Jeffrey E. Olgin

Role of Right Atrial Endocardial Structures as Barriers to Conduction During Human Type I Atrial Flutter Activation and Entrainment Mapping Guided by Intracardiac Echocardiography

BACKGROUND The importance of barriers in atrial flutter has been demonstrated in animals. We used activation and entrainment mapping, guided by intracardiac echocardiography (ICE), to determine whether the crista terminalis (CT) and eustachian ridge (ER) are barriers to conduction during typical atrial flutter in humans. METHODS AND RESULTS In eight patients, ICE was used to guide the placement of 20-pole and octapolar catheters along the CT and interatrial septum and a roving catheter to nine sites: just posterior (1) and anterior (2) to the CT along the lateral right atrium, at the fossa ovalis (3), and just posterior and anterior to the ER at the low posterolateral (4 and 5), low posterior (6 and 7), and low posteromedial (8 and 9) right atrium. Entrainment was performed, and each site was considered within the flutter circuit if the postpacing interval-flutter cycle length (PPI-FCL) and the stimulus time-activation time (stim time-act time) were < 10 msec. Split potentials were recorded along the CT with components activated in a low-to-high pattern and a high-to-low pattern. Conduction times, as percentage of FCL, were significantly different at sites on either side of the CT and ER: site 1 (33 +/- 13%) and site 2 (43 +/- 12%) (P = .02), site 4 (48 +/- 24%) and site 5 (75 +/- 8.9%) (P = .02), and site 6 (22 +/- 10%) and site 7 (82 +/- 5.3%) (P = .0009). During entrainment, no surface fusion was observed at sites 5, 7, or 9. The PPI-FCL and stim time-act time were not significantly different than 0 at sites 2, 7, 5, or 9, indicating that they were within the flutter circuit, whereas sites 1, 3, 4, and 6 were not. CONCLUSIONS ICE enabled the correlation of functional electrophysiological properties with specific anatomic landmarks, identifying the CT and ER as barriers to conduction during human atrial flutter.

Increased Vulnerability to Atrial Fibrillation in Transgenic Mice With Selective Atrial Fibrosis Caused by Overexpression of TGF-β1

Studies on patients and large animal models suggest the importance of atrial fibrosis in the development of atrial fibrillation (AF). To investigate whether increased fibrosis is sufficient to produce a substrate for AF, we have studied cardiac electrophysiology (EP) and inducibility of atrial arrhythmias in MHC-TGFcys33ser transgenic mice (Tx), which have increased fibrosis in the atrium but not in the ventricles. In anesthetized mice, wild-type (Wt) and Tx did not show significant differences in surface ECG parameters. With transesophageal atrial pacing, no significant differences were observed in EP parameters, except for a significant decrease in corrected sinus node recovery time in Tx mice. Burst pacing induced AF in 14 of 29 Tx mice, whereas AF was not induced in Wt littermates (P <0.01). In Langendorff perfused hearts, atrial conduction was studied using a 16-electrode array. Epicardial conduction velocity was significantly decreased in the Tx RA compared with the Wt RA. In the Tx LA, conduction velocity was not significantly different from Wt, but conduction was more heterogeneous. Action potential characteristics recorded with intracellular microelectrodes did not reveal differences between Wt and Tx mice in either atrium. Thus, in this transgenic mouse model, selective atrial fibrosis is sufficient to increase AF inducibility.

Activation and Entrainment Mapping Defines the Tricuspid Annulus as the Anterior Barrier in Typical Atrial Flutter

