Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure

David S. Park, Akshay Shekhar, Christopher Marra, Xianming Lin, Carolina Vasquez, Sergio Solinas, Kevin Kelley, Gregory Morley, Mitchell Goldfarb () and Glenn I. Fishman ()
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David S. Park: New York University School of Medicine
Akshay Shekhar: New York University School of Medicine
Christopher Marra: Hunter College of City University
Xianming Lin: New York University School of Medicine
Carolina Vasquez: New York University School of Medicine
Sergio Solinas: University of Sassari
Kevin Kelley: Mouse Genetics Core, Icahn Medical Institute
Gregory Morley: New York University School of Medicine
Mitchell Goldfarb: Hunter College of City University
Glenn I. Fishman: New York University School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract Fever is a highly conserved systemic response to infection dating back over 600 million years. Although conferring a survival benefit, fever can negatively impact the function of excitable tissues, such as the heart, producing cardiac arrhythmias. Here we show that mice lacking fibroblast growth factor homologous factor 2 (FHF2) have normal cardiac rhythm at baseline, but increasing core body temperature by as little as 3 °C causes coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normothermia. FHF2-deficient cardiomyocytes generate action potentials upon current injection at 25 °C but are unexcitable at 40 °C. The absence of FHF2 accelerates the rate of closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation rate to severely suppress cardiac sodium currents at elevated temperatures. Our experimental and computational results identify an essential role for FHF2 in dictating myocardial excitability and conduction that safeguards against temperature-sensitive conduction failure.

Date: 2016
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DOI: 10.1038/ncomms12966

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