Short QT syndrome

Baylor College of Medicine, Houston, Texas, United States
Canadian Medical Association Journal (Impact Factor: 5.96). 12/2005; 173(11):1349-54. DOI: 10.1503/cmaj.050596
Source: PubMed


The QT interval on an electrocardiogram signifies the time required for the heart to repolarize after depolarization. It has long been appreciated that a long QT interval predisposes patients to life-threatening ventricular arrhythmia. Short QT syndrome is a newly described disease characterized by a shortened QT interval and by episodes of syncope, paroxysmal atrial fibrillation or life-threatening cardiac arrhythmias. The syndrome usually affects young and healthy people with no structural heart disease and may be present in sporadic cases as well as in families. Our understanding of a new disease has rarely benefitted so quickly from research in genetics, molecular biology and biophysics. It was first described in 2000 in a handful of patients, and since then 3 different genes associated with the disease and the biophysical basis have been described, and therapy has been made available. Here we review the current understanding of the pathophysiology, clinical presentation and treatment of short QT syndrome.

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    • "However, the effects of acyl-CARs on outward currents participating in repolarization (hERG, Kv7.1/minK and KIR2.1 channels) have not been studied. Changes in the activity of these potassium channels are known to be associated with ventricular fibrillation and sudden death [14]–[15]. These arrhythmias could be either due to K+ channel blockade, by drugs or loss-of-function by mutations (long QT syndrome), or due to their activation by hyperkalemia, acidosis, digitalis toxicity, hyperthermia [16], or gain-of-function mutations [17]. "
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    ABSTRACT: In some pathological conditions carnitine concentration is high while in others it is low. In both cases,cardiac arrhythmias can occur and lead to sudden cardiac death. It has been proposed that in ischaemia, acylcarnitine (acyl-CAR), but not carnitine, is involved in arrhythmias through modulation of ionic currents. We studied the effects of acyl-CARs on hERG, K(IR)2.1 and K(v)7.1/minK channels (channels responsible for I(KR), I(K1) and I(KS) respectively). HEK293 cells stably expressing hERG, K(IR)2.1 or Kv7.1/minK were studied using the patch clamp technique. Free carnitine (CAR) and acyl-CAR derivatives from medium- (C8 and C10) and long-chain (C16 and C18:1) fatty acids were applied intra- and extracellularly at different concentrations. For studies on hERG, C16 and C18:1 free fatty acid were also used. Extracellular long-chain (LCAC), but not medium-chain, acyl-CAR,induced an increase of I(hERG) amplitude associated with a dose-dependent speeding of deactivation kinetics. They had no effect on K(IR)2.1 or Kv7.1/minK currents.Computer simulations of these effects were consistent with changes in action potential profile. CONCLUSIONS AND APPLICATIONS: Extracellular LCAC tonically regulates I(hERG) amplitude and kinetics under physiological conditions. This modulation may contribute to the changes in action potential duration that precede cardiac arrhythmias in ischaemia, diabetes and primary systemic carnitine deficiency.
    PLoS ONE 07/2012; 7(7):e41686. DOI:10.1371/journal.pone.0041686 · 3.23 Impact Factor
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    • "The findings of this study have further clinical relevance in a second, perhaps less expected, respect. The attenuated-inactivation N588K–HERG mutant used in this study has been shown recently to underlie the SQT1 familial form of the recently identified genetic ‘Short QT syndrome’, which carries a risk of cardiac arrhythmia and sudden death [27,60]. Pharmacological approaches to correcting the QT-interval of SQT1 patients are currently very limited. "
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    ABSTRACT: HERG (human ether-à-go-go-related gene) encodes channels responsible for the cardiac rapid delayed rectifier potassium current, I(Kr). This study investigated the effects on HERG channels of doxepin, a tricyclic antidepressant linked to QT interval prolongation and cardiac arrhythmia. Whole-cell patch-clamp recordings were made at 37 degrees C of recombinant HERG channel current (I(HERG)), and of native I(Kr) 'tails' from rabbit ventricular myocytes. Doxepin inhibited I(HERG) with an IC(50) value of 6.5+/-1.4 microM and native I(Kr) with an IC(50) of 4.4+/-0.6 microM. The inhibitory effect on I(HERG) developed rapidly upon membrane depolarization, but with no significant dependence on voltage and with little alteration to the voltage-dependent kinetics of I(HERG). Neither the S631A nor N588K inactivation-attenuating mutations (of residues located in the channel pore and external S5-Pore linker, respectively) significantly reduced the potency of inhibition. The S6 point mutation Y652A increased the IC(50) for I(HERG) blockade by approximately 4.2-fold; the F656A mutant also attenuated doxepin's action at some concentrations. HERG channel blockade is likely to underpin reported cases of QT interval prolongation with doxepin. Notably, this study also establishes doxepin as an effective inhibitor of mutant (N588K) HERG channels responsible for variant 1 of the short QT syndrome.
    Biochemical Pharmacology 09/2007; 74(3):425-37. DOI:10.1016/j.bcp.2007.04.024 · 5.01 Impact Factor
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    ABSTRACT: The past 2 decades have witnessed the emergence of many disease states related to ion-channel disorders, the so-called "channelopathies," usually associated with structurally normal hearts. The initial emphasis was directed toward the congenital long QT syndrome and the Brugada syndrome. Recently, the hereditary short QT syndrome has emerged as yet another rare channelopathy. This autosomal dominant syndrome can afflict infants, children, or young adults; often a remarkable family background of sudden cardiac death is elucidated. The electrocardiogram is characterized by a strikingly short QT interval (typically <320 milliseconds); virtual absence of the ST segment; and tall, peaked, narrow-based T waves. There is a marked propensity for paroxysmal atrial fibrillation, and increased risk for sudden cardiac death from ventricular tachyarrhythmias. At electrophysiology study, short atrial and ventricular refractory periods are found, with easily inducible atrial fibrillation and polymorphic ventricular tachycardia with programmed electrical stimulation. Gain-of-function mutations in 3 genes encoding potassium channels have been identified, which explain the abbreviated repolarization seen in this condition. The suggested treatment is an implantable cardioverter-defibrillator, though the possibilities of inappropriate shocks have caused some concern, especially in younger patients. The ability of quinidine and disopyramide to prolong the QT interval has the potential to be effective pharmacological therapy for patients with short QT syndrome, but awaits additional confirmatory clinical data.
    Cardiology in review 11/2009; 17(6):300-3. DOI:10.1097/CRD.0b013e3181c07592 · 2.41 Impact Factor
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