[Transmural ERP-dispersion from epi-, mid-and endomyocardium in healthy and hypertrophied dog myocardium].
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Animals↗
Biomedical subjects
W Schöls
Publications and source records attributed to W Schöls.
[Evaluation of syncope in geriatric patients: normal values, complications and outcome of invasive electrophysiological study].
Invasive electrophysiologic study (EPS) is an important tool in the assessment of patients with unexplained syncope. Especially in the elderly, the need for a complete diagnostic work-up is counterbalanced by the fear of complications associated with invasive procedures. Thus, the present study specifically addressed the question whether the risk/benefit ratio of EPS in geriatric patients with unexplained syncope justifies this invasive procedure. An invasive EPS was performed in 96 patients between 70 and 80 years and 21 patients older than 80 years. The control group consisted of 65 patients younger than 40 years. With increasing age, the diagnostic yield of EPS also increased (positive EPS finding in 20% of the control group and in 54% of the oldest patients). The majority of complications were of minor clinical significance and no significant differences were found between the three groups. Finally, no age-related difference in measured standard electrophysiological parameters was evident. Due to the high diagnostic value and the low complication rate, EPS can be recommended in elderly patients with unexplained syncope. An age-specific standardization of electrophysiologic parameters, measured during EPS, does not seem to be required.
Aged↗
Isoproterenol specifically modulates reverse rate-dependent effects of d,l-sotalol, d-sotalol, and dofetilide.
The modulation of antiarrhythmic and proarrhythmic properties of antiarrhythmic compounds by increased sympathetic activity is of experimental and clinical interest. However, the interaction of adrenergic stimulation with the rate-response pattern of class III antiarrhythmic agents is not well established. Using standard microelectrode techniques, we evaluated the effects of isoproterenol (iso) on the action of d,l-sotalol (d,l-sot), d-sotalol (d-sot), and dofetilide (dof) on action-potential parameters recorded from isolated canine cardiomyocytes. The cell-isolation procedure was performed from the endocardial layers of left ventricular myocardium from healthy beagle dogs. The following electrophysiologic parameters were recorded: resting membrane potential (RMP), action-potential amplitude (APA), action-potential duration at 90% repolarization (APD 90), and effective refractory period (ERP). After exposure to iso, the class III activity of d,l-sot was well maintained over the entire range of frequencies studied. In contrast, iso differentially antagonized the action of d-sot and dof. In comparison to dof, the class III action of d-sot was particularly sensitive to iso, predominantly at faster stimulation rates. Our observations demonstrate specific rate regulation of the class III action of d,l-sot, d-sot, and dof in response to adrenergic stimulation. The unfavorable rate-response pattern of d-sot compared with d,l-sot and dof might prove disadvantageous in high-catecholamine states.
Action Potentials↗
Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart.
BACKGROUND: Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers. METHODS AND RESULTS: In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates. CONCLUSIONS: At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.
Animals↗
Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A.
We investigated the role of protein kinase A (PKA) in regulation of the human ether-a-go-go-related gene (HERG) potassium channel activation. HERG clones with single mutations destroying one of four consensus PKA phosphorylation sites (S283A, S890A, T895A, S1137A), as well as one clone carrying all mutations with no PKA phosphorylation sites (HERG 4M) were constructed. These clones were expressed heterologously in Xenopus oocytes, and HERG potassium currents were measured with the two microelectrode voltage clamp technique. Application of the cAMP-specific phosphodiesterase (PDE IV) inhibitor Ro-20-1724 (100 microM), which results in an increased cAMP level and PKA stimulation, induced a reduction of HERG wild type outward currents by 19.1% due to a shift in the activation curve of 12.4 mV. When 100 microM Ro-20-1724 was applied to the HERG 4M channel, missing all PKA sites, there was no significant shift in the activation curve, and the current amplitude was not reduced. Furthermore, the adenylate cyclase activator forskolin that leads to PKA activation (400 microM, 60 min), shifted HERG wild type channel activation by 14.1 mV and reduced currents by 39.9%, whereas HERG 4M channels showed only a small shift of 4.3 mV and a weaker current reduction of 22.3%. We conclude that PKA regulates HERG channel activation, and direct phosphorylation of the HERG channel protein has a functional role that may be important in regulation of cardiac repolarization.
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone↗
Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels.
