Electrocardiographic and electrophysiologic effects of dexmedetomidine on children.

BACKGROUND: Dexmedetomidine (DEX) is a highly selective alpha-2-adrenergic agonist approved for short-term sedation and monitored anesthesia care in adults. Its effects on the electrocardiography and cardiac conduction tissue are not well described in the literature. Therefore, we aimed to characterize the electrocardiographic and electrophysiologic effects of DEX in children. METHODS: Twenty children (11 boys and nine girls) between the ages of eight and 17 undergoing electrophysiology study and ablation of the supraventricular tachycardia had hemodynamic and cardiac electrophysiologic variables measured before and during the administration of DEX (1 microgram/kg IV over 10 minutes followed by a 10-minute continuous infusion of 0.5 microgram/kg/h). RESULTS: A significant decrease in heart rate was seen after the administration of DEX, but the systolic-diastolic-mean arterial pressure, respiratory rate, and end-tidal carbon dioxide did not change. Corrected sinus node recovery times and baseline sinus cycle lengths, which are markers of sinus nodal function, were both lengthened with the administration of DEX. Atrioventricular (AV) nodal function, as evidenced by the Wenckebach cycle length, the ventriculoatrial block cycle length, and AV nodal effective refractory periods, was lengthened significantly. We also found that DEX increased the atrial refractory period and diminished atrial excitability. CONCLUSIONS: DEX significantly depressed sinus and AV nodal function in pediatric patients without significant electrocardiogram interval changes, other than a trend toward lower heart rates. Although no spontaneous AV nodal block and no clinically significant bradycardia were seen, we recommend that DEX be used with caution in patients at risk for bradycardia and/or AV nodal dysfunction due to its associated comorbidities.

Non-invasive evaluation of the effect of metoprolol on the atrioventricular node during permanent atrial fibrillation.

AIMS: During atrial fibrillation (AF), conventional electrophysiological techniques for assessment of refractory period or conduction velocity of the atrioventricular (AV) node cannot be used. We aimed at evaluating changes in AV nodal properties during administration of metoprolol from electrocardiogram data, and to support our findings with simulated data based on results from an electrophysiological study. METHODS AND RESULTS: Sixty patients (age 71 ± 9 years, 42 men) with permanent AF were included in the RATe control in Atrial Fibrillation (RATAF) study. Two 15 min segments, during baseline and metoprolol administration, starting at 2 pm were analysed in this study. Atrial fibrillatory rate (AFR), heart rate (HR), and AV nodal parameters were assessed. The AV nodal parameters account for the probability of an impulse not taking the fast pathway, the absolute refractory periods of the slow and fast pathways (aRPs and aRPf), representing the functional refractory period, and their respective prolongation in refractory period. In addition, simulated RR series were generated that mimic metoprolol administration through prolonged AV conduction interval and AV node effective refractory period. During metoprolol administration, AFR and HR were significantly decreased and aRP was significantly prolonged in both pathways (aRPs: 337 ± 60 vs. 398 ± 79 ms, P < 0.01; aRPf: 430 ± 91 vs. 517 ± 100 ms, P < 0.01). Similar results were found for the simulated RR series, both aRPs and aRPf being prolonged with metoprolol (aRPs: 413 ± 33 vs. 437 ± 43 ms, P = 0.01; aRPf: 465 ± 40 vs. 502 ± 69 ms, P = 0.02). CONCLUSION: The AV nodal parameters reflect expected changes after metoprolol administration, i.e. a prolongation in functional refractory period. The simulations confirmed that aRPs and aRPf may serve as an estimate of the functional refractory period.

Frequency-dependent electrophysiological remodeling of the AV node by hydroalcohol extract of Crocus sativus L. (saffron) during experimental atrial fibrillation: the role of endogenous nitric oxide.

