Torsade De Pointes Arrhythmias Research Articles

High-rate pacing suppresses Torsade de Pointes arrhythmias and reduces spatial dispersion of repolarization in the chronic AV-block dog model.

Background: An electrical storm of Torsade de Pointes arrhythmias (TdP) can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the IKr-blocker dofetilide. Earlier studies showed that these arrhythmias 1) arise from locations with high spatial dispersion in repolarization (SDR) and 2) can be suppressed by high-rate pacing. We examined whether suppression of TdP by high-rate pacing is established through a decrease in SDR in the CAVB dog. Methods: Dofetilide (25μg/kg in 5min) was administered to 5 anesthetized CAVB dogs to induce TdP arrhythmias. During the experiments, animals were continuously paced from the right ventricular apex at 50 beats/minute (RVA50). Upon TdP occurrence and conversion, RVA pacing was consecutively set to 100, 80 and 60 beats/minute for 2min, referred to as pacing blocks. To determine the additional anti-arrhythmic effects of HRP over defibrillation alone, the number of arrhythmic events and SDR at RVA100 were compared to data from three previously conducted experiments, in which dogs underwent the same experimental protocol but were paced at RVA60 upon TdP occurrence (RVA60retro). In all experiments, recordings included surface electrocardiogram and mapping by 56 intramural needles, each recording four electrograms, evenly inserted into the ventricular walls and septum. For each pacing block, the number of ectopic beats (EB), and TdP severity were scored. SDR was quantified as the average difference in repolarization time within four squared needles (SDRcubic). Results: In 4 out of 5 animals, pacing at RVA100 suppressed TdP occurrence. One dog could not be converted by defibrillation after the initial TdP. Compared to RVA50, pacing at RVA100, but not RVA80 and RVA60, significantly reduced the TdP score (78 ± 33 vs. 0 ± 0, p < 0.05 and vs. 12.5 ± 25 and 25 ± 50, both p > 0.05). The reduction in TdP score was reflected by a significant decrease in SDRcubic (125 ± 46ms before TdP vs. 49 ± 18ms during RVA100, p < 0.05), and SDR was smaller than in the RVA60retro animals (101 ± 52ms, p < 0.05 vs. RVA100). Conclusion: In CAVB dogs, high-rate pacing effectively suppresses TdP, which, at least in part, results from a spatial homogenization of cardiac repolarization, as reflected by a decrease in SDR.

Machine learning approach to evaluate TdP risk of drugs using cardiac electrophysiological model including inter-individual variability.

Introduction: Predicting ventricular arrhythmia Torsade de Pointes (TdP) caused by drug-induced cardiotoxicity is essential in drug development. Several studies used single biomarkers such as qNet and Repolarization Abnormality (RA) in a single cardiac cell model to evaluate TdP risk. However, a single biomarker may not encompass the full range of factors contributing to TdP risk, leading to divergent TdP risk prediction outcomes, mainly when evaluated using unseen data. We addressed this issue by utilizing multi-in silico features from a population of human ventricular cell models that could capture a representation of the underlying mechanisms contributing to TdP risk to provide a more reliable assessment of drug-induced cardiotoxicity. Method: We generated a virtual population of human ventricular cell models using a modified O'Hara-Rudy model, allowing inter-individual variation. and Hill coefficients from 67 drugs were used as input to simulate drug effects on cardiac cells. Fourteen features (, , , , , , , , , , , , qNet, qInward) could be generated from the simulation and used as input to several machine learning models, including k-nearest neighbor (KNN), Random Forest (RF), XGBoost, and Artificial Neural Networks (ANN). Optimization of the machine learning model was performed using a grid search to select the best parameter of the proposed model. We applied five-fold cross-validation while training the model with 42 drugs and evaluated the model's performance with test data from 25 drugs. Result: The proposed ANN model showed the highest performance in predicting the TdP risk of drugs by providing an accuracy of 0.923 (0.908-0.937), sensitivity of 0.926 (0.909-0.942), specificity of 0.921 (0.906-0.935), and AUC score of 0.964 (0.954-0.975). Discussion and conclusion: According to the performance results, combining the electrophysiological model including inter-individual variation and optimization of machine learning showed good generalization ability when evaluated using the unseen dataset and produced a reliable drug-induced TdP risk prediction system.

