Differential effects of class I antiarrhythmic drugs on the guinea pig pulmonary vein myocardium: Inhibition of automatic activity correlates with blockade of a diastolic sodium current component.

The effects of class I antiarrhythmic drugs on the automaticity of isolated guinea pig pulmonary vein myocardia were investigated using microelectrode and voltage clamp methods. All of the drugs examined reduced the maximum rate of rise of automatic action potentials. The firing frequency and rate of diastolic depolarization were decreased by aprindine, flecainide and propafenone, but not by cibenzoline, disopyramide and pilsicainide, which correlated with blockade of the sodium current component induced by ramp depolarization mimicking the diastolic depolarization. In conclusion, class I antiarrhythmic drugs which block the diastolic sodium current component inhibit the automaticity of the pulmonary vein myocardium.

Update on antiarrhythmic drug pharmacology.

Cardiac arrhythmias constitute a major public health problem. Pharmacological intervention remains mainstay to their clinical management. This, in turn, depends upon systematic drug classification schemes relating their molecular, cellular, and systems effects to clinical indications and therapeutic actions. This approach was first pioneered in the 1960s Vaughan-Williams classification. Subsequent progress in cardiac electrophysiological understanding led to a lag between the fundamental science and its clinical translation, partly addressed by The working group of the European Society of Cardiology (1991), which, however, did not emerge with formal classifications. We here utilize the recent Revised Oxford Classification Scheme to review antiarrhythmic drug pharmacology. We survey drugs and therapeutic targets offered by the more recently characterized ion channels, transporters, receptors, intracellular Ca2+ handling, and cell signaling molecules. These are organized into their strategic roles in cardiac electrophysiological function. Following analysis of the arrhythmic process itself, we consider (a) pharmacological agents directly targeting membrane function, particularly the Na+ and K+ ion channels underlying depolarizing and repolarizing events in the cardiac action potential. (b) We also consider agents that modify autonomic activity that, in turn, affects both the membrane and (c) the Ca2+ homeostatic and excitation-contraction coupling processes linking membrane excitation to contractile activation. Finally, we consider (d) drugs acting on more upstream energetic and structural remodeling processes currently the subject of clinical trials. Such systematic correlations of drug actions and arrhythmic mechanisms at different molecular to systems levels of cardiac function will facilitate current and future antiarrhythmic therapy.

Class 1C antiarrhythmic drugs in atrial fibrillation and coronary artery disease.

BACKGROUND: Class 1C antiarrhythmic drugs (AADs) are effective first-line agents for atrial fibrillation (AF) treatment. However, these agents commonly are avoided in patients with known coronary artery disease (CAD), due to known increased risk in the postmyocardial infarction population. Whether 1C AADs are safe in patients with CAD but without clinical ischemia or infarct is unknown. Reduced coronary flow capacity (CFC) on positron emission tomography (PET) reliably identifies myocardial regions supplied by vessels with CAD causing flow limitation. OBJECTIVE: To assess whether treatment with 1C AADs increases mortality in patients without known CAD but with CFC indicating significantly reduced coronary blood flow. METHODS: In this pilot study, we compared patients with AF and left ventricular ejection fraction ≥50% who were treated with 1C AADs to age-matched AF patients without 1C AAD treatment. No patient had clinically evident CAD (ie, reversible perfusion defect, known ≥70% epicardial lesion, percutaneous coronary intervention, coronary artery bypass grafting, or myocardial infarction). All patients had PET-based quantification of stress myocardial blood flow and CFC. Death was assessed by clinical follow-up and social security death index search. RESULTS: A total of 78 patients with 1C AAD exposure were matched to 78 controls. Over a mean follow-up of 2.0 years, the groups had similar survival (P = .54). Among patients with CFC indicating the presence of occult CAD (ie, reduced CFC involving ≥50% of myocardium), 1C-treated patients had survival similar to (P = .44) those not treated with 1C agents. CONCLUSIONS: In a limited population of AF patients with preserved left ventricle function and PET-CFC indicating occult CAD, treatment with 1C AADs appears not to increase mortality. A larger study would be required to confidently assess the safety of these drugs in this context.

