From circulating biomarkers to genomics and imaging in the prediction of cardiovascular events in the general population

Annals of Medicine

Volumn 44, Issue 5, 2012, Pages 433-447

  Fava, Cristiano ^a,b   Montagnana, Martina ^a,b   Guidi, Gian Cesare ^b   Melander, Olle ^a  

^a LUND UNIVERSITY   (Sweden)

^b UNIVERSITY HOSPITAL OF VERONA   (Italy)

Author keywords

Cardiovascular disease; Genetics; Marker; Risk factor; Risk score

Indexed keywords

1 ALKYL 2 ACETYLGLYCEROPHOSPHOCHOLINE ESTERASE; AMINO TERMINAL PRO BRAIN NATRIURETIC PEPTIDE; C REACTIVE PROTEIN; CALCIUM; CYSTATIN C; FIBRINOGEN; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MONOCYTE CHEMOTACTIC PROTEIN 1; PHOSPHOLIPASE A2; ROSUVASTATIN; TROPONIN I; TROPONIN T; TUMOR NECROSIS FACTOR ALPHA;

ADIPOCYTE; ARTERIAL WALL THICKNESS; ATHEROGENESIS; BRAIN ISCHEMIA; CALCIUM BLOOD LEVEL; CARDIAC IMAGING; CARDIOVASCULAR RISK; CLINICAL PRACTICE; CONGESTIVE CARDIOMYOPATHY; CORONARY ARTERY DISEASE; DNA METHYLATION; GENE EXPRESSION; GENETIC ASSOCIATION; GENETIC MARKER; GENETIC RISK; HEART INFARCTION; HUMAN; INFLAMMATION; INSULIN DEPENDENT DIABETES MELLITUS; MACROPHAGE; NON INSULIN DEPENDENT DIABETES MELLITUS; POPULATION GENETICS; PRIORITY JOURNAL; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; SUDDEN DEATH; SYSTEMATIC REVIEW;

BIOLOGICAL MARKERS; CARDIOVASCULAR DISEASES; GENETIC MARKERS; GENOMICS; HUMANS; INFLAMMATION; PHOSPHOLIPASES; RISK ASSESSMENT; RISK FACTORS;

EID: 84864033399     PISSN: 07853890     EISSN: 13652060     Source Type: Journal    
DOI: 10.3109/07853890.2011.582511     Document Type: Review

References (175)

1. Gaziano TA. Cardiovascular disease in the developing world and its cost-effective management. Circulation. 2005; 112:3547-53. (Pubitemid 43739531)
2. Pencina MJ, D 'A gostino RB, D 'A gostino RB, Vasan RS. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med. 2008;27:157-72. (Pubitemid 351193639)
3. Casas JP, Shah T, Cooper J, Hawe E, McMahon AD, Gaffney D, et al. Insight into the nature of the CRPcoronary event association using Mendelian randomization. Int J Epidemiol. 2006;35:922-31. (Pubitemid 44540742)
4. Lowe GD. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost. 2005;3:1618-27. (Pubitemid 41716547)
5. Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003;111:1805-12. (Pubitemid 38057722)
6. Clapp BR, Hirschfield GM, Storry C, Gallimore JR, Stidwill RP, Singer M, et al. Inflammation and endothelial function: direct vascular effects of human C-reactive protein on nitric oxide bioavailability. Circulation. 2005;111:1530-6. (Pubitemid 40470649)
7. Verma S, Wang C, Li S, Dumont AS, Fedak PWM, Badiwala MV, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002;106:913-9. (Pubitemid 34925323)
8. Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008; 359:1897-908.
9. Zethelius B, Berglund L, Sundstrom J, Ingelsson E, Basu S, Larsson A, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med. 2008;358:2107-16. (Pubitemid 351679597)
10. Wilson PWF, Nam B, Pencina M, D 'A gostino RBS, Benjamin EJ, O 'Donnell CJ. C-reactive protein and risk of cardiovascular disease in men and women from the Framingham Heart Study. Arch Intern Med. 2005;165: 2473-8. (Pubitemid 41720008)
11. Tzoulaki I, Murray GD, Lee AJ, Rumley A, Lowe GDO, Fowkes FGR. Relative value of inflammatory, hemostatic, and rheological factors for incident myocardial infarction and stroke: the Edinburgh Artery Study. Circulation. 2007; 115:2119-27. (Pubitemid 46659063)
12. Straczek C, Ducimetiere P, Barberger-Gateau P, Helmer C, Ritchie K, Jouven X, et al. Higher level of systemic C-reactive protein is independently predictive of coronary heart disease in older community-dwelling adults: the three-city study. J Am Geriatr Soc. 2010;58:129-35.
