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C-Reactive Protein and Reclassification of Cardiovascular Risk in the Framingham Heart Study
Open accessAbstract
Background— The relationship of circulating levels of high-sensitivity C-reactive protein (CRP) with cardiovascular disease (CVD) risk, particularly with consideration of effects at intermediate levels of risk, has not been fully assessed. Methods and Results— Among 3006 offspring participants in the Framingham Heart Study free of CVD (mean age, 46 years at baseline), there were 129 hard coronary heart disease (CHD) events and 286 total CVD events during 12 years of follow-up. Cox regression, discrimination with area under the receiver operating characteristic curve, and net reclassification improvement were used to assess the role of CRP on vascular risk. In an age-adjusted model that included both sexes, the hazard ratios for new hard CHD and total CVD were significantly associated with higher CRP levels. Similar analyses according to increasing homocysteine level showed significant protective associations for hard CHD but not for total CVD. In multivariable analyses that included age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, diabetes mellitus, current smoking, hypertension treatment, and homocysteine, the log CRP level remained significantly related to development of hard CHD and total CVD and provided moderate improvement in the discrimination of events. The net reclassification improvement when CRP was added to traditional factors was 5.6% for total CVD ( P =0.014) and 11.8% for hard CHD ( P =0.009). Conclusions— Circulating levels of CRP help to estimate risk for initial cardiovascular events and may be used most effectively in persons at intermediate risk for vascular events, offering moderate improvement in reclassification of risk.
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“It should be stressed, however, that although many risk factors other than the few included in the available risk functions have been identified [such as C-reactive protein (CRP) and homocysteine levels], their contribution to absolute cardiovascular risk estimations of individual patients (in addition to traditional risk factors) is generally modest.66”
From European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) (2012) · cites this paper as [66]
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MethodSelf-citationC-reactive protein is a mediator of cardiovascular disease
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Braunwald, E. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr310 · Cited by 64
Impaired retinal vasodilator responses in prediabetes and type 2 diabetes
Lott, M. E. J., Slocomb, J. E., Shivkumar, V., Smith, B., Quillen, D. A., Gabbay, R. A., Gardner, T. W., & Bettermann, K. (2013) · Acta Ophthalmologica · doi:10.1111/aos.12129 · Cited by 66
“2009) and heart disease (Wilson et al. 2008; Buckley et al. 2009) and risk of a having a myocardial infarction (Ridker 2004).”
BackgroundNew and Emerging Risk Factors for Coronary Heart Disease
Akhabue, E., Thiboutot, J. P., Cheng, J.-W., Lerakis, S., Vittorio, T. J., Christodoulidis, G., Grady, K. M., & Kosmas, C. E. (2013) · The American Journal of the Medical Sciences · doi:10.1097/maj.0b013e31828aab45 · Cited by 64
High-sensitivity C reactive protein and risk of cardiovascular disease in China-CVD study
Dong, Y., Wang, X., Zhang, L., Chen, Z., Zheng, C., Wang, J., Kang, Y., Shao, L., Tian, Y., & Wang, Z. (2018) · Journal of Epidemiology & Community Health · doi:10.1136/jech-2018-211433 · Cited by 60
Jiang, Y., Zhang, X., Ma, R., Wang, X., Liu, J., Keerman, M., Yan, Y., Ma, J., Song, Y., Zhang, J., et al. (2021) · Clinical Epidemiology · doi:10.2147/clep.s313343 · Cited by 63
Rana, J. S., Cote, M., Després, J., Sandhu, M. S., Talmud, P. J., Ninio, E., Wareham, N. J., Kastelein, J. J. P., Zwinderman, A. H., Khaw, K., et al. (2009) · Heart · doi:10.1136/hrt.2009.170134 · Cited by 58
C-reactive protein is a bystander of cardiovascular disease
Anand, S. S., & Yusuf, S. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq242 · Cited by 56
Epidemiology, Traditional and Novel Risk Factors in Coronary Artery Disease
Mack, M. C., & Gopal, A. (2014) · Cardiology Clinics · doi:10.1016/j.ccl.2014.04.003 · Cited by 59
Sever, P., Poulter, N. R., Chang, C., Hingorani, A. D., Thom, S., Hughes, A. D., Welsh, P. I., Sattar, N. A., & on behalf of the ASCOT Investigators (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr262 · Cited by 56
“These findings are broadly in line with other prospective studies showing statistically significant, but modest absolute improvements with the use of C-reactive protein in clinical risk prediction.(22,23)”
ResultSerum C-reactive protein level and prediabetes in two Asian populations
Sabanayagam, C., Shankar, A., Lim, S. C., Lee, J., Tai, E. S., & Wong, T. Y. (2011) · Diabetologia · doi:10.1007/s00125-011-2052-5 · Cited by 52
“We repeated the multivariable model in Table 2: (1) using quartiles of CRP (<0.4, 0.4–1.0, 1.1–2.6, >2.6 mg/l); (2) after excluding participants with hsCRP levels suggestive of clinical inflammation (>10 mg/l); and (3) after excluding participants with history of CVD.”
