Atrial Monophasic Action Potential Duration Research Articles

Effects of genetic background, sex, and age on murine atrial electrophysiology.

Genetically altered mice are powerful models to investigate mechanisms of atrial arrhythmias, but normal ranges for murine atrial electrophysiology have not been robustly characterized. We analyzed results from 221 electrophysiological (EP) studies in isolated, Langendorff-perfused hearts of wildtype mice (114 female, 107 male) from 2.5 to 17.7 months (mean 7 months) with different genetic backgrounds (C57BL/6, FVB/N, MF1, 129/Sv, Swiss agouti). Left atrial monophasic action potential duration (LA-APD), interatrial activation time (IA-AT), and atrial effective refractory period (ERP) were summarized at different pacing cycle lengths (PCLs). Factors influencing atrial electrophysiology including genetic background, sex, and age were determined. LA-APD70 was 18 ± 0.5 ms, atrial ERP was 27 ± 0.8 ms, and IA-AT was 17 ± 0.5 ms at 100 ms PCL. LA-APD was longer with longer PCL (+17% from 80 to 120 ms PCL for APD70), while IA-AT decreased (-7% from 80 to 120 ms PCL). Female sex was associated with longer ERP (+14% vs. males). Genetic background influenced atrial electrophysiology: LA-APD70 (-20% vs. average) and atrial ERP (-25% vs. average) were shorter in Swiss agouti background compared to others. LA-APD70 (+25% vs. average) and IA-AT (+44% vs. average) were longer in 129/Sv mice. Atrial ERP was longer in FVB/N (+34% vs. average) and in younger experimental groups below 6 months of age. This work defines normal ranges for murine atrial EP parameters. Genetic background has a profound effect on these parameters, at least of the magnitude as those of sex and age. These results can inform the experimental design and interpretation of murine atrial electrophysiology.

Late Sodium Current in Atrial Cardiomyocytes Contributes to the Induced and Spontaneous Atrial Fibrillation in Rabbit Hearts.

Increased late sodium current (INa) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late INa in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late INa enhancer and inhibitors. Late INa from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1-3 nM) or high (3-10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1-15 nM) were greater in hearts paced at slow than at fast rates (n = 5-10, P < 0.05). Both endogenous and ATX-II-enhanced late INa density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 μM, respectively. The IC50s for eleclazine and ranolazine to inhibit peak INa were 20.67 and 101.79 μM, respectively, in atrial myocytes. In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF.

Prolonged duration of repolarization and decreased conduction velocity in the atrial myocardium after hypothermic ischemia-reperfusion may be related to expressions of inward rectifier potassium channel 2.1 protein and connexin 40.

The study aimed to determine the role of inward rectifier potassium channel 2.1 protein and connexin 40 expressions in regulating the duration of repolarization and conduction velocity of right atrial myocardium in rats following hypothermic ischemia-reperfusion. The Langendorff isolated rat cardiac perfusion models were divided into control (C) and hypothermic ischemia-reperfusion groups, with 8 models in group C and 16 models in group ischemia-reperfusion. Depending on the incidence of atrial arrhythmia after reperfusion, the models in group ischemia-reperfusion were further divided into reperfusion non-atrial arrhythmia or reperfusion atrial arrhythmia subgroup. Right atrial monophasic action potential duration at 50% and 90% of repolarization after 30 minutes of continuous perfusion in group C and group ischemia-reperfusion (T0), 105 minutes of continuous perfusion in group C or after 15 minutes of reperfusion in group ischemia-reperfusion (T1) and 120 minutes of continuous perfusion in group C or 30 minutes of reperfusion in group ischemia-reperfusion (T2) were recorded. Right atrial conduction velocity and effective refractory period were recorded at T2. Then, the expressions of inward rectifier potassium channel 2.1 protein and connexin 40 in the right atrial myocardium were detected. Monophasic action potential duration at 50% and 90% were higher at T1 and T2 than those at T0 in subgroup reperfusion atrial arrhythmia (p < 0.05); monophasic action potential duration at 50% in subgroup reperfusion atrial arrhythmia were larger than group C and subgroup reperfusion non-atrial arrhythmia at T1 and T2 (p < 0.05); monophasic action potential duration at 90% in subgroup reperfusion atrial arrhythmia were larger than group C and subgroup reperfusion non-atrial arrhythmia at T1 and T2 (p < 0.05); effective refractory period in subgroup reperfusion atrial arrhythmia was greater than that in group C and subgroup reperfusion non-atrial arrhythmia, and the conduction velocity and the expressions of inward rectifier potassium channel 2.1 protein and connexin 40 were significantly lower than group C and subgroup reperfusion non-atrial arrhythmia (p < 0.05). The prolonged duration of repolarization and a decrease in conduction velocity of the atrial myocardium occur in rats after hypothermic ischemia-reperfusion. These observed effects may be related to the downregulated expressions of connexin 40 and inward rectifier potassium channel 2.1.

