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Pathophysiology of diastolic heart failure

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Pathophysiology of diastolic heart failure


Author Michael R Zile, MD Franz R Eberli, MD, FESC, FAHA Laura Wexler, MD, FACC, FAHA Section Editor Wilson S Colucci, MD Deputy Editor Susan B Yeon, MD, JD, FACC

Last literature review for version 16.1: January 31, 2008 | This topic last updated: March 9, 2007 INTRODUCTION Heart failure (HF) can be defined as the inability of the heart to provide sufficient forward output to meet the perfusion and oxygenation requirements of the tissues while maintaining normal filling pressures. There are three major mechanisms by which this can occur: Systolic dysfunction, in which there is impaired cardiac contractility. Diastolic dysfunction, in which there is abnormal cardiac filling. Pathologic myocardial remodeling, in which there are nonphysiologic changes in cardiac volume, mass, and geometry. The pathophysiology of diastolic HF will be reviewed here. The clinical manifestations, diagnosis, treatment and prognosis of diastolic HF, and the management of systolic heart failure are discussed separately. (See "Clinical manifestations and diagnosis of diastolic heart failure" and see "Treatment and prognosis of diastolic heart failure" and see "Overview of the therapy of heart failure due to systolic dysfunction"). TERMINOLOGY It is important to distinguish several terms when classifying patients with HF. Most notably, diastolic dysfunction and diastolic HF are not synonymous. A variety of patients, including those with systolic HF, can have a degree of diastolic dysfunction. The term diastolic HF is reserved for patients with clinical HF, a normal EF and predominant abnormalities in diastolic function. Systolic versus diastolic HF Patients with chronic HF can be divided into two broad categories, classified on the basis of characteristic changes in cardiovascular structure and function [ 1,2] : Systolic heart failure (SHF), which is characterized by progressive chamber dilation, eccentric remodeling, and abnormalities in systolic function (ie, reduced left ventricular ejection fraction [LVEF]). Diastolic heart failure (DHF), which is characterized by normal LV volume, concentric remodeling, normal LV chamber systolic properties, and abnormalities in diastolic function [2-7] . Thus, SHF and DHF are distinct syndromes, not a continuous spectrum of disorders. Patients with SHF may have evidence of diastolic dysfunction, particularly during periods of symptomatic decompensation [8-11] . However, such patients have predominant abnormalities in systolic properties, with secondary abnormalities in diastolic function. Thus, they are not considered to have DHF. Similarly, patients with DHF may have subtle abnormalities in regional systolic function, but they have predominant abnormalities in diastolic properties [ 2,7] .

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Diastolic dysfunction versus DHF Diastolic dysfunction and diastolic heart failure are not synonymous terms [12] . Diastolic dysfunction indicates a functional abnormality of diastolic relaxation, filling, or distensibility of the left ventricle (LV), regardless of whether the LVEF is normal or abnormal and whether the patient is asymptomatic or has symptoms and signs of HF. Thus, diastolic dysfunction refers to abnormal mechanical properties of the ventricle. DHF denotes the signs and symptoms of clinical HF in a patient with a normal LVEF and LV diastolic dysfunction. Diagnostic criteria There is ongoing discussion about the most appropriate nomenclature and diagnostic criteria to apply to HF patients. The approach to the diagnosis of DHF is presented separately. (See "Clinical manifestations and diagnosis of diastolic heart failure" ). NORMAL LEFT VENTRICULAR DIASTOLIC FUNCTION An appreciation of normal diastolic function permits a better understanding of the clinical features of DHF. Cardiac function is critically dependent upon diastolic physiologic mechanisms to provide adequate LV filling (cardiac input) in parallel with LV ejection (cardiac output). These processes must function under a variety physiologic conditions, both at rest and during exercise. LV diastolic pressure is determined by the volume of blood in the ventricle and the distensibility or compliance of the entire cardiovascular system. Cardiovascular compliance is determined principally by the LV, but is also influenced by the left atrium (LA), pulmonary vessels, right ventricle (RV), systemic arteries and pericardium. Pulmonary function is also dependent upon LV diastolic properties. During diastole the LV, LA, and pulmonary veins form a "common chamber" which is continuous with the pulmonary capillary bed ( show figure 1). Thus, an increase in LV diastolic pressure will increase pulmonary capillary pressure which can cause dyspnea, exercise limitation, and pulmonary congestion. Events during diastole Diastole begins with the relaxation of the contracted myocardium. This is a dynamic, energy-dependent, process that includes two phases ( show figure 2): Isovolumic relaxation Isovolumic relaxation is the period between aortic valve closure and mitral valve opening during which LV pressure declines with no change in volume. Auxotonic relaxation Auxotonic relaxation is the period between mitral valve opening and mitral valve closure during which the LV fills at variable pressure. During diastole, the rapid pressure decay associated with the "untwisting" and elastic recoil of the LV produce a suction effect that promotes ventricular filling by increasing the LA-LV pressure gradient and pulling blood into the ventricle. This process is augmented during exercise to compensate for the reduced diastolic filling period induced by the associated increase in heart rate. ( See "Normal response to exercise" below). During the later phases of diastole, cardiomyocytes are relaxed and the LV is compliant and readily distensible. In the normal heart, there is minimal resistance to additional LV filling over a normal volume range. Atrial contraction contributes 20 to 30 percent to total LV filling volume, but usually increases diastolic pressures by less then 5 mmHg. Normal diastolic properties allow LV filling to be accomplished by very low filling pressures in the LA and pulmonary veins, thereby preserving a low pulmonary capillary pressure (<12 mmHg) and a high degree of lung distensibility. Loss of normal LV diastolic relaxation and distensibility impairs LV filling , resulting in increases in LV, LA, and pulmonary venous pressures during diastole, which directly increase the pulmonary capillary pressure. Normal response to exercise Cardiac output can increase several-fold during exercise, an

