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Clinical utility of novel biomarkers for cardiovascular disease risk stratification

  • SYMPOSIUM – FUTURE AFTER FRAMINGHAM RISK SCORE
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Abstract

Over the past few decades, a number of coronary artery disease (CAD) and cardiovascular disease (CVD) risk factors have been identified. The predictive power of “conventional” risk factors have been validated by observational, prospective and intervention studies. Nevertheless, all attempts to exactly predict the individual risk for CAD have failed, biased by a large number of incorrectly risk-classified subjects. To improve cardiovascular (CV) risk prediction, a large number of genetic and/or non-genetic biomarkers have been discovered and tested against the “classical” risk factors for their power to predict CV risk. Only few of them had a significant improvement over the predictive models. In this paper, the most investigated biomarkers will be discussed and the evidence of their use as predictors of CV will be questioned.

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References

  1. Wilson PW, D’Agostino RB, Levy D et al (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97:1837–1847

    Article  PubMed  CAS  Google Scholar 

  2. Conroy RM, Pyorala K, Fitzgerald AP et al (2003) Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 24:987–1003

    Article  PubMed  CAS  Google Scholar 

  3. Hippisley-Cox J, Coupland C, Vinogradova Y et al (2007) Derivation and validation of QRISK, a new cardiovascular disease risk score for the United Kingdom: prospective open cohort study. BMJ 335:136

    Article  PubMed  Google Scholar 

  4. Helfand M, Buckley DI, Freeman M, Fu R, Rogers K, Fleming C, Humphrey LL (2009) Emerging risk factors for coronary heart disease: a summary of systematic reviews conducted for the U.S. Preventive Services Task Force. Ann Intern Med 151:496–507

    PubMed  Google Scholar 

  5. Atkinson AJ, Colburn WA, DeGruttola VG, DeMets DL, Downing GJ, Hoth DF, Oates JA, Peck CC, Schooley RT, Spilker RA, Woodcock J, Zeger SL (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89–95

    Article  Google Scholar 

  6. Biasillo G, Leo M, Della Bona R, Biasucci LM (2010) Inflammatory biomarkers and coronary heart disease: from bench to bedside and back. Intern Emerg Med 5(3):225–233

    Article  PubMed  Google Scholar 

  7. Ridker PM, Buring JE, Shih J, Matias M, Hennekens CH (1998) Prospective study of C-reactive protein and the risk of future cardiovascular events among apparently healthy women. Circulation 98(8):731–733

    Article  PubMed  CAS  Google Scholar 

  8. Boekholdt SM, Hack CE, Sandhu MS, Luben R, Bingham SA, Wareham NJ, Peters RJ, Jukema JW, Day NE, Kastelein JJ, Khaw KT (2006) C-reactive protein levels and coronary artery disease incidence and mortality in apparently healthy men and women: the EPIC-Norfolk prospective population study 1993–2003. Atherosclerosis 187(2):415–422

    Article  PubMed  CAS  Google Scholar 

  9. Folsom AR, Aleksic N, Catellier D, Juneja HS, Wu KK (2002) C-reactive protein and incident coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J 144(2):233–238

    Article  PubMed  CAS  Google Scholar 

  10. Bisoendial RJ, Kastelein JJ, Stroes ES (2007) C-reactive protein and atherogenesis: from fatty streak to clinical event. Atherosclerosis 195(2):e10–e18

    Article  PubMed  CAS  Google Scholar 

  11. Lagrand WK, Niessen HW, Wolbink GJ et al (1997) C-reactive protein colocalizes with complement in human hearts during acute myocardial infarction. Circulation 95(1):97–103

    Article  PubMed  CAS  Google Scholar 

  12. Torzewski M, Torzewski DE, Bowyer et al (1998) C-reactive protein frequently colocalizes with the terminal complement complex in the intima of early atherosclerotic lesions of human coronary arteries. Arterioscler Thromb Vasc Biol 18(9):1386–1392

    Article  PubMed  CAS  Google Scholar 

  13. Chang MK, Binder CJ, Torzewski M, Witztum JL (2002) C-reactive protein binds to both oxidized LDL and apoptotic cells through recognition of a common ligand: phosphorylcholine of oxidized phospholipids. Proc Natl Acad Sci USA 99(20):13043–13048

