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T B Clarkson

Publications and source records attributed to T B Clarkson.

At least 19 recordsLinked to original sources
PubMed1995

Dominant social status and contraceptive hormone treatment inhibit atherogenesis in premenopausal monkeys.

The stress of social subordination is associated with exacerbation of coronary artery atherosclerosis in premenopausal cynomolgus monkeys, possibly as a result of the ovarian dysfunction that reliably accompanies subordinate social status. The primary objective of the current study was to determine whether treatment with an oral contraceptive (OC) provides relative protection from development of atherosclerotic plaques, especially among animals made vulnerable to atherosclerosis by social subordination. In the present study, 193 adult female monkeys (Macaca fascicularis) were placed in social groups of 5 or 6 animals each. Half of the animals were then fed an atherogenic diet to which had been added a triphasic OC, while the remainder received only the atherogenic diet. At the end of 26 months, atherosclerosis was measured in an iliac artery biopsy taken from each monkey. The results demonstrated that among untreated animals subordinate individuals developed significantly more atherosclerosis than did their dominant counterparts (P < .01); however, OC treatment inhibited atherosclerosis in subordinate animals (P < .05) and eliminated the difference between dominant and subordinate animals that was observed in the untreated condition. Subordinate social status and OC treatment were both associated with reduced plasma concentrations of HDL cholesterol (P < .01 for both), and subordinate monkeys also had elevations in LDL cholesterol plus VLDL cholesterol (P < .01). Nonetheless, the interaction between social status and OC treatment remained significant even after covariance adjustment for variation in plasma lipids. Taken together, these results suggest that social subordination worsens, whereas OC treatment inhibits, atherosclerosis, and that these effects are independent of concomitant variability in plasma lipids.

Animals↗
PubMed1995

Regression of atherosclerosis in female monkeys.

The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.

Acetylcholine↗
PubMed1995

Accelerated cholesteryl ester transfer and altered lipoprotein composition in diabetic cynomolgus monkeys.

To determine whether nonhuman primates demonstrate the same alterations in transport of cholesteryl ester (CE) in plasma observed in diabetic humans, cholesteryl ester transfer (CET) was measured in cynomolgus monkeys with chronic spontaneous diabetes mellitus (glycated hemoglobin: diabetics 10.7 +/- 4.1%; controls 3.8 +/- 0.8%, P < 0.005). Among the plasma lipids, only triglycerides were significantly increased in diabetic monkeys (diabetics 303 +/- 294 mg/dl; controls 85 +/- 34 mg/dl; P < 0.05); total plasma, LDL, HDL2, and HDL3 cholesterol concentrations did not differ significantly from those of control animals. Similar to human beings with insulin-dependent and non-insulin-dependent diabetes mellitus, CET estimated both as the mass of cholesteryl ester transferred from HDL to the apoB-containing lipoproteins (VLDL + LDL) and as the loss of radiolabeled cholesteryl ester from HDL was significantly greater (P < 0.001) in diabetic compared to control monkeys. Glycated hemoglobin levels in the combined control and diabetic groups correlated directly with both the mass of cholesteryl ester transferred at 2 h (r = 0.75; P < 0.001) and the isotopic transfer (k) (r = 0.64; P < 0.005). The mass of cholesteryl ester transfer protein (CETP) tended to be higher in the diabetic animals (diabetic 4.06 +/- 0.73 microgram/ml versus control 3.05 +/- 0.93; P < 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Remodeling of coronary arteries in human and nonhuman primates.

OBJECTIVE: To compare coronary artery remodeling (compensatory enlargement) in human and nonhuman primates. DESIGN: Coronary artery data were analyzed retrospectively for 416 nonhuman primates and 100 men and women. SETTING: The monkeys had been in experiments involving diet-induced coronary artery atherosclerosis. The human hearts were obtained from the North Carolina Baptist Hospital, Winston-Salem, and age greater than 25 years was the only criterion. PATIENTS AND OTHER PARTICIPANTS: The left anterior descending coronary arteries from 100 humans, 328 cynomolgus monkeys, and 88 male rhesus monkeys were used. INTERVENTIONS: None; this was a cross-sectional observational study. MAIN OUTCOME MEASURES: Coronary artery size, lumen area, and plaque size. In the humans, we also examined demographic characteristics (ethnicity, sex, and history of hypertension) and pathologic criteria (eccentricity or concentricity of plaque area). RESULTS: On average, lumen size remained unaffected by plaque size. Lumen size was variable and could not be predicted by traditional risk factors for coronary heart disease. However, lack of compensation (decreased lumen size as plaques enlarged) and history of coronary heart disease were significantly correlated. CONCLUSIONS: The similarity of remodeling in human and nonhuman primates suggests that the process has general biologic significance. Lack of remodelling may be a major determinant of whether a person with coronary artery atherosclerosis develops its complications.