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appropriate response to the enhanced needs of exercising muscle. Multiple factors contribute to this response including an increase in heart rate, a modest rise in stroke volume, a reduction in peripheral vascular resistance, and an elevation in contractile force. The increase in cardiac output must be matched by a rise in left ventricular input. However, increased input cannot be accomplished by the same mechanisms that increase output. As an example, the rise in heart rate that contributes to increased output also shortens the duration of diastole. As a result, the diastolic filling rate during exercise may be increased to support the increase in cardiac output. Increased LV filling requires a rise in the rate of diastolic flow across the mitral valve (MV) , which in turn requires an increase in the transmitral diastolic pressure gradient. If this were achieved by increasing the pressure in the LA, this would have the deleterious effects of increasing pulmonary capillary pressure, possibly causing pulmonary congestion, dyspnea, and respiratory compromise. Instead, the normal LV permits a remarkable increase in diastolic filling rate during exercise by rapidly and markedly decreasing LV pressure during early diastole, thereby augmenting the left ventricular "suction" effect and enhancing the transmitral pressure gradient without increasing LA pressure ( show figure 3) [13-16] . Several mechanisms contribute to the enhanced left ventricular diastolic "suction" effect during exercise: The increased force of contraction during systole enhances early diastolic myocardial elastic recoil due to the greater systolic shortening forces and the extent of systolic fiber shortening, which is manifested as a smaller end-systolic volume [ 15] . In other words, an increase in systolic shortening results in an increase in restoring forces during diastole, which permits enhanced diastolic filling. Acceleration of myocyte relaxation occurs during exercise, due to an increased rate of calcium uptake by the sarcoplasmic reticulum (SR). Increased cyclic adenosine monophosphate (cAMP), generated by the beta adrenergic response to exercise, phosphorylates the regulatory SR membrane protein, phospholamban, to increase the rate of calcium uptake by the SR during diastole [17] . Some of the mechanisms that allow increases in cardiac output and cardiac input during exercise act in concert on systolic and diastolic function: The Treppe effect creates a relationship between the heart rate (or frequency of contraction), LV pressure (or systolic force development) and ejection fraction (or shortening) such that in a normal heart, an increase in heart rate is associated with an increase in stroke volume over a physiologic range of heart rates. This has been called the systolic "force-frequency relationship". The same mechanism governs the relationship between heart rate and diastolic relaxation rate where increased heart rate in a normal heart is associated with an increased relaxation rate, which in part allows LV diastolic pressures and PCWP to remain normal during exercise. During normal exercise, end-systolic volume decreases, and end-diastolic volume increases. The increase in end-diastolic volume allows the LV to use the Frank-Starling mechanism to augment stroke volume. However, it is the normal distensibility of the LV that permits an increase in end-diastolic volume with a negligible change in late diastolic pressure and no significant change in PCWP. In summary, the normal heart during exercise has an elegant balance of physiologic mechanisms to ensure that cardiac input keeps pace with cardiac output, with preservation of a low pulmonary capillary pressure. These mechanisms result in an increase in measured LV distensibility, as manifested by a downward shift of the LV diastolic pressure-volume (P-V) curve, especially during early diastole ( show figure 4) [18,19] .