    Article  PubMed  CAS  Google Scholar 

  14. Burke AP, Tracy RP, Kolodgie F et al (2002) Elevated C-reactive protein values and atherosclerosis in sudden coronary death: association with different pathologies. Circulation 105(17):2019–2023

    Article  PubMed  CAS  Google Scholar 

  15. Mora S, Ridker PM (2006) Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)–can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol 97(2A):33A–41A

    Article  PubMed  CAS  Google Scholar 

  16. Norata GD, Garlanda C, Catapano AL (2010) The long pentraxin PTX3: a modulator of the immunoinflammatory response in atherosclerosis and cardiovascular diseases. Trends Cardiovasc Med 20(2):35–40

    Article  PubMed  CAS  Google Scholar 

  17. Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78(6):539–552

    Article  PubMed  CAS  Google Scholar 

  18. Aukrust P, Halvorsen B, Yndestad A, Ueland T, Øie E, Otterdal K, Gullestad L, Damås JK (2008) Chemokines and cardiovascular risk. Arterioscler Thromb Vasc Biol 28(11):1909–1919

    Article  PubMed  CAS  Google Scholar 

  19. Hung MJ, Cheng WJ, Cheng CW, Li LF (2006) Comparison of serum levels of inflammatory markers in patients with coronary vasospasm without significant fixed coronary artery disease versus patients with stable angina pectoris and acute coronary syndromes with significant fixed coronary artery disease. Am J Cardiol 97(10):1429–1434

    Article  PubMed  CAS  Google Scholar 

  20. Hojo Y, Ikeda U, Takahashi M, Shimada K (2002) Increased levels of monocyte-related cytokines in patients with unstable angina. Atherosclerosis 161(2):403–408

    Article  PubMed  CAS  Google Scholar 

  21. Cusack MR, Marber MS, Lambiase PD, Bucknall CA, Redwood SR (2002) Systemic inflammation in unstable angina is the result of myocardial necrosis. J Am Coll Cardiol 39(12):1917–1923

    Article  PubMed  CAS  Google Scholar 

  22. Noto D, Cottone S, Baldassare Cefalù A, Vadalà A, Barbagallo CM, Rizzo M, Pernice V, Minà M, Fayer F, Cerasola G, Notarbartolo A, Rocco Averna M (2007) Interleukin 6 plasma levels predict with high sensitivity and specificity coronary stenosis detected by coronary angiography. Thromb Haemost 98(6):1362–1367

    PubMed  CAS  Google Scholar 

  23. Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ (1996) Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem 271:736–741

    Article  PubMed  CAS  Google Scholar 

  24. Wassmann S, Stumpf M, Strehlow K, Schmid A, Schieffer B, Bo¨hm M (2004) Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res 94(4):534–541

    Article  PubMed  CAS  Google Scholar 

  25. Yanes LL, Romero DG, Cucchiarelli VE, Fortepiani LA, Gomez-Sanchez CE, Santacruz F (2005) Role of endothelin in mediating postmenopausal hypertension in a rat model. Am J Physiol Regul Integr Comp Physiol 288(1):R229–R233

    Article  PubMed  CAS  Google Scholar 

  26. Anand SX, Viles-Gonzalez JF, Badimon JJ, Cavusoglu E, Marmur JD (2003) Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost 90:377–384

    PubMed  CAS  Google Scholar 

  27. Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C (2009) The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 54(8):669–677

    Article  PubMed  CAS  Google Scholar 

  28. de Lemos JA, Morrow DA, Blazing MA, Jarolim P, Wiviott SD, Sabatine MS, Califf RM, Braunwald E (2007) Serial measurement of monocyte chemoattractant protein-1 after acute coronary syndromes: results from the A to Z trial. J Am Coll Cardiol 50(22):2117–2124

    Article  PubMed  Google Scholar 

  29. Mulvihill N, Foley J, Murphy R, Crean P, Walsh M (2000) Evidence of prolonged inflammation in unstable angina and non-Q wave myocardial infarction. J Am Coll Cardiol 36:1210–1216

    Article  PubMed  CAS  Google Scholar 

  30. Blankenberg S, Rupprecht H, Bickel C, Peetz D, Hafner G, Tiret L, Meyer J (2001) Circulating cell adhesion molecules and death in patients with coronary artery disease. Circulation 104:1336–1342

