Topriceanu Constantin-Cristian, Vissing Christoffer Rasmus, Axelsson Raja Anna, Day Sharlene M, Russell Mark W, Zahka Kenneth, Pereira Alexandre C, Colan Steven D, Murphy Anne M, Canter Charles, Bach Richard G, Wheeler Matthew T, Rossano Joseph W, Owens Anjali T, Mestroni Luisa, Taylor Matthew R G, Moon James C, Captur Gabriella, Patel Amit R, Wilmot Ivan, Soslow Jonathan H, Becker Jason R, Seidman Christine E, Lakdawala Neal K, Bundgaard Henning, Tahir Usman A, Ho Carolyn Y
Department 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.).
UCL Institute of Cardiovascular Science, University College London, United Kingdom (C.-C.T., J.C.M., G.C.).
Circ Heart Fail. 2025 Jun;18(6):e012393. doi: 10.1161/CIRCHEARTFAILURE.124.012393. Epub 2025 May 9.
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 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 -test, Mann-Whitney test, linear mixed models, and generalized linear models, correcting for multiple testing using a 5% false discovery rate.
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.
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.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT01912534.
在肥厚型心肌病（HCM）中，致病性肌节变异（G+）导致左心室肥厚（LVH）的机制尚不清楚。
VANISH（缬沙坦用于减轻早期肌节肥厚型心肌病的疾病进展）是一项多中心、双盲、安慰剂对照的随机试验，旨在测试缬沙坦减轻早期肌节（G+LVH+）和亚临床HCM（G+LVH-）表型进展的能力。结局指标是一个综合z评分，反映从基线到第2年（研究结束）心脏重塑的变化。使用邻位延伸分析（瑞典Olink公司）对基线和第2年的血样进行检测，以定量276种蛋白质。我们探究了基线时早期和亚临床HCM之间蛋白质丰度的相对差异。此外，我们比较了亚临床HCM参与者中发生表型转化为早期HCM者（转化者）与未转化者；早期HCM参与者接受缬沙坦与安慰剂治疗；以及与表型进展z评分变化相关的蛋白质组学变化。使用t检验、Mann-Whitney检验、线性混合模型和广义线性模型进行比较，并使用5%的错误发现率校正多重检验。
对192名参与者（32名亚临床HCM和160名早期HCM[81名分配接受缬沙坦治疗]）的循环蛋白进行了分析。NT-proBNP（N末端前B型利钠肽）可区分早期和亚临床HCM，并与早期HCM的表型进展相关（z评分每恶化1个单位，NT-proBNP增加27%[95%CI，17-37%]）。一些细胞外基质重塑蛋白在早期HCM中比在亚临床HCM中丰度更高（如组织型纤溶酶原激活剂），或与早期HCM的疾病进展相关（核心蛋白聚糖）。一些生长因子在早期HCM中的相对丰度更高（如成纤维细胞生长因子-21）。虽然没有单个蛋白质能够区分表型转化者和未转化者，但包括lipocalin 2、凝集素样氧化低密度脂蛋白受体1以及NT-proBNP或白细胞介素-17受体A的多蛋白组合可以区分这些组。
NT-proBNP是最具信息量的蛋白质，与亚临床HCM相比，其在早期HCM中的丰度更高，并与早期HCM的表型进展z评分相关。研究涉及生长因子和细胞外基质重塑的途径可能会对肌节变异携带者和早期HCM疾病进展背后的机制有更多了解。
