic should be given for a brief period after sinus rhythm has been restored (for example, 1 month). Figure 12 provides an algorithm for management of new-onset atrial fibrillation proposed by the ACC/AHA/ESC Guidelines. In some patients (such as asymptomatic elderly patients), it is reasonable to monitor progression to permanent atrial fibrillation while paying close attention to anticoagulation and rate control. Therapy with an atrioventricular node blocking agent in addition to anticoagulation would be appropriate for the patient described in Case 9.
Long-Term Management of Atrial Fibrillation

If recurrences of paroxysmal atrial fibrillation are brief or minimally symptomatic, avoidance of long-term therapy with antiarrhythmic drugs is reasonable. Moreover, the results of the AFFIRM trial (Wyse et al.) suggest that rhythm control is reasonable even when atrial fibrillation is recurrent and persistent if symptoms are acceptable. In this study, 4060 patients with atrial fibrillation were randomized to rate control plus anticoagulation (2027 patients) or rhythm control (attempts to maintain sinus rhythm; 2033 patients). In both approaches, the use of anticoagulant drugs was recommended. At 5 years of follow-up, there were 310 deaths (21.3%) in the rate control group and 356 deaths (23.8%) in the rhythm control group (hazard ratio, 1.15; P = 0.08). The two groups did not significantly differ for the secondary end point of ischemic stroke (5.5% in the rate control vs. 7.1%; in the rhythm control group). The majority of strokes occurred in patients in whom warfarin therapy was discontinued or the international normalized ratio was subtherapeutic. More hospi-
Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347:1825-33. PMID: 12466506
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NEWLY DISCOVERED AF
FIGURE 12. Pharmacologic management of patients with newly discovered atrial fibrillation.
AF = atrial fibrillation; HF = heart failure Reproduced with permission from: ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation. J Am Coll Cardiol. 2001;38:1231-66.
Paroxysmal
Persistent
No therapy needed unless severe symptoms (e.g., hypotension, HF, angina pectoris)
Accept permanent AF
Rate control and anticoagulation as needed
Anticoagulation as needed Anticoagulation and rate control as needed Consider antiarrhythmic drug therapy
Cardioversion
Long-term antiarrhythmic drug therapy unnecessary
talizations and adverse drug reactions occurred in the rhythm control arm. This study implies that rhythm control offers no survival advantage over rate control and, consequently, rate control with appropriate anticoagulation is an acceptable alternative, particularly if patients tolerate the rhythm well. The mean age of patients in this study was approximately 70 years, the incidence of hypertension was 70%, and the left ventricular ejection fraction was abnormal in approximately 25% of patients. This study further emphasizes that all high-risk patients, regardless of whether they appear to maintain sinus rhythm, should continue therapeutic anticoagulation. Figure 13 shows a therapeutic guide for rate control in persistent or permanent atrial fibrillation. In contrast, if symptoms are troublesome and not improved with adequate rate control, antiarrhythmic therapy may be desirable. Several antiarrhythmic drugs may be effective, and drug selection is based on safety. Figure 14 shows an algorithm for management proposed by the ACC/AHA/ESC guidelines.
New Therapies
A small subset of patients has bradycardia-dependent or vagally mediated atrial fibrillation. Two randomized trials have demonstrated a potential benefit of atrial or atrioventricular synchronous pacing to reduce the incidence of atrial fibrillation in these patients compared with pacing the right ventricle alone (Andersen et al., 1997; Andersen et al., 1994).
Andersen HR, Nielsen JC, Thomsen PE, Thuesen L, Mortensen PT, Vesterlund T, Pedersen AK. Long-term follow-up of patients from a randomised trial of atrial versus ventricular pacing for sick-sinus syndrome. Lancet.1997. 25;350:1210-6. PMID: 9652562 Andersen HR, Thuesen L, Bagger JP, Vesterlund T, Thomsen PE. Prospective randomised trial of atrial versus ventricular pacing in sick-sinus syndrome. Lancet. 1994;344:1523-8. PMID: 7983951
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The U.S. Food and Drug Administration recently approved an implantable atrial defibrillator for management of patients with recurrent persistent atrial fibrillation. This device permits the patient to trigger cardioversion at home. These devices are only useful in a selected group of highly motivated patients who experience intolerable symptoms during atrial fibrillation and wish to avoid hospitalization. These patients must be receive long-term anticoagulation. This therapy is not appropriate for patients with short episodes of self-terminating atrial fibrillation or those with chronic atrial fibrillation.
Heart disease?
No (or minimal*)
Yes
Flecainide Propafenone Sotalol
HF
CAD
Hypertension
Amiodarone Dofetilide Amiodarone, Dofetilide
Sotalol
LVH greater than or equal to 1.4 cm
Amiodarone Dofetilide
Yes
No
Disopyramide Procainamide Quinidine
Consider nonpharmacological options
Disopyramide Procainamide Quinidine
Flecainide Propafenone Amiodarone
Amiodarone Dofetilide Sotalol
Disopyramide, Procainamide, Quinidine

FIGURE 13. Antiarrhythmic drug therapy to maintain sinus rhythm in patients with recurrent paroxysmal or persistent atrial fibrillation. Drugs are listed alphabetically and not in order of suggested use. *For adrenergic atrial fibrillation, -blockers or sotalol are the initial drugs of choice. Consider nonpharmacologic options to maintain sinus rhythm if drug failure occurs.
CAD = coronary artery disease; HF = heart failure; LVH = left ventricular hypertrophy Reproduced with permission from: ACC/AHA/ECS Guidelines for the Management of Patients with Atrial Fibrillation. J Am Coll Cardiol. 2001;38:1231-66.
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Traditionally, atrioventricular node ablation and pacemaker implantation has been offered to patients with uncontrollable ventricular rates or severe drug intolerance. In these patients, the atria continue to fibrillate and the ventricle is paced. Thus, long-term anticoagulation is indicated. Newer treatments for atrial fibrillation also involve catheter-based radiofrequency ablation. One of these techniques arose from the recognition that atrial fibrillation may be triggered by premature atrial contraction arising within atrial muscle that tracks into the pulmonary veins. The pulmonary veins are approached through an atrial septostomy, and radiofrequency is used to isolate them. Although this technique is gaining more widespread acceptance, the criteria for patient selection are not yet well established and pulmonary venous obstruction is a reported complication. Linear lesions in the right and left atria isolate electrical areas and may prevent propagation of the arrhythmia. The surgical technique is called the maze procedure. Recently, catheter-based radiofrequency creation of linear lesions mimics those created surgically but results have been marginal. In contrast, the surgical technique is most effective, with over 90% of patients achieving sinus rhythm. The success rate must, however, be weighed against the risks of surgery, and this procedure is generally reserved for patients with very symptomatic atrial fibrillation in whom multiple therapies have failed. Often this procedure is performed in conjunction with another cardiac procedure, such as valve replacement or coronary bypass. Catheter ablation of typical atrial flutter is feasible, with good long-term success rates. Newer types of mapping systems used in the electrophysiology laboratories have improved our ability to treat this arrhythmia with ablation.
RECURRENT PERSISTENT AF PERMANENT AF Minimal or no symptoms Disabling symptoms in AF
Anticoagulation and rate control* as needed
Anticoagulation and rate control* as needed
Anticoagulation and rate control
Antiarrhythmic drug therapy*
Electrical cardioversion as needed
Continue anticoagulation as needed and therapy to maintain sinus rhythm*
FIGURE 14. Pharmacologic management of patients with recurrent persistent or permanent atrial fibrillation (AF). *Initiate drug therapy before cardioversion to reduce the likelihood of early recurrence of AF.
Reproduced with permission from: ACC/AHA/ECS Guidelines for the Management of Patients with Atrial Fibrillation. J Am Coll Cardiol. 2001;38:1231-66.
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Bradyarrhythmias
KEYPOINTS
Bradyarrhythmias
What are common indications for pacemaker implantation? What are the two types of second-degree atrioventricular block? What are the indications for pacing in patients with congenital complete heart block? What patients benefit from rate-responsive pacing?
Sinus node dysfunction is frequently the primary diagnosis listed for implantation of a permanent pacemaker. Although pacing may relieve symptoms of bradycardia, it may not necessarily improve survival. Permanent pacemakers are indicated in patients with sinus node dysfunction who have documented symptomatic bradycardia, those with symptomatic iatrogenic bradycardia in whom treatment with the implicated drug cannot be stopped, and those with sinus node dysfunction who have symptomatic chronotropic incompetence associated with exercise intolerance. Pacing is indicated in patients with complete heart block if the symptomatic bradycardia is presumed to be due to atrioventricular block and in cases of iatrogenic atrioventricular block in which treatment with the implicated medication cannot be stopped. Pacemakers must also be implanted after catheter ablation of the atrioventricular node or after cardiac surgery when atrioventricular block persists. Pacing is indicated in patients with congenital complete heart block who have a wide QRS escape rhythm or ventricular dysfunction, those at risk for a bradycardia-dependent long QT interval and resultant arrhythmias, and infants with congenital complete heart block who has a ventricular rate less than 50 to 55/min or less than 70/min in the setting of congenital heart disease. Rate-responsive pacing is particularly useful in patients who are chronotropically incompetent. Resynchronization therapy is indicated in patients with class II to IV heart failure and significant prolongation of the QRS interval.
Gregoratos G, Cheitlin MD, Conill A, Epstein AE, Fellows C, Ferguson TB Jr, et al. ACC/AHA guidelines for implantation of cardiac pacemakers and antiarrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). J Am Coll Cardiol. 1998;31:1175-209. PMID: 9562026
Permanent pacemakers may be indicated in patients with sinus node dysfunction, in patients with complete heart block, after catheter ablation of the atrioventricular node or after cardiac surgery when atrioventricular block persists.
Sinus Node Dysfunction

Sinus node dysfunction is frequently the primary diagnosis listed for implantation of a permanent pacemaker. However, although symptoms of bradycardia may be relieved, pacing may not necessarily improve survival. Sinus node dysfunction can present as a wide spectrum of dysrhythmias. Persistent slow heart rates or the inability to accelerate the heart rate appropriately are common. Many patients will, however, present with a tachybrady syndrome. Permanent pacemakers are indicated in patients with sinus node dysfunction who have documented symptomatic bradycardia, which may include sinus pauses that produce symptoms. Pacing should also be implemented in patients with symptomatic iatrogenic bradycardia in whom treatment with the implicated drug cannot be stopped. Pacing is also indicated in patients with sinus node dysfunction who have symptomatic chronotropic incompetence associated with exercise intolerance (Gregoratos et al.).
Atrioventricular Nodal Block

Atrioventricular block is classified as first-, second-, or third-degree (complete) block. The level of atrioventricular block is defined anatomically as supra-, intra, or infra-His. First-degree block is present when there is as abnormal prolongation of the PR interval. There are two types of second-degree atrioventricular block. Type I, or Wenkebach, manifests as progressive prolongation of the PR interval before a blocked beat. In general, the QRS interval will be narrow. In type II second-degree block, there is no progressive prolongation of PR interval before the blocked beat. Type II block is usually associated with a wide QRS complex. Advanced atrioventricular block is said to be present when two or more consecutive P-waves fail to conduct. Third-degree atrioventricular block is defined as the complete absence of conduction of atrial impulses to the ventricle and is also called complete heart block. Symptoms vary in patients with atrioventricular block from an asymptomatic state to severe bradycardia-related symptoms. The latter patients may develop severe ventricular arrhythmias as a result of the bradycardia. Studies have shown that permanent pacing improves survival in patients with complete heart block, especially if syncope has occurred. No survival data are available, but some patients with prolonged first-degree atrioventricular block might benefit from pacing. Pacing is indicated in patients with complete heart block regardless of the anatomic level of block if the symptomatic bradycardia is presumed to be due to atrioventricular block. Pacing is also indicated in cases of iatrogenic atrioventricular block in which treatment with the implicated medication cannot be stopped. In asymptomatic patients, pacing is indicated for documented asystole lasting 3.0 seconds or longer or with ventricular escape rates less than 40/min while awake. Pacemakers must also be implanted after catheter ablation of the atrioventricular node or after cardiac surgery when atrioventricular block persists. Some patients with neuromuscular diseases develop heart block that can
58
Bradyarrhythmias
lead to sudden death. These patients should have pacemakers implanted if symptomatic second-degree atrioventricular block is present, regardless of the type or site of block.
Congenital Heart Block

The indications for permanent pacing in young patients with congenital complete atrioventricular block have evolved through greater understanding of the natural history of the disease. Recent studies have shown that implantation of a pacemaker may improve long-term survival, and serious symptoms, such as syncope, may be avoidable in patients with congenital complete atrioventricular block. Several criteria must be considered in asymptomatic patients with congenital complete atrioventricular block before implanting a pacemaker. In general, pacing is indicated in patients with congenital complete heart block who have a wide QRS escape rhythm or ventricular dysfunction. Pacing is also indicated in those at risk for a bradycardia-dependent long QT interval and resultant arrhythmias. Pacing should be considered in an infant with congenital complete heart block who has a ventricular rate less than 50 to 55 beats per minute or less than 70/min in the setting of congenital heart disease. Specific rate guidelines for adults with congenital complete heart block do not exist; however, the above concerns about bradycardia dependent-arrhythmias and ventricular dysfunction prompt many physicians to implant devices even in the absence of symptoms.
PacemakersWhats New; and the Role of Physiologic Pacing

Physiologic pacing is achieved by pacing the right atrium and right ventricle to maintain atrioventricular synchrony. Several trials have randomized patients to physiologic pacing or ventricular pacing. The largest of these trials is the Canadian Trial of Physiologic Pacing (CTOPP) trial. Among the 2568 randomized patients, no significant difference was observed in the primary end point of stroke or cardiovascular death or in all-cause mortality and 6-minute walk distance. One subset of patients who had low unpaced heart rates (<60/min) appeared to experience a lower mortality rate if physiologic pacing was used (Tang et al.). The results of the Pacemaker Selection in the Elderly (PASE) trial were similar, with a borderline significant benefit for physiologic pacing in patients with the sick sinus syndrome (Lamas et al.) In the PASE trial, approximately 25% of patients randomized to ventricular pacing crossed over to dual-chamber pacing because of symptoms due to the pacemaker syndrome. Symptoms may include dyspnea, syncope, throat tightness, and exercise intolerance. Physical examination reveals cannon A waves as the atrium contracts against a closed atrioventricular valve. Most current pacemakers have a rate-responsive feature that permits the heart rate to accelerate in response to exercise. A variety of incorporated sensors permit this feature. The most common is a piezoelectric crystal or an accelerometer that detects motion, vibration, pressure, or acceleration. Others incorporate sensors that measure minute ventilation, and some combine the two methods. Rate-responsive pacing is particularly useful in patients who are chronotropically incompetent. Pacemakers incorporating this feature been shown to improve quality of life. Another relatively new feature is mode switching. Pacemakers with this feature have dual-chamber sensing and pacing. If an atrial tachyarrhythmia, such as atrial fibrillation, occurs, the unit switches to a ventricular pacing mode to avoid inappropriate tracking of the atrial arrhythmia. Developments in lead technology have permitted greater longevity of leads. This advance is important, particularly for younger patients who face sev-
Tang AS, Roberts RS, Kerr C, Gillis AM, Green MS, Talajic M, et al. Relationship between pacemaker dependency and the effect of pacing mode on cardiovascular outcomes. Circulation. 2001;103:3081-5. PMID: 11425772 Lamas GA, Orav EJ, Stambler BS, Ellenbogen KA, Sgarbossa EB, Huang SK, et al. Quality of life and clinical outcomes in elderly patients treated with ventricular pacing as compared with dual-chamber pacing. Pacemaker Selection in the Elderly Investigators. N Engl J Med. 1998;338: 1097-104. PMID: 9545357
59
Ventricular Ectopy
KEYPOINTS
Premature ventricular contractions are abnormal heart beats that arise from the right or left ventricle; they are generally benign. Although premature ventricular contractions may be more frequent in patients with heart disease, they have minimal prognostic significance if the ejection fraction is preserved. Because of the implications of frequent premature ventricular contractions in postmyocardial infarction patients with depressed ejection fractions, structural heart disease should be sought in patients presenting with complex premature ventricular contractions. Regardless of their significance, symptomatic premature ventricular contractions can be treated with -blockers. Symptoms of frequent or repetitive ventricular ectopy may include palpitations, fatigue, and near syncope. Antiarrhythmics play little role in the management of premature ventricular contractions. In a structurally normal heart, ventricular tachycardia carries little prognostic significance. If the patient has clinically significant symptoms or if the ventricular tachycardia is of longer duration, treatment with a -blocker or calcium channel blocker may be useful. For frequent short runs or sustained ventricular tachycardia, catheter ablation can be helpful. Patients with coronary disease, nonsustained ventricular tachycardia, and left ventricular dysfunction have an increased risk for sudden cardiac death.
eral pacemaker revisions in their lifetime. A newer single-pass lead is available that incorporates poles for sensing (although not pacing) the atrium on the same lead as the ventricular sensing and pacing electrode. This system, which is indicated in patients with atrioventricular block and intact sinus node function, permits maintenance of an atrioventricular sequential rhythm with the use of a single lead. One of the most recent important developments in pacing is the biventricular pacemaker, which is used to resynchronize contraction of the left ventricle in patients with ventricular systolic dysfunction and interventricular conduction delay. The left ventricle is paced with a lead that is placed through the coronary sinus to a lateral epicardial vein. This form of pacing, called resynchronization therapy, is indicated in patients with class II to IV heart failure and significant prolongation of the QRS interval.
Ventricular Ectopy
Under what circumstances do premature ventricular contractions have prognostic importance? Does premature ventricular contractions suppression improve survival? Under what circumstances does nonsustained ventricular tachycardia have prognostic importance? How is risk reduced in patients with the long QT syndrome?
Premature Ventricular Contractions

Premature ventricular contractions are abnormal heart beats that arise from the right or left ventricle. Similar to premature atrial contractions, they are generally benign. Premature ventricular contractions were found on 24-hour ambulatory recordings in about 51% of healthy male military aviators. Although premature ventricular contractions may be more frequent in patients with heart disease, they have minimal prognostic significance if the ejection fraction is preserved. However, among patients with depressed ejection fractions after myocardial infarction, frequent premature ventricular contractions are associated with increased mortality (Bigger et al.). Nevertheless, suppression of premature ventricular contractions does not improve outcome, and therapy in these patients is more appropriately directed toward the underlying heart condition (Echt et al.). Because of the implications of frequent premature ventricular contractions in postmyocardial infarction patients with depressed ejection fractions, structural heart disease should be sought in patients presenting with complex premature ventricular contractions. Also, frequent premature ventricular contractions may be a harbinger of ventricular tachycardia in these patients, and appropriate monitoring should be instituted. Regardless of their significance, symptomatic premature ventricular contractions can be treated with -blockers. Symptoms of frequent or repetitive ventricular ectopy may include palpitations, fatigue, and near syncope. Antiarrhythmics play little role in the management of premature ventricular contractions.
Bigger JT Jr, Fleiss JL, Rolnitzky LM. Prevalence, characteristics and significance of ventricular tachycardia detected by 24-hour continuous electrocardiographic recordings in the late hospital phase of acute myocardial infarction. Am J Cardiol. 1986;58:1151-60. PMID: 3788801 Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781-8. PMID: 1900101
Ventricular Tachycardia
In a structurally normal heart, ventricular tachycardia carries little prognostic significance. Often, ventricular tachycardia in the structurally normal heart is catecholamine dependent. These arrhythmias can be triggered or automatic. They often arise from the right ventricular outflow tract. Short runs may be well
60
Ventricular Ectopy
tolerated and thus not require treatment. If the patient has clinically significant symptoms or if the ventricular tachycardia is of longer duration, treatment with a -blocker or calcium channel blocker may be useful. For frequent short runs or sustained ventricular tachycardia, catheter ablation can be helpful.
KEYPOINTS
(CONT'D)
Ischemic Heart Disease

The association between ventricular arrhythmias and mortality after myocardial infarction is well recognized. Patients with coronary disease, nonsustained ventricular tachycardia, and left ventricular dysfunction have an increased risk for sudden cardiac death. Many trials have attempted to predict which patients are at highest risk for sudden death so that only patients with indicators of high risk can be treated. Two randomized prospective trials, the Multicenter Unsustained Tachycardia Trial (MUSTT) and the Multicenter Automatic Defibrillator Implantation Trial (MADIT), used electrophysiologic testing for risk stratification in patients with left ventricular dysfunction and coronary artery disease. In MADIT, patients with inducible sustained ventricular tachycardia were randomized to receive implantable cardioverter-defibrillators (ICDs) or conventional therapy (Moss et al.). In MUSTT, inducible patients were randomized to receive no specific antiarrhythmic treatment or electrophysiologically guided therapy. Both trials showed a benefit of ICD implantation. The overall mortality rate was reduced by approximately 50% with ICD therapy. The MUSTT also showed that patients received no survival benefit with electrophysiologically guided drug treatment. However, patients in MUSTT with inducible sustained ventricular tachycardia had a worse prognosis than patients in whom sustained ventricular tachycardia could not be induced (Buxton et al.). A substudy of MUSTT showed that inducible sustained ventricular tachycardia could not be predicted on the basis of characteristics of nonsustained ventricular tachycardia. The recently completed Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) was designed to evaluate the effect of prophylactic ICD therapy on survival in patients with previous myocardial infarction and left ventricular dysfunction. Patients had chronic coronary artery disease with prior myocardial infarction. Their ejection fractions were 30% or less, and there was no baseline requirement for nonsustained ventricular tachycardia or elecrophysiologic testing. The data safety and monitoring board terminated this study prematurely when the ICD group showed a 31% reduction in mortality rate. Together, these three studies support the use of ICDs in patients with coronary artery disease and depressed ejection fraction who are at risk for sudden death.
Randomized studies support the use of implantable cardioverter-defibrillators (ICDs) in patients with coronary artery disease and depressed ejection fraction who are at risk for sudden death. Patients with the long QT syndrome are at risk for malignant ventricular arrhythmias, particularly polymorphic ventricular tachycardia. If the arrhythmia is controlled, the longterm prognosis is good. Prevention of arrhythmias is often accomplished by long-term treatment with -blockers, permanent pacing, or left cervicothoracic sympathectomy. Patients who have survived cardiac arrest and those who have had recurrent syncope or sustained ventricular tachycardia despite drug therapy should receive an ICD (class IIb recommendation). Several drugs can prolong the QT interval and place patients at risk for torsades de pointes due to acquired long QT syndrome. Risk factors for acquired long QT syndrome include female sex, hypokalemia, and hypomagnesemia.
Congenital and Acquired Long QT Syndromes

