- Email: [email protected]
How structurally normal are human atria in patients with atrial fibrillation?
VIEWPOINTS
ASSOCIATE EDITOR: YORAM RUDY
How structurally normal are human atria in patients with atrial fibrillation? Anton E. Becker, MD, PhD From the Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Atrial myocardium in humans shows structural changes that increase with aging. The most conspicuous are fibro-fatty replacement and patchy replacement fibrosis. The present study reveals that these structural changes are more extensive in hearts of patients with paroxysmal atrial fibrillation (AF) than in “no AF” hearts. The changes involve the myocardial sleeves on pulmonary veins and sites of rapid conduction, such as the terminal crest and Bachmann’s bundle. These structural changes should be taken into consideration as potential substrates for initiation and maintenance of atrial arrhythmias. KEYWORDS Atrial fibrillation; Atrial arrhythmias; Atrial fibrosis; Atrial infarction; Atrial myocardium; Terminal crest; Bachmann’s bundle; Pulmonary veins (Heart Rhythm 2004;1:627– 631) © 2004 Heart Rhythm Society. All rights reserved.
Introduction Most research into the mechanisms of atrial fibrillation (AF), particularly experimental animal studies, convey the implicit message that the atria basically are structurally normal. This message is somewhat surprising given that the vast majority of patients with AF have associated cardiovascular diseases, such as hypertensive, ischemic, or valvar heart disease. As early as 1972, Davies and Pomerance1 provided a detailed account of the histopathology of the atria in patients with AF on whom autopsy was performed. They demonstrated biatrial enlargement and extensive fibrosis in patients with a history of chronic AF. In 1997, Lie et al2 confirmed these observations and reported extensive pathology associated with AF, including focal degeneration and necrosis of atrial myocardium, extensive fibrosis, and fibro-fatty myocardial replacement. Another study involving endomyocardial right atrial septal biopsies taken from patients with lone AF, showed histologic abnormalities, compatible with a diagnosis of myocarditis, noninflammatory cardiomyopathy, or patchy fibrosis.3 In this context, it is interesting that heart failure induced in dogs also promotes AF and appears associated with a pathologic substrate similar to that observed in man.4 The question then arises, why do these data receive little attention in considerations regarding the genesis of AF? Address reprint requests and correspondence: Dr. Anton E. Becker, Emeritus Professor of Cardiovascular Pathology, Academic Medical Center, University or Amsterdam, IJsselmeerdijk 13, 1473 PP Warder, The Netherlands. E-mail address: [email protected].
Whatever the answer, it is worthwhile to briefly recapitulate some of our own observations in human atria in an attempt to revitalize interest in electrophysiologic-pathologic correlates in the arena of AF research.
Pulmonary veins Since the landmark publication by Haissaguerre et al5 it is widely accepted that pulmonary veins may provide a source of focal activity initiating AF. This publication also led to the rediscovery of left atrial myocardial extensions onto the pulmonary veins, known as myocardial sleeves, located on the epicardial side of the veins and separated from the smooth muscle media of the vein by a fibro-fatty tissue plane. At the site of the ostial junction, the sleeve is composed of several layers of myocardial fibers with different spatial orientations, producing a multilayered and multidirectional coating of the most proximal part of the vein. The sleeves gradually diminish in thickness and lose their multilayered composition toward the lung hilum. The more distal the location, the more the compact nature of the sleeve diminishes. Small strands of myocardium, representing the most distal extensions of the sleeve, are not uncommonly observed as almost isolated fascicles. In these instances, the complete circumference of the vein is no longer enveloped by left atrial myocardium— only a small part of its wall is enclosed. In tracing the sleeves from proximal (left atrium) to distal (lung hilum), perimysial fibrous tissue increases. The fibrosis initially encloses small groups of myocardial cells but eventually forms distinct fibrous strands and patches in which the myocardium gradually disappears
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2004.09.009
628
Figure 1 Histology of a myocardial sleeve extending onto a pulmonary vein. Upper panel: Low-power view showing the left atrial myocardial sleeve (Myo) on the epicardial side of the vein, separated from the smooth muscle media of the vein by a fibrofatty tissue plane. Note extensive band-like fibrosis (red) on the pulmonary vein side of the sleeve. Lower panel: Higher magnification of boxed area in A reveals patchy replacement fibrosis. Elastic van Gieson stain. (From Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary vein in humans: anatomic observation relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 2000;11:888 – 894, with permission.)