BACKGROUND The importance of anatomic barriers in the atrial flutter reentry circuit has been well demonstrated in canine models. It has been shown previously that the crista terminalis and its continuation as the eustachian ridge form a posterior barrier. In this study we tested the hypothesis that the tricuspid annulus forms the continuous anterior barrier to the flutter circuit. METHODS AND RESULTS Thirteen patients with typical atrial flutter were studied. A 20-pole halo catheter was situated around the tricuspid annulus. A mapping catheter was used for activation and entrainment mapping from seven sequential sites around the tricuspid annulus and from three additional sites including the tip of the right atrial appendage, at the fossa ovalis, and in the distal coronary sinus. Sites were considered to be within the circuit when the postpacing interval minus the flutter cycle length and the stimulus time minus the activation time were < or = 10 ms; sites were considered to be outside the circuit when these intervals were > 10 ms. All seven annular sites were within the circuit; activation occurred sequentially around the annulus and accounted for 100% of the flutter cycle length. The fossa ovalis, the distal coronary sinus, and the right atrial appendage were outside the circuit. CONCLUSIONS Closely spaced sites around the tricuspid annulus are activated sequentially, and are all within the flutter circuit according to entrainment criteria. This demonstrates that the tricuspid annulus constitutes a continuous anterior barrier constraining the reentrant wave front of human counterclockwise atrial flutter.

Prevention of atrial fibrillation: report from a national heart, lung, and blood institute workshop.

The National Heart, Lung, and Blood Institute convened an expert panel April 28 to 29, 2008, to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiological, and clinical literature about AF and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: (1) enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; (2) improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; (3) improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural, and electrical remodeling markers; (4) develop additional animal models reflective of the pathophysiology of human AF; (5) conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and (6) conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.The National Heart, Lung, and Blood Institute convened an expert panel April 28-29, 2008 to identify gaps and recommend research strategies to prevent atrial fibrillation (AF). The panel reviewed the existing basic scientific, epidemiologic and clinical literature about AF, and identified opportunities to advance AF prevention research. After discussion, the panel proposed the following recommendations: 1) Enhance understanding of the epidemiology of AF in the population by systematically and longitudinally investigating symptomatic and asymptomatic AF in cohort studies; 2) Improve detection of AF by evaluating the ability of existing and emerging methods and technologies to detect AF; 3) Improve noninvasive modalities for identifying key components of cardiovascular remodeling that promote AF, including genetic, fibrotic, autonomic, structural and electrical remodeling markers; 4) Develop additional animal models reflective of the pathophysiology of human AF; 5) Conduct secondary analyses of already-completed clinical trials to enhance knowledge of potentially effective methods to prevent AF and routinely include AF as an outcome in ongoing and future cardiovascular studies; and 6) Conduct clinical studies focused on secondary prevention of AF recurrence, which would inform future primary prevention investigations.

Arrhythmogenic Substrate of the Pulmonary Veins Assessed by High-Resolution Optical Mapping

Background—It has recently been recognized that atrial fibrillation can originate from focal sources in the pulmonary veins (PVs). However, the mechanisms of focal atrial fibrillation have not been well characterized. We assessed the electrophysiological characteristics of the PVs using high-resolution optical mapping. Methods and Results—Coronary-perfused, isolated whole-atrial preparations from 33 normal dogs were studied. Programmed electrical stimulation was performed, and a 4-cm2 area of the PV underwent optical mapping of transmembrane voltage to obtain 256 simultaneous action potentials. Marked conduction slowing was seen at the proximal PV, compared with the rest of the vein, on both the epicardial (31.3±4.47 versus 90.2±20.7 cm/s, P =0.001) and endocardial (45.8±6.90 versus 67.6±10.4 cm/s, P =0.012) aspects. Pronounced repolarization heterogeneity was also noted, with action potential duration at 80% repolarization being longest at the PV endocardium. Nonsustained reentrant beats were induced with single extrastimuli, and the complete reentrant loop was visualized (cycle length, 155±30.3 ms); reentrant activity could be sustained with isoproterenol. Sustained focal discharge (cycle length, 330 to 1100 ms) was seen from the endocardial surface in the presence of isoproterenol; each focus was localized near the venous ostium. Conclusions—The normal PV seems to have the necessary substrate to support reentry as well as focal activity. Although reentry occurred more distally in the vein, focal activity seemed to occur more proximally.

