Class IB Agents Research Articles

Resuscitated Sudden Cardiac Arrest of a Neonate with Congenital LQT Syndrome-Associated Torsades de Pointes: A Case Report and Literature Review

Sudden infant death syndrome (SIDS), the most common cause of infant death in developed countries, is attributed to diverse trigger factors. Malignant cardiac dysrhythmias are potentially treatable etiologies, and congenital long QT syndrome (LQTS) is the most common cardiac ionic channelopathy confronted. β-Blockers or class Ib agents are the drugs of choice for the control of arrhythmias, and an implantable cardioverter defibrillator (ICD) should be considered for secondary prevention in survivors of lethal cardiac death. We report the case of a 4-day old neonate, later genetically confirmed as LQT type 3 (LQT3), who survived a pulseless torsades de pointes (TdP) attack and was successfully treated with propranolol, mexiletine, and ICD implantation.

Inhibitory effects of class I antiarrhythmic agents on Na+ and Ca2+ currents of human iPS cell-derived cardiomyocytes.

IntroductionHuman induced pluripotent stem cells (hiPSCs) harboring cardiac myosin heavy chain 6 promoter can differentiate into functional cardiomyocytes called “iCell cardiomyocytes” under blasticidin treatment condition. While iCell cardiomyocytes are expected to be used for predicting cardiotoxicity of drugs, their responses to antiarrhythmic agents remain to be elucidated. We first examined electrophysiological properties of iCell cardiomyocytes and mRNA levels of ion channels and Ca handling proteins, and then evaluated effects of class I antiarrhythmic agents on their Na+ and Ca2+ currents.MethodsiCell cardiomyocytes were cultured for 8–14 days (38–44 days after inducing their differentiation), according to the manufacturer's protocol. We determined their action potentials (APs) and sarcolemmal ionic currents using whole-cell patch clamp techniques, and also mRNA levels of ion channels and Ca handling proteins by RT-PCR. Effects of three class I antiarrhythmic agents, pirmenol, pilsicainide and mexiletine, on Na+ channel current (INa) and L-type Ca2+ channel current (ICaL) were evaluated by the whole-cell patch clamp.ResultsiCell cardiomyocytes revealed sinoatrial node-type (18%), atrial-type (18%) and ventricular-type (64%) spontaneous APs. The maximum peak amplitudes of INa, ICaL, and rapidly-activating delayed-rectifier K+ channel current were −62.7 ± 13.7, −8.1 ± 0.7, and 3.0 ± 1.0 pA/pF, respectively. The hyperpolarization-activated cation channel and inward-rectifier K+ channel currents were observed, whereas the T-type Ca2+ channel or slowly-activating delayed-rectifier K+ channel current was not detectable. mRNAs of Nav1.5, Cav1.2, Kir2.1, HCN4, KvLQT1, hERG and SERCA2 were detected, while that of HCN1, minK or MiRP was not. The class Ia antiarrhythmic agent pirmenol and class Ic agent pilsicainide blocked INa in a concentration-dependent manner with IC50 of 0.87 ± 0.37 and 0.88 ± 0.16 μM, respectively; the class Ib agent mexiletine revealed weak INa block with a higher IC50 of 30.0 ± 3.0 μM. Pirmenol, pilsicainide and mexiletine blocked ICaL with IC50 of 2.00 ± 0.39, 7.7 ± 2.5 and 5.0 ± 0.1 μM, respectively.ConclusionsIn iCell cardiomyocytes, INa was blocked by the class Ia and Ic antiarrhythmic agents and ICaL was blocked by all the class I agents within the ranges of clinical concentrations, suggesting their cardiotoxicity.