The study assessed the hydroalcohol extract effects of Crocus sativus L. (saffron) on (i) the basic and rate-dependent electrophysiological properties of the AV node, (ii) remodeling of the AV node during experimental atrial fibrillation (AF) and (iii) the role of nitric oxide (NO) in the effects of saffron on the AV node. Stimulation protocols in isolated AV node were used to quantify AV nodal recovery, facilitation and fatigue in four groups of rabbits (n = 8-16 per group). In addition, the nodal response to AF was evaluated at multiple cycle lengths and during AF. Saffron had a depressant effect on AV nodal rate-dependent properties; further, it increased Wenckebach block cycle length, functional refractory period, facilitation and fatigue (p < 0.05). A NO-synthase inhibitor (L-NAME) prevented the depressant effects of saffron on the AV node (p < 0.05). Saffron increased the zone of concealment in experimental AF (p < 0.05). The present research showed, for the first time, established electrophysiological remodeling of the AV node during AF by saffron. Saffron increased the AV nodal refractoriness and zone of concealment. These depressant effects of saffron were mediated by endogenous NO.

Electrophysiological predictors of propafenone efficacy in prevention of atrioventricular nodal re-entrant and atrioventricular re-entrant tachycardia.

AIM: To assess the efficacy of propafenone in prevention of atrioventricular nodal reentrant tachycardia (AVNRT) and orthodromic atrioventricular tachycardia (AVRT) based on the clinical results of arrhythmia recurrence and find the electrophysiological predictor of propafenone effectiveness. METHODS: This retrospective study included 44 participants in a 12-month period, who were divided in two groups: group A - in which propafenone caused complete ventriculo-atrial block and group B - in which propafenone did not cause complete ventriculo-atrial block. RESULTS: Group A had significantly lower incidence of tachycardia than group B (95% vs 70.8%, P=0.038), and complete ventriculo-atrial block predicted the efficacy of propafenone oral therapy in the prevention of tachycardia (sensitivity 87.5%, specificity 52.8%, positive predictive value 95%, negative predictive value 29.2%). Patients with AVNRT in group B who did not experience the recurrences of tachycardia had significantly shorter echo zone before intravenous administration of propafenone than the patients who experienced episodes of sustained tachycardia (median 40 ms [range 15-60 ms] vs 79 ms [range 50-180 ms], P=0.008). CONCLUSION: In patients with non-inducible tachycardia, complete ventriculo-atrial block can be used as an electrophysiological predictor of the efficacy of propafenone oral therapy in the prevention of tachycardia. In patients with non-inducible AVNRT, but without complete ventriculo-atrial block, propafenone was more effective in patients with shorter echo zone of tachycardia.

Botulinum toxin injection in epicardial autonomic ganglia temporarily suppresses vagally mediated atrial fibrillation.

BACKGROUND: Autonomic denervation may suppress atrial fibrillation (AF) vulnerability. This study was designed to assess the short- to mid-term effects of botulinum toxin, a cholinergic neurotransmission blocker, on AF inducibility. METHODS AND RESULTS: A total of 23 mongrel dogs were studied. The sinus node and atrioventricular node epicardial fat pads were exposed through a right lateral thoracotomy. Botulinum toxin (Botox, 50 U per fat pad) or 0.9% normal saline (control) was injected into the center of each of the 2 fat pads. The electrophysiological effects were evaluated at 1, 2, and 3 weeks (7 to 8 animals at each time point) with and without cervical vagal stimulation. The vagal stimulation effects on the sinus and atrioventricular nodes were inhibited, and dispersion of atrial effective refractory period was lower at 1 week in the Botox group. Significant suppression of AF inducibility was observed at 1 week but disappeared at 2 and 3 weeks. These changes were not observed in the control group. CONCLUSIONS: Temporary suppression of vagally mediated AF, for at least 1 week, was achieved with botulinum toxin injection in this canine model. This effect might be associated with reduced dispersion of effective refractory period. A temporary autonomic block using botulinum toxin might be a novel therapeutic option for several clinical conditions such as post-cardiac surgery AF.

Assessing patients for catheter ablation during hospitalization for acute heart failure.

