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Focal source hypothesis of atrial fibrillation
Journal of ElectrocardiologyVol. 31 Supplement
Focal Source H y p o t h e s i s of Atrial Fibrillation
Peng-Sheng Chen, MD, Tsu-Juey Wu, MD, Takanori Ikeda, MD, J a m e s J. C. O n g , M D , Y o u n g - H o o n K i m , M D , M a s a a k i Y a s h i m a , M D , Rahul Doshi, MD, Chun Hwang, MD, a n d H r a y r S. K a r a g u e u z i a n , P h D
Computerized Mapping of the Atrial Tissues
Prinzmetal et al. (1) proposed in 1950 that a focal source of activation could explain the mechanisms of auricular arrhythmia, including atrial fibrillation (AF). This hypothesis was all but forgotten until recently, w h e n Haissaguerre and his coinvestigators (2,3) reported that radiofrequency catheter ablation at a focal site may successfully terminate AF and prevent its recurrence. The term focal source was used to indicate that ablation of a limited area can result in successful termination of AF irrespectively of its mechanism(s). It is possible that either an automatic mechanism (triggered activity or enhanced automatidty) or a reentrant excitation limited to a small area (less than a few cm) can cause focal arrhythmia. We have performed a series of computerized mapping studies of AF in vivo and in vitro. We found that a single meandering reentrant wavefront often underlies the mechanism of AF in many of the models studied.
To understand the mechanisms by which focal source of activation can result in AF, we performed computerized mapping studies in isolated canine atrial tissues (4-7). In most studies, a plaque electrode array with 477-channel closely (1.6 mm) spaced bipolar electrodes were used. The interelectrode distance was 1.6 ram, and the interpolar distance was 0.5 ram. The recording electrodes were connected to a computerized mapping system (EMAP, Uniservices, Auckland, New Zealand) (8,9). The electrograms were filtered with a highpass filter of 0.5 Hz and were acquired at 1,000 samples per second with 16 bits of accuracy. For in vivo studies, we designed plaque electrode arrays that covered both right and left atria (5).
Single Meandering Spiral Wave Underlies Acute and Chronic In Situ Canine Atrial Fibrillation
From the Division of Cardiology, Department of Medicine, CedarsSinai Medical Center and UCLA School of Medicine, Los Angeles, California. Supported in part by the Pauline and Harold Price Endowment, an AHA Wyeth-Ayerst Established Investigatorship Award (93002670), a Ralph M. Parsons Foundation Award, an NIH Specialized Center of Research (SCOR) grant in Sudden Death (P50-HL52319), an AHA Greater Los Angeles Affiliate Grant-inAid, an ECHO Foundation Award, an AHA National Center Grant-in-Aid (9750623N), and a grant from Tobacco-Related Disease Research Program (GRT-0020). The authors thank Dustan Hough, Avile McCullen, and Meiling Yuan for their technical assistance and Elaine Lebowitz for her secretarial assistance. The authors also wish to thank Peter Hunter, PhD, David Bullivant, PhD, Sylvain Martel, PhD, and Serge LaFontaine for constructing the mapping system. Reprint requests: Peng-Sheng Chen, MD, Rm 5342, CSMC, 8700 Beverly Blvd, Los Angeles, CA 90048-i865. Copyright © 1998 by Churchill Livingstone ® 0022-0736/98/310S- 100655.00/0
In intact animals, we found that a single meandering reentrant wavefront (RWF) can result in AF (5). The acute AF was induced by electrical stimulation in the adult canine hearts. The chronic AF was induced by intermittent rapid pacing over a period of 3 to 8 months (10). The results of both studies showed that in some AF episodes, a single meandering RWF was present in both left and right atria. Termination of this RWF was associated with termination of AF. In other incidences, multiple wavelets were coexistent in AF. These findings showed that it was possible for a single meandering 32
Focal Source Hypothesis of AF
RWF to result in irregular activity in the atrium. However, not all AF episodes were due to this mechanism. Gray et al. (11) has previously demonstrated that a single m e a n d e r i n g spiral wave can cause cardiac fibrillation. We subsequently f o u n d that the tissue mass is a major factor that determines w h e t h e r or not multiple wavelets can coexist (12). W h e n the tissue mass is large, multiple wavelets can coexist and cause fibrillation. W h e n the tissue mass is reduced, it can support only a single RWF. If the wavefront meanders, it results in rapid irregular activity characteristic of fibrillation. However, if the wavefront is stationary, it results in m o n o m o r p h i c ventricular tachycardia.
