Bernard Belhassen

Efficacy of Quinidine in High-Risk Patients With Brugada Syndrome

Background—Automatic implantable cardioverter-defibrillator therapy is considered the only effective treatment for high-risk patients with Brugada syndrome. Quinidine depresses Ito current, which may play an important role in the arrhythmogenesis of this disease. Methods and Results—The effects of quinidine bisulfate (mean dose, 1483±240 mg) on the prevention of inducible and spontaneous ventricular fibrillation (VF) were prospectively evaluated in 25 patients (24 men, 1 woman; age, 19 to 80 years) with Brugada syndrome. There were 15 symptomatic patients (including 7 cardiac arrest survivors and 7 patients with unexplained syncope) and 10 asymptomatic patients. All 25 patients had inducible VF at baseline electrophysiological study. Quinidine prevented VF induction in 22 of the 25 patients (88%). After a follow-up period of 6 months to 22.2 years, all patients are alive. Nineteen patients were treated with quinidine for 6 to 219 months (mean±SD, 56±67 months). None had an arrhythmic event, although 2 had non–arrhythmia-related syncope. Administration of quinidine was associated with a 36% incidence of side effects that resolved after drug discontinuation. Conclusions—Quinidine effectively prevents VF induction in patients with Brugada syndrome. Our data suggest that quinidine also suppresses spontaneous arrhythmias and could prove to be a safe alternative to automatic implantable cardioverter-defibrillator therapy for a substantial proportion of patients with Brugada syndrome. Randomized studies comparing these two therapies seem warranted.

Response of recurrent sustained ventricular tachycardia to verapamil.

A 28-year-old man is described with no demonstrable organic heart disease and recurrent paroxysmal attacks of sustained ventricular tachycardia. Lignocaine and ajmaline failed to terminate the first attack but a bolus infection of verapamil succeeded. This drug was subsequently successful on six more occasions. During electrophysiological study of the eighth attack, slow intravenous administration of verapamil significantly reduced the rate of the tachycardia and prevented its subsequent reinitiation by pacing. Two mechanisms are postulated to explain both the arrhythmia and the beneficial effects of verapamil in this case.

Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes

This international consensus statement is the collaborative effort of three medical societies representing electrophysiology in North America, Europe, and Asian-Pacific area: the Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), and the Asia Pacific Heart Rhythm Society. The objective of the consensus document is to provide clinical guidance for diagnosis, risk stratification, and management of patients affected by inherited primary arrhythmia syndromes. It summarizes the opinion of the international writing group members based on their own experience and on a general review of the literature with respect to the clinical data on patients affected by channelopathies. This document does not address the indications of genetic testing in patients affected by inherited arrhythmias and their family members. Diagnostic, prognostic, and therapeutic implications of the results of genetic testing are also not included in this document because this topic has been covered by a recent publication1 coauthored by some of the contributors of this consensus document, and it remains the reference text on this topic. Guidance for the evaluation of patients with idiopathic ventricular fibrillation, sudden arrhythmic death …

Idiopathic Ventricular Fibrillation

A review of the literature dealing with sudden death revealed 19 articles in which ostensibly healthy patients with documented VF unrelated to any known cardiac or noncardiac etiology are reported. Fifty-four patients fulfilling the criteria for idiopathic VF, including 14 patients investigated at our institution, are described. The mean age of patients for studies that reported age data was 36 years, with a male-to-female ratio of 2.5 to 1. Over 90% of the patients required resuscitation, while syncope due to nonsustained VF occurred in the rest. Diagnosis of VF was preceded by syncope in one fourth of the patients. Holter monitoring and exercise stress tests were often unrewarding. Available electrophysiologic data revealed a 69% inducibility rate of sustained ventricular tachyarrhythmias using nonaggressive protocols of ventricular stimulation in most cases. Induced tachyarrhythmias were poorly tolerated, and were mostly of polymorphic configuration. Class IA antiarrhythmic agents were highly effective in preventing reinduction of these arrhythmias. Available figures suggest an 11% rate of sudden death within 1 year of diagnosis. Appropriate antiarrhythmic therapy appears to improve prognosis. Reviewed data suggest that idiopathic VF represents an underestimated cause of sudden cardiac death in ostensibly healthy patients. An international registry of patients with idiopathic VF is warranted.

Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity.

The relationship of apparent steady-state serum concentrations of amiodarone and its metabolite, desethylamiodarone, to therapeutic and toxic effects was assessed in 127 patients who had treatment-resistant ventricular or supraventricular arrhythmias or were intolerant to other agents. After at least 2 months (mean, 9.8) of treatment with daily maintenance doses of 200 to 600 mg, arrhythmias were effectively suppressed in 78% of patients. Arrhythmias recurred in 47% of patients with serum amiodarone concentrations of less than 1.0 mg/L, whereas only 14% of patients with higher concentrations had recurrences (p less than 0.005). Side effects, most of them mild, occurred in 57%; only 9 patients required discontinuation of drug therapy. The risk of developing adverse reactions was related to serum amiodarone concentrations (p less than 0.0001). Adverse reactions were common in patients with serum values exceeding 2.5 mg/L, although pulmonary complications did occur at lower concentrations. Monitoring serum amiodarone concentrations may differentiate failure of drug therapy from suboptimal dosing and reduce the incidence of concentration-related side effects.

The Response of the QT Interval to the Brief Tachycardia Provoked by Standing: A Bedside Test for Diagnosing Long QT Syndrome

OBJECTIVES This study was undertaken to determine whether the short-lived sinus tachycardia that occurs during standing will expose changes in the QT interval that are of diagnostic value. BACKGROUND The QT interval shortens during heart rate acceleration, but this response is not instantaneous. We tested whether the transient, sudden sinus tachycardia that occurs during standing would expose abnormal QT interval prolongation in patients with long QT syndrome (LQTS). METHODS Patients (68 with LQTS [LQT1 46%, LQT2 41%, LQT3 4%, not genotyped 9%] and 82 control subjects) underwent a baseline electrocardiogram (ECG) while resting in the supine position and were then asked to get up quickly and stand still during continuous ECG recording. The QT interval was studied at baseline and during maximal sinus tachycardia, maximal QT interval prolongation, and maximal QT interval stretching. RESULTS In response to brisk standing, patients and control subjects responded with similar heart rate acceleration of 28 +/- 10 beats/min (p = 0.261). However, the response of the QT interval to this tachycardia differed: on average, the QT interval of controls shortened by 21 +/- 19 ms whereas the QT interval of LQTS patients increased by 4 +/- 34 ms (p < 0.001). Since the RR interval shortened more than the QT interval, during maximal tachycardia the corrected QT interval increased by 50 +/- 30 ms in the control group and by 89 +/- 47 ms in the LQTS group (p < 0.001). Receiver-operating characteristic curves showed that the test adds diagnostic value. The response of the QT interval to brisk standing was particularly impaired in patients with LQT2. CONCLUSIONS Evaluation of the response of the QT interval to the brisk tachycardia induced by standing provides important information that aids in the diagnosis of LQTS.

Modeling of catecholaminergic polymorphic ventricular tachycardia with patient-specific human-induced pluripotent stem cells.

