Diabetes Mellitus and Heart Failure
Diabetes Mellitus and Heart Failure
Type 2 diabetes mellitus substantially increases the lifetime risk of both developing and dying from heart failure. While this appears to be explained in part by the well-known association of diabetes with hypertension, dyslipidemia, and coronary atherosclerosis, additional pathophysiologic mechanisms linking type 2 diabetes and heart failure have recently been suggested. These include the potentially adverse effects of hyperglycemia on endothelial function and redox state, effects of excess circulating glucose and fatty acids on cardiomyocyte ultra-structure, intracellular signaling and gene expression, and the possibility that diabetes may impair recruitment of the myocardial insulin-responsive glucose transport system in response to ischemia. Because many of these putative pathophysiologic mechanisms should be amenable to normalization of the diabetic metabolic milieu, strategies designed to more carefully control circulating levels of glucose and fatty acids might conceivably delay or prevent the development of heart failure.
Type 2 diabetes mellitus affects more than 100 million persons worldwide and its prevalence is increasing in both developed and developing countries. Because type 2 diabetes is a predictable late consequence of sedentary behavior, obesity, and excessive caloric intake -- all common features of modern life -- this trend seems likely to continue. An association between type 2 diabetes and cardiovascular mortality has been apparent for more than a century and is supported by both longitudinal studies and registry data. This association is undoubtedly mediated in large part by the familiar effect of diabetes to accelerate coronary atherosclerosis. Thus, acute myocardial infarction is a more common mechanism of death in patients with type 2 diabetes than all other causes combined. However, several lines of evidence suggest that the cardiovascular mortality risk associated with type 2 diabetes may also reflect synergy in the development and progression of cardiomyopathy and congestive heart failure (CHF). The circumstantial evidence supporting an association of type 2 diabetes and cardiomyopathy is considerable. Patients with diabetes are over-represented in populations of subjects recruited for research studies of heart failure and have an increased lifetime risk of developing heart failure when followed longitudinally. On the macroscopic level, echocardiographic evaluation of large numbers of patients with diabetes has suggested a characteristic pattern of concentric left ventricular hypertrophy with mildly reduced systolic performance while Doppler studies have revealed qualitatively similar patterns of diastolic noncompliance in diabetic patients and animal models of diabetes. Nevertheless, the pathophysiologic mechanisms mediating the association of diabetes and heart failure remain uncertain. At least four factors contribute to this uncertainty. First, circulating glucose and insulin levels potentially influence a dauntingly large number of biologic processes important to cardiac function, including myocardial energy metabolism, myocyte growth and gene transcription, vascular and myocardial compliance, endothelial function, and thrombosis. Second, existing animal models of type 2 diabetes are at best uncertain mimics of the human disease, a chronic degenerative condition that appears to require decades-long exposure to specific environmental conditions in persons with a genetic tendency to the disease. The clinical relevance of the many pathologic changes described in animal models therefore awaits a more complete characterization of the physiology of type 2 diabetes in humans. Third, the morphologic and functional features of cardiomyopathy in patient and animal models of diabetes are difficult to distinguish from those of other conditions (e.g., hypertension) commonly associated with diabetes. Finally, few investigations have adequately addressed whether the adverse impact of diabetes on the development of heart failure can be ameliorated or prevented by diabetes-specific interventions. In the sections that follow, we will briefly review current theory regarding type 2 diabetes and heart failure.
Type 2 diabetes mellitus substantially increases the lifetime risk of both developing and dying from heart failure. While this appears to be explained in part by the well-known association of diabetes with hypertension, dyslipidemia, and coronary atherosclerosis, additional pathophysiologic mechanisms linking type 2 diabetes and heart failure have recently been suggested. These include the potentially adverse effects of hyperglycemia on endothelial function and redox state, effects of excess circulating glucose and fatty acids on cardiomyocyte ultra-structure, intracellular signaling and gene expression, and the possibility that diabetes may impair recruitment of the myocardial insulin-responsive glucose transport system in response to ischemia. Because many of these putative pathophysiologic mechanisms should be amenable to normalization of the diabetic metabolic milieu, strategies designed to more carefully control circulating levels of glucose and fatty acids might conceivably delay or prevent the development of heart failure.
Type 2 diabetes mellitus affects more than 100 million persons worldwide and its prevalence is increasing in both developed and developing countries. Because type 2 diabetes is a predictable late consequence of sedentary behavior, obesity, and excessive caloric intake -- all common features of modern life -- this trend seems likely to continue. An association between type 2 diabetes and cardiovascular mortality has been apparent for more than a century and is supported by both longitudinal studies and registry data. This association is undoubtedly mediated in large part by the familiar effect of diabetes to accelerate coronary atherosclerosis. Thus, acute myocardial infarction is a more common mechanism of death in patients with type 2 diabetes than all other causes combined. However, several lines of evidence suggest that the cardiovascular mortality risk associated with type 2 diabetes may also reflect synergy in the development and progression of cardiomyopathy and congestive heart failure (CHF). The circumstantial evidence supporting an association of type 2 diabetes and cardiomyopathy is considerable. Patients with diabetes are over-represented in populations of subjects recruited for research studies of heart failure and have an increased lifetime risk of developing heart failure when followed longitudinally. On the macroscopic level, echocardiographic evaluation of large numbers of patients with diabetes has suggested a characteristic pattern of concentric left ventricular hypertrophy with mildly reduced systolic performance while Doppler studies have revealed qualitatively similar patterns of diastolic noncompliance in diabetic patients and animal models of diabetes. Nevertheless, the pathophysiologic mechanisms mediating the association of diabetes and heart failure remain uncertain. At least four factors contribute to this uncertainty. First, circulating glucose and insulin levels potentially influence a dauntingly large number of biologic processes important to cardiac function, including myocardial energy metabolism, myocyte growth and gene transcription, vascular and myocardial compliance, endothelial function, and thrombosis. Second, existing animal models of type 2 diabetes are at best uncertain mimics of the human disease, a chronic degenerative condition that appears to require decades-long exposure to specific environmental conditions in persons with a genetic tendency to the disease. The clinical relevance of the many pathologic changes described in animal models therefore awaits a more complete characterization of the physiology of type 2 diabetes in humans. Third, the morphologic and functional features of cardiomyopathy in patient and animal models of diabetes are difficult to distinguish from those of other conditions (e.g., hypertension) commonly associated with diabetes. Finally, few investigations have adequately addressed whether the adverse impact of diabetes on the development of heart failure can be ameliorated or prevented by diabetes-specific interventions. In the sections that follow, we will briefly review current theory regarding type 2 diabetes and heart failure.
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