Search PubMed⌕ Search

Biomedical subjects

S Nattel

Publications and source records attributed to S Nattel.

At least 127 records · Page 7Linked to original sources
PubMed1994

Artificial intelligence versus logistic regression statistical modelling to predict cardiac complications after noncardiac surgery.

The traditional approach to developing models predictive of cardiac events has been to perform logistic regression (LR) analysis on a variety of potential predictors. An alternative to use an artificial intelligence system called a neural network (NN) which simulates biological intelligence. To evaluate the potential applicability of the latter method, we compared the ability of LR and NN techniques to predict cardiac events after noncardiac surgery. A total of 200 patients (training group) underwent cardiac risk assessment before major noncardiac surgery using 17 clinical parameters and 7 quantitative indices based on dipyridamole-thallium imaging. There were 21 post-operative myocardial infarctions and/or cardiac deaths. Data from the training group were used to develop two predictive models: one based on backward stepwise LR multivariate statistical analysis and the other one using a neural network. Both models were then validated on a second group of 160 consecutive patients also referred for preoperative risk stratification (validation group). The NN consisted of 14 input, 29 hidden, and 1 output neurons and used a back-propagation algorithm (learning rate 0.2, training tolerance 0.5, sigmoid transfer function). The sensitivity, specificity, positive and negative predictive accuracies for the prediction of postoperative events in the validation group of 160 patients were, respectively, 67% (6/9), 82% (124/151), 18% (6/33), and 98% (124/127) for LR, and 67% (6/9), 96% (145/151), 50% (6/12), and 98% (145/148) for the NN, with a difference in specificity which attained statistical significance (p < 0.01). Artificial intelligence may provide a useful alternative to conventional LR statistical analysis for the purpose of preoperative cardiac risk assessment.

Artificial Intelligence↗
PubMed1994

Rapid and slow components of delayed rectifier current in human atrial myocytes.

OBJECTIVE: Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components. METHODS: The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery. RESULTS: The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific IKr blocker E-4031 (5 microM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V 1/2) of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V 1/2 and k respectively. The envelope of tails analysis showed a time dependent change in IKtail/IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component. CONCLUSIONS: (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.

Arrhythmias, Cardiac↗
PubMed1994

Dynamic behavior of the atrioventricular node: a functional model of interaction between recovery, facilitation, and fatigue.

The wide variety of delays that the atrioventricular node can generate in response to an increased rate are explained by dynamic interactions between the three intrinsic properties of recovery, facilitation, and fatigue. The functional model presented suggests that any deviation of nodal conduction time from its minimum basal value represents, at any given time, the net sum of the effects produced by these properties. When a constant fast atrial rate is suddenly initiated, the node first "sees" a shortening in recovery time and responds by an increase in conduction time. This increase further shortens the recovery time of the ensuing beat, which is accordingly further delayed, and so on until a steady state is reached or a block occurs. However, these events do not occur alone. The second beat at the fast rate is conducted with a shorter conduction time than expected from the recovery time alone, and is therefore facilitated. These facilitatory effects develop within one short cycle and dissipate within one long cycle. They affect increasingly the conduction time of beats occurring with shorter cycle lengths. While steady-state effects of recovery and facilitation occur within seconds, nodal conduction time continues to increase slowly over several minutes when a rapid rate is maintained. This effect is attributed to fatigue, which develops and dissipates with a slow, symmetric time course. The dynamics of these properties can now be directly studied with selective stimulation protocols, and have many implications for the understanding of nodal behavior in the context of supraventricular tachyarrhythmias.

Animals↗
PubMed1994

Choline chloride activates time-dependent and time-independent K+ currents in dog atrial myocytes.

