Nodal Functional Refractory Period Research Articles

Arrhythmia and sudden death associated with elevated cardiac chloride channel activity

The identification and analysis of several cationic ion channels and their associated genes have greatly improved our understanding of the molecular and cellular mechanisms of cardiac arrhythmia. Our objective in this study was to examine the involvement of anionic ion channels in cardiac arrhythmia. We used a transgenic mouse model to overexpress the human cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cAMP-regulated chloride channel. We used RNase protection and in situ hybridization assays to determine the level of CFTR expression, and radiotelemetry and in vivo electrophysiological study in combination with pharmacological intervention to analyse the cardiac function. Cardiac CFTR overexpression leads to stress-related sudden death in this model. In vivo intracardiac electrophysiological studies performed in anaesthetized mice showed no significant differences in baseline conduction parameters including atrial-His bundle (AH) or His bundle-ventricular (HV) conduction intervals, atrioventricular (AV) Wenckebach or 2:1 AV block cycle length and AV nodal functional refractory period. However, following isoproterenol administration, there was marked slowing of conduction parameters, including high-grade AV block in transgenic mice, with non-sustained ventricular tachycardia easily inducible using programmed stimulation or burst pacing. Our sudden death mouse model can be a valuable tool for investigation of the role of chloride channels in arrhythmogenesis and, potentially, for future evaluation of novel anti-arrhythmic therapeutic strategies and pharmacological agents.

The assessment of autonomic function in chronic atrial fibrillation: description of a non-invasive technique based on circadian rhythm of atrioventricular nodal functional refractory periods

Heart rate variability (HRV) parameters can be used to assess autonomic function and to predict outcome, but this has been done exclusively in patients with sinus rhythm. Atrial fibrillation (AF) is the commonest sustained arrhythmia and is particularly prevalent in heart failure. We have developed a simple index to assess autonomic function in patients with chronic AF. Forty patients with chronic AF (>1 month) and symptoms of heart failure underwent ambulatory 24 h electrocardiography recording as well as evaluation of symptoms, exercise capacity (6 min walk distance), ventricular function (echocardiography and radionuclide ventriculography), and neuroendocrine activation. A number of standard HRV parameters shown to have prognostic significance in sinus rhythm were also determined. A modified in-house HRV statistical programme was used to filter labelled QRS intervals and to compute the 5th percentile RR interval in each hour. This parameter has been shown to approximate the functional refractory period (FRP) of the atrioventricular node (AVN). A cosine curve was fitted to hourly 5th percentile RR intervals for each patient and from this was estimated the diurnal change in hourly 5th percentile RR interval (approximating DeltaFRP of the AVN) and, by inference, diurnal variation in sympathovagal input to the AVN. Digoxin was the sole agent permitted for control of ventricular rate. DeltaFRP of the AVN varied and revealed a significant correlation, on multivariate analysis, with mean RR interval (P<0.001), SDARR (SD of 5-min average RR intervals during 24 h, P<0.001), and NYHA class of heart failure (classes III and IV heart failure vs. classes I and II, P=0.02). SDARR has previously been shown independently to predict mortality in patients with chronic AF and heart failure. This analysis describes a novel non-invasive method for assessing autonomic function in chronic AF. Whether DeltaFRP in chronic AF patients can independently predict adverse prognosis or sudden death requires further study.

Concealed conduction in nodal dual pathways: Depressed conduction, prolonged refractoriness, or reset excitability cycle?

