Premature Beats Elicit a Phase Reversal of Mechanoelectrical Alternans in Cat Ventricular Myocytes

Abstract

Background Alternans of the ST segment of the ECG is an important risk factor for sudden cardiac death. Premature beats during alternans and the development of discordant alternans are associated with the onset of ventricular tachycardia and ventricular fibrillation. Moreover, premature beats can switch the pattern of alternans from discordant to concordant alternans. The mechanisms of how a premature beat can elicit a pattern shift in alternans and develop malignant ventricular arrhythmias are not clear. The purpose of this cellular study was to determine the electrical and mechanical restitution properties during cycle length–induced alternans and to determine how premature and delayed beats affect the resultant phase of alternans. Methods and Results A perforated patch recording method and video-based edge detector were used to record action potentials and contractions, respectively, from single ventricular myocytes enzymatically isolated from the cat heart. Electrical and mechanical restitution curves were determined by programmed test beats delivered at different cycle lengths during mechanoelectrical alternans. At 35°C, 97.8% of cells exhibited concordant cellular alternans (action potentials with the larger action potential duration [APD] were associated with the larger contraction, and action potentials with the smaller APD exhibited the smaller contraction). The sequence or phase of concordant cellular alternans could be systematically reversed by (1) early premature beats that followed only action potentials with the shorter APD and smaller contraction (type 1 phase reversal; n=34) or (2) late delayed beats that followed only action potentials with the longer duration and the larger contraction (type 2 phase reversal; n=14). A phase reversal point was defined as a threshold time interval that resulted in switching the sequence of the alternating beats. A test stimulus at the phase reversal point caused temporary suppression of mechanoelectrical alternans. Lower temperatures (32°C) or decreases in the basic cycle length induced larger beat-to-beat changes in the magnitude of alternans (APD or contraction) and significantly shifted the phase reversal point to earlier premature intervals for type 1 phase reversal. The interval of the phase reversal point was a function of the contractile ratio (the magnitude of the larger contraction/smaller contraction for two consecutive beats, r =.93) and not the APD ratio (longer APD/shorter APD; r =.501). In cells stimulated at cycle lengths longer than the threshold of alternans, a single premature beat could elicit a damped form of concordant mechanoelectrical alternans. A critically timed second premature beat reversed the phase of the damped alternans. Conclusions Properly timed premature or delayed beats during cycle length–induced alternans consistently reversed the phase of cellular mechanoelectrical alternans. Reversal of the phase of alternans was dependent on recovery of mechanical activity, not electrical activity. The premature stimulus interval at the phase reversal point can be predicted by the magnitude of mechanical alternans. Thus, during cycle length–induced alternans, mechanical alternans governs the phase of electrical alternans. From the present results, a multicellular model is proposed that may explain how critically timed premature beats cause a regional change in the phase of mechanical alternans and thereby result in discordant electrical alternans or dispersion of refractoriness. Premature beats that induce phase reversal in mechanoelectrical alternans may contribute to the development of reentrant arrhythmias.