(Stroke. 2001;32:1931.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Letters to the Editor
Atrial Fibrillation and Stroke: More Concepts and Controversies
University Department of Medicine, City Hospital, Birmingham, England, UK
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To the Editor:
We wish to congratulate Hart and Halperin1 on their excellent overview of the current "concepts and controversies" surrounding atrial fibrillation (AF) and stroke.
In discussing the formation of thrombus within the left atrial appendage (LAA), they focus a large part of their discussion on the issue of blood stasis in the LAA that occurs in AF, suggesting this mechanism of thrombogenesis to perhaps be of greatest importance, although conceding that "many questions remain about the formation and embolism of left atrial thrombi and, consequently, about the pathogenesis of AF-associated stroke".1 They also comment that "endothelial lesions in the appendage have not been found, and systemic prothrombotic diastheses that contribute to thrombus formation have been suggested but not convincingly identified."1 We would suggest, however, that there is a growing body of evidence suggesting that endothelial (or endocardial, within the LAA) changes and hemorrheological (or prothrombotic) abnormalities may indeed play a role in the formation of intra-atrial thrombus and subsequent stroke and thromboembolism in AF, thus fulfilling the 3 components of Virchow’s "triad" of thrombogenesis.
Evidence of endothelial abnormalities among patients with AF is suggested by numerous studies documenting elevated plasma levels of circulating surrogate markers of endothelial damage/dysfunction, most notably von Willebrand factor (vWf). The latter has been demonstrated to independently predict the presence of LAA thrombus on transesophageal echocardiography (TEE).2 In addition, direct evidence of atrial endocardial abnormalities has been reported. From necropsy studies, endocardial fibroelastosis in the LAA3 and (among cases of fatal thromboembolic stroke) areas of left atrial endocardial denudation with thrombotic aggregations on scanning electron microscopy (SEM) have been reported,4 being more commonly seen in specimens from patients with AF than those in sinus rhythm.
Furthermore, in specimens collected during mitral valve surgery, we have recently reported SEM evidence of LAA endocardial damage in patients with mitral valve disease, which appears to be more advanced among those with mitral stenosis (compared with mitral regurgitation) and in those with AF (compared with those in sinus rhythm, although was not statistically significant due to small numbers).5 Of interest, the patients with more advanced LAA changes on SEM had significantly higher plasma levels of vWf.5 A recent study also reported greater macrophage tissue factor and vWf expression in the atrial tissue of patients with AF, again suggesting a role for the atria in thrombogenesis.6
Evidence of a prothrombotic or hypercoagulable state in AF comes from even more numerous studies, documenting abnormal levels of various markers of intravascular thrombosis, fibrinolysis, and platelet function; these indices appear to be independent of underlying etiology of AF and structural heart disease, and some revert to normal levels after successful cardioversion or the introduction of antithrombotic therapy.7 Furthermore, some indices such as ß-thromboglobulin (BTG) have independently predicted LAA thrombus on TEE.2 However, we also note that in the larger Stroke Prevention in Atrial Fibrillation (SPAF)-III TEE substudy, only high levels of plasma fibrinogen (but not BTG) were independently predictive of spontaneous echo contrast on TEE, which is itself predictive of LAA thrombus and stroke.8 Unfortunately, plasma fibrinogen, BTG, prothrombin fragment F1.2, and factor V Leiden levels did not predict stroke among another subgroup of SPAF-III participants,9 but many other endothelial, platelet, and coagulation markers were not assessed.
Despite the failure to date to identify a suitable predictive plasma marker for stroke in AF, the evidence for the presence of endothelial and hemorrheological abnormalities in AF and their relationship to intra-atrial thrombus formation is growing. Some controversy still remains whether the observed abnormalities are caused by AF itself or other underlying cardiovascular conditions.10 Importantly, many previous studies have not fully accounted for differences in hemostatic markers between patients with paroxysmal, persistent, and permanent AF, in light of possible differences in the prothrombotic state between these clinical subgroups.11
We would therefore suggest that continued investigation of endothelial (or endocardial) and prothrombotic abnormalities may still be of critical importance in unraveling the complex pathogenesis of AF-related thrombogenesis.
References
1.
Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke. 2001; 32: 803–808.
2.
Heppell RM, Berkin KE, McLenachan JM, Davies JA. Haemostatic and haemodynamic abnormalities associated with left atrial thrombosis in non-rheumatic atrial fibrillation. Heart. 1997; 77: 407–411.
3. Shirani J, Alaeddini J. Structural remodeling of the left atrial appendage in patients with chronic non-valvular atrial fibrillation: implications for thrombus formation, systemic embolism, and assessment by transesophageal echocardiography. Cardiovasc Pathol. 2000; 9: 95–101.[Medline] [Order article via Infotrieve]
4. Masawa N, Yoshida Y, Yamada T, Joshita T, Ooneda G. Diagnosis of cardiac thrombosis in patients with atrial fibrillation in the absence of macroscopically visible thrombi. Virchows Arch A Pathol Anat Histopathol. 1993; 422: 67–71.[Medline] [Order article via Infotrieve]
5. Goldsmith I, Kumar P, Carter P, Blann AD, Patel RL, Lip GYH. Atrial endocardial changes in mitral valve disease: a scanning electron microscopy study. Am Heart J. 2000; 140: 777–784.[Medline] [Order article via Infotrieve]
6. Al-Saady N, Haven AJ, Maarouf N, Gallagher MM, O’Callaghan P, Obel O, Murday AJ, Davies MJ, Camm AJ. Von Willebrand and tissue factors expressions increased in the atrial tissue of the fibrillating atrium. J Am Coll Cardiol. 2001; 7 (suppl A): 113A.Abstract.
7. Lip GYH. Does atrial fibrillation confer a hypercoagulable state? Lancet. 1995; 346: 1313–1314.[Medline] [Order article via Infotrieve]
8. Asinger RW, Koehler J, Pearce LA, Zabalgoitia M, Blackshear JL, Fenster PE, Strauss R, Hess D, Pennock GD, Rothbart RM, Halperin JL. Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation, II: dense spontaneous echocardiographic contrast (the Stroke Prevention in Atrial Fibrillation [SPAF-III] study). J Am Soc Echocardiogr. 1999; 12: 1088–1096.[Medline] [Order article via Infotrieve]
9.
Feinberg WM, Pearce LA, Hart RG, Cushman M, Cornell ES, Lip GYH, Bovill EG. Markers of thrombin and platelet activity in patients with atrial fibrillation: correlation with stroke among 1531 participants in the Stroke Prevention in Atrial Fibrillation III study. Stroke. 1999; 30: 2547–2553.
10. Feng D, D’Agostino RB, Silbershatz H, Lipinska I, Massaro J, Levy D, Benjamin EJ, Wolf PA, Tofler GH. Hemostatic state and atrial fibrillation (the Framingham Offspring Study). Am J Cardiol. 2001; 87: 168–171.[Medline] [Order article via Infotrieve]
11. Li Saw Hee FL, Blann AD, Lip GYH. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation: effects of cardioversion and return of left atrial function. Eur Heart J. In press.
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