A comparison of the pathological spectrum of hypertensive, diabetic, and hypertensive-diabetic heart disease

The hearts obtained at autopsy of 67 patients with hypertension, diabetes mellitus, or both were examined microscopically and histochemically, and the amount of fibrosis was determined. Significant differences in heart weight, interstitial fibrosis, replacement fibrosis, and perivascular fibrosis were found among the groups. The mean heart weight of the hypertensive-diabetic patients was significantly greater than that of the hypertensive patients and the diabetic patients. The amount of microscopic fibrosis increased between the groups, the lowest in hypertensive hearts, midrange in diabetic hearts, and highest in hypertensive-diabetic hearts. Total fibrosis correlated with heart weight among diabetic and hypertensive-diabetic patients and was significantly greater among patients with congestive heart failure, most of whom had histories of both hypertension and diabetes. The microscopic grade of fibrosis correlated significantly (p less than 0.01) with a quantitative, histochemical determination of the amount of collagen per milligram of total noncollagenous protein in the heart tissue. Myocardial fibrosis may contribute to the diastolic dysfunction typical of hypertensive-diabetic cardiomyopathy, in which congestive heart failure is a common sequela. The importance of hypertension in the pathogenesis of severe diabetic heart disease is discussed.     

Hypothesis: Is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (Microvascular spasm)?

In most congested, dilated cardiomyopathies, pathologic analysis reveals focal myocardial necrosis, microscopic scarring, interstitial fibrosis, and myocellular hypertrophy. The focal nature of these processes indicates that the cardiomyopathies may not be due to diffuse abnormalities of cardiac muscle cells, at least in the early stages, but that the changes may represent focal events affecting discrete, small volumes of tissue. Experimental evidence of microvascular hyperreactivlty (spasm), both In the hereditary cardiomyopathy of the Syrian hamster and in the acquired cardiomyopathy of the hypertensive-diabetic rat, suggests that transient spasm of the myocardial microcirculation may lead to focal myocellular necrosis and scarring, which then causes the unaffected myocardial cells to undergo compensatory hypertrophy in order to normalize the increased load per unit of myocardium. When enough myocardium is lost and the compensatory hypertrophy results in decreased contractility, congestive heart failure ensues as a systemic response to altered ventricular function. The efficacy of verapamil therapy in the Syrian hamster in preventing microvascular spasm, cell necrosis, and the subsequent development of a cardiomyopathy has provided hope that similar preventive treatment can be applied to patients with early stages of cardiomyopathy.     

Diabetic cardiomyopathy: possible pathogenetic role of coronary microcirculation]

The hypothesis that diabetes mellitus provokes a specific cardiomyopathy is supported by numerous clinical, epidemiological and anatomopathological studies. However, the frequent association of diabetes mellitus with other conditions, such as hypertension and coronary atherosclerosis, both capable of causing the dysfunction of the cardiac muscle, makes it difficult to interpret many of the data reported in the literature and contributes to the continuing debate regarding the effective existence of diabetic cardiomyopathy and its possible pathogenetic mechanisms. In clinical terms, diabetic cardiomyopathy is manifested both as an altered diastolic and/or systolic phase, assessed using various non-invasive techniques, or as congested cardiac decompensation. The pathogenesis of diabetic cardiomyopathy is still not altogether clear. The alteration of the smallest coronary vessels might be responsible for the increased interstitial fibrosis found in the heart of diabetic patients. In this paper numerous data from the literature on this argument are reported and the authors advance the hypothesis that endothelial dysfunction may play a pathogenetic role in the development of cardiopathy.     

Quantitative approach to the histopathology of the biopsied right ventricular myocardium in patients with diabetes mellitus

