Targeted Therapeutic Approaches in Hypertrophic Cardiomyopathy

Abstract

Hypertrophic Cardiomyopathy (HCM) is a common autosomal dominant inherited myocardial disease characterised by left ventricular hypertrophy, hypercontractility and diastolic dysfunction. Most cases are caused by mutations in sarcomeric protein genes, such as MYH7 or MYBPC3. Clinical manifestations are heterogeneous, varying from none or mild exercise intolerance to severe lifestyle-limiting symptoms, heart failure, ventricular arrhythmias or sudden cardiac death. Diagnosis relies on multimodal imaging techniques and genetic testing. Current management includes symptom control with β-blockers, calcium channel blockers, and antiarrhythmics, as well as invasive strategies like septal myectomy in obstructive forms. Recently, myosin inhibitors (e.g., Mavacamten, Aficamten) have demonstrated significant improvements in functional status and left ventricular outflow tract (LVOT) obstruction gradients in obstructive HCM, although their benefits in non-obstructive HCM remain limited.

Target therapies are emerging as a potentially disease-modifying approach that targets the underlying genetic defects, even before the onset of phenotype. In vitro and pre-clinical studies using animal models and human induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) have demonstrated that techniques such as gene replacement, gene editing, allelic silencing, and other RNA based therapies can restore normal cardiomyocyte function.

These approaches are designed to target cardiomyocytes, employing viral vectors or nanoparticle-based delivery systems to reduce off-target effects. Despite significant progress, many challenges remained unsolved, including efficient delivery, immune system responses, long-term safety, and determining the optimal timing for intervention. Even so, gene and RNA based approaches may represent a transformative shift in HCM treatment, moving from symptom management to directly targeting the underlying cause of the disease.