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.

Electrophysiologic therapeutics in heart failure in adult congenital heart disease.

Arrhythmias have long been recognized as a major cause of morbidity and mortality in the adult with congenital heart disease. It is important that the clinician accurately diagnoses these disturbances and is cognizant of the full array of antiarrhythmic agents and devices available to treat these conditions. This review discusses the most common arrhythmias encountered in this population and the therapeutic options available. Specific issues unique to this population are also addressed.

[New class III antiarrhythmic drugs for treatment of atrial fibrillation].

Last two decades have been dedicated to intensive search for new class III antiarrhythmic drugs, especially for atrial fibrillation. Here we present a review of the status this problem. Influence on transmembranous ion currents and mechanisms of antiarrhythmic action are described. Results of experimental and clinical studies are reviewed. Possible perspectives of newest atrial-selective medications are discussed. Russia's class III antiarrhythmic drugs are of special interest of the article. First data on efficacy and safety of newest agent niferidil are presented. This drug undergoes clinical testing at present time.

Mechanisms of termination and prevention of atrial fibrillation by drug therapy.

Atrial fibrillation (AF) is a disorder of the rhythm of electrical activation of the cardiac atria. It is the most common cardiac arrhythmia, has multiple aetiologies, and increases the risk of death from stroke. Pharmacological therapy is the mainstay of treatment for AF, but currently available anti-arrhythmic drugs have limited efficacy and safety. An improved understanding of how anti-arrhythmic drugs affect the electrophysiological mechanisms of AF initiation and maintenance, in the setting of the different cardiac diseases that predispose to AF, is therefore required. A variety of animal models of AF has been developed, to represent and control the pathophysiological causes and risk factors of AF, and to permit the measurement of detailed and invasive parameters relating to the associated electrophysiological mechanisms of AF. The purpose of this review is to examine, consolidate and compare available relevant data on in-vivo electrophysiological mechanisms of AF suppression by currently approved and investigational anti-arrhythmic drugs in such models. These include the Vaughan Williams class I-IV drugs, namely Na(+) channel blockers, ß-adrenoceptor antagonists, action potential prolonging drugs, and Ca(2+) channel blockers; the "upstream therapies", e.g., angiotensin converting enzyme inhibitors, statins and fish oils; and a variety of investigational drugs such as "atrial-selective" multiple ion channel blockers, gap junction-enhancers, and intracellular Ca(2+)-handling modulators. It is hoped that this will help to clarify the main electrophysiological mechanisms of action of different and related drug types in different disease settings, and the likely clinical significance and potential future exploitation of such mechanisms.

Effect of pilsicainide on dominant frequency in the right and left atria and pulmonary veins during atrial fibrillation: association with its atrial fibrillation terminating effect.

Dominant frequency reflects the peak cycle length of atrial fibrillation. In 34 patients with atrial fibrillation, bipolar electrograms were recorded from multiple atrial sites and pulmonary veins and the effect of pilsicainide, class Ic antiarrhythmic drug, on dominant frequency was examined. At baseline, mean dominant frequencies (Hz) in the right and left atria, coronary sinus and right and left superior pulmonary veins were 5.87 +/- 0.76, 6.08 +/- 0.60, 5.65 +/- 0.95, 6.12 +/- 0.88 and 6.59 +/- 0.89, respectively (P < 0.05, left superior pulmonary vein vs right atrium and coronary sinus). After pilsicainide (1.0 mg/kg/5 min), dominant frequency decreased at all sites in all patients. Atrial fibrillation was terminated at 5.9 +/- 2.2 min in 16 patients (Group A) with a decrease in the average of mean dominant frequencies at all sites from 5.80 +/- 0.72 to 3.57 +/- 0.63 Hz, was converted to atrial flutter at 7.3 +/- 1.4 min in 5 (Group B) with a decrease in the average dominant frequency from 5.83 +/- 0.48 to 3.08 +/- 0.19 Hz, and was not terminated in the other 13 (Group C) despite the average dominant frequency decrease from 6.59 +/- 0.76 to 4.42 +/- 0.52 Hz. In 14 of the 21 Groups A and B patients (67%), mean dominant frequencies at all recording sites were < 4.0 after pilsicainide, while they were < 4.0 in 1 of the 13 Group C patients (8%, P < 0.01). In conclusion, the degree of dominant frequency decrease by pilsicainide is closely related to its atrial fibrillation terminating effect: When dominant frequency in the atria decreases to < 4.0 Hz, atrial fibrillation is terminated with 93% positive and 63% negative predictive values.

