Omega-3 Polyunsaturated Fatty Acid Supplementation: Mechanism and Current Evidence in Atrial Fibrillation.
ABSTRACT: Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with considerable morbidity and mortality. Available pharmacologic antiarrhythmic therapies are often ineffective in preventing the recurrence of AF, possibly because these drugs target a single pathophysiological mechanism. Given their beneficial effects on ventricular arrhythmias, omega-3 polyunsaturated fatty acids (n-3 PUFAs) have recently been investigated as possible candidates in the treatment of supraventricular arrhythmias. In this review, we explore the current understanding of the antiarrhythmic effects attributed to n-3 PUFAs including direct modulation of ionic channels, improvement of membrane fluidity, anti-inflammatory and antifibrotic effects, and modulation of sympatho-vagal balance. We will then focus on the results of epidemiologic studies exploring the associations between nutritional intake of n3 PUFAs and the incidence of AF, and will review the findings of the clinical trials investigating the effects of n-3 PUFAs supplementation in the prophylaxis of AF and in the prevention of its recurrences.
Project description:Previous studies have suggested that n-3 polyunsaturated fatty acids (n-3 PUFAs) have antiarrhythmic effects on atrial fibrillation (AF). We aimed to assess the effects of therapy with n-3 PUFAs on the incidence of recurrent AF and on postoperative AF.Electronic searches were conducted in Web of Science, Medline, Biological Abstracts, Journal Citation Reports, and the Cochrane Central Register of Controlled Trials databases. In addition, data from the recently completed FOR?ARD and OPERA trials were included. We included randomized controlled trials comparing treatment with n-3 PUFAs versus control to (1) prevent recurrent AF in patients who underwent reversion of AF or (2) prevent incident postoperative AF after cardiac surgery. Of identified studies, 12.9% (16 of 124) were included, providing data on 4677 patients. Eight studies (1990 patients) evaluated n-3 PUFA effects on AF recurrence among patients with reverted AF and 8 trials (2687 patients) on postoperative AF. Pooled risk ratios through random-effects models showed no significant effects on AF recurrence (RR, 0.95; 95% CI, 0.79 to 1.13; I(2), 72%) or on postoperative AF (0.86; 95% CI, 0.71 to 1.04; I(2), 53.1%). A funnel plot suggested publication bias among postoperative trials but not among persistent AF trials. Meta-regression analysis did not find any relationship between doses and effects (P=0.887 and 0.833 for recurrent and postoperative AF, respectively).Published clinical trials do not support n-3 PUFAs as agents aimed at preventing either postoperative or recurrent AF.URL: http://www.crd.york.ac.uk/PROSPERO. Unique Identifier: CRD42012002199.
Project description:<h4>Background and aims</h4>Evaluating associations of circulating electrolytes with atrial fibrillation (AF) and burden of supraventricular arrhythmias can give insights into arrhythmia pathogenesis.<h4>Methods and results</h4>We conducted a cross-sectional analysis of 6398 participants of the Atherosclerosis Risk in Communities (ARIC) study, ages 71-90, with data on serum electrolytes (magnesium, calcium, potassium, phosphorus, chloride, sodium). Prevalence of AF was determined from electrocardiograms and history of AF hospitalizations. A subset of 317 participants also underwent electrocardiographic recordings for up to 14 days using the Zio® patch. Burden of other supraventricular arrhythmias [premature atrial contractions (PACs), supraventricular tachycardia] was determined with the Zio® patch. We used logistic and linear regression adjusting for potential confounders to determine associations of electrolytes with arrhythmia prevalence and burden. Among 6394 eligible participants, 614 (10%) had AF. Participants in the top quintiles of magnesium [odds ratio (OR) 0.82, 95% confidence interval (CI) 0.62, 1.08], potassium (OR 0.82, 95%CI 0.68, 1.00), and phosphorus (OR 0.73, 95%CI 0.59, 0.89) had lower AF prevalence compared to those in the bottom quintiles. No clear association was found for circulating chloride, calcium or sodium. Higher concentrations of circulating calcium were associated with lower prevalence of PACs in the 12-lead electrocardiogram, while higher concentrations of potassium, chloride and sodium were associated with higher PAC prevalence. Circulating electrolytes were not significantly associated with burden of PACs or supraventricular tachycardia among 317 participants with extended electrocardiographic monitoring.<h4>Conclusion</h4>Concentrations of circulating electrolytes present complex associations with selected supraventricular arrhythmias. Future studies should evaluate underlying mechanisms.
