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Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study

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Abstract

Background

In the Gutenberg Health Study, a random sample of the population was scanned with vascular ultrasound for early atherosclerosis. A continuous classical risk marker model (waist circumference, HbA1c, LDL/HDL ratio, pack years and pulse pressure) was compared to a model of modern biomarkers (C-reactive protein, troponin I, N-terminal pro B-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin, and asymmetric dimethylarginine) with regard to the ability of ruling out abnormal intima-media thickness (IMT), respectively, carotid plaques.

Methods

Data of the first consecutive 5,000 participants (aged 35–74 years; 2,540 men, 2,460 women) were analyzed. IMT was measured at both common carotid arteries using an edge detection system. Plaques were defined as protrusion of ≥1.5 mm in common, internal and external carotid artery.

Results

For classical risk factors, in comparison to a model of six modern biomarkers, regarding the variable (a) IMT>0.85 mm negative and positive predictive value (NPV and PPV) were 0.98 and 0.16 for both the classical risk factor model and the biomarker model. The second variable (b) presence of plaque could be ruled out with an NPV of 0.84 and identified with a PPV of 0.61 for classical risk factors, and 0.84 and 0.58 for biomarkers, respectively. Values were calculated using logistic regression analysis.

Conclusion

Classical risk factors allow ruling out pathologic IMT and presence of carotid plaques in a population of primary prevention in a reliable way. Modern biomarkers performed almost equally well but did not provide further information.

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Abbreviations

ADMA:

Asymmetric dimethylarginine

CCA:

Common carotid artery

CRP:

C-reactive protein

CVD:

Cardiovascular disease

GHS:

Gutenberg Health Study

IMT:

Intima-media thickness

MR-proADM:

Mid-regional pro-adrenomedullin

NPV:

Negative predictive value

NT-proBNP:

N-terminal pro B-type natriuretic peptide

PPV:

Positive predictive value

TnI:

Troponin I

References

  1. Bauer M, Mohlenkamp S, Lehmann N, Schmermund A, Roggenbuck U, Moebus S, Stang A, Mann K, Jockel KH, Erbel R (2009) The effect of age and risk factors on coronary and carotid artery atherosclerotic burden in males: results of the Heinz Nixdorf Recall Study. Atherosclerosis 205(2):595–602. doi:10.1016/j.atherosclerosis.2009.01.005

    Article  CAS  PubMed  Google Scholar 

  2. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE (1997) Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 96(5):1432–1437

    Article  CAS  PubMed  Google Scholar 

  3. Cao JJ, Arnold AM, Manolio TA, Polak JF, Psaty BM, Hirsch CH, Kuller LH, Cushman M (2007) Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation 116(1):32–38. doi:10.1161/CIRCULATIONAHA.106.645606

    Article  PubMed  Google Scholar 

  4. Dogan S, Kastelein JJ, Grobbee DE, Bots ML (2011) Mean common or mean maximum carotid intima-media thickness as primary outcome in lipid-modifying intervention studies. J Atheroscler Thromb 18(11):946–957 pii: JST.JSTAGE/jat/8623

    Article  PubMed  Google Scholar 

  5. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M (2007) Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysis. Circulation 115(4):459–467. doi:10.1161/CIRCULATIONAHA.106.628875

    Article  PubMed  Google Scholar 

  6. Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Volzke H, Tuomainen TP, Sander D, Plichart M, Catapano AL, Robertson CM, Kiechl S, Rundek T, Desvarieux M, Lind L, Schmid C, DasMahapatra P, Gao L, Ziegelbauer K, Bots ML, Thompson SG (2012) Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data. Lancet 379(9831):2053–2062. doi:10.1016/S0140-6736(12)60441-3

    Article  PubMed Central  PubMed  Google Scholar 

  7. Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M (2006) Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke 37(1):87–92. doi:10.1161/01.STR.0000196964.24024.ea

    Article  PubMed  Google Scholar 

  8. Oren A, Vos LE, Uiterwaal CS, Grobbee DE, Bots ML (2003) Cardiovascular risk factors and increased carotid intima-media thickness in healthy young adults: the Atherosclerosis Risk in Young Adults (ARYA) Study. Arch Intern Med 163(15):1787–1792. doi:10.1001/archinte.163.15.1787

    Article  PubMed  Google Scholar 

  9. Salonen R, Salonen JT (1991) Determinants of carotid intima-media thickness: a population-based ultrasonography study in eastern Finnish men. J Intern Med 229(3):225–231

