Search

Diabetes is one of the most prevalent chronic conditions that has a high association with death from cardiovascular disease(s). An impaired cardiac function independent of vascular disease suggests the existence of a primary myocardial defect in diabetes mellitus. We and others have documented that myocardial performance is impaired in the hearts of chronically diabetic rats and rabbits. Abnormalities in the contractile proteins and regulatory proteins could be responsible for the mechanical defects in streptozotocin (STZ)-diabetic hearts. The major focus of research on contractile proteins in the diabetic state has been on myosin ATPase and its isoenzymes. However, in the contractile protein system, this could be only one of the mechanisms that might be a controlling factor in myofilament contraction in diabetes. To define the role of cardiac contractile as well as regulatory proteins (troponin-tropomyosin) as a whole in the regulation of actomyosin system in diabetic cardiomyopathy, individual proteins of the cardiac system were reconstituted under controlled conditions. Enzymatic data confirmed a diminished calcium sensitivity in the regulation of the cardiac actomyosin system when regulatory protein(s) complex was recombined from diabetic hearts. This diminished calcium sensitivity along with shifts in cardiac myosin heavy chain (V1-->V3) could contribute to the impaired cardiac function in the hearts of chronic diabetic rats. It has also been reported that sarcomeric proteins such as myosin light chain-2 (MLC-2) and troponin I (TnI) could be involved in regulating muscle contraction and in calcium sensitivity. Since phosphorylation of cardiac TnI is associated with altered maximum enzymatic activity and calcium force relationship in isolated muscle preparations. TnI phosphorylation could contribute to depressed myocardial contractility in experimental diabetes. While we have yet to understand the exact function of each component in cardiac muscle and their behavior in concert where all of them act in tandem, we have focussed on the role of contractile proteins and their regulation in diabetes in this review. We have also included a brief discussions on other relevant intracellular components. In summary, there is substantial evidence to suggest that there are independent processes associated with diabetes which effect cardiac performance in experimental animals and in man. The focus of this review has been the explication of a biochemical defect which underlies cardiac contractile dysfunction in experimental models of diabetes.

Objective: The purpose of this study was to examine the degree to which mechanical alterations in left ventricular papillary muscles of renal hypertensive-diabetic rat hearts correlate with functional measurements made on the same hearts in situ. Methods: Female Wistar rats weighing 170–200 g were made hypertensive by placing a 0.24 mm clip on the left renal artery, and made diabetic 1 week later by a single intravenous injection of streptozotocin (60 mg/kg). Approximately 3–5 months later hemodynamic measurements including left ventricular pressure and dP/dtmax, arterial pressure and aortic flow were made on control and hypertensive-diabetic hearts in situ and correlated with mechanical measurements in left ventricular papillary muscles isolated from the same hearts. Body and tissue weights and biochemical and histological measurements were made at the time of sacrifice. Results: Hypertensive-diabetic rats which survived to the time of study had decreased body weights, increased left ventricular weights and increased right ventricular weight to body weight and lung weight to body weight ratios. Those rats which died before the scheduled in-situ measurements had significantly more severe hypertension, greater left ventricular hypertrophy, increased right ventricular and lung weights, and more interstitial fibrosis than either surviving hypertensive-diabetics or controls. Rates of isometric tension development (normalized) and relaxation as well as shortening and relaxation velocities were significantly depressed in papillary muscles from hypertensive-diabetic rat hearts despite unchanged developed tension and peak shortening. Time to peak tension and time to peak shortening were markedly prolonged. Mean aortic flow was maintained in the hypertensive-diabetic group despite significant depression of left ventricular dP/dtmax (normalized), peak aortic flow, peak aortic flow acceleration and heart rate. There was also significant depression of left ventricular −dP/dtmax. Ejection duration was markedly prolonged and correlated with both time to peak shortening in vitro and with stroke volume in vivo. Conclusions: Surviving hypertensive-diabetic rats were not in overt congestive heart failure; nevertheless, their hearts showed abnormal contractile performance which was qualitatively and quantitatively similar to that of left ventricular papillary muscles obtained from them. Depression of peak aortic flow, peak aortic flow acceleration and heart rate in the hypertensive-diabetic group was offset by increased ejection duration, resulting in normal mean aortic flow. The close correlation of ejection duration with time to peak shortening of the isolated papillary muscles suggests that it is a manifestation of an intrinsic change in the myocardium. To the extent that this prolongation is already maximized, further decreases in contractile speed would be expected eventually to cause depressed pump function and congestive heart failure. The possibility that this sequence of events occurred in the dying animals needs to be examined by evaluating in-vitro and in-vivo myocardial function at various stages of this disease model.

