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Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort

Abstract

Aims/hypothesis

Tenascin-C (TN-C) is an extracellular matrix glycoprotein highly expressed in inflammatory and cardiovascular (CV) diseases. Serum TN-C has not yet been specifically studied in individuals with type 2 diabetes, a condition associated with chronic low-grade inflammation and increased CV disease risk. In this study, we hypothesised that elevated serum TN-C at enrolment in participants with type 2 diabetes would be associated with increased risk of death and major adverse CV events (MACE) during follow-up.

Methods

We used a prospective, monocentric cohort of consecutive type 2 diabetes participants (the SURDIAGENE [SUivi Rénal, DIAbète de type 2 et GENEtique] cohort) with all-cause death as a primary endpoint and MACE (CV death, non-fatal myocardial infarction or stroke) as a secondary endpoint. We used a proportional hazard model after adjustment for traditional risk factors and the relative integrated discrimination improvement (rIDI) to assess the incremental predictive value of TN-C for these risk factors.

Results

We monitored 1321 individuals (58% men, mean age 64 ± 11 years) for a median of 89 months. During follow-up, 442 individuals died and 497 had MACE. Multivariate Cox analysis showed that serum TN-C concentrations were associated with an increased risk of death (HR per 1 SD: 1.27 [95% CI 1.17, 1.38]; p < 0.0001) and MACE (HR per 1 SD: 1.23 [95% CI 1.13, 1.34]; p < 0.0001). Using TN-C concentrations on top of traditional risk factors, prediction of the risk of all-cause death (rIDI: 8.2%; p = 0.0006) and MACE (rIDI: 6.7%; p = 0.0014) improved significantly, but modestly.

Conclusions/interpretation

In individuals with type 2 diabetes, increased serum TN-C concentrations were independently associated with death and MACE. Therefore, including TN-C as a prognostic biomarker could improve risk stratification in these individuals.

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Fig. 1

Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ANGPTL2:

Angiopoietin-like 2

CAD:

Coronary artery disease

CKD:

Chronic kidney disease

CRP:

C-reactive protein

CV:

Cardiovascular

ECM:

Extracellular matrix

LV:

Left ventricular

MACE:

Major adverse cardiovascular events

MI:

Myocardial infarction

NT-proBNP:

N-terminal pro-B-type natriuretic peptide

rIDI:

Relative integrated discrimination improvement

SBP:

Systolic BP

SURDIAGENE:

SUivi Rénal, DIAbète de type 2 et GENEtique

TN-C:

Tenascin-C

TNFR1:

TNF receptor 1

References

  1. 1.

    Bachmann KN, Wang TJ (2018) Biomarkers of cardiovascular disease: contributions to risk prediction in individuals with diabetes. Diabetologia 61(5):987–995. https://doi.org/10.1007/s00125-017-4442-9

  2. 2.

    Emerging Risk Factors Collaboration (2010) Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375(9733):2215–2222. https://doi.org/10.1016/S0140-6736(10)60484-9

  3. 3.

    Bannister CA, Poole CD, Jenkins-Jones S et al (2014) External validation of the UKPDS risk engine in incident type 2 diabetes: a need for new type 2 diabetes-specific risk equations. Diabetes Care 37(2):537–545. https://doi.org/10.2337/dc13-1159

  4. 4.

    Hayes AJ, Leal J, Gray AM, Holman RR, Clarke PM (2013) UKPDS outcomes model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82. Diabetologia 56(9):1925–1933. https://doi.org/10.1007/s00125-013-2940-y

  5. 5.

    Berezin AE, Kremzer AA (2013) Circulating osteopontin as a marker of early coronary vascular calcification in type two diabetes mellitus patients with known asymptomatic coronary artery disease. Atherosclerosis 229(2):475–481. https://doi.org/10.1016/j.atherosclerosis.2013.06.003

  6. 6.