1272Effect of age, genetic background and experimental conditions on left atrial monophasic action potential duration, effective refractory period and activation time in Langendorff-perfused murine hearts

Abstract Funding Acknowledgements Supported by EU [CATCH ME] 633196, British Heart Foundation FS/13/43/30324, AA/18/2/34218 LF, PK, DFG FA413 LF, Studienstiftung to JO. Background Studying cardiac electrophysiology in isolated perfused beating murine hearts is a well-established method. The range of normal values for left atrial action potential durations (LA-APD), activation times (LA-AT) and effective refractory periods (atrial ERP) in murine wildtype (WT) is not well known. Purpose This study aimed to establish reference values for LA-APD, LA-AT and atrial ERP and to identify factors that influence these electrophysiological parameters in wildtype (WT) mice. Method We combined results from isolated beating heart Langendorff experiments carried out in WT between 2005 and 2019 using an octopolar catheter inserted into the right atrium and a monophasic action potential electrode recording from the LA epicardium. Electrophysiological parameters (LA-APD at 50%, 70%, 90% repolarization (APD50, APD70, APD90), LA-AT and atrial ERP) at different pacing cycle lengths (PCL) were summarized. We analyzed effects of PCL, genetic background, age, gender, heart weight to body weight ratio (HW/BW), LA weight to body weight ratio (LAW/BW) as well as coronary flow and temperature as experimental conditions. Results Electrophysiological parameters from 222 isolated hearts (114 female, mean age 6.6 ± 0.25 months, range 2.47-17.7 months) of different backgrounds (77 C57BL/6, 23 FVB/N, 33 MF1, 69 129/Sv and 20 Swiss agouti) were combined. Coronary flow rate, flow temperature and start of isolation to cannulation time were constant experimental conditions over the timespan of experiments. LA-APD was longer while LA-AT decreased with longer PCL throughout all genetic backgrounds (Figure 1A). Genetic background showed strong effects on all electrophysiological parameters. LA activation was delayed in 129/Sv compared to other backgrounds (Figure 1D). LA-APD70 and atrial ERP were significantly shorter in Swiss agouti background compared to others. LA-APD70 was also significantly prolonged in 129/Sv background compared to MF1 (Figure 1C). Atrial ERP was longer in FVB/N compared to other backgrounds. Age effects were compared in groups. Atrial ERP was significantly longer in mice ≤ 3 months compared to all older mice. Atrial ERP was also significantly prolonged (+ 3.4ms, + 13.5%) in female mice compared to males (Figure 1B). Conclusion This dataset summarizes left atrial electrophysiological parameters in the beating mouse heart and can serve as a reference for design and interpretation of electrophysiological experiments in murine models of commonly used genetic backgrounds. We confirm that cycle length, genetic background, age and gender affect atrial electrophysiological parameters. Awareness of these will support successful experimental design. Abstract Figure 1

ASSA14-03-47 Ivabradine prolongs action potential duration and causes atrial arrhythmia in the heart