13. Rost NS, Wolf PA, Kase CS, Kelly-Hayes M, Silbershatz H, Massaro JM, et al. Plasma concentration of C-reactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke. 2001;32:2575-9. (Pubitemid 33055308)
14. Rana J, Arsenault B, Despres J, Cote M, Talmud P, Ninio E, et al. Inflammatory biomarkers, physical activity, waist circumference, and risk of future coronary heart disease in healthy men and women. Eur Heart J. 2011;32:336-44.
15. Olsen MH, Hansen TW, Christensen MK, Gustafsson F, Rasmussen S, Wachtell K, et al. N-terminal pro-brain natriuretic peptide, but not high sensitivity C-reactive protein, improves cardiovascular risk prediction in the general population. Eur Heart J. 2007;28:1374-81. (Pubitemid 47355969)
16. Melander O, Newton-Cheh C, Almgren P, Hedblad B, Berglund G, Engstrom G, et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA. 2009;302:49-57.
17. Makita S, Nakamura M, Satoh K, Tanaka F, Onoda T, Kawamura K, et al. Serum C-reactive protein levels can be used to predict future ischemic stroke and mortality in Japanese men from the general population. Atherosclerosis. 2009;204:234-8.
18. Koenig W, Lowel H, Baumert J, Meisinger C. C-reactive protein modulates risk prediction based on the Framingham Score: implications for future risk assessment: results from a large cohort study in southern Germany. Circulation. 2004;109:1349-53. (Pubitemid 38387819)
19. Folsom AR, Chambless LE, Ballantyne CM, Coresh J, Heiss G, Wu KK, et al. An assessment of incremental coronary risk prediction using C-reactive protein and other novel risk markers: the atherosclerosis risk in communities study. Arch Intern Med. 2006;166:1368-73. (Pubitemid 44036348)
20. Elkind MSV, Luna JM, Moon YP, Liu KM, Spitalnik SL, Paik MC, et al. High-sensitivity C-reactive protein predicts mortality but not stroke: the Northern Manhattan Study. Neurology. 2009;73:1300-7.
21. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. N Engl J Med. 2004;350:1387-97. (Pubitemid 38419992)
22. Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL, et al. C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation. 2005; 112:25-31. (Pubitemid 40962565)
23. Chen P, Chien K, Hsu H, Su T, Sung F, Lee Y. Metabolic syndrome and C-reactive protein in stroke prediction: a prospective study in Taiwan. Metabolism. 2009;58:772-8.
24. Cao JJ, Arnold AM, Manolio TA, Polak JF, Psaty BM, Hirsch CH, et al. 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. 2007;116:32-8. (Pubitemid 47016244)
25. Cao JJ, Thach C, Manolio TA, Psaty BM, Kuller LH, Chaves PHM, et al. C-reactive protein, carotid intimamedia thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. Circulation. 2003;108:166-70. (Pubitemid 36871298)
26. Blankenberg S, Zeller T, Saarela O, Havulinna AS, Kee F, Tunstall-Pedoe H, et al. Contribution of 30 biomarkers to 10-year cardiovascular risk estimation in 2 population cohorts: the MONICA, risk, genetics, archiving, and monograph (MORGAM) biomarker project. Circulation. 2010; 121:2388-97.
27. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Heiss G, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109:837-42. (Pubitemid 38252734)
28. Luc G, Bard J, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, et al. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: the PRIME Study. Arterioscler Thromb Vasc Biol. 2003;23: 1255-61. (Pubitemid 36871282)
29. Lowe GDO, Sweetnam PM, Yarnell JWG, Rumley A, Rumley C, Bainton D, et al. C-reactive protein, fibrin D-dimer, and risk of ischemic heart disease: the Caerphilly and Speedwell studies. Arterioscler Thromb Vasc Biol. 2004;24:1957-62. (Pubitemid 39350319)
30. Arima H, Kubo M, Yonemoto K, Doi Y, Ninomiya T, Tanizaki Y, et al. High-sensitivity C-reactive protein and coronary heart disease in a general population of Japanese: the Hisayama study. Arterioscler Thromb Vasc Biol. 2008; 28:1385-91.
31. Wang TJ, Gona P, Larson MG, Tofler GH, Levy D, Newton-Cheh C, et al. Multiple biomarkers for the prediction of first major cardiovascular events and death. N Engl J Med. 2006;355:2631-9. (Pubitemid 44969122)
32. St-Pierre AC, Cantin B, Bergeron J, Pirro M, Dagenais GR, Despres J, et al. Inflammatory markers and long-term risk of ischemic heart disease in men. A 13-year follow-up of the Quebec Cardiovascular Study. Atherosclerosis. 2005; 182:315-21. (Pubitemid 41267200)
33. Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Hansen JF. C-reactive protein, heart rate variability and prognosis in community subjects with no apparent heart disease. J Intern Med. 2006;260:377-87. (Pubitemid 44370911)
34. Rodondi N, Marques-Vidal P, Butler J, Sutton-Tyrrell K, Cornuz J, Satterfield S, et al. Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults. Am J Epidemiol. 2010;171:540-9.
