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Although the etiology of the metabolic syndrome remains unclear, recent evidence suggests that dysregulation of brain serotonergic activity may partly underlie the covariation of risk factors comprising the syndrome. In addition, prior studies have shown polymorphisms in the serotonin 2A receptor (HTR2A) gene to be associated with two syndrome components, hypertension and central adiposity. We conducted a study to confirm associations of HTR2A polymorphisms with elevated blood pressure and central adiposity and tested for association between these polymorphisms and the metabolic syndrome.The study sample included 934 unrelated individuals of European ancestry. We tested for association of two HTR2A polymorphisms, one in the promoter: (-1438[G/A]) and one in the first intron (2416 [C/T]), individually and as a diplotype, with elevated blood pressure, central adiposity, elevated fasting glucose, triglycerides, high density lipoprotein (HDL) cholesterol and presence of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung and Blood Institute (AHA/NHLBI) Scientific Statement Executive Summary.Confirming previous reports, elevated blood pressure (130/85 mm Hg) was associated with both the -1438 GG and 2416 TT genotypes and the GG/TT diplotype (ORs = 1.39-1.76); high waist circumference was associated with -1438 GG genotype only (OR = 1.57). In addition, both the -1438 GG and 2416 TT genotypes, and the GG/TT diplotype, predicted presence of the metabolic syndrome (ORs = 1.44-1.77). Fasting glucose, triglyceride and HDL cholesterol were not associated with either polymorphism.Elevated blood pressure, central adiposity, and the metabolic syndrome are associated with polymorphisms in HTR2A gene.

The aim of this study was to examine the association between the use of lipid-lowering medication and aggressive responding, hostility, cynicism, and depression scores in women undergoing coronary angiography.The cohort included 498 women from the National Heart, Lung and Blood Institute (NHLBI)-sponsored Women's Ischemia Syndrome Evaluation (WISE) study. WISE is a four-center study of women with chest pain who underwent quantitative coronary angiography for suspected myocardial ischemia. The psychosocial indices included the Cook Medley Hostility questionnaire, measuring aggression, hostility, and cynicism, and the Beck Depression Inventory (BDI).Compared to those not on lipid-lowering medication, women receiving lipid-lowering pharmacotherapy were older (62 vs. 55 years, p0.001) and had more hypertension, dyslipidemia, diabetes, and coronary artery disease (CAD, defined asor =50% stenoses in at least one epicardial artery) (all p0.003). Women on lipid-lowering medication had higher aggressive responding scores than those not on medication, 3.0 +/- 1.8 vs. 2.7 +/- 1.7, respectively (age-adjusted p0.003). This association persisted after adjustment for coronary risk factors, education, and extent of angiographic disease (CAD) (p0.005), and after exclusion of women using psychotropic medications (p0.001). Hostility, cynicism, and depression scores did not differ by medication use.

Objectives: The authors previously reported that individuals who rate their daily life as more demanding or less controllable by momentary electronic diary (ED) reports showed greater intima–medial thickness (IMT) by carotid ultrasonography. They now present prospective findings on this relation. Design. Three hundred thirty-five healthy individuals (ages 50–70 at study onset) completed ongoing ratings of activity and mood over a 6-day period, using ED assessments. Main Outcome Measures: Mean bilateral carotid artery IMT was measured at baseline and 36 months later. Results and Conclusion: Mean ratings of high demand and low control were significantly associated with IMT progression among men but not among women. These associations were not explained by traditional risk factors or by measures of occupational stress. Effects were partially accounted for by elevated ambulatory heart rates among those with low ratings of control. These data support the utility of ED-based measures for examining psychosocial risks in the prediction of cardiovascular disease progression.

Study Objectives: To determine whether a simple, structured self-report of overall sleep quality is associated with the presence of the metabolic syndrome and its component risk factors. Design: An observational, cross-sectional study comparing global scores on the Pittsburgh Sleep Quality Index with concurrently collected measures of the components of the metabolic syndrome and presence or absence of the syndrome. The metabolic syndrome criterion of the American Heart Association/National Heart, Blood, and Lung Institute was adopted. Setting: University laboratory. Patients/Participants: Two hundred ten volunteers with a mean age of 46 years (57% men) screened for the presence of serious illness and related medications. Interventions: N/A. Measurements and Results: All analyses were adjusted for sex and age. Logistic regression showed that poor global sleep-quality scores on the Pittsburgh Sleep Quality Index were related significantly to the presence of the metabolic syndrome-an increase of the global sleep score of 2.6 points (approximately 1 SD) was associated with an odds of having the metabolic syndrome of 1.44 (p = .04, confidence interval = 1.01-2.06). Linear-regression results showed that the Pittsburgh Sleep Quality Index global sleep-quality score was related significantly to waist circumference, body mass index, percentage of body fat, serum levels of insulin and glucose, and estimated insulin resistance. Conclusions: Self-reported global sleep quality is significantly related to the metabolic syndrome and several of its core components.