Animals↗
PubMed1994

Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys.

OBJECTIVES: We attempted to determine whether continuous and cyclic medroxyprogesterone acetate modulates the effects of estrogen on dilation of atherosclerotic coronary arteries in surgically postmenopausal female monkeys. BACKGROUND: Estrogen replacement in postmenopausal women preserves normal dilator responses of atherosclerotic coronary arteries. The effects of progestins on coronary artery reactivity have not been determined. METHODS: Repeated quantitative coronary angiography was used to study the effects after 1 month of 1) no hormone replacement (control) or oral administration of 2) continuous conjugated equine estrogens, 3) cyclic high dose medroxyprogesterone acetate (MPA) given on days 16 to 26 of the month, 4) conjugated equine estrogens plus continuous low dose MPA, or 5) conjugated equine estrogens plus cyclic high dose MPA on endothelium-mediated dilation of atherosclerotic coronary arteries in 12 cynomolgus monkeys. Change in diameter of the left circumflex coronary artery was measured in response to intracoronary infusions of acetylcholine (10(-6) mol/liter per min) and nitroglycerin (15 micrograms/min). RESULTS: Coronary arteries constricted during no hormone treatment (-8 +/- 3% [mean +/- SEM]), dilated during conjugated equine estrogen treatment (+3 +/- 1%, p < 0.05 vs. control) and constricted during cyclic MPA treatment (-3 +/- 2%). Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen inhibited acetylcholine responses by 50% (p < 0.05 vs. conjugated equine estrogens). There was no effect of treatment on vascular response to nitroglycerin (p > 0.05). CONCLUSIONS: Treatment with conjugated equine estrogens, but not MPA, augmented endothelium-mediated dilation of atherosclerotic coronary arteries. Addition of cyclic or continuous MPA to the conjugated equine estrogen regimen diminished endothelium-mediated dilation.

Animals↗
PubMed1994

Genetic estimates for plasma lipids and lipoproteins in cynomolgus monkeys under assortative mating.

Data obtained from cynomolgus monkeys selected for total plasma cholesterol (TPC) response to dietary cholesterol and nonselected controls were used to estimate heritability of TPC and lipoprotein concentrations. A total of 345 observations were collected on 57 progeny from 18 sires. Heritability estimates obtained by a paternal half-sib analysis and by regression of offspring on mid-parent values were 0.45 +/- 0.24 and 0.69 +/- 0.18 for TPC, 0.63 +/- 0.30 and 0.64 +/- 0.17 for LDLC, and 0.80 +/- 0.36 and 0.59 +/- 0.14 for HDLC, respectively. These results suggest that TPC and lipoprotein concentrations are influenced by additive genetic effects in cynomolgus monkeys, establishing their importance as an animal model for studying the genetics of lipoproteins.

Analysis of Variance↗
PubMed1994

Social status and coronary artery atherosclerosis in female monkeys.

While coronary heart disease is the leading cause of death in women in the United States, research in the area is lacking, especially concerning psychosocial risk factors. The purpose of this experiment was to study the effect of a known psychosocial risk factor in female monkeys, social status, and the effect of alteration of social status on coronary artery atherosclerosis. In previous experiments it has been demonstrated that social status is an enduring characteristic of the individual and that socially subordinate female monkeys have poor ovarian function and exacerbated coronary artery atherosclerosis. In the present experiment, adult female monkeys were fed an atherogenic diet and housed in small social groups, and social status was altered in half of the animals (subordinates became dominant and dominants became subordinate). The manipulation of social status had minimal effects on risk factors but significantly affected coronary artery atherosclerosis, supporting the hypothesis that social status affects atherogenesis in these females. However, all animals that changed social positions had worsened coronary artery atherosclerosis whether they became dominant or became subordinate, and this effect was independent of ovarian function. Subordinates that became dominant had 44% more and dominants that became subordinate had 500% more atherosclerosis than their counterparts that did not change social status. Thus, modification of this psychosocial risk factor was not effective in reducing coronary artery atherosclerosis. The manipulation of social status may have deleteriously altered a complex interaction between individuals and their psychosocial environment.

