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 Ca ²⁺ 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 Ca ²⁺ release, which promote triggered activity. The slowing of Ca ²⁺ 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.