Hysteresis Effect Implicates Calcium Cycling as a Mechanism of Repolarization Alternans

Abstract

Background— T-wave alternans is due to alternation of membrane repolarization at the cellular level and is a risk factor for sudden cardiac death. Recently, a hysteresis effect has been reported in patients whereby T-wave alternans, once induced by rapid heart rate, persists even when heart rate is subsequently slowed. We hypothesized that alternans hysteresis is an intrinsic property of cardiac myocytes, directly related to an underlying mechanism for repolarization alternans that involves intracellular calcium cycling. Methods and Results— Stepwise pacing was used to induce alternans in Langendorff-perfused guinea pig hearts from which optical action potentials were recorded simultaneously at 256 ventricular sites with voltage-sensitive dyes and in whole-cell patch-clamped cardiac myocytes treated with or without BAPTA-AM (1,2-bis[2-aminophenoxy]ethane- N , N , N ′, N ′-tetraacetic acid tetrakis [acetoxymethyl ester]). Alternans hysteresis was observed in every isolated heart: threshold heart rate for alternans was 280±12 bpm, but during subsequent deceleration of pacing, alternans persisted to significantly slower heart rates (238±5 bpm, P <0.05). Optical mapping showed that this effect also applied to the threshold for spatially discordant alternans (313±2.2 bpm during acceleration versus 250±6.6 bpm during deceleration, P <0.05). Alternans hysteresis was also observed in isolated cardiac myocytes. Moreover, calcium chelation by BAPTA-AM raised the threshold for alternans and inhibited hysteresis in a dose-dependent manner with no effect on baseline action potential duration. Conclusions— Alternans hysteresis is an intrinsic property of cardiac myocytes that can lead to persistence of arrhythmogenic discordant alternans even after heart rate is slowed. These results also support an important underlying role of calcium cycling in the mechanism of alternans.