Hans Vallin

Electrocardiographic and Clinical Predictors of Torsades de Pointes Induced by Almokalant Infusion in Patients with Chronic Atrial Fibrillation or Flutter: A Prospective Study

The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty‐two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 ± 114 vs 443 ± 54 ms [mean ± SD], P < 0.01), a larger precordial QT dispersion (50 ± 74 vs 27 ± 26 ms, P < 0.05), and a lower T wave amplitude (0.12 ± 0.22 vs 0.24 ± 0.16 mV. P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 ± 26 vs 489 ± 74 ms, P < 0.001), a larger QT dispersion in precordial (82 ± 7 vs 54 ± 52 ms, P < 0.01) and extremity leads (163 ± 0 vs 40 ± 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.

Electrophysiologic effects and clinical hazards of carbamazepine treatment for neurologic disorders in patients with abnormalities of the cardiac conduction system

Carbamazepine, a first-line drug for the treatment of epilepsy and neuralgia, may exert hazardous effects on the cardiac conduction system. Standard ECG and long-term ECG monitoring and invasive electrophysiologic testing were carried out in 10 patients who required this drug for neurologic disorders, but in whom its safe use had been questioned because of symptoms of ECG abnormalities. We observed depression of sinus node function and an atrioventricular conduction delay with a significant prolongation of the PQ interval of 16 msec (9%; 95% confidence interval: 1.9% to 16.5%; p less than 0.05), of which the HV interval was significantly prolonged but not the PA and AH intervals. These effects are in accordance with previously shown class 1A properties. However, the lack of effects on QRS, JT, and QT intervals at normal heart rates is a class 1B characteristic. Thus carbamazepine seems to have composite electropharmacologic actions. A cause effect relationship between carbamazepine treatment and significant arrhythmias was established in five patients. Thus the negative chronotropic and dromotropic effects of carbamazepine may, at least in predisposed patients, induce symptoms confusingly similar to the epileptic seizures it is used to prevent.

Clinical and electrophysiologic course of sinus node disease: Five-year follow-up study

Thirty patients with symptomatic sinus node disease (SND) who 5 years previously had undergone a clinical investigation including intracardiac electrophysiologic studies with pharmacologic inhibition of autonomic tone were followed up with respect to development of arrhythmias and cardiac conduction abnormalities. In 17 of these patients a reinvestigation, including a second intracardiac study, was performed. Stable atrial fibrillation developed in five patients, paroxysmal supraventricular tachycardia occurred in one patient, and complete heart block appeared in another patient. Paroxysmal atrial arrhythmias and radiographic atrial enlargement were more common at the initial investigation in patients who during follow-up developed either stable atrial fibrillation or paroxysmal supraventricular tachycardia. Development of complete heart block was associated with signs of severe conduction defects at the initial study. General progression of conduction dysfunction as evaluated by intracardiac techniques was not a finding in this study. Conduction abnormalities limited to the atrioventricular (AV) node did not in this context predict a clinically important progression. The results indicate that those patients with SND who are predisposed to develop high-grade AV block and atrial arrhythmias can be identified by Holter monitoring, chest x-ray examination, and an intracardiac electrophysiologic study. These possibilities improve the selection of patients suitable for pacing modes preserving atrial transport.

Atrioventricular block progression in patients with bifascicular block assessed by repeated electrocardiography and a bradycardia-detecting pacemaker.

Syncope may be due to intermittent high-degree atrioventricular (AV) block, but a cause-relation is sometimes difficult to prove. Diagnostic methods with high predictive value proven by instruments for safe and sensitive follow-up are needed. A bradycardia-detecting pacemaker was used in patients with bifascicular block, who had been the subjects of pharmacologic stress testing of the His-Purkinje system. Thirty-seven patients were included, of whom 26 had experienced at least 1 syncopal episode of suspected bradycardia origin, and 11 had previously documented transient high-degree AV block. The electrophysiologic study included injection of disopyramide 2 mg/kg (up to 150 mg) over 5 minutes. A positive test result was defined as spontaneous or pacing-induced His-Purkinje high-degree AV block after drug or a drug-induced HV prolongation of > or = 50%. Patients were followed an average 63 months with repeated electrocardiography and a diagnostic pacemaker (n = 23). Altogether, 24 patients had a significant bradycardia diagnosed by either or both methods. The sensitivity and positive predictive values were: HV interval > or = 70 ms at baseline, 47% and 88%; a positive disopyramide test result, 75% and 80%; and HV interval > or = 70 ms or a positive disopyramide test result, 93% and 74%, respectively. Thus, the diagnostic pacemaker is a safe and sensitive tool for evaluating the information obtained at electrophysiologic study, and pharmacologic stress testing with disopyramide has an informative value in patients with bifascicular block and syncope when results at baseline are inconclusive.