The congenital long QT syndromes are composed of a spectrum of electrophysiologic disorders. In general, it is an electrical disease without an associated structural abnormality. Patients with the long QT syndrome are at risk for malignant ventricular arrhythmias, particularly polymorphic ventricular tachycardia. Several genetic mutations affect potassium currents and sodium channels. If the arrhythmia is controlled, the long-term prognosis is good. Prevention of arrhythmias is often accomplished by long-term treatment with -blockers, permanent pacing, or left cervicothoracic sympathectomy. Patients who have survived cardiac arrest and those who have had recurrent syncope or sustained ventricular tachycardia despite drug therapy should receive an ICD (class IIb recommendation). Other patients with the long QT syndrome who should be considered for primary ICD implantation are those who present with aborted sudden death and those with a strong family history of sudden death.
Moss AJ, Hall WJ, Cannom DS, Daubert JP, Higgins SL, Klein H, et al. Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators. N Engl J Med. 1996;335:1933-40. PMID: 8960472 Buxton AE, Lee KL, Fisher JD, Josephson ME, Prystowsky EN, Hafley G. A randomized study of the prevention of sudden death in patients with coronary artery disease. Multicenter Unsustained Tachycardia Trial Investigators. N Engl J Med. 1999;341:1882-90. PMID: 10601507
61
Sudden Death
KEYPOINTS
In sudden death, the most common underlying disorder is ischemic heart disease. The key to survival of a cardiac arrest is rapid treatment, with early institution of cardiopulmonary resuscitation and quick arrival of medical personnel. The evidence is strong for the superiority of ICDs as primary prevention in patients with coronary artery disease in which the ejection fraction is depressed. Patients with an isolated episode of ventricular fibrillation who have undergone revascularization or who have moderately preserved left ventricular function are not likely to benefit from ICD therapy compared with amiodarone therapy. In the absence of structural heart disease, syncope, near syncope, and transient lightheadedness are generally benign. History and physical examination alone can identify the probable cause of syncope in about 50% of cases; electrophysiologic testing can be considered in patients with structural or ischemic heart disease. Neurocardiogenic syncope is a common cause of syncope in the absence of a cardiac arrhythmia or structural cardiac disease. The tilt-table test may be used to define different underlying mechanisms for neurocardiogenic syncope. Cardiac causes of syncope include bradyarrhythmias or tachyarrhythmias, pulmonary embolism, pulmonary hypertension, acute myocardial infarction, cardiac tamponade, or obstruction to left ventricular outflow (hypertrophic cardiomyopathy or aortic stenosis). Invasive electrophysiologic studies should be considered in patients at risk for or with cardiac disease to detect arrhythmias as a possible cause of syncope.
Bayes de Luna A, Coumel P, Leclercq JF. Ambulatory sudden cardiac death: mechanisms of production of fatal arrhythmia on the basis of data from 157 cases. Am Heart J. 1989;117:151-9. PMID: 2911968 Cairns JA, Connolly SJ, Roberts R, Gent M. Randomised trial of outcome after myocardial infarction in patients with frequent or repetitive ventricular premature depolarisations: CAMIAT. Canadian Amiodarone Myocardial Infarction Arrhythmia Trial Investigators. Lancet. 1997;349:675-82. PMID: 9078198
Several drugs can prolong the QT interval and place patients at risk for torsades de pointes due to acquired long QT syndrome. The list of drugs implicated in QT prolongation and risk for torsades de pointes is extensive and includes antiarrhythmics (classes Ia and III) and some antihistamines. Risk factors for acquired long QT syndrome include female sex, hypokalemia, and hypomagnesemia. An extensive list of offending agents can be found at http://www.torsades.org/druglist.cfm.
Sudden Death
What is the incidence of cardiac arrest? What arrhythmias are associated with sudden death? What are strategies for enhancing survival of cardiac arrest? What are strategies to prevent cardiac arrest? What are strategies to prevent recurrent cardiac arrest?
Epidemiology, Risk Factors, and Etiologies

Sudden death is a major health problem, with an incidence of 300,000 to 400,000 persons annually in the United States. Of these patients, only 2% to 15% survive to hospitalization, and half die before discharge. The most common underlying disorder is ischemic heart disease. In a study of Holter tapes of ambulatory patients who died while wearing Holter devices, the causative arrhythmia was ventricular tachycardia in 62%, ventricular fibrillation in 8%, torsades de pointes in 13%, and bradycardia in 17% (Bayes de Luna et al.).
Acute Treatment of Cardiac Arrest

The key to survival of a cardiac arrest is rapid treatment, with early institution of cardiopulmonary resusciation and quick arrival of medical personnel. The availability of automatic external defibrillators has increased access to emergency services, but mortality rates from cardiac arrest remains high. Figure 15 shows the new Advanced Cardiac Life Support universal guidelines.
Prevention of Sudden Cardiac Death

Given the high mortality rate associated with cardiac arrest, much effort has gone into determining who is at risk for sudden death so that primary prevention may be instituted. In addition to the device studies discussed above, two studies assessed the role of primary drug prevention of sudden death. The Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) assessed the effect of amiodarone on risk for sudden death in postmyocardial infarction patients with frequent premature ventricular contractions (Cairns et al.). The European Myocardial Infarct Amiodarone Trial (EMIAT) assessed the effect of amiodarone on the mortality rate in postmyocardial infarction patients with decreased left ventricular function, regardless of ventricular arrhythmias (Julian et al.). Both showed a reduction in arrhythmic death but no reduction in overall mortality rate. The evidence is strong for the superiority of ICDs as primary prevention in patients with coronary artery disease in which the ejection fraction is depressed. Data relevant to severe dilated cardiomyopathy are yet to come. The Sudden Cardiac Death Heart Failure Trial is designed to determine whether ICD implantation or amiodarone therapy will decrease the mortality rate in patients with coronary artery disease or nonischemic cardiomyopathy who are in New York Heart Association functional class II or III and have an ejection fraction less than 35%.
62
Sudden Death
Secondary Prevention Survivors of cardiac arrest remain at risk for a recurrent event. Cardiac arrest not associated with an acute myocardial infarction has a 1-year recurrence rate of approximately 30%. In patients with associated ischemia, revascularization with coronary artery bypass graft surgery has been shown to reduce the recurrence of cardiac arrest. Recent studies have examined the utility of cardiodefibrillators in survivors of cardiac arrest and in patients with an episode of hemodynamically unstable and sustained ventricular tachycardia. Three of these studies are compared in Table 21. Overall, the risk for death was reduced by 28%, due almost entirely to the observed 50% reduction in arrhythmic death. In each of these three studies, the greatest benefit was seen in patients with low ejection fractions. In contrast, patients with an isolated episode of ventricular fibrillation who have undergone revascularization or who have moderately preserved left ventricular function are not likely to benefit from ICD therapy compared with amiodarone therapy (Connolly et al.). Currently, class I indications for ICD implantation include the following: Cardiac arrest due to ventricular fibrillation or ventricular tachycardia not due to a transient or reversible cause. Spontaneous sustained ventricular tachycardia. Syncope of undetermined origin with clinically relevant, hemodynamically significant sustained ventricular tachycardia or ventricular fibrillation induced on an electrophysiologic study when drug therapy is ineffective, not tolerated, or not preferred. Nonsustained ventricular tachycardia with coronary disease, prior myocardial infarction, left ventricular dysfunction, and inducible ventricular fibrillation or sustained ventricular tachycardia on electrophysiologic study that is not suppressible by therapy with a class I antiarrhythmic drug. Workup of Syncope Syncope is defined as a transient loss of consciousness. About 30% of the population is expected to experience syncope at some point. In the absence of structural heart disease, syncope, near-syncope, and transient lightheadedness
Julian DG, Camm AJ, Frangin G, Janse MJ, Munoz A, Schwartz PJ, Simon P. Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators. Lancet. 1997;349:667-74. PMID: 9078197 Connolly SJ, Hallstrom AP, Cappato R, Schron EB, Kuck KH, Zipes DP, et al. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study. Eur Heart J. 2000;21:2071-8. PMID: 11102258
TA B L E 2 1 Comparison of Implantable Cardioverter-Defibrillator Trials Aimed at Primary Prevention of Sudden Death
Aspect of Study Protocol
CASH ICD vs. conventional therapy (mainly amiodarone and metprolol) Survivors of VF or sustained VT 46% Not significant May have been negative secondary to long recruitment
AVID ICD vs. amiodarone or sotalol
CIDS ICD vs. amiodarone
Patient characteristics
Mean ejection fraction Improvement in survival with ICD Take-home points
Survivors of VF; VT with syncope; VT with EF 40% 32% Significant Strongly supports ICD
Resuscitated VF, VT, or unmonitored syncope 33% Not significant 20% relative risk reduction in allcause mortality and 33% reduction arrhythmic mortality with ICD Reduction did not reach statistical significance, lends support for ICD.
AVID = Antiarrhythmics Versus Implantable Defibrillators; CASH = Cardiac Arrest Study Hamburg; CIDS = Canadian Implantable Defibrillator Study; EF = ejection fraction; ICD = implantable cardioverter-defibrillator; VF = ventricular fibrillation; VT = ventricular tachycardia
63
Evaluation of a Murmur
are generally benign, however, the recurrence rate is high (30%). A careful history and physical are critical in the evaluation of syncope and can help distinguish patients with benign syncope from those likely to have a malignant cause. History and physical examination alone can identify the probable cause of syncope in about 50% of cases. Other tests that may be useful in the investigation of syncope include electrocardiography and echocardiography. Electrophysiologic testing can be considered in patients with structural or ischemic heart disease. Neurocardiogenic syncope is a common cause of syncope in the absence of a cardiac arrhythmia or structural cardiac disease. The tilt-table test may be used to define different underlying mechanisms for neurocardiogenic syncope (Goldschlager et al.). Before the advent of head-up tilt-testing, a large prospective study showed that approximately 50% of patients had a definable cause of syncope, half of which were cardiovascular. In the remaining 50%, the cause remained obscure (Kapoor et al.). Subsequent studies using head-up tilt-testing diagnosed neurocardiogenic syncoope in patients without other definite etiologies. Cardiac causes of syncope include bradyarrhythmias or tachyarrhythmias, pulmonary embolism, pulmonary hypertension, acute MI, cardiac tamponade, or obstruction to left ventricular outflow (hypertrophic cardiomyopathy or aortic stenosis). Electrocardiography alone will rarely reveal the cause of syncope unless there is evidence of heart block or acute MI. A 24-hour Holter monitor may show footprints of likely causes of syncope but will not be definitive unless syncope occurs during the monitoring period. Various intermittent or implantable recorders may be used for prolonged monitoring to detect the cause of syncope. Invasive electrophysiologic studies should be considered in patients at risk for or with cardiac disease to detect arrhythmias as a possible cause of syncope. Whereas the prognosis of syncope is benign in patients without heart disease, syncope in the presence of cardiovascular disease carries a 30% mortality rate at 1 year.
Goldschlager N, Epstein AE, Grubb BP, Olshansky B, Prystowsky E, Roberts WC, et al. Etiologic considerations in the patient with syncope and an apparently normal heart. Arch Intern Med. 2003;163:151-62. PMID: 12546605 Kapoor WN, Karpf M, Wieand S, Peterson JR, Levey GS. A prospective evaluation and follow-up of patients with syncope. N Engl J Med. 1983;309:197-204. PMID: 6866032
Valvular Heart Disease

A heart murmur on physical examination is not uncommon. Some murmurs indicate underlying structural abnormalities of valvular, congenital, or other etiology, whereas others are innocent murmurs not indicative of underlying pathology. Although the proportion of pathologic and innocent murmurs varies by the group studied, a large proportion of murmurs are innocent. Because a murmur may be a significant clue (or the only sign) suggesting underlying disease, it is important to distinguish pathologic from innocent murmurs.
Are all murmurs a sign of cardiac pathology? What murmurs should prompt further evaluation?
Table 22 summarizes the typical characteristics of murmurs that are encountered in adults. The decision to evaluate a murmur further is based on the characteristics of the murmur and the presence of symptoms (Figure 16). In general, two types of murmurs do not require additional evaluation: murmurs that are not indicative of an underlying abnormality, and murmurs that can be ascribed to a benign underlying condition that requires neither specific therapy nor followup. Examples of the former type include innocent systolic flow murmurs and the continuous murmurs of a venous hum or mammary souffl. The most com65
KEYPOINTS
A murmur may be innocent or may reflect an underlying cardiac pathology. The characteristics of the murmur and the presence of symptoms determine whether echocardiographic imaging is required. A diastolic murmur is never normal.
mon example of the latter type is a murmur of aortic sclerosis in an elderly patient. Innocent flow murmurs typically are soft, mid-systolic murmurs without significant radiation. The murmur of aortic sclerosis is differentiated from that of aortic stenosis by its characteristics (less harsh than aortic stenosis, peaking in the first half of systole, and not encompassing S2), the absence of changes in the contour of peripheral pulses, and the absence of symptoms. The presence of symptoms in conjunction with a systolic murmur or the presence of any diastolic murmur should initiate further evaluation with echocardiographic imaging.
TA B L E 2 2 Characteristics of Cardiac Murmurs
Type Systolic Innocent flow murmur Aortic sclerosis
Timing
Quality
Location
Radiation
Effect of Maneuvers
Associated Findings
Mid-systolic Early- to midsystolic Mid- to latesystolic Variable systolic
Soft; crescendo decrescendo Crescendo decrescendo
Base Base (right 2nd ICS)
Variable; usually none None
None Decrease with handgrip or standing Decrease with handgrip or standing Decrease with handgrip; increase with standing Increase with handgrip Increase with inspiration
None None
Aortic stenosis
Harsh; crescendo Base (right decrescendo 2nd ICS) Late-peaking Base
Carotids; sometimes apex Carotids
Hypertrophic obstructive cardiomyopathy Mitral regurgitation Tricuspid regurgitation
Diminished A2; pulses delayed and diminished Pulses bifid
Usually pansystolic Usually pansystolic
Blowing; holosystolic Blowing; holosystolic
Apex Lower left sternal border
Variable; axilla if central jet Lower right sternal border
Left ventricular enlargement Prominent Vwave in neck; hepatic pulsation Widely split S2 Palpable thrill
Pulmonic stenosis Ventricular septal defect
Mid- to latesystolic Pan-systolic
Crescendo decrescendo High-pitched, peaking in mid-systole
Left 2nd ICS Left sternal border
Left sternal border Precordium
Increase with inspiration
Diastolic Aortic regurgitation Pan-diastolic or early diastolic High-pitched; decrescendo Left sternal border Variable; none or apex Loudest at endexpiration with patient leaning forward Loudest with patient in left lateral decubitus position Enlarged apical impulse; wide pulse pressure Possible opening snap
Mitral stenosis
Pulmonic regurgitation Tricuspid stenosis
Variable; early diastole or pandiastolic; presystolic accentuation if sinus rhythm Pan-diastolic or early diastolic Early diastolic or pan-diastolic; presystolic accentuation if sinus rhythm
Decrescendo; low- Apex pitched rumble
None (usually localized to small area)
Decrescendo Decrescendo; low-pitched rumble
Left 2nd3rd ICS Left lower sternal border
Left sternal border None
None Increase with inspiration
Right ventricular heave Possible opening snap
Continuous Patent ductus arteriosus

ICS = intercostal space
Continuous
Machinery-like
Left 2nd 3rd ICS
Back
66
Aortic Stenosis
Aortic Stenosis
How is severe aortic stenosis determined? Does anything affect the progression of aortic stenosis? Do asymptomatic patients with severe aortic stenosis have an adverse prognosis? What are the indications for aortic valve replacement? How are patients with severe stenosis and secondary ventricular systolic dysfunction differentiated from those with primary cardiomyopathy and mild or moderate stenosis?
Aortic stenosis in adults is predominantly caused by calcific degeneration. Rheumatic aortic stenosis typically is accompanied by aortic regurgitation and involvement of the mitral valve. Congenital aortic stenosis is seen in children and in younger adults. The normal area of the aortic valve in adults is 3.0 to 4.0 cm2. Symptoms usually are not present unless aortic stenosis is severe, typically defined as a valve area less than 1.0 cm2 and mean transvalvular gradient greater than 50 mm Hg. Two important considerations apply to the assessment of aortic stenosis severity. First, gradients depend on flow and may be low despite severe stenosis in the setting of left ventricular systolic dysfunction. Second, valve area should be considered in relation to patient size: Whereas a 1.0 cm2 valve area may not reflect severe stenosis in a small patient, it may be associated with hemodynamic significance and symptoms in a larger person. Adjusting the calculated aortic valve area by body surface area is the most widely used method to account for patient size. An aortic valve area of 0.45 cm2/m2 is considered severe. Evidence is accumulating that aortic stenosis is related to other atherosclerotic vascular lesions in its association with cardiac risk factors, especially lowdensity lipoprotein cholesterol level (Pohle et al.). Retrospective data demonstrate an inverse correlation between statin therapy and progression of aortic stenosis; although large, prospective trials to test efficacy of therapy are not yet reported.
Pohle K, Maffert R, Ropers D, Moshage W, Stilianakis N, Daniel WG, Achenbach S. Progression of aortic valve calcification: association with coronary atherosclerosis and cardiovascular risk factors. Circulation. 2001;104:1927-32. PMID: 11602496
Murmur
Systolic
Diastolic
No Symptoms
Cardiac Symptoms
Murmur Grade <3/6
Murmur Grade 3/6 or Holosystolic, ejection click
OBSERVATION
ECHOCARDIOGRAPHY
FIGURE 16. Suggested approach to the evaluation of a cardiac murmur.
67
Aortic Stenosis
Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med. 2000;343:611-7. PMID: 10965007 Monin JL, Monchi M, Gest V, DuvalMoulin AM, Dubois-Rande JL, Gueret P. Aortic stenosis with severe left ventricular dysfunction and low transvalvular pressure gradients: risk stratification by low-dose dobutamine echocardiography. J Am Coll Cardiol. 2001;37:2101-7. PMID: 11419894
KEYPOINTS
Aortic valve gradients are affected by flow; valve area should be assessed in the context of patient size. Progression of aortic stenosis is related to cardiac risk factors. Asymptomatic patients with severe aortic stenosis have a good prognosis. Aortic valve replacement should be considered in patients with symptomatic severe aortic stenosis and in some asymptomatic patients with severe stenosis and left ventricular dysfunction, marked left ventricular hypertrophy, hypotension on exercise testing, or moderate or greater valve calcification and a rapid increase in aortic jet velocity. Dobutamine echocardiography helps identify patients with severe stenosis and secondary left ventricular systolic dysfunction. Severe stenosis with contractile reserve suggests a more favorable prognosis with surgery.
Aortic stenosis has a long latent period in which stenosis gradually worsens without symptoms or an adverse prognosis. Angina, heart failure, or syncope suggests progression to hemodynamic instability and a poor prognosis without intervention. Aortic valve replacement is indicated in almost all patients with symptomatic aortic stenosis. Advanced age is not a contraindication to surgery, although comorbid diseases and left ventricular systolic dysfunction increase surgical risk. Balloon valvotomy can be used in young patients with noncalcific aortic stenosis. Among older adults, substantial procedure-related risk and restenosis within 1 year limit balloon valvotomy to a temporizing role in symptomatic patients who are not surgical candidates. Asymptomatic patients with severe aortic stenosis have a good prognosis. The rate of progression to symptoms is variable. Although there are reports of sudden cardiac death among asymptomatic patients, death appears to be preceded by the onset of symptoms (Rosenhek et al.). Aortic valve replacement may be reasonable in some asymptomatic patients if there is evidence of left ventricular systolic dysfunction, marked left ventricular hypertrophy, moderate or greater valve calcification coupled with a rapid increase in aortic jet velocity, or a hypotensive response on exercise testing. The recommended frequency of echocardiographic testing in the patient with asymptomatic aortic stenosis is based on severity: every 5 years in mild aortic stenosis, even 2 years in moderate aortic stenosis, and yearly in severe aortic stenosis. The latter is recommended primarily to detect the development of asymptomatic left ventricular dysfunction. Although exercise testing is contraindicated in the symptomatic patient with severe aortic stenosis, a carefully supervised exercise test in the asymptomatic patient may provide clinically useful information. Severely reduced exercise tolerance may be demonstrated in patients without symptoms. In addition, an adverse hemodynamic response to exercise with a decrease in blood pressure may be an indication for surgical intervention, according to recent guidelines. Patients with severe aortic stenosis and secondary left ventricular systolic dysfunction can be difficult to distinguish from those with primary cardiomyopathy and mild or moderate stenosis. In both cases, valve motion is diminished (because of stenosis in the former and low flow in the latter) and aortic valve gradients are not high. Doppler echocardiography during dobutamine infusion is useful to differentiate and guide therapy in such patients. Contractile reserve with a sharp increase in gradients suggests significant stenosis, whereas stable gradients during increased flow suggest less severe stenosis. Aortic valve replacement is associated with better long-term survival compared with medical therapy if there is severe stenosis with contractile reserve; conversely, valve replacement is associated with reduced survival compared with medical therapy in patients without contractile reserve (Monin et al.). There is an added risk for noncardiac surgery in a patient with severe aortic stenosis. When elective surgery is required in a patient with severe symptomatic stenosis, aortic valve replacement should be performed before noncardiac surgery, as the mortality rate in these patients may be as high as 10%. Occasionally, percutaneous balloon valvuloplasty may be considered when the patient is not a candidate for aortic valve replacement. If the patient is asymptomatic, surgery can be performed with close intraoperative monitoring, with only slightly increased risk.
68
Mitral Stenosis
Mitral Stenosis
What medical therapy is available for mitral stenosis? Which patients with mitral stenosis require anticoagulation? What are the options and indications for intervention in mitral stenosis? How are pregnant women who require intervention best treated?
Nearly all mitral stenosis in adults is due to previous rheumatic heart disease. Congenital mitral stenosis may be seen in children and adolescents. The normal mitral valve area is 4.0 to 5.0 cm2; moderate and severe stenosis are defined as a valve area of 1.0 to 1.5 cm2 and less than 1.0 cm2, respectively. Symptoms typically do not occur until stenosis is moderate or severe. Because of the increase in heart rate associated with a shorter diastolic filling period, physical exercise, emotional stress, fever, pregnancy, and atrial fibrillation all exacerbate symptoms of mitral stenosis. Medical therapy for mitral stenosis is limited to antibiotic prophylaxis against infective endocarditis and rheumatic fever, salt restriction or diuretics (or both), and negative chronotropic agents to prolong the diastolic filling period. Rheumatic fever prophylaxis should be given for at least 10 years after the last episode or until 40 years of age. Indefinite or lifelong prophylaxis is indicated in patients with frequent streptococcal exposure (teachers, for example). Long-term anticoagulation is indicated for those with chronic or paroxysmal atrial fibrillation or a prior thromboembolic event. Mechanical interventions include percutaneous balloon mitral valvotomy, open and closed commissurotomy, and mitral valve replacement. Relative merits of the procedures are summarized in Table 23. Intervention for mitral stenosis is indicated earlier among patients who are candidates for percutaneous balloon mitral valvotomy. Echocardiographic valve characteristics that predict the success of percutaneous balloon mitral valvotomy include the extent and severity of leaflet thickening, leaflet calcification, loss of leaflet pliability, and subvalvular involvement. Significant (3+ or 4+) mitral regurgitation or a left atrial thrombus are contraindications. Percutaneous balloon mitral valvotomy should be considered in symptomatic patients with moderate or severe stenosis and favorable valve morphology; in asymptomatic patients with favorable valve morphology and evidence of pulmonary hypertension; and in patients with a nonpliable, calcified valve but New York Heart
TA B L E 2 3 Comparison of Interventions in Mitral Stenosis
Intervention Percutaneous balloon mitral valvotomy Closed commissurotomy Open commissurotomy
Advantages Percutaneous approach; equivalent hemodynamic results to open commissurotomy in selected patients Avoids cardiac arrest and cardiopulmonary bypass Good hemodynamic results in selected patients; mitral regurgitation can be treated; feasible to perform additional surgical procedures Feasible for valves with heavy valvular and subvalvular sclerosis, calcification, with or without mitral regurgitation
Disadvantages Requires favorable valve anatomy; absence of significant mitral regurgitation or left atrial thrombus Less reproducible hemodynamic results than with percutaneous balloon or open commissurotomy Major surgical procedure with cardiopulmonary bypass
Patient Selection Pliable, non-calcified valve, 2+ mitral regurgitation, no other cardiac intervention required Only used in developing countries Relatively pliable, noncalcified valve, any amount of mitral regurgitation, other cardiac intervention required Calcified, nonpliable valves not suitable for percutaneous balloon valvotomy or open commissurotomy
Mitral valve replacement
Major surgical procedure with cardiopulmonary bypass; morbidity, mortality, anticoagulation associated with valve prosthesis
69
Chronic Mitral and Aortic Regurgitation
KEYPOINTS
Medical therapy for mitral stenosis includes antibiotic prophylaxis, heart rate control, and salt restriction or diuretics (or both). Anticoagulation is indicated for atrial fibrillation or prior thromboembolic event. Intervention options include percutaneous balloon mitral valvotomy, open commissurotomy, and mitral valve replacement. Echocardiographic variables predict the likelihood of success and of restenosis with percutaneous balloon mitral valvotomy. In pregnant women, percutaneous balloon mitral valvotomy is associated with fewer fetal complications compared with open commissurotomy.
Association class III or IV symptoms who are at high risk for surgery. Unlike aortic valvotomy, restenosis occurs relatively slowly among appropriately selected patients after percutaneous balloon mitral valvotomy. Echocardiographic characteristics of valve morphology are predictors of restenosis (Wang et al.). In pregnant women requiring therapy for mitral stenosis, percutaneous balloon mitral valvotomy has a high success rate and is associated with fewer fetal complications compared with open commissurotomy (de Souza et al.). In patients with asymptomatic mitral stenosis, yearly echocardiography is not recommended. Echocardiography should be performed promptly when there is a change in symptoms. The presence of mild to moderate pulmonary hypertension (pulmonary artery systolic pressure >40 mm Hg) may be an indication for more frequent follow-up.
Chronic Mitral and Aortic Regurgitation