The objective was to examine whether dietary intakes of macronutrients are associated with neuropsychological performance.Study participants were 3960 adults aged 20-59 years, who completed three neuropsychological tests and a 24-hour dietary recall as a part of the Third National Health and Nutrition Examination Survey, 1988-1994. Poor performance was defined as the test score below gender-specific 15th percentile.While holding the energy percentages from different macronutrients, additional 100 kcal intake of energy was associated with a reduced odds of poor performance on serial digital learning test (OR = 0.98, 95% CI = 0.96, 0.99) and symbol digital substitution test (OR = 0.97, 95% CI = 0.96, 0.99). Compared with equivalent energy from carbohydrates, each 5% of energy from poly-unsaturated fatty acids (PUFA) or total fat was associated with a reduced OR of poor performance on simple reaction time test (PUFA: OR = 0.77, 95% CI = 0.63-0.95 and total fat: OR = 0.93, 95% CI = 0.87, 0.99). Poor global cognition was associated with an additional intake of 100 mg cholesterol (OR = 1.14, 95% CI = 1.05, 1.23). These associations were more salient in men.Habitual intake of macronutrients is weakly but significantly associated with cognitive functioning. These relationships are more evident in men.

Low dietary intake of omega-3 polyunsaturated fatty acids has been linked to several features of psychiatric symptomatology, including depression, disorders of impulse control, and hostility. Preliminary intervention trials of omega-3 fatty acid supplementation for clinical depression and other disorders have reported benefit. However, few studies have investigated the relationships between these fatty acids and normative variability in mood, behavior and personality. Participants were 105 hypercholesterolemic, but otherwise healthy, non-smoking adults. Fasting serum alpha-linolenic (alpha-LNA), eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) were assayed with gas chromatography. Participants completed the Beck Depression Inventory (BDI), the NEO Five Factor Personality Inventory (NEO-FFI) and the Barratt Impulsiveness Scale (BIS). In multivariate analyses, higher levels of the long chain omega-3 PUFAs, EPA and DHA, were associated with significantly reduced odds of scoring >or=10 on the BDI. Similarly, DHA and EPA covaried inversely with NEO-Neuroticism scores, whereas DHA was positively associated with NEO-Agreeableness. On the BIS, DHA was inversely related to cognitive impulsivity and alpha-LNA was inversely related to motor and total impulsivity. These findings suggest that omega-3 fatty acid status is associated with variability in affect regulation, personality and impulse control.

A growing literature suggests that psychosocial factors, such as chronic stress and depression, are associated with increased vulnerability to inflammatory disease; however, the mechanisms of this effect remain unclear. One possibility is that these psychosocial characteristics are associated with activation of innate inflammatory pathways. Here, we explore relationships between a range of psychosocial risk factors for inflammatory disease and a measure of inflammatory potential, lipopolysaccharide-induced production of the monocyte-derived proinflammatory cytokines/chemokines interleukin (IL)-1beta, IL-6, TNF-alpha, and IL-8 among a community sample of 183 healthy adults aged 30-54 years. After controlling for demographic factors, health behavior practices, blood pressure, and white blood cell count, hierarchical regression analyses revealed a positive relationship between production of IL-8 and symptoms of depression, trait negative affect, and perceived stress. In contrast, there was an inverse relationship between IL-8 production and perceived social support. Relationships between IL-8 and symptoms of depression and perceived stress were attributable primarily to dispositional differences in NA. The relationship between negative affect measures and IL-8 was independent of social support. Although there were significant univariate associations between higher IL-6 production and symptoms of depression and less social support, these relationships did not withstand adjustment for demographic controls. There were no significant associations between IL-1beta or TNF-alpha and any of the psychosocial parameters. Our findings suggest that individuals at greater psychosocial risk for the development of inflammatory diseases, including cardiovascular disease, also show greater stimulated production of the proinflammatory chemokine, IL-8. Further exploration of this potential psychophysiological pathway is warranted.

