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Cardiovascular Research 2001 52(2):217-225; doi:10.1016/S0008-6363(01)00377-7
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Copyright © 2001, European Society of Cardiology

Remodeling of atrial dimensions and emptying function in canine models of atrial fibrillation

Yanfen Shia, Anique Ducharmea, Danshi Lia, Rania Gaspoa, Stanley Nattela,b,* and Jean-Claude Tardifa

aDepartment of Medicine, Montreal Heart Institute and University of Montreal, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
bDepartment of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6

* Corresponding author. Tel.: +1-514-376-3330 ext. 3990; fax: +1-514-376-1355 nattel{at}icm.umontreal.ca

Received 1 February 2001; accepted 1 June 2001


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Objectives: Atrial tachycardia-induced remodeling (ATR) and ventricular tachypacing-induced heart failure (HF) create experimental substrates for atrial fibrillation (AF), and both have been reported to produce atrial dilation and hypocontractility. The relative importance of changes in atrial size and contractility in the two models is unknown. This study compared changes in atrial dimensions and emptying in ATR versus HF dog models and related them to AF promotion. Methods: In ATR dogs (n=11), the right atrium (RA) was paced at 400/min for 42 days. In HF dogs (n=10), the right ventricle was paced at 240 bpm for 2 weeks, followed by 3 weeks at 220 bpm. Transthoracic echocardiography was performed at baseline and weekly thereafter. At a terminal electrophysiological study, RA effective refractory period (ERP) was recorded and AF induced repeatedly by atrial burst pacing to measure mean AF duration (DAF). Results: Left atrial (LA) systolic area increased by 10.0% in ATR versus 48.2% in HF dogs (P=0.008), with significant time-dependent changes in HF (P=0.0001), but not ATR (P=0.16). LA diastolic area increased over time in both groups (P=0.004, 0.0001 for ATR and HF respectively), but increases were much larger in CHF (80.2%) compared to ATR (24.2%, P=0.0002). Similar findings were obtained for RA. Fractional area shortening (FAS) decreased by 19.4% (ATR) versus 41.8% (HF, P=0.007) in LA and 13.7% (ATR) versus 33.7% (HF, P=0.03) in RA. RA ERP correlated with DAF in ATR dogs (r=–0.79, P<0.001), but not in HF dogs (r=0.20, P=NS). DAF and diastolic areas of RA and LA were highly correlated (r=0.71, 0.77; P<0.01 for each) in HF dogs, but not in ATR dogs (r=–0.18, 0.29; P=NS). Conclusions: Remodeling of atrial size and emptying function is much greater in HF than in ATR. Whereas in ATR, electrophysiological remodeling is of prime importance in AF promotion, structural remodeling (as reflected in changes in atrial size and contraction) appears much more important in HF-induced AF.

KEYWORDS Arrhythmia (mechanisms); Atrial function; Heart failure; Remodeling; Supraventr. arrhythmia

This article is referred to in the Editorial by R.B. Schuessler (pages 169–170) in this issue.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice and its incidence is increasing with the aging of the population [1–3]. Various experimental animal models have been used to study AF [4–12]. Among those, the rapid atrial pacing and the rapid ventricular pacing models are thought to correspond to clinical AF associated with atrial tachycardia-induced remodeling (ATR) and congestive heart failure (HF) respectively [6–8,10]. Atrial electrophysiological remodeling, including changes in atrial refractoriness, refractoriness heterogeneity and conduction, are prominent in ATR, and are believed to contribute importantly to the substrate for AF maintenance [6–9,12]. Alterations in local atrial conduction patterns associated with interstitial fibrosis are believed to be important in sustaining AF in the setting of experimental HF [8]. Both experimental paradigms, however, have been reported to produce atrial dilation and hypocontractility [7,10,11]. Atrial dilation has the capacity to promote AF maintenance by increasing the tissue mass that can support multiple circuit re-entry [13]. The potential role of atrial dilation in AF maintenance in ATR and HF models is unknown, as is the relative importance of changes in atrial macroscopic structure and emptying function in the two models. The purpose of this study was to use echocardiography to compare abnormalities in atrial dimensions and contraction caused by rapid atrial pacing-induced ATR vs. rapid ventricular pacing-induced HF, and to relate them to AF promotion.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1 Animal preparation
All animal care and handling procedures were evaluated by the Animal Research Ethics Committee of the Montreal Heart Institute and conformed to the guidelines of the Canadian Council on Animal Care.

