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(Circulation. 2008;117:e169.)
© 2008 American Heart Association, Inc.

Correspondence

Letter by Roldán et al Regarding Article, "Plasminogen Activator Inhibitor-1 as a Predictor of Postoperative Atrial Fibrillation After Cardiopulmonary Bypass"

Vanessa Roldán, MD, PhD

Department of Hematology and Clinical Oncology, Hospital Universitario Morales Meseguer, Murcia, Spain

Francisco Marín, MD, PhD

Department of Cardiology, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain

Gregory Y.H. Lip, MD, FESC

Haemostasis, Thrombosis, and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, England

To the Editor:

Pretorius et al¹ report that elevated plasminogen activator inhibitor-1 (PAI-1) levels are independent predictors of the development of atrial fibrillation (AF) after cardiopulmonary bypass, raising the possibility that postoperative AF is secondary to inflammation and fibrosis. PAI-1 also could promote myocardial remodeling by reducing matrix metalloproteinase activity because PAI-1 inhibits tissue plasminogen activator (tPA) and consequently plasmin, which is a potent activator of matrix metalloproteinases. There also is a link between fibrinolysis and inflammation, but elevated PAI-1 levels are part of various pathophysiological interactions. For example, elevated PAI-1 levels are found in the insulin resistance syndrome, so its prognostic value in different conditions often disappears after adjustment for body mass index, triglycerides, and high-density lipoprotein cholesterol.² As we have previously reviewed, the increased PAI-1 levels in AF have raised different hypotheses, including implications for thrombosis, endothelial damage/dysfunction, inflammation, or other confounders.³ Elevated PAI-1 levels also are reported in patients with mitral stenosis, including those in sinus rhythm,³ and more recently, high baseline PAI-1 activity has been shown to be a strong predictor of AF recurrence after electric cardioversion.⁴

The different facets of PAI-1 in AF merit some discussion. The fibrinolytic system plays an important role in preventing intravascular thrombosis; hence, the fibrinolytic function in the vasculature is dependent on the rate of secretion of tPA, the inhibition of tPA by PAI-1 and other inhibitors, and the hepatic clearance of tPA. The improvement in fibrinolytic markers in AF after "steady-state" oral anticoagulation³ supports the prothrombotic role of PAI-1.

Because endothelial cells also release tPA and PAI-1, it has been suggested that these indexes could be related as markers of endothelial cell damage or dysfunction. Rather than being a measure of fibrinolysis, tPA and PAI-1 antigen levels may therefore be a surrogate for vascular injury. Given that AF is associated with a reduced expression of NO synthase and NO^· bioavailability with a significant increase in PAI-1 expression in left atrium, PAI-1 abnormalities may simply reflect endothelial damage.⁵

Thus, there are several explanations for the significance of high PAI-1 levels in AF, reflecting the complex pathophysiology of this common arrhythmia. Pretorius et al¹ may be simplistic in attributing a causal role in predicting AF development to PAI-1. Of note, matrix metalloproteinase-9 concentration, a more established marker of matrix remodeling, offers no predictive information in their study.

	Acknowledgments

 
Disclosure

None.

	References

Top References

 
1. Pretorius M, Donahue BS, Yu C, Greelish JP, Roden DM, Brown NJ. Plasminogen activator inhibitor-1 as a predictor of postoperative atrial fibrillation after cardiopulmonary bypass. Circulation. 2007; 116 (suppl I): I-1–I-7.[Medline] [Order article via Infotrieve]

2. Juhan-Vague I, Alessi MC, Mavri A, Morange PE. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost. 2003; 1: 1575–1579.[CrossRef][Medline] [Order article via Infotrieve]

3. Marín F, Roldán V, Lip GY. Fibrinolytic function and atrial fibrillation. Thromb Res. 2003; 109: 233–240.[CrossRef][Medline] [Order article via Infotrieve]

4. Tveit A, Seljeflot I, Grundvold I, Abdelnoor M, Smith P, Arnesen H. Levels of PAI-1 and outcome after electrical cardioversion for atrial fibrillation. Thromb Res. 2008; 121: 447–453.[CrossRef][Medline] [Order article via Infotrieve]

5. Cai H, Li Z, Goette A, Mera F, Honeycutt C, Feterik K, Wilcox JN, Dudley SC Jr, Harrison DG, Langberg JJ. Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: potential mechanisms for atrial thrombosis and stroke. Circulation. 2002; 106: 2854–2858.[Abstract/Free Full Text]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Roldán, V. Articles by Lip, G. Y.H. Search for Related Content PubMed PubMed Citation Articles by Roldán, V. Articles by Lip, G. Y.H. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Atrial Fibrillation Related Collections Fibrinolysis CV surgery: other Other Vascular biology