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Key Points Various cardiovascular and noncardiovascular drugs can induce proarrhythmic adverse effects Pharmacokinetic risk factors and genetic predisposition can enhance proarrhythmia Antiarrhythmic, antimicrobial, antipsychotic, and antidepressant drugs are important drug classes with an associated risk of proarrhythmia Monitoring the QT interval might not be sufficient to assess the risk of proarrhythmia Spatial and temporal dispersion of repolarization, action-potential configuration, and occurrence of early afterdepolarizations are additional predictors of proarrhythmia Various cardiovascular and noncardiovascular drugs, including so-called antiarrhythmic drugs, can induce cardiac arrhythmias. In this Review, Frommeyer and Eckardt summarize important proarrhythmic risk factors (such as age, female sex, and structural heart disease) and the underlying electrophysiological mechanisms (such as spatial or temporal dispersion of repolarization, alterations in action-potential morphology, and development of early afterdepolarizations). Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes.

Recent versions of evidence-based guidelines on the management of atrial fibrillation (AF) have been published by the European Society of Cardiology (ESC) in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS), the American College of Cardiology, American Heart Association, and the Heart Rhythm Society (AHA/ACC/HRS), and the Canadian Cardiovascular Society/Canadian Heart Rhythm Society (CCS). As all societies refer to the same multicentric and usually multinational studies, the similarities undoubtedly outweigh the differences. Nonetheless, interesting differences can often be found in details, which are usually based on a different assessment of the same study, the availability of data in relation to the publication date and local preferences and availabilities of certain cardiovascular drugs. The following article aims at lining out these similarities and differences.

Previous studies suggest an impact of dexmedetomidine on cardiac electrophysiology. However, experimental data is sparse. Therefore, purpose of this study was to investigate the influence of dexmedetomidine on different experimental models of proarrhythmia. 50 rabbit hearts were explanted and retrogradely perfused. The first group (n = 12) was treated with dexmedetomidine in ascending concentrations (3, 5 and 10 µM). Dexmedetomidine did not substantially alter action potential duration (APD) but reduced spatial dispersion of repolarization (SDR) and rendered the action potentials rectangular, resulting in no proarrhythmia. In further 12 hearts, erythromycin (300 µM) was administered to simulate long-QT-syndrome-2 (LQT2). Additional treatment with dexmedetomidine reduced SDR, thereby suppressing torsade de pointes. In the third group (n = 14), 0.5 µM veratridine was added to reduce the repolarization reserve. Further administration of dexmedetomidine did not influence APD, SDR or the occurrence of arrhythmias. In the last group (n = 12), a combination of acetylcholine (1 µM) and isoproterenol (1 µM) was used to facilitate atrial fibrillation. Additional treatment with dexmedetomidine prolonged the atrial APD but did not reduce AF episodes. In this study, dexmedetomidine did not significantly alter cardiac repolarization duration and was not proarrhythmic in different models of ventricular and atrial arrhythmias. Of note, dexmedetomidine might be antiarrhythmic in acquired LQT2 by reducing SDR.

Background: The two antiepileptic drugs lacosamide and lamotrigine exert their antiepileptic effect by inhibiting sodium channels. Lacosamide enhances the inactivation of sodium channels, while lamotrigine inhibits the activation of the channel. Interactions with sodium channels also play an interesting role in cardiac pro- and antiarrhythmia, with inhibition of inactivation, in particular, being regarded as potentially proarrhythmic. Therefore, the ventricular electrophysiologic effects of lacosamide and lamotrigine were investigated in an established experimental whole-heart model. Methods: A total of 67 rabbit hearts were allocated to four groups. Retrograde aortic perfusion was performed using the Langendorff setup. The action potential duration at 90% repolarization (APD90), QT intervals, spatial dispersion of repolarization, effective refractory period, post-repolarization refractoriness, and VT incidence were determined. The electrophysiological effects of lacosamide and lamotrigine were investigated in increasing concentrations on the natively perfused heart. On the other hand, perfusion with the IKr-blocker sotalol was performed to increase arrhythmia susceptibility, followed by perfusion with lacosamide or lamotrigine to investigate the effects of both in a setting of increased arrhythmia susceptibility. Perfusion with lacosamide and lamotrigine tended to decrease APD90 and QT-interval. As expected, perfusion with sotalol led to a significant increase in APD90, QT interval, and arrhythmia incidence. Additive perfusion with lacosamide led to a further increase in arrhythmia incidence, while additive perfusion with lamotrigine led to a decrease in VT incidence. Conclusions: In this model, lacosamide showed proarrhythmic effects, especially in the setting of an additive prolonged QT interval. Lamotrigine showed no significant proarrhythmia under baseline conditions and rather antiarrhythmic effects with additive QT prolongation.

