Indications for predismissal testing with arrhythmia-induction in patients receiving an implantable cardioverter defibrillator.

UNLABELLED: Arrhythmia induction during implantation of cardioverter defibrillators (ICD) is a standard procedure. However, controversy exists regarding the need for routine arrhythmia induction before discharge from hospital (pre-hospital discharge (PHD) test). In order to reduce the number of tests we identified risk factors that predict relevant ICD malfunction. METHODS AND RESULTS: 965 patients receiving a first device implantation (n=724) or device/system replacement (n=241) between 1998 and 2004 were analysed. During implantation 176 (18%) complications (intraoperative undersensing of induced arrhythmias, unsuccessful arrhythmia-therapy or low DFT safety margin) occurred. Frequent (>4 times) intraoperative lead repositioning due to low sensing values was present in 44 patients (5%). 9% of the patients with first ICD implantation, 21% with device replacement and 27% with system replacement developed complications during PHD testing with arrhythmia induction. Intraoperative complications, although corrected during implantation, were independent risk factors for malfunction during PHD testing (p<0.05). Additional predictors for malfunction were intraoperative lead repositioning (>4 times) and a history of both VF and VT (p<0.05). Patients without intraoperative complications rarely developed malfunction during PHD testing (3.7% first device, 6.25% system replacement). Only in patients undergoing device replacement was a higher risk for failure (13%) evident. No risk factors could be identified for these subgroups. CONCLUSION: Routine arrhythmia induction during PHD is recommended in ICD patients with intraoperative complications, although corrected during implantation, as well as frequent intraoperatives lead repositioning. Patients undergoing device/system replacement uncomplicated implantation are not generally at low risk for device failure.

Regional differences in the dynamics of refractoriness in intact and hypertrophied in situ canine hearts.

OBJECTIVES: Functional re-entry is thought to represent the predominant mechanism underlying ventricular arrhythmias. Functional conduction block may be caused by regional dispersion of refractoriness (ERP). Dispersion of ERP may not be evident at baseline, but may occur with sudden changes in heart rate, as ventricular arrhythmias are commonly induced by short-long-short cycles. METHODS: We examined the dynamics of local ERPs at two left ventricular (LV) sites in dogs with either no structural heart disease or biventricular hypertrophy (BVH). ERPs were determined at each of four bipoles of two adjacent needle electrodes in the LV apex and the lateral wall. The stimulation protocol included two different basic cycle lengths, one or two longer cycles after a train of 6 or 5 shorter cycles, and one shorter cycle after a train of 6 longer cycles. RESULTS: In normal dogs, a significant apicolateral ERP gradient was only evident with the longer basic cycle length. One shorter cycle was sufficient to dissolve that gradient. One longer cycle was enough to create a regional ERP gradient. Dynamic regional gradients occurred because the apex responded more markedly and more readily to abrupt changes in cycle length. BVH led to an increase in ERP at both LV sites and to an aggravation of regional ERP gradients. CONCLUSIONS: Dynamic ERP behavior seems to depend on topography and underlying pathology. Abrupt changes in heart rate might induce dynamic refractory gradients between various regions of the normal heart, but also between adjacent regions inhomogenously affected by hypertrophy.

Identification and characterisation of a novel KCNQ1 mutation in a family with Romano-Ward syndrome.

Romano-Ward syndrome (RWS), the autosomal dominant form of the congenital long QT syndrome, is characterised by prolongation of the cardiac repolarisation process associated with ventricular tachyarrhythmias of the torsades de pointes type. Genetic studies have identified mutations in six ion channel genes, KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 and the accessory protein Ankyrin-B gene, to be responsible for this disorder. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequence analysis have identified a KCNQ1 mutation in a family that were clinically conspicuous due to several syncopes and prolonged QTc intervals in the ECG. The mutant subunit was expressed and functionally characterised in the Xenopus oocyte expression system. A novel heterozygous missense mutation with a C to T transition at the first position of codon 343 (CCA) of the KCNQ1 gene was identified in three concerned family members (QTc intervals: 500, 510 and 530 ms, respectively). As a result, proline 343 localised within the highly conserved transmembrane segment S6 of the KCNQ1 channel is replaced by a serine. Co-expression of mutant (KCNQ1-P343S) and wild-type (KCNQ1) cRNA in Xenopus oocytes produced potassium currents reduced by approximately 92%, while IKs reconstitution experiments with a combination of KCNQ1 mutant, wild-type and KCNE1 subunits yielded currents reduced by approximately 60%. A novel mutation (P343S) identified in the KCNQ1 subunit gene of three members of a RWS family showed a dominant-negative effect on native IKs currents leading to prolongation of the heart repolarisation and possibly increases the risk of malign arrhythmias with sudden cardiac death.

