Three perspectives on the molecular basis of hypercontractility caused by hypertrophic cardiomyopathy mutations

Abstract

Several lines of evidence suggest that the primary effect of hypertrophic cardiomyopathy mutations in human β-cardiac myosin is hypercontractility of the heart, which leads to subsequent hypertrophy, fibrosis, and myofilament disarray. Here, I describe three perspectives on the molecular basis of this hypercontractility. The first is that hypercontractility results from changes in the fundamental parameters of the actin-activated β-cardiac myosin chemo-mechanical ATPase cycle. The second considers that hypercontractility results from an increase in the number of functionally accessible heads in the sarcomere for interaction with actin. The final and third perspective is that load dependence of contractility is affected by cardiomyopathy mutations and small-molecule effectors in a manner that changes the power output of cardiac contraction. Experimental approaches associated with each perspective are described along with concepts of therapeutic approaches that could prove valuable in treating hypertrophic cardiomyopathy.

The molecular basis of hypercontractility caused by the hypertrophic cardiomyopathy mutations R403Q and R663H

“…It must be emphasized, however, that this is a highly hypothetical model, and the structure of the MyBP-C-HMM complex is entirely unknown. While we have depicted the C0-C2-HMM complex as an IHM complex, it is entirely possible that MyBP-C is sequestering myosin heads away from interaction with actin by binding the heads in a different folded conformation or even in a more open configuration (36). Thus, a high priority in the field is to obtain even a low-resolution structure of the MyBP-C-HMM complex.…”

Hypertrophic cardiomyopathy: the future of treatment

“…Hypercontractility appears to lie central to the pathogenesis of HCM with the vast majority of known mutations affecting sarcomeric proteins, and ∼70% of identifiable mutations involving cardiac β‐myosin heavy chain ( MYH7 ) and myosin‐binding protein C ( MYBPC ) . Myosin contains the ATPase involved in actin–myosin cross bridging and muscle fibre shortening – in this way serving as the molecular motor for myocardial contraction.…”

“…Hypertrophic cardiomyopathy (HCM) is a heterogeneous myocardial disease, most often caused by autosomal dominant sarcomeric gene mutations, and represents the most common monogenic cardiomyopathy in humans. The phenotypic expression of HCM is manifest by left ventricular (LV) hypertrophy, myocardial hypercontractility, reduced compliance, myofibrillar disarray, and fibrosis . Patients frequently experience reduced exercise capacity and symptoms of exertional dyspnoea and/or chest pain resulting from impaired relaxation and reduced compliance of the left ventricle, LV outflow tract (LVOT) obstruction, and mitral regurgitation (MR), as well as microvascular dysfunction and subendocardial ischaemia .…”

“…The phenotypic expression of HCM is manifest by left ventricular (LV) hypertrophy, myocardial hypercontractility, reduced compliance, myofibrillar disarray, and fibrosis. 1,2 Patients frequently experience reduced exercise capacity and symptoms of exertional dyspnoea and/or chest pain resulting from impaired relaxation and reduced compliance of the left ventricle, LV outflow tract (LVOT) obstruction, and mitral regurgitation (MR), as well as microvascular dysfunction and subendocardial ischaemia. 3 In addition to septal hypertrophy, abnormalities of the mitral valve and subvalvular apparatus contribute to systolic anterior motion (SAM) and LVOT obstruction, the characteristic features of obstructive HCM (oHCM).…”

Myocardial Contractility: Historical and Contemporary Considerations

“…Of particular relevance to the current discussion is the identification and investigation of genetic mutations and compounds that change the heart's inotropic state by altering sarcomeric protein cross-bridge (XB) kinetics (Spudich, 2011(Spudich, , 2014Ait Mou et al, 2015;Tardiff et al, 2015;Tang et al, 2017;Nanasi et al, 2018;Wang et al, 2018). The small molecule myosin regulator, omecamtiv mecarbil, for example, enhances sarcomeric force development by increasing the number and synchrony of strongly bound myosin crossbridges (XB's), thereby increasing sarcomeric force independent of changes in intracellular calcium concentration [Ca +2 ] i , calcium transients, shortening velocity or oxygen consumption (Malik et al, 2011;Tardiff et al, 2015;Utter et al, 2015;Hashem et al, 2017;Planelles-Herrero et al, 2017;Swenson et al, 2017;Kaplinsky and Mallarkey, 2018;Spudich, 2019;Kieu et al, 2019). Alternatively, compounds that reduce sarcomeric force without changing shortening velocity or the rate of myocardial relaxation (ex.…”