Loss-of-function long QT (LQT) mutations inducing LQT1 and LQT2 syndromes have been successfully translated to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) used as disease-specific models.
The study included 59 LQT1 and 72 LQT2 patients from the Rochester-based LQTS Registry with corrected QT (QT<sub>c</sub>) prolongation and a history of AD therapy.
A follow-up study covering a mean of 18.6 ± 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years.
The calculated QT intervals at an RR interval of 1200 ms were longer in the KCNE1(G38S) carriers and LQT1 and LQT2 patients than in the control subjects.
The present findings suggest that beta-blocker therapy should be routinely administered to all high-risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy.
The degree of QTc prolongation during exercise was greater in LQTS patients (LQT1 80 ± 47 ms, LQT2 64 ± 41 ms, Control 46 ± 20 ms, P = 0.02), with significant differences between LQT1 and LQT2 patients observed at heart rates ≥ 60% of the predicted maximum (P < 0.05).
Conversely, the LQT2 patients began recovery at its lowest mean QTc of 420 +/- 10 ms, which increased by 40 +/- 16 ms. At the end of recovery, a QTc cut-off value of 445 ms distinguished 92% of LQTS patients from unaffected controls, while a start-of-recovery QTc cut-off of 460 ms correctly identified genotype in 80% of LQT1 and 92% of LQT2 patients.
More recently, mutation site-specific differences in the clinical phenotype have been reported in LQT1 and LQT2 patients, indicating the possibility of mutation site-specific management or treatment.
Although the QTc interval also was longer in symptomatic patients, only the maximal amplitude ratio between late and early T-wave peaks was independently associated with symptoms in both LQT1 and LQT2 patients.
Overall, phenylephrine exerted no significant effect on either QTd or Tp-e except with subgroup analysis of symptomatic LQTS where LQT1 and LQT2 patients had a divergent response with TDR.
CONCLUSIONS; Age and gender have different, genotype-specific modulating effects on the probability of cardiac events and electrocardiographic presentation in LQT1 and LQT2 patients.
Combining measures for QT duration, rate dependence, and QT end - QT apex interval, derived from Holter recordings, complements the clinical differentiation between LQT1 versus LQT2 patients and between affected and unaffected persons for genotype screening purposes.
The QTc was much less prolonged at peak of epinephrine in LQT3 (478+/-44 to 532+/-41 ms; P<0.05, +11%) and controls (394+/-21 to 456+/-18 ms; P<0.0005, +16%) than in LQT1 and LQT2 patients, and shortened to the baseline levels (LQT3; 466+/-49 ms, -3%, controls; 397+/-16 ms, +1%; P=ns vs baseline) at steady state.
Until definitive data become available, antiadrenergic therapy remains the mainstay in the management of LQTS patients, however it may be soon worth considering the addition of a Na+ channel blocker such as mexiletine for LQT3 patients and of interventions such as K+ channel openers or increases in the extracellular concentration of potassium for LQT1 and LQT2 patients.