(Figure 1). It is tempting to speculate that these changes, which are highly reminiscent of ischemic events, induce microreentrant phenomena and, hence, are responsible for generating ectopic beats within pulmonary veins. An earlier concept promoted by Spach et al7 argued that development of extensive collagenous septa induced nonuniform anisotropic electrical propagation that could result in microreentry and thus form a basis for the high incidence of atrial tachyarrhythmias in older people.
Terminal crest and Bachmann’s bundle Impaired conduction in fast conducting pathways, such as the terminal crest, pectinate muscles and Bachmann’s bundle, could play a critical role in the pathophysiology of atrial tachycardias. A microscopic study was performed of 20 hearts, 10 from individuals with a known history of paroxysmal AF
Heart Rhythm, Vol 1, No 5, November 2004 and 10 without a history. Of the 10 patients with AF, five were male (mean age 74.4 years, range 61– 82) of the 10 patients in the no-AF group, seven were male (mean age 70.1 years, range 26 –92). Cardiac pathology was dominated by obstructive coronary artery disease (CAD) and mitral valve disease. The AF group demonstrated CAD with infarct scars and a coronary artery bypass graft (CABG) procedure in three patients, CAD with infarct scars in one, and CAD with an acute myocardial infarct in one. Degenerative mitral valve disease was observed in five patients and was associated with CAD in three. In the no-AF group, three patients had CAD with myocardial scarring, two had CAD with a coronary bypass, and one had CAD with degenerative mitral valve disease. Two patients had cardiac hypertrophy, possibly due to hypertension. No cardiac pathology was identified in two other patients (26 and 55 years). Sections were taken perpendicular to the long axis of the terminal crest at the level of the anticipated sinus node and more inferiorly at the site where the terminal crest just ends by fanning out into separate bundles. Sections were taken from Bachmann’s bundle along its long axis (right atrium– left atrium) and perpendicular to the long axis. Taking normal “textbook” myocardial histology as paradigm (parallel-oriented myocardial fibers enwrapped by endomysial collagen and myocardial bundles held together by perimysium), almost all sections, either from the terminal crest or Bachmann’s bundle, contained abnormalities. By far the most common abnormality was fibro-fatty replacement with a patchy distribution within the myocardium. The phenomenon itself was not different between hearts with and hearts without a history of AF. However, the phenomenon was much more extensive in hearts of AF patients. In some AF patients, the terminal crest or Bachmann’s bundle was almost totally replaced by fibro-fatty tissue (Figure 2). Extensive postinfarct replacement fibrosis (scarring) was observed in three patients with CAD and CABG, with additional foci of acute myocardial infarction observed in two of these three patients (Figure 3). Both of the patients were readmitted to the hospital where they had undergone their CABG procedure with signs and symptoms of ischemic cardiomyopathy. Thus, significant histopathologic changes appear to affect the fast conducting pathways, with fibro-fatty tissue replacement as a common denominator. The presence of this particular feature can be considered almost normal, at least in the elderly population. However, it is striking that, in general, patients with a history of AF had more highly pronounced changes than patients without AF, accepting the limitations of no quantitative data and a small series. This finding evokes considerations of the effects of focal disruption of parallel-oriented muscle fibers alluded to earlier. A relationship between the genesis of atrial tachyarrhythmias and a critical level of fibro-fatty disruption can be hypothesized. Another important point arising from these observations is that atrial myocardial infarction may be more common
Becker
Atrial Structure and AF
629
Figure 2 Histology of the terminal crest (upper panels) and Bachmann’s bundle (lower panels) showing “normal” histology on the left and extensive fibro-fatty replacement on the right. Hematoxylin-eosin stain. CT ⫽ terminal crest; endo ⫽ left atrial endocardium; SN ⫽ sinus node; Bachmann ⫽ Bachmann’s bundle epicardially.
