Abstract
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 Ca2+ transients produced under equivalent force conditions. We found that the duration of the simulated Ca2+ transient increases with decreasing sarcomere length for isometric contractions, and increases with decreasing afterload for work-loop contractions. At any given force, the Ca2+ transient for an isometric contraction is wider than that during a work-loop contraction. By driving simulated work-loops with wider Ca2+ 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 Ca2+ 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.
Highlights
The end-systolic force-length relationships (ESFLRs) occupy a special place in cardiovascular physiology, often used as a proxy for cardiac contractility
We used the coupled THR model to examine the role of Ca2+ in the end-systolic force-length (or pressure-volume) relationships (ESFLRs) of cardiac muscle contraction
We have demonstrated that mechano-calcium feedback in cardiac muscle produces Ca2+ transients, which are dependent on the mode of contraction
Summary
The end-systolic force-length (or pressure-volume) relationships (ESFLRs) occupy a special place in cardiovascular physiology, often used as a proxy for cardiac contractility. Frank’s findings arose from experiments performed on the isolated heart of the frog and clearly reveal the existence of two distinct protocol-dependent end-systolic relations. Despite Frank’s insight, and more than 100 years of research since, the mechanisms responsible for the protocol-dependence of the ESFLRs remain incompletely understood. This absence of a definitive explanation stands in stark contrast to the many experimental affirmations of the phenomenon, commencing with Brady (1967) and Gibbs et al (1967), who independently demonstrated that the isometric ESFLR of isolated papillary muscles lies to the left of the equivalent isotonic (or workloop) curve
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