Development Of Sustained Atrial Fibrillation Research Articles

Optimising Large Animal Models of Sustained Atrial Fibrillation: Relevance of the Critical Mass Hypothesis.

BackgroundLarge animal models play an important role in our understanding of the pathophysiology of atrial fibrillation (AF). Our aim was to determine whether prospectively collected baseline variables could predict the development of sustained AF in sheep, thereby reducing the number of animals required in future studies. Our hypothesis was that the relationship between atrial dimensions, refractory periods and conduction velocity (otherwise known as the critical mass hypothesis) could be used for the first time to predict the development of sustained AF.MethodsHealthy adult Welsh mountain sheep underwent a baseline electrophysiology study followed by implantation of a neurostimulator connected via an endocardial pacing lead to the right atrial appendage. The device was programmed to deliver intermittent 50 Hz bursts of 30 s duration over an 8-week period whilst sheep were monitored for AF.ResultsEighteen sheep completed the protocol, of which 28% developed sustained AF. Logistic regression analysis showed only fibrillation number (calculated using the critical mass hypothesis as the left atrial diameter divided by the product of atrial conduction velocity and effective refractory period) was associated with an increased likelihood of developing sustained AF (Ln Odds Ratio 26.1 [95% confidence intervals 0.2–52.0] p = 0.048). A receiver-operator characteristic curve showed this could be used to predict which sheep developed sustained AF (C-statistic 0.82 [95% confidence intervals 0.59–1.04] p = 0.04).ConclusionThe critical mass hypothesis can be used to predict sustained AF in a tachypaced ovine model. These findings can be used to optimise the design of future studies involving large animals.

Intermittent Atrial Tachycardia Promotes Repolarization Alternans and Conduction Slowing During Rapid Rates, and Increases Susceptibility to Atrial Fibrillation in a Free‐Behaving Sheep Model

Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood. Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF. This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation

Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear. The purpose of this study was to test the hypothesis that patterns of baseline autonomic nerve activity are important in the development of pacing-induced sustained AF. Radiotransmitters were implanted in 12 ambulatory dogs to record left stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA). Sustained (>48 hours) AF was induced with intermittent rapid atrial pacing. At baseline (before pacing), 1-minute integrated nerve activity between SGNA and VNA demonstrated either a single linear relationship with excellent correlation (group 1, N = 3, r = 0.816 ± 0.105) or nonlinear relationships with poor correlation (group 2, N = 9, r = 0.316 ± 0.162, P <.05 vs group 1). Group 1 dogs had higher VNA (97.0 ± 11.5 mV-s) compared to group 2 (33.4 ± 21.7 mV-s, P <.001). Group 1 dogs had more frequent sympathovagal co-activation episodes than did group 2 (50 ± 19 per day vs 15 ± 6 per day, P <.05) and more paroxysmal atrial tachycardia (PAT; 5 ± 1 per day vs 2 ± 1 per day, P <.05) at baseline. Sustained AF occurred after 16 ± 4 days (range 13-20 days) of pacing in group 1 and after 46 ± 18 days (range 23-72 days) of pacing in group 2 (P <.05). In the week before development of sustained AF, VNA of group 2 dogs was significantly increased compared to baseline (P <.05). Ambulatory dogs with good linear sympathovagal correlation and higher vagal tone at baseline have more PAT episodes at baseline and faster induction of sustained AF by rapid pacing. Rapid atrial pacing increased the VNA of the remaining dogs before induction of sustained AF.

Role of Progressive Widening of the Temporal Excitable Gap for Perpetuation of Atrial Fibrillation in the Goat

Previous studies suggest that a short temporal excitable gap exists between the fibrillation waves during atrial fibrillation (AF). The aim of this study was to investigate the role of that gap in the development of sustained AF in goats. Eight female goats were instrumented with left atrium (LA) electrodes, and sustained AF (>24 h) was induced by intermittent rapid atrial pacing for 9.3+/-4.6 days. In the process of sustained AF development, the atrial effective refractory period (AERP), refractory period during AF (RP(AF)), mean AF cycle length (AFCL), temporal excitable gap during AF (EG(AF) = AFCL - RP(AF)) and degree of fractionation of fibrillation electrograms at LA were studied. When the induced AF lasted for 3-10 min, AFCL, RP(AF) and EG(AF) were 98.3+/-11.0 ms, 90.5+/-13.2 ms and 7.8+/-2.4 ms, respectively. During sustained AF, the values were 84.9+/-5.2 ms, 63.0+/-4.8 ms and 21.9+/-3.5 ms, respectively (P<0.05). Percentage of single potentials was 94.2+/-3.9% and 75.6+/-5.5%, respectively (P<0.05). In this model progressive shortening of atrial refractoriness and widening of the temporal excitable gap induced by electrical remodeling created an electrophysiologic substrate for the perpetuation of AF.