Meandering Re-Entrant Wavefronts In Vitro W h e n induced in the in vitro canine atria, the RWFs might either meander, resulting in AF-like activity, or were stationary resulting in tachycardia. We reported that in the h u m a n atrial tissues, the RWFs often followed an irregular path (4). Because the tip of the r e e n t r a n t wave meandered, the bipolar electrogram s h o w e d irregularly irregular activity. A m e c h a n i s m by which irregular propagation occurs was the obstacle created by the large pectinate muscle structure. An anatomic obstacle, such as a hole or a large pectinate muscle, can also result in stabilization of the r e e n t r a n t wave fronts. Ikeda et al. (6) created a hole in isolated canine atrium. W h e n the diameter of the hole was < 6 ram, the RWFs m e a n d e r e d a r o u n d the hole, resulting in rapid and irregular activity. However, if the diameter of the hole was increased to 6 or 8 mm, the RWF stablized a r o u n d the hole. These findings indicate that the size of the obstacle is critically important in the stabilization of the r e e n t r a n t excitation. An RWF propagating a r o u n d an anatomical obstacle w i t h o u t attaching (anchoring) itself to it m a y result in AF-like activity. This occurs w h e n the obstacle diameter is smaller than a critical length. Naturally occurring anatomic obstacles, such as pectinate muscle, can also provide a site for reentry to anchor. We studied the relation b e t w e e n pectinate muscle and the behavior of the RWFs (7). We f o u n d that the pectinate muscle m a y serve as an a n c h o r for the reentry, converting AF to atrial tachycardia. However, because the size of the pectinate muscle is not fixed, but varies from site to site and tissue to tissue, various degrees of anchoring m a y occur. Separation of RWF from pectinate muscle m a y also convert atrial tachycardia to AF-like activity in vitro.
•
Chen et al.
33
Ligament of Marshall and the Focal ,Source of Atrial Fibrillation Marshall (13) in 18 5 0 described the presence of a "vestigial fold of the pericardium," which had until t h e n escaped attention. This fold is a developmental vestige of the left primitive veins. The location of the vestigial fold is in the back of the left auricle, running n o r t h - s o u t h . The upper end of the fold runs into the lower portion of the left superior p u l m o n a r y vein. Schlerlag et al. (14) later discovered the potential electrophysiologic importance of this vestigial fold. Preliminary studies from our laboratory indicate that the "two deflections" or double potentials characteristic of the bipolar recordings registered in the ligament of Marshall can be recorded in the left superior p u l m o n a r y vein in all patients. In some patients with paroxysmal AF, ablation at the site of double potential results in the cure of AF, We also s h o w e d that, during sympathetic stimulation, automatic r h y t h m m a y develop from the ligament of Marshall. These findings indicate that abnormal automatic activity from the ligament of Marshall m a y be the cause of atrial tachycardia and AF in some patients (15-17).
Conclusions We conclude that it is possible for a single m e a n d e r i n g RWF to g e n e r a t e irregularly irregular activity characteristic of AF. Naturally occurring a n a t o m i c obstacles (eg, p u l m o n a r y vein orifice or pectinate muscle structure) are i m p o r t a n t in m o d u l a t i n g the b e h a v i o r of these RWFs. In addition to RWFs, a u t o m a t i c i t y and triggered activity m a y also result in the g e n e r a t i o n of AF-like activity. F u r t h e r investigations will be n e e d e d to d e t e r m i n e if a u t o m a t i c activity or triggered activity can result in AF.
References 1. Prinzmetal M, Corday E, Brill IC et al: Mechanism of the auricular arrhythmias. Circulation 1:241, 1950 2. Haissaguerre M, Gencel L, Fischer B et al: Successful catheter ablation o f atrial fibrillation. J Cardiovasc Electrophysiol 5:1045, 1994 3. Jais P, Haissaguerre M, Shah DC et al: A focal source
34
4.
5.
6.
7.
8.
9.
10.