Heart rhythm problems are common among patients who are hospitalized with acute heart failure (HF). Although it is often difficult to determine whether a tachyarrhythmia is the major contributor to an acute HF decompensation or merely a consequence of the decompensation, both issues usually need to be addressed. There is also a subset of patients with HF who have a tachycardia-induced cardiomyopathy (TIC), where the sole cause of the ventricular dysfunction is the heart rhythm problem. In most cases, the management of a tachyarrhythmia in a patient with acute HF is not significantly different than the management of a heart rhythm problem in any patient, but there are several special clinical scenarios and important considerations. These considerations include the time urgency for an intervention, the usual need to be more aggressive and definitive, the need to stabilize a patient to allow for a heart rhythm intervention, such as catheter ablation to be performed safely, and the limitations of antiarrhythmic drugs in patients with ventricular dysfunction. Catheter ablation is a highly effective treatment option for many patients with supraventricular or ventricular tachycardias who are hospitalized with HF. This review will discuss the different types of tachyarrhythmias that can be associated with acute HF and are amenable to catheter ablation, and the assessment that needs to take place in potentially eligible patients to determine when catheter ablation is appropriate.

Atrioventricular junction ablation and pacemaker implantation for heart failure associated with atrial fibrillation: potential issues and therapies in the setting of acute heart failure syndrome.

Atrial fibrillation is the most common arrhythmia and is especially clinically important in patients with heart failure. Prolonged atrial fibrillation with high ventricular rate response may lead to development or worsening of left ventricular function. If adequate heart rate control cannot be obtained medically, often patients will undergo pacemaker implant and catheter ablation of the atrioventricular junction. This intervention can have profound effects on the course of heart failure. This article reviews the technique, complications, outcome data, and alternatives to this management strategy. The potential role of this therapeutic modality in those hospitalized with acute heart failure syndromes is discussed.

Prolongation of AV nodal refractoriness by Ruta graveolens in isolated rat hearts. Potential role as an anti-arrhythmic agent.

OBJECTIVE: To evaluate concentration-dependent effects of total extract of Ruta graveolens and its purified alkaloid fraction on the nodal basic and functional properties. METHODS: In the present experimental study, we used the Langendorff model for perfusion of isolated rat hearts to determine the effects of various concentrations of methanolic extract of Rue (1.25 x 10(-6) % weight per volume percent [W/V]; 2.5 x 10(-6) % W/V; 3.75 x 10(-6) % W/V) and total alkaloid of Rue (0.25 x 10(-6) % W/V; 0.5 x 10(-6) % W/V) on electrophysiological properties of cardiac tissue. Selective stimulation protocols were used to independently quantify atrioventricular AV nodal recovery, facilitation, and fatigue. We used 3 groups (N=24) of isolated perfused rat AV nodal preparations to assess the effect of Rue extracts. The study was carried out in October 2006 in the electrophysiology laboratory of the Cardiovascular Research Center of Golestan University of Medical Sciences, Golestan, Gorgan, Iran. RESULTS: Our results showed that both the total plant extract and the alkaloid fraction of Ruta graveolens had a similar trend of action on nodal conduction time and refractoriness. Furthermore, we observed increased atrioventricular conduction time (83+/-4 to 108+/-5) msec and functional refractory period (157.6+/-3 to 163.7+/-4 msec) at a maximum concentration of 3.75 x 10(-6) % W/V. CONCLUSION: The above results indicated a potential antiarrhythmic effect of Ruta graveolens in treating supra ventricular tachyarrhythmia.

The effects of dexmedetomidine on cardiac electrophysiology in children.

BACKGROUND: Dexmedetomidine (DEX) is an alpha2-adrenergic agonist that is approved by the Food and Drug Administration for short-term (<24 h) sedation in adults. It is not approved for use in children. Nevertheless, the use of DEX for sedation and anesthesia in infants and children appears to be increasing. There are some concerns regarding the hemodynamic effects of the drug, including bradycardia, hypertension, and hypotension. No data regarding the effects of DEX on the cardiac conduction system are available. We therefore aimed to characterize the effects of DEX on cardiac conduction in pediatric patients. METHODS: Twelve children between the ages of 5 and 17 yr undergoing electrophysiology study and ablation of supraventricular accessory pathways had hemodynamic and cardiac electrophysiologic variables measured before and during administration of DEX (1 microg/kg IV over 10 min followed by a 10-min continuous infusion of 0.7 microg x kg(-1) x h(-1)). RESULTS: Heart rate decreased while arterial blood pressure increased significantly after DEX administration. Sinus node function was significantly affected, as evidenced by an increase in sinus cycle length and sinus node recovery time. Atrioventricular nodal function was also depressed, as evidenced by Wenckeback cycle length prolongation and prolongation of PR interval. CONCLUSION: DEX significantly depressed sinus and atrioventricular nodal function in pediatric patients. Heart rate decreased and arterial blood pressure increased during administration of DEX. The use of DEX may not be desirable during electrophysiology study and may be associated with adverse effects in patients at risk for bradycardia or atrioventricular nodal block.