Effect of radiofrequency ablation on atrial myocardium.

OBJECTIVES: Successful RF ablation of atrial fibrillation supposedly requires the creation of continuous linear lesions. This study aimed to determine the potential role of functional modifications of atrial myocardium in the vicinity of anatomic RF lesions. METHODS: In 10 normal beagles (group A), a multiplexer mapping system and an epicardial multi-electrode were used to reconstruct atrial activation patterns during pacing at two cycle lengths before and after attempts to induce two linear right atrial lesions with a standard ablation catheter, respectively. An intercaval "drawback" was repeated 3 times over 5 min at a set temperature of 70 degrees C, followed by a transversal "point-by-point" ablation from the interatrial septum to the right-lateral tricuspid annulus at 70 degrees C/60 s each. Induction of atrial flutter was attempted before and after each ablation. In another 6 beagles (group B), a high-resolution multi-electrode was used to study epicardial functional effects resulting from single endocardial RF lesions on the free right atrial wall. Using three energy settings (60 degrees C/30 s, 60 degrees C/60 s, 70 degrees C/60 s), activation patterns were analyzed at two cycle lengths and local effective refractory periods were measured across the lesion. RESULTS: The lesions induced in group A only marginally affected atrial activation patterns and total activation times. However, as shown in dogs with atrial flutter, regional slow conduction was enhanced and functional conduction blocks were facilitated at high atrial rates, resulting in a significant prolongation in the revolution time of respective reentrant circuits. Apart from inducing anatomic lesions, single endocardial RF lesions (group B) were shown to delay epicardial conduction in adjacent myocardium in an energy- and rate-dependent way. Furthermore, an energy-dependent prolongation of effective refractory periods by far exceeding the size of anatomic lesions was observed. CONCLUSIONS: Continuous linear atrial lesions are hard to achieve with conventional ablation techniques. However, RF lesions induce changes in conduction and refractoriness around the anatomic lesion, which are likely to contribute to the overall effect of respective therapeutic interventions.

Far-field R wave oversensing in a dual chamber arrhythmia management device: predisposing factors and practical implications.

Initial experience with the Medtronic Jewel 7250, the ICD designed to detect and treat ventricular and supraventricular tachyarrhythmias, is very promising. Its effectiveness, however, depends on sensing performance, which has not yet been systematically examined. The aim of the study was to determine the incidence of, predisposing factors for, and practical implications of far-field R wave oversensing (FFRWOS) in this dual chamber ICD. During a total follow-up of 797 months in 48 patients who had the Jewel 7250, follow-up strip charts, 12-channel Holter recordings and, in particular cases, Holter recordings with intracardiac markers were analyzed for the presence of FFRWOS. FFRWOS was documented in ten (21.3%) patients. Compared to other lead locations, the right atrial appendage lead position was most frequently associated with FFRWOS (7/27 vs 3/21, P < 0.05). Patients with FFRWOS had significantly more treated and nontreated atrial episodes, many of which were judged to have been detected inappropriately. In one case, inappropriate atrial antitachycardia pacing due to R wave oversensing triggered sustained ventricular tachycardia, terminated eventually with a high energy shock. In dual chamber ICDs, FFRWOS may represent a frequent phenomenon possibly leading to serious consequences. For atrial leads, a lateral atrial wall position seems to be preferable. In most cases, FFRWOS can be eliminated by optimization of atrial sensing parameters. Given the possibility of ventricular proarrhythmia with atrial pacing therapy, the capability of ventricular backup defibrillation in respective devices is at least reassuring.

Classification of atrial flutter and regular atrial tachycardia according to electrophysiologic mechanism and anatomic bases: a statement from a joint expert group from the Working Group of Arrhythmias of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.

