Search PubMed⌕ Search

Biomedical subjects

T B Clarkson

Publications and source records attributed to T B Clarkson.

At least 199 records · Page 11Linked to original sources
PubMedDate not supplied

The nonhuman primate model of the relationship between gonadal steroids and coronary heart disease.

Experimental data derived from studies using cynomolgus macaque females provide strong evidence that estrogen influences both premenopausal and postmenopausal coronary artery atherosclerosis. Because the monkey studies are not hampered by selection bias, the data are supportive of the tentative conclusions from epidemiological studies indicating that the association between postmenopausal estrogen use and reduced coronary artery atherosclerosis is real. Present forms of HRT are not sufficiently acceptable to women to result in a compliance rate likely to affect the adverse impact of estrogen deprivation on coronary artery atherosclerosis. Nutritional supplementation may provide a more acceptable alternative.

Animals↗
PubMedDate not supplied

Behaviorally elicited heart rate reactivity and atherosclerosis in female cynomolgus monkeys (Macaca fascicularis).

We previously reported that the coronary atherosclerosis of cholesterol-fed, male cynomolgus monkeys (Macaca fascicularis) was exacerbated among animals that exhibited the largest heart rate (HR) reactions to a standard laboratory stressor. Here we report a similar relationship between behaviorally induced HR reactivity and atherosclerosis in females of the same species. Twenty-one female monkeys were fed a moderately atherogenic diet for 30 months. Near the end of this period, animals were fitted with electrocardiogram telemetry devices and their HRs were recorded under baseline and stressed conditions. Stress period HR measurements were obtained during a standard challenge involving threatened capture and physical handling of the animals. At necropsy, sections taken from the left anterior descending, left circumflex, and right coronary arteries were examined histologically. Mean intimal area measurements were then compared between animals identified as High (n = 7) and Low (n = 7) HR reactors. High HR reactive animals were found to have significantly greater coronary artery atherosclerosis than Low reactors; atherosclerosis at the right carotid bifurcation also differed significantly between High and Low reactive monkeys. Groups did not differ in baseline HR, blood pressure, and total or HDL cholesterol concentrations. Relative to Low HR reactors, however, High reactive animals weighed less and were less ponderous, had greater heart weights (adjusted for differences in body weight), were behaviorally less aggressive, and had lower luteal phase progesterone concentrations. These relationships were corroborated in correlation analyses employing data of all 21 study animals.

Aggression↗
PubMedDate not supplied

Psychosocial factors, sex differences, and atherosclerosis: lessons from animal models.

OBJECTIVE: Premenopausal women, compared with men, are relatively spared from coronary heart disease and the underlying atherosclerosis. Our purpose has been to elucidate the reason for this difference and to explore the role of behavioral factors in this phenomenon. METHODS: Studies employed socially housed cynomolgus macaques (Macaca fascicularis) fed an atherogenic diet and subjected to behavioral observations. Ovariectomy, with or without hormone replacement, was used to test specific hypotheses about estrogen's role in the protection of females from atherosclerosis and coronary heart disease. RESULTS: Female macaques, like women, are resistant to atherosclerosis. However, this resistance is modified by social status-dominant monkeys develop little atherosclerosis, whereas subordinates resemble males in the amount of lesion that occurs. Subordinate females also are characterized by hypercortisolemia, behavioral dysfunction, and impaired ovarian function; the resulting low concentrations of circulating estrogen perhaps explain their accelerated atherosclerosis. Notably, atherosclerosis is exacerbated in ovariectomized monkeys but is suppressed in association with pregnancy, a hyperestrogenic state. Moreover, exogenous estrogen (an oral contraceptive) inhibits atherosclerosis in premenopausal social subordinates. CONCLUSIONS: To the extent that our results apply to women, they highlight the potential importance of behavioral stressors and their effects on estrogen activity in the premenopausal development of atherosclerosis. The triad of hypercortisolism, ovarian impairment, and psychiatric morbidity found in monkeys also occurs in women and may represent a high-risk state for disorders of the cardiovascular system and perhaps, other estrogen-sensitive tissues.

Adrenocortical Hyperfunction↗
PubMedDate not supplied

Soy phytoestrogens improve radial arm maze performance in ovariectomized retired breeder rats and do not attenuate benefits of 17beta-estradiol treatment.

