Abstract 16452: Determinants of Vt Occurrence in Patients With Nonischemic and Dilated Cardiomyopathy: Insights From the Study of Explanted Human Hearts
Introduction: The molecular and cellular determinants of ventricular tachycardia (VT) in patients with non-ischemic dilated cardiomyopathy (NIDCM) remain poorly defined.
Hypothesis: Patients with idiopathic NIDCM and significant VT display different tissue and electrical remodeling when compared to other NIDCM patients with end stage heart failure but no history of ventricular arrhythmias.
Methods: History of clinically-significant VT was defined as symptomatic VT, cardiac arrest with documented VT/ventricular fibrillation or appropriate defibrillator shocks. A total of 21 explanted hearts were analyzed (VT=10, no VT=11) in a double-blind, case control study design. The molecular, cellular and histological features of adverse myocardial remodeling were assessed.
Results: The two groups were closely matched in sex (male= 80% vs 72%), LVEF (20.8% vs 20.6%, p=0.6), LVAD use (4/10 vs 6/11, p=0.66), and optimal medical therapy. Explanted hearts from patients with VT showed greater hypertrophic changes based on cardiomyocyte cross-sectional area and expression of disease markers, and increased myocardial fibrosis assessed by picrosirius red and Movat pentachrome staining. The increased myocardial fibrosis extended into the left ventricular and right ventricular outflow tract regions in hearts with VT. Analysis of cardiac connexin-43 levels and distribution showed increased levels in the VT group. mRNA microarray analysis of gene expression in the LV free wall revealed several families of genes expressed in the nuclear, cytoplasmic and extracellular regions which were differentially upregulated or downregulated in hearts with significant VT versus controls. Notably, we identified 4 ion channels whose expression was differentially regulated with reduced expression of Ca2+-activated K+ channel and increased expression of the transient receptor potential cation channel 7 (TRP7) and intracellular chloride channel 3 (ClC3).
Conclusions: In explanted human hearts with NIDCM, presence of significant VT is associated with greater hypertrophy and increased myocardial fibrosis, and differential gene expression signature indicative of a distinctive pattern of adverse myocardial remodeling leading to ventricular arrhythmias.
Author Disclosures: L. Valtuille: None. N. Parajuli: None. K.S. Famulski: None. P.F. Halloran: None. S. Consolato: None. G.Y. Oudit: Research Grant; Significant; Canadian Institute of Health Research (CIHR).
- © 2014 by American Heart Association, Inc.