    Article  CAS  PubMed  Google Scholar 

  10. Ziegelbauer K, Schaefer C, Steinmetz H, Sitzer M, Lorenz MW (2012) Clinical usefulness of carotid ultrasound to improve stroke risk assessment: ten-year results from the Carotid Atherosclerosis Progression Study (CAPS). Eur J Prev Cardiol. doi:10.1177/2047487312449589

    PubMed  Google Scholar 

  11. Bots ML, Grobbee DE, Hofman A, Witteman JC (2005) Common carotid intima-media thickness and risk of acute myocardial infarction: the role of lumen diameter. Stroke 36(4):762–767. doi:10.1161/01.STR.0000158924.71069.94

    Article  PubMed  Google Scholar 

  12. Bots ML, Hofman A, Grobbee DE (1997) Increased common carotid intima-media thickness. Adaptive response or a reflection of atherosclerosis? Findings from the Rotterdam Study. Stroke 28(12):2442–2447

    Article  CAS  PubMed  Google Scholar 

  13. Dogan S, Plantinga Y, Dijk JM, van der Graaf Y, Grobbee DE, Bots ML (2009) Manual B-mode versus automated radio-frequency carotid intima-media thickness measurements. J Am Soc Echocardiogr 22(10):1137–1144. doi:10.1016/j.echo.2009.07.008

    Article  PubMed  Google Scholar 

  14. Sinning C, Wild PS, Echevarria FM, Wilde S, Schnabel R, Lubos E, Herkenhoff S, Bickel C, Klimpe S, Gori T, Munzel TF, Blankenberg S, Espinola-Klein C (2011) Sex differences in early carotid atherosclerosis (from the community-based Gutenberg-Heart Study). Am J Cardiol 107(12):1841–1847. doi:10.1016/j.amjcard.2011.02.318

    Article  PubMed  Google Scholar 

  15. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, Najjar SS, Rembold CM, Post WS (2008) Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr 21(2):93–111. doi:10.1016/j.echo.2007.11.011 quiz 189–190

    Article  PubMed  Google Scholar 

  16. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Fatar M, Hernandez Hernandez R, Jaff M, Kownator S, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS, Zannad F, Zureik M (2007) Mannheim carotid intima-media thickness consensus (2004–2006). An update on behalf of the Advisory Board of the 3rd and 4th Watching the Risk Symposium, 13th and 15th European Stroke Conferences, Mannheim, Germany, 2004, and Brussels, Belgium, 2006. Cerebrovasc Dis 23(1):75–80. doi:10.1159/000097034

    Article  PubMed  Google Scholar 

  17. Schnabel RB, Yin X, Larson MG, Yamamoto JF, Fontes JD, Kathiresan S, Rong J, Levy D, Keaney JF Jr, Wang TJ, Murabito JM, Vasan RS, Benjamin EJ (2013) Multiple inflammatory biomarkers in relation to cardiovascular events and mortality in the community. Arterioscler Thromb Vasc Biol 33(7):1728–1733. doi:10.1161/ATVBAHA.112.301174

    Article  CAS  PubMed  Google Scholar 

  18. Breda L, Di Marzio D, Giannini C, Gaspari S, Nozzi M, Scarinci A, Chiarelli F, Mohn A (2013) Relationship between inflammatory markers, oxidant-antioxidant status and intima-media thickness in prepubertal children with juvenile idiopathic arthritis. Clin Res Cardiol 102(1):63–71. doi:10.1007/s00392-012-0496-3

    Article  CAS  PubMed  Google Scholar 

  19. Leistner DM, Klotsche J, Pieper L, Palm S, Stalla GK, Lehnert H, Silber S, Marz W, Wittchen HU, Zeiher AM (2013) Prognostic value of NT-pro-BNP and hs-CRP for risk stratification in primary care: results from the population-based DETECT study. Clin Res Cardiol 102(4):259–268. doi:10.1007/s00392-012-0530-5

    Article  PubMed  Google Scholar 

  20. Keller T, Ojeda F, Zeller T, Wild PS, Tzikas S, Sinning CR, Peetz D, Munzel T, Blankenberg S, Lackner KJ (2012) Defining a reference population to determine the 99th percentile of a contemporary sensitive cardiac troponin I assay. Int J Cardiol. doi:10.1016/j.ijcard.2012.04.063

    Google Scholar 

  21. Sinning C, Keller T, Zeller T, Ojeda F, Schluter M, Schnabel R, Lubos E, Bickel C, Lackner KJ, Diemert P, Munzel T, Blankenberg S, Wild PS (2013) Association of high-sensitivity assayed troponin I with cardiovascular phenotypes in the general population: the population-based Gutenberg health study. Clin Res Cardiol. doi:10.1007/s00392-013-0640-8

