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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ventricular pro-arrhythmic effects of antiarrhythmic drugs correspond either to an aggravation of a pre-existing arrhythmia or to the development of a new arrhythmia not yet observed for a patient. More easily inducible ventricular tachycardias (VT) take part in this latter category. The incidence of ventricular pro-arrhythmias is difficult to evaluate but should be close to 3 to 10% during antiarrhythmic treatments. Two main mechanisms can be involved in pro-arrhythmia: 1) reentry can cause sustained VT complicating a pre-existing cardiopathy when a sodium channel blocker is prescribed, 2) early post depolarizations can result in the occurrence of torsades de pointes complicating an antiarrhythmic treatment which prolongs ventricular repolarization and QT interval. The main risk factors of pro-arrhythmia are in the first case the existence of antecedents of VT or V fibrillation with an altered ventricular function and in the second case an important prolongation of QT with bradycardia and hypokalemia. The incidence of pro-arrhythmia should decrease when these risk factors are taken into consideration. However the diagnosis of pro-arrhythmia should be systematically evoked by clinicians since these unwanted side-effects can occur with any class Ia, Ic and III antiarrhythmic drug and any drug which prolongs QT. If this diagnosis is confirmed, the need for an antiarrhythmic treatment should then be systematically evaluated in any patient taking into consideration the benefit/risk ratio of the treatment.
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PMID:[Ventricular pro-arrhythmic effects of anti-arrhythmia drugs]. 129 19

The potential for proarrhythmic responses to the class IC sodium channel-blocking drugs encainide and flecainide has not been well described in young patients. Therefore, data were retrospectively collected from 36 institutions regarding 579 young patients who were administered encainide or flecainide for treatment of supraventricular tachycardias (encainide 86 patients, flecainide 369 patients) or ventricular arrhythmias (encainide 21 patients, flecainide 103 patients) to assess the frequency of proarrhythmia, cardiac arrest and death during therapy (adverse events). The two drugs were similar in regard to efficacy (flecainide 71.4%, encainide 59.8%) and rate of proarrhythmic responses (flecainide 7.4%; encainide 7.5%). However, patients receiving encainide more frequently experienced cardiac arrest (encainide 7.5% vs. flecainide 2.3%, p less than 0.05) or died during treatment (encainide 7.5% vs. flecainide 2.1%, p less than 0.05). Detailed data were provided for 44 patients experiencing one or more adverse events. Patient age, previous drug trials, concomitant therapy and days of inpatient monitoring were similar for patients receiving encainide or flecainide. However, echocardiographic left ventricular shortening before treatment was lower among patients receiving encainide (0.23 +/- 0.09) than among those receiving flecainide (0.34 +/- 0.06, p less than 0.05). Plasma drug concentrations were rarely elevated. Cardiac arrest (12 patients) and deaths (13 patients) occurred predominantly among patients with underlying heart disease, particularly among patients receiving flecainide for supraventricular tachycardia (8.3% vs. 0.3%, p less than 0.001). Fifteen patients with an ostensibly normal heart and normal ventricular function experienced proarrhythmia during treatment for supraventricular tachycardia, but only 3 of the 15 had a cardiac arrest or died. The relatively high incidence of adverse events should be considered when contemplating treatment with encainide or flecainide, particularly among patients with underlying heart disease.
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PMID:Proarrhythmia, cardiac arrest and death in young patients receiving encainide and flecainide. The Pediatric Electrophysiology Group. 190 3

The effects of two novel antiarrhythmic drugs, cibenzoline and flecainide, known to exert potent inhibitory effects on sodium channel, were investigated on intraventricular conduction in anaesthetized, closed-chest dogs. During this study, in which the heart was electrically stimulated, the pacing period was gradually reduced in the 500-200 msec range, and the pacing rate was abruptly altered (2 sec) or sustained (8 to 10 sec) in order to study the possible frequency- and time-dependency of the depression of conduction. In addition to the electrocardiogram, the conduction time was recorded in the ventricular contractile tissue between an electrode advanced to the apex and the pacing electrode positioned near the base. Effective refractory period (ERP) was concurrently measured according to the extrastimulus method, and the monophasic action potential (MAP) recorded. The drugs were infused at a rate of 0.2 mg/kg/min over a 10 min period after a 4.0 mg/kg loading dose. Conduction time was lengthened by approximately 50% at low frequencies and 100% at high frequencies. Widening of the ORS complexes paralleled this lengthening, whereas the drugs tended only to prolong ERP, without preventing its shortening induced by acceleration. Cardiac disorders were aggravated when high pacing rates were maintained for 8 to 10 sec.
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PMID:Frequency- and time-dependent depression of ventricular distal conduction by two novel antiarrhythmic drugs, cibenzoline and flecainide. 313 54