Concealed conduction is recognized as a major determinant of atrioventricular (AV) nodal filtering properties, but little is known about the underlying mechanisms. The purpose of this study was to consistently elicit concealed conduction through the AV node and to determine the involvement of slow and fast pathways in resultant changes in nodal function. The concealment zone (nodal effective refractory period minus nodal functional refractory period of atrium) was determined in six rabbit heart preparations with and without a conditioning cycle (10 ms longer than nodal effective refractory period). Nodal function curves were constructed for concealed cycle lengths selected within the concealment zone. Experiments were repeated after slow pathway ablation. When assessed with a blocked beat alone, a narrow concealment zone (22 +/- 12 ms, n = 3) was observed in 50% of the preparations. In contrast, when assessed with a blocked beat preceded by a conducted conditioning beat, a wider concealment zone (77 +/- 47 ms, n = 6, P <.03) was observed in all preparations. Increases in the concealed cycle length resulted in graded increases in the nodal effective refractory period and nodal functional refractory period and graded rightward shifts of the recovery curve as a whole, consistent with resetting of the excitability cycle in the slow and fast pathways. These effects were analogous to those expected from a conducted beat. Slow pathway ablation widened the concealment zone but failed to alter fast pathway resetting. Our approach reveals a wide concealment zone consistently displayed in all preparations. Concealed conduction acts as a resetting mechanism of the excitability cycle in the slow and fast pathways similar to that expected from a conducted beat.

Properties and substrate of slow pathway exposed with a compact node targeted fast pathway ablation in rabbit atrioventricular node.

The properties and substrates of slow and fast AV nodal pathway remain unclear. This applies particularly to the slow pathway (SP), which is largely concealed by fast pathway (FP) conduction. We designed a new FP ablation approach that exposes the SP over the entire cycle length range and allows for its independent characterization and ablation. Premature stimulation was performed before and after FP ablation with 5.4 +/- 1.9 lesions (300-microm diameter each; overall lesion size 1.4 +/- 0.5 mm) targeting the junction between perinodal and compact node tissues in seven rabbit heart preparations. The resulting SP recovery curve and control curve had the same maximum nodal conduction time (165 +/- 22 msec vs 164 +/- 24 msec; P = NS) and effective refractory period (101 +/- 10 msec vs 100 +/- 9 msec; P = NS). The two curves covered the same cycle length range. However, the SP curve was shifted up with respect to control one at intermediate and long cycle lengths and thus showed a longer minimum nodal conduction time (81 +/- 15 msec vs 66 +/- 10 msec; P < 0.01) and functional refractory period (180 +/- 11 msec vs 170 +/- 12 msec; P < 0.05). The SP curve was continuous and closely fitted by a single exponential function. Small local lesions (2 +/- 1) applied to the posterior nodal extension resulted in third-degree nodal block in all preparations. The posterior nodal extension can sustain effective atrial-His conduction at all cycle lengths and account for both the manifest and concealed portion of SP. Slow and FP conduction primarily arise from the posterior extension and compact node, respectively.

Connexin40-deficient mice exhibit atrioventricular nodal and infra-Hisian conduction abnormalities.

Previous electrophysiologic investigations have described AV conduction disturbances in connexin40 (Cx40)-deficient mice. Because expression of Cx40 occurs predominantly in the atria and His-Purkinje system of the mouse heart, the AV conduction disturbances were thought to be secondary to disruption in His-Purkinje function. However, the lack of a His-bundle electrogram recording in the mouse has limited further investigation of the importance of Cx40. Using a novel technique to record His-bundle recordings in Cx40-deficient mice, we define the physiologic importance of deficiencies in Cx40. Ten Cx40-/- mice and 11 Cx40+/+ controls underwent a blinded, in vivo, closed chest electrophysiology study at 9 to 12 weeks of age. In the Cx40-/- mice, the PR interval was significantly longer compared with Cx40+/+ mice (44.6+/-6.4 msec vs 36.0+/-4.1 msec, P = 0.002). Not only the HV interval (14.0+/-3.0 msec vs 10.4+/-1.2 msec, P = 0.003) but also the AH interval (33.2+/-4.8 msec vs 27.1+/-3.7 msec, P = 0.006), AV Wenckebach cycle lengths, and AV nodal effective and functional refractory periods were prolonged in Cx40-/- compared with Cx40+/+ mice. Cx40-deficient mice exhibit significant delay not only in infra-Hisian conduction, as would be expected from the expression of Cx40 in the His-Purkinje system but also in the electrophysiologic parameters that reflect AV nodal conduction. Our data suggest a significant role of Cx40 in atrionodal conduction and/or in proximal His-bundle conduction.