35. Kistorp C, Raymond I, Pedersen F, Gustafsson F, Faber J, Hildebrandt P. N-terminal pro-brain natriuretic peptide, C-reactive protein, and urinary albumin levels as predictors of mortality and cardiovascular events in older adults. JAMA. 2005;293:1609-16. (Pubitemid 40471791)
36. Dhingra R, Gona P, Nam B, D' A gostino RBS, Wilson PWF, Benjamin EJ, et al. C-reactive protein, inflammatory conditions, and cardiovascular disease risk. Am J Med. 2007;120:1054-62. (Pubitemid 350166233)
37. Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003;108:2317-22. (Pubitemid 37413536)
38. van der Meer IM, de Maat MPM, Kiliaan AJ, van der Kuip DAM, Hofman A, Witteman JCM. The value of C-reactive protein in cardiovascular risk prediction: the Rotterdam Study. Arch Intern Med. 2003;163:1323-8. (Pubitemid 36676197)
39. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557-65. (Pubitemid 35315836)
40. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132-40.
41. Wilson PWF, Pencina M, Jacques P, Selhub J, D' Agostino RS, O 'Donnell CJ. C-reactive protein and reclassification of cardiovascular risk in the Framingham Heart Study. Circ Cardiovasc Qual Outcomes. 2008;1:92-7.
42. Daniels LB, Laughlin GA, Sarno MJ, Bettencourt R, Wolfert RL, Barrett-Connor E. Lipoprotein-associated phospholipase A2 is an independent predictor of incident coronary heart disease in an apparently healthy older population: the Rancho Bernardo Study. J Am Coll Cardiol. 2008;51:913-9. (Pubitemid 351282456)
43. Rutter MK, Meigs JB, Sullivan LM, D 'A gostino RBS, Wilson PWF. C-reactive protein, the metabolic syndrome, and prediction of cardiovascular events in the Framingham Offspring Study. Circulation. 2004;110:380-5. (Pubitemid 38993845)
44. Koenig W, Khuseyinova N, Lowel H, Trischler G, Meisinger C. Lipoprotein-associated phospholipase A2 adds to risk prediction of incident coronary events by C-reactive protein in apparently healthy middle-aged men from the general population: results from the 14-year follow-up of a large cohort from southern Germany. Circulation. 2004;110:1903-8. (Pubitemid 39331899)
45. Rana JS, Cote M, Despres J, Sandhu MS, Talmud PJ, Ninio E, et al. Inflammatory biomarkers and the prediction of coronary events among people at intermediate risk: the EPIC-Norfolk prospective population study. Heart. 2009; 95:1682-7.
46. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:483-95.
47. Myers GL, Christenson RHM, Cushman M, Ballantyne CM, Cooper GR, Pfeiffer CM, et al. National Academy of Clinical Biochemistry Laboratory Medicine Practice guidelines: emerging biomarkers for primary prevention of cardiovascular disease. Clin Chem. 2009;55:378-84.
48. Persson M, Hedblad B, Nelson JJ, Berglund G. Elevated Lp-PLA2 levels add prognostic information to the metabolic syndrome on incidence of cardiovascular events among middle-aged nondiabetic subjects. Arterioscler Thromb Vasc Biol. 2007;27:1411-6. (Pubitemid 46823453)
49. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial Hypertension. J Hypertens. 2007;25:1751-62. (Pubitemid 47356612)
50. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-97.
51. Ridker PM, Danielson E, Fonseca FAH, Genest J, Gotto AMJ, Kastelein JJP, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-207.
52. Danesh J, Lewington S, Thompson SG, Lowe GDO, Collins R, Kostis JB, et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA. 2005;294:1799-809. (Pubitemid 41434626)
53. Woodward M, Tunstall-Pedoe H, Rumley A, Lowe GDO. Does fibrinogen add to prediction of cardiovascular disease? Results from the Scottish Heart Health Extended Cohort Study. Br J Haematol. 2009;146:442-6.
54. Sattar N, Murray HM, Welsh P, Blauw GJ, Buckley BM, Cobbe S, et al. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events? PLoS Med. 2009;6:e1000099.
55. Stafforini DM, Elstad MR, McIntyre TM, Zimmerman GA, Prescott SM. Human macrophages secret platelet-activating factor acetylhydrolase. J Biol Chem. 1990;265:9682-7.
