Procainamide-Provoked Brugada Pattern in a Patient Presenting with New-Onset Atrial Fibrillation or Flutter: When Does it Matter?

BACKGROUND: Brugada syndrome (BrS) is an inherited disease that can lead to sudden cardiac death. Medications, such as antidysrhythmics, and fevers can unmask or induce the Brugada pattern on an electrocardiogram (ECG). This case report highlights a patient who developed drug-induced Brugada type I pattern after a procainamide infusion for the treatment of new-onset atrial fibrillation (AF) or flutter and discusses the implications for this incidental but potentially lethal finding. CASE REPORT: We report a case of a young man who presented to the emergency department (ED) with new-onset AF with rapid ventricular response that began within 12 h of presentation. ED treatments included a crystalloid IV fluid bolus, diltiazem pushes, synchronized electrical cardioversion, and a procainamide infusion. After the procainamide infusion, the patient developed ECG findings consistent with Brugada pattern. Both the AF and Brugada pattern resolved spontaneously within 24 h. The patient was discharged without implantable cardioverter defibrillator placement due to presumed isolated procainamide-induced Brugada pattern and lack of concerning features, such as inducible dysrhythmia during electrophysiology study, family history of sudden death, and history of syncope. The patient was counseled to follow-up with genetics and avoid BrS-inducing medications. WHY SHOULD AN EMERGENCY PHYSICIANS BE AWARE OF THIS?: Procainamide, an option for the treatment of AF in the ED, can provoke Brugada pattern. If encountered, it is important to recall that some patients may not be diagnosed with BrS if determined to be low risk according to the Shanghai criteria. All patients should be referred to cardiology for further evaluation.

Electrocardiographic marker of the cardiac action potential triangulation induced by antiarrhythmic drugs in perfused guinea-pig heart.

NEW FINDINGS: What is the central question of this study? Can the triangular appearance of ventricular action potential, indicating proarrhythmic profile of antiarrhythmic agent, be approximated by specific changes on an electrocardiogram (ECG)? What are the main finding and its importance? The triangulation of the ventricular action potential seen when antiarrhythmic drugs induce a greater lengthening of the late repolarization compared to the initial repolarization in epicardium is closely approximated by a greater prolongation of the T wave upslope relative to the interval between the J point and the start of the T wave (the JTstart interval) on the ECG. These findings may improve the power of ECG assessments in predicting the drug-induced arrhythmia resulting from slowed phase 3 repolarization. ABSTRACT: Antiarrhythmic drugs prescribed to treat atrial fibrillation can occasionally precipitate ventricular tachyarrhythmia through a prominent slowing of the phase 3 repolarization. The latter results in the triangular shape of ventricular action potential, indicating high arrhythmic risk. However, clinically, the utility of triangulation assessments for predicting arrhythmia is limited owing to the invasive nature of the ventricular action potential recordings. This study examined whether the triangulation effect can be detected indirectly from electrocardiogram (ECG) analysis. Epicardial monophasic action potentials and the ECG were simultaneously recorded in perfused guinea-pig hearts. With antiarrhythmics (dofetilide, quinidine, procainamide and flecainide), a prolongation of the initial repolarization seen in the action potential recordings was closely approximated by lengthening of the interval between the J point and the start of the T wave (the JTstart interval) on the ECG, whereas a prolongation of the late repolarization was paralleled by widening of the T wave upslope. Dofetilide, quinidine and procainamide induced a prominent slowing of the phase 3 repolarization in epicardium, leading to triangulation of the action potential. These effects were accompanied by a greater prolongation of the T wave upslope compared to the JTstart interval. Flecainide elicited a proportional prolongation of the initial and the late ventricular repolarization, and therefore failed to induce triangulation, based on analysis of both epicardial action potential and ECG profiles. Collectively, these findings suggest that the ratio between the durations of the T wave upslope and the JTstart interval may represent the ECG metric of the ventricular action potential triangulation induced by antiarrhythmic drugs.

