Thomas H. Everett

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.

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.

Effects of the gap junction modifier rotigaptide (ZP123) on atrial conduction and vulnerability to atrial fibrillation.

Background— Altered conduction is associated with increased atrial fibrillation (AF) vulnerability in canine models of chronic mitral regurgitation (MR) and heart failure (HF). Rotigaptide (ZP123) augments gap junction conductance, improving cell-to-cell coupling. We studied the effects of rotigaptide on atrial conduction and AF vulnerability in the canine MR and HF models. Methods and Results— Twenty-one dogs in 3 groups were studied: control (n=7), chronic MR induced by mitral avulsion (n=7), and HF induced by ventricular tachypacing (n=7). Epicardial mapping of both atria was performed with a 512-electrode array at baseline and at increasing rotigaptide doses (10, 50, and 200 nmol/L). Conduction velocity increased in both atria in control animals and MR animals (maximum percentage increase: 24±5%, 38±6% [P<0.001, <0.001] in the left atrium and 19±9%, 18±3% [P<0.001, <0.001] in the right atrium). Conduction velocity did not change in the left atrium of the HF group and increased minimally in the right atrium (3±3%, 17±5% [P=NS, P=0.001]). AF duration was increased at baseline in MR and HF animals (control: 16±25 seconds, MR: 786±764 seconds, HF: 883±684 seconds; P=0.013). At 50 nmol/L of rotigaptide, duration of AF markedly decreased in the MR animals (96% reduction, P<0.001), reducing AF duration to that of control animals (control: 9±11 seconds, MR: 14±16 seconds, HF: 1622±355 seconds; P=0.04). Conclusions— Gap junction modulation with rotigaptide reduces AF vulnerability in a canine MR model of AF to a level similar to control animals but does not affect AF vulnerability in the canine HF model. This may be a novel therapeutic target in some forms of AF.

Mechanisms of Ventricular Fibrillation in Canine Models of Congestive Heart Failure and Ischemia Assessed by In Vivo Noncontact Mapping

Background—Much of the research performed studying the mechanism of ventricular fibrillation (VF) has been in normal ventricles rather than under a pathological condition predisposing to VF. We hypothesized that different ventricular substrates would alter the mechanism and characteristics of VF. Methods and Results—Three groups of dogs were studied: (1) control (n=8), (2) pacing-induced congestive heart failure (n=7), and (3) acute ischemia produced by 30 minutes of mid left anterior descending artery ligation (n=5). A noncontact mapping catheter (Ensite 3000, ESI) was placed via transseptal into the left ventricle (LV), along with an electrophysiology catheter. A multielectrode basket catheter (EP Technologies) was placed in the right ventricle, along with an electrophysiology catheter. Several episodes of VF were recorded in each animal. In addition to constructing isopotential and isochronal maps of the VF episodes, signals underwent frequency domain analysis as a fast Fourier transform was performed over a 2-second window every 1 second. From the fast Fourier transform, the dominant frequency was determined, and the organization was calculated. In control dogs, meandering, reentrant spiral wave activity was the main feature of the VF. The congestive heart failure group showed evidence of a stable rotor (n=3), evidence of a focal source (n=3), or no evidence of a driver in the LV (n=1). The ischemic group showed evidence of an initial focal mechanism that transitioned into reentry. In the control and ischemic groups, the LV always had higher dominant frequencies than the right ventricle. Conclusions—Different ventricular substrates produced by the different animal models altered the characteristics of VF. Thus, different mechanisms of VF may be present in the LV, depending on the animal model.

Transmural characteristics of atrial fibrillation in canine models of structural and electrical atrial remodeling assessed by simultaneous epicardial and endocardial mapping