Electrophysiological effects of Org 7797 in the closed‐chest anaesthetized dog

1. The intravenous electrophysiological effects of a new antifibrillatory agent, Org 7797, were studied in closed chest anaesthetized dogs. Effects of fast sodium and slow calcium-mediated action potentials were also examined in guinea-pig isolated papillary muscle. 2. The major effects of a known antifibrillatory dose of Org 7797 (0.5 mg kg-1) were a protracted slowing of AV nodal conduction (for at least 20 min) and prolongation of the AV nodal functional refractory period. Conduction in the atria and His-Purkinje system (reflected by the St-A and HV intervals) were not significantly modified whilst ventricular conduction (reflected by the QRS interval) and the ventricular functional refractory period were only transiently prolonged. No other electrophysiological changes were seen. 3. A higher dose of Org 7797 (1.5 mg kg-1) slowed conduction at all levels of the myocardium (as evidenced by increases in the St-A, AH, HV and QRS intervals), slightly shortened cardiac repolarization (as assessed from JTc) and decreased Wenckebach rate. Atrial refractory periods were increased whereas effects on ventricular refractory periods were modest. 4. Neither heart rate nor sinus node recovery time were modified by either dose of Org 7797. 5. Org 7797, at a concentration (20 microM) which reduced Vmax of fast sodium-mediated action potentials in isolated papillary muscle by 83%, did not modify Vmax of slow calcium-mediated action potentials. It prolonged duration of the latter but did not modify that of the former. However, the plateau phase of both the 'fast' and especially the 'slow' action potentials was prolonged. 6. It is concluded that the main electrophysiological effects of a known antifibrillatory dose of Org 7797 in dogs with normal cardiac function are seen at the level of the AV node, actions which are unlikely to be explained by calcium channel block. Higher doses display a class Ic profile. This preferential action on the AV node may contribute to the control of ventricular rate during atrial fibrillation in the absence of infra-nodal conduction disturbances.7. These results contrast with those previously obtained in infarcted dogs and might further suggest that myocardial infarction enhances the Class I action of Org 7797.

Radiofrequency versus pharmacologic modification of the atrioventricular node

Although transcatheter radiofrequency modification of the atrioventricular (AV) node has been proposed as curative treatment in AV nodal reentry tachycardias, its role for the control of the ventricular rate in atrial tachyarrhythmias remains unclear. The aim of this study was to analyze the acute effect of radiofrequency current on AV nodal conduction and refractoriness, and to compare it with the effects of two antiarrhythmic drugs such as amiodarone (class III) and flecainide (class I). Twenty-one dogs were studied: (1) radiofrequency group (5 W for less than 45 seconds; 2 to 12 discharges: seven dogs); (2) amiodarone group (5 mg/kg intravenously; seven dogs); and (3) flecainide group (2 mg/kg intravenously; seven dogs). The following parameters were measured under basal conditions and after each procedure: AH interval, AV nodal functional refractory period, Wenckebach cycle length, minimum R-R interval during atrial fibrillation, and fitting of AV nodal function curve to a hyperbolic equation using its linear transformation. The AV nodal effective refractory period could not be calculated in any dog in the basal study because it was shorter than the atrial functional refractory period. After radiofrequency, the percentage increment was greater for the AH interval than for the AV nodal functional refractory period (60 ± 28% versus 29 ± 16%, p ≤ 0.05); the percentage increment in the AH interval did not correlate with that of any other interval, whereas the percentage increment of the AV nodal functional refractory period correlated with that of the Wenckebach cycle length ( r = 0.83, p ≤ 0.05) and minimum R-R interval during atrial fibrillation ( r = 0.78, p ≤ 0.05). Neither after amiodarone (62 ± 16% versus 50 ± 21%, p = NS) nor after flecainide (18 ± 7% versus 12 ± 6%, p = NS) were there significant differences between the percentage incremento in the AH interval and AV nodal functional refractory period; furthermore, unlike radiofrequency, the percentage increment in the AH interval correlated with that of the AV nodal functional refractory period after amiodarone ( r = 0.87, p ≤ 0.01) and flecainide ( r = 0.86, p ≤ 0.01). The AV nodal function curve was displaced upwards and to the right with each procedure; the ordinate axis intercept of the straight line of the hyperbolic equation significantly decreased only with amiodarone. It was concluded that: (1) Radiofrequency current, unlike antiarrhythmic drugs, induces a dissociation between conduction and refractoriness, with a predominant modification of the former. (2) The prolongation of the parameters valuable in controlling ventricular rate in atrial tachyarrhythmias (Wenckeback cycle length and minimum R-R interval during atrial fibrillation) depends on the modification of AV nodal refractoriness and not on the increase in the AH interval. (3) The prolongation of the AH interval can be a misleading end point during the ablation procedures.

