Transcriptional Profiling of Septal Wall of the Right Ventricular Outflow Tract in Patients with Idiopathic Ventricular Arrhythmias

Abstract

Frequent, monomorphic premature ventricular contractions (PVC) and/or ventricular tachycardia (VT) in patients with structurally normal heart usually arise from the right ventricular outflow tract (RVOT). The underlying arrhythmogenic substrate for the genesis of RVOT tachycardias is largely unknown. The aim of this study was to investigate the genome-wide transcriptional profiling of the septal wall of the RVOT in patients with RVOT tachycardia and control subjects. Transcriptional profiling with Affymetrix 3' IVT microarray analysis (Affymetrix, Santa Clara, CA, USA) was performed on the endomyocardial biopsy samples obtained from the septal wall of the RVOT from three unrelated patients with RVOT tachycardia and three control subjects. All study subjects had normal right and left ventricular size and function. Microarray results were validated by real time polymerase chain reaction (PCR). There were 32 statistically significant up-regulated and 60 down-regulated genes in five biological networks in patient population compared with control subjects. Among those genes, there were eight down-regulated [ATP1A2, CACNA1C, Protein Phosphatase 2, Regulatory Subunit B, Gamma Isoform[PPP2R2C], PLCD3, GNAO1, Solute Carrier Family 6 (Transporter, Norepinephrine), Member 2(SLC6A2), CAMK2B, PIK3R2] and two up-regulated (CAMKK2 and ITPR3) genes related to myocardial intracellular calcium regulation. In addition, there were five down-regulated [T-box 3(TBX3), Bone Morphogenetic Protein 2(BMP2), Bone Morphogenetic Protein Receptor, Type IB(BMPR1B), MYH6, Ankyrin Repeat Domain 23 and 39(ANKRD23-39)] and one up-regulated gene (RGS1) related to cardiovascular functions. The expression of genes responsible for the regulation of myocardial intracellular calcium and the development of RVOT are significantly down-regulated in the septal wall of the RVOT in patients with RVOT tachycardia compared with control subjects.