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Thromb Haemost 2017; 117(03): 471-478
DOI: 10.1160/TH16-08-0600
Coagulation and Fibrinolysis
Schattauer GmbH

Prognostic significance of tPA/PAI-1 complex in patients with heart failure and preserved ejection fraction

Max-Paul Winter   *
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Marcus E. Kleber   *
2   Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
5   Mannheim Institute for Public Health, Social- and Preventive Medicine, Mannheim, Germany
,
Lorenz Koller
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Patrick Sulzgruber
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Hubert Scharnagl
6   Clinical Institute for Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
,
Graciela Delgado
2   Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
,
Georg Goliasch
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
,
Winfried März
2   Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
7   Clinical Institute of Medical and Chemical Laboratory Diagnostics, Graz Medical University, Graz, Austria
8   Synlab Academy, Synlab Services LLC, Mannheim, Germany
,
Alexander Niessner
1   Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
› Author Affiliations Financial support: The study was supported and received funding for materials by the ‘Association for the Promotion of Research in Atherosclerosis, Thrombosis and Vascular Biology’ (ATVB). (Vienna, Austria).
Further Information

Publication History

Received: 06 August 2016

Accepted after major revision: 16 November 2016

Publication Date:
28 November 2017 (online)

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Summary

Heart failure with preserved ejection fraction (HFpEF) represents a major epidemic, clinical and public health problem with rising patient numbers every year. Traditional markers for heart failure have been shown to be of limited sensitivity in patients with HFpEF, as those do not reflect pathophysiology of the disease properly. Dysregulation of haemostasis is thought to be central for the initiation and progression of HFpEF. For this reason, we aimed to assess markers of fibrinolytic activity as potential biomarkers for risk assessment in patients with HFpEF. We evaluated blood coagulation parameters in 370 patients with HFpEF included in the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. Within an observation period of 9.7 years, 40 percent of these patients died from any cause. tPA/PAI-1 complex significantly predicted all-cause mortality with a hazard ratio (HR) of 1.24 (95 % confidence interval [CI] 1.04–1.47) per increase of 1 SD and cardiovascular mortality with a HR 1.26 (95 % CI 1.02–1.56) per increase of 1 SD. Both associations remained significant after adjustment for cardiovascular risk factors, N-terminal pro–B-type natriuretic peptide (NT-proBNP) and frequent HFpEF- related comorbidities. Importantly, tPA/PAI-1 complex had additional prognostic value above and beyond NT-proBNP as indicated by integrated discrimination improvement (0.0157, p=0.017). In conclusion, the concentration of tPA/ PAI-1 complex is an independent predictor of mortality from all causes and from cardiovascular causes in patients with HFpEF. The concomitant measurement of tPA/PAI-1 complex might be useful in clinical practice to add prognostic value to traditional markers of heart failure.

Keywords

Heart failure and preserved ejection fraction (HFpEF) - tissue plasminogen activator (tPA) - plasminogen activator inhibitor 1(PAI-1)

Notes

* These authors contributed equally


 

