Vaughan-Williams Class Research Articles

Impact of photoplethysmography-based smartphone rhythm monitoring on atrial fibrillation detection and management after cardiac surgery: a pragmatic randomized trial

Abstract Introduction Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is common and associated with adverse outcomes. Systematic monitoring of POAF beyond discharge is cumbersome. The emergence of photoplethysmography (PPG)-based rhythm monitoring with digital consumer devices could potentially mitigate these hurdles. Selected smartphone applications leveraging this technology have demonstrated excellent usability and accuracy for the detection of atrial fibrillation (AF). However, the impact of PPG-detected POAF on real-life clinical practice remains uncertain. Purpose To determine whether intermittent PPG-based smartphone rhythm monitoring, after being discharged home following cardiac surgery, impacts AF management. Methods The SURGICAL-AF 2 study is a pragmatic, investigator-initiated, open-label, multicenter, randomized clinical trial, conducted in three Belgian centers. The intervention group performed one-minute rhythm checks three times daily with a smartphone-based PPG application after hospitalization for cardiac surgery until the first follow-up visit with a cardiologist, scheduled at 21 – 91 days. Rhythm monitoring was not mandated in the usual care group. The primary endpoint was a composite of initiation of oral anticoagulation (OAC), cardioversion, up-titration or initiation of antiarrhythmic drugs (Vaughan-Williams class I or III) or implantation of a cardiac implantable electronic device (CIED). Secondary endpoints were incidence of POAF and actionable POAF, defined as a detection in patients with CHA2DS2-VASc score ≥2 for women or ≥1 for men who are not treated with OAC. Results Of the 450 patients randomized (238 patients in the intervention group and 212 patients in the usual care group; mean [SD] age, 64.1 [9.2] years; 96 women [21.3%]; 130 patients with AF before inclusion [28.9%]; 103 patients on OAC [22.9%], median [interquartile range] CHA2DS2-VASc score, 2 [1-3]), 98.7% completed the trial. In the intent-to-treat analysis, the primary end point occurred in 24 patients (10.3%) in the intervention group versus 5 patients (2.4%) in the usual care group (odds ratio (OR) 4.7, 95% CI, 1.8 - 12.6; P =.002). POAF was detected in 44 patients (18.8%) in the intervention group and was actionable in 25 patients (10.7%) versus 4 patients (1.9%) in the usual care group and actionable in 2 patients (0.9%). (POAF detection, OR 12.0, 95% CI, 4.2 - 34.5; P < .001; actionable POAF, OR 12.5, 95% CI, 2.9 - 52.6; P < .001) Conclusions In unselected patients discharged home following cardiac surgery, PPG-based smartphone monitoring revealed significantly more POAF which led to changes in AF management (OAC initiation, rhythm control therapy or CIED insertion). Longer follow-up is needed to determine whether these changes will lead to improved outcomes.

Suicide attempt of young woman by Propafenone overdose - case report

Introduction and purpose: Over the last few years, the number of suicide attempts in Polish women has been steadily increasing. This report presents a case of a 18 years old woman hospitalized in the Toxicology and Cardiology Department due to poisoning with antiarrhythmic drug – Propafenone, taken for suicide purpose.
 Brief description of the state of knowledge: Propafenone is an antiarrhythmic drug which belongs to class IC according to the Vaughan-Williams classification. The overdose of this drug can cause various symptoms and complications such as cardiac arrhythmias, liver damage, cardiac arrest and even death. This drug has no specific antidote. 
 Conclusions: Propafenone poisoning is a significant clinical challenge and the consequences are often unpredictable and life-threatening. Treatment options such as natrium bicarbonicum, insulin, intravenous lipid emulsion, calcium gluconate seem to be good choices and the effects of treatment with these drugs are promising for the future.

Pharmacological cardioversion of atrial fibrillation: practical considerations.

