Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study.
BACKGROUND
Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown.


OBJECTIVE
To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk.


METHODS
Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75 343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years.


METHODS
Incidence of first myocardial infarction or death from CHD.


RESULTS
Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P<.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend =.002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP.


CONCLUSIONS
These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.
Center for Cardiovascular Disease Prevention, Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215-1204, USA.
Aruna D
AD
Pradhan
JoAnn E
JE
Manson
Jacques E
JE
Rossouw
David S
DS
Siscovick
Charles P
CP
Mouton
Nader
N
Rifai
Robert B
RB
Wallace
Rebecca D
RD
Jackson
Mary B
MB
Pettinger
Paul M
PM
Ridker
D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism*; D016022:Case-Control Studies; D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology*; D015914:Estrogen Replacement Therapy; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood*; D016015:Logistic Models; D017698:Postmenopause; D011446:Prospective Studies; D012307:Risk Factors; D018709:Statistics, Nonparametric
D015415:Biomarkers; D015850:Interleukin-6; D002097:C-Reactive Protein