Using the whole cell configuration of the patch-clamp technique, we studied the effect of isotonic replacement of bath sodium chloride (NaCl) by choline chloride (ChCl) in dog atrial myocytes. Our results show that ChCl triggered 1) activation of a time-independent background current, characterized by a shift of the holding current in the outward direction at potentials positive to the K+ equilibrium potential (EK), and 2) activation of a time- and voltage-dependent outward current, following depolarizing voltage steps positive to EK. Because the choline-induced current obtained by depolarizing steps exhibited properties similar to the delayed rectifier K+ current (IK), we named it IKCh. The amplitude of IKCh was determined by extracellular ChCl concentration, and this current was generally undetectable in the absence of ChCl. IKCh was not activated by acetylcholine (0.001-1.0 mM) or carbachol (10 microM) and could not be recorded in the absence of ChCl or when external NaCl was replaced by sucrose or tetramethylammonium chloride. IKCh was inhibited by atropine (0.01-1.0 microM) but not by the M1 antagonist pirenzepine (up to 10 microM). This current was carried mainly by K+ and was inhibited by CsCl (120 mM, in the pipette) or barium (1 mM, in the bath). We conclude that in dog atrial myocytes, ChCl activates a background conductance comparable to ACh-dependent K+ current, together with a time-dependent K+ current showing properties similar to IK.

Action Potentials↗
PubMed1994

Modulation of procainamide's effect on cardiac conduction in dogs by extracellular potassium concentration. A quantitative analysis.

BACKGROUND: Antiarrhythmic drugs are known to have state-dependent interactions with cardiac sodium channels, and these have potentially important implications for drug effects on cardiac conduction, particularly in situations of changed resting potential and heart rate. Recent advances in theoretical approaches permit beat-to-beat changes in sodium channel block to be inferred from conduction changes in vivo and allow for an analysis of state-dependent drug action from conduction changes occurring on the onset of pacing at different rates. The purpose of the present study was to use this method to analyze the interaction between hyperkalemia and procainamide's sodium channel-blocking action in terms of resulting changes in left ventricular conduction. METHODS AND RESULTS: Epicardial mapping with a 56-electrode array was used to assess ventricular conduction in open chest, anesthetized mongrel dogs with Formalin-induced atrioventricular block. Procainamide was infused as a series of loading and maintenance infusions until at least 20% conduction slowing was obtained at the shortest basic cycle length (300 milliseconds). Results in a control set of normokalemic dogs were compared with results in dogs with moderate hyperkalemia produced by a loading and maintenance infusion of potassium chloride. Plasma procainamide concentration was measured by high-performance liquid chromatography, and the constancy of serum potassium concentration was verified with ion-sensitive electrode measurement. Although hyperkalemia itself (mean +/- SEM potassium concentration, 6.64 +/- 0.66 mmol/L) did not alter conduction, it resulted in substantially increased conduction slowing by procainamide despite substantially lower plasma drug concentrations (102 +/- 10 mumol/L) compared with normokalemic dogs (potassium concentration, 3.87 +/- 0.24 mmol/L; procainamide concentration, 277 +/- 16 mumol/L). The onset of conduction slowing and block followed basic molecular theory, with an exponential time constant that was faster at longer cycle lengths and total block that increased as cycle length decreased. Piecewise exponential analysis of block during the rested and depolarized phases of the action potential showed that the enhancement of procainamide's action by hyperkalemia was due almost exclusively to increased rested-phase block. Hyperkalemia produced a bradycardia-dependent and slight reduction in action potential duration and antagonized the action potential-prolonging effect of procainamide, particularly at shorter cycle lengths. CONCLUSIONS: Hyperkalemia strongly enhances procainamide-induced conduction slowing by increasing the interaction between the drug and sodium channels during the rested phase of the cardiac cycle. These results indicate the applicability of basic molecular theories of antiarrhythmic drug action to understanding drug-induced changes in conduction velocity in vivo and highlight the potential importance of heterogeneous magnification of sodium channel-blocking drug action by the spatially variable hyperkalemia that occurs with acute myocardial ischemia. The latter could play an important role in the known proarrhythmic potential of sodium channel-blocking drugs in patients with coronary artery disease.