Rate and rhythm therapy in patients with atrial fibrillation and the risk of pacing and bradyarrhythmia.

BACKGROUND: Management of atrial fibrillation (AF) with rate and rhythm therapy can cause bradyarrhythmia. OBJECTIVES: To assess overall risk, temporal risk, and subgroup at risk of bradyarrhythmia-related events by rate and/or rhythm therapy drugs. METHODS: Using Danish nationwide registries, patients with AF between 2000 and 2014 were included if prescribed with rate-lowering drugs (RLDs) or antiarrhythmic drugs (AADs). An adjusted time-dependent Poisson regression model estimated the association between RLDs and AADs with a composite endpoint of pacemaker, temporary pacing, and bradyarrhythmia hospitalization. Secondary outcomes were each individual event. RESULTS: Among 135,017 AF patients, 9196 (6.8%) patients experienced the composite endpoint with a median follow-up of 3.7 (interquartile range [IQR]: 1.6-7.0) years. Median age was 74 (IQR: 65-82) years and 47.6% were women. With rate-lowering monotherapy as the reference, the incidence rate ratios (IRR) (95% confidence interval) for the composite endpoint were 1.36 (1.29-1.43) for rate-lowering dual therapy, 1.62 (1.43-1.84) for antiarrhythmic monotherapy, and 2.49 (2.29-2.71) for AAD combined with RLDs. Similar trend was found for each secondary outcome. Particularly amiodarone increased the risk. This association was strongest within the first 2 weeks of treatment. In those treated with AAD combined with RLDs, high-risk populations were patients ≥70 years (IRR: 3.35 [2.51-4.45] compared to patients <60 years), and women (IRR: 1.35 [1.15-1.57], compared to men). CONCLUSIONS: In real-world AF patients, rate-lowering dual therapy, antiarrhythmic monotherapy, and AADs combined with RLDs were positively associated with bradyarrhythmia-related events. The risk was highest in those treated with amiodarone, in the initial 2 weeks of treatment, in women, and in the elderly.

Modernized Classification of Cardiac Antiarrhythmic Drugs.

BACKGROUND: Among his major cardiac electrophysiological contributions, Miles Vaughan Williams (1918-2016) provided a classification of antiarrhythmic drugs that remains central to their clinical use. METHODS: We survey implications of subsequent discoveries concerning sarcolemmal, sarcoplasmic reticular, and cytosolic biomolecules, developing an expanded but pragmatic classification that encompasses approved and potential antiarrhythmic drugs on this centenary of his birth. RESULTS: We first consider the range of pharmacological targets, tracking these through to cellular electrophysiological effects. We retain the original Vaughan Williams Classes I through IV but subcategorize these divisions in light of more recent developments, including the existence of Na+ current components (for Class I), advances in autonomic (often G protein-mediated) signaling (for Class II), K+ channel subspecies (for Class III), and novel molecular targets related to Ca2+ homeostasis (for Class IV). We introduce new classes based on additional targets, including channels involved in automaticity, mechanically sensitive ion channels, connexins controlling electrotonic cell coupling, and molecules underlying longer-term signaling processes affecting structural remodeling. Inclusion of this widened range of targets and their physiological sequelae provides a framework for a modernized classification of established antiarrhythmic drugs based on their pharmacological targets. The revised classification allows for the existence of multiple drug targets/actions and for adverse, sometimes actually proarrhythmic, effects. The new scheme also aids classification of novel drugs under investigation. CONCLUSIONS: We emerge with a modernized classification preserving the simplicity of the original Vaughan Williams framework while aiding our understanding and clinical management of cardiac arrhythmic events and facilitating future developments in this area.

Feasibility of selection of antiarrhythmic drug treatment on the basis of arrhythmogenic mechanism - Relevance of electrical restitution, wavebreak and rotors.