    Google Scholar 

  22. Hojs R, Ekart R, Hojs Fabjan T, Balon BP, Gorenjak M (2005) Cardiac troponin T (cTnT) in hemodialysis patients with asymptomatic and symptomatic atherosclerosis. Arch Med Res 36(4):367–371. doi:10.1016/j.arcmed.2005.03.024

    Article  CAS  PubMed  Google Scholar 

  23. Schnabel RB, Wild PS, Schulz A, Zeller T, Sinning CR, Wilde S, Kunde J, Lubos E, Lackner KJ, Warnholtz A, Gori T, Blankenberg S, Munzel T (2012) Multiple endothelial biomarkers and noninvasive vascular function in the general population: the Gutenberg Health Study. Hypertension 60(2):288–295. doi:10.1161/HYPERTENSIONAHA.112.191874

    Article  CAS  PubMed  Google Scholar 

  24. Kara K, Mahabadi AA, Geisel MH, Lehmann N, Kalsch H, Bauer M, Neumann T, Dragano N, Moebus S, Mohlenkamp S, Jockel KH, Erbel R (2013) B-type natriuretic peptide: distribution in the general population and the association with major cardiovascular and coronary events: the Heinz Nixdorf Recall Study. Clin Res Cardiol. doi:10.1007/s00392-013-0628-4

  25. Oluleye OW, Folsom AR, Nambi V, Lutsey PL, Ballantyne CM (2012) Troponin T, B-type natriuretic peptide, C-reactive protein, and cause-specific mortality. Ann Epidemiol. doi:10.1016/j.annepidem.2012.11.004

    PubMed Central  PubMed  Google Scholar 

  26. Li X, Yang XC, Sun QM, Chen XD, Li YC (2013) Brain natriuretic peptide and copeptin levels are associated with cardiovascular disease in patients with chronic kidney disease. Chin Med J (Engl) 126(5):823–827

    CAS  Google Scholar 

  27. Wild PS, Schnabel RB, Lubos E, Zeller T, Sinning CR, Keller T, Tzikas S, Lackner KJ, Peetz D, Rupprecht HJ, Bickel C, Morgenthaler NG, Papassotiriou J, Tiret L, Munzel T, Blankenberg S (2012) Mid-regional pro-adrenomedullin for prediction of cardiovascular events in coronary artery disease: results from the AtheroGene study. Clin Chem 58(1):226–236. doi:10.1373/clinchem.2010.157842

    Article  CAS  PubMed  Google Scholar 

  28. Schnabel R, Blankenberg S, Lubos E, Lackner KJ, Rupprecht HJ, Espinola-Klein C, Jachmann N, Post F, Peetz D, Bickel C, Cambien F, Tiret L, Munzel T (2005) Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res 97(5):e53–e59. doi:10.1161/01.RES.0000181286.44222.61

    Article  CAS  PubMed  Google Scholar 

  29. Sydow K, Schmitz C, von Leitner EC, von Leitner R, Klinke A, Atzler D, Krebs C, Wieboldt H, Ehmke H, Schwedhelm E, Meinertz T, Blankenberg S, Boger RH, Magnus T, Baldus S, Wenzel U (2012) Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension. PLoS One 7(10):e48150. doi:10.1371/journal.pone.0048150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. von Leitner EC, Klinke A, Atzler D, Slocum JL, Lund N, Kielstein JT, Maas R, Schmidt-Haupt R, Pekarova M, Hellwinkel O, Tsikas D, D’Alecy LG, Lau D, Willems S, Kubala L, Ehmke H, Meinertz T, Blankenberg S, Schwedhelm E, Gadegbeku CA, Boger RH, Baldus S, Sydow K (2011) Pathogenic cycle between the endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine and the leukocyte-derived hemoprotein myeloperoxidase. Circulation 124(24):2735–2745. doi:10.1161/CIRCULATIONAHA.111.060541

    Article  Google Scholar 

  31. Siegerink B, Maas R, Vossen CY, Schwedhelm E, Koenig W, Boger R, Rothenbacher D, Brenner H, Breitling LP (2013) Asymmetric and symmetric dimethylarginine and risk of secondary cardiovascular disease events and mortality in patients with stable coronary heart disease: the KAROLA follow-up study. Clin Res Cardiol 102(3):193–202. doi:10.1007/s00392-012-0515-4