Objective: The aim was to study changes in contractile proteins which accompany marked hypertrophy and heart failure in mammalian hearts initially containing predominantly V3 isomyosin. Methods: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were measured in normal guinea pig hearts, in hearts which were hypertrophied as a result of progressive left ventricular systolic overload following ascending aortic banding, and in hypertrophied hearts from animals which showed signs of overt congestive heart failure. Male guinea pigs weighing 225-275 g at the time of aortic banding were used for the studies. Results: Left ventricular myosin and myofibrillar ATPase activity and right ventricular actomyosin ATPase activity were correlated with body weight, left and right ventricular weight, and left ventricular peak systolic pressure during aortic occlusion. Left ventricular myosin ATPase activity and right ventricular actomyosin ATPase activity were markedly depressed in hypertrophied ventricles compared to control ventricles. Cardiac myofibrillar ATPase activity was lower in hypertrophied failing hearts than in control hearts over a wide range of calcium concentrations. In control animals and in those without heart failure, there was a nearly identical inverse relationship between left ventricular mass up to 1600 mg and myosin ATPase activity. Hypertrophied failing hearts were larger but showed little further reduction in cardiac myosin ATPase activity. Representative gel scans of non-dissociating pyrophosphate gels of left ventricular myosin from an 8 d postoperative aortic constricted animal and from its age and weight matched control showed predominantly Vi isomyosin with small amounts of Vi isoenzyme. However, preparations taken from guinea pigs 16 d after aortic constriction showed only the Vi isoform, whereas the Vi isoform was still apparent in control. Hypertrophied failing left ventricles developed less pressure per unit mass during brief aortic occlusion than non-failing left ventricles with comparable myosin ATPase activities. Conclusions: These observations raise important questions as to the distribution of myosin isoforms in the normal adult guinea pig, and the possibility that myosin ATPase activity might be altered by post-translational modification. Although cardiac myosin ATPase activity correlates with left ventricular performance, it cannot fully explain the depressed performance of failing hearts in this model. Additional immunological studies of cardiac contractile proteins are required as well as studies designed to explore the implications of altered myosin ATPase activity for both contractile function and overall cellular homeostasis.

Study objective – The aim was to determine whether surviving myocardium in the infarcted rat heart retains the ability to respond to sustained increases in afterload. Design – Cardiac mass, ventricular function, and actomyosin ATPase activity were compared in animals subjected to coronary artery ligation to produce infarction, superimposed renal artery constriction 4 weeks after infarction, and in sham operated animals. Experimental material – Female Wistar rats obtained at 10 weeks of age (200-225 g) were used for the studies. Measurements and main results – Four weeks after coronary artery ligation, infarcted hearts showed a 22% increase in heart weight and a significant reduction in peak systolic pressure and +/- dP/dt during acute volume infusion and aortic occlusion compared to sham operated hearts. Eight weeks after the initial surgical intervention, the infarct group showed significant impairment in ventricular performance compared to the sham operated group but no further decrement was observed between hearts with infarction and those with infarct and superimposed renal artery constriction for peak systolic pressure and +/- dP/dt during volume infusion and aortic occlusion. Actomyosin ATPase activity, however, was depressed and the shift to V3myosin isoenzyme was greater in infarct and renal artery constriction compared to infarct alone. Conclusions – Left ventricular myocardium following infarction does not retain the ability to increase cardiac mass and shows depressed levels of actomyosin ATPase activity when exposed to a superimposed chronic afterload from renal artery constriction. However, cardiac function in situ is maintained.

Hearts of rats made hypertensive (BP greater than 150 mmHg) by left renal artery clipping and sham operated controls were studied in two series of experiments. In series I, cardiac function was studied in an isolated working heart apparatus at weeks 4, 9 to 10 and 16 to 17 post-surgery. In series II, coronary flow was studied during normoxic and anoxic retrograde perfusions at days 6 to 9 and at weeks 4 and 10 post-surgery. In series I, when compared with controls, hypertensives had lower body weights at weeks 4 and 9 to 10, and higher left ventricular weights at each period. Heart function was depressed for hypertensives when compared with controls as measured by lower stroke volume, peak left ventricular systolic pressure, stroke work, ejection fraction, positive dP/dt, peak aortic flow, and maximal flow acceleration. Relaxation rate as measured by negative dP/dt was also depressed. Hearts from hypertensives had significantly lower coronary flows and MVO2, and increased percent oxygen extraction and effluent lactate/pyruvate ratios. LVEDP was significantly elevated for hypertensives, when LVEDV (ml) was similar for hypertensives and controls. Myocardial actomyosin ATPase activity was depressed for hypertensives at weeks 9 to 10 and 16 to 17 post-surgery. In series II, when hearts were perfused retrogradely, coronary flow was lower for hypertensives than for controls during normoxia at days 6 to 9 and at week 4, and during anoxia at all time periods. The findings demonstrate that impaired coronary vascular reserve develops within days of the development of hypertension in rats, and this can be associated with impaired ventricular function.