Antiarrhythmic drug therapy has seen significant challenges over the past 3 decades with unexpected results from clinical trials such as CAST, SWORD and more recently PALLAS showing harm in patients whom antiarrhythmic drugs were given based on their intended antiarrhythmic actions and previously demonstrated efficacy. These results question whether the precise mechanism of action of the drugs was understood and highlight the complexity of the situation where there is the combination of multiple actions of the antiarrhythmic drugs on various molecular systems, some of which may be unknown with associated adverse outcome, and their interaction with pre-existing abnormality in disease states in patients treated. In addition, there is no effective drug strategy for complex arrhythmias such as atrial and ventricular fibrillation. Their complex dynamics are not adequately described by the classical mechanisms of automaticity, triggered activity and re-entry. Experimental data showing that flattening of the electrical restitution curve can convert ventricular fibrillation into stable tachycardia and prevent its initiation via wavebreak, and the advancement of computation biology in the describing the behaviour of wavetip and rotors in driving fibrillation have ignited the quest for more detailed understanding of the mechanisms underlying these complex arrhythmias. Their precise ionic basis which could be targeted for drug therapy remains to be fully characterised and tested in appropriate disease models and preparations. This review summarises some of these developments in the context of antiarrhythmic drug therapy consideration.

Prophylaxis Against Atrial Fibrillation After General Thoracic Surgery: Trial Sequential Analysis and Network Meta-Analysis.

BACKGROUND: Postoperative atrial fibrillation/flutter (POAF) is associated with significant morbidity and mortality after general thoracic surgery, but the need for and the best agent for prophylaxis remains obscure. METHODS: A systematic literature search was performed to identify randomized controlled trials that compared regimens for POAF prophylaxis after general thoracic surgery. Random-effects meta-analyses with trial sequential analyses were performed to compare the effects of medical prophylaxis vs placebo/usual care. The risk of POAF among patients receiving various prophylactic regimens was subjected to Bayesian network meta-analysis. RESULTS: Twenty-two trials (2,891 patients and 11 regimens) were included. Overall, medical prophylaxis reduced the incidence of POAF (OR, 0.33; 95% CI, 0.22-0.49) but not short-term mortality (OR, 0.85; 95% CI, 0.41-1.73). There was no significant difference in patient withdrawal due to adverse events (OR, 1.67; 95% CI, 0.67-4.16). Trial sequential analysis showed that as of 2012, sufficient evidence had accrued in support of the effectiveness of medical prophylaxis in reducing POAF after general thoracic surgery. In network meta-analysis, ß-blockers, angiotensin-converting enzyme inhibitors, amiodarone, magnesium, and calcium channel blockers significantly reduced the risk of POAF compared with placebo/usual care. ß-Blockers had the highest probability of being the most effective agents (OR, 0.12; 95% credible interval [CrI], 0.05-0.27; probability of being best, 77.7%; number needed to treat, 5.2). CONCLUSIONS: The current literature supports the effectiveness and tolerability of medical prophylaxis and the superiority of ß-blockers in preventing POAF after general thoracic surgery. ß-Blockers are recommended, taking into consideration the status of the bronchopulmonary system.

[MODERN MEANS FOR THE TREATMENT OF ATRIAL FIBRILLATION IN DIABETIC PATIENTS].

The authors discuss modern approaches to the treatment of atrial fibrillation with reference to diabetic patients. The studies carried out thus far showed the importance of differential anti-arrhythmic therapy taking account of the clinical form of ciliary arrhythmia. The possibility of surgical and preventive treatment (up-stream therapy) is demonstrated.

[CLASSIFICATION AND PRINCIPLES OF ACTION OF ANTIARRHYTHMIC AGENTS.]

Data on the pathophysiological mechanisms of arrhythmias and the elecrophysiological mechanisms of antiarrhythmic drug action are reviewed. Development of the classification of antiarrhythmic drugs is analyzed.

Propafenone shows class Ic and class II antiarrhythmic effects.

