Journal of the American College of Cardiology 2012 by the American College of Cardiology Foundation Published by Elsevier Inc.

Vol. 59, No. 5, 2012 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.10.875

Hyperglycemia and the Heart

Chronic Hyperglycemia and Subclinical Myocardial Injury

Jonathan Rubin, MD,* Kunihiro Matsushita, MD, PHD,* Christie M. Ballantyne, MD, Ron Hoogeveen, PHD, Josef Coresh, MD, PHD,* Elizabeth Selvin, PHD, MPH* Baltimore, Maryland; and Houston, Texas
Objectives Background
The purpose of this study was to examine the association between hyperglycemia and subclinical myocardial injury in persons without clinically evident coronary heart disease (CHD). Hyperglycemia is associated with an increased risk of cardiac events, but limited information is available on its relationship to subclinical myocardial damage. Elevated cardiac troponin T even below traditional detection levels can be detected by a novel high-sensitivity assay. We examined the association between baseline glycated hemoglobin (HbA1c) and high-sensitivity cardiac troponin T (hs-cTnT) in 9,661 participants free of CHD and heart failure in the ARIC (Atherosclerosis Risk in Communities) study. Multivariable logistic regression models characterized the association between clinical categories of HbA1c (5.7%, 5.7% to 6.4%, and 6.5%) and our primary outcome of elevated hs-cTnT (14 ng/l). Higher baseline values of HbA1c were associated in a graded fashion with elevated hs-cTnT (p for trend 0.001). After adjusting for traditional risk factors, compared to persons with HbA1c 5.7%, the odds ratios of elevated hs-cTnT for persons with HbA1c 5.7% to 6.4% and 6.5% were 1.26 (95% condence interval: 1.01 to 1.56) and 1.97 (95% condence interval: 1.44 to 2.70), respectively. Higher HbA1c is associated with elevated hs-cTnT among persons without clinically evident CHD, suggesting that hyperglycemia contributes to myocardial injury beyond its effects on development of clinical atherosclerotic coronary disease. (J Am Coll Cardiol 2012;59:4849) 2012 by the American College of Cardiology Foundation

Methods

Results

Conclusions

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among persons with diabetes mellitus (1). Although the excess cardiovascular risk observed in dysglycemic states has been partially explained by coexisting cardiovascular risk factors (e.g., obesity and hypertension), there is strong evidence supporting hyperglycemia, even below the threshold of diabetes, as an independent risk factor for coronary heart disease (CHD) morbidity and mortality (2). Glycated hemoglobin (HbA1c), a marker of chronic hyperglycemia, is associated with incident CHD

(3,4) and all-cause mortality (4 6) and has recently been recommended as a diagnostic test for diabetes mellitus (7). Much less is known about the association of chronic hyperglycemia with subclinical CHD. A small number of studies have used imaging techniques to examine the crosssectional relationship of HbA1c with subclinical atherosclerosis (8,9). There is limited information on the relationship between hyperglycemia and subclinical myocardial injury at earlier stages, before it can be detected by imaging modalities.
See page 490

From the *Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; and the Department of Medicine, Section of Atherosclerosis and Vascular Medicine, Baylor College of Medicine, Houston, Texas. The ARIC study is supported by National Heart, Lung, and Blood Institute (NHLBI) contracts N01-HC-55015 through N01-HC-55022. Dr. Rubin was supported by NHLBI grant 5T32HL007024, Dr. Selvin by NIH/NIDDK grants R21 DK080294 and K01 DK076595, and Dr. Coresh by NIH/NIDDK grant R01-DK-076770. The National Institutes of Health had no role in the collection, analysis, interpretation of the data or preparation, review, and approval of the manuscript. Dr. Ballantyne has received a grant to Baylor College of Medicine from Roche. All other authors have reported they have no relationships relevant to the contents of this paper to disclose. Manuscript received July 20, 2011; revised manuscript received September 27, 2011, accepted October 17, 2011.

