Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Novel metabolic biomarkers of cardiovascular disease

Key Points

  • Coronary heart disease accounts for one in six deaths in US individuals

  • Standard cardiovascular risk factors, including age, diabetes mellitus, smoking, hypertension and hypercholesterolaemia, are responsible for the majority of the risk of coronary heart disease

  • Ongoing scientific investigations in a number of areas of metabolism research have discovered several novel biomarkers that highlight the underlying biology of cardiovascular risk

  • The identification of novel biomarkers could result in improved diagnosis, risk assessment and treatment of patients

  • New therapies for cardiovascular disease could result from the development and use of novel biomarkers

Abstract

Coronary heart disease (CHD) accounts for one in every six deaths in US individuals. Great advances have been made in identifying important risk factors for CHD, such as hypertension, diabetes mellitus, smoking and hypercholesterolaemia, which have led to major developments in therapy. In particular, statins represent one of the greatest successes in the prevention of CHD. While these standard risk factors are important, an obvious opportunity exists to take advantage of ongoing scientific research to better risk-stratify individuals and to identify new treatment targets. In this Review, we summarize ongoing scientific research in a number of metabolic molecules or features, including lipoproteins, homocysteine, calcium metabolism and glycaemic markers. We evaluate the current state of the research and the strength of evidence supporting each emerging biomarker. We also discuss whether the associations with CHD are strong and consistent enough to improve current risk stratification metrics, and whether these markers enhance our understanding of the underlying biology of CHD and thus point towards new treatment options.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Involvement of cholesterol and lipoproteins in atherosclerosis.
Figure 2: Mineral metabolism and cardiovascular disease.
Figure 3: Markers of glycaemia and cardiovascular disease.

Similar content being viewed by others

References

  1. Roger, V. L. et al. Heart disease and stroke statistics—2012 update: a report from the American Heart Association. Circulation 125, e2–e220 (2012).

    Article  PubMed  Google Scholar 

  2. Prosser, L. A. et al. Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics. Ann. Intern. Med. 132, 769–779 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Goff, D. C. et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129, S49–S73 (2014).

    Article  PubMed  Google Scholar 

  4. Ridker, P. M., Buring, J. E., Cook, N. R. & Rifai, N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 107, 391–397 (2003).

    Article  PubMed  Google Scholar 

  5. NIH. Third report of the National Cholesterol Education Program (NECP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report [online], (2004).

  6. Gordon, T., Castelli, W. P., Hjortland, M. C., Kannel, W. B. & Dawber, T. R. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am. J. Med. 62, 707–714 (1977).

    Article  CAS  PubMed  Google Scholar 

  7. McQueen, M. J. et al. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case–control study. Lancet 372, 224–233 (2008).

    Article  CAS  PubMed  Google Scholar 

  8. Di Angelantonio, E. et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Sniderman, A. D. et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ. Cardiovasc. Qual. Outcomes 4, 337–345 (2011).

    Article  PubMed  Google Scholar 

  10. Corti, R. et al. Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years' follow-up by high-resolution noninvasive magnetic resonance imaging. Circulation 106, 2884–2887 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Grundy, S. M. et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 110, 227–239 (2004).

    Article  PubMed  Google Scholar 

  12. West, A. M. et al. The effect of ezetimibe on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis 218, 156–162 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cannon, C. P. et al. Rationale and design of IMPROVE–IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am. Heart J. 156, 826–832 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Superko, H. R. & King, S. III. Lipid management to reduce cardiovascular risk: a new strategy is required. Circulation 117, 560–568 (2008).

    Article  PubMed  Google Scholar 

  15. Grundy, S. M. Promise of low-density lipoprotein-lowering therapy for primary and secondary prevention. Circulation 117, 569–573 (2008).

    Article  PubMed  Google Scholar 

  16. Anuurad, E., Boffa, M. B., Koschinsky, M. L. & Berglund, L. Lipoprotein(a): a unique risk factor for cardiovascular disease. Clin. Lab. Med. 26, 751–772 (2006).

    Article  PubMed  Google Scholar 

  17. Hobbs, H. H. & White, A. L. Lipoprotein(a): intrigues and insights. Curr. Opin. Lipidol. 10, 225–236 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Marcovina, S. M. & Koschinsky, M. L. Lipoprotein(a) as a risk factor for coronary artery disease. Am. J. Cardiol. 82, 57U–66U (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Poon, M., Zhang, X., Dunsky, K. G., Taubman, M. B. & Harpel, P. C. Apolipoprotein(a) induces monocyte chemotactic activity in human vascular endothelial cells. Circulation 96, 2514–2519 (1997).

