Jay R. Kaplan

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.

Social dominance in monkeys: Dopamine D2 receptors and cocaine self-administration

Disruption of the dopaminergic system has been implicated in the etiology of many pathological conditions, including drug addiction. Here we used positron emission tomography (PET) imaging to study brain dopaminergic function in individually housed and in socially housed cynomolgus macaques (n = 20). Whereas the monkeys did not differ during individual housing, social housing increased the amount or availability of dopamine D2 receptors in dominant monkeys and produced no change in subordinate monkeys. These neurobiological changes had an important behavioral influence as demonstrated by the finding that cocaine functioned as a reinforcer in subordinate but not dominant monkeys. These data demonstrate that alterations in an organisms environment can produce profound biological changes that have important behavioral associations, including vulnerability to cocaine addiction.

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 fascicularls). 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 llpoproteln 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).

behaviorally Induced Heart Rate Reactivity and Atherosclerosis in Cynomolgus Monkeys

&NA; It has been suggested that individual differences in behaviorally induced cardiovascular reactivity may mediate associations between behavioral factors and atherosclerotic disease. The present study provides data relevant to this hypothesis within an animal model. Experimental animals were 26 adult, male cynomolgus monkeys that had been fed a moderately atherogenic diet for 22 months. In the weeks preceding termination of these animals, monkeys were fitted with electrocardiogram (EKG) telemetry devices and their heart rates (HRs) recorded under baseline and stressed conditions. Stress‐period HR measures were obtained during a standard challenge involving threatened capture and physical handling of the animals. At necropsy, the coronary arteries were subjected to pressure fixation and sections taken from the left main, left anterior descending, left circumflex, and right coronary arteries. Mean intimal area measurements, calculated for each artery, were then compared between animals identified as High (n = 8) and Low (n = 8) HR reactors during stress. Results indicated that High HR reactors had significantly greater coronary artery atherosclerosis than did Low HR reactive animals, both in individual arteries and on an overall coronary index. Atherosclerosis in the thoracic aorta was found to differ similarly between High and Low HR reactors. Additional analyses revealed that High HR reactors were significantly more aggressive, more ponderous, and had greater heart weights than did Low HR reactors. Although groups did not differ in resting HRs, body weights, or lipid values, high‐density lipoprotein (HDL) cholesterol comprised a slightly smaller fraction of the total serum cholesterol of High, relative to Low, HR reactive monkeys. It is concluded that these findings provide initial support for the hypothesis that cardiovascular hyperresponsiveness under stress is related to the development of atherosclerosis.

CHRONIC SOCIAL STRESS, SOCIAL STATUS, AND SUSCEPTIBILITY TO UPPER RESPIRATORY INFECTIONS IN NONHUMAN PRIMATES

Objective The objective of the study was to assess the roles of social stress and social status in susceptibility to upper respiratory infection. Method: Sixty male cynomolgus monkeys were randomly assigned to stable or unstable social conditions for 15 months. Two markers of social status, social rank and percent of behaviors that were submissive, were assessed at independent observation periods. Endocrine, immune, and behavioral responses were each assessed (at 3-month intervals) during the 9th through 14th months of the study. At the beginning of the 15th month, all animals were exposed to a virus (adenovirus) that causes a common-cold-like illness. The primary outcome was whether or not an animal developed an infection (shed virus) after viral exposure. Results: Although the social instability manipulation was associated with increased agonistic behavior as indicated by minor injuries and elevated norepinephrine responses to social reorganizations, the manipulation did not influence the probability of being infected by the virus. However, low social status (as assessed by either marker) was associated with a substantially greater probability of being infected. It was also associated with less body weight, greater elevated cortisol responses to social reorganizations, and less aggressive behavior. However, none of these characteristics could account for the relation between social status and infection. Conclusions: Social stress was not associated with susceptibility to infection. However, animals with lower social status were at higher risk than high social status animals.

Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.

&NA; Epidemiologic studies link plasma cholesterol reduction to increased mortality rates as a result of suicide, violence, and accidents. Deficient central serotonergic activity is similarly associated with violence and suicidal behavior. We investigated the relationship among dietary and plasma cholesterol, social behavior, and the serotonin system as a possible explanation for these findings. Juvenile cynomolgus monkeys (eight female and nine male) were fed a diet high in fat and either high or low in cholesterol. We then evaluated their behavior over an 8‐month period. Plasma lipids and cerebrospinal fluid metabolites of serotonin, norepinephrine, and dopamine were assessed on two occasions, at 4 and 5.5 months after the initiation of behavioral observations. Animals that consumed a low‐cholesterol diet were more aggressive, less affiliative, and had lower cerebrospinal fluid concentrations of 5‐hydroxyindoleacetic acid than did their high‐cholesterol counterparts (p < .05 for each). The association among dietary cholesterol, serotonergic activity, and social behavior was consistent with data from other species and experiments and suggested that dietary lipids can influence brain neurochemistry and behavior; this phenomenon could be relevant to our understanding of the increase in suicide and violence‐related death observed in cholesterol‐lowering trials.

