Subject(s)
Coronary Artery Disease , Diabetes Mellitus, Type 2 , Exercise Test , Asymptomatic Diseases , Coronary Artery Disease/diagnosis , Coronary Artery Disease/epidemiology , Coronary Artery Disease/etiology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/epidemiology , Humans , Mass Screening , Risk FactorsABSTRACT
OBJECTIVE: Osteoporosis trials suggest raloxifene decreased cardiovascular events in women with pre-existing 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 imaging (MRI) for baseline atherosclerosis, and randomized to control (OVX (ovariectomized control group), n=12), raloxifene 35-60 mg/kg/day by diet admixture (RLX (raloxifene therapy group), 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 (microCT) and molecular analysis. Unlike OVX, RLX reduced atheroma volume. Analysis for lesion inflammation revealed reductions in COX-2 (cyclooxygenase-2), MMP-1 (matrix metalloproteinase-1), MCP-1 (monocyte chemoattractant protein-1) expression and macrophage infiltration in RLX versus OVX with concomitant upregulation of estrogen receptor alpha (ERalpha). microCT showed similar total vascular calcification between groups, but calcifications in RLX were less nodular with better radial organization (mean calcific arc angle 63+/-7 degrees versus 33+/-6 degrees in OVX), the predicted result of a 53% increase in BMP-2 (bone-morphogenetic protein-2). CONCLUSIONS: Raloxifene treatment results in reduced lesion volume, enhanced mechanical stability of vascular calcification, and less inflamed lesions characterized by less macrophage infiltration and reduced COX-2, MMP-1 and MCP-1 expression.
Subject(s)
Atherosclerosis/drug therapy , Atherosclerosis/pathology , Menopause , Osteoporosis/drug therapy , Raloxifene Hydrochloride/therapeutic use , Selective Estrogen Receptor Modulators/therapeutic use , Animals , Atherosclerosis/metabolism , Chemokine CCL2/metabolism , Cyclooxygenase 2/metabolism , Disease Models, Animal , Female , Magnetic Resonance Imaging , Matrix Metalloproteinase 1/metabolism , Osteoporosis/metabolism , Osteoporosis/pathology , Ovariectomy , RabbitsABSTRACT
Direct and specific inhibition of factor Xa is an emerging therapeutic strategy for atherothrombotic disease. Parenteral factor Xa inhibitors promise efficacy comparable to standard therapies, which could be extended to ambulatory patients with oral agents. We evaluated the antithrombotic effect of the oral, direct factor Xa inhibitor DU-176b in a phase-I study. Healthy subjects (n = 12) received a single, 60 mg dose of DU-176b. Antithrombotic effects were assessed by comparing ex-vivo thrombus formation at 1.5, 5, and 12 hours post-dose versus baseline, along with factor Xa activity, thrombin generation and clotting parameters. Under venous flow after 1.5 and 5 hours, the thrombus was 28% and 21% smaller versus baseline, respectively (p < 0.05). Under arterial condition, the reduction was 26% and 17% (p < 0.05). Thrombin generation decreased by 28% at 1.5 hours and 10% at 5 hours. Changes in PT and INR correlated well with plasma drug concentrations (R2 = 0.79 and 0.78). Direct and specific inhibition of factor Xa by DU-176b significantly reduced ex-vivo thrombus formation at both venous and arterial rheologies, up to 5 hours post-dose. The effects mirrored changes in clotting parameters, suggesting their potential usefulness for monitoring in a clinical setting.