The choice between rhythm and rate control strategy represents one of the most intriguing dilemmas in the management of atrial fibrillation (AF). Although the advantage of rhythm over rate control in terms of outcome has not been equivocally proven, the initial management of patients with symptomatic episodes of AF frequently involves an attempt of early cardioversion. As electrical cardioversion (EC) is challenging in terms of fasting status and involvement of anesthesiology team, pharmacological cardioversion (PC) is usually selected as the first step towards rhythm conversion. Proper qualification for PC or EC is similar and should comprise assessment of hemodynamic status, estimation of duration of arrhythmic episode, evaluation of anticoagulation regimen, exclusion of other supraventricular arrhythmias and assessment of the chance of rhythm conversion and persistence of sinus rhythm. Finally, the choice of adequate antiarrhythmic drug (AAD) depends on the presence of structural heart disease and local experience. In patients without structural heart disease, complications occur rarely, hence traditional (propafenone, flecainide) or nonclassical Vaughan-Williams class I (antazoline) or class III (vernakalant, ibutilide or dofetilide) drugs are preferred. The presence of structural heart disease consistent with any left ventricular hypertrophy, heart failure, myocardial ischemia or valvular heart disease confines the choice of AAD to amiodarone. Given the risk of ventricular proarrhythmia of AAD, safety should always prevail over the enticing possibility of rhythm conversion. The present review aims to provide a comprehensible summary of proper qualification for PC, selection of suitable AAD and state-of-the-art periprocedural management of patients with recent-onset AF.

Thoracoscopic Surgical Ablation of Lone Atrial Fibrillation: Long-term Outcomes at 7 Years

BackgroundAntiarrhythmic drugs and transcatheter ablation in atrial fibrillation (AF) provide suboptimal rhythm control with a not negligible rate of failure in paroxysmal AF (PAF) and nonparoxysmal AF (n-PAF) at midterm and long-term follow-up. This study evaluated the safety profile and long-term efficacy of thoracoscopic ablation in patients with lone AF. MethodsA consecutive 153 patients with lone AF were prospectively enrolled and underwent thoracoscopic surgical ablation. Inclusion criteria were symptomatic AF refractory to pharmacologic therapy (Vaughan-Williams class I-III), age >18 years, and absence of left atrial thrombosis. Exclusion criteria were long-standing AF >5 years, left atrial diameter >55 mm, and contraindication to oral anticoagulation. The “box lesion set” (encircling of pulmonary veins) was always used. Exclusion of the left atrial appendage was performed only in selected cases. The primary study end point was freedom from AF. Secondary end points were overall survival and cumulative incidence function of cardiac event–related death, cerebrovascular accidents, and pacemaker implantation. ResultsThere was no in-hospital mortality. Early postoperative complications were pacemaker implantation (4/153 [2.6%]), cerebrovascular accident (2/153 [1.3%]) with full recovery of both, and bleeding requiring surgical revision (2/153 [1.3%]). Overall freedom from AF at 7 years was 86% ± 4% (76.9% in n-PAF, 96.1% in PAF). Survival freedom from AF in patients without antiarrhythmic drugs in PAF and n-PAF groups was 79.1% and 52.2%, respectively. ConclusionsThoracoscopic surgical ablation of lone AF by means of an isolated left atrial box lesion provided an excellent long-term rhythm outcome, even in long-standing persistent AF. The isolated left atrial ablation showed an excellent safety profile with low incidence of pacemaker implantation and postoperative complications.

Mechanisms Underlying the Antiarrhythmic Action of Compound ALM-802.

The mechanisms underlying the antiarrhythmic action of compound trihydrochloride N1-(2,3,4-trimethoxy)-N2-{2-[(2,3,4-trimethoxybenzyl)amino]ethyl}-1,2-ethane-diamine (code ALM-802) were studied in vitro. The experiments were performed on a culture of rat hippocampal neurons. The electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It is shown that the compound ALM-802 effectively blocks potential-dependent Na+ and K+ channels and does not affect the activity of potential-dependent Ca2+ channels. The inhibition of currents through these channels is dose-dependent; the IC50 of Na+ and K+ channels were 94±4 and 67±3 μM, respectively. These findings indicate that compound ALM-802 combines the properties of class I and class III antiarrhythmic agents according to the Vaughan-Williams classification.

Analysis of Electrophysiological Mechanisms of N-Deacetyllapaconitine Monochlorhydrate, the Main Metabolite of Lappaconitine Hydrobromide.

