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NHLBI Working Group
Mechanistic and Pre-Clinical Studies of
Diabetic Cardiovascular Complications

Executive Summary

Purpose

The National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group (WG) of investigators on June 7-8, 2006, in Bethesda, Maryland, on new research directions needed to understand diabetic cardiovascular complications. The WG met to (1) identify specific areas in which insight about the cardiovascular complications of diabetes is lacking, and (2) delineate the most fruitful areas for basic, pre-clinical, and clinical research. Particular attention was paid to the current status and use of pre-clinical animal models of diabetic complications.

Discussion

The clinical course of type 2 diabetes mellitus (T2DM) is marked by accelerated atherosclerosis and its subsequent complications. The impact of T2DM is manifest not only in coronary disease but also in cerebrovascular and peripheral vascular disease. Factors underlying these problems clearly involve hyperglycemia but also derive from hypertension and blood disorders, including abnormalities of leukocytes, red blood cells, the coagulation system, and the interactions of all of these elements with the arterial wall. Diabetes also has direct effects on the heart, altering the structure and function of the myocardium. The interplay between diabetes and cardiovascular disease is further complicated by the fact that both hyperglycemia (at levels diagnostic of diabetes) and diabetic atherosclerotic complications are relatively late-stage events in the natural history of these pathologies. The tightly intertwined nature of T2DM and all these cardiovascular complications is especially concerning given the epidemic of obesity and diabetes evident in America and among an increasingly younger population. Members of the WG agreed that the greatest opportunities for altering the natural history of diabetes and its cardiovascular complications likely rests in the earlier stages of these pathologic processes, including investigating mechanisms involved in the development of diabetes. Studies focusing on non-glycemic factors and pathways that predict and/or promote diabetes may have particular yield.

Diabetic macrovascular complications result from dysfunctions in many physiologic processes (e.g., lipid metabolism, glucose homeostasis, energy balance, coagulation, inflammation, and renal systems), involving a diversity of disciplines such as endocrinology, cardiology, nephrology, and lipidology. Conseqeuently, the WG also noted the need for broader, novel approaches to the growing challenges of diabetic macrovascular disease and indicated areas in which NHLBI’s leadership is needed. These include the need for (1) integrated training in metabolism and cardiovascular disease for scientists and clinicians; (2) interdisciplinary approaches to unresolved scientific questions; (3) promotion of integrated consortia across institutions that can provide the individual investigator with access to resources such as imaging, biochemical resources (mass spectroscopy, ‘-omic’ approaches), data mining resources, recombinant mouse models, and collaborative opportunities for studies in animals, including large animals; and (4) attraction of investigators in unrelated fields or those who have not previously studied pathways involved in diabetic macrovascular disease.

Recommendations

The WG made the following prioritized recommendations:

Define more precisely the nature of diabetic atherosclerosis by addressing the key unresolved question of how diabetic macrovascular disease replicates or diverges from non-diabetic atherosclerosis in terms of initiation, propagation, and complications.
Determine how metabolic changes like hyperglycemia, increased free fatty acid levels, dyslipidemia, triglyceride accumulation in tissues, and systemic insulin resistance translate into changes in the arterial wall. Prior work identifies reactive oxidant species and advanced glycation end-products as two pathways implicated in vascular complications.
Explore the role of adiposity and specifically visceral adiposity in diabetic cardiovascular complications, including studies on adipokines, inflammation in adipose tissue, and the relationship between adiposity and diabetic dyslipidemia.
Develop improved tools for translating molecular advances to in vivo models with greater relevance to human atherosclerosis, including increased use and access to studies in large animal models.
Conduct studies exploring gender differences in diabetes and its vascular complications and the mechanisms underlying these differences.
Investigate factors enhancing thrombotic response to vascular injury in diabetes, studying both specific mediators such as plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) as well as circulating elements such as changes in leukocytes and platelets.
Study the relationship between pathologic changes in the vasculature, and organ physiology and pathology, including the liver (fatty liver), the pancreas (beta cell failure, insulin production and release), the kidney (proteinuria, renal failure), and the musculoskeletal system (triglyceride accumulation, disproportionate benefits from exercise).
Discover how diabetes and the underlying insulin resistance alter the myocardium (1) under basal conditions and (2) after co-morbid insults, including hypertension and ischemia after infarction.