Podocan and Adverse Clinical Outcome in Patients Admitted With Suspected Acute Coronary Syndromes

Thomas Andersen, Thor Ueland, Pål Aukrust, Dennis W Nilsen, Heidi Grundt, Harry Staines, Frederic Kontny, Thomas Andersen, Thor Ueland, Pål Aukrust, Dennis W Nilsen, Heidi Grundt, Harry Staines, Frederic Kontny

Abstract

Background: Markers of bone and extracellular matrix (ECM) remodeling may be associated with adverse outcomes in atherosclerotic cardiovascular disease. Podocan is a newly discovered ECM glycoprotein, previously not studied in a chest pain population. We wanted to study the association between Podocan levels on admission and the risk of adverse outcomes in a chest pain population with suspected acute coronary syndromes.

Methods: A total of 815 patients from the Risk markers in Acute Coronary Syndrome (RACS) trial with suspected coronary chest pain were followed for 7 years. Blood samples were taken immediately after inclusion and stored in the biobank. Associations between Podocan and endpoints were assessed with Cox proportional hazards analyses.

Results: The median admission level of Podocan was 0.674 ng/ml (0.566-0.908 ng/ml). No significant association was found between Podocan quartile levels and all-cause death, neither at 1 year nor 2- or 7-years follow-up (p > 0.05 for all). Furthermore, no significant association could be shown between Podocan and cardiac death, myocardial infarction (MI), stroke, or the composites of all-cause death/MI/stroke or cardiac death/MI/stroke (p > 0.05 for all). Similarly, in a subgroup of patients with Troponin T-positive (n = 432) there was no significant association between Podocan and any of the outcome measures (p > 0.05 for all endpoints and points in time).

Conclusion: Podocan, a novel ECM biomarker, is not associated with all-cause mortality or other major cardiovascular adverse events in patients admitted with acute chest pain suspected to be of coronary origin.

Clinical trialsgov identifier: NCT00521976.

Keywords: Podocan; acute coronary syndrome; biomarkers; chest pain; extracellular matrix; risk factors.

Conflict of interest statement

DN has received support for travel and/or attending meetings from Stavanger Health Research in the last 36 months. HS is employed by Sigma Statistical Services. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Andersen, Ueland, Aukrust, Nilsen, Grundt, Staines and Kontny.

Figures

Figure 1
Figure 1
Kaplan-meier plots of endpoints by quartile of podocan, (A) all-cause death, (B) myocardial infarction, (C) stroke and (D) composite of all-cause death, myocardial infarction, or stroke.

