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Interdisciplinary Approaches to Diabetic Heart Disease: Mechanisms, Prevention, Early Detection and Therapeutic Targets Executive Summary
The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts in diabetic heart and vascular disease, cardiac progenitor/stem cells, angiogenesis, large animal models, mitochondrial dysfunction, myocardial substrate metabolism, and cardiovascular imaging on July 27-28, 2009 in Bethesda, Maryland, to advise the Institute on: 1) promising research strategies to find new diagnostic tools, disease risk stratification, and identify novel therapeutic targets for diabetic heart disease; 2) opportunities for fundamental and translational research to address the genetic, molecular and environmental underpinnings of the cardiovascular complications of diabetes, and 3) improved understanding of disease pathophysiology which will ultimately lead to more effective therapeutic interventions and diagnostic approaches to this serious health problem. This Working Group is responsive to NHLBI Strategic Plan Goals 1 & 2 and the Division of Cardiovascular Diseases Strategic Plan Goals 2, 2, 4c, d
Discussion - The Nature and Scope of the Problem
In 2008, 12 percent of US adults age 20 and older have diabetes. The American Diabetes Association estimates there will be nearly 50.2 million people with diabetes by 2025 due to the growing epidemic of obesity. According to estimates of the World Health Organization, the number of people with diabetes will double worldwide to 366 million by 2030, a problem of pandemic proportions. These numbers have grave implications for the public health of the US, which already struggles to provide care for millions of patients with diabetes, many of whom belong to vulnerable groups, such as the elderly or minorities. Cardiovascular disease is the leading cause of death of individuals with Type 1 and Type 2 diabetes. In addition to increased atherosclerotic vascular disease leading to myocardial ischemia/infarction and stroke, diabetes also increases the incidence of heart failure, even in the absence of ischemic insult or hypertension. The term ‘diabetic cardiomyopathy has been used to describe heart failure that is associated with diabetes and which is not obviously attributable to other etiologies. Diabetic cardiomyopathy may present as solely diastolic dysfunction or combined diastolic and systolic dysfunction via mechanisms that are likely distinct from myocardial ischemia. The unique pathogenesis of diabetic cardiomyopathy likely accounts for the observation that traditional cardiologic therapies are less effective in the diabetic population.
Given the dismal prognosis of diabetic heart failure and lack of highly effective therapy, particularly for diastolic dysfunction, the working group focused their effort on the review of the state of knowledge regarding the molecular pathogenesis of diabetic cardiomyopathy, screening for diabetic cardiac dysfunction, identification of new biomarkers, identification and validation of therapeutic targets, the development of clinically relevant models and technology platforms, and the testing of metabolic modulator therapies aimed at this important problem.
Diabetes-associated cardiac dysfunction is associated with mitochondrial dysfunction, derangements in fuel utilization, and altered cellular signaling. In particular, increased lipid uptake and incomplete oxidation lead to the accumulation of triglyceride and other lipids that may act as direct toxins or signaling mediators and may lead to remodeling of organellar membrane composition. This complex process has been termed ‘lipotoxicity’. Impaired glucose oxidation in the myocyte might also lead to “glucotoxicity” including increased O-GlcNAC modifications of mitochondrial and sarcoplasmic reticulum (SR) proteins leading to alterations in excitation-contraction coupling and contractile dysfunction. Diabetes adversely influences multiple cell types within the heart (cardiomyocytes, endothelial cells, stem cells). Paracrine interactions between these cells are incompletely understood, such as the contribution of microvascular dysfunction or potentially the loss of the progenitor stem cells to myocyte dysfunction or cell death.
Many patients with diabetes have other co-morbidities such as hypertension, myocardial ischemia and obesity. The interactions between these co-morbidities and diabetes need to be elucidated. Moreover, similarities and differences between the cardiac phenotypes of type 1 and type 2 diabetes need to be understood. Current imaging modalities have described altered substrate metabolic fluxes and triglyceride accumulation in diabetic hearts and have identified subtle changes in cardiac diastolic relaxation and changes in cardiac structure such as cardiac fibrosis and defects in microvascular perfusion. However questions remain including the role of such imaging approaches in early disease detection and in predicting long-term prognosis, outcomes and responses to therapy. In particular, more information is needed on how metabolic modulator therapies, if proven efficacious, impact on cardiac metabolism and function. Based upon this review of the state of the field, the working group identified the following key areas as targets for future research:
The Working Group report is planned for publication in a peer-reviewed journal.
Division of Heart and Vascular Sciences
Isabella Liang, Ph.D., NHLBI, NIH
Cristina Rabadan-Diehl, Ph.D., NHLBI, NIH
Patrice Desvigne-Nickens, M.D., NHLBI, NIH
Working Group Members
Last Updated September 10, 2009