Diabetic and Hypertensive Heart Disease

  1. Ehud Grossman, MD; and
  2. Franz H. Messerli, MD
  1. From The Chaim Sheba Medical Center, Tel-Hashomer, Israel; and the Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, Louisiana. Current Author Addresses: Dr. Grossman: Hypertension Unit, The Chaim Sheba Medical Center, Tel-Hashomer, 52621 Israel.
     
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    Abstract

    Objective: To review the literature on the cardiac effects of diabetes mellitus and hypertension.

    Data Sources: A MEDLINE search of English-language articles published between 1980 and January 1996 was done using the terms diabetes mellitus, hypertension or blood pressure, and heart. References cited in identified articles were also reviewed.

    Study Selection: Selected studies were divided into those addressing coronary artery disease or myocardial ischemia and those addressing nonischemic cardiomyopathy and its sequelae. Preference was given to articles about the cardiac complications of both diabetes mellitus and hypertension.

    Results: Patients with diabetes and hypertension have a higher incidence of coronary artery disease than do patients with diabetes or hypertension alone. The former patients also show impaired systolic and diastolic function and have more severe left ventricular hypertrophy as documented by echocardiography and at autopsy. The structural myocardial damage seen in these patients has been attributed primarily to hypertension; the myocellular dysfunction has been attributed primarily to diabetes. In diabetic hypertensive patients with cardiomyopathy, coronary artery disease as well as structural and functional cardiac abnormalities are more pronounced than would be expected from either diabetes or hypertension alone.

    Conclusions: Considerable evidence from both experimental animal models and humans points to hypertension as a critically important factor in the pathogenesis of severe heart disease in persons with diabetes. The pathogenetic sequelae of diabetes and hypertension are devastating to the heart and often lead to premature congestive heart failure, sudden cardiac death, and acute myocardial infarction. Strict control of arterial pressure and glycemia may prevent or even ameliorate heart disease in patients with hypertension and diabetes.

    Diabetes mellitus and hypertension—two disorders that frequently coexist in the same patient—lead to structural and functional cardiac impairments that accelerate progression to cardiovascular illness and death from cardiovascular causes [1, 2]. Clinical and experimental studies suggest that the presence of diabetes and hypertension in the same patient results in more severe cardiomyopathy than would be expected with either condition alone [3, 4]. We summarize the features of heart disease in patients with diabetes and hypertension.

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    Methods

    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.

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    Results

    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.

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    Discussion

    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 β-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 α-blockers, and calcium antagonists do not appear to adversely affect metabolic risk factors and therefore may be superior to diuretics and β-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.

