High variability of retrograde fast pathway sensitivity to adenosine.

BACKGROUND: Adenosine is widely used as a tool to assess the effectiveness of radiofrequency ablation of concealed accessory pathways. HYPOTHESIS: The goal of this study was to determine the reliability of this test by studying the retrograde fast pathway sensibility in a large patient population with typical atrioventricular (AV) nodal reentry tachycardias. We sought also to determine whether AV nodal properties were predictive of a retrograde fast pathway sensitivity to adenosine. METHODS: In all, 124 patients with inducible AV nodal reentrant tachycardia were included in this study. All patients received a clinically used standard dose of 12 mg adenosine during ventricular pacing, with 500 ms and a constant ventriculoatrial (VA) conduction via the fast pathway. Electrophysiologic parameters of the AV node were determined in all patients in order to correlate them with the adenosine sensitivity of the retrograde pathway. RESULTS: In 74 patients, the injection of 12 mg adenosine resulted in a transient VA block, whereas no VA block occurred in the remaining 50 patients. In two patients, concealed accessory pathways were unmasked after the injection of adenosine. The adenosine sensitivity of the retrograde fast pathway was associated with longer retrograde conduction times and cycle lengths during AV nodal reentrant tachycardias. CONCLUSION: This study shows a high variability of retrograde fast pathway sensitivity to adenosine. Thus, in 40% of patients the lack of VA block after adenosine injection is not specific for persistent accessory pathway function after radiofrequency ablation. Electrophysiologic properties of patients with AV nodal reentrant tachycardias were different in patients with and without adenosine-sensitive retrograde fast pathways, possibly indicating differential patterns of penetration of the retrograde fast pathway into the compact AV node.

Effect of amiodarone and sotalol on the defibrillation threshold in comparison to patients without antiarrhythmic drug treatment.

AIM OF THE STUDY: It is generally accepted that chronic therapy with antiarrhythmic drugs might increase the defibrillation threshold at implantation of an implantable cardioverter defibrillator. A recently published animal study showed a minor effect of the class 1 antiarrhythmic drug lidocaine on the defibrillation threshold if biphasic shocks were used. METHODS AND RESULTS: We therefore performed a retrospective analysis in 89 patients who received an ICD capable of monophasic (n=18) or biphasic (n=71) shocks with a transvenous lead system. In all patients the defibrillation threshold was determined according to the same step down protocol. In the 18 patients with a monophasic device the effects of chronic therapy with amiodarone (n=7) on the defibrillation threshold were evaluated in comparison to a group without antiarrhythmic treatment (n=11). In those patients receiving a biphasic device the effects of chronic therapy with amiodarone (n=29), sotalol (n=20) or no antiarrhythmic medication (n=22) on the defibrillation threshold were evaluated. The groups receiving a monophasic device did not differ in respect to age, sex, underlying cardiac disease, clinical arrhythmia (VT/VF), clinical functional status, left ventricular ejection fraction and the number of patients with additional subcutaneous electrodes. These parameters as well as the type of implanted device were not different between patient groups receiving a biphasic device. Patients on chronic amiodarone therapy receiving a monophasic device had a significantly higher defibrillation threshold (29.1 +/- 8.8 J) than patients without antiarrhythmic treatment (19.1 +/- 5.1 J, P = 0.021). The groups did not differ significantly in respect to the impedance measured at the shocking lead (P = 0.13). In three patients on chronic amiodarone an epicardiac lead system had to be implanted due to an inadequate monophasic defibrillation threshold compared to no patient without antiarrhythmic drug treatment (P = 0.043). In the patients with a biphasic device the intraoperative defibrillation threshold was not significantly different between the three study groups (P = 0.44). No patient received an epicardiac lead system. The defibrillation threshold in the amiodarone group was 15.3 +/- 7.3 J, in the sotalol group 14.4 +/- 7.2 J and in the patients without antiarrhythmic drug treatment 17 +/- 6.1 J. As well, no significant difference was seen between the groups in respect of the impedance of the high voltage electrode (P = 0.2). CONCLUSION: With the use of a biphasic device in combination with a transvenous lead system the intraoperative defibrillation threshold is not significantly different between patients on chronic amiodarone in comparison to patients without antiarrhythmic drug treatment or patients on chronic oral sotalol. This is in contrast to our findings with a monophasic device.

Long-term reproducibility of electrophysiologically guided therapy with sotalol in patients with ventricular tachyarrhythmias.