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MEASUREMENT OF DIASTOLIC FUNCTION Complete characterization of LV diastolic properties requires simultaneous measurement of pressure and volume. Although some of these measurements can be made using noninvasive methods, invasive assessment with a high-fidelity micromanometer provides the most comprehensive evaluation. Changes in both afterload (systolic pressure) and diastolic load (LA diastolic pressure) can affect measurements of diastolic function. Such changes do not reflect alteration in intrinsic relaxation properties. Thus, no index of relaxation can be considered an index of "intrinsic" relaxation rate unless loading conditions and other modulators are held constant or are at least specified. Several indices of diastolic function can be quantitatively assessed, and some can be quantified by more than one measure. Rate of isovolumic relaxation The rate of LV pressure decline, or the rate of isovolumic relaxation, reflects early diastolic function. Accurate assessment requires a high-fidelity micromanometer catheter. Measures of this property include (show figure 5): Peak (-) dP/dt Peak negative dP/dt is the peak instantaneous rate of LV pressure decline. Tau Tau is the time constant of the isovolumic LV pressure decay [ 20] . When the natural log of LV diastolic pressure is plotted versus time, Tau is the slope of this linear relationship. Stated in more conceptual terms, Tau is the time required for LV pressure to fall by approximately two-thirds of its initial value. Isovolumic relaxation time (IVRT) IVRT can be measured with noninvasive echocardiographic techniques. When the relaxation rate is decreased (ie, abnormal diastolic function), both (-) dP/dt and Tau are increased. Rate and extent of LV filling The normal LV has a characteristic pattern of filling and transmitral inflow velocities. A number of measures characterize the rate of LV filling, including: LV filling rate The time-to-peak-filling rate (TPFR) Transmitral flow velocity Tissue velocity, strain, and strain rate. When filling is abnormal, early filling rate and extent are decreased, TPFR is prolonged, and the filling rate that results from atrial contraction is increased. E and A waves on Doppler echocardiography The E and A waves that quantify flow velocities across the mitral valve are among the most commonly used measures of LV relaxation properties ( show figure 6). In the normal heart, the rate of LV filling is greatest early in diastole, immediately after mitral valve opening. Similarly, LV inflow velocity across the mitral valve is most rapid in this early stage, reflected by a tall E wave on the transmitral Doppler echocardiogram. Because most LV filling occurs in early and mid diastole, the amount of blood transported by atrial contraction at the end of diastole is relatively small, and the velocity imparted by atrial contraction (the A wave of the transmitral inflow Doppler echocardiogram) is also relatively low. Thus, the normal E/A wave ratio is greater than one and approaches a value of two in younger individuals. The typical pattern associated with diastolic dysfunction includes increased isovolumic relaxation time and a decreased E/A ratio. This LV inflow pattern is referred to as "abnormal relaxation".

