Thorsten Beyer

Implantable Cardioverter Defibrillator: Possible Hazards of Electromagnetic Interference

We report on three patients with an automatic, implantable Cardioverter defibrillator (AICD, CPI) in whom the device had been deactivated due to electromagnetic interference. In all cases, the source of the electromagnetic disturbances could be identified.

Impaired Function of Inhibitory G Proteins During Acute Myocardial Ischemia of Canine Hearts and Its Reversal During Reperfusion and a Second Period of Ischemia: Possible Implications for the Protective Mechanism of Ischemic Preconditioning

A brief antecedent period of myocardial ischemia and reperfusion can delay cellular injury during a subsequent ischemic condition. Recent observations suggest that this protective mechanism depends on the continued activation of adenosine A1 receptors and Gi proteins. During acute myocardial ischemia, sufficient amounts of adenosine for maximal activation of adenosine A1 receptors are released, independent of a preconditioning ischemia. Hence, the protective mechanism of ischemic preconditioning may not exclusively be explained by activation of adenosine A1 receptors. As a working hypothesis, an increased responsiveness of Gi proteins toward receptor-mediated activation, leading to an increased response of Gi-regulated effectors, was tested in this study. In 47 anesthetized dogs, ischemia was induced by proximal ligation of the left anterior descending coronary artery. Animals underwent either a single period of 5 minutes of ischemia (n = 9), a single period of 15 minutes of ischemia (n = 10), 5 minutes of ischemia followed by 15 minutes of reperfusion (n = 8), 15 minutes of ischemia followed by 60 minutes of reperfusion (n = 5), or 5 minutes of ischemia followed by 15 minutes of reperfusion and a second period of 5 minutes of ischemia (n = 15). Sarcolemmal membranes were prepared from the central ischemic area and from the posterior left ventricular wall, which served as the control. During ischemia, carbochol-stimulated GTPase decreased by 38% (control, 33.5 +/- 17.7; ischemia, 24.2 +/- 15 pmol.min-1.mg protein-1; n = 9; P < .001). The decrease in carbachol-stimulated GTPase activity was associated with a 45% decrease in carbachol-mediated inhibition of adenylyl cyclase (control, 28.9 +/- 2.4% maximal inhibition; ischemia, 15.1 +/- 2.6% maximal inhibition; n = 5; P < .001). Prolongation of the ischemic period to 15 minutes did not lead to a further reduction of the Gi-mediated signal transduction. The binding properties of muscarinic receptors were not affected by ischemia. Furthermore, as demonstrated by carbachol-stimulated binding of [gamma-35S]GTP to sarcolemmal membranes, high- and low-affinity binding sites for the muscarinic antagonist carbachol, the EC50 for carbachol-stimulated GTPase activity and the substrate dependency of the high-affinity GTPase, the interaction between muscarinic receptors and inhibitory G proteins, and GTP binding to G proteins were not altered (n = 14). Immunoblotting with alpha 1- and alpha 2-specific antibodies did not indicate a loss of Gi proteins during ischemia that could explain the reduced GTPase activity.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential Rate and Potassium-Dependent Effects of the Class III Agents d-Sotalol and Dofetilide on Guinea Pig Papillary Muscle

The class III agents d-sotalol and dofetilide have been shown to exhibit differential effects in large controlled clinical trials. The aim of this study was to investigate the basic electrophysiological properties of these two antiarrhythmia agents in an in vitro experimental model with regard to potential antiarrhythmic and proarrhythmic action. Using standard microelectrode techniques, we evaluated the electrophysiological effects of d-sotalol and dofetilide on action potential parameters recorded from guinea pig papillary muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The following parameters were recorded: resting membrane potential (RMP), action potential amplitude (APA), action potential duration at 90% repolarization (APD 90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d-sotalol and dofetilide exhibited highly selective reverse rate-dependent class III action. In contrast to dofetilide, the class III activity of d-sotalol was markedly influenced by changes in extracellular potassium concentrations, predominantly at low pacing rates. Hypokalemia enhanced the action potential–prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In addition, reverse rate dependence associated with dofetilide was significantly more pronounced than reverse rate dependence associated with d-sotalol. Our observations provide a potential electrophysiological basis for differential antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.

