Timing and Magnitude of Prestretch Strongly Affect Cardiac Muscle Tension Development

Abstract

Ectopic ventricular pacing leads to regional myocardial prestretch. In-vivo studies suggest that the timing of prestretch determines the effect on pump function and can lead to regional wall remodeling. Here we measure the direct effects of prestretch timing on the magnitude of tension development in isolated cardiac muscle. Prestretch strongly affected tension development but primarily during a brief interval of the twitch. The effects of prestretch were simulated using excised murine right ventricular papillary muscles. A high-speed computer-controlled motor was used to impose precisely timed stretches, while a force transducer measured force output and strain was monitored using a CCD camera and topical markers. The timing of the stretches greatly influenced tension production. A critical stretch timing interval was observed to begin 25 ms after stimulation and extending until 100 ms after stimulation, where stretches occurring in this interval exhibited statistically significant increases in peak tension of as much as 500%. Muscle shortening occurring in the critical interval (from stretches initiated prior to stimulation) showed the opposite effect of stretching in the interval, with peak tension inhibited significantly by as much as 40%. A simple model showed that the varying impact of stretch timing could not be explained by time-varying elastance alone. Therefore, a more detailed and mechanistic myofilament model that included cooperative activation (Campbell et al 2010) was refined to include length dependence and strain-dependent cross-bridge kinetics. By comparing model results and experimental measurements, the strain history dependent mechanisms of these observations was evaluated. These evaluations have led us to the conclusion that even prestretches performed at slow physiologic velocities cause alterations in twitch kinetics that cannot be explained by time varying elastance.