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Elimination of the Left Atrial Appendage To Prevent Stroke or Embolism?^*

Anatomic, Physiologic, and Pathophysiologic Considerations

^* From the Medizinische Abteilung (Dr. Stöllberger) and the Neurologische Abteilung (Dr. Finsterer), Krankenanstalt Rudolfstiftung, Vienna, Austria; and the Klinik für Kardiologie (Dr. Schneider), Sana Kliniken, Lübeck, Germany.

Correspondence to: Claudia Stöllberger, MD, Steingasse 31/18, A-1030 Wien, Austria; e-mail: claudia.stoellberger{at}chello.at

	Abstract

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
The "elimination" of the left atrial appendage (LAA) seems to be an attractive alternative to oral anticoagulation in the treatment of atrial fibrillation, especially in patients with contraindications to oral anticoagulation therapy. The LAA, however, plays an important role in the maintenance and regulation of the cardiac function, in arterial hypertension, atrial fibrillation, coronary heart disease, valvular heart disease, and heart failure. Data, mainly from animal studies, indicate that elimination of the LAA may impede thirst in patients with hypovolemia, may impair hemodynamic response to volume or pressure overload, may decrease cardiac output, and may promote heart failure. It may have adverse effects in humans as well. Further studies on the hemodynamic and neurohumoral consequences of left atrial appendage elimination are required to advance our understanding of LAA physiology and pathophysiology.

Key Words: atrial fibrillation • heart failure • left atrial appendage • stroke

	Introduction

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Oral anticoagulation significantly reduces the rate of stroke or embolism in patients with atrial fibrillation (AF).¹ Although oral anticoagulation therapy has been shown to be safe and effective, especially in patients who monitor it by themselves,² it is often difficult to achieve a well-controlled therapeutic range of anticoagulation over long periods of time.^{1 3 4} Contraindications to oral anticoagulation exist in a considerable number of patients.⁵ Even in AF patients without contraindications for oral anticoagulation, it is underused due to patient-related, physician-related, and health-care-related barriers. Only < 50% of patients with AF receive oral anticoagulants.⁶ Because in patients with nonrheumatic, nonvalvular AF > 90% of the thrombi are located in the left atrial appendage (LAA), an "elimination" of the LAA, either by resection or occlusion, seems to be an attractive alternative to oral anticoagulation.⁷ The elimination of the LAA may be performed as an additional procedure during cardiac valve or coronary bypass surgery,^{8 9 10} as part of the maze procedure,¹¹ as an isolated procedure by thoracoscopy,^{12 13} or as percutaneous intervention by means of the percutaneous LAA transcatheter occlusion (PLAATO) system.^{14 15} Although frequently regarded as a useless appendage,¹³ several studies have stressed the importance of the LAA in regulating intravascular volume status and hemodynamic conditions. Thus, the aim of the present review was to compile the current knowledge about the LAA, its anatomy, physiology, and pathology, and to show the reasons why the risks and potential benefits of LAA elimination in patients with AF should be carefully considered before a procedure is performed.

	Anatomy

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
The LAA is the remnant of the original embryonic left atrium (LA) that develops during the third week of gestation. The main smooth-walled LA cavity develops later and is formed from the outgrowth of the pulmonary veins.¹⁶ The LAA orifice into the LA cavity has a diameter of 10 to 40 mm and is located between the left upper pulmonary vein and the left ventricle.^{17 18} The circumflex branch of the left coronary artery runs close to the LAA basal orifice. The cardiac lymphatic drainage of the left ventricle has its entry beneath the LAA in the rat¹⁹ and passes under the LAA in pigs.²⁰ In humans, the cardiac lymphatic system is assumed to have a similar course.^{19 20 21} The LAA is a long, tubular, hooked structure of variable morphology and size, ranging from 0.77 to 19.27 cm³.¹⁷ It is trabeculated with muscle bars, so-called pectinate muscles. When casting the LAA, the cavities between the pectinate muscles appear as "branches" (also called lobes), "twigs" or "fine structures" (Fig 1 ).^{17 18}

View larger version (81K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Postmortem LAA casts. The cast on the left side is from a 52-year-old man who had antemortem sinus rhythm. The cast volume is 5.880 cm3. The cast has more than five branches and 20 to 40 twigs, and is densely covered with fine structures. The cast on the right side is from a 76-year-old woman who had antemortem atrial fibrillation. The cast volume is 18.670 cm3. The cast has more than five branches, > 40 twigs, and no fine structures.

