Cardiovascular disorders in patients with diabetes mellitus

Abstract

Diabetes mellitus is a disease with multiorgan involvement. Besides retinopathy, nephropathy and peripheral neuropathy induced by microangiopathy, both cardiovascular and cerebrovascular complications are significant. Both cardiomyopathy and coronary artery disease are observed in patients with diabetes, and the latter is clinically more important because of its high incidence and seriousness.

Diabetes mellitus is a disease with multiorgan involvement. Besides retinopathy, nephropathy and peripheral neuropathy induced by microangiopathy, both cardiovascular and cerebrovascular complications are significant. Both cardiomyopathy and coronary artery disease are observed in patients with diabetes, and the latter is clinically more important because of its high incidence and seriousness.

DIABETIC CARDIOMYOPATHY

Diabetic cardiomyopathy is a condition in which the myocardium is damaged due to unknown etiology without any changes in the coronary arteries. It was first reported by Rubler et al (1) and subsequently supported by Hamby et al (2) and Regan et al (3). Diabetic cardiomyopathy is characterized by cardiac diastolic dysfunction, but it is doubtful whether systolic dysfunction or conditions similar to dilated cardiomyopathy are present. If systolic dysfunction occurs in diabetic patients who have no coronary abnormalities, then arterial hypertension or associated cardiomyopathy is often present. The clinical significance of diabetic cardiomyopathy is that it aggravates cardiac dysfunction in patients who already have coronary artery disease. Diastolic dysfunction is the first change that appears in the heart of a diabetic patient. Cardiac diastolic dysfunction can be induced by interstitial fibrosis and/or decreased sarcoplasmic Ca²⁺ uptake by the myocardium. Changes in the myocardial subcellular organelles are shown in Table 1 (4–12). Diastolic dysfunction can be easily assessed by Doppler echocardiography. In normal hearts, the E wave, which indicates a rapid rate of filling into the left ventricle, is taller than the A wave, which indicates the flow rate due to atrial contraction. In hearts with diastolic dysfunction, the height of the A wave increases, and the E to A wave ratio becomes lower. Cardiac scintigraphy is useful for estimating the metabolic condition of the heart. Disorders of the cardiac autonomic nervous system and disorders of myocardial fatty acid metabolism can be detected by cardiac scintigraphy. With regard to genetic abnormalities in diabetic patients, mitochondrial gene mutations are responsible for approximately 1% of cases of type II diabetes. Mitochondria have their own genes, consisting of 16,569 base pairs, and the DNA is double-stranded and circular. The main mutation in patients with diabetes is a point mutation of adenine to guanine at position 3243 (13,14). If the mutation is abundant in the myocardium, then the cardiomyopathy occurs.

TABLE 1.

Changes in myocardial subcellular organelles in diabetes mellitus

Sarcolemma Decrease in beta-receptor (including depressed responsiveness to catecholamines) Decrease in Ca2+ binding

Sarcoplasmic reticulum Decrease in Ca2+ uptake Decrease in Ca2+-ATPase

Contractile proteins Decrease in myosin ATPase Increase in myosin isozyme V3

Myocardial fibrosis

ISCHEMIC HEART DISEASE

Coronary artery disease is the most important cardiac disorder in patients with diabetes, in whom the incidence of myocardial infarction is two to three times higher in diabetic patients than in healthy persons (15). Multicoronary vessel abnormalities and asymptomatic myocardial infarction are observed more frequently in diabetic than in nondiabetic patients with myocardial infarction. Approximately one-half of diabetic patients have arterial hypertension, and the incidence of heart disease is higher in such patients. According to the Hisayama-cho study, which is a representative epidemiological study of 40- to 79-year-old individuals spanning a 40-year period, the incidences of ischemic heart disease and cerebrovascular disease were significantly higher in diabetic patients with a systolic blood pressure exceeding 130 mmHg than in nondiabetic patients. According to the Tanno-Sobetsucho study, spanning a 25-year period, the incidence of cardiovascular death was significantly higher in diabetic patients with a systolic blood pressure exceeding 130 mmHg and a diastolic blood pressure exceeding 80 mmHg. Some important guidelines for the treatment of arterial hypertension, such as the Guidelines of the Japanese Society of Hypertension, the European Society of Hypertension-European Society of Cardiology Guidelines 2003 (16), the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (17), and the World Health Organization/International Society of Hypertension 2003 guidelines (18), which were formulated on the basis of large clinical trials (19,20), have stipulated that the goal of treatment for arterial hypertension should be a systolic blood pressure below 130 mmHg and a diastolic blood pressure below 80 mmHg. Antihypertensive drugs that do not aggravate insulin sensitivity or lipid metabolism should be chosen for the treatment of arterial hypertension in patients with diabetes. The first stage of treatment for arterial hypertension in diabetic patients should include angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors or long-acting calcium channel blockers. If a combination of three types of antihypertensive drugs is adopted, beta-blockers as well as diuretics are useful for the third stage of treatment. Beta 1-selective beta-blockers are preferable to avoid undesirable side effects. Beta 1-blockers without intrinsic sympathomimetic action are preferable for patients both with diabetes and hypertension and with associated ischemic heart disease, whereas beta 1-blockers with intrinsic sympathomimetic action, exerting a vasodilative action, are useful for diabetic hypertensive patients without ischemic heart disease because they do not aggravate insulin sensitivity and lipid metabolism. The intrinsic insulin defect in diabetic patients results in low lipoprotein lipase activity and the release of very low density lipoprotein. The former induces a disturbance of very low density lipoprotein metabolism and decreases the production of high density lipoprotein. These changes result in an increase of serum triglyceride levels and a decrease of serum high density lipoprotein cholesterol levels. There are reports indicating that statins are useful to reduce cardiovascular events in patients with diabetes (21,22).