Epidemiology and Disease Pathology of Cardiovascular Disease

About 65% of people with diabetes die from cardiovascular disease, making it the leading cause of premature death among people with diabetes.[1] In fact, from the point of view of cardiovascular medicine, type 2 diabetes is a cardiovascular disease. The chronic hyperglycemia associated with diabetes leads to damage to many of the body's tissues, but particularly to the vascular system. As a result, macrovascular complications, which include cardiovascular, cerebrovascular, and peripheral vascular disease, are common complications in people with diabetes.

Classification

Cardiovascular disease can be roughly divided into cardiomyopathy and atherothrombic disease.

Cardiomyopathy may be divided into primary or idiopathic cardiomyopathy and secondary or 'specific' cardiomyopathy. The World Health Organization has subdivided this classification further; primary or idiopathic has been divided into four broad categories – dilated, hypertrophic, restrictive, and arrhythmogenic right ventricular, while specific or secondary cardiomyopathy is now reserved to define heart muscle disease associated with specific cardiac or systemic disorders such as ischemic, valvular and hypertensive conditions.[2]

Epidemiology

Prevalence

Despite a substantial decline in overall cardiovascular mortality in the US over the past 30 years, this decline has not translated to people with diabetes. Age-adjusted mortality due to heart disease in men with diabetes decreased by only 13.1%, compared with a 36.4% decline in non diabetic men.[3] In the same study, women with diabetes lost part of their inherent sex-associated protection against cardiovascular disease, with cardiovascular mortality in this patient population increasing by 23%, compared with a 27% decrease in women without diabetes.[3]

A Finnish study found that middle-aged people (aged 45 to 64 years) with type 2 diabetes have the same high risk for myocardial infarction (MI) as people without diabetes who have previously suffered an MI.[4] Furthermore, the 1-year mortality rate after the first MI is greater in people with diabetes compared with people without diabetes, for both men (44.2% vs 32.6%, respectively) and women (36.9% vs 20.2%, respectively).[5]

Demographic trends

People at high risk of premature mortality and/or morbidity due to cardiovascular complications of diabetes include[6]:

• People with a family history of diabetes, particularly those with a first degree relative who has type 2 diabetes
• People who are overweight or obese and people who are physically inactive
• Older people
• The following populations: African Americans, Hispanic/Latino Americans, American Indians, Asian Americans and Pacific Islanders
• Smokers

Economic consequences

A study designed to assess lifetime costs of complications resulting from type 2 diabetes in the US found that macrovascular disease was the largest cost component, accounting for 85% of cumulative costs of complications over the first 5 years of the study. The costs of complications were estimated to be $47,240 per patient over 30 years, on average. The management of macrovascular disease was estimated to be the largest cost component, accounting for 52% of costs.[7]

Cardiovascular disease is the most costly complication of type 2 diabetes, accounting for more than $7 million of the $44.1 billion in direct medical expenditures attributed to diabetes in 1997.[8] Significant cost savings were associated with a sustained reduction in A1C levels among adults with diabetes within 1 to 2 years.[9]

Etiology and pathogenesis

Numerous factors underlie the increased risk of macrovascular disease observed in type 2 diabetes.[10] Research has shown that traditional risk factors account for only 25% to 50% of the increased risk of macrovascular disease associated with diabetes[11] and that insulin resistance in itself is associated with a 2-fold increase in macrovascular events.[12]

Insulin resistance in skeletal muscle results in hyperglycemia, increased circulating free fatty acids, and hyperinsulinemia.[10] It has been suggested that hyperglycemia plays an accelerating role in macrovascular disease, owing to glucose-related activation of protein kinase C (PKC), accumulation of advanced glycation end-products (AGE), excess polyol flux and accumulation of glucosamine.[13] Hyperglycemia promotes nonenzymatic interactions between glucose and free amino groups on polypeptides or lipids.[14,15,16,17,18] Formation of early glycation end-products, such as Schiff bases and Amadori products, is reversible, for example, the formation of glycosylated hemoglobin A1C.[15] In contrast, AGE are more stable and are the result of further molecular rearrangements, often involving oxidation.[15]

The buildup of AGE-modified macromolecules in individuals with type 2 diabetes has been recognized for many years.[16] In addition, the cross-linkage of AGE with collagen in the vasculature results in increased arterial stiffness and reduced vessel wall compliance.[19] However, the novel relationship between AGE-modified proteins and altered behaviour of cells involved in the development of arterial disease has only recently been described.[15] A cell surface receptor for AGE (RAGE) has been characterized, isolated and cloned.[15,20] RAGE is a member of the immunoglobulin superfamily of cell surface molecules and studies in human and rodent tissues have revealed a characteristic pattern of RAGE expression.[21,22,23] Moreover, studies suggest that blockade of RAGE may offer a novel strategy to stabilize atherosclerosis and vascular inflammation in diabetes, thus minimizing macrovascular complications.[14,24]

Classification

Atherosclerotic disease

Myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes.[25] Thus diagnosis may be delayed and multivessel atherosclerosis may develop before the appearance of ischemic symptoms allows recognition and subsequent intervention, which might explain the poor prognoses for many patients with diabetes.

