Nodal Conduction Time Research Articles

NASPE Young Investigator Awardee-1993. Computer model of the atrioventricular node predicts reentrant arrhythmias.

Following atrial premature beats, the AV node may exhibit sustained reentrant tachyarrhythmias, isolated echo beats, or discontinuities in the recovery curve (the plot of conduction time versus atrial cycle length). A computer model was used to examine the hypothesis that spatial variation of AV nodal passive electrical resistance may account for these phenomena. A computer model of a rectangular lattice of electrotonically linked elements whose ionic kinetics simulated nodal ionic flux was developed. The model showed that there exists a resistance value that minimizes the effective refractory period, because high resistance prevents depolarization of distal elements, while low resistance allows leakage of depolarizing current by electrotonic transmission, preventing activation of proximal elements. High resistances stabilized reentry by slowing conduction. Simulations incorporating equal resistance values between elements predicted increased AV nodal conduction times with increasing prematurity of atrial impulses. A model with a gradual change in resistance between fibers produced discontinuities and tachycardia, but not both simultaneously. Uniform anisotropy produced preferential transverse block, leading to echo beats and "fast-slow" tachycardia, but not recovery curve discontinuities. Nonuniform anisotropy could produce reentry, but tachycardia often occurred without discontinuities. Dividing the lattice into two electrotonically linked parallel pathways with different resistance values ("dual pathway model") predicted recovery curve discontinuities, echo beats, and tachycardia. At critical atrial cycle lengths, only the (high resistance) slow pathway conducted antegradely, while the fast pathway conducted retrogradely, to generate the typical "slow-fast" tachycardia. Responses of the dual pathway model to ablation were consistent with clinical data, including the previous observation of a decrease in fast pathway effective refractory period after slow pathway ablation. Differences in passive electrical resistance of electronically linked dual pathways within the AV node may account for functional longitudinal dissociation, reentrant arrhythmias, and responses to catheter ablation therapy.

Improved beat-to-beat timing measurements of His-bundle signal.

A simplified bioelectric model of the atrioventricular (AV) junction is proposed to better understand the underlying biophysical generation of intracardiac His-bundle signal and to analyze the effects of electrocatheter displacements on waveform morphology and estimation of AV node conduction time (AVCT). Based on this model, an inverse problem approach has been developed to estimate electrode displacements occurring in real recordings. A measurement correction method is proposed to improve estimation of AVCT. Results illustrate autonomic influences on AVCT, a phenomenon hardly measured with common techniques.

Electrophysiologic properties of sotalol and d-sotalol. A current view.

Although discovered more than two decades ago, the clinical applications of sotalol are still a matter of debate. Together with amiodarone, sotalol is considered a prototype of a new class of antiarrhythmic agents characterized by repolarization-prolonging effects (class III). Lengthening of repolarization is associated with an increase in the effective refractory period of cardiac tissues. There is no change in the maximum rate of rise during phase 0, a finding that supports the lack of sotalol effect on the fast sodium channel. The electrophysiologic action of the drug in humans provides evidence for direct cardiac effects of sotalol in addition to beta blockade. The beta-blocking properties play a major role in the sinus-rate slowing and lengthening of the atrioventricular nodal conduction time observed after sotalol administration. However, the drug also prolongs refractoriness in atria, His-Purkinje tissue, ventricular muscle and accessory atrioventricular connections. These latter changes are absent or minimal with conventional beta blockers and are likely to reflect sotalol-induced prolongation of cardiac repolarization. They result in an increase in the QT interval, an effect that is dose-dependent and more marked during chronic therapy. The dextrorotatory isomer, d-sotalol, shares a similar electrophysiologic profile. Lengthening of repolarization in cardiac cells following d-sotalol is of the same magnitude as that produced by the levoisomer. This finding provides further evidence for a class III action of sotalol, as the dextroisomer is almost devoid of beta-blocking properties. In humans, the electrical effects of both drugs are similar. However, d-sotalol-induced changes in sinus rate and atrioventricular nodal conduction are modest.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanism of the negative dromotrophic effect of adenosine 5′‐triphosphate in the guinea pig heart in vivo