than often believed. The fact that the present small series (with a limited number of microscopic sections from only two selected sites) revealed two cases with acute microinfarction is telling. The study provides evidence suggesting that small patches of replacement fibrosis, often encountered in atria, are micro-scars of ischemic events. The atrial coronary artery branches usually are not affected by atherosclerosis, but this lack of association does not preclude the possibility of ischemic events. Postmortem coronary angiograms from hearts with extensive obstructive multivessel CAD show that collaterals exist between the left and right ventricular systems via the atrial arteries, creating the potential of a “steal” phenomenon. Occurrence of recent atrial infarcts provides a substrate for initiation of atrial tachyarrhythmias, such as those originating from infarcted ventricles. Hence, the atrial pathology encountered is diverse, and a distinction must be made between acute conditions (infarcts, infection, metastatic invasion) and chronic events, of
which fibro-fatty replacement of (as yet) unknown origin appears the most common.
Conclusion Considering human atria of patients with AF as structurally normal appears to be an illusion. It also is an illusion to think that atria in older people do not undergo histologic changes. In the early 1960s, Lev and McMillan reported increases in collagen and fatty replacement of atrial myocardium from the third decade on (see reference2). The fact that almost all microscopic sections reveal structural changes supports past observations, which seem to be largely forgotten. In this setting, it is fascinating that the degree and extent of fibro-fatty replacement and patchy replacement fibrosis are much more prominent in atria of patients with paroxysmal AF than in “no AF” hearts. Caution is warranted, however,
630
Heart Rhythm, Vol 1, No 5, November 2004
Figure 3 Histology of the inferior part of the terminal crest. Upper left panel: Low-power view showing extensive replacement fibrosis (scarring). Upper right panel: Higher magnification of left upper panel. Lower left panel: Low-power view showing recent hemorrhagic micro-infarcts (boxed area) and extensive replacement fibrosis. Lower right panel: Higher magnification of boxed area in lower left panel showing greater detail of changes. Hematoxylin-eosin stain. CT ⫽ terminal crest.
because no quantification of changes is available, and conclusions are based on a limited number of sections and hearts. Nevertheless, it is tempting to believe a critical level of histopathologic changes provides the substrate for initiation of an atrial arrhythmia and its subsequent maintenance. Although the genesis of structural changes is not fully clarified, ischemic events cannot be ruled out. Acute atrial myocardial micro-infarction was seen, albeit in patients with severe CAD. This finding raises the question of whether ischemic events are responsible for areas with replacement fibrosis, which are commonly encountered in the atria. To appreciate this option, recall that ischemia and infarction are not necessarily related to coronary artery occlusion. Other circumstances may create an imbalance between myocardial oxygen demand and consumption. A steal phenomenon through atrial coronary arteries may leave some parts of the atrial myocardium insufficiently perfused. Similarly,
replacement fibrosis in the peripheral parts of the myocardial sleeves on pulmonary veins may be due to the likely possibility that these sites are “watershed” zones. In summary, human atria of older individuals (ⱖ30 years) demonstrate a range of structural changes that should not be ignored as substrates for initiation and maintenance of atrial tachyarrhythmias. The heterogeneity fits with recent evidence suggesting that “ectopic activity, single circuit reentry and multiple circuit reentry may all be involved in AP.”8
References 1. Davies MJ, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J 1972;34:530 –525. 2. Lie JT, Falk RH, James TN. Cardiac anatomy and pathologic correlates
Becker
Atrial Structure and AF
of atrial fibrillation. In: Falk RH, Podrid PJ, editors. Atrial Fibrillation: Mechanisms and Management. Second Edition Philadelphia: Lippincott-Raven, 1997:23–52. 3. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997;96:1180 –1184. 4. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 1999;100:87–95. 5. Haissaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Matayer P, Clementy J. Spontaneous
631 initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659 – 660. 6. Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 2000;11:888 – 894. 7. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356 –371. 8. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002; 415:219 –226.