	Noninvasive Imaging Methods

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

Other imaging modalities, such as cardiac CT scanning or MRI, are not able to adequately visualize the LAA because of its complex morphology.

	Invasive Atrial Study Methods

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Via a transseptal approach, the LAA can be visualized during cardiac catheterization by left atriography.¹⁵ During cardiac surgery, the LAA can be inspected directly during the opening of the LA cavity. Tissue from the LAA can be obtained for histologic examination and immunohistochemistry testing for the detection of endothelial cell markers.²⁸

	Investigations Postmortem

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
At autopsy, the LAA can be investigated by direct inspection²⁹ and by casting the LAA (Fig 1) .¹⁷ Another method is the inspection of the LAA in hearts after formalin fixation.¹⁸ When applying this method and measuring LAA dimensions, the fact that formalin fixation induces tissue shrinkage has to be taken into account.^{30 31}

	Physiology

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Physiologic functions attributed to the LAA consist of the following:

1. The LAA plays a role in mediating thirst. In an in vivo study in sheep, the LAA was eliminated by mechanical compression after thoracotomy. Sheep with crushed LAAs did not increase their water intake after volume depletion, whereas control sheep with intact LAAs did. These findings suggest that stretch receptors of the LAA play a role in mediating thirst in hypovolemia.⁹
   
2. The LAA modulates the relationship between pressure and volume. In dogs, the LAA has a higher in vivo distensibility than does the LA body, and compliance of the LA is decreased after the removal of the LAA.^{32 33 34 35} This reservoir function of the LAA also has been shown in humans undergoing cardiac surgery because of coronary heart disease or mitral regurgitation. In these patients, who were investigated intraoperatively by hemodynamic measurements and TEE, LAA clamping led to an increase in diastolic transmitral and pulmonary flow velocities, and to an increase in LA mean pressure and size.³⁶ Further in vivo studies in dogs^{37 38} have shown that distension of the LAA influences urine flow and induces an increase in heart rate. The increase in heart rate is most probably due to a reflex phenomenon, with the efferent pathway located in the sympathetic nerves and the afferent pathway partially in the cervical vagal nerve.³⁹
   
3. The LAA plays a role in maintaining cardiac output. In the isolated working hearts of guinea pigs, the LAA was ligated in one group, whereas it remained intact in the other group.⁴⁰ Compared to hearts with ligated LAAs, the cardiac output of hearts with intact LAAs was almost twice as high. This difference in cardiac output was attributed to the preserved ability of the LAA to contract, with subsequent improved filling of the left ventricle.⁴⁰
   
4. The LAA is an endocrine organ. The LAA is an important structure for the release of atrial natriuretic peptide (ANP) and, possibly, also for brain natriuretic peptide, which are peptide hormones that have natriuretic, diuretic, and vasodilatory properties.^{41 42} Endothelial cells of the LAA are specialized in the production and release of natriuretic peptides. In healthy human hearts, ANP concentration is 40-fold higher in the LAA than in the rest of the atrial free wall and in the ventricles.⁴¹ In animal experiments performed in rats, monkeys, and dogs,^{43 44 45 46} the removal of both atrial appendages attenuated the release of ANP during volume expansion, and reduced the natriuretic and diuretic responses. Only a small amount of data are available about the consequences of LAA removal on natriuretic peptides in humans. In studies with patients who had undergone the maze procedure and bilateral atrial appendectomy had been performed, attenuation of natriuretic peptide secretion and water retention in the early postoperative phase were found.^{47 48} One of these studies⁴⁸ reinvestigated the patients 2 years after they had undergone the maze procedure and found that the response of ANP secretion by exercise was still attenuated compared with patients who had not undergone the maze procedure. Both studies, however, were flawed by the heterogeneity of the patients, in whom not only the maze procedure had been performed but also valve surgery.^{47 48}
   

	LAA Dysfunction or "LAA Myopathy"

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Decreased contractility of the LAA myocardium in association with low flow velocities (ie, < 20 to 25 cm/s) is assumed due to a myopathic process (called LAA myopathy).^{24 49} Signs of LAA dysfunction, detected by TEE, are regarded as indicators for an embolic risk.^{25 50 51 52 53} TEE findings that are associated with LAA dysfunction are LAA enlargement and spontaneous echocardiographic contrast, a phenomenon indicating blood stasis.^{50 51 53} Additionally, thrombus formation might be enhanced by LAA dysfunction. This is substantiated by autoptic findings¹⁷ in which LAAs with thrombi were larger than LAAs without thrombi. Furthermore, it has been shown that von Willebrand factor, a platelet adhesion molecule, is increased in the endocardium of overloaded human LAA, which may be a local predisposing factor for intra-atrial thrombogenesis.^{28 54} Recently, LAA dysfunction has been shown to be associated with increased plasma brain natriuretic peptide.⁵⁵