AbstractTo test the hypothesis that the vagus nerve does not play a major mechanistic role in the cardiac electrophysiologic action of adenosine 5′‐triphosphate (ATP), the negative dromotropic actions of the nucleotide and adenosine on atrioventricular (AV) nodal conduction were quantitated in an in vivo guinea pig model. Anesthetized animals were divided into three groups. In group 1, ATP and adenosine (0.1–10.0 μmol/kg, iv) were given at random as a rapid bolus during right atrial pacing (paced cycle length 220–270 msec). This protocol was repeated following the administration of atropine (0.2 mg/kg, iv) followed by propranolol (1 mg/kg, iv). In group 2, ATP and adenosine (1.6 μmol/kg, iv) were given in the absence and presence of the selective A1‐adenosine receptor antagonist, N6‐endonorbornan‐2‐yl‐9‐methyladenine (N‐0861, 30 μmol/kg, iv), and in group 3, ATP and adenosine were given as in group 2 but instead of N‐0861, an adenosine transport blocker, dipyridamole (250 μg/kg, iv), was used. Standard lead I and II electrocardiogram, right atrial, right ventricular, and His bundle electrogram as well as systemic arterial blood pressure were continuously monitored and recorded. AV nodal conduction time was quantitated as AH interval. ATP and adenosine were equipotent in suppressing AV nodal conduction. For example, maximal AH interval following the highest dose of ATP and adenosine was 102 ± 10 and 112 ± 7 msec, respectively. These effects were not significantly altered by either muscarinic cholinergic or β‐adrenergic blockade. Furthermore, N‐0861 attenuated and dipyridamole enhanced the effects of ATP and adenosine similarly. It was concluded that the electrophysiologic action of ATP in the guinea pig AV node in vivo is independent of the vagus nerve and mediated by its degradation to adenosine and the action of the latter on A1‐adenosine receptors. © 1993 Wiley‐Liss, Inc.

A stochastic network model of the interaction between cardiac rhythm and artificial pacemaker.

The electrical interaction between the heart and an artificial pacemaker is often complex. Because of the sophistication and diversity of dual-chamber device algorithms, even experienced cardiologists can have difficulty interpreting paced electrocardiograms (ECG's). In order to study heart-pacemaker interaction (HPI), a computer model of the cardiac conduction system has been developed which includes the effects of artificial pacemaker function and failure. The stochastic network model of cardiac conduction consists of five vertices, each representing a functional electrophysiologic element. Electrophysiologic multidimensional conditional probability functions determine the depolarization status of each vertex. The atrioventricular (AV) node is emulated using a mathematical model which includes the influence of past cycle lengths on AV nodal conduction time. Twenty-three classes of arrhythmias may be simulated and, for pacing simulation, one of 12 antibradycardia pacing modes may be chosen. Random effects of pacemaker malfunction including oversensing, undersensing, or failure-to-capture may be simulated through the use of probability distribution functions. This model should prove useful in the development of pacemaker algorithms, determining patient-specific pacemaker therapy, and predicting causes for apparent pacemaker malfunction. The model has been used in the development of an expert system to analyze paced ECG's for pacemaker function and malfunction.

Negative dromotropism of adenosine under beta-adrenergic stimulation with isoproterenol

Adenosine depresses atrioventricular (AV) nodal function by binding to specific A 1 receptors which activate the acetylcholine, adenosine-regulated potassium current. In addition, adenosine can act to antagonize the effects of β-adrenergic stimulation on AV nodal function. To assess the negative dromotropic effects of adenosine under β-adrenergic stimulation, 15 patients were studied during clinical electrophysiologic study. During high right atrial pacing at a cycle length of 400 to 600 ms, adenosine was injected intravenously at an initial dose of 0.5 mg followed by a stepwise increment of 0.5 or 1.0 mg given at 5-minute intervals until a maximal dose of 12 mg was achieved or AV block developed. Intravenous isoproterenol (1 to 3 μg/min) was then infused to accelerate sinus rate by 20 to 30% during which intravenous injection of incremental doses of adenosine as described was repeated. The AV nodal conduction time (AH interval) was measured at each dose of adenosine. Dose-response curves of AV nodal conduction time (expressed as percent increase in AH interval) were studied during the control state and during isoproterenol infusion. The dose of adenosine required to produce AV nodal Wenckebach block, the increase in the AH interval by 50% (ED 50) and the maximal response (E max) were 3.4 ± 0.9 mg, 1.8 ± 0.9 mg and 60 ± 4%, respectively, in the control state, and 3.7 ± 0.8 mg, 2.0 ± 0.7 mg and 56 ± 4%, respectively, during isoproterenol infusion. No significant changes in ED 50, E max and the dose of adenosine yielding AV nodal Wenckebach block could be demonstrated between the control state and during isoproterenol infusion. Thus, the negative dromotropic effects of adenosine on AV nodal conduction remained unchanged with β-adrenergic stimulation. These findings suggest that adenosine may remain efficacious in terminating catecholamine-sensitive supraventricular tachycardia involving the AV node as part of the reentrant circuit.

