Cardiac myosin inhibitors: Game-changers in obstructive hypertrophic cardiomyopathy management

Cardiac myosin inhibitors (CMIs) for obstructive hypertrophic cardiomyopathy (HCM) offer effective treatment targeting the underlying pathophysiology of the disease and are recommended as a second-line (2L) option in latest international guidelines. At the 10^th Asian Preventive Cardiology & Cardiac Rehabilitation Conference, Dr Raymond H Chan of the Hypertrophic Cardiomyopathy Clinic, University Health Network, Peter Munk Cardiac Center in Toronto, Canada, discussed why CMIs are game-changers in HCM management and presented a patient case illustrating real-world benefits of the first-in-class CMI, mavacamten.

Diagnosis: Proper echocardiography, Valsalva manoeuvre
HCM is characterized by primary left ventricular (LV) hypertrophy with pathologi­cally enhanced cardiac actin-myosin interactions. Core pathophysiological features include hypercontractility, diastolic abnormal­ities, and dynamic LV outflow tract (LVOT) obstruction. [Lancet 2020;396:759-769]

Obstructive HCM is diagnosed based on echocardiography or cardiac MRI show­ing maximal LV end-diastolic wall thickness ≥15 mm, along with peak LVOT gradient ≥30 mm Hg on echocardiography either at rest or with provocation. Echocardiograph­ic measurement of maximal wall thickness and identification of LV apical aneurysms help inform disease severity and risk stratification. [J Am Coll Cardiol 2024;83:2324-2405]

Of note, LVOT obstruction is dynamic and is primarily caused by systolic anterior motion (SAM) of the mitral valve (MV). “LVOT gradients should be measured with proper Valsalva manoeuvres,” Chan emphasized. “This is because LVOT gradients are dy­namic, and many patients need provoca­tion for LVOT obstruction to be identified and accurately rated.” [J Am Coll Cardiol 2024;83:2324-2405]

CMIs: Now available for obstructive HCM
Traditional medical therapies for ob­structive HCM include beta-blockers, non-dihydropyridine calcium-channel blockers, and disopyramide. These agents provide symptomatic relief but are not HCM-specific. [Lancet 2020;396:759-769]

Mavacamten’s efficacy
Mavacamten, a first-in-class CMI, targets the underlying pathophysiology of HCM by reducing actin-myosin cross-bridge formation, thereby reducing con­tractility and improving myocardial ener­getics. In the phase III EXPLORER-HCM trial in 251 patients with LVOT gradient ≥50 mm Hg and New York Heart Associ­ation (NYHA) class II–III symptoms, more patients in the mavacamten vs placebo group achieved the primary endpoint of ≥1.5 mL/kg/min increase in peak oxygen consumption (pVO2; a measure of exer­cise capacity) and ≥1 NYHA class reduc­tion, or ≥3.0 mL/kg/min increase in pVO2 without NYHA class worsening (37 vs 17 percent; p=0.0005). “Early and sustained reductions in resting and Valsalva LVOT gradients were observed with mavaca­mten vs placebo,” noted Chan. [Lancet 2020;396:759-769]

At week 30, mean changes from baseline in resting and Valsalva LVOT gra­dients were -37.6 and -47.6 mm Hg, respectively, for mavacamten, vs -5.2 and -11.2 mm Hg, respectively, for place­bo. [Lancet 2020;396:759-769]

Guideline-recommended 2L therapy
Latest guidelines of the European Society of Cardiology and American car­diology societies recommend mavacam­ten as a 2L treatment option for patients with symptomatic obstructive HCM. For patients with drug-refractory symptoms, invasive septal reduction therapy should be considered. (Figure 1) [Eur Heart J 2023;44:3503-3626; J Am Coll Cardiol 2024;83:2324-2405]

Practical considerations in Asia
“We would usually start mavacamten at 2.5 mg QD unless CYP2C19 phenotype is determined,” Chan advised. “Echocardi­ography should be performed in weeks 4, 8 and 12 to [measure Valsalva LVOT gradient and] ensure LV ejection fraction [LVEF] is ≥50 percent. A clinic visit in week 12 should be planned to review the need for uptitration of mavacamten. From week 12 onwards, echocardiography should be performed every 12 weeks if the dose re­mains unchanged. If there is uptitration at week 12, an additional echocardiography should be performed 4 weeks later [and 8 weeks later for CYP2C19 poor metaboliz­ers or undetermined phenotype].” [Mava­camten Hong Kong Prescribing Informa­tion, September 2023]

Conclusion
Proper echocardiography with Valsalva manoeuvre is essential for diagnosis of ob­structive HCM. Mavacamten, a first-in-class CMI, effectively reduces LVOT gradients and improves symptoms and exercise ca­pacity, and is recommended by internation­al guidelines as 2L therapy in patients with symptomatic obstructive HCM.