Inflammatory, lipid, thrombotic, and genetic markers of coronary heart disease risk in the women's health initiative trials of hormone therapy.
BACKGROUND
Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit.


METHODS
This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus.


RESULTS
In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events.


CONCLUSIONS
Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD.


BACKGROUND
clinicaltrials.gov Identifier: NCT00000611.
Rossouw
Jacques E
JE
Women's Health Initiative Branch, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, 6701 Rockledge Dr, Rockledge 2 Bldg, Ste 10018, Bethesda, MD 20892, USA. rossouwj@nih.gov
Cushman
Mary
M
Greenland
Philip
P
Lloyd-Jones
Donald M
DM
Bray
Paul
P
Kooperberg
Charles
C
Pettinger
Mary
M
Robinson
Jennifer
J
Hendrix
Susan
S
Hsia
Judith
J
D000368:Aged; D015415:Biomarkers / Q000097:blood*; D016022:Case-Control Studies; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003327:Coronary Disease / Q000097:blood*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004966:Estrogens, Conjugated (USP) / Q000008:administration & dosage / Q000009:adverse effects; D005169:Factor VIII / Q000032:analysis; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007044:Hysterectomy; D007249:Inflammation / Q000097:blood*; D007328:Insulin / Q000097:blood; D039661:Integrin beta3 / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008525:Medroxyprogesterone / Q000008:administration & dosage / Q000009:adverse effects; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013927:Thrombosis / Q000097:blood*; D014280:Triglycerides / Q000097:blood; D014841:von Willebrand Factor / Q000032:analysis
D015415:Biomarkers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004966:Estrogens, Conjugated (USP); D005338:Fibrin Fibrinogen Degradation Products; D007328:Insulin; D039661:Integrin beta3; D015850:Interleukin-6; D014280:Triglycerides; C036309:fibrin fragment D; D014841:von Willebrand Factor; D006710:Homocysteine; D005169:Factor VIII; D002784:Cholesterol; D020780:Matrix Metalloproteinase 9; D008525:Medroxyprogesterone