Short QT syndrome and atrial fibrillation caused by mutation in KCNH2

BACKGROUND: The short QT syndrome is a newly described clinical entity characterized by the presence of a short QT interval associated with cardiac tachyarrhythmias including sudden cardiac death at a young age in otherwise healthy individuals. A genetic basis has been identified linking the disease to mutations in KCNH2 in the familial forms and a mutation in KCNQ1 in a sporadic form of the disease. METHODS AND RESULTS: We identified a family with short QT syndrome with a high incidence of paroxysmal atrial fibrillation in their members and no known history of sudden cardiac death. QT interval ranged from 225 to 240 ms within normal heart rate ranges in the affected individuals. Programmed electrical stimulation (PES) was performed in all affected members, which revealed a remarkably short atrial and ventricular refractory period, and inducibility of atrial and ventricular fibrillation. Treatment with propafenone has maintained the individuals free of atrial fibrillation to date. Genetic analysis identified a missense mutation (C to G substitution at nucleotide 1764) which resulted in the amino acid change (N588K) in KCNH2. This mutation had been previously described in two other families with a high incidence of sudden cardiac death. CONCLUSIONS: Our study confirms that N588K is a hotspot for familial form of the short QT syndrome. The disease is clinically heterogeneous, as indicated by the fact that, in the three families with the same mutation, there is a wide range of symptoms, varying from atrial to ventricular fibrillation and sudden death. While the implantation of a defibrillator appears warranted due to the inducibility at PES, the clinical follow-up provides indication that the class Ic agent propafenone could be effective to prevent episodes of paroxysmal atrial fibrillation.