Cardiovascular risk, obesity, and myocardial blood flow in postmenopausal women.

BACKGROUND: This study was designed to determine whether overweight or obese status is independently associated with myocardial flow reserve (MFR), an established predictor of cardiovascular mortality, in a group of postmenopausal women with no previous cardiovascular disease. Postmenopausal women are the largest group of overweight and physically inactive individuals in the United States. Increased body mass index (BMI) is consistently associated with increased cardiovascular mortality in this population. Whether this is because of obesity itself or the accompanying increase in cardiovascular risk factors (CRFs) remains controversial. METHODS: We examined the relationship of myocardial blood flow (MBF), coronary vascular resistance, and MFR to BMI in 60 postmenopausal women with no coronary heart disease. Subjects underwent dynamic N-13 ammonia positron emission tomography for the measurement of MBF and MFR. Baseline demographics, CRF, and hemodynamic parameters were recorded for each subject. Datasets were divided into 3 groups according to BMI: normal (18 to 24), overweight (25 to 29), and obese (>or=30). RESULTS: The overweight and obese groups showed significantly higher resting MBF and lower MFR than the normal-weight group (both P < .001), even after adjusting for CRF. A further analysis of subjects without any CRF (n = 35) showed that the MFR remained significantly lower in the obese compared with normal-weight subjects (P = .05). Levels of known markers of vascular inflammation (high-sensitivity C-reactive protein and homocysteine) and high-density lipoprotein cholesterol levels correlated with declining MFR. CONCLUSIONS: These findings provide a mechanistic link between obesity and coronary heart disease in this population.

Combined continuous ethinyl estradiol/norethindrone acetate does not improve forearm blood flow in postmenopausal women at risk for cardiovascular events: a pilot study.

OBJECTIVE: This study sought to determine whether combined continuous ethinyl estradiol and norethindrone acetate, a postmenopausal hormone therapy (HT) combination designed to have fewer side effects than cyclical therapies and therapies using medroxyprogesterone acetate (MPA), could improve vascular endothelial function in postmenopausal women with risk factors for cardiovascular disease (CVD). METHODS: Eighteen postmenopausal women (mean age 62 +/- 11 years) participated in a randomized, placebo-controlled, crossover design trial of 10 microg estradiol/1 mg norethindrone acetate given once daily for 3 months, with a 1-month washout period between placebo and active treatment phases. Vascular reactivity was assessed at each phase of the study using high-frequency brachial artery ultrasound in response to flow-mediated hyperemia, cold pressor testing, and sublingual nitroglycerin. Markers of cardiovascular risk, including cholesterol levels, inflammatory markers, fibrinolytic markers, and solubilized adhesion molecules, were also measured at each phase. RESULTS: We found no significant difference in vascular reactivity measurements during active treatment with ethinyl estradiol/norethindrone acetate vs. placebo. C-reactive protein (CRP) levels increased significantly during active treatment, and high-density lipoprotein (HDL) levels decreased significantly. Vascular cell adhesion molecule-1 (VCAM-1) levels declined during active treatment. Plasminogen activator inhibitor-1 (PAI-1) levels were inversely correlated with flow-mediated hyperemic vascular reactivity, independent of active treatment or placebo phases. CONCLUSIONS: In this older postmenopausal population with at least one cardiovascular risk factor, treatment with combined continuous ethinyl estradiol and norethindrone acetate failed to improve vascular endothelial function. The agent's proinflammatory effect or subclinical atherosclerosis in this population may have contributed to this finding.

Comparison of retinal arteriolar and venular variability in healthy subjects.

Study of retinal autoregulation is important because vascular dysfunction is a precursor of many retinal diseases. Previous research has focused on venular blood flow because the minimal venular pulsatility was thought to provide more reproducible results. This study compared the variability of arteriolar and venular blood flow measurements in response to isocapnic hyperoxia, a provocation known to constrict blood vessels and reduce blood velocity. Data was collected using a non-invasive laser Doppler instrument that permitted the simultaneous measurement of retinal blood velocity and vessel diameter, allowing the derivation of blood flow. Measurements were collected from 20 young subjects before, during and after exposure to hyperoxia. Isocapnia was maintained throughout hyperoxia using a previously validated sequential re-breathing circuit. Arteriolar and venular diameters decreased during hyperoxia by 8.7% (p=0.0001) and 14.2% (p=0.0001), respectively. Hyperoxia caused significant decreases in arteriolar and venular blood velocity (31.2%, p=0.0001 and 18.0%, p=0.0001, respectively) and flow (43.2%, p=0.0001 and 40.0%, p=0.0002, respectively). The coefficients of variation for intra-individual measurements of diameter, velocity and flow were comparable in magnitude between the two vessel types. Measures of arteriolar pulsatility, such as Pulsatility ratio, Resistivity ratio and Pulsatility index, increased significantly during hyperoxia, indicating increased downstream vascular resistance. We conclude that retinal arterioles and venules provide equally reproducible results for autoregulation studies and that arteriolar pulsatility profiles provide additional useful information regarding vascular resistance.

Synthesis and biological activity of tetralone abscisic acid analogues.

Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active.