Thrombosis Research 127 (2011) 189–192

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Regular Article

Markers of fibrinolysis as predictors for maintenance of sinus rhythm afterelectrical cardioversion

Jonas Andersson a,⁎, Henrik Almroth b, Niklas Höglund c, Steen Jensen c, Per Tornvall d, Anders Englund b,Mårten Rosenqvist e, Kurt Boman a

a Department of Medicine and Geriatrics, Skellefteå County Hospital, S-931 86 Skellefteå, Swedenb Department of Cardiology, Örebro University Hospital, S-701 85 Örebro, Swedenc Department of Cardiology, Heart Centre, University Hospital, S-901 85 Umeå, Swedend Department of Cardiology, Karolinska University Hospital, S-171 76 Stockholm, Swedene Department of Cardiology, Karolinska Institutet at Stockholm South Hospital, S-118 83 Stockholm, Sweden

⁎ Corresponding author. Department of Medicine anHospital SE–931 86 Skellefteå (Sweden). Tel.: +46 910 7

E-mail address: jonas.so.andersson@vll.se (J. Anders

0049-3848/$ – see front matter © 2010 Elsevier Ltd. Aldoi:10.1016/j.thromres.2010.06.002

a b s t r a c t

a r t i c l e i n f o

Article history:

Received 31 March 2010Received in revised form 26 May 2010Accepted 2 June 2010Available online 14 January 2011

Introduction: Inflammation, endothelial dysfunction and metabolic pathways provide possible links betweenthe inflammatory and hypofibrinolytic states in atrial fibrillation. Our aim was to explore the role of massconcentrations of PAI-1 and tPA, activities of PAI-1 and tPA as predictors of recurrence of atrial fibrillationadjusted for CRP.Materials and methods: The study included 129 patients with persistent atrial fibrillation. Laboratory analyseswere performed including PAI-1 activity, PAI-1 mass, tPA activity, tPA mass and CRP in baseline. Patients

were then randomized to atorvastatin (40 mg, two tablets once daily) or placebo, initiated at least 14 daysbefore the elective cardioversion. Further samples and follow-up were made at day 2 and 30 days aftercardioversion.Results: In univariate logistic regression no fibrinolytic variable was significantly correlated with rhythm inday 30. In multivariate analysis lower PAI-1 mass was significantly associated with sinus rhythm in allmodels including fibrinolytic variables, CRP, metabolic components, age, hypertension and smoking. Afteradding treatment allocation to the fully adjusted model, PAI-1 mass remained significantly associated withsinus rhythm both at day 2 and 30 (OR 0.98; 95% CI 0.95–1.00).Conclusions: No fibrinolytic component alone was found to be a predictor of recurrence of atrial fibrillation.In multivariate models lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP,markers of the metabolic syndrome and treatment with atorvastatin. Our findings suggest a patophysio-logical link between AF and PAI-1 mass but the relation to inflammation remains unclear.

© 2010 Elsevier Ltd. All rights reserved.

Introduction

The first evidence of atrial fibrillation (AF) as an inflammatorydisease emerged in the late 1990s [1,2]. Subsequent studiesdemonstrated inflammatory infiltrates in atrial biopsies from AFpatients and found that CRP was a predictor not only of the presenceof and the risk of developing future AF but also the recurrence of AFafter electrical cardioversion [3–7].

A hypofibrinolytic state with increased plasminogen activatorinhibitor type 1 mass concentration (PAI-1 mass) and its complexwith tissue plasminogen activator (t-PA/PAI-1 complex) levels wasalso described in AF [8–10] and PAI-1 has been found to predict therecurrence of AF [11,12]. Inflammation, endothelial dysfunction andmetabolic pathways provided possible links between the inflamma-

d Geriatrics Skellefteå County71 294; fax: +46 910 771 125.son).

l rights reserved.

tory and hypofibrinolytic states in AF [9,13,14]. There is a well knowninteraction between inflammation and fibrinolysis as components ofthe fibrinolytic system act as acute phase reactants. The describedassociation between PAI-1 and recurrence of AF may thus reflect aninflammatory state rather than a disturbed fibrinolytic system.Moreover, treatment with statins has been found to reduce bothPAI-1 and C-reactive protein (CRP) and suggested as a new treatmentoption to prevent recurrence of AF [15,16]. We here present new dataon components of the fibrinolytic system taking into account theinflammatory state with and without treatment with atorvastatin.Our null hypothesis was the components of the fibrinolytic system donot predict maintenance of SR when adjusted for CRP.