Regular atrial tachycardias classically are classified into flutter or tachycardia, depending on the rate and presence of a stable baseline on the ECG. However, current understanding of electrophysiology atrial tachycardias makes this classification obsolete, because it does not correlate with mechanisms. The proposed classification is based on electrophysiologic mechanisms, defined by mapping and entrainment. Radiofrequency ablation of a critical focus or isthmus can afford proof. Focal tachycardias are characterized by radial spread of activation and endocardial activation not covering the whole cycle. Ablation of the focus of origin interrupts the tachycardia. The mechanism of focal firing is difficult to ascertain by clinical methods. Macroreentrant tachycardias are characterized by circular patterns of activation that cover the whole cycle. Fusion can be shown during entrainment on the ECG or by multiple endocardial recordings. Ablation of a critical isthmus interrupts the tachycardia. Macroreentry can occur around normal structures (terminal crest, eustachian ridge) or around atrial lesions. The anatomic bases of these tachycardias must be defined, to guide appropriate treatment. Atrial flutter is a mere description of continuous undulation on the ECG, and only some strictly defined typical flutter patterns correlate with right atrial macroreentry bounded by the tricuspid valve, terminal crest, and caval vein orifices. This classification should be considered open, as some classically described tachycardias, such as reentrant sinus tachycardia, inappropriate sinus tachycardia, and type II atrial flutter, cannot be classified accurately. Furthermore, the possibility of fibrillatory conduction makes the limits with atrial fibrillation still ill defined.

Worldwide clinical experience with a new dual-chamber implantable cardioverter defibrillator system.

INTRODUCTION: Management of atrial tachyarrhythmias represents a significant challenge in patients with implantable cardioverter defibrillators (ICDs). Drug therapy of these arrhythmias is limited by moderate efficacy, ventricular proarrhythmia, and drug-device interactions. This study tested the safety and efficacy of a new dual-chamber ICD to detect and treat atrial as well as ventricular tachyarrhythmias. METHODS AND RESULTS: A dual-chamber ICD (Medtronic 7250 Jewel AF) was implanted in 293 of 303 patients at 49 centers in Europe, Canada, and North America. Specific data were collected at implant and during a mean follow-up period of 7.9+/-4.7 months. There were no clinically evident failures to detect and treat ventricular arrhythmias. In patients with at least one of the dual-chamber detection criteria activated, 1,056 of 1,192 episodes of ventricular tachycardia or fibrillation detected were judged to be appropriate (89% positive predictive accuracy). Therapy efficacy was 100% in the ventricular fibrillation zone and 98% in the ventricular tachycardia zone. Positive predictive accuracy for detection of atrial episodes was 95% (1,052/1,107). For episodes classified as atrial tachycardia by the device, the efficacy of atrial antitachycardia pacing and high-frequency (50-Hz) burst pacing was 55% and 17%, respectively. High-frequency burst pacing terminated 16.8% of episodes classified as atrial fibrillation, and atrial defibrillation had an estimated efficacy of 76%. The actuarial estimates of 6-month complication-free survival and total survival were 88% and 94%, respectively. CONCLUSION: This novel dual-chamber ICD is capable of safely and effectively discriminating atrial from ventricular tachyarrhythmias and of treating atrial tachyarrhythmias without compromising detection and treatment of ventricular tachyarrhythmias.

Effects of propafenone on anisotropic conduction properties within the three-dimensional structure of the canine ventricular wall.

BACKGROUND: Structural complexities of the intact ventricular wall cause a very complex spread of activation. The effects of regional tissue damage and of antiarrhythmic drugs on directional differences in activation should help to further elucidate intramural conduction patterns. METHODS AND RESULTS: In 10 healthy dogs and in 5 dogs with subacute anterior wall infarction, 6 parallel rows of 6 needle electrodes with 4 bipolar electrode pairs per needle were inserted into the left anterior ventricular wall. Using a computerized multiplexer-mapping system, the spread of activation in epi-, endo- and midmyocardial muscle layers and in the surviving epicardium, respectively, was reconstructed. Marked differences in conduction velocities relative to fiber orientation were evident in the surviving epicardium of infarcted hearts. Directional differences in conduction velocities, although less pronounced, were still preserved throughout the intact ventricular wall. Epicardial transverse conduction in intact hearts was significantly faster than transverse conduction in infarcted hearts (0.87 +/- 0.11 m/s vs 0.68 +/- 0.1 m/s). In normal hearts, propafenone (2 mg/kg) decreased conduction velocities primarily in longitudinal directions (-27 +/- 10%), but also moderately in transverse directions (-13 +/- 7 %) of all muscle layers, with no significant effect on straight (-4 +/- 8 %), but on oblique transmural conduction (-33 +/- 18 %). In infarcted hearts propafenone decreased conduction particularly in longitudinal direction (-23 +/- 14 %) without affecting conduction transverse to the fiber orientation (+3 +/- 6%). CONCLUSIONS: Longitudinal intramural shortcircuits reduce directional differences in activation. Transmural infarction results in a loss of alternative intramural pathways, unmasking marked anisotropy in the surviving epicardium. Conduction delay in intramural pathways explains the effects of propafenone on transverse and oblique transmural conduction. Primarily longitudinal conduction delay results in reduced tissue anisotropy.