References

    1. Collet JP, Thiele H, Barbato E, Barthelemy O, Bauersachs J, Bhatt DL, et al. . 2020 Esc guidelines for the management of acute coronary syndromes in patients presenting without persistent st-segment elevation. Eur Heart J. (2021) 42:1289–367. 10.1093/eurheartj/ehaa909
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, et al. . Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. (2017) 377:1119–31. 10.1056/NEJMoa1707914
    1. Kosmopoulos M, Paschou SA, Grapsa J, Anagnostis P, Vryonidou A, Goulis DG, et al. . The emerging role of bone markers in diagnosis and risk stratification of patients with coronary artery disease. Angiology. (2019) 70:690–700. 10.1177/0003319718822625
    1. Gialeli C, Shami A, Goncalves I. Extracellular matrix: paving the way to the newest trends in atherosclerosis. Curr Opin Lipidol. (2021) 32:277–85. 10.1097/MOL.0000000000000775
    1. Berezin AE, Berezin AA. Adverse cardiac remodelling after acute myocardial infarction: old and new biomarkers. Dis Markers. (2020) 2020:1215802. 10.1155/2020/1215802
    1. Ureche C, Nedelcu AE, Sascau RA, Statescu C, Kanbay M, Covic A. Role of collagen turnover biomarkers in the noninvasive assessment of myocardial fibrosis: an update. Biomark Med. (2020) 14:1265–75. 10.2217/bmm-2020-0298
    1. Shimizu-Hirota R, Sasamura H, Kuroda M, Kobayashi E, Saruta T. Functional characterization of podocan, a member of a new class in the small leucine-rich repeat protein family. FEBS Lett. (2004) 563:69–74. 10.1016/S0014-5793(04)00250-9
    1. Holm Nielsen S, Jonasson L, Kalogeropoulos K, Karsdal MA, Reese-Petersen AL., Auf dem Keller U, et al. . Exploring the role of extracellular matrix proteins to develop biomarkers of plaque vulnerability and outcome. J Intern Med. (2020) 287:493–513. 10.1111/joim.13034
    1. Ross MD, Bruggeman LA, Hanss B, Sunamoto M, Marras D, Klotman ME, et al. . Podocan, a novel small leucine-rich repeat protein expressed in the sclerotic glomerular lesion of experimental hiv-associated nephropathy. J Biol Chem. (2003) 278:33248–55. 10.1074/jbc.M301299200
    1. Didangelos A, Yin X, Mandal K, Baumert M, Jahangiri M, Mayr M. Proteomics characterization of extracellular space components in the human aorta. Mol Cell Proteomics. (2010) 9:2048–62. 10.1074/mcp.M110.001693
    1. Hutter R, Huang L, Speidl WS, Giannarelli C, Trubin P, Bauriedel G, et al. . Novel small leucine-rich repeat protein podocan is a negative regulator of migration and proliferation of smooth muscle cells, modulates neointima formation, and is expressed in human atheroma. Circulation. (2013) 128:2351–63. 10.1161/CIRCULATIONAHA.113.004634
    1. Watthanasuntorn K, Shrestha B, Bethuel N, Thongprayoon C, Leungsuwan K, Victory J, et al. . Podocan a novel circulating wnt-pathway inhibitor predicts major adverse cardiovascular events in patients with coronary artery disease independent of framingham cardiovascular risk factors in synergy with dickkopf-1. Circulation. (2019) 140:A14785-A.
    1. Watthanasuntorn K, Kandala J, Shrestha B, Thongprayoon C, Victory J, Scribani M, et al. . The novel small leucin-rich repeat protein podocan is an independent predictor of major adverse cardiac events in patients with angiographically-defined coronary artery disease. Eur Heart J. (2019) 40. 10.1093/eurheartj/ehz748.0511
    1. Brugger-Andersen T, Ponitz V, Staines H, Grundt H, Hetland O, Nilsen DW. The prognostic utility of d-dimer and fibrin monomer at long-term follow-up after hospitalization with coronary chest pain. Blood Coagul Fibrinol. (2008) 19:701–7. 10.1097/MBC.0b013e32830b1512
    1. Leon de., la Fuente R, Naesgaard PA, Nilsen ST, Woie L, Aarsland T, Gallo P, et al. . B-type natriuretic peptide and high sensitive c-reactive protein predict 2-year all cause mortality in chest pain patients: a prospective observational study from salta, argentina. BMC Cardiovasc Disord. (2011) 11:57. 10.1186/1471-2261-11-57
    1. Brugger-Andersen T, Ponitz V, Staines H, Pritchard D, Grundt H, Nilsen DW. b-type natriuretic peptide is a long-term predictor of all-cause mortality, whereas high-sensitive c-reactive protein predicts recurrent short-term troponin t positive cardiac events in chest pain patients: a prognostic study. BMC Cardiovasc Disord. (2008) 8:34. 10.1186/1471-2261-8-34
    1. Hutter R, Huang L, Fuster V, Klotman P, Badimon JJ. The novel extracellular matrix protein podocan shows a distinct expression pattern in human primary versus restenotic atherosclerotic coronary lesions and its lack of extra-cellular expression in restenotic tissue is associated with increased wnt-pathway activation. Circulation. (2011) 124:A17034-A.
    1. Speidl WS, Shenje L, Badimon JJ, Schneider DJ, Klotman P, Hutter R. Deficiency in the novel small leucin-rich repeat protein podocan promotes pressure load-induced cardiac hypertrophy. Circulation. (2013) 128:A18184-A.
    1. Watthanasuntorn K, Bethuel N, Shukla A, Leungsuwan K, Khavandi M, Victory J, et al. . Podocan, a wingless-regulatory molecule, is associated with atrial fibrillation. Circulation. (2019) 140:A14021-A.
    1. Schaefer L, Iozzo RV. Biological functions of the small leucine-rich proteoglycans: from genetics to signal transduction. J Biol Chem. (2008) 283:21305–9. 10.1074/jbc.R800020200
    1. Lyck Hansen M, Beck HC, Irmukhamedov A, Jensen PS, Olsen MH, Rasmussen LM. Proteome analysis of human arterial tissue discloses associations between the vascular content of small leucine-rich repeat proteoglycans and pulse wave velocity. Arterioscler Thromb Vasc Biol. (2015) 35:1896–903. 10.1161/ATVBAHA.114.304706
    1. Seifirad S, Haghpanah V. Inappropriate modeling of chronic and complex disorders: how to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine. EPMA J. (2019) 10:195–209. 10.1007/s13167-019-00176-z
    1. Andersen T, Nilsen DW, Grundt H, Staines H, Ueland T, Aukrust P, et al. . The novel wnt-pathway inhibitor podocan is not associated with all-cause mortality or cardiovascular outcome in patients admitted with suspected acute coronary syndrome. Circulation. (2021) 144:A9149.

Source: PubMed

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