  • References

  • 1 Roger VL.. Epidemiology of heart failure. Circulation Res 2013; 113: 646-659.
    CrossrefPubMedSearch in Google Scholar
  • 2 Borlaug BA.. The pathophysiology of heart failure with preserved ejection fraction. Nature Rev Cardiol 2014; 11: 507-515.
    CrossrefPubMedSearch in Google Scholar
  • 3 Sanderson JE.. HFNEF, HFpEF, HF-PEF, or DHF: what is in an acronym?. J Am Coll Cardiol Heart Fail 2014; 02: 93-94.
    PubMedSearch in Google Scholar
  • 4 Owan TE, Hodge DO, Herges RM. et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 2006; 355: 251-259.
    CrossrefPubMedSearch in Google Scholar
  • 5 Borlaug BA, Redfield MM.. Diastolic and systolic heart failure are distinct phenotypes within the heart failure spectrum. Circulation 2011; 123: 2006-2014.
    CrossrefPubMedSearch in Google Scholar
  • 6 Bhuiyan T, Maurer MS.. Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma. Curr Cardiovasc Risk Rep 2011; 05: 440-449.
    CrossrefPubMedSearch in Google Scholar
  • 7 van Veldhuisen DJ, Linssen GC, Jaarsma T. et al. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll Cardiol 2013; 61: 1498-1506.
    CrossrefPubMedSearch in Google Scholar
  • 8 Felker GM, Hasselblad V, Hernandez AF. et al. Biomarker-guided therapy in chronic heart failure: a meta-analysis of randomized controlled trials. Am Heart J 2009; 158: 422-430.
    CrossrefPubMedSearch in Google Scholar
  • 9 Zannad F.. Pharmacotherapy in heart failure with reduced ejection fraction during the last 20 years, and the way ahead for precision medicine. Eur Heart J Cardiovasc Pharmacother 2015; 01: 10-12.
    CrossrefPubMedSearch in Google Scholar
  • 10 Paulus WJ, Tschope C.. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013; 62: 263-271.
    CrossrefPubMedSearch in Google Scholar
  • 11 Chong AY, Lip GY.. Viewpoint: the prothrombotic state in heart failure: a maladaptive inflammatory response?. Eur J Heart Fail 2007; 09: 124-128.
    CrossrefPubMedSearch in Google Scholar
  • 12 Lip GY, Gibbs CR.. Does heart failure confer a hypercoagulable state? Virchow’s triad revisited. J Am Coll Cardiol 1999; 33: 1424-1426.
    CrossrefPubMedSearch in Google Scholar
  • 13 Yndestad A, Damas JK, Oie E. et al. Role of inflammation in the progression of heart failure. Curr Cardiol Rep 2007; 09: 236-241.
    CrossrefPubMedSearch in Google Scholar
  • 14 Gibbs CR, Blann AD, Watson RD. et al. Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy. Circulation 2001; 103: 1746-1751.
    CrossrefPubMedSearch in Google Scholar
  • 15 Jug B, Vene N, Salobir BG. et al. Prognostic impact of haemostatic derangements in chronic heart failure. Thromb Haemost 2009; 102: 314-320.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 Iwaki T, Urano T, Umemura K.. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012; 157: 291-298.
    CrossrefPubMedSearch in Google Scholar
  • 17 Jug B, Vene N, Salobir BG. et al. Procoagulant state in heart failure with preserved left ventricular ejection fraction. Intern Heart J 2009; 50: 591-600.
    PubMedSearch in Google Scholar
  • 18 Winkelmann BR, Marz W, Boehm BO. et al. Rationale and design of the LURIC study--a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001; 2 1 (Suppl. 01) S1-73.
    PubMedSearch in Google Scholar
  • 19 Borlaug BA, Paulus WJ.. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011; 32: 670-679.
    CrossrefPubMedSearch in Google Scholar
  • 20 Paulus WJ, Tschope C, Sanderson JE. et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007; 28: 2539-2550.
    CrossrefPubMedSearch in Google Scholar
  • 21 Pencina MJ, D’Agostino Sr. RB, Steyerberg EW.. Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Statistics Med 2011; 30: 11-21.
    CrossrefPubMedSearch in Google Scholar
  • 22 Akkus MN, Polat G, Yurtdas M. et al. Admission levels of C-reactive protein and plasminogen activator inhibitor-1 in patients with acute myocardial infarction with and without cardiogenic shock or heart failure on admission. Intern Heart J 2009; 50: 33-45.
    PubMedSearch in Google Scholar
  • 23 Li YH, Teng JK, Tsai WC. et al. Prognostic significance of elevated hemostatic markers in patients with acute myocardial infarction. J Am Coll Cardiol 1999; 33: 1543-1548.
    CrossrefPubMedSearch in Google Scholar
  • 24 Lowe GD, Danesh J, Lewington S. et al. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 2004; 25: 252-259.
    CrossrefPubMedSearch in Google Scholar
  • 25 Armaghan Y., Soomro AG, Dru J.. Nichols, Javed Suleman, George D.Dangas The current role and future prospects of D-dimer biomarker. Eur Heart J Cardiovasc Pharmacother 2016; 02: 175-184.
    CrossrefPubMedSearch in Google Scholar
  • 26 Kleber ME, Koller L, Goliasch G. et al. Von Willebrand factor improves risk prediction in addition to N-terminal pro-B-type natriuretic peptide in patients referred to coronary angiography and signs and symptoms of heart failure and preserved ejection fraction. Circ Heart Fail 2015; 08: 25-32.
    CrossrefPubMedSearch in Google Scholar
  • 27 Previtali E, Bucciarelli P, Passamonti SM. et al. Risk factors for venous and arterial thrombosis. Blood Transfusion 2011; 09: 120-138.
    PubMedSearch in Google Scholar
  • 28 Caruana L, Petrie MC, Davie AP. et al. Do patients with suspected heart failure and preserved left ventricular systolic function suffer from „diastolic heart failure“ or from misdiagnosis? A prospective descriptive study. Br Med J 2000; 321: 215-218.
    CrossrefPubMedSearch in Google Scholar
  • 29 Nordenhem A, Leander K, Hallqvist J. et al. The complex between tPA and PAI-1: risk factor for myocardial infarction as studied in the SHEEP project. Thrombosis Res 2005; 116: 223-232.
    CrossrefPubMedSearch in Google Scholar
  • 30 Gorog DA.. Prognostic value of plasma fibrinolysis activation markers in cardiovascular disease. J Am Coll Cardiol 2010; 55: 2701-2709.
    CrossrefPubMedSearch in Google Scholar