IKs Activator ML277 Mildly Affects Repolarization and Arrhythmic Outcome in the CAVB Dog Model

Long QT syndrome type 1 with affected IKs is associated with a high risk for developing Torsade de Pointes (TdP) arrhythmias and eventually sudden cardiac death. Therefore, it is of high interest to explore drugs that target IKs as antiarrhythmics. We examined the antiarrhythmic effect of IKs channel activator ML277 in the chronic atrioventricular block (CAVB) dog model. TdP arrhythmia sensitivity was tested in anesthetized mongrel dogs (n = 7) with CAVB in series: (1) induction experiment at 4 ± 2 weeks CAVB: TdP arrhythmias were induced with our standardized protocol using dofetilide (0.025 mg/kg), and (2) prevention experiment at 10 ± 2 weeks CAVB: the antiarrhythmic effect of ML277 (0.6-1.0 mg/kg) was tested by infusion for 5 min preceding dofetilide. ML277: (1) temporarily prevented repolarization prolongation induced by dofetilide (QTc: 538 ± 65 ms at induction vs. 393 ± 18 ms at prevention, p < 0.05), (2) delayed the occurrence of the first arrhythmic event upon dofetilide (from 129 ± 28 s to 180 ± 51 s, p < 0.05), and (3) decreased the arrhythmic outcome with a significant reduction in the number of TdP arrhythmias, TdP score, arrhythmia score and total arrhythmic events (from 669 ± 132 to 401 ± 228, p < 0.05). IKs channel activation by ML277 temporarily suppressed QT interval prolongation, delayed the occurrence of the first arrhythmic event and reduced the arrhythmic outcome in the CAVB dog model.

A deep learning platform to assess drug proarrhythmia risk.

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an invitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of invitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of invitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia in people. The risk profile of the test drugs was similar across hiPSC-CMs derived from different healthy donors. In contrast, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high-risk drugs in the hiPSC-CMs. Thus, deep learning can identify invitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia.

Abstract 13503: Assessment of Automatic Measurement of Short-Term Variability of Repolarization for Arrhythmic Risk Monitoring in a Porcine Model of Ischemic Ventricular Fibrillation

Background: Short-term variability of repolarization derived from the QT-interval (STV-QT) has previously been demonstrated to increase prior to arrhythmias in both humans and animals. To continuously monitor the arrhythmic risk by a cardiovascular implantable electronic device (CIED), a fully automatic method to determine STV on intracardiac electrograms (STV-EGM auto ) has been developed. This method demonstrated high effectiveness in monitoring and predicting Torsade de Pointes arrhythmias in the CAVB dog model. However, this technique has not been evaluated in arrhythmias related to ischemia yet. Purpose: To assess the novel automatic method of arrhythmic risk monitoring by CIEDs through STV-EGM auto measurements in a porcine model of ischemia-induced ventricular fibrillation (VF). Methods: Myocardial infarction was induced in 8 anesthetized pigs by balloon occlusion of the left anterior descending coronary artery for 75 minutes, followed by reperfusion. Monitoring included a 12-lead ECG and a duodecapolar EGM catheter in the right ventricle. STV-EGM auto and STV-QT, our gold standard calculated by the method of fiducial segment averaging, were assessed at baseline, occlusion, one minute before VF and just before VF. The STV values and the percentual changes from baseline to the successive three timepoints were compared between STV-EGM auto and STV-QT. Results: VF occurred 21±8.8 minutes after occlusion. Both STV-EGM auto and STV-QT increased significantly from baseline to VF (1.1±0.8 ms vs 2.4±1.5 ms, p&lt;0.05; 1.0±0.5 ms vs 2.2±0.9 ms, p&lt;0.05, respectively). The percentual change in STV-EGM auto from baseline to occlusion, one minute before VF and VF showed an excellent correlation with the changes in STV-QT from baseline to the successive timepoints (r 2 = 0.94; p&lt;0.001). Bland-Altman analysis of the values showed a small bias of 0.26 ms and 95% limits of agreement between -1.1 and 1.6 ms. Conclusion: The STV values derived from the fully-automatic method for continuous STV measurements on intracardiac EGM signals (STV-EGM auto ) show values and trends similar to the clinically validated STV-QT in a porcine model of ischemia-related VF. Future integration of this technique in CIEDs can furnish continuous monitoring of arrhythmic risk.