Electrophysiological effects of carvedilol on rabbit heart pacemaker cells.

The electrophysiological effects of carvedilol, a beta-blocking agent with vasodilating actions, have been studied on rabbit pacemaker cells using the whole-cell patch clamp technique. Nystatin-perforated patch recordings from the sinoatrial (SA) and atrioventricular (AV) nodes demonstrated that 1-3 microM of carvedilol caused a decrease in the spontaneous firing frequency, depolarization of the maximal diastolic potential, and prolongation of the action potential duration in both species. Voltage clamp experiments were performed using SA and AV node myocytes to identify and define the carvedilol-induced changes in the Ca(2+) current, I(Ca), delayed rectifier K(+) current, I(K), and hyperpolarization-activated inward current, I(f). In the SA node cells, 1 microM of carvedilol blocked I(K), I(Ca), and I(f) by 72%, 47%, and 22%, respectively. In the AV node cells, the corresponding reductions were 64% (I(K)) and 46% (I(Ca)), respectively. In both the SA and AV nodes the decrease in I(K) appeared to be mainly due to the rapidly activating component of the delayed rectifier, I(Kr), since the high dose of carvedilol blocked I(K) in the SA and AV nodes to a submaximal degree. In conclusion, effective doses of carvedilol have classical class III antiarrhythmic actions and a negative chronotropic effect resulting from the inhibition of I(K) and I(Ca). Both actions may be efficacious for treating supraventricular tachyarrhythmias.

Atrial, SA nodal, and AV nodal electrophysiology in standing horses: normal findings and electrophysiologic effects of quinidine and diltiazem.

BACKGROUND: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. HYPOTHESES: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. ANIMALS: Fourteen healthy horses. METHODS: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). RESULTS: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. CONCLUSIONS AND CLINICAL IMPORTANCE: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation.

[Morphology and function of the intrinsic cardiac nervous system]. / Morphologie und Funktion des intrinsischen kardialen Nervensystems.

Access to the intrinsic cardiac autonomic nervous system can now be achieved via percutaneous catheter stimulation techniques. Thereby, cardiac functions like atrioventricular nodal conduction, sinus cycle length and ventricular inotropy can be dynamically regulated. The present article provides examples of this new technique in acute and chronic models but also first human applications.

Effects of cardioactive medications on retrograde conduction: continuing relevance for current devices.

INTRODUCTION: Retroconduction (ventriculo-atrial conduction) remains a problem for patients with implanted cardiac rhythm devices. Pacemaker algorithms can detect and terminate endless loop tachycardia (ELT), but actual prevention of ELT may require anti-arrhythmic drugs (AADs). Similarly, AADs can affect ICD rhythm discrimination algorithms that depend on atrio-ventricular ratios. There is concern whether these drugs remain effective during stress situations. METHODS: Electrophysiologic studies that included retroconduction testing using slow ramp pacing were done in 1332 patients. The presence or absence of retroconduction at baseline and with drug was recorded, as was the rate at block. As a stress surrogate, isoproterenol was used to test retroconduction and reversal of drug-induced block. RESULTS: Procainamide, mexiletine, phenytoin, disopyramide, quinidine, beta-blockers, encainide, and amiodarone caused complete retrograde block or decreased the rate at which block occurred (mean 76% of patients, p < 0.008), whereas digoxin, lidocaine, diltiazem, and verapamil did not. Isoproterenol (in the absence of AADs) increased the rate at block in 82% of 404 patients with retroconduction at baseline (p < 0.005). Of 319 patients without retroconduction at baseline, 134 (42%) developed retroconduction after isoproterenol. Isoproterenol reversed retrograde block in 39% of patients with block on an AAD. Amiodarone, digoxin, and the combination of digoxin plus a beta-blocker were most effective at resisting this reversal of ventriculo-atrial block (80%, 68%, and 75% respectively). CONCLUSION: Most of the AADs reviewed increase the cycle length at block or abolish retroconduction, while isoproterenol has the opposite effect. Anti-arrhythmic medications, particularly amiodarone, digoxin, and the combination of digoxin plus a beta-blocker may be considered for a patient with multiple ELT episodes or certain ICD detection problems.