“Cristal Tachycardias”: Origin of Right Atrial Tachycardias From the Crista Terminalis Identified by Intracardiac Echocardiography

OBJECTIVES We sought to use intracardiac echocardiography (ICE) to identify the anatomic origin of focal right atrial tachycardias and to define their relation with the crista terminalis (CT). BACKGROUND Previous studies using ICE during mapping of atrial flutter and inappropriate sinus tachycardia have demonstrated an important relation between endocardial anatomy and electrophysiologic events. Recent studies have suggested that right atrial tachycardias may also have a characteristic anatomic distribution. METHODS Twenty-three consecutive patients with 27 right atrial tachycardias were included in the study. ICE was used to facilitate activation mapping in relation to endocardial structures. A 20-pole catheter was positioned along the CT under ICE guidance. ICE was also used to assist in guiding detailed mapping with the ablation catheter in the right atrium. RESULTS Of 27 focal right atrial tachycardias, 18 (67%, 95% confidence interval [CI] 46% to 83%) were on the CT (2 high medial, 8 high lateral, 6 mid and 2 low). ICE identified the location of the tip of the ablation catheter in immediate relation to the CT in all 18 cases. The 20-pole mapping catheter together with echocardiographic visualization of the CT provided a guide to the site of tachycardia origin along this structure. Radiofrequency ablation was successful in 26 (96%) of 27 (95% CI 81% to 100%) right atrial tachycardias. CONCLUSIONS This study demonstrates that approximately two thirds of focal right atrial tachycardias occurring in the absence of structural heart disease will arise along the CT. Recognition of this common distribution may potentially facilitate mapping and ablation of these tachycardias.

Alterations in Atrial Electrophysiology and Tissue Structure in a Canine Model of Chronic Atrial Dilatation Due to Mitral Regurgitation

Background—Clinically, chronic atrial dilatation is associated with an increased incidence of atrial fibrillation (AF), but the underlying mechanism is not clear. We have investigated atrial electrophysiology and tissue structure in a canine model of chronic atrial dilatation due to mitral regurgitation (MR). Methods and Results—Thirteen control and 19 MR dogs (1 month after partial mitral valve avulsion) were studied. Dogs in the MR group were monitored using echocardiography and Holter recording. In open-chest follow-up experiments, electrode arrays were placed on the atria to investigate conduction patterns, effective refractory periods, and inducibility of AF. Alterations in tissue structure and ultrastructure were assessed in atrial tissue samples. At follow-up, left atrial length in MR dogs was 4.09±0.45 cm, compared with 3.25±0.28 at baseline (P <0.01), corresponding to a volume of 205±61% of baseline. At follow-up, no differences in atrial conduction pattern and conduction velocities were noted between control and MR dogs. Effective refractory periods were increased homogeneously throughout the left and right atrium. Sustained AF (>1 hour) was inducible in 10 of 19 MR dogs and none of 13 control dogs (P <0.01). In the dilated MR left atrium, areas of increased interstitial fibrosis and chronic inflammation were accompanied by increased glycogen ultrastructurally. Conclusions—Chronic atrial dilatation in the absence of overt heart failure leads to an increased vulnerability to AF that is not based on a decrease in wavelength.

Biphasic versus monophasic shock waveform for conversion of atrial fibrillation: the results of an international randomized, double-blind multicenter trial.

OBJECTIVES This study compared a biphasic waveform with a conventional monophasic waveform for cardioversion of atrial fibrillation (AF). BACKGROUND Biphasic shock waveforms have been demonstrated to be superior to monophasic shocks for termination of ventricular fibrillation, but data regarding biphasic shocks for conversion of AF are still emerging. METHODS In an international, multicenter, randomized, double-blind clinical trial, we compared the effectiveness of damped sine wave monophasic versus impedance-compensated truncated exponential biphasic shocks for the cardioversion of AF. Patients received up to five shocks, as necessary for conversion: 100 J, 150 J, 200 J, a fourth shock at maximum output for the initial waveform (200 J biphasic, 360 J monophasic) and a final cross-over shock at maximum output of the alternate waveform. RESULTS Analysis included 107 monophasic and 96 biphasic patients. The success rate was higher for biphasic than for monophasic shocks at each of the three shared energy levels (100 J: 60% vs. 22%, p < 0.0001; 150 J: 77% vs. 44%, p < 0.0001; 200 J: 90% vs. 53%, p < 0.0001). Through four shocks, at a maximum of 200 J, biphasic performance was similar to monophasic performance at 360 J (91% vs. 85%, p = 0.29). Biphasic patients required fewer shocks (1.7 +/- 1.0 vs. 2.8 +/- 1.2, p < 0.0001) and lower total energy delivered (217 +/- 176 J vs. 548 +/- 331 J, p < 0.0001). The biphasic shock waveform was also associated with a lower frequency of dermal injury (17% vs. 41%, p < 0.0001). CONCLUSIONS For the cardioversion of AF, a biphasic shock waveform has greater efficacy, requires fewer shocks and lower delivered energy, and results in less dermal injury than a monophasic shock waveform.