For the purpose of studying the clinicopathology of the biopsied myocardium in patients with diabetes mellitus, the diameter of right ventricular myocardial cells and diffuse perimysial fibrosis of biopsied myocardium were measured quantitatively. Seven healthy controls and nine diabetic patients without hypertension or coronary arterial disease were subjected to this study. The degree of diabetic complications was mild to moderate. The diameter of myocardial cells was measured and the degree of diffuse perimysial fibrosis was assessed by the point-counting method using a square grid, in which the distance between the points was 10 micron. Over 2000 points which lay on the longitudinally cut myocardial cells and on the interstitial fibrosis stained by the Mallory-Azan method were measured. Percentage fibrosis was calculated according to the formula: percentage fibrosis = (points lying on the interstitial fibrosis)/[(points lying on the myocardial cell) + (points lying on the interstitial fibrosis)] X 100. The results were as follows. The mean diameter of right ventricular myocardial cells in patients with diabetes mellitus was significantly larger than that of controls (P less than 0.01). The percentage fibrosis of diabetic patients was significantly higher than that of controls (P less than 0.01). There was no significant correlation between the histopathological measurements and clinical features. It is concluded that hypertrophy of myocardial cells and interstitial fibrosis of the myocardium exist even in mild diabetes mellitus.     

A comparison of ultrastructural changes on endomyocardial biopsy specimens obtained from patients with diabetes mellitus with and without hypertension

Summary The pathogenesis of diabetic cardiomyopathy is unknown. The synergistic, or enhanced, effect of hypertension on pathological changes in the heart of diabetic patients has been highly suspected. The purpose of this study was to evaluate the myocardial changes related to diabetes mellitus with and without hypertension, using biopsy specimens. We examined the ultrastructural changes in biopsy specimens of the endomyocardium obtained from 25 patients. They were divided into four groups: controls without hypertension or diabetes mellitus (n=6), and patient with hypertension (n=3), diabetes mellitus (n=8), and diabetes with hypertension (n=8). The diabetic patients showed nearly normal or mildly depressed systolic left ventricular function. Ultrastructural pictures were analyzed for thickening of the capillary basement membrane, presence of toluidine blue-positive materials (i.e., materials showing metachromasia) in the myocytes, size of myocytes, and interstitial fibrosis. The thickening of the capillary basement membrane, the accumulation of toluidine blue-positive materials, and interstitial fibrosis were all significantly greater in the patients with diabetes mellitus compared to the control subjects. The myocytes tended to be small (cell atrophy) in the diabetes group. Although these pathological changes in the heart were characteristic of diabetic patients, irrespective of the presence or absence of hypertension, the presence of hypertension increased the pathological changes of myocardial cells as well as abnormality in the capillary vessels in patients with diabetes mellitus. Alterations in the myocardial cells and capillaries, caused by diabetes mellitus, may lead to myocardial cell injury and interstitial fibrosis and, ultimately, to ventricular systolic and diastolic dysfunction, especially when the diabetes is accompanied by hypertension.     

Microvascular spasm as a cause of cardiomyopathies and the calcium-blocking agent verapamil as potential primary therapy

The origin of cardiomyopathies, a major cause of cardiac disability and death, has been largely unexplained. Pathologic features, common to all cardiomyopathies independent of origin, include ventricular hypertrophy and diffuse scarring with variable amounts of ventricular dilatation. This problem was studied experimentally in 2 models of congestive cardiomyopathy: the hereditary cardiomyopathic Syrian hamster and the hypertensive-diabetic rat. In both the genetic and the acquired disease models, there is focal myocytolytic necrosis followed by healing with focal scars, ventricular wall hypertrophy, ventricular dilatation with congestive heart failure and, ultimately, death. In view of the heterogeneous pathologic features of both diseases, silicone rubber perfusions have been used to study the microcirculation of the heart in these animals; microvascular spasm has been demonstrated early in the disease associated with small areas of myocytolytic necrosis that undergo subsequent fibrosis. Reactive hypertrophy then ensues as a compensatory response to this myocellular necrosis; it is the combination of cell loss and slowly decreasing contractility resulting from the reactive hypertrophy, which culminates in a cardiomyopathy. Administration of verapamil or prazosin to the cardiomyopathic Syrian hamster prevents microvascular spasm and development of cardiomyopathic changes in the myocardium. In view of these and other findings related to the anatomy and hyperreactivity of microcirculation, it is concluded that hypertrophic congestive cardiomyopathies may be caused by focal cell loss due to microvascular spasm and reperfusion injury, with the subsequent development of focal fibrosis and reactive hypertrophy in response to the myocardial necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diabetische Kardiomyopathie

