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
(A) Spontaneous or pacing-induced VF events recorded using 2 perfusion protocols: immediate perfusion at 39°C (protocol 1), or initial perfusion temperature at 35°C with a slow ramp to 37°C (protocol 2). (B) Representative spontaneous ventricular arrhythmias in SCN5AE558X/+ hearts recorded on volume-conducted ECG. Scale bar: 1 second. (C) Brightfield image of the RV free wall. Scale bar: 2 cm. Sequential activation maps were recorded in an SCN5AE558X/+ heart during an episode of VF. Numbers indicate the relative start time of activation maps in each panel. Volume-conducted ECG of tachycardia is shown below. Scale bar: 1 second. (D) Representative TTC staining of WT and SCN5AE558X/+ hearts after Langendorff perfusion.