IJBEM, Vol. 4, No. 2, 2002.

Dynamic nature of the atrial fibrillation substrate during the development and reversal of heart failure in dogs

K. Shinagawa¹, Y-F. Shi¹, J-C. Tardif¹, T-K. Leung¹, S. Nattel^1,2
¹Institut de cardiologie de Montréal, Université de Montréal,
5000 Bélanger est, Montréal, Québec, CANADA H1T 1C8
²McGill University
3801 University Street, Montreal, Quebec, CANADA, H3A 2B4

Abstract: Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of atrial structural remodeling upon removal of the underlying stimulus has not been studied. Dogs were subjected to 4-6 weeks of ventricular tachypacing (VTP, 220-240/min) to induce congestive heart failure (CHF), followed by a 5-week recovery-period leading to hemodynamic normalization at 5-week recovery (Wk5_rec). The duration of pacing-induced AF (DAF) under ketamine/diazepam/isoflurane anesthesia increased during VTP and recovered towards baseline during the recovery-period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under morphine/chloralose anesthesia. Wk5_rec dogs showed no recovery of CHF-induced atrial fibrosis (3±0.3% controls vs. 11±1% CHF, 12±1% Wk5_rec) or local conduction abnormalities. One week of atrial-tachypacing failed to alter atrial effective refractory period (ERP) in CHF dogs, but caused highly-significant ERP reductions and atrial-vulnerability increases in Wk5_rec dogs. We conclude that reversal of CHF is followed by normalized atrial function and decreased DAF; however, fibrosis and conduction abnormalities are irreversible and a substrate that can support prolonged AF remains.

INTRODUCTION

Experimental CHF produces a substrate for AF maintenance characterized by atrial interstitial fibrosis similar to atrial histopathology in clinical CHF [1] and in mitral valve disease. CHF and valve dysfunction can be improved by medical therapy and mitral-valve surgery respectively; however, the extent to which the AF substrate subsequently resolves is unknown. We have previously shown that atrial tachycardia (AT)-remodeling effects in the presence of CHF differ from those in normal hearts [2] - whether AT effects are modified by previous CHF is unknown. This study was designed to evaluate time-dependent changes in AF substrate upon development and reversal of VTP-induced CHF, and to compare AT-remodeling in active vs previous CHF.

METHODS

Dogs were subjected to 4-6 weeks of VTP to induce CHF, followed by a 5-week recovery-period leading to hemodynamic normalization. Electrophysiological studies (EPS) were performed at least weekly during and after VTP, using indwelling atrial electrodes. Atrial ERP was measured at multiple basic cycle lengths (BCLs). DAF was based on the average of 10 burst-pacing inductions for AF£20 minutes and 5 for 20-30 minute AF. AF>30 minutes was terminated by external synchronized DC cardioversion. Two-dimensional echocardiographic studies were performed.

Open-Chest Study and Histology

After closed-chest EPS at Wk5_rec, dogs were instrumented for mapping and studied as previously described [1]. Similar open-chest studies were performed in acute control (CTL) dogs and CHF dogs (same VTP without recovery).

Tissue samples obtained from 6 atrial regions were stained with Masson-trichrome. Microscopic images were analyzed with SigmaScan 4.0 (Jandel Scientific).

Evaluation of AT-Remodeling

Right atrial-pacing (400 bpm) was performed in additional normal dogs (AT-only), CHF dogs (CHF+AT, 1-week AT superimposed on the last week of VTP) and Wk5_rec dogs (1-week AT beginning 5 weeks after stopping VTP). Atrial vulnerability was defined as the % of sites in each dog at which AF could be induced by single extrastimuli.

Data Analysis

Data are mean ±SEM. Phase-delay analysis was used to evaluate local conduction abnormalities as previously described [1,2]. Statistical comparisons were by ANOVA and chi-squared.

RESULTS

Time-dependent Changes During Development and Recovery of CHF

DAF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered towards baseline during recovery-period. DAF at control EPS (Day0), mid-VTP period (middle), end-VTP (CHF_max), 7 (Day7_rec) days, and 5 (Wk5_rec) weeks after VTP termination were 2±1, 217±72, 591±155 (**P<0.01 vs. Day0), 521±190 (**), and 65±24 s, respectively. The % of dogs with a sustained AF increased significantly at middle (43%, *P<0.05 vs. Day0) and CHF_max (79%**), and remained elevated until Day7_rec(36%*). There were no significant changes in atrial ERP.

Closed-chest EPSs were done under diazepam/ketamine/ isoflurane to allow repeated assessments, but open-chest EPSs were performed with morphine/chloralose to reproduce more closely the physiological vagotonic rested-state. Closed-chest DAF under morphine/a-chloralose anesthesia at Wk5_rec averaged 1575±225 s (**). Thus, although DAF decreases during recovery from VTP-induced CHF, a substrate for AF remains and can be unmasked by the use of a different anesthetic. VTP increased LA areas, decreased LV fractional shortening and increased filling pressures. All normalized with recovery.