Chronically altered ventricular activation causes pro-arrhythmic cardiac electrical remodelling in the chronic AV block dog model.

Altered ventricular activation (AVA) causes intraventricular mechanical dyssynchrony (MD) and impedes contraction, promoting pro-arrhythmic electrical remodelling in the chronic atrioventricular block (CAVB) dog. We aimed to study arrhythmogenic and electromechanical outcomes of different degrees of AVA. Following atrioventricular block, AVA was established through idioventricular rhythm (IVR; n = 29), right ventricular apex (RVA; n = 12) pacing or biventricular pacing [cardiac resynchronization therapy (CRT); n = 10]. After ≥3 weeks of bradycardic remodelling, Torsade de Pointes arrhythmia (TdP) inducibility, defined as ≥3 TdP/10 min, was tested with specific IKr-blocker dofetilide (25 μg/kg/5 min). Mechanical dyssynchrony was assessed by echocardiography as time-to-peak (TTP) of left ventricular (LV) free-wall minus septum (ΔTTP). Electrical intraventricular dyssynchrony was assessed as slope of regression line correlating intraventricular LV activation time (AT) and activation recovery interval (ARI). Under sinus rhythm, contraction occurred synchronous (ΔTTP: -8.6 ± 28.9 ms), and latest activated regions seemingly had slightly longer repolarization (AT-ARI slope: -0.4). Acute AV block increased MD in all groups, but following ≥3 weeks of remodelling IVR animals became significantly more TdP inducible (19/29 IVR vs. 5/12 RVA and 2/10 CRT, both P < 0.05 vs. IVR). After chronic AVA, intraventricular MD was lowest in CRT animals (ΔTTP: -8.5 ± 31.2 vs. 55.80 ± 20.0 and 82.7 ± 106.2 ms in CRT, IVR, and RVA, respectively, P < 0.05 RVA vs. CRT). Although dofetilide steepened negative AT-ARI slope in all groups, this heterogeneity in dofetilide-induced ARI prolongation seemed least pronounced in CRT animals (slope to -0.8, -3.2 and -4.5 in CRT, IVR and RVA, respectively). Severity of intraventricular MD affects the extent of electrical remodelling and pro-arrhythmic outcome in the CAVB dog model.

IKs inhibitor JNJ303 prolongs the QT interval and perpetuates arrhythmia when combined with enhanced inotropy in the CAVB dog

IntroductionImpaired IKs induced by drugs or due to a KCNQ1 mutation, diagnosed as long QT syndrome type 1 (LQT1) prolongs the QT interval and predisposes the heart to Torsade de Pointes (TdP) arrhythmias. The anesthetized chronic AV block (CAVB) dog is inducible for TdP after remodeling and IKr inhibitor dofetilide. We tested the proarrhythmic effect of IKs inhibition in the CAVB dog, and the proarrhythmic role of increased contractility herein. MethodsDofetilide-inducible animals were included to test the proarrhythmic effect of 1) IKs inhibition by JNJ303 (0.63 mg/kg/10min i.v.; n = 4), 2) IKs inhibition combined with enhanced inotropy (ouabain, 0.045 mg/kg/1min i.v.; n = 6), and 3) the washout period of the anesthetic regime (n = 10). ResultsJNJ303 prolonged the QTc interval (from 477 ± 53 ms to 565 ± 14 ms, P < 0.02) resembling standardized dofetilide-induced QTc prolongation. Single ectopic beats (n = 4) and ventricular tachycardia (VT) (n = 3) were present, increasing the arrhythmia score (AS) from 1.0 ± 0 to 7.1 ± 6.5. JNJ303 combined with ouabain increased contractile parameters (LVdP/dtmax from 1725 ± 273 to 4147 ± 611 mmHg/s, P < 0.01). Moreover, TdP arrhythmias were induced in 4/6 dogs and AS increased from 1.0 ± 0 to 20.2 ± 19.0 after JNJ303 and ouabain (P < 0.05). Finally, TdP arrhythmias were induced in 4/10 dogs during the anesthesia washout period and the AS increased from 1.1 ± 0.3 to 9.2 ± 11.2. ConclusionMimicking LQT1 using IKs inhibitor JNJ303 prolongs the QTc interval and triggers ectopic beats and non-sustained VT in the CAVB dog. Induction of the more severe arrhythmic events (TdP) demands a combination of IKs inhibition with enhanced inotropy or ending the anesthetic regime.

