Solving a century-old conundrum underlying cardiac force-length relations

In the late 19th century, Otto Frank presented a diagram (Frank O. Z Biol 37: 483-526, 1899) showing that cardiac end-systolic pressure-volume relations are dependent on the mode of contraction: one for isovolumic contractions that locate above that for afterloaded ejecting contractions. Conflicting results to Frank's have been subsequently demonstrated in various species, both within and among preparations, ranging from the whole hearts to single myocytes, showing a single pressure-volume or force-length relation that is independent of the mode of contraction. Numerous explanations for these conflicting results have been proposed but are mutually contradictory and hence unsatisfying. The present study aimed to explore how these conflicting findings can be reconciled. We thus explored the cardiac force-length relation across a wide spectrum of both preloads and afterloads, encompassing the physiological working range. Experiments were performed using isolated ventricular trabeculae at physiological temperature and stimulus frequency. The force-length relation obtained from isometric contractions was indeed located above a family of those obtained from shortening contractions. Low preload conditions rendered the relation contraction mode independent. High afterload conditions also showed a comparable effect. Our exploration allowed us to reveal the loading conditions that can explain the apparent single, contraction mode-independent, force-length relation that is in contrast with that presented by Frank. Resolving this century-old cardiac conundrum highlights the caution that must be taken when using the end-systolic force-length relation to illustrate as well as to understand the concepts of the Frank-Starling law of the heart, "potential energy," and cardiac contractility. NEW & NOTEWORTHY Our exploration of the cardiac force-length relation under wide ranges of preload and afterload has allowed us to reconcile conflicting results in the literature regarding its length dependency. We show that the relation is dependent on the mode of contraction but can appear to be otherwise under certain conditions. This finding highlights the need for caution when using the force-length relation to understand key concepts in cardiac physiology.