Newly identied biomarkers allow for the noninvasive identication of subclinical myocardial damage (10). Cardiac troponin-T (cTnT) has been independently associated with CHD (11,12). A novel high-sensitivity cardiac troponin-T (hs-cTnT) assay allows for the detection of hs-cTnT levels below clinical thresholds or detection levels of earlier assays. Using this novel assay, troponin levels below the conventional limit of detection have recently been shown to predict cardiovascular events and death in persons with congestive heart failure (CHF) (13), CHD (14), and in the general population (1517). Some have suggested that

JACC Vol. 59, No. 5, 2012 January 31, 2012:4849

Rubin et al. HbA1c and Myocardial Injury

485

minimally elevated troponin levels may represent subclinical cardiac injury (18,19) and hs-cTnT may now allow for the identication of previously undetected early stages of myocardial injury. The objective of this study was to test the hypothesis that in persons without clinically evident CHD or heart failure, chronic hyperglycemiaassessed by HbA1cwould be independently associated with subclinical myocardial injury measured by elevated hs-cTnT.

Results

Methods More detailed methods are described in the online Supplement. Briey, we explored the association between categories of HbA1c and hs-cTnT in participants without CHD in the ARIC (Atherosclerosis Risk in Communities) study. The cTnT was measured using a novel high-sensitivity assay, Elecsys Troponin T (Roche Diagnostics, Indianapolis, Indiana) with a lower limit of detection of 3.0 ng/l. Elevated hs-cTnT was dened as levels above the previously reported 99th percentile value (14 ng/l) in a healthy subpopulation ages 20 to 70 years. Statistical analysis. The HbA1c was modeled as a continuous variable and by clinical categories: 5.7%, 5.7% to 6.4%, and 6.5% (7), and baseline characteristics were compared across these categories. Linear splines (with knots at clinical cut-points) were used to characterize the shape of the association between HbA1c and hs-cTnT and multivariable logistic regression to assess the association between categories of HbA1c and elevated hs-cTnT (14.0 ng/l). For continuous models, undetectable levels of hs-cTnT were assigned a value of 1.5 ng/l (i.e., one-half the lower limit of detection). In participants who fasted 8 h at the time of visit 2 (n 9,550), we evaluated the association of categories of fasting glucose: 100 mg/dl, 100 to 125 mg/dl, and 126 mg/dl, with elevated hs-cTnT. We implemented 4 models for the adjustment of covariates: model 1 unadjusted; model 2 adjusted for age, sex and race; model 3 adjusted for eld center, body mass index, education, systolic and diastolic blood pressures, smoking, low-density lipoprotein and high-density lipoprotein cholesterol, alcohol, hypertension medication, left ventricular hypertrophy, history of diabetes, and estimated glomerular ltration rate; and model 4a adjusted for fasting glucose and model 4b adjusted for HbA1c. Sensitivity analyses excluded persons with atrial brillation, estimated glomerular ltration rate 60 ml/min/1.73 m2 or stroke, before or at visit 4. We also excluded persons with incident CHD up to 6 months after hs-cTnT samples were obtained. We tested for interaction with age, race, and sex. Analyses were conducted using STATA 11.1 (StataCorp., College Station, Texas), and a p value of 0.05 was statistically signicant.