What medical therapy is available for severe aortic or mitral regurgitation? What are the indications for surgical intervention? What are the respective advantages of mitral valve repair and replacement?
Wang A, Krasuski RA, Warner JJ, Pieper K, Kisslo KB, Bashore TM, Harrison JK. Serial echocardiographic evaluation of restenosis after successful percutaneous mitral commissurotomy. J Am Coll Cardiol. 2002;39:328-34. PMID: 11788227 de Souza JA, Martinez EE Jr, Ambrose JA, Alves CM, Born D, Buffolo E, Carvalho AC. Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy. J Am Coll Cardiol. 2001;37:900-3. PMID: 11693768
Mitral regurgitation is caused by abnormalities of the mitral leaflets (organic mitral regurgitation, including myxomatous degeneration, rheumatic valve disease, and infective endocarditis) or is secondary to dilation of or geometric changes affecting the left ventricle (dilated cardiomyopathy or prior myocardial infarction). Aortic regurgitation is caused by abnormalities of the aortic cusps (including infective endocarditis, rheumatic valve disease, and calcific degeneration) or is secondary to dilation or dissection of the ascending aorta. Both aortic and mitral regurgitation are conditions of chronic left ventricular volume overload. Forward cardiac output is preserved by compensatory left ventricular chamber dilation with eccentric hypertrophy, but at the expense of increased wall stress. Afterload is increased in chronic severe aortic regurgitation but is normal or decreased in chronic mitral regurgitation. In both lesions, symptoms occur late and typically after the onset of irreversible left ventricular systolic dysfunction. Therefore, intervention should ideally precede the onset of symptoms. Medical therapy for both aortic and mitral regurgitation should include prophylaxis against infective endocarditis. Patients with chronic severe aortic regurgitation and systolic hypertension benefit from vasodilator therapy with an angiotensin-converting enzyme inhibitor or a calcium channel blocker. Vasodilator therapy may delay the onset of heart failure or need for surgery but is not a substitute for surgical intervention. In mitral regurgitation, the role of afterload reduction depends on the chronicity of the lesion and on the mechanism of mitral regurgitation (organic or functional). Although vasodilators improve hemodynamics in patients with acute mitral regurgitation, their role in chronic severe organic mitral regurgitation has not been adequately studied. Thus, in asymptomatic patients who do not have an indication for surgical intervention, routine use of afterload reduction is not recommended. If there is coexistent hypertension, vasodilator therapy should be used in lieu of alternative therapy, such as a -blocker. In contrast, afterload reducers are indicated in patients with functional mitral regurgitation complicating underlying cardiomyopathy of ischemic or nonischemic etiology. Recommendations for serial echocardiography in asymptomatic patients with aortic or mitral regurgitation are based on lesion severity: only in the presence of new symptoms or a change on examination in mild regurgitation, yearly in moderate regurgitation, and every 6 to 12 months in severe regurgitation. In
70
Acute Valvular Regurgitation
severe regurgitation, the shorter interval between echocardiograms is recommended when the ventricular dimensions begin to approach those that would warrant surgery. Surgical intervention for aortic regurgitation is usually aortic valve replacement, although aortic valve reconstructive procedures may be feasible in a selected group of young patients with congenital, noncalcific disease. Surgery is indicated in symptomatic patients, those with left ventricular systolic dysfunction and asymptomatic patients with severe aortic regurgitation and marked left ventricular dilation (end-systolic diameter >50 to 55 mm or end-diastolic diameter >70 to 75 mm, although patient size should be considered). Surgical intervention for mitral regurgitation includes mitral valve repair and mitral valve replacement with or without chordal preservation (Table 24). Survival is superior after mitral valve repair compared with replacement, and durability is equivalent (Mohty et al.). Surgery should be considered for patients with severe mitral regurgitation and symptoms and in asymptomatic patients with atrial fibrillation, pulmonary hypertension, or evidence of left ventricular systolic dysfunction (ejection fraction 60% or end-systolic diameter 45 mm). Intervention should be considered earlier if successful mitral valve repair is likely. Ischemic mitral regurgitation (caused by alteration of left ventricular geometry after myocardial infarction) is associated with a poor prognosis and is not adequately treated with revascularization alone (Aklog et al.). The anorectic drugs fenfluramine (alone or in combination with phentermine) and dexfenfluramine have been associated with acquired mitral and aortic valve regurgitation among patients exposed for longer than 6 months, with higher risk among those exposed for more than 2 years. Regurgitation appears to regress in the first year after discontinuation of exposure (Mast et al., Weissman et al.).
KEYPOINTS
Vasodilator therapy is useful in asymptomatic patients with severe aortic regurgitation and systolic hypertension. Indications for aortic valve replacement in chronic severe aortic regurgitation include symptoms, left ventricular systolic dysfunction, or significant left ventricular dilation. Indications for surgery in chronic severe mitral regurgitation include symptoms, left ventricular systolic dysfunction, atrial fibrillation, or pulmonary hypertension. Intervention for chronic severe mitral regurgitation should be considered earlier if successful mitral valve repair is likely. Ischemic mitral regurgitation is not adequately treated with revascularization alone. Aortic and mitral regurgitation appear to regress in the first year after discontinuation of exposure to the anorectic drugs fenfluramine and dexfenfluramine.
Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation. 2001;104(Suppl 1):I1-I7. PMID: 11568020 Aklog L, Filsoufi F, Flores KQ, Chen RH, Cohn LH, Nathan NS, et al. Does coronary artery bypass grafting alone correct moderate ischemic mitral regurgitation? Circulation. 2001;104(Suppl 1):I68-75. PMID: 11568033 Mast ST, Jollis JG, Ryan T, Anstrom KJ, Crary JL. The progression of fenfluramineassociated valvular heart disease assessed by echocardiography. Ann Intern Med. 2001;134:261-6. PMID: 11182835 Weissman NJ, Panza JA, Tighe JF, Gwynne JT. Natural history of valvular regurgitation 1 year after discontinuation of dexfenfluramine therapy. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;134:267-73. PMID: 11182836
Acute Valvular Regurgitation

What are the causes of acute severe aortic or mitral regurgitation? How are these conditions diagnosed? What treatments are useful in patients with acute severe aortic or mitral regurgitation?
Acute severe aortic regurgitation is caused by infective endocarditis, ascending aortic dissection, or trauma. Because the left ventricle has not had time to compensate with chamber dilation and eccentric hypertrophy, left ventricular diastolic pressure increases. Despite reflex tachycardia, stroke volume and forward cardiac output decrease, with resulting pulmonary edema and cardiogenic shock. Many of the physical findings in chronic aortic regurgitation are absent: There is no increase in pulse pressure, and the diastolic murmur is soft and of short duration. Diagnosis is made by transthoracic or transesophageal echocardiography. Medical therapy includes nitroprusside and inotropic agents. Intraaortic balloon counterpulsation is contraindicated. Increasing the heart rate by using chronotropic agents or temporary pacing decreases the diastolic period and lessens the severity of regurgitation. Emergent aortic valve replacement is required for patients with cardiogenic shock. Acute severe mitral regurgitation is caused by valve destruction complicating infective endocarditis, papillary muscle rupture complicating acute myocardial infarction, or chordal rupture complicating myxomatous degeneration. Similar to acute severe aortic regurgitation, the absence of compensatory left ventricular dilation and eccentric hypertrophy associated with chronic regurgitation result in a decrease in forward stroke volume and cardiac output. The abrupt increase in left atrial volume is not accommodated by the normal-sized left atrium, resulting in pulmonary edema. In acute severe mitral regurgitation,
71
Mitral Valve Prolapse
TA B L E 2 4 Comparison of Interventions in Mitral Regurgitation
Intervention Mitral valve repair
Advantages Preserves MV apparatus and chords; preserves LV function; avoids prosthesis-related complications and anticoagulation Relative preservation of LV function; feasible in most patients Feasible in any patient
Disadvantages Technically more demanding; not feasible for all valves
Patient Selection Most patients with myxomatous degeneration, ischemic MR; some patients with infective endocarditis, rheumatic disease Most unrepairable valves
Mitral valve replacement with chordal preservation Mitral valve replacement without chordal preservation
Prosthesis-related complications, anticoagulation LV systolic dysfunction; prosthesisrelated complications; anticoagulation
Patients with rheumatic disease and unrepairable valves, severe subvalvular sclerosis, calcification
LV = left ventricle; MR = mitral regurgitation; MV = mitral valve
KEYPOINTS
Patients with acute severe aortic or mitral regurgitation are symptomatic and may present with cardiogenic shock. Many physical findings associated with chronic severe regurgitation are not present in patients with acute severe regurgitation. Diagnosis is made with transthoracic or transesophageal echocardiography. Nitroprusside with or without inotropic agents may improve hemodynamics. Intra-aortic balloon counterpulsation is useful in patients with acute severe mitral regurgitation but is contraindicated in patients with aortic regurgitation. Urgent or emergent surgical intervention is usually indicated in acute mitral or aortic regurgitation.
the murmur may not be holosystolic, and the apical impulse is not hyperdynamic. Diagnosis is made by transthoracic or transesophageal echocardiography. Medical therapy includes nitroprusside with or without inotropic agents. Intra-aortic balloon counterpulsation increases forward cardiac output and can be a useful temporizing measure. Urgent or emergent surgical intervention may be required.
Mitral Valve Prolapse

What is mitral valve prolapse? What is the prognosis of patients with mitral valve prolapse?
KEYPOINTS
Most patients with mitral valve prolapse have a good prognosis. Patients with myxomatous disease are at risk for premature valve degeneration with mitral regurgitation. Endocarditis prophylaxis should be used in patients with mitral regurgitation or leaflet thickening.
Mitral valve prolapse is defined by systolic billowing of one or both mitral leaflets into the left atrium. Although rheumatic and ischemic diseases can lead to mitral valve prolapse, the term is typically used to describe primary myxomatous degeneration of the valve. True mitral valve prolapse should be differentiated from pseudoprolapse caused by dehydration or annular distortion. Mitral valve prolapse due to myxomatous degeneration is accompanied by leaflet thickening or some amount of mitral regurgitation (or both). The high prevalence of mitral valve prolapse reported in the past among asymptomatic young women likely reflects inappropriate diagnoses based on echocardiographic imaging. Most patients with mitral valve prolapse have a good prognosis. Patients with significant leaflet thickening are predisposed to premature degeneration of the valve and mitral regurgitation. The risk of infective endocarditis is increased, and antibiotic prophylaxis is warranted if there is leaflet thickening on echocardiography or auscultory or echocardiographic evidence of mitral regurgitation. Palpitations and atypical chest pain occur as part of the mitral valve prolapse syndrome. Palpitations caused by nonsustained atrial or ventricular tachyarrhythmias often respond to therapy with a -adrenergic antagonist. There is a low (<1% per year) incidence of sudden death associated with mitral valve prolapse. Using the current standards for diagnosis, risk for embolic or cryptogenic neurologic events does not seem to be increased among patients with mitral valve prolapse.
Prosthetic Valves
What are the relative merits of different valve prostheses? How should anticoagulation be managed in patients with a mechanical prosthesis? What criteria should be considered in the selection of a valve prosthesis?
72
Prosthetic Valves
Heart valve prostheses can be divided into three main groups: mechanical prostheses (caged ball, tilting disk, and bileaflet valves), stented bioprostheses (porcine xenograft or constructed bovine pericardial valves), and stentless biologic valves (autograft, allograft, or stentless xenograft valves). The features of each type are summarized in Table 25. Bioprosthetic valves are more durable in older compared with younger patients and in the aortic compared with the mitral position. Thromboembolic risk is lower for tissue than for mechanical prostheses and lower for the same prosthesis type in the aortic compared with the mitral position. Mechanical prostheses have the advantage of increased durability, whereas bioprostheses have a lower thromboembolic potential and obviate the need for long-term anticoagulation. However, freedom from valve-related adverse events is similar at 11 years among patients having undergone mechanical and tissue valve replacement (Hammermeister et al.). More patients with a tissue prosthesis suffer structural failure and require reoperation, whereas more patients with a mechanical prosthesis suffer a thromboembolic or serious hemorrhagic event. Valve replacement with a stentless bioprosthesis is more technically demanding, although hemodynamics and durability are better than with stented bioprostheses (Pibarot and Dumesnil). Patients with a prosthetic valve require prophylaxis against endocarditis. Recommendations for anticoagulation therapy are summarized in Table 26. At the time of writing, no data support the use of low-molecular-weight heparin as a substitute for warfarin or intravenous heparin. During noncardiac or dental surgery, anticoagulation for a prosthetic valve should be interrupted for the minimum feasible interval. Among patients at high risk for thrombosis or thromboembolism, intravenous heparin should be administered after the international normalized ratio falls below 2.0, and again within 24 hours after surgery until warfarin treatment is reinitiated and the international normalized ratio is 2.0 or greater. Mechanical valve dysfunction is due to thrombosis or pannus formation, or to fracture or dislodging of part of the occluder mechanism or its housing. Bioprosthetic dysfunction typically occurs with progressive calcification of the prosthesis, often complicated by cusp fracture and acute regurgitation. Diagnosis is based on a change in clinical status or physical examination, and is supported by transthoracic or transesophageal echocardiographic imaging. The choice of prosthesis should take into consideration the patients age, comorbid conditions, lifestyle, and desires. Traditional recommendations were that tissue valve replacement should be reserved for patients older than 65 to 70 years of age because valve durability would suffice relative to the older
Hammermeister K, Sethi GK, Henderson WG, Grover FL, Oprian C, Rahimtoola SH. Outcomes 15 years after valve replacement with a mechanical versus a bioprosthetic valve: final report of the Veterans Affairs randomized trial. J Am Coll Cardiol. 2000;36:1152-8. PMID: 11028464 Pibarot P, Dumesnil JG. Hemodynamic and clinical impact of prosthesis-patient mismatch in the aortic valve position and its prevention. J Am Coll Cardiol. 2000;36: 1131-41. PMID: 11028462
TA B L E 2 5 Comparison of Valve Prostheses
Prosthesis Mechanical
Construction Prosthetic materials
Examples Caged-ball, tilting disk, bileaflet Porcine xenograft, constructed bovine pericardium
Advantages Durability; good hemodynamics in current generation Lower thromboembolic risk than mechanical; no long-term anticoagulation requirement Hemodynamics, durability better than stented bioprostheses
Disadvantages Thromboembolic risk; requires long-term anticoagulation Limited durability, especially in younger patients; suboptimal hemodynamics with smaller valve sizes Technically more demanding implantation; limited availability of allografts
Stented bioprosthetic
Strut-mounted tissue (porcine or bovine)
Stentless bioprosthetic
Stentless tissue (human or animal)
Autograft, allograft, stentless xenograft
73
Acute Pericarditis
KEYPOINTS
Mechanical valves are more durable than bioprosthetic valves but require long-term anticoagulation therapy because of greater thromboembolic risk. Freedom from adverse valve-related events at 11 years is similar for mechanical and bioprosthetic valves. Continuing advances in prosthesis design force patients and physicians to make choices without outcome data from large, randomized trials.
patients shorter life expectancy. However, improved durability of second- and third-generation stented bioprostheses, anticalcification therapies used with some stentless and third-generation stented bioprostheses, and decreasing the mortality rate associated with reoperation procedures have prompted a shift toward greater use of bioprostheses in progressively younger patients. Because clinical outcomes for prosthetic valves are measured over years and decades and because prosthesis designs continue to evolve, patients and physicians must make choices about which prosthesis to use without outcome data from large, randomized trials.
TA B L E 2 6 Recommendations for Anticoagulation in Patients with a Prosthetic Heart Valve
Type of Prosthesis Mechanical First 3 months after replacement >3 months after replacement Aortic valve Aortic valve + risk factors* Mitral valve (with or without risk factors) Tissue First 3 months after replacement >3 months after replacement Aortic valve Aortic valve + risk factors* Mitral valve Mitral valve + risk factors*
INR = international normalized ratio
*Atrial
Warfarin, INR
Aspirin, mg
2.53.5 2.03.0 2.53.5 2.53.5 2.53.5 None 2.03.0 None 2.53.5
80100
80100 80100 80100 80100 80100 80100 80100
fibrillation, left ventricular systolic dysfunction, previous thromboembolic event, or hypercoagulable state.
Pericardial Disease, Restrictive Cardiomyopathy, and Hypertrophic Cardiomyopathy