Tissue-architecture and Electrophysiology

There was extensive interstitial fibrosis in CHF and Wk5_recdogs. In each of 6 atrial regions, fibrous-tissue content was similar for CHF and Wk5_recdogs, and both were significantly greater than for CTL dogs (P<0.01). Overall, mean fibrous-tissue content averaged 10.7±1.0% for CHF, 12.0±0.8% for Wk5_rec and 3.1±0.3% for CTL dogs (P<0.01).

At open-chest EPS, DAF was increased significantly and to a similar extent in CHF (759±269s, P<0.05) and Wk5_rec dogs (827±368s, P<0.05) compared to CTL dogs (29±13s). Local conduction slowing and the conduction heterogeneity index were equally prolonged in CHF and Wk5_rec dogs.

Effects of AT-induced Remodeling on CHF Dogs and Dogs having recovered from CHF s

We previously showed that in the presence of CHF, AT-remodeling changes in ERP are greatly attenuated. [2] In that study, it was impossible to determine whether the interaction was due to CHF-induced atrial fibrosis or to some feature of the CHF state (e.g., cross-talk in signal transduction). In the present study, the atrial fibrotic substrate characterizing CHF is maintained in Wk5rec dogs when hemodynamics and cardiac function have normalized. In CTL and Wk5_rec dogs, AT substantially reduced ERP and ERP rate-adaptation, whereas changes were greatly attenuated in CHF dogs. AT substantially increased vulnerability to AF induction in CTL dogs (4% vs. 56%, P<0.01) , but didn’t significantly alter vulnerability in CHF dogs (7% vs. 16%, ns). In contrast, atrial vulnerability was greatly enhanced by AT in Wk5_rec dogs (6% vs. 77%, P<0.01), producing vulnerability even greater than that noted in CTL dogs with AT-remodeling (P<0.05).

DISCUSSION

We showed that the atrial fibrotic changes caused by 5 weeks of VTP do not reverse during a recovery period that allows for reversal of CHF-associated changes in cardiac function and dimensions. Despite the persistence of fibrosis, DAF decreased under some conditions but the persistence of an arrhythmogenic milieu was revealed under others.

Potential Significance

This is the first study of changes in the arrhythmia substrate upon removal of the initiating stimulus for arrhythmogenic atrial structural remodeling.

CHF and rheumatic valve disease strongly predispose to AF, and both produce prominent interstitial fibrosis in man.The hemodynamic consequences of both may potentially be reversed by medical treatment. Cardioversion of AF after corrective mitral valve surgery permits restoration and maintenance of sinus rhythm in some patients, but many relapse into AF. The results of the present study suggest that once fibrotic atrial structural remodeling has occurred, it is irreversible. It may therefore be very important to intervene early to prevent atrial structural remodeling. Indeed, a recent study found that early mitral valve replacement reduces the long-term incidence of chronic AF. [3]

The potential importance of the atrial-fibrotic substrate was indicated by the occurrence of prolonged AF under morphine/chloralose anesthesia and the increased atrial vulnerability of dogs subjected to AT following recovery from CHF. On the other hand, our results also indicate that atrial fibrosis is not the only determinant of prolonged AF. Factors other than fibrosis and conduction abnormalities that could contribute to the AF substrate in CHF include atrial dilation, tissue-stretch, and neurohumoral factors.

AT in Wk5_rec dogs caused ERP changes similar to normal dogs, whereas changes were greatly attenuated in CHF dogs. This indicates that the attenuation of AT-remodeling in CHF is due to CHF per se, and not to CHF-induced interstitial fibrosis. Furthermore, it implies that atrial tachyarrhythmias will have different remodeling effects in subjects with active CHF compared to subjects with atrial fibrosis due to previous pathology (eg, repaired mitral-valve disease), in which important ERP reductions combined with residual fibrosis lead to substantial increases in atrial vulnerability.

Prevention of the development of the AF substrate is an attractive treatment of AF, and has been shown to be feasible in animal models. [4] The present study suggests that such interventions may need to be applied early, before irreversible fibrotic changes occur.

Acknowledgments: Work supported by the Canadian Institutes of Health Research (CIHR), the Quebec Heart and Stroke Foundation and the Mathematics of Information Technology and Complex Systems (MITACS) network of centers for excellence. K. Shinagawa is a CIHR fellow. We thank C. Maltais and N. L'Heureux for technical assistance.

REFERENCES

[1] D. Li, S. Fareh, T-K. Leung, et al. “Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort” Circulation, vol. 100, pp. 87-95, 1999.

[2] K. Shinagawa, D. Li, T-K. Leung, et al. “The consequences of atrial tachycardia-induced remodeling depend on the pre-existing atrial substrate” Circulation, vol. 105, pp. 251-257, 2002.

[3] L.H. Ling, M. Enriquez-Sarano, J.B. Seward, et al. “Early surgery in patients with mitral regurgitation due to flail leaflets: a long-term outcome study” Circulation, vol. 96, pp. 1819-1825, 1997.

[4] D. Li, K. Shinagawa, L. Pang, et al. “Effects of angiotensin converting enzyme inhibition on the development of the atrial fibrillation substrate in dogs with ventricular tachypacing-induced congestive heart failure” Circulation, vol. 104, pp. 2608-2614, 2001.