Diabetic cardiomyopathy is a myocardial disease caused by diabetes mellitus unrelated to vascular and valvular pathology or systemic arterial hypertension. Clinical and experimental studies have shown that diabetes mellitus causes myocardial hypertrophy, apoptosis and necrosis, and increases interstitial tissue. The pathophysiology of diabetic cardiomyopathy is incompletely understood and several mechanistical approaches are under debate. Metabolic impairments like hyperglycemia, hyperlipidemia, hyperinsulinemia, and alterations in the cardiac metabolism lead to structural and functional changes which show cellular effects leading to increased oxidative stress, interstitial fibrosis, myocyte death, and disturbances in ion transport and homeostasis. Diastolic dysfunction which consecutively results in systolic dysfunction with increased left ventricular volume and reduced ejection fraction is an early diagnostic parameter. Treatment of diabetic cardiomyopathy does not differ from myocardiopathies of other etiologies and therefore has to follow the appropriate guidelines. Early intervention to reverse metabolic toxicity is the most effective method of prevention.     

Histologic and ultrastructural studies on the myocardium in spontaneously diabetic KK mice: A new animal model of cardiomyopathy

The hearts from spontaneously diabetic KK mice and control mice were examined by light and electron microscopy. Myocardial degeneration, myocardial fibrosis and calcium deposits in the myocardium were extensive in KK mice aged 8 weeks. In myocytes of newborn KK mice, an irregular arrangement of myofibrils and poorly formed Z bands were found. Ultrastructural changes in myocytes of KK mice aged 4 weeks consisted of destruction of mitochondria, degenerated myofibrils and abnormalities of Z bands. However, increased mucopolysaccharides in interstitium and thickened basement membranes of capillaries were not found in KK mice, in contrast to the previous reports of myocardial changes in diabetic C57BL/KsJ mice, alloxan-diabetic dogs and hypertensive-diabetic rats. These observations suggest that the cardiomyopathy found in KK mice is not secondary to diabetes mellitus but is caused by other factors.In conclusion, myocardial ultrastructural abnormalities are present in newborn KK mice. Thus, this animal can be used as a model of cardiomyopathy.     

Diabetic cardiomyopathy

Diabetic cardiomyopathy is a myocardial disease caused by diabetes mellitus unrelated to vascular and valvular pathology or systemic arterial hypertension. Clinical and experimental studies have shown that diabetes mellitus causes myocardial hypertrophy, necrosis, and apoptosis, and increases interstitial tissue. The pathophysiology of diabetic cardiomyopathy is incompletely understood. It appears that metabolic perturbations such as hyperlipidemia, hyperinsulinemia, hyperglycemia, and changes in cardiac metabolism are involved in cellular consequences leading to increased oxidative stress, interstitial fibrosis, myocyte death, and altered intracellular ions transient and calcium homeostasis. Clinically, an early detection of asymptomatic diastolic dysfunction is possible. When patients develop signals and symptoms of heart failure, isolated diastolic dysfunction is usually detected. Systolic dysfunction is a late finding. Treatment of heart failure due to diabetic cardiomyopathy is not different from myocardiopathies of other etiologies and must follow the guidelines according to ventricular function, whether diastolic or diastolic and systolic impairment.     

A cross-sectional study of echocardiographic indices, treadmill exercise capacity and microvascular complications in Nigerian patients with hypertension associated with diabetes mellitus.

Associations between hypertension and cardiovascular complications of diabetes mellitus in Nigerians, were examined in a cross-sectional study. 20 hypertensive-diabetic patients, 16 hypertensive patients, 10 non-hypertensive diabetic patients and 10 age- and sex-matched healthy controls, underwent M-mode and cross-sectional echocardiography, and Bruce-protocol treadmill exercise performance. Left ventricular (LV) mass indices (+/- SD) were significantly higher in hypertensive patients (164 +/- 12gm-2), diabetic (158 +/- 17gm-2) and hypertensive diabetic patients (125 +/- 129gm-2) compared with normal controls (111 +/- 17gm-2) p < 0.01. However, the LV mass index in the hypertensive-diabetic patients was significantly less than in hypertensive (p < 0.05) or normotensive diabetic patients (p < 0.05). Systolic cardiac contractility measured as fractional fibre shortening, was preserved in the hypertensive patients (24 +/- 4%) compared with the healthy controls (23 +/- 4%), but was depressed in diabetic patients (19 +/- 3%) and to a greater extent in the hypertensive-diabetic patients (15 +/- 4% p < 0.01). Treadmill exercise tolerance time was reduced independently in hypertension (309 +/- 73 seconds) or diabetes (321 +/- 119 seconds), p < 0.05, but was further impaired in hypertensive-diabetic patients (289 +/- 110 seconds) p < 0.01 compared to the healthy controls (490 +/- 156 seconds). The patients with hypertension and diabetes had a greater degree of proteinuria (p < 0.001) and a higher frequency of retinopathy (p < 0.001), in comparison to those with hypertension or diabetes alone.     

