Atrial Fibrillation In Man Research Articles

Mechanisms of Action of the KCa2-Negative Modulator AP30663, a Novel Compound in Development for Treatment of Atrial Fibrillation in Man.

AimsSmall conductance Ca2+-activated K+ channels (SK channels, KCa2) are a new target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of KCa2 channels that is currently in clinical development for treatment of AF. The aim of this study is to present the electrophysiological profile and mechanism of action of AP30663 and its efficacy in prolonging atrial refractoriness in rodents, and by bioinformatic analysis investigate if genetic variants in KCNN2 or KCNN3 influence the expression level of these in human heart tissue.Methods and ResultsWhole-cell and inside-out patch-clamp recordings of heterologously expressed KCa2 channels revealed that AP30663 inhibits KCa2 channels with minor effects on other relevant cardiac ion channels. AP30663 modulates the KCa2.3 channel by right-shifting the Ca2+-activation curve. In isolated guinea pig hearts AP30663 significantly prolonged the atrial effective refractory period (AERP) with minor effects on the QT-interval corrected for heart rate. Similarly, in anaesthetized rats 5 and 10 mg/kg of AP30663 changed the AERP to 130.7±5.4% and 189.9±18.6 of baseline values. The expression quantitative trait loci analyses revealed that the genome wide association studies for AF SNP rs13376333 in KCNN3 is associated with increased mRNA expression of KCNN3 in human atrial appendage tissue.ConclusionsAP30663 is a novel negative allosteric modulator of KCa2 channels that concentration-dependently prolonged rodent atrial refractoriness with minor effects on the QT-interval. Moreover, AF associated SNPs in KCNN3 influence KCNN3 mRNA expression in human atrial tissue. These properties support continued development of AP30663 for treatment of AF in man.

P700The SK channel inhibitor AP30663, converts vernakalant-resistant persistent AF and prevents its reinduction in pigs

Abstract Background Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of SK-channels that is currently undergoing clinical trials for treatment of AF. Here we present preclinical data from conscious pigs with persistent AF treated with AP30663. Purpose To examine the pharmakokintetics (PK) of AP30663 in anaesthetized pigs and to test whether AP30663 could cardiovert AF that was resistant to treatment by 4 mg/kg vernakalant in pigs. Methods A total of 12 Danish landrace pigs (gilts) were used for the experiments (2 for PK and 10 for cardioversion of AF). Ten conscious pigs with implanted neurostimulators were tachypaced in the right atrium for 17±5 days until persistent AF that did not respond to treatment with 4 mg/kg vernakalant was obtained. After 3±2 days of vernakalant-resistant AF, the pigs received an infusion of 20 mg/kg AP30663 over 60 minutes. During the infusion the pigs remained conscious and the ECG was monitored. If AF reverted within this period, burst pacing with 50 Hz was applied thrice. Cardioversion was considered successful if sustained AF was reverted. Protection against reinduction of AF was considered successful if no episodes of AF lasting for more than 10 minutes could be reinduced by burst pacing. Results Six out of ten pigs with vernakalant-resistant AF cardioverted during infusion of 20 mg/kg AP30663 over 60 minutes. Four out of six pigs were protected against re-induction of AF by burst pacing. The average time to cardioversion was 29±18 minutes corresponding to calculated free plasma concentrations of 1.0–1.4 μM AP30663. In all the conscious pigs AP30663 was well tolerated with no adverse events. The maximal plasma concentration (Cmax) of AP30663 observed at the end of infusion was 4532±844 ng/ml corresponding to an unbound concentration of 1.54±0.29 μM. The plasma concentrations during infusion were described well by first-order kinetics with a half-time of 5.2 minutes, whereas the plasma concentrations after infusion followed Michaeilis-Menten kinetics with a fast half-life of 6.8 minutes and a slow half-life of 93.7 minutes. Thus, it seems that there is a fast distribution to other tissues and an elimination half-life of approximately 90 minutes. The plasma concentration during infusion reached 90% of the steady state concentration after 17 minutes. Conclusion In an advanced pig model of persistent AF where clinically relevant doses of vernakalant could no longer convert the AF to SR, AP30663 able to convert the pigs to sinus rhythm and protect against reinduction of AF. No signs of adverse events were observed during or after infusion of AP30663. The SK channel inhibitor AP30663 had a fast distribution and an elimination half-life of approximately 90 minutes. The results support the development of AP30663 for treatment of AF in man.