Drug-induced systemic lupus: revisiting the ever-changing spectrum of the disease using the WHO pharmacovigilance database.

OBJECTIVE: Drug-induced lupus (DIL) is an idiosyncratic side effect of treatments in which symptoms overlap with those of systemic lupus erythematosus (SLE). The spectrum of DIL constantly evolves with that of the pharmacopoeia. Here, we used VigiBase, the WHO global individual case safety reports (ICSRs) database, to identify the main drugs associated with DIL. METHODS: We analysed all ICSRs classified as 'systemic lupus erythematosus' according to the Medical Dictionary for Drug Regulatory Activities term (preferred term level) in VigiBase. The drugs considered in the analysis were those not used to treat SLE, with a positive lower end of the 95% credibility interval for the information component (IC025) ≥0, an indicator value for disproportionate Bayesian reporting. RESULTS: A total of 12 166 DIL ICSRs were identified using VigiBase. From those, 8163 ICSRs reporting on 118 suspected drugs with IC025 ≥0 were extracted. The median age at DIL onset was 49 years and the female to male sex ratio was 4.3. The median delay between start of suspected treatment and DIL occurrence was 172 days. DIL was reported as serious adverse event in 55.4%. Among the 118 suspected drugs, 42 had not been previously reported in association with DIL. The drugs associated with the highest number of DIL cases were infliximab, adalimumab, etanercept, procainamide and hydralazine. CONCLUSION: This study enables the identification of 118 drugs associated with DIL. The list of suspected drugs may prove useful to physicians when confronted with potential DIL cases. TRIAL REGISTRATION NUMBER: NCT03480529.

Drug-induced lupus erythematosus: an update on drugs and mechanisms.

PURPOSE OF REVIEW: Rapid introduction of newly developed drugs in the absence of clear understanding of the pathophysiologic mechanisms behind drug-induced lupus erythematosus (DILE) can sometimes make DILE difficult to recognize in clinical practice. The purpose of this review is to summarize drugs most recently reported to be involved in DILE and discuss the current landscape of diverse mechanisms involved. RECENT FINDINGS: A large number of proton pump inhibitor (PPI)-induced subacute cutaneous lupus erythematosus cases have been reported, suggesting a shift over time in the spectrum of drugs implicated in DILE. Twenty-two articles comprising 29 DILE case reports published within the last 2 years are summarized in this review, including 12 (41.4%) systemic DILE. Antitumor necrosis factor (anti-TNF) drugs were the most frequently (41.7%) reported to introduce systemic DILE in these cases. Chemotherapeutic drugs were the most common drug class (54.5%) involved in subacute cutaneous lupus erythematosus, with an observed higher incidence in female patients. Enhanced neutrophil extracellular trap (NET) formation induced by procainamide and hydralazine could be a new mechanism contributing to the pathogenesis of DILE. SUMMARY: The list of drugs implicated in triggering DILE is expanding as new drugs with novel mechanisms of action are being developed. It is important to recognize culprit drugs that may induce lupus erythematosus, as discontinuation usually results in improvement of drug-induced manifestations. Characterizing the mechanisms involved might help better understand the cause of idiopathic autoimmunity.

Randomized comparison of intravenous procainamide vs. intravenous amiodarone for the acute treatment of tolerated wide QRS tachycardia: the PROCAMIO study.