OBJECTIVES: Goal of this study was to assess the long-term reproducibility of electrophysiologic drug testing in patients with ventricular tachyarrhythmias (VT/VF). BACKGROUND: Programmed ventricular stimulation (PVS) is still widely used to guide antiarrhythmic therapy in patients with sustained ventricular tachycardia/fibrillation (VT/VF). Sotalol is considered as one of the most effective drugs for VT/VF. Because there is no proof of long-term reproducibility of a successful drug test with sotalol, we investigated the long-term reproducibility of drug testing with sotalol. METHODS: Thirty patients with VT/VF (age: 57+/-11 years, 20 patients with coronary heart disease, 7 patients with no structural heart disease, 3 with others) and reproducible induction of VT/VF (28 patients VT, two patients VF) in a baseline PVS, were suppressible with sotalol (mean dosage 395+/-137 mg) in a subsequent PVS. After a mean follow-up of 13+/-10 months a PVS was again performed in patients, who had no evidence of progressive cardiac disease, who did not experience any arrhythmia recurrences or who were drug compliant. Irrespective of the inducibility after long-term therapy with sotalol, all patients were kept on the initial sotalol regimen. All 30 patients had a stable cardiac condition, were free of VT/VF recurrences and were drug compliant. RESULTS: Despite the clinical efficacy of sotalol, in 12 patients (40%) VT/VF could again be induced after 13+/-10.2 months. Inducibility was independent of age, heart disease, ejection fraction and follow-up time. During a further follow-up of 22.1+/-10.9 months, five patients experienced nonfatal VT recurrences independently of the prior inducibility. CONCLUSIONS: This study shows a lacking long-term reproducibility of an initial effective PVS with sotalol. Despite an uneventful clinical follow-up, late electrophysiologic testing showed a VT/VF inducibility in a high portion of patients. Hence, electrophysiologic testing performed late after the initial drug test may no longer be predictive of outcome.

Ambasilide prolongs the action potential and blocks multiple potassium currents in human atrium.

Ambasilide (LU 47110) is a new class III antiarrhythmic drug with a unique profile of action in mammals; however, the effects on human atrial repolarization are not known. We tested the effects of ambasilide on action potentials and repolarizing potassium currents in single atrial myocytes. Ambasilide delayed all phases of repolarization in a concentration-dependent manner [i.e., 10 microM prolonged the action potential duration to 90% repolarization at 1 Hz from 217.8 +/- 34.1 to 360.6 +/- 63.0 ms (p < 0.05 vs. control)]. Action-potential prolongation was independent of the applied stimulation frequency over a range of 0.5-2 Hz; the drug therefore did not display reverse use dependence. Ambasilide produced a concentration-dependent block of the inward rectifier potassium current (IK1) and the acetylcholine-activated potassium current (IKACh) with a median effective concentration (EC50) of 6.0 and 2.3 microM, respectively. Ambasilide also led to a concentration-dependent inhibition of the transient outward current (Ito1; EC50 = 5.7 microM) and the sustained potassium outward current (ISO; EC50 = 43.6 microM). The effect of ambasilide was independent of the step voltage (in the range of +20 to +60 mV) or the applied stimulation frequency (0.5-2 Hz). Inactivation kinetics were not altered. Ambasilide is a new class III antiarrhythmic drug with a distinct profile of action. Its frequency-independent prolongation of the human atrial action potential makes this group of compounds a promising alternative to currently available class III antiarrhythmic drugs.

Suppression of sustained ventricular tachyarrhythmias: a comparison of d,l-sotalol with no antiarrhythmic drug treatment.

OBJECTIVES: This study evaluates the clinical efficacy of d,l-sotalol in patients with sustained ventricular tachyarrhythmias. BACKGROUND: D,l-sotalol is an important antiarrhythmic agent to prevent recurrences of sustained ventricular tachyarrhythmias (VT/VF). However, evidence is lacking that an antiarrhythmic agent like d,l-sotalol can reduce the incidence of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment. METHODS: A prospective study was performed in 146 consecutive patients with inducible sustained ventricular tachycardia or ventricular fibrillation. In 53 patients, oral d,l-sotalol prevented induction of VT/VF during electrophysiological testing and patients were discharged on oral d,l-sotalol (sotalol group). In 93 patients, VT/VF remained inducible and a defibrillator (ICD) was implanted. After implantation of the device patients were randomly assigned to oral treatment with d,l-sotalol (ICD/sotalol group, n=46) or no antiarrhythmic medication (n=47, ICD-only group). RESULTS: During follow-up, 25 patients (53.2%) in the ICD-only group had a VT/VF recurrence in comparison to 15 patients (28.3%) in the sotalol group and 15 patients (32.6%) in the ICD/sotalol group (p=0.0013). Therapy with d,l-sotalol, amiodarone or metoprolol was instituted in 12 patients (25.5%) of the ICD-only group due to frequent VT/VF recurrences or symptomatic supraventricular tachyarrhythmias. In nine patients, 17% of the sotalol group, an ICD was implanted after VT/VF recurrence, three patients (5.7%) received amiodarone. Total mortality was not different between the three groups. CONCLUSIONS: D,l-sotalol significantly reduces the incidence of recurrences of sustained ventricular tachyarrhythmias in comparison to no antiarrhythmic drug treatment.