Cardiomyopathy

Prior to 1972, the increased cardiovascular morbidity and mortality that people with diabetes had endured had been attributed to vascular disease. In 1972, Rubler et al. proposed the existence of a diabetic cardiomyopathy based on their experience with four adult diabetic patients who suffered from congestive heart failure (CHF) in the absence of discernable coronary artery disease, valvular or congenital heart disease, hypertension, or alcoholism.[26] Alternative explanations for CHF, such as anemia and vascular and renal disease in these four patients, gave rise to criticisms, but a wave of subsequent studies in the 1970s and 1980s provided credence to this new disease entity.

A review of studies done since 1972 appears to support the concept of a diabetic cardiomyopathy independent of atherosclerotic cardiovascular disease. The exact mechanism is still questionable, and several possibilities have been proposed, including small and microvascular disease, autonomic dysfunction, metabolic derangement, and interstitial fibrosis. However, the weight of evidence leans toward the development of fibrosis, possibly caused by the accumulation of a peroxidase acid Schiff-positive glycoprotein, leading to myocardial hypertrophy and diastolic dysfunction.[27]

Natural history

The glycation of proteins leads to covalent cross-linking and abnormal structural stabilization of extracellular matrix proteins. Glycation occurs when glucose, in its aldehyde form, reacts with the amino groups of protein to form a Schiff base which subsequently rearranges to a stable ketoamine adduct.[6] This process, nonenzymatic glycation of protein, occurs naturally in the body. Glycation not only affects the structure and function of protein, but also initiates a series of Maillard or Browning reactions that eventually lead to cross-linking and denaturation of proteins. All proteins in the body are subject to these reactions, but long-lived proteins such as collagen, which represents over 30% of body protein, accumulate chemical damage with age. The increased rate of glycation of collagen during hyperglycemia is implicated in the development of complications of diabetes, such as blindness and renal and vascular disease.[8]

References

1. Geiss LS et al. Diabetes in America. Bethesda MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 1995:233–257.
2. Brooks City Base. Cardiomyopathy. Available at: http://www.brooks.af.mil/web/consult_service/waiver%20guide/Cardiovascular/Cardiomyopathy.htm. Accessed April, 2004.
3. Gu K et al. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281:1291–1297.
4. Haffner S et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998; 339:229–234.
5. Miettinen H et al. Impact of diabetes on mortality after the first myocardial infarction. Diabetes Care. 1998; 21:69–75.
6. Grundy SM et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Diabetes Care.1999;100:1134–1146.
7. Caro J, et al. Lifetime costs of complications resulting from type 2 diabetes in the US. Diabetes Care. 2002; 225:476-481.
8. American Diabetes Association. Economic consequences of diabetes mellitus in the US in 1997. Diabetes Care. 1998;21:296–309.
9. Wagner EH et al. Effect of improved glycemic control on health care costs and utilization. JAMA. 2001;285:182–189.
10. Zarich SW. Treating the diabetic patient: appropriate care for glycemic control and cardiovascular disease risk factors. Rev Cardiovasc Med. 2003;4:S19–S28.
11. Bierman EL George Lyman Duff Memorial Lecture. Atherogenesis in diabetes. Arterioscler and Thromb. 1992;12:647–656.
12. Haffner SM, Miettinen H, Gaskill SP et al. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes. 1995;44:1386–1391.
13. Reusch JE. Diabetes, microvascular complications, and cardiovascular complications: what is it about glucose? J Clin Invest. 2003;112:986–988.
14. Yan SF, Ramasamy R, Naka Y et al. Glycation, inflammation, and RAGE: a scaffold for the macrovascular complications of diabetes and beyond. Circ Res. 2003;93:1159–1169.
15. Schmidt AM, Yan SD, Wautier JL et al. Activation of receptor for advanced glycation end products: a mechanism for chronic vascular dysfunction in diabetic vasculopathy and atherosclerosis. Circ Res.1999;84:489–497.
16. Libby P, Plutzky J. Diabetic macrovascular disease: the glucose paradox? Circulation. 2002; 106:2760–2763.
17. Giardino I, Edelstein D, Brownlee M. Nonenzymatic glycosylation in vitro and in bovine endothelial cells alters basic fibroblast growth factor activity. A model for intracellular glycosylation in diabetes. J Clin Invest. 1994;94:110–117.
18. Giardino I, Edelstein D, Brownlee M. BCL-2 expression or antioxidants prevent hyperglycemia-induced formation of intracellular advanced glycation end products in bovine endothelial cells. J Clin Invest. 1996;97:1422–1428.
19. Bate KL, Jerums G. Preventing complications of diabetes. Med J Aust. 2003;179:498–503.
20. Schmidt AM, Hori O, Brett J . Cellular receptors for advanced glycation end products. Implications for induction of oxidant stress and cellular dysfunction in the pathogenesis of vascular lesions. Arterioscler and Thromb. 1994;14:1521–1528.
21. Hori O, Brett J, Slattery T, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem. 1995;270:25752–25761.
22. Brett J, Schmidt AM, Yan SD et al. Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol.1993;143:1699–1712.
23. Ritthaler U, Deng Y, Zhang Y et al. Expression of receptors for advanced glycation end products in peripheral occlusive vascular disease. Am J  Pathol. 1995;146:688–694.
24. Bucciarelli LG, Wendt T, Qu W, et al. RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 2002;106:2827–2835.
25. Wingard DL et al. Prevalence of cardiovascular and renal complications in older adults with normal or impaired glucose tolerance or NIDDM: a population-based study. Diabetes Care. 1993;16:1022–1025.
26. Rubler S, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1993;30:595–602.
27. Spector KS. Diabetic cardiomyopathy. Clin Cardiol. 1998;21:885–887.