BackgroundInfluentialC-reactive protein and cardiovascular risk in the general population
Kurt, B., Reugels, M., Schneider, K. M., Spießhoefer, J., Milzi, A., Gombert, A., Fordyce, C. B., Wenzl, F. A., Pagidipati, N. J., Rocha, V. Z., et al. (2025) · European Heart Journal · doi:10.1093/eurheartj/ehaf937 · Cited by 53
CVD screening in low-risk, asymptomatic adults: clinical trials needed
Polonsky, T. S., & Greenland, P. (2012) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2012.114 · Cited by 50
Clinical usefulness of novel prognostic biomarkers in patients on hemodialysis
Ortíz, A., Massy, Z. A., Fliser, D., Lindholm, B., Więcek, A., Martínez‐Castelao, A., Covic, A. C., Goldsmith, D. J. A., Süleymanlar, G., London, G. M., et al. (2011) · Nature Reviews Nephrology · doi:10.1038/nrneph.2011.170 · Cited by 50
“002% discrimination power to predictions made on the basis of Framingham risk factors, but was useful for risk reclassification of coronary heart disease events”
Elevated Pulmonary Artery Systolic Pressure Predicts Heart Failure Admissions in African Americans
Choudhary, G., Jankowich, M. D., & Wu, W. (2014) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001366 · Cited by 49
“8% when added to a multivariable prediction model in the Framingham Offspring cohort in predicting coronary heart disease events).(28) Future studies will be needed to determine if PASP and N-terminal prohormone of brain natriuretic peptide have overlapping or synergistic effects when added together to the ARIC model.”
MethodHigh-Sensitive C-Reactive Protein: Universal Prognostic and Causative Biomarker in Heart Disease?
Rietzschel, E. R., & Buyzere, M. D. (2012) · Biomarkers in Medicine · doi:10.2217/bmm.11.108 · Cited by 49
Association of Serum Procalcitonin With Cardiovascular Prognosis in Coronary Artery Disease
Sinning, C., Sinning, J., Schulz, A., Schnabel, R. B., Lubos, E., Wild, P. S., Papassotiriou, J., Bergmann, A., Blankenberg, S., Münzel, T. F., et al. (2011) · Circulation Journal · doi:10.1253/circj.cj-10-0638 · Cited by 47
Abd, T. T., Eapen, D. J., Bajpai, A., Goyal, A., Dollar, A. L., & Sperling, L. S. (2011) · Current Atherosclerosis Reports · doi:10.1007/s11883-011-0164-5 · Cited by 47
“7% for CVD and 24% for the hard endpoints of CHD [35].”