The major pericardial diseases are acute pericarditis, recurrent pericarditis, pericardial effusion, and constrictive pericarditis. Restrictive cardiomyopathy is a rare disorder of diastolic filling caused by myocardial fibrosis or infiltration. Hypertrophic cardiomyopathy is a genetic disease of the cardiac sarcomere.
Acute Pericarditis
What is the first-line therapy for acute pericarditis? What is the role of corticosteroids in the treatment of acute pericarditis?
Acute pericarditis is inflammation or irritation of the pericardium (and often the epicardium) that is usually painful. Acute pericarditis has many etiologies, but most often arises in the context of presumed viral upper respiratory tract infection. Patients often present with a low-grade febrile illness and chest pain. The chest pain is often position related or pleuritic in nature. Associated symptoms may include diaphoresis, tachycardia, and tachypnea (because deep breaths are painful). The hallmark feature on physical examination is a three-component friction rub. However, the absence of the friction rub does not exclude the diagnosis. An elevated erythrocyte sedimentation rate and characteristic electro74
Recurrent Pericarditis
cardiographic finding of diffuse ST elevation and PR depression support the clinical diagnosis. About 50% of patients with acute pericarditis have an effusion on echocardiography; however, this feature cannot be used for clinical diagnosis. The primary role of echocardiography is to detect pericardial effusion in patients with elevated jugular venous pressure or signs and symptoms of congestive heart failure. Other tests that may useful to guide the clinical management include cardiac biomarkers in patients with increased risk for coronary artery disease or autoimmune evaluation in patients with recurrent pericarditis. The first-line therapy for acute pericarditis is a nonsteroidal anti-inflammatory agent in relatively high doses for 2 to 4 weeks. Steroids are effective in relieving symptoms, but they should be avoided because pericarditis tends to recur whenever the steroid dose is decreased.
KEYPOINTS
Nonsteroidal anti-inflammatory drugs are the therapy of choice for acute pericarditis. Corticosteroids should be avoided in the treatment of acute or recurrent pericarditis.
Recurrent Pericarditis
When is pericarditis more likely to recur? What is the role of colchicine in the treatment of recurrent pericarditis?
Recurrent pericarditis is manifested by return of symptoms and signs of inflammation (elevated erythrocyte sedimentation rate) within days to weeks after discontinuing the anti-inflammatory drug used to treat the initial episode of acute pericarditis. It tends to occur more often when corticosteroids are used in the management of acute pericarditis or when systemic inflammation is ongoing. Examples of the latter situation include rheumatologic disorders, Dresslers syndrome (pleuropericarditis after acute myocardial infarction), or the post-pericardiotomy syndrome. Recurrent pericarditis usually responds to high-dose aspirin, salicylate, or other nonsteroidal anti-inflammatory drugs. In recurrent pericarditis, these agents should be used for at least 1 month, with slow tapering of the dose thereafter. Nonrandomized, observational studies indicate that the addition of colchicine (1 mg/d, in divided doses) can aid in the initial management of recurrent pericarditis (Adler et al.). The need for a loading dose of 2 to 3 mg/d is unproven. Long-term maintenance therapy with colchicine (0.5 mg once or twice daily) has also been observed to prevent subsequent recurrence (Oakley).
Adler Y, Finkelstein Y, Guindo J, Rodriguez de la Serna A, Shoenfeld Y, Bayes-Genis A, et al. Colchicine treatment for recurrent pericarditis. A decade of experience. Circulation. 1998;97:2183-5. PMID: 9626180 Oakley CM. Myocarditis, pericarditis and other pericardial diseases Heart. 2000;84:449-54. PMID: 10995424
KEYPOINTS
The use of corticosteroids in the treatment of acute pericarditis can lead to recurrent pericarditis when the dose is decreased. The addition of colchicine, 1 mg/d, to a nonsteroidal anti-inflammatory drug regimen can facilitate the treatment of recurrent pericarditis.
Pericardial Effusion
What is needed to make the diagnosis of pericardial tamponade? When should therapeutic pericardiocentesis be performed?
Pericardial effusions have the same etiology as acute pericarditis. Most pericardial effusions do not result in cardiac tamponade or clinical symptoms. Hemodynamic consequences are related to the rapidity of fluid accumulation rather than the absolute volume of fluid. Low voltage identified on 12-lead electrocardiography (with or without electrical alternans) or an enlarged cardiac silhouette can suggest effusion. Echocardiography is the preferred imaging technique in most cases, but computed tomography and magnetic resonance imaging can also readily demonstrate pericardial effusion. Cardiac tamponade occurs when pericardial effusion restricts diastolic left or right ventricular filling. Patients have signs and symptoms of reduced cardiac output, including tachycardia, breathlessness, elevated jugular venous pressure, hypotension, and exaggerated pulsus paradoxus. The echocardiogram can confirm the clinical suspicion of effusion and can even show signs of preclinical hemodynamic compromise, the classic echocardiographic finding of pericardial tamponade. Pericardiocentesis is the treatment for clinical cardiac tamponade. 75
Constrictive Pericarditis
KEYPOINTS
Cardiac tamponade is a clinical, bedside diagnosis and is effectively treated with pericardiocentesis of the presence of tamponade is confirmed by detection of an effusion, usually on echocardiography and supported by additional Doppler-echocardiographic signs. Pericardiocentesis is ideally performed in a controlled setting, such as the cardiac catheterization laboratory, by physicians with experience in this technique. Guidance with echocardiography can reduce associated complications.
Classically, pericardiocentesis has been performed using a subxyphoid blind approach. In current practice, echocardiography can help identify sites for pericardiocentesis and should be used as a routine part of the procedure. A pericardial drainage catheter is often left in place until there is no further accumulation of pericardial fluid. In rare cases, resection of the pericardium may be necessary for chronic, recurrent effusions (Tsang et al.).
Constrictive Pericarditis
What is needed to diagnose constrictive pericarditis?
Tsang TS, Seward JB, Barnes ME, Bailey KR, Sinak LJ, Urban LH, Hayes SN. Outcomes of primary and secondary treatment of pericardial effusion in patients with malignancy. Mayo Clin Proc. 2000;75: 248-53. PMID: 10725950 Hancock EW. Differential diagnosis of restrictive cardiomyopathy and constrictive pericarditis. Heart. 2001;86:343-9. PMID: 11514495 Senni M, Redfield MM, Ling LH, Danielson GK, Tajik AJ, Oh JK. Left ventricular systolic and diastolic function after pericardiectomy in patients with constrictive pericarditis: Doppler echocardiographic findings and correlation with clinical status. J Am Coll Cardiol. 1999;33:1182-8. PMID: 10193714
KEYPOINTS
Constrictive pericarditis should be suspected in any patient with profound signs and symptoms of right-heart failure that are out of proportion to any ventricular or valvular abnormalities. Differentiating constrictive pericarditis from restrictive cardiomyopathy often requires a full spectrum of noninvasive and invasive tests, including simultaneous right and left heart catheterization. Up to 10% of patients with pericardial constriction have no demonstrable pericardial thickening on computed tomography or magnetic resonance imaging. While the majority of patients will improve clinically following complete pericardectomy, recovery may be delayed for months. In radiation-associated pericardial disease, there may be coexistent restrictive cardiomyopathy, and the prognosis even with pericardectomy is poor.
Constrictive pericarditis is a contraction of the pericardium, often due to chronic inflammation, that prevents the heart from filling completely. The condition is manifest by signs and symptoms of overt right-heart failure (venous congestion) and poor cardiac output that are out of proportion to the degree of left ventricular dysfunction or valvular heart disease that may be present. Peripheral edema, ascites, jugular venous distention, fatigue, and dyspnea may be seen. Currently, the main differential diagnosis is restrictive cardiomyopathy (Hancock). The etiology of constrictive pericarditis is similar to that of the other pericardial processes, with the addition of a history of radiation therapy to the chest (often used to treat breast cancer or Hodgkins lymphoma). Differentiating restrictive cardiomyopathy from constrictive pericarditis can be very challenging and often requires a full spectrum of diagnostic techniques, both noninvasive and invasive. Complicating the diagnostic evaluation is the relatively frequent coexistence of these two conditions, especially in the case of radiation-induced disease. Pericardial calcification on chest radiography is highly suggestive of constrictive pericarditis but is present in fewer than 50% of patients with this diagnosis. Echocardiography is the primary diagnostic tool for the diagnosis of constrictive pericarditis, with well-described morphologic and Doppler characteristics. Newer Doppler echocardiography techniques, such as Doppler tissue imaging, have been helpful in differentiating constriction from restriction. Computed tomography and magnetic resonance imaging can readily detect the presence of pericardial thickening; however, constriction can be seen with normal pericardial thickness in approximately 10% of patients. Finally, cardiac catheterization with simultaneous pressure recordings from the right and left ventricles demonstrating equalization of the diastolic pressures may be required to confirm constriction. Complete pericardiectomy is the treatment of choice for constrictive pericarditis. Although some patients with mild symptoms may be managed with careful use of diuretics, the operative mortality rate is significant if pericardiectomy is delayed until advanced symptoms (New York Heart Association class III or IV) are present. While the majority of patients will improve after pericardectomy, the clinical recovery is often delayed for months and there may be continued evidence of diastolic abnormalties on echocardiography (Senni et al.). The worst outcome after pericardectomy, including the highest mortality rate and the least improvement, is seen in radiation-associated disease.
Restrictive Cardiomyopathy
When should restrictive cardiomyopathy be suspected? What are the factors that influence prognosis in restrictive cardiomyopathy?
Restrictive cardiomyopathy is in the differential diagnosis of any patient presenting with signs and symptoms of congestive heart failure. Generally, patients have nondilated and nonhypertrophied ventricles with preserved systolic function.
76
Hypertrophic Cardiomyopathy
Some infiltrative diseases, such as cardiac amyloidosis, result in secondary restrictive cardiomyopathy, but with increased left ventricular wall thickness. Additional echocardiographic features include significant biatrial enlargement and Doppler evidence of advanced diastolic dysfunction. If the diagnosis of restrictive cardiomyopathy versus constrictive pericarditis remains uncertain after invasive and noninvasive evaluations, right-heart biopsy may be indicated to detect infiltrative diseases, such as amyloid cardiomyopathy and hemochromatosis. Treatment of restrictive cardiomyopathy is also difficult. Careful control of fluid balance is crucial. Patients often present with indications of fluid excess but require relatively high preload to maintain cardiac output. Treatment of any underlying or coexistent diseases that affect diastolic function (for example, hypertension, diabetes, or ischemic heart disease) is also essential. The prognosis of patients with restrictive cardiomyopathy is poor and influenced by the cause of the restrictive cardiomyopathy, advancing age, worsening functional classification, and left atrial size (Ammash et al.). In amyloid cardiomyopathy, use of digitalis and calcium channel blockers should be avoided because binding of these agents to the amyloid protein may increase the risk of toxicity. Patients are unlikely to benefit from therapy with -blockers. Conduction abnormalities often preclude their use. Moreover, because stroke volume is reduced and relatively fixed, so reduction in heart rate may be associated with a significant decrease in cardiac output. In cardiomyopathy associated with primary amyloid, treatment with melphalan and prednisone may prolong survival. In patients with familial amyloidosis associated with abnormal transthyretin, disease regression has been reported with liver transplantation. Cardiac transplantation alone is not indicated because amyloid may accumulate in the graft, with eventual development of restrictive cardiomyopathy.
Ammash NM, Seward JB, Bailey KR, Edwards WD, Tajik AJ. Clinical profile and outcome of idiopathic restrictive cardiomyopathy. Circulation. 2000;101:2490-6. PMID: 10831523
KEYPOINTS
The main differential diagnosis of restrictive cardiomyopathy is constrictive pericarditis. Restrictive physiology (ischemic or hypertensive heart disease) is seen in many patients who do not have restrictive cardiomyopathy. The treatment of restrictive cardiomyopathy is limited. Digoxin and calcium channel blockers should be avoided in patients with cardiac amyloid. -Blockers usually have no role. The prognosis of cardiac involvement in primary amyloid may be improved with use of melphalan and prednisone.
Hypertrophic Cardiomyopathy
What is the genetic basis of hypertrophic cardiomyopathy, and how does it influence screening? What is the best strategy to assess for risk of sudden death in hypertrophic cardiomyopathy? How should hypertrophic cardiomyopathy be managed? What are the indications for surgical versus percutaneous treatment strategies in hypertrophic cardiomyopathy?
More than 150 mutations in at least 10 different genes have been associated with hypertrophic cardiomyopathy. Most of the mutations involve the proteins that make up the cardiac sarcomere. These abnormal proteins may lead to secondary myocardial hypertrophy through alterations in sarcomeric function, or possibly to direct hypertrophy. The mutations are transmitted in an autosomal dominant pattern. The large number of mutations makes genetic screening impractical for general clinical use. Screening of family members of known affected persons continues to rely on physical examination, electrocardiography, and echocardiography. Screening of relatives should be done periodically throughout adolescence and adulthood, as some mutations are known to have early and others, late clinical expression (penetrance) in the fifth or sixth decade of life (Maron et al.). Presentation in childhood is uncommon. The annual incidence of sudden cardiac death in hypertrophic cardiomyopathy, as established in population-based studies, is approximately 1%. Patients who have survived cardiac arrest or have documented sustained ventricular tachycardia or ventricular fibrillation are at the highest risk and should receive implantable cardioverter-defibrillators. Other identified risk factors include nonsustained ventricular tachycardia on Holter monitoring, abnormal blood pressure response to
Maron BJ, Moller JH, Seidman CE, Vincent GM, Dietz HC, Moss AJ, et al. Impact of laboratory molecular diagnosis on contemporary diagnostic criteria for genetically transmitted cardiovascular diseases: hypertrophic cardiomyopathy, longQT syndrome, and marfan syndrome: a statement for healthcare professionals from the councils on clinical cardiology, cardiovascular disease in the young, and basic science, american heart association. Circulation. 1998;98:1460-71. PMID: 9760303
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Aortic Aneurysm
Elliott PM, Gimeno Blanes JR, Mahon NG, Poloniecki JD, McKenna WJ. Relation between severity of left-ventricular hypertrophy and prognosis in patients with hypertrophic cardiomyopathy. Lancet. 2001;357:420-4. PMID: 11273061 Nagueh SF, Ommen SR, Lakkis NM, Killip D, Zoghbi WA, Schaff HV, et al. Comparison of ethanol septal reduction therapy with surgical myectomy for the treatment of hypertrophic obstructive cardiomyopathy. J Am Coll Cardiol. 2001;38:1701-6. PMID: 11704383
KEYPOINTS
Genetic testing for hypertrophic cardiomyopathy is not yet clinically available. Other than out-of-hospital cardiac arrest or sustained ventricular arrhythmia, no single risk factor for sudden death in hypertrophic cardiopmyopathy is adequate to warrant placement of an implantable cardioverter-defibrillator. Most symptomatic patients with hypertrophic cardiomyopathy can be managed medically using agents with negative inotropic and chronotropic properties, such as -blockers. Surgical septal myomectomy or percutaneous septal ablation can be considered in symptomatic patients who do not respond to medical therapy.
exercise, syncope in younger patients, family history of sudden cardiac death in two or more family members, and perhaps the severity of hypertrophy. The presence or absence of any single risk factor is not sufficient to justify device implantation, but this should be considered if two or more factors coexist (Elliott et al.)( Figure 17). The treatment of symptomatic hypertrophic cardiopmyopathy is well described for the 30% of patients with left ventricular outflow tract obstruction. Initial management is with medications that have negative inotropic and negative chronotropic properties: -blockers, nondihydropyridine calcium channel blockers, or disopyramide. Their use in the asymptomatic patient has not been systematically studied. Table 27 lists pharmacologic and nonpharmacologic things to avoid in obstructive hypertrophic cardiomyopathy. The treatment of nonobstructive hypertrophic cardiomyopathy is difficult and not well studied. For patients with continued symptoms despite pharmacologic therapy, several invasive strategies are available. Dual-chamber pacing has been used to reduce obstruction, but results were disappointing in randomized trials. Surgical septal myectomy has been established as the definitive therapy. In experienced hands, this operation is safe and effective. A catheter-based alternative to septal myectomy has recently emerged. Percutaneous septal ablation is performed by instilling alcohol into the septal perforator artery that supplies the obstructing myocardium. The resulting focal infarction halts myocardial contraction in this territory, and over time, leads to scarring and thinning in this area. Short- to intermediate-term studies suggest similar symptomatic improvement as septal myectomy. The procedural mortality is similar to myectomy, but there is more need for permanent pacemaker implantation owing to infarctrelated complete heart block with the ablation procedure (Nagueh et al.). Long-term safety data are not yet available for this procedure. For patients with drug-refractory symptoms, septal debulking by either procedure should be considered. Patients with isolated basal septal hypertrophy are the best candidates for either procedure. Patients with concomitant valvular pathology (mitral valve flail or prolapse), abnormal papillary muscles, or more diffuse hypertrophy can be more definitively managed via the surgical approach.
Aortic Disease
The following aortic diseases are discussed in this chapter: aortic aneurysm, aortic dissection, aortic atheroembolic disease, and Marfan syndrome.
Aortic Aneurysm
Who should be screened for abdominal aortic aneurysm? What are the indications for aneurysm repair? When should percutaneous repair of an abdominal aneurysm be considered?
Case 10 A 76-year-old man with a history of stable coronary artery disease presents for intermittent right upper quadrant pain. He stopped smoking 5 years earlier when he had an inferior myocardial infarction. He takes metoprolol, 50 mg twice daily, and acetylsalicylic acid, 325 mg/d. On physical examination, blood pressure is 145/85, pulse rate is 62/min, and temperature is normal. Cardiovascular examination reveals normal jugulovenous pressure, a sustained apical impulse, S4, and no murmur. Abdominal examination is significant only for mild 78
Aortic Aneurysm
right upper quadrant tenderness. Laboratory values, including complete blood count, alkaline phosphatase, and amylase, are normal. Abdominal ultrasonography reveals cholelithiasis without dilated biliary ducts, and a 4.3-cm suprarenal aneursym is noted. Aortic aneurysm is defined a dilatation of the aortic that is at least 1.5 times normal or larger than 3.0 cm in adults. The abdominal aorta is the most common site. Risk factors for aortic aneurysm include smoking, white race, male sex, age older than 60 years, coronary artery disease, and family history. Most abdominal aortic aneurysms are asymptomatic. Abdominal or back pain may signify an expanding aneurysm. Distal embolic disease may result from atheroma or superimposed mobile thrombus within the aneurysm. Aneurysms larger than 5.5 cm in diameter and those expanding at a rate greater than 0.5 cm in 6 months are at highest risk for rupture. The need for routine screening, other than directed physical examination, for an asymptomatic abdominal aortic aneurysm remains controversial. Physical examination is highly sensitive for an aneurysm larger than 5.0 cm in a patient with an abdominal girth less than 100 cm (Fink et al.). Ultrasonography is a sensitive and specific screening technique, but results are technician dependent
TA B L E 2 7 Things To Avoid In
Obstructive Hypertrophic Cardiomyopathy* Nonpharmacologic Dehydration Alcohol Hot tub or sauna Anaerobic exercise Isometric exercise Competitive athletics Intra-aortic balloon pump Pharmacologic Any pure vasodilators Nitrates Dihydropyridine calcium channel blockers Hydralazine Angiotensin-converting enzyme inhibitors Angiotensin receptor blockers -Adrenergic antagonists Minoxidil Sildenafil Any positive inotropes Epinephrine Norepinephrine Isoproteronol Dopamine Dobutamine Digoxin High-dose diuretics
History ECG Echo Exercise test Holter
Sustained or symptomatic VT or VF
Identify and treat TRIGGERS
NO sustained VT or VF
Over-the-counter stimulants, including caffeine and tobacco

*
These are general guidelines. The riskbenefit ratio needs to consider each patient individually. Research is ongoing regarding several of the above pharmacologic agents, particularly for nonobstructive hypertrophic cardiomyopathy.
? DNA Diagnosis ?
RISK FACTOR STRATIFICATION

Fink HA, Lederle FA, Roth CS, Bowles CA, Nelson DB, Haas MA. The accuracy of physical examination to detect abdominal aortic aneurysm. Arch Intern Med. 2000;160:833-6. PMID: 10737283
ICD amiodarone
2 Risk factors
1 Risk factor
0 Risk factor Reassure adults and reassess children
FIGURE 17. Algorithm for risk stratification and prevention of sudden death.
ECG = electrocardiography; Echo = echocardiography; ICD = implantable cardioverter defibrillator; VF = ventricular fibrillation; VT = ventricular tachycardia Reproduced with permission from: McKenna WJ, Behr ER. Hypertrophic Cardiomyopathy: management, risk stratification and prevention of sudden death. Heart 2002;87:169-76.
Individualize decision
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Aortic Aneurysm
Gadowski GR, Pilcher DB, Ricci MA. Abdominal aortic aneurysm expansion rate: effect of size and beta-adrenergic blockade. J Vasc Surg. 1994;19:727-31. PMID: 7909340 Lederle FA, Wilson SE, Johnson GR, Reinke DB, Littooy FN, Acher CW, et al. Immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346:1437-44. PMID: 12000813 Long-term outcomes of immediate repair compared with surveillance of small abdominal aortic aneurysms. N Engl J Med. 2002;346:1445-52. PMID: 12000814 Howell MH, Strickman N, Mortazavi A, Hallman CH, Krajcer Z. Preliminary results of endovascular abdominal aortic aneurysm exclusion with the AneuRx stentgraft. J Am Coll Cardiol. 2001;38:1040-6. PMID: 11583879 Guo D, Hasham S, Kuang SQ, Vaughan CJ, Boerwinkle E, Chen H, et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13-14. Circulation. 2001;103:2461-8. PMID: 11369686
KEYPOINTS
Routine screening other than a directed physical examination for abdominal aortic aneurysm is not indicated. Patients with abdominal aortic aneurysm 4.0 to 5.4 cm in size should have surveillance with computed tomography or ultrsonography every 6 months. Repair is indicated for abdominal aortic aneurysms 5.5 cm or larger or rapidly expanding aneurysms (>0.5 cm in 6 months). Repair is indicated for thoracic aortic aneurysms larger than 5.0 cm in the ascending aorta or larger than 6.0 in the descending aorta and rapidly expanding aneurysms (>1.0 cm in 1 year). Symptomatic patients should be referred for repair independent of location. Percutaneous endovascular repair can be performed by experienced operators, with a high procedural success rate and negligible mortality. Indications for choosing the percutaneous approach over surgery are not yet established.
and it may be less sensitive than computed tomography or magnetic resonance angiography in measuring small changes in aneurysm dimension. The risk of rupture of an abdominal aortic aneurysm is related to the initial diameter of the aneurysm at the time of diagnosis. According to several older studies in the literature, the 5-year risk of rupture is less than 5% for aneurysms smaller than 5.0 cm and approximately 25% for those 5.0 cm or larger. Very large aneursyms (>6.0 cm) have an even higher rate of rupture. Additional information suggests that larger aneurysms (>5.0 cm) expand more rapidly than smaller ones. The rate of expansion is greater among aneurysms that rupture (approximately 0.8 cm/y) than among those that do not rupture (approximately 0.4 cm/y). Therapy with -blockers may reduce the rate of expansion (Godowski et al.). Two recently published large randomized trials in patients with abdominal aortic aneurysm measuring 4.0 cm to 5.5 cm demonstrate that early intervention with surgery is not associated with improved survival compared with surveillance and intervention when the diameter reaches 5.5 cm. In the Aneurysm Detection and Management study, the operative mortality rate was low (2.1%). The rate of cross-over to surgery was 61% and was highest in patients with the largest aneurysms at entry (Lederle et al.). In the UK Small Aneurysm Trial, there was a slight but statistically significant improvement in total survival in the surgically treated group at 8 years that was not attributable to a decreased rate of rupture. Women were at an increased risk for rupture, suggesting that a cutoff of 5.5 cm for surgical referral may be too high in women. The decrease in total mortality in the early surgery group may be attributed to the higher rate of smoking cessation in this group, leading to reduced cardiovascular mortality from stroke and myocardial infarction (UK Small Aneurysm Trial). In Case 10, the abdominal pain is unlikely to be related to the aneurysm and is more likely related to cholelithiasis. Surgical intervention would offer no clear advantage, and the patient should be followed every 6 to 12 months with computed tomography or ultrasonography. The greater cost of magnetic resonance imaging probably does not warrant its use. Percutaneous endovascular repair is now possible for many infrarenal abdominal aortic aneurysms. Precise criteria for patient selection have not been established. Initial reports of the procedural success rate have ranged from 60% to 99%. Leaks between the graft and the aneurysm (endoleaks) are common. Their management is controversial. Some close spontaneously and others require further intervention, but the need for surgical repair is uncommon (Howell et al.). Further ongoing study and comparison of percutaneous endovascular repair to surgery is needed. Thoracic aortic aneurysms are far less common and, therefore, less well studied. The etiologies of thoracic aortic aneurysm have been enumerated (Table 28). Recently, a familial form of thoracic aneurysm has been linked to gene 5q13-14 (Guo et al.). No features of Marfan syndrome or other connective tissue disease were present, and there appeared to be an autosomal dominant pattern of inheritance. Screening of family members may be warranted. The risk of rupture varies with the size of the aneurysm and approaches 60% in aneurysms larger than 6.0 cm. Moreover, the rate of aneurysm expansion is greatest in patients with the largest aneurysms. Indications for surgery include symptoms, a diameter larger than 5.0 cm in the ascending aorta or larger than 6.0 in the descending aorta, and rapid expansion (>1.0 cm in 1 year). Another complication of ascending aortic aneurysm that involve the aortic root is aortic insufficiency. In these patients, serial echocardiography is required not only to follow aortic root expansion but also to assess severity of aortic insufficiency and left ventricular size and function. Endovascular repair is now being performed for descending thoracic aneurysm in some centers.
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Aortic Dissection
Aortic Dissection
What are the major risk factors for aortic dissection? How should aortic dissection be managed acutely? What is the best test for diagnosing aortic dissection? How should patients with chronic aortic dissection be followed?
TA B L E 2 8 Etiologies and Risk Factors in Thoracic Aortic Aneurysm and Dissection
Aneurysm or dissection: Atherosclerosis Hypertension Marfan syndrome Bicuspid aortic valve Coarctation of the aorta EhlersDanlos syndrome Aneurysm only: Infectious Syphilis Myocotic aneurysm due to endocarditis HLA-B27related diseases and other arthritidies Ankylosing spondylitis Reiters syndrome Reactive arthritis Psoriatic arthritis Rheumatoid arthritis Other Giant-cell arteritis Takyasuss disease Wegeners granulomatosis Dissection only: Pregnancy Trauma
Case 11 A 58-year-old man presents with a 1-hour history of severe chest pain that came on suddenly. No specific maneuvers changed the severity of the pain. He denied a history of angina or hypertension. He was told in the past that he had a heart murmur and took antibiotics before dental work. On examination, blood pressure is 128/60 mm Hg and heart rate is 95/min, and the patient is afebrile. There is an early systolic click, a soft S2, a 2/6 systolic ejection murmur, and a 3/6 short diastolic murmur beginning after S2. Electrocardiography shows left ventricular hypertrophy with secondary T-wave changes. Chest radiography shows cardiomegaly and widening of the mediastinum. The patient is referred for transesophageal echocardiography. Aortic dissection is a potentially life-threatening event, especially when it involves the ascending aorta. The most common risk factor for dissection is hypertension. In younger patients, risk factors include connective tissue diseases, such as Marfan syndrome; bicuspid aortic valve; coarctation of the aorta; trauma; and pregnancy (Table 28). Sudden onset of pain is the presenting symptom in most patients. A recent large registry showed a low prevalence of classic signs, with aortic insufficiency in 32% of patients and pulse deficits in 15%. Transesophageal echocardiography and helical computed tomography are the preferred methods for diagnosis because of their high diagnostic accuracy and the rapidity with which they can be performed. Magnetic resonance angiography is preferred to follow patients with chronic dissection. Ultimately, the best diagnostic method for a given patient depends on local availability and expertise. Invasive aortography is indicated only when accurate localization of the tear is needed and in the setting of coexisting coronary ischemia. The patient described in Case 11 is hemodynamically stable and requires prompt relief of pain. His history and physical examination suggest bicuspid aortic valve, which may be associated with chronic aortic insufficiency. However, the chest pain should raise the clinical suspicion of dissection. Dissections should be defined anatomically as involving the ascending aorta (type A) or descending aorta (type B). Other important features include the severity of aortic root dilation and aortic insufficiency, involvement of coronary arteries and great vessels, and rupture. Acute management typically requires aggressive antihypertensive therapy with agents that reduce shear stress on the aortic wall. The best agents are those with -blocking activity that can be administered rapidly with the goal of reducing the systolic blood pressure to 100 to 120 mm Hg; these agents include metoprolol, inderal and labetolol. If -blockers are absolutely contraindicated, diltiazem or verapamil can be substituted. Vasodilators, such as nitroprusside, should not be used without a -blocker. Hypotension may be due to contained rupture with tamponade, rupture with exsanguination or cardiogenic shock due to severe aortic insufficiency, or associated myocardial infarction. In all cases, rapid triage to surgery may be life-saving, although the mortality rate is high.
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Aortic Atheroembolic Disease
KEYPOINTS
Sudden chest pain is the most common presenting symptom in aortic dissection. Transesophageal echocardiography and helical computed tomography are the preferred methods for diagnosis because of their high diagnostic accuracy and the rapidity with which they can be performed. In general, surgery is indicated acutely for type A dissection and medical therapy for type B dissection. -Blockers are the primary treatment for hypertension in acute and chronic dissection. Vasodilators should be used only with -blockers. In medically treated patients, continued surveillance with magnetic resonance angiography is indicated for aortic dilatation, which may be an indication for surgery (type A >5.0 cm or type B >6.0 cm).
In acute type A dissection, emergency surgery is indicated to avoid tamponade and rupture. In a recent international registry of 464 patients, the mortality rate was 26% with early surgical treatment and 58% with medical management in patients excluded from surgery because of advanced age or significant comorbid conditions. According to recently published guidelines from the European Society of Cardiology, surgery is indicated in acute type B dissection only for complications, such as recurrent or persistent pain, early expansion, rupture, or peripheral ischemia. Recent registry data showed a mortality rate in type B dissection of 31% with early surgery and 11% with medical therapy (Hagan et al.; Erbel et al.). There are an increasing number of reports of successful endovascular stenting in acute and chronic aortic dissection. Long-term therapy in survivors should include continued antihypertensive management and avoidance of strenuous exercise. The 10-year survival rate is approximately 50%. Indications for late surgery in medically treated survivors with type A dissection include progressive aortic insufficiency or dilation. In patients with type B dissection, repair is indicated if the descending thoracic aortic diameter expands to greater than 6 cm. Magnetic resonance angiography should be performed every 6 months for the first year and then, if stable, yearly.
Aortic Atheroembolic Disease

