title: Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure.
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.
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: Akshay
authors.initials: A
authors.lastname: Shekhar
authors.affiliation: Hunter College of City University, Department of Biological Sciences, Room HN810, 695 Park Avenue, New York, New York 10065, USA.|Graduate Center of City University, Neuroscience Subprogram, 365 Fifth Avenue, New York, New York 10016, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Marra
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Lin
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Vasquez
authors.affiliation: University of Sassari, Department of Biomedical Science, Viale San Pietro 43/c, 07100 Sassari, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Solinas
authors.affiliation: Mouse Genetics Core, Icahn Medical Institute, 1425 Madison Avenue, New York, New York 10029, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Kelley
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Morley
authors.affiliation: Hunter College of City University, Department of Biological Sciences, Room HN810, 695 Park Avenue, New York, New York 10065, USA.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Goldfarb
authors.affiliation: The Leon H Charney Division of Cardiology, New York University School of Medicine, 522 First Avenue, Smilow 801, New York, New York 10016, USA.
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
mesh_terms: D000200:Action Potentials; D000483:Alleles; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D003198:Computer Simulation; D004452:Echocardiography; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D057809:HEK293 Cells; D006321:Heart / Q000502:physiology; D006339:Heart Rate; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000378:metabolism; D012984:Software; D013696:Temperature
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568321:Scn5a protein, mouse; C108111:fibroblast growth factor 13; D005346:Fibroblast Growth Factors