Diabetes and the Heart: Is There Objective Evidence of a Human Diabetic Cardiomyopathy?

The concept of a “diabetic cardiomyopathy” has been invoked to explain the higher than expected occurrence of congestive heart failure (CHF) in subjects with diabetes (1,2). However, the evidence supporting the existence of such a condition in humans is mostly inferential. Cardiomyopathies are chronic diseases of the myocardium in which the heart is abnormally enlarged, thickened, and/or stiffened. The weakened heart muscle has a reduced ability to pump blood effectively. Diabetic cardiomyopathy is frequently considered to be present when there is any abnormality of myocardial diastolic or systolic function, even when very mild, in a diabetic subject (or animal) without known hypertension or coronary artery disease. Isolated metabolic or biochemical abnormalities in the heart have also been taken as evidence of this entity. It has been referred to as a “specific” cardiomyopathy that may include features such as left ventricular (LV) hypertrophy, myocardial fibrosis, altered myocardial energetics, and variable degrees of myocardial mechanical dysfunction. There is some controversy about the existence and/or nature of a diabetic cardiomyopathy because there are inconsistencies in the definition of the syndrome, there is a high reliance on findings in small animal models, there are problems with referral bias in many clinical studies, and there is a lack of prospective or longitudinal human studies (3,4). It may be argued that the simple criteria frequently used to characterize this condition are not adequate for defining a cardiomyopathy. The structural, mechanical, histological, and biochemical features mentioned above also are not specific to one disease state. Rather they are common features of nearly all myocardial diseases. Inclusion of type 2 diabetic patients in studies of diabetic cardiomyopathy is problematic because it is very difficult to separate the cardiovascular effects of obesity and diabetes. If we draw analogy to clinical guidelines, the level of evidence supporting the existence of a specific diabetic cardiomyopathy in humans would likely be “C,” based on expert opinion rather than on results of large, randomized clinical trials. In this issue, we are treated to an article by Genuth et al. (5) showing findings after 21 years of total follow-up in a large cohort of type 1 diabetic patients who were enrolled in the Diabetes Control and Complications Trial (DCCT) (6) and subsequently the Epidemiology of Diabetes Intervention and Complications (EDIC) study (7). Between 1983 and 1989, DCCT randomized 1,441 subjects with type 1 diabetes to intensive versus conventional treatment for a mean of 6.5 years (8). Patients were followed for an additional 15 years in EDIC. In Genuth et al., 1,017 members (74%) of the original DCCT cohort underwent cardiac MRI for measurement of LV volumes, mass, ejection fraction, and aortic distensibility at w21 years after initial enrollment. The DCCT/EDIC study showed that intensive compared with conventional treatment during the DCCT was associated with a 57% reduction in a composite outcome of nonfatal myocardial infarction, stroke, or cardiovascular death from baseline DCCT through 11 years of EDIC (9). A summary of results from DCCT and EDIC relevant to the cardiovascular system is shown in Fig. 1. A history of microalbuminuria or albuminuria increased the risk of cardiovascular disease by a factor of 2.5 (9). At the time of the cardiac MRI in Genuth et al., mean age of the subjects was 49 years and mean duration of diabetes was 27 years. The main findings of the current study were that after 6.5 years of randomized treatment and 15 years of additional follow-up, there were no differences between the subjects in the DCCT intensive treatment versus the conventional treatment group in terms of LV end-diastolic volume (EDV), end-systolic volume, stroke volume, cardiac output, LV mass, LV ejection fraction, LV mass/EDV, or aortic distensibility. Surprisingly, in this large population with long-standing diabetes and only fair long-term diabetes control (mean HbA1c over the course of the study was 7.7–8.3%), LV size, geometry, and function were remarkably normal and not different from reported values in nondiabetic subjects. The mean LV EDV in the study was w137 mL, stroke volume w84 mL, ejection fraction w61%, and LV mass w137 g. None of these parameters are very suggestive of cardiomyopathy, a condition in which we would anticipate finding dilated chambers, increased LV mass, and reduced ejection fraction. It may be argued that subtle diastolic and systolic parameters, such as those derived from myocardial strain analysis or tissue Doppler recordings, were not measured in this study and, thus, evidence of a diabetic cardiomyopathy was missed. However, subclinical myocardial dysfunction that is not progressive over time and does not result in chamber enlargement, hypertrophy, or clinical heart failure is not necessarily indicative of a cardiomyopathy. Subclinical systolic and diastolic dysfunction that can only be detected with strain imaging is often seen in healthy aging, obesity, hypertension, and many other conditions. Therefore, such findings, even when present, are not specific to diabetes. Although there were no differences in cardiac geometry or function between the intensively and conventionally treated DCCT groups, the current study did show statistically significant relationships between mean HbA1c over the From the Medical College of Georgia, Georgia Regents University, Augusta, Georgia. Corresponding author: Sheldon E. Litwin, [email protected]. DOI: 10.2337/db13-0683 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 3561.