In in vitro experiments on isolated rat hippocampal neurons, we studied the electrophysiological mechanisms of the antiarrhythmic effects of N-deacetyllappaconitine monochlorhydrate (DALCh), active metabolite of lappaconitine hydrobromide (allapinin). Electrical activity of neurons was recorded by the patch-clamp method in the whole cell configuration. It was shown that DALCh increased the duration of both slow and fast depolarization phases and decreased the amplitude of the action potential. DALCh effectively inhibited transmembrane currents of Na+ ions and partially K+ ions through the corresponding transmembrane voltage-gated ion channels. Thus, DALCh, in contrast to lappaconitine hydrobromide, belongs not to 1C, but to the 1A class of antiarrhythmics according to the Vaughan-Williams classification.

Cardiac sodium channel inhibition by lamotrigine: In vitro characterization and clinical implications.

Lamotrigine, approved for use as an antiseizure medication as well as the treatment of bipolar disorder, inhibits sodium channels in the brain to reduce repetitive neuronal firing and pathological release of glutamate. The shared homology of sodium channels and lack of selectivity associated with channel blocking agents can cause slowing of cardiac conduction and increased proarrhythmic potential. The Vaughan‐Williams classification system differentiates sodium channel blockers using biophysical properties of binding. As such, Class Ib inhibitors, including mexiletine, do not slow cardiac conduction as measured by the electrocardiogram, at therapeutically relevant exposure. Our goal was to characterize the biophysical properties of NaV1.5 block and to support the observed clinical safety of lamotrigine. We used HEK‐293 cells stably expressing the hNaV1.5 channel and voltage clamp electrophysiology to quantify the potency (half‐maximal inhibitory concentration) against peak and late channel current, on‐/off‐rate binding kinetics, voltage‐dependence, and tonic block of the cardiac sodium channel by lamotrigine; and compared to clinically relevant Class Ia (quinidine), Ib (mexiletine), and Ic (flecainide) inhibitors. Lamotrigine blocked peak and late NaV1.5 current at therapeutically relevant exposure, with rapid kinetics and biophysical properties similar to the class Ib inhibitor mexiletine. However, no clinically meaningful prolongation in QRS or PR interval was observed in healthy subjects in a new analysis of a previously reported thorough QT clinical trial (SCA104648). In conclusion, the weak NaV1.5 block and rapid kinetics do not translate into clinically relevant conduction slowing at therapeutic exposure and support the clinical safety of lamotrigine in patients suffering from epilepsy and bipolar disorder.

Drug Interactions Affecting Antiarrhythmic Drug Use.

Antiarrhythmic drugs (AAD) play an important role in the management of arrhythmias. Drug interactions involving AAD are common in clinical practice. As AADs have a narrow therapeutic window, both pharmacokinetic as well as pharmacodynamic interactions involving AAD can result in serious adverse drug reactions ranging from arrhythmia recurrence, failure of device-based therapy, and heart failure, to death. Pharmacokinetic drug interactions frequently involve the inhibition of key metabolic pathways, resulting in accumulation of a substrate drug. Additionally, over the past 2 decades, the P-gp (permeability glycoprotein) has been increasingly cited as a significant source of drug interactions. Pharmacodynamic drug interactions involving AADs commonly involve additive QT prolongation. Amiodarone, quinidine, and dofetilide are AADs with numerous and clinically significant drug interactions. Recent studies have also demonstrated increased morbidity and mortality with the use of digoxin and other AAD which interact with P-gp. QT prolongation is an important pharmacodynamic interaction involving mainly Vaughan-Williams class III AAD as many commonly used drug classes, such as macrolide antibiotics, fluoroquinolone antibiotics, antipsychotics, and antiemetics prolong the QT interval. Whenever possible, serious drug-drug interactions involving AAD should be avoided. If unavoidable, patients will require closer monitoring and the concomitant use of interacting agents should be minimized. Increasing awareness of drug interactions among clinicians will significantly improve patient safety for patients with arrhythmias.

