Abstract Body (Do not enter title and authors here): Background: Cardiac myosin inhibitors (CMIs) reduce myocardial contractility, alleviating symptoms and improving cardiac function in hypertrophic cardiomyopathy (HCM). They offer a targeted alternative to conventional therapies such as beta-blockers and calcium channel blockers.

Research question: How do cardiac myosin inhibitors compare to placebo (beta-blockers or calcium channel blockers) in improving cardiac structure and function in hypertrophic cardiomyopathy?

Methods: A systematic review was conducted according to PRISMA guidelines using PubMed, Google Scholar, Scopus, and ClinicalTrials.gov. Randomized controlled trials (RCTs) assessing CMIs in obstructive and non-obstructive HCM were included. Primary outcomes were changes in Valsalva and resting left ventricular outflow tract gradients (LVOT-G), left ventricular mass index (LVMI), and New York Heart Association (NYHA) functional class. Secondary outcomes included cardiac troponin I (cTnI), left atrial volume index (LAVI), Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (KCCQ-CSS), and NT-proBNP levels. Safety outcomes included treatment-emergent (TEAEs) and serious adverse events (SAEs). Random-effects models were used for pooled analyses. P-value < 0.05 was considered statistically significant.

Results: Six RCTs comprising 827 patients (443 CMI vs. 384 placebo) were included. Compared to placebo, CMIs significantly improved NYHA class (RR 2.21; 95% CI: 1.75–2.80; p < 0.00001) and reduced Valsalva LVOT-G (MD −49.41; 95% CI: −53.66 to −45.15; p < 0.00001), resting LVOT-G (MD −42.42; 95% CI: −57.91 to −26.93; p < 0.00001), LVEF (MD −4.74%; 95% CI: −7.22 to −2.26; p = 0.0002), LVMI (MD −21.31; 95% CI: −31.58 to −11.05; p < 0.0001), LAVI (MD −6.94; 95% CI: −8.57 to −5.31; p < 0.00001), NT-proBNP (SMD −13.25; 95% CI: −17.51 to −8.98; p < 0.00001), cTnI (SMD −11.90; 95% CI: −15.07 to −8.72; p < 0.00001), and improved KCCQ-CSS (MD 7.69; 95% CI: 4.92–10.47; p < 0.00001). No significant differences were found in SAEs (RR 1.08; 95% CI: 0.95–1.24; p = 0.24) or TEAEs (RR 1.06; 95% CI: 0.98–1.16; p = 0.15). Subgroup analyses indicated consistent effects across different CMI classes.

Conclusion: CMIs significantly improve functional status and reverse structural remodeling in patients with both obstructive and non-obstructive HCM. While a modest decline in LVEF was observed, the overall safety and efficacy profile supports the use of CMIs, particularly in improving patient-centered outcomes.