Abstract 17568: Arrhythmogenic Myocardial Remodeling in Adults with Surgically Corrected Tetralogy of Fallot
Introduction: Adults after repair of Tetralogy of Fallot (ToF) have an increased risk of heart failure, arrhythmias and sudden death.
We hypothesize that electrophysiological remodeling of the right atrium (RA), right ventricle (RV) and right ventricular outflow tract (RVOT) is responsible.
Methods: We collected RA, RV and RVOT biopsies from 10 ToF patients (6 male) at the time of pulmonary valve replacement. Biopsies were also taken from 9 control patients (4 male) with left ventricular outflow tract obstruction without evidence of septal defects, previous arrhythmia or right-sided heart disease. We performed: (i) extracellular matrix (ECM) quantification; (ii) RT-qPCR to quantify mRNA for ion channels, transporters, connexins, inflammatory markers and ECM constituents; (iii) proteomics (liquid chromatography and mass spectrometry (MS)) on 6 patients per group to quantify ~1600 proteins; and (iv) Western Blot for selected proteins.
Results: Mean age at surgery was 32±4 and 22±2 years in the ToF and control groups respectively. There were significant changes in the relative abundance of mRNAs for ion channels, adrenergic receptors, ECM, and heart failure markers (ANP and BNP) in ToF patients compared with controls. MS highlighted over 300 significant differences, specifically changes in proteoglycans and downregulation of mitochondrial respiratory complexes 1 and 3 in ToF patients compared with controls. No significant difference in fibrosis on histological analysis between the two groups was seen. A selection of changes is displayed in Table 1.
Conclusion: The RA and RVOT undergo significant remodeling in ToF. Changes in ion channels, transporters and Ca2+-handling (especially SERCA2A, RYR2, Calsequestrin) as well as gap junction proteins (Cx43) are likely to alter ionic currents, with increased arrhythmia risk. This remodeling is similar to changes in heart failure and ischemia-reperfusion and may contribute to the arrhythmias seen in ToF.
Author Disclosures: H. Schneider: None. O. Monfredi: None. L. Murfitt: None. H. Bennett: None. I.P. Temple: None. D. Knight: None. R. O’Cualain: None. H. Dobrzynski: None. J. Selley: None. P. Sharma: None. G. Hart: None. A. Kitmitto: None. A.J. Hoschtitzky: None. M.R. Boyett: None. V.S. Mahadevan: None.
- © 2014 by American Heart Association, Inc.