Efficacy and proarrhythmia with the use of d,l-sotalol for sustained ventricular tachyarrhythmias.

This study prospectively evaluated the clinical efficacy, the incidence of torsades de pointes, and the presumable risk factors for torsades de pointes in patients treated with d,l-sotalol for sustained ventricular tachyarrhythmias. Eighty-one consecutive patients (54 with coronary artery disease, and 20 with dilated cardiomyopathy) with inducible sustained ventricular tachycardia or ventricular fibrillation received oral d,l-sotalol to prevent induction of the ventricular tachyarrhythmia. During oral loading with d,l-sotalol, continuous electrocardiographic (ECG) monitoring was performed. Those patients in whom d,l-sotalol prevented induction of ventricular tachycardia or ventricular fibrillation were discharged with the drug and followed up on an outpatient basis for 21 +/- 18 months. Induction of the ventricular tachyarrhythmia was prevented by oral d,l-sotalol in 35 (43%) patients; the ventricular tachyarrhythmia remained inducible in 40 (49%) patients; and two (2.5%) patients did not tolerate even 40 mg of d,l-sotalol once daily. Four (5%) patients had from torsades de pointes during the initial oral treatment with d,l-sotalol. Neither ECG [sinus-cycle length (SCL), QT or QTc interval, or U wave] nor clinical parameters identified patients at risk for torsades de pointes. However, the oral dose of d,l-sotalol was significantly lower in patients with torsades de pointes (200 +/- 46 vs. 328 +/- 53 mg/day; p = 0.0017). Risk factors associated with the development of torsades de pointes were the appearance of an U wave (p = 0.049), female gender (p = 0.015), and significant dose-corrected changes of SCL, QT interval, and QTc interval (p < 0.05). During follow-up, seven (20%) patients had a nonfatal ventricular tachycardia recurrence, and two (6%) patients died suddenly. One female patient with stable cardiac disease had recurrent torsades de pointes after 2 years of successful treatment with d,l-sotalol. Torsades de pointes occurred early during treatment even with low doses of oral d,l-sotalol. Pronounced changes in the surface ECG (cycle length, QT, and QTc) in relation to the dose of oral d,l-sotalol might identify a subgroup of patients with an increased risk for torsades de pointes. Other ECG parameters before the application of d,l-sotalol did not identify patients at increased risk for torsades de pointes. Recurrence rates of ventricular tachyarrhythmias are high despite complete suppression of the arrhythmia during programmed stimulation. Therefore programmed electrical stimulation in the case of d,l-sotalol seems to be of limited prognostic value.

[High incidence of isolator fractures in transvenous implantation of cardioverter defibrillators]. / Hohe Inzidenz von Isolatorbrüchen bei transvenös implantierten Kardioverter-Defibrillatoren.

With the growing complexity of transvenous ICD-lead systems the incidence of lead complications might increase in comparison to usual pacemaker leads. The incidence of insulation defects of transvenous leads was determined during a mean follow-up time of 23.8 +/- 10.9 months. Among 130 transvenous ICD-patients, eight insulation-breaks in seven patients (6%) could be identified after a mean follow-up of 28 +/- 13 months. After a follow-up period of 12 months no lead defect was identified, after 24 months 96.3 +/- 1.8% of all transvenous leads were free of complications, after 36 months 87.9 +/- 6% and after 48 months in 61.2 +/- 18.7% of all leads no isolator fracture was found. In seven cases an operative revision was required. All insulation-defects were exclusively found in abdominally implanted silicone lead-systems type Endotak/CPI (Cardiac Pacemakers, Inc., USA): isolator fractures occurred in 12% of all Endotak leads used, 19% of the Endotak C models 62, 64, 72 and 74 were affected. In none of 66 implanted Transvene lead systems (Medtronic, Inc., USA) were isolator defects found. In six patients the proximal part of the sensing lead near the device was affected. All of these patients experienced potentially harmful repetitive device discharges. In one patient during elective ICD-replacement an isolation break of the proximal shock electrode was found, in another patient between the proximal and distal shock-electrode. Despite regular follow-ups with impedance-measurements, only in one case was the insulation break foreseeable. Stored electrograms were helpful to disclose insulation defects. With increasing age of the transvenous lead systems a growing number of insulation defects has to be expected. Especially the isolators of the first Endotak C models 60-74 seem to create major problems with increasing age.