What is the significance of mobile atheroma identified by transesophageal echocardiography in a patient with a recent stroke? What is the appropriate treatment in this setting?
Hagan PG, Nienaber CA, Isselbacher EM, Bruckman D, Karavite DJ, Russman PL, et al. The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease. JAMA. 2000;283:897-903. PMID: 10685714 Erbel R, Alfonso F, Boileau C, Dirsch O, Eber B, Haverich A, et al. Diagnosis and management of aortic dissection. Eur Heart J. 2001;22:1642-81. PMID: 11511117
KEYPOINTS
Case 12 A 68-year-old woman is referred for transesophageal echocardiography after a transient episode of monocular blindness. Carotid ultrasonography was negative for obstructive disease. Mobile plaques were present in the descending aorta. A patent foramen ovale was not identified. Aortic atherosclerotic disease with plaques protruding more than 4 mm into the lumen is a well-recognized risk factor for embolic disease, including stroke, peripheral embolization, and renal embolic disease. Ulcerated plaques and mobile debris are associated findings evident in the thoracic aorta on transesophageal echocardiography. The presence of a pedunculated mobile plaque is associated with the highest risk of emboli. In patients with a history of embolic events, warfarin has been shown to reduce the recurrence rate (Dressler et al.; Salem et al.).
Atherosclerotic disease in the thoracic aorta is a risk factor for cerebral, renal, and peripheral embolic events. Warfarin reduces the incidence of recurrent stroke in patients with mobile aortic atheroma.
Dressler FA, Craig WR, Castello R, Labovitz AJ. Mobile aortic atheroma and systemic emboli: efficacy of anticoagulation and influence of plaque morphology on recurrent stroke. J Am Coll Cardiol. 1998;31:134-8. PMID: 9426031 Salem DN, Daudelin HD, Levine HJ, Pauker SG, Eckman MH, Riff J. Antithrombotic therapy in valvular heart disease. Chest. 2001;119:207S-219S. PMID: 11157650 Loeys B, Nuytinck L, Delvaux I, De Bie S, De Paepe A. Genotype and phenotype analysis of 171 patients referred for molecular study of the fibrillin-1 gene FBN1 because of suspected Marfan syndrome. Arch Intern Med. 2001;161: 2447-54. PMID: 11700157
Marfan Syndrome
What is the risk associated with aortic dilation in the patient with Marfan syndrome? What is the role of prophylactic -blocker therapy?
Case 13 A 28-year-old woman with suspected Marfan syndrome presents for counseling regarding pregnancy. She has a family history of sudden death due to suspected aortic dissection. She is tall with long arms. Blood pressure is 110/75 mm Hg and pulse rate is 65/min. The apical impulse is not displaced. A soft diastolic murmur is detected along the right sternal border. A midsystolic click and a late systolic murmur are audible at the apex. Electrocardiography is normal. Chest radiography shows prominence of the ascending aorta.
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Acyanotic Congenital Heart Disease
Marfan syndrome is a congenital disorder caused by various mutations of the fibrillin-1 gene (FBN-1). These mutations are uncommon in patients who do not fulfill clinical criteria for the disease (Loeys et al.). Marfan syndrome may be inherited in an autosomal dominant pattern, but new mutations result in sporadic occurrence. Clinical criteria for diagnosis have been enumerated (Table 29). Aortic disease is a major source of morbidity and the primary source of mortality because of the risk of dissection and rupture. Dilation occurs in as many as 50% of children and progresses with age. Yearly echocardiography is indicated to follow the size of the aortic root until it reaches 4.5 cm and should then be repeated every 6 months. Recent studies suggests that aortic distensibility is reduced. Therapy with -blockers, specifically propranolol, has been shown to reduce the rate of aortic dilation and the risk of dissection (Rossi-Foulkes et al.). Elective repair is indicated when the aortic diameter reaches 5.5 cm. Earlier intervention may be indicated in women who desire pregnancy despite the increased risk of pregnancy. Most patients will require a composite graft that contains a prosthetic valve. Long-term results with this procedure are excellent, with 83% survival at 20 years (Gott et al.). The patient described in Case 13 has mild aortic insufficiency on examination. Echocardiography revealed an aortic root dimension of 5.2 cm. She had mitral valve prolapse with elongated leaflets and mild mitral insufficiency. She was advised to have elective aortic root replacement before proceeding with pregnancy.
Rossi-Foulkes R, Roman MJ, Rosen SE, Kramer-Fox R, Ehlers KH, OLoughlin JE, et al. Phenotypic features and impact of -blocker or calcium antagonist therapy on aortic lumen size in the Marfan syndrome. Am J Cardiol. 1999;83:1364-8. PMID: 10235096 Gott VL, Cameron DE, Alejo DE, Greene MarfanPS, Shake JG, Caparrelli DJ, Dietz HC. Aortic root replacement in 271 patients: a 24-year experience. Ann Thorac Surg. 2002;73:438-43. PMID: 11845856
KEYPOINTS
Congenital Heart Disease in the Adult

With the availability of life-saving palliative surgical and nonsurgical interventions, the number of adult patients with congenital heart disease has increased to more than 500,000 in the United States. This section addresses the most common acyanotic and cyanotic lesions. Genetic counseling should be considered in all patients with congenital heart disease (Hoess et al.). Patterns of inheritance are rarely clearly defined. The risk of congenital heart disease in the offspring and siblings of patients is increased. Knowledge of the genetic basis for specific lesions is emerging (Brickner et al.).
Aortic disease is a major source of morbidity and the primary source of mortality in Marfan syndrome. A family history of aortic disease is an important risk factor for dissection. Yearly echocardiography is indicated to follow aortic dimension until it reaches 4.5 cm, when it should be repeated every 6 months. Propranolol has been shown to reduce the rate of dilatation. Calcium channel blockers can be substituted in patients intolerant of -blockers. Elective aortic repair is indicated when the diameter exceeds 5.5 cm, or earlier in women who desire pregnancy.
Hoess K, Goldmuntz E, Pyeritz RE. Genetic counseling for congenital heart disease: new approaches for a new decade. Curr Cardiol Rep. 2002;4:68-75. PMID: 11743925 Brickner ME, Hillis LD, Lange RA. Congenital heart disease in adults. First of two parts. N Engl J Med. 2000;342:256-63. PMID: 10648769

What are the indications for closure of atrial septal defect in the adult? When should device closure be considered as an alternative to surgical closure? What are the indications for closure of a patent foramen ovale?
KEYPOINTS
Atrial Septal Defect

Atrial septal defect is the second most common congenital heart lesion encountered in adults (after bicuspid aortic valve). Atrial septal defects are classified according to location (Figure 18). Ostium secundum defects in the mid portion of the septum account for the majority. Ostium primum defects are in the lower portion of the septum and are associated with abnormalities of the atrioventricular valves. Sinus venosus defects are usually located near the entrance of the superior vena cava and are associated with partial anomalous pulmonary venous drainage. In the absence of pulmonary vascular disease, the shunt direction is left to right, predominantly during diastole, resulting in volume overload of the right ventricle. With advancing age, diminished left ventricular compliance can lead to an increase in the shunt fraction, with consequent right heart
The indication for closure of atrial septal defects and ventricular septal defects is a pulmonary-to-systemic shunt ratio of 1.7:1 or greater, with evidence of right ventricular or left ventricular volume overload, respectively. A patent ductus arteriosus associated with a murmur should be closed even when the shunt is small to reduce the risk of endoarteritis. Percutaneous device closure of atrial septal defects, patent foramen ovale, and patent ductus arteriosus is now possible in most patients. The specific indications for closure of a patent foramen ovale after a cerebral embolic event remain uncertain.
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TA B L E 2 9 Major and Minor Manifestations of Marfan Syndrome
Skeletal findings Major (4 of 8 required) Upper to lower segment ratio 0.85 (normal, 0.93) Arm span > height (ratio >1.05) Arachnodactyly of fingers and toes with positive wrist and thumb signs Scoliosis >20 or kyphosis Pectus carinatum or pectus excavaatum requiring surgery Reduced extension of elbows (<170) Medial displacement of medial malleolus, causing pes planus Protrusio acetabulae Minor Dolichostenomelia (limbs disproportionately large for trunk size) Dolichocephaly Tall stature (>95th percentile) Generalized joint hypermobility Osteopenia or osteoporosis Cardiovascular findings Major (1 of 2 required) Dilatation of the aorta involving sinuses of Valsalva Dissecting aortic aneurysm Minor Mitral valve prolapse Mitral regurgitation Left ventricular dilatation Dilation of the pulmonary artery (<40 years of age) Calcification of the mitral annulus (<40 years of age) Dilation or dissection of descending aorta (<50 years of age) Tricuspid valve prolapse Ocular findings Major Ectopia lentis Secondary myopia, retinal detachment, glaucoma, and iritis Minor Myopia Flat cornea Increased axial globe length Other Major Dural ectasia affecting the lumbosacral spinal canal Minor Spontaneous pneumothorax Apical blebs Cutaneous striae distensae Recurrent or incisional hernias
Reproduced with permission from: Shapiro, JR, Wright, MJ. The Marfan Syndrome. In UpToDate, Rose BD (Ed), UpToDate, Inc., Wellesley, MA 2003.
failure. Atrial fibrillation is common in older adults with atrial septal defects. The frequency of atrial fibrillation and the potential for paradoxical embolism lead to a high incidence of embolic stroke.
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SVC Sinus venosus ASD Ostium secundum ASD Ostium primum ASD
FIGURE 18. Atrial septal defects (ASD).

IVC = inferior vena cava; FO = fossa ovalis; RV = right atrium; SVC = superior vena cava; TV = tricuspid valve
TV Interatrial septum viewed from right atrium FO
RV IVC
Case 14 A 42-year-old fireman is referred for routine physical examination. He has no specific medical symptoms. His medical history is significant only in that he was told he had mitral valve prolapse at a sports physical examination in high school when he tried out for the football team. He played during all four years of high school and now exercises for 1 hour daily, by running 3 to 4 miles and lifting weights up to 150 lb. He has used amoxicillin for antibiotic prophylaxis before dental work, on the basis of his diagnosis of mitral valve prolapse. On physical examination, the patient is fit and well developed. Blood pressure is 124/70 mm Hg, pulse rate is 70/min and regular. Jugulovenous pressure is estimated at 5 cm. The lungs are clear, and there are no thoracic abnormalities. Cardiac examination reveals at prominent right parasternal impulse, nondiplaced apical impulse, normal S1, fixed split S2, 2/6 early peaking systolic murmur at the upper left sternal border, and no diastolic murmur. Case 14 typifies the presentation with a systolic flow murmur at the upper left sternal border and the pathognomonic fixed split S2. In the majority of cases, electrocardiography shows an incomplete right bundle-branch block and rightaxis deviation consistent with the right ventricular overload. Chest radiography shows right ventricular prominence on the lateral film and pulmonary plethora. The diagnosis is suspected on transthoracic echocardiography in the presence of right ventricular enlargement and increased pulmonary flow. Color flow Doppler imaging may demonstrate flow across the interatrial septum. However, the left-sided appearance of agitated saline after intravenous injection is more definitive. Transesophageal echocardiography provides clear anatomic definition, which is important for sizing the defect and determining suitability for percutaneous closure. The indications for closing an atrial septal defect include a systemic-topulmonary shunt ratio of 1.7:1 or greater or evidence of right ventricular volume overload (Figure 19). In a recent prospective study (Attie et al.), 473 patients with atrial septal defects, a systemic-to-pulmonary shunt ratio of 1.7:1 or greater, and a pulmonary artery systolic pressure less than 70 mm Hg were randomized to medical or surgical therapy. The primary end point, a composite index of major cardiovascular events (cardiac-related death, heart failure, pul-
Attie F, Rosas M, Granados N, Zabal C, Buendia A, Calderon J. Surgical treatment for secundum atrial septal defects in patients >40 years old. A randomized clinical trial. J Am Coll Cardiol. 2001;38:2035-42. PMID: 11738312
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Morris CD, Reller MD, Menashe VD. Thirty-year incidence of infective endocarditis after surgery for congenital heart defect. JAMA. 1998;279:599-603. PMID: 9486754
monary or systemic embolism, recurrent pulmonary infection, sustained ventricular tachyarrhythmia, and progression of pulmonary hypertension) was less frequent in the surgically treated group (11.1% vs. 20.7%). The improved outcome was mainly due to a reduced incidence of pneumonia and fewer sudden deaths at a mean follow-up of 7.3 years. Risk factors for primary events were age and mean pulmonary artery pressure of greater than 35 mm Hg. Percutaneous devices for atrial septal defect closure were recently approved by the U.S. Food and Drug Administration. Device closure is feasible in most ostium secundum atrial septal defects. In the hands of experienced operators, it can be performed with low risk. Surgical closure is required for ostium primum and sinus venosus atrial septal defects. No data are available comparing device closure to surgical closure. Before repair, prophylaxis for endocarditis is not indicated for atrial septal defects unless there are associated valvular or other congenital abnormalities (Morris et al.). Following atrial septal defect closure, antibiotic prophylaxis for bacterial endocarditis is recommended for the first 6 months until the patch or device becomes endothelialized, then indefinitely if there are residual abnormalities.
Patent Foramen Ovale

In the fetus, the foramen ovale permits oxygenated placental blood to reach the systemic circulation. In approximately 20% of people, this interatrial communication persists. They vary in size and may be associated with redundancy of the interatrial septum that leads to an interatrial septal aneurysm. They can be diagnosed on contrast echocardiography by demonstration of right-to-left shunting during a maneuver that increases right atrial pressure sufficiently to force the flap valve open, such as cough or release of the Valsalva maneuver. Because shunting is rarely present in the basal state, there is usually no right ventricular enlargement. The major clinical significance of a patent foramen ovale is its association with cerebrovascular events due to paradoxical embolization. A recent study suggested that among patients taking aspirin, recurrent embolic events are far more common in patients with interatrial septal aneurysm and
ASD Vena cavae RA LA Pulmonary veins
Qshunt
FIGURE 19. Indications for closure of an atrial septal defect (ASD). In the presence of a left-to-right shunt, the pulmonary flow (Qp) is equal to the systemic flow (Qs) plus the flow across the defect (Q shunt). The shunt is considered hemodynamically significant when the shunt flow is more than 70% of systemic flow. In that case, the ratio of pulmonary to systemic flow (Qp:Qs) would be 1.7:1.
LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle
RV
LV
Pulmonary artery
Qp
Qs
Aorta
86
patent foramen ovale than in those with patent foramen ovale alone (Mas et al.). The optimal treatment for patients with patent foramen ovale and stroke is as yet undetermined, although device closure is now feasible (Hung et al.). Other clinical syndromes associated with patent foramen ovale include orthodeoxiaplatypnea (cyanosis in the upright position), severe decompression illness in divers, and hypoxemia associated with right heart failure (for example, after right ventricular infarction). Occasionally, patients with these conditions require surgical or percutaneous closure. It was suggested that migraine episodes may decrease or resolve after closure of a patent foramen ovale, but this observation requires further study before its clinical significance is known (Wilmshurst et al.). Likewise, use of prophylactic antithrombotic therapy in asymptomatic patients with the incidental finding of patent foramen ovale or an atrial septal defect too small for closure is unresolved (Albers et al.). Low-dose aspirin therapy is considered optional, as no prospective data support its use.
Mas JL, Arquizan C, Lamy C, Zuber M, Cabanes L, Derumeaux G, Coste J. Recurrent cerebrovascular events associated with patent foramen ovale, atrial septal aneurysm, or both. N Engl J Med. 2001;345:1740-6. PMID: 11742048 Hung J, Landzberg MJ, Jenkins KJ, King ME, Lock JE, Palacios IF, Lang P. Closure of patent foramen ovale for paradoxical emboli: intermediate-term risk of recurrent neurological events following transcatheter device placement. J Am Coll Cardiol. 2000;35:1311-6. PMID: 10758974 Wilmshurst PT, Nightingale S, Walsh KP, Morrison WL. Effect on migraine of closure of cardiac right-to-left shunts to prevent recurrence of decompression illness or stroke or for haemodynamic reasons. Lancet. 2000;356:1648-51. PMID: 11089825 Albers GW, Amarenco P, Easton JD, Sacco RL, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke. Chest. 2001;119:300S-320S. PMID: 11157656
Other Acyanotic Congenital Heart Lesions

The most common congenital anomaly is the bicuspid aortic valve. It is more common in men and can progress to hemodynamically significant aortic insufficiency or stenosis. This lesion should be suspected in the presence of an early systolic ejection click associated with an outflow murmur. Early recognition and diagnosis by echocardiography are important because of the relatively high associated risk of endocarditis. Indications for surgical intervention are similar to those for acquired aortic valve disease and are covered in that section. The aortopathy associated with bicuspid aortic valve poses an added risk of aortic dissection in these patients. Bicuspid aortic valve and coarctation of the aorta are strongly associated, and up to 6% of patients with the former condition also have coarctation of the aorta. Screening for coarctation should be performed at the time of transthoracic echocardiography with a suprasternal notch view. Simultaneous palpation of the brachial and femoral pulses may reveal a pulse delay in the femoral artery. Familial clustering of bicuspid aortic valve suggests that genetic counseling is warranted. In the acyanotic adult with a ventricular septal defect, the shunt is usually small. Larger ventricular septal defects usually present in childhood, with congestive heart failure or pulmonary hypertension. The most common location in adults is the perimembranous region near the tricuspid valve. A loud holosystolic murmur is typically associated with a small defect and normal pulmonary vascular resistance. The natural history of unoperated patients with small ventricular septal defects and no clear surgical indications during childhood (systemic-to-pulmonary shunt ratio <1.5:1, normal pulmonary vascular resistance, and no significant aortic insufficiency) is excellent, with 95% event-free survival at 8 years reported in a recent series. The incidence of endocarditis was 1.8%, and there were no deaths (Gabriel et al.). Closure of ventricular septal defects is not indicated for prevention of endocarditis alone. In adulthood, indications for closure include a large shunt fraction with a systemic-to-pulmonary shunt ratio of 1.7:1.0 or greater or left ventricular volume overload. Left ventricular volume overload occurs because the shunt is primarily confined to systole and the right ventricle never serves as a reservoir for the shunted blood. The left ventricular diastolic volume is increased because the stroke volume includes both forward flow and shunted flow. The physical examination in a patient with a hemodynamically significant ventricular septal defect may reveal a displaced apical impulse, a mitral diastolic rumble, and an S3, even in the absence of heart failure. There is usually echocardiographic evidence of left ventricular hypertrophy. The presence of right ventricular hypertrophy suggests pulmonary hypertension or associated pulmonary valve stenosis.
Gabriel HM, Heger M, Innerhofer P, Zehetgruber M, Mundigler G, Wimmer M, et al. Long-term outcome of patients with ventricular septal defect considered not to require surgical closure during childhood. J Am Coll Cardiol. 2002;39:1066-71. PMID: 11897452
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Cyanotic Congenital Heart Disease
Rao PS. Long-term follow-up results after balloon dilatation of pulmonic stenosis, aortic stenosis, and coarctation of the aorta: a review. Prog Cardiovasc Dis. 1999;42:59-74. PMID: 10505493 Hamdan MA, Maheshwari S, Fahey JT, Hellenbrand WE. Endovascular stents for coarctation of the aorta: initial results and intermediate-term follow-up. J Am Coll Cardiol. 2001;38:1518-23. PMID: 11691533
In the acyanotic adult patient with a patent ductus arteriosus, the communication is usually small. The murmur is usually soft and confined to systole, and the diagnosis is made by echocardiography. Most adults with large patent ductus arteriosus have pulmonary vascular disease with Eisenmengers physiology and are not candidates for surgery. In these patients, the physical examination is dominated by signs of pulmonary hypertension with cyanosis and clubbing in the toes, but not in the fingers. The murmur across the patent ductus arteriosus is no longer present. Occasionally, elevated pulmonary pressures are due to increased pulmonary flow, and the resistance is low enough to permit closure. The extracardiac left-to-right shunt at the level of the great vessels results in a volume overload to the left ventricle. Similar to patients with large ventricular septal defects, there is evidence of left ventricular hypertrophy on physical examination and echocardiography. In these patients, the murmur is usually loud and continuous. Percutaneous closure with a coil or device is now possible in many patients. Most experts agree that closure is indicated if the patent ductus arteriosus is associated with a murmur to prevent the complication of endarteritis independent of the magnitude of the shunt. Closure of a silent patent ductus arteriosus, one that is incidentally found on echocardiography, remains controversial. Valvular pulmonary stenosis is relatively uncommon in adults. When severe, it may present with exercise intolerance. Right-heart failure only occurs in the very late stages of the disease. Clinical hallmarks are a systolic ejection click and systolic murmur over the second left intercostal space. Echocardiography shows right ventricular hypertrophy and right-axis deviation. Indications for treatment include a peak resting gradient greater than 40 mm Hg. Intervention should also be considered in patients with exercise-induced gradients greater than 50 mm Hg and echocardiographic evidence of right ventricular hypertrophy, independent of severity of the resting gradient. Echocardiography is usually adequate for diagnosis. Percutaneous balloon valvuloplasty can be performed by experienced operators, with excellent long-term results in adults (Rao). Coarctation of the aorta should be excluded in young adults who present with hypertension. Physical examination may reveal a radial-to-femoral pulse delay and lower blood pressure in the legs. Chest radiography may show the classic 3 sign and rib notching due to dilated intercostal arteries that provide collateral blood flow to the descending aorta. Doppler echocardiography can define the gradient across the area of coarctation, whereas magnetic resonance angiography provides excellent anatomic definition that can guide percutaneous or surgical repair. Repair is usually indicated when there is proximal hypertension and a gradient exceeding 20 mm Hg. A discrete coarctation is usually amenable to percutaneous repair, while longer segments may require surgical intervention. Small series of properly selected adult patients undergoing percutaneous repair using angioplasty with an intravascular stent have demonstrated a high rate of success and low complication rate (Hamdan et al.). Antibiotic prophylaxis is indicated for almost all patients with unoperated congenital heart disease. An exception is an isolated atrial septal defect.