ASSOCIATE EDITOR: YORAM RUDY
How structurally normal are human atria in patients with atrial fibrillation? Anton E. Becker, MD, PhD From the Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Atrial myocardium in humans shows structural changes that increase with aging. The most conspicuous are fibro-fatty replacement and patchy replacement fibrosis. The present study reveals that these structural changes are more extensive in hearts of patients with paroxysmal atrial fibrillation (AF) than in “no AF” hearts. The changes involve the myocardial sleeves on pulmonary veins and sites of rapid conduction, such as the terminal crest and Bachmann’s bundle. These structural changes should be taken into consideration as potential substrates for initiation and maintenance of atrial arrhythmias. KEYWORDS Atrial fibrillation; Atrial arrhythmias; Atrial fibrosis; Atrial infarction; Atrial myocardium; Terminal crest; Bachmann’s bundle; Pulmonary veins (Heart Rhythm 2004;1:627– 631) © 2004 Heart Rhythm Society. All rights reserved.
Introduction Most research into the mechanisms of atrial fibrillation (AF), particularly experimental animal studies, convey the implicit message that the atria basically are structurally normal. This message is somewhat surprising given that the vast majority of patients with AF have associated cardiovascular diseases, such as hypertensive, ischemic, or valvar heart disease. As early as 1972, Davies and Pomerance1 provided a detailed account of the histopathology of the atria in patients with AF on whom autopsy was performed. They demonstrated biatrial enlargement and extensive fibrosis in patients with a history of chronic AF. In 1997, Lie et al2 confirmed these observations and reported extensive pathology associated with AF, including focal degeneration and necrosis of atrial myocardium, extensive fibrosis, and fibro-fatty myocardial replacement. Another study involving endomyocardial right atrial septal biopsies taken from patients with lone AF, showed histologic abnormalities, compatible with a diagnosis of myocarditis, noninflammatory cardiomyopathy, or patchy fibrosis.3 In this context, it is interesting that heart failure induced in dogs also promotes AF and appears associated with a pathologic substrate similar to that observed in man.4 The question then arises, why do these data receive little attention in considerations regarding the genesis of AF? Address reprint requests and correspondence: Dr. Anton E. Becker, Emeritus Professor of Cardiovascular Pathology, Academic Medical Center, University or Amsterdam, IJsselmeerdijk 13, 1473 PP Warder, The Netherlands. E-mail address: [email protected].
Whatever the answer, it is worthwhile to briefly recapitulate some of our own observations in human atria in an attempt to revitalize interest in electrophysiologic-pathologic correlates in the arena of AF research.
Pulmonary veins Since the landmark publication by Haissaguerre et al5 it is widely accepted that pulmonary veins may provide a source of focal activity initiating AF. This publication also led to the rediscovery of left atrial myocardial extensions onto the pulmonary veins, known as myocardial sleeves, located on the epicardial side of the veins and separated from the smooth muscle media of the vein by a fibro-fatty tissue plane. At the site of the ostial junction, the sleeve is composed of several layers of myocardial fibers with different spatial orientations, producing a multilayered and multidirectional coating of the most proximal part of the vein. The sleeves gradually diminish in thickness and lose their multilayered composition toward the lung hilum. The more distal the location, the more the compact nature of the sleeve diminishes. Small strands of myocardium, representing the most distal extensions of the sleeve, are not uncommonly observed as almost isolated fascicles. In these instances, the complete circumference of the vein is no longer enveloped by left atrial myocardium— only a small part of its wall is enclosed. In tracing the sleeves from proximal (left atrium) to distal (lung hilum), perimysial fibrous tissue increases. The fibrosis initially encloses small groups of myocardial cells but eventually forms distinct fibrous strands and patches in which the myocardium gradually disappears
1547-5271/$ -see front matter © 2004 Heart Rhythm Society. All rights reserved.
doi:10.1016/j.hrthm.2004.09.009
628
Figure 1 Histology of a myocardial sleeve extending onto a pulmonary vein. Upper panel: Low-power view showing the left atrial myocardial sleeve (Myo) on the epicardial side of the vein, separated from the smooth muscle media of the vein by a fibrofatty tissue plane. Note extensive band-like fibrosis (red) on the pulmonary vein side of the sleeve. Lower panel: Higher magnification of boxed area in A reveals patchy replacement fibrosis. Elastic van Gieson stain. (From Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary vein in humans: anatomic observation relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 2000;11:888 – 894, with permission.)