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    References

    1. 1.↵
      Five-year findings of the hypertension detection and follow-up program. II. Mortality by race-sex and age. Hypertension Detection and Follow-up Program Cooperative Group. JAMA. 1979; 242:2572-7.
    2. 2.↵
      Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol. 1974; 34:29-34.
    3. 3.↵
      Factor SM, Minase T, Sonnenblick EH. Clinical and morphological features of human hypertensive-diabetic cardiomyopathy. Am Heart J. 1980; 99:446-58.
    4. 4.↵
      van Hoeven KH, Factor SM. A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation. 1990; 82:848-55.
    5. 5.↵
      Fein FS, Scheuer J. Heart disease in diabetes. In: Rifkin H, Porte D Jr, eds. Diabetes Mellitus: Theory and Practice. 4th ed. New York: Elsevier; 1990:812-23.
    6. 6.↵
      Robertson WB, Strong JP. Atherosclerosis in persons with hypertension and diabetes mellitus. Lab Invest. 1968; 18:538-51.
    7. 7.↵
      Hambly RI, Sherman L, Mehta J, Aintablian A. Reappraisal of the role of the diabetic state in coronary artery disease. Chest. 1976; 70:251-7.
    8. 8.↵
      Waller BF, Palumbo PJ, Lie JT, Roberts WC. Status of the coronary arteries at necropsy in diabetes mellitus with onset after age 30 years. Analysis of 229 diabetic patients with and without clinical evidence of coronary heart disease and comparison to 183 control subjects. Am J Med. 1980; 69:498-506.
    9. 9.↵
      Herlitz J, Malmberg K, Karlson BW, Ryden L, Hjalmarson A. Mortality and morbidity during a five-year follow-up of diabetics with myocardial infarction. Acta Med Scand. 1988; 224:31-8.
    10. 10.↵
      Orlander PR, Goff DC, Morrissey M, Ramsey DJ, Wear ML, Labarthe DR, et al. The relation of diabetes to the severity of acute myocardial infarction and post-myocardial infarction survival in Mexican-Americans and non-Hispanic whites. The Corpus Christi Heart Project. Diabetes. 1994; 43:897-902.
    11. 11.↵
      Kuusisto J, Mykkanen L, Pyorala K, Laakso M. NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes. 1994; 43:960-7.
    12. 12.↵
      Genuth S. Exogenous insulin administration and cardiovascular risk in non–insulin-dependent and insulin-dependent diabetes mellitus. Ann Intern Med. 1996; 124:104-9.
    13. 13.↵
      Elliott TG, Viberti G. Relationship between insulin resistance and coronary heart disease in diabetes mellitus and the general population: a critical appraisal. Baillieres Clin Endocrinol Metab. 1993; 7:1079-103.
    14. 14.↵
      MacRury SM, Lowe GD. Blood rheology in diabetes mellitus. Diabetic Med. 1990; 7:285-91.
    15. 15.↵
      Giles TD, Sander GE. Myocardial disease in hypertensive-diabetic patients. Am J Med. 1989; 87:235-85.
    16. 16.↵
      Ewing DJ, Campbell IW, Clarke BF. Mortality in diabetic autonomic neuropathy. Lancet. 1976; 1:601-3.
    17. 17.↵
      Bellavere F, Ferri M, Guarini L, Bax G, Piccoli A, Cardone C, et al. Prolonged QT period in diabetic autonomic neuropathy: a possible role in sudden cardiac death? Br Heart J. 1988; 59:379-83.
    18. 18.↵
      Ewing DJ, Boland O, Neilson JM, Cho CG, Clarke BF. Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients. Diabetologia. 1991; 34:182-5.
    19. 19.↵
      Nesto RW, Phillips RT, Kett KG, Hill T, Perper E, Young E, et al. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy. Ann Intern Med. 1988; 108:170-5.
    20. 20.↵
      Ambepityia G, Kopelman PG, Ingram D, Swash M, Mills PG, Timmis AD. Exertional myocardial ischemia in diabetes: a quantitative analysis of anginal perceptual threshold and the influence of autonomic function. J Am Coll Cardiol. 1990; 15:72-7.
