Insights From Computational Modeling Into the Contribution of Mechano-Calcium Feedback on the Cardiac End-Systolic Force-Length Relationship

In experimental studies on cardiac tissue, the end-systolic force-length relation (ESFLR) has been shown to depend on the mode of contraction: isometric or isotonic. The isometric ESFLR is derived from isometric contractions spanning a range of muscle lengths while the isotonic ESFLR is derived from shortening contractions across a range of afterloads. The ESFLR of isotonic contractions consistently lies below its isometric counterpart. Despite the passing of over a hundred years since the first insight by Otto Frank, the mechanism(s) underlying this protocol-dependent difference in the ESFLR remain incompletely explained. Here, we investigate the role of mechano-calcium feedback in accounting for the difference between these two ESFLRs. Previous studies have compared the dynamics of isotonic contractions to those of a single isometric contraction at a length that produces maximum force, without considering isometric contractions at shorter muscle lengths. We used a mathematical model of cardiac excitation-contraction to simulate isometric and force-length work-loop contractions (the latter being the 1D equivalent of the whole-heart pressure-volume loop), and compared Ca 2+ transients produced under equivalent force conditions. We found that the duration of the simulated Ca 2+ transient increases with decreasing sarcomere length for isometric contractions, and increases with decreasing afterload for work-loop contractions. At any given force, the Ca 2+ transient for an isometric contraction is wider than that during a work-loop contraction. By driving simulated work-loops with wider Ca 2+ transients generated from isometric contractions, we show that the duration of muscle shortening was prolonged, thereby shifting the work-loop ESFLR toward the isometric ESFLR. These observations are explained by an increase in the rate of binding of Ca 2+ to troponin-C with increasing force. However, the leftward shift of the work-loop ESFLR does not superimpose on the isometric ESFLR, leading us to conclude that while mechano-calcium feedback does indeed contribute to the difference between the two ESFLRs, it does not completely account for it.