    Article  CAS  PubMed  Google Scholar 

  20. Nielsen, L. B., Gronholdt, M. L., Schroeder, T. V., Stender, S. & Nordestgaard, B. G. In vivo transfer of lipoprotein(a) into human atherosclerotic carotid arterial intima. Arterioscler. Thromb. Vasc. Biol. 17, 905–911 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Helgadottir, A. et al. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J. Am. Coll. Cardiol. 60, 722–729 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Nielsen, L. B., Juul, K. & Nordestgaard, B. G. Increased degradation of lipoprotein(a) in atherosclerotic compared with nonlesioned aortic intima–inner media of rabbits: in vivo evidence that lipoprotein(a) may contribute to foam cell formation. Arterioscler. Thromb. Vasc. Biol. 18, 641–649 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Danik, J. S. et al. Lipoprotein(a), polymorphisms in the LPA gene, and incident venous thromboembolism among 21,483 women. J. Thromb. Haemost. 11, 205–208 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Erqou, S. et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302, 412–423 (2009).

    Article  CAS  PubMed  Google Scholar 

  25. Nordestgaard, B. G. et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur. Heart J. 34, 3478a–3490a (2013).

    Article  CAS  Google Scholar 

  26. Boerwinkle, E. et al. Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations. J. Clin. Invest. 90, 52–60 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mooser, V. et al. The Apo(a) gene is the major determinant of variation in plasma Lp(a) levels in African Americans. Am. J. Hum. Genet. 61, 402–417 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tregouet, D. A. et al. Genome-wide haplotype association study identifies the SLC22A3LPAL2LPA gene cluster as a risk locus for coronary artery disease. Nat. Genet. 41, 283–285 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Kamstrup, P. R., Tybjaerg-Hansen, A., Steffensen, R. & Nordestgaard, B. G. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301, 2331–2339 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Holmer, S. R. et al. Association of polymorphisms of the apolipoprotein(a) gene with lipoprotein(a) levels and myocardial infarction. Circulation 107, 696–701 (2003).

    Article  PubMed  Google Scholar 

  31. Insull, W. Jr et al. Efficacy of extended-release niacin with lovastatin for hypercholesterolemia: assessing all reasonable doses with innovative surface graph analysis. Arch. Intern. Med. 164, 1121–1127 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Albers, J. J. et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM–HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglyceride and Impact on Global Health Outcomes). J. Am. Coll. Cardiol. 62, 1575–1579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bregar, U., Jug, B., Keber, I., Cevc, M. & Sebestjen, M. Extended-release niacin/laropiprant improves endothelial function in patients after myocardial infarction. Heart Vessels 29, 313–319 (2013).

    Article  PubMed  Google Scholar 

  34. Bruckert, E., Labreuche, J. & Amarenco, P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 210, 353–361 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. HSP2–THRIVE Collaborative Group. HPS2–THRIVE randomized placebo-controlled trial in 25,673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J. 34, 1279–1291 (2013).

  36. Takagi, H. & Umemoto, T. Atorvastatin decreases lipoprotein(a): a meta-analysis of randomized trials. Int. J. Cardiol. 154, 183–186 (2012).

    Article  PubMed  Google Scholar 

  37. Maher, V. M. et al. Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 274, 1771–1774 (1995).

    Article  CAS  PubMed  Google Scholar 

  38. Berg, K. et al. Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study. Clin. Genet. 52, 254–261 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Merki, E. et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J. Am. Coll. Cardiol. 57, 1611–1621 (2011).

    Article  CAS  PubMed  Google Scholar 

  40. Merki, E. et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 118, 743–753 (2008).

    Article  CAS  PubMed  Google Scholar 

  41. Kolski, B. & Tsimikas, S. Emerging therapeutic agents to lower lipoprotein (a) levels. Curr. Opin. Lipidol. 23, 560–568 (2012).

    Article  CAS  PubMed  Google Scholar 

  42. Taleb, A., Witztum, J. L. & Tsimikas, S. Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark. Med. 5, 673–694 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Bertoia, M. L. et al. Oxidation-specific biomarkers and risk of peripheral artery disease. J. Am. Coll. Cardiol. 61, 2169–2179 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ozkanlar, S. & Akcay, F. Antioxidant vitamins in atherosclerosis—animal experiments and clinical studies. Adv. Clin. Exp. Med. 21, 115–123 (2012).

