Revisiting Diagnosis and Treatment of Hypertrophic Cardiomyopathy: Current Practice and Novel Perspectives

Abstract

Sarcomeric hypertrophic cardiomyopathy (HCM) is a prevalent genetic disorder characterised by left ventricular hypertrophy, myocardial disarray, and an increased risk of heart failure and sudden cardiac death. Despite advances in understanding its pathophysiology, treatment options for HCM remain limited. This narrative review aims to provide a comprehensive overview of current clinical practice and explore emerging therapeutic strategies for sarcomeric HCM, with a focus on cardiac myosin inhibitors. We first discuss the conventional management of HCM, including lifestyle modifications, pharmacological therapies, and invasive interventions, emphasizing their limitations and challenges. Next, we highlight recent advances in molecular genetics and their potential applications in refining HCM diagnosis, risk stratification, and treatment. We delve into emerging therapies, such as gene editing, RNA-based therapies, targeted small molecules, and cardiac myosin modulators like mavacamten and aficamten, which hold promise in modulating the underlying molecular mechanisms of HCM. Mavacamten and aficamten, selective modulators of cardiac myosin, have demonstrated encouraging results in clinical trials by reducing left ventricular outflow tract obstruction and improving symptoms in patients with obstructive HCM. We discuss their mechanisms of action, clinical trial outcomes, and potential implications for the future of HCM management. Furthermore, we examine the role of precision medicine in HCM management, exploring how individualised treatment strategies, including exercise prescription as part of the management plan, may optimise patient outcomes. Finally, we underscore the importance of multidisciplinary care and patient-centred approaches to address the complex needs of HCM patients. This review also aims to encourage further research and collaboration in the field of HCM, promoting the development of novel and more effective therapeutic strategies, such as cardiac myosin modulators, to hopefully improve the quality of life and outcome of patients with sarcomeric HCM.

Pooled Genetic Screenings to Identify Likely Pathogenic Variants in Hypertrophic Cardiomyopathy

“…Furthermore, myosin inhibitors, the first in class therapy to be considered disease modifying may be ineffective and potentially cause catastrophic problems in nonsarcomeric disease, underscoring the importance of accurate genotyping. 8 The genetic heterogeneity of HCM makes genetic testing through classical Sanger sequencing particularly costly and challenging. Genetic screening in patients with HCM and relatives has recently benefited greatly from the development of next-generation sequencing-based genomic approaches such as whole exome sequencing and whole genome sequencing, allowing to screen all potential causal genes simultaneously.…”

An overview of the treatments for hypertrophic cardiomyopathy

“…patients with HCM. There are two main types of myosin inhibitors being studied, mavacamten and aficamten (57,58).…”

“…The emergence of cardiac myosin inhibitors has compensated for the shortcomings of traditional drugs that only control symptoms but do not improve cardiac function, and has brought new hope for the prognosis of patients with HCM. There are two main types of myosin inhibitors being studied, mavacamten and aficamten ( 57 , 58 ).…”

Hypertrophic Cardiomyopathy—Current Challenges and Future Perspectives

“…Recently, an improved comprehension of the underlying causes of HCM has paved the way for the creation of treatments specifically designed to target the underlying substrate, emphasizing the need for an aetiological characterization of patients with HCM [ 26 ]. Thus, Ottaviani et al furnish a comprehensive overview of the present clinical approaches and delve into emerging therapeutic avenues for sarcomeric HCM, with particular attention to cardiac myosin inhibitors [ 27 ].…”