Objective Ivabradine (IVA) selectively inhibits I f current in the sinus node and is used to treat inappropriate sinus tachycardia. Previous studies indicated that IVA also inhibited I Kr at concentrations higher than therapeutic range. However, the proarrhythmic risk of IVA has not been fully determined. Sea anemone toxin (ATX) –II treated hearts have an increased risk of proarrhythmia and therefore was used to detect low-risk QT prolonging drugs. The objective of this study was to determine the effect of IVA on the atrial and ventricular monophasic action potential duration (MAPD) and the arrhythmic activities in the absence and presence of ATX-II. Methods Female rabbit isolated hearts were perfused by Langendorff mode. Hearts were paced at right atria appendage, and left atrial and ventricular MAPD 90 were recorded and analysed. Results When hearts were paced at 2.8 Hz, the atrial, and endocardial and epicardial ventricular MAPD 90 were 49.6 ± 3, 136.3 ± 7 and 127.4 ± 4 ms. IVA (3–10 μm) significantly prolonged them by 15.9 ± 2 (n = 6, p 90 by 41.2 ± 3 and 31.6 ± 4 ms (n = 5, p 90 by 36.5 ± 5 ms, and LV endocardial and epicardial MAPD 90 by 19.9 ± 3 and 19.5 ± 4 ms. In the continued presence of ATX-II (3 nM), IVA (6–10 μm) reduced the atrial MAPD 90 by 14.4 ± 4 ms (n = 6, p 90 by 36.2 ± 7 and 27.5 ± 5 ms (n = 6, p 90 and transmural dispersion of MAPD 90 , and caused no ventriculararrhythmia both in the absence and presence of ATX-II, (n = 6, p > 0.05; n = 6, p > 0.05) . Conclusion IVA prolongs both atrial and ventricular MAPD and causes atrial arrhythmias in hearts when late sodium current is increased, without proarrhythmic activities in the ventricles. This result may explain the results in clinical research.

Effects of intravenous amiodarone and ibutilide on action potential duration and atrial conduction kinetics in patients with persistent atrial fibrillation.

Class III antiarrhythmic drugs have been shown to be effective for termination of atrial fibrillation (AF). The aim of this study was to determine the steady state and non-steady state effects of amiodarone and ibutilide on the atrial monophasic action potential (MAP) duration (MAPD), effective refractory period (ERP), and intra-atrial conduction time (IACT) in human persistent AF.Fourteen patients with persistent AF who underwent internal atrial defibrillation were included in the study. The atrial MAP was recorded at the high right atrium. IACT was measured from the pacing spike to the distal coronary sinus. MAPD and IACT were assessed during the steady state and at the shortest diastolic interval (DI) at a basic cycle length (CL) of 600 msec and after a premature stimulus. Amiodarone did not affect MAPD or the ERP at the basic CL, but it increased MAPD at the shortest DI. Amiodarone increased IACT at both the basic CL and the shortest DI. Ibutilide increased the MAPD and ERP at the basic CL and at the shortest DI. Ibutilide did not affect IACT at the basic CL or the shortest DI.Ibutilide increases atrial MAPD not only in the steady state but also at the shortest DI, but it does not affect IACT in patients with persistent AF. Amiodarone does not affect MAPD or ERP, but it increases IACT in the steady state, and it increases MAPD and IACT at the shortest DI.

Rate-Dependent Electrophysiologic Effects of the Class III Antiarrhythmic Drugs Nifekalant, Amiodarone, and Ibutilide on the Atrium in Patients With Persistent Atrial Fibrillation

Persistent atrial fibrillation (AF) is characterized by electrical remodeling, ie, marked decreases in the atrial effective refractory period (ERP), ERP rate adaptation, and atrial conduction velocity. Little information is available on the effects of class III antiarrhythmic drugs on the remodeled atrium. We studied the effects of the class III antiarrhythmic drugs nifekalant, ibutilide, and amiodarone on rate-dependent changes in atrial action potential duration in patients with persistent AF. Right atrial (RA) monophasic action potential duration (MAPD) and intra-atrial conduction time (IACT) were measured at pacing cycle lengths (CLs) of 800, 700, 600, 500, 400, 350, 300, and 250 ms before and after administration of nifekalant (0.4 mg/kg + 0.3 mg/kg/hr, iv), amiodarone (5 mg/kg, iv), or ibutilide (0.01 mg/kg, iv) in 31 patients after successful internal cardioversion of chronic AF of > 2 months duration. Nifekalant and ibutilide significantly increased RA MAPD and the ERP at each CL in a reverse rate-dependent manner. Amiodarone did not affect RA MAPD. Nifekalant did not affect IACT, whereas amiodarone increased IACT at each CL in a rate-dependent manner, and ibutilide increased IACT at CLs ≤ 350 ms. The atrial electrophysiologic effects of the class III antiarrhythmic drugs nifekalant, amiodarone, and ibutilide differ, depending on the degree of electrical and structural remodeling and the effects of the drugs on the depolarizing and repolarizing currents.