Animals↗
PubMed1994

Class III antiarrhythmic drug action in experimental atrial fibrillation. Differences in reverse use dependence and effectiveness between d-sotalol and the new antiarrhythmic drug ambasilide.

BACKGROUND: Drug therapy to maintain sinus rhythm in patients with atrial fibrillation (AF) is limited by adverse effects and inadequate efficacy. There has been an increased interest in the use of class III drugs to treat AF, and several new agents have been developed, but there is little information available about mechanisms of class III drug action in AF. The present study was designed to compare the effects of two class III agents, d-sotalol and ambasilide, in dog models of experimental AF. METHODS AND RESULTS: A previously developed dog model of sustained vagotonic AF was used to assess the ability of equal loading doses of d-sotalol and ambasilide (2 mg/kg, followed by maintenance infusions), to terminate AF and prevent its induction. At this dose, ambasilide terminated AF in 12 of 12 dogs and prevented AF induction in 10 of 12 dogs; d-sotalol terminated AF in 1 of 8 dogs (P = .001 versus ambasilide) and prevented AF induction in none of 8 dogs (P = .002). An additional dose of d-sotalol (cumulative load, 8 mg/kg) terminated AF in 7 of 8 dogs and prevented induction in 5 of 8 dogs. In an additional 6 dogs with sterile pericarditis and inducible AF, ambasilide prevented AF induction in all 6. An equal dose of d-sotalol (2 mg/kg) failed to suppress AF induction in any dog, but 8 mg/kg of d-sotalol suppressed AF induction in all. Atrial effective refractory period (AERP) was increased by both drugs. However, the effects of d-sotalol on AERP showed strong reverse use dependence, whereas those of ambasilide did not. Neither ambasilide nor d-sotalol significantly altered conduction velocity, and both increased ventricular refractoriness, with d-sotalol once again showing more reverse use dependence. Effective doses of both agents increased AERP and the wavelength for atrial reentry at rapid rates, slowing atrial activation and terminating the arrhythmia. CONCLUSIONS: The class III drugs d-sotalol and ambasilide terminate AF by increasing AERP and the wavelength for reentry. Ambasilide, which has been reported to block both the rapid and slow components of the delayed rectifier (IKr and IKs), shows less reverse use dependence of effects on refractoriness than the pure IKr blocker d-sotalol, possibly explaining the greater effectiveness of ambasilide at an equal dose level. These results indicate that class III drugs can exhibit different profiles of rate-dependent action on AERP and suggest that it may be possible to develop agents that have more desirable rate-dependent profiles than pure blockers of Ikr.

Aminobenzoates↗
PubMed1994

Properties of single outwardly rectifying Cl- channels in heart.

A variety of potentially important macroscopic Cl- currents have been described in the heart. Although the single-channel properties of the cAMP-dependent current (ICl.cAMP) have been well described, the single-channel equivalents of the other forms of cardiac Cl- current remain unknown. Unlike ICl.cAMP, many of these currents show prominent outward rectification in the presence of symmetrical transmembrane Cl- gradients and sensitivity to disulfonic stilbene Cl- transport blockers. We used the patch-clamp technique to search for single Cl- channels in inside-out patches from rabbit atrial cell membranes, under conditions minimizing the chances of observing channels carrying Na+, Ca2+, or K+. Under symmetrical Cl- conditions, single-channel activity was seen in 14 (9%) of 155 patches. Channels showed strong outward rectification and a unitary conductance of 60 +/- 3 picosiemens (mean +/- SEM) at positive voltages. The current-voltage relation was not altered by replacement of cations by the impermeant cation N'-methyl-D-glucamine (NMDG) and shifted as expected for a Cl(-)-selective channel when methanesulfonate was substituted for Cl-. The Cl- transport blockers DIDS (diisothiocyanatostilbene-2,2'-disulfonic acid, 100 mumol/L) and SITS (4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid, 1 mmol/L) strongly and reversibly inhibited channel activity when added to the bath and caused channel flickering suggesting open-channel block. Ensemble-average currents showed no time dependence, and the form of the ensemble-average current-voltage relation was similar to that of macroscopic background Cl- current.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1994