Mean age was 56.6 years, and CHD coronary heart 58.9% were female (Table 1). disease Participants with higher HbA1c CI condence interval were more likely to be African CHF congestive heart American, hypertensive, and failure have higher body mass index and CVD cardiovascular low-density lipoprotein cholesdisease terol, and lower high-density liHbA1c glycated poprotein cholesterol. A total of hemoglobin 6,400 subjects (66.3%) had dehs-cTnT high-sensitivity tectable levels of hs-cTnT. In cardiac troponin-T persons with and without a hisOR odds ratio tory of diagnosed diabetes, the corresponding percentages were 81.9% and 65.2%. Baseline HbA1c was positively associated with hs-cTnT in a linear fashion (tests for differences in the slope at clinical cut-points of HbA1c were not signicant) (Fig. 1). Compared to persons with HbA1c 5.7%, hs-cTnT values were 25% higher in persons with HbA1c 5.7% to 6.4% and 70% higher among participants with HbA1c 6.5%. In fully adjusted models, every 1-percentage point higher HbA1c value was associated with a 0.7 ng/l higher value of hs-cTnT (95% condence interval [CI]: 0.5 to 1.0; p 0.001). Overall, 7.3% of participants had elevated hs-cTnT (14 ng/l). In persons with and without diabetes, the corresponding percentages were 21.8% and 6.3%. In this population of persons without clinically evident CHD or heart failure, the 99th percentile of hs-cTnT was 30 ng/l. The corresponding 99th percentiles were 27 ng/l and 54 ng/l for persons without and with a history of diabetes, respectively. Increasing HbA1c categories were associated in a graded fashion with elevated hs-cTnT (Fig. 2). In analysis adjusted for age, sex, and race, the percentage of persons with elevated hs-cTnT among persons with a HbA1c 5.7%, 5.7% to 6.4%, and 6.5% was 3.8%, 5.7%, and 14.0%, respectively. Compared to persons with HbA1c 5.7%, higher HbA1c values were strongly associated with elevated hscTnT (Table 2). In age, race, and sex adjusted analyses, increasing HbA1c categories was signicantly associated with elevated hs-cTnT for HbA1c of 5.7% to 6.4% (odds ratio [OR]: 1.51; 95% CI: 1.23 to 1.85) and for HbA1c 6.5% (OR: 4.09; 95% CI: 3.25 to 5.15). After adjusting for other cardiovascular risk factors, the association was attenuated but remained signicant. This association was unaltered by further adjustment for fasting glucose (Table 2, Model 4a). Analysis performed stratied by previously diagnosed diabetes demonstrated a similar association (Online Table 1). Excluding participants with estimated glomerular ltration rate 60 ml/min/1.73 m2, stroke, atrial brillation before or at visit 4, and persons with incident CHD within 6 months after hs-cTnT measurement did not alter the results (Online Table 2).

Abbreviations and Acronyms

486

Rubin et al. HbA1c and Myocardial Injury

JACC Vol. 59, No. 5, 2012 January 31, 2012:4849

Baseline by Clinical Categories Glycated Hemoglobin Table 1 Characteristics Baseline Characteristics by Clinicalof Categories of Glycated Hemoglobin
Total (n 9,661) 5.4 (5.25.8) 109.7 34.8 56.6 5.6 58.9 22.0 132.2 35.9 50.9 16.7 27.8 5.3 85.7 17.8 31.3 6.3 1.7 <5.7% (n 7,169) 5.3 (5.16.5) 100.6 10.4 56.3 5.6 59.3 14.5 130.5 35.3 52.3 17.0 27.0 4.7 84.7 16.8 26.2 1.1 1.1 5.7%6.4% (n 1,729) 5.9 (5.86.1) 111.3 16.6 57.6 5.6 56.0 40.7 137.0 36.7 48.1 14.9 29.3 5.8 87.6 19.5 41.5 5.6 3.2 >6.5% (n 763) 7.5 (6.89.5) 191.7 76.4 57.5 5.7 62.4 49.8 137.7 37.9 44.8 14.0 31.8 5.9 90.7 21.2 56.1 56.5 3.6

Characteristic Glycated hemoglobin, % Fasting glucose, mg/dl Age, yrs Female, % African American, % LDL-cholesterol, mg/dl HDL-cholesterol, mg/dl Body mass index, kg/m2* eGFR, ml/min/1.73 m2 Hypertension, % History of diabetes, % Left ventricular hypertrophy, % Education, % Less than high school High school or equivalent College or above Alcohol use, % Current Former Never Smoking status, % Current Former Never

18.1 42.4 39.5

14.3 43.6 42.1

27.1 39.6 33.3

33.3 37.2 29.5

58.9 18.5 22.6

63.7 15.5 20.8

48.8 25.4 25.8

36.2 31.2 32.6

19.1 37.6 43.3

17.6 38.0 44.3

25.4 36.1 38.4

18.1 36.4 45.5

Values are median (25th to 75th percentiles), mean SD, or proportions. *The body-mass index is the weight in kilograms divided by the square of the height in meters. Left ventricular hypertrophy calculated by electrocardiographic Cornell criteria. eGFR estimated glomerular ltration rate; LDL low-density lipoprotein; HDL high-density lipoprotein.

In age, race, and sex adjusted analyses, compared to persons with a fasting glucose 100 mg/dl, higher fasting glucose levels were associated with elevated hs-cTnT (OR for glucose 126 mg/dl: 2.93, 95% CI: 2.30 to 3.75) (Table 3). This association was no longer signicant after adjusting for additional cardiovascular risk factors or after further adjustment for HbA1c (Table 3, Model 4b).