PO-705-08 HIGH-RATE PACING SUPPRESSES TORSADE DE POINTES ARRHYTHMIAS BY REDUCING SPATIAL DISPERSION OF REPOLARIZATION

An electrical storm of Torsade de Pointes (TdP) arrhythmias can be reproducibly induced in the anesthetized chronic AV-block (CAVB) dog by infusion of the Ikr-blocker dofetilide. Previous studies showed that these arrhythmias arise from a location with high spatial dispersion in repolarization (SDR) and are suppressed by high-rate pacing.

QT interval prolongation, torsades de pointes and psychotropic medication

QT interval reflects the duration of action potential of myocardial cells. Its prolongation in electrocardiogram is related to risk of torsades de pointes (TdP), a form of polymorphous ventricular tachycardia, and sudden cardiac death, which is one of the main causes of early mortality in psychiatric patients. The fact that only a proportion of patients with drug-induced QT prolongation manifest TdP or die shows that QT prolongation alone is not the perfect biological predictive marker of arrhythmia manifestation. Yet, it continues to be useful but needs to be combined with other known risk factors. This paper is a narrative review based on search in reference books and in PubMed and ScienceDirect databases using the terms [Torsades de pointes OR QT prolongation] AND [Psychotropic drugs OR antipsychotics OR antidepressants]. Its aim is to present basic knowledge about the pathophysiology of TdP arrhythmia and QT prolongation and their relationship with psychotropic drugs. TdP is a relatively slow-rate tachycardia and, in some cases, may stop abruptly without manifestation of clinical symptoms. The diagnosis is based on electrocardiographic findings, the symptoms are similar to those of any tachyarrhythmia and they are related to heart rate and its effects on arterial pressure and cardiac work. QT interval prolongation and TdP result from structural and functional disorders of ion channels and related proteins which are implicated in the process of ventricular repolarization. Psychotropic drugs are commonly used not only in psychiatric patients but in many patients with somatic disease as well. They can affect transmission of electrical impulses from sinus node to ventricular myocardium in various ways and most of its classes prolong QT interval in therapeutic doses or in cases of intoxication. Thus, their careful administration and monitoring of patients, especially hospitalized ones, are of vital importance. More data is available concerning the effects of antipsychotic and antidepressant medication. Among the first group, first generation, classical antipsychotics, especially the lower potency drugs, are considered to carry greater risk. Caution should be exercised when administering thioridazine, haloperidol, pimozide, sertindole and ziprasidone. Among antidepressants, caution is warranted when administering tricyclic antidepressants, citalopram and escitalopram. Among the other psychotropics, much information is available about methadone.

Kv1.3 Channel Blockade Improves Inflammatory Profile, Reduces Cardiac Electrical Remodeling, and Prevents Arrhythmia in Type 2 Diabetic Rats