АНАЛИЗ ФАРМАКОЛОГИЧЕСКОЙ ТЕРАПИИ У ПАЦИЕНТОВ КАРДИОЛОГИЧЕСКОГО СТАЦИОНАРА С ЛЕКАРСТВЕННО-ИНДУЦИРОВАННЫМ СИНДРОМОМ УДЛИНЕННОГО ИНТЕРВАЛА QT

Background: The most common reason for drug-induced long QT syndrome is the intake of class III antiarrhythmic agents (according to the Vaughan-Williams classification). Their therapeutic effect is based on the ventricular repolarization deceleration and QT interval prolongation. Combined therapy with antiarrhythmic agents and other drugs increases the risk of QT interval prolongation. Objective: To assess the quantitative and qualitative structure of pharmacological therapy in patients who receive antiarrhythmic therapy during their inpatient treatment in a cardiology hospital. Material and methods: A retrospective analysis of the medical records of 120 patients, predominantly of those with ischemic heart disease, arterial hypertension and cardiac arrhythmias was carried out. All patients were divided into 2 groups based on the degree of QT interval prolongation in response to antiarrhythmic therapy. All drug therapies were recorded (name, dose, frequency and duration of drug intake, indicated in the prescription sheet). Only the drugs included in the international Crediblemeds Database were considered to have influence on the duration of the QT interval. Results: The patients of both groups had no statistically significant differences in terms of the total number of drugs taken (7.3±2.4 in the first group versus 6.92±1.6 in the second group, p=0.12). The percentage ratio of drugs that affect the duration of the QT interval to the total amount of the drugs used was 26±15% in the first group and 20.5±8% in the second group, p=0.71. When assessing the duration of the corrected QT interval depending on the structure of the combinations of drugs used, the highest incidence of torsades de pointes and the highest corrected QT interval values (503.45±23.9 ms) were recorded in the subgroup of patients taking 3 such drugs at the same time. Conclusions: A positive correlation was established between the number of drugs that prolong the QT interval and the value of the corrected QT interval. No statistically significant differences were found in the quantitative and qualitative structure of pharmacological therapy in patients with and without prolongation of the QT interval.

Rate control drugs differ in the prevention of progression of atrial fibrillation.

AimsWe hypothesize that in patients with paroxysmal atrial fibrillation (AF), verapamil is associated with lower AF progression compared to beta blockers or no rate control.Methods and resultsIn this pre-specified post hoc analysis of the RACE 4 randomized trial, the effect of rate control medication on AF progression in paroxysmal AF was analysed. Patients using Vaughan-Williams Class I or III antiarrhythmic drugs were excluded. The primary outcome was a composite of first electrical cardioversion (ECV), chemical cardioversion (CCV), or atrial ablation. Event rates are displayed using Kaplan–Meier curves and multivariable Cox regression analyses are used to adjust for baseline differences. Out of 666 patients with paroxysmal AF, 47 used verapamil, 383 used beta blockers, and 236 did not use rate control drugs. The verapamil group was significantly younger than the beta blocker group and contained more men than the no rate control group. Over a mean follow-up of 37 months, the primary outcome occurred in 17% in the verapamil group, 33% in the beta blocker group, and 33% in the no rate control group (P = 0.038). After adjusting for baseline characteristics, patients using verapamil have a significantly lower chance of receiving ECV, CCV, or atrial ablation compared to patients using beta blockers [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.19–0.83] and no rate control (HR 0.64, 95% CI 0.44–0.93).ConclusionIn patients with newly diagnosed paroxysmal AF, verapamil was associated with less AF progression, as compared to beta blockers and no rate control.

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.

