Back to Search
Start Over
Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias
- Source :
- Journal of Clinical Investigation. January, 2015, Vol. 125 Issue 1, p403, 10 p.
- Publication Year :
- 2015
-
Abstract
- SCN5A encodes the a subunit of the major cardiac sodium channel [Na.sub.V]1.5. 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. [SCN5A.sup.E55SX/+] pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused [SCN5A.sup.E55SX/+] 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 [SCN5A.sup.E55SX/+] pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.<br />Introduction The pore-forming subunit of the cardiac sodium channel (NaV1.5; encoded by SCN5A) is a critical determinant of myocardial excitability and conduction. Loss-of-function mutations in SCN5A diminish the magnitude of [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 125
- Issue :
- 1
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.401506588
- Full Text :
- https://doi.org/10.1172/JCI76919