PurposeKv1.3 channel regulates the activity of lymphocytes, macrophages, or adipose tissue and its blockade reduces inflammatory cytokine secretion and improves insulin sensitivity in animals with metabolic syndrome and in genetically obese mice. Thus, Kv1.3 blockade could be a strategy for the treatment of type 2 diabetes. Elevated circulating levels of TNFα and IL-1b mediate the higher susceptibility to cardiac arrhythmia in type 2 diabetic rats. We hypothesized that Kv1.3 channel blockade with the psoralen PAP1 could have immunomodulatory properties that prevent QTc prolongation and reduce the risk of arrhythmia in type 2 diabetic rats.MethodsType 2 diabetes was induced to Sprague-Dawley rats by high-fat diet and streptozotocin injection. Diabetic animals were untreated, treated with metformin, or treated with PAP1 for 4 weeks. Plasma glucose, insulin, cholesterol, triglycerides, and cytokine levels were measured using commercial kits. ECG were recorded weekly, and an arrhythmia-inducing protocol was performed at the end of the experimental period. Action potentials were recorded in isolated ventricular cardiomyocytes.ResultsIn diabetic animals, PAP1 normalized glycaemia, insulin resistance, adiposity, and lipid profile. In addition, PAP1 prevented the diabetes-induced repolarization defects through reducing the secretion of the inflammatory cytokines IL-10, IL-12p70, GM-CSF, IFNγ, and TNFα. Moreover, compared to diabetic untreated and metformin-treated animals, those treated with PAP1 had the lowest risk of developing the life-threatening arrhythmia Torsade de Pointes under cardiac challenge.ConclusionKv1.3 inhibition improves diabetes and diabetes-associated low-grade inflammation and cardiac electrical remodeling, resulting in more protection against cardiac arrhythmia compared to metformin.

Short-term variability of repolarization is equally modulated by atrial and (bi)ventricular high rate pacing in patients with an indication for an implantable cardioverter defibrillator

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Background An increase in temporal dispersion of repolarization, quantified as short-term variability of the QT-interval (STV-QT), precedes ventricular arrhythmias and has therefore been proposed as a marker for monitoring of imminent arrhythmic risk. A reversal of an increased STV by high rate pacing at 100 bpm was anti-arrhythmic in the chronic atrioventricular block dog model susceptible to Torsade de Pointes arrhythmias upon challenge with an IKr-blocker. The objective of the current study was to investigate the physiological modulation of STV by pacing in patients with an indication for an implantable cardioverter defibrillator (ICD), and to compare atrial and ventricular pacing. Methods ECG recordings were obtained with a sampling frequency of 1200 Hz in 10 dual chamber ICD patients and 10 patients with cardiac resynchronization therapy with defibrillation function (CRT-D) during the implantation or replacement. One-minute recordings were made during sinus rhythm (SR), and during pacing at 80 and 100 beats per minute (bpm) from the atrium (AAI), atrium and right ventricle (DDD RVp), and during atrio-biventricular pacing (DDD BiVp). The QT-interval was determined offline with fiducial segment averaging at one minute of each pacing rate, and 31 consecutive beats were used to calculate STV-QT with the following formula: ∑|D(n + 1)-Dn |/(N×√2), where D represents the determinant of repolarization (in this case the QT interval), and N represents the number of beats taken into account minus 1. Results In the patients overall, STV-QT decreased from 1.27 ± 0.38 ms in SR (±58 bpm) to 0.86 ± 0.26 ms* during AAI80, and to 0.68 ± 0.22 ms*† during AAI100 (*p &amp;lt; 0.05 compared to SR, †p &amp;lt; 0.05 compared to 80 bpm). The same decrease was seen during DDD80 RVp (0.81 ± 0.28 ms*) and during DDD100 RVp (0.66 ± 0.22 ms*†) (fig. 1). Additionally, DDD BiVp decreased STV-QT to 0.78 ± 0.20 ms* at 80 bpm and to 0.62 ± 0.19 ms* at 100 bpm in CRT-D patients (fig. 2). Conclusion Pacing at 80 and 100 bpm decreases STV-QT compared to sinus rhythm both in dual chamber ICD patients and CRT-D patients. The modulation of STV-QT is similar during atrial, and atrio- right ventricular and atrio-biventricular pacing. Abstract Figure. Modulation of STV-QT by AAI and DDD RVp

Cardiac TdP risk stratification modelling of anti-infective compounds including chloroquine and hydroxychloroquine.