The discovery of the selective I(f) current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease.

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries, despite the advances in pharmacological treatments, risk factor control and the beneficial effect of myocardial revascularization procedures. Medical anti-ischemic treatment is still essential in most patients, but should be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement of the quality of life and symptom control. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most of the ischemic episodes but also as an independent predictor of mortality, inhibition of the pacemaker I(f) current to induce a direct and selective decrease in heart rate represents an attractive therapeutic approach for coronary artery disease. The screening of original benzocycloalkane compounds, at Servier Research Institute, has led to the selection of ivabradine for clinical development. Preclinical data showed that ivabradine inhibits the I(f) current of the sinus node, induces a selective reduction in heart rate, both at rest and during exercise, preserves myocardial contractility, atrio-ventricular conduction and ventricular repolarization. Ivabradine prevents exercise-induced myocardial ischemia as effectively as a beta-blocker while offering better protection of regional myocardial contractility. These data have been confirmed in humans, and in particular, the anti-ischemic efficacy of ivabradine, at least as effective as a beta-blocker, in patients with stable angina. Large ongoing clinical trials aim to assess the therapeutic value of ivabradine to improve the prognosis of patients with stable coronary disease and left ventricular systolic dysfunction by reducing mortality and the occurrence of major cardiovascular events.

Acute electrophysiologic effects of inhaled salbutamol in humans.

STUDY OBJECTIVES: Although inhaled beta2-agonists are in widespread use, several reports question their potential arrhythmogenic effects. The purpose of this study was to evaluate the cardiac electrophysiologic effects of a single, regular dose of an inhaled beta2-agonist in humans. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Six patients with bronchial asthma and 12 patients with mild COPD. INTERVENTIONS: All patients underwent an electrophysiologic study before and after the administration of salbutamol solution (5 mg in a single dose). MEASUREMENTS AND RESULTS: Sinus cycle length, sinus node recovery time (SNRT), interval from the earliest reproducible rapid deflection of the atrial electrogram in the His bundle recording to the onset of the His deflection (AH), interval from the His deflection to the onset of ventricular depolarization (HV), Wenckebach cycle length (WCL), atrial effective refractory period (AERP), and ventricular effective refractory period (VERP) were evaluated just before and 30 min after the scheduled intervention. Salbutamol, a selective beta2-agonist, administered by nebulizer had significant electrophysiologic effects on the atrium, nodes, and ventricle. The AH length decreased from 86.1 +/- 19.5 ms at baseline to 78.8 +/- 18.4 ms (p < 0.001), and the WCL decreased from 354.4 +/- 44.2 to 336.6 +/- 41.7 ms (p = 0.001). Salbutamol significantly decreased the AERP and VERP too while leaving the HV unchanged. Additionally, inhaled salbutamol increased heart rate (from 75.5 +/- 12.8 beats/min at baseline to 93.1 +/- 16 beats/min, p < 0.001) and shortened the SNRT (from 1,073.5 +/- 178.7 to 925.2 +/- 204.9 ms, p = 0.001). CONCLUSION: Inhaled salbutamol results in significant changes of cardiac electrophysiologic properties. Salbutamol enhances atrioventricular (AV) nodal conduction and decreases AV nodal, atrial, and ventricular refractoriness in addition to its positive chronotropic effects. These alterations could contribute to the generation of spontaneous arrhythmias.