Aim

Our primary aim was to explore the role of mass concentrations ofPAI-1 and tPA, activities of PAI-1 and tPA as predictors of maintenanceof SR in a non-postoperative situation with adjustment for CRP.

190 J. Andersson et al. / Thrombosis Research 127 (2011) 189–192

Method

We conducted a pre-specified hypothesis generating study withina double-blinded, placebo-controlled, randomized, prospective, in-vestigator-initiated multicentre study of the effects of atorvastatin onrecurrence of AF after cardioversion which has previously beendescribed in detail [17]. Between August 2004 and January 2007, atotal of 234 patients with persistent AF and an indication forcardioversion were included. Five of the participating centrescollected blood samples from their 129 patients for the presentstudy. Persistent AF was defined as AF with duration more than7 days. Patients below 18 years and over 80 years of age wereexcluded as were patients with paroxysmal AF, atrial flutter, contra-indications against atorvastatin, ongoing treatment with lipid-lowering drugs, ongoing treatment with class I or class III antiar-rhythmic treatment, known liver disease or a myopathy, as well aspatients with a previous electrical cardioversion the last 12 month.Treatment with betareceptor-blocking agents, calcium antagonists,diuretics, digoxin, ACE-inhibitors, ARBs, and acetylsalicylic acid wereused when clinically indicated. Warfarin was given to all patientsaccording to national guidelines, i.e. international ratio (INR) of 2–3,Nthree weeks before cardioversion, checked weekly. Before random-ization, i.e. baseline, a detailed medical history was obtained andtransthoracic echocardiographic examination, 12-lead electrocardi-ography, and basic laboratory analysis were performed including PAI-1 activity, PAI-1 mass, tPA activity, tPA mass, von Willebrand factor(vWF), CRP and blood lipids. Patients were then randomized toatorvastatin (40 mg, two tablets once daily) or placebo, initiated atleast 14 days before the elective cardioversion. Further samples andfollow-up were made at day 2 and 30 days after cardioversion.Compliance was monitored at cardioversion and 30 days aftercardioversion (end of treatment) by pill counting. For analysis offibrinolytic markers blood were collected into Stabilyte tubes andanalysis was carried out using an enzyme-linked immunosorbentassay (ELISA). Chromolize PAI-1 and Chromolize t-PA from BiopoolAB, Sweden, was used to determine activities of PAI-1 and t-PArespectively. Tintelize PAI-1 and Tintelize t-PA was used to determinemass concentrations of PAI-1 and tPA respectively. Von Willebrandfactor was determined with enzyme-linked immunosorbent assays(ELISA) from DAKO in Denmark. Plasma CRP was determined with anautomated high sensitive C-reactive protein method, (IMMULITE,Diagnostic Products Corporation, USA). Cardioversion was performedaccording to local standard clinical practice on an elective outpatientbasis. Patients were instructed to contact the study team if theyexperienced symptoms suggesting AF between scheduled visits. Nopatient was lost during follow-up.

Table 1Baseline characteristics according to rhythm at 30-days post cardioversion.

Sinus rhythm Atrial fibrillation

Number (n) 53 74

Age (years) 67 (59; 75) 66 (59; 72)Sex M/F n (% men) 42/11 (79) 53/21 (72)Smokers n (%) 2 (3.8) 9 (12.2)Weight (kg) 84 (75; 100) 87 (77; 95)Body mass index (kg/m2) 27 (25; 31) 28 (25; 31)Total cholesterol (mmol/L) 5.20 (4.65; 6.00) 5.30 (4.90; 5.90)HDL (mmol/L) 1.26 (1.04; 1.38) 1.24 (1.06; 1.53)LDL (mmol/L) 3.27 (2.79; 3.69) 3.31 (2.79; 3.92)Triglycerides (mmol/L) 1.59 (1.12; 2.01) 1.58 (1.00; 1.85)Hypertension n (%) 25 (47.2) 28 (37.8)Stroke n (%) 2 (3.8) 2 (2.7)ICH n (%) 4 (7.5) 4 (5.4)Left atrial size (mm) 45 (40; 49) 44 (40; 48)Normal ejection fraction n (%) 35 (66) 60 (81)

Median and 25th and 75th percentiles are given.

