W11 - CVD biomarkers - Phase II: strokes after Feb. 2001

Investigator Names and Contact Information

Introduction/Intent

W6 - HT CVD Biomarkers Case-Control Study of CHD, Stroke, and VTE was conducted in several stages: Phase I: cases within 2 years of randomization; and Phase II: > 2 years after randomization. See also

• W11-Assays on Strokes Identified After Feb 2001 and
• W14-Additional Assays on W6 CVD Biomarkers described below.

The purpose of this proposal is to include additional CVD analytes to the initial W6 - HT CVD Biomarkers Study to help elucidate the E+P intervention effect on early increases in cardiovascular events (as defined by coronary heart disease, cerebrovascular accidents and venous thromboembolic events).

Initial and secondary tiers of analytes to explore the CVD outcomes from the E+P are complete or in progress. However, there have been scientific advances in the field of explanatory analytes that might be valuable addition or substitutions to the analytes already approved that would help WHI contribute to a greater understanding of this early CVD risk. Specific analytes proposed for consideration of incorporation are listed below. The proposed analytes and a brief description is:

1. NMR lipoprofiles (www.liposcience.com) for CHD/stroke baseline & year 1– Assay quantifies 10 lipoprotein subfractions, as well as LDL particle size and LDL particle concentration, which predict coronary risk and are modulated by hormone therapy (JAMA 2003;290:2030).

2. Progesterone receptor polymorphisms – Very few previously reported. David Herrington has identified 75 SNPs, but doesn’t know which (if any) are clinically relevant.

3. Substitute panel of cytokines for TGF-beta and IL-1beta (Vermont), which were on original list, but not yet run. IL-6 was associated with stroke risk in our study (OR ~10, p for interaction with E+P = 0.02). In unpublished paper from EPIC-Norfolk study, adjusted OR 1.98 (1.09, 3.61) for CHD by IL-8 quartile.

4. Change activated protein C resistance (Vermont) in CHD/stroke/VTE cases/control to better assay, APC – ETP (endogenous thrombin potential), currently performed in Dr. Rosendaal’s lab. The new APC-ETP has been shown in recent studies to be associated with hormone-induced changes that would make it very interesting to examine in the E+P and E-alone CT for all CVD outcomes. Dr. Rosendaal provided unpublished paper showing OR 4.7 (95% CI 1.4, 15.6) for venous thrombosis cases in postmenopausal women.

5. Substitute free and total TFPI (tissue factor pathway inhibitor) antigen + TFPI activity instead of factor VII antigen (Vermont) in CHD/stroke/VTE cases/controls. TFPI falls 20% with hormones (J Thromb Haemost 2003;1:1208); OR 1.6 for VTE (Blood 2003;101:4387). Some suggestion of role in CHD (Circ 2003;108:2864)

• 1-4: W14 - New tests on W6 cases
• 5-6: W11 - New Strokes

W6-Previously identified cases and controls 10 lipopro-tein subfrac-tions, LDL particle size, and LDL particle conc

• 1. Includes early stroke cases (before Feb 2001)
• 2. Tests done only on correspondign controls, not all controls

See Publications: 204, 210, 222, 273, 345, 347, 350, 429, 445, 462, 526, 854, 866, 972, 1114. WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Papers of this website.