The treatment of atrial fibrillation. An evaluation of drug therapy, electrical modalities and therapeutic considerations.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice, and is responsible for considerable morbidity. Basic studies have shown that AF is usually due to the coexistence of multiple functional atrial re-entry circuits, and that the main determinant of its haemodynamic manifestations is the ventricular response rate. The major adverse clinical consequences of AF include palpitations, impaired cardiac function and thromboembolism. One approach to treating AF is to convert the patient's cardiac rhythm to sinus rhythm by direct current electrical cardioversion, which is initially successful in about 90% of cases. However, the AF recurrence rate over the year subsequent to cardioversion is very high, in the order of 75% in patients receiving no drug therapy. Class I and class III antiarrhythmic drugs reduce the rate of recurrence of AF, but at the expense of a variety of potential adverse effects including ventricular proarrhythmia. The latter is a rare effect (occurring in 1 to 2% of patients receiving most drugs), but can be lethal. A second approach to therapy is to leave the patient in AF, but to control the ventricular response rate and to prevent thromboemboli with oral anticoagulants. Disadvantages of this approach include the possibilities of functional limitations imposed by the arrhythmia, adverse effects of drug therapy, and major bleeding related to anticoagulation. New approaches currently under study include surgery to prevent AF from sustaining itself, implantable cardioverter devices to maintain sinus rhythm, and modification of AV nodal function by the induction of controlled radiofrequency injury.

Animals↗
PubMed1994

Prognostic implications of transient left ventricular cavitary dilation during exercise and dipyridamole-thallium imaging.

OBJECTIVE: To determine the prognostic implication of exercise and dipyridamole-induced transient left ventricular cavitary dilation (TLVD). DESIGN: TLVD was observed and a follow-up obtained in 61 patients after exercise and in 62 patients following dipyridamole infusion. PATIENTS: There was no statistical difference between groups in terms of sex, history of hypertension, diabetes, renal failure, previous myocardial infarction, severity of angina syndrome, congestive heart failure, resting electrocardiographic (ECG) abnormalities, clinical or ECG signs of ischemia during stress, number of reversible perfusion defects on thallium images or duration of follow-up (21 months). RESULTS: Dipyridamole patients were slightly older (64 versus 57 years) and displayed more thallium redistribution (P = 0.002). After a mean follow-up of 21 months, both fatal and nonfatal (myocardial infarction or cardiac death) cardiac events were more frequent in the dipyridamole group (50% versus 9%, P = 0.0001). CONCLUSIONS: Patients with dipyridamole-induced TLVD are at greater risk than those with exercise-induced TLVD at the authors' institution.

Aged↗
PubMed1993

Comparative mechanisms of action of antiarrhythmic drugs.

The most widely used classification of antiarrhythmic drugs, formulated by Singh and Vaughan Williams, divides antiarrhythmic agents into 4 categories: (1) sodium channel blockers; (2) sympatholytic agents; (3) drugs that delay repolarization; and (4) calcium antagonists. Despite some controversy regarding its value, the available evidence indicates that this classification relates well to the most important clinically relevant mechanisms of antiarrhythmic drug action. Amiodarone is unique in that it possesses properties belonging to all 4 of the Singh and Vaughan Williams classes; moreover, all 4 properties contribute to the beneficial actions of the drug. Class 1 effects are responsible for amiodarone's ability to slow ventricular tachycardias, making them hemodynamically better tolerated, and are likely important in amiodarone's premature ventricular complex-suppressing properties. Class 2 effects may contribute to atrioventricular (AV) node-suppressing actions and may confer protection against sudden death in the postmyocardial infarction population. Class 3 actions contribute to amiodarone's ability to prevent reentrant atrial and ventricular arrhythmias, and may be responsible for a superior ability to maintain sinus rhythm after cardioversion of atrial fibrillation. Class 4 properties contribute to amiodarone's ability to slow the ventricular response in atrial fibrillation and to prevent AV node reentrant arrhythmias. Calcium channel antagonism may also suppress arrhythmias (such as torsades de pointes) caused by early after-depolarizations and contribute to the apparent infrequency of torsades, despite substantial QT prolongation, among patients treated with amiodarone. Consideration of the link between amiodarone's pharmacologic properties and clinical effects illustrates well the various mechanisms of antiarrhythmic drug action.