AimsThe aim of this study is to evaluate retinal and optic nerve head (ONH) perfusion in patients with systolic chronic heart failure (CHF) compared to healthy control subjects.MethodsTwenty-seven eyes of 27 patients with CHF (study group) and 31 eyes of 31 healthy subjects (control group) were prospectively included in this study. CHF Patients had a left ventricular ejection fraction (LVEF) < 50% and were classified by New York Heart Association (NYHA) class. OCT-A was performed using RTVue XR Avanti with AngioVue (Optovue, Inc, Fremont, CA, USA). The area of the foveal avascular zone (FAZ) and flow density (FD) data were extracted and analyzed.ResultsThere was no significant difference in the signal strength index between the study group (group 1) and the control group (group 2) (ONH: p = 0.015; macula: p = 0.703). The difference in the area of the foveal avascular zone between the two groups was also not significant (p = 0.726). The flow density (whole en face) in the ONH (RPC) in group 1 was significantly lower compared to control (group 1 = 48.40 ± 2.48 (49.0 [46.7, 50.3]); group 2 = 50.15 ± 1.85 (50.6 [48.5, 51.70]); p = 0.008). There was a significant and strong correlation between LVEF and the macular flow density (whole en face) (superficial: rs = 0.605 deep: rs = 0.425, p < 0.01).ConclusionsPatients with CHF showed reduced flow density compared with healthy controls. The reduced FD correlated with the LVEF and the functional (NYHA) class. Retinal perfusion as measured using OCTA might provide an insight into the global microperfusion and hemodynamic state of heart failure patients.

Lidocaine is classified as a class Ib anti‐arrhythmic that blocks voltage‐ and pH‐dependent sodium channels. It exhibits well investigated anti‐arrhythmic effects and has been the anti‐arrhythmic of choice for the treatment of ventricular arrhythmias for several decades. Lidocaine binds primarily to inactivated sodium channels, decreases the action potential duration, and increases the refractory period. It increases the ventricular fibrillatory threshold and can interrupt life‐threatening tachycardias caused by re‐entrant mechanisms, especially in ischemic tissue. Its use was pushed into the background in the era of amiodarone and modern electric device therapy. Recently, lidocaine has come back into focus for the treatment of acute sustained ventricular tachyarrhythmias. In this brief overview, we review the clinical pharmacology including possible side effects, the historical course, possible indications, and current Guideline recommendations for the use of lidocaine.

    Purpose of Review Arrhythmias are common in patients with heart failure (HF) and are associated with a significant risk of mortality and morbidity. Optimal antiarrhythmic treatment is therefore essential. Here, we review current approaches to antiarrhythmic treatment in patients with HF. Recent Findings In atrial fibrillation, rhythm control and ventricular rate control are accepted therapeutic strategies. In recent years, clinical trials have demonstrated a prognostic benefit of early rhythm control strategies and AF catheter ablation, especially in patients with HF with reduced ejection fraction. Prevention of sudden cardiac death with ICD therapy is essential, but optimal risk stratification is challenging. For ventricular tachycardias, recent data support early consideration of catheter ablation. Antiarrhythmic drug therapy is an adjunctive therapy in symptomatic patients but has no prognostic benefit and well-recognized (proarrhythmic) adverse effects. Summary Antiarrhythmic therapy in HF requires a systematic, multimodal approach, starting with guideline-directed medical therapy for HF and integrating pharmacological, device, and interventional therapy.