AIMS: Propafenone is a well-known Class Ic antiarrhythmic agent. It has the typical chemical structure of a beta-blocker, but human studies on its beta-blocking effects revealed conflicting results. METHODS AND RESULTS: Twelve healthy males received single oral doses of 600 mg propafenone and placebo according to a randomized, double-blind, placebo-controlled, cross-over protocol. Four hours following drug intake, heart rate and blood pressure were measured, and plasma concentrations of propafenone were determined at rest, during exercise and after recovery. At exercise, propafenone significantly decreased heart rate (-6%, P < 0.05), systolic blood pressure (-6%, P < 0.05), and the rate-pressure product (-11%, P < 0.05). Plasma concentrations of propafenone increased during exercise (+23%, P < 0.05) and decreased during recovery (-33%, P < 0.05). CONCLUSION: Both effects on heart rate and blood pressure as well as the changes of plasma concentrations of propafenone during exercise represent two particular features of beta-blockers. Therefore, we conclude that propafenone is both a Class Ic and a Class II antiarrhythmic agent, and 600 mg propafenone, i.e. the dose recommended in current guidelines for cardioversion of paroxysmal atrial fibrillation, cause clinically significant beta-blockade. Thus, single oral doses of 600 mg propafenone appear also suitable for cardioversion of paroxysmal atrial fibrillation in patients with structural heart disease since beta-blockers are explicitly indicated in the treatment of both coronary artery disease and heart failure.

Recent Advances in the Pharmacological Management of Atrial Fibrillation.

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia that leads to hospitalizations for complications and adverse events each year. Despite significant improvement in our therapeutic approaches in the past decade, management of AF remains a difficult task. Novel therapies have failed to terminate AF and prevent its recurrence, and patients with AF continue to have thromboembolic complications. With the increasingly aging population and associated conditions, the prevalence of AF is expected to progressively increase, becoming a public health problem. Most patients with AF have multiple comorbidities and are of advanced age, making long-term anticoagulation challenging. This article provides an overview of the current pharmacological therapies for the management of AF, with particular emphasis on the emerging agents.

Antiarrhythmic drugs in pregnancy.

The risk of arrhythmia development or recurrence is increased during pregnancy. For those arrhythmias that are unresponsive to conservative therapy, such as vagal maneuvers or life style interventions, or that present a higher risk to the mother or fetus, medical therapy may be necessary. In each case, the patient and provider must carefully consider the risks and benefits of a particular therapy. This requires an understanding of the data regarding the safety and efficacy of any particular drug, which in some cases may be extensive and in others quite limited. Fortunately, options exist for the treatment of arrhythmias during pregnancy.

Management of Brugada Syndrome: Thirty-Three-Year Experience Using Electrophysiologically Guided Therapy With Class 1A Antiarrhythmic Drugs.

BACKGROUND: Information on long-term clinical outcome of patients with Brugada syndrome treated with electrophysiologically guided class 1A antiarrhythmic drugs (AAD) is limited. METHODS AND RESULTS: An aggressive protocol of programmed ventricular stimulation was performed in 96 patients with Brugada syndrome (88% males; mean age, 39.8±15.9 years). Ten patients were cardiac arrest survivors, 27 had presented with syncope, and 59 were asymptomatic. Ventricular fibrillation was induced in 66 patients, including 100%, 74%, and 61% of patients with cardiac arrest, syncope, and no symptoms, respectively. All but 6 of the 66 patients with inducible ventricular fibrillation underwent electrophysiological testing on quinidine (n=54), disopyramide (n=2), or both (n=4). Fifty-four (90%) patients were electrophysiological responders to >1 AAD with similar efficacy rates (≈90%) in all patients groups. Patients with no inducible ventricular fibrillation at baseline were left on no therapy. After a mean follow-up of 113.3±71.5 months, 92 patients were alive, whereas 4 died from noncardiac causes. No arrhythmic event occurred during class 1A AAD therapy in any of electrophysiological drug responders and in patients with no baseline inducible ventricular fibrillation. Arrhythmic events occurred in only 2 cardiac arrest survivors treated with implantable cardioverter-defibrillator alone but did not recur on quinidine. All cases of recurrent syncope (n=12) were attributed to a vasovagal (n=10) or nonarrhythmic mechanism (n=2). Class 1A AAD therapy resulted in 38% incidence of side effects that resolved after drug discontinuation. CONCLUSIONS: Our data suggest that electrophysiologically guided class 1A AAD treatment has a place in our therapeutic armamentarium for all types of patients with Brugada syndrome.