2.1.1 ATR group
Mongrel dogs (n=11) were anesthetized with sodium pentobarbital (30 mg/kg intravenously, additional doses of 4 mg/kg as needed). Respiration was maintained via an endotracheal tube and a mechanical ventilator. Under sterile conditions, a unipolar screw-in pacing lead (Medtronic, Minneapolis, MN) was inserted via the right external jugular vein and fixed in the right atrial appendage under fluoroscopic guidance. The lead was then connected to a Medtronic pacemaker unit (model 8084, modified to stimulate at rates up to 400/min) in a subcutaneous pocket in the neck. Twenty-four hours later, the pacemaker was programmed to capture the atrium at 400 bpm with 4-ms pulses at twice-threshold current. The atrium was stimulated at this rate for a period of 42 days. The surface ECG was verified after 24 h and then weekly.

2.1.2 HF group
Mongrel dogs (n=10) were instrumented under pentobarbital anesthesia (30 mg/kg IV) with the sterile technique previously described [8]. A ventricular pacemaker (model 8084, Medtronic) was implanted in a subcutaneous pocket in the neck and attached to a pacing lead in the right ventricular apex. The pacemaker was programmed to capture the right ventricle at 240 bpm for 3 weeks, followed by 2 weeks at 220 bpm to diminish early death from severe HF. HF was established by clinical signs (lethargy, dyspnea, and edema), and confirmed by echocardiographic results and hemodynamic measurements.

2.2 Transthoracic echocardiography
Serial transthoracic echocardiographic studies were performed at baseline and after 1, 2, and 5 weeks in the HF group, and after 2, 4, and 6 weeks in the ATR group. Dogs were placed in the left lateral to super decubitus position, sedated with intramuscular atravet (0.07 mg/kg) and buprenorphine (0.009 mg/kg), with the pacemaker off, and each echocardiographic examination performed with the dog in sinus rhythm. The heart rates at each time point for echocardiographic evaluation are provided in Table 1. Although heart rate tended to increase over the course of the study, changes were modest and not statistically significantly different for ATR vs. HF dogs. We used a 2.5-MHz phased-array transducer and a standard echocardiographic system (Hewlett-Packard, Andover, MA). The apical 4-chamber and 2-chamber views were obtained and recorded on videotape for subsequent off-line measurements. For both the left and right atrium, the largest atrial area during ventricular systole (termed the ‘systolic area’) and the smallest atrial area during ventricular diastole (termed the ‘diastolic area’) were measured. Atrial fractional area shortening (FAS) was calculated as (systolic area–diastolic area)/systolic areax100. Simpson’s method of discs was used to measure the left ventricular ejection fraction. The average of three consecutive cardiac cycles was used for each measurement, both for atrial and left ventricular evaluations. Special care was taken to obtain similar imaging planes on serial examinations.


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  		Table 1 Heart rate during echocardiographic study at each time point in ATR vs. HF group

 
In order to validate our measurements, we subjected 10 echocardiograms to three repeated measurements in a blinded fashion, with three consecutive cardiac cycles analyzed for each recording. The inter-cycle coefficient of variation (standard deviation÷meanx100%) of the measurements of three consecutive cardiac cycles of the 10 echocardiograms averaged 3.2±1.5% and 5.4±2.1% for left and right atrial systolic area, and 3.6±2.5% and 6.0±4.2% for left and right atrial diastolic area, respectively. The coefficient of variation among three separate blinded readings, each based on the average of three cycles, averaged 1.6±0.6% and 3.3±2.3% for left and right atrial systolic area, and 2.3±1.2% and 4.3±2.7% for left and right atrial diastolic area respectively for these 10 echocardiograms.