The role of action potential alternans in the initiation of atrial fibrillation in humans: a review and future directions

This review highlights the role of atrial monophasic action potential duration (APD) in understanding atrial electrical properties in paroxysmal, persistent, and permanent atrial fibrillation (AF) states. Alternans of APD and rate maladaptation in a spatially divergent way appear mechanistically involved in AF initiation, development, and persistence. The underlying pathophysiology warrants further investigation.

Antifibrillatory Properties of Mivacurium in a Canine Model of Atrial Fibrillation

The electrophysiologic actions of the competitive neuromuscular blocker mivacurium (0.05-0.8 mg/kg IV; N = 10) and atropine sulfate [0.01-0.16 mg/Kg intravenously (IV), N = 6] were determined under control conditions, during right vagus nerve stimulation, and during anterior right ganglionated plexus stimulation. Both drugs suppressed shortening of right atrial monophasic action potential (MAP) duration, right atrial refractoriness, and right superior pulmonary vein sleeve refractoriness produced by vagus nerve or ganglionated plexus stimulation and suppressed the induction of atrial fibrillation. Suppression of atrial fibrillation by atropine was accompanied by improved sinus and atrioventricular (AV) nodal function, increasing the ventricular heart rate observed during sinus rhythm and atrial fibrillation and eliminating the depressant actions of vagus nerve stimulation on sinoatrial (SA) and AV nodal function. Unlike atropine, mivacurium selectively antagonized the effects of vagus nerve and ganglionated plexus stimulation on atrial and pulmonary vein sleeve myocardium (shortening of action potential duration/refractoriness and increased atrial vulnerability) without altering sinus or AV nodal function under control conditions or during vagus nerve stimulation. The selective inhibition of parasympathetic nervous system effects in atrium versus sinus and AV nodes by mivacurium may represent a selective mechanism for the suppression of atrial fibrillation without altering SA and AV nodal function.

Electrophysiological Properties of the Atrium After Cardioversion of Chronic Atrial Fibrillation Relation to the Plasma Brain Natriuretic Peptide Level

Brain natriuretic peptide (BNP) level has been shown to increase in patients with chronic atrial fibrillation (CAF) without overt heart failure (HF). Although atrial electrical remodeling associated with CAF has been described, little is known about the effects of the BNP level on the electrophysiological properties in CAF patients. In 42 CAF patients without overt HF, the atrial monophasic action potential duration (MAPD) at pacing cycle lengths (CLs) of 300-800 msec and P-wave signal-averaged electrograms were recorded after cardioversion. The MAPDs for all CLs were significantly longer in patients with a BNP concentration greater than the 50th percentile (group 1, BNP = 215 +/- 118.2 pg/mL) than in patients with a concentration less than the 50th percentile (group 2, BNP = 68.3 +/- 20.9 pg/mL), resulting in a similar value in the MAPDs at CLs of 350 and 600 msec for group 1 and the control patients (n = 8). The slope value of the MAPDs between CLs of 350 and 600 msec was normal in group 1, but slightly lower in group 2 than in group 1 and control patients. The filtered P-wave duration did not differ between the two groups. These electrophysiological characteristics related to the BNP level suggest that the atrial repolarization may be affected by a latent ventricular dysfunction.