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Although commonly associated with diastolic dysfunction, abnormal relaxation is a nonspecific finding. When diastolic dysfunction occurs, relaxation is slowed and incomplete. Early LV diastolic pressures increase, early diastolic suction falls, and LV filling becomes increasingly dependent upon an increase in LA pressure to push blood into the LV during diastole. Initially this process produces the expected decreased E/A ratio. However, as LA pressures rise further, early diastolic velocities will also rise and the E wave increases, causing the E/A ratio to increase to a "normal" (or pseudonormal) value ( show figure 6). If left atrial pressures are severely increased, a "restrictive" pattern may develop in which the isovolumic relaxation time may be decreased and the E/A ratio is further increased to supernormal levels [21] . More advanced Doppler echocardiographic techniques can help to distinguish normal diastolic function, impaired relaxation, pseudonormalization, and restriction [ 22] . These measures include: Pulmonary venous flow velocity Tissue Doppler myocardial velocity, strain, and strain rate Color M-mode flow acceleration patterns In particular, myocardial velocity measures made by tissue Doppler echocardiography (TDE) appear less sensitive to alteration in LV loading conditions than other measures. E' measures the rate of early diastolic myocardial lengthening and when combined with transmitral Doppler E wave data can be used to estimate PCWP [23] . (See "Tissue Doppler echocardiography", section on Assessment of diastolic function). Passive elastic stiffness properties LV diastolic stiffness and distensibility are quantified by the position and shape of the LV diastolic pressure-volume (P-V) relationship. This relationship is defined by a plot of LV pressure and volume throughout diastole. A relatively stiff, nondistensible ventricle will require higher pressures to achieve a given volume. Thus, an increase in LV diastolic chamber stiffness (or decrease in distensibility) shifts the diastolic P-V curve upwards, and often also increases its slope. (See "Pathophysiology of heart failure: Left ventricular pressure-volume relationships" ). Defining the entire LV filling curve throughout diastole requires the simultaneous measurement of diastolic pressure and volume. This can be done either throughout a single cardiac cycle (to define the diastolic pressure versus volume relationship) or by measuring the end-diastolic pressure-volume coordinate over a series of variably loaded cardiac cycles (to define the end-diastolic pressure versus volume relationship). Volume measurements can be made by angiography, echocardiography, or radionuclide imaging techniques. Simultaneous measurements of LV diastolic pressure are usually made invasively. Alternatively, noninvasive Doppler echocardiographic techniques can be used to estimate pulmonary capillary wedge pressure (PCWP). Together with echocardiographically measured end-diastolic volume (EDV), an index of instantaneous diastolic stiffness (PCWP/EDV ratio) can be derived [ 24] . ABNORMAL CARDIOVASCULAR STRUCTURE AND FUNCTION DHF is typically associated with significant remodeling that effects the left ventricular (LV) and left atrial (LA) chambers, the cardiomyocytes and the extracellular matrix. Structural abnormalities The structural remodeling that occurs in DHF differs dramatically from that in SHF. Cardiomyocyte and extracellular matrix remodeling The differences in organ morphology and geometry are paralleled by differences at the microscopic level. In DHF, the cardiomyocyte exhibits an increased diameter with little or no change in cardiomyocyte length, corresponding to the increase in LV

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wall thickness with no change in LV volume. By contrast, in SHF the cardiomyocytes are elongated with little or no change in diameter, corresponding to the increase in LV volume with no change in LV wall thickness. In DHF, there is an increase in the amount of collagen with a corresponding increment in the width and continuity of the fibrillar components of the extracellular matrix [ 2,25,26] . There is also serologic evidence of an active fibrotic process in the myocardium of patients with DHF [ 27] . In SHF, there is degradation and disruption of the fibrillar collagen, at least early in the development of SHF [ 2,25,26] . In end-stage SHF, replacement fibrosis and regional ischemic scarring may result in an overall increase in fibrillar collagen within the extracellular matrix. A detailed discussion of the cellular mechanisms of diastolic dysfunction is presented separately. ( See "Cellular mechanisms of diastolic dysfunction" ). Chamber remodeling Patients with DHF generally exhibit a concentric pattern of LV remodeling and a hypertrophic process that is characterized by the following features [ 1,2,5,7,24-26] : A normal or near-normal end-diastolic volume Increased wall thickness An increased ratio of mass to volume An increased ratio of wall thickness to chamber radius By contrast, patients with SHF exhibit a pattern of eccentric remodeling with an increase in end-diastolic volume, an increase in LV mass but little increase in wall thickness, and a substantial decrease in the ratio of mass to volume and thickness to radius [1,2,5,7,24-26] . Diastolic dysfunction in DHF In DHF, abnormalities in diastolic function form the dominant pathophysiologic basis for the development of HF [ 3,5-7,22,24-26,28] . The major abnormalities in LV diastolic function that contribute to the development of DHF include: Slowed, delayed and incomplete myocardial relaxation Impaired rate and extent of LV filling Shift of filling from early to late diastole Decreased early diastolic suction/recoil Increased LA pressure during the early filling Increased passive stiffness and decreased distensibility of the LV Impaired ability to augment cardiac output during exercise Impaired ability to augment relaxation during exercise Inability to utilize the Frank-Starling mechanism during exercise Increased diastolic LV, LA, pulmonary venous pressure at rest and/or during exercise. In a given patient, impairment in one or more of these parameters will result in decreased LV chamber distensibility and an increase in diastolic pressure at any given LV volume. When myocardial relaxation is impaired, the rate and amount of early diastolic LV filling are reduced. This reduction requires a relative shift of LV filling to the later part of diastole, with atrial contraction making a