Transesophageal echo phase imaging for localizing accessory pathways during adenosine-induced preexcitation in patients with the Wolff-Parkinson-White syndrome

Transesophageal phase images and precordial electrocardiography (ECG) were used to localize accessory pathways during adenosine-induced preexcitation in 30 patients (18 men, mean age +/- SD 33 +/- 14 years) undergoing endocardial mapping for suspected Wolff-Parkinson-White syndrome. Digitized 2-dimensional echocardiographic cine loops were mathematically transformed using a first harmonic Fourier algorithm before and after catheter ablation. Endocardial mapping found single accessory pathways with anterograde conduction in 20 patients, concealed pathways in 7, and atrioventricular reentry circuits in 3 patients. At baseline, precordial ECG correctly localized 8 pathways (40%) with anterograde conduction and predicted 5 adjacent locations (25%), but findings were normal in 7 patients (35%). Phase imaging correctly identified only 3 pathway locations (15%), findings were normal in 15 (75%), and could not be obtained in 2 patients (10%). Adenosine augmented manifest but minimal preexcitation in 9 patients and unmasked latent preexcitation in 7. In 4 patients, preexcitation was already maximal at baseline. During adenosine-augmented preexcitation, ECG correctly identified 13 locations (65%), but still predicted 7 adjacent locations (35%). However, phase imaging correctly identified 15 locations (75%) and predicted only 3 adjacent locations (15%). All midseptal (n = 2) and anteroseptal (n = 2) locations were correctly identified by phase imaging, but none by ECG. On follow-up studies in 16 patients, successful catheter ablation (n = 13) was equally well confirmed by ECG and phase imaging. Therefore, transesophageal echocardiographic phase imaging during adenosine-induced preexcitation is a readily available and safe procedure that appears clinically most useful for identifying septal pathways.

Acute Efficacy and Chronic Follow‐Up of Patients with Non‐Thoracotomy Third Generation Implantahle Defibrillators

Non‐thoracotomy implantation of implantable cardioverter defibrillators (ICDs) has simplified the process of device inserfion, promising to decrease associated procedural coniplications while providing sudden death protection at least equal to epicardial systems. This study presents the acute and chronic results of 110 patients who underwent attempted non‐thoracotomy ICD impiuntation wiih the Medtronic Transvene lead system and PCD model 7217 or 7219. Of the 110 patients attempted, 100 (91%) had the system successfully implanted without the need for an epicar‐dial patch. One patient died 1 week postoperatively of septic shock related to the implantation (0.9% perioperative mortality). During folloiv‐up of 16 ± 11 months, 45% of the patients had an event detected as ventricular tachycardia; 26% of these detections were felt clinically to be due to supraventricular rhythms. Of the remainder, 87% were successfully treated with the first VT therapy, and 98% were terminated by the final therapy; 66% of the patients had at least one episode of ventricular fibrillation, of which 5% were felt to be inappropriate detections; 65% of the appropriate episodes were successfully treated with the first VF therapy, and all were converted by the final therapy. Total mortality at 6, 12, and 24 months was 3%, 11%, and 19% respectively. Only one patient had sudden cardiac death, occurring at 13 months postimplant. Overall, the non‐thoracotomy lead system for this ICD displayed infrequent implant complications and proved to be reliable ai terminating arrhythmias and maintaining a low rate of sudden cardiac death in this high risk popuiation.

Differential effects of quinidine on transmembrane action potentials of normal and infarcted canine Purkinje fibers

Summary Fourteen days after proximal ligation of the left anterior descending coronary artery (LAD) of mongrel dogs, the effects of quinidine on action potentials of normal and infarcted Purkinje fibers were evaluated. The concentration-dependent (10-7-3 × 10-5 M) and frequency-dependent (1 and 3 Hz) actions of quinidine were evaluated by the following parameters: maximum upstroke velocity (Vmax), action potential duration at 50 and 95% repolarization (APD50, APD95), effective refractory period (ERP), resting membrane potential (RMP), and action potential amplitude (APA). Quinidine reduced Vmax in normal and abnormal Purkinje fibers in a concentration-and frequency-dependent manner; these effects were more pronounced in infarcted tissue. The APD50 was shortened significantly at 1 Hz in noninfarcted Purkinje fibers, whereas in infarcted Purkinje fibers quinidine had no effect on APD50. The APD95 was not significantly altered by quinidine in normal Purkinje fibers; in infarcted areas APD95 was significantly prolonged at 1 and 3 Hz. The effective refractory period (ERP) was prolonged in normal and infarcted Purkinje fibers, these effects were more marked in ischemically damaged fibers. No effects were observed on resting membrane potential (RMP). APA was reduced significantly after quinidine at 1 and 3 Hz; there was no difference between normal and infarcted tissue. These data indicate a differential effect of quinidine in normal and infarcted Purkinje fibers which may be an important mechanism of action of quinidine in infarcted tissue.

Electrophysiologic and antiarrhythmic effects of D-sotalol

There is extensive experimental and clinical experience concerning the antiarrhythmic potency of DL-sotalol, a β-adrenergic antagonist that lengthens the cardiac action potential duration. More recently, its dextrorotatory isomer, D-sotalol, has been evaluated in experimental studies and preliminary clinical trials. Whereas the isomer is almost free of β-blocking activity, both experimental and clinical data demonstrate the potent class III activity of D-sotalol. Further investigations, particularly in patients with life-threatening arrhythmias, are needed to delineate the clinical usefulness of this compound.

