Prevention Conference VI: Diabetes and Cardiovascular Disease

D iabetes is associated with increased atherosclerosis and other causes of myocardial dysfunction.The pathogenesis of cardiovascular disease (CVD) in diabetes is multifactorial and can be affected by metabolic and other factors.Under physiological conditions, the endothelial cell (EC) layer acts as a barrier to separate circulating factors and cells from the arterial intima and media.It also serves as an anticoagulant and fibrinolytic surface producing tissue plasminogen activator, which counters the effects of procoagulant factors such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1).Endothelial cells produce nitric oxide (NO), which is a vasodilator and restrains smooth muscle cell (SMC) migration and proliferation.Circulating factors (hyperglycemia, increased free fatty acids, altered lipoproteins, and derivatives of glycation and oxidation) and hypertension, all of which are common in diabetes, can damage ECs, leading to their dysfunction.Plasma proteins, among them lipoproteins, cross the endothelial barrier, where they can be retained by subendothelial matrix molecules such as collagen and proteoglycans. 1 These and other matrix molecules are produced by ECs and SMCs.Blood components can be modified, eg, by oxidation and glycation.2 Modified proteins and lipids can alter EC and SMC gene expression, leading to increased production of procoagulants, adhesion molecules, chemotactic factors, and cytokines.The net effect is the adhesion and penetration of circulating monocytes into the arterial intima, where they undergo differentiation and activation to macrophages.Lipids can accumulate intracellularly after uptake of modified lipoproteins (glycation, oxidation, and glycoxidation) by different scavenger receptors on macrophages and SMCs, as well as extracellularly by attaching to matrix molecules.3 The resulting lesion is termed the fatty streak.Both ECs and macrophages produce cytokines and growth factors that permit SMCs to migrate from the media to the intima.In the intima, SMCs proliferate in response to several growth factors.These SMCs and the matrix molecules that they secrete form the fibrous cap, a hallmark of the advanced atherosclerotic plaque.Cell death occurs after exposure of cells to various compounds, eg, glucose, free fatty acids (FFAs), glycoxidation products, and modified lipoproteins in the milieu of the arterial intima.The presence of a large lipid core, necrotic tissue, macrophages, and a thin fibrous cap predisposes to plaque rupture.4 Conversely, a relative absence of lipid and macrophages and the presence of a thick fibrous cap renders a plaque stable.Thrombosis results from an imbalance between coagulation and fibrinolysis.Plaque rupture and hemorrhage can occur as a result of proteases secreted by vascular cells and from hemodynamic stress, leading to disruption of the fibrous cap. 5 Plaque rupture and thrombosis often underlie clinical events such as acute coronary syndromes, including myocardial infarction.Ruptures also can heal, resulting in complex and sometimes stable plaques.All of these processes can be potentiated by diabetes, as described below.Diabetes can also affect cardiac function independently of coronary artery atherosclerosis.The processes by which cardiac dysfunction might occur include endothelial dysfunction in the microcirculation, reduced cardiac compliance, microangiopathy, disturbed sympathetic function, impaired calcium cycling, limited myocardial glycolytic oxidative metabolism, and diastolic dysfunction.6 The pathophysiology underlying diabetic cardiomyopathy requires further investigation. Metabolic FactorsMetabolic derangements associated with diabetes mellitus include hyperglycemia and its derivatives, advanced glycation end products (AGEs), increased levels of FFAs, and lipoprotein abnormalities.These alterations have been found in persons with type 1 and type 2 diabetes.Most of these abnormalities are also found in individuals with the insulinThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel.Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.