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

BACKGROUND: In hypertrophic cardiomyopathy (HCM), the mechanisms through which pathogenic sarcomere variants (G+) lead to left ventricular hypertrophy (LVH) are not understood. METHODS: test, linear mixed models, and generalized linear models, correcting for multiple testing using a 5% false discovery rate. RESULTS: 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 a higher abundance (eg, tissue-type plasminogen activator) in early compared with subclinical HCM or tracked with disease progression (decorin) in early HCM. Some growth factors had a higher relative abundance in early HCM (eg, fibroblast growth factor-21). While no individual protein was able to distinguish phenotypic convertors from nonconvertors, multiprotein panels including lipocalin 2, lectin-like oxidized low-density lipoprotein receptor 1, and either NT-proBNP or interleukin-17 receptor A, could distinguish these groups. CONCLUSIONS: NT-proBNP was the most informative protein, showing a higher abundance in early compared with subclinical HCM and tracking with the phenotypic progression z-score in early-stage HCM. Studying pathways involving growth factors and extracellular matrix remodeling may yield additional insights into the mechanisms behind disease progression in sarcomevere variant carriers and early HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.