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Dose is an important parameter in terms of both efficacy and adverse effects in pharmacological treatment of atrial fibrillation (AF). Both of the class III antiarrhythmics dofetilide and amiodarone have documented anti-AF effects. While dofetilide has dose-related ventricular side effects, amiodarone primarily has adverse non-cardiac effects. Pharmacological inhibition of small conductance Ca2+-activated K+ (SK) channels has recently been reported to be antiarrhythmic in a number of animal AF models. In a Langendorff model of acutely induced AF on guinea pig hearts, it was investigated whether a combination of the SK channel blocker N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) together with either dofetilide or amiodarone provided a synergistic effect. The duration of AF was reduced with otherwise subefficacious concentrations of either dofetilide or amiodarone when combined with ICA, also at a subefficacious concentration. At a concentration level effective as monotherapy, dofetilide produced a marked increase in the QT interval. This QT prolonging effect was absent when combined with ICA at non-efficacious monotherapy concentrations. The results thereby reveal that combination of subefficacious concentrations of an SK channel blocker and either dofetilide or amiodarone can maintain anti-AF properties, while the risk of ventricular arrhythmias is reduced.

Aging is associated with electrical and structural changes of the myocardium. The response to catecholamines is also reduced and the baroreceptor reflex activity is blunted. These aspects conceivably affect the response to antiarrhythmic drugs in the elderly. Furthermore, physiological parameters change in older age, affecting the pharmacokinetics of drugs. In this article, the literature on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs in elderly subjects is reviewed with the purpose of improving their optimal and safe prescription. Pharmacokinetic studies of antiarrhythmic drugs in the elderly are sparse, and there are no data available for procainamide and propafenone. Mean dose reductions calculated for elderly patients relative to younger patients are 60% for digoxin, 19% for diltiazem, 32% for disopyramide, 31% for flecainide, 40% for metoprolol, 35% for quinidine, 29% for sotalol and 26% for verapamil. No dose reductions are required for dofetilide or dronedarone. The clearance of dofetilide is not affected by age after correction for renal function. The dosage of dofetilide is individualized according to an algorithm based on the corrected QT (QTc) interval and renal function. Although the area under the plasma concentration-time curve (AUC) for dronedarone is larger in elderly patients, the dose should not be reduced because the registered dose has specifically been studied in an elderly population. In elderly patients with renal insufficiency, hepatic impairment, heart failure or certain genetic variants, the pharmacokinetics of antiarrhythmic drugs might be affected to an even greater extent, meaning additional dosage adjustments are necessary. With increasing age, the number of prescribed drugs increases because of co-morbidity, making interactions between drugs more likely. Several drugs interact with antiarrhythmic drugs, leading to clinically relevant changes in drug concentrations or AUC values. Furthermore, several drugs with non-cardiovascular indications appear to have QTc prolonging effects. The combination of these drugs with antiarrhythmic drugs that affect the QTc interval increases the risk of developing torsades de pointes and should therefore be avoided. Altered effects of drugs in the elderly can also be the result of age-related changes in the cardiovascular system. For example, atenolol and sotalol show greater effects, i.e. reductions in heart rate and increased probability of adverse effects, at a given plasma concentration in older subjects compared with younger subjects. It remains unclear whether old age as such is a determinant for reduced or modified efficacy of antiarrhythmic drugs. In a randomized study it was found that patients aged ≥65 years with atrial fibrillation had better survival with rate control than with rhythm control. However, different treatment strategies were compared and the results cannot be extrapolated to indicate better survival with a specific antiarrhythmic drug. Antiarrhythmic drugs will remain the first-line approach in most patients for the prevention or suppression of atrial and ventricular arrhythmias. As a rule of thumb, a 50% reduction in the starting dose of antiarrhythmic drugs compared with younger patients appears a wise approach in elderly patients. However, this does not apply to dofetilide and dronedarone. The selection of antiarrhythmic drugs in the elderly is predominantly determined by factors such as the treatment target, assumed patient compliance, possible drug interactions, co-morbidity, and renal and liver function. Efficacy and safety monitoring should take into account symptoms, ECG findings, rhythm recordings, plasma drug concentrations and other laboratory parameters. [PUBLICATION ABSTRACT]