Statistical analysis

TheMann-Whitney U test was used for calculations between groupsand the Wilcoxon signed ranks test for calculations within the groups.Chi-square was used for grouped variables when comparing thesubgroup with the entire population. Correlation between variableswas tested with Spearman´s test. Logistic regression was used tocalculate the odds ratio (OR) and 95% confidence interval forcomponents of the fibrinolytic system to predict rhythm at 30 daysadjusting for potential confounding factors. In the multivariate analysisfor fibrinolytic variables, PAI-1 activity was excluded due to a highcorrelation (r=0.80) with tPA activity. In the initial model fibrinolyticvariables were analysed, thereafter was the contribution of inflamma-tion (CRP) analysed. The components of the metabolic syndrome(hypertension, triglycerides, BMI and cholesterol) were then added andat age and smoking. For all analyses pb0.05 (two-tailed)was consideredstatistically significant. All analysis was performed using StatisticalPackage for the Social Sciences (SPSS) version 17.0 (Chicago, IL, USA).

Ethics

The Ethics Committee at Karolinska Institute and the SwedishMedical Product Agency approved this study that also complied withthe Declaration of Helsinki. Written informed consent was obtainedfrom all patients.

Results

In total 129 patients (97males, 75%, 32 females, 25%, andmean age65) were eligible for the substudy. Baseline characteristics accordingto rhythm at the 30-day follow up are presented in Table 1. Thesubstudy was well-balanced with the main study with regard tobaseline characteristics and treatment (placebo=64, atorvasta-tin=65). Levels of biomarkers at baseline, two days after cardiover-sion and at the 30 day are presented in Table 2. Only HDL (p=0.048)was significantly different in baseline between the two treatmentgroups in the substudy.

Effect of cardioversion and rhythm

At day 30 recurrent AF was observed in 74 patients and atrialflutter in two. Two days after cardioversion PAI-1 activity, PAI-1 massand tPA mass had decreased significantly and CRP had increasedsignificantly compared to baseline (Table 2). Among the 53 indivi-duals who remained in sinus rhythm after 30 days PAI-1 activity, tPAactivity and tPA mass was significantly lower at day two aftercardioversion compared to baseline and in the AF group only PAI-1mass was significantly lower. In within group analysis there were nosignificant change between baseline and day 30 in any fibrinolyticvariable or vWF among neither those who remained in sinus rhythmnor among those with recurrent AF at day 30. However CRP wassignificantly lower at day 30 compared to baseline among those whoremained in sinus rhythm (p=0.04). In between group analysis,there were no significant differences for any fibrinolytic variable, vWFor CRP neither at baseline nor at day 30. Among those with recurrentAF at day 30 there were no significant changes in fibrinolytic variablesfrom baseline to day 30.

Predictors of rhythm

In univariate logistic regression no fibrinolytic variable or vWFwassignificantly correlated with rhythm in day 30. However, in themultivariate analysis lower baseline PAI-1 mass was significantlyassociated with sinus rhythm in all models, Table 3. Lower baselinePAI-1 mass was also predictive of sinus rhythm at day 2 (OR 0.98; 95%CI 0.97–1.00, p=0.02) and remained significant after adjusting for all

Table 2Median values for the markers of inflammation and fibrinolysis and VWF.

Baseline Day 2 after cardioversion p Day 30 p

PAI-1 activity (IU/mL) 11.9 (5.52; 21.5) 7.42 (3.36; 18.0) 0.001 12.6 (4.6; 24.7) 0.15PAI-1 mass (ng/mL) 27.1 (19.4; 40.2) 22.8 (15.2; 35.0) 0.003 28.1 (18.9; 43.8) 0.28tPA activity (IU/mL) 0.79 (0.46; 1.14) 0.89 (0.55; 1.26) 0.084 0.70 (0.43; 1.05) 0.53tPA mass (ng/mL) 10.7 (8.63; 138.8) 0.7 (8.63; 13.8) 0.000 11.1 (8.70; 13.7) 0.73CRP (mg/L) 2.30 (1.20; 3.60) 2.30 (1.20; 5.40) 0.025 1.75 (0.92; 3.45) 0.15VWF (% of normal) 87 (141; 245) 184 (143; 243 0.662 179 (140; 230) 0.88

Median and 25th and 75th percentiles are given. P is calculated between baseline and day 2 and baseline and day 30, respectively (entire group: both atorvastain and placebo).