Project description:BACKGROUND:Arrhythmias are common in the pediatric population. In patients unable to take oral medications or in need of acute therapy, options of intravenous (IV) antiarrhythmic medications are limited. Recently IV sotalol has become readily available, but experience in children is limited. OBJECTIVE:The purpose of this study was to describe our initial experience with the use of IV sotalol in the pediatric population. METHODS:A retrospective study of all pediatric patients receiving IV sotalol was performed. Patient demographic characteristics, presence of congenital heart disease, arrhythmia type, efficacy of IV sotalol use, and adverse effects were evaluated. RESULTS:A total of 47 patients (26 (55%) male and 24 (51%) with congenital heart disease) received IV sotalol at a median age of 2.05 years (interquartile range 0.07-10.03 years) and a median weight of 12.8 kg (interquartile range 3.8-34.2 kg), and 13 (28%) received IV sotalol in the acute postoperative setting. Supraventricular arrhythmias occurred in 40 patients (85%) and ventricular tachycardia in 7 (15%). Among 24 patients receiving IV sotalol for an active arrhythmia, acute termination was achieved in 21 (88%). Twenty-three patients received IV sotalol as maintenance therapy for recurrent arrhythmias owing to inability to take oral antiarrhythmic medications; 19 (83%) were controlled with sotalol monotherapy. No patient required discontinuation of IV sotalol secondary to adverse effects, proarrhythmia, or QT prolongation. CONCLUSION:IV sotalol is an effective antiarrhythmic option for pediatric patients and may be an excellent agent for acute termination of active arrhythmias. It was well tolerated, with no patient requiring discontinuation secondary to adverse effects.
Project description:Only few pharmacologic compounds have been validated for treatment of atrial fibrillation (AF) in horses. Studies investigating the utility and safety of flecainide to treat AF in horses have produced conflicting results, and the antiarrhythmic mechanisms of flecainide are not fully understood.To study the potential of flecainide to terminate acutely induced AF of short duration (? 15 minutes), to examine flecainide-induced changes in AF duration and AF vulnerability, and to investigate the in vivo effects of flecainide on right atrial effective refractory period, AF cycle length, and ventricular depolarization and repolarization.Nine Standardbred horses. Eight received flecainide, 3 were used as time-matched controls, 2 of which also received flecainide.Prospective study. The antiarrhythmic and electrophysiologic effects of flecainide were based on 5 parameters: ability to terminate acute pacing-induced AF (? 15 minutes), and drug-induced changes in atrial effective refractory period, AF duration, AF vulnerability, and ventricular depolarization and repolarization times. Parameters were assessed at baseline and after flecainide by programmed electrical stimulation methods.Flecainide terminated all acutely induced AF episodes (n = 7); (AF duration, 21 ± 5 minutes) and significantly decreased the AF duration, but neither altered atrial effective refractory period nor AF vulnerability significantly. Ventricular repolarization time was prolonged between 8 and 20 minutes after initiation of flecainide infusion, but no ventricular arrhythmias were detected.Flecainide had clear antiarrhythmic properties in terminating acute pacing-induced AF, but showed no protective properties against immediate reinduction of AF. Flecainide caused temporary prolongation in the ventricular repolarization, which may be a proarrhythmic effect.