Beat-to-beat changes in AV nodal refractory and recovery properties during Wenckebach cycles.

The roles of changes in refractory and recovery properties of the atrioventricular node as affected by facilitation and fatigue in the genesis of Wenckebach periodicity were studied in isolated rabbit heart preparations. The contribution of nodal recovery time, facilitation, and fatigue to beat-to-beat changes in nodal conduction time (NCT) and effective (ERPN) and functional refractory periods of node (FRPN) occurring during stable 4:3 Wenckebach cycles was determined with premature stimulation protocols performed during these cycles. Fatigue prolonged, equally for each beat, NCT, ERPN, and FRPN, and therefore did not contribute to Wenckebach periodicity. Beat-to-beat increases in facilitation broadened the range of recovery times for which conduction was successful and decreased NCT, ERPN, and FRPN below the values expected from fatigue alone. However, ERPN and NCT increased overall from beat to beat because of NCT-induced (effects of NCT on ensuing refractoriness) increases in nodal refractoriness and consequent shortenings of the recovery time. These findings establish a complementary role for the recovery and refractory properties in generating the Wenckebach periodicity and demonstrate the modulating roles of facilitation and fatigue on this phenomenon.

Reversal of Electrophysiologic and Hemodynamic Effects Induced by High Dose of Bupivacaine by the Combination of Clonidine and Dobutamine in Anesthetized Dogs

The ability of clonidine and dobutamine to correct bupivacaine-induced cardiac electrophysiologic and hemodynamic impairment was evaluated in an experimental electrophysiologic model on closed-chest dogs. Five groups (n = 6) of pentobarbital-anesthetized dogs were given atropine (0.2 mg/kg IV). Group 1 was given a saline solution; all other dogs were given bupivacaine (4 mg/kg IV) over a 10-s period. Group 2 was given only bupivacaine. Group 3 was given clonidine (0.01 mg/kg IV) over a 1-min period. Group 4 was given a dobutamine infusion at 5 micrograms.kg-1.min-1. Group 5 was given the combination of clonidine and dobutamine. Bupivacaine induced bradycardia, prolonged atrioventricular conduction time (PR interval), atrioventricular node conduction time (AH interval), His-Purkinje conduction time (HV interval), and QRS duration. Bupivacaine decreased left ventricular (LV) dP/dt max and increased LV end-diastolic pressure (LVEDP). Clonidine improved QRS duration and HV interval but enhanced AH interval, bradycardia, and hemodynamic depression induced by bupivacaine. Dobutamine infusion improved LV dP/dt max but did not modify bupivacaine-induced ventricular electrophysiologic impairment. The combination of clonidine and dobutamine corrected not only the electrophysiologic impairment induced by bupivacaine but also the hemodynamic depression. As the HV interval and the QRS duration could be correlated with ventricular conduction velocities, we conclude that (a) clonidine reversed the slowing of ventricular conduction velocities induced by bupivacaine, and (b) the combination of clonidine and dobutamine was able to correct the cardiac disturbances induced by bupivacaine in anesthetized dogs.

Evidence of spare A1-adenosine receptors in guinea pig atrioventricular node.

