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Proteomic Analysis of Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy
Constantin-Cristian Topriceanu1,2,3,4, Christoffer Rasmus Vissing5, Anna Axelsson Raja5
1Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.E.S., N.K.L., C.Y.H.).
Insights
N-terminal pro-B-type natriuretic peptide (NT-proBNP) effectively tracks hypertrophic cardiomyopathy progression. Growth factors and extracellular matrix proteins offer insights into disease mechanisms.
Area of Science:
- Cardiology
- Proteomics
- Genetics
Background:
- Mechanisms linking sarcomere variants to left ventricular hypertrophy in HCM remain unclear.
- The VANISH trial investigated valsartan's effect on disease progression in early and subclinical HCM.
- This study analyzed proteomic changes in relation to HCM progression and treatment.
Purpose of the Study:
- To identify circulating proteins associated with hypertrophic cardiomyopathy (HCM) progression.
- To explore proteomic differences between early and subclinical HCM.
- To assess proteomic changes in response to valsartan and their correlation with disease progression.
Main Methods:
- A multicenter, double-blind, placebo-controlled randomized trial (VANISH) was conducted.
- 276 proteins were quantified using proximity extension assay in baseline and year 2 blood samples.
- Statistical analyses included t-tests, Mann-Whitney U tests, linear mixed models, and generalized linear models.
Main Results:
- NT-proBNP differentiated early from subclinical HCM and correlated with disease progression.
- Extracellular matrix proteins (tissue-type plasminogen activator, decorin) and growth factors (fibroblast growth factor-21) showed altered abundance in early HCM.
- Multoprotein panels could distinguish converters from nonconverters, though individual proteins could not.
Conclusions:
- NT-proBNP is a key biomarker for tracking HCM progression.
- Investigating growth factor and extracellular matrix remodeling pathways may elucidate disease mechanisms.
- Proteomic analysis provides valuable insights into HCM pathogenesis and progression.
Background:
In hypertrophic cardiomyopathy (HCM), the mechanisms through which pathogenic sarcomere variants (G+) lead to left ventricular hypertrophy (LVH) are not understood.
Methods:
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 change in 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 (convertors) versus nonconvertors; early HCM participants receiving valsartan versus placebo; and in association with changes in the phenotypic progression z-score. Comparisons were made using the t-test, Mann-Whitney U 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.