In recent years, there has been a major shift from the use of antiarrhythmic drugs that act by slowing conduction to those that exert their beneficial actions by lengthening cardiac repolarisation. Such a shift is occurring because sodium channel blockers may increase mortality, especially in patients with structural heart disease, and because drugs such as sotalol and amiodarone are effective, with a potential for decreasing arrhythmic mortality. In this context, the electrophysiological and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol, are of major importance. d-Sotalol is essentially devoid of beta-blocking actions and may be considered a pure class III compound. It has been assumed that its clinical efficacy would approximate that of amiodarone and sotalol, but without the complex adverse effect profile of amiodarone and the adverse beta-blocker effects of racemic sotalol. d-Sotalol has pharmacokinetic properties that resemble those of the racemate. It lengthens the QT/QTc interval but does not affect other electrocardiographic (ECG) intervals. It increases the refractory period in the atria, ventricles, bypass tracts and the His-Purkinje system while minimally slowing the heart rate. In preliminary studies, it had a weak suppressant effect on premature ventricular contractions, prevented inducibility of ventricular tachycardia or fibrillation in about 40% of patients, and demonstrated the potential to terminate atrial flutter and fibrillation and maintain stability of sinus rhythm during prophylactic administration. The drug exhibits little or no negative inotropic actions. Thus, it is likely to be better tolerated in patients with congestive heart failure dependent on sympathetic stimulation for compensation. Because it produces less bradycardic effect than the racemate, it is believed that the drug might induce a lower rate of torsade de pointes. The role of d-sotalol in controlling cardiac arrhythmias is being addressed in a number controlled clinical trials. However, one such double-blind, placebo-controlled trial, Survival With Oral d-Sotalol (or SWORD), in survivors of myocardial infarction with depressed ventricular function was recently terminated prematurely because of a strikingly greater all-cause mortality compared with placebo (4.6 versus 2.6%). These preliminary findings, still to be fully analysed and interpreted for clinical significance, nevertheless raise valid concerns regarding the currently popular concept of controlling cardiac arrhythmias by the selective or isolated prolongation of repolarisation ('pure' class III action) as an antiarrhythmic principle.
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PMID:Pharmacodynamic, pharmacokinetic and antiarrhythmic properties of d-sotalol, the dextro-isomer of sotalol. 760 Oct 9

Propafenone hydrochloride, a class 1C antiarrhythmic agent, combines sodium channel-blocking effects with beta-blocking capacities and a weak calcium antagonism. The drug exerts marked electrophysiologic effects on accessory atrioventricular pathways. In patients with atrioventricular nodal reentry tachycardia, propafenone is able to block conduction in the fast conducting pathway. In addition, propafenone is very effective in young patients with supraventricular tachycardia based on enhanced abnormal automaticity. In pediatric patients, left ventricular performance remains unimpaired. Proarrhythmic events have been noted in children only occasionally. In accordance with the electrophysiologic profile, intravenous and oral propafenone is an effective agent for treatment of supraventricular tachycardia based on a reentry mechanism and due to abnormal automaticity (i.e., supraventricular tachycardia based on an accessory atrioventricular pathway, atrioventricular nodal reentry tachycardia, junctional ectopic tachycardia, and atrial ectopic tachycardia). In children with ventricular dysrhythmias, efficacy seems to be related to the underlying cardiac diagnosis. Propafenone is well tolerated in the majority of young patients. Incidence of proarrhythmic events seems to be lower with propafenone than with other class 1C agents. However, the risk of these serious adverse events should be taken into account when therapy with propafenone is considered, particularly in patients with structural heart disease.
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PMID:New antiarrhythmic drugs in pediatric use: propafenone. 799 37