	LAA in Cardiovascular Disorders

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 

1. The LAA is affected in arterial hypertension. LAA areas, measured by TEE, are larger and the emptying velocities are lower in hypertensive patients who are in sinus rhythm than in nonhypertensive control patients.^{22 56 57} At autopsy, the LAAs of patients with left ventricular hypertrophy are larger than those of patients without hypertrophy.¹⁷ Possibly, the marked elevation of afterload imposed on the LA may involve both the LA and the LAA, resulting in LAA dysfunction. LAA dysfunction in hypertension, facilitating thrombus formation, might also contribute to the increased risk of stroke in hypertensive AF patients.¹
   
2. In heart failure, the LAA may play an important role because of its hemodynamic and endocrine activities. In an in vivo experiment in dogs,⁵⁸ it has been shown that LA and LAA failure have little effect on cardiac output in the presence of a normally contracting left ventricle, whereas in the presence of left ventricular dysfunction, the impairment of LA contraction caused a decrease in cardiac output. In a further study in dogs with experimental high-output heart failure,⁴³ atrial appendectomy reduced cardiac output. There is only one study⁵⁹ in humans that has investigated the LAA function in 10 patients with heart failure and left ventricular systolic dysfunction. This study showed that, after the treatment of heart failure, LAA function, as assessed by LAA size, area, ejection fraction, and emptying velocities, improved markedly. After treatment, there was a greater reduction in LAA size than in LA size. This suggests that the LAA is more compliant than the LA body, contributing to the prevention of an elevation in intra-atrial pressure, and thereby pulmonary congestion, in patients with heart failure.⁵⁹ Little is known about the endocrine activity of the LAA in heart failure. In dogs with experimental high-output heart failure, the atrial appendages contain approximately 30% of the total amount of ANP, and atrial appendectomy decreased the secretory function of ANP.⁴³ In failing human hearts, ANP concentrations in the LAA are increased 5-fold to 10-fold compared with nonfailing hearts, especially the concentrations of the prohormones ß-ANP and -ANP.⁴¹
   
3. AF, a common rhythm disorder, has been shown by many studies to influence the size and function of the LAA. At autopsy, patients with AF macroscopically had significantly larger LAA volumes, larger luminal surfaces, and less pectinate muscle compared to those with sinus rhythm (Fig 1) .^{17 29} Histologically, the LAA in patients with AF shows endocardial thickening with fibrous and elastic tissue, fibrosis, vacuolar degeneration, myocyte hypertrophy, myocyte dystrophy with myolysis, apoptosis, gap junction disorganization and down-regulation of the L-type calcium channel, and the sarcoplasmic reticular Ca(2+)-adenosine triphosphatase gene.^{29 60 61 62} These findings suggest that LAA remodeling (ie, dilation, stretching, reduction in pectinate muscle volume, and endocardial fibroelastosis) occurs frequently in patients with permanent AF. These abnormalities could result from a common and nonspecific adaptive response to changes in the working conditions of the atrial myocardium and may be a consequence of AF, as well as a contributory factor for AF. Probably, these abnormalities are also the substrate for "electrical remodeling," a process in chronic AF in which the atrial effective refractory period shortens and impairs its rate adaptive response.⁶³ Furthermore, these histologic abnormalities could be due to an inflammatory process, which has been made responsible in promoting the persistence of AF.⁶⁴ LAA dysfunction, detected by TEE, is a frequent finding in AF.^{17 25 29 50 51 52 53 65 66 67 68} Whether TEE findings that are indicative for LAA dysfunction are independent predictors for stroke or embolism in patients with AF has not been definitively confirmed by prospective studies.^{67 68 69}
   
4. No direct effect of coronary heart disease on LAA function has been described. At autopsy, it has been found¹⁷ that the LAAs in patients with myocardial scars were larger than those in patients without myocardial scars.
   
