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

Abstract

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.

Energetics Equivalent of the Cardiac Force-Length End-Systolic Zone: Implications for Contractility and Economy of Contraction

“…Our isometric ESSLR protocol characterizes the peak stress development of twitching trabeculae over a range of muscle lengths in response to isoproterenol (Figure 5). An important implication of our ESZ framework is that an accurate assessment of changes in contractility requires identical loading conditions to be applied (Han et al, 2019). In Figure 5A, the change of contractility can be assessed by comparing either the isometric ESSLR or the work-loop ESSLR between the control and isoproterenol cases.…”

“…The divergence of these two force-length relations, exemplified particularly under conditions of either high preloads or low afterloads, reveals a region that encompasses all possible endsystolic force-length points. This zone has been coined the "cardiac end-systolic zone, " and is applicable to preparations ranging from the whole-heart (Frank, 1899;Kissling et al, 1985) to isolated cardiac tissues (Gülch and Jacob, 1975;Han et al, 2019) and myocytes (Iribe et al, 2014), as illustrated in Figure 7 of Han et al (2019). For over a century, it was unclear why some experimentalists observed a single end-systolic relation for both isometric and afterloaded shortening contractions while others observed two separate relations.…”

“…For over a century, it was unclear why some experimentalists observed a single end-systolic relation for both isometric and afterloaded shortening contractions while others observed two separate relations. The demonstration of the existence of a cardiac end-systolic zone by Han et al (2019) has resolved this long-standing puzzle in the field of cardiac mechanics.…”

Mechanical loading of isolated cardiac muscle with a real‐time computed Windkessel model of the vasculature impedance

“…For well over a century (Coats, ; Patterson et al, ; Frank, ; Zimmer, ), clinician‐scientists have interrogated the mechanical function of the ex vivo heart by recording its pressure‐volume‐time behavior in response to physiological and pharmacological perturbations. Since such early studies, experimental physiologists have commonly adopted simpler preparations, namely: isolated tissues (Elzinga and Westerhof, ; Mellors et al, ; Han et al, ) or cells (Iribe et al, ; Helmes et al, ), where force and length become proxies for pressure and volume. In such cases, researchers endeavor to approximate physiological conditions as closely as possible by adopting contraction patterns that mimic those of the heart in vivo.…”

“…Under this scenario, experimental approximation of both isovolumic phases has generally been acceptable; that of the shortening phase has not. In contrast to the auxotonic nature of ejection in vivo, in vitro simulations have usually been performed isotonically, thereby producing “flat‐topped” work‐loops (Gibbs et al, ; Elzinga and Westerhof, ; Helmes et al, ; Han et al, ). These oversimplified work‐loop protocols only approximately replicate the ejection mechanics of the ventricle.…”