Propafenone is a sodium channel blocking agent with a mild beta- and calcium channel-blocking activity. Several controlled and noncomparative studies have documented its efficacy in a variety of supraventricular arrhythmias in both adults and children. Propafenone is comparable with other Vaughan-William class I antiarrhythmic drugs for acute conversion of atrial fibrillation. It is also comparable with other drugs for prevention of recurrences in paroxysmal atrial fibrillation and for maintenance of sinus rhythm following successful cardioversion of chronic atrial fibrillation. Although propafenone is effective in the acute management of junctional reentrant tachycardias, the availability of safer drugs precludes its routine use for these arrhythmias. It may, however, be preferred for the acute management of haemodynamically well tolerated pre-excited atrial fibrillation in patients with the Wolff-Parkinson-White (WPW) syndrome. It also has documented efficacy in the long term therapy of patients with junctional tachycardias, and is a useful first-line drug in the management of arrhythmias in patients with the WPW syndrome, particularly when there is a short anterograde refractory period of the accessory pathway. Noncomparative studies were confirmed good efficacy and tolerability of propafenone in the short and long term management of paediatric supraventricular arrhythmias. It seems to be particularly effective for the treatment of ectopic atrial and junctional tachycardias, which are generally difficult arrhythmias to manage. Propafenone appears to have an acceptable adverse effect profile during both short and long term therapy. As with most other antiarrhythmic agents, there is a proarrhythmic potential. This has also been observed in children. There is a theoretical possibility that the beta-blocking properties of propafenone may protect against its proarrhythmic potential. However, this has not been confirmed in clinical studies. In conclusion, propafenone appears to be effective in the management of a wide spectrum of supraventricular arrhythmias. It should be considered among the first line drugs for management of these arrhythmias in patients without structural heart disease.
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PMID:Guidelines for the use of propafenone in treating supraventricular arrhythmias. 852 58

Long QT syndrome (LQT) is an inherited cardiac disorder that causes syncope, seizures and sudden death from ventricular tachyarrhythmias. We used single-strand conformation polymorphism (SSCP) and DNA sequence analyses to identify mutations in the cardiac sodium channel gene, SCN5A, in affected members of four LQT families. These mutations include two identical intragenic deletions and two missense mutations. These data suggest that SCN5A mutations cause LQT. The location and character of these mutations suggest that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
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PMID:Cardiac sodium channel mutations in patients with long QT syndrome, an inherited cardiac arrhythmia. 854 46

The kinetics of global use-dependent conduction slowing produced by sodium channel blockers in the human heart, estimated as a change in the QRS width, are known to be similar to those of use-dependent block of the maximum rate of depolarization in in vitro studies. However, the kinetics of the regional use-dependent decrease in conductivity have not been investigated. We examined whether the rise time of the monophasic action potential would be clinically useful as a marker of the local use-dependent decrease in conductivity by sodium channel blockers. In 12 patients without organic heart disease, monophasic action potentials (MAPs) were recorded at the right ventricular endocardium using a contact electrode before and after the administration of disopyramide (n = 6, 2 mg/kg, i.v.) or pilsicainide (class Ic agents, n = 4, 1 mg/kg, i.v., and n = 2, 150 mg, po) while the stimulus frequency was abruptly increased from 100/min to 150/min. The rise time, defined as the interval from the pacing pulse to the first peak deflection of the monophasic action potential, and the ORS width were measured simultaneously. In the absence of the sodium channel blockers, the abrupt increase in heart rate did not alter the QRS width or the rise time. In the presence of the agents, both variables were lengthened exponentially. The rate constants of onset changes in the QRS width and the rise time were 2.1 +/- 0.5 beats and 2.1 +/- 0.4 beats after the administration of disopyramide, and 7.5 +/- 3.0 beats and 8.2 +/- 4.0 beats after pilsicainide, respectively. The rate constant of the rise time was closely correlated with that of the QRS width. The present results are very closely comparable with the onset rate constants of use-dependent block of the maximum rate of depolarization in in vitro studies. These results suggest that (1) the rise time is a good indicator of local use-dependent decrease in conductivity by sodium channel blockers in human hearts and (2) the local use-dependent decrease in conductivity has kinetics similar to those of use-dependent sodium channel blocks.
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PMID:The rise time of the monophasic action potential--a new index of local use-dependent conductivity by sodium channel blockers in human myocardium. 941 61