Antiarrhythmic drug therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Prevalence increases with advancing age and so as its associated comorbidities, like heart failure. Choice of pharmacologic therapy depends on whether the goal of treatment is maintaining sinus rhythm or tolerating AF with adequate control of ventricular rates. Antiarrhythmic therapy and conversion of AF into sinus rhythm comes with the side effect profile, and we should select best antiarrhythmic therapy, individualized to the patient. New antiarrhythmic drugs are being tested in clinical trials. Drugs that target remodeling and inflammation are being tested for their use as prevention of AF or as upstream therapy.

[Idiopathic arrhythmias: possibilities of complex nosological diagnosis, and differentiated treatment].

AIM: of the study was to elucidate nosological nature of "idiopathic" arrhythmias by means of complex clinical-morphological examination and to assess efficacy of differentiated (including etiotropic and pathogenetic) treatment. MATERIAL AND METHODS: We examined 190 patients (117 women, mean age 45.33 ± 14.84 years) with "idiopathic" arrhythmias: atrial fibrillation (38.9%) (AF,) and flutter (11.1%), supraventricular (44.7%) and ventricular (55.3%) extrasystoles (SVE and VE), bouts of ventricular tachycardia (15.8%), atrioventricular block (22,6%) et al. Mean number of antiarrhythmic drugs per patient was 3 (from 1 to 8). Examination included Holter ECG monitoring, echocardiography, determination of anticardiac antibodies (97.4%) and markers of cardiotropic viruses (87.4%), treadmill test (26.3%), transesophageal cardiac pacing (12.1%), electrophysiological investigation (10%), multispiral computed tomography (22.1%), magnetic resonance tomography (21.6%), scintigraphy (27.4%), coronary angiography (10.0%), endomyocardial biopsy (EMB) (10.0%), DNA diagnostics (8.9%). RESULTS: EMB revealed immune-inflammatory (myo/endocarditis, systemic/myocardial vasculitis) or genetic pathology in 78.9 and 21.1% of cases, respectively. Level of anticardiac antibodies (including specific antinuclear factor) most closely correlated with EMB findings. On the basis of comparison of EMB data with data of complex examination we created algorithm of nosological diagnostics in "idiopathic" arrhythmias. According to nosology all patients were distributed in the following way: 1) chronic infectious-immune myocarditis (n=144, 75.7%), morphologically verified in 14, viral in 27 patients; 2) genetic cardiomyopathy (n=15, 7.9%), morphologically verified in 4, virus positive in 1 (arrhythmogenic right ventricular dysplasia, non-compaction myocardium, Fabri disease, Brugada syndrome, undetermined); in 4 patients mutations in plakophilin 2, desmoglein, desmin, -galactosidase A genes were found; 3) combination of genetic diseases with myocarditis (n=18; 9.5%) including viral (n=3); 4) isolated myocardiodystrophy (tonsillogenic< dyshormonal, n=3, 1.6%); 5) proper idiopathic arrhythmias (n=10, 5.3%). Therapy of myocarditis included antiviral (43.2%) and immunosuppressive (76.3%) drugs. Cardiotropic and antiarrhythmic therapy was also administered. Only in patients with myocarditis it was possible to withdraw effective antiarrhythmic (16.7%) and to improve effect of previously ineffective drugs. Surgical treatment (implantation of pacemaker or cardioverter-defibrillator, radiofrequency ablation) was more frequently used in patients with genetic (39.4%) and idiopathic arrhythmias (53.8%) than in patients with myocarditis (16.0%). CONCLUSION: Etiology of idiopathic arrhythmias can be established in most cases. Their main causes are immune-inflammatory diseases, genetic cardiomyopathies and their combination. Therapy of myocarditis improves antiarrhythmic activity of treatment, in some patients allows to withdraw antiarrhythmic drugs, decrease requirements in surgical treatment and to optimally prepare patients to radiofrequency ablation.