Evidence of mechanoelectric feedback in the atria of patients with atrioventricular nodal reentrant tachycardia

Patients with atrioventricular nodal reentrant tachycardia (AVNRT) could serve as a clinical model to study the effects of mechanical stretch in the electrical properties of atrial myocardium. We studied 14 patients with AVNRT. Peak, mean and minimal atrial pressures, atrial refractoriness (ERP) in the right atrial appendage and high right atrial lateral wall and monophasic action potential duration at 90% of repolarisation (MAPd90) in the right atrial appendage were assessed during atrial pacing at 500 and 400 ms and after 2 min of pacing at the tachycardia cycle length. Measurements were repeated from the same positions after ventricular pacing at the same cycle lengths and after 2 min of tachycardia. Susceptibility to atrial fibrillation (AF) was assessed by noting whether AF was induced during ERP evaluation. Atrial pressure showed a statistically significant increase during ventricular pacing compared to baseline. This increase remained substantially unchanged when the tachycardia was induced. A significant reduction in atrial ERP and MAPd90 was also observed during ventricular pacing at all cycle lengths compared to atrial pacing. Two minutes of spontaneous tachycardia were enough to change the atrial ERP and MAPd90 to values significantly lower than those during atrial pacing at the cycle length of tachycardia. During the ERP evaluation AF was induced more often during the tachycardia (28%) than during ventricular (14%) and atrial pacing (0%). In AVNRT patients, ventricular pacing and reentrant tachycardia significantly increase right atrial pressures and subsequently shorten ERP and MAPd90, leading to an enhanced propensity for AF.

Atrial-specific drug AVE0118 is free of torsades de pointes in anesthetized dogs with chronic complete atrioventricular block

The novel compound AVE0118 has been shown to prevent and terminate persistent atrial fibrillation. AVE0118 blocks I(Kur), I(KAch), and I(to), leading to prolongation of atrial repolarization with no change in ventricular repolarization. This finding suggests that AVE0118 may be devoid of proarrhythmic side effects. Experimentally, AVE0118 has been antiarrhythmic against some specific ventricular arrhythmias. The purpose of this study was to investigate the proarrhythmic and antiarrhythmic effects of AVE0118 in anesthetized dogs with chronic complete AV block, known for a high proclivity for torsades de pointes (TdP). AVE0118 was administered intravenously as a fast infusion (0.5 mg/kg/5 min) and a slow infusion (3 or 10 mg/kg/60 min). Dofetilide was given to induce TdP. ECG and monophasic action potentials were recorded. Short-term beat-to-beat variability (STV) of the left ventricular monophasic action potential duration (MAPD) was calculated. We examined whether AVE0118 (1) caused ventricular proarrhythmia (both infusions), (2) prevented dofetilide-induced TdP (slow infusion + dofetilide after 30 minutes), and (3) abolished TdP (fast infusion). At 0.55 +/- 0.10 microg/mL (fast infusion at 10 minutes), AVE0118 did not increase ventricular repolarization or induce TdP; however, right atrial MAPD(50) and MAPD(90) were significantly increased by 26% +/- 9% and 10% +/- 5%, respectively (P <.05 vs baseline). At 1.9 +/- 0.5 microg/mL and 6.1 +/- 1.2 microg/mL (30 minutes of 3 or 10 mg/kg/h), AVE0118 did not induce TdP (0/6 and 0/4) nor prevent dofetilide-induced TdP (6/6 and 2/2). Dofetilide significantly increased all repolarization parameters, including STV from 2.1 +/- 0.4 ms to 4.6 +/- 1.8 ms (P <.05 vs baseline), which were not changed by AVE0118 (to 2.1 +/- 0.3 ms after 30 minutes). Rapid infusion of AVE0118 did not suppress dofetilide-induced TdP. In the anesthetized chronic complete AV block dog, the atrial-specific drug AVE0118 is free of TdP and has no antiarrhythmic properties against dofetilide-induced torsades de pointes.

Recurrence of Atrial Fibrillation After Internal Cardioversion of Persistent Atrial Fibrillation Prognostic Importance of Electrophysiologic Parameters