Intercaval block in normal canine hearts : role of the terminal crest.

BACKGROUND: The intriguing monotony in the occurrence of intercaval conduction block during typical atrial flutter suggests an anatomic or electrophysiological predisposition for conduction abnormalities. METHODS AND RESULTS: To determine the location of and potential electrophysiological basis for conduction block in the terminal crest region, a high-density patch electrode (10x10 bipoles) was placed on the terminal crest and on the adjacent pectinate muscle region in 10 healthy foxhounds. With a multiplexer mapping system, local activation patterns were reconstructed during constant pacing (S(1)S(1)=200 ms) and introduction of up to 2 extrastimuli (S(2), S(3)). Furthermore, effective refractory periods were determined across the patch. If evident through online analysis, the epicardial location of conduction block was marked for postmortem verification of its endocardial projection. Marked directional differences in activation were found in the terminal crest region, with fast conduction parallel to and slow conduction perpendicular to the intercaval axis (1.1+/-0.4 versus 0.5+/-0.2 m/s, P<0.01). In the pectinate muscle region, however, conduction velocities were similar in both directions (0.5+/-0.3 versus 0.6+/-0.2 m/s, P=NS). Refractory patterns were relatively homogeneous in both regions, with local refractory gradients not >30 ms. During S(3) stimulation, conduction block parallel to the terminal crest was inducible in 40% of the dogs compared with 0% in the pectinate muscle region. CONCLUSIONS: Even in normal hearts, inducible intercaval block is a relatively common finding. Anisotropic conduction properties would not explain conduction block parallel to the intercaval axis in the terminal crest region, and obviously, refractory gradients do not seem to play a role either. Thus, the change in fiber direction associated with the terminal crest/pectinate muscle junction might form the anatomic/electrophysiological basis for intercaval conduction block.

[Predictive value of frequency, duration and rate of ventricular salvos in ambulatory ECG for inducibility of sustained ventricular tachycardia]. / Prädiktiver Wert der Frequenz, der Dauer und der Häufigkeit ventrikulärer Salven im Langzeit-EKG für die Induzierbarkeit anhaltender Kammertachykardien.

Identification of high risk patients with coronary artery disease (CAD) prone to sudden cardiac death still remains a difficult issue. In 211 patients with CAD diagnosed by coronary angiography and documented non-sustained ventricular tachycardia (NSVT), programmed ventricular stimulation (PVS) was performed. NSVTs documented during Holter monitoring were analysed concerning frequency, duration and rate. To relate those parameters to the inducibility of sustained monomorphic ventricular tachycardias (MVT) during PVS, the total population was divided in different groups; patients with 1, 2-5 or > 5 salvos within 24 h; patients having salvos with a rate of > or = 150/min or < 150/min; patients with 3-5, 6-10 or > 10 consecutive extra beats. It could be demonstrated that in patients with CAD and NSVTs, induction of MVTs during PVS is more likely if the rate of the spontaneously occurring NSVT is > or = 150/min (22.1 vs 8.9%; p = 0.042). In contrast, there is apparently no correlation between the duration and incidence of NSVTs and the prevalence of MVTs during PVS. Multivariate analysis revealed the rate of documented NSVTs (odds ratio 2.98, p = 0.0314) and a decrease of left ventricular ejection fraction (odds ratio 1.69; p = 0.0013) as independent risk factors for the inducibility of MVTs. Conclusions CAD patients with fast salvos (> or = 150 beats/min) and reduced left ventricular ejection fraction are more likely to reveal inducible MVT during PVS and should, therefore, preferably be subjected to invasive risk stratification. The number of salvos per day and the number of consecutive beats, on the other hand, do not seem to be of relevant predictive value.

Role of sodium channels in ventricular fibrillation: a study in nonischemic isolated hearts.