2.3 Electrophysiological assessment
After 5 weeks of pacing for HF dogs and after 6 weeks for ATR dogs, the animals were anesthetized with morphine (2 mg/kg SC) and {alpha}-chloralose (120 mg/kg IV, followed by 29.25 mg/kg/h) and ventilated to maintain physiological arterial blood gases. Median sternotomy was performed. The right atrial appendage effective refractory period (ERP) was recorded in each dog. AF was induced in all dogs with 10-Hz, 2-ms stimuli at four times the threshold current (burst pacing). AF was considered sustained if it required electrical cardioversion for termination (cardioversion was performed when AF had persisted 30 min since AF onset). Electrical cardioversion was performed with internally-applied, QRS complex-synchronized direct current shocks. To estimate the mean AF duration, AF was induced 10 times if AF was <20 min, and five times if AF lasted between 20 and 30 min. AF>30 min was defined as sustained, and if sustained AF was induced on two occasions, no further AF induction was performed. When electrical cardioversion was applied, a 30-min rest period was allowed before the experiment was continued.

2.4 Statistical analysis
All data are expressed as mean±standard deviation, except in the figures (for which 95% confidence intervals are shown). To analyze the evolution of the variables, mixed-model repeated-measures analysis of covariance controlling for the baseline value [14] were used to extract the group–time interaction and the time and group main effects. When the group–time interaction was significant, which means that groups showed a significant difference in evolution, slice effect (also known as simple effect) [15] analyses were performed to evaluate differences among groups at each time level and to test the evolution of each group. These analyses were performed with the mixed procedure of SAS 6.12 to handle missing data. Pearson’s correlation coefficient was used to evaluate the relation between atrial variables and AF duration. A P-value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
In the HF group, two dogs died from severe cardiac dysfunction before the last echocardiographic follow-up was obtained (one at 2 weeks, one at 5 weeks of pacing). Transthoracic echocardiography could not be performed at the last follow-up study in one other dog in this group, with the echocardiogram therefore being done in the open-chest condition. There were no deaths over the study course in the ATR group. Mean AF duration was not recorded in three dogs in this group, and transthoracic echocardiography could not be performed at the last follow-up study in one of these three dogs.

3.1 Echocardiographic results
Fig. 1 illustrates atrial systolic and diastolic frames under control conditions (A) and after 42 days (B) of ATR, as well as corresponding images for a HF dog at baseline (C) and after 5 weeks (D). In the representative examples shown, there are clearly much greater alterations in atrial dimensions and contractile function in HF than in ATR. Baseline atrial areas were not significantly different for any dimension between ATR (Table 2A and HF (Table 2B) dogs. Left and right atrial systolic and diastolic areas increased from baseline to final follow-up in both groups. Left atrial systolic area increased by 10.0±14.2% in ATR dogs compared to 48.2±29.8% in the HF group (P=0.008, HF vs. ATR).


Figure 1
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  		Fig. 1 Apical 4-chamber diastolic (left) and systolic (right) views at baseline, B.L. (A) and 42 days (End-study=E.S.) (B) in a representative ATR dog, and at baseline, B.L. (C) and 5 weeks (End-study=E.S.) (D) in a representative HF dog. Atrial outlines are indicated by the white dashed lines. Computer-generated area and circumference (CIRC) values are shown, with A corresponding to the LA recordings and B to the RA recordings.

 

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  		Table 2 A. Serial echocardiographic analyses of atrial area and function in ATR group

 
There were also significant differences between groups in the evolution of left atrial systolic area: the HF group showed a significant evolution over time (P=0.0001), but the ATR group did not (P=0.16), as illustrated in Fig. 2A. Left atrial diastolic area increased by 24.2±19.7% and by 80.2±29.1% in ATR and HF dogs respectively (P=0.0002, HF vs. ATR), with both groups evolving significantly over time, as shown in Fig. 2B. Similar findings were obtained for the RA (Table 2A and B).


Figure 2
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  		Fig. 2 (A) Evolution of left atrial systolic area over time in atrial tachy-pacing remodeling (ATR) and heart failure (HF) dogs. Results are mean and 95% confidence interval (CI). (B) Evolution of the left atrial diastolic area over time in atrial tachy-pacing remodeling (ATR) and heart failure (HF) dogs. Results are mean and 95% confidence interval (CI).