In normoxic, isolated perfused guinea pig hearts instrumented for measurement of atrioventricular nodal conduction time (AVCT), an analysis utilizing the irreversible A1-adenosine (Ado) antagonist, meta-1,3-phenylene diisothiocyanate xanthine amine cogener (m-DITC-XAC), a novel isothiocyanate derivative of 1,3-dialkylxanthine, was used to investigate whether spare A1-Ado receptors exist in the guinea pig atrioventricular (AV) node and the degree of amplification (reserve) between A1-Ado receptor occupancy and dromotropic response (e.g., AVCT slowing). The potency, dose dependency, and kinetic profile (time dependence of washout and washin) of m-DITC-XAC was determined and compared with those of known competitive (reversible) A1-Ado receptor antagonists. In the presence of m-DITC-XAC, Ado and N6-cyclopentyladenosine (CPA) produced submaximal dromotropic responses. In a series of 19 hearts, m-DITC-XAC caused 100% apparent antagonism of the effect of Ado on AVCT even after 60 min of washout. In contrast, greater than 90% of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and XAC-induced antagonism of the effect of Ado on AVCT dissipated within 35 min. Unlike XAC, which caused maximal attenuation of Ado's AVCT effect within 5 min and remained constant thereafter, m-DITC-XAC showed marked time- and concentration-dependent behavior. It was found that 5 min of 0.5 microM m-DITC-XAC pretreatment irreversibly inactivated 72% of the A1-Ado receptors mediating the dromotropic effect, and the estimated agonist equilibrium dissociation constant for CPA was 84 +/- 4 nM. The percent of spare A1-Ado receptors at the EC50 and extrapolated maximal S-H interval prolongation levels was 20 and 54%, respectively, and the reserve (coupling amplification) varied from 1 to 2.3 within the 0-50% maximal response range. In summary, m-DITC-XAC appears to specifically and irreversibly antagonize the negative dromotropic effect of Ado and CPA, and guinea pig AV nodal tissue possesses spare A1-Ado receptors.

Interactive effects of verapamil and sympathetic nerve stimulation on the sinus and AV nodes in the canine hearts.

The interactive effects of verapamil and sympathetic nerve stimulation on the sinus and atrioventricular (AV) nodes were studied in 33 bilaterally stellectomized and vagotomized dogs. Sinus cycle length (SCL) and AV nodal conduction time (AH) at a constant drive cycle length (600 msec) were recorded. Sympathetic nerve stimulation (SNS) was performed for 40 sec by electrical stimulation of the right stellate ganglion. Several doses of verapamil (0.5-2.0 microgram/ml, 1.0 ml) were injected directly into the sinus and AV node arteries at 20 sec of SNS. In addition, SNS was repeated at two different intensities after verapamil administration. Verapamil significantly increased the SCL and the AH in a dose dependent fashion, which was reduced by SNS. The reductions of SCL and AH by the SNS were attenuated in the presence of verapamil when the stimulation intensity was weak, but not when the stimulation intensity was strong. It is concluded that verapamil and sympathetic nerve activity interact antagonistically on the sinus node automaticity and AV nodal conduction.

Electrophysiologic effects of sotalol on the immature mammalian heart.

Sotalol is a beta-blocker with class III antiarrhythmic properties that has recently been used in children for the treatment of supraventricular and ventricular arrhythmias. However, little is known about its electrophysiologic effects on the immature heart. Using intracardiac electrocardiographic recordings and stimulation techniques, 15 canine neonates (8-15 days) and 15 adult mongrel dogs were studied with cumulative doses of sotalol (0.5, 1, 2, and 4 mg/kg plus an additional dose of 8 mg/kg for neonates). Heart rate decreased significantly in the two groups, but more in adult dogs (-43% in adult dogs versus -25% in neonates, p less than 0.05). There was no significant change for QRS duration and His-Purkinje system conduction time interval. QT and atrioventricular nodal conduction time intervals increased in adult dogs and neonates. Sinus node recovery time increased significantly in the two groups, but more in adult dogs. Refractory periods of the atrioventricular (AV) node increased significantly in neonates. Atrial flutter was no longer inducible in 12 of 15 neonates after the 2 mg/kg dose. Atrial effective refractory period increased significantly more in neonates (96%, p less than 0.001) than in adult dogs (58%, p less than 0.001). Ventricular effective refractory periods increased significantly both in neonates (46%) and adult dogs (50%), in a similar way. In conclusion, sotalol has greater electrophysiologic effects on the immature heart at the atrial level when compared to the adult, and similar effects on the refractory period of AV node and ventricle.

Investigation of Electrophysiologic Mechanisms for the Antiarrhythmic Actions of R 56865 in Cardiac Glycoside Toxicity

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.

