Editorial: Hypertrophic Cardiomyopathy and Precision Medicine in Cardiovascular Disease

Abstract

Molecular targets in diseased cells and tissues are the basis for precision medicine that stratifies patients into specific subgroups to develop targeted therapies. Myosin heavy chain (MHC) gene isoforms encode the proteins that form the thick filaments in muscle that enable muscle contraction. Management of familial hypertrophic cardiomyopathy has relied on surgical and symptomatic medical (pharmacological) treatment. However, in April 2022, the US Food and Drug Administration (FDA) approved a small molecule that selectively but reversibly inhibits sarcomeric myosin, mavacamten (MYK-461, Camzyos) for adults with symptomatic hypertrophic cardiomyopathy, New York Heart Association (NYHA) class II–III. Mavacamten is a first-in-class, precision medicine for patients with symptomatic hypertrophic obstructive cardiomyopathy that inhibits cardiac myosin and reduces actin-myosin interactions to reduce left ventricular outflow tract obstruction, improve exercise capacity, and reduce symptoms. This editorial aims to introduce how understanding the genetic and molecular basis of hypertrophic cardiomyopathy has resulted in a novel approach to precision medicine in cardiovascular disease.

In 2019, cardiovascular disease was estimated to affect up to 523 million people worldwide, which was almost double the figure of two decades previously [1]. Of concern was that one in three deaths from cardiovascular disease occurred in people <70 years of age, which was a change in the demographic disease pattern believed to be driven by poor lifestyle and socioeconomic factors [1]. By 2030, at least 44% of adults in the US (116 million people) are projected to have one or more forms of cardiovascular disease due to an increasing aging population, and rates of obesity and diabetes [1,2]. This US projection contrasts with the World Heart Federation (WHF) global vision to reduce mortality from cardiovascular disease by 30% by 2030 [3]. The WHF recommends that mortality from cardiovascular disease can be reduced by addressing known risk factors, including lack of physical inactivity, poor diet, tobacco use, and alcohol abuse, and prevention and management of disease associations, including hypertension, hyperlipidemia, metabolic syndrome, and diabetes [3]. However, a further challenge to reducing mortality from cardiovascular disease is the existence of non-modifiable factors that not only include age and gender, but also family history and genetics [3].

Molecular targets in diseased cells and tissues are the basis for precision medicine that stratifies patients into specific subgroups to develop targeted therapies [4,5]. Personalized medicine is a broader term that implies treatments tailored to individual patients, with consideration of environmental, genetic, and lifestyle factors [4,5]. Although the terms are used interchangeably, precision medicine is a more data-driven approach to personalized patient care that uses -omics technologies (genomics, proteomics, and metabolomics) to match treatments to individual patient profiles [4]. For several decades, individual and population recommendations have been directed at known environmental and lifestyle factors [3]. However, precision medicine has yet to find a place in cardiovascular medicine [6,7].

For more than half a century, the main approach to common cardiovascular disease, mainly atherosclerosis and ischemic heart disease, has been directed to lifestyle modifications and methods to control or reduce hyperlipidemia [1]. Worldwide, cardiovascular disease remains the leading cause of death and accounts for up to 32% of all global deaths, with the expectation that this number will rise to >23.6 million deaths annually by 2030 [1–3]. The influence of comorbidities and broad heterogeneity in the clinical profiles and outcomes of individuals with cardiovascular disease is a significant challenge but highlights the need for precision phenotyping that may begin with cardiovascular conditions that have an identifiable molecular basis [7].