Amiodarone exacerbates brain injuries after hypoxic\u2013ischemic insult in mice

BackgroundSodium ion transportation plays a crucial role in the pathogenesis of hypoxic–ischemic brain injury. Amiodarone, a Vaughan-Williams class III antiarrhythmic drug, has been widely used to treat life-threatening arrhythmia and cardiac arrest worldwide. In addition to its inhibitory effects on the potassium channel, amiodarone also blocks various sodium ion transporters, including the voltage-gated sodium channel, sodium pump, and Na+/Ca+ exchanger. Considering these pharmacological profile, amiodarone may affect the influx–efflux balance of sodium ion in the hypoxic–ischemic brain. Previous studies suggest that the blockade of the voltage-gated sodium channel during hypoxic–ischemic brain injury exerts neuroprotection. On the contrary, the blockade of sodium pump or Na+/Ca+ exchanger during hypoxia–ischemia may cause further intracellular sodium accumulation and consequent osmotic cell death. From these perspectives, the effects of amiodarone on sodium ion balance on the hypoxic–ischemic brain can be both protective and detrimental depending on the clinical and pathophysiological conditions. In this study, we therefore investigated the effect of amiodarone on hypoxic–ischemic brain injury using a murine experimental model.ResultsCompared with the control group mice, mice that received amiodarone after induction of 40-min hypoxic–ischemic brain injury exhibited lower survival rates over 7 days and worse neurological function. After 25-min hypoxic–ischemic brain injury, amiodarone treated mice exhibited larger infarct volumes (16.0 ± 6.9 vs. 24.2 ± 6.8 mm3, P < 0.05) and worse neurological function. In addition, the brains harvested from the amiodarone-treated mice contained larger amounts of sodium (194.7 ± 45.1 vs. 253.5 ± 50.9 mEq/kg dry weight, P < 0.01) and water (259.3 ± 8.9 vs. 277.2 ± 12.5 mg, P < 0.01). There were no significant differences in hemodynamic parameters between groups.ConclusionsAmiodarone exacerbated brain injuries and neurological outcomes after hypoxic–ischemic insults. Severe brain sodium accumulation and brain edema were associated with the detrimental effects of amiodarone. Amiodarone at the clinical dose can exacerbate brain injury after hypoxic–ischemic insult by affecting sodium ion transportation and facilitate intracellular sodium accumulation in the brain.

Multicenter Analysis of Dosing Protocols for Sotalol Initiation.

Sotalol, a Vaughan-Williams Class III antiarrhythmic medication, is used to manage atrial arrhythmias. Due to its QT-prolonging effect and subsequent increased risk of torsade de pointes, many centers admit patients during the initial dosing period. Despite its widespread use, little information is available regarding dosing protocols during this period. In this multicenter investigation, dosing protocols in patients initiating sotalol therapy were examined to identify predictors of successful sotalol initiation. Over a 4-year period, patients admitted to 5 hospitals in the United States for inpatient telemetry monitoring during initiation for nonresearch purposes were enrolled. A 3-day course of 5 of 6 doses of sotalol was considered successful completion of the loading protocol. Of the 213 enrolled patients, over 90% were successfully discharged on sotalol. Significant bradycardia, ineffectiveness, and excessive QT prolongation were reasons for failed completion. Absence of a dose adjustment was a strong predictor of successful initiation (odds ratio: 6.6, 95% confidence interval: 1.3-32.7, P = .02). Hypertension, use of a calcium channel blocker, use of a separate β-blocker, and presence of a pacemaker were predictors of dose adjustments. Marginal structural models (ie, inverse probability weighting based on probability of a dose adjustment) verified that these factors also predicted successful initiation via preventing any dose adjustment and suggests that considering these factors may result in a higher likelihood of successful initiation in future investigations. In conclusion, we found that the majority of patients admitted for sotalol initiation are successfully discharged on the medication. The study findings suggest that factors predicting need for dose adjustment can be used to identify patients who could undergo outpatient initiation. Prospective studies are needed to verify this approach.

Maastricht antiarrhythmic drug evaluator (MANTA): A computational tool for better understanding of antiarrhythmic drugs