P699Mechanisms of action of the small conductance Ca2+-activated K+-channel modulator AP30663, a novel compound being developed for treatment of atrial fibrillation in man

Abstract Background Small conductance Ca2+-activated K+-channels (SK-channels) are a promising new atrial selective target for treatment of atrial fibrillation (AF). AP30663 is a small molecule inhibitor of SK-channels that is effective in converting vernakalant-resistant AF in tachy-paced pigs. Detailed understanding of the molecular mechanism of AP30663 is important for the development of SK channel inhibition for use in man. Purpose To establish the electrophysiological profile, mechanism of action and efficacy in prolonging atrial refractoriness ex vivo of AP30663. Methods AP30663 potency and mechanism of action were established by whole cell and inside-out patch clamp recordings of expressed SK channels. The ion channel selectivity profile of AP30663 was investigated on heterologous expressed channels. Effects of AP30663 or vehicle (DMSO) on atrial refractoriness (AERP) and ventricular repolarization (QTcB) were investigated on isolated perfused guinea pig hearts. Results AP30663 was found to be a selective negative allosteric modulator of SK channels (IC50=0.77±x0.13 μM) with no or minor effects on a panel of other cardiac ion channels, including hERG/KV11.1, (IKr), KV7.1/KCNE1 (IKs), KV4.3/KChiP2 (Ito), Kir2.1 (IK1), Kir3.1/Kir3.4 (IKACh), KV1.5 (IKur), NaV1.5 (INa) and CaV1.2 (ICa). AP30663 inhibited the SK-channel by right-shifting the calcium activation curve of the SK-channel (the EC50 of Ca2+ increased from 0.43±0.02 μM (control, n=6) to 1.37±0.05 μM (in the presence of 7μM AP30663, n=6). In isolated guinea pig hearts, administration of vehicle had no effect on AERP or QTcB. AP30663 significantly prolonged the AERP in 3 μM (to 131±6% of baseline) and 10 μM (to 165±3% of baseline) without any effects on the QTcB. Conclusion AP30663 is a selective negative allosteric modulator of SK channels, acting by means of shifting the calcium dependence of SK-channel activation. AP30663 prolonged atrial refractoriness without affecting the QT-interval in isolated perfused heart preparations. These properties support continued development of AP30663 for treatment of AF in man. Acknowledgement/Funding Innovation Fund Denmark, Wellcome Trust

Electrophysiological Changes of the Atrium in Patients with Lone Paroxysmal Atrial Fibrillation.

The "Pill-in-Pocket" (PIP) is an approach to atrial fibrillation (AF) where oral anti-arrhythmics at 75% to 100% of the normal daily dose, given as a single dose, is used to convert recent-onset AF. Pro-arrhythmic risk has limited this approach to patients without structural heart disease (SHD). Ranolazine is an anti-anginal agent, which inhibits the abnormal late Na+ channel current resulting in decreased Na+/Ca++ overload. This inhibits after-depolarizations and reduces pulmonary vein firing, which have been implicated in the initiation and propagation of AF. Ranolazine increases atrial refractoriness and has no known pro-arrhythmic affects. Ranolazine is routinely given to patients with SHD. The ability of Ranolazine to terminate AF in man has not been described but if useful could be a safer PIP agent with application in the presence or absence of SHD. We describe our experience using oral Ranolazine to convert new or recurrent AF. 2000 mg of ranolazine was administered to 35 patients with new (16 patients) or recurrent (19 patients) AF of at least 3 but not greater than 48 hours duration. Clinical features, echocardiographic data, and SHD were noted. Success was defined as restoring sinus rhythm within 6 hours of Ranolazine. All but 4 patients had some form of SHD. Twenty-five patients were in the hospital, 5 were in the office, and 5 were at home at the time Ranolazine was administered. Twenty-five of 35 patients converted to sinus rhythm. No pro-arrhythmic effects, hemodynamic instability, adverse rate effects, or perceived intolerance were noted. The 71% conversion rate was comparable to other reported PIP protocols and much higher than reported placebo conversion rates. High dose oral Ranolazine shows utility as a possible safe agent to convert new or recurrent AF. Larger placebo-controlled studies would appear to be warranted.