The purpose of this study was to determine whether the extent of atrial electrical remodeling affects the recurrence of atrial fibrillation (AF) after cardioversion of persistent AF (PAF). Internal atrial cardioversion was performed in 47 patients with PAF. The right atrial monophasic action potential duration (RA-MAPD) at pacing cycle lengths (PCLs) of 800-300 ms and P wave signal-averaged electrocardiogram were recorded after cardioversion. Bepridil (150-200 mg/day) and carvedilol (10 mg/day) were administered to all patients after cardioversion. Of the 47 patients, 20 had recurrent AF within 3 months. No relation was observed between age, left atrial dimension, left ventricular ejection fraction, and AF recurrence. The AF duration was significantly longer (p<0.05) and RA-MAPD at PCLs of 800 to 300 ms were significantly shorter (p<0.05) in patients with AF recurrence than in those without recurrence. The mean slope of the RA-MAPD for PCLs between 600 and 300 ms did not differ between the patients with and without AF recurrence. The filtered P-wave duration (FPD) was significantly longer in the patients with AF recurrence than in those without (p<0.05). Multivariate analysis also showed that the RA-MAPD at a PCL of 300 ms and FPD were predictors of AF recurrence (RAMAPD: p=0.038; FPD: p=0.052). These results suggest that electrical remodeling related to the repolarization and depolarization may be the main contributors to early AF recurrence after cardioversion under the administration of bepridil and carvedilol.

Atrial refractoriness and action potential duration after sudden reversal of atrioventricular sequence.

To address the potential of atrioventricular (AV) asynchrony to provoke cardiac arrhythmias, atrial electrophysiology was examined during normal and reversed AV interval in anesthetized pigs. A new automatic stimulation technique was adapted to monitor rapid changes in the effective refractory period (ERP), using continuous AV sequential pacing, incremental extrastimulus interval scanning, and automatic detection of capture. Right atrial ERP using 2-8 ms stimulus interval increments and right atrial and ventricular monophasic action potential (MAP) duration were determined simultaneously when the AV interval was changed from normal (+80 ms) to reversed (-40 ms) and back. During reversed AV interval the peak right atrial pressure increased from 8 +/- 3 to 14 +/- 4 mmHg (P < 0.001) and mean arterial pressure decreased from 86 +/- 18 to 65 +/- 21 mmHg (P < 0.001). At new steady state, atrial ERP and MAP duration at 90% level of repolarization were lengthened by 22 +/- 16 and 42 +/- 12 ms respectively (P < 0.001). Ventricular MAP duration did not change. A statistically significant lengthening in atrial ERP could be demonstrated in 5-10 seconds. After reversion of the AV sequence, the ratio of atrial ERP to MAP duration decreased from 1.27 to 0.94 (P < 0.001) on average for 15 seconds, the change being thought to favor reentry. Thus atrial wall stress from contraction during ventricular systole even for a short period of time modifies atrial electrophysiology. Deficient AV synchrony may immediately contribute to the development of atrial arrhythmias.

Effect of 60 minutes of rapid atrial pacing on atrial action potential duration in the in-situ canine heart.

Right atrial monophasic action potentials were recorded before and after 60 minutes of rapid atrial pacing (pacing cycle length (CL); 127 +/- 10 ms) in 12 closed-chest dogs. The right atrial (RA) monophasic action potential (MAP) duration at 90% repolarization (RAMAPD) was measured at CLs of 400 ms and 250 ms. CL-dependent changes in RAMAPD (CL 400 ms - 250 ms) before and after rapid atrial pacing were 24 +/- 1 ms and 16 +/- 5 ms, respectively (p < 0.02). RAMAP was recorded at each atrial pacing CL starting at 240 ms decreasing by 10-ms increments. RAMAPD alternans was observed in 10 of 12 dogs at a CL of 163 +/- 17 ms before and in 10 of 12 dogs at s CL of 198 +/- 29 ms (p < 0.01) after rapid atrial pacing. Sustained atrial fibrillation (AF) (>5 minutes) was induced in 1 of 12 dogs at a pacing CL of 130 ms before rapid atrial pacing and in 4 of 12 dogs at a pacing CL of 135 +/- 17 ms after rapid atrial pacing. Onset of AF was always preceded by the RAMAPD alternans. Sixty minutes of rapid atrial pacing leads to diminution of rate adaptation of atrial action potential duration (APD) and appearance of APD alternans of greater magnitude at longer CL, both of which may contribute to the initiation and perpetuation of AF during its early phase.

Significant prolongation of atrial monophasic action potential duration: short-term reverse electrophysiological changes after internal cardioversion of atrial fibrillation.

