Altered Myocardial Function and Metabolism in Chronic Diabetes Mellitus without Ischemia in Dogs

Abstract

Myocardial disease in diabetes mellitus is usually attributed to coronary atherosclerosis. To examine the influence of uncomplicated diabetes on the left ventricle, a mild noninsulin-requiring diabetes was produced in male mongrel dogs after three intravenous doses of alloxan were administered at monthly intervals. There was a persistent decline in glucose tolerance and a reduced insulin content in the pancreas of each alloxan-diabetic dog at the termination of the experiment. The dogs were anesthetized for hemodynamic and metabolic studies after approximately 11 months. Left ventricular end-diastolic volume and cardiac output were measured by the indicator-dilution method. An increase in afterload with moderate aortic pressure elevations elicited a significant rise in end-diastolic volume and stroke volume in normal control dogs. In diabetes, despite a similar end-diastolic pressure response, the end-diastolic volume and the stroke volume responses were significantly less than those in control dogs. During acute volume expansion of the ventricle with saline, the end-diastolic pressure increment in diabetic dogs was twice that in control dogs. These responses were attributed to an increased stiffness of the left ventricle that was apparently due to accumulation of glycoprotein (measured by periodic acid-Schiff staining) in the interstitium. Since similar abnormalities were observed in dogs with diabetes occurring spontaneously and were absent when the pancreatic effects of alloxan were inhibited in a separate group of dogs, the pathogenetic role of alloxan via a direct action on myocardium was excluded. Analysis of lipids in the left ventricle revealed elevated triglyceride and cholesterol concentrations despite normal plasma levels. During infusion of 14 C-1-oleic acid, cardiac oxidation appeared to be normal, but fatty acid incorporation, which was predominantly into phospholipid in the control dogs, was diverted to triglyceride in the diabetic dogs. Since an aberration of de novo synthesis was not found during studies with 14 C-acetate, triglyceride accumulation was attributed to altered intracellular metabolism, perhaps related to glycerol phosphate acyl transferase activity. The basis for cholesterol accumulation was less clear, since neither 14 C-acetate nor 14 C-oleate incorporation into sterol was enhanced. Myocardial ischemia was excluded on the basis of patency of coronary arteries and normal coronary blood flow, myocardial cation content, and mitochondrial morphology. Thus, it was concluded that chronic diabetes mellitus can alter myocardial composition and function independent of vascular effects.

The ACE-inhibitor captopril improves myocardial perfusion in spontaneously diabetic (BB) rats

“…This diminution of EDP can be taken as an indicator of an improved relaxation of the diabetic heart. Since the velocity of relaxation delayed in diabetes was not influenced by captopril and since the diabetes-induced increase in EDP largely reflects the increased stiffness of ventricles in diabetes by accumulation of collagen and other matrix proteins [4,9,19,25], we assume that the diminution of the end diastolic pressure reflects changes in the texture of cardiac vasculature and wall, but not an effect of the ACE inhibitor on the electric properties of the heart. In line with this assumption it has been shown that ACE inhibitors inhibit the deposition of collagen and other matrix proteins and thus can prevent the development of interstitial fibrosis [25].…”

“…Additionally or alternatively, our results could be explained by a delayed degradation of bradykinin. Bradykinin has been shown to increase the nutritional flow and the permeability of coronary vasculature leading to an improved local myocardial perfusion [17,19,30]. Furthermore, it has been shown that ACE inhibition and delayed degradation of bradykinin can prevent endothelial dysfunction induced by a variety of pathophysiological states [27,48].…”

“…Microangiopathic changes [14][15][16], abnormalities in vascular reactivity [15,17], altered autonomic function [9,18], increased stiffness of the ventricular wall and perivascular thickening, interstitial accumulation of connective tissue and matrix proteins [4,9,18,19], and defects in the regulation of calcium homeostasis [20] have been claimed to contribute as aetiological factors to disturbances of heart function in diabetes.…”

Diabetes Mellitus Induces Changes in Cardiac Myosin of the Rat

“…2 " 4 Decreased cardiac contractility in diabetic animals seems quite well established. 5 ' 6 The pathophysiologic mechanisms that underlie the decreased contractility are currently unclear. In particular, it is unknown if changes in the state of contractile proteins contribute to the decreased contractility of the diabetic heart.…”

Morfometria das fibras colágeno cardíaco em ratos sadios e diabéticos suplementados com vitamina C

“…Já Rubler et al (1972), Arduino (1973), Regan et al (1974), Kannel & Mcgee (1979), Koltai et al (1984), Chen (2000), Bell (2003) e Gilles (2003) são autores que descreveram a etiologia, a patologia e a sintomatologia do Diabetes mellitus, que foi a doença de estudo deste trabalho. Goodfellow (1997), Neckar et al (2001), referem-se ao acú-mulo de colágeno em corações diabéticos ser o principal fator pela alteração funcional do miocárdio.…”