OBJECTIVE: Soy phytoestrogens (SPEs) seem to have beneficial effects on the cardiovascular system with no adverse effects on the breast and uterus. Our objective was to examine the effects of oral estradiol alone, soy protein with phytoestrogens alone, and combinations of estradiol and SPEs on working memory of ovariectomized retired breeder female rats using the radial arm maze test. DESIGN: Eighty-four bilaterally ovariectomized retired breeder female rats were randomized into 12 groups to examine the effects of chronic treatment (10 months) with oral micronized estradiol (0, 0.5, 1, and 2 mg/1,800 Cal), SPEs (0, 72, and 144 mg/1,800 Cal), and all combinations of these doses of estradiol and SPEs on working memory. RESULTS: Oral administration of estradiol or SPEs resulted in a dose-dependent improvement in the performance of the radial arm maze tests. In addition, at each of the three doses of oral micronized estradiol tested, the performance of the radial arm tests was not significantly different in the presence or absence of SPEs. CONCLUSIONS: Our data suggest that SPEs may function as estrogen agonists in improving working memory in the ovariectomized retired breeder female rats and that SPEs do not antagonize the beneficial effects of estradiol on the working memory of these rats. No additional benefits on the radial arm maze test performance were observed with the tested combinations of estradiol and SPEs.

Animals↗
PubMedDate not supplied

A comparison of oral micronized estradiol with soy phytoestrogen effects on tail skin temperatures of ovariectomized rats.

OBJECTIVE: Whether phytoestrogen-containing soy supplements have beneficial effects on hot flashes of postmenopausal women and how those effects, if any, compare to estrogen replacement therapy has been uncertain. It is possible that the uncertainty is due to the low doses of soy isoflavones (30-60 mg per day) used in the studies. We used ovariectomized retired breeder rats and a higher dose of soy phytoestrogens to approach these uncertainties experimentally. DESIGN: The treatment groups were as follows: (1) Control group fed a casein/lactalbumin-based diet; (2) Soy(-) group fed alcohol-washed soy protein isolate with the phytoestrogens extracted; (3) Soy(+) group fed phytoestrogen-containing soy protein (equivalent to a woman's dose of 144 mg isoflavones per day)--a dose two to three times higher than that in most studies with women; and (4) E2 group fed oral micronized estradiol (E2) at a dose equivalent to a woman's dose of 1 mg per day. A temperature-transponder was taped to the surface of the tail to measure temperature. Tail skin temperature was significantly increased within a week after ovariectomy. The animals were pair-fed during the last 21 days of treatment for daily temperature measurement. RESULTS: Soy(-) had no effect on skin temperature. E2 had a large effect on skin temperature (about 1.4 degrees C reduction from Control). Soy(+) was intermediate between the E2 treatment and no treatment (about 0.8 degrees C reduction from Control). CONCLUSIONS: Soy phytoestrogens have a modest effect on average skin temperatures, being about half that of E2, even at high doses in the rat model.

Administration, Oral↗
PubMedDate not supplied

Carotid artery atherosclerosis in cholesterol-fed female cynomolgus monkeys. Effects of oral contraceptive treatment, social factors, and regional adiposity.

Female cynomolgus monkeys, a previously established model of carotid and coronary artery atherosclerosis, were used to study the relationships between potential risk factors and carotid artery atherosclerosis. Over a 24-month treatment period, one-third of the monkeys (n = 25) were given the oral contraceptive Ovral, one-third of the monkeys (n = 26) were given the oral contraceptive Demulen, and the remaining monkeys constituted a control group (n = 26). At necropsy, the atherosclerosis extent was measured in the left and right common carotid arteries and the left and right carotid bifurcations. Plasma lipid concentrations, regional adiposity, and social status were related to carotid artery atherosclerosis extent. The relationships between regional adiposity and social status and carotid artery atherosclerosis were accounted for, at least in part, by plasma lipid concentrations. Oral contraceptives had an adverse effect on plasma cholesterol concentrations and a protective effect against carotid artery atherosclerosis after adjusting for their effect on plasma lipids. The net result of these effects was little or no change in atherosclerosis extent in the carotid arteries due to oral contraceptive treatment.

Adipose Tissue↗
PubMedDate not supplied

Inhibition of coronary artery atherosclerosis by 17-beta estradiol in ovariectomized monkeys. Lack of an effect of added progesterone.

Although controversy continues, the preponderance of evidence indicates that estrogen replacement therapy favorably influences the risk of coronary heart disease in postmenopausal women. It remains uncertain how this effect is mediated and whether the cyclic addition of a progestin may influence adversely an estrogen-related cardioprotective effect. We investigated the influence of sex hormone replacement therapy on diet-induced coronary artery atherosclerosis in estrogen-deficient (ovariectomized) adult female cynomolgus monkeys. Monkeys were assigned randomly to one of three treatment groups: 1) no hormone replacement (n = 17), 2) continuously administered 17-beta estradiol plus cyclically administered progesterone (n = 20), and 3) continuously administered 17-beta estradiol (n = 18). The physiologic patterns of plasma estradiol and progesterone concentrations were maintained by administering the hormones in sustained-release subcutaneous Silastic implants. The experiment lasted 30 months. At necropsy, coronary artery atherosclerosis was inhibited similarly (reduced by approximately one-half) in animals in both hormone replacement groups (p less than or equal to 0.05). Antiatherogenic effects of hormone replacement were independent of variation in total plasma cholesterol, lipoprotein cholesterol, apoprotein A-1 and B concentrations, high density lipoprotein subfraction heterogeneity, and low density lipoprotein molecular weight. We conclude that physiologic estrogen replacement therapy with or without added progesterone inhibits atherosclerosis progression in ovariectomized monkeys. This may explain why estrogen replacement therapy results in reduced risk of coronary heart disease in postmenopausal women.

Animals↗
PubMedDate not supplied

Lipoprotein(a) in diet-induced atherosclerosis in nonhuman primates.

Lipoprotein(a) (Lp[a]) is a low density lipoprotein particle that contains plasminogen-like apolipoprotein(a). Recent studies suggest an association of Lp(a) with atherosclerotic vascular disease. We have studied the accumulation of Lp(a) in atherosclerotic arteries of monkeys with diet-induced atherosclerosis. Immunohistochemistry with monospecific Lp(a) antisera revealed striking accumulations of Lp(a) in atherosclerotic coronary artery lesions. There was no Lp(a) in the normal, nonatherosclerotic arteries. Analysis of paired tissue and serum samples from 17 male hyperlipoproteinemic monkeys revealed a significant correlation between aortic wall Lp(a) and serum Lp(a) levels. The serum cholesterol level failed to correlate with either aortic Lp(a) or serum Lp(a). These results add further evidence for the potential role of Lp(a) in the pathogenesis of atherosclerosis.

Animals↗
PubMedDate not supplied

Social status, environment, and atherosclerosis in cynomolgus monkeys.

The purpose of this experiment was to examine the effects of social environment and social status on coronary artery and aortic atherosclerosis in adult male cynomolgus monkeys (Macaca fascicularis). Thirty experimental animals were assigned to six groups of five members each, and all animals were fed a moderately atherogenic diet (43% of calories as fat, 0.34 mg cholesterol/Cal) for 22 months. Group memberships were changed periodically among 15 monkeys (unstable social condition) and remained fixed throughout the experiment in the remaining animals (stable social condition). Within each condition, individual monkeys were classified as either dominant or subordinate animals, based on dyadic patterns of aggression and submission. At necropsy, the coronary arteries were subjected to pressure fixation and five sections each were taken from the left anterior descending, left circumflex, and right coronary arteries. The mean intimal area measurement, based on all arterial sections, served as a coronary index for each animal. Results indicated that dominant animals in the unstable condition had significantly greater coronary artery atherosclerosis than dominant monkeys housed in stable social groups. Coronary artery atherosclerosis in the unstable dominants was also greater than among similarly housed (i.e., unstable) subordinates. A similar pattern was observed in the abdominal aorta, but was not statistically significant. No significant differences or similar patterns were seen in the thoracic aorta. Additional analyses revealed that the coronary artery effects were not due to concomitant differences in total serum cholesterol or high density lipoprotein cholesterol concentrations, blood pressures, ponderosity, or fasting glucose concentrations among the experimental animals. Behaviorally, manipulation of group memberships intensified agonistic encounters and disrupted patterns of affiliative interaction between dominant and subordinate monkeys. Overall, these results suggest that social dominance (an individual behavioral characteristic) is associated with increased coronary artery atherosclerosis, but only under social conditions that provide recurrent threats to the status of dominant animals (i.e., under behavioral challenge).