191J. Andersson et al. / Thrombosis Research 127 (2011) 189–192

variables that correlated with a p-value of b0.05 (OR 0.98; 95% CI0.97–1.00, p=0.04). After adding treatment allocation to the fullyadjusted model, PAI-1 mass remained significantly associated withsinus rhythm both at day 2 and 30 (OR 0.98; 95% CI 0.95–1.00).Increased tPA mass was significantly associated with sinus rhythm atday 30 (OR 1.13; 95% CI 1.01–1.27) with the fibrinolytic variables PAI-1 mass and tPA activity and CRP, but not when it was further adjusted,Table 3.

Discussion

Our main finding was that in univariate analysis no component ofthe fibrinolytic system or vWF was significantly associated withmaintenance of sinus rhythm one month after cardioversion.However, in all the other models and after further adjustment fortreatment, lower PAI-1 mass was still predictive of sinus rhythm bothat 2 days and 30 days after cardioversion. Our findings differsomewhat from those of the CAPRAF study, using a design similar toours, where Tveit [12] found that baseline PAI-1 activity, rather thanPAI mass, was significantly lower in patients in sinus rhythm sixmonths after cardioversion for AF. Their results might depend ondifferent patient selection as our patients had almost twice as highfrequency of hypertension, which in CAPRAF was correlated to PAI-1activity and the fact that they used candesartan instead of atorvastatinin the active treatment arm. Different times for primary endpoint andexclusion of patients with previous cardioversion (one month vs. oneyear) might also explain the different results. Pretorius [11] has alsoshown that PAI-1 level was an independent predictor of developmentof AF after cardiac surgery.

The fibrinolytic function in AF has been proposed to depend onendothelial dysfunction, inflammation and insulin resistance [9]. Aseptic chock with disseminated intravascular coagulation is anapparent example of the link between inflammation and coagulation.The fibrinolytic factors and CRP are known to interact, CRP inducesPAI-1 expression and activity in endothelial cells [18] and PAI-1 inturn acts as an acute-phase reactant [13,19]. PAI-1 as a predictor ofmaintenance of SR seems however independent of inflammatory

Table 3Univariate and multivariate logistic regression analysis for predicting sinus rhythm 30 days

Univariate Fibrinolytic components

PAI-1 mass (ng/mL) 0.99; 0.97–1.00 0.98; 0.96–1.00*PAI-1 activity (IU/mL) 0.99; 0.97–1.01 ExcludedtPA activity (IU/mL) 0.91; 0.45–1.82 0,75; 0,34–1,64tPA mass (ng/mL) 1.05; 0.96–1.15 1.09; 0.98–1.20VWF (% of normal) 1.00; 1,00–1.01 NiMCRP (mg/L) 0.95; 0.87–1.05 0.95; 0.85–1.06Triglycerides (mmol/L) 1.44; 0.96–2.17 NiMBMI (kg/m2) 0.98; 0.92–1.05 NiMHypertension (yes/no) 0.68; 0.33–1.39 NiMCholesterol (mmol/L) 1.01; 0.70–1.46 NiMAge (years) 1.00; 0.97–1.04 NiMSmoker (yes/no) 0.28; 0,06–1.37 NiM

Excluded=In multivariate analysis PAI-1 activity was excluded due to high correlation witNiM=Variable not included in the present model.* denotes pb0,05.

effects as adding CRP to our model did not change the result. On theother hand was increased tPA mass significantly associated tomaintenance of sinus rhythm in a model with the fibrinolyticvariables only when adjusting for CRP. The prognostic value of PAI-1levels often disappears after adjustment for metabolic factors as PAI-1is elevated in the insulin resistance syndrome [20]. Contrary we foundthat PAI-1 mass remained significantly associated with sinus rhythmwhen adding BMI, cholesterol and hypertension to our model. Theseresults question the role of metabolic factors and inflammation asexplanatory factors for PAI-1 as a predictor for rhythm. Future studieson the interaction between inflammatory, metabolic and fibrinolyticfactors in AF may enlighten the pathophysiology behind AF.