    Article  CAS  PubMed  Google Scholar 

  32. McGorrian C, Yusuf S, Islam S, Jung H, Rangarajan S, Avezum A, Prabhakaran D, Almahmeed W, Rumboldt Z, Budaj A, Dans AL, Gerstein HC, Teo K, Anand SS (2011) Estimating modifiable coronary heart disease risk in multiple regions of the world: the INTERHEART Modifiable Risk Score. Eur Heart J 32(5):581–589. doi:10.1093/eurheartj/ehq448

    Article  PubMed  Google Scholar 

  33. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L (2004) Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 364(9438):937–952. doi:10.1016/S0140-6736(04)17018-9

    Article  PubMed  Google Scholar 

  34. Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, Csiba L, Desvarieux M, Ebrahim S, Hernandez Hernandez R, Jaff M, Kownator S, Naqvi T, Prati P, Rundek T, Sitzer M, Schminke U, Tardif JC, Taylor A, Vicaut E, Woo KS (2012) Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 34(4):290–296. doi:10.1159/000343145

    Article  PubMed Central  PubMed  Google Scholar 

  35. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35

    Article  CAS  PubMed  Google Scholar 

  36. Team RDC (2011) R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing. http://www.R-project.org

  37. Neumann JT, Tzikas S, Funke-Kaiser A, Wilde S, Appelbaum S, Keller T, Ojeda-Echevarria F, Zeller T, Zwiener I, Sinning CR, Jagodzinski A, Schnabel RB, Lackner KJ, Munzel T, Blankenberg S, Wild PS, Sydow K (2013) Association of MR-pro-adrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease. Atherosclerosis. doi:10.1016/j.atherosclerosis.2013.03.006

    Google Scholar 

  38. Tzikas S, Keller T, Wild PS, Schulz A, Zwiener I, Zeller T, Schnabel RB, Sinning C, Lubos E, Kunde J, Munzel T, Lackner KJ, Blankenberg S (2013) Mid-regional pro-atrial natriuretic peptide in the general population/insights from the Gutenberg Health Study. Clin Chem Lab Med 51(5):1125–1133. doi:10.1515/cclm-2012-0541

    Article  CAS  PubMed  Google Scholar 

  39. Anderssohn M, Rosenberg M, Schwedhelm E, Zugck C, Lutz M, Luneburg N, Frey N, Boger RH (2012) The l-arginine-asymmetric dimethylarginine ratio is an independent predictor of mortality in dilated cardiomyopathy. J Card Fail 18(12):904–911. doi:10.1016/j.cardfail.2012.10.011

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements:

The Gutenberg Health Study is funded through the government of Rheinland-Pfalz (“Stiftung Rheinland Pfalz für Innovation,” Contract No. AZ 961–386261/733), the research programs “Wissen schafft Zukunft” and “Schwerpunkt Vaskuläre Prävention” of the Johannes Gutenberg-University of Mainz, and its contract with Boehringer Ingelheim and Philips Medical Systems including unrestricted support for the GHS as well as support from Abbott Diagnostics. The testkits for Copeptin and MR-proADM were provided by B.R.A.H.M.S Hennigsdorf and for Nt-proBNP by Roche Diagnostics Mannheim at no cost ADMA measurements were paid for by the “Stiftung für Biochemie” of the University Hamburg-Eppendorf, Department for Experimental Pharmacology and Toxicology.

Conflict of interest

None declared.

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Authors and Affiliations

  1. University Hospital Hamburg-Eppendorf, University Heart Center Hamburg, Hamburg, Germany

    Christoph Sinning, Arne Kieback, Renate B. Schnabel, Francisco Ojeda, Sebastian Appelbaum, Tanja Zeller, Edith Lubos, Eike S. Debus & Stefan Blankenberg

  2. Department of Medicine 2, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Philipp S. Wild, Thomas Munzel & Christine Espinola-Klein

  3. Institute of Experimental Pharmacology and Toxicology, University Hamburg-Eppendorf, Hamburg, Germany

    Edzard Schwedhelm

  4. Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    Karl J. Lackner

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  1. Christoph Sinning
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  2. Arne Kieback
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  3. Philipp S. Wild
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Correspondence to Christoph Sinning.

Additional information

For the Gutenberg Health Study.

C. Sinning and A. Kieback contributed equally to this work.

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Sinning, C., Kieback, A., Wild, P.S. et al. Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study. Clin Res Cardiol 103, 477–485 (2014). https://doi.org/10.1007/s00392-014-0674-6

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