Adenosine use during pregnancy

Adenosine is a naturally occurring endogenous nucleoside that suppresses atrioventricular nodal conduction time, terminates supraventricular tachycardia, and restores sinus rhythm. Its use has been reported in children and adults but not in pregnant patients. This case documents the successful termination of a supraventricular tachycardia in a 39-week pregnant hypotensive patient. Emergency physicians may wish to consider adenosine use in pregnant patients needing emergency therapy or when conventional therapy fails.

Quantitation of dynamic AV nodal properties and application to predict rate-dependent AV conduction

A number of functional properties of the atrioventricular (AV) node have been described in response to changes in the atrial input rate. The purpose of this study was 1) to develop quantitative descriptors of these properties, and 2) to determine whether they can account for rate-dependent changes in AV nodal conduction. The delay in AV nodal conduction of single premature beats (recovery) was found to be an exponential function of coupling interval with a time constant of 66 +/- 2 (+/- SE) ms. A single abbreviated (facilitation) cycle did not alter the time constant of recovery or basal conduction for a subsequent beat but shifted its recovery curve to the left to an extent exponentially related to the facilitation cycle length. The induction of a tachycardia with HA interval fixed so as to control the recovery and facilitation variables resulted in a first-order onset of AV conduction slowing (fatigue). The fatigue process had a time constant in the range of 70 beats and a magnitude that was a decaying exponential function of HA interval. An equation incorporating quantitative descriptors of recovery, facilitation, and fatigue accurately predicted rate-dependent changes in AH interval. We conclude that 1) the AV nodal properties of recovery, facilitation, and fatigue are amenable to quantitative characterization, and 2) rate-dependent changes in AV nodal conduction time can be well described in terms of these underlying properties.

Electrophysiologic Effects of Verapamil Metabolites in the Isolated Heart

The electrophysiologic effects of the metabolites of verapamil are unknown and may contribute to the observed differences between intravenous and oral verapamil. We examined the electrophysiologic effects of verapamil and its metabolites (norverapamil, N-dealkylverapamil (D617), and N-dealkylnorverapamil (D620)) at estimated, free therapeutic concentrations, in the retrogradely perfused, isolated rabbit heart. Verapamil at 5 and 10 ng/ml significantly prolonged anterograde (11 and 27%, respectively) and retrograde (10 and 25%, respectively) atrioventricular (AV) nodal block cycle lengths. Anterograde and retrograde AV nodal conduction times and refractory periods were also prolonged. Norverapamil at 100 ng/ml had qualitatively similar effects equivalent to 20-50% that observed with verapamil at 10 ng/ml. D620 had small but statistically significant effects on some AV nodal parameters. D617 had no effect. The combination of verapamil plus its principal metabolite, norverapamil, had additive effects. None of the compounds had any measurable effect on atrial conduction, His-Purkinje conduction, or atrial refractoriness. Ventricular refractoriness was significantly prolonged only by norverapamil. In conclusion, some of the metabolites of verapamil have important electrophysiologic AV nodal effects and may contribute to the clinical effects observed during chronic oral verapamil dosing.

Conduction Properties of the Antegrade Fast and Slow AV Nodal Pathways Associated with AV Nodal Reentrant Tachycardia.

To elucidate differences in conduction properties among the normal atrioventricular (AV) node and the antegrade fast and slow dual AV nodal pathways (DAVNPW), AV nodal conduction curves were analyzed quantitatively in 38 patients. Eighteen patients had antegrade DAVNPW with AV nodal reentrant tachycardia (AVNRT) (dual pathways group) and the remaining 20 had smooth AV nodal conduction curves, without evidence of AV nodal dysfunction (control group). The effective refractory period (ERP) of the antegrade fast pathway was longer than that of the normal AV node (at both basic cycle lengths of 700 and 500 msec, p less than 0.01). Although the atrial premature beats were delayed by a longer ERP in the fast pathway, there was no significant difference in the degree of prolongation of AV nodal conduction time related to shortening of the coupling interval (i.e., ratio of A2H2 increment to A1A2 decrement) between these two pathways. On the other hand, the ERP of the antegrade slow pathway was similar to that of the normal AV node. The degree of prolongation of AV nodal conduction time (relative to the shortening of the coupling interval) was greater in the antegrade slow pathway than in the normal AV node. In conclusion, these findings suggest that in DAVNPW with AVNRT: (1) the antegrade fast pathway is similar to the AV node and its conduction properties are unlikely to be better than those of the normal AV node and (2) the antegrade slow pathway has quantitatively poorer conduction properties than the normal AV node, since it has a greater degree of decremental conduction.

