Short QT Syndrome as a genetically heterogenous disease, but mainly due to mutations in three genes (KCNH2, KCNQ1 and KCNJ2) encoding for potassium channels (IKs, IKr and IK1) leading to gain of function and accelerated repolarization with shortening of the action potentials in both atria and ventricles, and consequently shortening of the QT interval.
Shortening of refractoriness is one of the key elements in the re-entry mechanism behind many arrhythmias and likely the main reason for the increased propensity to atrial and ventricular fibrillation seen in SQTS, but it has also been shown that the abbreviation of the action potential can effect different cells differently leading to dispersion of refractoriness as an additional arrhythmogenic factor. The discrepancy between heart rate and QT interval duration in patients with Short QT Syndrome is most pronounced during bradycardia and at least two observations suggest that the potential for developing life-threatening tachy-arrhythmias is highest at slow heart rates. In a report by Yaxun Sun and coworkers of a Chinese family with Short QT Syndrome all 4 patients dying suddenly, died during sleep, and the first patient with Short QT Syndrome reported being saved from VF by an ICD also had the episode at night during sleep. However, in the follow-up study by Giustetto et al. it was not possible to find a uniform trigger for arrhythmic events since cardiac arrest and syncope occurred both at rest and during effort.