Understanding Gradient Reduction Therapy and Cardiac Myosin Inhibitors in oHCM Care

The notion of “gradient reduction therapy,” originally articulated by James Udelson,MD, is presented as a logical next step in the management of oHCM.

In this video, Matthew Martinez, MD, raises the question of whether it is acceptable to leave patients with high resting or provocable LVOT gradients (eg, ≥130 mm Hg) if they appear asymptomatic and have preserved exercise capacity. Both he and Mariko Harper, MD, argue that although definitive outcomes data are not yet available, it is physiologically plausible that sustained severe obstruction promotes adverse remodeling, including progressive left ventricular hypertrophy, left atrial enlargement, mitral regurgitation, and myocardial fibrosis, all of which may increase long-term cardiovascular risk.

Harper emphasizes that emerging long-term data from mavacamten—the first FDA-approved cardiac myosin inhibitor—demonstrate favorable cardiac remodeling, with reductions in left ventricular mass, left atrial size, and systolic anterior motion of the mitral valve, as well as sustained biomarker improvement over several years. This experience suggests that earlier gradient elimination may have disease-modifying potential, though conclusive data on atrial fibrillation, heart failure events, and other hard outcomes are still pending. In parallel, both clinicians note the similarity to the evolution of aortic stenosis care, where earlier intervention has been associated with improved long-term outcomes as procedural risk declined.

Traditional agents, including β-blockers, non-dihydropyridine calcium channel blockers, and disopyramide, remain part of background therapy but no longer dominate the treatment algorithm in expert practice. Martinez explains that he still initiates these agents given their low upfront risk, but he no longer escalates to high doses or complex combinations before switching to a myosin inhibitor. Instead, he introduces a cardiac myosin inhibitor relatively early and, once gradient and symptoms improve, often de-escalates or discontinues background drugs. In this segment, Martinez and Harper present a nuanced, forward-looking view of gradient reduction as a primary therapeutic goal and outline how cardiac myosin inhibitors are displacing escalating polypharmacy with traditional negative inotropes.