Since short action potentials and short refractory periods facilitate the induction of atrial reentry, this maladaptation has been proposed as the pathophysiological basis of the frequent immediate recurrences of atrial fibrillation (IRAF) after internal cardioversion. However, short-term reverse electrophysiological changes of the atria after cardioversion have not been studied in humans. Thirty-seven patients with chronic atrial fibrillation of 16+/-19 months and ten patients with an atrial fibrillation duration < or =48 h underwent internal cardioversion. Antiarrhythmic medication was only continued in 10 patients (21%), who were on amiodarone before cardioversion. Atrial monophasic action potential duration at 90% repolarization (APD(90)), sinus rate, P wave duration and interatrial conduction times between high right atrium and coronary sinus were recorded at min 0, 1, 3, 5, 10, 15 and 20 after cardioversion. Internal cardioversion was successful in all patients, but twelve of the patients with chronic AF (32%) and three of the patients with intermittent AF (30%) had one to four episodes of IRAF after 16+/-28 s. There was a significant 52+/-30 ms APD(90) prolongation, 83% of which occurred in min 0-3 (P<0.0001) and 17% in min 3-20 (P<0.05) after internal cardioversion. There was no significant temporal change in sinus rate, P-wave and interatrial conduction time during the time studied. APD(90) prolongation and its time dependence did not show a detectable difference in subgroups with chronic AF, IRAF, left atrial size >40 mm and treatment with amiodarone. There is a significant prolongation of action potential duration in min 0-3 after internal cardioversion of atrial fibrillation, whereas sinus rate and intra- and interatrial conduction time remain unchanged. APD(90) prolongation in min 0-3 shows a temporal relationship to the high rate of immediate recurrences of atrial fibrillation during this time interval. The data imply that there is a transient recovery of atrial refractoriness after cardioversion and suggest a mechanism of the high rate of early recurrences of atrial fibrillation.

Acute effects of zatebradine on cardiac conduction and repolarization.

Zatebradine, a potent bradycardic agent, is believed to act selectively at the sinoatrial node. The selectivity of such a property relative to various electrophysiologic classes of action is not well defined. To characterize the electrophysiologic properties of zatebradine, the corrected sinus node recovery time, sinoatrial conduction time, conduction intervals, atrial effective refractory period and monophasic action potential duration in the ventricle were measured before and after incremental doses of zatebradine (0.1-1.5 mg/kg) in 15 anesthetized dogs. The electrophysiologic effects of zatebradine developed immediately after a single i.v. bolus dose, reaching steady-steady-state at 15 minutes with the maximum effect evident at 0.75 mg/kg. The IC(50) was 0.23 mg/kg. There was no significant effect on the sinus node recovery time. The PR interval on the electrocardiogram was significantly increased when the dose was higher than 0.25 mg/kg. The duration of the P wave and the PA interval were not changed. Zatebridine greatly increased the AH (from 135 to 178 milliseconds) without changing the HH and HV intervals in His bundle recordings. The EC(50) of this effect was 0.58 mg/kg. The QRS interval was not changed. The QTc was significantly increased from 0.43 to 0.56 s(1/2) (P < 0.05). The action potential duration was significantly increased by high dose zatebradine (> 0.5 mg/kg), the EC(50) for this effect was 0.76 mg/kg. The atrium effective refractory period was significantly increased (31%) with an EC(50) 0.69 mg/kg. These results indicate that zatebradine selectively inhibits sinus node automaticity at low doses. The inhibition of the AV nodal conduction and the lengthening of the refractory period and repolarization in the atria and the ventricles occur at higher dose.

Oita International Electrocardiology Symposium 2000 “Electrophysiology and Management of Lethal Arrhythmias in the New Millennium: From Genes to Bedside”

We investigated the effects of short period (60 min) of rapid atrial pacing and sustained atrial fibrillation (At) induced by rapid atrial pacing on right atrial monophasic action potential duration (MAPD) and effective refractory period (ERP) and its rate adaptation in the dog. Short period of rapid atrial pacing leads to diminution of rate adaptation of MAPD and appearance of MAPD alternans at longer cycle length (CL) . Sustained Af leads to electrical remodeling with shorter MAPD, loss of rate-adaptation of MAPD and MAPD alternans at longer CL. Induction of Af in sustained Af (1/8 in control vs 8/8 in sustained At) was always preceded by the alternans of MAPD. Changes in MAPD restitution may also contribute to the initiation of Af.