AIMS: Intravenous procainamide and amiodarone are drugs of choice for well-tolerated ventricular tachycardia. However, the choice between them, even according to Guidelines, is unclear. We performed a multicentre randomized open-labelled study to determine the safety and efficacy of intravenous procainamide and amiodarone for the acute treatment of tolerated wide QRS complex (probably ventricular) tachycardia. METHODS AND RESULTS: Patients were randomly assigned to receive intravenous procainamide (10 mg/kg/20 min) or amiodarone (5 mg/kg/20 min). The primary endpoint was the incidence of major predefined cardiac adverse events within 40 min after infusion initiation. Of 74 patients included, 62 could be analysed. The primary endpoint occurred in 3 of 33 (9%) procainamide and 12 of 29 (41%) amiodarone patients (odd ratio, OR = 0.1; 95% confidence interval, CI 0.03-0.6; P = 0.006). Tachycardia terminated within 40 min in 22 (67%) procainamide and 11 (38%) amiodarone patients (OR = 3.3; 95% CI 1.2-9.3; P = 0.026). In the following 24 h, adverse events occurred in 18% procainamide and 31% amiodarone patients (OR: 0.49; 95% CI: 0.15-1.61; P: 0.24). Among 49 patients with structural heart disease, the primary endpoint was less common in procainamide patients (3 [11%] vs. 10 [43%]; OR: 0.17; 95% CI: 0.04-0.73, P = 0.017). CONCLUSIONS: This study compares for the first time in a randomized design intravenous procainamide and amiodarone for the treatment of the acute episode of sustained monomorphic well-tolerated (probably) ventricular tachycardia. Procainamide therapy was associated with less major cardiac adverse events and a higher proportion of tachycardia termination within 40 min.

Diagnosis and classification of drug-induced autoimmunity (DIA).

Since sulfadiazine associated lupus-like symptoms were first described in 1945, certain drugs have been reported to interfere with the immune system and induce a series of autoimmune diseases (named drug-induced autoimmunity, DIA), exemplified by systemic lupus erythematosus (SLE). Among the drugs, procainamide and hydralazine are considered to be associated with the highest risk for developing lupus, while quinidine has a moderate risk, and all other drugs have low or very low risk. More recently, drug-induced lupus has been associated with the use of newer biological modulators, such as tumor necrosis factor (TNF)-alpha inhibitors and cytokines. In addition to lupus, other major autoimmune diseases, including vasculitis and arthritis, have also been associated with drugs. Because resolution of symptoms generally occurs after cessation of the offending drugs, early diagnosis is crucial for treatment strategy and improvement of prognosis. Unfortunately, it is difficult to establish standardized criteria for DIA diagnosis. Diagnosis of DIA requires identification of a temporal relationship between drug administration and the onset of symptoms, but the relative risk with respect to dose and duration for each drug has rarely been determined. DIA is affected by multiple genetic and environmental factors, leading to difficulties in establishing a list of global clinical features that are characteristic of most or all DIA patients. Moreover, the distinction between authentic DIA and unmasking of a latent autoimmune disease also poses challenges. In this review, we summarize the highly variable clinical features and laboratory findings of DIA, with an emphasis on the diagnostic criteria.

Accelerated AV nodal conduction with use of procainamide in atrial fibrillation.

BACKGROUND: Atrial fibrillation is a common dysrhythmia seen in the emergency department (ED). Chemical or electrical cardioversion may be performed on patients who have had atrial fibrillation for < 48 h duration and who are at low risk for thromboembolic events. Multiple studies suggest that intravenous procainamide is an appropriate agent in the treatment of acute atrial fibrillation due to its relatively low risk profile and high conversion rate. OBJECTIVES: A case is presented that demonstrates an adverse reaction to the use of intravenous procainamide for chemical cardioversion of atrial fibrillation in an otherwise hemodynamically stable patient. CASE REPORT: We report a case of lone paroxysmal atrial fibrillation in a patient with a structurally normal heart who suffered paradoxical accelerated atrioventricular nodal conduction and secondary hypotension in response to procainamide administration. CONCLUSION: When administering procainamide for chemical cardioversion of atrial fibrillation, a low threshold should be maintained for administration of a complementary rate-controlling agent, and facilities for immediate electrical cardioversion always must be available.

Variation in management of recent-onset atrial fibrillation and flutter among academic hospital emergency departments.