    Ozturk D, Celik O, Satilmis S et al (2015) Association between serum galectin-3 levels and coronary atherosclerosis and plaque burden/structure in patients with type 2 diabetes mellitus. Coron Artery Dis 26(5):396–401. https://doi.org/10.1097/MCA.0000000000000252

  7. 7.

    Gellen B, Thorin-Trescases N, Sosner P et al (2016) ANGPTL2 is associated with an increased risk of cardiovascular events and death in diabetic patients. Diabetologia 59(11):2321–2330. https://doi.org/10.1007/s00125-016-4066-5

  8. 8.

    Saulnier PJ, Gand E, Ragot S et al (2014) Association of serum concentration of TNFR1 with all-cause mortality in patients with type 2 diabetes and chronic kidney disease: follow-up of the SURDIAGENE cohort. Diabetes Care 37(5):1425–1431. https://doi.org/10.2337/dc13-2580

  9. 9.

    Price AH, Welsh P, Weir CJ et al (2014) N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in older patients with type 2 diabetes: the Edinburgh type 2 diabetes study. Diabetologia 57(12):2505–2512. https://doi.org/10.1007/s00125-014-3375-9

  10. 10.

    von Scholten BJ, Reinhard H, Hansen TW et al (2015) Additive prognostic value of plasma N-terminal pro-brain natriuretic peptide and coronary artery calcification for cardiovascular events and mortality in asymptomatic patients with type 2 diabetes. Cardiovasc Diabetol 14:59. https://doi.org/10.1186/s12933-015-0225-0

  11. 11.

    Gerstein HC, Pare G, McQueen MJ et al (2015) Identifying novel biomarkers for cardiovascular events or death in people with dysglycemia. Circulation 132(24):2297–2304. https://doi.org/10.1161/CIRCULATIONAHA.115.015744

  12. 12.

    Gerstein HC, Pare G, McQueen MJ, Lee SF, Hess S (2017) Validation of the ORIGIN cardiovascular biomarker panel and the value of adding troponin I in dysglycemic people. J Clin Endocrinol Metab 102(7):2251–2257. https://doi.org/10.1210/jc.2017-00273

  13. 13.

    Looker HC, Colombo M, Agakov F et al (2015) Protein biomarkers for the prediction of cardiovascular disease in type 2 diabetes. Diabetologia 58(6):1363–1371. https://doi.org/10.1007/s00125-015-3535-6

  14. 14.

    Giblin SP, Midwood KS (2015) Tenascin-C: form versus function. Cell Adh Migr 9(1–2):48–82. https://doi.org/10.4161/19336918.2014.987587

  15. 15.

    Midwood KS, Chiquet M, Tucker RP, Orend G (2016) Tenascin-C at a glance. J Cell Sci 129(23):4321–4327. https://doi.org/10.1242/jcs.190546

  16. 16.

    Chiquet-Ehrismann R, Chiquet M (2003) Tenascins: regulation and putative functions during pathological stress. J Pathol 200(4):488–499. https://doi.org/10.1002/path.1415

  17. 17.

    Imanaka-Yoshida K (2012) Tenascin-C in cardiovascular tissue remodeling: from development to inflammation and repair. Circ J 76(11):2513–2520. https://doi.org/10.1253/circj.cj-12-1033

  18. 18.

    Midwood KS, Hussenet T, Langlois B, Orend G (2011) Advances in tenascin-C biology. Cell Mol Life Sci 68(19):3175–3199. https://doi.org/10.1007/s00018-011-0783-6

  19. 19.

    Sato A, Aonuma K, Imanaka-Yoshida K et al (2006) Serum tenascin-C might be a novel predictor of left ventricular remodeling and prognosis after acute myocardial infarction. J Am Coll Cardiol 47(11):2319–2325. https://doi.org/10.1016/j.jacc.2006.03.033

  20. 20.

    Sato A, Hiroe M, Akiyama D et al (2012) Prognostic value of serum tenascin-C levels on long-term outcome after acute myocardial infarction. J Card Fail 18(6):480–486. https://doi.org/10.1016/j.cardfail.2012.02.009

  21. 21.

