Intrinsic left atrial histoanatomy as the basis for reentrant excitation causing atrial fibrillation/flutter in rats
Introduction
Atrial fibrillation/flutter (AF/AFL) is a common rhythm disorder1 that is initiated by ectopic firing and then persists by complex reentrant impulse propagation within the atria.2, 3 Of various regions in the atria, the muscle sleeves of the pulmonary veins (PVs) have been pinpointed as important sites of origin for paroxysmal AF and are therefore regarded as effective therapeutic targets for catheter ablation to terminate and preclude the arrhythmia.4 However, ablation of the PVs has limited efficacy for persistent AF,5 which is mediated by reentrant propagation within the atria.2, 3 Several lines of evidence suggest that the left atrium (LA), especially the posterior wall including the LA roof, can be a culprit site for AF/AFL reentrant activity. For example, high-resolution optical mapping in isolated failing sheep hearts revealed that vortex-like reentry emerges through the posterior LA.6 Clinical studies involving electroanatomical mapping also revealed reentrant activity via conduction block at the posterior LA.7 Furthermore, a role for the LA roof in reentrant AF was suggested by suppression after ablation of this region in both clinical and experimental studies.8, 9, 10 However, compared with that of the PVs, the histoanatomy of the LA underlying reentrant propagation in AF/AFL has not been fully described. This is because persistent AF principally occurs as a result of many forms of functional and structural atrial remodeling produced by various underlying heart diseases.2, 3 Nevertheless, certain histoanatomic substrates responsible for reentrant propagation in AF/AFL, if residing even in the LA of nondiseased rat atria, may be a clue to understanding the mechanism of persistent AF/AFL in humans. To address this issue, we sought to induce AF/AFL in ex vivo perfused hearts from healthy rats and we conducted functional and histoanatomic studies of the whole atria by combining optical imaging of impulse propagation with histologic examination. We used excised rat hearts rather than in situ hearts of larger animals because (1) less complicated spatiotemporal patterns of AF/AFL can be detected readily owing to the small size of the atria,11 (2) the entire atrial histology can be assessed systematically on a single glass slide, and (3) excision of the heart is essential for spatiotemporally precise fluorescence analysis of the posterior aspects of the LA. We unveiled intrinsic histoanatomic features of the LA, especially of the LA roof, that contribute to the formation of reentrant circuits in AF/AFL.
Section snippets
Methods
Experimental methods are described in detail in the Expanded Materials and Methods section of the Online Supplemental Material. Briefly, male Wistar rats were used in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985) and with approval of the Animal Care Committee of the Kyoto Prefectural University of Medicine. Di-4-ANEPPS-stained, perfused heart-lung preparations (Figure 1) were used for
Optical imaging of reentrant AF/AFL
AF/AFL was induced in 15 (78.9%) of the 19 hearts by a single extrastimulus (S2) after consecutive 5-Hz pacing (S1) at the RA appendage. A representative electrocardiogram tracing and isochronal maps for the initiation of AF/AFL are shown in Figure 2. During RA (S1) pacing at 5 Hz, the electrical impulse traveled from the RA to the left and right PVs, respectively, along the LA roof and toward the LA appendage through the coronary sinus (CS) across the posterior wall of the LA (Figure 2B),
Rationale for the study
Because of the complex and variable excitation patterns of persistent AF in humans,12 major difficulties are encountered in clinical electrical mapping studies used to explore the exact arrhythmogenic substrates for AF. Such electrical complexities are due to the large size of the human atria and the various forms of structural and electrical remodeling, for example, fibrosis and altered distribution of gap junctions and refractoriness, which result from aging or disease states.2, 3 However,
Conclusions
We have shown in rat heart-lung preparations that regional histoanatomic heterogeneity in the LA may contribute to the generation of reentrant impulse propagation in AF/AFL. Validation of our present findings in persistent AF in remodeled atria of humans or large animals awaits further study.
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Radiofrequency ablation of left atrial flutter mediated with double potentials in a seemingly normally structured heart
2014, International Journal of CardiologyCitation Excerpt :Pak et al. demonstrated that the morphologic enlargement of the anterior wall of the LA is more extensive in the setting of left atrial remodeling [20]. Matsuyama et al. reported that histologic quantification revealed significantly lower myocardial density in the septum around the mitral annulus of rat, which is consistent with the slower impulse propagation there [21]. Similarly, in our study, the DP area near the mitral annulus matched with the LA–aorta contiguity which is responsible for the low voltage of the anterior wall of the LA.
Localising re-entry in atrial fibrillation: Anatomical clues to the substrate of rotors
2013, Journal of ArrhythmiaThe left atrial myocardium: Naturally "wired" for arrhythmogenicity?
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2019, Anatomy and Cell BiologyAn automated hybrid bioelectronic system for autogenous restoration of sinus rhythm in atrial fibrillation
2019, Science Translational Medicine
This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (C09016631 and B20390115) and Intramural Research Fund for Cardiovascular Disease of the National Cerebral and Cardiovascular Center (22-1-2).