Miller, Virginia M.

Abstract Context: In women, cortical bone mass decreases significantly at menopause. By contrast, loss of trabecular bone begins in the third decade and accelerates after menopause. Objective: The aim of the study was to investigate the effects of estrogen on cortical and trabecular bone. Design: The Kronos Early Estrogen Prevention Study is a double-blind, randomized, placebo-controlled trial of menopausal hormone treatment (MHT) in women, enrolled within 6–36 months of their final menstrual period. Setting: The study was conducted at the Mayo Clinic, Rochester, Minnesota. Intervention: Subjects were treated with placebo (n = 31), or .45 mg/d conjugated equine estrogens (n = 20), or transdermal 50 μg/d 17β-estradiol (n = 25) with pulsed micronized progesterone. Main Outcome Measures: Cortical and trabecular microarchitecture at the distal radius was assessed by high-resolution peripheral quantitative computed tomography. Results: At the distal radius, cortical volumetric bone mineral density (vBMD) decreased, and cortical porosity increased in the placebo group; MHT prevented these changes. By contrast, MHT did not prevent decreases in trabecular microarchitecture at the radius. However, MHT prevented decreases in trabecular vBMD at the thoracic spine (assessed in a subset of subjects; n = 51). These results indicate that MHT prevents deterioration in radial cortical vBMD and porosity in recently menopausal women. Conclusion: The maintenance of cortical bone in response to estrogen likely has important clinical implications because cortical bone morphology plays an important role in bone strength. However, effects of MHT on trabecular bone at the radius differ from those at the thoracic spine. Underlying mechanisms for these site-specific effects of MHT on cortical vs trabecular bone require further investigation.

Menopausal hormone treatment (MHT) may limit progression of cardiovascular disease (CVD) but poses a thrombosis risk. To test targeted candidate gene variation for association with subclinical CVD defined by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC), 610 women participating in the Kronos Early Estrogen Prevention Study (KEEPS), a clinical trial of MHT to prevent progression of CVD, were genotyped for 13,229 single nucleotide polymorphisms (SNPs) within 764 genes from anticoagulant, procoagulant, fibrinolytic, or innate immunity pathways. According to linear regression, proportion of European ancestry correlated negatively, but age at enrollment and pulse pressure correlated positively with CIMT. Adjusting for these variables, two SNPs, one on chromosome 2 for MAP4K4 gene (rs2236935, β = 0.037, P value = 2.36 × 10−06) and one on chromosome 5 for IL5 gene (rs739318, β = 0.051, P value = 5.02 × 10−05), associated positively with CIMT; two SNPs on chromosome 17 for CCL5 (rs4796119, β = −0.043, P value = 3.59 × 10−05; rs2291299, β = −0.032, P value = 5.59 × 10−05) correlated negatively with CIMT; only rs2236935 remained significant after correcting for multiple testing. Using logistic regression, when we adjusted for waist circumference, two SNPs (rs11465886, IRAK2, chromosome 3, OR = 3.91, P value = 1.10 × 10−04; and rs17751769, SERPINA1, chromosome 14, OR = 1.96, P value = 2.42 × 10−04) associated positively with a CAC score of >0 Agatston unit; one SNP (rs630014, ABO, OR = 0.51, P value = 2.51 × 10−04) associated negatively; none remained significant after correcting for multiple testing. Whether these SNPs associate with CIMT and CAC in women randomized to MHT remains to be determined.

Background Experiments were designed to define cardiac function in dogs with single lung allografts during acute rejection of the allografted lung. Methods and Results Left lungs were either autotransplanted (n=4) or allotransplanted (n=8) in adult male mongrel dogs. All allotransplanted animals were maintained on triple-drug immunosuppression (cyclosporine, azathioprine, and steroids) for 5 days after the operation. In 4 allotransplanted animals, treatment was discontinued, allowing the animals to reject (usually after a further 3 days; rejecting group); 4 other allotransplanted animals were maintained on immunosuppression for an additional 3 days (immunosuppressed group). Another group of dogs were not operated on but were maintained on the same immunosuppression as the rejecting group (controls). All experimental animals underwent fast computed tomographic scanning with measurement of left ventricular pressure and calculation of ventricular chamber volumes, cross-sectional areas of coronary arteries, myocardial perfusion, and intramyocardial blood volume. Neither cardiac output, left ventricular mass, left ventricular pressure, nor myocardial oxygen consumption was altered during acute rejection of lung allografts. However, left ventricular contractility (systolic elastance, E max ) and ejection fraction were depressed to approximately one half ( P <.05) in acutely rejecting animals compared with other groups. The cross-sectional area of the coronary arteries was less in autotransplanted and allotransplanted treated animals than in animals that were not operated on. Cross-sectional area of the coronary arteries was decreased by an additional 30% in the rejecting group ( P <.05). Conclusions The results of this study indicate that acute rejection of a single lung allograft decreases cardiac performance and reduces diameter of coronary arteries in the recipient. Alterations of circulating humoral factors and activated leukocytes may contribute to these changes.