Blood pressure variability and brain morphology in elderly women without cardiovascular disease.

OBJECTIVE: To examine the relationship between blood pressure (BP) variability (BPV), brain volumes, and cognitive functioning in postmenopausal women with few modifiable cardiovascular risk factors. METHODS: Study participants consisted of postmenopausal women enrolled in the Women's Health Initiative Memory MRI study (WHIMS-MRI) without cardiovascular disease, diabetes mellitus, hypertension, or current smoking at baseline (1996-1999). BP readings were taken at baseline and each annual follow-up visit. BPV was defined as the SD associated with a participant's mean BP across visits and the SD associated with the participant's regression line with BP regressed across visits. Brain MRI scans were performed between 2004 and 2006. Cognitive functioning was assessed at baseline and annually thereafter with the Modified Mini-Mental State Examination (3MSE) scoring until 2008. The final sample consisted of 558 women (mean age 69 years, median follow-up time [interquartile range] 8 [0.8] years). RESULTS: In adjusted models including mean systolic BP, women in the highest tertile of systolic BPV had lower hippocampal volumes and higher lesion volumes compared to women in the lowest tertile. No relationship between BPV and 3MSE scoring was detected. CONCLUSIONS: In postmenopausal women with few modifiable cardiovascular risk factors, greater visit-to-visit systolic BPV was associated with reductions in hippocampal volume and increases in lesion volumes at later life. These data add evidence to the emerging importance of BPV as a prognostic indicator even in the absence of documented cardiovascular risk factors.

Optimism, pessimism, cynical hostility, and biomarkers of metabolic function in the Women's Health Initiative.

BACKGROUND: Psychological attitudes reflecting expectations about the future (optimism, pessimism) and people (cynical hostility) independently predict incident cardiovascular disease and possibly diabetes, but underlying biologic pathways are incompletely understood. Herein we examined the cross-sectional relationship between optimism, pessimism, and cynicism and biomarkers of metabolic function in the Women's Health Initiative. METHODS: Among 3443 postmenopausal women, biomarkers of metabolic function (fasting insulin [FINS] and glucose) were measured at baseline and used to calculate insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) and pancreatic ß-cell activity (homeostasis model assessment of ß-cell function [HOMA-B]). Psychological attitudes were assessed by the Life Orientation Test, Revised (full scale, and optimism and pessimism subscales) and the Cook-Medley cynicism subscale. Multivariable linear regression modeled the association of psychological attitudes with biomarker levels, adjusting for sociodemographics, health conditions, and health behaviors. Because obesity promotes insulin resistance and obese individuals tend to report higher levels of pessimism and cynical hostility, an interaction with body mass index (BMI) was explored. RESULTS: In fully adjusted models, only pessimism remained independently associated with higher FINS and insulin resistance (HOMA-IR). Scoring 1 point higher on the pessimism subscale was associated with a 1.2% higher FINS, whereas scoring 1 SD higher was associated with a 2.7% higher FINS (P = 0.03); results were similar for HOMA-IR. An interaction term with BMI was not significant. CONCLUSIONS: In multivariable models, higher dispositional pessimism was associated with worse metabolic function; these findings were not modified by obesity status. Results extend prior work by linking pessimism to an objective biomarker of insulin resistance in elderly women.

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 1).

Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.

Discovery of potent, nonsystemic apical sodium-codependent bile acid transporter inhibitors (Part 2).

In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.