STUDY OBJECTIVE: Although recent-onset atrial fibrillation and flutter are common arrhythmias managed in the emergency department (ED), there is insufficient evidence to help physicians choose between 2 competing treatment strategies, rate control and rhythm control. We seek to evaluate variation in ED management practices for recent-onset atrial fibrillation and flutter patients at multiple Canadian sites and to determine whether hospital site was an independent predictor of attempted cardioversion. METHODS: We conducted a cross-sectional survey by health records review on an observational cohort of all eligible adult recent-onset atrial fibrillation and flutter cases, with onset of symptoms less than 48 hours, treated at 8 academic hospital EDs during a 12-month period, and evaluated the variation in practice among sites for important management strategies. RESULTS: Among the 1,068 study patients, 88.3% had atrial fibrillation and 11.7% had atrial flutter. The proportion of cases managed with rhythm control was 59.4% (interhospital range 42% to 85%) and, among these, electrocardioversion was attempted first for 44.2% (range 7% to 69%). There was variation in most management strategies, including use of rate control drugs 54.9% (range 37% to 65%), choice of procainamide as rhythm control drug 62.1% (range 15% to 89%), referral to cardiology in the ED 30.7% (range 16% to 64%), use of heparin 13.7% (range 1% to 29%), and outpatient cardiology referral 43.0% (range 30% to 65%). Adverse events were relatively uncommon and transient for patients undergoing attempts at pharmacologic (13.0%) or electrocardioversion (12.1%). Overall, 83.3% of patients were discharged home from the ED (range 73% to 90%). After controlling for 12 covariates, multivariate logistic regression found that factors independently associated with attempted cardioversion were age (odds ratio [OR] 0.97; 95% confidence interval [CI] 0.95 to 0.98), history of electrocardioversion (OR 2.73; 95% CI 1.56 to 4.80), associated heart failure (OR 0.29; 95% CI 0.09 to 0.95), and hospital site (ORs ranged from 0.38 to 3.05). CONCLUSION: We demonstrated a high degree of variation in management approaches for recent-onset atrial fibrillation and flutter patients treated in academic hospital EDs. Individual hospital site, age, previous cardioversion, and associated heart failure were independent predictors for the use of rhythm control.

Drug-induced lupus: an update on its dermatologic aspects.

Drug-induced lupus erythematosus (DILE) is defined as an entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic lupus but which is temporally related to continuous drug exposure and resolves after discontinuation of the offending drug. Similar to idiopathic lupus, DILE can be divided into systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE) and chronic cutaneous lupus erythematosus (CCLE). Based on the literature review and retrospective analysis of our case series, we focused on the dermatological aspects of DILE. The cutaneous features of drug-induced SLE are protean, including particularly purpura, erythema nodosum and photosensitivity as well as the skin lesions characterizing both urticarial and necrotizing vasculitis. The typical laboratory profile of systemic DILE consists of positive antinuclear antibodies (ANA) and antihistone antibodies, the latter being regarded as the serum marker of this subset. The drugs most frequently implicated in the development of systemic DILE are hydralazine, procainamide, isoniazid and minocycline. Drug-induced SCLE usually presents with annular polycyclic or papulosquamous cutaneous manifestations as in the idiopathic form, but blisters or targetoid lesions mimicking erythema multiforme cannot rarely be associated. The clinical presentation is often generalized, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are usually present, whereas antihistone antibodies are uncommonly found. Drugs associated with SCLE include particularly calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine and the recently reported tumour necrosis factor (TNF)-alpha antagonists. Drug-induced CCLE is very rarely described in the literature and usually refers to fluorouracile agents or TNF-alpha antagonists. The picture is characterized by the occurrence of classic discoid lesions, but aspects of lupus tumidus can occasionally develop. ANA are demonstrated in around two-thirds of the cases. Management of DILE is based on the withdrawal of the offending drug. Topical and/or systemic corticosteroids and other immunosuppressive agents should be reserved for resistant cases.