(Figure 1). It is tempting to speculate that these changes, which are highly reminiscent of ischemic events, induce microreentrant phenomena and, hence, are responsible for generating ectopic beats within pulmonary veins. An earlier concept promoted by Spach et al7 argued that development of extensive collagenous septa induced nonuniform anisotropic electrical propagation that could result in microreentry and thus form a basis for the high incidence of atrial tachyarrhythmias in older people.
Terminal crest and Bachmann’s bundle Impaired conduction in fast conducting pathways, such as the terminal crest, pectinate muscles and Bachmann’s bundle, could play a critical role in the pathophysiology of atrial tachycardias. A microscopic study was performed of 20 hearts, 10 from individuals with a known history of paroxysmal AF
Heart Rhythm, Vol 1, No 5, November 2004 and 10 without a history. Of the 10 patients with AF, five were male (mean age 74.4 years, range 61– 82) of the 10 patients in the no-AF group, seven were male (mean age 70.1 years, range 26 –92). Cardiac pathology was dominated by obstructive coronary artery disease (CAD) and mitral valve disease. The AF group demonstrated CAD with infarct scars and a coronary artery bypass graft (CABG) procedure in three patients, CAD with infarct scars in one, and CAD with an acute myocardial infarct in one. Degenerative mitral valve disease was observed in five patients and was associated with CAD in three. In the no-AF group, three patients had CAD with myocardial scarring, two had CAD with a coronary bypass, and one had CAD with degenerative mitral valve disease. Two patients had cardiac hypertrophy, possibly due to hypertension. No cardiac pathology was identified in two other patients (26 and 55 years). Sections were taken perpendicular to the long axis of the terminal crest at the level of the anticipated sinus node and more inferiorly at the site where the terminal crest just ends by fanning out into separate bundles. Sections were taken from Bachmann’s bundle along its long axis (right atrium– left atrium) and perpendicular to the long axis. Taking normal “textbook” myocardial histology as paradigm (parallel-oriented myocardial fibers enwrapped by endomysial collagen and myocardial bundles held together by perimysium), almost all sections, either from the terminal crest or Bachmann’s bundle, contained abnormalities. By far the most common abnormality was fibro-fatty replacement with a patchy distribution within the myocardium. The phenomenon itself was not different between hearts with and hearts without a history of AF. However, the phenomenon was much more extensive in hearts of AF patients. In some AF patients, the terminal crest or Bachmann’s bundle was almost totally replaced by fibro-fatty tissue (Figure 2). Extensive postinfarct replacement fibrosis (scarring) was observed in three patients with CAD and CABG, with additional foci of acute myocardial infarction observed in two of these three patients (Figure 3). Both of the patients were readmitted to the hospital where they had undergone their CABG procedure with signs and symptoms of ischemic cardiomyopathy. Thus, significant histopathologic changes appear to affect the fast conducting pathways, with fibro-fatty tissue replacement as a common denominator. The presence of this particular feature can be considered almost normal, at least in the elderly population. However, it is striking that, in general, patients with a history of AF had more highly pronounced changes than patients without AF, accepting the limitations of no quantitative data and a small series. This finding evokes considerations of the effects of focal disruption of parallel-oriented muscle fibers alluded to earlier. A relationship between the genesis of atrial tachyarrhythmias and a critical level of fibro-fatty disruption can be hypothesized. Another important point arising from these observations is that atrial myocardial infarction may be more common
Becker
Atrial Structure and AF
629
Figure 2 Histology of the terminal crest (upper panels) and Bachmann’s bundle (lower panels) showing “normal” histology on the left and extensive fibro-fatty replacement on the right. Hematoxylin-eosin stain. CT ⫽ terminal crest; endo ⫽ left atrial endocardium; SN ⫽ sinus node; Bachmann ⫽ Bachmann’s bundle epicardially.
than often believed. The fact that the present small series (with a limited number of microscopic sections from only two selected sites) revealed two cases with acute microinfarction is telling. The study provides evidence suggesting that small patches of replacement fibrosis, often encountered in atria, are micro-scars of ischemic events. The atrial coronary artery branches usually are not affected by atherosclerosis, but this lack of association does not preclude the possibility of ischemic events. Postmortem coronary angiograms from hearts with extensive obstructive multivessel CAD show that collaterals exist between the left and right ventricular systems via the atrial arteries, creating the potential of a “steal” phenomenon. Occurrence of recent atrial infarcts provides a substrate for initiation of atrial tachyarrhythmias, such as those originating from infarcted ventricles. Hence, the atrial pathology encountered is diverse, and a distinction must be made between acute conditions (infarcts, infection, metastatic invasion) and chronic events, of
which fibro-fatty replacement of (as yet) unknown origin appears the most common.
