Editorials |
From the Department of Pediatrics, Duke University Medical Center, Durham, NC.
Correspondence to Madison S. Spach, MD, Department of Pediatrics, P.O. Box 3475, Duke University Medical Center, Durham, NC 27710. E-mail cspach{at}duke.edu
See related article, pages 839–847
Key Words: atrial fibrillation fibrosis reentry triggered activity
| Introduction |
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In recent years considerable new information has appeared concerning AF mechanisms that occur in different regions of the atria in different cardiac states.3 This point is highlighted by the report of Tanaka et al4 in this issue of Circulation Research. These authors used high-resolution electrophysiological and microstructural techniques, along with computer model simulations, to study wavefront dynamics during acetylcholine (ACh)-induced AF in heart failure sheep hearts. The heart failure hearts had developed prominent fibrotic patches in the posterior left atrium near the pulmonary veins, whereas in the control (normal) hearts patches of fibrosis were smaller, diffusely distributed, and more centrally located with respect to the 4 pulmonary vein ostia. In the heart failure hearts, during AF variable wavefront breakthroughs to the endocardium occurred in the area of fibrotic patches adjacent to the pulmonary veins. The authors concluded that scroll waves within the posterior left atrial wall produced a microreentry source for the endocardial breakthroughs in the region of the larger collagen patches, thus providing the underlying mechanism of AF.4
A myriad of reports provide varied information about substrates and mechanisms of AF as a background for the study of Tanaka et al4 To simplify, a minimum degree of complexity of AF factors is considered here (Figure); ie, ionic currents, atrial anatomy, fibrosis, and wavefront dynamics.
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| Stepwise Increase in Information About AF Electrical Activity |
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Scherfs aconitine experiments subsequently indicated that AF was attributable to "rapid impulse formation in a single center".6 For different conditions, in 1964 Moe et al7 reported their widely known computer model results, which indicated that "multiple wavelets" produced AF. Over 2 decades later Allessie et al8 demonstrated in human and canine atria that multiple interactive wavelets of macro size supported Moes theory of AF. Schuessler et al9 then expanded reentrant mechanisms by demonstrating that a single rapid reentrant circuit can produce multiple wavelets in ACh-induced AF. Haïssguerre et al10 subsequently reported in 1998 that in humans AF frequently is initiated by repetitive activity in the pulmonary veins, and ablation of these areas abolished AF. Since then, triggered activity within small areas has been considered important in both the initiation and maintenance of AF.11 With respect to repetitive activity in small atrial areas, however, Mandapati et al12 demonstrated in healthy sheep hearts that repetitive reentry in the posterior left atrium near or at pulmonary vein ostia can produce microreentrant sources for AF. Consequently, a challenge at present is to clarify whether the mechanism is triggered activity versus microreentry as the source of repetitive activity within small atrial areas.
In regard to repetitive activity, the results of Tanaka et al4 may be clinically relevant because their results in sheep hearts had similarities to those of Wu et al13 in humans with permanent AF. The patients with AF also demonstrated rapid repetitive activity in the posterior left atrium at or near the pulmonary veins. However, both Tanaka et al4 and Wu et al13 were unable to resolve whether microreentry versus focal discharges produced the rapid repetitive activities they found. Interestingly, associated computer simulations by Tanaka et al4 predicted that whether the AF was attributable to reentry or focal discharges, the larger fibrotic patches in heart failure had the major effect on AF wavefront dynamics. Thus, it is worth looking at some of the remodeling features of 2 common AF conditions, heart failure and aging, to answer questions about the origin of AF mechanisms.
| Atrial Ionic Remodeling With Heart Failure and Aging |
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| Remodeling Atrial Collagen (Fibrosis) With Heart Failure and Aging |
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We found premature stimuli to initiate anisotropic conduction abnormalities that led to reentry within areas as small as 1.6 mm2 in aging human atrial bundles.19,20 There were 2 major underling conduction disturbances that produced the reentry in such a small area: one was a very low effective velocity with conduction across fibers (as low as in the AV node), and the other was decremental conduction to failure. Similar conduction disturbances and reentry did not occur in younger adult bundles. These conduction differences were related to the aging proliferation of connective tissue septa. In the younger adult bundles collagenous septa were short and scattered, whereas in bundles over 60 years of age there were extensive lengthy collagenous septa (microfibrosis). As to electrical mechanisms, collagenous septa mark areas in which there is an absence of side-to-side coupling between fibers.19 Interestingly, Miragoli et al21 recently demonstrated effects on conduction of high density myofibroblasts in cultured strands. The density of myofibroblasts and their effects provide an unexplored area in diseased hearts with collagenous septa.22
Electrophysiologically, we have considered fibrosis to be an abnormality of gap junctions with regard to their distribution because of the loss of cellular connectivity across areas of collagen deposition.19,20 When wavefronts propagate in a direction to cross collagenous septa, there is no cell-to-cell coupling between fibers on each side of the septa. Thus, these sites produce an obstacle by breaking the intracellular component of the circuit of currents necessary for the propagation of depolarization. A recent computer model of human aging atrial microstructure with collagenous septa20 reproduced the experimental results19 after premature stimuli, both the conduction disturbances and "microreentry". The conduction events were related to INa-fibrosis interactions in which variations in the magnitude of INa were associated with decremental conduction (decreasing INa) that either failed (no INa turn-on) or led to incremental conduction (increasing INa).20 However, experimental techniques are not yet available to measure INa during propagating depolarization. Until such experimental measurements are achieved, use of computer microstructural models provides a promising alternative to gain insight to arrhythmogenic INa-microstructural interactions.
Although the precise signaling processes involved in the development of atrial fibrosis are unknown, the molecular pathways involved are beginning to emerge. The potentially important role of TGF-beta1 and the renin-angiotensin system in AF is presented in a recent article by Everett and Olgin.23 Thereby, the results of Tanaka et al4 in this issue of Ciruculation Research provide an additional stimulus to resolve important unanswered questions about the origin of fibrosis and its electrical effects that enhance atrial fibrillation.
| Acknowledgments |
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This work was supported by NIH Grant H50537.
Disclosures
None.
| Footnotes |
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| References |
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