Diabetic Cardiomyopathy Does It Exist

In addition to the epidemiological data mentioned above, there are a host of other observations, both clinical and experimental, that point toward cardiomyopathic manifestations specifically related to the presence of diabetes. (In reviewing clinical data for this purpose, it is important to search for evidence of cardiomyopathy in the absence of the confounding presence of coronary artery disease and hypertension, both of which can cause CHF by themselves.)

The occurrence of dilated cardiomyopathy in patients with diabetes who do not have coronary disease or hypertension is well documented. In an individual patient, it is impossible to know whether this represents a specific diabetic cardio-myopathy or simply the chance occurrence of two common diseases. Stronger evidence of a specific, underlying cardiomyopathic process comes from studies of patients with diabetes, typically younger, who do not have clinical signs or symptoms of heart disease. These subjects have normal contraction patterns but a high incidence (on the order of one-third to one-half) of abnormal mitral inflow patterns detected by Doppler echocardiography (e.g., increased E to A ratios) consistent with slowed myocardial relaxation and/or decreased compliance. In addition, they have on average a larger myocardial mass than age-matched controls and frequently have increased myocardial ultrasonic backscatter. The latter is a nonspecific finding that can be caused by abnormalities of the myocardial tissue (e.g., increased collagen content and possibly other alterations of matrix proteins). Several studies demonstrate abnormal left ventricular contractile responses during dynamic exercise in asymptomatic diabetic patients, although this finding has not been uniform. It is noteworthy that the cardiomyopathic abnormalities described above have been reported in a broad spectrum of diabetic patients, including juvenile and adult onset, and insulin and non-insulin-requiring subjects. -o

In general, clinical signs of cardiomyopathy are positively correlated with the |

prevalence and severity of other complications of diabetes such as retinal vascu-lopathy, nephropathy, and neuropathy. g

Recently, we have obtained preliminary evidence of a depressed force- <j frequency relationship (FFR) in strips dissected from left ventricular epicardial Ji biopsies obtained from diabetic patients undergoing coronary bypass surgery compared with nondiabetic controls (Fig. 1). Although the presence of coronary a

g 5 12 36~,_eÖ~H~84—'"7O8~H~132 ' 156 ' 180 D- Stimulation Frequency fBPM)

Figure 1 Relation between isometric twitch force and frequency of stimulation in isolated myocardial strips obtained from patients with diabetes (DBM) and coronary artery disease (CAD) and nondiabetic CAD controls at time of coronary bypass surgery. Note reduced augmentation of force in diabetic patients as well as lower optimum frequency (see text).

g 5 12 36~,_eÖ~H~84—'"7O8~H~132 ' 156 ' 180 D- Stimulation Frequency fBPM)

Figure 1 Relation between isometric twitch force and frequency of stimulation in isolated myocardial strips obtained from patients with diabetes (DBM) and coronary artery disease (CAD) and nondiabetic CAD controls at time of coronary bypass surgery. Note reduced augmentation of force in diabetic patients as well as lower optimum frequency (see text).

artery disease is a potential confounding feature, we restricted our studies to patients with a normal left ventricular contraction pattern who did not have either hypertension or a clinical history of myocardial infarction. Thus, we excluded patients with conventional markers of ischemic myocardial dysfunction. As shown in Figure 1, normal humans have a markedly positive FFR (i.e., an increase in contractility as a function of stimulation frequency until an optimal frequency is reached, at which point contractility decreases as rate increases further). The positive FFR is thought to result from frequency-dependent increases in calcium pumping by the sarcoplasmic reticulum, with resultant increased calcium delivery to the myofilaments. Phosphorylation of phospholamban by calcium activated calmodulin kinase may be an important mechanism. The positive FFR is of great physiological importance because it is the most important mechanism whereby myocardial function is augmented during dynamic exercise. In contrast, patients with dilated cardiomyopathy have repeatedly been shown to have marked depression of the FFR as well as a decrease in optimal frequency; indeed, many have an inverted FFR, with decreasing contractility as frequency increases. These ab- g normalities have been correlated with alterations in calcium cycling protein expression.

As shown in Figure 1, diabetic patients are indistinguishable from nondia-betics at typical basal frequencies of around 60/min, but have a smaller augmen- a

& u tation in contractile performance as frequency is increased and a lower optimal frequency. This extent of FFR depression is less marked than that observed in patients with dilated cardiomyopathy patients, but could account for abnormal functional responses during exercise. It is tempting to speculate that it could also contribute to impaired contractile responses during myocardial infarction with resultant heart failure.

Various experimental animal preparations have been used to delineate the effects of diabetes on the myocardium. The most common utilize destruction of pancreatic islet cells by streptozotocin, but a number of others have also been employed, including obese, insulin-resistant rat strains and genetically engineered mice lacking insulin receptors. Some animal models display evidence of impaired coronary tone consistent with endothelial dysfunction, but they do not exhibit the type of coronary artery disease present in diabetic patients that confounds efforts to distinguish the effects of diabetes on the myocardium from those of coronary stenoses. However, great caution must be exercised in extrapolating results from experimental animal models to patients, in whom diabetes is obviously much more chronic. Nonetheless, although the details differ, it is remarkable that cardiac functional abnormalities can be detected in almost any experimental model of diabetes. These abnormalities include depressed contractile performance, slowed relaxation, and, in some instances, decreased diastolic compliance. Defects in both excitation-contraction coupling due to abnormal calcium cycling and in the contractile machinery have been documented as factors underlying the abnormalities of contraction and relaxation.

Thus, in patients selected to exclude other diseases that could alter myocar-dial function, as well as in a number of experimental diabetes models, there is considerable evidence supporting the concept of a diabetic cardiomyopathy. The manifestations are diverse, and it is not yet clear how or if they relate to each other mechanistically.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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