Electrophysiologic Effects of Salbutamol, a β2‐Selective Agonist

Introduction: A positive chronotropic effect of β2 stimulation is well known. Case reports of ventricular arrhythmias during β2‐inhalation therapy have been published. The aim of this study was to asses the overall electrophysiologic effects of the β2‐agonist salbutamol.

Analysis of sinus cycle variation: A new method for evaluation of suspected sinus node dysfunction

Momentary sinus cycle variations in 30 patients with unequivocal sinus node disease (SND) were compared with those found in 18 healthy control subjects to assess their potential diagnostic value. The range of variation of sinus cycle length (SCL; standardized by dividing by mean SCL) and the maximal change in SCL between any two consecutive cycles (max delta SCL) were measured in short (about 1 minute) continuous ECG recordings from invasive electrophysiologic investigations. Age-stratified reference values from 1 minute surface ECG recordings obtained at rest during quiet breathing in about 70 healthy persons were applied. For diagnosing SND, an increased standardized variation range had a sensitivity of 63%, a specificity of 94%, and a predictive value of a positive test of 95%. The corresponding figures for an increased max delta SCL were 77%, 78%, and 85%, respectively. A combination of increased range of variation and increased max delta SCL was observed in 63% of the patients but not in any healthy subject, which gives a specificity and a predictive value of a positive test of 100% for this combination.

Electrophysiologic effects of mental stress in healthy subjects: a comparison with epinephrine infusion.

Mental stress has been associated with serious cardiac arrhythmias, including ventricular tachycardia and ventricular fibrillation. The purpose of this study was to assess cardiac electrophysiologic effects of mental stress and compare them with those of epinephrine infusion. Ten healthy male volunteers participated. Electrophysiologic and hemodynamic variables were measured at baseline, during mental stress produced by Stroops color word conflict test and during epinephrine infusion at 2 rates (0.025 micromol/kg/min and 0.3 micromol/kg/min). Mental stress produced significant effects on the electrophysiologic properties of the heart with shortening of all measured electrophysiologic variables except atrial, most markedly those of the sinus and the atrioventricular nodes. The effects on the right ventricular myocardium and the His-Purkinje conduction system were less pronounced. During infusion of epinephrine, corresponding effects could only be reproduced at a much higher plasma level. Circulating epinephrine apparently plays a minor role as a mediator of mental stress effects on the heart.

Sinus Node Recovery Time Assessment Revisited: Role of Pharmacologic Blockade of the Autonomic Nervous System

Sinus Node Recovery and Autonomic Blockade. Sinus node recovery time assessment is used to diagnose clinically significant sinus node dysfunction (SND) when Holter has failed to prove a relationship between sinus bradyarrhythmias and symptoms, but consensus has not been reached as to the value of including assessment after pharmacologic blockade of the autonomic nervous system. This issue was addressed in the present study performed on 52 patients with syncope or presyncope/dizziness (n = 48), sinus bradyarrhythmias (n = 45), or both (n = 41). Group 1 consisted of 13 patients with a proven relationship between symptoms and sinus bradyarrhythmias. Group 2 consisted of 39 patients with suspected SND. The protocol included three pacing periods at two pacing rates and was performed at baseline (n = 52), after single doses of atropine and propranolol (0.02 mg/kg and 0.1 mg/kg, respectively) (n = 41), and again after a second dose (n = 29). The sensitivity of prolonged recovery times was 77% in group 1. Among group 2 patients, 56% had prolonged recovery times at baseline (79% when including the results after the first dose of drugs). The second dose did not contribute diagnostic information, but it caused significant adverse reactions in 7 of 29 patients (P < 0.001). These 7 patients were all older than 60 years. Assessment of sinus node recovery time after pharmacologic blockade of the autonomic nervous system thus increases the sensitivity of the method in patients with suspected SND and normal baseline results. However, only 50% of the initially suggested doses of atropine and propranolol is sufficient and eliminates the risk for significant adverse reactions.