Project description:Myocardial infarction causes sympathetic activation and parasympathetic dysfunction, which increase risk of sudden death due to ventricular arrhythmias. Mechanisms underlying parasympathetic dysfunction are unclear. The aim of this study was to delineate consequences of myocardial infarction on parasympathetic myocardial neurotransmitter levels and the function of parasympathetic cardiac ganglia neurons, and to assess electrophysiological effects of vagal nerve stimulation on ventricular arrhythmias in a chronic porcine infarct model. While norepinephrine levels decreased, cardiac acetylcholine levels remained preserved in border zones and viable myocardium of infarcted hearts. In vivo neuronal recordings demonstrated abnormalities in firing frequency of parasympathetic neurons of infarcted animals. Neurons that were activated by parasympathetic stimulation had low basal firing frequency, while neurons that were suppressed by left vagal nerve stimulation had abnormally high basal activity. Myocardial infarction increased sympathetic inputs to parasympathetic convergent neurons. However, the underlying parasympathetic cardiac neuronal network remained intact. Augmenting parasympathetic drive with vagal nerve stimulation reduced ventricular arrhythmia inducibility by decreasing ventricular excitability and heterogeneity of repolarization of infarct border zones, an area with known proarrhythmic potential. Preserved acetylcholine levels and intact parasympathetic neuronal pathways can explain the electrical stabilization of infarct border zones with vagal nerve stimulation, providing insight into its antiarrhythmic benefit.
Project description:Ranolazine is a Food and Drug Administration-approved antianginal agent. Experimental and clinical studies have shown that ranolazine has antiarrhythmic effects in both ventricles and atria. In the ventricles, ranolazine can suppress arrhythmias associated with acute coronary syndrome, long QT syndrome, heart failure, ischemia, and reperfusion. In atria, ranolazine effectively suppresses atrial tachyarrhythmias and atrial fibrillation (AF). Recent studies have shown that the drug may be effective and safe in suppressing AF when used as a pill-in-the pocket approach, even in patients with structurally compromised hearts, warranting further study. The principal mechanism underlying ranolazine's antiarrhythmic actions is thought to be primarily via inhibition of late I(Na) in the ventricles and via use-dependent inhibition of peak I(Na) and I(Kr) in the atria. Short- and long-term safety of ranolazine has been demonstrated in the clinic, even in patients with structural heart disease. This review summarizes the available data regarding the electrophysiologic actions and antiarrhythmic properties of ranolazine in preclinical and clinical studies.
Project description:BACKGROUND:Antiarrhythmic drugs are widely used to treat patients with atrial fibrillation (AF), but the mechanisms conveying their variable effectiveness are not known. Recent data suggested that paired like homeodomain-2 transcription factor (PITX2) might play an important role in regulating gene expression and electrical function of the adult left atrium (LA). OBJECTIVES:After determining LA PITX2 expression in AF patients requiring rhythm control therapy, the authors assessed the effects of Pitx2c on LA electrophysiology and the effect of antiarrhythmic drugs. METHODS:LA PITX2 messenger ribonucleic acid (mRNA) levels were measured in 95 patients undergoing thoracoscopic AF ablation. The effects of flecainide, a sodium (Na+)-channel blocker, and d,l-sotalol, a potassium channel blocker, were studied in littermate mice with normal and reduced Pitx2c mRNA by electrophysiological study, optical mapping, and patch clamp studies. PITX2-dependent mechanisms of antiarrhythmic drug action were studied in human embryonic kidney (HEK) cells expressing human Na channels and by modeling human action potentials. RESULTS:Flecainide 1 ?mol/l was more effective in suppressing atrial arrhythmias in atria with reduced Pitx2c mRNA levels (Pitx2c+/-). Resting membrane potential was more depolarized in Pitx2c+/- atria, and TWIK-related acid-sensitive K+ channel 2 (TASK-2) gene and protein expression were decreased. This resulted in enhanced post-repolarization refractoriness and more effective Na-channel inhibition. Defined holding potentials eliminated differences in flecainide's effects between wild-type and Pitx2c+/- atrial cardiomyocytes. More positive holding potentials replicated the increased effectiveness of flecainide in blocking human Nav1.5 channels in HEK293 cells. Computer modeling reproduced an enhanced effectiveness of Na-channel block when resting membrane potential was slightly depolarized. CONCLUSIONS:PITX2 mRNA modulates atrial resting membrane potential and thereby alters the effectiveness of Na-channel blockers. PITX2 and ion channels regulating the resting membrane potential may provide novel targets for antiarrhythmic drug development and companion therapeutics in AF.
