BACKGROUNDData suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.METHODSA total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.RESULTSAfter a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.CONCLUSIONSOral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).

Background Adults infected with HIV have increased atherosclerosis potentially associated with both HIV and non‐HIV associated factors. We characterized risk factors for atherosclerosis as measured by noninvasive vascular imaging. Methods and Results We used B‐mode ultrasound to examine levels and correlates of echogenicity and vessel wall thickness of the carotid artery intima‐media complex in 1282 HIV‐infected and 510 HIV‐uninfected women of the Women's Interagency HIV Study. Levels of gray scale median (GSM, a measure of echogenicity) did not vary between HIV infection groups. In both groups, smokers had increased GSM, whereas age, diabetes, elevated blood pressure, and high BMI were associated with lower (rather than higher) GSM. Each of these non‐lipid CVD risk factors, especially age and blood pressure, was also associated with higher levels of carotid artery intima‐media thickness (cIMT). Higher serum triglyceride levels were associated with lower GSM in both HIV‐infected and HIV‐uninfected groups. Additional lipid risk factors for low GSM including high LDL cholesterol and low HDL cholesterol levels were identified in HIV uninfected but not in HIV infected women. In contrast to findings for GSM, among the lipid parameters only LDL cholesterol level had an association with cIMT, which was observed only in the HIV uninfected group. Conclusions Lipid and non‐lipid risk factor associations with echolucency of the carotid artery and the thickness of the common carotid artery intima‐media layer suggest that these measures capture different aspects of atherosclerosis.

The present invention is directed to the field of ultrasonographic vascular visualization and vascular structure measurements and, more particularly, to standardized, reliable and reproducible ultrasonographic vascular imaging and structural measurements including intima-media thickness and vessel diameter determinations to yield anatomical and physiologic measurements.

Background and Purpose-Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness progression.Methods-In a double-blind, placebo-controlled trial, 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7 years.Results-Overall, mean (95% CI) carotid artery intima-media thickness progression rate was 4.77 (3.39-6.16) mu m/year in the ISP group and 5.68 (4.30-7.06) mu m/year in the placebo group. Although carotid artery intima-media thickness progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (P=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower carotid artery intima-media thickness progression rate than placebo participants 2.16 (-1.10 to 5.43) versus 6.79 (3.56-10.01) mu m/year (P=0.05). ISP supplementation had a null effect on women who were >5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation.Conclusions-ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggests that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for cardiovascular disease who were <5 years postmenopausal. These first trial results of their kind warrant further investigation.

Background and Purpose— Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression. Methods— In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 μmol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B 12 +50 mg vitamin B 6 ) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome). Results— Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found ( P =0.31). However, among subjects with baseline tHcy ≥9.1 μmol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo ( P =0.02); among subjects with a baseline tHcy <9.1 μmol/L, there was no significant treatment effect (probability value for treatment interaction=0.02). B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups. Conclusion— High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin “replete” individuals at low risk for cardiovascular disease with a fasting tHcy ≥9.1 μmol/L.

BACKGROUND AND PURPOSE:Although plasma total homocysteine (tHcy) levels are associated with cardiovascular disease, it remains unclear whether homocysteine is a cause or a marker of atherosclerotic vascular disease. We determined whether reduction of tHcy levels with B vitamin supplementation reduces subclinical atherosclerosis progression. METHODS:In this double-blind clinical trial, 506 participants 40 to 89 years of age with an initial tHcy >8.5 micromol/L without diabetes and cardiovascular disease were randomized to high-dose B vitamin supplementation (5 mg folic acid+0.4 mg vitamin B(12)+50 mg vitamin B(6)) or matching placebo for 3.1 years. Subclinical atherosclerosis progression across 3 vascular beds was assessed using high-resolution B-mode ultrasonography to measure carotid artery intima media thickness (primary outcome) and multidetector spiral CT to measure aortic and coronary artery calcium (secondary outcome). RESULTS:Although the overall carotid artery intima media thickness progression rate was lower with B vitamin supplementation than with placebo, statistically significant between-group differences were not found (P=0.31). However, among subjects with baseline tHcy >or=9.1 micromol/L, those randomized to B vitamin supplementation had a statistically significant lower average rate of carotid artery intima media thickness progression compared with placebo (P=0.02); among subjects with a baseline tHcy <9.1 micromol/L, there was no significant treatment effect (probability value for treatment interaction=0.02). B vitamin supplementation had no effect on progression of aortic or coronary artery calcification overall or within subgroups. CONCLUSIONS:High-dose B vitamin supplementation significantly reduces progression of early-stage subclinical atherosclerosis (carotid artery intima media thickness) in well-nourished healthy B vitamin "replete" individuals at low risk for cardiovascular disease with a fasting tHcy >or=9.1 micromol/L.

