Objective-Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with preexisting atherosclerosis. We assessed the hypothesis that selective estrogen receptor modulation induces plaque stability in "menopausal" animals.Methods and Results-Atherosclerosis was induced in 42 ovariectomized New Zealand White rabbits by cholesterol feeding and mechanical injury. Animals were imaged by magnetic resonance (MRI) for baseline atherosclerosis, and randomized to control (OVX, n=12), raloxifene 35-60 mg/kg/day by diet admixture (RLX, n=24), or immediate sacrifice (n=6) for immunohistopathologic correlation of MRI. Six months later, rabbits underwent repeat MRI then sacrifice for micro-computed tomography (μCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2, MMP-1, MCP-1 expression and macrophage infiltration in RLX vs. OVX with concomitant upregulation of estrogen receptor α. μCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63 ± 7° vs. 33 ± 6° in OVX), the predicted result of a 53% increase in BMP-2. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conclusions-Raloxifene
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Author ManuscriptAtherosclerosis. Author manuscript; available in PMC 2012 July 02. Recent efforts at female-specific pharmacologic therapies have focused on selective estrogen receptor modulators (SERMs). Most pertinently, post-hoc analysis from an osteoporosis treatment trial in post-menopausal women (the Multiple Outcomes of Raloxifene Evaluation, MORE) found that those women at high-risk for coronary artery disease (i.e., a secondary prevention population most likely to have established atherosclerotic lesions) treated with the SERM raloxifene had 40 percent fewer cardiovascular events than those on placebo. 5 The Raloxifene Use for the Heart (RUTH) study, which was a double-blind, placebo-controlled, randomized clinical trial of this SERM's use in a patient population without pre-specified osteoporosis did not confirm this benefit. 6, 7The mechanism of raloxifene's potential effects upon atherosclerotic lesions is not completely understood. Pre-clinical animal models have shown that raloxifene, similar to HT, inhibits atherosclerosis, 8, 9 but its effect upon vascular calcification is unknown. HT results in less calcified plaques 10 without clear reduction in cardiovascular events, 11 yet statins, a therapy with clear reductions in cardiovascular events, increase calcifi...