Abstract
Surgical repair of TOF is highly successful but may be complicated in adulthood by arrhythmias, sudden death, and right ventricular (RV) dysfunction. RV overload leads to interventricular septum (IVS) bulging and paradoxical movement but its contribution to RV dysfunction and arrhythmias remains unclear. We aimed at characterizing IVS remodeling in a pig model of RV volume overload and a model of repaired TOF with combined pressure and volume overload. Young piglets underwent surgery to induce RV volume overload (PINS, N = 5) or combined volume and pressure overload (rTOF, N = 5) and were compared to Sham animals (SHAM, N = 5). Animals came back for terminal experiments 4 months post-surgery. Cardiac function was assessed using MRI. Animals were euthanized, tissue samples were collected for molecular biology or fixed for histological analysis. RV end-systolic and diastolic volumes were increased and RV ejection fraction was decreased in rTOF and PINS pigs ( P < 0.05). MRI cine images also revealed leftward IVS bulging and paradoxical contraction in rTOF and PINS pigs which was absent in SHAM pigs. Heart weight to body weight ratio was increased by 22% in PINS and 38% in rTOF pigs as a result of RV and IVS hypertrophy. BNP mRNA expression was increased in rTOF but not in PINS IVS. KCND3 mRNA expression was decreased in the IVS of rTOF and PINS pigs as observed in the RV of rTOF pigs and this was confirmed at the protein level ( P < 0.05). Moreover, we found a decrease in KCNJ2 expression in the rTOF IVS ( P < 0.05). Protein levels for Connexin-40 were reduced in rTOF and PINS IVS ( P < 0.05) while Connexin-43 expression did not change. These results suggest the presence of a pro-arrhythmic remodeling of the IVS in the overloaded RV which may lead to prolonged repolarization and increased excitability. Interestingly the conduction system may also be remodeled as indicated by the decrease in Connexin-40 expression.
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