Action Potentials↗
PubMed1993

Rate-dependent functional properties of retrograde atrioventricular nodal conduction in experimental animals.

While rate-dependent atrioventricular (AV) nodal functional properties play a major role in determining antegrade AV nodal conduction, their existence and characteristics have not been assessed during retrograde AV nodal impulse propagation. Pacing protocols were used to study selectively AV nodal recovery, facilitation, and fatigue in 6 isolated, superfused rabbit AV nodal preparations and in 11 morphine-chloralose anesthetized dogs. All three properties were identifiable during retrograde AV nodal activation in rabbits. Retrograde recovery and fatigue were clearly demonstrated in dogs, but facilitation could not be evaluated because of echo beats during retrograde premature stimulation. Functional properties were qualitatively similar during retrograde and antegrade propagation; however, important quantitative differences were noted. The time constant for recovery from activation was significantly greater in the retrograde [rabbits, 69 +/- 8 (SE) ms; dogs, 93 +/- 11 ms] compared with the antegrade direction (rabbits, 50 +/- 5 ms; dogs, 58 +/- 4 ms; P < 0.05 vs. retrograde for each species). The magnitude of fatigue resulting from sustained increases in rate was also substantially greater in the retrograde direction in both rabbits (17 +/- 2 vs. 10 +/- 1 ms antegrade, P = 0.01) and dogs (20 +/- 4 vs. 6 +/- 1 ms antegrade, P < 0.01). Conduction time and refractory period were both greater in the retrograde compared with antegrade direction, and directional differences in conduction properties were magnified as activation rate increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Comparative mechanisms of antiarrhythmic drug action in experimental atrial fibrillation. Importance of use-dependent effects on refractoriness.

BACKGROUND: Antiarrhythmic drugs are considered to terminate atrial fibrillation by prolonging refractoriness, but direct experimental evaluation of this concept has been limited. The atria are activated rapidly during atrial fibrillation, and antiarrhythmic drugs are known to have important rate-dependent actions. The potential role of such properties in determining drug effects during atrial fibrillation has not been evaluated. METHODS AND RESULTS: We evaluated the effects of representative class Ia (procainamide), Ic (propafenone), and III (sotalol) antiarrhythmic drugs on sustained cholinergic atrial fibrillation and atrial electrophysiological properties in anesthetized, open-chest dogs. Loading and maintenance doses were used to produce stable plasma concentrations, and computer-based 112-electrode epicardial mapping was used to study atrial conduction and activation during atrial fibrillation. Clinically used doses of procainamide and propafenone terminated atrial fibrillation in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, but a dose of sotalol (2 mg/kg IV) in the clinical range terminated atrial fibrillation in only 2 of 8 (25%) dogs (P = .0005 vs procainamide, P = .08 vs propafenone). Procainamide and propafenone prevented atrial fibrillation induction in 13 of 13 (100%) and 7 of 10 (70%) dogs, respectively, compared with none of 8 dogs for 2 mg/kg sotalol (P < .0001 vs procainamide, P = .004 vs propafenone). A larger dose of sotalol (cumulative dose, 8 mg/kg) was uniformly effective in terminating atrial fibrillation and preventing its induction. All drugs significantly increased atrial refractory period, with effects that were use dependent for propafenone but reverse use dependent for sotalol. Effective doses of all drugs significantly increased the wavelength for reentry at rapid atrial rates in the presence of vagal stimulation into the range observed under drug-free conditions in the absence of vagal input. The inefficacy of clinical doses of sotalol was explained by the reverse use dependence of its effects on refractoriness, which resulted in reduced effects on wavelength at rapid rates. The effects of propafenone on refractoriness were significantly increased at rapid rates, contributing to its ability to increase wavelength and terminate atrial fibrillation. Activation mapping showed that drugs terminated atrial fibrillation by reducing the number and increasing the size of reentry circuits, leading to termination by mechanisms related to block in the remaining circuit(s). CONCLUSIONS: We conclude that antiarrhythmic drugs terminate experimental atrial fibrillation by increasing the wavelength for reentry at rapid rates, leading to a reduction in the number of functional reentry circuits and, eventually, failure of reentrant excitation. Use-dependent effects on refractoriness can limit (in the case of the reverse use dependence of sotalol) or contribute (in the case of propafenone) to antiarrhythmic drug efficacy against atrial fibrillation by determining drug-induced changes in wavelength at rapid atrial rates.