Expression of mineralocorticoid receptor and 11-beta-hydroxysteroid dehydrogenase type 2 in human atria during chronic atrial fibrillation: study of 25 cases

To investigate the mRNA and protein expression of mineralocorticoid receptor (MR) and 11-beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), which plays a crucial role in the human heart to confer specificity on MR, in patients with chronic atrial fibrillation. Twenty-five patients of rheumatic heart valve disease, 12 with sinus rhythm, and 13 with chronic atrial fibrillation for 6 months or over, underwent transthoracic echocardiography and mitral/aortic valve replacement operation during which right atrial lateral wall tissue samples were obtained and left atrial lateral wall tissue samples were obtained from 14 of them in addition. Realtime quantitative PCR was used to determine the mRNA expression of MR and 11betaHSD2 and Western blotting was employed to detect the protein expression of MR and 11betaHSD2 in the atrial myocardium. The left atrial diameters increased markedly in the atrial fibrillation group as compared to the sinus rhythm group (P < 0.01). The mRNA expression of MR in the right atrium of the patients with atrial fibrillation was 5.37 +/- 1.15, significantly higher than that of the patients with sinus rhythm (2.67 +/- 1.09, P < 0.01), the mRNA expression of MR in the left atrium of the patients with atrial fibrillation was 5.19 +/- 1.14, significantly higher than that of the patients with sinus rhythm (270 +/- 0.82, P < 0.01). The mRNA expression of 11betaHSD2 in the right atrium of the patients with atrial fibrillation was 0.86 +/- 0.14, significantly higher than that of the patients with sinus rhythm (0.33 +/- 0.12, P < 0.01), and the mRNA expression of 11betaHSD2 in the left atrium of the patients with atrial fibrillation was 0.95 +/- 0.15, significantly higher than that of the patients with sinus rhythm (0.37 +/- 0.10, P < 0.01). The protein expression of MR in the right atrial tissue of the patients with atrial fibrillation was 1.65 +/- 0.72, significantly higher than that of the patients with sinus rhythm (0.86 +/- 0.33, P < 0.01); and the protein expression of MR in the left atrial tissue of the patients with atrial fibrillation was 1.72 +/- 0.62, significantly higher than that of the patients with sinus rhythm (0.97 +/- 0.37a, P < 0.05). The protein expression of 11betaHSD2 in the right atrial tissue of the patients with atrial fibrillation was 1.18 +/- 0.64, significantly higher than that of the patients with sinus rhythm (0.71 +/- 0.21, P < 0.05); and the protein expression of 11betaHSD2 in the left atrial tissue of the patients with atrial fibrillation was 1.36 +/- 0.58, significantly higher than that of the patients with sinus rhythm (0.85 +/- 0.15, P < 0.05). The mRNA expression and protein expression of MR and 11betaHSD2 were not significantly different between the left atria and right atria both in the fibrillation and sinus groups (all P > 0.05). The mRNA expression and protein expression of MR and 11betaHSD2 are upregulated in atrial fibrillation and aldosterone antagonists may be effective to arrest the development of sustained atrial fibrillation.

Atrial extracellular matrix remodeling and the maintenance of atrial fibrillation.

Remodeling occurs in both ventricle and atrium in dilated cardiomyopathy and heart failure. However, the alteration of atrial extracellular matrix components during remodeling and its effect on the electrical remodeling and atrial arrhythmia have never been explored. Atrial tissue samples of 53 explanted hearts from patients with dilated cardiomyopathy and end-stage heart failure who underwent heart transplantation were examined. Nineteen patients had permanent atrial fibrillation (PmAF), 18 had persistent AF (PsAF), and 16 had no documented AF (NAF). Sixteen donor left atria (LA) were used as controls (CNs). Western Blot analysis revealed a selective downregulation of tissue inhibitor of metalloproteinase (TIMP)-2 in PmAF and PsAF groups compared with the NAF and CN groups and an upregulation of atrial metalloproteinase (MMP)-2 that was most pronounced in the PmAF group followed by the PsAF and NAF groups. Immunofluorescent staining revealed that in the LA, type I collagen volume fraction (CVF-I) increased significantly in the PmAF group followed by the PsAF and NAF groups compared with that in CN. LA CVF-I significantly correlated with LA dimension and TIMP-2 to MMP-2 ratio. In the PsAF group, CVF-I/CVF-III ratio was significantly correlated with AF duration and the frequency of AF recurrence. Atrial extracellular matrix remodeling manifested by the selective downregulation of TIMP-2 along with upregulation of MMP-2 and CVF-I in the atrium is associated with the development of sustained atrial fibrillation in patients with cardiomyopathy and heart failure.