What are the indications for phlebotomy in patients with cyanotic heart disease? Which cyanotic patients are at risk for stroke? Which patients are at highest risk for complications of endocarditis, heart failure, and arrhythmias after repair of congenital heart disease? Which patients should be followed in a specialized center for adults with congenital heart disease?
88
Case 15 A 35-year-old woman with Downs syndrome and a history of heart disease presented with a 2-day history of nausea and vomiting. Her caretaker claims that she was working daily in a workshop before the recent illness. She has been refusing to eat and has been very lethargic. On examination, blood pressure of is 95/60 mm Hg, pulse rate is 98/min, and temperature is 38 C (100.4 F). She is cyanotic and clubbed. The lungs are clear. Cardiac examination reveals an RV left, a loud P2, and no murmur. The abdomen is soft, and bowel sounds are normal. Laboratory values are as follows: leukocyte count, 14,300/L; hemoglobin, 22 g/dL; hematocrit, 74%; blood urea nitrogen, 32 mg/dL; and serum creatinine, 1.2 mg/dL. Most patients with unoperated cyanotic heart disease have developed Eisenmengers syndrome, severe pulmonary vascular disease due to a lesion originally associated with a large left-to-right shunt (atrial septal defect, patent ductus arteriosus or ventricular septal defect). With the development of pulmonary hypertension, shunt reversal occurs, leading to cyanosis. Secondary erythrocytosis is compensatory and usually not associated with symptoms. The hyperviscosity syndrome can develop when the hematocrit is greater than 65 mg/dL; however, phlebotomy is indicated only to treat symptoms. Phlebotomy in an asymptomatic patient can lead to iron depletion and a decompensated state. Iron deficiency, rather than the absolute hemoglobin level, in such patients is associated with stroke. When necessary, phlebotomy should be followed by isovolumic saline repletion to avoid hypovolemia. In the presence of heart failure, 5% dextrose in water should be used. In Case 15, the elevated hematocrit is due to volume depletion; volume repletion is indicated, not phlebotomy. Pregnancy is strictly contraindicated in patients with Eisenmengers syndrome. The maternal mortality rate exceeds 50%, with death usually occurring in the early post-partum period. No evidence indicates that cesarean section offers an advantage over normal vaginal delivery. Most other categories of patients with cyanotic congenital heart disease have had palliative surgery in childhood. These patients remain at high risk for endocarditis, arrhythmias, sudden death, and heart failure. Pregnancy is usually well tolerated in the absence of overt heart failure, uncontrolled arrhythmias, and pulmonary vascular disease, as long as the patient is in functional class I. All cyanotic patients should be followed in conjunction with a center specializing in adult congenital heart disease (32nd Bethesda Conference). Tetralogy of Fallot is the most common form of cyanotic congenital heart disease. Occasionally, a patient with only a palliative aortopulmonary shunt procedure is encountered. Most adults have had a total intracardiac repair, with closure of the ventricular septal defect and relief of the pulmonary stenosis. Pulmonary valve insufficiency leading to right-heart dilation is common. The appropriate timing for pulmonary valve replacement remains uncertain. Recent studies suggest that the yearly mortality rate increases after 25 years, predominantly because of sudden death. A QRS duration greater than 180 ms seems to be the best predictor of sudden death. Because of the apparent interaction between progressive right-heart dilation and lengthening of the QRS, there is general agreement that pulmonary valve replacement is indicated when the QRS exceeds 180 ms. Most adult patients with transposition of the great arteries have had an atrial switch procedure (Mustard or Senning operation). The morphologic right ventricle continues to support the systemic circulation and is subject to failure. Survival is highly dependent on right ventricular function. The sick sinus syn-
Summary of recommendationscare of the adult with congenital heart disease. J Am Coll Cardiol. 2001;37:1167-9. PMID: 11300417
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Clinical Evaluation
KEYPOINTS
In patients with cyanotic heart disease, phlebotomy should be used only to treat hyperviscosity symptoms when the hematocrit is greater than 65 mg/dL; iron deficiency should be avoided. The risk of endocarditis is substantial except in operated patients with pulmonary stenosis, atrial septal defect, ventricular septal defect, and patent ductus arteriosus. If residual ventricular septal defect or patent ductus arteriosus leaks are present, the risk persists postoperatively. Adult patients with congenital heart disease, except those with operated pulmonary stenosis, atrial septal defect, ventricular septal defect and patent ductus arteriosus, should be followed in conjunction with a specialized center for adult congenital heart disease.
drome and atrial arrhythmias will frequently require pacemaker insertion, radiofrequency ablation, or use of antiarrhythmic drugs. Patients with rarer forms of cyanotic heart disease and a pulmonary circulation protected from vascular disease may remain surgical candidates as adults.
Peripheral Arterial Disease

Peripheral arterial disease affects approximately 12% of U.S. adults and is equally prevalent in men and women. More than half of patients with peripheral arterial disease are asymptomatic and do not have symptoms of claudication on exertion or limb ischemia at rest. Approximately one third of patients have claudication (pain in the legs on walking, primarily in the calves, that does not go away with continued walking and is relieved by rest). Less than 5% to 10% of patients have critical leg ischemia (ischemic pain in the distal foot, ischemic ulceration, or gangrene); risk of limb loss in these patients is substantial.
Clinical Evaluation
What are the clinical characteristics of peripheral arterial disease? What is the natural history of peripheral arterial disease in terms of mortality risk and symptoms? On what basis can clinicians recognize and screen for peripheral arterial disease?
KEYPOINTS
The prevalence of peripheral arterial disease defined by the ankle/brachial index (values <0.90) is 12% among adults but increases to more than 20% among elderly persons. More than half of patients with peripheral arterial disease do not have classic symptoms of claudication, approximately 30% to 40% have claudication during exertion, and less than 10% experience symptoms of critical leg ischemia (pain in the distal foot at rest and ischemic ulceration). The history and physical examination can suggest the presence of peripheral arterial disease, but confirmation requires measurement of the ankle brachial index. An index less than 0.90 is considered diagnostic for peripheral arterial disease. Patients with peripheral arterial disease, whether symptomatic or not, are at high risk for myocardial infarction, stroke, and death. This risk is increased sixfold compared with persons without peripheral arterial disease. In contrast to the severe natural history of the systemic disease, symptoms of claudication remain stable over 5 years. These patients are at low risk of limb loss.
Palpation of arterial pulses, including the brachial, femoral, and pedal arteries, should be performed in all patients. Absence of a femoral pulse indicates inflow disease of the aorta or iliac arteries. Patients with a palpable femoral pulse but no pedal pulse have disease confined to the arteries in the leg. Any patient with reduced or absent pulses in the leg should be suspected of having peripheral arterial disease and should have ankle blood pressure measured. Patients with critical leg ischemia develop pain in the distal foot at rest that can progress to ischemic ulceration and gangrene. The ulcers are painful, do not bleed when manipulated, and often have a dark necrotic base. Physical examination reveals pallor of the foot on elevation because of inadequate arterial pressure and flow. When the foot is dependent, it becomes red because of chronic dilation of the peripheral vascular bed distal to server and multiple occlusions. The foot may be edematous from being kept continually dependent in an attempt to relieve the ischemic pain. Recent studies have evaluated the diagnostic accuracy of the history (intermittent claudication) and examination (absent pulses) for periphereal artery disease as objectively diagnosed by the anklebrachial index. A history of leg pain on exertion (typical or atypical claudication) significantly underdiagnoses periphereal arterial disease, and a pulse abnormality overestimates disease prevalence.
Natural History
In patients with claudication, symptoms remain relatively stable over 5 years, in that only 25% will develop worsening claudication and 4% will undergo amputation. Despite this relatively benign natural history, symptomatic patients have severely limited walking ability and functional capacity. In contrast, patients with peripheral arterial disease have a threefold increased risk of all-cause mortality and a sixfold increased risk of cardiovascular mortality. The mortality risk is approximately equal between men and women and is increased even in asymptomatic patients. In addition, the severity of peripheral arterial disease in the legs is closely associated with the risk of myocardial infarction, ischemic stroke, and vascular death. The lower the anklebrachial index, the greater the risk of cardiovascular events. Patients with critical leg ischemia have an annual mortality rate of 25%.
90
Clinical Evaluation
AnkleBrachial Index
Patients who meet the criteria in Figure 20 should be considered at risk for peripheral arterial disease. These patients should have measurement of systolic blood pressure in the arms and ankles by using a simple, continuous-wave Doppler. In each ankle, pressures are obtained in the posterior tibial and dorsalis pedis arteries; those values are divided by the value obtained from the arm with the highest pressure. In healthy persons, the anklebrachial index is greater than 1.00; ratios of 0.90 or less are considered diagnostic of peripheral arterial disease. When performed in primary care office sites, this simple test detected significant peripheral arterial disease in 29% of patients older than 70 years of age or those 50 to 69 years of age who had diabetes or smoked. In patients considered for revascularization, further disease localization can be performed noninvasively in a vascular laboratory.
Age 5069 years and smoking or diabetes Age 70 years Leg symptoms with exertion Abnormal leg vascular examination, or ischemia Coronary, carotid, or renal arterial disease
Measure ABI
>1.30
0.911.30
0.90
Vascular laboratory: PVR Toe pressure Duplex imaging
Claudication symptoms ABI treadmill test
Normal postexercise ABI: no PAD
Decreased postexercise ABI
Normal results: no PAD
Abnormal results
Evaluate other causes of leg symptoms

FIGURE 20. Evaluation of patients in whom peripheral arterial disease (PAD) is suspected. Patients should be evaluated for PAD if they if they are at increased risk from age or presence of atherosclerotic risk factors, have leg symptoms on exertion, or have distal limb ulceration for which history and examination do not provide an obvious explanation.
ABI = anklebrachial index; PVR = pulse volume recordings Reprinted with permission from: Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21.
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Management of Atherosclerotic Risk Factors
Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg. 2000;31:S1-S296. PMID: 10666287 Hirsch AT, Criqui MH, Treat-Jacobson D, Regensteiner JG, Creager MA, Olin JW, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:1317-24. PMID: 11560536 MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebocontrolled trial. Lancet. 2002;360:7-22. PMID: 12114036 The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:2413-46. PMID: 9385294 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-53. PMID: 10639539

What are the risk factors for peripheral arterial disease? What medications reduce the risk of ischemic events in peripheral arterial disease? How should symptomatic patients be treated for claudication and critical leg ischemia?
KEYPOINTS
The risk factors for peripheral arterial disease are similar to those for coronary artery disease. All patients require aggressive risk modification by smoking cessation, decreasing of glucose levels, reduction of low-density lipoprotein cholesterol level to less than 100 mg/dL, and control of blood pressure. All patients with peripheral arterial disease should receive antiplatelet therapy, including aspirin or clopidogrel. Medical therapy for claudication is most effectively accomplished with a supervised exercise program or medications, such as cilostazol. Angioplasty is most effective for patients with disease of the iliac artery. This procedure may be indicated in patients with severe claudication not responsive to medical therapy or those with critical leg ischemia. Peripheral vascular surgery is required for patients with critical leg ischemia.
The major risk factors for peripheral arterial disease include increasing age after 40 years, cigarette smoking, and diabetes mellitus. Hyperlipidemia, hypertension and hyperhomocysteinemia are also important risk factors. Given these risk factors, the systemic nature of atherosclerosis, and the high risk for ischemic events, patients with peripheral arterial disease should be considered candidates for secondary prevention strategies that include aggressive risk factor modification and use of antiplatelet drugs. Observational studies have suggested that smoking cessation will slow the progression to critical leg ischemia and reduce the risk of myocardial infarction and vascular death. Smoking cessation is also critical to the success of angioplasty or vascular surgery in terms of maintaining patency. In patients with diabetes, intensive blood glucose control prevents microvascular complications, but the benefits on arterial disease are less certain. Several studies have shown that intensive therapy was associated with a trend toward fewer cardiovascular events, but the risk of peripheral arterial disease was not reduced, because patients with peripheral arterial disease received less intensive treatment for lipid disorder and hypertension (Dormandy and Rutherford; Hirsch et al.). Lipid-lowering therapy has been shown to reduce the risk for peripheral arterial disease and symptoms of claudication. The Heart Protection Study demonstrated that use of a statin in patients with peripheral arterial disease (with or without prior cardiac disease) reduced the risk of subsequent myocardial infarction, stroke, and vascular death (MRC/BHF Heart Protection Study). The current recommendation for patients with peripheral arterial disease is to achieve a low-density lipoprotein cholesterol level less than 100 mg/dL and a triglyceride level less than 150 mg/dL. A statin should be given as initial therapy. Niacin is also an important drug because it increases serum high-density cholesterol concentrations, decreases serum triglyceride concentrations, and does not worsen glucose metabolism in these patients. Hypertension should be treated according to the guidelines of the Sixth Joint National Committee, taking into account that patients with peripheral arterial disease are at particularly high risk for cardiovascular events (Sixth Report of the Joint National Committee). Data from the Heart Outcomes Prevention Evaluation Study suggest that angiotensin-converting enzyme inhibitors are particularly beneficial in patients with peripheral arterial disease to prevent myocardial infarction, stroke, and death and to decrease blood pressure (Yusuf et al.). -Adrenergic antagonist drugs were once thought to worsen symptoms of claudication. However, a meta-analysis and a critical review of several randomized, controlled studies concluded that -adrenergic antagonists are safe in patients with peripheral arterial disease. -Blockers should also be considered in patients undergoing vascular surgery, since these drugs reduce the preoperative risk of cardiovascular events.
Antiplatelet Therapy
In patients with cardiovascular disease, antiplatelet drugs reduce the risk of subsequent nonfatal myocardial infarction, ischemic stroke, and vascular death. These conclusions are based primarily on the meta-analyses conducted by the Antiplatelet Trialists Collaboration of antiplatelet drug therapy. Among patients with peripheral arterial disease, antiplatelet therapy was associated with 92
a statistically significant 23% reduction in the likelihood of cardiovascular events (Collaborative meta-analysis of randomised trials of antiplatelet therapy). In terms of drug selection, aspirin is approved for secondary prevention in patients with a history of cardiac disease and ischemic stroke. Among patients with peripheral arterial disease, aspirin was associated with a nonsignificant 18% reduction in the likelihood of events. Although only a trend toward benefit was found, the American College of Chest Physicians recommends aspirin at dosages of 81 to 325 mg/d in patients with peripheral arterial disease. Clopidogrel, a thienopyridine drug, may be superior to aspirin in peripheral arterial disease on the basis of the results of the Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study. Clopidogrel is the only antiplatelet agent that is approved by the U.S. Food and Drug Administration for use in patients with peripheral arterial disease who do not also have a history of myocardial infarction or ischemic stroke (CAPRIE Steering Committee).
Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71-86. PMID:11786451 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329-39. PMID: 8918275 Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21. PMID: 11372014 Stewart KJ, Hiatt WR, Regensteiner JG, Hirsch AT. Exercise training for claudication. N Engl J Med. 2002;347:1941-51. PMID: 12477945 Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med. 2000;109:523-30. PMID: 11063952
Medical Treatment of Claudication

Patients with claudication have marked impairment in exercise performance, with peak oxygen consumption that is 50% of the age-predicted value; this finding is similar to that in patients with New York Heart Association class III heart failure. Thus, the goals of therapy for claudication are to relieve exertional symptoms, improve walking capacity, and increase quality of life (Figure 21). These goals are similar for patients with critical leg ischemia, with the additional desired outcomes of relieving ischemic rest pain, healing ischemic ulceration, and preventing limb loss (Hiatt). Patients with claudication should first consider a formal exercise training program. Exercise improves not only treadmill walking distance but also quality of life and community-based functional capacity. Furthermore, an exercise program for claudication results in clinical benefits similar to those of surgical bypass and possibly greater benefits than angioplasty. The best results require a motivated patient in a supervised setting, typically modeled after cardiac rehabilitation. A reimbursement code is now available for these programs (Stewart et al.). Drug therapy can also be considered for claudication. Pentoxifylline is approved by the U.S. Food and Drug Administration, but most patients may not notice an improvement in walking distance, and the drug has been shown in multiple randomized, controlled studies to be no more effective than placebo. Cilostazol is also approved, and several randomized, controlled trials have documented a benefit in terms of walking distance and quality of life (Dawson et al.). Cilostazol cannot be recommended in patients with claudication who also have heart failure. This black box warning was required by the U.S. Food and Drug Administration because of the known association of this class of drugs with excess mortality in patients with heart failure.
Indications and Results of Angioplasty and Vascular Surgery

Patients with critical leg ischemia should be considered for vascular surgery or angioplasty, which is necessary to heal ischemic lesions, relieve ischemic rest pain, and prevent amputation. Angioplasty can also be considered to treat claudication. Angioplasty guidelines emphasize that more proximal lesions have better patency rates and durability than do more distal lesions. Below the inguinal ligament, rates of initial success and long-term patency have been less well studied but are not as good as for more proximal lesions. Surgery is principally used to treat severe critical leg ischemia rather than claudication because of the associated morbidity and mortality of surgery, the relatively benign nat-
93
Assess cardiovascular risk factors
Assess claudication severity: Treadmill ACD and ICD SF-36 and WIQ
Critical leg ischemia
Risk factor modification: Smoking cessation LDL cholesterol <100 mg/dL HbA1c <7.0% BP <130/85 mm Hg ACE inhibition Antiplatelet therapy Aspirin or clopidogrel
Claudication therapy: Supervised exercise Cilostazol
Improved symptoms
Symptoms deteriorate
Continue
Localize the lesion: Hemodynamic localization Duplex ultrasonography MRA Conventional angiography
Revascularization Angioplasty Bypass surgery
FIGURE 21. Treatment of peripheral arterial disease. All patients with peripheral arterial disease, regardless of symptom severity, should undergo risk factor modification to achieve the listed treatment goals and receive antiplatelet therapy with aspirin or clopidogrel. Angiotensin-converting-enzyme (ACE) inhibitors should be considered to help prevent ischemic events independent of blood pressure (BP) lowering. Treadmill testing can be considered to define changes in the absolute claudication distance (ACD) and the initial claudication distance (ICD) before and after therapy. Questionnaires, including the Medical Outcomes Short Form 36 (SF-36) and the Walking Impairment Questionnaire (WIQ), can provide information on changes in functional status and quality of life with claudication therapy. Patients who do not improve and remain disabled and those have worsening symptoms should have additional localization of the occlusive lesions to plan endovascular or surgical intervention.
HbA1c = hemoglobin A1c; LDL = low-density lipoprotein; MRA = magnetic resonance angiography Reprinted with permission from: Hiatt WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21.
94
Valve Disease in Pregnancy, Including Anticoagulation
ural history of claudication, and the efficacy of medical (particularly exercise) therapies. In aortoiliac disease, prosthetic materials are usually implanted. Aortoiliac surgery is associated with an average mortality rate of 3% and morbidity rate of 8%. In patients with femoropopliteal disease, the best conduit is saphenous vein. Femoropopliteal surgery with vein bypass is associated with a mortality rate of 2%, a morbidity rate of 5% to 10%, and a 5-year patency rate of 70% to 80%. The use of prosthetic material (which is required if a vein is not available) reduces 5-year patency rates to 50%. Distal femorotibial operations for limb salvage have similar morbidity and mortality rate as does femoropopliteal surgery but slightly lower 5-year patency rates of 50% to 60%.
Pregnancy and Cardiovascular Disease

Approximately 2% of pregnancies occur in women with heart disease. Congenital heart disease is the predominant form of heart disease among pregnant women in developed countries, whereas rheumatic heart disease predominates in developing countries. Heart disease does not preclude successful pregnancy, but the risk to mother and fetus is increased and requires special management.

