Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy (VANISH) Clinical Trial.

In hypertrophic cardiomyopathy (HCM), the mechanisms through which pathogenic sarcomere variants (G+) lead to left ventricular hypertrophy (LVH) are not understood. VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) was a multicenter, double-blind, placebo-controlled randomized trial testing valsartan's ability to attenuate phenotypic progression in early sarcomeric (G+LVH+) and subclinical HCM (G+LVH-). The outcome was a composite Z score reflecting cardiac remodeling from baseline to year 2 (end of study). Baseline and year 2 blood samples were used to quantify 276 proteins using a proximity extension assay (Olink, Sweden). We explored relative differences in protein abundance between early and subclinical HCM at baseline. In addition, we compared proteomic changes between baseline and year 2 in subclinical HCM participants who experienced phenotypic conversion to early HCM (converters) versus nonconverters; early HCM participants receiving valsartan versus placebo; and in association with changes in Z score. Comparisons were made using t test/Mann-Whitney U test, linear mixed models, and generalized linear models, correcting for multiple testing. Circulating proteins were analyzed in 192 participants (32 subclinical and 160 early HCM [81 allocated to valsartan]). NT-proBNP (N-terminal pro-B-type natriuretic peptide) differentiated early from subclinical HCM and tracked with phenotypic progression in early HCM (1-unit worsening in Z score associated with a 27% increase in NT-proBNP [95% CI, 17-37%]). Some extracellular matrix remodeling proteins showed higher abundance (tissue-type plasminogen activator) in early compared with subclinical HCM or tracked with disease progression (decorin) in early HCM. Growth factors had higher relative abundance in early HCM (fibroblast growth factor-21). While no individual protein was able to distinguish converters from nonconverters, multiprotein the panels lipocalin 2, lectin-like oxidized low-density lipoprotein receptor 1, and either NT-proBNP or interleukin-17 receptor A, could distinguish these groups. NT-proBNP was the most robust protein to track progression. Studying pathways involving growth factors and extracellular matrix remodeling may yield additional insights into mechanisms behind disease progression. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.