Screening for sinus node dysfunction by analysis of short-term sinus cycle variations on the surface electrocardiogram

A new noninvasive screening method for diagnosing sinus node dysfunction (SND) was evaluated. Sinus cycle variations from 1-minute electrocardiograms (ECG) were described by two variables: the variation range around the mean cycle length (percentage) and the maximal change between any two consecutive cycles (milliseconds). SND was diagnosed when both variables were increased. Part 1: Validation of this method against Holter and sinus node recovery time assessment in 69 patients with proven or possible sick sinus syndrome (SSS). Part 2: Application of the method to 60 patients with clinically significant cardiovascular and pulmonary disorders (group 3), but without any pretest suspicion of SND. Part 1: Sinus cycle variations and sinus node recovery times were abnormal in similar proportions, 55% and 63%, respectively. The sensitivities in proven SSS were 72% and 71%, respectively. Sinus node function was concordantly classified in 80% of 64 patients undergoing both tests. When sinus cycle variations were abnormal the probability of a prolonged recovery time was 89%. Part 2: Asymptomatic SND was found in 12% of patients in group 3. Thus, analysis of short-term beat-to-beat variations in the surface ECG has a sensitivity of approximately 70% and a specificity of 100% for diagnosing SND.

Selective Ik blocker almokalant exhibits class III--specific effects on the repolarization and refractoriness of the human heart: a study of healthy volunteers using right ventricular monophasic action potential recordings.

Almokalant, a recently developed potassium-channel blocker, has exhibited properties of a selective class III agent in vitro and in animal experiments. We report the first invasive study in humans in which the electrophysiological characteristics of almokalant were assessed. Thirty-four healthy males received bolus and maintenance infusions of almokalant to two of our target plasma concentrations of 20, 50, 100, and 150 nM. Electrophysiological variables were assessed during stimulation at 100 and 120 beats/min at baseline and at two consecutive targeted levels. Almokalant dose-dependently increased the duration of the monophasic action potential (MAP) above a mean plasma concentration of 60 nM. The duration at 90% repolarization significantly increased by 20% from baseline at 100 beats/min (p < 0.00005), and by 19% at 120 beats/min (p < 0.00005), at a mean plasma concentration of 116 nM. During atrial stimulation, there was a significant increase in the QT interval, amounting to 24% at 100 beats/min (p < 0.00005) and to 30% at 120 beats/min (p = 0.0006), at 124 nM. During right ventricular stimulation in the apical region, the QT interval significantly increased by 17% at 100 beats/min (p < 0.00005), and 13% at 120 beats/min (p < 0.00005). During stimulation from the right ventricular outflow tract, the QT interval increased to a lesser extent and significantly only at 120 beats/min: 9% at 100 beats/min (p = NS) and 6% at 120 beats/min (p = 0.001) at 118 nM. The effective refractory period (ERP) of the atria increased by 18% at 100 beats/min at 119 nM (p = 0.005). The right ventricular ERP increased by 16% at both heart rates (HR) (p < 0.00005) during stimulation from the apical region, and by 11% during stimulation from the outflow tract (p = 0.0001 at 100 beats/min and p = 0.0006 at 120 beats/min). There was no effect on the ERP of the atrioventricular node, (AVN) on the sinus node function or cardiac conduction. Two individuals experienced a transient metallic taste during bolus infusion aiming at 50 and 100 nM, but this side effect did not occur in the group receiving the highest doses. Pronounced T-wave/U-wave (TU) morphology changes were observed in 4 individuals. Almokalant exhibited characteristics of a pure class III agent with no effects on cardiac conduction or sinus node function when given intravenously. Although no proarrhythmias were observed, the development of TU morphology changes and increased spatial dispersion of repolarization after the highest doses warrants further studies regarding the safety profile of the drug.