Methods

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We searched the MEDLINE database for English-language articles published between 1980 and January 1996; we used the terms diabetes mellitus, hypertension or blood pressure, and heart. We also reviewed pertinent articles cited in the identified papers.

The term "diabetes mellitus" included insulin-dependent and non-insulin-dependent diabetes mellitus; however, in some studies, the type of diabetes was not specified. We indicate the type of diabetes if this information was available. We divided the articles into those that addressed coronary artery disease or myocardial ischemia and those that addressed nonischemic cardiomyopathy and its sequelae. Articles about cardiac complications that result from the combination of diabetes mellitus and hypertension were emphasized.

Results

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Diabetic Heart Disease

Long-standing diabetes has been documented to cause structural and functional cardiac impairment and to lead to ischemic heart disease, cardiomyopathy, and congestive heart failure.

Ischemic Heart Disease

Diabetes mellitus is an independent risk factor for the development of coronary artery disease [5, 6]. At coronary angiography or autopsy, diabetic patients have a higher incidence of double- and triple-vessel disease and a lower incidence of single-vessel disease than do their nondiabetic counterparts [5, 7]. In one large study [8], 83% of patients with non-insulin-dependent diabetes mellitus had severe two- or three-vessel involvement at autopsy. Of patients who had no known coronary artery disease, 31% had severe narrowing of at least one major coronary artery.

The presence of diabetes mellitus reduces survival after myocardial infarction. The 5-year mortality rate after acute myocardial infarction can be as great as 55% in diabetic patients but only reaches 30% in patients without diabetes, and the rate of reinfarction may be as much as 60% higher in diabetic than in nondiabetic patients [9]. In a recent study of Mexican-American and non-Hispanic white persons, Orlander and coworkers [10] found higher short-term and long-term mortality rates and a higher rate of pump failure in persons with diabetes mellitus than in persons without the disease. The effect of non-insulin-dependent diabetes mellitus on mortality and morbidity in coronary heart disease is more marked in women than in men [11].

Accelerated atherosclerosis in patients with diabetes mellitus may be related to lipid disorders, hyperinsulinemia, and poor glycemic control. Hyperinsulinemia, particularly from exogenous insulin, may exert both a beneficial effect (by reducing hypoglycemia) and an adverse effect (by directly promoting atherogenesis, thrombogenesis, or both) [12, 13].

In addition to accelerating atherosclerosis, diabetes mellitus is associated with abnormal platelet function, coagulation, fibrinolysis, and endothelial function that may favor coronary thrombosis [14]. Autonomic neuropathy related to diabetes mellitus also contributes to the occurrence of ischemic myocardial events. Diabetic autonomic neuropathy initially involves the parasympathetic nerve fibers, leading to a relative increase in sympathetic tone with tachycardia at rest and exaggerated coronary vasoconstriction and, later (in advanced diabetic autonomic neuropathy), to sympathetic dysfunction with postural hypotension [15]. Autonomic neuropathy in patients with diabetes is also associated with an increased rate of sudden death caused by ventricular arrhythmia [16]. Ventricular arrhythmia may be secondary to silent myocardial ischemia or to the combination of a prolonged QT interval and increased sympathetic tone [16-18].

Diabetic patients have a decreased perception of ischemic pain, which contributes to a high prevalence of silent ischemia. Nesto and colleagues [19] showed that during ischemia on thallium exercise testing, angina is less common in diabetic patients than in nondiabetic patients. The time interval from the onset of ST-segment depression to the occurrence of angina is longer in diabetic than in nondiabetic patients and correlates with the extent of autonomic nervous dysfunction [20]. Asymptomatic infarction is almost twice as common in diabetic patients as in nondiabetic patients [21, 22]. These data are consistent with autopsy results showing that myocardial scars, in the absence of a history of infarction, are three times more common in diabetic patients than in nondiabetic patients [23].

Diabetic Cardiomyopathy

Several clinical and experimental studies [2, 24-33] have indicated that diabetes mellitus is associated with cardiomyopathy that is independent of atherosclerotic coronary artery disease. Macroscopic changes include muscular hypertrophy with pale appearance and firmness to palpation. Microscopic changes include thickening of the capillary basement membranes, intimal proliferation of small myocardial arterioles and capillary microaneurysms, and focal myocardial fibrosis with an accumulation of interstitial glycoprotein and collagen [34]. Electron microscopy shows perivascular damage with loss of contractile myocardial elements and deposition of either glycoprotein or material that is positive on periodic acid-Schiff stain [31].