    PubMed  Google Scholar 

  45. Schaloske, R. H. & Dennis, E. A. The phospholipase A2 superfamily and its group numbering system. Biochim. Biophys. Acta 1761, 1246–1259 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Asano, K. et al. Cellular source(s) of platelet-activating-factor acetylhydrolase activity in plasma. Biochem. Biophys. Res. Commun. 261, 511–514 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Tsimihodimos, V. et al. Atorvastatin preferentially reduces LDL-associated platelet-activating factor acetylhydrolase activity in dyslipidemias of type IIA and type IIB. Arterioscler. Thromb. Vasc. Biol. 22, 306–311 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Stafforini, D. M., Prescott, S. M. & McIntyre, T. M. Human plasma platelet-activating factor acetylhydrolase. Purification and properties. J. Biol. Chem. 262, 4223–4230 (1987).

    Article  CAS  PubMed  Google Scholar 

  49. Zalewski, A. & Macphee, C. Role of lipoprotein-associated phospholipase A2 in atherosclerosis: biology, epidemiology, and possible therapeutic target. Arterioscler. Thromb. Vasc. Biol. 25, 923–931 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Rosenson, R. S. & Stafforini, D. M. Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2. J. Lipid Res. 53, 1767–1782 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Vittos, O., Toana, B., Vittos, A. & Moldoveanu, E. Lipoprotein-associated phospholipase A2 (Lp–PLA2): a review of its role and significance as a cardiovascular biomarker. Biomarkers 17, 289–302 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Ali, M. & Madjid, M. Lipoprotein-associated phospholipase A2: a cardiovascular risk predictor and a potential therapeutic target. Future Cardiol. 5, 159–173 (2009).

    Article  CAS  PubMed  Google Scholar 

  53. McConnell, J. P. & Hoefner, D. M. Lipoprotein-associated phospholipase A2. Clin. Lab. Med. 26, 679–697 (2006).

    Article  PubMed  Google Scholar 

  54. Mallat, Z., Lambeau, G. & Tedgui, A. Lipoprotein-associated and secreted phospholipases A(2) in cardiovascular disease: roles as biological effectors and biomarkers. Circulation 122, 2183–2200 (2010).

    Article  PubMed  Google Scholar 

  55. Mohler, E. R. III et al. The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study. J. Am. Coll. Cardiol. 51, 1632–1641 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. White, H. D. et al. Darapladib for preventing ischemic events in stable coronary heart disease. N. Engl. J. Med. 370, 1702–1711 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Rosenson, R. S. et al. Translation of high-density lipoprotein function into clinical practice: current prospects and future challenges. Circulation 128, 1256–1267 (2013).

    Article  PubMed  Google Scholar 

  58. Movva, R. & Rader, D. J. Laboratory assessment of HDL heterogeneity and function. Clin. Chem. 54, 788–800 (2008).

    Article  CAS  PubMed  Google Scholar 

  59. Nissen, S. E. et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304–1316 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Barter, P. J. et al. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109–2122 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Briel, M. et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 338, b92 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. McPherson, R. et al. A common allele on chromosome 9 associated with coronary heart disease. Science 316, 1488–1491 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aulchenko, Y. S. et al. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat. Genet. 41, 47–55 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Voight, B. F. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 380, 572–580 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. de Souza, J. A. et al. Metabolic syndrome features small, apolipoprotein A-I-poor, triglyceride-rich HDL3 particles with defective anti-apoptotic activity. Atherosclerosis 197, 84–94 (2008).

    Article  CAS  PubMed  Google Scholar 

  67. Onat, A., Can., G., Ayhan, E., Kaya, Z. & Hergenc, G. Impaired protection against diabetes and coronary heart disease by high-density lipoproteins in Turks. Metabolism 58, 1393–1399 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Wilkins, J. T. et al. Coronary heart disease risks associated with high levels of HDL cholesterol. J. Am. Heart Assoc. 3, e000519 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Khera, A. V. et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N. Engl. J. Med. 364, 127–135 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Li, X. M. et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler. Thromb. Vasc. Biol. 33, 1696–1705 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Asztalos, B. F. et al. High-density lipoprotein subpopulation profile and coronary heart disease prevalence in male participants of the Framingham Offspring Study. Arterioscler. Thromb. Vasc. Biol. 24, 2181–2187 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Mora, S. et al. Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women. Circulation 119, 931–939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Parish, S. et al. Lipids and lipoproteins and risk of different vascular events in the MRC/BHF Heart Protection Study. Circulation 125, 2469–2478 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Stampfer, M. J., Sacks, F. M., Salvini, S., Willett, W. C. & Hennekens, C. H. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N. Engl. J. Med. 325, 373–381 (1991).