There was no interaction between HbA1c and sex or race for elevated hs-cTnT (p 0.110 for both). There was evidence that age may modify the association between HbA1c and elevated hs-cTnT (p for interaction

Figure 1

Linear Spline Models

Figure 2

Percentage of Subjects With Elevated hs-cTnT, by HbA1c Category

Plotted values using linear spline models with knots at glycated hemoglobin (HbA1c) of 5.7% and 6.5%. Adjusted for age, sex, and race, and truncated at HbA1c of 13%. Shaded areas represent 95% condence intervals.

Percentage and 95% condence intervals of subjects with elevated high-sensitivity cardiac troponin-T (hs-cTnT), by category of glycated hemoglobin (HbA1c). Adjusted for age, sex, and race.

JACC Vol. 59, No. 5, 2012 January 31, 2012:4849

Rubin et al. HbA1c and Myocardial Injury

487

Odds Ratios (95% Ratios CI) for (95% Elevated hs-TnT by Clinical Categories HbA1c of HbA1c Table 2 Odds CI) for Elevated hs-TnT by Clinicalof Categories
Model 1 HbA1c Category 5.7% (Reference) 5.7% to 6.4% 6.5% p value for trend overall OR 1.00 1.91 4.30 0.001 (95% CI) (Reference) 1.582.30 3.505.29 OR 1.00 1.51 4.09 0.001 Model 2 (95% CI) (Reference) 1.231.85 3.255.15 OR 1.00 1.26 1.97 0.001 Model 3 (95% CI) (Reference) 1.011.56 1.442.70 OR 1.00 1.23 1.70 0.003 Model 4a (95% CI) (Reference) 0.991.53 1.172.46

Model 1 unadjusted. Model 2 adjusted for age, race, and sex. Model 3 model 2 plus eld center, body mass index, education, systolic and diastolic blood pressures, smoking, low-density lipoprotein and high-density lipoprotein cholesterol, alcohol use, hypertension medication use, estimated glomerular ltration rate, left ventricular hypertrophy, and history of diagnosed diabetes mellitus. Model 4a model 3 plus fasting glucose concentration. CI condence interval; HbA1c glycated hemoglobin; hs-TnT highly sensitive troponin T; OR odds ratio.

0.048). When stratied by median age (56 years), compared to persons with HbA1c 5.7%, HbA1c 6.5% was more strongly associated with elevated hs-cTnT among younger persons (OR: 2.13; 95% CI: 1.23 to 3.69) than among older ones (OR: 1.88; 95% CI: 1.28 to 2.76). Discussion In a community-based population of almost 10,000 subjects without clinically evident CHD, chronic hyperglycemia was independently associated with subclinical myocardial injury, as assessed by elevated levels of hs-cTnT in both persons with and without diabetes. Elevated troponin levels have been previously associated with cardiovascular events (11). Using conventional assays, troponin can be detected in 0.7% of the population (20) and is associated with myocardial infarction and death (11). In contrast, the novel high-sensitivity troponin assay allows for the detection of troponin at levels far below previous detection limits. We observed that hs-cTnT was present in 66.3% of the ARIC study population without clinically evident CHD. The 99th percentile value for hs-cTnT in our study (30 ng/l) was considerably higher than that reported by the manufacturer (14 ng/l) in a healthy population ages 20 to 70 years. Firm reference ranges for this assay have not yet been established. Others have recently shown in both the ARIC study (17) and in other cohorts (15,16) that troponin levels measured with the highly sensitive assay independently predict cardiovascular events. In the ARIC study, hs-cTnT levels above the 99th percentile were associated with all-cause mortality (OR: 3.69, 95% CI: 3.21 to 4.88) (17). Also of