Various metabolic derangements [35-53] that can contribute to the development of diabetic cardiomyopathy are beyond the scope of this review.

Microvascular Disease

Small-vessel coronary artery disease frequently occurs in patients with diabetes [34]. On the basis of necropsy findings, Hamby and associates [28] suggested that changes in small vessels of the myocardium are responsible for diabetic cardiomyopathy. Fein and Sonnenblick [51] reported that patients with diabetes have increased sensitivity to catecholamines, which may cause myocardial ischemia through the focal vasoconstriction of small coronary arteries.

Altered Cardiac Function

Structural changes in patients with diabetes are associated. with impaired ventricular performance. Using echocardiography, Shapiro [54] found abnormal diastolic function in patients with diabetes mellitus who did not have heart disease. Diabetes mellitus seems to have less effect on systolic function, as was shown in a study by Borow and colleagues [55] in which indices of contractility and contractile reserve after stimulation with dobutamine were normal. Structural changes suggestive of cardiomyopathy can be detected with echocardiography on the basis of quantitative backscatter imaging, even before ventricular function is impaired [56]. Mustonen and coworkers [57] found similar resting ejection fractions in diabetic patients and controls. However, during 4 years of follow-up, the left ventricular ejection fraction at rest markedly decreased only in the patients with non-insulin-dependent diabetes mellitus. Several studies have shown that ejection fractions after myocardial infarction are lower in diabetic than in nondiabetic patients [10, 58, 59]. Contractile abnormalities are more pronounced in postmenopausal diabetic women than in diabetic men [58]. Not surprisingly, congestive heart failure is a common and serious complication of diabetes mellitus. Data from the Framingham study showed that men with diabetes had a 2.4-fold greater risk for heart failure than did men without diabetes [2].

Hypertensive Heart Disease

Sustained hypertension can cause structural and functional cardiac abnormalities that lead to myocardial ischemia, congestive heart failure, and sudden cardiac death.

Ischemic Heart Disease in Patients with Hypertension

Myocardial ischemia is common in patients with hypertension [60, 61]. Pathogenic mechanisms that may lead to myocardial ischemia include the following. First, long-standing hypertension accelerates arteriosclerosis in systemic and coronary arteries [62]. Second, an increase in arterial pressure increases left ventricular wall stress, wall tension, and stroke work. Third, resistance of the coronary microvasculature (microvascular angina) is abnormally elevated in hypertensive patients even in the absence of left ventricular hypertrophy [63]. Fourth, long-standing hypertension causes left ventricular hypertrophy, which is associated with an increase in the diameter of myocardial cells without a proportional proliferation of the capillary vasculature; this leads to an increased diffusion distance [64]. Fifth, vasodilator reserve appears to be compromised in the coronary circulation of hearts in patients with left ventricular hypertrophy [65, 66]. Finally, left ventricular hypertrophy itself (that is, the increased myocardial muscle mass seen with this condition) requires an enhanced supply of oxygen to the myocardium. It should be noted that hypertensive patients, especially those with left ventricular hypertrophy, are as susceptible to silent myocardial ischemia as patients with diabetes [67-69].

Hypertensive Cardiomyopathy

The classic cardiac adaptation to a sustained pressure overload is concentric left ventricular hypertrophy. Hemodynamic factors offer a reasonable explanation for increased left ventricular mass; however, in several groups of patients with uncomplicated essential hypertension, physicians' measurements of blood pressure have been only weakly related to left ventricular mass on echocardiography [70]. Therefore, such nonhemodynamic factors as sodium intake, activity of growth-promoting hormones (such as insulin and thyroxine), activity of the sympathetic nervous system, renin angiotensin systems, whole-blood viscosity, glucose levels, and genetics probably contribute to the development of left ventricular hypertrophy [71]. Cardiac hypertrophy is not a homogeneous process, and growth of nonmyocytic cells, which include endothelial cells, vascular smooth-muscle cells, fibroblasts, and macrophages, participate in the development of left ventricular hypertrophy [72]. In addition, in several experimental models of rats with mechanical overload and left ventricular hypertrophy, isoenzymatic changes of cardiac myosin have been described [73].