    Article  CAS  PubMed  Google Scholar 

  75. Williams, P. T. & Feldman, D. E. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman's Livermore Cohort. Atherosclerosis 214, 196–202 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. van der Steeg, W. A. et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J. Am. Coll.Cardiol. 51, 634–642 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Schwartz, G. G. et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089–2099 (2012).

    Article  CAS  PubMed  Google Scholar 

  78. Rubins, H. B. et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N. Engl. J. Med. 341, 410–418 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Asztalos, B. F. et al. Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial. Arterioscler. Thromb. Vasc. Biol. 25, 2185–2191 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Asztalos, B. F. et al. Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Metabolism 57, 77–83 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Alaupovic, P. Significance of apolipoproteins for structure, function, and classification of plasma lipoproteins. Methods Enzymol. 263, 32–60 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Shah, A. S., Tan, L., Long, J. L. & Davidson, W. S. Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond. J. Lipid Res. 54, 2575–2585 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Huang, Y. et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat. Med. 20, 193–203 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Jensen, M. K., Rimm, E. B., Furtado, J. D. & Sacks, F. M. Apolipoprotein C-III as a potential modulator of the association between HDL-cholesterol and incident coronary heart disease. J. Am. Heart Assoc. 1, jah3–e000232 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Mendivil, C. O., Rimm, E. B., Furtado, J., Chiuve, S. E. & Sacks, F. M. Low-density lipoproteins containing apolipoprotein C-III and the risk of coronary heart disease. Circulation 124, 2065–2072 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jensen, M. K., Furtado, J. D., Rimm, E. B., Sacks, F. M. & Overvad, K. Presence of apolipoprotein C-III defines a high density lipoprotein subtype that is not inversely associated with incident coronary events [abstract 023]. Circulation 127 (Suppl. 12), A023 (2013).

    Google Scholar 

  87. Kawakami, A. et al. Apolipoprotein CIII in apolipoprotein B lipoproteins enhances the adhesion of human monocytic cells to endothelial cells. Circulation 113, 691–700 (2006).

    Article  CAS  PubMed  Google Scholar 

  88. Graham, M. J. et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112, 1479–1490 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Splaver, A., Lamas, G. A. & Hennekens, C. H. Homocysteine and cardiovascular disease: biological mechanisms, observational epidemiology, and the need for randomized trials. Am. Heart J. 148, 34–40 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. McCully, K. S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am. J. Pathol. 56, 111–128 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Boushey, C. J., Beresford, S. A., Omenn, G. S. & Motulsky, A. G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA 274, 1049–1057 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Yang, Q. et al. Improvement in stroke mortality in Canada and the United States, 1990 to 2002. Circulation 113, 1335–1343 (2006).

    Article  PubMed  Google Scholar 

  93. Strain, J. J., Dowey, L., Ward, M., Pentieva, K. & McNulty, H. B-vitamins, homocysteine metabolism and CVD. Proc. Nutr. Soc. 63, 597–603 (2004).

    Article  CAS  PubMed  Google Scholar 

  94. Clarke, R. et al. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37,485 individuals. Arch. Intern. Med. 170, 1622–1631 (2010).

    Article  CAS  PubMed  Google Scholar 

  95. Wang, X. et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet 369, 1876–1882 (2007).

    Article  CAS  PubMed  Google Scholar 

  96. Saposnik, G., Ray, J. G., Sheridan, P., McQueen, M. & Lonn, E. Homocysteine-lowering therapy and stroke risk, severity, and disability: additional findings from the HOPE 2 trial. Stroke 40, 1365–1372 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Wang, L., Manson, J. E., Song, Y. & Sesso, H. D. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann. Intern. Med. 152, 315–323 (2010).

    Article  PubMed  Google Scholar 

  98. Holick, M. F. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am. J. Clin. Nutr. 79, 362–371 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Bikle, D. D. et al. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J. Clin. Endocrinol. Metab. 63, 954–959 (1986).