Project description:Amiodarone, one of the most widely prescribed antiarrhythmic drugs to treat both ventricular and supraventricular arrhythmias, has been identified as a candidate drug for use against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We present the rationale of using amiodarone in the COVID-19 scenario, as well as whether or not amiodarone administration represents a potential strategy to prevent SARS-CoV-2 infection, rather than simply used to treat patients already symptomatic and/or with severe coronavirus disease 2019 (COVID-19), based on current evidence.
Project description:BACKGROUND:Omega-3 polyunsaturated fatty acids (n3-PUFAs) might have antiarrhythmic properties, but data conflict on whether n3-PUFAs reduce rates of atrial fibrillation (AF) after coronary artery bypass graft surgery (CABG). We hypothesized that n3-PUFAs would reduce post-CABG AF, and we tested this hypothesis in a well-powered, randomized, double-blind, placebo-controlled, multicenter clinical trial. METHODS AND RESULTS:Patients undergoing CABG were randomized to pharmaceutical-grade n3-PUFAs 2 g orally twice daily (minimum of 6 g) or a matched placebo ?24 hours before surgery. Gas chromatography was used to assess plasma fatty acid composition of samples collected on the day of screening, day of surgery, and postoperative day 4. Treatment continued either until the primary end point, clinically significant AF requiring treatment, occurred or for a maximum of 2 weeks after surgery. Two hundred sixty patients were enrolled and randomized. Before surgery, n3-PUFA dosing increased plasma n3-PUFA levels from 2.9% to 4% and reduced the n6:n3-PUFA ratio from 9.1 to 6.4 (both P<0.001). Similar changes were noted on postoperative day 4. There were no lipid changes in the placebo group. The rate of post-CABG AF was similar in both groups (30% n3-PUFAs versus 33% placebo, P=0.67). The post-CABG AF odds ratio for n3-PUFAs relative to placebo was 0.89 (95% confidence interval 0.52-1.53). There were no differences in any secondary end points. CONCLUSIONS:Oral n3-PUFA supplementation begun 2 days before CABG did not reduce AF or other complications after surgery. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov Unique identifier: NCT00446966. (J Am Heart Assoc. 2012;1:e000547 doi: 10.1161/JAHA.111.000547.).
Project description:Ischemic heart disease is a significant public health problem with high mortality and morbidity. Extensive scientific investigations from basic sciences to clinics revealed multilevel alterations from metabolic imbalance, altered electrophysiology, and defective Ca<sup>2+</sup>/Na<sup>+</sup> homeostasis leading to lethal arrhythmias. Despite the recent identification of numerous molecular targets with potential therapeutic interest, a pragmatic observation on the current pharmacological R&D output confirms the lack of new therapeutic offers to patients. By contrast, from recent trials, molecules initially developed for other fields of application have shown cardiovascular benefits, as illustrated with some anti-diabetic agents, regardless of the presence or absence of diabetes, emphasizing the clear advantage of "old" drug repositioning. Ranolazine is approved as an antianginal agent and has a favorable overall safety profile. This drug, developed initially as a metabolic modulator, was also identified as an inhibitor of the cardiac late Na<sup>+</sup> current, although it also blocks other ionic currents, including the hERG/Ikr K<sup>+</sup> current. The latter actions have been involved in this drug's antiarrhythmic effects, both on supraventricular and ventricular arrhythmias (VA). However, despite initial enthusiasm and promising development in the cardiovascular field, ranolazine is only authorized as a second-line treatment in patients with chronic angina pectoris, notwithstanding its antiarrhythmic properties. A plausible reason for this is the apparent difficulty in linking the clinical benefits to the multiple molecular actions of this drug. Here, we review ranolazine's experimental and clinical knowledge on cardiac metabolism and arrhythmias. We also highlight advances in understanding novel effects on neurons, the vascular system, skeletal muscles, blood sugar control, and cancer, which may open the way to reposition this "old" drug alone or in combination with other medications.