The human ether-a-go-go-related gene (HERG) encodes a K+ channel with biophysical properties nearly identical to the rapid component of the cardiac-delayed rectifier K+ current (I(Kr)). HERG channels are one primary target for the pharmacological management of arrhythmias. In this study, we investigated the acute effects of the class III antiarrhythmic drug amiodarone on HERG channels expressed heterologously in Xenopus oocytes by use of the two-microelectrode voltage clamp technique. Amiodarone blocked HERG channels with an IC50 of 9.8 microM with a maximum outward tail current reduction of 62.8%. The block consisted of two main components, a closed channel block that could not be reversed within the time of experiments and an open channel block with a slow unblock, having a recovery time constant of 73 s at -80 mV. Inactivation of the HERG channel at very positive potentials could not prevent amiodarone block. These results indicate that HERG channels can be blocked by amiodarone in closed, open and inactivated states. The block of open channels was cumulative, use-dependent and voltage-dependent. In summary, our data suggest that the strong class III antiarrhythmic action of amiodarone is at least partially based upon its acute inhibitory effects on HERG potassium channels.
Amiodarone↗
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.
Action Potentials↗
[Atrial fibrillation: a frequent problem in clinical practice].
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Anti-Arrhythmia Agents↗
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.
Action Potentials↗
[Thoracic pain in a power athlete].
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Adult↗
[Calcium antagonists in treatment of ventricular tachycardia].
Of the traditional antiarrhythmic agents administered in the treatment of ventricular tachycardias, those belonging to Class III are most commonly used. However, some ventricular tachycardias displaying special clinical, electrocardiographic and/or electrophysiologic characteristics have been successfully treated with calcium antagonists. Otherwise, Class IV antiarrhythmic agents are primarily used in the treatment of supraventricular tachyarrhythmias. It is reasonable to suspect that calcium-dependent phenomena underlie ventricular tachyarrhythmias in a number of patients. Verapamil-sensitive sustained left ventricular tachycardias represent a typical example. Sufficient response to calcium antagonists has also been demonstrated for exercise-induced ventricular tachycardias and repetitive monomorphic ventricular tachycardias. Characteristically, these arrhythmias occur in young patients with no structural heart disease. The long-term prognosis of these patients is in fact very good, but because of intrusive symptoms, pharmacological or nonpharmacological (radiofrequency ablation) treatment is often indicated. Through correct diagnosis and implementation of a short- and long-term therapy with calcium antagonists, and excellent alternative to the potentially harmful therapy with Class I and Class III antiarrhythmic agents can be offered.
Anti-Arrhythmia Agents↗
[New aspects of defibrillator therapy].
The implantable cardioverter defibrillator is currently a therapy of first choice in patients with malignant therapy refractory ventricular arrhythmias. The occurrence of malignant ventricular tachycardia cannot be suppressed by the defibrillator but is treated using antitachycardia pacing, cardioversion or defibrillation. During recent years, electrodes, defibrillation shockforms and device size were continuously optimized. The development of transvenous lead systems resulted in significant reduction of perioperative mortality and morbidity. With the availability of biphasic shockforms and single-lead unipolar devices marked reduction of defibrillation thresholds were achieved and transvenous lead systems without subcutaneous could be implanted. Improvements in device technology lead to smaller devices which can be implanted subpectorally even using local anaesthesia. But there is still enormous potential to develop an ideal antiarrhythmic device. One of the most significant problems of the defibrillator therapy represents the delivery of inappropriate shocks due to supraventricular tachyarrhythmias and sinustachycardia. To solve this problem different approaches are currently developed. Extension in memory allows to store several data logs and intracardiac electrograms for individual adapted adjustment of the therapy. Intracardiac electrogram width measurement for discrimination between ventricular and supraventricular arrhythmias is currently evaluated. Dual-chamber arrhythmia discrimination algorithms of an integrated dual-chamber pacemaker and defibrillator are clinically studied. Hemodynamic sensors for determining the severity of the arrhythmia are currently under experimental evaluation. The combination of latissimus dorsi dynamic cardiomyoplasty and ICD therapy may improve survival in patients with severely depressed left ventricular function and malignant ventricular arrhythmias. Several randomized prospective trials are currently in progress potentially expanding the use of the ICD in patients at risk for sudden cardiac death. The high costs of defibrillator therapy is still a limitation for its use, but higher production figures and advancing technology could reduce the system prize.
Anti-Arrhythmia Agents↗
[Atrial fibrillation and flutter: experimental and clinical electrophysiology].
Several early publications already provided indirect evidence that atrial fibrillation is due to multiple, simultaneously activated reentrant wavelets. However, direct proof of this "multiple wavelet hypothesis" could only be obtained by means of activation mapping, which was conducted more recently in experimental as well as clinical atrial fibrillation. The surgical techniques for the treatment of atrial fibrillation are based on the knowledge on the pathophysiology of the arrhythmia. Similarly, early studies already suggested single, large reentrant circuits as the mechanism underlying atrial flutter. It could be demonstrated that a surgical lesion between the superior and inferior vena cava provided the basis for stable reentry around this large anatomical obstacle. But not only anatomical, but also functional obstacles, may be found in the center of a reentrant circuit. In typical atrial flutter, a long arc of functional conduction block extends from the inferior to the superior vena cava. In atypical atrial flutter, the central obstacle may be found anywhere in the right or, less frequently, in the left atrium. These experimental findings are supported by the clinical observation that a lesion in the area between the inferior vena cava and the nearby AV ring reproducibly terminates typical atrial flutter.