Which valve lesions are poorly tolerated in pregnancy? What are the risks of and options for anticoagulation for a woman with a mechanical heart valve who wishes to become pregnant?
KEYPOINTS
During normal pregnancy, physical findings may mimic heart disease. The pulmonic S2 may be prominent, and there often is persistent splitting of the second heart sound. S3 is audible in more than 80% of normal pregnant women. An early peaking ejection systolic murmur is audible in more than 90% of normal pregnant women and is caused by a pulmonary outflow murmur (Figure 22). Abnormal physical findings include S4, a loud (3/6) systolic murmur, and a diastolic murmur or fixed splitting of S2. Because of the blood volume expansion and resultant increase in stroke volume and cardiac output during pregnancy, fixed obstructive cardiac lesions, particularly left-sided obstructive lesions (such as mitral and aortic valve stenosis), generally are poorly tolerated during pregnancy. In contrast, regurgitant valve lesions are relatively well tolerated because of the decrease in systemic vascular resistance. The effect of pregnancy on a patient with valve disease depends on the effect of the specific valve lesion on ventricular function and pulmonary artery pressures and on the New York Heart Association (NYHA) functional class (Hameed et al.).
Normal physical findings during pregnancy may be misinterpreted as abnormal. Cardiac output increases by 30% to 50% during normal pregnancy and to about 80% above baseline during labor and delivery. Use of warfarin during the first trimester of pregnancy is associated with an increased risk of miscarriage and warfarin embryopathy, but it may be the preferred method of anticoagulation for patients with older mechanical mitral prostheses, particularly if the warfarin dose is low. Vaginal delivery is the preferred mode of delivery in most women with heart disease; however, cesarean delivery should be performed if labor occurs during warfarin anticoagulation because of the risk of fetal intracranial hemorrhage.
Percutaneous Valve Intervention

Interventional procedures are effective alternatives to surgery in several cardiac disorders that occur during pregnancy. Preliminary reports are optimistic; however, no large series have reported on the safety of cardiac interventions during pregnancy. Percutaneous mitral commissurotomy is the strategy of choice in pregnant women with severe mitral stenosis whose symptoms cannot be controlled with medication. Marked relief of symptoms and excellent maternal and fetal outcomes have been reported (de Souza et al.). This procedure should be attempted only in centers that have extensive experience with percutaneous mitral procedures and also have surgical backup. Special considerations for balloon valvuloplasty in the gravid state include radiation exposure and pregnancy
Hameed A, Karaalp IS, Tummala PP, Wani OR, Canetti M, Akhter MW, et al. The effect of valvular heart disease on maternal and fetal outcome of pregnancy. J Am Coll Cardiol. 2001;37:893-9. PMID: 11693767 de Souza JA, Martinez EE Jr, Ambrose JA, Alves CM, Born D, Buffolo E, Carvalho AC. Percutaneous balloon mitral valvuloplasty in comparison with open mitral valve commissurotomy for mitral stenosis during pregnancy. J Am Coll Cardiol. 2001;37:900-3. PMID: 11693768
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Estrogens Low-resistance Placental Circulation
Renin
Sympathetic Output
Enlarged Uterus
Ang II Aldo
+
Estrogens, PG, Heat Production Vena caval Obstruction
H2O & Na+ Retention
Vasodilation hCSm, Prl, Epo Systemic Vascular Resistance
Stroke Volume
Plasma Volume
Erythrocytes
Total Blood Volume
Heart rate 30-50% Increase in Cardiac Output
Stroke Volume
Stroke Volume
16
24
32
40
Weeks of Pregnancy
FIGURE 22. Normal hemodynamics of pregnancy.
Aldo = aldosterone; Ang II = angiotensin II; Epo = erythropoietin; hCSm = human chorionic somatomammotropin; PG = prostaglandins; Prl = prolactin Reproduced with permission from: Teerlink JR, Foster E. Valvular heart disease in pregnancy. A contemporary perspective. Cardiol Clin. 1998;16:573-98.
Bhargava B, Agarwal R, Yadav R, Bahl VK, Manchanda SC. Percutaneous balloon aortic valvuloplasty during pregnancy: use of the Inoue balloon and the physiologic antegrade approach. Cathet Cardiovasc Diagn. 1998;45:422-5. PMID: 9863752 Chambers CE, Clark SL. Cardiac surgery during pregnancy. Clin Obstet Gynecol. 1994;37:316-23. PMID: 8033446
outcome. No increase in the incidence of reported congenital malformations or abortions has been reported with fetal radiation exposure of less than 500 cGy, which can be achieved by shielding the gravid uterus and keeping fluoroscopy time to a minimum. Transesophageal echocardiographic guidance has also been used during the procedure to reduce radiation exposure. Percutaneous balloon aortic valvuloplasty has been reported as a safe and effective palliative procedure during pregnancy (Bhargava et al.). Pulmonary balloon valvuloplasty is rarely required during pregnancy but has been reported. These procedures should be considered alternatives to surgery in patients with severe symptomatic nativevalve stenosis identified during pregnancy.
Cardiac Surgery during Pregnancy

Cardiac surgery should be reserved for patients refractory to medical management in whom further delay would prove detrimental to maternal health. Cardiopulmonary bypass can adversely affect both the mother and fetus (Chambers and Clark). High-flow, high-pressure, normothermic perfusion appears safest from a fetal standpoint. Fetal heart rate monitoring is recom-
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mended during cardiopulmonary bypass. When cardiac surgery is necessary during pregnancy, the optimal time is between the 24th and 28th week of pregnancy, and the duration of cardiopulmonary bypass should be kept as short as possible. A multidisciplinary team approach is required to optimize maternal and fetal outcomes. The data on maternal and fetal outcome for cardiac surgery requiring cardiopulmonary bypass are mostly derived from small, single-center series. The maternal mortality rate ranges from 1% to 5%, and fetal mortality rates are 15% to 38%.
Anticoagulation during Pregnancy

Case 16 A 25-year-old woman with a St. Jude mitral prosthesis is in her early first trimester of pregnancy. She is referred for review of recommended anticoagulation options. Hematologic changes that occur during normal pregnancy result in an overall increased risk of thrombosis or embolism. The safety of anticoagulation during pregnancy (Chan et al.) raises serious concerns, including the fact that heparin may not prevent mechanical valve thrombosis and that warfarin can cause embryopathy. In addition, although the data are divergent, accelerated bioprosthesis deterioration has been reported during pregnancy (Salazar et al., 1999).
Prosthetic Heart Valves

The management of patients with mechanical prosthetic valves or other conditions that require anticoagulation during pregnancy poses a therapeutic dilemma because of the competing risks to mother and fetus. Patients should undergo prepregnancy counseling to discuss the risks and benefits to mother and fetus. Data are limited on the safety of various anticoagulation regimens, and controversy persists regarding the best treatment option. The best type of heart valve prosthesis to use in women of childbearing age who require valve replacement is debated. Some data have suggested that premature valve deterioration may occur in bioprosthetic valves during pregnancy, but this has not been documented conclusively or demonstrated experimentally (North et al.). One report suggested that reoperation (required for most young patients with bioprosthetic valves) carries a higher risk of morbidity and mortality than does the risk of anticoagulation during pregnancy. Pregnant women with a mechanical heart valve have approximately a 10% risk for development of prosthetic valve thrombosis or another life-threatening complication. The best management for a pregnant woman who requires anticoagulation is controversial.
Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature. Arch Intern Med. 2000;160:191-6. PMID: 10647757 Salazar E, Espinola N, Roman L, Casanova JM. Effect of pregnancy on the duration of bovine pericardial bioprostheses Am Heart J. 1999;137(4 Pt 1):714-20. PMID: 10097235 North RA, Sadler L, Stewart AW, McCowan LM, Kerr AR, White HD. Long-term survival and valve-related complications in young women with cardiac valve replacements. Circulation. 1999;99:2669-76. PMID: 10338461 Salazar E, Izaguirre R, Verdejo J, Mutchinick O. Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses. J Am Coll Cardiol. 1996;27:1698-703. PMID: 8636556 Elkayam UR. Anticoagulation in pregnant women with prosthetic heart valves: a double jeopardy. J Am Coll Cardiol. 1996;27:1704-6. PMID: 8636557
Heparin
Heparin does not cross the placenta. The primary concern with heparin use is the 12% to 24% incidence of thromboembolic complications, including fatal valve thrombosis, in high-risk pregnant women given subcutaneous unfractionated heparin. The efficacy of adjusted-dose subcutaneous heparin has not been established (Salazar et al., 1996; Elkayam). The heparin dose should be adjusted so that the partial thromboplastin time is at least two to three times the control value 6 hours after the dose is administered. Recent reports have suggested that subcutaneous heparin may not provide sufficient anticoagulation for very high-risk patients (for example, those with caged-ball or tilting-disk mechanical mitral prosthesis) (Figure 23).
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FIGURE 23. Anticoagulation options during pregnancy.

PTT = partial thromboplastin time
Current Recommendations
First Trimester Early warfarin cessation Subcutaneous heparin PTT >2.5 times control OR Continue warfarin High-risk patient Informed consent Dose <5 mg/day
Second Trimester Warfarin Treatment of choice INR adjusted
Third Trimester Discontinue warfarin 36-38 weeks Start IV heparin Stop peripartum Resume heparin 4 hr after delivery
Prolonged heparin therapy (intravenous or subcutaneous) can result in thrombocytopenia, osteoporosis, and alopecia. Erratic absorption of subcutaneously delivered heparin may occur, and frequent monitoring of the partial thromboplastin time to ensure therapeutic anticoagulation is mandatory.
Warfarin
Because warfarin has a low molecular weight, it crosses the placenta and results in fetal anticoagulation. The effect of warfarin on the fetus is greater than that on the mother because of reduced vitamin Kdependent factors in the fetal liver. Fetal anticoagulation increases the risk for spontaneous abortion, prematurity, fetal deformity, and stillbirth. Retroplacental hemorrhage and fetal intracranial hemorrhage are additional risks to the fetus. Historic reports describe a 30% risk of embryopathy with administration of warfarin during the first trimester. More recent data suggest the incidence of warfarin embryopathy to be between 4% and 10%. The maternal dose of warfarin during the first trimester appears to be important. The risk of warfarin embryopathy appears to be very low with a warfarin dose less than 5 mg/d (Vitale et al.). The risk is highest if exposure occurs during the 6th to 12th week of gestation. Warfarin embryopathy results in bone and cartilaginous abnormalities with chondrodysplasia, nasal hypoplasia optic atrophy, blindness, mental retardation, and seizures. Warfarin does not enter breast milk and, thus, can be administered safely to women who breast-feed their infants.
Vitale N, De Feo M, De Santo LS, Pollice A, Tedesco N, Cotrufo M. Dose-dependent fetal complications of warfarin in pregnant women with mechanical heart valves. J Am Coll Cardiol. 1999;33:1637-41. PMID: 10334435 Bonow RO, Carabello B, de Leon AC Jr, Edmunds LH Jr, Fedderly BJ, Freed MD, et al. Guidelines for the management of patients with valvular heart disease: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Valvular Heart Disease). Circulation. 1998;98:1949-84. PMID: 9799219
Anticoagulation Management during Pregnancy

The American Heart Association and American College of Cardiology provided recommendations regarding anticoagulation during pregnancy (Bonow et al.). For patients with high-risk prostheses or prior thromboembolic events, continuous intravenous heparin during the first trimester or continuation of warfarin and aspirin are considered the treatment options of choice. Subcutaneous doseadjusted heparin with a partial thromboplastin time two to three times the control value is considered a less safe regimen. In the United States, owing to the risk of embryopathy, informed consent should be obtained if warfarin is used during the first trimester of pregnancy. Warfarin is the anticoagulation agent of choice for patients during the second trimester of pregnancy. The warfarin dose should be adjusted to the international normalized ratio.
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Cardiomyopathy during Pregnancy, including Peripartum Cardiomyopathy
During the third trimester, warfarin therapy should be continued until 36 weeks of pregnancy. In anticipation of delivery, patients should be hospitalized and treatment with intravenous heparin should be started. The partial thromboplastin time should be 2.5 to 3.5 times the control value. Labor and delivery is a particularly high-risk time for patients who require anticoagulation during pregnancy. Delivery should be planned, and intravenous heparin treatment should be stopped peripartum and resumed 4 to 6 hours after delivery, in the absence of bleeding. Vaginal delivery is the preferred mode of delivery in most women with heart disease; however, cesarean delivery should be performed if labor occurs during warfarin anticoagulation because of the risk of fetal intracranial hemorrhage (Table 30). Heparin should be resumed 4 to 6 hours after delivery in the absence of bleeding. Currently, data are insufficient to support use of low-molecular-weight heparin for anticoagulation during pregnancy. No teratogenic effects have been reported with low-molecular-weight heparins, and they do not cross the placenta. The Sixth ACCP Conference on Antithrombotic Therapy supports use of low-molecular-weight heparin (adjusted dose: enoxaparin, 1 mg/kg every 12 hours subcutaneously, or dalteparin, 200 IU/kg daily) throughout pregnancy except 24 hours before delivery, when the recommendation is to switch to intravenous unfractionated heparin (American College of Chest Physicians). However, a recent advisory from the U.S. Food and Drug Administration has changed the product labeling to state that enoxaparin is not recommended for prosthetic valves, including during pregnancy. Low-dose aspirin (81 mg) is safe to use during pregnancy. It is recommended for patients with shunts (for example, those with atrial septal defect), cyanosis, or a biologic-valve prosthesis. However, the antiplatelet effect has not been proven. A low dose of aspirin may also decrease the incidence of preeclampsia. Dipyridamole should not be used during pregnancy. No data are available on the effects of ticlopidine or clopidigrel during pregnancy. Information is limited on administration of glycoprotein IIB/IIIA inhibitors during pregnancy. Thrombolytic therapy has been used in pregnancy, and several cases of emergency use have been reported. Thrombolytic therapy should be considered in the critically ill patient with valve thrombosis or acute coronary syndrome who is not a candidate for cardiac surgery or percutaneous intervention.
TA B L E 3 0 Indications for Cesarean Section in Women with Cardiovascular Disease
Obstetric reasons Anticoagulation with warfarin Fixed obstructive cardiac lesion* Pulmonary hypertension* Unstable aortic lesion*
*
These items are controversial.
American College of Chest Physicians. Sixth ACCP Consensus Conference on Antithrombotic Therapy. Available at: http://www.chestnet.org/guidelines/ antithrombotic/. Siu SC, Sermer M, Colman JM, Alvarez AN, Mercier LA, Morton BC, et al. Prospective multicenter study of pregnancy outcomes in women with heart disease. Circulation. 2001;104:515-21. PMID: 11479246

Is the risk of pregnancy increased in a patient with a left ventricular ejection fraction less than 40%? Are angiotensin-converting enzyme inhibitors safe to use during pregnancy? Is pregnancy contraindicated in a patient with a history of peripartum cardiomyopathy?
The management of pregnant women with cardiomyopathy in NYHA functional class I or II should include limiting strenuous exercise, getting adequate sleep and rest, maintaining a low-salt diet, avoiding anemia (maintaining a hemoglobin level >11 g), and undergoing frequent prenatal examinations (both obstetric and cardiovascular). A Holter monitor is indicated to screen for malignant arrhythmias. In symptomatic women (NYHA functional class >II) and those with systemic ventricular function less than 40%, pregnancy should be avoided because of the risk of pregnancy-related complications (Siu et al.). The option to continue or interrupt the pregnancy should be discussed with the patient. If the patient opts to continue her pregnancy, bed rest is often required
99
KEYPOINTS
Fifty percent of women with peripartum cardiomyopathy have improvement in left ventricular function within 6 months after delivery. Because recurrence of peripartum cardiomyopathy is common, repeated pregnancy is contraindicated. Administration of angiotensin-converting enzyme inhibitors and angiotensin II inhibitors is contraindicated during pregnancy. Digoxin and hydralazine are considered safe during pregnancy and breast feeding. Pregnancy should be avoided if the left ventricular ejection fraction is less than 40% or the NYHA functional class is higher than II.
during part of the pregnancy, and close cardiac and obstetric monitoring are mandatory. Treatment of congestive heart failure is more difficult in pregnant than in nonpregnant women. Conservative measures are very important; however, pharmacologic therapy may be required.
Pharmacologic Therapy for Congestive Heart Failure during Pregnancy

Diuretics can be used to treat congestive heart failure that is not controlled by sodium restriction and other conservative measures. No single diuretic is clearly contraindicated. Experience is greatest with the thiazide diuretics and furosemide. Diuretics impair uterine blood flow and placental perfusion. Continuation of diuretic therapy initiated before conception does not seem unfavorable. However, routine initiation of diuretic medications during pregnancy is not recommended. Use of diuretics should be limited to the treatment of symptomatic congestive heart failure with clear evidence of elevated central venous pressure. Use of angiotensin-converting enzyme inhibitor therapy is contraindicated during pregnancy. Maternalfetal transfer of captopril has been documented, and, in animals, exposure to angiotensin-converting enzyme inhibitors during pregnancy produced prolonged fetal hypotension and death. In addition, use of angiotensin-converting enzyme inhibitors during pregnancy increases the risk for early delivery, low birth weight, oligohydramnios, or neonatal anuria and renal failure (or some combination of these). Angiotensin II blocking agents should also be avoided during pregnancy, as similar problems with these agents have been reported. Digoxin can be administered safely during pregnancy. -Blockers, particularly metoprolol, atenolol, and labetolol, have been safely used during pregnancy. Fetal monitoring is recommended because of the risk of intrauterine growth retardation and fetal bradycardia. Hydralazine and nitrate therapy in combination can also be used to treat congestive heart failure during pregnancy.
Peripartum Cardiomyopathy
Case 17 A 29-year-old woman with a history of peripartum cardiomyopathy and mild persistent left ventricular dysfunction is referred for pregnancy counseling. She has one healthy child and is interested in having another pregnancy. Peripartum cardiomyopathy is defined as congestive heart failure that occurs late in pregnancy or during the early postpartum period (the last trimester or up to 6 months postpartum) in the absence of congenital, coronary, or valvular heart disease or another recognized cause of heart failure. Most commonly, it is diagnosed during the first month postpartum. The incidence ranges from 1:1,300 to 1:15,000 pregnancies in the United States and is higher in certain parts of Africa. Peripartum cardiomyopathy occurs more frequently in twin pregnancies, multiparous women, women older than 30 years of age, and black women. The cause is unknown and the prognosis varies; improvement in left ventricular function within 6 months after delivery is expected in 50% of women (Pearson et al.). Management is supportive and includes standard treatment for congestive heart failure. Recurrence with subsequent pregnancies is common, and the risk of recurrence is greater in women with persistent left ventricular dysfunction (Elkayam et al.). Thus, women who have a history of a serious episode of peripartum cardiomyopathy and those with persistent left ventricular dysfunction should be counseled to avoid pregnancy.
Pearson GD, Veille JC, Rahimtoola S, Hsia J, Oakley CM, Hosenpud JD, et al. Peripartum cardiomyopathy: National Heart, Lung, and Blood Institute and Office of Rare Diseases (National Institutes of Health) workshop recommendations and review. JAMA. 2000;283:1183-8. PMID: 10703781 Elkayam U, Tummala PP, Rao K, Akhter MW, Karaalp IS, Wani OR, et al. Maternal and fetal outcomes of subsequent pregnancies in women with peripartum cardiomyopathy. N Engl J Med. 2001;344:1567-71. PMID: 11372007
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Congenital Heart Disease in Pregnancy
Congenital Heart Disease in Pregnancy

Is the risk of congenital heart disease higher in the offspring of a mother with congenital heart disease than in the general population? Is prophylaxis against endocarditis required during an uncomplicated delivery in a patient with repaired congenital heart disease?
Case 18 A 25-year-old woman presents at 18 weeks of gestation. Physical examination and echocardiography confirm a 1.5-cm secundum atrial septal defect with a normal right ventricular pressure. Elective closure of an atrial septal defect with an important left-to-right shunt before pregnancy is usually recommended. Closure during pregnancy is not recommended in the absence of symptoms. Meticulous management around the time of delivery is recommended to avoid paradoxical embolism (Zuber et al.). Currently, an increasing number of women with congenital heart disease are reaching childbearing age and are considering pregnancy (Colman et al.). This is primarily because congenital heart disease is being diagnosed and managed earlier. Patients should be counseled about pregnancy and the increased risk of congenital heart disease in the fetus (Romano-Zelekha et al.). The incidence of congenital heart disease in the general population is about 1%. The offspring of women with congenital heart disease have a 5% to 6% incidence of congenital heart disease. Usually, the lesion in the offspring is not the same kind as in the mother, except for syndromes in which the incidence of recurrence with each pregnancy may be up to 50% (for example, Marfan syndrome or hypertrophic cardiomyopathy). Occasionally, familial left-sided obstructive lesions and atrial septal defects may occur. Patients with Marfan syndrome, bicuspid aortic valve, coarctation of the aorta, and other aortopathies are predisposed to aortic dissection and aneurysm formation, particularly during pregnancy. Prepregnancy aortic assessment is imperative in these patients. Once pregnancy occurs, -blockers may decrease the rate of dilation of the aortic root; this therapy should be considered in all pregnant patients with aortopathy. Regular aortic follow-up is recommended during pregnancy in patients with Marfan syndrome or other aortopathies. Fetal echocardiography is used routinely in women with congenital heart disease to detect congenital heart disease in the fetus. Endocarditis prophylaxis is generally recommended around the time of delivery in high-risk patients. Cyanosis inhibits fetal growth and development. Pregnancy is generally contraindicated in women with severe cyanosis. Surgical repair of the underlying cardiac anomaly should be considered before pregnancy, if possible (for example, Ebsteins anomaly with right-to-left shunt related to an atrial septal defect). In patients with repaired complex congenital heart disease, uncertainty remains about the ability to conceive, the effects of pregnancy on maternal heart disease, and the effects of heart disease on the fetus.
Zuber M, Gautschi N, Oechslin E, Widmer V, Kiowski W, Jenni R. Outcome of pregnancy in women with congenital shunt lesions. Heart. 1999;81:271-5. PMID: 10026351 Colman JM, Sermer M, Seaward PG, Siu SC. Congenital heart disease in pregnancy. Cardiol Rev. 2000;8:166-73. PMID: 11174890 Romano-Zelekha O, Hirsh R, Blieden L, Green M, Shohat T. The risk for congenital heart defects in offspring of individuals with congenital heart defects. Clin Genet. 2001;59:325-9. PMID: 11359463
KEYPOINTS
Congenital heart disease is the most common form of structural heart disease that affects women of childbearing age in the United States. Pregnant cyanotic women have a high risk of fetal loss. Cyanosis is a recognized handicap to fetal growth, resulting in low-birth-weight infants. The incidence of congenital heart disease in the offspring of women with congenital heart disease is about 5%.
Primary and Secondary Pulmonary Hypertension

Is severe pulmonary hypertension always a contraindication to pregnancy? Above what pulmonary artery pressure is it unsafe to proceed with pregnancy?
Case 19 A 31-year-old woman presents with dyspnea during early pregnancy. She has severe primary pulmonary hypertension. You are asked to review the management options. 101
Primary and Secondary Pulmonary Hypertension
Avila WS, Grinberg M, Snitcowsky R, Faccioli R, Da Luz PL, Bellotti G, Pileggi F. Maternal and fetal outcome in pregnant women with Eisenmengers syndrome. Eur Heart J. 1995;16:460-4. PMID: 7671889
KEYPOINTS
Severe pulmonary hypertension is an absolute contraindication to pregnancy.
Severe pulmonary hypertension in pregnancy (pulmonary artery pressure >70% systemic), whether primary or secondary, carries a 30% to 50% risk of maternal death. If pulmonary hypertension is identified, the patient should be counseled against pregnancy. If pregnancy occurs in a patient with established severe pulmonary hypertension, she should be counseled against continuing the pregnancy. If the pregnancy is continued, meticulous medical monitoring is recommended (Avila et al.). Pregnancy should be avoided in certain cardiac conditions, and if pregnancy occurs, termination should be considered (Table 31). Additional contraindications to pregnancy are also outlined in this table.
Exercise Guidelines
Fletcher GF, Blair SN, Blumenthal J, Caspersen C, Chaitman B, Epstein S, et al. Statement on exercise. Benefits and recommendations for physical activity programs for all Americans. A statement for health professionals by the Committee on Exercise and Cardiac Rehabilitation of the Council on Clinical Cardiology, American Heart association. Circulation. 1992;86:340-4. PMID: 1617788 U.S. Department of Health and Human Services: Physical activity and health: a report of the Surgeon General. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, 1996. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, et al. Physical activity and public health. A recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine. JAMA. 1995;273:402-7. PMID: 7823386 Myers J, Prakash M, Froelicher V, Do D, Partington S, Atwood JE. Exercise capacity and mortality among men referred for exercise testing. N Engl J Med. 2002;346:793-801. PMID: 11893790
In 1992, the American Heart Association declared that physical inactivity is an independent risk factor for coronary artery disease (Fletcher et al., 1992). Consequently, promotion of physical activity has become an integral part of the national public health agenda in the United States, as seen in the publication of the Report of the U.S. Surgeon General on Physical Activity and Health (U.S. Department of Health and Human Services). Physical activity is defined as any bodily movement produced by skeletal muscles that results in energy expenditure. Exercise is a subset of physical activity that is planned, structured, repetitive, and purposeful in the sense that improvement or maintenance of physical fitness is the objective. Physical fitness includes cardiorespiratory fitness, muscle strength, body composition, and flexibility, comprising a set of attributes that people have or achieve that relates to the ability to perform physical activity. When defining the amount of physical activity or exercise, an important interrelationship exists between the total dose of activity and the intensity at which the activity is performed. Dose refers to the total amount of energy expended in physical activity, whereas intensity reflects the rate of energy expenditure during such activity (Pate et al.). Low levels of physical fitness are associated with an increased risk of all-cause and cardiovascular disease mortality, with age-adjusted relative risks of approximately 4.0 for unfit groups compared with their most fit counterparts (Myers et al.). Most studies with multiple increments of physical activity demonstrate a gradient of decreasing risk of disease or mortality with increasing levels of physical activity, wherein the risk of cardiovascular disease increases as physical activity decreases. However, the exact upper and lower dose limits and the intensity of activity required to confer a benefit have not been fully elucidated. Exercise training among persons with known coronary artery disease has been shown to yield various important benefits, including reduced mortality, reduced levels of myocardial ischemia at a given level of effort, and improved myocardial perfusion.
TA B L E 3 1 Cardiac Contraindications to Pregnancy
Severe pulmonary hypertension (pulmonary artery pressure >70% systemic) Eisenmengers syndrome Cardiomyopathy with New York Heart Association class II or higher congestive heart failure or left ventricular ejection fraction <40% Severe obstructive cardiac lesions Marfan syndrome with aortic root diameter 40 mm Severe cyanosis Previous peripartum cardiomyopathy with persistent left ventricular dysfunction or a serious episode of heart failure during a previous pregnancy
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Exercise Training Responses
It is now clear that exercise modulates many biologic domains to confer cardioprotection. Although exercise appears to modify and improve cardiovascular risk factors (hypertension, lipid profile, insulin resistance, and obesity), the beneficial effect of physical activity cannot be accounted for solely by means of risk factor reduction, since the association with reduced mortality is independent of other coronary risk factors. Emerging data demonstrate that exercise appears to positively affect several integral components of cardiovascular physiology, including endothelial function, thrombosis and hemostasis, and autonomic function.
KEYPOINTS
Exercise Training Responses