    Nozato T, Sato A, Hikita H et al (2015) Impact of serum tenascin-C on the aortic healing process during the chronic stage of type B acute aortic dissection. Int J Cardiol 191:97–99. https://doi.org/10.1016/j.ijcard.2015.05.009

  22. 22.

    Yokokawa T, Sugano Y, Nakayama T et al (2016) Significance of myocardial tenascin-C expression in left ventricular remodelling and long-term outcome in patients with dilated cardiomyopathy. Eur J Heart Fail 18(4):375–385. https://doi.org/10.1002/ejhf.464

  23. 23.

    Gao W, Li J, Ni H et al (2019) Tenascin C: a potential biomarker for predicting the severity of coronary atherosclerosis. J Atheroscler Thromb 26(1):31–38. https://doi.org/10.5551/jat.42887

  24. 24.

    Kobayashi Y, Yoshida S, Zhou Y et al (2016) Tenascin-C promotes angiogenesis in fibrovascular membranes in eyes with proliferative diabetic retinopathy. Mol Vis 22:436–445

  25. 25.

    Castellon R, Caballero S, Hamdi HK et al (2002) Effects of tenascin-C on normal and diabetic retinal endothelial cells in culture. Invest Ophthalmol Vis Sci 43(8):2758–2766

  26. 26.

    To M, Goz A, Camenzind L et al (2013) Diabetes-induced morphological, biomechanical, and compositional changes in ocular basement membranes. Exp Eye Res 116:298–307. https://doi.org/10.1016/j.exer.2013.09.011

  27. 27.

    Liabeuf S, Barreto DV, Kretschmer A et al (2011) High circulating levels of large splice variants of tenascin-C is associated with mortality and cardiovascular disease in chronic kidney disease patients. Atherosclerosis 215(1):116–124. https://doi.org/10.1016/j.atherosclerosis.2010.11.038

  28. 28.

    Ulusoy S, Ozkan G, Mentese A et al (2015) A new predictor of mortality in hemodialysis patients; tenascin-C. Life Sci 141:54–60. https://doi.org/10.1016/j.lfs.2015.09.011

  29. 29.

    Hadjadj S, Fumeron F, Roussel R et al (2008) Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 31(9):1847–1852. https://doi.org/10.2337/dc07-2079

  30. 30.

    Levey AS, Stevens LA, Schmid CH et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006

  31. 31.

    Hicks KA, Tcheng JE, Bozkurt B et al (2015) 2014 ACC/AHA key data elements and definitions for cardiovascular endpoint events in clinical trials: a report of the American College of Cardiology/American Heart Association Task Force on clinical data standards (Writing Committee to develop cardiovascular endpoints data standards). J Am Coll Cardiol 66(4):403–469. https://doi.org/10.1016/j.jacc.2014.12.018

  32. 32.

    Fernandez-Juarez G, Villacorta Perez J, Luno Fernandez JL et al (2017) High levels of circulating TNFR1 increase the risk of all-cause mortality and progression of renal disease in type 2 diabetic nephropathy. Nephrology 22(5):354–360. https://doi.org/10.1111/nep.12781

  33. 33.

    Hata J, Mukai N, Nagata M et al (2016) Serum angiopoietin-like protein 2 is a novel risk factor for cardiovascular disease in the community: the Hisayama study. Arterioscler Thromb Vasc Biol 36(8):1686–1691. https://doi.org/10.1161/ATVBAHA.116.307291

  34. 34.

    Huang CL, Wu YW, Wu CC, Hwang JJ, Yang WS (2015) Serum angiopoietin-like protein 2 concentrations are independently associated with heart failure. PLoS One 10(9):e0138678. https://doi.org/10.1371/journal.pone.0138678

  35. 35.

    Lee JE, Gohda T, Walker WH et al (2013) Risk of ESRD and all cause mortality in type 2 diabetes according to circulating levels of FGF-23 and TNFR1. PLoS One 8(3):e58007. https://doi.org/10.1371/journal.pone.0058007

  36. 36.