The association between omega-3 (n-3 polyunsaturated fatty acids) and the clinical outcome of patients with cardiovascular diseases such as coronary heart disease is currently unclear, especially regarding its possible antiarrhythmic effects and the not quite understood mechanisms of action. In the last 15 years, several epidemiological studies have shown a lower incidence of sudden cardiac death with a diet rich in omega-3 or fish consumption. The antiarrhythmic properties related to omega-3 have been related to modulation of sodium-dependent ion channels or sodium-calcium exchangers of myocytes through a reduction of their excitability especially in ischaemic or damaged myocardial tissue. However, the results of experimental studies have not always been consistent. Although the role of omega-3 in preventing sudden cardiac death has been evaluated in several clinical trials that included patients with coronary artery disease (particularly in patients with post-myocardial infarction), the interpretation of such data must be treated with extreme caution. In particular, while a reduction in cardiac death was demonstrated by a meta-analysis of several randomized clinical trials, a reduced risk of sudden cardiac death has been described only in the GISSI-Prevenzione study, while in other studies the evidence that emerged is more controversial, with wide confidence intervals that support the possibility of heterogeneity in the distribution of the factors involved in the efficacy of treatment. Omega-3 is probably involved in the prevention of cardiovascular mortality through different mechanisms, and it is crucial to study its association with other drugs such as ACE inhibitors or calcium channel blockers. The study of antiarrhythmic drugs has been divided into prevention of supraventricular and ventricular arrhythmias. In these conditions, the role of omega-3 seems to be more pronounced in atrial tachyarrhythmias such as atrial fibrillation, but does not have a role in ventricular arrhythmias. In summary, the antiarrhythmic effect of omega-3 is not clearly evident and further studies are needed to investigate its beneficial effect in cardiac mortality compared with arrhythmic death. Received for publication 30 October 2012; accepted for publication 2 November 2012. [PUBLICATION ABSTRACT]

Omega-3 (n-3 polyunsaturated fatty acids) has demonstrated its ability to reduce global mortality, obtaining an indication for the prevention of sudden death in patients with myocardial infarction of the anterior wall. These observations have led to the design of several clinical studies aimed at demonstrating the potential antiarrhythmic effect of omega-3. These studies have given contradictory results, probably due to differences in the populations and doses used. Observations supporting the use of omega-3 as anti-arrhythmic agents come from a study in patients with post-ischaemic dilatative cardiomyopathy and carriers of implantable cardioverter defibrillators (ICDs), without cardiovascular events in the last 12 months. In this population a combination of nutraceuticals containing omega-3 (Ritmonutra ®) has been able to reduce the number of ventricular and supraventricular arrhythmias without modification of the left ventricle function. Specifically, a 46% reduction of premature ventricular contractions (BEV), 54.2% of premature supraventricular contractions (BESV), 48% of BESV run and 33% of sustained or non-ventricular tachycardia were observed (all significant, p < 0.0001). In a following study, the antiarrhythmc effect of Ritmonutra® was evaluated by Holter ECG for 24 hours in patients with essential hypertension, without ischaemia, preserved left ventricular function and positive anamnesis for arrhythmia. The results showed that omega-3 treatment produced a significant reduction of ventricular and supraventricular arrhythmias compared with placebo, without modification of heart rate, intra-cardiac conduction and contractility. A recent meta-analysis of studies conducted on omega-3 and possible reduction of cardiovascular events concluded that no significant beneficial effects are related to omega-3 treatment on reducing death for all cardiovascular events. Do these conclusions exclude omega-3 as an anti-arrhythmic? We currently have no antiarrhythmic therapies showing a clear reduction of mortality, with the exception of amiodarone and β-blockers (β-adrenoceptor antagonists). This consideration is even more important for treatment of arrhythmias in healthy subjects, when the first goal is the relief of symptoms and improvement in quality of life. Keeping these last points in mind, the answer to the previous question is a loud 'NO', also taking into account the fact that omega-3, in contrast to the other antiarrhythmics, do not negatively affect myocardial contractility. Received for publication 22 October 2012; accepted for publication 5 November 2012. [PUBLICATION ABSTRACT]