    Article  PubMed  CAS  Google Scholar 

  31. Rallidis L, Gika H, Zolindaki M, Xydas TA, Paravolidakis KE, Velissaridou AH (2003) Usefulness of elevated levels of soluble vascular cell adhesion molecule-1 in predicting in-hospital prognosis in patients with unstable angina pectoris. Am J Cardiol 92:1195–1197

    Article  PubMed  CAS  Google Scholar 

  32. Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci 1(14):1403–1413

    Article  Google Scholar 

  33. Choi KM, Yoo HJ, Kim HY, Lee KW, Seo JA, Kim SG, Kim NH, Choi DS, Baik SH (2009) Association between endogenous secretory RAGE, inflammatory markers and arterial stiffness. Int J Cardiol 132(1):96–101

    Article  PubMed  CAS  Google Scholar 

  34. Geroldi D, Falcone C, Minoretti P, Emanuele E, Arra M, D’Angelo A (2006) High levels of soluble receptor for advanced glycation end products may be a marker of extreme longevity in humans. J Am Geriatr Soc 54:1149–1150

    Article  PubMed  Google Scholar 

  35. Palazzuoli A, Antonelli G, Quatrini I, Nuti R (2011) Natriuretic peptides in heart failure: where we are, where we are going. Int Emerg Med 6(1):63–68

    Article  Google Scholar 

  36. Nishikimi T, Kuwahara K, Nakao K (2011) Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides. J Cardiol 57(2):131–140

    Article  PubMed  Google Scholar 

  37. Doi Y, Ninomiya T, Hata J, Hata J, Hirakawa Y, Mukai N, Mukai N, Mukai N, Ikeda F, Fukuhara M, Iwase M, Kiyohara Y, Kiyohara Y (2011) N-terminal pro-brain natriuretic peptide and risk of cardiovascular events in a Japanese community: the Hisayama Study. Arterioscler Thromb Vasc Biol 31(12):2997–3003

    Article  PubMed  CAS  Google Scholar 

  38. Rodseth RN, Lurati Buse GA, Bolliger D, Burkhart CS, Cuthbertson BH, Gibson SC, Mahla E, Leibowitz DW, Biccard BM (2011) The predictive ability of pre-operative B-type natriuretic peptide in vascular patients for major adverse cardiac events: an individual patient data meta-analysis. J Am Coll Cardiol 58(5):522–529

    Article  PubMed  Google Scholar 

  39. Gaede P, Hildebrandt P, Hess G, Parving HH, Pedersen O (2005) Plasma N-terminal pro-brain natriuretic peptide as a major risk marker for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. Diabetologia 48(1):156–163

    Article  PubMed  CAS  Google Scholar 

  40. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, Jacques PF, Rifai N, Selhub J, Robins SJ, Benjamin EJ, D’Agostino RB, Vasan RS (2006) Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med 355(25):2631–2639

    Article  PubMed  CAS  Google Scholar 

  41. Cushman M, Arnold AM, Psaty BM et al (2005) C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the Cardiovascular Health Study. Circulation 112:25–31

    Article  PubMed  CAS  Google Scholar 

  42. Lloyd-Jones DM, Nam BH, D’Agostino RB, Levy D, Murabito JM, Wang TJ et al (2004) Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults. JAMA 291:2204–2211

    Article  PubMed  CAS  Google Scholar 

  43. Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG et al (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079

    Article  PubMed  CAS  Google Scholar 

  44. McPherson R, Pertsemlidis A, Kavaslar N, Stewart AFR, Roberts R, Cox DR et al (2007) A common allele on chromosome 9 associated with coronary heart disease. Science 316:1488–1491

    Article  PubMed  CAS  Google Scholar 

  45. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A et al (2007) A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science 316:1491–1493

    Article  PubMed  CAS  Google Scholar 

  46. Palomaki GE, Melillo S, Bradley LA (2010) Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA 303:648–656

    Article  PubMed  CAS  Google Scholar 

  47. Assimes TL, Knowles JW, Basu A, Iribarren C, Southwick A, Tang H et al (2008) Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet 17:2320–2328