Hydroxychloroquine (HCQ), the hydroxyl derivative of chloroquine (CQ), is widely used in the treatment of rheumatological conditions (systemic lupus erythematosus, rheumatoid arthritis) and is being studied for the treatment and prevention of COVID-19. Here, we investigate through mathematical modelling the safety profile of HCQ, CQ and other QT-prolonging anti-infective agents to determine their risk categories for Torsade de Pointes (TdP) arrhythmia. We performed safety modelling with uncertainty quantification using a risk classifier based on the qNet torsade metric score, a measure of the net charge carried by major currents during the action potential under inhibition of multiple ion channels by a compound. Modelling results for HCQ at a maximum free therapeutic plasma concentration (free Cmax) of approximately 1.2 µM (malaria dosing) indicated it is most likely to be in the high-intermediate-risk category for TdP, whereas CQ at a free Cmax of approximately 0.7 µM was predicted to most likely lie in the intermediate-risk category. Combining HCQ with the antibacterial moxifloxacin or the anti-malarial halofantrine (HAL) increased the degree of human ventricular action potential duration prolongation at some or all concentrations investigated, and was predicted to increase risk compared to HCQ alone. The combination of HCQ/HAL was predicted to be the riskiest for the free Cmax values investigated, whereas azithromycin administered individually was predicted to pose the lowest risk. Our simulation approach highlights that the torsadogenic potentials of HCQ, CQ and other QT-prolonging anti-infectives used in COVID-19 prevention and treatment increase with concentration and in combination with other QT-prolonging drugs.

Effects of Estrogens on the Actions of hERG

Regulation of cardiac ion channels by sex hormones accounts for gender-differences in susceptibility of Torsades de Pointes (TdP) arrhythmias associated with QT prolongation, that is: women are more prone to develop drug-induced arrhythmias which can lead cardiac sudden death. We previously found that β-estradiol (E2) directly interacts with a drug-binding site, F656 of the hERG channel, and alters the effect of a selective hERG blocker. Although these actions were observed for other estrogens, the effect of estrogen on other drugs has been unknown. In this study, to reveal impacts of the actions of estrogens on hERG currents, we compared the hERG screen data in the absence and the presence of estrogens using manual and automated patch-clamp experiments. HEK293 cells stably-expressing the hERG channels were seeded into 384-well plates, and were cultured in a steroid-free condition. Whole-cell hERG currents were recorded by the patch-clamp technique with SyncroPatch 384i (Nanion). Effects of 22 compounds were assessed by percentage changes of hERG peak tail currents with or without estrogens (E2, estrone sulfate; E1S, and ethynylestradiol; EE2) and by molecular docking simulations. Our hERG screening depicted that some estrogens showed distinct effects on respective blockers. Estrogens did not change the degree of hERG block by most of compounds. However, we have newly found that inhibitory action of one drug was increased by E2, and that of another drug was decreased by EE2. This means that specific combinations of an estrogen and a hERG blocker can alter the hERG blockade significantly. Indeed, some combinations resulted in larger hERG currents. This study suggests potential risks using estrogen therapy/medication and the necessity of taking sex hormonal differences into consideration for more accurate prediction of QT prolongation proclivity of drug candidates.

Assessment of Contractility in Human iPS Cell-Derived Cardiomyocytes Using Motion Vector Analysis.

Human-induced pluripotent stem cell (iPSC) technology paves the way for next-generation drug-safety assessment. In particular, human iPSC-derived cardiomyocytes, which exhibit electrical activity, are useful as a human cell model for assessing QT-interval prolongation and the risk of the lethal arrhythmia Torsade de Pointes (TdP). In addition to proarrhythmia assay, contractile behavior has received increased attention in drug development. In this study, we developed a novel high-throughput in vitro assay system using motion vectors to evaluate the contractile activity of iPSC-derived cardiomyocytes as a physiologically relevant human platform. The methods presented here highlight the use of commercially available iPSC-derived cardiomyocytes, iCell cardiomyocytes, for contractility evaluation recorded by the motion vector system.

High rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias autonomically by an ICD

Abstract Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p&amp;lt;0.05). During the prevention experiment, all dogs reached the STV threshold. HRP decreased STV-offline from 2.02±1.12 to 0.78±0.28 ms*, which was accompanied by prevention of TdPs in 7/8 dogs* (Figure 1). Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs.

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion and reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged the frequency-corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations, blocked I Kr in isolated cardiomyocytes (Class III effects), and reduced the maximum rate of depolarization (V max) at cycle lengths smaller than 1000ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent reentry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

Predictive factors for cardiac conduction abnormalities with hydroxychloroquine-containing combinations for COVID-19

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR=11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR=1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR=4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.

Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog

Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device.Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog.Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs.Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between −0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects.Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

Hydroxychloroquine is protective to the heart, not harmful: a systematic review.

Hydroxychloroquine (HCQ) has been shown to be at least somewhat effective in treating patients with coronavirus disease 2019 (COVID-19). Recently the US Food and Drug Administration and Centers for Disease Control and Prevention warnings of fatal cardiac toxicity from torsades de pointes (TDP) arrhythmia from HCQ receipt have been made, notwithstanding the long safe provision of HCQ to treat lupus and rheumatoid arthritis. This has resulted in restricted access of HCQ for COVID-19 treatment. We hypothesized that HCQ and azithromycin have not been reported to cause significant acute cardiac arrhythmic mortality. We performed a literature search for the effects of HCQ and azithromycin on the heart. No TDP or related deaths were found to have been reported as a result of HCQ and azithromycin receipt in the peer-reviewed literature. On the contrary, HCQ and azithromycin were both found to substantially reduce cardiac mortality and also decrease thrombosis, arrhythmia and cholesterol in treated patients in recent peer-reviewed studies and meeting presentations. HCQ and azithromycin do not cause TDP cardiac mortality; rather, HCQ decreases cardiac events. HCQ should not be restricted in COVID-19 patients out of fear of cardiac mortality.

Revisiting the hERG safety margin after 20 years of routine hERG screening

IntroductionIt has been two decades since screening new molecules and potential clinical drug candidates against the hERG potassium channel became a routine part of safety pharmacology. The earliest heuristic for what was an adequate safety margin to separate molecules with a potential liability to cause the arrhythmia torsade de pointes (TdP) from those with no such liability emerged in 2002 and was determined to be a hERG IC50 value 30-fold above the therapeutic free plasma concentration (Webster, Leishman, & Walker, 2002). In the intervening years nonclinical and clinical ICH guidance has been introduced and intense scrutiny has been applied to the QT interval of the electrocardiogram in animals and man. Has the 30-fold heuristic stood the test of time? MethodsThe hERG margins between the IC50 value and the therapeutic unbound plasma concentrations were examined for 367 compounds. These margins were compared against the categories used by www.CredibleMeds.com to classify a drug's TdP risk. A subset of 336 of these drugs were compared against their US product labels with respect to black box warnings on QTc prolongation or TdP, warnings and precautions on QTc or TdP, and QTc language in the clinical pharmacology section. ResultsAgainst the CredibleMeds classification the means of the margins for Known, Conditional, or Possible Risk of TdP, and Not Listed (presumably no TdP liability) were 4.8, 28, 71 and 339, respectively. Against the US label language the means of margins for black boxes and warnings were 3.1 and 26, respectively. The average margins associated with, positive QTc outcome, negative QTc outcome and no QTc language were 16, 479 and 204, respectively. Based on ROC curves the optimal hERG margin thresholds to separate “Known risk of TdP” from “Not Listed” and, QTc prolongation positive from QTc negative were 37- and 50-fold, respectively. ConclusionsThe observed optimal margin of 50-fold in the current study is not appreciably different from a previously reported 45-fold optimal margin (Gintant, 2011). The margin falls between the margins for negative (QTc outcome or no QTc language) and positive (positive QTc outcome, warnings or black boxes) compounds. The observed optimal margin of 37-fold in the current study is not appreciably different from the commonly used 30-fold optimal margin (Webster et al., 2002). This margin falls between those for drugs with a known or conditional TdP risk and those where it is at best a possible risk, and from the 240 drugs not listed on www.CredibleMeds.com. It is expected that there would be a small numerical difference (e.g. 37 vs. 50, or as previously published 30 vs. 45) between optimal cut-offs for the TdP liability and QTc prolongation predictions since some QTc positive drugs are described on CredibleMeds.com as having only a “Possible Risk of TdP” as they are not associated with TdP when used as directed.The fact that the margins in each category form distributions is also expected given biologic variability. However, we argue that a more consistent manner of assessing hERG potency and evaluating relevant exposures would be likely to reduce the spread in these distributions and make margins even more useful as a decision-making data point.