Dissociation of atrioventricular conduction and refractoriness following application of radiofrequency energy to the canine atrioventricular node: acute and chronic observations.

The electrophysiology of AV nodal modification induced by radiofrequency energy (n = 5) or a sham procedure (n = 5) was studied in ten dogs. The five dogs that received radiofrequency energy had an AH prolongation > 100% from baseline values and this prolongation persisted throughout the 2-month study. The AV nodal functional refractory period was prolonged only acutely. These data indicate a dissociation between the effects on AV nodal conduction and refractoriness that was induced by this procedure. The five sham treated controls showed no acute or chronic electrophysiological changes. In the dogs that received radiofrequency energy, there was fibrosis of the approaches to the AV node and the region of the AV node itself. It is concluded that chronic modification of AV nodal conduction without concomitant changes in refractoriness can be induced by radiofrequency energy delivered in the proximal portion of the AV node. It would be anticipated that this procedure would not decrease the ventricular response to atrial fibrillation or flutter, may be effective in preventing AV nodal reentrant tachycardia by interfering with conduction either in the AV node or perinodal region. Since the AV node itself suffers at least moderate pathological damage, there may be an appreciable incidence of the late development of complete heart block after this procedure.

Determinants of Acute Hemodynamic and Electrophysiologic Effects of Verapamil in Humans: Role of Myocardial Drug Uptake

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.

Efficacy, safety, and tolerance of d-sotalol in patients with refractory supraventricular tachyarrhythmias

The efficacy, safety, and electrophysiologic effects of intravenous and oral d-sotalol, an investigational class III antiarrhythmic agent, are not yet well characterized. We evaluated the electrophysiologic, antiarrhythmic, and hemodynamic effects of d-sotalol infusion (1.5 to 2.75 mg/kg) and of chronic oral therapy (200 to 400 mg bid) in 10 patients with chronic, paroxysmal supraventricular tachyarrhythmias refractory to 5 ± 2 standard agents. Four patients had paroxysmal supraventricular tachycardia (PSVT), four had paroxysmal atrial fibrillation, two had atrial flutter, and one had nonparoxysmal reciprocating junctional tachycardia (NPRJT). PSVT was inducible or spontaneously present in 4 of 4 before d-sotalol. After intravenous d-sotalol PSVT was noninducible in three patients and slowed by 40% in one. Atrial fibrillation was inducible or spontaneously present in 4 of 4 before therapy. After intravenous d-sotalol, one became noninducible, and three achieved rate-slowing (the mean falling from 69 to 61 bpm). In one patient, atrial flutter became noninducible; in another, d-sotalol slowed the rate of atrial flutter by 28%. D-sotalol restored sinus rhythm in the patient with NPRJT. Intravenous d-sotalol increased the sinus cycle length; the QTc, PR, and AH intervals; and the AV nodal functional refractory period, the AV nodal effective refractory period; and the right ventricular effective refractory period significantly. The atrial effective refractory period, sinoatrial conduction time, and corrected sinus recovery time tended to increase, but did not reach statistical significance. The QRS, PA, and HV intervals did not change. Mean BP fell 13.4 ± 9.2% after intravenous d-sotalol, but no adverse symptoms developed. Oral d-sotalol caused hypotension (predrug 120/80, post-sotalol 80/60) and had to be discontinued in one patient. Sustained benefit during chronic therapy was noted in 9 of 10 patients (mean followup, 7.4 ± 5.1 months), with no adverse effects other than mild light intolerance in one patient and fatigue (which responded to dose reduction) in another. The electrocardiogram and electrophysiologic parameters measured an oral d-sotalol were not different than those produced by intravenous d-sotalol. Thus, d-sotalol is usually effective and well-tolerated in patients with refractory PSVT. Also, intravenous testing appears predictive of chronic oral efficacy.

