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, Glenn I. Fishman

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Article number12966
JournalNature Communications
Volume7
DOIs
Publication statusPublished - Oct 4 2016

Fingerprint

deletion
Gene Deletion
genes
Heart Failure
Genes
conduction
Temperature
causes
Fever
Fibroblast Growth Factors
Sodium Channels
fever
Body Temperature
Cardiac Myocytes
Action Potentials
temperature
Cardiac Arrhythmias
Sodium
deactivation
Injections

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Park, D. S., Shekhar, A., Marra, C., Lin, X., Vasquez, C., Solinas, S., ... Fishman, G. I. (2016). Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nature Communications, 7, [12966]. https://doi.org/10.1038/ncomms12966

Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. / Park, David S.; Shekhar, Akshay; Marra, Christopher; Lin, Xianming; Vasquez, Carolina; Solinas, Sergio; Kelley, Kevin; Morley, Gregory; Goldfarb, Mitchell; Fishman, Glenn I.

In: Nature Communications, Vol. 7, 12966, 04.10.2016.

Research output: Contribution to journalArticle

Park, DS, Shekhar, A, Marra, C, Lin, X, Vasquez, C, Solinas, S, Kelley, K, Morley, G, Goldfarb, M & Fishman, GI 2016, 'Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure', Nature Communications, vol. 7, 12966. https://doi.org/10.1038/ncomms12966
Park DS, Shekhar A, Marra C, Lin X, Vasquez C, Solinas S et al. Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nature Communications. 2016 Oct 4;7. 12966. https://doi.org/10.1038/ncomms12966
Park, David S. ; Shekhar, Akshay ; Marra, Christopher ; Lin, Xianming ; Vasquez, Carolina ; Solinas, Sergio ; Kelley, Kevin ; Morley, Gregory ; Goldfarb, Mitchell ; Fishman, Glenn I. / Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. In: Nature Communications. 2016 ; Vol. 7.
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