Effects of Androgens on Coronary Artery Atherosclerosis and Atherosclerosis-Related Impairment of Vascular Responsiveness

The factors responsible for the marked gender differences in risk of coronary heart disease and atherosclerosis severity remain largely undetermined. While some clinical and experimental evidence supports a protective effect of endogenous estrogen on the initiation and progression of atherosclerosis and incidence of coronary heart disease, much of the epidemiological data do not support this conclusion. The possibility that endogenous androgens may have adverse effects on atherosclerosis progression and coronary risk has received little attention. We investigated the effects of experimentally induced hyperandrogenism in female cynomolgus monkeys with diet-induced atherosclerosis. Animals were assigned randomly to one of four treatment groups: (1) untreated controls, (2) ovariectomized (sex hormone-deficient) controls, (3) treated with androstenedione and estrone (mild hyperandrogenism), or (4) treated with testosterone (male plasma androgen pattern). At necropsy, coronary atherosclerosis was approximately twice as extensive (P < .05) in testosterone-treated animals relative to untreated controls, while treatment with androstenedione and estrone had no effect on atherosclerosis extent. Coronary plaque size was positively correlated with lumen size in intact and ovariectomized controls; however, there was no evidence of a similar relation between animals in either androgen treatment group. The atherogenic effects of testosterone were independent of variations in plasma lipoprotein and nonlipoprotein risk variables. Although chronic hyperandrogenism had adverse effects on atherosclerosis progression, it reversed (P < .03) atherosclerosis-related impairment of endothelium-dependent vasodilator responses. We conclude that an experimentally induced male plasma androgen pattern results in exacerbation of diet-induced atherosclerosis-related arterial remodeling in female monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials

Abstract Objective: To investigate the association between cholesterol lowering interventions and risk of death from suicide, accident, or trauma (non-illness mortality). Design: Meta-analysis of the non-illness mortality outcomes of large, randomised clinical trials of cholesterol lowering treatments. Studies reviewed: 19 out of 21 eligible trials that had data available on non-illness mortality. Interventions reviewed: Dietary modification, drug treatment, or partial ileal bypass surgery for 1-10 years Main outcome measure: Deaths from suicides, accidents, and violence in treatment groups compared with control groups. Results: Across all trials, the odds ratio of non-illness mortality in the treated groups, relative to control groups, was 1.18 (95% confidence interval 0.91 to 1.52; P=0.20). The odds ratios were 1.28 (0.94 to 1.74; P=0.12) for primary prevention trials and 1.00 (0.65 to 1.55; P=0.98) for secondary prevention trials. Randomised clinical trials using statins did not show a treatment related rise in non-illness mortality (0.84, 0.50 to 1.41; P=0.50), whereas a trend toward increased deaths from suicide and violence was observed in trials of dietary interventions and non-statin drugs (1.32, 0.98 to 1.77; P=0.06). No relation was found between the magnitude of cholesterol reduction and non-illness mortality (P=0.23). Conclusion: Currently available evidence does not indicate that non-illness mortality is increased significantly by cholesterol lowering treatments. A modest increase may occur with dietary interventions and non-statin drugs.

Social Impulsivity Inversely Associated with CSF 5-HIAA and Fluoxetine Exposure in Vervet Monkeys

Animal and human research suggests that the central serotonin system is involved in the inhibition of impulsive behavior. Two studies were designed to assess this relationship in male vervet monkeys (Cercopithecus aethiops sabaeus) using a standardized test of impulsivity in a social context: the Intruder Challenge. In the first study, an index of impulsivity in response to an unfamiliar adult male intruder (including latency to approach and aggressive and assertive interactions) was inversely correlated with levels of the serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA) in cisternal cerebrospinal fluid (r = −0.33, p < .01, n = 138). The approach, but not aggressive, component of the Impulsivity Index was the primary contributor to this relationship (partial r = −0.27, p < .01). The second experiment compared responses to the Intruder Challenge after 9 weeks of daily treatment with fluoxetine (2 mg/kg, i.m.) or vehicle. Fluoxetine-treated subjects (n = 6) had significantly lower Impulsivity Index scores than controls (n = 12). The results from these two investigations provide evidence for serotonergic influences on social impulsivity.

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 persons 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.