Journal of Electrocardiology Vol. 31 Supplement of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 95:572, 1997 Ikeda T, Czer L, Trento A et al: Induction of meandering functional RWF in isolated h u m a n atrial tissues. Circulation 96:3013, 1997 Ong JJC, W u T-J, Karagueuzian HS et al: Single meandering spiral wave of excitation underlies acute and chronic in situ canine atrial fibrillation. PACE 20-II:1081, 1997 Ikeda T, Yashima M, Uchida T et al: Attachment of meandering reentrant wave fronts to anatomic obstacles in the atrium. Role of the obstacle size. Circ Res 81:753, 1997 W u TJ, Yashima M, Xie F et al: Role of pectinate muscle bundles in the generation and maintenence of intraatrial reentry: Potential implications for the mechanism of conversion between atrial fibrillation and atrial flutter. Circ Res 83:448, 1998 Ikeda T, Uchida T, Hough D et ah Mechanism of spontaneous termination of functional reentry in isolated canine right atrium: Evidence for the presence of an excitable but nonexcited core. Circulation 94:1962, 1996 Bonometti C, Hwang C, Hough D et al: Interaction between strong electrical stimulation and reentrant wavefronts in canine ventricular fibrillation. Circ Res 77:407, 1995 Wijffels MCEF, Kirchhof CJHJ, Dorland R et al: Atrial fibrillation begets atrial fibrillation. A study in awake
I 1. 12.
13.
14. 15.
16.
i7.
chronically instrumented goats. Circulation 92:1954, 1995 Gray RA, Jalife J, Panfilov A V e t al: Mechanisms of cardiac fibrillation. Science 270:1222, 1995 Kim YH, Garfinkel A, Ikeda T et ah Spatiotemporal complexity of ventricular fibrillation revealed by tissue mass reduction in isolated swine right ventricle. Further evidence for the quasiperiodic route to chaos hypothesis. J Clin Invest 100:2486, 1997 Marshall J: On the development of the great anterior veins in m a n and mammalia: including an account of certain remnants of foetal structure found in the adult, a comparative view of these great veins in the different mammalia, and an analysis of their occasional peculiarities in the h u m a n subject. Phil Trans Royal Soc Lond 140:I33, 1850 Scherlag BJ, Yeh BK, Robinson MJ: Inferior interatrial pathway in the dog. Circ Res 31:18, I972 EIwang C, Karagueuzian HS, Chen P-S: The left atrial tract within the ligament of Marchall as the source for focal atrial fibrillation. PACE 21:804, 1998 Doshi RN, W u T-J, Yashima M e t al: Catecholamineinduced focal source of activation arising from the ligament of Marshall in normal dogs. PACE 21:831, 1998 Hwang C, Chen P-S: Demonstration of ligament of Marshall potential at the orifice of left superior pulmonary vein in humans. PACE 21:936, I998
Focal Source H y p o t h e s i s of Atrial Fibrillation
Peng-Sheng Chen, MD, Tsu-Juey Wu, MD, Takanori Ikeda, MD, J a m e s J. C. O n g , M D , Y o u n g - H o o n K i m , M D , M a s a a k i Y a s h i m a , M D , Rahul Doshi, MD, Chun Hwang, MD, a n d H r a y r S. K a r a g u e u z i a n , P h D
Computerized Mapping of the Atrial Tissues
Prinzmetal et al. (1) proposed in 1950 that a focal source of activation could explain the mechanisms of auricular arrhythmia, including atrial fibrillation (AF). This hypothesis was all but forgotten until recently, w h e n Haissaguerre and his coinvestigators (2,3) reported that radiofrequency catheter ablation at a focal site may successfully terminate AF and prevent its recurrence. The term focal source was used to indicate that ablation of a limited area can result in successful termination of AF irrespectively of its mechanism(s). It is possible that either an automatic mechanism (triggered activity or enhanced automatidty) or a reentrant excitation limited to a small area (less than a few cm) can cause focal arrhythmia. We have performed a series of computerized mapping studies of AF in vivo and in vitro. We found that a single meandering reentrant wavefront often underlies the mechanism of AF in many of the models studied.
To understand the mechanisms by which focal source of activation can result in AF, we performed computerized mapping studies in isolated canine atrial tissues (4-7). In most studies, a plaque electrode array with 477-channel closely (1.6 mm) spaced bipolar electrodes were used. The interelectrode distance was 1.6 ram, and the interpolar distance was 0.5 ram. The recording electrodes were connected to a computerized mapping system (EMAP, Uniservices, Auckland, New Zealand) (8,9). The electrograms were filtered with a highpass filter of 0.5 Hz and were acquired at 1,000 samples per second with 16 bits of accuracy. For in vivo studies, we designed plaque electrode arrays that covered both right and left atria (5).