OBJECTIVES The goal of this study was to establish a patient-specific human-induced pluripotent stem cells (hiPSCs) model of catecholaminergic polymorphic ventricular tachycardia (CPVT). BACKGROUND CPVT is a familial arrhythmogenic syndrome characterized by abnormal calcium (Ca(2+)) handling, ventricular arrhythmias, and sudden cardiac death. METHODS Dermal fibroblasts were obtained from a CPVT patient due to the M4109R heterozygous point RYR2 mutation and reprogrammed to generate the CPVT-hiPSCs. The patient-specific hiPSCs were coaxed to differentiate into the cardiac lineage and compared with healthy control hiPSCs-derived cardiomyocytes (hiPSCs-CMs). RESULTS Intracellular electrophysiological recordings demonstrated the development of delayed afterdepolarizations in 69% of the CPVT-hiPSCs-CMs compared with 11% in healthy control cardiomyocytes. Adrenergic stimulation by isoproterenol (1 μM) or forskolin (5 μM) increased the frequency and magnitude of afterdepolarizations and also led to development of triggered activity in the CPVT-hiPSCs-CMs. In contrast, flecainide (10 μM) and thapsigargin (10 μM) eliminated all afterdepolarizations in these cells. The latter finding suggests an important role for internal Ca(2+) stores in the pathogenesis of delayed afterdepolarizations. Laser-confocal Ca(2+) imaging revealed significant whole-cell [Ca(2+)] transient irregularities (frequent local and large-storage Ca(2+)-release events, broad and double-humped transients, and triggered activity) in the CPVT cardiomyocytes that worsened with adrenergic stimulation and Ca(2+) overload and improved with beta-blockers. Store-overload-induced Ca(2+) release was also identified in the hiPSCs-CMs and the threshold for such events was significantly reduced in the CPVT cells. CONCLUSIONS This study highlights the potential of hiPSCs for studying inherited arrhythmogenic syndromes, in general, and CPVT specifically. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care, and aid in the development of new therapies.

Idiopathic ventricular fibrillation: inducibility and beneficial effects of class I antiarrhythmic agents.

Ventricular fibrillation in patients without recognizable heart disease is uncommon and electrophysiologic data on such patients is limited. Over a 7 year period, five patients (three men and two women, ranging in age from 24 to 52 years) without demonstrable heart disease underwent electrophysiologic studies with pharmacologic drug testing because of single (four patients) or multiple (one patient) documented episodes of ventricular fibrillation. The arrhythmic event was unrelated to myocardial ischemia or infarction, metabolic or electrolyte disturbances, drug toxicity, preexcitation, or prolonged QT syndromes. In all three patients receiving no antiarrhythmic drugs and in two pretreated with amiodarone, a rapid poorly tolerated ventricular tachyarrhythmia requiring cardioversion was induced by programmed ventricular stimulation with up to two extrastimuli. In all instances, addition of either oral quinidine or oral disopyramide prevented the induction of sustained ventricular arrhythmias. All five patients were placed on antiarrhythmic drug regimens found effective during electrophysiologic studies and remained asymptomatic during follow-up periods ranging from 12 to 93 (mean 52) months. We conclude that in the patients with idiopathic ventricular fibrillation in our study: programmed ventricular stimulation reliably replicated the spontaneous arrhythmia, class I antiarrhythmic agents effectively prevented induction of the arrhythmia in the laboratory, and in contrast to the severity of the presenting arrhythmia, a benign clinical course was observed during long-term therapy with class I antiarrhythmic agents.

The "Short-Coupled" Variant of Right Ventricular Outflow Ventricular Tachycardia: A Not-So-Benign Form of Benign Ventricular Tachycardia?

Idiopathic ventricular tachycardia (VT) originating from the right ventricular outflow tract (RVOT‐VT) and idiopathic RVOT‐extrasystoles are generally considered benign arrhythmias. We described three cases who originally presented with typical “benign looking” RVOT‐extrasystoles or RVOT‐VT but developed malignant polymorphic VT during follow‐up. The unusual aspect of their RVOT‐extrasystoles was their coupling interval, which appears to be intermediate between the ultra‐short coupling interval of idiopathic VF and the long coupling interval seen in the truly benign RVOT‐VT.

Electrophysiologic effects of adenosine triphosphate and adenosine on the mammalian heart: Clinical and experimental aspects

Adenosine triphosphate (ATP) and adenosine have strong negative chronotropic and dromotropic effects on the mammalian heart. The sensitivity of the sinus node and the atrioventricular node to ATP and adenosine manifests pronounced variability among species. For more than three decades, ATP has been used routinely in Europe in the acute therapy of paroxysmal supraventricular tachycardia. Preliminary clinical trials with adenosine in the United States suggest that this compound may have a similar therapeutic value. The exact mechanisms of action of ATP and adenosine on the mammalian heart are still not fully known. However, the vast clinical experience indicates that ATP, and probably also adenosine, can be safely and repetitively used in the acute therapy of paroxysmal supraventricular tachycardia.