Anti-arrhythmic drug therapy for atrial fibrillation: current anti-arrhythmic drugs, investigational agents, and innovative approaches.

By 2050, atrial fibrillation (AF) will be present in 2% of the general population and in a far higher proportion of elderly patients. Currently, we are content with rate control and anticoagulation in elderly asymptomatic patients, whereas in younger patients with symptomatic recurrent AF, pulmonary vein isolation is the treatment of choice. However, in a large number of patients, there remains a genuine choice between anti-arrhythmic therapy to suppress the arrhythmia and rate control to control the ventricular rate. This review provides a contemporary evidence-based insight into the buoyant development of new anti-arrhythmic agents, exploring new mechanisms of action or novel combinations of established anti-arrhythmic activity. An attractive prospect for AF therapy is the introduction of agents with selective affinity to ion channels specifically involved in atrial repolarization, so-called atrial repolarization-delaying agents. Presently, there are several potential anti-arrhythmic drugs with this mode of action, which are currently in pre-clinical and clinical development. Vernakalant is in the most advanced phase of investigation and its intravenous formulation has recently been recommended for approval for pharmacological cardioversion of AF. However, although this agent has some electrophysiological effects which are specific to the atria, it has others which affect both the atria and the ventricles. Other drugs, such as XEND0101, block a single atrial-specific membrane current. The success of such agents depends critically on their atrial electrophysiological selectivity, freedom from cardiac adverse effects, and general safety. Other possibilities include modified analogues of traditional anti-arrhythmic drugs with additional novel mechanisms of action and less complex metabolic profiles. Dronedarone is an investigational agent with multiple electrophysiological effects, which is devoid of iodine substituents and is believed to have a better side effect profile than its predecessor amiodarone. The development portfolio of dronedarone is practically complete and approval for several indications in AF may soon be assessed. Innovative anti-arrhythmic agents with unconventional anti-arrhythmic mechanisms, such as stretch receptor antagonism, sodium-calcium exchanger blockade, late sodium channel inhibition, and gap junction modulation, have not yet reached clinical studies in AF. Gene- and cell-based therapies, which can selectively target individual currents, could provide ideal one-time only curative therapy for arrhythmias, and the first proof-of-concept studies have been reported. There is accumulating evidence in support of the anti-arrhythmic effects of non-anti-arrhythmic drugs. Treatments with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, statins, and omega-3 fatty acids all seem promising, over and above any effect related to the treatment of underlying heart disease. However, despite exciting results from animal experiments and promising outcomes from retrospective analyses, there is no robust evidence of specific effects of these drugs to transform current clinical practice.

Electrophysiological interventions for treatment of congestive heart failure in pediatrics and congenital heart disease.

Heart failure therapy, while well tested in the adult population, therapeutic interventions are less well defined in the pediatric population. Several treatment strategies are available for the adult patient with heart failure, thought few of these therapies have been proven in children. Morbidity and mortality in the pediatric population with a failing heart is significant, and rhythm management as well as strategies to improve hemodynamics are important in the care of these children. This review will address issues of rhythm management and resynchronization therapy in pediatric and congenital heart disease patients with heart failure.

CPU86017: a novel Class III antiarrhythmic agent with multiple actions at ion channels.

CPU86017 is a novel Class III antiarrhythmic agent derived from berberine and with an improved pharmacological profile, solubility and bioavailability. It is active in suppressing arrhythmias in several animal models. The ED(50) of CPU86017 for suppressing ischemia/reperfusion arrhythmias in rats was 0.22 mg/kg against 2.23 mg/kg for lidocaine. CPU86017 is about 10-fold more potent than lidocaine. It blocks I(K(R.tail)), I(K(S)), and I(Ca(L)) currents with IC(50) values of 25, 14.4, and 11.5 microM, respectively. The plasma t(1/2) of CPU86017, i.v. bolus, in rabbits and dogs is approximately 90 min. The effective plasma levels of CPU86017 in rabbits required to delay the appearance of oubain-induced ventricular arrhythmias is in the range of 0.13-0.31 microg/mL. Higher levels of the drug are required to eliminate ventricular arrhythmias produced by two-stage ligation of the coronary artery in anesthetized dogs. Drug levels in myocardium are much higher than in plasma. CPU80617 has an antioxidant effect that is likely to contribute to its antiarrhythmic activity. The abnormal expression of the ryanodine receptor type 2 (RyR2) and of FKBP12.6 is reduced by CPU80617 during its ventricular tachyarrhythmia-suppressing action. CPU86017 appears to be a promising antiarrhythmic agent with a cardioprotective action. It can be expected to protect from malignant arrhythmias and sudden cardiac death by suppressing molecular events caused by channelopathies.