Fibrinolysis has been suggested to affect arterial wall remodellingthereby causing AF [21,22]. PAI-1 inhibits t-PA which means that lessplasmin will be formed from plasminogen [23]. Plasmin is importantfor degradation of extracellular matrix in twoways, it is an activator ofmatrix metalloproteinase's which regulates collagen matrix homeo-stasis and is itself a proteolytic enzyme [23,24]. Together metallopro-teinase's and plasmin can degrade most extracellular matrixcomponents [23,24]. These interrelated proteolytic systems are thusinvolved inmatrix degradation and arterial wall remodelling and bothare inhibited by PAI-1 providing a possiblemechanism behind the linkbetween PAI-1 mass and maintenance of SR.

Two days after cardioversion there were lower levels of PAI-1 mass,PAI-1 activity and tPA mass suggesting a rapid improvement offibrinolysis, possible an effect of sinus rhythm, but no difference wasseen after 30 days, maybe because of recurrence of AF in someindividuals during this time. The findingmay thus suggest an improvedfibrinolysis in sinus rhythm compared to AF but further research isneeded to confirm this finding.When studying those 53 individuals stillin sinus rhythm after one month only CRP was significantly lowercompared to baseline suggesting that rhythmmayhave an effect on CRPlevels. The increase of CRP two days after cardioversion may be a resultof the electrical damage to the underlying tissue and this change did notremain at day 30.

The clinical implications of our findings are so far uncertain. There isa relationship betweenPAI-1mass and recurrence of AF onemonth after

after cardioversion. Odds ratio per unit with 95% confidence interval are presented.

+ hsCRP +Metabolic components All variables, pb0.05

0.98; 0.96–1.00* 0.98;0.96–1.00* 0.98;0.96–1.00*Excluded Excluded Excluded0.75; 0.34–1.68 0.62; 0.26–1.49 0.62; 0.25–1.501.11; 1.00–1.24* 1.13; 1.00–1.28 1.13; 0.99–1.29NiM NiM NiM- 0.95; 0.84–1.06 0.94; 0.84–1.06NiM 1.47; 0.87–2.48 1.44; 0.85–2.45NiM 0.94; 0.86–1.03 0.94; 0.85–1.04NiM 0.54; 0,24–1.25 0.60; 0.25–1.43NiM 0.73; 0.44–1.20 0.72; 0.43–1.18NiM NiM 1.00; 0.95–1.04NiM NiM 0.46; 0.08–2.55

h tPA activity (r=0,8).

192 J. Andersson et al. / Thrombosis Research 127 (2011) 189–192

electrical cardioversion but the study does not give us an answer on theclinical usefulness of fibrinolytic markers as predictors for recurrence inAF. It should rather be regarded as an insight to patophysiologicalmechanisms behind AF.

Limitations

This is an explorative substudy why the results should only beregarded as hypothesis generating. The number of patients in ourexplorative study is a limitation; it is underpowered to detect weakerassociations. The studied predictors may be dependent on the studiedpopulation and there was a relatively large proportion of screenedpatients who already were on statin treatment (39% in the mainstudy), and therefore not eligible for the study. Our patients may thusrepresent a cardiovascular low risk group. Another limitation is thatperiods of asymptomatic AF, which is known to be common, was notdetected unless they coincidedwith the follow-up after cardioversion.

Conclusion

No component alone of the fibrinolytic system or vWF was foundto be a predictor for maintenance of sinus rhythm, while inmultivariate models lower PAI-1 mass was associated with sinusrhythm. This finding wasmaintained after adjusting for CRP and somemarkers of the metabolic syndrome as well as treatment withatorvastatin. Our findings suggest a patophysiological link betweenAF and PAI-1 mass but the relation to inflammation remains unclear.

Conflict of interest

We declare that none of the authors have any financial or otherrelationships that might lead to a conflict of interest regarding thispaper.

The manufacturer of atorvastatin, Pfizer, provided study medica-tion and an unrestricted research grant but had no other involvementin the study.

Acknowledgement

The manufacturer of atorvastatin, Pfizer, provided study medica-tion and an unrestricted research grant but had no other involvementin the study.

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