Pathways to Precision Medicine in Hypertrophic Cardiomyopathy: Opportunities and Challenges in Plasma Proteomics

Hypertrophic cardiomyopathy (HCM) is a genetic disease marked by substantial heterogeneity in clinical presentation, ranging from asymptomatic individuals to heart failure and sudden cardiac death.The phenotypic expression of a single pathogenic mutation can exhibit significant variability, even within the same HCM-affected family.Moreover, the majority of individuals with HCM do not have a sarcomere pathogenic mutation on genetic testing, implicating polygenic, somatic and non-sarcomere related factors in disease development (1,2).Thus, while genetic insights in HCM have been instrumental in our understanding of disease mechanisms (3), they may be insufficient to fully understand HCM pathology (4).Proteins, as closer proxies to disease phenotypes, capture both genetic and environmental influences, making them critical for understanding disease biology.Proteomics-the systematic study of proteins-has emerged as a powerful tool to uncover novel biomarkers, elucidate disease heterogeneity, and identify new drug targets.Recent advances in proteomic technologies now enable the measurement of thousands of proteins in blood samples, facilitating comprehensive proteomic profiling across large cohorts to identify novel risk markers and illuminate disease biology (5,6).In this issue of the journal, Akita et al. perform plasma proteomic profiling of over 5,000 proteins to identify distinct pathways and protein signatures associated with HCM compared to other etiologies of left ventricular hypertrophy (LVH), including hypertension, aortic stenosis, and transthyretin (TTR) cardiomyopathy (7).The authors highlight biological processes that appear specific to the development of HCM based on proteomic comparisons between these LVH phenotypes.Notably, they identify dysregulation of the mitogenactivated protein kinase (MAPK) and hypoxia-inducible factor-1 (HIF-1) pathways in HCM.In a prior proteomics study featuring a smaller proteomic platform, the authors found the RAS/MAPK pathway to be dysregulated in HCM compared to hypertensive LVH controls (8).The current study builds on these findings, identifying the dysregulation of MAPK pathway -a key signaling pathway involved in the development of cardiac hypertrophy-in HCM, using an expanded proteomic platform with comparisons across additional LVH phenotypes.The HIF-1 pathway, which plays a role in cellular adaptations