Conclusion Considering human atria of patients with AF as structurally normal appears to be an illusion. It also is an illusion to think that atria in older people do not undergo histologic changes. In the early 1960s, Lev and McMillan reported increases in collagen and fatty replacement of atrial myocardium from the third decade on (see reference2). The fact that almost all microscopic sections reveal structural changes supports past observations, which seem to be largely forgotten. In this setting, it is fascinating that the degree and extent of fibro-fatty replacement and patchy replacement fibrosis are much more prominent in atria of patients with paroxysmal AF than in “no AF” hearts. Caution is warranted, however,
630
Heart Rhythm, Vol 1, No 5, November 2004
Figure 3 Histology of the inferior part of the terminal crest. Upper left panel: Low-power view showing extensive replacement fibrosis (scarring). Upper right panel: Higher magnification of left upper panel. Lower left panel: Low-power view showing recent hemorrhagic micro-infarcts (boxed area) and extensive replacement fibrosis. Lower right panel: Higher magnification of boxed area in lower left panel showing greater detail of changes. Hematoxylin-eosin stain. CT ⫽ terminal crest.
because no quantification of changes is available, and conclusions are based on a limited number of sections and hearts. Nevertheless, it is tempting to believe a critical level of histopathologic changes provides the substrate for initiation of an atrial arrhythmia and its subsequent maintenance. Although the genesis of structural changes is not fully clarified, ischemic events cannot be ruled out. Acute atrial myocardial micro-infarction was seen, albeit in patients with severe CAD. This finding raises the question of whether ischemic events are responsible for areas with replacement fibrosis, which are commonly encountered in the atria. To appreciate this option, recall that ischemia and infarction are not necessarily related to coronary artery occlusion. Other circumstances may create an imbalance between myocardial oxygen demand and consumption. A steal phenomenon through atrial coronary arteries may leave some parts of the atrial myocardium insufficiently perfused. Similarly,
replacement fibrosis in the peripheral parts of the myocardial sleeves on pulmonary veins may be due to the likely possibility that these sites are “watershed” zones. In summary, human atria of older individuals (ⱖ30 years) demonstrate a range of structural changes that should not be ignored as substrates for initiation and maintenance of atrial tachyarrhythmias. The heterogeneity fits with recent evidence suggesting that “ectopic activity, single circuit reentry and multiple circuit reentry may all be involved in AP.”8
References 1. Davies MJ, Pomerance A. Pathology of atrial fibrillation in man. Br Heart J 1972;34:530 –525. 2. Lie JT, Falk RH, James TN. Cardiac anatomy and pathologic correlates
Becker
Atrial Structure and AF
of atrial fibrillation. In: Falk RH, Podrid PJ, editors. Atrial Fibrillation: Mechanisms and Management. Second Edition Philadelphia: Lippincott-Raven, 1997:23–52. 3. Frustaci A, Chimenti C, Bellocci F, Morgante E, Russo MA, Maseri A. Histological substrate of atrial biopsies in patients with lone atrial fibrillation. Circulation 1997;96:1180 –1184. 4. Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 1999;100:87–95. 5. Haissaguerre M, Jaïs P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Matayer P, Clementy J. Spontaneous
631 initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med 1998;339:659 – 660. 6. Saito T, Waki K, Becker AE. Left atrial myocardial extension onto pulmonary veins in humans: anatomic observations relevant for atrial arrhythmias. J Cardiovasc Electrophysiol 2000;11:888 – 894. 7. Spach MS, Dolber PC. Relating extracellular potentials and their derivatives to anisotropic propagation at a microscopic level in human cardiac muscle: evidence for electrical uncoupling of side-to-side fiber connections with increasing age. Circ Res 1986;58:356 –371. 8. Nattel S. New ideas about atrial fibrillation 50 years on. Nature 2002; 415:219 –226.