Previously unreported, the induction of the magnet mode is time-dependent, according to the cardiac implantable electronic device (CIED) manufacturer, directly after device interrogation. The aim of this study was to systematically investigate the response of CIED from all major manufacturers to the application of a magnet. CIED from all manufacturers were utilized and connected to an interactive heart simulator (InterSim III, IB Lang). After the end of CIED interrogation, a CIED magnet was placed over the device, and the response was analyzed. Fifteen ICD and eight pacemakers were included. ICDs from the manufacturers Abbott, Boston Scientific, Medtronic and Microport reacted immediately to magnet application by inhibiting antitachycardia function directly after interrogation. In the Biotronik ICD, the magnet mode was only inducible five to seven minutes after the end of the interrogation. In addition, after eight hours of magnet application, the antitachycardia function was automatically and permanently reactivated in all Biotronik ICDs. Pacemakers of Biotronik, Abbott, Boston Scientific, and Microport responded immediately after device interrogation regarding the magnet application. In contrast, Medtronic pacemakers responded only 1.5 min after device interrogation. Magnet mode induction directly after CIED interrogation is manufacturer-specific. Our findings might be of importance when performing invasive procedures with devices that cause electrical interference and in palliative care.

There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to elucidate the risk of propofol-induced TdP and to investigate the impact of propofol in drug-induced long QT syndrome. 35 rabbit hearts were perfused employing a Langendorff-setup. 10 hearts were perfused with increasing concentrations of propofol (50, 75, 100 µM). Propofol abbreviated action potential duration (APD 90 ) in a concentration-dependent manner without altering spatial dispersion of repolarization (SDR). Consequently, no proarrhythmic effects of propofol were observed. In 12 further hearts, erythromycin was employed to induce prolongation of cardiac repolarization. Erythromycin led to an amplification of SDR and triggered 36 episodes of TdP. Additional infusion of propofol abbreviated repolarization and reduced SDR. No episodes of TdP were observed with propofol. Similarly, ondansetron prolonged cardiac repolarization in another 13 hearts. SDR was increased and 36 episodes of TdP occurred. With additional propofol infusion, repolarization was abbreviated, SDR reduced and triggered activity abolished. In this experimental whole-heart study, propofol abbreviated repolarization without triggering TdP. On the contrary, propofol reversed prolongation of repolarization caused by erythromycin or ondansetron, reduced SDR and thereby eliminated drug-induced TdP.

Background: Previous studies suggest a direct effect of sacubitril on cardiac electrophysiology and indicate potential arrhythmic interactions between sacubitril and antiarrhythmic drugs. Therefore, the aim of this study was to explore the electrophysiologic effects of combining sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine in isolated hearts. Methods and results: A total of 25 rabbit hearts were perfused using a Langendorff setup. Following baseline data collection, hearts were treated with mexiletine (25 µM, 13 hearts) or d,l-sotalol (100 µM, 12 hearts). Monophasic action potential demonstrated an abbreviation of action potential duration (APD90) after administration of mexiletine. Spatial dispersion of repolarization remained unchanged after mexiletine treatment, whereas effective refractory periods (ERP) were significantly prolonged. D,l-sotalol prolonged cardiac repolarization and amplified spatial dispersion. Further infusion of sacubitril (5 µM) led to a significant reduction in APD90 and ERP in the mexiletine group. In the d,l-sotalol group, additional administration of sacubitril shortened cardiac repolarization duration without affecting spatial dispersion. No proarrhythmic effect was observed after mexiletine treatment as assessed by a predefined pacing protocol. Additional sacubitril treatment did not increase ventricular vulnerability. When potassium concentration was reduced, 30 episodes of torsade de pointes tachycardia occurred after d,l-sotalol treatment. Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (eight episodes) in the d,l-sotalol-group. Conclusions: In class IB- and class III-pretreated hearts, sacubitril shortened refractory periods and cardiac repolarization duration. The combination of sacubitril with the antiarrhythmic drugs d,l-sotalol and mexiletine demonstrates a safe electrophysiologic profile and sacubitril reduces the occurrence of class III-related proarrhythmia, i.e., torsade de pointes tachycardia.