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more important contribution to ventricular filling than in normal subjects. The redistribution of filling from early to late diastole makes patients with diastolic dysfunction more sensitive than in normals to the effects of tachycardia and the loss of atrial contraction (such as occurs with atrial fibrillation). An increase in heart rate shortens the duration of diastole and truncates the important late phase of diastolic filling. Decompensated DHF Abnormal LV diastolic function is a universal finding in patients with DHF. Even when clinically compensated, patients with DHF have evidence of diastolic dysfunction, with abnormal relaxation, filling, and stiffness and increased diastolic pressures. ( See "Measurement of diastolic function" above). Further changes in diastolic function occur when patients develop decompensated DHF [ 29,30] . As examples, atrial fibrillation, tachycardia, or uncontrolled hypertension can lead to rapid increases in LA pressures. The rise in pressure causes a significant change in transmitral Doppler flow pattern, and may result in "pseudonormalization." ( See "E and A waves on Doppler echocardiography" above). Changes in diastolic relaxation and filling patterns are associated with changes in LV distensibility. The LV diastolic pressure volume (P-V) relationship is shifted upwards indicating decreased diastolic distensibility. Decompensated DHF may be caused by both cardiovascular and noncardiovascular factors (or "triggers"). Such triggers act on the already preexisting structural and functional abnormalities to precipitate the development of acute pulmonary edema. Potential triggers for decompensated DHF include [ 1,8,31-37] : Uncontrolled hypertension Increased salt and water intake and/or retention Tachyarrhythmias Chronic kidney disease Anemia These comorbidities act upon the substrate to precipitate acute decompensated DHF. Exacerbation of diastolic dysfunction during exercise Abnormalities in diastolic function become exaggerated during exercise [38-40] . As noted above, complex changes in diastolic properties are required to increase LV filling in parallel with LV output during periods of exercise. ( See "Normal response to exercise" above). Increased heart rates and cardiac output during exercise require more rapid LV filling. Normally, this is accomplished by accelerated LV relaxation, which lowers LV diastolic pressures and increases the LA-LV pressure gradient. Patients with diastolic dysfunction are not able to increase the rate of LV relaxation that is necessary to lower LV diastolic pressure and allow more rapid early diastolic filling. Instead, early diastolic filling is increased by an elevation in LA pressure. The increase in LA pressure results in pulmonary congestion with exercise, a hallmark of DHF ( show figure 3). In addition , patients with DHF are unable to increase LV end-diastolic volume and recruit Frank-Starling forces. As a result, there is a limited ability to increase cardiac output. In conjunction with increased pulmonary pressures, this results in a marked truncation of exercise capacity. These abnormal responses to exercise are made worse by the exaggerated increase in arterial blood pressure that frequently accompanies exercise in patients with DHF.

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Abnormal diastolic function also plays a role in exercise intolerance suffered by patients with SHF. In SHF, systolic dysfunction causes the left ventricle to lose the ability to augment diastolic filling in response to exercise by the normal mechanism of accentuated elastic recoil and early diastolic suction described above [13-15] . (See "Normal left ventricular diastolic function" above ). Systolic function in DHF By definition, the left ventricular ejection fraction (LVEF) is normal or nearly normal in patients with DHF. However, subtle abnormalities, particularly in regional systolic function, are detected in some patients. A full assessment of the global contractile behavior of the ventricle goes beyond the LVEF and includes the combined use of indices that reflect LV systolic performance (eg, stroke work) and contractility (eg, peak (+) dP/dt, end-systolic elastance, and endocardial stress-shortening relationships). Patients with DHF have no significant change in any of these global measures compared to age and gender matched normal controls [7] . In contrast, regional systolic properties such as midwall fractional shortening and long axis shortening extent and rate are abnormal in some patients (less then 50 percent) with DHF [ 2] . However, these regional abnormalities do not appear to be causally linked to either the pathophysiology of diastolic dysfunction or the development of DHF [2] . These observations reinforce the premise that SHF and DHF are distinct pathophysiologic phenomena. Dyssynchrony in DHF In patients with systolic HF, dyssynchronous contraction is a relatively common abnormality that can further reduce the performance of a failing ventricle. Tissue Doppler echocardiography (TDE) is commonly used to quantify systolic dyssynchrony. TDE also contributes to the general assessment of diastolic function. More recently, TDE has been used to identify dyssynchronous relaxation during diastole. ( See "Tissue Doppler echocardiography", and see "Cardiac resynchronization therapy (biventricular pacing) in heart failure" , section on Tissue Doppler imaging, and See "Echocardiographic evaluation of left ventricular diastolic function" , section on Tissue Doppler echocardiography) The prevalence of systolic and diastolic dyssynchrony in patients with DHF was assessed in two observational series [41,42] . Using TDI, systolic and diastolic dyssynchrony were noted in 33 to 39 percent and 36 to 58 percent of DHF patients, respectively. This prevalence was similar to that observed in patients with systolic HF. However, whether or not dyssynchrony is an important contributor to the pathophysiology of DHF remains uncertain. In selected patients with heart failure due to systolic dysfunction, treatment of dyssynchrony with cardiac resynchronization therapy (CRT) with biventricular (BiV) pacing can improve both symptoms and survival. CRT is not used for the treatment of DHF. The clinical significance and treatment of dyssynchrony in patients with systolic HF are discussed in detail separately. ( See "Cardiac resynchronization therapy (biventricular pacing) in heart failure" ). MECHANISMS BY WHICH CARDIAC DISEASES CAUSE DHF A variety of cardiac diseases can cause the development of abnormal diastolic function. The two most common pathways are ischemia and left ventricular hypertrophy. Cardiovascular disorders that lead to DHF include: Coronary artery disease and myocardial ischemia. Chronic hypertension with concentric remodeling. ( See "Clinical implications and treatment of left ventricular hypertrophy in hypertension" ). Valvular aortic stenosis. (See "Pathophysiology and clinical features of valvular aortic stenosis in adults").