BackgroundMethodInfluentialThe Emerging Role of Inflammation in Cardiovascular Disease
Martinez, B. K., & White, C. M. (2018) · Annals of Pharmacotherapy · doi:10.1177/1060028018765939 · Cited by 50
Risk and the Physics of Clinical Prediction
McEvoy, J. W., Diamond, G. A., Detrano, R., Kaul, S., Blaha, M. J., Blumenthal, R. S., & Jones, S. R. (2014) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2014.01.418 · Cited by 46
C-Reactive Protein and Colorectal Cancer Mortality in U.S. Adults
Goyal, A., Terry, M. B., Jin, Z., & Siegel, A. B. (2014) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-13-0577 · Cited by 45
Early identification of atherosclerotic disease by noninvasive imaging
Fuster, V., Lois, F., & Franco, M. (2010) · Nature Reviews Cardiology · doi:10.1038/nrcardio.2010.54 · Cited by 46
Shaw, L. J., Wilson, P. W. F., Hachamovitch, R., Hendel, R. C., Borges‐Neto, S., & Berman, D. S. (2010) · JACC. Cardiovascular imaging · doi:10.1016/j.jcmg.2010.09.008 · Cited by 43
“Several eports have noted this as an effective method for valuating the added value of high sensitivity -reactive protein beyond that of the Framingham isk score (12,13,19,20).”
MethodSelf-citationDent, T. (2010) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2010.06.021 · Cited by 46
Park, C., Do, J. G., Lee, Y., & Yoon, K. J. (2018) · BMJ Open · doi:10.1136/bmjopen-2017-021232 · Cited by 42
Lee, J., Ryu, S., Cheong, E., & Sung, K. (2016) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2016.08.003 · Cited by 40
Methods for evaluating novel biomarkers - a new paradigm
Cook, N. R. (2010) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2010.02469.x · Cited by 39
Cardoso, C. R. L., Leite, N. C., & Salles, G. F. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.004554 · Cited by 34
Ormseth, M. J., Solus, J. F., Sheng, Q., Chen, S., Ye, F., Wu, Q., Oeser, A. M., Allen, R. M., Raggi, P., Vickers, K. C., et al. (2021) · Clinical Rheumatology · doi:10.1007/s10067-020-05573-8 · Cited by 36
“799 for total cardiovascular disease [23].”
Wang, X., Wang, J., Wu, S., Ni, Q., & Chen, P. (2021) · International Journal of General Medicine · doi:10.2147/ijgm.s328882 · Cited by 36
Metadata
- Authors
- Wilson, P. W. F., Pencina, M., Jacques, P., Selhub, J., D'Agostino, R., & O'Donnell, C. J.
- Affiliations
- Boston University (US)
- From EPICORE (P.W.F.W.), Emory University School of Medicine, and the Atlanta VAMC Epidemiology and Genetics Section, Atlanta, Ga; National Heart, Lung, and Blood Institute (C.J.O.D.); National Heart, Lung and Blood Institute’s Framingham Heart Study (M.P., R.D.A., C.J.O.D.), Framingham Mass; Department of Mathematics (M.P., R.D.A.), Boston University, Boston, Mass; Tufts USDA Nutrition Center (P.J., J.S.), Boston, Mass.
- Venue
- Circulation: Cardiovascular Quality and Outcomes
- Published
- 2008-11
- Volume
- 1
- Issue
- 2
- Pages
- 92-97
- ISSN
- 1941-7705 (ISSN-L)
- 1941-7713
- PMC
- PMC3033831
- OpenAlex
- W2144684988
- Cited by
- 299
- References
- 38
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 3 · 2023: 13 · 2022: 8 · 2021: 16 · 2020: 6 · 2019: 5 · 2018: 19 · 2017: 12 · 2016: 20 · 2015: 15 · 2014: 21 · 2013: 18 · 2012: 36
- FWCI
- 29.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Cardiovascular Quality and Outcomes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- School of Medicine, Boston University
- Centre International de Recherche sur le Cancer
- National Institutes of Health (n01hc25195-41-0-1)
- National Heart, Lung, and Blood Institute (R01HL073272, N01‐HC25195, N01-HC-025195)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Risk Factors
- Keywords
- C-reactive protein, cardiovascular risk reclassification, coronary artery disease, cardiovascular disease, intermediate cardiovascular risk, homocysteine, risk prediction, net reclassification improvement
- MeSH terms
- Adult, C-Reactive Protein, Coronary Disease, Female, Follow-Up Studies, Homocysteine, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Biomarkers, Prevalence, Risk Assessment
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