Abstract 20006: RNA Sequencing of Human Hypertrophic Cardiomyopathy Tissue Reveals Diverse Pathways Modulating the Myocardial Tissue Microenvironment

Abstract

Introduction: Hypertrophic Cardiomyopathy (HCM) is a common inherited cardiac disease and cause of sudden death in adolescents and young adults. Despite significant advances in understanding the genetic underpinnings of HCM, there remains an incomplete understanding of how myofilament mutation carriers and non-carriers ultimately develop myocardial hypertrophy. Hypothesis: Human hypertrophic cardiomyopathy tissue differentially regulates gene expression involved in cellular growth. Methods: RNA was extracted from 5 control human septal tissue samples and 8 HCM septal tissue samples. The HCM tissue samples were from both myofilament mutation positive and negative patients. RNA sequencing was performed using Illumina HiSeq 2500 at a depth of 30 million paired-end reads per sample. Sequencing data was aligned to the hg19 genome using TopHat (splice-aware aligner). Cufflinks was used to estimate transcript abundance and differential expression. Pathway enrichment analysis was carried out on significant genes (q<0.05) using DAVID (v6.7). Only pathways with an enrichment score greater than 2 were evaluated. Results: Cluster and principal component analysis showed highly distinct RNA expression signatures between control and HCM tissues. There were 1500 differentially expressed sequences (q<0.05), which included 1286 annotated genes, 168 novel isoforms, and 46 long noncoding RNA sequences. Gene functional classification revealed 40 differentially regulated gene clusters in HCM tissue compared to controls. The most enriched gene clusters induced in human HCM tissue were associated with secreted peptides involved in promoting cell growth and modulation of extracellular structure (enrichment scores > 10). Highly enriched gene clusters that were suppressed in human HCM tissue were associated with secreted peptides involved in regulating inflammation and immune defense response (enrichment scores > 5). Conclusion: Our data reveals human HCM tissue differentially regulates a diverse array of genes involved in regulation of the myocardial tissue microenvironment. The strong similarity in gene expression across HCM samples suggests shared pathophysiological mechanisms independent of the underlying genetic etiology.