    21. 21.↵
      Niakan E, Harati Y, Rolak LA, Comstock JP, Rokey R. Silent myocardial infarction and diabetic cardiovascular autonomic neuropathy. Arch Intern Med. 1986; 146:2229-30.
    22. 22.↵
      Margolis JR, Kannel WS, Feinleib M, Dawber TR, McNamara PM. Clinical features of unrecognized myocardial infarction—silent and symptomatic. Eighteen year follow-up: the Framingham study. Am J Cardiol. 1973; 32:1-7.
    23. 23.↵
      Cabin HS, Roberts WC. Quantitative comparison of extent of coronary narrowing and size of healed myocardial infarct in 33 necropsy patients with clinically recognized and in 28 with clinically unrecognized (silent) previous acute myocardial infarction. Am J Cardiol. 1982; 50:677-81.
    24. 24.↵
      Factor SM, Bhan R, Minase T, Wolinsky H, Sonnenblick EH. Hypertensive-diabetic cardiomyopathy in the rat: an experimental model of human disease. Am J Pathol. 1981; 102:219-28.
    25. 25.↵
      D'Elia JA, Weinrauch L, Healy RW, Libertino JA, Bradley RF, Leland OS Jr. Myocardial dysfunction without coronary artery disease in diabetic renal failure. Am J Cardiol. 1979; 43:193-9.
    26. 26.↵
      Giacomelli F, Wiener J. Primary myocardial disease in the diabetic mouse. An ultrastructural study. Lab Invest. 1979; 40:460-73.
    27. 27.↵
      Haider B, Ahmed SS, Moschos CB, Oldewurtel HA, Regan TJ. Myocardial function and coronary blood flow response to acute ischemia in chronic canine diabetes. Circ Res. 1977; 40:577-83.
    28. 28.↵
      Hamby RI, Zoneraich S, Sherman L. Diabetic cardiomyopathy. JAMA. 1974; 229:1749-54.
    29. 29.↵
      Regan TJ, Ettinger PO, Khan MI, Jesrani MU, Lyons MM, Oldewurtel HA, et al. Altered myocardial function and metabolism in chronic diabetes mellitus without ischemia in dogs. Circ Res. 1974; 35:222-37.
    30. 30.↵
      Regan TJ, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, Haider B, et al. Cardiomyopathy and regional scar in diabetes mellitus. Trans Assoc Am Phys. 1975; 88:217-23.
    31. 31.↵
      Regan TJ, Lyons MM, Ahmed SS, Levinson GE, Oldewurtel HA, Ahmad MR, et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest. 1977; 60:884-99.
    32. 32.↵
      Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972; 30:595-602.
    33. 33.↵
      Sohar E, Ravid M, Ben-Shaul Y, Reshef T, Gafni J. Diabetic fibrillosis. A report of three cases. Am J Med. 1970; 49:64-9.
    34. 34.↵
      Factor SM, Okun EM, Minase T. Capillary microaneurysms in the human diabetic heart. N Engl J Med. 1980; 302:384-8.
    35. 35.↵
      Taegtmeyer H, Passmore JM. Defective energy metabolism of the heart in diabetes. Lancet. 1985; 1:139-41.
    36. 36.↵
      Rosenthal T, Frohlich ED. Cardiac implications of hypertension and diabetes. Curr Opin Cardiol. 1993; 8:746-56.
    37. 37.↵
      Allo SN, Lincoln TM, Wilson GL, Green FJ, Watanabe AM, Schaffer SW. Non-insulin-dependent diabetes-induced defects in cardiac cellular calcium regulation. Am J Physiol. 1991; 260(6 pt 1):C1165-71.
    38. 38.↵
      Tanaka Y, Konno N, Kako KJ. Mitochondrial dysfunction observed in situ in cardiomyocytes of rats in experimental diabetes. Cardiovasc Res. 1992; 26:409-14.
    39. 39.↵
      Lee SL, Ostadalova I, Kolar F, Dhalla NS. Alterations in Ca(2+)-channels during the development of diabetic cardiomyopathy. Mol Cell Biochem. 1992; 109:173-9.
    40. 40.↵
      Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol. 1983; 244:E528-35.
    41. 41.↵
