Advances in Cardiovascular Pharmacotherapy. I. Cardiac Myosin Inhibitors

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. The disease is characterized by asymmetric left ventricular (LV) remodeling with myocyte disarray and interstitial fibrosis, a hypercontractile state, dynamic subaortic obstruction of the LV outflow tract, impaired LV diastolic function, atrial and ventricular arrhythmias, and sudden cardiac death. HCM occurs as a result of pathological alterations in the cardiac myocyte's chemomechanical cycle, in which an enhanced rate of myosin-actin crossbridge formation and destabilization of the energy-conserving "super-relaxed off-actin state" of myosin play essential roles. For decades, management of HCM has been limited almost exclusively to medications (eg, beta-blockers, calcium channel blockers, disopyramide) and interventions (eg, septal reduction therapy, implanted cardioverter-defibrillator devices) that palliate symptoms, but do not address the disease's underlying causative mechanisms. A new class of cardiovascular medications, cardiac myosin inhibitors, has surged to the forefront of HCM treatment in recent years. These drugs, including mavacamten and aficamten, show great promise to profoundly affect the disease's clinical course. In this article, the authors review the molecular mechanisms of action of cardiac myosin inhibitors, discuss in detail the most recent data from mavacamten and aficamten clinical trials, describe future planned studies designed to address unanswered questions about their clinical utility in HCM phenotypes, and comment on their potential application to patients with other forms of heart failure with preserved ejection fraction. The possible anesthetic implications of mavacamten and aficamten are also discussed because it is highly likely that patients who are treated with these medications will begin to present for perioperative care with increasing regularity.

Keywords: NYHA classification; aficamten; cardiac myosin inhibitors; hypertrophic cardiomyopathy; left ventricular diastolic function; left ventricular outflow tract gradient; mavacamten; peak O(2) consumption.