Diabetic cardiomyopathy: concept,heart function,and pathogenesis

The diabetic cardiomyopathy is a disease caused by diabetes and is characterised by the presence of diastolic and/or systolic left ventricular dysfunction. Diabetes may produce metabolic alterations, interstitial fibrosis, myocellular hypertrophy, microvascular disease and autonomic dysfunction. It is thought that all of them may cause cardiomyopathy. Other abnormalities that are usually associated with diabetes such as hypertension, coronary artery disease and nephropathy should be excluded before diagnosing diabetic cardiomyopathy. There is no evidence that diabetic cardiomyopathy alone can produce heart failure. However, subclinical ventricular dysfunction has been described in young asymptomatic diabetic patients without other diseases that could affect the cardiac muscle. In these cases we should consider that diabetes is the only cause of the myocardial disease. More studies are needed to know the natural history of diabetic cardiomyopathy.     

Diabetes mellitus und Herzinsuffizienz – Inzidenz und chirurgische Therapieoptionen

The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4-6% in control populations. Epidemiologic studies have demonstrated an increased risk of heart failure in diabetics. Experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis.The knowledge of the diabetes status may help to define the optimal therapeutic strategy for heart failure patients. In ischemic cardiomyopathy the choice of the surgical treatment may differ according to diabetes status, coronary atherosclerosis and left ventricular function.At present, surgical revascularization techniques seem to be superior to interventional revascularization procedures.In the last decade a growing part of diabetics presenting severe heart failure underwent heart transplantation. Thereby, it was found that the survival rates of patients with uncomplicated diabetes mellitus and of nondiabetics did not differ. The survival rates in patients with severe and progressive form of diabetes mellitus are discussed controversially in the literature. Because of donor organ shortage each diabetic patient presenting severe heart failure should be evaluated to find the best therapy including permanent mechanical circulatory support ("destination therapy").     

Diabetic cardiomyopathy: ongoing controversies in 2012

Diabetic cardiomyopathy is a controversial clinical entity that in its initial state is usually characterized by left ventricular diastolic dysfunction in patients with diabetes mellitus that cannot be explained by coronary artery disease, hypertension, or any other known cardiac disease. It was reported in up to 52?C60% of well-controlled type-II diabetic subjects, but more recent studies, using standardized tissue Doppler criteria and more strict patient selection, revealed a much lower prevalence. The pathological substrate is myocardial damage, left ventricular hypertrophy, interstitial fibrosis, structural and functional changes of the small coronary vessels, metabolic disturbance, and autonomic cardiac neuropathy. Hyperglycemia causes myocardial necrosis and fibrosis, as well as the increase of myocardial free radicals and oxidants, which decrease nitric oxide levels, worsen the endothelial function, and induce myocardial inflammation. Insulin resistance with hyperinsulinemia and decreased insulin sensitivity may also contribute to the left ventricular hypertrophy. Clinical manifestations of diabetic cardiomyopathy may include dyspnea, arrhythmias, atypical chest pain, and dizziness. Currently, there is no specific treatment of diabetic cardiomyopathy that targets its pathophysiological substrate, but various therapeutic options are discussed that include improving diabetic control with both diet and drugs (metformin and thiazolidinediones), the use of ACE inhibitors, beta blockers, and calcium channel blockers. Daily physical activity and a reduction in body mass index may improve glucose homeostasis by reducing the glucose/insulin ratio and the increase of both insulin sensitivity and glucose oxidation by the skeletal and cardiac muscles.     

