RESUMEN
Background: Congenital long-QT syndrome (LQTS) is a major cause of sudden cardiac death (SCD) in young individuals, calling for sophisticated risk assessment. Risk stratification, however, is challenging as the individual arrhythmic risk varies pronouncedly, even in individuals carrying the same variant. Materials and Methods: In this study, we aimed to assess the association of different electrical parameters with the genotype and the symptoms in patients with LQTS. In addition to the heart-rate corrected QT interval (QTc), markers for regional electrical heterogeneity, such as QT dispersion (QTmax-QTmin in all ECG leads) and delta Tpeak/end (Tpeak/end V5 - Tpeak/end V2), were assessed in the 12-lead ECG at rest and during exercise testing. Results: QTc at rest was significantly longer in symptomatic than asymptomatic patients with LQT2 (493.4 ms ± 46.5 ms vs. 419.5 ms ± 28.6 ms, p = 0.004), but surprisingly not associated with symptoms in LQT1. In contrast, post-exercise QTc (minute 4 of recovery) was significantly longer in symptomatic than asymptomatic patients with LQT1 (486.5 ms ± 7.0 ms vs. 463.3 ms ± 16.3 ms, p = 0.04), while no such difference was observed in patients with LQT2. Enhanced delta Tpeak/end and QT dispersion were only associated with symptoms in LQT1 (delta Tpeak/end 19.0 ms ± 18.1 ms vs. -4.0 ms ± 4.4 ms, p = 0.02; QT-dispersion: 54.3 ms ± 10.2 ms vs. 31.4 ms ± 10.4 ms, p = 0.01), but not in LQT2. Delta Tpeak/end was particularly discriminative after exercise, where all symptomatic patients with LQT1 had positive and all asymptomatic LQT1 patients had negative values (11.8 ± 7.9 ms vs. -7.5 ± 1.7 ms, p = 0.003). Conclusion: Different electrical parameters can distinguish between symptomatic and asymptomatic patients in different genetic forms of LQTS. While the classical "QTc at rest" was only associated with symptoms in LQT2, post-exercise QTc helped distinguish between symptomatic and asymptomatic patients with LQT1. Enhanced regional electrical heterogeneity was only associated with symptoms in LQT1, but not in LQT2. Our findings indicate that genotype-specific risk stratification approaches based on electrical parameters could help to optimize risk assessment in LQTS.
RESUMEN
Background: Oxytocin is used therapeutically in psychiatric patients. Many of these also receive anti-depressant or anti-psychotic drugs causing acquired long-QT-syndrome (LQTS) by blocking HERG/IKr. We previously identified an oxytocin-induced QT-prolongation in LQT2 rabbits, indicating potential harmful effects of combined therapy. We thus aimed to analyze the effects of dual therapy with oxytocin and fluoxetine/risperidone on cardiac repolarization. Methods: Effects of risperidone, fluoxetine and oxytocin on QT/QTc, short-term variability (STV) of QT, and APD were assessed in rabbits using in vivo ECG and ex vivo monophasic AP recordings in Langendorff-perfused hearts. Underlying mechanisms were assessed using patch clamp in isolated cardiomyocytes. Results: Oxytocin, fluoxetine and risperidone prolonged QTc and APD in whole hearts. The combination of fluoxetine + oxytocin resulted in further QTc- and APD-prolongation, risperidone + oxytocin tended to increase QTc and APD compared to monotherapy. Temporal QT instability, STVQTc was increased by oxytocin, fluoxetine / fluoxetine + oxytocin and risperidone / risperidone + oxytocin. Similar APD-prolonging effects were confirmed in isolated cardiomyocytes due to differential effects of the compounds on repolarizing ion currents: Oxytocin reduced IKs, fluoxetine and risperidone reduced IKr, resulting in additive effects on IKtotal-tail. In addition, oxytocin reduced IK1, further reducing the repolarization reserve. Conclusion: Oxytocin, risperidone and fluoxetine prolong QTc / APD. Combined treatment further prolongs QTc/APD due to differential effects on IKs and IK1 (block by oxytocin) and IKr (block by risperidone and fluoxetine), leading to pronounced impairment of repolarization reserve. Oxytocin should be used with caution in patients in the context of acquired LQTS.