Effects of Na+ Channel Blockers on Extrasystolic Stimulation-evoked Changes in Ventricular Conduction and Repolarization

Antiarrhythmic agents which belong to class Ia (quinidine) and Ic (flecainide) reportedly increase propensity to ventricular tachyarrhythmia, whereas class Ib agents (lidocaine and mexiletine) are recognized as safe antiarrhythmics. Clinically, tachyarrhythmia is often initiated by a premature ectopic beat, which increases spatial nonuniformities in ventricular conduction and repolarization thus facilitating reentry. This study examined if electrical derangements evoked by premature excitation may be accentuated by flecainide and quinidine, but unchanged by lidocaine and mexiletine, which would explain the difference in their safety profile. In perfused guinea pig hearts, a premature excitation evoked over late repolarization phase was associated with prolonged epicardial activation time, reduced monophasic action potential duration (APD), and increased transepicardial dispersion of the activation time and APD. Flecainide and quinidine increased conduction slowing evoked by extrasystolic stimulation, prolonged APD, and accentuated spatial heterogeneities in ventricular conduction and repolarization associated with premature excitation. Spontaneous episodes of nonsustained monomorphic ventricular tachycardia were observed in 50% of heart preparations exposed to drug infusion. In contrast, lidocaine and mexiletine had no effect on extrasystolic stimulation-evoked changes in ventricular conduction and repolarization or arrhythmic susceptibility. These findings suggest that flecainide and quinidine may promote arrhythmia by exaggerating electrophysiological abnormalities evoked by ectopic beats.

Impact of Na+ channel blockers on transmural dispersion of refractoriness and arrhythmic susceptibility in guinea-pig left ventricle

Clinically, class Ib antiarrhythmic agents (selective INa blockers) are considered to be safe drugs, whereas class Ia and Ic agents (non-selective blockers of both INa and IKr, the rapid component of the delayed rectifier) may evoke proarrhythmia. I hypothesized that this difference is accounted for by differential drug effects on transmural dispersion of refractoriness, in the presence of the reciprocal distribution profile of INa and IKr across ventricular wall, as determined in previous studies. Specifically, less epicardial than endocardial INa reserve would likely contribute to a greater prolongation of the effective refractory period (ERP) at epicardium by the INa blocker, thereby reducing epicardial-to-endocardial ERP dispersion, with resulting antiarrhythmic effect. In contrast, less endocardial than epicardial IKr reserve would likely contribute to a greater prolongation of repolarization at the endocardium by the IKr blocker, thereby amplifying transmural ERP dispersion and inducing arrhythmia. In perfused guinea-pig hearts, dofetilide, a specific IKr blocker, as well as class Ia (quinidine, procainamide) and class Ic agents (flecainide), were found to prolong the QT interval and monophasic action potential duration, and elicited greater endocardial than epicardial ERP prolongation, thus markedly increasing transmural ERP dispersion. These changes were associated with episodes of monomorphic ventricular tachycardia in 30–40% of experiments. In contrast, class Ib agents (lidocaine, mexiletine) evoked greater epicardial than endocardial ERP lengthening, thereby decreasing transmural ERP dispersion, and produced no tachyarrhythmia. These findings suggest that transmural ERP dispersion is the electrophysiological determinant which may shape the profile of class I agent effects on arrhythmic susceptibility.

Outpatient prescribing of antiarrhythmic drugs from 1995 to 2000

There is growing evidence that some class III antiarrhythmic drugs, unlike class I agents, are not associated with an increased risk of death in patients with prior myocardial infarction and left ventricular dysfunction. 1‐14 For this reason, we evaluated the extent to which the current prescribing of antiarrhythmic medications complies with the evidence that supports the use of class III rather than class I agents. Using pharmaceutical marketing research data, we reviewed outpatient antiarrhythmic drug prescriptions in the United States from 1995 through the third quarter of 2000, to characterize the prescribing of these drugs and to examine drug use trends over this period. ••• Data on antiarrhythmic drug prescribing were derived from 2 audits owned by IMS Health (Plymouth Meeting, Pennsylvania): the National Prescription Audit (NPA) Plus and the National Disease and Therapeutic Index (NDTI). The NPA Plus audit measures the retail outflow of prescriptions in the United States. This includes prescriptions dispensed by retail pharmacies and mailorder pharmacies. The NDTI audit contains data on drug mentions associated with a diagnosis during a specific clinic visit. These data are collected by a continuing survey of 343,655 physicians in officebased practices in the United States. An NDTI panel of physicians, a subset of 343,655, is selected every 2 weeks to provide demographic information, diagnoses, and recommended drugs for each diagnosis on all patients encountered. This is then projected to the national level. The NPA Plus audit was queried for all class I and class III antiarrhythmic drugs for which an oral dosage form was marketed and sold in the United States between January 1995 and September 2000. The numbers presented for the year 2000 represent a 9-month period. Class I agents included the class IA agents quinidine, procainamide, and disopyramide, the class IB agents mexiletine and tocainide, and the class IC agents flecainide, propafenone, and moricizine. Class III agents included amiodarone and sotalol. We limited this analysis to class I and III antiarrhythmic drugs because it would be difficult to determine whether blockers (class II antiarrhythmic agents) and calcium channel blockers (class IV antiarrhythmic agents) were prescribed solely for an arrhythmic indication. The NDTI audit was queried for all oral class I and class III antiarrhythmic agents strati fied by physician specialty and diagnoses for which the agent(s) was used. Trends in antiarrhythmic drug prescriptions were evaluated based on physician specialty and the diagnosis for which each agent or class of agents was reported to be prescribed.