    Neirynck N, Glorieux G, Schepers E, Verbeke F, Vanholder R (2015) Soluble tumor necrosis factor receptor 1 and 2 predict outcomes in advanced chronic kidney disease: a prospective cohort study. PLoS One 10(3):e0122073. https://doi.org/10.1371/journal.pone.0122073

  37. 37.

    Horstrup JH, Gehrmann M, Schneider B et al (2002) Elevation of serum and urine levels of TIMP-1 and tenascin in patients with renal disease. Nephrol Dial Transplant 17(6):1005–1013. https://doi.org/10.1093/ndt/17.6.1005

  38. 38.

    Piccinini AM, Midwood KS (2010) DAMPening inflammation by modulating TLR signalling. Mediat Inflamm 2010:672395. https://doi.org/10.1155/2010/672395

  39. 39.

    Turner NA (2016) Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs). J Mol Cell Cardiol 94:189–200. https://doi.org/10.1016/j.yjmcc.2015.11.002

  40. 40.

    Williams AS, Kang L, Wasserman DH (2015) The extracellular matrix and insulin resistance. Trends Endocrinol Metab 26(7):357–366. https://doi.org/10.1016/j.tem.2015.05.006

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Acknowledgements

All participants included and followed in the cohort study are warmly thanked for their kind participation in this research. Their general practitioners (GPs) are acknowledged for their help in collecting clinical information. E. Migault (Inserm CIC1402, Poitiers, France) and the staff of the Diabetes Department at Poitiers hospital are acknowledged for their help with data collection and monitoring. We thank A. Pavy, M.-C. Pasquier (Information Technology Department, CHU de Poitiers, Poitiers, France) and A. Neveu and J. Guignet (Medical Information Department, CHU de Poitiers, Poitiers, France). J. Arsham (CHU de Poitiers, Poitiers, France) carried out English language editing of the manuscript. A list of centres and staff involved in SURDIAGENE recruitment and adjudication is given as electronic supplementary material (ESM). Some of the data were presented as an abstract at the 30th European Meeting of the French Society of Cardiology (Journées européennes de la Société française de cardiologie, JESFC) meeting in 2020.

Funding

The SURDIAGENE cohort was supported by grants from the French Ministry of Health (PHRC-Poitiers 2004; PHRC-IR 2008), the Association Française des Diabétiques (Research Grant 2003) and the Groupement pour l’Etude des Maladies Métaboliques et Systémiques (GEMMS Poitiers, France). TN-C measurements were supported by a research grant from ELSAN, France (2016).

Author information

BG conceived the work, obtained the grant for the measurement of TN-C and wrote the manuscript. NT-T conceived the work and wrote the manuscript. ET was involved with data analysis and interpretation and edited the manuscript. EG performed statistical analysis, contributed to drafting and revision of the manuscript. PS was involved in the study design, collected data, adjudicated clinical endpoints, and revised the manuscript. SB performed the assay for TN-C and contributed to the drafting of the manuscript. SH conceived and constituted the SURDIAGENE cohort, collected data, was involved with data analysis and interpretation, and revised the manuscript. VR, DM, VJ, YP and PG adjudicated clinical endpoints, interpreted data and contributed to the drafting and revision of the manuscript. XP collected data and contributed to the drafting and revision of the manuscript. P-JS collected data, was involved with data analysis and interpretation and wrote the manuscript. All authors critically revised the article. BG and PJS are the guarantors of this work and take full responsibility for the contents of the article.

Correspondence to Barnabas Gellen.

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Gellen, B., Thorin-Trescases, N., Thorin, E. et al. Serum tenascin-C is independently associated with increased major adverse cardiovascular events and death in individuals with type 2 diabetes: a French prospective cohort. Diabetologia (2020). https://doi.org/10.1007/s00125-020-05108-5

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Keywords

  • Cardiovascular risk
  • MACE
  • Tenascin-C
  • Type 2 diabetes