Abstract
BACKGROUND: Hypertrophic cardiomyopathy (HCM) is caused by mutations in genes coding for proteins essential for myocardial contraction. However, it remains unclear through which signaling pathways these gene mutations mediate HCM pathogenesis. Growing evidence indicates that microRNAs (miRNAs) play an important role in the regulation of gene expression. We hypothesized that transcriptomics profiling of plasma miRNAs would reveal circulating biomarkers and dysregulated signaling pathways in HCM. METHODS: We conducted a multicenter case-control study of cases with HCM and controls with hypertensive left ventricular hypertrophy. We performed plasma transcriptomics profiling of miRNAs using RNA sequencing. We developed a transcriptomics-based discrimination model using samples retrieved during the first two-thirds of the study period at one institution (training set). We prospectively tested its discriminative ability in samples collected thereafter from the same institution (prospective test set). We also externally validated the model by applying it to samples collected from the other institutions (external test set). We executed pathway analysis of dysregulated miRNAs with univariable P<0.05. RESULTS: This study included 555 patients (392 cases and 163 controls). One thousand one hundred forty-one miRNAs passed our quality control filters. The area under the receiver operating characteristic curve of the transcriptomics-based model derived from the training set was 0.86 (95% CI, 0.79-0.93) in the prospective test set and 0.94 (95% CI, 0.90-0.97) in the external test set. Pathway analysis revealed dysregulation of the Ras-MAPK (mitogen-activated protein kinase) pathway and pathways related to inflammation in HCM. CONCLUSIONS: This study utilized comprehensive transcriptomics profiling with RNA sequencing in HCM, revealing circulating miRNA biomarkers and dysregulated pathways.