A Newly Characterized SCN5A Mutation Underlying Brugada Syndrome Unmasked by Hyperthermia

Abstract

Febrile illness has been rarely reported to modulate ST segment elevation in right precordial leads on ECG or even precipitate ventricular fibrillation in patients with Brugada syndrome. We report the case of a patient whose Brugada ECG pattern was unmasked by hyperthermia secondary to acute cholangitis. Serial ECGs showed progressive attenuation of ST segment elevation as body temperature gradually returned to normal. Structural heart disease was ruled out. Intravenous flecainide injection reproduced a less remarkable ST segment elevation. Genetic screening demonstrated a single amino acid substitution (H681P) in the SCN5A gene, thus confirming the diagnosis of Brugada syndrome. In vitro expression of this newly characterized genetic defect revealed novel biophysical abnormalities consisting of a shift in both steady-state activation and inactivation, resulting in a 60% reduction of sodium window current. Thus, SCN5A-H681P mutation induces a significant loss of transmembrane current and is clinically associated with a pathologic phenotype that is elicited by hyperthermia. Overall the observed clinical features are in agreement with previous observations and strongly suggest that fever may be an environmental modifier among Brugada syndrome patients with a detrimental (and possibly arrhythmogenic) effect on cardiac repolarization.

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

“…Thus, temperature fluctuations, rather than fever per se, may explain the proarrhythmic behavior observed in Langendorff-perfused hearts and febrile BrS patients, and conceivably even in BrS patients who develop sudden cardiac death during sleep, when core body temperature may significantly decline (35). It is worth noting that a subset of SCN5A mutations displays biophysical abnormalities that may diminish I Na at elevated temperatures, including the sodium window current (36,37). While we consider it unlikely, it is possible that the truncated protein dominantly influences the biophysical properties of the coexpressed WT α subunit, producing aberrant temperature sensitivity (38).…”

ACC/AHA/ESC 2006 Guidelines for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death

“…Cardiac events (syncope or cardiac arrest) occur predominantly in males in the third and fourth decades of life, although presentation with cardiac arrest in neonates or children have been reported (104,777,820). Fever is a predisposing factor for cardiac arrest in the Brugada syndrome (800,818,(821)(822)(823)(824).…”

A hot topic

“…98 Close monitoring and antipyretic treatment of BrS patients can be recommended as a preventative therapy.…”