Atrioventricular Nodal Conduction and Refractoriness Following Abrupt Changes in Cycle Length

The properties of the atrioventricular (AV) nodal conduction and effective refractory period in man are generally evaluated at a constant basic cycle length (CL) and, in most cases, they demonstrate an inverse relationship to the drive cycle. The response of AV node to abrupt change in CL is less defined. We therefore studied the effects of abrupt changes in CL on AV nodal conduction time and refractoriness in 18 patients. AV nodal conduction time, and effective and functional refractory periods were measured during: (1) a constant long CL, (2) a constant short CL, and (3) after an abrupt increase in CL just prior to the introduction of extrastimuli. In 10 of the 18 patients a constant long CL of 600 ms, a constant short CL of 400 ms and a sudden short-to-long change in CL (400 to 600 ms) were tested. AV nodal conduction times (A2H2) were measured at the shortest and longest comparable A1A2 intervals. The mean value of the shortest A2H2 intervals for constant CL of 600 ms was 144 +/- 18 ms; for a constant CL of 400 ms it was 162 +/- 17 ms; after a sudden short-to-long change in CL (400 to 600 ms) it was 142 +/- 14 ms. The mean value of the longest A2H2 intervals at a constant CL of 600 ms was 185 +/- 18 ms; at a constant CL of 400 ms it was 236 +/- 26 ms (p less than 0.01) and after a short-to-long change in CL (400 to 600 ms) 199 +/- 21 ms. AV nodal effective refractory periods measured at the same three CLs had mean values of 279 +/- 13 ms; 300 +/- 15 ms and 294 +/- 13 ms, respectively. Similar results were obtained when other CLs such as 700 to 900, 500 to 900, and 400 to 700 ms were tested. The data suggest that after abrupt short-to-long changes in CL, AV nodal function curves shift from long constant CL toward short constant CL as the coupling intervals decrease, indicating a cumulative pattern. Although the return to baseline conduction time after the fast basic rate is known to be slow, the limitation of this effect to the very early premature beat in the human has not been reported previously.

Electrophysiologic properties of intravenous isradipine in persons with normal sinus node and atrioventricular nodal function

Isradipine (PN 200-110) is a new dihydropyridine calcium entry blocker with powerful vasodilating properties. Plasma concentrations obtained after commonly used dosage do not decrease myocardial contractility. However, in vitro studies have demonstrated negative chronotropic action with only minor dromotropic influence. Therefore, the electrophysiologic properties of intravenous isradipine 0.3 μg/kg for 30 minutes in persons with normal sinus and atrioventricular nodal function were investigated. There were no unwanted side effects. Mean blood pressure decreased slightly, but not significantly (107 ± 19 to 100 ± 9 mm Hg). Sinus cycle length decreased from 798 ± 176 to 730 ± 163 msec (p <0.01). The atrioventricular nodal functional refractory period decreased from 418 ± 40 to 399 ± 47 (p <0.05) and the atrial His interval decreased from 95 ± 20 to 91 ± 20 (p <0.01). The His ventricle interval, corrected sinus node recovery time, Wenckebach cycle length, and QRS duration remained unchanged. The QT c was prolonged from 417 ± 39 to 427 ± 40 (p <0.01). It was concluded that isradipine has no depressant effect on normal sinus and atrioventricular node function in humans and is well tolerated. The electrophysiologic effects seem to be the results of enhanced sympathetic tone provoked by peripheral vasodilatation.