Cardiac arrhythmias cause more than 300,000 sudden deaths each year in the USA alone. Long QT syndrome (LQT) is a cardiac disorder that causes sudden death from ventricular tachyarrhythmias, specifically torsade de pointes. Four LQT genes have been identified: KVLQT1 (LQT1) on chromosome 11p15.5, HERG (LQT2) on chromosome 7q35-36, SCN5A (LQT3) on chromosome 3p21-24, and MinK (LQT5) on chromosome 21q22. SCN5A encodes the cardiac sodium channel, and LQT-causing mutations in SCN5A lead to the generation of a late phase of inactivation-resistant whole-cell inward currents. Mexiletine, a sodium channel blocker, is effective in shortening the QT interval corrected for heart rate (QTc) of patients with SCN5A mutations. HERG encodes the cardiac I(Kr) potassium channel. Mutations in HERG act by a dominant-negative mechanism or by a loss-of-function mechanism. Raising the serum potassium concentration can increase outward HERG potassium current and is effective in shortening the QTc of patients with HERG mutations. KVLQT1 is a cardiac potassium channel protein that interacts with another small potassium channel MinK to form the cardiac I(Ks) potassium channel. Like HERG mutations, mutations in KVLQT1 and MinK can act by a dominant-negative mechanism or a loss-of-function mechanism. An effective treatment for LQT patients with KVLQT1 or MinK mutations is expected to be developed based on the functional characterization of the I(Ks) potassium channel. Genetic testing is now available for some patients with LQT.
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PMID:Genetics, molecular mechanisms and management of long QT syndrome. 955 90

Reorientation in drug therapy to control cardiac arrhythmias continues to evolve in the wake of ongoing refinements in techniques and indications for radiofrequency ablation and the use of implantable devices for atrial and ventricular arrhythmias. The role of sodium channel blockers continues to be questioned, and data from clinical trials indicate that the use of this class of drugs should be limited to control symptoms in patients who have arrhythmias and either no or minimal heart disease. The decline in the use of sodium channel blockers has led to greater use of beta blockers and complex Class III agents, such as sotalol and amiodarone, as both primary therapy and adjunctive therapy with implantable defibrillators in patients with cardiac disease of varying degrees of ventricular dysfunction. Success with these Class III agents in the context of their side effects has led to the synthesis and characterization of compounds with simpler ion channel-blocking properties. The need for such compounds stemmed from the observation that atrial fibrillation (AF) as an arrhythmia is, for the most part, still not amenable to curative therapy by interventional procedures. The isolated block of the rapid component of the delayed rectifier current (IKr) has been found to have either a neutral (e.g., dofetilide) or deleterious (e.g., d-sotalol) effect on mortality in survivors of myocardial infarction. Thus, the objective of drug development should be the appropriate match between the substrate and an antiarrhythmic drug. The so-called pure Class III agents have been shown to have beneficial antifibrillatory effects in patients with AF. They are effective in inducing acute chemical conversion, preventing paroxysmal AF, and maintaining sinus rhythm in patients with persistent AF restored to sinus rhythm with DC cardioversion. AF is a complex arrhythmia, undoubtedly a result of multifaceted derangement of atrial ionic currents. Attention has therefore focused on newer compounds that have the propensity to block more than one ion channel. Examples of such agents are tedisamil and azimilide, the latter having been studied extensively in humans. It is the first of the Class III agents that block both components (IKr and IKs) of the delayed rectifier current, which results in a spectrum of electrophysiologic properties that includes lack of rate or use dependency in terms of effect on repolarization and refractoriness of atrial and ventricular myocardium. Available but unpublished clinical data indicate that azimilide may be effective over a wide range of tachycardia cycle lengths with a low incidence of torsades de pointes. In these respects, its properties, at least in terms of its use in AF, resemble those of amiodarone. However, the drug has little or no effect on AV conduction, which precludes the modulation of ventricular response in patients relapsing to AF.
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PMID:Current antiarrhythmic drugs: an overview of mechanisms of action and potential clinical utility. 1009 Feb 35


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