Cardiac thin filament regulation and the Frank–Starling mechanism

Abstract

The heart has an intrinsic ability to increase systolic force in response to a rise in ventricular filling (the Frank–Starling law of the heart). It is widely accepted that the length dependence of myocardial activation underlies the Frank–Starling law of the heart. Recent advances in muscle physiology have enabled the identification of the factors involved in length-dependent activation, viz., titin (connectin)-based interfilament lattice spacing reduction and thin filament “on–off” regulation, with the former triggering length-dependent activation and the latter determining the number of myosin molecules recruited to thin filaments. Patients with a failing heart have demonstrated reduced exercise tolerance at least in part via depression of the Frank–Starling mechanism. Recent studies revealed that various mutations occur in the thin filament regulatory proteins, such as troponin, in the ventricular muscle of failing hearts, which consequently alter the Frank–Starling mechanism. In this article, we review the molecular mechanisms of length-dependent activation, and the influence of troponin mutations on the phenomenon.

Cardiovascular Remodeling and Dysfunction Across a Range of Growth Restriction Severity in Small for Gestational Age Infants – Implications for Fetal Programming –

“…Interestingly, cardiac samples from human IUGR fetus autopsies have also demonstrated shorter sarcomeres. 22 Shorter sarcomeres have been shown to lead to reduced contraction force 23 and diastolic cardiac function 24 in experimental studies. Short sarcomeres reduce energy consumption in SGA group (392±121) and mild SGA group (295±50) than in the AGA group (242±30).…”

Skeletal muscle tissue in movement and health: positives and negatives

“…Titin's elastic properties have been implicated as a key to this phenomenon (Fukuda and Granzier, 2004). Among the purported roles of titin in cardiac muscle are the following: (1) titin has a key function in stress-sensing signaling (Anderson and Granzier, 2012); (2) titin passive tension triggers an increase in Ca 2+ sensitivity and thus increased contractility (Lee et al, 2010); (3) titin is involved in length-dependent thin filament regulation (Kobirumaki-Shimozawa et al, 2014); and finally (4) titin functions "as a 'bidirectional spring' that … determines not only ventricular rigidity and diastolic function, but also systolic cardiac function" (Castro-Ferreira et al, 2011). In other words, once this 'undiscovered' filament found its place in cardiac muscle, a number of elusive features of cardiac muscle gained clarity.…”

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].…”

“…Physiological importance of Frank-Starling's law is acknowledged in attuning right and left cardiac output [21]; apart of that, it is considered somewhat to compensate for lacking neuro-humoral regulation (elderly [19]), transplant recipients [5]) or arrhythmia [16,28]. It has been stated that Starling's law cannot readily been demonstrated even by gross volume changes in healthy subjects, due to autonomic nervous counteraction [25]; subsequent studies relativised this notion [22,26].…”

“…Hearts in state of depressed contractility may be found unable to present with this phenomenon, due to an already exploited Frank-Starling mechanism. Furthermore, mutated troponin, depressing this mechanism, is found in pathological hearts [22]. Left heart catheters, provided with pacing electrodes and pressure sampling facility, and a few seconds of respiratory arrest (or compensatory data processing) should suffice to obtain the data.…”