Comparative quantitative electrophysiologic effects of adenosine triphosphate on the sinus node and atrioventricular node

A pharmacologic approach was used to characterize the sinus node (SN) and atrioventricular (AV) node responses to intravenous adenosine triphosphate (ATP) in 21 patients during electrophysiologic testing. ATP produced dose-dependent prolongation of spontaneous sinus cycle length. The mean maximal increase in sinus cycle length was 294 ± 60 ms (n = 10). The mean dose of ATP required to produce this maximal sinus cycle length prolongation was 3.5 ± 1.0 mg. The dose-response curve for sinus cycle length prolongation was sigmoid in shape with an EC 50 of 0.39 mg derived from a median effect plot. There was a negative correlation between the control sinus cycle length and the dose of ATP required to produce the maximal prolongation of cycle length (p < 0.05). In contrast, the mean dose of ATP producing AV block was 4.4 ±0.97 mg and the EC 50 was 2.98 mg. There was a positive correlation between the AV nodal functional refractory period and the prolongation of the AH interval with a 2 mg dose (p < 0.05). Consistent with the AV nodal dose-response curves, 8 mg ATP terminated paroxysmal reentrant supraventricular tachycardia at the AV node in 8 of 9 patients. Thus, SN and AV node responses to ATP have differences in their electrophysiologic correlates and EC 50. These findings suggest that ATP has potentially different mechanisms of action on SN automaticity and AV nodal conduction that requires further investigation.

Electrophysiologic effects of intravenous magnesium in patients with normal conduction systems and no clinical evidence of significant cardiac disease

Parenteral magnesium has been used for several decades in the empiric treatment of various arrhythmias, but the data on its electrophysiologic effects in man are limited. We evaluated the electrophysiologic effects of magnesium sulfate (MgSO 4) administration in eight normomagnesemic patients with normal mononuclear cell magnesium content, who had no clinically significant heart disease and had normal baseline electrophysiologic properties. After administration of intravenous MgSO 4, serum magnesium rose significantly from 1.9 ± 0.1 to 4.4 ± 1.7 mg/dl ( p < 0.02). During a maintenance magnesium infusion, we observed significant prolongation of the ECG PR interval (145 ± 18 to 155 ± 26 msec, p < 0.05), AH interval (77 ± 27 to 83 ± 26 msec, p < 0.002), antegrade atrioventricular (AV) nodal effective refractory period (278 ± 67 to 293 ± 67 msec, p < 0.05), and sinoatrial conduction time (60 ± 34 to 76 ± 32 msec, p < 0.02). No significant effect was observed on sinus cycle length, sinus node recovery time, intra-atrial or intraventricular conduction times, QRS duration (during both sinus rhythm and ventricular pacing), QT interval, HV interval, paced cycle length resulting in AV nodal Wenckebach block, AV nodal functional refractory period, retrograde ventriculoatrial (VA) effective refractory period, or atrial and ventricular refractory periods. These findings, in conjunction with the demonstrated ability of magnesium to block slow channels for sodium movement, may provide an explanation of the mechanism by which magnesium exerts its effect in the treatment of atrial and junctional arrhythmias.

Atrioventricular nodal function in the immature canine heart [corrected and republished article orginally printed in Pediatr Res 1987 Nov;22(5):616-20

Previous studies have suggested that the atrioventricular nodal functional refractory period in the neonate is equal to or shorter than that of the ventricle, providing little or no protection to the ventricle against rapid atrial rates and allowing closely coupled atrial beats to fall within the ventricular vulnerable period. We evaluated atrioventricular node function in 21 mongrel neonatal puppies, 3-15 days old, and 15 adult dogs utilizing intracardiac His bundle recording and stimulation techniques. The mean atrioventricular nodal functional refractory period (173.1 +/- 20.0 ms) exceeded both the ventricular effective refractory period (139.5 +/- 14.3) and ventricular functional refractory period (163.3 +/- 14.5) in the neonates. Furthermore, the atrioventricular node was the site of limiting antegrade conduction in all neonates. No ventricular arrhythmias were induced by atrial extrastimulation in any of the neonates. The site of conduction delay during atrial extrastimulation was confined to the atrioventricular node in 15/16 neonates (94%) while 1/16 (6%) had combined nodal and infranodal delay. The neonates developed Wenckebach, at significantly faster heart rates than the adults, but both groups developed Wenckebach at approximately twice the resting heart rate. Retrograde conduction was a consistent finding in the neonates. However, antegrade Wenckebach occurred at a significantly faster heart rate than retrograde Wenckebach suggesting different functional properties. Our data suggest that in the neonatal canine, the atrioventricular node functional refractory period is longer than both the ventricular effective refractory period and ventricular functional refractory period. Furthermore, the degree of protection offered by the neonatal atrioventricular node to the ventricle appears to be comparable to that of the adult.