Animals↗
[Arrhythmogenic right ventricular disease].
In patients with arrhythmogenic right ventricular disease (ARVD), life threatening ventricular tachyarrhythmias and sudden cardiac death mostly occur in adolescence, or in young adults before the age of 40. In the right ventricle, progressive fibrolipomatous replacement of the ventricular myocardium is pathognomonic. In severe cases progressive congestive right heart failure can develop although mild forms are extremely difficult to recognized. In most cases the disease can be diagnosed only by elaborate investigation. Right ventricular cineangiography, myocardial biopsy, MRI, and electrophysiological investigation are the most important diagnostic procedures. If the disease is diagnosed in an early stage the risk of life-threatening arrhythmias can be reduced by carefully selected antiarrhythmic therapy.
Adolescent↗
[The implantable cardioverter/defibrillator (ICD). Developments up to the present time and future perspectives].
The implantable cardioverter/defibrillator is gaining increasing significance in the therapy of life-threatening ventricular arrhythmias. Independently, the team of Mirowski and the team of Schuder started to develop experimental automatic implantable defibrillators in the seventies. In 1980, the first human implant of an automatic defibrillator was done by Levi Watkins together with the team of Mirowski in Baltimore, USA. Since 1989 implantable cardioverter/defibrillators exhibit multiple functions among which are high energy defibrillation therapy, low energy cardioversion, antitachycardia pacing, permanent and post therapy antibradycardia pacing, diagnostic counters, and device status parameters. This offers a markedly improved technical device to the patients. Evaluation of the patient's diagnostic counters provide a detailed overview about the patient's arrhythmia history and information for optimizing antitachycardia pacing therapy and additional antiarrhythmic drug therapy. The availability of non-thoractomy transvenous lead systems and biphasic shock forms allows the insertion of the device without open chest surgery and even without subcutaneous leads resulting in low mortality rates and an exclusively transvenous system. Single-lead unipolar devices are currently investigated in clinical trials. Future development of atrial sensing lead systems may further reduce inappropriate shock therapy triggered by sinus tachycardia or atrial tachyarrhythmias, e.g. atrial fibrillation, and may be used for dual chamber stimulation. Hemodynamic sensors for determining the severity of the arrhythmia are currently under experimental evaluation. Possible prognostic indications of ICD therapy in patients without a history of malignant arrhythmias are currently studied in several prospective trials. All new directions hold promise to expand and improve the use of ICDs in patients at risk for sudden cardiac death.
Death, Sudden, Cardiac↗
Acute and chronic antiarrhythmic efficacy of d-sotalol in patients with sustained ventricular tachyarrhythmias.
To evaluate the clinical efficacy of d-sotalol, 84 patients with a history of sustained ventricular tachycardia (VT) or ventricular fibrillation (VF), who had inducible sustained VT/VT at baseline electrophysiologic study (EPS), were investigated after intravenous (IV) d-sotalol (1.5-2.5 mg.kg-1). A total of 29 additional patients received only oral d-sotalol, (400-600 mg.day-1). Acute success of antiarrhythmic therapy was defined as suppression of inducible sustained VT/VF. The overall success rate of IV d-sotalol was 38% (32/84) after a mean of 4.3 drugs failed to suppress inducibility. A 78% success rate (31/40) was demonstrated in patients who were also assessed after oral d-sotalol. Torsade de pointes type VT was seen in one patient. After 1 year, only 16% of patients with a positive EPS had a recurrence compared to 43% of patients with a negative EPS (P < 0.05). Estimated survival rates were 95 and 88% after 1 and 2 years of follow-up, respectively. Only five of 56 patients discontinued d-sotalol therapy because of adverse effects. IV d-sotalol appears to be an effective antiarrhythmic agent. Its long-term efficacy is predictable on the basis of therapy guided by electrophysiologic testing in patients with refractory ventricular tachyarrhythmias. The efficacy of d-sotalol seems comparable to that reported for d,l-sotalol.
Cardiac Pacing, Artificial↗
[Ventricular tachyarrhythmia in acute and chronic myocardial ischemia: non-drug therapy and evaluation of outcome].
In recent years new methods of non-pharmacological therapy of ventricular tachyarrhythmias have gained increasing importance. The development of implantable defibrillators and increasing experience with catheter ablation techniques represent important alternatives to pharmacological antiarrhythmic therapy which is presently employed only in a subgroup of patients with life-threatening tachyarrhythmias and coronary heart disease.
Catheter Ablation↗
Pros and cons of drugs that prolong ventricular refractoriness.
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Action Potentials↗