Modeling short-term interval-force relations in cardiac muscle

This study employs two modeling approaches to investigate short-term interv al-force relations. The first approach is to develop a low-order, discrete- time model of excitation-contraction coupling to determine which parameter combinations produce the degree of postextrasystolic potentiation seen expe rimentally. Potentiation is found to increase 1) for low recirculation frac tion, 2) for high releasable fraction, i.e., the maximum fraction of Ca2+ r eleased from the sarcoplasmic reticulum (SR) given full restitution, and 3) for strong negative feedback of the SR release on sarcolemmal Ca2+ influx. The second modeling approach is to develop a more detailed single ventricu lar cell model that simulates action potentials, Ca2+-handling mechanisms, and isometric force generation by the myofilaments. A slow transition from the adapted state of the ryanodine receptor produces a gradual recovery of the SR release and restitution behavior. For potentiation, a small extrasys tolic release leaves more Ca2+ in the SR but also increases the SR loading by two mechanisms: 1) less Ca2+-induced inactivation of L-type channels and 2) reduction of action potential height by residual activation of the time -dependent delayed rectifier K+ current, which increases Ca2+ influx. The c ooperativity of the myofilaments amplifies the relatively small changes in the Ca2+ transient amplitude to produce larger changes in isometric force. These findings suggest that short-term interval-force relations result main ly from the interplay of the ryanodine receptor adaptation and the SR Ca2loading, with additional contributions from membrane currents and myofilame nt activation.