    Article  CAS  PubMed  Google Scholar 

  100. Bikle, D. D., Siiteri, P. K., Ryzen, E. & Haddad, J. G. Serum protein binding of 1,25-dihydroxyvitamin D: a reevaluation by direct measurement of free metabolite levels. J. Clin. Endocrinol. Metab. 61, 969–975 (1985).

    Article  CAS  PubMed  Google Scholar 

  101. Lou, Y. R. et al. 25-Hydroxyvitamin D(3) is an agonistic vitamin D receptor ligand. J. Steroid Biochem. Mol. Biol. 118, 162–170 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Dobnig, H. et al. Independent association of low serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels with all-cause and cardiovascular mortality. Arch. Intern. Med. 168, 1340–1349 (2008).

    Article  CAS  PubMed  Google Scholar 

  103. Zittermann, A. Vitamin D and disease prevention with special reference to cardiovascular disease. Prog. Biophys. Mol. Biol. 92, 39–48 (2006).

    Article  CAS  PubMed  Google Scholar 

  104. Zehnder, D. et al. Synthesis of 1,25-dihydroxyvitamin D3 by human endothelial cells is regulated by inflammatory cytokines: a novel autocrine determinant of vascular cell adhesion. J. Am. Soc. Nephrol. 13, 621–629 (2002).

    Article  CAS  PubMed  Google Scholar 

  105. Brøndum-Jacobsen, P., Benn, M., Jensen, G. B. & Nordestgaard, B. G. 25-hydroxyvitamin D levels and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analyses of 18 and 17 studies. Arterioscler. Thromb. Vasc. Biol. 32, 2794–2802 (2012).

    Article  PubMed  CAS  Google Scholar 

  106. Sokol, S. I., Tsang, P., Aggarwal, V., Melamed, M. L. & Srinivas, V. S. Vitamin D status and risk of cardiovascular events: lessons learned via systematic review and meta-analysis. Cardiol. Rev. 19, 192–201 (2011).

    Article  PubMed  Google Scholar 

  107. Wang, L. et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: a meta-analysis of prospective studies. Circ. Cardiovasc. Qual. Outcomes 5, 819–829 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Grandi, N. C., Breitling, L. P. & Brenner, H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev. Med. 51, 228–233 (2010).

    Article  CAS  PubMed  Google Scholar 

  109. Forman, J. P. et al. Plasma 25-hydroxyvitamin D levels and risk of incident hypertension. Hypertension 49, 1063–1069 (2007).

    Article  CAS  PubMed  Google Scholar 

  110. Mattila, C. et al. Serum 25-hydroxyvitamin D concentration and subsequent risk of type 2 diabetes. Diabetes Care 30, 2569–2570 (2007).

    Article  CAS  PubMed  Google Scholar 

  111. Shea, M. K. et al. Vitamin K and vitamin D status: associations with inflammatory markers in the Framingham Offspring Study. Am. J. Epidemiol. 167, 313–320 (2008).

    Article  PubMed  Google Scholar 

  112. Tomson, J. et al. Vitamin D and risk of death from vascular and non-vascular causes in the Whitehall study and meta-analyses of 12,000 deaths. Eur. Heart J. 34, 1365–1374 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Marco, M. P. et al. Higher impact of mineral metabolism on cardiovascular mortality in a European hemodialysis population. Kidney Int. Suppl. 85, S111–S114 (2003).

    Article  Google Scholar 

  114. Naves-Diaz, M. et al. Oral active vitamin D is associated with improved survival in hemodialysis patients. Kidney Int. 74, 1070–1078 (2008).

    Article  CAS  PubMed  Google Scholar 

  115. Shoji, T. et al. Lower risk for cardiovascular mortality in oral 1α-hydroxy vitamin D3 users in a haemodialysis population. Nephrol. Dial. Transplant. 19, 179–184 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Teng, M. et al. Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J. Am. Soc. Nephrol. 16, 1115–1125 (2005).

    Article  CAS  PubMed  Google Scholar 

  117. Wolf, M. et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 72, 1004–1013 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Hsia, J. et al. Calcium/vitamin D supplementation and cardiovascular events. Circulation 115, 846–854 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Forman, J. P. et al. Effect of vitamin D supplementation on blood pressure in blacks. Hypertension. 61, 779–785 (2013).

