Multiple Defects in Intracellular Calcium Cycling in Whole Failing Rat Heart

Background— A number of defects in excitation-contraction coupling have been identified in failing mammalian hearts. The goal of this study was to measure the defects in intracellular Ca2+ cycling in left ventricular epicardial myocytes of the whole heart in an animal model of congestive heart failure (CHF). Methods and Results— Intracellular Ca2+ transients were measured using confocal microscopy in whole rat hearts from age-matched Wistar-Kyoto control rats and spontaneously hypertensive rats at ≈23 months of age. Basal Ca2+ transients in myocytes in spontaneously hypertensive rats were smaller in amplitude and longer in duration than Wistar-Kyoto control rats. There was also greater variability in transient characteristics associated with duration between myocytes of CHF than Wistar-Kyoto controls. Approximately 21% of CHF myocytes demonstrated spontaneous Ca2+ waves compared with very little of this activity in Wistar-Kyoto control rats. A separate population of spontaneously hypertensive rat myocytes showed Ca2+ waves that were triggered during pacing and were absent at rest (triggered waves). Rapid pacing protocols caused Ca2+ alternans to develop at slower heart rates in CHF. Conclusions— Epicardial cells demonstrate both serious defects and greater cell-to-cell variability in Ca2+ cycling in CHF. The defects in Ca2+ cycling include both spontaneous and triggered waves of Ca2+ release, which promote triggered activity. The slowing of Ca2+ repriming in the sarcoplasmic reticulum is probably responsible for the increased vulnerability to Ca2+ alternans in CHF. Our results suggest that defective Ca2+ cycling could contribute both to reduced cardiac output in CHF and to the establishment of repolarization gradients, thus creating the substrate for reentrant arrhythmias. Received July 31, 2008; accepted March 4, 2009.