Animals↗
PubMed1993

Mechanism of selective epicardial activation delay during acute myocardial ischemia in dogs.

BACKGROUND: Previous studies have shown that acute myocardial ischemia in the dog results in much greater activation delays in epicardial than endocardial tissue. These results have been interpreted to indicate enhanced sensitivity of epicardial conduction properties to acute ischemia. This study was designed to test the hypothesis that the ischemic epicardial activation delay during supraventricular rhythms is due to slow conduction across the ischemic myocardial wall prior to epicardial activation and not to enhanced epicardial conduction slowing per se. METHODS AND RESULTS: Changes in epicardial and endocardial activation were measured with transmural decapolar needle electrodes during successive 5-minute left anterior descending coronary artery (LAD) occlusions separated by 30-minute reperfusion periods. Occlusions were performed during left atrial pacing, right ventricular pacing with a stimulating electrode located along the longitudinal axis of epicardial fiber orientation in the ischemic zone, or left ventricular pacing in nonischemic tissue located on a line transverse to fiber orientation in the ischemic zone. During both atrial and left ventricular pacing, activation in the ischemic zone began in the endocardium. Epicardial activation resulted from transmural conduction and was markedly delayed compared with endocardial activation during acute myocardial ischemia. During right ventricular stimulation, the ischemic zone epicardium was activated via longitudinal epicardial conduction, and its activation was only slightly delayed by acute ischemia. Epicardial activation mapping was used to assess ischemia-induced changes in longitudinal epicardial conduction velocity and to compare them with changes in transmural velocity during atrial or left ventricular pacing. Longitudinal conduction in the ischemic epicardium was slowed by 13 +/- 4% (mean +/- SE) relative to preischemic control values in contrast to transmural conduction, which was slowed 50 +/- 4% by LAD occlusion during atrial pacing and 49 +/- 5% during left ventricular pacing (both P < .001 versus longitudinal epicardial conduction). Transmural activation studies showed that the midmyocardium is the site of most of the ischemic activation delay during transmural propagation. CONCLUSIONS: Epicardial activation is more delayed than endocardial by acute ischemia during supraventricular rhythms in dogs because of slowed conduction across the myocardial wall, not because of enhanced sensitivity of epicardial conduction to depression by acute ischemia.

Acute Disease↗
PubMed1993

Effects of adenosine on rate-dependent atrioventricular nodal function. Potential roles in tachycardia termination and physiological regulation.