      Garber DW, Everett AW, Neely JR. Cardiac function and myosin ATPase in diabetic rats treated with insulin, T3, and T4. Am J Physiol. 1983; 244:H592-8.
    42. 42.↵
      Malhotra A, Penpargkul S, Fein FS, Sonnenblick EH, Scheuer J. The effect of streptozotocin-induced diabetes in rats on cardiac contractile proteins. Circ Res. 1981; 49:1243-50.
    43. 43.↵
      Penpargkul S, Fein F, Sonnenblick EH, Scheuer J. Depressed cardiac sarcoplasmic reticular function from diabetic rats. J Mol Cell Cardiol. 1981; 13:303-9.
    44. 44.↵
      Pierce GN, Dhalla NS. Cardiac myofibrillar ATPase activity in diabetic rats. J Mol Cell Cardiol. 1981; 13:1063-9.
    45. 45.↵
      Noda N, Hayashi H, Miyata H, Suzuki S, Kobayashi A, Yamazaki N. Cytosolic Ca2+ concentration and pH of diabetic rat myocytes during metabolic inhibition. J Mol Cell Cardiol. 1992; 24:435-6.
    46. 46.↵
      Rude RK. Magnesium deficiency and diabetes mellitus. Causes and effects. Postgrad Med. 1992; 92:217-9, 222-4.
    47. 47.↵
      Schnider SL, Kohn RR. Glucosylation of human collagen in aging and diabetes mellitus. J Clin Invest. 1980; 66:1179-81.
    48. 48.↵
      Schnider SL, Kohn RR. Effects of age and diabetes mellitus on the solubility and nonenzymatic glucosylation of human skin collagen. J Clin Invest. 1981; 67:1630-5.
    49. 49.↵
      Brownlee M, Vlassara H, Cerami A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann Intern Med. 1984; 101:527-37.
    50. 50.↵
      Brownlee M, Cerami A, Vlassara H. Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med. 1988; 318:1315-21.
    51. 51.↵
      Fein FS, Sonnenblick EH. Diabetic cardiomyopathy. Prog Cardiovasc Dis. 1985; 27:255-70.
    52. 52.↵
      Tahiliani AG, McNeill JH. Diabetes-induced abnormalities in the myocardium. Life Sci. 1986; 38:959-74.
    53. 53.↵
      Dillmann WH. Diabetes mellitus induces changes in cardiac myosin of the rat. Diabetes. 1980; 29:579-82.
    54. 54.↵
      Shapiro LM. Echocardiographic features of impaired ventricular function in diabetes mellitus. Br Heart J. 1982; 47:439-44.
    55. 55.↵
      Borow KM, Jaspan JB, Williams KA, Neumann A, Wolinski-Walley P, Lang RM. Myocardial mechanics in young adult patients with diabetes mellitus: effects of altered load, inotropic state and dynamic exercise. J Am Coll Cardiol. 1990; 15:1508-17.
    56. 56.↵
      Perez JE, McGill JB, Santiago JV, Schechtman KB, Waggoner AD, Miller JG, et al. Abnormal myocardial acoustic properties in diabetic patients and their correlation with the severity of disease. J Am Coll Cardiol. 1992; 19:1154-62.
    57. 57.↵
      Mustonen JN, Uusitupa MI, Laakso M, Vanninen E, Lansimies E, Kuikka JT, et al. Left ventricular systolic function in middle-aged patients with diabetes mellitus. Am J Cardiol. 1994; 73:1202-8.
    58. 58.↵
      Iwasaka T, Sugiura T, Abe Y, Karakawa M, Matsui Y, Wakayama Y, et al. Residual left ventricular pump function following acute myocardial infarction in postmenopausal diabetic women. Coron Artery Dis. 1994; 5:237-42.
    59. 59.↵
      Iwasaka T, Takayama Y, Izuoka T, Takehana K, Sugiura T, Matsui Y, et al. Effect of ventriculoarterial coupling on residual left ventricular pump function in diabetic patients with myocardial infarction. Cardiology. 1994; 85:1-7.
    60. 60.↵
      Hoffman JI. A critical view of coronary reserve. Circulation. 1987; 75(1 Pt 2):I6-11.
    61. 61.↵
      Strauer BE. Myocardial oxygen consumption in chronic heart disease: role of wall stress, hypertrophy and coronary reserve. Am J Cardiol. 1979; 44:730-40.
    62. 62.↵
      Chobanian AV, Brecher PI, Haudenschild CC. Effects of hypertension and antihypertensive therapy on atherosclerosis: state of the heart lecture. Hypertension. 1986; 8(Suppl 1):115-21.