Atriovenous Nodal Function in the Immature Canine Heart

ABSTRACT. Previous studies have suggested that the atriovenous nodal functional refractory period in the neonate is equal to or shorter than that of the ventricle, providing little or no protection to the ventricle against rapid atrial rates and allowing closely coupled atrial beats to fall within the ventricular vulnerable period. We evaluated atriovenous node function in 21 mongrel neonatal puppies, 3-15 days old, and 15 adult dogs utilizing intracardiac His bundle recording and stimulation techniques. The mean atriovenous nodal functional refractory period (173.1 ± 20.0 ms) exceeded both the ventricular effective refractory period (139.5 ± 14.3) and ventricular functional refractory period (163.3 ± 14.5) in the neonates. Furthermore, the atriovenous node was the site of limiting antegrade conduction in all neonates. No ventricular arrhythmias were induced by atrial extrastimulation in any of the neonates. The site of conduction delay during atrial extrastimulation was confined to the atriovenous node in 15/16 neonates (94%) while 1/16 (6%) had combined nodal and infranodal delay. The neonates developed Wenckebach, at significantly faster heart rates than the adults, but both groups developed Wenckebach at approximately twice the resting heart rate. Retrograde conduction was a consistent finding in the neonates. However, antegrade Wenckebach occurred at a significantly faster heart rate than retrograde Wenckebach suggesting different functional properties. Our data suggest that in the neonatal canine, the atriovenous node functional refractory period is longer than both the ventricular effective refractory period and ventricular functional refractory period. Furthermore, the degree of protection offered by the neonatal atriovenous node to the ventricle appears to be comparable to that of the adult.

Acute electrophysiologic effects of pirmenol in normal subjects and in patients with Wolff-Parkinson-White syndrome

The acute electrophysiologic effects of pirmenol are reported in 8 normal subjects and in 8 patients with Wolff-Parkinson-White (WPW) syndrome. Standard electrophysiologic testing was performed before and after a 50-mg intravenous bolus and a 60-minute infusion of 150 mg of pirmenol. After pirmenol administration, AH interval, atrial refractory period, atrioventricular (AV) nodal functional refractory period and Wenckebach cycle length did not change; however, sinus cycle length decreased from 743 ±169 to 650 ± 133 ms (p < 0.001), sinoatrial conduction time from 103 ± 35 to 78 ± 37 ms (p < 0.05) and AV nodal effective refractory period from 308 ± 51 to 272 ± 23 ms (p < 0.01). Pirmenol increased the HV interval from 43 ± 5 to 48 ± 6 ms (p < 0.05) and ventricular functional refractory period from 247 ± 21 to 260 ± 21 ms (p < 0.005). Anterograde effective refractory period of the accessory AV pathway increased in 4 of 6 patients with ventricular preexcitation and retrograde effective refractory period increased in all patients. Pirmenol treatment prolonged the shortest preexcited RR interval from 253 ± 38 to 459 ± 19 ms (p < 0.05) and the average RR interval from 354 ± 26 to 421 ± 60 ms (p < 0.01) during atrial fibrillation in all 6 patients with preexcitation. Pirmenol did not influence the inducibility or cycle length of AV reciprocating tachycardia in the patients with WPW syndrome. The pirmenol infusions were well tolerated. Thus, pirmenol therapy has a direct depressant effect and an indirect vagolytic action on electrophysiologic measurements, a clinically beneficial effect in slowing the ventricular response to atrial fibrillation in WPW syndrome and little effect on reciprocating AV tachycardia.

