Myocardial twitch duration and the dependence of oxygen consumption on pressure-volume area: Experiments and modelling

Abstract

We tested the proposition that linear length-dependence of twitch duration underlies the well-characterised linear dependence of oxygen consumption (VO[sub]2[/sub]) on pressure-volume area (PVA) in the heart. By way of experimental simplification, we reduced the problem from three dimensions to one by substituting cardiac trabeculae for the classically-investigated whole-heart. This allowed adoption of stress-length area (SLA) as a surrogate for PVA, and heat as a proxy for VO[sub]2[/sub]. Heat and stress (force per cross-sectional area), at a range of muscle lengths and at both 1 mM and 2 mM [Ca[sup]2+[/sup]][sub]o[/sub], were recorded from continuously superfused rat right-ventricular trabeculae undergoing fixed-end contractions. The heat-SLA relations of trabeculae (reported here, for the first time) are linear. Twitch duration increases monotonically (but not strictly linearly) with muscle length. We probed the cellular mechanisms of this phenomenon by determining: (i) the length-dependence of the duration of the Ca[sup]2+[/sup]-transient, (ii) the length-dependence of the rate of force redevelopment following a length-impulse (an index of Ca[sup]2+[/sup]-binding to troponin-C), (iii) the effect on the simulated time-course of the twitch of progressive deletion of length- and Ca[sup]2+[/sup]-dependent mechanisms of crossbridge cooperativity, using a detailed mathematical model of the crossbridge cycle, and (iv) the conditions required to achieve these multiple length-dependencies, using a greatly simplified model of twitch mechano-energetics. From the results of these four independent investigations, we infer that the linearity of the heat-SLA relation (and, by analogy, the VO[sub]2[/sub]-PVA relation) is remarkably robust in the face of departures from linearity of length-dependent twitch duration.