DOI: 10.1161/jaha.126.051256 ISSN: 2047-9980

Efficacy and Safety of Pharmacologic Therapies in Nonobstructive Hypertrophic Cardiomyopathy: A Systematic Review

Shivam Patel, Akash Gandhi, Arman Pabani, Richa Shah, Pal Shah, Matthew W. Martinez, Aakash Bavishi
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Background

Nonobstructive hypertrophic cardiomyopathy (HCM) affects approximately one‐third of all patients with HCM and carries substantial morbidity, yet no approved disease‐modifying therapies exist. We conducted a systematic review of prospective interventional studies evaluating pharmacologic therapies in adults with nonobstructive HCM.

Methods

A systematic search of PubMed, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov was performed through September 2025. Eligible studies included randomized and nonrandomized prospective interventional trials. A narrative synthesis was performed by pharmacologic class and outcome domain.

Results

Twenty‐nine clinical trials evaluating 9 pharmacologic classes were identified: cardiac myosin inhibitors, cardiac sarcomere modulators, metabolic modulators, angiotensin II receptor blockers, angiotensin receptor‐neprilysin inhibitors, mineralocorticoid receptor antagonists, SGLT2 (sodium‐glucose cotransporter 2) inhibitors, beta blockers, and calcium channel blockers. Cardiac myosin inhibitors demonstrated reductions in left ventricular hypertrophy, improvements in diastolic function, and marked reductions in cardiac biomarkers, although improvements in exercise capacity and symptoms were variable. SGLT2 inhibition showed concordant improvements in diastolic function, atrial remodeling, biomarkers, and functional status in patients with symptomatic nonobstructive HCM and comorbid type 2 diabetes. Angiotensin receptor blockade showed signals of structural remodeling with valsartan and candesartan without consistent functional benefit. Mineralocorticoid receptor antagonism and angiotensin receptor‐neprilysin inhibition demonstrated largely neutral effects. Among metabolic modulators, ninerafaxstat improved ventilatory efficiency and quality of life in patients with greater baseline symptom burden.

Conclusions

Pharmacologic responsiveness in nonobstructive HCM is variable and appears to be mechanism‐ and disease stage‐dependent. Ongoing trials evaluating cardiac myosin inhibitors, SGLT inhibitors, and novel therapeutic agents including ninerafaxstat and EDG‐7500 will be critical in further defining the therapeutic landscape.

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