A randomized controlled trial of magnesium sulfate, in addition to usual care, for rate control in atrial fibrillation.

STUDY OBJECTIVES: We examine the safety and efficacy of magnesium sulfate infusion, in addition to usual care, for acute rate reduction in patients with atrial fibrillation and a rapid ventricular response rate. METHODS: This was a prospective, randomized, double-blind, placebo-controlled trial of intravenous magnesium sulfate in adult emergency department patients with rapid atrial fibrillation. Study solutions were given in addition to any therapy the treating physician would normally consider appropriate, including the use of standard rate-reduction agents. Patients received either 20 mEq (2.5 g, 10 mmol) magnesium sulfate over a 20-minute period, followed by 20 mEq (2.5 g, 10 mmol) over a 2-hour period intravenously, or placebo. RESULTS: One hundred ninety-nine patients were randomized, 102 to receive magnesium sulfate and 97 to receive placebo. The antiarrhythmic drug most commonly used by treating physicians was digoxin. Magnesium sulfate was more likely than placebo to achieve a pulse rate of less than 100 beats/min (63 [65%] of 97 versus 32 [34%] of 93, relative risk [RR] 1.89; 95% confidence interval [CI] 1.38 to 2.59; P <.0001) and more likely to convert to sinus rhythm (25 [27%] of 94 patients versus 11 [12%] of 91 patients; RR 2.20; 95% CI 1.15 to 4.21; P =.01). Comparative mean pulse rate reductions in the magnesium sulfate group did not reach predetermined clinical significance levels (> or =15 beats/min reduction) at any of the measured time points. Magnesium sulfate was more likely to be associated with an adverse event (14 [15%] of 95 patients versus 5 [5%] of 92 patients; RR 2.71; 95% CI 1.02 to 7.23; P =.04). CONCLUSION: Magnesium sulfate, when used to supplement other standard rate-reduction therapies, enhances rate reduction and conversion to sinus rhythm in patients with rapid atrial fibrillation.

Site of origin and molecular substrate of atrioventricular junctional rhythm in the rabbit heart.

During failure of the sinoatrial node, the heart can be driven by an atrioventricular (AV) junctional pacemaker. The position of the leading pacemaker site during AV junctional rhythm is debated. In this study, we present evidence from high-resolution fluorescent imaging of electrical activity in rabbit isolated atrioventricular node (AVN) preparations that, in the majority of cases (11 out of 14), the AV junctional rhythm originates in the region extending from the AVN toward the coronary sinus along the tricuspid valve (posterior nodal extension, PNE). Histological and immunohistochemical investigation showed that the PNE has the same morphology and unique pattern of expression of neurofilament160 (NF160) and connexins (Cx40, Cx43, and Cx45) as the AVN itself. Block of the pacemaker current, If, by 2 mmol/L Cs+ increased the AV junctional rhythm cycle length from 611+/-84 to 949+/-120 ms (mean+/-SD, n=6, P<0.001). Immunohistochemical investigation showed that the principal If channel protein, HCN4, is abundant in the PNE. As well as the AV junctional rhythm, the PNE described in this study may also be involved in the slow pathway of conduction into the AVN as well as AVN reentry, and the predominant lack of expression of Cx43 as well as the presence of Cx45 in the PNE shown could help explain its slow conduction.

In vivo canine cardiac electrophysiologic profile of 1,4-benzodiazepine IKs blockers.