56. Tselepis AD, John Chapman M. Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoproteinassociated phospholipase A2, platelet activating factoracetylhydrolase. Atheroscler Suppl. 2002;3:57-68. (Pubitemid 38234487)
57. Dada N, Kim NW, Wolfert RL. Lp-PLA2: an emerging biomarker of coronary heart disease. Expert Rev Mol Diagn. 2002;2:17-22. (Pubitemid 34654407)
58. Caslake MJ, Packard CJ. Lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase) and cardiovascular disease. Curr Opin Lipidol. 2003;14: 347-52. (Pubitemid 36951899)
59. Lerman A, McConnell JP. Lipoprotein-associated phospholipase A2: a risk marker or a risk factor? Am J Cardiol. 2008;101:11F-22F.
60. Daniels LB, Laughlin GA, Clopton P, Maisel AS, Barrett-Connor E. Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults: results from the Rancho Bernardo Study. J Am Coll Cardiol. 2008;52:450-9. (Pubitemid 352040812)
61. Winkler K, Abletshauser C, Friedrich I, Hoffmann MM, Wieland H, Marz W. Fluvastatin slow-release lowers platelet-activating factor acetyl hydrolase activity: a placebocontrolled trial in patients with type 2 diabetes. J Clin Endocrinol Metab. 2004;89:1153-9. (Pubitemid 38368404)
62. Packard CJ, O' R eilly DS, Caslake MJ, McMahon AD, Ford I, Cooney J, et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med. 2000;343:1148-55.
63. Oei HS, van der Meer IM, Hofman A, Koudstaal PJ, Stijnen T, Breteler MMB, et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation. 2005;111:570-5. (Pubitemid 40216483)
64. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007; 27:1788-95. (Pubitemid 47207175)
65. Elkind MSV, Tai W, Coates K, Paik MC, Sacco RL. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med. 2006;166:2073-80. (Pubitemid 44631394)
66. Blake GJ, Dada N, Fox JC, Manson JE, Ridker PM. A prospective evaluation of lipoprotein-associated phospholipase A(2) levels and the risk of future cardiovascular events in women. J Am Coll Cardiol. 2001;38:1302-6. (Pubitemid 33033002)
67. Ballantyne CM, Hoogeveen RC, Bang H, Coresh J, Folsom AR, Chambless LE, et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005;165:2479-84. (Pubitemid 41720009)
68. Thompson A, Gao P, Orfei L, Watson S, Di Angelantonio E, Kaptoge S, et al. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet. 2010;375:1536-44.
69. Davidson MH, Corson MA, Alberts MJ, Anderson JL, Gorelick PB, Jones PH, et al. Consensus panel recommendation for incorporating lipoprotein-associated phospholipase A2 testing into cardiovascular disease risk assessment guidelines. Am J Cardiol. 2008;101:51F-57F.
70. Hurt-Camejo E, Camejo G, Peilot H, Oorni K, Kovanen P. Phospholipase A(2) in vascular disease. Circ Res. 2001; 89:298-304.
71. Fujioka D, Kugiyama K. Novel insights of secretory phospholipase a(2) action in cardiology. Trends Cardiovasc Med. 2009;19:100-3.
72. Mallat Z, Steg PG, Benessiano J, Tanguy M, Fox KA, Collet J, et al. Circulating secretory phospholipase A2 activity predicts recurrent events in patients with severe acute coronary syndromes. J Am Coll Cardiol. 2005;46: 1249-57. (Pubitemid 41615545)
73. Liu P, Li Y, Tsai W, Chao T, Tsai L, Wu H, et al. Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary intervention. Eur Heart J. 2003;24:1824-32. (Pubitemid 37280248)
74. Kugiyama K, Ota Y, Sugiyama S, Kawano H, Doi H, Soejima H, et al. Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol. 2000;86:718-22.
75. Koenig W, Vossen CY, Mallat Z, Brenner H, Benessiano J, Rothenbacher D. Association between type II secretory phospholipase A2 plasma concentrations and activity and cardiovascular events in patients with coronary heart disease. Eur Heart J. 2009;30:2742-8.
76. Boekholdt SM, Keller TT, Wareham NJ, Luben R, Bingham SA, Day NE, et al. Serum levels of type II secretory phospholipase A2 and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol. 2005;25:839-46. (Pubitemid 40463879)
77. Takahashi T, Nakamura M, Onoda T, Ohsawa M, Tanno K, Itai K, et al. Predictive value of plasma B-type natriuretic peptide for ischemic stroke: a community-based longitudinal study. Atherosclerosis. 2009;207:298-303.
78. Linssen GCM, Bakker SJL, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, et al. N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. Eur Heart J. 2010;31:120-7.
79. Laukkanen JA, Kurl S, Ala-Kopsala M, Vuolteenaho O, Ruskoaho H, Nyyssonen K, et al. Plasma N-terminal fragments of natriuretic propeptides predict the risk of cardiovascular events and mortality in middle-aged men. Eur Heart J. 2006;27:1230-7.