The future of atrial fibrillation therapy.

Today management of atrial fibrillation (AF) centers on restoration and maintenance of normal sinus rhythm or control of the ventricular rate response to AF. Current guidelines state that rhythm and rate control strategies should be considered therapeutically equivalent, but recognize that no "one size fits all," an approach consistent with growing recognition of the heterogeneity of AF. As data from the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial clearly demonstrate, conventional antiarrhythmics have a role in highly symptomatic AF accompanied by decreased quality of life. However, for many AF patients such drugs lack efficacy, have potentially serious side effects, and are poorly tolerated. In parallel with the development of more effective and safer antiarrhythmics, nontraditional approaches to prevention and treatment of AF are being explored. Treatments not considered "antiarrhythmic" that may prevent or forestall AF include aggressive antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and some, but not all, beta-blockers and calcium channel antagonists, especially when used as adjunctive therapy. Other approaches include statins, steroids, and fish oil to reduce atrial fibrosis and inflammation, and pacemakers to prevent bradycardia-mediated AF and as a pacing preventive strategy in selected patients. Ablative techniques with potential to cure AF are gaining popularity, but are not yet simple, straightforward, and risk-free procedures. In the future, treatment of AF will progress beyond today's focus on AF as a purely electrocardiographic disease toward a patient and context-specific management strategy involving multiple treatment modalities.

Tedisamil: a new novel antiarrhythmic.

Solvay Pharmaceuticals is currently developing tedisamil (KC-8857), a novel antiarrhythmic with additional anti-ischaemic properties, which acts via potassium channel blockade. This drug can be categorised as a class III antiarrhythmic agent due to its effects of action potential and QT interval prolongation in these patients. This agent was initially developed for its anti-ischaemic properties and Phase I trials have shown tedisamil to be an effective bradycardic agent, as well as causing a reverse rate-dependent QT interval prolongation. Subsequent Phase II results have confirmed that in patients with ischaemic heart disease, tedisamil had beneficial haemodynamic and anti-ischaemic effects. Phase III studies in patients with ischaemic heart disease indicated that tedisamil is an effective agent for the treatment of angina, resulting in a dose-dependent increase in anginal threshold (with a decrease in anginal attacks, increased exercise capacity during treadmill exercise and decreased electrocardiographic signs of exercise induced ischaemia) in comparison to placebo. Although tedisamil has been shown to be an effective anti-ischaemic agent, with Phase III trials for angina pectoris now completed, the company are now pursuing the use of tedisamil for the treatment of atrial fibrillation, for which tedisamil is still in Phase II/III clinical trials. Launch data are not yet known.

Electrophysiologic and antiarrhythmic effects of the new class III antiarrhythmic drug KCB-328 in experimental canine atrial flutter.

BACKGROUND: The electrophysiologic and antiarrhythmic effects of a new class III antiarrhythmic drug (KCB-328), a delayed rectifier potassium current (IKr) blocker with minimal reverse use-dependent effect on atrial repolarization, were evaluated in the canine night atrial crush-injury model of atrial flutter (AFL). METHODS: Ten anesthetized, open-chest dogs, were studied after right atrial crush-injury. Atrial effective refractory period (ERP), conduction velocity (CV), wavelength, and dispersion of refractoriness were determined during programmed stimulation (S1S2 at S1S1 = 200, 300, 400, and 500 msec) at four sites via a mapping plaque sutured on the right atrial free wall. Right and left ventricular ERP were similarly measured at single sites. Electrophysiological parameters were determined at baseline and following sequential cumulative doses of KCB-328 (10, 30, 100, and 300 microg/kg). RESULTS: Sustained AFL was inducible in 7/10 dogs by rapid pacing following baseline electrophysiologic measurements. KCB-328 significantly prolonged sinus cycle length, but had no effect on PR interval, and prolonged QTc only at the highest dose level. KCB-328 significantly prolonged atrial ERP and wavelength and ventricular ERP, and significantly reduced dispersion of atrial refractoriness. KCB-328 significantly prolonged AFL cycle length, and increasing doses progressively terminated sustained AFL and prevented its reinduction by pacing. No adverse hemodynamic or ventricular proarrhythmic effects were observed. CONCLUSIONS: The electrophysiologic profile of KCB-328 in this canine model of AFL, particularly its lack of reverse use-dependent effect on atrial refractoriness, suggests that it may have significant antiarrhythmic potential in treatment of atrial arrhythmias.

