By 1995, the three major LQT1, 2, and 3 genetic loci were identified, and shortly thereafter it was appreciated that the ECG manifestations and the clinical course of LQTS were different among the three common genotypes. Each of the three long QT syndrome genotypes was associated with somewhat distinctive ECG repolarization features.5
Among affected individuals, the QTonset-c was unusually prolonged in those individuals with LQT3 mutations (lead II QTonsetc
: LQT1, 243 ±73 ms; LQT2, 290 ±56 ms; LQT3, 341 ±42 ms; p<0.001); Tamplitude was generally quite small in the LQT2 genotype (lead II Tamplitude, mV: LQT1, 0.37 ±0.17; LQT2, 0.13 ±0.07;LQT3, 0.36 ±0.14; p<0.001); and Tduration was particularly long in LQT1 genotype (lead II Tdurationc
, ms: LQT1, 262 ±65; LQT2, 191 ±51; LQT3, 187 ±33; p<0.001).
Life-threatening cardiac events tend to occur under specific circumstances in a gene-specific manner ().6
LQT1 patients were shown to experience 68% of their lethal events during exercise, whereas most LQT2 and LQT3 patients experience lethal events during rest/sleep, respectively.6
The triggering role of sympathetic activation in LQT1 patients has important therapeutic implications, as it suggests that protection could be expected by the use of anti-adrenergic interventions. It should also be noted that although most events in LQT2 and LQT3 patients occur at rest or during sleep, the triggers associated with lethal events for LQT2 and LQT3 patients show a different pattern since LQT2 patients are particularly sensitive to startling and sudden noises, such as a telephone or alarm clock ring ().6
Figure 1 Triggers for lethal cardiac events according to 3 genotypes. Numbers in parentheses indicate number of triggers, not number of patients. (Reproduced with permission; Fig. 1 from Schwartz PJ, et al. Genotype-phenotype correlation in the long-QT syndrome: (more ...)
In the 246 genotyped patients reported by Zareba, et al.3
the frequency of cardiac events was significantly higher among subjects with mutations at the LQT1 locus (63 percent) or the LQT2 locus (46 percent) than among subjects with mutations at the LQT3 locus (18 percent) (). However, the likelihood of dying during a cardiac event was significantly higher among families with mutations at the LQT3 locus (20 percent) than among those with mutations at the LQT1 locus (4 percent) or the LQT2 locus (4 percent).
Figure 2 Kaplan-Meier estimate of the cumulative probability of an LQTS-related cardiac event in LQT1, LQT2, and LQT3 genotyped patients. Reproduced with permission; Fig. 2 from Zareba W, et al. Influence of genotype on the clinical course of the long-QT syndrome. (more ...)
The genotypic risk is also influenced by age and sex of the patient. Priori, et al showed that the genotype of the causative mutation affects the clinical course of the long-QT syndrome and modulates the effects of the QTc and sex on clinical manifestations.7
Goldenberg, et al.8
reported in children age 1 to 12 years that the three major LQTS genotypes were associated with similar risks for life-threatening cardiac events after adjustment for clinical factors (LQT1 vs. LQT2: hazard ratio = 1.61, p=0.56; LQT3 vs. LQT2: hazard ratio = 2.37; p=0.49). Similar risk results were observed for the three genotypes during adolescence.9
However, in adults age 18 to 40 years, patients with the LQT2 genotype had a significantly higher cardiac event rate than patients with the other two genotypes, and this was especially so in women.10
The risk by genotype was also examined in female patients during their childbearing years.11
Compared with a time period before a woman’s first conception, the pregnancy time was associated with a reduced risk of cardiac events (hazard ratio 0.28, p=0.01), whereas the 9-month postpartum time had an increased risk (hazard ratio 2.7, p<0.001). Genotype analysis showed that women with the LQT2 genotype were more likely to experience a post-partum cardiac event than women with the LQT1 or LQT3 genotype (). In the only study looking at the clinical course of patients older than 40 years, Goldenberg, et al. showed that LQT3 genotype carriers exhibited the highest cumulative lethal event rate (35%) compared with LQT2, LQT1, and genotype negative subjects (24% and 14%, and 10%, respectively; p=0.001).12
Figure 3 Annualized LQTS-related cardiac event rates by genotype in LQT1, LQT2, and LQT3 genotyped patients for defined pregnancy-related time periods. None of the 12 LQT3 women had a cardiac event during the post-postpartum period. (Reproduced and modified with (more ...)
A summary of the risk of cardiac events by the LQT1, 2, and 3 genotypes for four different age groups is presented in . The risk for cardiac events is augmented in female LQT2 patients in age 20-40 years and in LQT3 patients over age 40 years.
Risk for Aborted Cardiac Arrest or LQTS Death by Genotype and Age