BACKGROUNDnEpicardial mapping has shown that atrial substrate may play a role in the characteristics of the resulting atrial fibrillation (AF). However, it is not known whether these differences also occur in 3 dimensions.nnnOBJECTIVEnThis study sought to examine the 3-dimensional characteristics of AF by simultaneously analyzing AF on the epicardial and endocardial surfaces.nnnMETHODSnDogs were divided into 5 groups: congestive heart failure (CHF), rapid atrial pacing (RAP), mitral regurgitation (MR), control, and methylcholine. A noncontact mapping catheter (Ensite 3000 [Endocardial Solutions, Inc., St. Paul, Minnesota]) was placed in the left atrium (LA), and electrode plaques (240 unipoles) were placed over the epicardial surface. Several AF episodes of at least 30 s were recorded, and isopotential videos of activation and isochronal maps were constructed. In addition, each pair of matched electrograms were cross-correlated (XC) and analyzed with a fast Fourier transform (FFT).nnnRESULTSnThe RAP model was the only one with an AF mechanism of multiple wavelets in every dog on both surfaces. In addition, when individual signals were compared, the RAP model had the least amount of similarities between the recording surfaces, whereas the CHF model had the most as it had a higher percentage of signals with XC coefficients >0.8 and a higher percentage of signals with similar dominant frequencies (30 +/- 35% vs. 12 +/- 13% and 66 +/- 30% vs. 26 +/- 10%, P < .05).nnnCONCLUSIONnAlthough the RAP model had similar AF mechanisms in 3 dimensions, this did not correlate to transmural similarities. Focal mechanisms of AF may have a more uniform wavefront of activation, whereas models with mechanisms of multiple wavelets may have more 3-dimensional properties.

Basic mechanisms of atrial fibrillation

The mechanism of AF remains controversial as support still exists for multiple wavelets, mother rotor, and focal sources. These mechanisms need not be mutually exclusive. For example, the mother rotor hypothesis may not be distinct form the focal AF, if the rotor is of small size (ie, microre-entry). With the development of several animal models to study AF, along with improving technologies and mapping techniques, a further understanding of the pathophysiology of AF is being gained. Each animal model has unique electrophysiological and structural abnormalities, and one may not be able to generalize from one model to the next. It is likely that there is not one mechanism for all AF, but that there are substrate-specific mechanisms, and that AF may be comprised of several different mechanisms.

Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model

BACKGROUNDnRemodeling occurs after myocardial infarction (MI), leading to fibrosis, dysfunction, and ventricular tachycardias (VTs). Adenosine via the A2B adenosine receptor (A2BAdoR) has been implicated in promoting fibrosis.nnnOBJECTIVEnTo determine the effects of GS-6201, a potent antagonist of the A2BAdoR, on arrhythmogenic and functional cardiac remodeling after MI.nnnMETHODSnRats underwent ischemia-reperfusion MI and were randomized into 4 groups: control (treated with vehicle), angiotensin-converting enzyme inhibitor (treated with enalapril 1 day after MI), GS-6201-1d (treated with GS-6201 1 day after MI), GS-6201-1w (treated with GS-6201 administered 1 week after MI) . Echocardiography was performed at baseline and 1 and 5 weeks after MI. Optical mapping, VT inducibility, and histologic analysis were conducted at follow-up.nnnRESULTSnTreatment with the angiotensin-converting enzyme inhibitor improved ejection fraction (57.8% ± 2.5% vs 43.3% ± 1.7% in control; P < .01), but had no effect on VT inducibility. Treatment with GS-6201 improved ejection fraction (55.6% ± 2.6% vs 43.3% ± 1.7% in control; P < .01) and decreased VT inducibility (9.1% vs 68.4% in control; P < .05). Conduction velocities were significantly higher at border and infarct zones in hearts of rats treated with GS-6201 than in those of other groups. The conduction heterogeneity index was also significantly lower in hearts of rats treated with GS-6201. Histologic analysis showed that while both GS-6201 and enalapril decreased fibrosis in the noninfarct zone, only GS-6201 reduced the heterogeneity of fibrosis at the border, which is consistent with its effect on VT reduction.nnnCONCLUSIONSnTreatment with an A2BAdoR antagonist at 1 week results in the improvement in cardiac function and decreased substrate for VT. The inhibition of fibrogenesis by A2BAdoR antagonists may be a new target for the prevention of adverse remodeling after MI.

Role of atrial substrate and spatiotemporal organization in atrial fibrillation.

Atrial fibrillation (AF) is a heterogeneous disease that presents in a wide range of clinical scenarios. Correspondingly, a diverse array of large animal models has developed for the study of AF. Different atrial substrate exists in these models, and quantitative analysis of the AF that develops in each case reveals unique characteristics. This article reviews the defining properties of several prominent AF animal models, with a focus on how spatiotemporal organization can discriminate between AF substrates. It addresses how spatiotemporal assessments have been extended to human AF and discusses the insights gained from these new analyses.

Internal atrial defibrillation revisited: how low can we go?

Atrial fibrillation (AF) remains the most common and expensive supraventricular arrhythmia. It is the most frequently encountered diagnosis among hospitalized patients and is estimated to cost the U.S. healthcare system more than

Assessment of cardiac conduction: basic principles of optical mapping.

5 billion dollars annually [(1)][1]. Although catheter ablation holds