Absence of correlation between coronary arteria atherosclerosis and severity or duration of diabetes mellitus of adult onset

The relation between the severity and duration of diabetes mellitus and the severity of ischemic heart disease is uncertain. The clinical findings and the findings at autopsy were studied in 185 patients with diabetes mellitus of adult onset who ranged in age from 37 to 91 years and had a clinical diagnosis of diabetes established for a few days to 50 years before death. No statistically significant association was demonstrated either by simple correlation or by multivariate regression analysis between the clinically diagnosed severity or duration of diabetes and either the overall coronary disease, the number of diseased vessels or the number of myocardial infarctions. The presence of other expected correlations in the multivariate analysis suggested that the results of this study were not spurious. However, comparison with 185 age- and sex-matched control patients revealed that on the average, diabetic patients have more overall coronary disease (p < 0.002), more diffuseness of coronary disease (p < 0.005), more coronary collateralizatlon (p < 0.001), more vessels involved by atherosclerosis (p < 0.001) and more myocardial infarcts (p < 0.001). The results suggest that although diabetes mellitus of adult onset is a condition in which the larger coronary arteries are subject to more atherosclerosis than are those in nondiabetic subjects, the progression of the atherosclerotic disease is unrelated to the duration or severity of the diabetes mellitus.     

Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications

The presence of a diabetic cardiomyopathy, independent of hypertension and coronary artery disease, is still controversial. This systematic review seeks to evaluate the evidence for the existence of this condition, to clarify the possible mechanisms responsible, and to consider possible therapeutic implications. The existence of a diabetic cardiomyopathy is supported by epidemiological findings showing the association of diabetes with heart failure; clinical studies confirming the association of diabetes with left ventricular dysfunction independent of hypertension, coronary artery disease, and other heart disease; and experimental evidence of myocardial structural and functional changes. The most important mechanisms of diabetic cardiomyopathy are metabolic disturbances (depletion of glucose transporter 4, increased free fatty acids, carnitine deficiency, changes in calcium homeostasis), myocardial fibrosis (association with increases in angiotensin II, IGF-I, and inflammatory cytokines), small vessel disease (microangiopathy, impaired coronary flow reserve, and endothelial dysfunction), cardiac autonomic neuropathy (denervation and alterations in myocardial catecholamine levels), and insulin resistance (hyperinsulinemia and reduced insulin sensitivity). This review presents evidence that diabetes is associated with a cardiomyopathy, independent of comorbid conditions, and that metabolic disturbances, myocardial fibrosis, small vessel disease, cardiac autonomic neuropathy, and insulin resistance may all contribute to the development of diabetic heart disease.     

Congestive heart failure in a patient with systemic hypertension

A 70-year-old man developed hypertension many years previously and had a bout with severe congestive heart failure 4 to 5 years before his death. Autopsy showed congestion and edema characteristic of heart failure, an enlarged heart, and slight focal interstitial left ventricular fibrosis, but only slight to moderate coronary atherosclerosis.     

Role of differential signaling pathways and oxidative stress in diabetic cardiomyopathy

Diabetes mellitus increases the risk of heart failure independently of underlying coronary artery disease, and many believe that diabetes leads to cardiomyopathy. The underlying pathogenesis is partially understood. Several factors may contribute to the development of cardiac dysfunction in the absence of coronary artery disease in diabetes mellitus. There is growing evidence that excess generation of highly reactive free radicals, largely due to hyperglycemia, causes oxidative stress, which further exacerbates the development and progression of diabetes and its complications. Hyperglycemia-induced oxidative stress is a major risk factor for the development of micro-vascular pathogenesis in the diabetic myocardium, which results in myocardial cell death, hypertrophy, fibrosis, abnormalities of calcium homeostasis and endothelial dysfunction. Diabetes-mediated biochemical changes show cross-interaction and complex interplay culminating in the activation of several intracellular signaling molecules. Diabetic cardiomyopathy is characterized by morphologic and structural changes in the myocardium and coronary vasculature mediated by the activation of various signaling pathways. This review focuses on the oxidative stress and signaling pathways in the pathogenesis of the cardiovascular complications of diabetes, which underlie the development and progression of diabetic cardiomyopathy.     