Antiarrhythmic agents and proarrhythmia

The Vaughn Williams classification divides antiarrhythmic agents into four groups according to their effects on various ion channels. Class I agents block sodium channels and are subdivided into three groups. The use of class Ia agents is gradually on the decline, secondary to lack of a favorable risk/benefit ratio. Class Ib agents include lidocaine, which is extensively used for the acute treatment of ventricular tachyarrhythmias. Class Ic drugs are not advisable for patients with structural cardiac abnormalities secondary to a high risk of proarrhythmia. They are mainly used for supraventricular tachyarrhythmias. beta blockers form class II. Class III agents, such as amiodarone and sotalol, prolong action potential duration and repolarization and are among the most widely used antiarrhythmics. They are the subject of active research, and newer agents are being developed. Calcium-channel blockers are grouped under class IV. Digoxin and adenosine have unique antiarrhythmic properties, which can be useful in the management of selected patients. All antiarrhythmic drugs have the potential to provoke arrhythmias and, therefore, should be used with caution. The risk of proarrhythmia is increased in patients with abnormal cardiac substrate, with electrolyte abnormalities, and during drug initiation. Correction of electrolyte imbalance and prevention of bradycardia while the drug is metabolized and/or excreted are the cornerstones of proarrhythmia management.

Electrophysiologic effects and predictors of success of combination therapy with class Ia and Ib antiarrhythmic drugs for sustained ventricular arrhythmias

Antiarrhythmic drugs remain the first line of therapy in patients with sustained ventricular arrhythmias. Although success with class la antiarrhythmic medications has been limited, there is evidence that the addition of a class Ib agent may improve results. A total of 110 consecutive patients referred for electrophysiologic evaluation who had inducible sustained ventricular arrhythmias resistant to a class la agent underwent repeat electrophysiologic study after the addition of a class Ib drug. Patients with ejection fraction >40% and ventricular fibrillation inducible in the baseline study had an 80% response rate, whereas those with inducible ventricular tachycardia and ejection fraction ≤40% responded 11% of the time. Responders demonstrated marked prolongation of ventricular refractoriness and slight shortening of the QRS, whereas nonresponders had QRS prolongation and a more modest increase in ventricular refractoriness. Thus, the efficacy of class Ia/Ib combination therapy in patients with inducible sustained ventricular arrhythmias refractory to a class la drugs alone can be predicted by baseline variables. Marked prolongation of ventricular refractoriness in the absence of QRS prolongation appears to be a key factor in the success of this combination.

Mexiletine antagonizes effects of sotalol on QT interval duration and its proarrhythmic effects in a canine model of torsade de pointes