Effect of different pacing protocols on the induction of atrial fibrillation in a transvenously paced sheep model.

In different animal models rapid atrial stimulation led to a shortening and maladaptation to rate of the atrial effective refractory period (AERP). This atrial electrical remodeling resulted in an increased vulnerability to atrial fibrillation (AF). These experimental findings formed the rationale for a stringent pursuit of sinus rhythm in patients with AF, since this would prevent or reverse atrial remodeling. This study tested the hypothesis that a reduction of arrhythmia burden would lead to a decreased vulnerability for AF. Different rapid atrial pacing protocols in a sheep model were used. During 15 weeks, 13 animals were continuously rapid paced and 7 animals were intermittently burst-paced, resulting in rapid atrial activation during 100% versus 33 +/- 4% of the time, respectively. In the continuously paced group, 77% of the animals developed sustained AF (i.e., > 1 hour) versus only 29% in the burst-paced group (P < 0.05). However, there was no difference in mean AERP shortening over time, nor maximal AERP shortening per animal, between both protocols. Minimal AERP was 103 +/- 5 ms in the continuously paced group and 107 +/- 5 in the burst-paced group (P = NS). Significant changes could be identified in effect on P wave duration, AVN function, and atrial dilation. Conduction slowing was more pronounced in the continuously paced group with a maximal P wave duration of 136 +/- 4 ms in this group versus 116 +/- 5 in the burst-paced group (P < 0.05). In the continuously paced group, the right atrial area significantly increased from 2.5 +/- 0.1 cm2 at baseline to 4.2 +/- 0.2 cm2. In the burst-paced group there was no significant atrial dilatation (from 2.6 +/- 0.1 to 2.8 +/- 0.1 cm2). In conclusion, limiting atrial arrhythmia burden slowed the development of sustained AF in this sheep model. This was not mediated by a decreased influence on atrial refractoriness but seemed to be dependent on smaller changes in atrial conduction and dimensions.

Electrophysiological Remodeling of the Heart Owing to Rate

Although damage to the heart from inflammation and infarction are well-established stimuli that trigger major cardiac remodeling, it has been known since 1954 that a persistent supraventricular tachycardia also can alter cardiac structure and function.1 This clinical observation was exploited 8 years later when it was demonstrated that rapid stimulation of the normal heart could produce reversible congestive heart failure.2 Since then, rapid pacing has been used frequently to create an investigational animal model of heart failure. The effects of prolonged pacing-induced tachycardia, in the range of 250 bpm for 3 or 4 weeks, has been studied in depth in several animal species and has been shown to cause extensive myocardial remodeling. Biventricular enlargement with reduced wall thickness and no increase in muscle mass, reduced cross-sectional myocyte area and increased length, disarray of myofibril alignment and cytoarchitecture, increases in contractile protein degradation, and destruction of the supporting myocardial collagen matrix represent some of the structural changes contributing to reduced ventricular function.3 Diminished responsiveness to β-adrenoceptor stimulation caused by a reduction in β-receptor density and a variety of alterations in the adrenergic signaling processes also occur.4 Replacement fibrosis, loss of cells, and reactive hypertrophy of the remaining cells have been noted recently.5 mRNA levels for specific cytoskeletal proteins increase, along with alterations in cytoskeletal architecture6 and abnormalities in phospholamban.7 In pigs subjected to 3 weeks of a tachycardia-induced cardiomyopathy, myocyte action potential showed reduced membrane resting potential, reduced amplitude and upstroke velocity, and prolonged duration at 90% repolarization. Peak L-type Ca2+ current density was reduced because of an absolute reduction in L-type Ca2+ current flow into the myocyte possibly caused by reduced open probability of the channel.8 However, in dogs that had rapid ventricular pacing for 3 to 4 weeks, action …