Electrophysiologic effects of isoproterenol in patients with atrioventricular reentrant tachycardia treated with flecainide

The electrophysiologic effects of isoproterenol in patients treated with flecainide for atrioventricular (AV) reentrant tachycardia were studied to evaluate the mechanism of tachycardia inducibility after isoproterenol and the value of isoproterenol challenge as a predictor of spontaneous arrhythmia recurrence. Seventeen patients underwent electrophysiologic study before and after oral flecainide administration and after the addition of isoproterenol to flecainide. No patient had inducible sustained supraventricular tachycardia after flecainide alone. Two patients had inducible sustained and six had inducible nonsustained tachycardia after isoproterenol was added to flecainide. The patients were then followed up on the same flecainide dose they received at the time of the electrophysiologic study.Findings:1) Flecainide treatment prolonged HV and VA intervals, and the addition of isoproterenol did not affect these variables. 2) Isoproterenol shortened anterograde and retrograde block cycle length and the refractory period of the accessory pathway and the AV node. It also decreased the tachycardia cycle length, an effect that was due solely to shortening of AV node conduction time. 3) Flecainide treatment prevented tachycardia induction by affecting retrograde conduction over the accessory pathway. Isoproterenol allowed for tachycardia induction and for more sustained episodes of tachycardia by reversing the effect of flecainide on retrograde accessory pathway conduction. 4) Tachycardia recurred during follow-up in all three patients in whom tachycardia of ≥ 10 s duration was induced after isoprottrenol but in no patient who had no or shorter episodes of induced tachyrardia (and who did not have a change in medical regimen).Conclusions:1) Isoproterenol reverses flecainide-induced prolongation of block cycle length and refractory periods of the accessory pathway and AV node. 2) Isoproterenol reverses flecainide-induced prevention of tachycardia induction through reversal of the effects of flecainide on the retrograde accessory pathway. 3) The addition of isoproterenol during flecainide restudy is valuable in predicting long-term drug efficacy.

Determinants of the ventricular rate during atrial fibrillation

Determinants of the ventricular cycle length during atrial fibrillation were examined in 52 patients. Thirty-three patients had structural heart disease and none had an accessory atrioventricular (AV) connection. The AV node effective and functional refractory periods, the shortest atrial pacing cycle length associated with 1:1 conduction, the AV node conduction time and indexes of concealed conduction in the AV node were measured in the baseline state (36 patients) and after modification of sympathetic tone by infusion of isoproterenol or propranolol (8 patients each). Atrial fibrillation was then induced with rapid atrial pacing, and the mean, shortest and longest ventricular cycle lengths were measured.Variables that correlated most strongly with the mean RR interval during atrial fibrillation were the AV node effective refractory period (r = 0.93; p < 0.001), AV node functional refractory period (r = 0.87; p < 0.001) and shortest atrial pacing cycle length associated with 1:1 conduction (r = 0.91; p < 0.001). The AH interval during sinus rhythm (r = 0.74; p < 0.001) and during atrial pacing at the shortest cycle length with 1:1 conduction (r = 0.52; p < 0.001) had weaker correlations. Measures of concealed conduction did not improve the prediction of the mean or longest ventricular cycle length during atrial fibrillation.In conclusion, the refractory periods and conductivity of the AV node are the best indicators of the potential of the node to transmit atrial impulses to the ventricles during atrial fibrillation. The degree of concealed conduction in the AV node is a less important determinant of the mean ventricular rate during atrial fibrillation.

Species-dependent effects of adenosine on heart rate and atrioventricular nodal conduction. Mechanism and physiological implications.