What are the physiologic effects of exercise training? How much exercise is needed for consistent benefit?
Exercise training affects such factors as maximal oxygen uptake, central hemodynamic function, autonomic nervous system function, peripheral vascular and muscular function, as well as submaximal exercise capacity. Collectively, these adaptations result in an exercise training effect, which allows a person to exercise to higher peak work rates with lower heart rates at each submaximal level of exercise. The increase in maximal oxygen uptake (VO2max ) as a result of training in healthy persons is due to a higher maximum cardiac output and to greater extraction of oxygen from the systemic circulation, reflecting both central and peripheral adjustments. Submaximal heart rate is reduced after training, but cardiac output remains unchanged because stroke volume is increased. Greater oxidative potential in the skeletal muscles after training also contributes to more endurance.
Emerging data demonstrate that exercise appears to positively affect several integral components of cardiovascular physiology. Exercise training affects such factors as maximal oxygen uptake, central hemodynamic function, autonomic nervous system function, peripheral vascular and muscular function, as well as submaximal exercise capacity. Any activity performed for training should prescribed in terms of intensity, frequency, duration, mode, and progression. The intensity of activity needed to improve physical conditioning varies among individuals and may be as low as 40% of VO2max for 20 minutes three times weekly. Significant health benefits can be obtained by including a moderateintensity activity for 30 minutes on most or all days of the week, aiming for a minimum total energy expenditure of 700 to 1000 kcal/wk.
Quality and Quantity of Exercise Needed for a Beneficial Effect

Physical activity may be measured in terms of metabolic equivalents (METs), a unit used to estimate the metabolic cost, or oxygen required to perform a given activity. One MET equals the resting metabolic rate of approximately 3.5 mL O2/kg/min. Cardiorespiratory fitness is best assessed by measurements of peak VO2. This can be accurately determined by measuring the composition of expired air and respiratory volume during maximal exercise, or it can be estimated from the peak exercise workload, or MET level, during maximal exercise without measuring expired gases. Any activity performed for training should be assessed in terms of intensity, frequency, duration, mode, and progression. Dose refers to the total amount of energy expended in physical activities that require repetitive muscular movement (usually expressed in kilojoules or kilocalories). Intensity can be defined in absolute or relative terms. Absolute intensity reflects the rate of energy expenditure during exercise and is usually expressed in METs, kJ/min1, or kcal/min1. Relative intensity refers to the relative percentage of maximal aerobic power that is maintained during exercise, and is expressed as a percentage of maximal heart rate or a percentage of VO2max. For example, brisk walking at 4.8 km/h1, or 3 mi/h1, has an absolute intensity of approximately 4 METs. In relative terms, this intensity is considered light for a 20-year-old healthy person but difficult for an 80-year-old. Activities that are 40% to 60% of VO2max are generally categorized as moderate. This concept is well illustrated and further defined in Table 32 (American College of Sports Medicine). The intensity of activity needed to improve physical conditioning varies among individuals and may be as low as 40% of VO2max for 20 minutes three times weekly. However, the relationship of exercise intensity to duration suggests that lowintensity exercise requires more time to increase functional capacity than does higher-intensity exercise. From a health and conditioning standpoint, the major
American College of Sports Medicine Position Stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults.Med Sci Sports Exerc. 1998;30:975-91. PMID: 9624661
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How to Develop the Exercise Prescription
TA B L E 3 2 Classification of Physical Activity Intensity
Intensity
Endurance-Type Activity
Strength-Type Exercise: Relative Intensity, as Maximum Voluntary Contraction (%)*
Relative Intensity Maximum VO2max or Heart Rate Heart RPE Reserve (%) Rate (%) Score Very light Light Moderate Hard Very hard Maximum <20 2039 4059 6084 85 100 <35 3554 5569 7089 90 100 <10 1011 1213 1416 1719 20
Absolute Intensity in Healthy Adults (METs) Young (2039 Years) <2.4 2.44.7 4.87.1 7.210.1 10.2 12.0 MiddleAged (4064 Years) <2.0 2.03.9 4.05.9 6.08.4 8.5 10.0 Old (6579 Years) <1.6 1.63.1 3.24.7 4.86.7 6.8 8.0 Very Old (80 Years) 1.0 1.11.9 2.02.9 3.04.25 4.25 5.0
RPE Score <10 1011 1213 1416 1719 20 <30 3049 5069 7084 85 100
MET = metabolic equivalent; RPE = Borg rating of relative perceived exertion (scale of 6 to 20)
*
Based on 8 to 12 repetitions for persons younger than 50 to 60 years of age and 10 to 15 repetitions for persons 50 to 60 years of age or older. Absolute intensity (metabolic equivalents [METs]) values are approximate mean values for men. Mean values for women are approximately 1 to 2 METs lower than those for men. values are mean values achieved during maximum exercise by healthy adults.
Maximum
Adapted from American College of Sports Medicine Position Stand. The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc. 1998;30:975-91.
KEYPOINTS
Although many factors affect risk of exercise, three of the most important are age, presence of heart disease, and intensity of exercise. Screening procedures can be used that identify a person who is at risk for an exercise-related cardiac event, and although these procedures are not perfect, they can be helpful in reducing such events.
Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104:1694-740. PMID: 11581152 26th Bethesda Conference: recommendations for determining eligibility for competition in athletes with cardiovascular abnormalities. January 6-7, 1994.J Am Coll Cardiol. 1994;24:845-99. PMID: 7798484
advantage of low- to moderate-intensity exercise is the decreased likelihood of cardiovascular and musculoskeletal complications, whereas vigorous exercise has the advantage of accomplishing the goal in less time. A threshold of intensity is probably required to achieve benefit, although the exact value is not known and may vary from one person to another. Although a threshold cannot be defined from available information, much of the exercise described in published reports and associated with good health is moderate in intensity, such as brisk walking. Significant health benefits can be obtained by including a moderate-intensity activity for 30 minutes on most or all days of the week, aiming for a minimum total energy expenditure of 700 to 1000 kcal/wk.

What factors should be considered when prescribing exercise to an individual patient? What exercise options are available? What are the particular considerations in patients with cardiovascular disease?
Detailed recommendations on the preexercise medical evaluation and exercise training prescription are provided in the American Heart Association Exercise Standards for Testing and Training (Fletcher et al., 2001). These recommendations are summarized in the following sections. Exercise has both risks and benefits, and the challenge to the physician and other health care professionals is to provide guidelines that minimize risks and maximize benefits. Although many factors affect risk of exercise, three of the most important are age, presence of heart disease, and intensity of exercise. Screening procedures can be used that identify a person who is at risk for an exercise-related cardiac event, and although these procedures are not perfect, they can be helpful in reducing such events. It is generally believed that the ben-
104
efits of exercise exceed the risks, and people should be encouraged to exercise prudently. The following preexercise screening procedures and activity classifications are presented as a means of beginning exercise with the lowest possible risk. They do not consider comorbid conditions (for example, morbid obesity, severe pulmonary disease, or debilitating neurologic or orthopedic conditions) that may necessitate closer supervision during training sessions. As a person gains experience, the decision may be made to place that person in another category.
KEYPOINTS
(CONT'D)
Preexercise Screening
Before a person starts an exercise program, the following recommendations should be applied. 1. A recent medical history and physical examination should be performed. a. If the history or physical examination indicates significant cardiovascular disease, risk stratification and exercise prescription should be provided according to the guidelines that follow in the next section. Examples of cardiovascular disease include previous myocardial infarction, coronary artery bypass surgery, angina pectoris, valvular heart disease, heart failure, and congenital heart disease. b. If the person knows of no cardiovascular disease but has symptoms or signs that suggest the presence of significant disease or major coronary risk factors, an exercise test is needed before beginning an exercise program to evaluate for the presence of a high-risk condition. Further evaluation should follow accordingly. If an exercise test cannot be performed, activity should be limited. 2. Age should be considered. a. Among men younger than 45 years of age and women younger than 55 years of age without known or suspected cardiovascular disease, no further cardiovascular workup is needed, provided that the person is healthy according to the criteria outlined above. b. Among men 45 years of age or older and women 55 years of age or older, particularly those with diabetes or two other risk factors for cardiovascular disease: (1) An exercise test should be recommended if vigorous exercise is planned. If the test is normal, no further restrictions are needed. (Because of changes in blood glucose that may occur after exercise, diabetic persons require special consideration and counseling.) If the test is abnormal, further work-up should follow accordingly and, for the purposes of exercise, the person should be treated as if he or she has coronary artery disease. (2) If the person chooses not to undergo an exercise test, he or she should follow the activity guidelines outlined for class B in Table 33 (26th Bethesda Conference).
Classification for Exercise Risk

After the medical evaluation is complete, persons can be classified by risk on the basis of their characteristics. This classification (Table 33) is used to determine the need for subsequent supervision and the level of monitoring required. When resistance training is prescribed in clinical populations, the hemodynamic response (heart rate and blood pressure product) is often less that that attained during endurance exercise. Thus, the risk classification provided should be considered for endurance training as well as resistance training. Aortic diseases (for example, aortic aneurysm) are not specifically addressed in the risk classification schema. Therefore, individual judgment on the part of the clinician should guide the prescription or prohibition of endurance or resistance training in such patients.
Before a person starts an exercise program, a recent medical history and physical examination should be performed; if significant cardiovascular disease, is suspected, risk stratification and exercise prescription should be provided. If the person knows of no cardiovascular disease but has symptoms or signs that suggest the presence of significant disease or major coronary risk factors, an exercise test is needed before beginning an exercise program to evaluate for the presence of a high-risk condition. Among men younger than 45 years of age and women younger than 55 years of age without known or suspected cardiovascular disease, no further cardiovascular workup is needed, provided that the person is healthy. Among men 45 years of age or older and women 55 years of age or older, particularly those with diabetes or two other risk factors for cardiovascular disease, an exercise test should be recommended if vigorous exercise is planned; if the test is normal, no further restrictions are needed, and if it is abnormal, further work-up should follow and, for the purposes of exercise, the person should be treated as if he or she has coronary artery disease. Exercise training should consist of periods of warm-up and cool-down, endurance exercise (e.g., walking or running), flexibility exercise, and resistance training (weight-lifting). Endurance exercise should be should performed at least three times weekly for a minimum of 30 minutes per session at a minimum intensity of 40% to 60% VO2max, and up to 85% VO2max for those who have appropriately progressed to this level. Persons initiating a resistance training program should be carefully screened for cardiovascular limitations and preexisting orthopedic problems. For persons with cardiovascular disease, exercise testing allows establishment of appropriate specific safety precautions, target exercise training heart rate, and initial levels of exercise training work rates; it should be performed on all cardiac patients entering an exercise training program and should be repeated annually or at any time the patients condition warrants.
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TA B L E 3 3 American Heart Association Risk Classification for Exercise Training
Class A: Apparently healthy persons A1: Children, adolescents, men <45 years, and women <55 years who have no symptoms or known presence of heart disease or major coronary risk factors. A2: Men 45 years, and women 55 years who have no symptoms or known presence of heart disease and with <2 major cardiovascular risk factors. A3: Men 45 years, and women 55 years who have no symptoms or known presence of heart disease and with 2 major cardiovascular risk factors. Activity guidelines: No restrictions other than basic guidelines Supervision required: None* ECG and blood pressure monitoring: Not required Class B: Presence of known, stable cardiovascular disease with low risk for complications with vigorous exercise, but slightly greater risk than that in apparently healthy persons This classification includes persons with any of the following diagnoses: Coronary artery disease (angina. myocardial infarction, coronary revascularization, abnormal exercise test, and abnormal coronary angiograms) whose condition is stable and who have the clinical characteristics outlined below Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics as outlined below Congenital heart disease: risk stratification for patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations Cardiomyopathy: ejection fraction 30%; includes stable patients with heart failure with clinical characteristics as outlined below; not hypertrophic cardiomyopathy or recent myocarditis Exercise test abnormalities that do not meet any of the high risk criteria outlined in class C Clinical characteristics (must include all of the following): New York Heart Association class 1 or 2 Exercise capacity 6 METs No evidence of congestive heart failure. No evidence of myocardial ischemia or angina at rest nor on the exercise test at or below 6 METs Appropriate increase in systolic blood pressure during exercise Absence of sustained or nonsustained ventricular tachycardia at rest or with exercise Ability to satisfactorily self-monitor intensity of activity Activity guidelines: Activity should be individualized, with exercise prescription provided by qualified person and approved by primary health care provider Supervision required: Medical supervision during initial prescription session is beneficial. Supervision by appropriate trained nonmedical personnel for other exercise sessions until the patient understands how to monitor his or her activity Medical personnel should be trained and certified in Advanced Cardiac Life Support; nonmedical personnel should be trained and certified in Basic Life Support (which includes cardiopulmonary resuscitation) ECG and blood pressure monitoring: Useful during the early prescription phase of training, usually 6 to 12 sessions (Continued on next page)
Exercise Training Techniques

Exercise training should consist of periods of warm-up and cool-down, endurance exercise, flexibility exercise, and resistance training (Table 34) (Shephard and Balady). Such activities aim to reduce the risk of injury or other events associated with sudden onset of activity, increase functional capacity and muscular strength, improve the ability to sustain activities of daily living, and promote personal independence and positive self-image.
Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation. 1999;99:963-72. PMID: 10027821
Warm-up and cool-down

Exercising at a low intensity for 5 to 10 minutes before (warm-up) and after (cool-down) the training session is recommended to help stretch and warm up muscles and ligaments in preparation for the activity session. The cool-down period also prevents hypotension, which may occur with sudden cessation of exercise. 106
TA B L E 3 3 ( c o n t d ) American Heart Association Risk Classification for Exercise Training
Class C: Those at moderate to high risk for cardiac complications during exercise or unable to self-regulate activity or to understand recommended activity level This classification includes persons with any of the following diagnoses: Coronary artery disease with the clinical characteristics outlined below Valvular heart disease, excluding severe valvular stenosis or regurgitation with the clinical characteristics as outlined below. Congenital heart disease: risk stratification for patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations Cardiomyopathy: ejection fraction <30%; includes stable patients with heart failure with clinical characteristics as outlined below; not hypertrophic cardiomyopathy or recent myocarditis Complex ventricular arrhythmias not well controlled. Clinical characteristics (any of the following): HA class 3 or 4 Exercise test results. Exercise capacity <6 METs Angina or ischemic ST depression at a workload <6 METs Decrease in systolic blood pressure below resting levels during exercise Nonsustained ventricular tachycardia with exercise Previous episode of primary cardiac arrest: i.e., cardiac arrest that did not occur in the presence of an acute myocardial infarction or during a cardiac procedure A medical problem that the physician believes may be life-threatening. Activity guidelines: Activity should be individualized with exercise prescription provided by qualified persons and approved by primary health care provider Supervision: Medical supervision during all exercise sessions until safety is established. ECG and blood pressure monitoring: Continuous during exercise sessions until safety is established, usually 12 sessions or more. Class D: Unstable disease with activity restriction; exercise for conditioning purposes is not recommended This classification includes persons with any of the following: Unstable ischemia Severe and symptomatic valvular stenosis or regurgitation Congenital heart disease: criteria for risk that would prohibit exercise conditioning in patients with congenital heart disease should be guided by the 26th Bethesda Conference recommendations Heart failure that is not compensated Uncontrolled arrhythmias Other medical conditions that could be aggravated by exercise Activity guidelines: No activity is recommended for conditioning purposes. Attention should be directed to treating the patient and restoring him or her to class C or better. Daily activities must be prescribed on the basis of individual assessment by the patients personal physician
ECG = electrocardiogram; METs = metabolic equivalents
*It
is suggested that persons classified as class A2 and particularly class A3 undergo a medical examination and possibly a medically supervised exercise test before engaging in vigorous exercise. C patients who have successfully completed a series of supervised exercise sessions may be reclassified to class B provided that the safety of exercise at the prescribed intensity is satisfactorily established by appropriate medical personnel and that the patient has demonstrated the ability to self-monitor. Information from: Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation. 2001;104:1694-740.
Class
Endurance exercise
Activities that cause the greatest increase VO2max are dynamic in nature and involve high-repetition and high-frequency movements using large muscle groups: for example, walking or running. Exercise should be should performed at least three times weekly for a minimum of 30 minutes per session at a minimum intensity of 40% to 60% VO2max, and up to 85% VO2max for those who have appropriately progressed to this level. More simply, a heart rate method to prescribe intensity can be used, in which the training heart rate range is 50% to 75% (and up to 90%) of maximum predicted heart rate. The maximum predicted heart rate can be calculated by using the equation (220 age). Another useful 107
TA B L E 3 4 Exercise Prescription for Endurance and Resistance Training
Characteristic Frequency Intensity Duration Example Lower extremity
Endurance Exercise 35 d wk1

*
Resistance Training 23 d wk1 13 sets of 815 RM for each muscle group Leg extensions, curls, press Adductor/abductor Biceps curl Triceps extension Bench or overhead press Lateral pull-down or raises Bench-over or seated row
50%70% maximum heart rate, or 40%60% maximum VO2 or heart rate reserve 2060 min Walking Jogging/running Stairclimber Arm ergometry
Upper extremity
Combined
Rowing Cross-country ski machine Combined arm/leg cycle Swimming Aerobics
RM = maximum number of times a load can be lifted before fatigue; VO2 = measured oxygen uptake
*Maximum Heart
heart rate = 220 age, or peak heart rate on exercise test
rate reserve = (peak heart rate resting heart rate ) % (+ resting heart rate)
Types of exercise listed are not all-inclusive.
Adapted from: Shephard RJ, Balady GJ. Exercise as cardiovascular therapy. Circulation. 1999;99:963-72.
approach to activity prescription is to identify the desirable rating of perceived exertion and instruct participants to adhere to that intensity. A suggested rating of perceived exertion for most healthy persons is 12 to 16 (somewhat hard to hard) on a Borg scale of 6 to 20, an approach that is both effective and acceptable (Table 35). The prescription of exercise intensity differs for patients with cardiovascular disease (see below). Calculation of maximum predicted heart rate by using the equation (220 age) is not valid for persons taking cardioactive medications that slow the heart rate.
Resistance training
Resistance exercise training, which involves activities that use low- or moderatefrequency movements against high resistance, has been accepted as a primary component of a comprehensive exercise program for both apparently healthy persons and patients with cardiovascular disease (Pollock et al.). Although the effect of resistance exercise has less influence on risk factor modification than does traditional endurance exercise, the increases in strength and potential for increased muscle mass may improve a persons ability to become more physically active and increase the basal metabolic rate. Persons initiating a resistance training program should be carefully screened for cardiovascular limitations and preexisting orthopedic problems. Programs including a single set (8 to 12 repetitions) of 8 to 10 different exercises that train the major muscle groups, performed 2 or 3 days per week, will elicit favorable adaptation and improvement. Although greater frequencies of training and more sets may be used, the additional gains among those in adult fitness programs are usually small. Training the front and back of major muscle groups (for example, chest and back, biceps and triceps) is recommended. For detailed recommendations on resistance training, see the American Heart Association Advisory Resistance Exercise in Individuals with and without Cardiovascular Disease.
Pollock ML, Franklin BA, Balady GJ, Chaitman BL, Fleg JL, Fletcher B, et al. AHA Science Advisory. Resistance exercise in individuals with and without cardiovascular disease: benefits, rationale, safety, and prescription: An advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association; Position paper endorsed by the American College of Sports Medicine. Circulation. 2000;101:828-33. PMID: 10683360
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Cardiovascular Medicine

Risk Factors and Primary Prevention of Coronary Artery Disease

Major Risk Factors and Risk Assessment

TA B L E 1 Risk Factors for Coronary Artery Disease

Major risk factors Hypertension

Major Risk Factors and Risk Assessment

Major Risk Factors and Risk Assessment

TA B L E 2 Estimate of 10-Year Risk for Men (Framingham Point Scores)

If Untreated 0 0 1 1 2 Point Total 11 12 13 14 15 16 17

If Treated 0 1 2 2 3 10-Year Risk (%) 8 10 12 16 20 25 30

BP = blood pressure; HDL = high-density lipoprotein

Major Risk Factors and Risk Assessment

TA B L E 3 10-Year Risk Estimates for Women (Framingham Point Scores)

If Untreated 0 1 2 3 4 10-Year Risk (%) <1 1 1 1 1 2 2 3 4 5 6 8 Point Total 20 21 22 23 24 25

If Treated 0 3 4 5 6 10-Year Risk (%) 11 14 17 22 27 30

BP = blood pressure; HDL = high-density lipoprotein

Major Risk Factors and Risk Assessment

A 10 Cumulative Incidence (%) 8 6 4 2 0

Women High normal

B 14 Cumulative Incidence (%) 12 10 8 6 4 2 0

Men High normal Normal

995 1039 879

973 1012 857

962 982 819

934 952 795

892 892 726

454 520 441

Major Risk Factors and Risk Assessment

Major Risk Factors and Risk Assessment

16 Proportion of patients with first event (%) 14 12 10 8 6 4 2 0 0 Number at risk

Primary composite endpoint Atenolol Losartan

Major Risk Factors and Risk Assessment

The Metabolic Syndrome

Major Risk Factors and Risk Assessment

Newer Risk Factors for Coronary Artery Disease

Inflammation and C-Reactive Protein

Major Risk Factors and Risk Assessment

Therapies in Primary Prevention

Therapies in Primary Prevention

Therapies in Primary Prevention

TA B L E 5 Drug Therapy Considerations and Goals of Therapy for Primary Prevention

Therapies in Primary Prevention

Aspirin and Other Antiplatelet Agents

Simvastatinallocated (10 269) 587 (57%) 194 (19%) 781 (76%)

Placeboallocated (10 267) 707 (69%) 230 (22%) 937 (91%)

Death rate ratio (95% Cl)

083 (075091) p<0-0001

359 (35%) 90 (0 9%)

82 (08%) 16 (02%) 547 (5 3%)

Therapies in Primary Prevention

Hormone Replacement Therapy

Therapies in Primary Prevention

Acute Coronary Syndromes

Acute Coronary Syndrome

Myocardial Infarction Unstable Angina NQMI QwMI

Unstable Angina and NonST-Segment Elevation Myocardial Infarction

Unstable Angina and NonST-Segment Elevation Myocardial Infarction

Unstable Angina and NonST-Segment Elevation Myocardial Infarction

Rest angina New-onset angina Increasing angina

Unstable Angina and NonST-Segment Elevation Myocardial Infarction

CAD = coronary artery disease; ECG = electrocardiography

6-Month Death/MI/ACS Rehosp (%)

Unstable Angina and NonST-Segment Elevation Myocardial Infarction