Arrhythmogenic drugs can amplify spatial heterogeneities in the electrical restitution in perfused guinea-pig heart: An evidence from assessments of monophasic action potential durations and JT intervals.

Non-uniform shortening of the action potential duration (APD90) in different myocardial regions upon heart rate acceleration can set abnormal repolarization gradients and promote arrhythmia. This study examined whether spatial heterogeneities in APD90 restitution can be amplified by drugs with clinically proved proarrhythmic potential (dofetilide, quinidine, procainamide, and flecainide) and, if so, whether these effects can translate to the appropriate changes of the ECG metrics of ventricular repolarization, such as JT intervals. In isolated, perfused guinea-pig heart preparations, monophasic action potentials and volume-conducted ECG were recorded at progressively increased pacing rates. The APD90 measured at distinct ventricular sites, as well as the JTpeak and JTend values were plotted as a function of preceding diastolic interval, and the maximum slopes of the restitution curves were determined at baseline and upon drug administration. Dofetilide, quinidine, and procainamide reverse rate-dependently prolonged APD90 and steepened the restitution curve, with effects being greater at the endocardium than epicardium, and in the right ventricular (RV) vs. the left ventricular (LV) chamber. The restitution slope was increased to a greater extent for the JTend vs. the JTpeak interval. In contrast, flecainide reduced the APD90 restitution slope at LV epicardium without producing effect at LV endocardium and RV epicardium, and reduced the JTpeak restitution slope without changing the JTend restitution. Nevertheless, with all agents, these effects translated to the amplified epicardial-to-endocardial and the LV-to-RV non-uniformities in APD90 restitution, paralleled by the increased JTend vs. JTpeak difference in the restitution slope. In summary, these findings suggest that arrhythmic drug profiles are partly attributable to the accentuated regional heterogeneities in APD90 restitution, which can be indirectly determined through ECG assessments of the JTend vs. JTpeak dynamics at variable pacing rates.

Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation.

OBJECTIVE: Aberrant neutrophil extracellular trap (NET) formation has been implicated as a mechanism to induce autoreactivity in individuals at risk of autoimmune diseases. The objective of this study was to assess whether medications implicated in cases of drug-induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug-induced autoimmunity (minocycline and clozapine) induce NET formation and/or prevent NET degradation. METHODS: Human neutrophils were incubated with the drugs of interest and resultant NET formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with NET degradation by serum nuclei was assessed. Pathways of drug-induced NET formation were studied with pharmacologic inhibitors of reactive oxygen species (ROS), peptidylarginine deiminases (PADs), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if NET protein cargo varies by drug stimulus and/or neutrophil source, proteomic analysis of NET lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases. RESULTS: Hydralazine and procainamide significantly induced NET formation while minocycline and clozapine did not. None of the medications significantly impaired NET degradation. NETosis induced by these drugs required NADPH oxidase and PAD4 activation. Procainamide triggered NETs via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in NETs induced by hydralazine and procainamide. CONCLUSION: Medications commonly implicated in drug-induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NETosis may play a role in the pathogenesis of drug-induced autoimmunity.

Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin.

Increasing evidence suggests that autoantibodies in the rheumatic diseases are a consequence of immune selection by self-material, but the nature of the in vivo immunogen is unknown. Insight into this problem may be obtained by measuring autoantibody binding to various forms of a target antigen. Antihistone antibodies arising as a side effect of therapy with various drugs offer an opportunity to explore this premise because many forms of histone have been characterized and adapted to ELISA formats. Two patterns of antibody reactivity were observed. All 21 patients with symptomatic procainamide-induced lupus and 7 of 12 patients with quinidine-induced lupus had IgG antibodies reacting predominantly with the (H2A-H2B)-DNA complex and with chromatin. In contrast, antibodies in 19 of 24 patients taking procainamide without accompanying lupus-like symptoms did not show any pattern. The second pattern was observed in 18/19 chlorpromazine-treated patients and 14/17 patients with hydralazine-induced lupus in which IgM antibodies displayed more reactivity with DNA-free histones than with the corresponding histone-DNA complexes and almost no binding to H1-stripped chromatin. Absorption studies were entirely consistent with these results. Thus, the two patterns of reactivity with nucleosomal components reflect the molecular substructure of chromatin, suggesting that two processes underlie antihistone antibody induction by drugs. In one, IgG autoantibodies appear to be elicited by chromatin, whereas in the other, autoimmune tolerance to native chromatin appears largely intact, and IgM antibodies may be driven by DNA-free histone.

Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.

IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.

A comparative study of the efficacy and safety of procainamide versus propafenone versus amiodarone for the conversion of recent-onset atrial fibrillation.

The appropriate treatment for the restoration of sinus rhythm in patients with atrial fibrillation (AF) of recent onset is still the subject of controversy. In this prospective, randomized, single-blind, placebo-controlled clinical study, we investigated the effectiveness and safety of procainamide, propafenone, and amiodarone, administered intravenously, for the conversion of recent-onset AF. We enrolled 362 consecutive patients (183 men; age 34 to 86 years; mean 65+/-10) with AF duration of no >48 hours. Of these patients, 89 were given procainamide, 91 propafenone, 92 amiodarone, and 90 placebo. Treatment was considered successful if conversion to sinus rhythm was achieved within the 24-hour study period. Baseline clinical characteristics were similar in the 4 groups. The treatment was successful in 61 of the 89 patients who received procainamide (68.53%; median time 3 hours), 73 of the 91 patients who received propafenone (80.21%; median time 1 hour), 82 of the 92 patients who received amiodarone (89.13%; median time 9 hours), and 55 of the 90 patients who received placebo (61.11%; median time 17 hours; p<0.05 for all medicated groups vs placebo; p<0.05 for amiodarone and propafenone vs procainamide). In conclusion, all 3 medications, when administered intravenously, are effective in the restoration of sinus rhythm in recent-onset AF. Amiodarone and propafenone are more effective whereas procainamide and propafenone are faster.

Isolated perfused and paced guinea pig heart to test for drug-induced changes of the QT interval.

INTRODUCTION: One of the biomarkers for assessing the risk of a cardiac adverse event is drug-induced prolongation of the QT interval. A model is needed for evaluating the potential liability of test compounds on QT interval in vitro. Since QT intervals can be generated from paced or spontaneously beating hearts, data so generated can also be used for validating QT(c) correction equations. METHODS: Isolated guinea pig hearts were perfused in Locke's solution according to the Langendorff method. QT intervals were routinely measured from Lead II ECG waveforms. RESULTS: Compounds known to inhibit HERG channel, such as dofetilide, prolonged the QT interval in this model. (+/-)Bay K8644, a calcium channel activator, prolonged the QT interval, while verapamil, a calcium channel blocker, shortened it. Procainamide, a sodium channel blocker, also prolonged the QT interval. Many of the compounds, which prolonged the QT interval, also prolonged PR interval, suggesting dual inhibition of the Ikr channel, the rapid component of delayed rectifier potassium channel, and the calcium channel. The QT/RR intervals exhibited a curvilinear relationship, which could be corrected into nearly straight horizontal lines by using correction equations derived from linear, parabolic, and hyperbolic models. However, these correction equations yielded different results on the QT prolongation produced by sotalol, which also slowed down the heart rate. With the data set obtained in this investigation, correction equations derived from linear and parabolic models worked better than the equations derived from the hyperbolic model. The exponential model did not fit at all. CONCLUSION: QT intervals obtained under paced conditions provide the most direct and reliable QT information for a drug. The isolated perfused and paced guinea pig heart is a convenient model for studying the effect of compounds on QT interval in vitro.

Sotalol and type IA drugs in combination prevent recurrence of sustained ventricular tachycardia.