80. Rutten JH, Mattace-Raso FUS, Steyerberg EW, Lindemans J, Hofman A, Wieberdink RG, et al. Amino-terminal pro-B-type natriuretic peptide improves cardiovascular and cerebrovascular risk prediction in the population: the Rotterdam study. Hypertension. 2010;55:785-91.
81. Di Angelantonio E, Chowdhury R, Sarwar N, Ray KK, Gobin R, Saleheen D, et al. B-type natriuretic peptides and cardiovascular risk: systematic review and meta-analysis of 40 prospective studies. Circulation. 2009;120:2177-87.
82. Zethelius B, Johnston N, Venge P. Troponin I as a predictor of coronary heart disease and mortality in 70-year-old men: a community-based cohort study. Circulation. 2006; 113:1071-8.
83. deFilippi CR, de Lemos JA, Christenson RH, Gottdiener JS, Kop WJ, Zhan M, et al. Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JAMA. 2010;304:2494-502.
84. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503-12.
85. Abrahamson M, Dalboge H, Olafsson I, Carlsen S, Grubb A. Efficient production of native, biologically active human cystatin C by Escherichia coli. FEBS Lett. 1988; 236:14-18.
86. Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, et al. Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med. 2005;352:2049-60. (Pubitemid 40664306)
87. Shlipak MG, Katz R, Fried LF, Jenny NS, Stehman-Breen CO, Newman AB, et al. Cystatin-C and mortality in elderly persons with heart failure. J Am Coll Cardiol. 2005;45: 268-71. (Pubitemid 40094736)
88. Luc G, Bard J, Lesueur C, Arveiler D, Evans A, Amouyel P, et al. Plasma cystatin-C and development of coronary heart disease: The PRIME Study. Atherosclerosis. 2006; 185:375-80.
89. Fried LF, Katz R, Sarnak MJ, Shlipak MG, Chaves PHM, Jenny NS, et al. Kidney function as a predictor of noncardiovascular mortality. J Am Soc Nephrol. 2005;16: 3728-35. (Pubitemid 46211295)
90. Lorenz MW, Schaefer C, Steinmetz H, Sitzer M. Is carotid intima media thickness useful for individual prediction of cardiovascular risk? Ten-year results from the Carotid Atherosclerosis Progression Study (CAPS). Eur Heart J. 2010;31:2041-8.
91. van der Meer IM, Bots ML, Hofman A, del Sol AI, van der Kuip DAM, Witteman JCM. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam Study. Circulation. 2004;109: 1089-94. (Pubitemid 38332611)
92. Rosvall M, Janzon L, Berglund G, Engstrom G, Hedblad B. Incidence of stroke is related to carotid IMT even in the absence of plaque. Atherosclerosis. 2005;179:325-31. (Pubitemid 40364627)
93. Rosvall M, Janzon L, Berglund G, Engstrom G, Hedblad B. Incident coronary events and case fatality in relation to common carotid intima-media thickness. J Intern Med. 2005;257:430-7. (Pubitemid 40604547)
94. Prati P, Tosetto A, Vanuzzo D, Bader G, Casaroli M, Canciani L, et al. Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events. Stroke. 2008;39:2470-6.
95. Ohira T, Shahar E, Iso H, Chambless L, Rosamond W, Sharrett A, et al. Carotid artery wall thickness and risk of stroke subtypes: The Atherosclerosis Risk in Communities Study. Stroke. 2011;42:397-403.
96. O' L eary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SKJ. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340: 14-22. (Pubitemid 29024679)
97. Lorenz MW, von Kegler S, Steinmetz H, Markus HS, Sitzer M. Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke. 2006;37:87-92. (Pubitemid 43732053)
98. Kitamura A, Iso H, Imano H, Ohira T, Okada T, Sato S, et al. Carotid intima-media thickness and plaque characteristics as a risk factor for stroke in Japanese elderly men. Stroke. 2004;35:2788-94. (Pubitemid 39565172)
99. Johnsen SH, Mathiesen EB, Joakimsen O, Stensland E, Wilsgaard T, Lochen M, et al. Carotid atherosclerosis is a stronger predictor of myocardial infarction in women than in men: a 6-year follow-up study of 6226 persons: the Tromso Study. Stroke. 2007;38:2873-80. (Pubitemid 350035678)
100. Iglesias del Sol A, Bots ML, Grobbee DE, Hofman A, Witteman JCM. Carotid intima-media thickness at different sites: relation to incident myocardial infarction; The Rotterdam Study. Eur Heart J. 2002;23:934-40. (Pubitemid 35203871)
101. Hollander M, Hak AE, Koudstaal PJ, Bots ML, Grobbee DE, Hofman A, et al. Comparison between measures of atherosclerosis and risk of stroke: the Rotterdam Study. Stroke. 2003;34:2367-72. (Pubitemid 37221943)
102. Folsom AR, Kronmal RA, Detrano RC, O' L eary DH, Bild DE, Bluemke DA, et al. Coronary artery calcification compared with carotid intima-media thickness in the prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med. 2008;168:1333-9. (Pubitemid 351930841)
103. Chien K, Su T, Jeng J, Hsu H, Chang W, Chen M, et al. Carotid artery intima-media thickness, carotid plaque and coronary heart disease and stroke in Chinese. PLoS ONE. 2008;3:e3435.
104. Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, et al. Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol. 2000; 151:478-87. (Pubitemid 30471022)
105. Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR, et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol. 1997;146:483-94. (Pubitemid 27391409)
106. Bots ML, Grobbee DE, Hofman A, Witteman JCM. Common carotid intima-media thickness and risk of acute myocardial infarction: the role of lumen diameter. Stroke. 2005;36:762-7.
107. Bots ML, Hoes AW, Koudstaal PJ, Hofman A, Grobbee DE. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation. 1997;96:1432-7. (Pubitemid 27375333)
108. Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, et al. Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol. 2010;55:1600-7.
109. S harma RK, Sharma RK, Voelker DJ, Singh VN, Pahuja D, Nash T, et al. Cardiac risk stratification: role of the coronary calcium score. Vasc Health Risk Manag. 2010;6:603-11.
110. Taylor AJ, Bindeman J, Feuerstein I, Cao F, Brazaitis M, O 'Malley PG. Coronary calcium independently predicts incident premature coronary heart disease over measured cardiovascular risk factors: mean three-year outcomes in the Prospective Army Coronary Calcium (PACC) project. J Am Coll Cardiol. 2005;46:807-14. (Pubitemid 41224803)
111. Doherty TM, Tang W, Detrano RC. Racial differences in the significance of coronary calcium in asymptomatic black and white subjects with coronary risk factors. J Am Coll Cardiol. 1999;34:787-94. (Pubitemid 29436185)
112. Detrano RC, Wong ND, Doherty TM, Shavelle RM, Tang W, Ginzton LE, et al. Coronary calcium does not accurately predict near-term future coronary events in high-risk adults. Circulation. 1999;99:2633-8. (Pubitemid 29237449)
113. Vliegenthart R, Oudkerk M, Hofman A, Oei HS, van Dijck W, van Rooij FJA, et al. Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation. 2005;112:572-7. (Pubitemid 41060798)
114. Polonsky TS, McClelland RL, Jorgensen NW, Bild DE, Burke GL, Guerci AD, et al. Coronary artery calcium score and risk classification for coronary heart disease prediction. JAMA. 2010;303:1610-6.
115. LaMonte MJ, FitzGerald SJ, Church TS, Barlow CE, Radford NB, Levine BD, et al. Coronary artery calcium score and coronary heart disease events in a large cohort of asymptomatic men and women. Am J Epidemiol. 2005; 162:421-9. (Pubitemid 41191427)
116. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC. Coronary artery calcium score combined with Framingham score for risk prediction in asymptomatic individuals. JAMA. 2004;291:210-5. (Pubitemid 38082815)
117. Erbel R, Mohlenkamp S, Moebus S, Schmermund A, Lehmann N, Stang A, et al. Coronary risk stratification, discrimination, and reclassification improvement based on quantification of subclinical coronary atherosclerosis: the Heinz Nixdorf Recall study. J Am Coll Cardiol. 2010;56: 1397-406.
118. Elias-Smale SE, Proenca RV, Koller MT, Kavousi M, van Rooij FJA, Hunink MG, et al. Coronary calcium score improves classification of coronary heart disease risk in the elderly: the Rotterdam study. J Am Coll Cardiol. 2010;56:1407-14.
119. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358:1336-45. (Pubitemid 351468410)
120. Arad Y, Goodman KJ, Roth M, Newstein D, Guerci AD. Coronary calcification, coronary disease risk factors, C-reactive protein, and atherosclerotic cardiovascular disease events: the St. Francis Heart Study. J Am Coll Cardiol. 2005;46:158-65. (Pubitemid 40905145)
121. Arking DE, Chakravarti A. Understanding cardiovascular disease through the lens of genome-wide association studies. Trends Genet. 2009;25:387-94.
122. Humphries SE, Yiannakouris N, Talmud PJ. Cardiovascular disease risk prediction using genetic information (gene scores): is it really informative? Curr Opin Lipidol. 2008; 19:128-32. (Pubitemid 351483299)
123. Samani NJ, Erdmann J, Hall AS, Hengstenberg C, Mangino M, Mayer B, et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007;357:443-53. (Pubitemid 47204873)
124. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, et al. A common allele on chromosome 9 associated with coronary heart disease. Science. 2007; 316:1488-91. (Pubitemid 46906617)
125. Helgadottir A, Thorleifsson G, Manolescu A, Gretarsdottir S, Blondal T, Jonasdottir A, et al. A common variant on chromosome 9p21 affects the risk of myocardial infarction. Science. 2007;316:1491-3. (Pubitemid 46906618)
126. Karvanen J, Silander K, Kee F, Tiret L, Salomaa V, Kuulasmaa K, et al. The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts. Genet Epidemiol. 2009; 33:237-46.
