Ventricular arrhythmias initiated by programmed stimulation in four groups of patients with healed myocardial infarction

Programmed electrical stimulation of the heart was prospectively used in 160 patients with healed myocardial infarction to study the incidence and characteristics of ventricular arrhythmias induced. Thirty-five patients had neither documented nor suspected ventricular arrhythmias (Group A); 37 patients had documented nonsus-tained ventricular tachycardia (Group B); 31 patients had been resuscitated from ventricular fibrillation (Group C); and 57 patients had documented sustained mono-morphic ventricular tachycardia (Group D). No electrophysiologic differences were found between patients in Group A and Group B, but patients in both groups differed significantly from patients in Group C and Group D. In the last two groups, sustained monomorphic ventricular tachycardia was more frequently induced, the cycle length of the induced ventricular tachycardia was slower and a lesser number of premature stimuli was required for induction. No differences were found in the incidence, rate or mode of induction of nonsustained monomorphic ventricular tachycardia, but nonsustained polymorphic ventricular tachycardia and ventricular fibrillation were more frequently induced in Groups A and B.It is concluded that the substrate for sustained ventricular arrhythmia is present in at least 42% of patients after myocardial infarction. The electrophysiologic characteristics of the substrate for ventricular tachycardia seem to be the major determinant of the clinical occurrence of sustained ventricular arrhythmia. Changes in the electrophysiologic properties of the substrate of ventricular tachycardia, either spontaneously with time or induced by ischemia or antiarrhythmic drugs, can contribute to the clinical occurrence of sustained ventricular arrhythmias in patients with an old myocardial infarction

Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS

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. © 2022 The Author

Oxytocin exerts harmful cardiac repolarization prolonging effects in drug-induced LQTS.

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

Transgenic LQT2, LQT5, and LQT2-5 rabbit models with decreased repolarisation reserve for prediction of drug-induced ventricular arrhythmias

Background and Purpose Reliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S , loss of IKr; LQT2), KCNE1 (KCNE1‐G52R , decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart. Experimental Approach Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts. Key Results LQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT. Conclusion and Implications LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates

Mechano‐electrical interactions and heterogeneities in wild‐type and drug‐induced long QT syndrome rabbits

Electromechanical reciprocity – comprising electro-mechanical (EMC) and mechano-electric coupling (MEC) – provides cardiac adaptation to changing physiological demands. Understanding electromechanical reciprocity and its impact on function and heterogeneity in pathological conditions – such as (drug-induced) acquired long QT syndrome (aLQTS) – might lead to novel insights in arrhythmogenesis. Our aim is to investigate how electrical changes impact on mechanical function (EMC) and vice versa (MEC) under physiological conditions and in aLQTS. To measure regional differences in EMC and MEC in vivo, we used tissue phase mapping cardiac MRI and a 24-lead ECG vest in healthy (control) and IKr-blocker E-4031-induced aLQTS rabbit hearts. MEC was studied in vivo by acutely increasing cardiac preload, and ex vivo by using voltage optical mapping (OM) in beating hearts at different preloads. In aLQTS, electrical repolarization (heart rate corrected RT-interval, RTn370) was prolonged compared to control (P < 0.0001) with increased spatial and temporal RT heterogeneity (P < 0.01). Changing electrical function (in aLQTS) resulted in significantly reduced diastolic mechanical function and prolonged contraction duration (EMC), causing increased apico-basal mechanical heterogeneity. Increased preload acutely prolonged RTn370 in both control and aLQTS hearts (MEC). This effect was more pronounced in aLQTS (P < 0.0001). Additionally, regional RT-dispersion increased in aLQTS. Motion-correction allowed us to determine APD-prolongation in beating aLQTS hearts, but limited motion correction accuracy upon preload-changes prevented a clear analysis of MEC ex vivo. Mechano-induced RT-prolongation and increased heterogeneity were more pronounced in aLQTS than in healthy hearts. Acute MEC effects may play an additional role in LQT-related arrhythmogenesis, warranting further mechanistic investigations

Comparative assessment of “plaque/media” change on three modalities of IVUS immediately after implantation of either everolimus-eluting bioresorbable vascular scaffold or everolimus-eluting metallic stent in Absorb II study

The purpose of the study to assess the comparability of immediate changes in plaque/media volume (PV) on three modalities of intravascular ultrasound (IVUS) after implantation of either bioresorbable vascular scaffold (BVS) or everolimus-eluting metallic stent (EES) in Absorb II Study. The two devices have different device volume and ultrasound backscattering that may interfere with the "plaque/media" assessed by three modalities on IVUS: grayscale, backscattering of radiofrequency and brightness function. In a multicenter randomized controlled trial, 501 patients with stable or unstable angina underwent documentary IVUS pre- and post- implantation. The change in plaque/media volume (PV) was categorized into three groups according to the relative PV change in device segment: PV "increased" >+5% (PVI), PV unchanged ±5% (PVU), and PV decreased <-5% (PVD). The change in PV was re-evaluated three times: after subtraction of theoretical device volume, after analysis of echogenicity based on brightness function. In 449 patients, 483 lesions were analyzed pre- and post-implantation. "PVI" was more frequently observed in BVS (53.8%) than EES group (39.4%), p = 0.006. After subtraction of the theoretical device volume, the frequency of "PVI" decreased in both BVS (36.2%) and EES (32.1%) groups and became comparable (p = 0.581). In addition, the percentage of "PVI" was further reduced in both device groups after correction for either radiofrequency backscattering (BVS 34.4% vs. EES 22.6%) or echogenicity (BVS 25.2% vs. EES 9.7%). PV change in device segment was differently affected by BVS and EES devices implantation due to their differences in device volume and ultrasound backscattering. It implies that the lumen volume was also artifactually affected by the type of device implanted. Comparative IVUS assessment of lumen and plaque/media volume changes following implantation of BVS and EES requires specific methodological adjustmen

Gene- and variant-specific efficacy of serum/glucocorticoid-regulated kinase 1 inhibition in long QT syndrome types 1 and 2.

AIMS Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. METHODS AND RESULTS Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM-10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2-p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3-10 µM (by 20-32%/25-30%/44-45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1-p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1-p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1-p.A341V hiPSC-CMs or KCNQ1-p.Y315S rabbit CMs at 0.3-3 µM. CONCLUSION A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS