GDF-15 and TRAIL-R2 are powerful predictors of long-term mortality in patients with acute myocardial infarction

Abstract

Background

The Proximity Extension Assay proteomics chip provides a large-scale analysis of 92 biomarkers linked to cardiovascular disease or inflammation. We aimed to identify the biomarkers that best predicted long-term all-cause mortality in patients with acute myocardial infarction.

Methods

In this prospective cohort study, 92 biomarkers were analysed in 847 consecutive patients from the Västmanland Myocardial Infarction Study with a median follow-up of 6.9 years.

Results

The mean (± standard deviation) age of the patients was 70 (11.8) years and 32.7% were female. Two hundred and seven patients had died after follow-up. The biomarkers most strongly linked to all-cause mortality were growth differentiation factor 15 (GDF-15) and tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2). Cox regression analysis showed that GDF-15 (hazard ratio 1.25 per unit change, 95% confidence interval, 1.02–1.53, p = 0.031) and TRAIL-R2 (hazard ratio 1.37 per unit change, 95% confidence interval 1.12–1.67, p = 0.002) were independent predictors of long-term all-cause mortality after adjusting for age, gender, diabetes, previous myocardial infarction, stroke, heart failure, hypertension, smoking, hypercholesterolaemia, body mass index, ST-elevation myocardial infarction, left ventricular ejection fraction, troponin I, estimated glomerular filtration rate, N-terminal pro-brain natriuretic peptide and C-reactive protein. The combination of GDF-15 and TRAIL-R2 with established risk factors and biomarkers showed a discriminating accuracy of separating survivors from non-survivors with a cross-validated area under the receiving operating characteristics curve of 0.88 within five years.

Conclusion

GDF-15 and TRAIL-R2 were the most powerful Proximity Extension Assay chip biomarkers in predicting long-term all-cause mortality in patients with acute myocardial infarction.

Keywords

Myocardial infarction biomarkers mortality

Get full access to this article

View all access options for this article.

References

White

Chew

. Acute myocardial infarction. Lancet 2008; 372: 570–584.

Frangogiannis

. The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol 2014; 11: 255–265.

Schnabel

Yin

Larson

et al.

Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. Arterioscler Thromb Vasc Biol 2013; 33: 1728–1733.

Christia

Frangogiannis

. Targeting inflammatory pathways in myocardial infarction. Eur J Clin Invest 2013; 43: 986–995.

Sabatine

Morrow

de Lemos

et al.

Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: Simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002; 105: 1760–1763.

Lippi

Franchini

Cervellin

. Diagnosis and management of ischemic heart disease. Semin Thromb Hemost 2013; 39: 202–213.

Assarsson

Lundberg

Holmquist

et al.

Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One 2014; 9: e95192–e95192.

Conden

Rosenblad

Wagner

et al.

Is type D personality an independent risk factor for recurrent myocardial infarction or all-cause mortality in post-acute myocardial infarction patients?

Eur J Prev Cardiol 2017; 24: 522–533.

Alpert

Thygesen

Antman

et al.

Myocardial infarction redefined – a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000; 36: 959–969.

10.

Lang

Badano

Mor-Avi

et al.

Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16: 233–270.

11.

Hedberg

Hammar

Selmeryd

et al.

Left ventricular systolic dysfunction in outpatients with peripheral atherosclerotic vascular disease: Prevalence and association with location of arterial disease. Eur J Heart Fail 2014; 16: 625–632.

12.

Matsushita

Mahmoodi

Woodward

et al.

Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA 2012; 307: 1941–1951.

13.

Carlsson

Sundstrom

Carrero

et al.

Use of a proximity extension assay proteomics chip to discover new biomarkers associated with albuminuria. Eur J Prev Cardiol 2017; 24: 340–348.

14.

Wollert

Kempf

Peter

et al.

Prognostic value of growth-differentiation factor-15 in patients with non-ST-elevation acute coronary syndrome. Circulation 2007; 115: 962–971.

15.

Kempf

Eden

Strelau

et al.

The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ Res 2006; 98: 351–360.

16.

Hedman

Enroth

et al.

Genome-wide DNA methylation study identifies genes associated with the cardiovascular biomarker GDF-15. Hum Mol Genet 2016; 25: 817–827.

17.

Ago

Sadoshima

. GDF15, a cardioprotective TGF-beta superfamily protein. Circ Res 2006; 98: 294–297.

18.

Daniels

Clopton

Laughlin

et al.

Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: The Rancho Bernardo Study. Circulation 2011; 123: 2101–2110.

19.

Wallentin

Zethelius

Berglund

et al.

GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men. PLoS One 2013; 8: e78797–e78797.

20.

Lind

Wallentin

Kempf

et al.

Growth-differentiation factor-15 is an independent marker of cardiovascular dysfunction and disease in the elderly: Results from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study. Eur Heart J 2009; 30: 2346–2353.

21.

Gao

. Growth differentiation factor 15 in cardiovascular diseases: From bench to bedside. Biomarkers 2011; 16: 466–475.

22.

Hagstrom

James

Bertilsson

et al.

Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: Results from the PLATO study. Eur Heart J 2016; 37: 1325–1333.

23.

Wollert

Kempf

Lagerqvist

et al.

Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome. Circulation 2007; 116: 1540–1548.

24.

Muhlenbeck

Schneider

Bodmer

et al.

The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation. J Biol Chem 2000; 275: 32208–32213.

25.

Kavurma

Bennett

. Expression, regulation and function of trail in atherosclerosis. Biochem Pharmacol 2008; 75: 1441–1450.

26.

Gonzalvez

Ashkenazi

. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene 2010; 29: 4752–4765.

27.

Walczak

Degli-Esposti

Johnson

et al.

TRAIL-R2: A novel apoptosis-mediating receptor for TRAIL. EMBO J 1997; 16: 5386–5397.

28.

Michowitz

Goldstein

Roth

et al.

The involvement of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in atherosclerosis. J Am Coll Cardiol 2005; 45: 1018–1024.

29.

Osmancik

Teringova

Tousek

et al.

Prognostic value of TNF-related apoptosis inducing ligand (TRAIL) in acute coronary syndrome patients. PLoS One 2013; 8: e53860–e53860.

30.

Nagata

. Apoptosis by death factor. Cell 1997; 88: 355–365.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.08 MB