BACKGROUND: Adenosine is well known to depress atrioventricular (AV) nodal conduction, but the potential interactions between adenosine and functional AV nodal properties have not been explored. The purpose of the present study was to determine (1) whether exogenous adenosine modifies the rate-dependent properties of the AV node, (2) to what extent such changes underlie the actions of adenosine in an in vitro model of AV reentrant tachycardia (AVRT), and (3) the potential role of endogenous adenosine in rate-induced AV nodal responses. METHODS AND RESULTS: The functional properties of AV nodal recovery (defining the conduction delay of a single premature activation), facilitation (effect of short cycles on subsequent nodal recovery), and fatigue (slowly developing AV nodal delay at a rapid rate) were studied selectively in isolated, superfused rabbit and guinea pig cardiac preparations. Exogenous adenosine increased AV nodal fatigue and attenuated facilitation, resulting in tachycardia-dependent increases in AH interval and AV nodal effective refractory period (AVERP). In experimental AVRT, adenosine caused greater increases in tachycardia cycle length (T) and AVERP as tachycardia rate increased. AVRT was sustained when AVERP/T was < 1, and adenosine suppressed AVRT by increasing the slope of the AVERP/T versus tachycardia rate relation, causing the critical ratio of 1 to be attained at slower rates. A mathematical model incorporating quantitative descriptors of recovery, facilitation, and fatigue accounted for changes in AH interval, AVERP, tachycardia cycle length, and AVERP/T under control conditions and in the presence of adenosine. In the absence of exogenous adenosine, 8-phenyltheophylline (10 mumol/L), an adenosine receptor antagonist, did not alter recovery or facilitation but significantly reduced rate-related fatigue (by 31 +/- 8%, mean +/- SEM, P < .05, in rabbit hearts; 46 +/- 5%, P < .01, in guinea pig hearts). Combined inhibition of adenosine deaminase (with erythro-9-[2-hydroxy-3-nonyl]-adenine hydrochloride, 5 mumol/L) and adenosine uptake (with dipyridamole, 1 mumol/L) increased fatigue in the absence of exogenous adenosine by 57 +/- 20% (P < .05). CONCLUSIONS: We conclude that (1) exogenously administered adenosine increases AV nodal fatigue and reduces facilitation, without altering AV nodal recovery; (2) these changes cause rate-dependent AV nodal depression, which plays a role in adenosine's actions on experimental AVRT; and (3) endogenous adenosine receptor activation plays a role in physiological AV nodal fatigue. Adenosine's ability to terminate reentrant supraventricular tachycardia may be due, at least in part, to its ability to enhance the physiological conduction slowing that results from sustained increases in AV nodal activation rate.

Adenosine↗
PubMed1993

Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current.

In human myocardium, the nature of the K+ currents mediating repolarization of the action potential is still speculative. Delayed rectifier channels have recently been cloned from human myocardium, but it is unclear whether or not these currents are involved in the termination of the cardiac action potential plateau. In intact human atrial myocytes, we have identified a rapid delayed rectifier K+ current with properties and kinetics identical to those expressed by a K+ channel clone (fHK) isolated from human heart and stably incorporated into a human cell line for the first time. The myocyte current amplitude was 3.6 +/- 0.2 pA/pF (at +20 mV, n = 15) and activated with a time constant of 13.1 +/- 2 milliseconds at 0 mV (n = 15). The half-activation potential (V0.5) was -6 +/- 2.5 mV (n = 10) with a slope factor (k) of 8.6 +/- 2.2 (n = 10). The heterologously expressed fHK current amplitude was 136 pA/pF (at +20 mV, n = 9) with an activation time constant of 11.8 +/- 4.6 milliseconds at 0 mV; V0.5 was 4.1 +/- 2.4 mV (mean +/- SEM, n = 8); and k was 7.0. The conductance of single fHK channels was 16.9 picosiemens in 5 mM bath K+. Both native and cloned channel currents inactivated partially during sustained depolarizing pulses. Both currents were blocked by micromolar concentrations of 4-aminopyridine and were relatively insensitive to tetraethylammonium ions and class III antiarrhythmic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Delayed rectifier outward current and repolarization in human atrial myocytes.