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Hypertrophic cardiomyopathy. (See "Pathophysiology of obstructive hypertrophic cardiomyopathy" and see "Clinical manifestations of hypertrophic cardiomyopathy" ). These mechanisms can act individually to alter diastolic function but often act in concert to cause the development of DHF. For ease of understanding, these mechanisms will first be discussed individually. Ischemia Ischemia can cause a reversible impairment in myocyte relaxation and diastolic function. The resultant slowing or failure of myocyte relaxation causes a fraction of actin-myosin crossbridges to persist and continue to generate tension throughout diastole, especially in early diastole, creating a state of "partial persistent systole." Two kinds of ischemia can alter diastolic function: demand ischemia created by an increase in energy utilization that outstrips the necessary supply; and supply ischemia created by a decrease in myocardial blood flow without a change in energy utilization. Demand ischemia Demand ischemia typically occurs during exercise or pharmacologically induced stress. It results from an increase in oxygen demand in the setting of limited coronary flow reserve due to a coronary stenosis and/or ventricular hypertrophy. During demand ischemia, diastolic dysfunction may be related to myocardial ATP depletion, a decrease in free energy release from ATP hydrolysis and a concomitant increase in ADP [43,44] , resulting in rigor (rigor bond formation) [43,45] . Although ischemia is also associated with persistence of an increased intracellular calcium concentration during diastole, it is not clear if elevated calcium levels contribute directly to diastolic dysfunction [ 46] . (See "Excitation-contraction coupling in myocardium" ). As a result of rigor, LV pressure decay, as assessed by tau, is impaired and the LV is stiffer than normal during diastole. This will result in retardation of LV filling [ 47] . Supply ischemia Supply ischemia results from a marked reduction in coronary flow. The net effect is inadequate coronary perfusion even in the resting state. Acute supply ischemia causes an initial transient downward and rightward shift of the diastolic P-V curve such that end-diastolic volume increases relative to end-diastolic pressure, indicating a "paradoxical" increase in diastolic compliance [ 48] . By contrast, during demand ischemia, diastolic compliance falls acutely [48-50] . These opposite initial compliance changes with demand and supply ischemia may be explained by differences in the pressure and volume within the coronary vasculature, by the mechanical effects of the normal myocardium adjacent to the ischemic region, and by tissue metabolic factors. The differences between supply and demand ischemia are transient. After more sustained ischemia of 30 to 60 minutes or longer, both types result in decreased diastolic compliance. Ischemia and pulmonary symptoms Ischemia, either spontaneous or during exercise, prevents the normal increase in LV distensibility and can also cause a rapid and marked increase in LV diastolic chamber stiffness. In the latter setting, LV diastolic pressures quickly increase, resulting in acute pulmonary congestion (show figure 7 and show figure 8). This upward shift of the left ventricular diastolic P-V curve is completely reversible with recovery of myocardial perfusion [ 19] . The effects of ischemia explain why many patients with coronary disease have respiratory symptoms with their anginal pain, including wheezing, an inability to take a deep breath, or shortness of breath. Such respiratory symptoms may occur in the absence of anginal pain and are often referred to as "anginal equivalents." (See "Pathophysiology and clinical presentation of ischemic chest pain" ). These respiratory symptoms are similar to those of HF, which is not surprising since the responsible mechanism is an elevation in pulmonary capillary pressure. One study, for example, showed that the