[Shock-induced, but not terminated ventricular tachycardia in a patient with implantable defibrillator]. / Schockinduzierte, aber nicht terminierte Kammertachykardie bei einem Patienten mit implantierbarem Defibrillator.

A 62-year-old male patient with coronary artery disease and drug refractory sustained ventricular tachycardia received an implantable cardioverter defibrillator (PRX III, model 1720, CPI) with a transvenous lead system (Endotak, model 0115, CPI) in combination with a subcutaneous array electrode (SQ array, model 049, CPI). The intraoperative defibrillation threshold was 15 J and was confirmed 1 week later at the hospital discharge test. Three months after discharge from hospital the patient reported 5 shocks during moderate physical exertion followed by a tachycardia associated with dizziness which terminated spontaneously. The print out of the stored electrogram showed a supraventricular tachycardia (probably sinus tachycardia) with a heart rate of 154/min which activated the device. Antitachycardia pacing did not terminate the supraventricular tachycardia, and hence shock therapy was delivered. The first shock (34 J) converted the supraventricular tachycardia to a ventricular tachycardia with a heart rate of 178/min, which was not terminated by four consecutive 34 J DC shocks. There was no hint of a device or lead failure. Determination of the defibrillation threshold reconfirmed the 15 J value for termination of ventricular fibrillation. However, neither a 1 J shock nor a 34 J shock terminated a monomorphic sustained ventricular tachycardia (cycle length 340 ms) induced by noninvasive programmed electrical stimulation. The ventricular tachycardia was, however, reproducibly terminate by antitachycardia pacing. It is concluded that an inappropriate high-energy DC shock might induce a sustained ventricular tachycardia. However, a sufficient defibrillation threshold for the termination of ventricular fibrillation does not necessarily mean that a sustained ventricular tachycardia will be terminated by a high-energy DC shock.

[Catheter ablation in sinus node tachycardia]. / Katheterablation bei Sinusknotentachykardie.

Sinus node tachycardia is an uncommon cause of paroxysmal supraventricular tachycardia. Of those patients who were referred to our clinic for electrophysiologic evaluation and catheter ablation, four patients (1 male, 3 female) were found to have sinus node tachycardia. The diagnosis of sinus node tachycardia required all of the following: The P-wave during sinus rhythm had to be similar to the P-wave during the tachycardia, the atrial activation sequence during sinus rhythm and tachycardia had to be similar, the origin of the tachycardia had to be in the high right atrium. In one patient the tachycardia was incessant. The other three patients had paroxysmal sinus node tachycardia that could be induced by programmed atrial stimulation. No patient had overt cardiac disease. One patient had an inducible av nodal reentrant tachycardia and one patient had a second atrial tachycardia originating from the basal right atrium. Activation mapping during tachycardia was performed in all patients. Local atrial activation at the site of successful ablation preceded the P-wave in the surface electrocardiogram by 54 +/- 43 ms. In three patients the interval from the local atrial activation at the site of successful catheter ablation to the onset of the signal from the high right atrium (HRA) ranged from 25 ms to 125 ms, in one patient the signal from the high right atrium was the earliest recorded signal during tachycardia. In all patients the tachycardia was terminated with the application of radiofrequency current. Two to a maximum of 12 radiofrequency current applications were necessary; complications were not observed. In all patients a second electrophysiologic study was performed 8 +/- 2 weeks after successful catheter ablation; no patient had inducible sinus node or atrial tachycardia. During a follow-up of 5 +/- 2 months, no patient had a recurrence of sinus node tachycardia or required antiarrhythmic medication. It is concluded that catheter ablation in patients with sinus node tachycardia is an effective and safe treatment.

Long-term efficacy of d/l sotalol in patients with sustained ventricular tachycardia refractory to class I antiarrhythmic drugs.