OBJECTIVES: This study assessed the efficacy of the combination of sotalol and either quinidine or procainamide in preventing sustained ventricular tachycardia inducibility and recurrence and prospectively evaluated the ability of the drug combination to prevent ventricular tachycardia recurrence when the arrhythmia remained inducible but was modified. BACKGROUND: Individual antiarrhythmic drugs are often ineffective in preventing the induction and recurrence of sustained ventricular tachycardia. Beta-adrenergic blockade and prolongation of refractoriness may be important components of successful antiarrhythmic therapy in patients with ventricular tachycardia. We reasoned that the combination of sotalol, which has beta-adrenergic blocking properties and prolonged ventricular refractoriness, and quinidine or procainamide, two agents that slow conduction and prolong refractory periods, would be effective therapy in such patients. METHODS: We administered low dose sotalol (205 +/- 84 mg/day) plus quinidine sulfate (1,278 +/- 479 mg/day) or procainamide (2,393 +/- 1,423 mg/day) to 50 patients with spontaneous sustained ventricular tachycardia or fibrillation and inducible ventricular tachycardia. RESULTS: In 21 (46%) of 46 patients, ventricular tachycardia was rendered noninducible at electrophysiologic study (group I), and in 17 patients (37%), inducible tachycardia was modified according to prospectively identified criteria (group II), for a combined 83% response rate. Ventricular refractory periods increased from 252 +/- 24 to 316 +/- 28 ms and from 265 +/- 33 to 316 +/- 24 ms in groups I and II, respectively (p < 0.001), but from 234 +/- 19 to only 286 +/- 13 ms in the group of patients with unmodified ventricular tachycardia inducibility (n = 8, group III, p < 0.001). Cycle length of induced ventricular tachycardia slowed from 324 +/- 62 to 432 +/- 70 ms in group II patients (p < 0.001), whereas it slowed less in group III patients (279 +/- 73 to 314 +/- 63 ms, p = NS). Forty-two of the 50 patients (including all patients in groups I and II) were discharged on treatment with the drug combination. After 25 +/- 19 months of follow-up, the actuarial recurrence rate of ventricular tachycardia was 6%, 6% and 11% at 1, 2 and 3 years, respectively. Among patients in whom this drug combination was unsuccessful at electrophysiologic study (group III) and in those who received alternative therapy after combination therapy was discontinued because of side effects, actuarial recurrence rates were 9%, 14% and 32% at 1, 2 and 3 years, respectively. CONCLUSIONS: The combination of sotalol plus quinidine or procainamide markedly prolongs ventricular refractoriness and slows induced ventricular tachycardia in a high proportion of patients. Patients with modified or noninducible tachycardia have a low rate of arrhythmia recurrence in follow-up. This drug combination deserves further evaluation.

Proarrhythmic effects of antiarrhythmic drugs during programmed ventricular stimulation in patients without ventricular tachycardia.

The proarrhythmic effects of class IA antiarrhythmic drugs were prospectively evaluated during programmed ventricular stimulation in 24 consecutive patients with frequent ventricular premature beats whose baseline study, performed while no antiarrhythmic drugs were being taken, showed no inducible sustained ventricular arrhythmias. No patient had nonsustained (greater than 5 beats) or sustained ventricular tachycardia by history or baseline 24 hour ambulatory electrocardiographic monitoring. Sequential stimulation studies using up to three extra-stimuli were performed after administration of procainamide, quinidine and disopyramide on different days. Proarrhythmic response was defined as induction of one or more of the following: sustained monomorphic ventricular tachycardia; sustained polymorphic ventricular tachycardia; ventricular fibrillation; reproducibly inducible nonsustained monomorphic ventricular tachycardia. During 55 antiarrhythmic drug trials (24 of procainamide, 21 of quinidine, 10 of disopyramide) in the 24 patients, 6 patients had a proarrhythmic response: sustained monomorphic ventricular tachycardia in 3, ventricular fibrillation in 2, nonsustained monomorphic ventricular tachycardia in 1. Thus, 11% of drug trials resulted in a proarrhythmic response and 25% of patients had a proarrhythmic response to one of the drugs tested. A proarrhythmic response to one drug did not predict a similar response to another drug of the same class. The 6 patients with a proarrhythmic response did not differ significantly from the other 18 patients with regard to underlying heart disease, electrocardiographic or baseline 24 hour ambulatory electrocardiographic characteristics; however, they did have a higher incidence of digoxin usage (p less than 0.02), a shorter baseline right ventricular effective refractory period (p less than 0.01) and a smaller increment in effective refractory period during antiarrhythmic drug testing (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Hemodynamic effects of intravenous sematilide in patients with congestive heart failure: a class III antiarrhythmic agent without cardiodepressant effects.