Nerve Supply of the Human Pulmonary Veins: An Anatomical Study

Atrial ectopic discharges originating in the pulmonary veins (PVs) are known to initiate atrial fibrillation (AF), which may be terminated by catheter-based PV isolation. Because a functional relationship exists between cardiac autonomic effects and PVs in arrhythmogenesis, it has been suggested that discharges of the nerves that proceed to the PVs and interconnect with intrinsic ganglionated nerve plexuses are potential triggers of AF in man. This study sought to determine the characteristics and distribution of neural routes by which autonomic nerves supply the human PVs. We examined the intrinsic neural structures of 35 intact (nonsectioned) left atrial (LA)-PV complexes stained transmurally for acetylcholinesterase using a stereomicroscope. The epicardial ganglionated nerves pass onto the extrapulmonary segments of the human PVs from the middle, left dorsal, and dorsal right atrial subplexuses. The left and right inferior PVs involved a lesser number of ganglia than the left and right superior PVs. Abundant extensions of epicardial nerves penetrate transmurally the PV walls and form a patchy neural network beneath the endothelium of PVs. The subendothelial neural meshwork with numerous free nerve endings, which appeared to be typical sensory compact nerve endings, was mostly situated at the roots of the 4 PVs. No ganglia were identified beneath the endothelium of the human PVs. The richest areas containing epicardial ganglia, from which intrinsic nerves extend to the human PVs, are concentrated at the inferior surface of both the inferior and left superior PVs. Therefore, these locations might be considered as potential targets for focal pulmonary vein ablation in catheter-based therapy of AF.

Indices of Electrical and Contractile Remodeling During Atrial Fibrillation in Man

Atrial electrical and contractile remodeling have been demonstrated to coincide during atrial fibrillation (AF) in experimental studies. We explored whether electrical and contractile remodeling correlate in man and explored its clinical implications. Forty-nine patients with persistent AF were studied. Electrical remodeling was assessed noninvasively using spectral analysis to estimate the average fibrillatory rate (AFR). Atrial contractility was assessed by transesophageal echocardiography (TEE) measurement of left atrial appendage outflow velocity (LAAOV). The AFR was 403+/-43 fibrillations per minute (fpm) and the LAAOV was 0.27+/-0.14 m/s. A significant correlation was found between AFR and LAAOV (r=-0.47, P=0.001). In patients with a LAAOV>or=0.25 m/s, the AFR was 387+/-48 fpm compared to 419+/-31 fpm among patients with LAAOV<0.25 m/s (P<0.01). This study demonstrates that indices of electrical and contractile remodeling are strongly correlated in persistent AF in man. The interindividual overlap, however, is too large to allow predictions of LAAOV based on fibrillatory frequency alone.

One hundred years of atrial fibrillation

One hundred years of atrial fibrillation

Temporal changes in atrial refractoriness following DC cardioversion of persistent atrial fibrillation in man.

Studies have demonstrated shortening of the atrial effective refractory period (ERP) after episodes of atrial fibrillation (AF). This is termed atrial remodelling. It is unclear whether restoration of SR after persistent AF in patients with a clinical substrate results in reversal of this shortening and whether this is maintained long term. The ERP was determined at mid-lateral right atrial wall (MLRA) and right atrial appendage (RAA) at 600 ms and 400 ms drive cycle lengths and at basic sinus cycle length in 81 patients with persistent AF immediately, 24 h and 2 weeks following external DC cardioversion. All atrially active drugs were stopped for at least 5 half lives. (1) Prolongation of the ERP was observed at both atrial sites and all cycle lengths up to 24 h post cardioversion (p < 0.0001). (2) However, between 24 h and 2 weeks a subsequent shortening occurred in the ERP returning it to near post cardioversion levels. (3) The ERP was significantly longer at 24 h post cardioversion in patients who remained in SR for 2 weeks or longer compared with those who reverted to AF. Prolongation of the atrial ERP occurred following restoration of SR in persistent AF patients but was not maintained and displayed a biphasic pattern such that by 2 weeks the ERP had returned to baseline values. Despite this finding, a longer ERP at 24 h post cardioversion was associated with maintenance of SR in the medium-term.

Catheter mapping of spontaneous and induced atrial fibrillation in man.