The efficacy of d/l sotalol was investigated in 50 patients (43 men, seven women; 33 with coronary artery disease, 15 with dilated cardiomyopathy; ejection fraction 33 +/- 10%) with inducible sustained ventricular tachycardia. Before d/l sotalol a mean of 2 +/- 1 (1 to 4) class I antiarrhythmic drugs were ineffective. In 24 patients (48%) oral d/l sotalol (320 +/- 47 mg.day-1) prevented induction of the ventricular tachycardia; in 23 patients the ventricular tachycardia remained inducible (d/l sotalol 326 +/- 50 mg.day-1). The electrophysiological effects of d/l sotalol did not differ between patients in whom d/l sotalol prevented induction of ventricular tachycardia and those in whom the ventricular tachycardia remained inducible. In two patients, torsade des pointes developed after oral application of d/l sotalol; one patient suffered from severe hypotension even with 80 mg of sotalol per day. During long-term follow-up (27 +/- 12 months) 5/24 patients (21%) had a non-fatal recurrence of ventricular tachycardia (1 week to 21 months), one patient died suddenly and another from progressive heart failure. In patients in whom the ventricular tachycardia could be induced despite oral application of d/l sotalol, control of the ventricular tachyarrhythmia was attempted by the use of sotalol in combination with mexiletine (n = 2), amiodarone (n = 9), catheter ablation (n = 2), antitachycardia surgery (n = 1) or the implantation of an automatic cardioverter defibrillator (n = 12). Recurrence of ventricular tachycardia was observed in four patients without an implanted cardioverter defibrillator. Seven out of 12 patients with an implanted cardioverter defibrillator received appropriate shocks or successful antitachycardia pacing. Although no patient died suddenly, overall mortality was 17% in this group. It is concluded that d/l sotalol is highly effective in the suppression of sustained monomorphic ventricular tachycardia inducible by programmed electrical stimulation. However during a mean follow-up of 27 +/- 12 months a recurrence of ventricular tachycardia was seen in 21% of patients, and one patient died suddenly.

The control of the contraction of myocytes from guinea-pig heart by the resting membrane potential.

1. The influence of different holding potentials (-120 to -70 mV) on the contraction of enzymatically dispersed myocytes from guinea-pig hearts was evaluated. Contractions were elicited by repetitive depolarizations to 0 mV at 0.5 Hz. 2. While ineffective at 140 and 5 mmol l-1 [Na+]o and pipette Na+, respectively, depolarization of the resting membrane with the holding potential increased myocyte shortening at reduced Na+ gradients ([Na+]o 70 or [Na+]i 10-15 mmol l-1). Elevated intracellular Na+ after Na(+)-pump inhibition with ouabain 1-10 mumol l-1 was similarly effective with regard to the inotropic response to different holding potentials. 3. At -70 mV holding potential, reduction of [Na+]o from 140 to 70 mmol l-1 increased myocyte shortening and induced an inwardly directed component of the holding current which peaked at -44 +/- 10 pA and declined thereafter in parallel with the inotropic effect. The relation of this inward current to [Ca2+]i was confirmed by experiments at high Ca2+ buffer capacity where [Na+]o reduction induced a Ni(2+)-insensitive, outwardly directed component (36 +/- 15 pA) of the holding current. The observed inward current is suggested to reflect the extrusion of [Ca2+]i in exchange for [Na+]o as a counter-regulatory mechanism which limits the increase of [Ca2+]i. 4. The interventions which increased the strength of the contraction also enhanced the transient tail current after repolarization, suggesting its close relation to [Ca2+]i. This finding confirmed the pattern found with cell shortening. 5. It is concluded that under certain conditions, voltage-dependent and Na(+)-dependent Na(+)-Ca2+ exchange during the interval between the contractions is relevant to the diastolic concentration of [Ca2+]i which in turn determines the accumulation of Ca2+ in the sarcoplasmic reticulum and the magnitude of the subsequent contraction.

The association with receptors regulates the Na+,K(+)-ATPase inhibitory potency of some cardioactive steroids.

The onset of inhibition of Na+,K(+)-ATPase from guinea-pig myocardium was quantified with pseudo-first-order rate constants in a series of 14 cardioactive steroids. From these data the association and dissociation rate constants of the steroid-receptor complex were calculated. It was then found that the association of the steroids with receptors but not the dissociation of the steroid-receptor complex determined the largely different inhibitory potencies. Consistent with this finding, at equieffective steroid concentrations the rates of inhibition varied only slightly. The correlation of the association rate with the hydrophobicity of the compounds suggests that hydrophobic interactions facilitate the access of the steroid to the receptor. A conformational transition of the vicinity of the receptor subsequent to the formation of the steroid-receptor complex seems to alter the hydrophobic properties of the receptor environment to make the dissociation rate independent from hydrophobicity.