Hypertrophic obstructive cardiomyopathy is a primary myocardial disease that is characterized by hypertrophy of the left ventricle, with impaired ventricular relaxation following hyperdynamic contraction [8]. These anatomic and functional anomalies arise from genetically altered sarcomere function that includes mutations in genes encoding sarcomeric proteins [8,9]. Thick filaments are composed of myosin II and proteins, including titin and myosin binding protein C, which, with thin actin filaments, are organized into sarcomeres or the contractile units of cardiac myocytes [10]. The myosin heavy chain (MHC) gene isoforms encode the proteins that form the thick filaments in muscle that enable muscle contraction [10]. In 1990, at the Seidman laboratory, Harvard Medical School, a familial study identified a common point mutation in exon 13 of the gene encoding the beta cardiac myosin heavy chain in familial hypertrophic cardiomyopathy [11,12]. This point mutation was found to convert the highly conserved arginine residue, Arg-403, to a glutamine in the MHC gene [11]. This early study demonstrated that the identification of unique mutations within cardiac MHC genes in familial hypertrophic cardiomyopathy showed that mutations disrupted the critical role of myosin in familial hypertrophic cardiomyopathy [11,12].

Patient management in hypertrophic cardiomyopathy has relied on surgical treatment, including cardiac transplantation, and symptomatic medical (pharmacological) treatment [8,9]. However, in April 2022, the US Food and Drug Administration (FDA) approved a small molecule that selectively but reversibly inhibits sarcomeric myosin, mavacamten (MYK-461, Camzyos), for adults with symptomatic hypertrophic cardiomyopathy, New York Heart Association (NYHA) class II–III [13,14]. Mavacamten has been described as a first-in-class, precision medicine for patients with symptomatic hypertrophic obstructive cardiomyopathy and acts as a targeted therapy on actin-myosin interactions to reduce left ventricular outflow tract obstruction, improve exercise capacity, and reduce symptoms, such as shortness of breath [9].

Regulatory approval of mavacamten in 2022 was based on safety and efficacy data from a placebo-controlled phase 3 randomized clinical trial, EXPLORER-HCM of 30 weeks duration (NCT03470545) [15], which showed that 37% of patients with hypertrophic obstructive cardiomyopathy treated with mavacamten had improved symptoms and exercise capacity when compared to 17% of patients in the placebo group [15]. However, because mavacamten reduces cardiac muscle contractility, patients with cardiac arrhythmia and other comorbidities may have an increased risk of heart failure; therefore, post-treatment monitoring with imaging and echocardiograms was advised [14,15]. Initially, mavacamten (Camzyos) was only available through the Camzyos Risk Evaluation and Mitigation Strategy (REMS), which is a restricted treatment program to ensure safety and lower the risk of heart failure associated with impaired cardiac muscle contractility [14,15].

However, nonobstructive hypertrophic cardiomyopathy involves thickening of the ventricular wall but without ventricular outflow obstruction [8]. Since 2022, the results from clinical trials on the role of mavacamten in nonobstructive hypertrophic cardiomyopathy have been awaited. In September 2025, Desai and colleagues published the findings from the ODYSSEY-HCM phase 3 trial, an international double-blind, placebo-controlled trial on mavacamten in patients with symptomatic nonobstructive hypertrophic cardiomyopathy (NCT05582395) [16]. This trial was conducted at 201 sites in 22 countries and included 580 patients with NYHA functional class II or III, a mean age of 56 years, and 43.3% of patients had a family history of hypertrophic cardiomyopathy [16]. At 48 weeks, mavacamten treatment was not associated with significant improvements in patient-reported health status or peak oxygen consumption compared with placebo in patients with symptomatic nonobstructive hypertrophic cardiomyopathy [16]. Further studies of the effects of mavacamten in subgroups of patients with longstanding nonobstructive hypertrophic cardiomyopathy are still awaited.

Conclusions

A role for precision medicine in cardiovascular disease remains unclear and has been controversial. However, familial hypertrophic cardiomyopathy has a genetic basis and several potential gene targets have been identified, including sarcomeric genes (MYH7 and MYBPC3), sarcomere-related genes (ACTC1, TNNT2, and TNNI3), and novel genes (FRZB and PRMT5), which require further investigation for their role in disease progression, diagnosis, and therapies that could also include gene replacement therapies [6,17].