 
Left and right atrial FAS decreased from baseline to final follow-up in each group. Left atrial FAS evolution in ATR and HF groups is illustrated in Fig. 3. At the final study, FAS in the left atrium decreased by 19.4±16.4% in the ATR group and by 41.8±13.6% in HF dogs (P=0.007, HF vs. ATR). FAS in the right atrium decreased from baseline to final follow-up by 13.7±18.1% in the ATR group and by 33.7±17.6% in HF dogs (P=0.032, HF vs. ATR). The FAS evolution over time was statistically significant in both groups for both the left and right atrium. Left ventricular ejection fraction decreased from baseline to final follow-up by 10.3±11.3% (from 59.5±3.5% to 53.2±8.1%) in the ATR group and by 46.9±11.7% (from 59.3±3.7% to 31.8±7.3%) in HF dogs (P<0.001, HF vs. ATR).


Figure 3
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  		Fig. 3 Evolution of the left atrial fractional area shortening (FAS) over time in atrial tachy-pacing remodeling (ATR) and heart failure (HF) dogs. Results are mean and 95% confidence interval (CI).

 
3.2 Electrophysiological assessment
ERP at follow-up was 89±6 ms at a basic cycle length of 300 ms in ATR dogs and 139±8 ms in the HF group (P<0.001 between groups). Mean AF duration was 40.8±12.0 min and 12.0±8.2 min in ATR and HF dogs respectively (P<0.001, ATR vs. HF). ERP correlated with AF duration in ATR dogs (r=–0.79, P<0.001), but not in HF dogs (r=0.20, P=NS). In contrast, a strong correlation was found between AF duration and both right and left atrial diastolic areas at the last follow-up study in HF dogs (r=0.71 and 0.77; P<0.01 for each; Fig. 4A). Mean AF duration was not correlated with diastolic areas in ATR dogs (r=–0.18 and 0.29, P=NS). Decreases in FAS also correlated with AF duration in HF dogs (r=0.74 and 0.84 for left and right atrium respectively, P<0.01 for both; Fig. 4B) but did not in ATR dogs (r=–0.42 and 0.09, P=NS). Systolic dimensions were not significantly correlated with AF duration in either group.


Figure 4
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  		Fig. 4 (A) Correlation between duration of atrial fibrillation and atrial diastolic areas at last follow-up restudy in heart failure (HF) dogs. (B) Correlation between duration of atrial fibrillation and relative decreases of atrial fractional area shortening (FAS) over the study course in heart failure (HF) dogs.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present study constitutes the first detailed echocardiographic comparison of atrial dimensions and contraction between ATR and HF models of AF. The results demonstrate that there is substantially more remodeling of atrial size and emptying function in HF than in ATR dogs. Furthermore, AF duration is correlated with atrial dimension and contraction indices in HF dogs, but not in ATR dogs.

4.1 Comparison with previous studies of altered atrial dimensions in animal models of AF
The increases in atrial areas observed in ATR dogs in our study were substantially smaller than those reported by Morillo et al. using a similar model [7]. Morillo et al. described increases of 45 and 67% in left and right atrial areas over a 6-week period of atrial pacing at 400 bpm. An important methodological difference is that, in the latter report, there is no mention that atrial dimensions were evaluated at a systematic point in the cardiac cycle. As shown in Table 2A and B, atrial areas in atrial diastole are 50% larger than in atrial systole. Because of this, we measured separately systolic and diastolic areas (defined as the largest and smallest areas during each cardiac cycle) in each dog. In addition, the method of sedation and the position for echocardiography were different between the studies. Power et al. [10] reported an approximately 100% increase in atrial diastolic area in a 6-week right ventricular pacing ovine HF model, while the increase in atrial diastolic area in our 5-week ventricular pacing HF dog model was of the same order (80.2%). Our study differed from the study by Power et al. in that we also analyzed atrial systolic area and FAS, compared changes in HF with those in ATR (which was not examined in the Power study), and related changes in atrial size and contraction to AF duration.