interest, minimally elevated levels of hs-cTnT (3 to 5 ng/l) were associated with all-cause mortality (OR: 1.37, 95% CI: 1.14 to 1.65). Numerous studies have demonstrated associations between hyperglycemia and macrovascular and microvascular complications (2 4,6). The use of this high sensitivity assay allowed for the detection of minimally elevated troponin levels thought to represent subclinical cardiac injury (1820). Although hyperglycemia is traditionally thought to be associated with cardiovascular events through atherosclerosis, our results suggest that hyperglycemia may contribute to cardiovascular events by alternate mechanisms. A potential mechanism by which hyperglycemia induces myocardial injury is hyperglycemia-mediated coronary microvascular dysfunction (21,22). Other mechanisms include oxidative stress (21), advanced glycation end-products (23,24), and myocardial brosis (25). Diabetic subjects have increased oxidative stress (26), and administration of antioxidant vitamin C has been shown to improve endothelial dysfunction in diabetic patients (27). Finally, hyperglycemia may also be associated with myocardial damage through silent atherosclerotic disease and, as others have shown, as many as 12% of asymptomatic diabetic subjects had coronary artery stenosis 75% (28). Although some have demonstrated associations of hyperglycemia with subclinical CVD using imaging modalities (8,9), we have demonstrated an association between hyperglycemia and early subclinical myocardial injury. Recent studies using this new highly sensitive assay for cTnT suggest that the association with cardiac outcomes is medi-

Odds Ratios (95% Ratios CI) for (95% Elevated hs-TnT by Clinical Categories Glucose of Glucose Table 3 Odds CI) for Elevated hs-TnT by Clinicalof Categories
Model 1 Glucose Category 100 mg/dl (Reference) 100 to 126 mg/dl 126 mg/dl p value for trend OR 1.00 1.64 3.99 0.001 1.361.97 3.175.03 (95% CI) OR 1.00 1.17 2.93 0.001 0.961.42 2.303.75 Model 2 (95% CI) OR 1.00 0.95 1.30 0.075 0.781.16 0.951.78 Model 3 (95% CI) OR 1.00 0.91 0.88 0.501 0.741.11 0.621.25 Model 4b (95% CI)

Model 1 unadjusted. Model 2 adjusted for age, race, and sex. Model 3 model 2 plus eld center, body mass index, education, systolic and diastolic blood pressures, smoking, low-density lipoprotein and high-density lipoprotein cholesterol, alcohol use, hypertension medication use, estimated glomerular ltration rate, left ventricular hypertrophy, and history of diagnosed diabetes mellitus. Model 4b model 3 plus glycated hemoglobin. Abbreviations as in Table 2.

488

Rubin et al. HbA1c and Myocardial Injury

JACC Vol. 59, No. 5, 2012 January 31, 2012:4849

ated by mechanisms independent of atherosclerosis (1417). While left ventricular mass was independently associated with detectable levels of hs-cTnT, coronary artery calciuma marker of coronary atherosclerosiswas not (16). The hs-cTnT had a stronger association with total mortality and heart failure than with CHD (17). Furthermore, the association with nonfatal CHD was even weaker than for fatal CHD, again suggesting that hs-cTnT is related to outcomes by mechanisms other than atherosclerosis. Nevertheless, because of the observational nature of these investigations, the mechanisms remain unclear. Our results suggest that HbA1c performs better as a marker of subclinical myocardial damage compared to fasting glucose and are consistent with the growing body of literature demonstrating that HbA1c is an important marker of cardiovascular risk (4). Our data support new recommendations for the use of HbA1c for the diagnosis of diabetes and identication of persons at high risk for development of complications (7). Study limitations. Measurements of HbA1c and hs-cTnT were not available at the same visit. Although in sensitivity analysis we excluded persons with any history of clinical CHD at visit 4 and incident CHD in the 6 months after hs-cTnT measurement, we cannot rule out the possibility that a number of subjects had elevated troponin levels at the baseline visit. Although elevated hs-cTnT levels have now been associated with increased CVD (1517), whether clinical management should be modied on the basis of chronically elevated levels of troponin is unknown. Because we excluded persons who died or had CHD between visit 2 and visit 4 and because HbA1c is associated with both elevated troponin levels and mortality, there is a possibility that this resulted in selection bias. That would tend to underestimate the true association. Although we adjusted for known risk factors for CHD, we cannot exclude the possibility of residual confounding in this observational study. There were 679 people excluded from our analysis (10% of the study sample) due to missing data. Nonetheless, this study represents one of the largest community-based studies of HbA1c and hs-cTnT. Additional major strengths of this study include the large sample of persons with and without diabetes, including a large number of African Americans, rigorous measurement of cardiovascular risk factors, and our ability to exclude clinical CHD cases utilizing comprehensive and adjudicated surveillance data for clinical events.