coronary, cervical, and femoral angiographic trial of colestipol plus niacin, included a pilot study of standardized carotid ultrasound imaging. Methods and Results. Seventy-eight subjects had ultrasound studies at baseline, 2, and 4 years. Twenty-four drug and 22 placebo subjects had carotid ultrasound images at baseline, 2, and 4 years with matching cervical angiograms. Computer image processing was applied to ultrasound images ofcommon carotid (far wall) and cervical angiograms. Computer operators were blind to treatment group. Carotid ultrasound measurements were tested for treatment effects and compared with measurements ofatherosclerosis in coronary and cervical angiograms. Drug subjects showed significant progressive reduction in carotid thickness at 2 (P=.OOO1) and 4 years (P=.OOO1); placebo subjects significantly increased wall thickness at 2 and 4 years. Reduced levels of apolipoprotein B and increased levels of high density lipoprotein cholesterol and apolipoprotein C-M were

The 2-year therapy effect on femoral atherosclerosis was evaluated in the Cholesterol Lowering Atherosclerosis Study (CLAS), a randomized, placebo-plus-diet-controlled angiographic trial of colestipol-niacin therapy plus diet in men with previous coronary bypass surgery. Different diet compositions were prescribed to enhance the differential in blood cholesterol responses between the two groups. The annual rate of change in computer-estimated atherosclerosis (CEA), a measure oflumen abnormality, was evaluated between treatment groups. A significant per-segment therapy effect was found in segments with moderately severe atherosclerosis (p <0.04) and in proximal segments (p <0.02). When segmental CEA measures were combined into a per-patient score using an adaptation of the National Heart, Lung, and Blood Institute scoring procedure, a significant therapy effect was observed (p <0.02). Total variance of the annual change rate in CEA was as predicted from pilot studies, but measurement variation was larger. The therapy effect observed in femoral arteries, although significant, was less marked than the strong and consistent benefit previously reported for both native coronary arteries and aortocoronary bypass grafts. (Circulation 1991;83:438-447)

Overall, the average rate of progression of subclinical atherosclerosis was slower in healthy postmenopausal women taking unopposed estrogen replacement therapy with 17β-estradiol than in women tak...

B-mode ultrasound has gained popularity as a non-invasive method for direct visualization of superficial vessels. With B-mode ultrasound, arterial stiffness can be directly measured since image acquisition of the arterial wall thickness and vessel diameter can be obtained simultaneously in a dynamic fashion throughout the cardiac cycle. Recently, a method was developed to measure carotid arterial diameter and intima-media thickness (IMT) from B-mode images that utilizes computerized edge tracking-multiframe image processing that automatically measures arterial diameter and IMT in multiple sequential frames spanning several cardiac cycles. To evaluate this method, replicate B-mode common carotid artery ultrasound examinations and blood pressure measurements were obtained in 24 subjects 1-2 weeks apart. Approximately 80 sequential frames spanning two cardiac cycles were analyzed from each ultrasound examination to obtain maximum arterial diameter (D(max)), minimum arterial diameter (D(min)), and IMT using a computerized edge detection method. The intraclass correlations of D(max), D(min), and IMT were 0.97-0.99 and the mean absolute difference for these measurements were 0.03-0.11 mm. The coefficient of variation for D(max) and D(min) were 1.28 and 1.18%, respectively. The intraclass correlation for several standard arterial stiffness indices, Peterson's elastic modulus, Young's modulus, arterial distensibility, compliance, and the beta stiffness index ranged between 0.84 and 0.89. Additionally, it was determined that averaging IMT over five frames centered at D(min) reduced single frame IMT measurement variability by 27% (P=0.005) compared with IMT measured from a single frame corresponding to D(min). Comparison of the phasic relationship of D(max) and D(min) measured from the B-mode ultrasound image with the simultaneously recorded electrocardiogram (ECG) signal in the 24 subjects, provided a more accurate method of frame selection for arterial diameter extrema independent of the ECG signal. The method of computerized edge detection-sequential multiframe image processing presented in this paper represents a technological advance for image analysis of B-mode ultrasound images of common carotid arterial dimensions that is highly reproducible and directly applicable to noninvasive imaging of atherosclerosis.