This study 1) compares the negative chronotropic and dromotropic actions of adenosine in guinea pig, rat, and rabbit hearts; 2) investigates the mechanism(s) for the different responses; and 3) determines the physiological implications. Isolated perfused hearts were instrumented for measurement of atrial rate and atrioventricular (AV) nodal conduction time. Differences in metabolism of adenosine were determined in the absence and presence of dipyridamole (nucleoside uptake blocker) and erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, adenosine deaminase inhibitor). Dipyridamole plus EHNA decreased adenosine's EC50 for the negative dromotropic effect by 14-fold in guinea pig heart and 1.6-fold in rat heart. This is consistent with the greater number of [3H]nitrobenzylthioinosine binding sites measured in membranes from guinea pig (1,231 +/- 68 fmol/mg protein) compared with rat (302 +/- 31 fmol/mg protein) and rabbit (260 +/- 28 fmol/mg protein) atria. The potency of adenosine to slow atrial rate and prolong AV nodal conduction time was greater in guinea pig than in rat or rabbit hearts. This rank order of potency correlated well with the number of binding sites for the specific adenosine receptor radioligand 125I-aminobenzyladenosine in guinea pig (102 +/- 13 fmol/mg protein), rat (11 +/- 0.5 fmol/mg protein), and rabbit (8 +/- 1 fmol/mg protein) atrial membranes. Hypoxia increased the rate of adenosine release by severalfold and caused slowing of heart rate and AV block. In spontaneously beating hearts, the main effect of hypoxia was a slowing of ventricular rate, which in the guinea pig heart was due to AV block and in the rat heart to atrial slowing. In atrial paced hearts, hypoxia caused a marked prolongation of AV nodal conduction time in guinea pig (39 +/- 4 msec) and rabbit (29 +/- 5 msec) hearts, but only small effect in rat hearts (10 +/- 2 msec). The differences in response to hypoxia could be accounted for by the species-dependent differences in the 1) amount of adenosine released and metabolized, 2) sensitivity of the hearts to adenosine, and 3) dependency of AV nodal conduction on atrial rate. The findings indicate that the results from physiological or pharmacological studies on adenosine in one species may not be applicable to others, and the ultimate effect of adenosine and hypoxia is to slow ventricular rate.

Effects of Diltiazem, Verapamil, and Inhalation Anesthetics on Electrophysiologic Properties Affecting Reentrant Supraventricular Tachycardia in Chronically Instrumented Dogs

Paroxysmal supraventricular tachycardia (PSVT) is likely due to reentry involving the atrioventricular (AV) node, AV node with AV bypass pathway, sinus node, or atria. Intravenous diltiazem (DIL) or verapamil (VER) might be used to treat PSVT in anesthetized patients, and either drug could be more or less effective or produce adverse circulatory effects in this circumstance because the available inhalation anesthetics are known to elevate plasma concentrations of acutely administered iv DIL or VER. Because human studies were precluded and there are no reliable animal models for most reentrant PSVT, the authors determined the effects of iv DIL or VER and potent inhalation anesthetics (enflurane, halothane, isoflurane) on supraventricular electrophysiologic (EP) properties affecting the likelihood of reentrant PSVT in chronically instrumented dogs. Measurements of supraventricular EP properties in awake dogs without drugs served as control. DIL and VER were then administered iv to achieve clinically relevant plasma concentrations in awake dogs and EP properties were again measured. Finally, anesthetic effects on EP properties in dogs with DIL or VER were tested at end-tidal concentrations equivalent to 1.2 or 1.6 MAC for enflurane, halothane, or isoflurane. In awake dogs, DIL or VER increased AV node conduction time. Wenckebach point and functional refractoriness, and also reduced the range of premature atrial intervals for and likelihood of producing sinus node interpolation or reentry with atrial extrastimulation (P less than 0.05, ANOVA). AV node conduction time, Wenckebach point, and functional refractoriness were further increased in anesthetized dogs (all agents) with DIL or VER compared with control (P less than 0.05, ANOVA). All anesthetics with DIL or VER abolished sinus node interpolation and reentry. Atrial effective and functional refractory periods were not affected by DIL or VER in awake dogs and were increased by any of the anesthetics in dogs with DIL (P less than 0.05, ANOVA). Atrial refractory periods were little affected by anesthetics with VER. Adverse circulatory effects, including systolic arterial pressure less than 50 mmHg and second-degree (type 1) AV block or sinus arrest with escape rhythms, were most common with VER and any (especially enflurane) of the anesthetics. Finally, anesthetized animals with sinus arrest and escape rhythms (any test condition) could be paced from the atrium at physiologic rates (up to 120 beats/min).(ABSTRACT TRUNCATED AT 400 WORDS)