The Impact of Mavacamten on the Pathophysiology of Hypertrophic Cardiomyopathy: A Narrative Review

Abstract

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states. Supplementary Information The online version contains supplementary material available at 10.1007/s40256-022-00532-x.

Mavacamten: First Approval

“…Although LV diastolic dysfunction often occurs, LV ejection fraction (LVEF) is preserved or increased [ 2 ]. HCM is recognised as a disease of the cardiac sarcomere [ 7 ]. Histological features of HCM include myocyte hypertrophy and disarray and interstitial fibrosis [ 2 , 7 ]; at a molecular level, excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are evident [ 7 , 8 ].…”

“…HCM is recognised as a disease of the cardiac sarcomere [ 7 ]. Histological features of HCM include myocyte hypertrophy and disarray and interstitial fibrosis [ 2 , 7 ]; at a molecular level, excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are evident [ 7 , 8 ]. While HCM has a relatively benign course in most affected individuals, it is associated with chronic, progressive heart failure symptoms.…”

“…Mavacamten (Camzyos™) is a small-molecule allosteric and reversible inhibitor of cardiac myosin ATPase [ 7 , 8 , 11 ]. It targets the sarcomere hypercontractility that is one of the characteristics of HCM [ 8 , 12 ] and inhibits excessive myosin actin cross-bridge formation, shifting the overall myosin population towards an energy-sparing, recruitable, super-relaxed state [ 8 ].…”

Mavacamten: A First-in-class Oral Modulator of Cardiac Myosin for the Treatment of Symptomatic Hypertrophic Obstructive Cardiomyopathy

“…6,[18][19][20][21] Sarcomere hyperactivity leading to myocardial hypercontractility is an important process in the pathophysiology of HCM because it has been linked to an increase in cellular signalling that leads to hypertrophic changes. 22,23 Ultimately, this results in detrimental cardiac remodelling brought about by fibrotic change, myofibre hypertrophy with disarray secondary to increased activation of pathways involving hypertrophy, inflammation and fibrosis (Figure 1). [18][19][20] These changes lead to outflow tract obstruction and diastolic dysfunction; they thus lead to an increase in cardiac workload, rendering the heart an ineffective pump, hence leading to the development of symptoms of heart failure (i.e.…”

“…[5][6][7][8] Furthermore, these molecular changes from mavacamten optimize the mechanical environment of the sarcomere by reducing diastolic tension with improved relaxation, increasing ventricular chamber size, reducing myocardial contraction velocity and ultimately decreasing outflow obstruction. 5,17,20,23 The primary focus in hypertrophic obstructive cardiomyopathy: The left ventricular outflow tract gradient HOCM is the most prevalent subgroup of HCM, making up approximately 70% of HCM occurrences; Its definying features include asymmetric ventricular septal hypertrophy and systolic anterior motion of the mitral valve. 2 The presence of LVOT obstruction at rest, defined as an LVOT gradient of ≥30 mm, is associated with a twofold increase in the risk of HCM-related death, 3 suggesting that obstruction in HCM is not only causing symptoms but is also a treatment target for improving patients' longevity.…”