5. Mitral stenosis may lead to an extremely distended LAA. By TEE, patients with AF and valvular abnormalities have been found to have more frequent LAA dysfunction than patients without valvular abnormalities.⁷⁰ After percutaneous mitral valvuloplasty, an increase in LAA flow both in patients with normal sinus rhythm and AF has been found.⁷¹
   

	Interventions on the LAA

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 

1. During the maze procedure, both atria are surgically opened, the appendages are excised, and multiple incisions of the atrial wall are made in order to interrupt the conduction routes of the most common reentrant circuits to prevent AF.¹¹ Because of concern about the reduced secretion of ANP and a decrease of atrial transport function, however, the performance of a bilateral appendage-preserving maze procedure is suggested, and it has been shown that this procedure improves atrial transport function and ANP secretion without decreasing its effectiveness concerning AF.⁷²
   
2. The ligation of the LAA is performed during mitral valve or aortocoronary bypass surgery or by thoracoscopy to cut it off from the circulation and to eliminate it as a potential source of systemic embolism.^{8 10 12 13} Although the complete obliteration of the LAA is the surgical goal, residual communication between the LA cavity and the LAA has been reported in as much as 36% of patients after mitral valve surgery.⁷³ Thrombi within an incompletely ligated LAA may occur and embolize.⁷⁴ When the LAA is closed directly from inside the LA cavity, the circumflex coronary artery may inadvertently be injured because of its proximity to the base of the LAA. Thus, a staple closure of the LAA has been developed.⁷⁵
   
3. The PLAATO procedure is carried out via a transseptal approach. A permanent occlusion device (a nitinol cage with a cover made of synthetic material [Gore-Tex; WL Gore and Associates; Newark, DE]) is placed in the LAA in order to close it and prevent thrombus formation. For the percutaneous delivery of the nitinol cage into the LAA, a single-lumen catheter and an introducer sheath (X-Sept transseptal sheath and transition catheter; Appriva Medical, Inc; Sunnyvale, CA) are used.^{14 15} Recently, early clinical experiences with PLAATO in 50 patients have been reported.^{15 76} Although the PLAATO technique seems attractive, it is an invasive procedure with a 6 to 7% risk of developing a hemopericardium. Furthermore, PLAATO does not obviate antithrombotic therapy with acetylsalicylic acid and clopidogrel, a therapy known to induce bleeding complications.⁷⁷
   

	Concerns About LAA Elimination

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Eliminating the LAA in persons with AF to prevent stroke or embolism raises several concerns, as follows:

1. All LAA elimination procedures in AF patients assume that the LAA thrombus is the only source of embolism. Although it is an important source, the pathogenesis of stroke or embolism in AF patients is multifactorial and is not determined only by the presence of an LAA thrombus.⁶⁷ Thrombogenesis is multifocal. Ventricular thrombi, aortic, carotid, or vertebral arterial plaques, or venous thrombi via right-to-left-shunting are also embolic sources. These other sources of stroke or embolism are not influenced by LAA elimination.
   
2. Although LAA elimination in humans has been performed for several years, few data about its consequences are available. Since LAA elimination destroys intravascular volume and neurohumoral regulation in a regulatory system, it may promote heart failure and, thus, increase embolic risk.
   
3. Incomplete surgical LAA occlusion is a frequent problem. No data are available at present about whether the PLAATO device is safe against dislocation and thrombus formation.
   
4. Hypercoagulability that is reported in patients with AF will not be treated by LAA elimination.^{28 54}
   

	Conclusion

TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 
Much data, mainly from animal studies, are available, indicating that the elimination of the LAA may impede thirst in the case of hypovolemia, may impair the hemodynamic response to volume or pressure overload, may decrease cardiac output, and may promote heart failure. Also in humans, LAA elimination may have potential adverse effects. Further studies on the hemodynamic and neurohumoral consequences of LAA elimination are required to advance our understanding of LAA physiology and pathophysiology.

	Footnotes

 
Abbreviations: AF = atrial fibrillation; ANP = atrial natriuretic peptide; LA = left atrium, atrial; LAA = left atrial appendage; PLAATO = percutaneous left atrial appendage transcatheter occlusion; TEE = transesophageal echocardiography

Received for publication December 5, 2002. Accepted for publication April 28, 2003.

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TOP Abstract Introduction Anatomy Noninvasive Imaging Methods Invasive Atrial Study Methods Investigations Postmortem Physiology LAA Dysfunction or "LAA... LAA in Cardiovascular Disorders Interventions on the LAA Concerns About LAA Elimination Conclusion References

 

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