127. Palomaki GE, Melillo S, Bradley LA. Association between 9p21 genomic markers and heart disease: a meta-analysis. JAMA. 2010;303:648-56.
128. Gudbjartsson DF, Bjornsdottir US, Halapi E, Helgadottir A, Sulem P, Jonsdottir GM, et al. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction. Nat Genet. 2009;41:342-7.
129. Erdmann J, Grosshennig A, Braund PS, Konig IR, Hengstenberg C, Hall AS, et al. New susceptibility locus for coronary artery disease on chromosome 3q22.3. Nat Genet. 2009;41:280-2.
130. Kathiresan S, Voight BF, Purcell S, Musunuru K, Ardissino D, Mannucci PM, et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009;41:334-41.
131. Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, et al. Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. Am J Hum Genet. 2009;85:628-42.
132. Chasman DI, Pare G, Mora S, Hopewell JC, Peloso G, Clarke R, et al. Forty-three loci associated with plasma lipoprotein size, concentration, and cholesterol content in genome-wide analysis. PLoS Genet. 2009;5:e1000730.
133. Willer CJ, Sanna S, Jackson AU, Scuteri A, Bonnycastle LL, Clarke R, et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat Genet. 2008;40:161-9. (Pubitemid 351171403)
134. Kathiresan S, Melander O, Guiducci C, Surti A, Burtt NP, Rieder MJ, et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat Genet. 2008;40:189-97. (Pubitemid 351171402)
135. Kooner JS, Chambers JC, Aguilar-Salinas CA, Hinds DA, Hyde CL, Warnes GR, et al. Genome-wide scan identifies variation in MLXIPL associated with plasma triglycerides. Nat Genet. 2008;40:149-51. (Pubitemid 351171393)
136. Hiura Y, Shen C, Kokubo Y, Okamura T, Morisaki T, Tomoike H, et al. Identification of genetic markers associated with high-density lipoprotein-cholesterol by genomewide screening in a Japanese population: the Suita study. Circ J. 2009;73:1119-26.
137. Ober C, Nord AS, Thompson EE, Pan L, Tan Z, Cusanovich D, et al. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res. 2009;50:798-806.
138. Lopez S, Buil A, Ordonez J, Souto JC, Almasy L, Lathrop M, et al. Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels. Eur J Hum Genet. 2008;16: 1372-9.
139. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518-28.
140. Wei Z, Wang K, Qu H, Zhang H, Bradfield J, Kim C, et al. From disease association to risk assessment: an optimistic view from genome-wide association studies on type 1 diabetes. PLoS Genet. 2009;5:e1000678.
141. Cooper JD, Smyth DJ, Smiles AM, Plagnol V, Walker NM, Allen JE, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet. 2008;40:1399-401.
142. Barrett JC, Clayton DG, Concannon P, Akolkar B, Cooper JD, Erlich HA, et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet. 2009;41:703-7.
143. Zeggini E, Scott LJ, Saxena R, Voight BF, Marchini JL, Hu T, et al. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008;40: 638-45. (Pubitemid 351601209)
144. Saxena R, Voight BF, Lyssenko V, Burtt NP, de Bakker PIW, Chen H, et al. Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007;316:1331-6. (Pubitemid 46871653)
145. Ruchat S, Elks CE, Loos RJF, Vohl M, Weisnagel SJ, Rankinen T, et al. Association between insulin secretion, insulin sensitivity and type 2 diabetes susceptibility variants identified in genome-wide association studies. Acta Diabetol. 2009;46:217-26.
146. van Hoek M, Dehghan A, Witteman JCM, van Duijn CM, Uitterlinden AG, Oostra BA, et al. Predicting type 2 diabetes based on polymorphisms from genome-wide association studies: a population-based study. Diabetes. 2008;57: 3122-8.
147. Lu Q, Song Y, Wang X, Won S, Cui Y, Elston RC. The effect of multiple genetic variants in predicting the risk of type 2 diabetes. BMC Proc. 2009;3 Suppl 7:S49.
148. Cornelis MC, Qi L, Zhang C, Kraft P, Manson J, Cai T, et al. Joint effects of common genetic variants on the risk for type 2 diabetes in U.S. men and women of European ancestry. Ann Intern Med. 2009;150:541-50.
149. Wang K, Li M, Hakonarson H. Analysing biological pathways in genome-wide association studies. Nat Rev Genet. 2010;11:843-54.
150. Padmanabhan S, Melander O, Johnson T, Di Blasio AM, Lee WK, Gentilini D, et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet. 2010; 6:e1001177.