Cardiac electrophysiologic actions of SCH 19927 (dilevalol), the R, R-isomer of labetalol

The cardiac electrophysiologic, hypotensive and antiadrenergic actions of SCH 19927, the R,R-isomer of labetalol, were evaluated in urethane-anesthetized dogs. The cumulative administration of 0.3, 1.0 and 3.0 mg/kg i.v. decreased mean arterial pressure by 18 to 26 mm Hg from a pretreatment value of 106 +/- 6 mm Hg and slightly enhanced atrioventricular nodal conduction. After 3.0 mg/kg of SCH 19927, sinoatrial (SA) conduction times were decreased, whereas intraventricular conduction was depressed slightly. SCH 19927, 10.0 mg/kg, reduced mean arterial pressure by 39 mm Hg and enhanced SA nodal conduction and recovery after overdrive pacing (decreased SA conduction time and corrected sinus node recovery times), whereas intraventricular conduction times and the rate-corrected QTc interval were prolonged. Sinus heart rate, atrial, ventricular and atrioventricular nodal functional and effective refractory periods were unaltered by SCH 19927, 0.3 to 10.0 mg/kg. The administration of SCH 19927 produced significant beta adrenergic receptor blockade, as determined by inhibition of the positive chronotropic and peripheral vasodilatory response to isoproterenol, but did not alter the alpha-1 adrenergic receptor-mediated vasopressor response to phenylephrine. The results indicate that SCH 19927, in beta adrenergic receptor blocking and hypotensive dosages, does not depress SA nodal or atrioventricular nodal function, thus suggesting an electrophysiologic spectrum of activity different from that of other beta adrenergic receptor antagonists.

Electrophysiological Effects of a New Antiarrhythmic Agent, Nicainoprol, in Humans

The electrophysiological effects of nicainoprol, a new antiarrhythmic drug, were evaluated in a heterogeneous group of 23 patients aged 59 +/- 15 (mean +/- standard deviation) years. Nicainoprol was administered intravenously as a bolus of 1-2 mg/kg followed by continuous infusion at two dose levels. Electrophysiologic study was performed before and during the infusion at a steady-state drug level on each dose. The sinus node recovery time was unaltered in patients with normal sinus node function and was markedly prolonged in three of six patients with sinus node dysfunction. The intranodal conduction time (p less than 0.01) and the infranodal conduction time (p less than 0.001) increased, and the QRS duration (p less than 0.05) lengthened significantly even during 1 mg/kg/h. During 2 mg/kg/h, these times were further prolonged and, in addition, the intra-atrial conduction time (p less than 0.05), atrioventricular nodal effective and functional refractory periods (p less than 0.01), as well as the Wenckebach cycle length (p less than 0.001) also increased significantly. Similar depressant effects on the retrograde ventriculoatrial conduction system were also produced by nicainoprol. Retrograde His-atrioventricular nodal conduction was blocked in six of eight patients with this condition and was prolonged in the remaining two. Sustained supraventricular tachycardia was induced in seven patients, five of whom received nicainoprol during the tachycardia. The termination of supraventricular tachycardia was exclusively due to ventriculoatrial block in all five subjects, three with orthodromic circus movement tachycardia and two with atrioventricular nodal reentrant tachycardia of the slow-fast type. The reinducibility of supraventricular tachycardia could be prevented in five of seven patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiologic effects of amrinone

Patients with congestive heart failure (CHF) have a high prevalence of complex ventricular arrhythmias. Accordingly, the electrophysiologic effects of new drugs for the treatment of CHF should be studied to determine whether they are safe in this population of patients. Fifteen patients with New York Heart Association functional classes II to IV CHF underwent hemodynamic and electrophysiologic testing during control conditions, and after 10 to 20 μg/kg/min of intravenous amrinone (dosages that increased cardiac output and decreased left ventricular filling pressures). All cardioactive drugs were stopped for at least 5 half-lives before entry into the study. Amrinone decreased the atrial effective refractory period from 256 to 240 ms (p = 0.015) and the AV nodal functional refractory period from 374 to 356 ms (p <0.05), and enhanced maximal 1:1 AV nodal conduction from 371 to 334 ms (p = 0.006). Prolonged HV intervals were present in 9 of 15 patients and were not affected by amrinone. Holter monitoring was performed in 10 patients during acute oral administration of amrinone. There were no significant changes in the frequency of ventricular extrasystoles or ventricular tachycardia, although the frequency of ventricular couplets tended to increase slightly. Amrinone therefore enhances AV conduction and does not appear to have significant arrhythmogenic potential during acute administration.