Can antiarrhythmic agents be selected based on mechanism of action?

When selecting an antiarrhythmic agent the clinician needs to be able to accurately predict the probability that a particular drug will serve its intended purpose in a given patient. This is difficult because of the complexity of variables which govern the relationship between drug administration and clinical outcome. The efficacy of a drug may potentially be predicted from its mechanism of action. At least two classifications of antiarrhythmic agents based on mechanism of action have been proposed. The Vaughan Williams classification is based on the predominant electrophysiological effects of a drug on the action potential. In the Sicilian Gambit approach, a number of potential targets ('vulnerable parameters') for drug action are identified and antiarrhythmic drugs or substances that affect cardiac electrophysiology are characterised by their actions on each of these. The usefulness of these classification systems in predicting antiarrhythmic drug efficacy are limited. Furthermore, in the Vaughan Williams classification not all drugs in the same class have identical effects, whereas some drugs in different classes have overlapping actions. The Sicilian Gambit requires in-depth knowledge regarding cellular and molecular targets of antiarrhythmic agents which may make it intimidating or simply impractical for regular clinical use. Surrogate measures such as 24-hour Holter monitoring and programmed electrical stimulation have been used to predict anti-arrhythmic drug efficacy. However, studies such the Cardiac Arrhythmia Suppression Trial (CAST) have shown that suppression of ventricular ectopy on Holter monitoring does not necessarily correlate with improved survival and may in fact be dangerous. Conversely, studies using programmed electrical stimulation to assess drug effect on variables such as tachycardia inducibility, refractory period and ventricular tachycardia cycle length show that suppression of tachycardia inducibility, prolongation of refractory period and prolongation of ventricular tachycardia cycle length, are all associated with reduced recurrence of tachycardia and possibly improved survival. The most practical use of the current classification systems applied to antiarrhythmic agents may be in their ability to predict with reasonable accuracy, the risk and type of proarrhythmia based on the mechanism of action of an agent.

[Preventive drug therapy of recurrence of atrial fibrillation]. / Prévention médicamenteuse des récidives de fibrillation auriculaire.

Without treatment, about 60% of atrial arrhythmia patients suffer a relapse within 3 months and 70% within one year. Antiarrhythmic treatment intended to reduce this percentage is therefore justified, on condition that it is well tolerated. Several preliminary questions have to be settled before this medical prophylaxis: 1) Justification of antiarrhythmic treatment (sometimes pointless to deal with very occasional episodes); 2) Treatment of the underlying heart disease (valve disease, cardiothyrotoxicosis, etc.) or promoting factors (potassium depletion etc.); 3) Accurate assessment of any associated conduction abnormalities, which may constitute a contraindication to antiarrhythmic treatment (WPW syndrome in the case of verapamil and the digitalis-like drugs) or require additional treatment (pacemaker); 4) Definition of the mechanism (vagal or sympathotonic) inducing arrhythmia; 5) Evaluation of the hemodynamic parameters of the underlying heart disease (size of the atria, ventricular function, coronary or valvular lesions) which may limit the efficacy of the treatment. Once these parameters have been identified, the primary treatment should be type la or lb antiarrhythmics, which have been shown to be effective, despite the fact that they are not without arrhythmic risks (the Ib antiarrhythmics are less effective and have a poor safety profile). The beta-blockers have preferential indications (hypersympatheticotonia, hyperthyroidism, hypertrophic myocardiopathy, mitral prolapse, angina etc.) and can be replaced by verapamil or bepridil if there are non-cardiac contraindications (ulcers, asthma, diabetes). Amiodarone is extremely effective, but its poor extracardiac safety restricts its long-term use. Complementary treatments (digitalis-like, anticoagulants or anti-PAF and cardiostimulant drugs) should be added if necessary. Recurrences (to be confirmed by ECG or Holter) should lead to rigorous confirmation of therapeutic compliance and observance of simple hygienic and dietary measures (no excessive exertion, elimination of stimulants etc.). With strict clinical and ECG monitoring, it would then be possible either to increase the dose levels (accompanied by plasma determinations if possible) or to switch to a treatment with more effective, but more aggressive drugs (amiodarone, flecainide) or to use drug associations (la and lb, la and II etc.). Repeated failure of such attempts should lead to a non-medical approach to treatment.