Cardiac arrhythmias are a global health burden, contributing significantly to morbidity and mortality worldwide. Despite technological advances in catheter ablation therapy, antiarrhythmic drugs (AADs) remain a cornerstone for the management of cardiac arrhythmias. Experimental and translational studies have shown that commonly used AADs exert multiple effects in the heart, the manifestation of which strongly depends on the exact experimental or clinical conditions. This diversity makes the optimal clinical application of AADs challenging.Here, we present a novel computational tool designed to facilitate a better understanding of the complex mechanisms of action of AADs (the Maastricht Antiarrhythmic Drug Evaluator, MANTA). In this tool, we integrated published computational cardiomyocyte models from different species (mouse, guinea pig, rabbit, dog, and human), regions (atrial, ventricular, and Purkinje cells) and disease conditions (atrial fibrillation- and heart failure-related remodeling). Subsequently, we investigated the effects of clinically available AADs (Vaughan-Williams Classes I, III, IV and multi-channel blockers) on action potential (AP) properties and the occurrence of proarrhythmic effects such as early afterdepolarizations. Steady-state drug effects were simulated based on a newly compiled overview of published IC50 values for each cardiac ion channel and by integrating state-dependent block of the cardiac Na+-current by Class I AADs using a Markov-model approach. Using MANTA, we demonstrated and characterized important species-, rate-, cell-type-, and disease-state-specific AAD effects, including 1) a stronger effect of Class III AADs in large mammals than in rodents; 2) a rate-dependent decrease in upstroke velocity with Class I AADs and reverse rate-dependent effects of Class III AADs on action potential duration; 3) ventricular-predominant effects of pure IKr blockers; 4) preferential reduction in atrial AP upstroke velocity with vernakalant; and 5) excessive AP prolongation with Class III AADs other than amiodarone under heart failure conditions.In conclusion, the effects of AADs are highly complex and strongly dependent on the experimental or clinical conditions. MANTA is a powerful and freely available tool reproducing a wide range of AAD characteristics that enables analyses of the underlying ionic mechanisms. Use of MANTA is expected to improve our understanding of AAD effects on cellular electrophysiology under a wide range of conditions, which may provide clinically-relevant information on the safety and efficacy of AAD treatment.

Hybrid thoracoscopic surgical and transvenous catheter ablation versus transvenous catheter ablation in persistent and longstanding persistent atrial fibrillation (HARTCAP-AF): study protocol for a randomized trial

BackgroundSuccess rates with conventional transvenous endocardial pulmonary vein isolation in patients with persistent and longstanding persistent atrial fibrillation (AF) are variable due to advanced electrical and structural remodeling of the atria. As a consequence, more extensive endocardial lesions, minimally invasive thoracoscopic surgical techniques, and hybrid ablation (combining thoracoscopic epicardial surgical and endocardial catheter ablation) have been developed.HypothesisThe HARTCAP-AF trial hypothesizes that hybrid AF ablation is more effective than (repeated) transvenous endocardial catheter ablation in (longstanding) persistent AF, without increasing the number of associated major adverse events.MethodsThis randomized controlled trial will include 40 patients with persistent or longstanding persistent AF who will be 1:1 randomized to either hybrid ablation or (repeated) catheter ablation. The procedures and follow-up are conducted according to the guidelines. The primary effectiveness endpoint is freedom from any supraventricular arrhythmia lasting longer than 5 min without the use of Vaughan-Williams class I or III antiarrhythmic drugs through 12 months of follow-up after the last procedure. In the catheter ablation arm, a second procedure planned within 6 months after the index procedure is allowed for obtaining the primary endpoint. Additionally, adverse events, cost-effectiveness, and quality of life data will be recorded.Trial registrationClinicalTrials.gov, NCT02441738. Registered on 12 May 2015.

Analgesic effects of amiodarone in mouse models of pain.

Purpose: Although amiodarone is classified as a Vaughan-Williams class Ⅲ antiarrhythmic drug, it has inhibitory effects on voltage-gated sodium and calcium channels and on β-adrenergic receptors. Given these pharmacological profiles, amiodarone may have analgesic properties. Most patients who are prescribed amiodarone possess multiple cardiovascular risk factors. Despite the fact that pain plays a crucial role as a clinical indicator of cardiovascular events, the effects of amiodarone on pain have not been investigated. The aim of the current study was to investigate the analgesic effects of amiodarone by using mouse models of pain in an effort to elucidate underlying mechanisms.Methods: Adult male C57B6 mice received single bolus intraperitoneal injections of amiodarone at doses of 25, 50, 100, and 200 mg/kg, while the mice in the control group received only normal saline. The analgesic effects of amiodarone were evaluated using the acetic acid-induced writhing test, formalin test, and tail withdrawal test. In addition, the potassium channel opener NS1643, voltage-gated sodium channel opener veratrine, calcium channel opener BAYK8644, and selective β-adrenergic agonist isoproterenol were used to uncover the underlying mechanism.Results: During the acetic acid-induced writhing test, formalin test, and tail withdrawal test, amiodarone induced analgesic responses in a dose-dependent manner. The analgesic effects of amiodarone were abolished by veratrine but not by NS1643, BAYK8644, or isoproterenol.Conclusion: Amiodarone induced analgesic responses in a dose-dependent manner, likely by blocking voltage-gated sodium channels. These results indicate that clinical doses of amiodarone can affect nociception and may mask or attenuate pain induced by acute cardiovascular events.

