Peter J. Schwartz

Risk factors for recurrent syncope and subsequent fatal or near-fatal events in children and adolescents with long QT syndrome

OBJECTIVESnWe aimed to identify risk factors for recurrent syncope in children and adolescents with congenital long QT syndrome (LQTS).nnnBACKGROUNDnData regarding risk assessment in LQTS after the occurrence of the first syncope episode are limited.nnnMETHODSnThe Prentice-Williams-Peterson conditional gap time model was used to identify risk factors for recurrent syncope from birth through age 20 years among 1,648 patients from the International Long QT Syndrome Registry.nnnRESULTSnMultivariate analysis demonstrated that corrected QT interval (QTc) duration (≥500 ms) was a significant predictor of a first syncope episode (hazard ratio: 2.16), whereas QTc effect was attenuated when the end points of the second, third, and fourth syncope episodes were evaluated (hazard ratios: 1.29, 0.99, 0.90, respectively; p < 0.001 for the null hypothesis that all 4 hazard ratios are identical). A genotype-specific subanalysis showed that during childhood (0 to 12 years), males with LQTS type 1 had the highest rate of a first syncope episode (p = 0.001) but exhibited similar rates of subsequent events as other genotype-sex subsets (p = 0.63). In contrast, in the age range of 13 to 20 years, long QT syndrome type 2 females experienced the highest rate of both first and subsequent syncope events (p < 0.001 and p = 0.01, respectively). Patients who experienced ≥1 episodes of syncope had a 6- to 12-fold (p < 0.001 for all) increase in the risk of subsequent fatal/near-fatal events independently of QTc duration. Beta-blocker therapy was associated with a significant reduction in the risk of recurrent syncope and subsequent fatal/near-fatal events.nnnCONCLUSIONSnChildren and adolescents who present after an episode of syncope should be considered to be at a high risk of the development of subsequent syncope episodes and fatal/near-fatal events regardless of QTc duration.

Early afterdepolarizations induced in vivo by reperfusion of ischemic myocardium. A possible mechanism for reperfusion arrhythmias.

Recent studies in vitro have shown that afterdepolarizations may develop during reperfusion after hypoxia, thus suggesting that these afterdepolarizations may contribute to the genesis of reperfusion arrhythmias. We recorded monophasic action potentials (MAPs) during myocardial ischemia and reperfusion to investigate whether afterdepolarizations develop in vivo when reperfusion arrhythmias occur. In 15 anesthetized cats, 24 trials of 10 minutes of occlusion of the left anterior descending coronary artery were followed by reperfusion. In 13 of 24 (54%) trials, afterdepolarizations developed at the moment of reperfusion, with a mean amplitude of 2.4 +/- 1.1 mV (13 +/- 8% of MAP amplitude). When cycle length was either increased by vagal stimulation or decreased by atrial pacing, early afterdepolarization (EAD) amplitude was modified, according to what has been described for EAD in vitro, with a positive linear correlation between cycle length and EAD amplitude (r = 0.91, p less than 0.0001). The occurrence of EAD was not related to rapid changes in left ventricular pressure. In the eight of 13 (62%) cases in which EAD development was associated with reperfusion arrhythmias, the coupling interval of the EAD and of premature ventricular contractions showed a significant correlation (r = 0.86, p less than 0.0001). However, in five of 13 (38%) cases, occurrence of reperfusion arrhythmias was not accompanied by the presence of EAD on the MAP recording. In two animals, a 2:1 block of EAD conduction was observed, and this was reflected on the intracavitary electrocardiogram as T wave alternans. Thus, EADs occur frequently after reperfusion in vivo, with a time course that parallels the onset of reperfusion arrhythmias. This finding further supports the role of triggered activity in the genesis of reperfusion arrhythmias in vivo.

Long QT Syndrome: Genotype-Phenotype Correlations

The publication at the end of March 1995 1 2 of the identification of the first two genes involved in the long QT syndrome (LQTS) has had multiple major consequences. It represented a major breakthrough not only for cardiac electrophysiology but also for cardiology as a whole and paved the way for the understanding of how tight the relation between molecular and clinical cardiology can be. Indeed, the impressive correlation between specific mutations and critical alterations in the ionic control of ventricular repolarization has made of LQTS a unique paradigm and the best example to date for the specificity and value of the correlation between genotype and phenotype. It seems fair to say that scores of cardiologists who until the mid-1990s had been unimpressed by the clinical relevance of molecular biology changed their minds largely on the basis of the rapid developments that contributed to unravel this life-threatening disorder, which represents a sort of Rosetta stone for sudden cardiac death. 3 Similarly, many basic science investigators who had not even heard of LQTS became involved in LQTS-related research because of its obvious potential to help elucidate key mechanisms also underlying more common and complex clinical disorders.

Genotype-specific QT correction for heart rate and the risk of life-threatening cardiac events in adolescents with congenital long-QT syndrome

BACKGROUNDnA prolonged QT interval corrected for heart rate (QTc) is a major risk factor in patients with long QT syndrome (LQTS). However, heart rate-related risk in this genetic disorder differs among genotypes.nnnOBJECTIVEnThis study hypothesized that risk assessment in LQTS patients should incorporate genotype-specific QT correction for heart rate.nnnMETHODSnThe independent contribution of 4 repolarization measures (the absolute QT interval, and Bazetts, Fridericias, and Framinghams correction formulas) to the risk of aborted cardiac arrest or sudden cardiac death during adolescence, before and after further adjustment for the RR interval, was assessed in 727 LQTS type 1 and 582 LQTS type 2 patients. Improved QT/RR correction was calculated using a Cox model, dividing the coefficient on log(RR) by that on log(QT).nnnRESULTSnMultivariate analysis demonstrated that in LQTS type 1 patients 100-ms increments in the absolute QT interval were associated with a 3.3-fold increase in the risk of life-threatening cardiac events (P = .020), and 100-ms decrements in the RR interval were associated with a further 1.9-fold increase in the risk (P = .007), whereas in LQTS type 2 patients, resting heart rate was not a significant risk factor (hazard ratio 1.11; P = .51; P value for heart rate × genotype interaction = .036). Accordingly, analysis of an improved QT correction formula showed that patients with the LQTS type 1 genotype required a greater degree of QT correction for heart rate (improved QTc = QT/RR⁰·⁸) than LQTS type 2 patients (improved QTc = QT/RR⁰·²).nnnCONCLUSIONnOur findings suggest that risk stratification for life-threatening cardiac events in LQTS patients can be improved by incorporating genotype-specific QT correction for heart rate.