In this study, we randomly compared single oral doses of flecainide, amiodarone and propafenone versus placebo for the conversion of recent atrial fibrillation (AF) (within 48 hours). This is a randomized prospective, placebo-controlled single-blind study that included 160 consecutive patients with recent AF who were randomly assigned to single oral doses of flecainide (3 mg/kg of weight, n=40), amiodarone (30 mg/kg weight, n=40), propafenone (8.5 mg/kg of weight, n=40) or placebo (n=40). The primary end-point was conversion rate at 24 hours after the drug intake. The association between antiarrhythmic use and conversion rate was tested with multiple logistic regressions. The primary end-point was achieved in 87.5% of patients with flecainide, 85% of patients with amiodarone, 85% of patients with propafenone and 17.5% of patients with placebo (p<0.001 compared with placebo for all 3 drugs). Conversion rate within 3 hours after drug intake was greater with propafenone (57.5%) or flecainide (45%) compared with amiodarone (0%) or placebo (10%). Between 6 and 24 hours, significantly more patients were converted to sinus rhythm with amiodarone than with flecainide or propafenone. The use of antiarrhythmic drugs was a significant predictor of conversion to sinus rhythm compared to placebo (adjusted OR=19.53, 95% CI 3.14-121.55, p<0.001). No serious side effect occurred. In patients with recent-onset AF, oral flecainide, amiodarone or propafenone are superior to placebo in restoring sinus rhythm within the 24-hour period following the drug intake.

BACKGROUND AND PURPOSE: Female sex hormones may protect pre-menopausal women from sudden cardiac death. We therefore investigated the effects of the main female sex hormone, 17beta-estradiol, on ischaemia-induced cardiac arrhythmias and on the L-type Ca2+ current (ICaL). EXPERIMENTAL APPROACH: In vivo experiments were performed in pentobarbital-anaesthetized rats subjected to acute coronary artery occlusion. ICaL was measured by the whole-cell patch-clamp technique, in rat isolated ventricular myocytes. KEY RESULTS: Acute intravenous administration of 17beta-estradiol as a bolus dose followed by a continuous infusion, commencing 10 min before coronary artery occlusion, had dose-dependent antiarrhythmic activity. In female rats 300 ng kg(-1) + 30 ng kg(-1) min(-1) 17beta-estradiol significantly reduced the number of ventricular premature beats (VPBs) and the incidence of ventricular fibrillation (VF). A ten fold higher dose of 17beta-estradiol was required to cause similar effects in male rats. In vitro 17beta-estradiol reduced peak ICaL in a concentration-dependent manner. The EC50 was ten-fold higher in male myocytes (0.66 microM) than in females (0.06 microM). CONCLUSIONS AND IMPLICATIONS: These results indicate that 17beta-estradiol has marked dose-dependent antiarrhythmic activity that is greater in female rats than in males. A similar differential potency in blocking ICaL in myocytes from female and male rats can account for this effect. This provides an explanation for the antiarrhythmic activity of 17beta-estradiol and gender-selective protection against sudden cardiac death.

IntroductionAppropriate selection of antiarrhythmic drugs (AADs) in atrial fibrillation (AF) requires consideration of structural heart disease, renal and hepatic function, arrhythmia burden, and drug contraindications. CLARA is an artificial intelligence-powered decision support system that uses a WhatsApp chatbot interface integrated with an Excel-based clinical rules engine to guide AAD selection based on individualised patient profiles.MethodsA synthetic dataset of 150,000 patients with atrial fibrillation was created with varied clinical variables including left ventricular ejection fraction (LVEF), left atrial (LA) size, renal and liver function, AF type, prior AAD exposure, and comorbidities. CLARA was programmed to deliver AAD recommendations. To assess performance, CLARA was tested against cardiologist consensus recommendations in a cohort of 100 complex AF cases, including patients with left ventricular dysfunction, significant structural heart disease, and multiple prior AAD failures (figure 1).ResultsCLARA achieved 91% concordance with expert cardiologist recommendations in selecting the appropriate class and dose of AAD. In 29 patients with LVEF <40%, CLARA correctly excluded Class IC drugs in all cases and recommended amiodarone or rate control. In 18 patients with significant left atrial enlargement, rhythm control was appropriately deprioritised. For patients with prior AAD intolerance (n=26), CLARA accurately identified contraindicated agents. Median response time was under 2 minutes per case.Conclusions/ImplicationsCLARA demonstrates high clinical accuracy and responsiveness in recommending antiarrhythmic therapy in complex AF patients. Its integration of expert-derived algorithms with real-time chatbot interaction offers scalable, structured support for personalising rhythm control strategies. Future work will validate its use in prospective real-world AF populations and explore its integration with electronic health records.Abstract 43 Figure 1[Image Omitted. See PDF.]