Effects of volatile anesthetics on atrial and AV nodal electrophysiological properties in guinea pig isolated perfused heart.

Knowledge of the anesthetic effects on atrial and atrioventricular (AV) nodal electrophysiologic properties is fundamental to understand the modulatory role of anesthetics on the pathogenesis of supraventricular tachycardias, and to individualize the perioperative management of patients with supraventricular tachycardias or AV nodal conduction disturbances. Therefore the authors studied the effects of three commonly used volatile anesthetics on the electrophysiologic properties of the atrium and AV node. The concentration-dependent electrophysiologic effects of halothane, isoflurane, and desflurane (0-2 minimum alveolar concentration [MAC]) were studied in guinea pig Langendorff-perfused hearts fit with instruments to simultaneously measure atrial and AV nodal conduction times and atrial monophasic action potential duration. Atrial and AV nodal effective refractory periods were measured simultaneously using a computer-assisted premature stimulation protocol. The concentrations of anesthetics in the gas phase were monitored by an infrared gas analyzer. Volatile anesthetics caused markedly different concentration-dependent effects on atrial conduction, repolarization, and refractoriness, and on AV nodal function. At equianesthetic concentrations, halothane depressed atrial conduction the most, whereas desflurane caused the greatest shortening of atrial monophasic action potential duration. Halothane had no significant effect on atrial refractoriness, whereas at 2 MAC desflurane significantly shortened and isoflurane significantly prolonged atrial effective refractory periods by 18.1+/-13.5% and 13.2+/-14.7%, respectively. On an equi-MAC basis, the rank order of potency for the anesthetics to prolong AV nodal conduction time and AV nodal ERP was halothane > desflurane > isoflurane. The different electrophysiologic effects of volatile anesthetics in the atrium and AV node suggest that these agents may modulate atrial dysrhythmogenesis in distinctly different ways.

Validation of Furchgott's method to determine agonist-dependent A1-adenosine receptor reserve in guinea-pig atrium.

1. The ubiquitous distribution of A1-adenosine receptors (A1AdoR) represents an impediment to achieve organ and/or response selectivity of A1AdoR agonists. Differential receptor reserve may be exploited to overcome this problem. We hypothesize that A1AdoR reserve is agonist-dependent and can be accurately estimated with Furchgott's method. 2. Concentration-response curves were constructed from measurement of the atrial monophasic action potential duration in guinea-pig, isolated hearts treated with R(-) N6-(2-phenylisopropyl)adenosine (R-PIA) or 2-chloro-N6-cyclopentyl-adenosine (CCPA) before and after treatment with the selective, irreversible A1AdoR antagonist 8-cyclopentyl-3-[3-[[4-(fluorosulphonyl)benzoyl]oxy]propyl]-1-prop ylxanthine (FSCPX). Using Furchgott's method, we determined the equilibrium dissociation constant (KA) of R-PIA and CCPA, and the fraction of non-inactivated A1AdoRs remaining after FSCPX treatment (q(functional)). Values of q(functional) were correlated to the fraction of specific binding sites after FSCPX treatment labelled by [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-CPX) derived from saturation binding normalized to control (q(binding)). 3. Both R-PIA and CCPA are full A1AdoR agonists, but have significantly different potencies (pD2 [EC50]=6.84+/-0.04 [145 nM] vs 7.36+/-0.04 [44 nM], respectively), receptor affinities (pKA [KA]= 6.54+/-0.10 [288 nM] vs 6.13+/-0.03 [734 nM]), and pharmacological shift ratios defined as KA/EC50 (2.2+/-0.6 vs 15.9+/-1.5). Values for q(functional) and q(binding) were highly correlated (r2=0.96). The ratio between the intrinsic efficacies of CCPA and R-PIA derived from Furchgott's analysis was 5.9, a value similar to the ratio of 6.2-6.6 calculated from previously obtained binding data. 4. Radioligand binding studies validated the use of Furchgott's method to estimate A1AdoR reserve. A1AdoR reserve was agonist-dependent. CCPA was shown to be a high intrinsic efficacy, low affinity agonist, whereas R-PIA was found to be a low intrinsic efficacy, high affinity agonist.