Comparative Effects of d-Sotalol and 1-Sotalol on the Atrioventricular Node of the Rabbit Heart

Summary: The purpose of this study was to compare the dose-dependent effects of d-sotalol and 1-sotalol (3 x 10 -7 M to 10 -4 M) on electrophysiological parameters in isolated preparations of the rabbit atrioventricular (AV) node. Standard microelectrode techniques were used in recording transmembrane action potentials from cells of the upper and lower AV node. Twelve New Zealand white Rabbits of either sex weighing between 1.5 and 2.6 kg were used. In both cell types studied, d-sotalol as well as 1-sotalol prolonged action potential duration to the same extent. No significant effects were observed with either isomer on maximum diastolic potential, action potential amplitude, or maximum upstroke velocity of the action potential (Vmax). The rate of spontaneous discharge in AV nodal cells was decreased to the same extent by both isomers; this effect was caused by action potential prolongation; no effect on the rate of diastolic depolarization or Vmax was observed. Both d-sotalol and 1-sotalol prolonged AV nodal conduction to the same degree by lengthening the action potential duration in AV nodal cells. The effects of 10-4 M d-sotalol on AV nodal reentrant tachycardia were studied in one preparation in which AV nodal reentrant tachycardias could reproducibly be initiated by atrial premature stimulation. d-Sotalol abolished the occurrence of this tachycardia by lengthening refractoriness in AV nodal cells; this effect can be ascribed to a Class HI antiarrhythmic effect.

Differential effects of d-sotalol on subendocardial Purkinje myocytes isolated from normal or 10 to 14 days postinfarction canine hearts: role of extracellular potassium concentration.

Electrophysiologic properties of surviving Purkinje cardiomyocytes in the late postmyocardial-infarction phase are not well established. By using standard microelectrode techniques, we evaluated the effects of the class III agent d-sotalol on action potential parameters of single Purkinje cardiomyocytes isolated from normal canine hearts or those 10-14 days after infarction. Measurements were obtained at 2.5, 3.5, and 6 mM extracellular potassium concentrations. Action-potential parameters recorded at baseline did not differ significantly between normal and infarct-surviving Purkinje cardiomyocytes. At 3.5 and 6 mM extracellular potassium concentrations, surviving Purkinje cells appeared to be more sensitive to the effects of d-sotalol than normal Purkinje cells. In contrast, at 2.5 mM extracellular potassium concentration, the differential responses of normal and infarct-surviving Purkinje cells to d-sotalol was abolished. Reverse rate dependence was more prominent in normal than in postinfarction Purkinje cells, independent of the extracellular potassium concentration studied. The previously described enhanced sensitivity of subacutely infarcted tissue to class III agents seems to persist on a cellular level 10-14 days after myocardial infarction, even after full normalization of baseline action-potential parameters. Differential membrane-regulation mechanisms, dependent on the extracellular potassium concentrations, may account for the increased susceptibility to antiarrhythmia agents in the late postinfarction phase.

RATE AND TIME DEPENDENT EFFECTS OF D-SOTALOL ON THE MONOPHASIC ACTION POTENTIAL AFTER SUDDEN INCREASE OF THE HEART RATE

Experimental and clinical data suggests that almost all Class III antiarrhythmic agents diminish their ability to prolong cardiac repolarization at fast heart rates. However, only limited data exists about the time course of efficacy decay of Class III agents after sudden increase of the heart rate. In the present study, we assessed both rate and time dependent changes of the efficacy of d‐sotalol in higher stimulation frequencies following an abrupt increase in heart rate. This might imitate the situation seen in the development of paroxysmal tachycardias. Monophasic action potentials were recorded from the right ventricular apex during sinus rhythm and constant stimulation with the paced cycle length (PCL) of 550 ms, 400 ms, and 330 ms in the baseline and 20 minutes after intravenous administration of d‐sotalol (2.5 mg/kg) in seven patients with documented life‐threatening ventricular tachyarrhythmias. D‐sotalol significantly prolonged monophasic action potential duration at different steady‐state heart rates (sinus rhythm: 21.1%± 3.6%; PCL 550 ms: 16.6%± 4.3%, 400 ms: 11.2%± 2.7%, 330 ms: 5.8%± 2.1%). The prolongation is significantly shorter in higher steady‐state pacing, confirming a pronounced reverse‐use dependent decrease of the efficacy of d‐sotalol at faster stimulation frequencies. After the abrupt increase in heart rate, the beat‐to‐beat adaptation of the postdrug action potential prolongation exhibits only slight reverse‐use dependent shortening. The decrease of the efficacy of d‐sotalol is insignificant for the first 20 consecutive beats at the stimulation frequency of the PCL of 400 msec (from 16.6% at PCL of 550 ms to 14.6% at the 20th beat of the PCL of 400 ms), and for the first ten consecutive beats at the stimulation frequency of the PCL of 330 ms (from 16.8% at PCL of 550 ms to 12.3% at the 10th beat of the PCL of 330 ms). This slow decay of action potential prolongation after an abrupt increase in heart rate might contribute to the antiarrhythmic action of d‐sotalol in cardiac tachyarrhythmias.