Neuroprotective effects of amiodarone in a mouse model of ischemic stroke

BackgroundIon channels play a crucial role in the development of ischemic brain injury. Recent studies have reported that the blockade of various types of ion channels improves outcomes in experimental stroke models. Amiodarone, one of the most effective drugs for life-threatening arrhythmia, works as a multiple channel blocker and its characteristics cover all four Vaughan-Williams classes. Although it is known that amiodarone indirectly contributes to preventing ischemic stroke by maintaining sinus rhythm in patients with atrial fibrillation, the direct neuroprotective effect of amiodarone has not been clarified. The purpose of this study was to investigate the direct effect of amiodarone on ischemic stroke in mice.MethodsFocal cerebral ischemia was induced via distal permanent middle cerebral artery occlusion (MCAO) in adult male mice. The amiodarone pre-treatment group received 50 mg/kg of amiodarone 1 h before MCAO; the amiodarone post-treatment groups received 50 mg/kg of amiodarone immediately after MCAO; the control group received vehicle only. In addition, the sodium channel opener veratrine and selective beta-adrenergic agonist isoprotelenol were used to elucidate the targeted pathway. Heart rate and blood pressure were monitored perioperatively. Infarct volume analysis was conducted 48 h after MCAO. The body asymmetry test and the corner test were used for neurological evaluation.ResultsAmiodarone pre-treatment and post-treatment reduced the heart rate but did not affect the blood pressure. No mice showed arrhythmia. Compared with the control group, the amiodarone pre-treatment group had smaller infarct volumes (8.9 ± 2.1% hemisphere [mean ± SD] vs. 11.2 ± 1.4%; P < 0.05) and improved functional outcomes: lower asymmetric body swing rates (52 ± 17% vs. 65 ± 18%; P < 0.05) and fewer left turns (7.1 ± 1.2 vs. 8.3 ± 1.2; P < 0.05). In contrast, amiodarone post-treatment did not improve the outcomes after MCAO. The neuroprotective effect of amiodarone pre-treatment was abolished by co-administration of veratrine but not by isoproterenol.ConclusionsAmiodarone pre-treatment attenuated ischemic brain injury and improved functional outcomes without affecting heart rhythm and blood pressure. The present results showed that amiodarone pre-treatment has neuroprotective effects, at least in part, via blocking the sodium channels.

Ventricular arrhythmias and sudden cardiac death

### Key points There are 50–100 unexpected, sudden cardiac deaths (SCDs) per 100 000 population per year in Europe and USA, categorized by symptom onset to cardiac arrest time of <1 h.1 Despite the decline in coronary artery disease mortality and advancements in resuscitation services, survival from these events remains low. Unfortunately, they often occur outside the hospital environment and are associated with a survival rate of <10%. The majority occur in adults over 35 yr of age and at least half of these events can be attributed to ventricular arrhythmias, although the true incidence is unknown due to inevitable degeneration to asystole if unwitnessed. These arrhythmias may be the presenting complaint in the emergency department and may feature throughout the perioperative period, including at preoperative assessment, during surgery and in the recovery phase, for example in intensive care. They may also be the direct target of therapy in the case of electrophysiological catheter ablation and implantable cardioverter defibrillators (ICDs). They are more frequent and carry greater risks in patients with structural heart disease, but younger patients with ion-channel abnormalities can also be susceptible.2 This review classifies the causes and significance of ventricular arrhythmias based on the presence or absence of structural heart disease and provides a simple system to aid confident distinction from supraventricular arrhythmias. …

FLECAINIDE TOXICITY MIMICKING INCESSANT VENTRICULAR TACHYCARDIA

Flecainide is a Vaughan-Williams Class 1c antiarrhythmic drug indicated for use in pharmacologic cardioversion and maintenance of sinus rhythm in atrial fibrillation and other supraventricular tachycardias in patients without structural heart disease. However, flecainide has a narrow therapeutic

Antihypertensive drugs

Antihypertensive drugs