Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias
David S. Park, … , Larry A. Chinitz, Glenn I. Fishman
David S. Park, … , Larry A. Chinitz, Glenn I. Fishman
Published December 15, 2014
Citation Information: J Clin Invest. 2015;125(1):403-412. https://doi.org/10.1172/JCI76919.
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Research Article

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

Abstract

SCN5A encodes the α subunit of the major cardiac sodium channel NaV1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5AE558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5AE558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5AE558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.

Authors

David S. Park, Marina Cerrone, Gregory Morley, Carolina Vasquez, Steven Fowler, Nian Liu, Scott A. Bernstein, Fang-Yu Liu, Jie Zhang, Christopher S. Rogers, Silvia G. Priori, Larry A. Chinitz, Glenn I. Fishman

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Figure 2

Electrophysiological analysis of SCN5AE558X/+ pigs at baseline and during sodium channel blocker challenge.

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Electrophysiological analysis of SCN5AE558X/+ pigs at baseline and durin...
(A) Representative ECG traces (lead II) of WT and SCN5AE558X/+ pigs. (B) Average P and QRS wave duration, as well as average PR and JTc intervals at baseline, in WT (n = 18, age 17 ± 5 months) and SCN5AE558X/+ (n = 19, age 16 ± 5 months) pigs. *P < 0.001. (C and D) Comprehensive EPS was performed on WT (n = 8, age 22 ± 2 months) and SCN5AE558X/+ (n = 8, age 22 ± 1 months) pigs. (C) Average baseline intracardiac intervals. AH, atrial-His; HV, His-ventricular. (D) Average electrophysiological parameters. Basic cycle length (in ms) is shown below. cSNRT, corrected sinus node recovery time; WCL, Wenckebach cycle length, ERP, effective refractory period; AERP, atrial ERP. *P < 0.05; ‡P < 0.00001. (E and F) Flecainide challenge was performed in 2 groups of animals: a young cohort of WT (n = 6, age 4 ± 1 months) and SCN5AE558X/+ (n = 5, age 4 months) pigs, and an adult cohort of WT (n = 5, age 10 ± 1 months) and SCN5AE558X/+ (n = 5, age 15 ± 2 months) pigs. (E) Average P, PR, QRS, and JTc intervals at baseline and after 1 mg/kg flecainide challenge. *P < 0.05; **P < 0.01; †P < 0.001; ‡P < 0.0001. (F) Average PR and QRS increase after 1 mg/kg flecainide challenge. **P < 0.02; ‡P < 0.0001. (G) Representative ECG traces (lead II) in adult WT and SCN5AE558X/+ pigs at baseline and after infusion of 1 mg/kg flecainide. (H) Representative precordial lead ECG of an adult SCN5AE558X/+ pig after administration of 1 mg/kg flecainide.