[New developments in the antiarrhythmic therapy of atrial fibrillation]. / Neue Entwicklungen in der antiarrhythmischen Therapie des Vorhofflimmerns.

Atrial fibrillation often affects elderly people with cardiovascular disease and takes a progressive course with increasing resistance to treatment. For the latter, electrical and structural changes (remodelling) seem to be responsible that are directly related to the high excitatory rate in the atria. Therapeutic strategies for atrial fibrillation consist of (i) treating the underlying cardiovascular disease, (ii) re-establishing sinus rhythm and (iii) reducing ventricular rate. Rapid pharmacological or electrical cardioversion is expected to prevent remodelling. Classical antiarrhythmic drugs are notoriously ineffective and burdened with serious cardiac and extracardiac side effects so that there is an urgent need for effective and safe novel compounds. In this review the three recently introduced drugs dronedarone, vernakalant and ranolazine are discussed with respect to the use in atrial fibrillation. Other new antiarrhythmic agents are still in the developmental phase and aim at atria-selective mechanisms thereby excluding ventricular proarrhythmic effects. The mechanisms of action will be discussed in the context of the present understanding of the pathophysiology of onset and maintenance of atrial fibrillation.

[Medicinal rhythm control in atrial fibrillation]. / Medikamentöse Rhythmuskontrolle bei Vorhofflimmern.

Medicinal antiarrhythmic therapy is either used in the acute setting to convert atrial fibrillation to sinus rhythm or as chronic medication to preserve sinus rhythm if a rhythm control strategy is followed. The choice of the antiarrhythmic agent is based on the presence or absence of structural heart disease. In addition, oral anticoagulation should be established according to current guidelines. In the acute setting the armamentarium comprises flecainide, propafenone, vernakalant and amiodarone. Usually, combination therapy with an atrioventricular (AV) node slowing drug (a beta blocker or verapamil) is used. For chronic rhythm control a class IC drug, such as sotalol, dronedarone and amiodarone is given depending on the comorbidities. In the absence of structural heart disease, rare episodes of paroxysmal atrial fibrillation can be treated by a pill-in-the-pocket strategy, i.e. self-administered pharmacological cardioversion with flecainide or propafenone. Despite recent advances in catheter ablation of atrial fibrillation, medical rhythm control continues to play an important role due to its ubiquitous availability and relatively easy use. The risk for proarrhythmia has to be evaluated in all patients.

[Medicinal rate control in atrial fibrillation]. / Medikamentöse Frequenzkontrolle bei Vorhofflimmern.

Atrial fibrillation is the most common form of persistent arrhythmia. Atrial fibrillation frequently causes rapid ventricular response with severe clinical symptoms requiring acute control of the ventricular rate. This leads to hemodynamic stabilization and improvement of symptoms. The long-term treatment target is to minimize patient symptoms and prevention of complications. As a rhythm control strategy does not provide a survival benefit compared to a rate control strategy, decisions on the best long-term treatment have to be individualized. Important factors affecting this decision are age of the patient, chances to re-establish and maintain sinus rhythm, tolerance of antiarrhythmic medication and accompanying diseases of the heart. For younger patients a rhythm control strategy will usually be the preferred option. For rate control beta blockers are considered first line therapy, alternative drugs include calcium antagonists and digoxin. Occasionally, amiodarone may also be used for rate control. If pharmacological rate management fails ablation of the atrioventricular (AV) node may be an option to control the ventricular rate.

[Medicinal treatment of atrial fibrillation in special situations]. / Medikamentöse Therapie des Vorhofflimmerns in speziellen Situationen.

The treatment of atrial fibrillation has to take into account the underlying cardiac and extracardiac diseases. A successful treatment of the underlying disease will only be sufficient treatment of atrial fibrillation in very rare situations. Therefore, this review focuses on the consequences of underlying heart disease, the hemodynamics and concomitant clinical situations on the treatment of atrial fibrillation.