    Article  CAS  PubMed  Google Scholar 

  120. Shimada, T. et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J. Bone. Miner. Res. 19, 429–435 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Gutierrez, O. M. et al. Fibroblast growth factor 23 and left ventricular hypertrophy in chronic kidney disease. Circulation 119, 2545–2552 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Gutierrez, O. M. et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N. Engl. J. Med. 359, 584–592 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Isakova, T. et al. Fibroblast growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA 305, 2432–2439 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Mirza, M. A., Larsson, A., Melhus, H., Lind, L. & Larsson, T. E. Serum intact FGF23 associate with left ventricular mass, hypertrophy and geometry in an elderly population. Atherosclerosis 207, 546–551 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Parker, B. D. et al. The associations of fibroblast growth factor 23 and uncarboxylated matrix Gla protein with mortality in coronary artery disease: the Heart and Soul Study. Ann. Intern. Med. 152, 640–648 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Seiler, S. et al. The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation. Eur. Heart J. 32, 2688–2696 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Faul, C. et al. FGF23 induces left ventricular hypertrophy. J. Clin. Invest. 121, 4393–4408 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Shalhoub, V. et al. FGF23 neutralization improves chronic kidney disease-associated hyperparathyroidism yet increases mortality. J. Clin. Invest. 122, 2543–2553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Touchberry, C. D. et al. FGF23 is a novel regulator of intracellular calcium and cardiac contractility in addition to cardiac hypertrophy. Am. J. Physiol. Endocrinol. Metab. 304, E863–E873 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Dominguez, J. R., Shlipak, M. G., Whooley, M. A. & Ix, J. H. Fractional excretion of phosphorus modifies the association between fibroblast growth factor-23 and outcomes. J. Am. Soc. Nephrol. 24, 647–654 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Oh, D. K., Ciaraldi, T. & Henry, R. R. Adiponectin in health and disease. Diabetes Obes. Metab. 9, 282–289 (2007).

    Article  CAS  PubMed  Google Scholar 

  132. Stefan, N. & Stumvoll, M. Adiponectin—its role in metabolism and beyond. Horm. Metab. Res. 34, 469–474 (2002).

    Article  CAS  PubMed  Google Scholar 

  133. Li, S., Shin, H. J., Ding, E. L. & van Dam, R. M. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 302, 179–188 (2009).

    Article  CAS  PubMed  Google Scholar 

  134. Hotta, K. et al. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 50, 1126–1133 (2001).

    Article  CAS  PubMed  Google Scholar 

  135. Ouchi, N. et al. Adipocyte-derived plasma protein, adiponectin, suppresses lipid accumulation and class A scavenger receptor expression in human monocyte-derived macrophages. Circulation 103, 1057–1063 (2001).

    Article  CAS  PubMed  Google Scholar 

  136. Pischon, T. et al. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA 291, 1730–1737 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Sattar, N. et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation 114, 623–629 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Lindsay, R. S. et al. Adiponectin and coronary heart disease: the Strong Heart Study. Arterioscler. Thromb. Vasc. Biol. 25, e15–e16 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Heidemann, C. et al. Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women. Ann. Intern. Med. 149, 307–316 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Pischon, T. et al. Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women. Atherosclerosis 219, 322–329 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kizer, J. R. et al. Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults. J. Clin. Endocrinol. Metab. 98, 255–263 (2013).

    Article  CAS  PubMed  Google Scholar 

  142. Rathmann, W. & Herder, C. Adiponectin and cardiovascular mortality: evidence for “reverse epidemiology”. Horm. Metab. Res. 39, 1–2 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Wilson, S. R. et al. Assessment of adiponectin and the risk of recurrent cardiovascular events in patients presenting with an acute coronary syndrome: observations from the Pravastatin Or atorVastatin Evaluation and Infection Trial–Thrombolysis in Myocardial Infarction 22 (PROVE IT–TIMI 22). Am. Heart J. 161, 1147–1155 (2011).

    Article  CAS  PubMed  Google Scholar 

  144. Onat, A., Hergenc, G., Can., G. & Kucukdurmaz, Z. Serum adiponectin confers little protection against diabetes and hypertension in Turkish men. Obesity (Silver Spring) 17, 564–570 (2009).

    Article  CAS  Google Scholar 

  145. Menzaghi, C. et al. A haplotype at the adiponectin locus is associated with obesity and other features of the insulin resistance syndrome. Diabetes 51, 2306–2312 (2002).