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acute decrease in left ventricular distensibility and increase in diastolic pressure during angina caused an increase in airway resistance and a reduction lung compliance [ 51] . A similar symptom complex can occur in patients with concentric LVH even in the absence of epicardial CAD. ( See "LV concentric hypertrophy" below). Reperfusion Ischemic diastolic dysfunction can continue after normal myocardial blood flow has been reestablished (ie, reperfusion). This phenomenon has been noted both after cardiac surgery and after primary reperfusion therapy for an acute myocardial infarction [ 52-54] . Postischemic mechanical dysfunction results in both systolic and diastolic dysfunction, and the latter may be a more sensitive parameter of ischemic injury [48] . During reperfusion, LV diastolic chamber stiffness is increased [52,53] . Over time, diastolic dysfunction resolves and it is therefore reasonable to refer to this process as postischemic diastolic stunning. Recognition of this phenomenon is important because a reduced cardiac output or elevated pulmonary capillary wedge pressure in the early postoperative period or early after treatment of acute coronary syndrome may reflect an increase in LV diastolic chamber stiffness rather than a reduction in contractile function. This distinction can be made readily with echocardiography. LV concentric hypertrophy Widespread use of noninvasive methods of cardiac imaging has led to the recognition that LV diastolic dysfunction and DHF are commonly induced by the myocardial hypertrophy associated with hypertensive, coronary, or valvular heart disease. The resistance to diastolic filling is usually the result of common structural abnormalities including concentric LV remodeling, cardiomyocyte hypertrophy, altered extracellular matrix structure and composition, and increased fibrillar collagen. All of these hypertrophy associated changes lead to impaired cellular and myocardial relaxation. (See "Cellular mechanisms of diastolic dysfunction" ). LVH and ischemia have important interactions; for a given degree of ischemia; a greater decline in diastolic function is seen in hypertrophied hearts [ 5,55] . Hearts with concentric LVH are highly susceptible to subendocardial ischemia for several reasons [ 56] : There is some evidence of inadequate coronary growth relative to muscle mass, with a resultant decrease in capillary density [ 57] . The ensuing increase in capillary to myocyte oxygen diffusion distance renders the hypertrophied myocyte more susceptible to ischemia. The increase in ventricular wall thickness raises the epicardial-endocardial distance The coronary arterial circulation consists of epicardial vessels which penetrate transmurally, giving rise to mid-myocardial branches which perfuse the thickened left ventricular wall before supplying the subendocardium. Thus, coronary perfusion pressure is dissipated in proportion to left ventricular wall thickness, leaving the subendocardium as the region most vulnerable to ischemia [56] . Coronary arterial remodeling accompanies concentric hypertrophy and is manifested by an increase in coronary arterial medial thickness and perivascular fibrosis, which can restrict the extent of coronary arterial vasodilatation. Vascular tone at rest is often abnormally reduced and coronary flow at rest is increased in the hypertrophied heart [58,59] . Enhanced coronary flow is required in the resting state to supply the increased muscle mass. However, since maximal achievable coronary flow is similar to that of normal ventricles, coronary flow reserve is diminished. Endothelial dysfunction also may contribute to the reduction in coronary reserve, although the response to exogenous nitric oxide is preserved [60,61] . Thus, when metabolic demand and the need for oxygen increases, coronary reserve is often inadequate to meet the increased oxygen requirements, and ischemia ensues [59] .

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Increased left ventricular diastolic pressures can cause vascular compression, thereby reducing coronary flow and perfusion of the subendocardial layer [56] . The incidence and severity of coronary atherosclerosis is increased in the presence of systemic arterial hypertension, a frequent cause of concentric LVH. Thus, patients with concentric LVH on a hypertensive basis often have significant concomitant coronary artery disease. These factors make the heart with concentric LVH exquisitely sensitive to subendocardial ischemia. The hypertrophied ventricle also cannot relax normally in diastole with exercise. Thus, to produce the necessary increase in ventricular input, there is an increase in left atrial pressure rather than the normal reduction in ventricular pressure, which produces a suction effect as described above. This can lead to an elevation in pulmonary capillary pressure that is sufficient to induce pulmonary congestion. Exercise-induced subendocardial ischemia can produce an "exaggerated" impairment of diastolic relaxation of the hypertrophied myocardium.