Animals↗
PubMed1994

Determinants of coronary artery reactivity in premenopausal female cynomolgus monkeys with diet-induced atherosclerosis.

BACKGROUND: The purpose of this study was to identify determinants of coronary artery reactivity among premenopausal female monkeys. Estrogen replacement therapy in postmenopausal females modulates reactivity of atherosclerotic coronary arteries. However, no studies have evaluated the factors that modulate coronary artery reactivity among premenopausal females. METHODS AND RESULTS: Twenty-five adult premenopausal female monkeys were fed an atherogenic diet for 32 months. During this time, monkeys were housed in small social groups and determined to be socially dominant (associated with normal ovarian function) or subordinate (associated with impaired ovarian function). After 32 months, coronary artery vasomotor responses to intracoronary acetylcholine, nitroglycerin, and serotonin were assessed by computer-assisted quantitative coronary angiography. Coronary arteries of dominant monkeys dilated (+9 +/- 2%), whereas those of subordinate monkeys constricted (-6 +/- 2%) in response to acetylcholine (P < .05). There was no effect of social status on vascular response to nitroglycerin or serotonin (P > .10). Vascular responses to acetylcholine were independent of social status effects on plasma lipids, blood pressure, and atherosclerosis extent. The correlation between acetylcholine responses and plasma estradiol concentration measured on the day of angiography was r = .7 (P = < .01). Furthermore, dilation occurred only if plasma estradiol concentrations were greater than 60 pg/mL. CONCLUSIONS: Psychosocial factors and endogenous estrogen production are important modulators of acetylcholine-mediated dilation of atherosclerotic coronary arteries among premenopausal female monkeys.

Acetylcholine↗
PubMed1994

Effects of estrogen treatment on arterial wall structure and function.

Premenopausal women are relatively protected against coronary heart disease (CHD) compared with men, but lose this advantage after surgical or natural menopause. Consequently, estrogens are believed to confer significant protection against coronary artery atherosclerosis (CAA). In addition, epidemiological studies have shown lower rates of CHD in postmenopausal users of estrogen replacement therapy than in women not taking hormone therapy. The cynomolgus monkey model (Macaca fascicularis) has proved valuable for gaining a better understanding of the effects of estrogen on coronary artery function and CAA. We have found that premenopausal cynomolgus monkeys have less CAA than male monkeys and surgically postmenopausal female monkeys, and that the hyperestrogenic state of pregnancy further inhibits CAA progression. Ovarian-deficient stressed females had more extensive CAA and impaired vascular function compared with unstressed monkeys, and estrogen-treated females (premenopausal or postmenopausal) had less CAA than untreated monkeys. The treatment effect in this model appears to be partially mediated by a decrease in low density lipoprotein uptake and/or degradation, and an improvement in coronary artery vascular function.

Animals↗
PubMed1994

Estrogens, progestins, and coronary heart disease in cynomolgus monkeys.

OBJECTIVE: To determine the effects of estrogen deprivation and estrogen replacement on coronary artery atherosclerosis. DESIGN: Randomized trials using female cynomolgus monkeys as subjects. SETTING: Comparative Medicine Clinical Research Center of an academic medical center. PATIENTS: Premenopausal and postmenopausal female cynomolgus monkeys fed diets comparable in fat and cholesterol to those consumed by human beings. INTERVENTIONS: Menopause was induced by ovariectomy; coronary vasomotion was evaluated during coronary angiography. Treatments involved estrogens and progestins, and coronary artery atherosclerosis was evaluated at necropsy. MAIN OUTCOME MEASURE: Coronary artery atherosclerosis extent. RESULTS: Premenopausal stress induces ovarian dysfunction and exacerbates coronary artery atherosclerosis. Physiologic replacement of ovarian hormones reduces in half the extent of coronary atherosclerosis of surgically menopausal monkeys. Hormone replacement therapy did not enhance regression of established coronary atherosclerosis. CONCLUSION: Estrogen deprivation exacerbates and estrogen diminishes coronary artery atherosclerosis of female cynomolgus monkeys fed atherogenic diets.

Animals↗
PubMed1992

Short-term administration of estrogen and vascular responses of atherosclerotic coronary arteries.