The clinical electrophysiologic study of atrial fibrillation [AF] has recently progressed from static characterization of the substrate to the dynamic investigation of both induced and spontaneous AF in man. Prior studies have demonstrated inhomogeneity and greater dispersion of atrial refractoriness in patients with AF, but recently atrial electrical remodeling with consequent abbreviation of atrial refractory periods has also been reported. Yet further experimental observations have suggested the existence of additional arrhythmogenic mechanisms for certain AF subsets. These include studies that have demonstrated a stable atrial flutter circuit in one atrium with fibrillatory conduction or a focal atrial tachyarrhythmia arising commonly in the left atrium. Efforts at catheter mapping of AF are now in progress. New mapping techniques and novel devices are currently being employed. We have performed catheter mapping simultaneously in right and left atrial sites at onset and during sustained pacing-induced and spontaneous AF in patients with ischemic and/or hypertensive heart disease. Atrial premature complexes that initiated spontaneous AF typically had coupling intervals ranging from 260 to 400 ms and most frequently arose in the crista terminalis, right atrioventricular junction or superior left atrium. AF at onset showed discrete electrograms at virtually all right and left atrial regions mapped and the region of earliest atrial activation during AF was in close proximity to the premature complexes in over 90% of patients. The regional atrial activation sequence for the first 10 AF beats demonstrated stable or unstable patterns in individual patients. In contrast to spontaneous AF, the initial arrhythmia of induced AF was seen to have a significantly different site of earliest atrial activation but similar discrete electrograms in different atrial regions. However, as with spontaneous AF, the site of extrastimulus delivery was in close proximity to the first induced beat. We conclude that regional catheter mapping of AF is feasible and safe in man and organized electrical activity is frequently observed at AF onset in patients with heart disease. Both right and left atrial regions can be the source of atrial premature complexes and at the onset of spontaneous AF. Induced AF may have differing activation patterns than spontaneous AF but both demonstrate earliest activation in proximity to the initiating atrial premature complex. These findings may help explain therapeutic benefits of right and left atrial interventions and pacing therapies in AF.

Electrophysiological heterogeneity of atrial fibrillation and local effect of propafenone in the human right atrium: analysis based on symbolic dynamics.

A recently developed algorithm that is based on symbolic dynamics and computation of the normalized algorithmic complexity (C(alpha)) was applied to basket-catheter mapping of the atrial fibrillation (AF). The aim of our study was to analyze the spatial distribution of the C(alpha) during AF and effects of propafenone on this distribution. During right atrial mapping in 25 patients with AF 31 intra-atrial and 1 surface bipolar channels were acquired. The anatomical location of the intra-atrial electrodes was defined fluoroscopically. C(alpha) was calculated for a moving window (size: 2000 points; step 500 points). Generated C(alpha) was analyzed within 10 minutes before and after administration of propafenone. The inter-regional C(alpha) distribution was analyzed using the Friedman-test (intra-individually) and Kruskall-Wallis-H-test (inter- individually). A value of p=0.05 was set for an error probability. Inter-regional C(alpha) differences were found in all patients (p<0.001). The right atrium could be divided in high- and low complexity areas according to individual patterns. A significant C(alpha) increase in cranio-caudal direction (with the exception of septum) was confirmed inter-individually (p<0.01). The administration of propafenone enlarged the areas of low complexity. This new method utilizing the combination of symbolic dynamics and adaptive power estimation can provide complex evaluation of the dynamics of AF in man. High-density mapping will be required for further evaluation of results.

System identification of atrial activation during chronic atrial fibrillation in man

To further clarify the mechanisms maintaining chronic atrial fibrillation (CAF). a method for system identification of activation patterns of the atria was developed. Data were obtained as repeated recordings of 8 s duration, each of 56 atrial bipolar electrograms, simultaneously acquired during open-heart surgery at multiple sites in the right atrial free wall in 12 patients with stable sinus rhythm (SR) and during artificial pacing and 16 patients with chronic atrial fibrillation (AF). Realization theory was applied to fit and reproduce the multivariate electrograms corresponding to individual beats during SR and type I activations during AF, respectively—in all cases and for all subjects tested with good accuracy. The local electrogram was a predictable signal in all cases tested and the proposed method may be used for further investigations concerning the deterministic and predictive nature of atrial activation during atrial fibrillation.

Alterations in atrial electrophysiology associated with chronic atrial fibrillation in man.