4.1.1 Atrial electrophysiological remodeling
As previously described, rapid atrial activation causes atrial electrophysiological remodeling, including time-dependent decreases in atrial ERP, ERP adaptation to rate, conduction velocity and in wavelength, which, along with increased heterogeneity, provide a substrate for AF in the ATR model [6–9,16,17]. Additional potential electrophysiological contributors to AF promotion include conduction slowing [6,7,16], changes in connexin density and distribution [16,18,19], and cellular structural remodeling with myolysis and glycogen accumulation [20]. Atrial dilation, with increased mass for AF maintenance, has been considered a potential contributor to AF promotion in dogs with ATR based on the report of Morillo et al. [7]. In 1997, Wijffels et al. showed that the effects of acute atrial volume change do not support a primary role for atrial dilation in AF promotion by short-term (24 h) ATR [21]. However, the effects of acute volume changes produced by altering preload may be quite different from those of slowly-developing structural changes in atrial dimensions. The results of the present study suggest that changes in atrial dimensions play little, if any, role in AF promotion by 6 weeks of atrial tachycardia.

Previous studies have also shown that heart failure does not alter atrial ERP in a fashion that would be expected to favor AF [8,10]. Alterations in local atrial conduction properties associated with interstitial fibrosis may play an important role in stabilizing the re-entry that maintains AF in the failing heart [8]. In the present study, we found that atrial macroscopic structural/contractile remodeling (as indicated by atrial dimensions and fractional shortening respectively) strongly correlate with AF duration in HF dogs. This association may indicate that the considerable increase in atrial size in HF dogs contributes to the AF substrate (e.g., by providing critical circuit sizes for re-entry). Alternatively, atrial dilation could reflect microstructural changes (e.g., tissue fibrosis) that are themselves important in AF promotion, or could simply be an indicator of the severity of the HF process leading to the AF substrate. The increased atrial pressure associated with atrial dilation in CHF could also contribute to AF promotion by stimulating stretch-activated non-selective cation channels [22]. The different electrophysiological substrates for AF associated with ATR compared to HF result in potentially important differences in the response to antiarrhythmic agents [23].

4.2 Potential clinical relevance
Patients with sustained AF often present biatrial enlargement and left atrial dysfunction [24–26], and it has been suggested that long-term AF per se contributes to atrial enlargement [24]. Suarez et al. followed 23 subjects with lone AF for an average of 6.2 years, and observed a slow and progressive increase in left atrial size independent of changes in left ventricular size and function [26]. Subjects with persistent AF had a larger percentage increase in left atrial size than those with paroxysmal AF (18.9 vs. 10.8%). In some studies, left atrial enlargement has been found to predict the recurrence of clinical AF after active conversion to sinus rhythm [27–29], although this has not been a uniform observation. We observed a very significant correlation between atrial dimensions and AF stability (as indicated by AF duration) in dogs with HF. The absence of such a correlation in dogs with ATR likely reflects the strong AF-promoting effects of the electrophysiological changes caused by 6 weeks of atrial tachycardia and the relatively smaller degree of atrial macroscopic structural remodeling in this group. Nonetheless, the significant increase in atrial diastolic dimensions and quite significant decrease in FAS in ATR dogs is consistent with the progressive but relatively slow (months to years) increases in atrial dimensions observed in patients with persistent AF. The differences in the strength of the relationship between atrial areas and AF duration in ATR vs. HF dogs may help to explain the discrepancies among studies of the value of LA area in predicting AF recurrence after direct current cardioversion in patients. Some patients may have arrhythmic substrates analogous to those in HF dogs, in which atrial dilation is strongly related to AF vulnerability, whereas others may have substrates dominated by ATR or similar pathologies, for which atrial dimensions are a poor predictor. The predictive value of left atrial size in an individual study would then depend on the specific mix of patients in the population evaluated.