    Article  CAS  PubMed  Google Scholar 

  146. ADIPOGen Consortium [online], (2014).

  147. CARDIoGRAMplusC4D Consortium [online], (2013).

  148. Dastani, Z. et al. The shared allelic architecture of adiponectin levels and coronary artery disease. Atherosclerosis 229, 145–148 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Kissebah, A. H. et al. Quantitative trait loci on chromosomes 3 and 17 influence phenotypes of the metabolic syndrome. Proc. Natl Acad. Sci. USA 97, 14478–14483 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Dastani, Z. et al. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals. PLoS Genet. 8, e1002607 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kadowaki, T. et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J. Clin. Invest. 116, 1784–1792 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Coppola, A. et al. Effect of weight loss on coronary circulation and adiponectin levels in obese women. Int. J. Cardiol. 134, 414–416 (2009).

    Article  PubMed  Google Scholar 

  153. Selvin, E. et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N. Engl. J. Med. 362, 800–811 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Selvin, E. et al. Glycemic control and coronary heart disease risk in persons with and without diabetes: the atherosclerosis risk in communities study. Arch. Intern. Med. 165, 1910–1916 (2005).

    Article  PubMed  Google Scholar 

  155. Pradhan, A. D., Rifai, N., Buring, J. E. & Ridker, P. M. Hemoglobin A1c predicts diabetes but not cardiovascular disease in nondiabetic women. Am. J. Med. 120, 720–727 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Khaw, K. T. et al. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann. Intern. Med. 141, 413–420 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Adams, R. J. et al. Independent association of HbA1c and incident cardiovascular disease in people without diabetes. Obesity (Silver Spring) 17, 559–563 (2009).

    Article  CAS  Google Scholar 

  158. Lawlor, D. A., Fraser, A., Ebrahim, S. & Smith, G. D. Independent associations of fasting insulin, glucose, and glycated haemoglobin with stroke and coronary heart disease in older women. PLoS Med. 4, e263 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Pai, J. K. et al. Hemoglobin a1c is associated with increased risk of incident coronary heart disease among apparently healthy, nondiabetic men and women. J. Am. Heart Assoc. 2, e000077 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Blake, G. J. et al. Hemoglobin A1c level and future cardiovascular events among women. Arch. Intern. Med. 164, 757–761 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Sarwar, N. et al. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik prospective study and systematic review. PLoS Med. 7, e1000278 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Sarwar, N. et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 375, 2215–2222 (2010).

    Article  CAS  PubMed  Google Scholar 

  163. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 32, 1327–1334 (2009).

  164. Gerstein, H. C. Glycosylated hemoglobin: finally ready for prime time as a cardiovascular risk factor. Ann. Intern. Med. 141, 475–476 (2004).

    Article  CAS  PubMed  Google Scholar 

  165. Marshall, S. M. & Barth, J. H. Standardization of HbA1c measurements—a consensus statement. Diabet. Med. 17, 5–6 (2000).

    Article  CAS  PubMed  Google Scholar 

  166. Sander, D. et al. Combined effects of hemoglobin A1c and C-reactive protein on the progression of subclinical carotid atherosclerosis: the INVADE study. Stroke 37, 351–357 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Vlassara, H., Brownlee, M., Manogue, K. R., Dinarello, C. A. & Pasagian, A. Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 240, 1546–1548 (1988).

    Article  CAS  PubMed  Google Scholar 

  168. King, D. E., Mainous, A. G. III, Buchanan, T. A. & Pearson, W. S. C-reactive protein and glycemic control in adults with diabetes. Diabetes Care 26, 1535–1539 (2003).

    Article  PubMed  Google Scholar 

  169. Verma, S. et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation 106, 913–919 (2002).

    Article  CAS  PubMed  Google Scholar 

  170. Giugliano, D. et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation 95, 1783–1790 (1997).

    Article  CAS  PubMed  Google Scholar 

  171. Gerstein, H. C. More insights on the dysglycaemia-cardiovascular connection. Lancet 375, 2195–2196 (2010).

    Article  PubMed  Google Scholar 

  172. Gerstein, H. C. & Yusuf, S. Dysglycaemia and risk of cardiovascular disease. Lancet 347, 949–950 (1996).

    Article  CAS  PubMed  Google Scholar 

  173. Emerging Risk Factors Collaboration. Glycated hemoglobin measurement and prediction of cardiovascular disease. JAMA 311, 1225–1233 (2014).

  174. Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  175. Orchard, T. J. et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann. Intern. Med. 142, 611–619 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Ratner, R. et al. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the diabetes prevention program. Diabetes Care 28, 888–894 (2005).

