Obstructive hypertrophic cardiomyopathy (HCM) is a complicated heart condition that affects the normal functioning of the heart muscles. It’s a genetic disorder that typically runs in families, and it can lead to various complications, including arrhythmia, chest pain, and even sudden death. Fortunately, recent studies have shown that mavacamten, a new medication, is effective in treating obstructive HCM. This article will provide an in-depth look at mavacamten and its potential as a treatment option for obstructive HCM. We’ll explore the mechanism of action, efficacy, safety, and its potential impact on the management of HCM.
Hypertrophic Cardiomyopathy, commonly referred to as HCM, is a genetic condition affecting the sarcomere. The disease causes hypertrophy, or thickening of the heart muscle, in the absence of other causes, in individuals at a prevalence estimated to be greater than 1 in 500. HCM can be divided into obstructive (oHCM) and non-obstructive (nHCM), with the former defined as a resting left ventricular outflow gradient greater than 30mmHg. Symptoms in oHCM include dyspnea, chest pain, exertional intolerance, syncope, or sudden cardiac death.
The disease is largely a clinical diagnosis, requiring identification of left ventricular hypertrophy by echocardiography or cardiac magnetic resonance imaging (CMR). Typically, LV wall thickness greater than 15mm or greater than 13mm with pertinent family history should raise suspicion for HCM. Hypertrophy occurs most commonly in the basal septum but can vary in different morphologies of HCM. However, mimickers such as hypertension, aortic stenosis, amyloidosis, muscular dystrophies, Fabry’s disease, and lysosomal disorders should be excluded prior to diagnosing HCM.
There are traditional pharmacotherapy and invasive therapies for HCM. For patients with oHCM, first-line therapy includes non-vasodilating beta-blockers and nondihydropyridine calcium channel blockers. Current guidelines from the American Heart Association and American College of Cardiology recommend titrating these medications to either effectiveness or maximally tolerated dose. Unfortunately, use of these agents is often limited by side effects. If symptoms persist, then the addition of disopyramide or evaluation of intervention at an experienced center should be pursued. For patients with nHCM, treatment is sparse, and surgical apical myectomy can be considered for carefully selected patients with apical HCM experiencing symptoms refractory to medical therapy per guidelines.
This review focuses on mavacamten, a novel cardiac myosin inhibitor that was recently approved by the Food and Drug Administration for patients with oHCM. Mavacamten directly targets the hypercontractility that plays a central role in the pathophysiology of HCM. Normally, ATP is hydrolyzed to ADP once bound to myosin through ATPase. This reaction generates energy stored in the myosin head. When phosphate dissociates from myosin, myosin binds to actin, and shortening occurs as filaments slide past each other, creating myocardial contraction. In HCM, there is an upregulation of cardiac contractility with only 15–20% of myosin heads in an inactive state compared 40–50% in the inactive state normally.
Mavacamten selectively inhibits beta-cardiac myosin ATPase through allosteric binding, decreasing the amount of myosin-actin bridges. In addition, this first-in-class drug targets the rate-limiting step by preventing phosphate release. Furthermore, the drug slows the rates of myosin binding to actin in both the ADP-bound and ADP-released state. Combined, these mechanisms decrease the force generated by sarcomeres and reduce cardiac contractility. Its pharmacokinetic profile includes excellent oral bioavailability of greater than 85% and rapid absorption, with time to maximum concentration of 1 hour. The drug has a high distribution volume and long elimination phase. The mean half-life elimination is about 8 days in normal CYP2C19 metabolizers.
Preclinical animal studies with mice heterozygous for human mutation in myosin heavy chain have shown that mavacamten decreases ATPase activity, myocardial tension, and fractional shortening in a dose-dependent manner. Furthermore, mice on mavacamten showed decreased contractility and profibrotic gene expression. Similar findings have been replicated in a study comparing wild-type mice to those with knockout of the cardiac myosin-binding protein-C. Exposure to mavacamten in both groups leads to a dose-dependent decrease in myocardial force that was most noticeable at low calcium activation. In Maine coon or mixed-breed founder cats that had oHCM, mavacamten was also seen in a dose-dependent manner to decrease contractility, LVOT gradients, and SAM.
There have been multiple human studies published demonstrating the efficacy of mavacamten, including PIONEER-HCM, EXPLORER-HCM, and VALOR-HCM. The drug carries a boxed warning for the risk of heart failure and recommends against starting mavacamten in patients with left ventricular ejection fraction less than 55%. Cessation of the drug is recommended if EF is less than 50%, heart failure symptoms develop or worsening clinical status. In conclusion, mavacamten is a promising novel therapeutic option for patients with oHCM and its superior efficacy will pave the path to its wider usage in clinics with more studies expected in the near future.
In conclusion, mavacamten represents a promising treatment option for patients with obstructive hypertrophic cardiomyopathy. Given its ability to improve symptoms, reduce LVOT obstruction, and potentially prevent disease progression, mavacamten represents a significant advance in the management of this challenging condition. While further research is needed to fully understand the long-term effects of mavacamten and its role in the overall management of hypertrophic cardiomyopathy, the early results are encouraging and suggest that mavacamten could be a game-changer in the treatment of this condition. Healthcare providers should stay up to date with the latest research on this drug to provide the best possible care for their patients with obstructive hypertrophic cardiomyopathy.