Transient atrial mechanical dysfunction is a very significant factor in post-cardioversion thromboembolic events among AF patients [30,31]. The highly-significant reductions in FAS caused by ATR are consistent with suggestions that an atrial tachycardiomyopathy may be involved in post-cardioversion contractile dysfunction. Steady-state FAS decreases were observed within 2 weeks of the onset of atrial tachycardia, consistent with clinical observations of atrial thromboembolic events occurring after relatively short (1 week or less) periods of AF [32]. ATR-induced contraction abnormalities were greater in the left than right atrium (Table 2A). Pulmonary emboli are a less common complication after AF cardioversion than systemic emboli. Our results raise the question of whether this finding may in part be due to more important ATR-related contraction abnormalities in the left compared to right atrium.

Decreased left atrial appendage function is associated with elevated ventricular filling pressure in patients with congestive heart failure [33]. Based on studies of the left atrial contribution to ventricular filling during the evolution of HF, it has been proposed that the increased workload imposed on the left atrial myocardium from chronically elevated left ventricular end-diastolic pressure may lead to progressive intrinsic left atrial dysfunction [34]. Hoit et al. reported a significant upregulation of β-myosin heavy chain in the left atrial body, but not in the appendage, of dogs with pacing-induced HF [35]. This isoform switch was associated with decreased velocity of left atrial contraction and increased atrial mechanical work. Our study is the first of which we are aware to document the evolution of right and left atrial dimensions and FAS in an animal model of HF. Diastolic areas increased more than systolic areas in both ATR and HF groups (Table 2A and B). This likely reflects a decrease in emptying that exceeded the change in elastic properties of the atria, and was possibly due to increased ventricular diastolic pressures (as measured in previous studies [8]) that strongly impair atrial emptying.

Antiarrhythmic drug therapy to prevent AF has traditionally been designed to alter electrophysiological properties to make atrial re-entry less likely [3,36]. Our observation of a good correlation between atrial macroscopic structural and functional remodeling and AF duration in HF dogs supports the rationale for intervening at the level of the structural substrate in order to prevent AF. The results of the TRACE study, showing AF prevention by converting enzyme inhibitor therapy in patients with left ventricular dysfunction after acute myocardial infarction [37], are consistent with this notion.

4.3 Potential limitations
We chose slightly different time points for performing echocardiography in ATR vs. HF dogs. This was done because of the differing designs of the ATR and HF studies, which evaluated dogs subjected to 6 versus 5 weeks of intervention respectively in order to facilitate comparisons with previously-published studies in the ATR and HF models [6,8]. Because our observations were longitudinal and the changes we saw were quite consistent over time in each group (e.g., see Figs. 2 and 3Go), we don’t believe that the different observation points affected the interpretability of our results. Changes in atrial dimensions were quite limited over the observation period in dogs with ATR. This does not, however, exclude the possibility that larger changes would occur and contribute to AF maintenance with substantially greater periods of atrial tachycardia, as typically occur in patients with months of persistent AF.

Dogs subjected to atrial tachypacing had intact atrioventricular conduction, which might have led to periods of rapid ventricular response and a potential component of ventricular tachycardiomyopathy. The small (~10%) decrease in left ventricular ejection fraction over the course of the study in ATR dogs may have been in part due to periods of rapid ventricular rates. This change should, if anything, have increased the changes in atrial dimensions and atrial contraction in ATR dogs, and made it harder to show a difference from HF dogs. Thus, any component of ventricular tachycardiomyopathy in ATR dogs must have been small and insufficient to obscure the large difference between ATR and HF groups. Controlling the ventricular response rate in ATR dogs would have required drugs like digoxin, beta-blockers or Ca2+-antagonists, which could have directly affected the remodeling process, or the performance of AV nodal ablation, with resulting radiofrequency damage and a loss of AV synchrony with potential effects on atrial dimensions and contraction.

Time for primary review 21 days.


   Acknowledgements
 
The authors thank Chantal St-Cyr and Chantal Maltais for excellent technical support, and Diane Campeau for secretarial help with the manuscript. This study was supported by grants from the Quebec Heart and Stroke Foundation and the Canadian Institutes of Health Research. Danshi Li was a Heart and Stroke Scientific Corporation of Canada/Astra Zeneca Research Fellow, and Jean-Claude Tardif is a Clinical Research Scholar of the Fonds de la Recherche en Santé du Québec.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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