Echocardiographic features of hypertensive-diabetic heart muscle disease

Computerized M-mode echocardiography was used to evaluate left ventricular anatomy and function in 20 patients with hypertension and diabetes mellitus, without signs of overt heart disease. A similar study was performed in 20 patients with hypertension of similar severity and duration and in 20 normal subjects. Mean posterior wall thickness and mean septal thickness were increased in hypertensive patients compared to normal (p less than 0.001), but diabetic patients had thicker septa with respect to nondiabetics (p less than 0.05). All hypertensive-diabetic patients had reduced peak lengthening rate and/or peak velocity of posterior wall thinning. Six of them also had reduced peak Vcf and/or peak velocity of posterior wall thickening. Only 9 of the 20 patients with hypertension alone had abnormal diastolic function; 4 out of these 9 also had abnormal systolic function. We conclude that diabetes causes more severe impairment of left ventricular function in patients with a similar degree of hypertension. The more consistent abnormalities are reduced rate of dimension increase during filling and slower wall thinning, suggesting impaired left ventricular relaxation and distensibility.     

Beneficial effects of diltiazem on the natural history of hypertensive diabetic cardiomyopathy in rats.

Hypertensive diabetic rats develop a cardiomyopathy characterized by systolic and diastolic ventricular dysfunction, myocardial hypertrophy and fibrosis, pulmonary congestion and a very high mortality rate. Alterations in contractile proteins and sarcoplasmic reticular calcium (Ca2+) transport in diabetic myocardium and their partial reversal with verapamil suggest that calcium channel blockade may prevent death from congestive heart failure in hypertensive diabetic rats. A large group of rats with renovascular hypertension and streptozotocin diabetes were divided into four groups: untreated animals (Group 1) and animals treated with 100 (Group 2), 300 (Group 3) or 600 (Group 4) mg/kg per day of sustained release diltiazem mixed in their food. Treatment was begun shortly after the onset of hypertension and diabetes. Mortality rates after 4 months were 59% (19 of 32), 53% (17 of 32), 27% (7 of 26) and 35% (12 of 34) in Groups 1, 2, 3 and 4, respectively; the mortality rate in age-matched control rats was 5% (1 of 19). The reductions in mortality rates in Groups 3 and 4 were statistically significant. Diltiazem did not change systolic blood pressure, serum glucose concentration, heart rate or left ventricular mass. There was a trend to decreased left ventricular interstitial fibrosis and perivascular fibrosis in diltiazem-treated animals. Ventricular collagen concentration was similar in untreated hypertensive diabetic and control rats; levels were higher in hypertensive diabetic rats that died than in those that survived. There was a trend to decreased collagen concentration as diltiazem dose increased. Myosin isoenzyme distribution was not changed in Groups 3 and 4 (in comparison with Group 1). In all hypertensive diabetic groups, rats that died had a higher blood pressure, heart rate, relative left ventricular mass, lung weight and lung water than did survivors. The mortality rate was two to three times higher among rats with an initial blood pressure greater than or equal to 180 mm Hg. The beneficial effects of diltiazem on survival were most significant among rats with severe hypertension.     

Permeability of small coronary arteries and myocardial injury in hypertensive diabetic rats

Damage to the coronary artery and myocardium is known to be more marked when hypertension is complicated by diabetes than when either is present alone. The reason is not clear, but one possible factor is vascular permeability. Therefore, we investigated vascular permeability using sodium fluorescein of 70 mg/kg body weight, in 12-week-old streptozotocin-induced diabetic spontaneously hypertensive rats. Non-diabetic spontaneously hypertensive rats, diabetic rats with normal blood pressure, and non-diabetic rats with normal blood pressure of the same age were used as controls and treated similarly. H-E and Azan staining were used to examine vascular abnormality and mycoardial damage. The diabetic spontaneously hypertensive rats showed marked sodium fluorescein in the coronary artery wall and surrounding area, demonstrating greater vascular permeability than non-diabetic spontaneously hypertensive rats, diabetic and non-diabetic normotensive rats. Heart weights and diameters of myocytes were smaller in the diabetic than in the non-diabetic spontaneously hypertensive rats. Diabetic spontaneously hypertensive rats also exhibited marked perivascular fibrosis and focal necrosis. Thus, increased vascular permeability may play a role in vascular and myocardial changes in diabetic spontaneously hypertensive rats.