OBJECTIVES: This experiment sought to determine the effect of short-term administration of estrogen on endothelium-dependent dilation in the coronary arteries of 13 surgically postmenopausal female cynomolgus monkeys. BACKGROUND: Long-term estrogen replacement therapy prevents impaired endothelium-dependent dilation of atherosclerotic coronary arteries in postmenopausal female monkeys. However, it remains unclear whether this action of estrogen is due to long-term effects on plasma lipids and atherogenesis or to direct short-term effects on the endothelium. METHODS: The monkeys consumed an atherogenic diet for 18 months after bilateral ovariectomy. Vascular responses were measured just before euthanasia and necropsy. Dextrose in water (control), acetylcholine, 10(-6)M, and nitroglycerin were infused for 2.5 min each both before and 20 min after intravenous injection of 54 ng ethinyl estradiol. RESULTS: Quantitative coronary angiography revealed that the arteries constricted (-17 +/- 3%) in response to intracoronary infusion of acetylcholine before estrogen treatment but dilated (+5 +/- 3%) 20 min after intravenous injection of ethinyl estradiol (p less than 0.05). Coronary arteries dilated in response to nitroglycerin both before and after administration of estrogen (p greater than 0.05). Vascular responses of coronary arteries, both before and after administration of estrogen, were not associated with variation in plasma lipid concentrations, blood pressure, heart rate or plaque size. CONCLUSIONS: Estrogen affects endothelium-dependent coronary dilation within 20 min of administration and may have rapid direct effects on the vascular endothelium.

Acetylcholine↗
PubMed1992

Regional differences in arterial low density lipoprotein metabolism in surgically postmenopausal cynomolgus monkeys. Effects of estrogen and progesterone replacement therapy.

To determine if arterial lipoprotein metabolism may be involved in mediating well-known anatomic regional differences in susceptibility to atherosclerosis, arterial low density lipoprotein (LDL) metabolism and extent of atherosclerosis were studied in 17 ovariectomized female cynomolgus monkeys. The animals were fed an atherogenic diet for 18 weeks, during which time one group received 17 beta-estradiol and cyclic progesterone treatment (n = 9) and the controls received no hormone replacement therapy (n = 8). As reported previously, hormone replacement markedly reduced the accumulation of LDL in coronary arteries without affecting plasma lipoprotein patterns. We report here that LDL metabolism differed among arterial sites. LDL accumulation, LDL degradation rate, and the concentration of undegraded LDL were greatest in the coronary arteries and carotid bifurcations compared with the aorta, iliac arteries, and cerebral arteries. Although hormone replacement decreased indexes of LDL metabolism, there was no effect on intimal thickness or indexes of endothelial injury, such as leukocyte adhesion and endothelial cell turnover rate. There were, however, regional differences in these morphological parameters. The intima was thickest in the aorta, and leukocyte adhesion and endothelial cell turnover rates were greatest in the carotid bifurcation and thoracic aorta. The decreased accumulation and metabolism of LDL caused by hormone replacement therapy was specific to the arterial system and did not occur in the liver or other peripheral tissues.

Animals↗
PubMed1991

Accuracy and precision of lumbar bone mineral content by dual-energy X-ray absorptiometry in live female monkeys.

Dual-energy X-ray absorptiometry (DXA) was used to determine the in vivo bone mineral content (BMC) of lumbar vertebrae in 20 feral adult female cynomolgus macaques (Macaca fascicularis). The ash weight of the third lumbar vertebra (L3) was compared to the measured L3BMC of the in vivo DXA analyses. Correlation between the estimated L3BMC by DXA and the actual ash weight was significant (r = 0.965, P less than 0.01); however, DXA methodology underestimated ash weight on the average of 6.2%. Correlation was significant between two sequential in vivo DXA scans (r = 0.988, P less than 0.001). Noninvasive in vivo DXA was a fast, precise, and effective method for measuring the lumbar BMC in female cynomolgus macaques.

Absorptiometry, Photon↗
PubMed1991

Effects of oestrogens and progestogens on coronary atherosclerosis and osteoporosis of monkeys.