    Article  PubMed  CAS  Google Scholar 

  48. Chen Z, Qian Q, Ma G, Wang J, Zhang X, Feng Y et al (2009) A common variant on chromosome 9p21 affects the risk of early-onset coronary artery disease. Mol Biol Rep 36:889–893

    Article  PubMed  CAS  Google Scholar 

  49. Assimes TL, Knowles JW, Basu A, Iribarren C, Southwick A, Tang H et al (2008) Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study. Hum Mol Genet 17:2320–2328

    Article  PubMed  CAS  Google Scholar 

  50. Pasmant E, Laurendeau I, He′ ron D, Vidaud M, Vidaud D, Bie` che I (2007) Characterization of a germline deletion, including the entire INK4/ARF locus, in a melanoma-neural system tumor family: identification of ANRIL, an antisense noncoding RNA whose expression coclusters with ARF. Cancer Res 67:3963–3969

    Article  PubMed  CAS  Google Scholar 

  51. Patel RS, Su S, Neeland IJ, Ahuja A, Veledar E, Zhao J et al (2010) The chromosome 9p21 risk locus is associated with angiographic severity and progression of coronary artery disease. Eur Heart J 31:3017–3023

    Article  PubMed  CAS  Google Scholar 

  52. Ardissino D, Berzuini C, Merlini PA, Mannucci MP, Surti A, Burtt N et al (2011) Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction. J Am Coll Cardiol 58:426–434

    Article  PubMed  Google Scholar 

  53. Anderson JL, Horne BD, Kolek MJ, Muhlestein JB, Mower CP, Park JJ et al (2008) Genetic variation at the 9p21 locus predicts angiographic coronary artery disease prevalence but not extent and has clinical utility. Am Heart J 156:1155–1162

    Article  PubMed  CAS  Google Scholar 

  54. Dandona S, Stewart AFR, Roberts R (2010) Genomics in coronary artery disease: past, present and future. Can J Cardiol 26(Suppl A):56A–59A

    Article  PubMed  CAS  Google Scholar 

  55. Preuss M, König IR, Thompson JR, Erdmann J, Absher D, Assimes TL et al and on behalf of the CARDIoGRAM Consortium. Design of the coronary ARtery disease genome-wide replication and meta-analysis (CARDIoGRAM) study: a genome-wide association meta-analysis involving more than 22,000 cases and 60,000 controls. Circ Cardiovasc Genet. 2010;3:475–483

    Google Scholar 

  56. Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H et al (2011) Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 43:333–338

    Article  PubMed  CAS  Google Scholar 

  57. Reilly MP, Li M, He J, Ferguson JF, Stylianou IM, Mehta NN et al (2011) Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 377:383–392

    Article  PubMed  CAS  Google Scholar 

  58. Paynter NP, Chasman DI, Pare′ G, Buring J, Cook NR, Miletich JP, Ridker PM (2010) Association between a literature-based genetic risk score and cardiovascular events in women. JAMA 303:631–637

    Article  PubMed  CAS  Google Scholar 

  59. Davies RW, Dandona S, Stewart AFR, Chen L, Ellis S, Tang WH et al (2010) Improved prediction of cardiovascular disease based on a panel of single nucleotide polymorphisms identified through genome-wide association studies. Circ Cardiovasc Genet 3:468–474

    Article  PubMed  CAS  Google Scholar 

  60. Talmud PJ, Cooper JA, Palmen J, Lovering R, Drenos F, Hingorani AD, Humphries SE (2008) Chromosome 9p21.3 coronary heart disease locus genotype and prospective risk of CHD in healthy middle-aged men. Clin Chem 54:467–474

    Article  PubMed  CAS  Google Scholar 

  61. Roberts R, Stewart A (2012) 9p21 and the genetic revolution for coronary artery disease. Clin Chem 58:104–112

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Internal Medicine and Medical Specialties-DIMIS, University of Palermo, Palermo, Italy

    Maurizio Averna

  2. Department of Emerging Diseases, University Hospital (AOUP) “Paolo Giaccone”, University of Palermo, Palermo, Italy

    Davide Noto

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  1. Maurizio Averna
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Correspondence to Maurizio Averna.

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Averna, M., Noto, D. Clinical utility of novel biomarkers for cardiovascular disease risk stratification. Intern Emerg Med 7 (Suppl 3), 263–270 (2012). https://doi.org/10.1007/s11739-012-0830-9

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