151. Newton-Cheh C, Johnson T, Gateva V, Tobin MD, Bochud M, Coin L, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666-76.
152. Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41: 677-87.
153. Adeyemo A, Gerry N, Chen G, Herbert A, Doumatey A, Huang H, et al. A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet. 2009;5:e1000564.
154. T impson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day INM, Palmer LJ, et al. C-reactive protein and its role in metabolic syndrome: Mendelian randomisation study. Lancet. 2005;366:1954-9. (Pubitemid 41713985)
155. Lange LA, Carlson CS, Hindorff LA, Lange EM, Walston J, Durda JP, et al. Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. JAMA. 2006;296:2703-11. (Pubitemid 44917547)
156. Elliott P, Chambers JC, Zhang W, Clarke R, Hopewell JC, Peden JF, et al. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA. 2009;302:37-48.
157. Hou L, Chen S, Yu H, Lu X, Chen J, Wang L, et al. Associations of PLA2G7 gene polymorphisms with plasma lipoprotein-associated phospholipase A2 activity and coronary heart disease in a Chinese Han population: the Beijing atherosclerosis study. Hum Genet. 2009;125: 11-20.
158. Hoffmann MM, Winkler K, Renner W, Winkelmann BR, Seelhorst U, Wellnitz B, et al. Genetic variants and haplotypes of lipoprotein associated phospholipase A2 and their influence on cardiovascular disease (The Ludwigshafen Risk and Cardiovascular Health Study). J Thromb Haemost. 2009;7:41-8.
159. Abuzeid AM, Hawe E, Humphries SE, Talmud PJ. Association between the Ala379Val variant of the lipoprotein associated phospholipase A2 and risk of myocardial infarction in the north and south of Europe. Atherosclerosis. 2003;168:283-8. (Pubitemid 36703327)
160. Morrison AC, Bare LA, Chambless LE, Ellis SG, Malloy M, Kane JP, et al. Prediction of coronary heart disease risk using a genetic risk score: the Atherosclerosis Risk in Communities Study. Am J Epidemiol. 2007;166: 28-35. (Pubitemid 47234300)
161. Anderson JL, Horne BD, Camp NJ, Muhlestein JB, Hopkins PN, Cannon-Albright LA, et al. Joint effects of common genetic variants from multiple genes and pathways on the risk of premature coronary artery disease. Am Heart J. 2010;160:250-6.
162. Kathiresan S, Melander O, Anevski D, Guiducci C, Burtt NP, Roos C, et al. Polymorphisms associated with cholesterol and risk of cardiovascular events. N Engl J Med. 2008;358:1240-9. (Pubitemid 351439225)
163. Hastings PJ, Lupski JR, Rosenberg SM, Ira G. Mechanisms of change in gene copy number. Nat Rev Genet. 2009; 10:551-64.
164. Laird P. Principles and challenges of genome-wide DNA methylation analysis. Nat Rev Genet. 2010;11:191-203.
165. Fazzari MJ, Greally JM. Introduction to epigenomics and epigenome-wide analysis. Methods Mol Biol. 2010;620: 243-65.
166. Pastinen T. Genome-wide allele-specific analysis: insights into regulatory variation. Nat Rev Genet. 2010;11:533-8.
167. Meyer KB, Maia A, O' R eilly M, Teschendorff AE, Chin S, Caldas C, et al. Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol. 2008; 6:e108.
168. Azuaje F, Devaux Y, Wagner DR. Integrative pathwaycentric modeling of ventricular dysfunction after myocardial infarction. PLoS One. 2010;5:e9661.
169. Cookson W, Liang L, Abecasis G, Moffatt M, Lathrop M. Mapping complex disease traits with global gene expression. Nat Rev Genet. 2009;10:184-94.
170. Cirulli ET, Goldstein DB. Uncovering the roles of rare variants in common disease through whole-genome sequencing. Nat Rev Genet. 2010;11:415-25.
171. Ashley EA, Butte AJ, Wheeler MT, Chen R, Klein TE, Dewey FE, et al. Clinical assessment incorporating a personal genome. Lancet. 2010;375:1525-35.
172. Knoops KT, de Groot LC, Kromhout D, Perrin A, Moreiras-Varela O, Menotti A, et al. Mediterranean diet, lifestyle factors, and 10-year mortality in elderly European men and women: the HALE project. JAMA. 2004;292: 1433-9. (Pubitemid 39258335)
173. Fung TT, Rexrode KM, Mantzoros CS, Manson JE, Willett WC, Hu FB. Mediterranean diet and incidence of and mortality from coronary heart disease and stroke in women. Circulation. 2009;119:1093-100.
174. Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, et al.; American Heart Association. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56:e50-103.
175. Guttmacher AE, McGuire AL, Ponder B, Stefansson K. Personalized genomic information: preparing for the future of genetic medicine. Nat Rev Genet. 2010;11:161-5.