Previous work has suggested that the primary time-dependent repolarizing current in human atrium is the transient outward current (Ito), but interventions known to alter the magnitude of the delayed rectifier current (IK) affect atrial electrophysiology and arrhythmias in humans. To explore the potential role of IK in human atrial tissue, we used the whole-cell configuration of the patch-clamp technique to record action potentials and ionic currents in isolated myocytes from human atrium. A delayed outward current was present in the majority of myocytes, activating with a time constant ranging from 348 +/- 61 msec (mean +/- SEM) at -20 mV to 129 +/- 25 msec at +60 mV. The reversal potential of tail currents was linearly related to log [K+]o with a slope of 55 mV per decade, and fully activated tail currents showed inward rectification. The potassium selectivity, kinetics, and voltage dependence were similar to those reported for IK in other cardiac preparations. In cells with both Ito and IK, IK greatly exceeded both components of Ito (Ito1 and Ito2) within 50 msec of a voltage step from -70 to +20 mV. Based on the relative magnitude of Ito and IK, three types of cells could be distinguished: type 1 (58% [73/126] of the cells) displayed a large Ito together with a clear IK, type 2 (13% [17/126] of the cells) displayed only IK, and type 3 (29% [36/126] of the cells) was characterized by a prominent Ito and negligible IK. Consistent differences in action potential morphology were observed, with type 2 cells having a higher plateau and steeper phase 3 slope and type 3 cells showing a triangular action potential and lesser phase 3 slope compared with type 1 cells. We conclude that IK is present in a majority of human atrial myocytes and may play a significant role in their repolarization and that previously observed variability in human atrial action potential morphology may be partially due to differences in the relative magnitude of time-dependent outward currents.

Action Potentials↗
PubMed1993

Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents.

Depolarization of human atrial myocytes activates a transient outward current that rapidly inactivates, leaving a sustained outward current after continued depolarization. To evaluate the ionic mechanism underlying this sustained current (Isus), we applied whole-cell voltage-clamp techniques to single myocytes isolated from right atrial specimens obtained from patients undergoing coronary bypass surgery. The magnitude of Isus was constant for up to 10 seconds at +30 mV and was unaffected by 40 mmol/L tetraethylammonium, 100 nmol/L dendrotoxin, 1 mmol/L Ba2+, 0.1 mumol/L atropine, or removal of Cl- in the superfusate. Isus could be distinguished from the 4-aminopyridine (4AP)-sensitive transient outward current (Ito1) by differences in voltage-dependent inactivation (1000-millisecond prepulse to -20 mV reduced Ito1 by 91.7 +/- 0.1% [mean +/- SEM], P < .001, versus 9.4 +/- 0.4% reduction of Isus) and 4AP sensitivity (IC50 for block of Ito1, 1.96 mmol/L; for Isus, 49 mumol/L). Isus activation had a voltage threshold near -30 mV, a half-activation voltage of -4.3 mV, and a slope factor of 8.0 mV. Isus was not inactivated by 1000-millisecond prepulses but was reduced by 16 +/- 8% (P < .05) at a holding potential of -20 mV relative to values at a holding potential of -80 mV. Isus activated very rapidly, with time constants (tau) at 25 degrees C ranging from 18.2 +/- 1.8 to 2.1 +/- 0.2 milliseconds at -10 to +50 mV, two orders of magnitude faster than previously described kinetics of the rapid component of the delayed rectifier K+ current. At 16 degrees C, Isus activation was greatly slowed (tau at +10 mV, 46.7 +/- 4.1 milliseconds; tau at 25 degrees C, 7.1 +/- 0.8 milliseconds; P < .01), and the envelope of tails test was satisfied. The reversal potential of Isus tail currents changed linearly with log [K+]o (slope, 55.3 +/- 2.9 mV per decade), and the fully activated current-voltage relation showed substantial outward rectification. Selective inhibition of Isus with 50 mumol/L 4AP increased human atrial action potential duration by 66 +/- 11% (P < .01). In conclusion, Isus in human atrial myocytes is due to a very rapidly activating delayed rectifier K+ current, which shows limited slow inactivation, is insensitive to tetraethylammonium, Ba2+, and dendrotoxin, and is highly sensitive to 4AP. These properties resemble the characteristics of channels encoded by the Kv1.5 group of cardiac cDNAs and may represent a physiologically significant manifestation of such channels in human atrium.

4-Aminopyridine↗