ALTERED CALCIUM HANDLING IN LEFT-VENTRICULAR PRESSURE OVERLOAD HYPERTROPHY AS DETECTED WITH AEQUORIN IN THE ISOLATED, PERFUSED FERRET HEART

The purpose of this study was to test the hypothesis that systolic and diastolic dysfunction in left ventricular pressure-overload hypertrophy is caused by abnormal intracellular calcium handling. Experiments were performed with intact, buffer-perfused, isovolumic ferret hearts (n = 9 hypertrophied, n = 9 control) that were loaded with the bioluminescent indicator aequorin to monitor changes in cytoplasmic calcium. In each experiment, left ventricular pressure and intracellular calcium transients were simultaneously recorded. Compared with their age-matched controls, significant hypertrophy of the left ventricle developed 4 weeks after postvalvular aortic banding; at the time the animals were killed, the left ventricular weight/body weight ratio was increased in the banded animals (5.3 X 10(-3) versus 3.6 x 10(-3), p < 0.001). As indicated by the diastolic pressure-volume relation, left ventricular distensibility was significantly diminished in the hypertrophied hearts. In comparison to the controls, the hypertrophied hearts demonstrated a prolonged duration of isovolumic contraction (time to 90% decline from peak: 278 +/- 5.4 versus 247 +/- 10.2 msec, p < 0.05), but a marked decrease in peak systolic midwall stress (22.4 +/- 5.0 versus 38.6 +/- 5.7 g/cm2, p < 0.05). The increased duration of isovolumic contraction correlated with a similar prolongation of the calcium transient (time to 90% decline from peak: 245 +/- 19.5 versus 127 +/- 13.2 msec, p < 0.05), indicating that the rate of sequestration and perhaps release of calcium by the sarcoplasmic reticulum is decreased in hypertrophy. In contrast, control and hypertrophied hearts had similar peak systolic calcium levels (pCa: 6.4 +/- 0.2 versus 6.6 +/- 0.1, p = NS), indicating that the diminution in peak left ventricular midwall stress developed by the hypertrophied hearts was not due to decreased availability of activator calcium. We conclude that the prolonged time course of left ventricular pressure development, but not the diminished peak isovolumic midwall stress or decreased diastolic distensibility, may be related to alterations in intracellular calcium handling.