Most diabetic patients with CHF have it in conjunction with some other known cause(s) of CHF, usually coronary artery disease and/or hypertension. Thus, there are relatively few patients with CHF in whom the only predisposing factor is diabetes. Stated another way, although there is strong evidence that cardiomyopa-thy is caused by diabetes, it is unusual for it to account for overt CHF by itself. Moreover, in an individual patient, it is usually impossible to delineate the qualitative and quantitative contributions of diabetic cardiomyopathy as opposed to hypertension or ischemia caused by coronary artery disease. As noted above, diabetes in combination with hypertension and coronary artery disease is not merely additive, but interacts with either or both in a way that seems to potentiate myocardial failure.
Accordingly, when diabetic patients have CHF in association with coronary artery disease, they typically have conventional manifestations of myocardial ischemia (i.e., acute and chronic infarction, stunned and/or hibernating myocardium) that result in both systolic failure, characterized by a reduced ejection fraction and ventricular chamber dilatation (when the process is chronic), and diastolic failure, characterized by upward displacement of the diastolic pressure-volume relationship due to slowed or incomplete relaxation and/or decreased passive compliance (with or without a decrease in ejection fraction). In addition, remodeling of noninfarcted myocardium in patients with chronic infarction may also contribute to systolic failure. A depressed and even inverted FFR is a common manifestation of ischemic as well as nonischemic dilated cardiomyopathy.
The cellular and molecular mechanisms of systolic failure specifically related to ischemia are multiple, and include necrosis, apoptosis, reversible proteo-lytic damage to calcium cycling, and contractile proteins and perhaps phenotypic changes in these same proteins. In addition, a variety of mechanisms are generic to dilated cardiomyopathy, both ischemic and nonischemic, such as downregula-tion of calcium cycling proteins, alterations in protein kinase A and C activity, and neurohumoral and cytokine-mediated adverse effects on the myocardium. Ischemia causes diastolic failure mediated by some of the same phenomena (e.g., impaired function or damage to calcium cycling proteins), and also by virtue of scar formation following infarction. In addition, because they often do not have
& u typical chest discomfort in conjunction with ischemia, diabetic patients with ''demand ischemia'' may present with exertional dyspnea as the main symptom. Dyspnea caused by demand ischemia is a form of reversible heart failure primarily ascribable to diastolic dysfunction.
Hypertension, when present in diabetic patients, can also cause CHF through multiple mechanisms. When hypertension is ''compensated'' (i.e., ejection fraction is normal), it causes concentric left ventricular hypertrophy, which in turn can cause symptoms of CHF (mainly dyspnea). This form of diastolic dysfunction may result from depressed calcium pumping by the sarcoplasmic reticulum and reduced chamber compliance related to decreased volume:mass ratio and increased connective tissue content. Concentric hypertrophy can cause subendocardial ischemia when energy demands increase even in the absence of coronary artery disease. When concentric hypertrophy becomes decompensated, the ejection fraction decreases and systolic failure ensues.
In view of the manifestations of and mechanisms underlying diabetic cardiomyopathy discussed above, it is not difficult to envision how the presence of diabetes might interact with both the ischemic consequences of coronary artery disease and hypertension to increase the incidence and worsen the manifestations of CHF. A few examples make this clear. Diabetes-related damage to ion exchange and pumping functions would obviously be expected to compound abnormalities of calcium cycling and further compromise systolic function and relaxation. A depressed FFR limits an important adaptation to acute stress and may help explain the high incidence of heart failure in diabetic subjects who sustain an acute myocardial infarction. Diabetes-related alterations in connective tissue would compound the effects of increased collagen due to myocardial ischemia and/or hypertension. In fact, the combination of hypertension and diabetes seems to result in much more exuberant fibrosis than that seen with either alone. Although little is known about the contribution of microvasculopathy to diabetic cardiomyopathy, interactions may exist related to the endothelial dysfunction that is common to coronary atherosclerosis, hypertension, and diabetes.
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