Previous cardiac electrophysiologic studies of blockers of the slowly activating delayed rectifier (IKs) current have focused primarily on ventricular repolarization. This report summarizes an extensive in vivo cardiac electrophysiologic profile of four 1,4-benzodiazepine IKs blocker analogues (L-761334, L-763540, L-761710, and L-768673) in dogs. At 3.0 mg/kg intravenously, all four analogues elicited 14.5%-21.4% increases in ventricular refractoriness and 19.2%-22.6% increases in QTc interval. Concomitant 11.1%-13.5% increases in atrial refractoriness were noted with all four analogues. Decreases in sinus heart rate of 8.4%-17.3% were noted with all four compounds. No effects on atrial, His Purkinje, ventricular conduction or atrial and ventricular excitation were observed. One analogue, L-761710, significantly delayed atrioventricular (AV) nodal conduction (40.7+/-17.4% increase in atrial-to-His interval) and increased the AV conduction system functional refractory period 19.9+/-6.2%. The lack of effect of the other three 1,4-benzodiazepine IKs blockers on AV nodal function at dosages producing comparable effects on atrial and ventricular refractoriness suggest that the AV nodal effects of L-761710 were unrelated to IKs blockade. These findings indicate IKs plays important roles in both atrial and ventricular refractoriness as well as pacemaker function in the dog heart, suggesting potential utility for IKs blockers in the treatment of atrial and ventricular arrhythmias.

Effects of continuous enhanced vagal tone on dual atrioventricular node and accessory pathways.

BACKGROUND: The aim of this study was to test the electrophysiological effects of continuous enhanced vagal tone on dual atrioventricular (AV) nodal and accessory pathways. METHODS AND RESULTS: This study included 10 patients with typical, slow-fast AV nodal reentrant tachycardia (AVNRT) and 10 patients with AV reciprocating tachycardia. Electrophysiological data were measured before and during continuous vagal enhancement by using phenylephrine infusion (0.6 to 1.5 microg/kg per min). For patients with AVNRT, during phenylephrine infusion, 1:1 conduction times over the anterograde fast and slow and retrograde fast pathways were prolonged (453+/-64 to 662+/-120 ms, P<0.001; 379+/-53 to 443+/-95 ms, P<0.05; 405+/-112 to 442+/-118 ms, P<0.05). The effective refractory period and functional refractory period of the anterograde fast pathway were prolonged with phenylephrine (394+/-73 to 544+/-128 ms, P<0.001; 454+/-60 to 596+/-118 ms, P<0.001). In contrast, the effective refractory period and functional refractory period of the anterograde slow and retrograde fast were not significantly changed. No significant change was observed in the conduction or refractoriness of the accessory pathways in patients with AV reciprocating tachycardia nor in atrial or ventricular refractoriness. CONCLUSIONS: Enhanced vagal tone produces disparate effects on the refractoriness of the slow and fast AV nodal conduction pathways, with the anterograde fast pathway being the most sensitive. These changes are conducive to induction of AVNRT with a premature atrial complex and may explain in part the relatively common occurrence of AVNRT during sleep or other periods of presumed increased parasympathetic tone.

Identification and characterization of atrioventricular parasympathetic innervation in humans.

INTRODUCTION: We hypothesized that in humans there is an epicardial fat pad from which parasympathetic ganglia supply the AV node. We also hypothesized that the parasympathetic nerves innervating the AV node also innervate the right atrium, and the greatest density of innervation is near the AV nodal fat pad. METHODS AND RESULTS: An epicardial fat pad near the junction of the left atrium and right inferior pulmonary vein was identified during cardiac surgery in seven patients. A ring electrode was used to stimulate this fat pad intraoperatively during sinus rhythm to produce transient complete heart block. Subsequently, temporary epicardial wire electrodes were sutured in pairs on this epicardial fat pad, the high right atrium, and the right ventricle by direct visualization during coronary artery bypass surgery in seven patients. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness at each catheter site was determined in the presence and absence of parasympathetic nerve stimulation (via the epicardial wires). In all seven patients, an AV nodal fat pad was identified. Fat pad stimulation during and after surgery caused complete heart block but no change in sinus rate. Fat pad stimulation decreased the right atrial effective refractory period at 1 cm (280 +/- 42 msec to 242 +/- 39 msec) and 2 cm (235 +/- 21 msec to 201 +/- 11 msec) from the fat pad (P = 0.04, compared with baseline). No significant change in atrial refractoriness occurred at distances >2 cm. The response to stimulation decreased as the distance from the fat pad increased. CONCLUSION: For the first time in humans, an epicardial fat pad was identified from which parasympathetic nerve fibers selectively innervate the AV node but not the sinoatrial node. Nerves in this fat pad also innervate the surrounding right atrium.