Altered Cardiac Function

Hypertensive cardiomyopathy is associated with impaired cardiac function. We recently showed that contractility deteriorated as left ventricular mass increased in hypertensive patients [74]. Several investigators [75-77] have found that peak filling rate is decreased and time to peak filling is increased in patients with mild to moderate hypertension. In early hypertensive heart disease, impaired filling is predominantly caused by decreased ventricular relaxation during early diastole [76]. In more severe hypertensive heart disease, compliance during late diastole becomes impaired because of an increase in myocardial wall thickness. Patients with decreased ventricular filling are usually asymptomatic during resting conditions. However, during exercise, the stiff left ventricles are unable to accommodate the increased blood volume. We found [78] that hypertensive patients with impaired left ventricular filling (unlike patients with preserved left ventricular filling) did not appropriately increase cardiac output during isometric stress.

A progressive decline in ventricular function may lead to congestive heart failure. Data from the Framingham study [79] showed that hypertension was the primary cause of congestive heart failure in 35% of cases and played a role in this condition in another 40%. The incidence of congestive heart failure was approximately eight times greater according to electrocardiographic criteria if left ventricular hypertrophy was present [80-82].

Ventricular Dysrhythmia

Hypertensive patients with left ventricular hypertrophy are susceptible to sudden death [83]. We have documented that hypertensive patients with left ventricular hypertrophy have an increased frequency of ventricular arrhythmias, including ventricular extrasystoles, ventricular couplets, and short runs of ventricular tachycardia, compared with both normotensive controls and hypertensive patients without left ventricular hypertrophy. Other studies have corroborated and expanded on our findings [84, 85], further supporting the association between ventricular arrhythmias and left ventricular hypertrophy. The electrogenesis of ventricular arrhythmias seems to be caused by many factors: Hemodynamic factors (such as pressure overload, volume overload, and contraction-excitation-feedback coupling), myocardial factors (such as enlarged myocytes with multiple intercalated bridges, local areas of fibrosis, and ischemia leading to reentry mechanisms), and neuroendocrine factors (such as enhanced activity of the sympathetic nervous system, the renin angiotensin system, and intracellular electrolyte shifts) may all play a role.

Discussion

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Considerable evidence—both experimental and clinical—indicates that an elevation in arterial pressure is of critical importance in the pathogenesis of diabetic heart disease. Hypertension has a high prevalence in diabetic patients and may occur in as many as 50% of patients with non-insulin-dependent diabetes mellitus [86]. Hypertension, obesity, dyslipidemia, and glucose intolerance usually occur in the same patient even before overt diabetes mellitus appears. Thus, insulin resistance and the consequent hyperinsulinemia may be the common denominator in the pathogenesis of hypertension and diabetes [86].

The link between hyperinsulinemia and hypertension can be explained by 1) the fact that insulin enhances renal sodium reabsorption in the distal tubule and consequently increases water retention or 2) insulin's stimulation of the sympathetic nevous system [87]. Insulin may also increase both the pressor response to angiotensin II and angiotensin II-mediated production of aldosterone, and it may stimulate smooth-muscle proliferation [87]. The coexistence of hyperinsulinemia, hypertension, and diabetes mellitus results in more severe cardiomyopathy than would be expected with either hypertension or diabetes mellitus alone.

Ischemic Heart Disease in Patients with Diabetes and Hypertension

Coronary artery disease is much more common in patients with both diabetes and hypertension than in patients with hypertension or diabetes mellitus alone [88]. In 2681 male participants in the PROCAM trial who had none of three risk factors (hypertension, diabetes mellitus, or hyperlipidemia), the incidence of coronary artery disease was 6 per 1000 in 4 years. In participants who had hypertension or diabetes mellitus, but not both, the incidence of coronary artery disease was 14 per 1000 and 15 per 1000, respectively, in 4 years. When the same patient had both risk factors, the incidence rate increased to 48 per 1000 [88]. Samuelsson and associates [89] followed 686 hypertensive men 47 to 54 years of age for 15 years and found that the presence of diabetes mellitus at study entry more than doubled the risk for coronary heart disease.

Development of atherosclerosis in coronary arteries is accelerated when diabetes mellitus and hypertension coexist [90]. Hypertension may also increase the tendency toward fissuring of the atherosclerotic plaque. Using an arthrometric system in 472 patients at autopsy, Fernandez-Britto and colleagues [90] found that diabetes and hypertension had both strongly influenced the rate at which coronary atherosclerosis had progressed. The effect of diabetes seems to be more pronounced and is particularly expressed by the severe plaques, whereas the effect of hypertension is especially visible in the fibrous plaques. Arora and coworkers [91] reported that the coronary perfusion reserve index was decreased compared with controls in both patients with hypertension and patients with diabetes but that this index was further reduced in patients with both diabetes and hypertension.