Because the role of sodium channels in the initiation and maintenance of VF is not fully elucidated, we studied the significance of sodium channel activity in VF using sodium channel blockers. In nonischemic isolated feline hearts, the following electrophysiologic parameters were measured before and after application of tetrodotoxin (5 x 10(-7) M, n = 6) or lidocaine (1 x 10(-5) M, n = 8): (a) during pacing, epicardial conduction time; refractoriness; the fastest rate for 1:1 pacing/response capture, and all tissue resistivity, indirectly reflecting intercellular electrical resistance; (b) during 8 min of electrically induced tachyarrhythmias, all tissue resistivity; peak frequency (to measure average frequency based on fast-Fourier transformation analysis); and normalized entropy (to measure the degree of arrhythmia organization). In nonischemic isolated rabbit hearts (n = 4), three-dimensional mapping was performed before and after application of lidocaine (1 x 10(-5) M). In feline hearts, lidocaine and tetrodotoxin application resulted in: (a) more spontaneous arrhythmia termination (63-67%) than in nontreated hearts (7%); (b) transformation from mainly VF into ventricular tachycardia with increased organization; and (c) prolongation of conduction time (155-248%) (p < 0.01 for all parameters). The ventricular refractory period was slightly prolonged by tetrodotoxin in the right ventricle and exhibited rate-dependent shortening in control and with lidocaine. Tetrodotoxin and lidocaine reduced the pacing rate for 1:1 pacing/response capture, and all tissue resistivity was not significantly affected. Peak frequency was decreased by tetrodotoxin and lidocaine mainly in the left ventricle (p < 0.01). In nontreated left ventricles, peak frequency was increased over time but was attenuated by lidocaine. In isolated rabbit hearts, several simultaneous wave fronts were detected during VF in nontreated hearts and were reduced to only one or two major wavefronts after application of lidocaine. Suppression of sodium channel activity that primarily slowed conduction time and had little or no effect on ventricular refractory period and all tissue resistivity resulted in less stable and more organized arrhythmias and reduced tachyarrhythmia rate compared with nontreated hearts. These results suggest an active role for sodium channels in the maintenance of ventricular fibrillation.

Electrophysiologic effects of the new I(Ks)-blocking agent chromanol 293b in the postinfarction canine heart. Preserved positive use-dependence and preferential prolongation of refractoriness in the infarct zone.

OBJECTIVES: Aim of the present study was to investigate site- and rate dependent effects of the IKs-blocking agent chromanol 293b on conduction and refractoriness in normal, infarcted, and transitional regions of in-situ canine hearts. METHODS: In five dogs with subacute myocardial infarction, three-dimensional mapping was performed after insertion of 6 x 6 needle electrodes in the left ventricle. Before and after application of chromanol 293b (10 mg/kg), activation patterns and local refractory periods (ERPs) at pacing intervals of 300, 500 and 850 ms were obtained for the surviving epicardial muscle layer of the infarct zone (IZ) and for epi-, endo-, and midmyocardial muscle layers of both the normal zone (NZ) and the border zone (BZ) separating normal and infarcted areas. RESULTS: At baseline, both the NZ and the BZ exhibited uniform ERPs throughout the ventricular wall. Epicardial ERPs were longer in the IZ than in the NZ, and intermediate in the BZ. Chromanol 293b did not affect total activation times. However, at fast heart rates regional areas of slow conduction occurred. Chromanol 293b ubiquitously prolonged local ERPs, most markedly in the IZ. A preferential effect on individual muscle layers of the NZ or BZ and, thus, drug-induced transmural dispersion of ERP could not be observed. Again ubiquitously, the effect on ERP was more pronounced at faster than at slower heart rates, that is, positive use-dependent. At a basic cycle length of 300 ms, chromanol 293b prolonged local ERPs in the IZ by 46 +/- 24 %, in the BZ by 34 +/- 26%, and in the NZ by 20 +/- 17% (p < or = 0.05). CONCLUSIONS: At least in theory, the electrophysiologic properties of chromanol 293 b, that is, preferential prolongation of refractoriness in ischemic myocardium, more pronounced at faster than at slower heart rates, but homogeneously throughout the intact ventricular wall, appear to be favorable. Whether this translates into a clinical benefit, particularly in the treatment of ischemia-related ventricular tachyarrhythmias, remains to be determined.

Multisite pacing for prevention of atrial tachyarrhythmias: potential mechanisms.