We have used the cynomolgus macaque as a model for the study of the effects of endogenous and exogenous sex steroid hormones on atherosclerosis and osteoporosis. As in human beings, premenopausal female cynomolgus macaques develop much less extensive coronary artery atherosclerosis than their male counterparts. Furthermore, surgical menopause results in a more atherogenic plasma lipoprotein pattern and an approximate doubling of atherosclerosis extent. Frequent pregnancy, a hyperoestrogenic state, results in an approximate 50% reduction in atherosclerosis extent. Physiological replacement with 17 beta-oestradiol alone or in combination with progesterone prevents the increase in coronary artery atherosclerosis extent associated with ovariectomy. This effect is independent of plasma lipoprotein concentrations and appears to be accounted for, at least in part, by an inhibitory effect of oestrogen replacement therapy on the uptake and degradation of LDL by the artery wall. Also, as in human beings, treatment with certain types of combination oral contraceptives results in marked decreases in plasma HDL-C concentration. Nonetheless, coronary artery atherosclerosis extent is reduced in monkeys by oral contraceptive treatment, and this effect is most pronounced among animals at highest risk due to theoretically adverse plasma lipoprotein profiles. It appears that, as with oestrogen replacement therapy, this effect can be accounted for, at least in part, by an inhibition of the uptake and degradation of low density lipoprotein by the artery wall. The monkey also appears to be a good model for studies of postmenopausal bone loss. As in women, surgical menopause results in significant diminution of bone mineral density and bone mineral content. Also, serum biomarkers of bone turnover (total alkaline phosphatase, acid phosphatase, tartrate-resistant acid phosphatase and osteocalcin) are increased in surgically postmenopausal monkeys, indicating increased bone turnover resulting from the surgical menopause. These increases in bone loss and indices of bone turnover were prevented by physiological oestrogen replacement therapy. Cynomolgus monkeys seem to be exceptionally useful models for studies of the effects of sex steroid hormones on atherosclerosis and osteoporosis, two major public health problems in postmenopausal women.

Animals↗
PubMed1991

Endothelial dysfunction in response to psychosocial stress in monkeys.

The current study was designed to evaluate the effects of a disrupted social environment on the endothelial integrity of various vascular segments in male cynomolgus monkeys (Macaca fascicularis). Each of 20 single-caged adult monkeys was fed a diet comparable to a person's ingestion of 240 mg cholesterol/day for a 10-week baseline period and then was introduced as a stranger into a four-member social group for 3 days. Half of the monkeys received a beta-adrenergic blocking agent (metoprolol) via subcutaneous implant 2 days before and during group housing. The social manipulation produced persistent sympathetic arousal as evidenced by significantly elevated heart rates among untreated monkeys (p less than 0.01) but not among their metoprolol-treated counterparts, whose heart rate declined (p less than 0.05). After the social manipulation, all monkeys were necropsied and evaluated for endothelial incorporation of immunoglobulin G (as an indicator of cell death), endothelial cell replication, the presence of adherent leukocytes, and arterial low density lipoprotein permeability and concentration. At branching sites in the thoracic aorta, immunoglobulin G incorporation and endothelial cell replication were significantly greater in untreated monkeys than in metoprolol-treated monkeys (p less than 0.01 for both analyses); no differences existed at nonbranch sites. Endothelial cell replication in the coronary arteries (where immunoglobulin G incorporation was not examined) was also greater among untreated than among metoprolol-treated monkeys. No significant differences were observed between treatment groups in arterial low density lipoprotein permeability or leukocyte adherence; estimates of arterial low density lipoprotein concentrations were higher among untreated than among metoprolol-treated monkeys, but only in the abdominal portion of the aorta. These results indicate that social disruption is associated with both sympathetic nervous system arousal and indexes of endothelial dysfunction, effects that may be prevented by treatment with a beta-adrenergic blocking agent.

Animals↗
PubMed1991

Estrogen and progesterone replacement therapy reduces low density lipoprotein accumulation in the coronary arteries of surgically postmenopausal cynomolgus monkeys.

The effect of estrogen and progesterone replacement therapy on the initiating events in atherogenesis was studied in surgically postmenopausal cynomolgus monkeys. Monkeys were ovariectomized and divided randomly into two groups, one receiving 17 beta-estradiol and cyclic progesterone treatment (n = 9) and ovariectomized controls receiving no hormone replacement therapy (n = 8). The monkeys were fed a moderately atherogenic diet for 18 wk to accelerate the early pathogenic processes but not to be of sufficient duration to produce grossly visible atherosclerotic lesions. Sex hormone replacement therapy decreased the accumulation of LDL and products of LDL degradation in the coronary arteries by greater than 70% while having no significant effect on plasma lipid, lipoprotein, or apoprotein concentrations. Arterial intimal lesions were small with no difference between groups. The reduction in arterial LDL metabolism occurred very early in the pathogenesis of atherosclerosis and was independent of indices of endothelial cell injury, such as enhanced endothelial cell turnover or leukocyte adhesion to the endothelium. Results of this study suggest that one mechanism by which sex hormone treatment inhibits the initiation of atherosclerosis is a direct effect at the level of the arterial wall by suppressing the uptake and/or degradation of LDL.

Animals↗