The slow force response to stretch in atrial and ventricular myocardium from human heart: Functional relevance and subcellular mechanisms

Abstract

Mechanical load is an important regulator of cardiac force. Stretching human atrial and ventricular trabeculae elicited a biphasic force increase: an immediate increase (Frank-Starling mechanism) followed by a further slow increase (slow force response, SFR). In ventricle, the SFR was unaffected by AT-and ET-receptor antagonism, by inhibition of protein-kinase-C, PI-3-kinase, and NOsynthase, but attenuated by inhibition of Na + /H + -(NHE) and Na + /Ca 2+ -exchange (NCX). In atrium, however, neither NHE-nor NCX-inhibition affected the SFR. Stretch elicited a large NHE-dependent [Na + ] i increase in ventricle but only a small, NHE-independent [Na + ] i increase in atrium. Stretchactivated non-selective cation channels contributed to basal force development in atrium but not ventricle and were not involved in the SFR in either tissue. Interestingly, inhibition of AT-receptors or pre-application of angiotensin II or endothelin-1 reduced the atrial SFR. Furthermore, stretch increased phosphorylation of atrial myosin light chain 2 (MLC2) and inhibition of myosin light chain kinase (MLCK) attenuated the SFR in atrium and ventricle. Thus, in human heart both atrial and ventricular myocardium exhibit a stretch-dependent SFR that might serve to adjust cardiac output to increased workload. In ventricle, there is a robust NHE-dependent (but angiotensin II-and endothelin-1-independent) [Na + ] i increase that is translated into a [Ca 2+ ] i and force increase via NCX. In atrium, on the other hand, there is an angiotensin II-and endothelin-dependent (but NHE-and NCX-independent) force increase. Increased myofilament Ca 2+ sensitivity through MLCK-induced phosphorylation of MLC2 is a novel mechanism contributing to the SFR in both atrium and ventricle.

Pharmacological modifications of the stretch-induced effects on ventricular fibrillation in perfused rabbit hearts

“…Furthermore, in this series, the time-related decay in VF acceleration observed during the last minutes of the stretching period was less accentuated than in the control series. We do not know whether this behavior may be related to modification of the recently described slow force decline after the maximal force increase induced by stretch (32). Thus, regarding the actions of the adenosine A 2 receptor antagonist SCH-58261, the results obtained in the experimental model used in this study show that it does not avoid the stretch-induced electrophysiological changes leading to VF acceleration.…”

Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage

“…In this regard, GsMTx4 may be able to serve as a chondroprotective agent to prevent and treat osteoarthritis and other mechanically induced forms of the disease such as those caused by joint instability, misalignment, or obesity, by altering pathologic mechanical signal transduction pathways. Given the benign toxicity profile of GsMTx4, e.g., lack of cardiac effects (71,72), future studies will examine this approach in animal models of joint injury, paving the way to human clinical trials.…”

Rainbow trout myocardium does not exhibit a slow inotropic response to stretch

“…However, to our knowledge, it has not been investigated in any non-mammalian vertebrate or invertebrate heart tissue. In mammals, the SFR may be a protective mechanism that comes into play to protect a diseased heart and allow it to continue to generate force in circumstances of increased venous pressure (Kockskamper et al, 2008). If this is the origin of the SFR, then it may not be surprising that an organism which relies on stretch of the ventricle to regulate cardiac output and exhibits such an exquisitely sensitive Frank-Starling response does not exhibit the SFR.…”

“…The Frank-Starling response occurs because of an increase in the Ca 2+ sensitivity of the myofilaments rather than an increase in the amplitude of the intracellular [Ca 2+ ] ([Ca 2+ ] i ) transient in both fish (Shiels et al, 2006) and mammals (Allen and Kurihara, 1982;Kentish and Wrzosek, 1998). The Frank-Starling response links cardiac filling to cardiac ejection and plays a major physiological role in adjusting output between the left and right sides of the heart in mammals (Kockskamper et al, 2008).…”

“…The Anrep effect is the positive inotropy invoked in response to a prolonged increase in end diastolic volume due an increase in aortic pressure (von Anrep, 1912). It has also been suggested that the SFR is a protective mechanism that supplements cardiac force in a diseased myocardium in circumstances of increased preload and/or afterload (Kockskamper et al, 2008). The physiological relevance of the SFR is still under debate as is the precise balance of mechanisms by which it occurs.…”