Single Meandering Spiral Wave Underlies Acute and Chronic In Situ Canine Atrial Fibrillation
From the Division of Cardiology, Department of Medicine, CedarsSinai Medical Center and UCLA School of Medicine, Los Angeles, California. Supported in part by the Pauline and Harold Price Endowment, an AHA Wyeth-Ayerst Established Investigatorship Award (93002670), a Ralph M. Parsons Foundation Award, an NIH Specialized Center of Research (SCOR) grant in Sudden Death (P50-HL52319), an AHA Greater Los Angeles Affiliate Grant-inAid, an ECHO Foundation Award, an AHA National Center Grant-in-Aid (9750623N), and a grant from Tobacco-Related Disease Research Program (GRT-0020). The authors thank Dustan Hough, Avile McCullen, and Meiling Yuan for their technical assistance and Elaine Lebowitz for her secretarial assistance. The authors also wish to thank Peter Hunter, PhD, David Bullivant, PhD, Sylvain Martel, PhD, and Serge LaFontaine for constructing the mapping system. Reprint requests: Peng-Sheng Chen, MD, Rm 5342, CSMC, 8700 Beverly Blvd, Los Angeles, CA 90048-i865. Copyright © 1998 by Churchill Livingstone ® 0022-0736/98/310S- 100655.00/0
In intact animals, we found that a single meandering reentrant wavefront (RWF) can result in AF (5). The acute AF was induced by electrical stimulation in the adult canine hearts. The chronic AF was induced by intermittent rapid pacing over a period of 3 to 8 months (10). The results of both studies showed that in some AF episodes, a single meandering RWF was present in both left and right atria. Termination of this RWF was associated with termination of AF. In other incidences, multiple wavelets were coexistent in AF. These findings showed that it was possible for a single meandering 32
Focal Source Hypothesis of AF
RWF to result in irregular activity in the atrium. However, not all AF episodes were due to this mechanism. Gray et al. (11) has previously demonstrated that a single m e a n d e r i n g spiral wave can cause cardiac fibrillation. We subsequently f o u n d that the tissue mass is a major factor that determines w h e t h e r or not multiple wavelets can coexist (12). W h e n the tissue mass is large, multiple wavelets can coexist and cause fibrillation. W h e n the tissue mass is reduced, it can support only a single RWF. If the wavefront meanders, it results in rapid irregular activity characteristic of fibrillation. However, if the wavefront is stationary, it results in m o n o m o r p h i c ventricular tachycardia.
Meandering Re-Entrant Wavefronts In Vitro W h e n induced in the in vitro canine atria, the RWFs might either meander, resulting in AF-like activity, or were stationary resulting in tachycardia. We reported that in the h u m a n atrial tissues, the RWFs often followed an irregular path (4). Because the tip of the r e e n t r a n t wave meandered, the bipolar electrogram s h o w e d irregularly irregular activity. A m e c h a n i s m by which irregular propagation occurs was the obstacle created by the large pectinate muscle structure. An anatomic obstacle, such as a hole or a large pectinate muscle, can also result in stabilization of the r e e n t r a n t wave fronts. Ikeda et al. (6) created a hole in isolated canine atrium. W h e n the diameter of the hole was < 6 ram, the RWFs m e a n d e r e d a r o u n d the hole, resulting in rapid and irregular activity. However, if the diameter of the hole was increased to 6 or 8 mm, the RWF stablized a r o u n d the hole. These findings indicate that the size of the obstacle is critically important in the stabilization of the r e e n t r a n t excitation. An RWF propagating a r o u n d an anatomical obstacle w i t h o u t attaching (anchoring) itself to it m a y result in AF-like activity. This occurs w h e n the obstacle diameter is smaller than a critical length. Naturally occurring anatomic obstacles, such as pectinate muscle, can also provide a site for reentry to anchor. We studied the relation b e t w e e n pectinate muscle and the behavior of the RWFs (7). We f o u n d that the pectinate muscle m a y serve as an a n c h o r for the reentry, converting AF to atrial tachycardia. However, because the size of the pectinate muscle is not fixed, but varies from site to site and tissue to tissue, various degrees of anchoring m a y occur. Separation of RWF from pectinate muscle m a y also convert atrial tachycardia to AF-like activity in vitro.
•
Chen et al.
