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