Acute Myocardial Response to Stretch: What We (don't) Know

Abstract

Myocardial stretch, as result of acute hemodynamic overload, is one of the most frequent challenges to the heart and the ability of the heart to intrinsically adapt to it is essential to prevent circulatory congestion. In this review, we highlight the historical background, the currently known mechanisms, as well as the gaps in the understanding of this physiological response. The systolic adaptation to stretch is well-known for over 100 years, being dependent on an immediate increase in contractility—known as the Frank-Starling mechanism—and a further progressive increase—the slow force response. On the other hand, its diastolic counterpart remains largely unstudied. Mechanosensors are structures capable of perceiving mechanical signals and activating pathways that allow their transduction into biochemical responses. Although the connection between these structures and stretch activated pathways remains elusive, we emphasize those most likely responsible for the initiation of the acute response. Calcium-dependent pathways, including angiotensin- and endothelin-related pathways; and cGMP-dependent pathways, comprising the effects of nitric oxide and cardiac natriuretic hormones, embody downstream signaling. The ischemic setting, a paradigmatic situation of acute hemodynamic overload, is also touched upon. Despite the relevant knowledge accumulated, there is much that we still do not know. The quest for further understanding the myocardial response to acute stretch may provide new insights, not only in its physiological importance, but also in the prevention and treatment of cardiovascular diseases.

Impact of titin strain on the cardiac slow force response

“…It is well established that the SFR is the result of a slowly developing increase in the magnitude of the intracellular calcium transient(17)(6)(5)(12)(3). Therefore, to properly asses the SFR and compare this parameter between groups, it was important to first establish the sensitivity of HM rat myocardium to extracellular [Ca 2+ ] o at 25 °C.…”

“…The main short-term mechanisms (seconds to minutes) by which circulatory homeostasis is achieved are heart rate, contractility, and stroke volume. Long-term mechanisms (hours to weeks) include renal fluid regulation and cardiac chamber remodeling(17). …”

“…As was the Frank-Starling mechanism, the slower response was first described over a century ago by von Anrep(4) and has been termed the “Anrep” effect. The phenomenon can be demonstrated at the whole heart level, both in-situ and ex-vivo(17). The classical manifestation of the Anrep phenomenon is the response to a sudden increase in cardiac afterload that initially induces increases in both end-diastolic and end-systolic volume; this allows for immediate increased cardiac pressure generation by virtue of the Frank-Starling mechanism.…”

“…The cellular mechanisms that underlie altered calcium homeostasis during the SFR are unknown (for a recent reviews see(17)(6)(5)). One proposed mechanism involves activation of transmembrane stretch sensitive ion channels(23).…”

Autocorrelation Patterns in the Left-Ventricular Pressure Course of Isolated Working Hearts at Sinus Rhythm

“…up to the highest possible ventricular stretching [19,21] and responds very sensitively (e.g., eightfold twitch force by 15% fiber length increase [19]). The response curve is adjusted (shifted) by other regulatory pathways and attributed to Ca 2+ sensitivity of the myocardial filament which increases with precontraction sarcomere length (length dependent activation) [20,22,23,24]. As standing to reason, this effect has been thoroughly investigated by sudden preload changes [25,26] and in the presence of spontaneous [16] or artificially induced ventricular arrhythmia [27,28].…”