Animals↗
PubMedDate not supplied

Ovariectomy, social status, and atherosclerosis in cynomolgus monkeys.

Evidence is contradictory regarding the effects of natural or surgical menopause on "female protection" against coronary artery atherosclerosis. We evaluated atherosclerosis, plasma lipids, blood pressure, and carbohydrate tolerance in 21 ovariectomized and 23 intact female cynomolgus macaques fed a moderately atherogenic diet for 30 months. We also evaluated the influence of social dominance status, with particular emphasis on a possible relationship with ovarian endocrine function. Atherosclerosis was two to 10 times as extensive in coronary, carotid, and iliaco-femoral arteries of the ovariectomized females; this could be explained, in part, by 15% to 20% increases in total plasma and LDL cholesterol concentrations. Socially dominant intact females were protected against advanced atherosclerotic lesions (plaques) of the coronary arteries, while subordinate females and ovariectomized females were not. Increased susceptibility to advanced coronary artery atherosclerosis in subordinate intact females may have been related in some way to chronic ovarian dysfunction observed in seven of 12 of these individuals. As a group, subordinate intact females also had enlarged adrenal glands, suggestive of mechanisms that may influence atherogenesis independently. The results indicate that, in this species, ovariectomy and chronic ovarian dysfunction related to subordinate social status are associated with a more atherogenic plasma lipid pattern and abolish "female protection" against coronary artery atherosclerosis.

Adrenal Glands↗
PubMedDate not supplied

Relationship of plasma lipoproteins and the monocyte-macrophage system to atherosclerosis severity in cholesterol-fed pigeons.

The purpose of this study was to determine if there was a relationship between plasma beta-VLDL concentrations and atherosclerosis severity in cholesterol-fed pigeons, and if so, whether this correlated with cholesterol accumulation in tissues rich in cells of the monocyte-macrophage system (liver, spleen, peritoneal macrophages). Among individual birds consuming a cholesterol-containing diet, plasma beta-VLDL concentrations ranged from 14 to 1979 mg/dl. In these animals the cholesterol content of peritoneal macrophages, liver, and spleen was positively correlated with plasma concentrations of beta-VLDL and LDL, but not with HDL. When added in vitro to peritoneal macrophages from control pigeons, beta-VLDL stimulated a nearly 200-fold increase in cholesterol accumulation, but there was no relationship between the ability of beta-VLDL to stimulate macrophage cholesterol accumulation and the extent of atherosclerosis in the animal from which the beta-VLDL was obtained. Cholesterol feeding for up to 6 months increased the severity of atherosclerosis in both atherosclerosis-susceptible White Carneau and resistant Show Racer pigeons, but there was no correlation of atherosclerosis severity with beta-VLDL or HDL concentrations, and only a weak relationship with LDL concentrations. The results are consistent with the conclusion that atherosclerosis susceptibility in pigeons cannot be explained by quantitative or qualitative differences in plasma beta-VLDL. Instead, differences in susceptibility are probably mediated at the level of the arterial wall, perhaps by genetic differences that influence the way an individual animals' arterial cells (endothelial, smooth muscle, macrophages) interact with specific plasma lipoproteins.

Animals↗
PubMedDate not supplied

Body fat distribution as a risk factor for coronary artery atherosclerosis in female cynomolgus monkeys.

Central fat deposition is associated with increased risk of coronary heart disease morbidity and mortality in women. Subcutaneous fat distribution was investigated as a potential factor that might exacerbate diet-induced coronary artery atherosclerosis (CAA) in female cynomolgus monkeys (Macaca fascicularis) which share with North American Caucasian women a gender-related protection against CAA. In a retrospective necropsy study (n = 36), the distribution of the antemortem ratio of subscapular/triceps skinfold thickness was divided at the mean and the two resulting groups were designated high and low for this variable. CAA was quantified as the mean cross-sectional intimal area based on nine coronary artery sections. The extent of CAA was significantly greater in the high skinfold ratio group as compared to the low skinfold ratio group. Ponderosity was closely associated with the skinfold ratio but was not a useful predictor of CAA. These findings suggest that female cynomolgus macaques may provide a primate model of the health consequences of regional fat distribution in women.

Adipose Tissue↗