The arrhythmogenic and electrophysiologic properties of sotalol, a class III antiarrhythmic drug, administered alone and in combination with mexiletine, a class I antiarrhythmic drug, were compared in conscious dogs predisposed to torsade de pointes arrhythmias. The utility of sotalol is limited by proarrhythmia related to excessive delays in repolarization. The addition of mexiletine may limit the risk of torsade de pointes because it reduced in vitro the sotalol-induced increase in action potential duration. Two studies were performed in eight hypokalemic dogs (plasma potassium level < or = 3.2 mmol/liter) with chronic atrioventricular block (mean ventricular cycle length, RR 1,100 ms) at 3-day intervals using a crossover protocol. Intravenous sotalol (4.5 + 1.5 mg/kg body weight per h) alone was given for 2 h, or, on another day, an intravenous mexiletine infusion (4.5 + 1.5 mg/kg per h) was begun 30 min before sotalol infusion. Spontaneous ventricular cycle length and QT interval and ventricular effective refractory period at the 1,000-ms pacing cycle length were measured at baseline and 30 min after the onset of each drug infusion. The electrocardiogram (ECG) was continuously monitored for torsade de pointes. Sotalol plus mexiletine and sotalol alone had a significant (p < or = 0.05) and similar effect on ventricular cycle length (+ 800 +/- 93 vs. + 690 +/- 104 ms [mean +/- SEM]) and ventricular effective refractory period (+ 20 +/- 4 vs. + 25 +/- 4 ms), but sotalol plus mexiletine had a lesser effect on QT interval (+ 20 +/- 6 vs. + 50 +/- 8 ms, p < or = 0.05). Torsade de pointes is less frequent (one of eight dogs vs. six of eight dogs, p = 0.02) with sotalol plus mexiletine than with sotalol alone. The coadministration of a class Ib agent can reduce the proarrhythmic potential of a class III drug in experimental animals predisposed to torsade de pointes arrhythmias and further suggests the clinical utility of such a strategy.

Differential effects on action potential duration of class IA, B and C antiarrhythmic drugs: modulation by stimulation rate and extracellular K+ concentration.

1. Standard microelectrode techniques were used to study the effects on the action potential duration (APD) of canine Purkinje fibres of a therapeutic concentration of nine Class I antiarrhythmic drugs. At an extracellular K+ concentration of 5.6 mmol/L all nine agents reduced APD at all drive rates studied (range of interstimulus intervals = 200-1000 ms). At lower levels of K+, quinidine (5 mumol/L) and disopyramide (10 mumol/L) (Class Ia agents) revealed dual effects on APD. At the lowest levels of K+ (2 mmol/L) and the longest interstimulus interval used (2000 ms), both agents significantly prolonged APD. Under all other conditions, APD was either unchanged or reduced. Lignocaine, 15 mumol/L (Class Ib agent) reduced APD at all rates and all K+ concentrations and this effect was greatest at the slowest rates. 2. Flecainide (1 mumol/L) (Class Ic) shortened APD at K+ = 5.6 and 4 mmol/L but had no effect at K+ = 2 mmol/L. 3. We conclude that these data result from opposing drug actions on inward sodium and outward potassium currents flowing during the plateau of the action potential. 4. Class Ia drugs exhibit significant depression of both currents, with the resultant effect on APD being modulated by external K+ concentration and drive rate. 5. Class Ib agents predominantly depress the sodium current and hence shorten APD, and Ic compounds have intermediate actions. 6. These differential effects on APD must be considered when planning antiarrhythmic therapy, and are directly relevant to the proarrhythmic propensities of these agents.

Efficacy and tolerance of the new class IB antiarrhythmic barucainide: An intravenous dose-finding study

Barucainide is a new class IB antiarrhythmic agent that was studied for efficacy and safety after intravenous administration in patients with severe ventricular arrhythmias. All patients received 80 mg/hr barucainide intravenously for 7 hours or until ventricular arrhythmias were suppressed by greater than 90%. In responders a maintenance dose was given for 24 hours, aimed to achieve steady-state conditions. At baseline and during the treatment and washout periods 24-hour Holter recordings were performed. In addition, electrocardiogram, blood pressure, and plasma concentration of barucainide were measured. In 9 of 12 patients dose titration was effective (mean dose, 185 mg). In six of nine patients arrhythmia suppression persisted during maintenance therapy (mean dose, 18 mg/hr). Plasma concentrations correlated with given doses, rather than with antiarrhythmic efficacy. During the washout period, five patients required more than 12 hours for recurrence of arrhythmias. Treatment was stopped in one patient because of proarrhythmia; one patient had moderate heat sensations. Thus barucainide is a potent class IB agent, with a favorable side effect profile.

Clinical implications of new studies in the treatment of benign, potentially malignant and malignant ventricular arrhythmias

For purposes of clinical management, ventricular arrhythmias have been divided into risk categories of benign, prognostically important (potentially malignant) and malignant. Benign arrhythmias occur in the setting of structurally normal hearts and do not require therapy unless associated with debilitating symptoms. Malignant arrhythmias such as sustained ventricular tachycardia or fibrillation deserve aggressive therapy to prevent recurrence. Arrhythmias occurring in the presence of organic heart disease (often ischemic disease) are frequently asymptomatic but prognosticaHy important as a risk factor for sudden death or cardiac arrest. The common empiric practice to treat such arrhythmias (by about 40 to 50% of cardiologists in the United States) needs to be reassessed in the face of the Cardiac Arrhythmia Suppression Trial. For malignant arrhythmias, class IA agents (procainamide and quinidine) continue to be the standard of treatment, and class IB agents (e.g., mexiletine) may be used as alternative or additive therapy. Class IC agents are used as second-line therapy, especially in the setting of ischemic heart disease. Class III therapy with amiodarone is reserved for refractory patients because of potential toxicity. Sotalol, a new class II–III agent, may become a first-line drug. For prognostically important arrhythmias, β blockers remain the agents of choice, class IC agents are contraindicated, and class IA or IB drugs, or both, should be used conservatively (i.e., only for symptomatic arrhythmias). For symptomatic but benign arrhythmias requiring treatment, β blockers are safe although not always effective. Class IA, IB and IC agents may then be considered. In these patients, the proarrhythmic potential of quinidine and class IC agents remains a concern. Better tolerated and safer drugs are needed for symptomatic arrhythmias. Some promising class I drugs under development include moricizine, pirmenol and recainam. Treatment algorithms will evolve as new study results and new drugs become available.

Potassium channels as targets for antiarrhythmic drug action

AbstractRecent cellular electrophysiologic studies have begun to clarify the basis of antiarrhythmic drug action. The Class I agents have been shown to block cardiac sodium channels in a use‐dependent manner, and the kinetics and potency of sodium channel block correlated with molecular weight and lipid solubility of drug. The Class IA agents, like quinidine, which increase cardiac action potential duration and refractory period in addition to their effects on conduction, also appear to have potent blocking actions on the potassium channels responsible for repolarization in myocardial cells, whereas the Class IB agents, like lidocaine, shorten action potential duration and are relatively specific in their block of sodium channels. In contrast, Class III agents, which prolong the action potential without slowing conduction, appear to exert their primary blocking action on the potassium channel only. Conversion from Class I to Class III electrophysiologic profiles can be achieved by the substitution of electron‐withdrawing groups (e.g., NO2) in place of electron‐donating groups (e.g., NH2) on the aromatic portion of the basic local anesthetic pharmacophore. Class III agents appear to be most effective against ventricular fibrillation and ventricular tachycardia due to re‐entry, but are generally without activity in the 24 hr Harris dog arrhythmia model. Further evaluation of the mechanism of antiarrhythmic drug action will require use of well‐defined arrhythmia models in a combination with a detailed understanding of drug‐channel interactions.

Second Generation Antidysrhythmic Agents

Several new antidysrhythmic agents have been or are about to be approved for the prevention and/or treatment of life-threatening or symptomatic ventricular arrhythmias. Prior to use in clinical practice, however, their relative risk/benefit ratio must be assessed. Whereas relief of bothersome symptoms of ventricular dysrhythmias may improve the patient's return to a more active role in society, one must be aware, at the same time, that these antidysrhythmics have adverse effects of their own that may significantly limit their effectiveness. None of these new antidysrhythmic agents has been shown to prevent suddent cardiac death in controlled trials. At the present time, studies are being conducted to assess the efficacy of these agents in preventing sudden cardiac death. The new antidysrhythmic agents are highly effective in treating a wide variety of ventricular, and in some cases, supraventricular dysrhythmias. These agents are orally effective and, because of their unique pharmacokinetic profile, can often be prescribed less often per day than first generation antidysrhythmics. Side effects, for the most part, are predictable and involve the gastrointestinal and central nervous systems. In most cases, such side effects are reversible with dosage reduction. Upon treating a patient for a potentially lethal dysrhythmia, a Class IC agent such as encainide, flecainide, or propafenone, may be considered as the first-line therapy. Class IB agents, although less effective when used alone, show augmented antidysrhythmic efficacy with a reduction in side effects when administered concomitantly with a Class IA agent, such as quinidine or procainamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological characterisation of a re-entry model for atrial tachycardia in conscious dogs