OBJECTIVES: This study sought to evaluate the hemodynamic effects of intravenous sematilide hydrochloride, a selective class III antiarrhythmic agent, in patients with heart failure and left ventricular systolic dysfunction. BACKGROUND: Class I antiarrhythmic agents, which primarily slow conduction, can depress ventricular function, particularly in patients with heart failure. In contrast, pure class III agents, which selectively prolong repolarization, do not adversely affect hemodynamic variables in animal models, but there are no data evaluating their hemodynamic effects in humans. METHODS: In 39 patients with congestive heart failure and a left ventricular ejection fraction < 40%, hemodynamic and electrocardiographic measurements were obtained at baseline, after a loading dose and during a maintenance infusion of intravenous sematilide using either a low (0.75 then 0.3 mg/min) or high dose (1.5 then 0.6 mg/min) regimen. The study had an 80% power to detect clinically meaningful differences in hemodynamic variables. RESULTS: Both low (n = 20) and high (n = 19) dose sematilide infusions produced dose-dependent increases in QT interval (5 +/- 8% [mean +/- SD] and 18 +/- 10%, respectively) and corrected QT interval (4 +/- 8% and 14 +/- 10%), and high dose sematilide decreased heart rate by 7 +/- 10% (all p < 0.025 vs. baseline). Neither dose regimen had a statistically significant effect on any other hemodynamic variable, including mean arterial, right atrial, pulmonary artery and pulmonary capillary wedge pressures; cardiac index, stroke volume, systemic and pulmonary vascular resistances; and left ventricular stroke work index. Sematilide showed no adverse hemodynamic effects in patients with left ventricular ejection fraction < or = 25% or > 25% and in patients with cardiac index < 2 or > or = 2 liters/min per m2. Sustained polymorphic ventricular tachycardia (n = 1) and excessive QT prolongation (n = 4) were seen during the high dose. CONCLUSIONS: Sematilide, in the doses administered, prolonged repolarization but did not alter hemodynamic variables in patients with heart failure. These data suggest that class III antiarrhythmic agents, which selectively prolong repolarization, are not cardiodepressant but may be proarrhythmic in humans, especially at high doses.

Bone marrow granulomas and neutropenia associated with procainamide. Report of a case.

Bone marrow granulomas and neutropenia occurred in a 77-year-old man following the ingestion of procainamide hydrochloride for 50 days. Although neutropenia has occasionally occurred following procainamide therapy, granulomas in the bone marrow have not previously been associated with the use of this drug. There was no other apparent agent that could have been responsible for the granulomas. Eighteen days after administration of the drug had been discontinued, the WBC count returned to normal and there were no granulomas present in the bone marrow.

Procainamide-induced agranulocytosis and thrombocytopenia.

Procainamide therapy has frequently been reported as a cause of agranulocytosis, but severe thrombocytopenia associated with the use of this drug has been noted only once. We report a case of simultaneously occurring agranulocytosis and profound thrombocytopenia in a patient receiving procainamide hydrochloride. Different mechanisms appeared to be responsible for the two cytopenias.