OBJECTIVES: To determine the effects of single-, dual-, triple- and quadruple-site atrial pacing on atrial activation and refractoriness in normal canine hearts. BACKGROUND: Multisite pacing has been suggested to be superior to single-site pacing for prevention of atrial tachyarrhythmias. However, the underlying electrophysiological mechanisms are undetermined at the moment, as is the rationale for the selection of pacing locations and the number of pacing sites. METHODS: In 13 normal beagle dogs, an epicardial multielectrode (128 bipoles) and a multiplexer mapping system were used to reconstruct epicardial atrial activation patterns obtained during simultaneous stimulation from up to four electrodes located in the high and low right and left atrium, respectively. For all pacing modes (single-, dual-, triple- and quadruple-site pacing), total activation times and local effective refractory periods at eight randomly selected sites as well as local recovery intervals were determined. In a subgroup of five dogs, total epicardial activation times were also obtained during single-site septal stimulation (septal group). RESULTS: Activation times and local recovery intervals were minimized by triple-site stimulation, whereas a fourth site did not produce further shortening. Septal stimulation produced epicardial activation times comparable to quadruple-site stimulation. Local refractory periods and their dispersion always remained unaffected. Functional conduction blocks apparent during single-site were found to resolve during multisite stimulation. CONCLUSIONS: Multisite pacing can prevent functional conduction blocks by multidirectional excitation and a reduction in total activation time. Triple-site and, possibly, septal pacing modes are expected to be most efficient because both minimize total activation times and maximize the multidirectionality of excitation. In spite of unaffected local refractory periods, the shortening of local recovery intervals might homogenize atrial repolarization and, thus, contribute to the preventive effects of multisite pacing.

Cesium chloride induced ventricular arrhythmias in dogs: three-dimensional activation patterns and their relation to the cesium dose applied.

INTRODUCTION: Cesium chloride has widely been used in experimental models to produce various ventricular arrhythmias. The study was designed to evaluate whether type and mechanism of these arrhythmias are dose-dependent. METHODS: In 7 dogs with acute AV-block, 60 pins containing 4 bipolar electrodes each were inserted into both ventricles to provide 240 endo-, epi- and midmyocardial recording sites. A computerized mapping system was used to determine three-dimensional activation patterns of ventricular arrhythmias induced by three injections of 1 mmol/kg cesium chloride at 20 minute intervals. RESULTS: Out of all arrhythmias induced, 25 ventricular extrasystoles, 31 monomorphic and 47 polymorphic ventricular tachycardias were mapped. Nonsustained ventricular tachycardias were readily inducible by a single bolus of cesium chloride, whereas sustained episodes required repetitive injections (1.45 +/- 0.61 vs. 2.61 +/- 0.57 doses, p < 0.05). Polymorphic tachycardias were observed more commonly than monomorphic tachycardias (87 vs. 31). Initiation and maintenance of cesium induced arrhythmias were exclusively based on focal mechanisms originating from the subendocardium, irrespective of morphology and dosage. All monomorphic arrhythmias were caused by repetitive firing of single immobile foci located in either the right or the left ventricle. Bi- and multifocal mechanisms, however, were found to underlie the polymorphic episodes. CONCLUSIONS: Although there is a dose-dependence as to the sustenance of mono- or polymorphic tachycardias, this does not reflect on the three-dimensional activation pattern of cesium induced arrhythmias, which are due to mono- or multifocal activation originating from the subendocardium.

Functional coupling of human beta 3-adrenoreceptors to the KvLQT1/MinK potassium channel.

The slow component of the delayed rectifier potassium current (IKs) plays an important role during repolarization in the human heart. Life-threatening arrhythmias can be triggered by sympathetic stimulation, presumably acting on IKs. The ion channel responsible for the IKs current is made of two proteins, the KvLQT1 protein and the MinK protein. In this study, we investigated the effects of adrenergic stimulation on the KvLQT1/MinK channel by coexpressing KvLQT1/MinK channels with the human beta(3)-adrenoreceptor subunit heterologously in Xenopus oocytes. Western blot experiments revealed that beta(3)-adrenoreceptor proteins appear in the cell membrane of Xenopus oocytes, when the corresponding cRNA was injected. In electrophysiological measurements we found that stimulation with the beta-adrenergic agonist isoproterenol increased the current amplitude of the beta(3)/KvLQT1/MinK complex up to 237% with an ED(50) of 8 nm, a value similar to that found on IKs in guinea pig cardiomyocytes. When oocytes with beta(3)/KvLQT1/MinK were preincubated with cholera toxin (2 microg/ml), an activator of G(S) proteins, the basal current amplitude of the beta(3)/KvLQT1/MinK complex was increased 3.1-fold, and the current amplitude increase by isoproterenol was drastically reduced, indicating that the signal transduction cascade was mediated via G(s) proteins. The knowledge about functional coupling of the human beta(3)-adrenoreceptor to KvLQT1/MinK channels reveals interesting aspects about the genesis and therapy of arrhythmias.