[HTML][HTML] Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

DS Park, M Cerrone, G Morley… - The Journal of …, 2015 - Am Soc Clin Investig
DS Park, M Cerrone, G Morley, C Vasquez, S Fowler, N Liu, SA Bernstein, FY Liu, J Zhang…
The Journal of clinical investigation, 2015Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation