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.
Highlights
Fever is a highly conserved systemic response to infection dating back over 600 million years
Elevation in core body temperature by fever or external heating[3] is a known trigger for ventricular fibrillation/malignant syncope in patients with Brugada syndrome (BrS)[4], an inherited arrhythmia condition diagnosed by characteristic electrocardiographic (ECG) abnormalities in the right precordial leads
Fhf2KO mice have normal cardiac rhythm at baseline, but exhibit temperature-sensitive electrocardiographic changes, including coved-type ST elevations and progressive conduction failure that is fully reversible upon return to normal body temperature
Summary
Fever is a highly conserved systemic response to infection dating back over 600 million years. 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. Biophysical analyses of mutant sodium channels from febrile BrS patients have not identified a unifying mechanism for the temperature-sensitive phenotype[6,7]. These data suggest that factors in addition to SCN5A are playing important roles in regulating the sodium current that predispose BrS patients to fever-induced arrhythmias. Our experimental and computational results demonstrate that FHF2 is a key regulator of myocardial excitability, protecting the heart against conduction failure under hyperthermic conditions
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