    Article  PubMed  Google Scholar 

  177. Li, G. et al. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2, 474–480 (2014).

    Article  PubMed  Google Scholar 

  178. Gerstein, H. C. et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J.Med. 358, 2545–2559 (2008).

    Article  CAS  PubMed  Google Scholar 

  179. Wright, E. E. Jr., Stonehouse, A. H. & Cuddihy, R. M. In support of an early polypharmacy approach to the treatment of type 2 diabetes. Diabetes Obes. Metab. 12, 929–940 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Tuomilehto, J. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N. Engl. J. Med. 344, 1343–1350 (2001).

    Article  CAS  PubMed  Google Scholar 

  181. Lindstrom, J. et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet 368, 1673–1679 (2006).

    Article  PubMed  Google Scholar 

  182. [No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).

  183. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560–2572 (2008).

    Article  CAS  PubMed  Google Scholar 

  184. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Levy, A. P. et al. Haptoglobin: basic and clinical aspects. Antioxid. Redox Signal. 12, 293–304 (2010).

    Article  CAS  PubMed  Google Scholar 

  186. Cahill, L. E. et al. Currently available versions of genome-wide association studies cannot be used to query the common haptoglobin copy number variant. J. Am. Coll. Cardiol. 62, 860–861 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Langlois, M. R. & Delanghe, J. R. Biological and clinical significance of haptoglobin polymorphism in humans. Clin. Chem. 42, 1589–1600 (1996).

    Article  CAS  PubMed  Google Scholar 

  188. Levy, A. P. et al. Haptoglobin phenotype and prevalent coronary heart disease in the Framingham offspring cohort. Atherosclerosis 172, 361–365 (2004).

    Article  CAS  PubMed  Google Scholar 

  189. De Bacquer, D. et al. Haptoglobin polymorphism as a risk factor for coronary heart disease mortality. Atherosclerosis 157, 161–166 (2001).

    Article  CAS  PubMed  Google Scholar 

  190. Asleh, R., Guetta, J., Kalet-Litman, S., Miller-Lotan, R. & Levy, A. P. Haptoglobin genotype- and diabetes-dependent differences in iron-mediated oxidative stress in vitro and in vivo. Circ. Res. 96, 435–441 (2005).

    Article  CAS  PubMed  Google Scholar 

  191. Asleh, R. et al. Haptoglobin genotype is a regulator of reverse cholesterol transport in diabetes in vitro and in vivo. Circ. Res. 99, 1419–1425 (2006).

    Article  CAS  PubMed  Google Scholar 

  192. Asleh, R. et al. Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res. 92, 1193–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  193. Cahill, L. E. et al. Haptoglobin genotype is a consistent marker of coronary heart disease risk among individuals with elevated glycosylated hemoglobin. J. Am. Coll. Cardiol. 61, 728–737 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Levy, A. P. et al. Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study. J. Am. Coll. Cardiol. 40, 1984–1990 (2002).

    Article  PubMed  Google Scholar 

  195. Gerstein, H. C. et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N. Engl. J. Med. 364, 818–828 (2011).

    Article  CAS  PubMed  Google Scholar 

  196. Carter, K. & Worwood, M. Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases. Int. J. Lab. Hematol. 29, 92–110 (2007).

    Article  PubMed  Google Scholar 

  197. Vickers, A. J. & Pepe, M. Does the net reclassification improvement help us evaluate models and markers? Ann. Intern. Med. 160, 136–137 (2014).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

M.K.J., M.L.B., L.E.C., I.A., E.B.R. and K.J.M. researched data for the article, provided substantial contributions to discussions of the content, contributed to writing the article and to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Majken K. Jensen.

Ethics declarations

Competing interests

M.K.J. and E.B.R. have received unrestricted research support from Roche to measure HDL subtypes in the Multi-Ethnic Study of Atherosclerosis. M.K.J and E.B.R are listed as co-inventors on a patent application filed by Harvard University for HDL ApoC-III (US Patent Application 13/046,682, filed March 11, 2011: “Assay and prediction of cardiovascular risk based on HDL subtypes according to apoC-III”.). M.L.B., L.E.C., I.A. and K.J.M. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jensen, M., Bertoia, M., Cahill, L. et al. Novel metabolic biomarkers of cardiovascular disease. Nat Rev Endocrinol 10, 659–672 (2014). https://doi.org/10.1038/nrendo.2014.155

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2014.155

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research