Short QT Syndrome: A New Genetic Cause of Sudden Death

We discussed long QT syndrome (LQTS) in the January issue of EP Lab Digest.^1-6 Briefly, most patients (90%) with LQTS harbor a genetic mutation in their DNA which renders the cardiac potassium channel (IKs or IKr; slow versus rapid) non-functional. The potassium channel should open and close, but these mutations cause a loss of function to the channel, or the potassium channel is always closed. Patients with LQTS usually show a prolonged QTc interval on ECG (QTc > 450 ms) and may experience sudden death, aborted cardiac arrest, or syncope.^1-6 Although it is an autosomal dominant disorder, most symptomatic patients are females. The disorder is treated with defibrillator (ICD) implantation or beta-blocker therapy, depending on the severity of the symptoms. Short QT syndrome is basically the opposite of long QT syndrome. SQTS was mentioned briefly by Dr. Gussak and colleagues in 2000.⁷ It has been described in greater detail in a total of three white (European descent) families by one research group.⁸ These families present with a long family history of unexplained sudden death or cardiac arrest, paroxysmal atrial fibrillation, and very short QTc interval (QTc 9 Because the affected families were too small, the authors performed a focused search for the SQTS mutations among the known LQTS genes. In an elegant piece of work, they found missense mutations in the S5-P loop region of the cardiac IKr channel HERG in two of the three SQTS families. They performed patch-clamp analysis on these mutations to see how they affected the function of the potassium ion channel. Briefly, patch-clamp analysis is a laborious molecular lab technique to study an ion channel s function (ability to transmit ion current). The authors generated each family s SQTS mutation they had found, placed the mutations into larger gene vectors, and put those vectors into HEK cells (human embryonic kidney cells). They measured the amount of potassium current across the cells in normal HEK cells and in those with the SQTS mutations. Interestingly, the two SQTS mutations that have been identified cause a gain of function in the IKr (HERG channel) potassium channel, or the HERG potassium channel is always open. It is the exact opposite of what LQTS does! What these mutations do is affect the ability of the cardiac myocyte to repolarize. The mutations increase the repolarizing currents that are working during the early phase of the action potential, which shortens ventricular repolarization and thus shortens the QT interval. Given that this shortening of repolarization is heterogeneous, that would set up the substrate for reentrant arrhythmias like atrial fibrillation or ventricular fibrillation (and sudden death). Indeed, the authors have found that these SQTS patients have shorter atrial and ventricular effective refractory periods than controls, which explains why these arrhythmias can occur.10 In the literature, Dr. Schimpf et al. implanted defibrillators in the affected individuals.¹¹ It's unclear how common short QT syndrome is. We presumably miss many cases of it since we are trained to simply look for a long QT interval on ECG (when we bother to look at the QT interval at all). It likely is rare, but it may be a cause of SIDS or another genetic cause of sudden death.