In the LQT1 and LQT2 syndromes, the fundamental arrhythmogenic triggering mechanisms are linked to the decreased outward potassium currents. The loss of function in potassium currents results in ventricular repolarization delay increasing the window of vulnerability to ar-rhythmia. It facilitates the triggering of early after-depolarization (EAD) through increased repolarization heterogeneity: global heterogeneity sets conditions for sustained arrhythmia while increased transmural dispersion of action potentials provides a substrate for reentry and prolongs the time window for calcium channels to remain open.
Triggers for LQT1 and LQT2 patients are associated with adrenergic activation, nonetheless, differences are observed. Clinical cases of cardiac events in LQT1 patients generally preceded by exercise or swimming. In LQT2, increased adrenergic tone plays an important role too, but cardiac events in these patients are mainly associated with emotional stress or exposure to auditory stimuli 10–12
and suggest a somewhat different mechanism of arrhythmia generation. Consistently to genotyped specific mechanism, pause induced EADs have been shown to precede TdP for LQT2 but not LQT1 patients13
. The slow component of the potassium repolarizing current (IK s
) is strongly stimulated by activation of β-adrenergic receptors via increase in intracellular cAMP concentrations and activation of protein kinase A (PKA).14
The β-adrenergic stimulation increases IKs
and results in rate dependent action potential shortening A decrease in IKs
function due to mutations associated with LQT1 is expected to disrupt this rate dependent regulation. During exercise, delay of the repolarization at high heart rates combined with an increase in sympathetically activated calcium channel function may predispose to arrhythmias. For LQT2, increase calcium release that follows a pause in rhythm, combined with a prolonged repolarization due to decrease in IKr
function, may contribute to EAD generation, beta-adrenergic activation of IKs
may not be fast enough during acute emotional stress and auditory stimuli to compensate for the decreased mutant IKr currents. Local release of catecholamines and catecholamine-induced EADs have been reported in LQTS patients15
, and may represent the primary arrhythmogenic mechanism in these LQTS type.
It is noteworthy that different mutations within the same gene (hERG or KCNQ1) can lead to different phenotypic expression and carry different level of risks. An increasing number of investigations support the concept that certain mutations, their location, and their topology, are more arrhythmogenic than others (pore, non-pore region 10
, transmembrane or cytoplasmic domains).16–18
These emerging investigations are likely to unravel further the arrhythmogenic mechanisms involved in these syndromes.
In the acquired and congenital forms of the long QT syndrome, there is a clear clinicalconsensus about the boundary for QTc interval duration (>500msec) above which the risk for ventricular arrhythmias is of concern. However, the definition of a lower boundary of QTc in the SQTS and its association with increased cardiac risk is less clear. The threshold for the lower boundary of QTc suggesting the syndrome was, in earlier work, described by the ratio of QT/QTp ≤ 80% 19
, with QTp being the predicted QT based on Rautaharju’s formula 20
. While in an earlier report, Viskin et al. proposed gender-specific thresholds of QTc: <360 msec in males and QTc <370 msec in females, based on 28 patients with idiopathic VF. Another example of a remarkable endeavor to define QTc shortening threshold for the SQTS is from Watanabe et al. This group conducted a large retrospective analysis of ECGs in a general hospital (Nigaata, Japan) from a database consisting of 86,068 ECGs acquired between 2003 and 2009. The patients without history of cardiac events or cardiovascular disease, or any medication were reviewed for short QTc interval. Forty four individuals were found with QTc <330 msec representing 0.3% of this population.21
This group was compared to a group of patients with QTc <360msec and documented ventricular fibrillation, resuscitated SDC and syncope, or SQTS genotyping. The electrocardiographic parameters such as QT apex, TpTe interval and QTc interval were compared between these two groups. The T-peak to T-end interval prolongation was the most significant parameter between these two groups, but not the QTc interval. Today, a QTc <320 msec is definitely accepted as an abnormal QTc value 20
, yet the prevalence of a short QT interval in 12-lead standard resting ECGs of the general population is not systematically associated with cardiac risk. As reported by Anttonen et al. in a group of middle-aged randomly selected individuals from Finland (N=10,957), 0.1% of the studied population was associated with QTc <320 msec , and this short QT was not associated with life-threatening events. This lack of association between abnormally shorten QTc interval and cardiac events was confirmed by another large independent study from Japan 22
, published shortly after, in which 26,350 ECGs were reviewed. Using a QTc <300 msec threshold, 0.03% of the population exhibited a short QT interval, and none of these individuals had the dangerous clinical symptoms of the SQTS. Consequently, the short QT interval in the SQTS seems to be a phenotypic expression lacking association with ar-rhythmia risks. Importantly, one would note the use of heart rate correction formula and the method used for measuring the QT interval may have non-negligible effect in the studies that have described the abnormal lower boundary for QTc interval in the SQTS.
Interestingly, an electrocardiographic pattern associated with the SQTS, and commonly reported, is the lack of an ST segment and the presence of peaked and tall T-waves. Unfortunately, none of the reports investigating short QT reported information related to T-wave amplitude or other morphological aspect of the T-wave. The late portion of the T-wave i.e. the T-peak to T-end interval (TpTe) is statistically prolonged in most SQTS reports; so the role of repolariza-tion heterogeneity (global or transmural) as the primary arrhythmogenic mechanism involved in the SQTS syndrome may carry more clinically relevant information than the QT/QTc interval duration. I will discuss two aspects: transmural dispersion associated with the shortening of the actions potentials and early repolarization patterns.