Diabetes and, to a lesser extent, hypertension diminish the perception of ischemic pain, leading to a high prevalence of silent ischemia. In 21 of 35 diabetic patients with essential hypertension, Melina and associates [92] found episodes of asymptomatic ST-segment depression. The number of episodes of ST-segment depression was significantly related to glycosylated hemoglobin levels, left ventricular mass index, and variability and peaks in ambulatory systolic and diastolic blood pressure.

Cardiomyopathy in Patients with Diabetes and Hypertension

Factor and colleagues [3] described the pathologic features found at autopsy in nine diabetic patients with hypertension and compared those features with those seen in normal persons and in patients with either diabetes or hypertension, but not both. Of the four groups, patients with both diabetes and hypertension had the greatest left ventricular wall thickness and the heaviest hearts. These hearts also had the greatest amount of microscopic fibrosis, with focal areas of gross scarring and a firm, waxy consistency. The most striking microscopic finding in the hearts of hypertensive patients with diabetes was the distribution of dense interstitial connective tissue throughout the myocardium. These findings were later confirmed in a large group of patients [4]. Echocardiographic studies have also shown increased left ventricular mass in hypertensive patients with diabetes [93, 94]. Venco and colleagues [93] found that the interventricular septum was increased in diabetic patients with hypertension compared with nondiabetic patients with hypertension. Grossman and coworkers [94] found that septal and posterior wall thicknesses were increased in patients with hypertension and non-insulin-dependent diabetes mellitus compared with nondiabetic patients with hypertension. The prevalence of left ventricular hypertrophy was 72% in the diabetic hypertensive patients and 32% in the nondiabetic hypertensive patients; degrees of blood pressure elevation in the two groups were similar.

Cardiac Function in Patients with Diabetes and Hypertension

Cardiomyopathy of diabetes and hypertension is associated with impaired ventricular function and a high prevalence of congestive heart failure [95].

Echocardiographic studies have shown that ventricular function is impaired in diabetic patients with hypertension [93, 94, 96]. Venco and colleagues [93] found impaired diastolic function in diabetic hypertensive patients that was manifested by reductions in the velocity of thinning of the posterior wall and the velocity of increase of left ventricular dimension in early diastole. Grossman and coworkers [94] described decreased left ventricular contractility (as reflected by the ratio of end-systolic wall stress to end-systolic volume index) in diabetic patients with hypertension compared with nondiabetic patients with hypertension. The hearts of diabetic patients appear to be particularly vulnerable to increased blood pressure [97]. An echocardiographic evaluation of 32 patients with insulin-dependent diabetes mellitus and a wide range of systemic arterial blood pressure showed subclinical diastolic dysfunction that correlated positively with systolic blood pressure and left ventricular mass compared with 32 normotensive, nondiabetic persons [97]. In these studies, the diabetic hypertensive patients had increased left ventricular mass; thus, the impaired ventricular function may have been related to the ventricular hypertrophy. However, Nagano and associates [96] also reported cardiac diastolic dysfunction in the absence of cardiac hypertrophy in hypertensive patients with glucose intolerance.

Therapeutic Considerations in Patients with Diabetes and Hypertension

It has been well documented that decreasing arterial pressure through the use of diuretic-based therapy diminishes not only the risk for stroke but also the risk for coronary death [98]. In the Systolic Hypertension in the Elderly Program [99], the effect of antihypertensive therapy on the primary end points was not statistically different in the 10% of patients who had diabetes. In contrast, no solid clinical documents show that tight glycemic control improves or prevents cardiac disease in patients with non-insulin-dependent diabetes mellitus, although indirect evidence does indicate this [100]. However, glycemic control has been shown to improve cardiomyopathy in animals [35]. For long-term therapy of diabetic hypertensive patients, it therefore seems reasonable to select antihypertensive drugs that decrease arterial pressure without having a negative effect on insulin resistance or other metabolic risk factors. Although diuretics and diuretic-based ß-blocker therapy have been found to be effective in reducing cardiovascular-related morbidity and mortality in patients with hypertension, they may adversely affect glucose tolerance and lipid profile. In contrast, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, peripheral -blockers, and calcium antagonists do not appear to adversely affect metabolic risk factors and therefore may be superior to diuretics and ß-blockers. However, this superiority (particularly in diabetic hypertensive patients) needs to be documented. Prospective trials are urgently needed to assess the effects of glycemic control and to compare different classes of antihypertensive drugs with regard to safety and efficacy in this high-risk population.

Dr. Messerli: Ochsner Clinic, 1514 Jefferson Highway, New Orleans, LA 70121.