Reprint requests and correspondence: Dr. Elizabeth Selvin, Johns Hopkins Bloomberg School of Public Health, 2024 East Monument Street, 2-600, Baltimore, Maryland 21205. E-mail: lselvin@jhsph.edu.
REFERENCES

Conclusions In this community-based study of persons without clinically evident CHD, HbA1c was associated with hs-cTnT in a graded fashion. Our ndings suggest that hyperglycemia contributes to myocardial injury beyond its effects on the development of clinical atherosclerotic coronary disease.

1. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA 1979;241:2035 8. 2. Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010;375:221522. 3. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:40512. 4. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:80011. 5. Khaw KT, Wareham N, Luben R, et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European Prospective Investigation of Cancer and Nutrition (EPIC-Norfolk). BMJ 2001;322:15 8. 6. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med 2004;141:42131. 7. Diagnosis and classication of diabetes mellitus. Diabetes Care 2011;34 Suppl:629. 8. Sander D, Schulze-Horn C, Bickel H, Gnahn H, Bartels E, Conrad B. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke 2006;37:3517. 9. McNeely MJ, McClelland RL, Bild DE, et al. The association between A1C and subclinical cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis. Diabetes Care 2009;32:172733. 10. Melander O, Newton-Cheh C, Almgren P, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009;302:49 57. 11. Daniels LB, Laughlin GA, Clopton P, Maisel AS, Barrett-Connor E. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study. J Am Coll Cardiol 2008;52:450 9. 12. Januzzi JL Jr., Bamberg F, Lee H, et al. High-sensitivity troponin T concentrations in acute chest pain patients evaluated with cardiac computed tomography. Circulation 2010;121:122734. 13. Latini R, Masson S, Anand IS, et al. Prognostic value of very low plasma concentrations of troponin T in patients with stable chronic heart failure. Circulation 2007;116:12429. 14. Omland T, de Lemos JA, Sabatine MS, et al. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med 2009;361:2538 47. 15. deFilippi CR, de Lemos JA, Christenson RH, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA 2010;304:2494 502. 16. de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA 2010;304:250312. 17. Saunders JT, Nambi V, de Lemos JA, et al. Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease, heart failure, and mortality in the Atherosclerosis Risk in Communities study. Circulation 2011;123:136776. 18. Morrow DA, Antman EM. Evaluation of high-sensitivity assays for cardiac troponin. Clin Chem 2009;55:5 8. 19. Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J 2009;30:1629. 20. Wallace TW, Abdullah SM, Drazner MH, et al. Prevalence and determinants of troponin T elevation in the general population. Circulation 2006;113:1958 65. 21. Di Carli MF, Janisse J, Grunberger G, Ager J. Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes. J Am Coll Cardiol 2003;41:138793.

JACC Vol. 59, No. 5, 2012 January 31, 2012:4849 22. Williams SB, Goldne AB, Timimi FK, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998;97:1695701. 23. Huebschmann AG, Regensteiner JG, Vlassara H, Reusch JE. Diabetes and advanced glycoxidation end products. Diabetes Care 2006;29: 1420 32. 24. Monnier VM, Sell DR, Genuth S. Glycation products as markers and predictors of the progression of diabetic complications. Ann N Y Acad Sci 2005;1043:567 81. 25. Asbun J, Villarreal FJ. The pathogenesis of myocardial brosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 2006;47:693700. 26. Monnier L, Mas E, Ginet C, et al. Activation of oxidative stress by acute glucose uctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 2006;295:16817.

Rubin et al. HbA1c and Myocardial Injury

489

27. Timimi FK, Ting HH, Haley EA, Roddy MA, Ganz P, Creager MA. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998;31:5527. 28. Rivera JJ, Nasir K, Choi E-K, et al. Detection of occult coronary artery disease in asymptomatic individuals with diabetes mellitus using non-invasive cardiac angiography. Atherosclerosis 2009;203: 442 8. Key Words: diabetes mellitus y epidemiology y hyperglycemia.
APPENDIX

For supplemental tables, please see the online version of this article.