Drug-Induced Arrhythmias: A Scientific Statement From the American Heart Association. Tisdale James E,Chung Mina K,Campbell Kristen B,Hammadah Muhammad,Joglar Jose A,Leclerc Jacinthe,Rajagopalan Bharath, Circulation Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important. 10.1161/CIR.0000000000000905

Arrhythmia-Induced Cardiomyopathy. Sossalla Samuel,Vollmann Dirk Deutsches Arzteblatt international BACKGROUND:Heart failure affects 1–2% of the population and is associated with elevated morbidity and mortality. Cardiac arrhythmias are often a result of heart failure, but they can cause left-ventricular systolic dysfunction (LVSD) as an arrhythmia-induced cardiomyopathy (AIC). This causal relationship should be borne in mind by the physician treating a patient with systolic heart failure in association with cardiac arrhythmia. METHODS:This review is based on pertinent publications retrieved by a selective search in PubMed (1987–2017) and on the recommendations in current guidelines. RESULTS:The key criterion for the diagnosis of an AIC is the demonstration of a persistent arrhythmia (including pathological tachycardia) together with an LVSD whose origin cannot be explained on any other basis. Nearly any type of tachyarrhythmia or frequent ventricular extrasystoles can lead, if persistent, to a progressively severe LVSD. The underlying pathophysiologic mechanisms are incompletely understood; the increased ventricular rate, asynchronous cardiac contractions, and neurohumoral activation all seem to play a role. The most common precipitating factors are supraventricular tachycardias in children and atrial fibrillation in adults. Recent studies have shown that the causal significance of atrial fibrillation in otherwise unexplained LVSD is underappreciated. The treatment of AIC consists primarily of the treatment of the underlying arrhythmia, generally with drugs such as beta-blockers and amiodarone. Depending on the type of arrhythmia, catheter ablation for long-term treatment should also be considered where appropriate. The diagnosis of AIC is considered to be well established when the LVSD normalizes or improves within a few weeks or months of the start of targeted treatment of the arrhythmia. CONCLUSION:An AIC is potentially reversible. The timely recognition of this condition and the appropriate treatment of the underlying arrhythmia can substantially improve patient outcomes. 10.3238/arztebl.2018.0335

IRS2 Signaling Protects Against Stress-Induced Arrhythmia by Maintaining Ca Homeostasis. Circulation BACKGROUND:The docking protein IRS2 (insulin receptor substrate protein-2) is an important mediator of insulin signaling and may also regulate other signaling pathways. Murine hearts with cardiomyocyte-restricted deletion of (cIRS2-KO) are more susceptible to pressure overload-induced cardiac dysfunction, implying a critical protective role of IRS2 in cardiac adaptation to stress through mechanisms that are not fully understood. There is limited evidence regarding the function of IRS2 beyond metabolic homeostasis regulation, particularly in the context of cardiac disease. METHODS:A retrospective analysis of an electronic medical record database was conducted to identify patients with variants and assess their risk of cardiac arrhythmias. Arrhythmia susceptibility was examined in cIRS2-KO mice. The underlying mechanisms were investigated using confocal calcium imaging of ex vivo whole hearts and isolated cardiomyocytes to assess calcium handling, Western blotting to analyze the involved signaling pathways, and pharmacological and genetic interventions to rescue arrhythmias in cIRS2-KO mice. RESULTS:The retrospective analysis identified patients with variants of uncertain significance with a potential association to an increased risk of cardiac arrhythmias compared with matched controls. cIRS2-KO hearts were found to be prone to catecholamine-sensitive ventricular tachycardia and reperfusion ventricular tachycardia. Confocal calcium imaging of ex vivo whole hearts and single isolated cardiomyocytes from cIRS2-KO hearts revealed decreased Ca²⁺ transient amplitudes, increased spontaneous Ca²⁺ sparks, and reduced sarcoplasmic reticulum Ca²⁺ content during sympathetic stress, indicating sarcoplasmic reticulum dysfunction. We identified that overactivation of the AKT1/NOS3 (nitric oxide synthase 3)/CaMKII (Ca²⁺/calmodulin-dependent protein kinase II)/RyR2 (type 2 ryanodine receptor) signaling pathway led to calcium mishandling and catecholamine-sensitive ventricular tachycardia in cIRS2-KO hearts. Pharmacological AKT inhibition or genetic stabilization of RyR2 rescued catecholamine-sensitive ventricular tachycardia in cIRS2-KO mice. CONCLUSIONS:Cardiac IRS2 inhibits sympathetic stress-induced AKT/NOS3/CaMKII/RyR2 overactivation and calcium-dependent arrhythmogenesis. This novel IRS2 signaling axis, essential for maintaining cardiac calcium homeostasis under stress, presents a promising target for developing new antiarrhythmic therapies. 10.1161/CIRCULATIONAHA.123.065048