Abstract Body (Do not enter title and authors here): Background: Valsartan has previously been shown to attenuate cardiac remodeling among individuals with early-stage sarcomeric hypertrophic cardiomyopathy (HCM), a condition characterized, in part, by increased cardiomyocyte size. Cardiac magnetic resonance (CMR) imaging parameters, such as late gadolinium enhancement (LGE), are associated with disease progression and outcomes in HCM, but whether valsartan influences these parameters remains uncertain.

Methods: In this prespecified CMR substudy of the international, multicenter, phase 2 VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric HCM) trial, we evaluated treatment effects of valsartan versus placebo on cardiac structure and function, including indexed extracellular volume (iECV), indexed intracellular volume (iICV; reflecting cell size or number), and LGE. Between-group differences in CMR parameters from baseline to 2 years were evaluated using multivariable mixed effects models.

Results: Overall, 137 (77%) VANISH participants (mean age 23±10 years; 37% female; 97% White) had CMR imaging available at baseline and 2 years. Baseline characteristics and CMR parameters were well-balanced between the treatment arms. Baseline non-indexed ECV and ICV (available at baseline and year 2 in 52 participants) were 32±7% and 68±7%, respectively. Among those with detectable LGE (n=37; 27%), the median [IQR] global LGE mass was 10 [2-28] grams. Between baseline and 2 years, iICV was significantly reduced with valsartan vs. placebo (between-group difference, -5.0 mL/m², 95% CI -9.7 to -0.4; P=0.032) (Figure). Valsartan was also associated with improved left ventricular end-diastolic volume index vs. placebo (between-group difference, +3.3 mL/m², 95% CI 0.4 to 6.2; P=0.027); no significant between-group differences were observed for other CMR parameters, including iECV and global LGE mass.

Conclusions: These findings provide important mechanistic insights into the effect of valsartan in early-stage HCM, showing potential benefits on myocardial intracellular volume. These findings support and extend those of the primary VANISH trial, stressing the need for further research efforts to identify cellular mechanisms of valsartan on HCM progression.