Abnormal Myocardial Calcium Handling in the Early Stage of Adriamycin Cardiomyopathy

Abstract

Metabolic changes have been shown to precede mechanical abnormalities in the early stages of adriamycin cardiotoxicity. This study examines the early changes in calcium homeostasis and their mechanical implications in a model of adriamycin cardiomyopathy. Hearts isolated from control and adriamycin-treated rats were coronary-perfused and isovolumic left ventricular (LV) pressure, coronary perfusion pressure and calcium transients from aequorin-loaded cardiomyocytes were recorded. Treated rats received three injections of adriamycin (6 mg/kg) for a period of 1 week. They were sacrificed for experiments 1-2 or 4-5 weeks after the final injection. The LV systolic and end-diastolic pressures were similar in both groups at varied external calcium concentrations (0.5-2.0 mM). However, systolic levels of myoplasmic calcium were substantially higher in the adriamycin-treated hearts, the difference being less at higher external calcium concentrations. Similar responses in both groups to paired pulse stimulation, increased stimulation frequency and caffeine (0.5-2.0 mM) were observed. However, adriamycin-treated hearts exhibited a smaller rise in LV developed pressure, as well as in systolic and diastolic calcium levels, in response to elevated coronary perfusion pressure. The elevated intracellular systolic calcium level is suggestive of an early but persistent effect of adriamycin on the calcium release channels of the sarcoplasmic reticulum. That the elevated systolic myoplasmic calcium levels are not accompanied by an increase in inotropy suggests a decrease in myofibrillar calcium sensitivity in this model of the early stage of adriamycin cardiomyopathy.