Atrial Fibrillation Produced by Prolonged Rapid Atrial Pacing Is Associated With Heterogeneous Changes in Atrial Sympathetic Innervation

BACKGROUND Structural and electrophysiological changes of the atria occur with prolonged rapid rates; however, the effects of sustained atrial fibrillation (AF) on autonomic innervation of the atria are unknown. We hypothesized that electrophysiological remodeling from rapid atrial rates is accompanied by altered atrial autonomic innervation. METHODS AND RESULTS Six dogs (paced group) underwent atrial pacing at 600 bpm; 9 dogs (control animals) were not paced. All paced dogs developed sustained AF by week 4 of pacing. All 15 animals underwent positron emission tomography imaging of the atria with [C-11] hydroxyephedrine (HED) to label sympathetic nerve terminals. HED retention in the atria was significantly greater in paced dogs compared with control animals (P=0.03). Tissue samples from the atrial appendages had a greater concentration of norepinephrine in paced animals than in control animals (P=0.01). The coefficient of variation of HED retention was also greater in paced animals (P=0.05) and was greater in the right atrium than in the left atrium (P=0.004). Epicardial activation maps of AF were obtained in the paced animals at baseline and with autonomic manipulation. Mean AF cycle length was longer in the right atrium (109.2+/-5 ms) than in the left atrium (85.8+/-5.5 ms) at baseline (P=0.005). AF cycle length did not vary significantly from baseline (97.6+/-13.4 ms) with stellate stimulation (100.5+/-6 ms) but lengthened with propranolol (107.5+/-6.1 ms, P=0.03). CONCLUSIONS Rapid rates of AF produce a heterogeneous increase in atrial sympathetic innervation. These changes parallel disparate effects of rapid pacing-induced AF on atrial electrophysiology.

Pirfenidone Prevents the Development of a Vulnerable Substrate for Atrial Fibrillation in a Canine Model of Heart Failure

Background— Atrial fibrosis is an important substrate in atrial fibrillation (AF), particularly in the setting of structural heart disease. In a canine model, congestive heart failure (CHF) produces significant atrial fibrosis and the substrate for sustained AF. This atrial remodeling is a potential therapeutic target. The objective of the present study is to evaluate the effects of the antifibrotic drug pirfenidone (PFD) on arrhythmogenic atrial remodeling in a canine CHF model. Methods and Results— We studied 15 canines, divided equally into 3 groups: control, CHF canines not treated with PFD, and CHF canines treated with PFD. CHF was induced by ventricular tachypacing (220 bpm for 3 weeks), and oral PFD was administered for the 3-week pacing period. We performed electrophysiology and AF vulnerability studies, atrial fibrosis measurements, and atrial cytokine expression studies. Only canines in the untreated CHF group developed sustained AF (>30 minutes, 4 of 5 canines; P<0.05). Treatment of CHF canines with PFD resulted in an attenuation of arrhythmogenic left atrial remodeling, with a significant reduction in left atrial conduction heterogeneity index (median [25% to 75% interquartile range] 4.96 [3.53 to 5.64] versus 2.52 [2.11 to 2.82], P<0.01; pacing cycle length 300 ms), left atrial fibrosis (16.0% [13.0% to 17.5%] versus 8.7% [5.7% to 10.6%], P<0.01), and AF duration (1800 [1020 to 1800] seconds versus 6 [5 to 22] seconds, P<0.01). Immunoblotting studies demonstrated the drug’s effects on multiple cytokines, including a reduction in transforming growth factor-&bgr;1 expression. Conclusions— Treatment of CHF canines with PFD results in significantly reduced arrhythmogenic atrial remodeling and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.