Antiarrhythmic drug therapy: new drugs and changing concepts.

The effective treatment of life-threatening ventricular arrhythmias (VA) leading to sudden cardiac death remains a major health problem. Cellular electrophysiological techniques that have provided insight into the underlying mechanisms of these arrhythmias have also provided a convenient classification of antiarrhythmic drugs based on their dominant electrophysiological action. Traditional pharmacological approaches to the management of VA have involved primarily class I agents. Newer drugs in this class are potent conduction depressants (class IC agents), which, however, have been limited in their clinical impact on VA because of unwanted cardiac and extracardiac side effects. Other recent approaches include the introduction of class III agents, which are thought to interrupt primarily reentrant impulses by specific prolongation of action potential duration and refractoriness without compromising normal cardiac conduction. Newer approaches may also include drugs with greater specificity of action, agents with combinations of electrophysiological effects (class I/III, I/II), drugs exemplifying novel mechanisms of action such as anion antagonism (class V), and agents controlling sympathetic neural outflow. The growing awareness of the potential proarrhythmic effects of antiarrhythmic drugs has also become important in drug development and assessment, as emphasized by the search for improved methods of drug selection (e.g., programmed electrical stimulation). Finally, the desired characteristics of a new antiarrhythmic agent are presented as a goal for future drug development.

Symposium on the management of ventricular dysrhythmias. Antifibrillatory versus antiectopic therapy.

The concept of antifibrillatory action distinct from antiarrhythmic effect has recently been recognized. An antiarrhythmic (antiectopic) action leads to a decrease in the frequency of ventricular ectopic beats. In contrast, an antifibrillatory drug action increases myocardial electric stability, decreasing the propensity for ventricular fibrillation. Agents with predominant antiarrhythmic action (designated class I) include lidocaine, quinidine, procainamide and disopyramide. Bretylium is an agent with predominant antifibrillatory action (class III). Amiodarone and sotalol are experimental class III drugs. The beta-blockers (class II) also possess antifibrillatory action, particularly in ischemic heart disease. The rationale for the use of agents with antiarrhythmic (antiectopic) effects is the reduction of triggering events for more complex ventricular tachyarrhythmias. These agents act by slowing conduction, decreasing abnormal automaticity and affecting phase IV depolarization. In contrast, agents with antifibrillatory action may exert little effect on cardiac conduction and automaticity. However, they raise the energy threshold required for premature electrical discharge to initiate ventricular fibrillation (ventricular fibrillation threshold). The inhomogeneity of electrophysiologic properties and adrenergic tone in different portions of the heart may be reduced or eliminated. Direct electrophysiologic effects of agents such as bretylium include a general lengthening of the refractory period and the action potential duration in the heart and a diminution in the disparity of their durations between normal and abnormal myocardium. Clinical studies are incomplete, but they support the concept of antifibrillatory therapy. In postmyocardial infarction patients at intermediate risk of sudden death, the broad use of oral antiarrhythmic agents has not decreased the incidence of sudden death, whereas high-dose beta-blocker therapy, which exerts experimental antifibrillatory effects, may reduce sudden death by 30 to 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical relevance of experimentally obtained electrophysiologic data on antiarrhythmic drugs.

An extrapolation of electrophysiological findings to a specific clinical situation is not always feasible since successful arrhythmia analysis frequently is not achieved and even in the presence of a known arrhythmic mechanism, the predominant effect of a given antiarrhythmic agent cannot be predicted with respect to therapeutic relevance. These assertions are additionally supported by the fact that the effects of antiarrhythmic agents, which have been primarily studied in healthy myocardium, may be entirely different in the presence of myocardial ischemia. Furthermore, in spite of a certain degree of agreement among data of experimentally-induced and clinical myocardial ischemia, the findings do not imply complete applicability. Theoretical considerations indicate that a reentry mechanism may not only be favourable influenced by an agent rendering improved conduction velocity and shortened refractory periods but also influenced by an agent effecting oppositely directed changes. Although an effective therapeutic regimen can generally be achieved with no exact knowledge of the arrhythmic mechanism or of the specific action of a given drug, future investigations hould augment existing information to yield a more rational means of treatment and prevention of arrhythmias as well as to aid in the development of new antiarrhythmic agents.