33
Ligament of Marshall and the Focal ,Source of Atrial Fibrillation Marshall (13) in 18 5 0 described the presence of a "vestigial fold of the pericardium," which had until t h e n escaped attention. This fold is a developmental vestige of the left primitive veins. The location of the vestigial fold is in the back of the left auricle, running n o r t h - s o u t h . The upper end of the fold runs into the lower portion of the left superior p u l m o n a r y vein. Schlerlag et al. (14) later discovered the potential electrophysiologic importance of this vestigial fold. Preliminary studies from our laboratory indicate that the "two deflections" or double potentials characteristic of the bipolar recordings registered in the ligament of Marshall can be recorded in the left superior p u l m o n a r y vein in all patients. In some patients with paroxysmal AF, ablation at the site of double potential results in the cure of AF, We also s h o w e d that, during sympathetic stimulation, automatic r h y t h m m a y develop from the ligament of Marshall. These findings indicate that abnormal automatic activity from the ligament of Marshall m a y be the cause of atrial tachycardia and AF in some patients (15-17).
Conclusions We conclude that it is possible for a single m e a n d e r i n g RWF to g e n e r a t e irregularly irregular activity characteristic of AF. Naturally occurring a n a t o m i c obstacles (eg, p u l m o n a r y vein orifice or pectinate muscle structure) are i m p o r t a n t in m o d u l a t i n g the b e h a v i o r of these RWFs. In addition to RWFs, a u t o m a t i c i t y and triggered activity m a y also result in the g e n e r a t i o n of AF-like activity. F u r t h e r investigations will be n e e d e d to d e t e r m i n e if a u t o m a t i c activity or triggered activity can result in AF.
References 1. Prinzmetal M, Corday E, Brill IC et al: Mechanism of the auricular arrhythmias. Circulation 1:241, 1950 2. Haissaguerre M, Gencel L, Fischer B et al: Successful catheter ablation o f atrial fibrillation. J Cardiovasc Electrophysiol 5:1045, 1994 3. Jais P, Haissaguerre M, Shah DC et al: A focal source
34
4.
5.
6.
7.
8.
9.
10.
Journal of Electrocardiology Vol. 31 Supplement of atrial fibrillation treated by discrete radiofrequency ablation. Circulation 95:572, 1997 Ikeda T, Czer L, Trento A et al: Induction of meandering functional RWF in isolated h u m a n atrial tissues. Circulation 96:3013, 1997 Ong JJC, W u T-J, Karagueuzian HS et al: Single meandering spiral wave of excitation underlies acute and chronic in situ canine atrial fibrillation. PACE 20-II:1081, 1997 Ikeda T, Yashima M, Uchida T et al: Attachment of meandering reentrant wave fronts to anatomic obstacles in the atrium. Role of the obstacle size. Circ Res 81:753, 1997 W u TJ, Yashima M, Xie F et al: Role of pectinate muscle bundles in the generation and maintenence of intraatrial reentry: Potential implications for the mechanism of conversion between atrial fibrillation and atrial flutter. Circ Res 83:448, 1998 Ikeda T, Uchida T, Hough D et ah Mechanism of spontaneous termination of functional reentry in isolated canine right atrium: Evidence for the presence of an excitable but nonexcited core. Circulation 94:1962, 1996 Bonometti C, Hwang C, Hough D et al: Interaction between strong electrical stimulation and reentrant wavefronts in canine ventricular fibrillation. Circ Res 77:407, 1995 Wijffels MCEF, Kirchhof CJHJ, Dorland R et al: Atrial fibrillation begets atrial fibrillation. A study in awake
I 1. 12.
13.
14. 15.
16.
i7.
chronically instrumented goats. Circulation 92:1954, 1995 Gray RA, Jalife J, Panfilov A V e t al: Mechanisms of cardiac fibrillation. Science 270:1222, 1995 Kim YH, Garfinkel A, Ikeda T et ah Spatiotemporal complexity of ventricular fibrillation revealed by tissue mass reduction in isolated swine right ventricle. Further evidence for the quasiperiodic route to chaos hypothesis. J Clin Invest 100:2486, 1997 Marshall J: On the development of the great anterior veins in m a n and mammalia: including an account of certain remnants of foetal structure found in the adult, a comparative view of these great veins in the different mammalia, and an analysis of their occasional peculiarities in the h u m a n subject. Phil Trans Royal Soc Lond 140:I33, 1850 Scherlag BJ, Yeh BK, Robinson MJ: Inferior interatrial pathway in the dog. Circ Res 31:18, I972 EIwang C, Karagueuzian HS, Chen P-S: The left atrial tract within the ligament of Marchall as the source for focal atrial fibrillation. PACE 21:804, 1998 Doshi RN, W u T-J, Yashima M e t al: Catecholamineinduced focal source of activation arising from the ligament of Marshall in normal dogs. PACE 21:831, 1998 Hwang C, Chen P-S: Demonstration of ligament of Marshall potential at the orifice of left superior pulmonary vein in humans. PACE 21:936, I998