Comprehensive Proteomics Profiling Identifies Circulating Biomarkers to Distinguish Hypertrophic Cardiomyopathy from Other Cardiomyopathies with Left Ventricular Hypertrophy.

Abstract

Background: Distinguishing hypertrophic cardiomyopathy (HCM) from other cardiomyopathies with left ventricular hypertrophy (LVH), such as hypertensive LVH, transthyretin amyloid cardiomyopathy (ATTR-CM), and aortic stenosis (AS), is sometimes challenging. Using plasma proteomics profiling, we aimed to identify circulating biomarkers and dysregulated signaling pathways specific to HCM. Methods: In this multicenter case-control study, plasma proteomics profiling was performed in cases with HCM and controls with hypertensive LVH, ATTR-CM, and AS. Two-thirds of patients enrolled earlier in each disease group were defined as the training set, and the remaining one-third as the test set. Protein concentrations in HCM were compared with those in hypertensive LVH (comparison 1), ATTR-CM (comparison 2), and AS (comparison 3). Candidate proteins that meet the following 2 criteria were selected: (1) Higher abundance in HCM throughout all 3 comparisons or lower abundance in HCM throughout all 3 comparisons with univariable P<0.05 and |log₂(fold change)| >0.5 in both the training and test sets and (2) Independently associated with HCM with multivariable P<0.05 after adjusting for clinical parameters significantly different between HCM and controls. Using the selected candidate proteins, a logistic regression model to distinguish HCM from controls was developed in the training set and applied to the test set. Finally, pathway analysis was performed in each comparison using proteins with different abundance. Results: Overall, 4,979 proteins in 1,415 patients (HCM, n=879; hypertensive LVH, n=331; ATTR-CM, n=169; AS, n=36) were analyzed. Of those, 5 proteins were selected as candidate proteins. The logistic regression model with these 5 proteins had an area under the receiver-operating-characteristic curve of 0.86 (95% CI 0.82-0.89) in the test set. The MAPK and HIF-1 pathways were dysregulated in HCM throughout the 3 comparisons. Conclusions: This study identified circulating biomarkers that distinguish HCM from other cardiomyopathies with LVH independently from confounders and revealed signaling pathways associated with HCM.