The purpose of this study was to determine the changes in atrial electrophysiology associated with chronic persistent atrial fibrillation in man. Atrial monophasic action potential duration at 90% repolarization and the effective refractory period were measured in 13 patients with chronic persistent atrial fibrillation after low-energy endocardial cardioversion, and compared to eight controls without a history of atrial fibrillation. Measurements were made at the right atrial appendage and midlateral right atrial wall at basic, 600 ms and 400 ms drive cycle lengths. In control patients, the effective refractory periods were significantly longer at the atrial appendage than the lateral wall at 600 ms (right atrial appendage 265 ms, midlateral right atrial wall 228 ms, P<0.05), and 400 ms cycle lengths (right atrial appendage 270 ms, midlateral right atrial wall 218 ms, P<0.05), but this was not evident in patients with atrial fibrillation. The monophasic action potentials and effective refractory periods at both atrial sites were shorter in the atrial fibrillation patients compared to controls; however, only the effective refractory periods at atrial appendage at 600 ms (atrial fibrillation 210 ms, controls 265 ms, P<0.001), and 400 ms cycle lengths (atrial fibrillation 200 ms, controls 270 ms, P>0.001) reached statistical significance. Effective refractory period dispersion was significantly greater in controls than in patients with atrial fibrillation (cycle length 600 ms: controls 36, atrial fibrillation 13, P=0.01; cycle length 400 ms: controls 54, atrial fibrillation 18, P<0.01). In patients without a history of atrial fibrillation, the refractory period at the right atrial appendage is significantly longer than at the midlateral right atrial wall. This 'normal' pattern of atrial refractory dispersion is lost in patients with chronic persistent atrial fibrillation, with marked shortening of the effective refractory period at the right atrial appendage. This may explain the high risk of recurrence of atrial fibrillation following successful electrical cardioversion.

Reversal of atrial electrical remodeling following cardioversion of long-standing atrial fibrillation in man.

In animal studies, atrial fibrillation has been shown to shorten the atrial refractory period and impair its rate adaptation. However, little is known about the effects of chronic atrial fibrillation on atrial electrophysiology and its recovery course in humans. Nineteen patients, mean age 64 +/- 14 years, with chronic atrial fibrillation of more than six months duration were included in this study. All of them were successfully converted to sinus rhythm with an external defibrillator. Atrial effective refractory periods at right atrial appendage and distal coronary sinus were determined with five pacing cycle lengths (300, 400, 500, 600 and 700 ms) at 30 min after cardioversion and once a day for four days. The atrial conduction properties, including P wave duration of surface ECG, and right and left atrial conduction times, were also measured at the same time interval. Twenty age-matched patients without a history of atrial tachyarrhythmia were evaluated as controls. In comparison with controls, chronic atrial fibrillation significantly shortened the atrial effective refractory period, impaired its rate adaptation response, especially at distal coronary sinus, and depressed the conduction properties of atria. The atrial conduction properties did not change during the four-day follow-up period; however, the atrial effective refractory period was gradually prolonged and its rate adaptation response improved after restoration of sinus rhythm. In humans, chronic atrial fibrillation significantly shortened the atrial effective refractory period, and impaired its rate adaptation response. Restoration and maintenance of sinus rhythm could reverse these electrophysiological changes.

Non-invasive assessment of magnitude and dispersion of atrial cycle length during chronic atrial fibrillation in man.

Atrial fibrillation cycle lengths can be assessed from right precordial ECG leads and the unipolar oesophageal ECG using a non-invasive method called Frequency Analysis of Fibrillatory ECG. The purpose of this report is to present the results from application of this method in a large group of patients with long-term atrial fibrillation and to examine the differences between patients with 'coarse' and 'fine' atrial fibrillation. Simultaneous 15 min recordings from V1, V2 and an oesophageal lead at a position behind the posterior atrium were obtained in 28 patients, aged 41 to 78 years, with long-term (> 1 month) atrial fibrillation. In each lead, using the time averaging technique, the QRST complexes were suppressed. Thereafter, the frequency distribution of the residual ECG was estimated by means of Fast Fourier Transform. In the 3-12 Hz range of each lead, the dominant atrial cycle length, the power maximum and the spectral width were calculated. In 26 patients (93%), frequency spectra in the 3-12 Hz range could be obtained. The dominant atrial cycle length ranged from 120 to 175 ms, mean 150+/-16 (SD) ms in V1, and from 120 to 190 ms, mean 150+/-16 in an oesophageal lead (ns). The absolute difference in the dominant atrial cycle length between V1 and the oesophageal lead was 10.4+/-7.7 ms. There was no significant difference in the dominant atrial cycle length in V1 between patients with coarse and fine atrial fibrillation. The power maximum in V1 was significantly greater in patients with coarse compared to fine atrial fibrillation (P=0.01). The spectral widths ranged from 10 to 55 ms and demonstrated significantly higher mean values in lead V2 compared to V1 (P=0.001). Compared to V1, the mean values tended to be smaller in the oesophageal lead (P=0.05). Using the Frequency Analysis of Fibrillatory ECG method, the dominant atrial cycle length, power maximum and spectral width can be estimated from the frequency spectra in the majority of patients with atrial fibrillation. Spatial dispersion of the dominant atrial cycle length occurs in some patients and may be an important proarrhythmic marker. The distinction between coarse and fine atrial fibrillation cannot be used as a marker of the atrial cycle length.