We studied the effects of intravenously administered autonomic agents, the calcium channel blocker diltiazem, and Class I and III anti-arrhythmic agents on a re-entry model for atrial tachycardia in seven conscious dogs. The model was created by a Y-shaped incision in the intercaval region and front free wall of the right atrium. Acetylcholine (30 micrograms.kg-1) transiently but significantly shortened the cycle length of atrial tachycardia (CL) by 9 (SD 5)% while atropine (0.2 mg.kg-1) alone did not change or terminate the rhythm. Isoprenaline (4 micrograms.kg-1) briefly reduced CL, by 13(6)% whereas propranolol (1 mg.kg-1) alone significantly prolonged the CL and terminated the arrhythmia in 50% of the trials. Diltiazem (200 micrograms.kg-1) did not significantly change the CL. Class Ia agents procainamide (30 mg.kg-1) and quinidine (3.5 approximately 20 mg.kg-1, effective doses) increased CL by 60(30) and 43(28)% respectively and terminated the arrhythmias. Class Ib agents, phenytoin (5 and 10 mg.kg-1, cumulative doses), lignocaine (3.2 approximately 7 mg.kg-1), and mexiletine (6 approximately 20 mg.kg-1), prolonged CL by 31(14), 40(15), and 72(13)%; however, consistent conversion of the rhythm occurred only with mexiletine. Ic agents flecainide (0.5 approximately 3 mg.kg-1) and encainide (0.6 approximately 6.4 mg.kg-1) lengthened the CL by 58(17) and 75(43)% and converted the rhythm in all cases. Class III agents clofilium (0.5 mg.kg-1), d-sotolol (3.2 approximately 20 mg.kg-1), and N-acetylprocainamide (15 approximately 120 mg.kg-1) prolonged the CL by 14(4), 16(5), and 19(7)% and terminated the arrhythmia in all trials. The magnitudes of CL prolongation by the Class III agents were significantly smaller than those by the Class Ia, Ib, or Ic agents. These results show that in this re-entrant model for atrial tachycardia endogenous adrenergic but not cholinergic systems play a major role in maintaining impulse propagation and that calcium channel mediated slow inward currents do not participate in the impulse generation processes. Further, using CL as an index, the model serves as a useful tool for differentiating Class III from Class I anti-arrhythmic activities.

Resting, and rate-dependent depression of Vmax of guinea-pig ventricular action potentials by amiodarone and desethylamiodarone.

1 The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea-pig ventricular myocardium by use of standard microelectrode techniques. 2 Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations. 3 The Class I effects were rate-dependent, with small (0-16%) falls in maximum depolarization rate in the absence of stimulation ('resting block') and progressively larger effects at decreasing interstimulus intervals (range 1200-300 ms). 4 The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class Ib agents). 5 It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.

Antiarrhythmic effects of beta-adrenergic blocking agents in benign or potentially lethal ventricular arrhythmias

Classification of ventricualr arrhythmias into those that are benign, potentially lethal and lethal is based on their associated risk for producing sudden cardiac death. This classification system is useful in defining indications for the treatment of ventricular arrhythmias and predicting differential rates of antiarrhythmic drug efficacy and toxicity. Whether the reduction of potentially lethal ventricular arrhythmias will prevent sudden cardiac death remains to be determined. The class II antiarrhythmic agents—the β-adrenergic blocking drugs—have been shown to reduce sudden cardiac death in postmyocardial infarction patients, but the precise mechanism of their effect has not been defined, β blockers are efficaclous in approximately 50% of patients with benign or potentially lethal ventricular arrhythmias. This response is comparable to that seen with the class IA agent disopyramide or the class IB agents tocainide and mexiletine. β blockers have favorable side-effect profiles including a low incidence of proarrhythmia and a lack of organ toxicity such as hepatitis, pulmonary fibrosis or agranulocytosis, which are concerns with class I and class III antiarrhythmic drugs. The proper dosage of the β blocker is critical in limiting adverse effects. In a study of 23 patients with benign or potentially lethal ventricular arrhythmias, 11 (48%) of the patients responded to nadolol with a reduction of >75% in arrhythmia frequency, and several patients responded at nadolol dosages as low as 10 mg daily. Thus, it is plausible to consider β blockers as first-choice antiarrhythmic therapy, even in patients with left ventricular dysfunction when sympathetic tone is not required to maintain cardiac compensation.