Background Progression of coronary artery disease is assumed to be a surrogate end point for clinical coronary events. Because no single method or measure for a coronary angiographic end point is uniformly accepted as optimal, the utility and validity of surrogate end points for predicting clinical coronary events remain unsettled. Methods and Results The Cholesterol Lowering Atherosclerosis Study randomized 162 nonsmoking, 40- to 59-year-old men with previous coronary artery bypass graft surgery to colestipol/niacin plus diet or placebo plus diet. Atherosclerosis change on 2-year coronary angiograms was evaluated by a consensus panel and by quantitative coronary angiography (average per-subject change in percent diameter stenosis [%S] and minimum lumen diameter [MLD]). With all three end points, the benefit of colestipol/niacin treatment on coronary artery atherosclerosis has been reported. Annual follow-up for an average of 7 years (range, 6.3 months to 10 years) has been carried out on all subjects who completed the 2-year angiogram. Clinical coronary events (need for revascularization, nonfatal acute myocardial infarction, and coronary death) have been documented. Risk of clinical coronary events was positively related to coronary lesion progression for all three surrogate end points ( P <.05). New lesion formation in bypass grafts ( P =.02) and progression of mild/moderate lesions (<50%S) were predictive of clinical coronary events ( P <.01). Change in MLD contributed significantly to the prediction of clinical coronary events beyond a model with %S alone ( P <.05). Conclusions In this population of nonsmoking men with previous bypass surgery, both the consensus panel– and quantitative coronary angiography–based end points of coronary artery disease progression predict clinical coronary events. Subjects who demonstrate greater coronary artery lesion progression have an increased risk of future clinical coronary events. Design of shorter, smaller trials of antiatherosclerotic agents is justified.

CLAS, a placebo controlled trial of Colestipol/Niacin therapy in men with previous coronary artery bypass surgery, obtained 188 baseline, 162 two year and 103 four year angiograms. Human panel readers evaluated all films with treatment assignment and film order masked. All lesions in native arteries and grafts were identified, assigned percent stenosis estimates, lesion change estimates and an overall change score. In a 50% random sample, all processable segments have been computer evaluated with multiple lesion and segment based algorithms derived by the USC-Caltech/JPL method. Among nonocclusive lesions, 350 were evaluated for percent stenosis by panel and computer methods with correlation between the two methods of 0.70 p < 0.0001). Four hundred forty-two lesions (principally more severe) could only be evaluated by humans. Seventy-nine early lesions could be evaluated only by computer. Seven hundred thirty-one native coronary segments were analyzed by QCA including 302 segments without discrete lesions in addition to the 429 segments with discrete lesions that were compared with the panel evaluation. After accounting for baseline effects, position relative to grafts and within subject correlation, significant therapy effects were demonstrated by computer measures of both stenosis and vessel edge roughness. These data confirm that computer analsis of angiograms can reduce subject numbers compared to human panel reading and offer different endpoint measures.

Report describes experiment to investigate effects of isotonic and isokinetic leg exercises in counteracting effects of bed rest upon physical and mental conditions of subjects. Data taken on capacity for work, endurance and strength, tolerance to sitting up, equilibrium, posture, gait, atrophy, mineralization and density of bones, endocrine analyses concerning vasoactivity and fluid and electrolyte balances, intermediary metabolism of muscles, mood, and performance.