System identification of atrial activation during chronic atrial fibrillation in man

To clarify the mechanisms maintaining chronic atrial fibrillation (CAF), a method for system identification of activation patterns of the atria during sinus rhythm (SR), artificial atrial pacing and atrial fibrillation, was developed. Data were obtained as repeated recordings of 8 sec in duration, each of 56 atrial bipolar electrograms, simultaneously acquired during open-heart surgery at multiple sites in the right atrial-free wall in 12 patients with stable SR and during artificial pacing and 16 patients with CAF. The realization theory was applied to fit the multivariate electrograms corresponding to individual beats during SR and type-I activations during AF, respectively. It was concluded that the local electrogram is a predictable signal during SR, artificial pacing, as well as during type-I atrial activation, and the proposed method may be used for further investigations concerning the deterministic and predictive nature of atrial activation during atrial fibrillation.

Organized activation during atrial fibrillation in man: endocardial and electrocardiographic manifestations.

Atrial fibrillation is not entirely random, but little is known about the spatiotemporal endocardial organization and its surface ECG manifestations. In 16 patients with atrial fibrillation (chronic, n = 14), endocardial mapping of the trabeculated, the posteroseptal smooth right atrium, and the coronary sinus was performed using multipolar catheters. The surface ECG was analyzed by determining "fibrillation wave" (F wave) amplitude, rate, and polarity. During 50 minutes of atrial fibrillation, an organized activation was present 72% +/- 32% of the analyzed time on the trabeculated, 19% +/- 15% on the smooth right atrium (P < 0.01), and 51% +/- 33% along the coronary sinus (P < 0.05). The direction of organized activation was craniocaudal in 72% +/- 16%, caudocranial in 10% +/- 9% (P < 0.01), and indeterminable in 18% +/- 11%. The mean surface F wave amplitude in lead V1 was 0.128 +/- 0.06 mV during 28 seconds of atrial fibrillation with a craniocaudal direction of activation and 0.065 +/- 0.02 mV during a disorganized activation (P < 0.01). A stable relation between surface F waves and organized trabeculated right atrial activation was observed, and the mean F wave cycle length (190 +/- 27 msec) was highly comparable to the simultaneously measured endocardial cycle length (191 +/- 27 msec, correlation coefficient 0.97). F wave polarity in V1 was positive in 12 of 14 patients during craniocaudal and negative in 11 of 14 patients during caudocranial right atrial free-wall activation. An organized activation during atrial fibrillation with a predominant craniocaudal direction on the trabeculated right atrium is frequently present and influences the appearance of "coarse" or "fine" atrial fibrillation as well as F wave polarity on the surface ECG.

Non-invasive assessment of the atrial cycle length during atrial fibrillation in man: introducing, validating and illustrating a new ECG method.

Atrial fibrillation (AF) in man has previously been shown to include a wide variety of atrial activity. Assessment of the characteristics of this arrhythmia with a commonly applicable tool may therefore be important in the choice and evaluation of different therapeutic strategies. As the AF cycle length has been shown to correlate locally with atrial refractoriness and globally with the degree of atrial organization, with, in general, shorter cycle length during apparently random AF compared to more organized AF, we have developed a new method for non-invasive assessment of the AF cycle length using the surface and the esophagus (ESO) ECG. From the frequency spectrum of the residual ECG, created by suppression of the QRST complexes, the dominant atrial cycle length (DACL) was derived. By comparison with multiple intracardiac simultaneously acquired right and left AF cycle lengths in patients with paroxysmal AF, we found that the DACL in lead V1, ranging from 130 to 185 ms, well represented a spatial average of the right AF cycle lengths, whereas the DACL in the ESO ECG, ranging from 140 to 185 ms, reflected both the right and the left AF cycle length, where the influence from each structure depended on the atrial anatomy of the individual, as determined by MRI. In patients with chronic AF, the method was capable of following changes in the AF cycle length due to administration of D,L-sotalol and 5 min of ECG recording was sufficient for the DACL to be reproducible. We conclude that this new non-invasive method, named 'Frequency Analysis of Fibrillatory ECG' (FAF-ECG), is capable of assessing both the magnitude and the dynamics of the atrial fibrillation cycle length in man.