    63. 63.↵
      Brush JE Jr, Cannon RO 3d, Schenke WH, Bonow RO, Leon MB, Maron BJ, et al. Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy. N Engl J Med. 1988; 319:1302-7.
    64. 64.↵
      Tomanek RJ. The role of prevention or relief of pressure overload on the myocardial cell of the spontaneously hypertensive rat: a morphometric and stereologic study. Lab Invest. 1979; 40:83-91.
    65. 65.↵
      Marcus ML, Harrison DG, Chilian WM, Koyanagi S, Inou T, Tomanek RJ, et al. Alterations in the coronary circulation in the hypertrophied ventricles. Circulation. 1987; 75(Suppl 1):119-25.
    66. 66.↵
      Duncker DJ, Zhang J, Bache RJ. Coronary pressure-flow relation in left ventricular hypertrophy. Importance of changes in back pressure versus changes in minimum resistance. Circ Res. 1993; 72:579-87.
    67. 67.↵
      Kannel WB, Dannenberg AL, Abbott RD. Unrecognized myocardial infarction and hypertension: the Framingham study. Am Heart J. 1985; 109(3 Pt 1):581-5.
    68. 68.↵
      O'Kelley BF, Tubau JF, Szlahcic J, Daiss K, Massie BM. Detection of silent coronary artery disease in hypertensive patients [Abstract]. Hypertension. 1988; 12:344.
    69. 69.↵
      Dunn FG, Pringle SD. Left ventricular hypertrophy and myocardial ischemia in systemic hypertension. Am J Cardiol. 1987; 60:191-221.
    70. 70.↵
      Drayer JI, Gardin JM, Brewer DD, Weber MA. Disparate relationships between blood pressure and left ventricular mass in patients with and without left ventricular hypertrophy. Hypertension. 1987; 9(2 Pt 2):1161-4.
    71. 71.↵
      Frohlich ED, Apstein C, Chobanian AV, Devereux RB, Dustan HP, Dzau V, et al. The heart in hypertension. N Engl J Med. 1992; 327:998-1008.
    72. 72.↵
      Weber KT, Brilla CG, Janicki JS. Signals for the remodeling of cardiac interstitium in systemic hypertension. J Cardiovasc Pharmacol. 1991; 17(Suppl 2):S14-9.
    73. 73.↵
      Mercadier JJ, Lompre AM, Wisnewsky C, Samuel JL, Bercovici J, Swynghedauw B, et al. Myosin isoenzyme changes in several models of rat cardiac hypertrophy. Circ Res. 1981; 49:525-32.
    74. 74.↵
      Grossman E, Oren S, Messerli FH. Left ventricular mass and cardiac function in patients with essential hypertension. J Hum Hypertens. 1994; 8:417-21.
    75. 75.↵
      Inouye I, Massie B, Loge D, Topic N, Silverstein D, Simpson P, et al. Abnormal left ventricular filling: an early finding in mild to moderate systemic hypertension. Am J Cardiol. 1984; 53:120-6.
    76. 76.↵
      Devereux RB. Left ventricular diastolic dysfunction: early diastolic relaxation and late diastolic compliance. J Am Coll Cardiol. 1989; 13:337-9.
    77. 77.↵
      Phillips RA, Goldman ME, Ardeljan M, Arora R, Elson HB, Yu BY, et al. Determinants of abnormal left ventricular filling in early hypertension. J Am Coll Cardiol. 1989; 14:979-85.
    78. 78.↵
      Grossman E, Oren S, Messerli FH. Left ventricular filling and stress response pattern in essential hypertension. Am J Med. 1991; 91:502-6.
    79. 79.↵
      Kannel WB, Castelli WP, McNamara PM, McKee PA, Feinleib M. Role of blood pressure in the development of congestive heart failure. The Framingham study. N Engl J Med. 1972; 287:781-7.
    80. 80.↵
      Kannel WB, Gordon T, Offutt D. Left ventricular hypertrophy by electrocardiogram. Prevalence, incidence, and mortality in the Framingham study. Ann Intern Med. 1969; 71:89-105.
    81. 81.↵
      Kreger BE, Kannel WB, Cupples LA. Electrocardiographic precursors of sudden unexpected death: the Framingham Study. Circulation. 1987; 75(3 Part 2):1122-4.
