**Genetically engineeredSCN5Amutant pig hearts exhibit conduction defects and arrhythmias**

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

¹Leon H. Charney Division of Cardiology and
²Heart Rhythm Center, New York University School of Medicine, New York, New York, USA.
³Exemplar Genetics, Coralville, Iowa, USA.
⁴Fondazione Maugeri IRCCS, Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Address correspondence to: Glenn I. Fishman, Leon H. Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA. Phone: 212.263.3967; E-mail: [email protected].

Submitted: May 7, 2014; Accepted: October 16, 2014; previously published online December 15, 2014

Conflict of interest: Christopher S. Rogers is an employee and shareholder of Exemplar Genetics.

Reference information:J Clin Invest. 2015;125(1):403-412. doi:10.1172/JCI76919.

See the related Commentary beginning on page 99.

Journal of Clinical Investigation 125(1):p 403-412, January 2, 2015. | DOI: 10.1172/JCI76919

SCN5Aencodes the α subunit of the major cardiac sodium channel Na_V1.5. Mutations inSCN5Aare 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 pigSCN5Agene.SCN5A^E558X/+pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfusedSCN5A^E558X/+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 theSCN5A^E558X/+pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.