Mechanism of Antiarrhythmic Effects of Class Ic Drugs in Paroxysmal Atrial Fibrillation in Man

While class Ic antiarrhythmic drugs are effective in treating patients with atrial fibrillation, their mechanism of action is poorly understood. We performed electrophysiological studies before and after their administration to 22 patients with paroxysmal atrial fibrillation. Atrial refractoriness, maximal interatrial conduction delay and the wavelength index were measured at two basic cycle lengths (600 or 400 ms). Both drugs studied increased atrial refractoriness and wavelength index. Flecainide reduced the maximal interatrial conduction delay, but pilsicainide did not. Each drug increased the wavelength index in a tachycardia-dependent manner. Class Ic drugs may reduce atrial vulnerability by increasing the wavelength of the reentrant circuit during periods of rapid heart rate.

A new method for analysis of atrial activation during chronic atrial fibrillation in man

To further clarify the mechanisms maintaining chronic atrial fibrillation (CAF), a method identifying preferable activation patterns of the atria during fibrillation, by time averaging of multiple discrete excitation vectors, was developed. Repeated recordings, each of 56 atrial bipolar electrograms simultaneously acquired during 8 s, were made at multiple sites in the right atrial free wall and the left atrial appendage in 16 patients with CAF using a 2.17 x 3.54 cm electrode array. The local activation times (LAT's) in each recording were estimated as the median activation time at the respective measurement point. By calculating the time difference between the LAT's at adjacent measurement points in two spatial dimensions, a direction vector was created for each activation wave passing each set of measurement points, a total of 42 sets. By time averaging of the individual direction vectors (typically n = 55) at each set of measurement points, preferable activation patterns were determined. Three types of activation patterns were found: 1) inconsistent activation (n = 5), 2) consistent activation with preferential propagation directions (n = 7) and 3) consistent activation with impulses originating from a localizable site within the recording area (n = 4). All activation patterns were reproducible and the two latter patterns were proven significant using statistical tests. We conclude that this new method is useful in further clarification of the mechanisms involved in the maintenance of atrial fibrillation.

Nonlinear Analysis of Epicardial Atrial Electrograms of Electrically Induced Atrial Fibrillation in Man

We applied methods from the theory of nonlinear dynamics to characterize unipolar epicardial right atrial electrograms of electrically induced atrial fibrillation (AF) in man. Electrograms were selected from a high-density mapping study, which confirmed the existence of at least 3 different types of induced AF (types I, II, and III) in patients undergoing open chest surgery. We analyzed sets of 5 electrograms (4 sec, sampling frequency 1 kHz, resolution 8 bits) in 9 patients (AF type I, n = 3; type II, n = 3; type III, n = 3). The Grassberger-Procaccia method was applied to estimate the correlation dimension and correlation entropy from the electrograms. In 2 patients (AF type I) some electrograms (2 of 5 and 3 of 5, respectively) showed scaling at normalized distances ranging from 0.2 to 0.5 in phase space. Correlation dimension D ranged from 1.8 to 3.2 and correlation entropy K from 2.2 to 3.8 nats/sec. The patients were ranked according to increasing coarse-grained correlation dimension Dcg (range 3.7 to 7.9) and coarse-grained correlation entropy Kcg (range 5.6 to 18.6 nats/sec). The method of surrogate data was applied to detect nonlinearity in the electrograms. Using the correlation integral as test statistic, it could be excluded that electrograms of type I AF have been generated by linear stochastic dynamics. Episodes of sinus rhythm (D ranging from 1.0 to 5.1 and K from 2.0 to 8.6 nats/sec) and induced atrial flutter (D ranging from 2.7 to 4.2 and K from 2.2 to 4.2 nats/sec) in 2 different patients showed features of low-dimensional chaos. Nonlinear analysis discriminated between electrograms during electrically induced AF in humans. The results are consistent with a classification of AF into 3 types based on the spatiotemporal complexity of right atrial activation patterns.