Abnormalities in Intracellular Calcium Regulation and Contractile Function in Myocardium from Dogs with Pacing-induced Heart Failure

Abstract

24 d of rapid ventricular pacing induced dilated cardiomyopathy with both systolic and diastolic dysfunction in conscious, chronically instrumented dogs. We studied mechanical properties and intracellular calcium (Ca?') transients of trabeculae carneae isolated from 15 control dogs (n = 32) and 11 dogs with pacing-induced cardiac failure (n = 26). Muscles were stretched to maximum length at 30'C and stimulated at 0.33 Hz; a subset (n = 17 control, n = 17 myopathic) was loaded with the ICa2+h indicator aequorin. Peak tension was depressed in the myopathic muscles, even in the presence of maximally effective (i.e., 16 mM) [Ca2"] in the perfusate. However, peak ICa2+li was similar (0.80±0.13 vs. 0.71±0.05 aM; ICa2+L = 2.5 mM), suggesting that a decrease in Ca? ' availability was not responsible for the decreased contractility. The time for decline from the peak of the Ca? ' transient was prolonged in the myopathic group, which correlated with prolongation of isometric contraction and relaxation. However, similar end-diastolic ICa2+i1 was achieved in both groups (0.29±0.05 vs. 0.31±0.02 MM), indicating that Cal ' homeostasis can be maintained in myopathic hearts. The inotropic response of the myopathic muscles to milrinone was depressed compared with the controls. However, when cAMP production was stimulated by pretreatment with forskolin, the response of the myopathic muscles to milrinone was improved. Our findings provide direct evidence that abnormal ICa2?ij handling is an important cause of contractile dysfunction in dogs with pacing-induced heart failure and suggest that deficient production of cAMP may be an important cause of these changes in excitation-contractio