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REFERENCES
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GRAPHICS
Elevated left ventricular end-diastolic pressure causes pulmonary congestion

The heart is seen in diastole when the mitral valve is open and the left ventricle (LV), left atrium (LA), and pulmonary veins forms a common chamber, continuous with the pulmonary capillary bed. The LV end diastolic pressure determines the pulmonary capilalry pressure and the presence or absence of pulmonary congestion or edema.

Phases of diastole

Effects of exercise on left ventricular filling dynamics

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Changes in left ventricular (LV) pressure (PLV), left atrial pressure changes (PLA), and the rate of change of PLV (dV/dt) at rest and during exercise. Top panel: During exercise in normals, minimal PLV decreases without any change in PLA, leading to an increase in the peak mitral valve gradient and producing a higher peak filling rate (E). Bottom panel: In congestive heart failure (panel B), the peak LV filling rate (E) increases during exercise due to an increase in the early transmitral valve pressue gradient. However, the gradient is produced by an increase in left atrial pressure instead of a reduction in PLV as occurs in normals.

Left ventricular pressure/volume relationships

The left ventricular (LV) pressure/volume relationships at rest and during exercise at early, mid, and end- diastole are shown. The simultaneous measurements of LV diastolic pressure and volume define distensibility or compliance. In the normal individual with normal compliance (left panel), exercise causes a dowward shift of the diastolic pressure/volume curve in early diastole, indicating an increase in LV distensibility; the increase in cardiac output occurs without an increase in LV diastolic pressure. In a patient with ischemia (middle panel), exercise causes a marked upward shift in the curve, indicating a reduction in LV distensibility, or diastolic

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dysfunction, and there is a significant increase in LV and pulmonary capillary wedge pressures as LV volume or cardiac output increases. This may result in the development of pulmonary congestion and respiratory symptoms. In the patient with a previous myocardial infarction and an LV scar (right panel), the early increase in diastolic distensibility with exercise is lost but there is no change in the pressure/volume curve in the absence of ischemia. Data from Carroll, JD, Hess, OM, Hirzel, HO, et al,
Circulation 1983; 68:59.

Measures of isovolumic relax

Doppler findings in diastolic heart failure

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Schematic representation of LV and left atrial (LA) pressures during diastole, transmitral Doppler LV inflow velocity, pulmonary vein Doppler velocity, and Doppler tissue velocity in normals and in different types of diastolic heart failure. Compared to the normal pattern, Doppler of mitral flow in patients with an abnormality in relaxation due to diastolic dysfunction shows a reduced peak early diastolic flow velocity (E), a prolonged E wave diastolic deceleration time of early diastolic filling (DDT), and an increased peak diastolic flow velocity with atrial contraction (A). With myocardial restriction, there is an increase in E, but a shortened DDT and a decrease in A. IVRT indicates isovolumic relaxation time; PVs, systolic pulmonary vein velocity; PVd, diastolic pulmonary vein velocity; PVa, pulmonary vein velocity resulting from atrial contraction; Sm, myocardial velocity during systole; Em, myocardial velocity during early filling; and Am, myocardial velocity during filling produced by atrial contraction. Reproduced with permission from:
Zile, MR, Brutsaert, DL. New concepts in diastolic dysfunction and diastolic heart failure: Part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 2002; 105:1387. Copyright 2002 Lippincott Williams &Wilkins.

PCWP increases during exercise in diastolic dysfunction

During symptom-limited upright exercise, normal subjects have an increase in left ventricular end diastolic volume (LVEDV), associated with a modest increase in pulmonary capillary wedge pressure (PCWP) which remains within a normal range (red arrow). In contrast, patients with normal systolic function who have left ventricular hypertrophy, diastolic dysfunction, and a stiff, nondistensible left ventricle have a marked increase in PCWP with exercise, often to levels associated with pulmonary edema (blue arrow), but no change in LVEDV. This is consistent with exercise-induced ischemia and an exaggerated impairment of diastolic relaxation of the hypertrophied myocardium. Data from Kitzman, DW,
Higginbotham, MB, Cobb, FR, et al, J Am Coll Cardiol 1991; 17:1065.

Pressure volume exercise

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