    82. 82.↵
      Kannel WB. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med. 1983; 75:4-11.
    83. 83.↵
      Messerli FH, Ventura HO, Elizardi DJ, Dunn FG, Frohlich ED. Hypertension and sudden death. Increased ventricular ectopic activity in left ventricular hypertrophy. Am J Med. 1984; 77:18-22.
    84. 84.↵
      McLenachan JM, Henderson E, Morris KI, Dargie HJ. Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med. 1987; 317:787-92.
    85. 85.↵
      Levy D, Anderson KM, Savage DD, Balkus SA, Kannel WB, Castelli WP. Risk of ventricular arrhythmias in left ventricular hypertrophy: the Framingham Heart Study. Am J Cardiol. 1987; 60:560-5.
    86. 86.↵
      Barnett AH. Diabetes and hypertension. Br Med Bull. 1994; 50:397-407.
    87. 87.↵
      Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988; 37:1595-607.
    88. 88.↵
      Assmann G, Schulte H. The Prospective Cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. Am Heart J. 1988; 116(6 Pt 2):1713-24.
    89. 89.↵
      Samuelsson O, Hedner T, Persson B, Andersson O, Berglund G, Wilhelmesen L. The role of diabetes mellitus and hypertriglyceridaemia as coronary risk factors in treated hypertension: 15 years of follow-up of antihypertensive treatment in middle-aged men in the Primary Prevention Trial in Goteberg, Sweden. J Intern Med. 1994; 235:217-27.
    90. 90.↵
      Fernandez-Britto JE, Bacallao J, Castillo JA, Campos R, Wong R, Guski H. Atherosclerosis in diabetes and hypertension. A comparative morphometric study of their progression using an atherometric system. Zentralbl Pathol. 1991; 137:487-91.
    91. 91.↵
      Arora GD, Reeves WC, Movahed A. Alteration of coronary perfusion reserve in hypertensive patients with diabetes. J Hum Hypertens. 1994; 8:51-7.
    92. 92.↵
      Melina D, Colivicchi F, Melina G, Pristipino C. Prevalence of silent ST segment depression during long-term ambulatory electrocardiographic monitoring in asymptomatic diabetic patients with essential hypertension. Minerva Med. 1993; 84:301-5.
    93. 93.↵
      Venco A, Grandi A, Barzizza F, Finardi G. Echocardiographic features of hypertensive-diabetic heart muscle disease. Cardiology. 1987; 74:28-34.
    94. 94.↵
      Grossman E, Shemesh J, Shamiss A, Thaler M, Carroll J, Rosenthal T. Left ventricular mass in diabetes-hypertension. Arch Intern Med. 1992; 152:1001-4.
    95. 95.↵
      Sahai A, Ganguly PK. Congestive heart failure in diabetes with hypertension may be due to uncoupling of the atrial natriuretic peptide receptor-effector system in the kidney basolateral membrane. Am Heart J. 1991; 122(1 Pt 1):164-70.
    96. 96.↵
      Nagano N, Nagano M, Yo Y, liyama K, Higaki J, Mikami H, et al. Role of glucose intolerance in cardiac diastolic function in essential hypertension. Hypertension. 1994; 23(6 Pt 2):1002-5.
    97. 97.↵
      Danielsen R. Factors contributing to left ventricular diastolic dysfunction in long-term type I diabetic subjects. Acta Med Scand. 1988; 224:249-56.
    98. 98.↵
      Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991; 265; 3255-64.
    99. 99.↵
      Implications of the systolic hypertension in the elderly program. The Systolic Hypertension in the Elderly Program Cooperative Research Group. Hypertension. 1993; 21:335-43.
    100. 100.↵
      Davidoff F. Control, complications, confidence: the Regenstrief Conference on the risks and benefits of intensive management in NIDDM [Editorial]. Ann Intern Med. 1996; 124(1 Pt 1):65-6.
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