Individuals labelled as having hypertension tend to report poor self-rated health (SRH), but it is unclear whether this association is independent of actual hypertension, socioeconomic status and adiposity, and extends across racial and ethnic groups. In a cross-sectional study we compared hypertensive and normotensive individuals (N = 19,057) who varied in whether they had ever been labelled hypertensive. Blood pressure was measured in participants' homes and mobile examination centres in the United States as part of the Third National Health and Nutrition Examination Survey, 1988-1994. The main outcome measure was global SRH. Hypertensive labelling was associated with poorer SRH and was independent of established SRH predictors, antihypertensive medication use, body mass index, and hypertension status (adjusted odds ratio (OR) = 1.79, 95% confidence interval (CI), 1.61-1.99). Hypertension was also associated with poorer SRH (OR = 1.26; 95% CI 1.09-1.46) but this association was eliminated by adjustment for hypertensive labelling (OR 1.06; 95% CI 0.92-1.22). These effects were consistent across non-Hispanic white, non-Hispanic black, and Hispanic subgroups. Individuals labelled hypertensive are more likely to have lower SRH and this labelling effect predominates over that of actual hypertension. Public health efforts to increase the number of individuals screened for high blood pressure may successfully detect the presence of hypertension but may also reduce health-related quality of life as measured by global SRH.

The dietary guidelines developed for adults have been extended to children, but the role of serum cholesterol in the neurodevelopment of children is poorly understood. In the Third National Health and Nutrition Examination Survey (1988-1994), serum total cholesterol was measured in 4,852 children aged 6-16 years. Psychosocial development was evaluated by interviewing the mother regarding the child's history of school suspension or expulsion and difficulty in getting along with others. After adjustment for family socioeconomic status, maternal marital status and education, children's nutrition, and academic performance, the odds ratios of children with various concentrations of total cholesterol showed the children to be equally comfortable in their own peer subculture and not to be different in the proportion that had seen a mental health professional. However, non-African-American children with a serum total cholesterol concentration below the 25th percentile (

Background: Current international recommendations advise aggressive treatment of relative hypercholesterolemia despite an incomplete understanding of any neurobehavioral effects of low or lowered serum cholesterol. Objective: The objective was to examine the relation between serum cholesterol concentrations and performance in immediate memory, visuomotor speed, and coding speed tests. Design: The participants were 4110 adults aged 20 –59 y who completed a set of neurobehavioral tests and had blood specimens collected as a part of the third National Health and Nutrition Examination Survey, 1988 –1994. Results: After adjustment for sociodemographic variables, serum trace elements and vitamins, dietary energy intake, and risk factors for cardiovascular disease, we found inverse linear associations of serum total cholesterol and non-HDL cholesterol with visuomotor speed in men. The least-squares mean ( SE) visuomotor speeds were 231.6 2.6, 224.0 2.2, and 218.9 2.5 ms, respectively, for men with serum total cholesterol concentrations below the 25th, between the 25th and the 75th, and at or above the 75th percentile (P for trend 0.001) and were 231.7 2.7, 225.8 2.4, and 214.1 2.3 ms, respectively, for men with a non-HDL-cholesterol concentration below the 25th, between the 25th and the 75th, and at or above the 75th percentile (P for trend 0.001). No significant associations were observed between memory or coding speed and the selected serum cholesterol measures in men, and the scores of the 3 neurobehavioral tests were unrelated to serum cholesterol in women. Conclusion: Low serum total cholesterol and non-HDL cholesterol are associated with slow visuomotor speed in young and middleaged men. Am J Clin Nutr 2004;80:291– 8.

The neuroendocrine response to intravenous citalopram may provide an acute, functional, in vivo measure of the neural serotonin (5-HT) system.To refine the quantification of acute neuroendocrine responses following intravenous citalopram in studies of 5-HT function.In 75 adult healthy subjects taking part in four similar protocols, we measured plasma prolactin and cortisol, as well as serial citalopram concentrations following intravenous citalopram (10 mg, 20 mg, 40 mg, 0.33 mg/kg) and placebo. The relationship between the AUC for intravenous citalopram during the first 150 min (AUC(150)) and the magnitude of the neuroendocrine response was determined. The role of pharmacokinetic (PK) parameters, as well as sensitivity to placebo injections, in influencing the neuroendocrine response to citalopram was then evaluated.Citalopram produced a dose-dependent increase in cortisol and prolactin. The maximal increase from baseline correlated significantly but modestly with citalopram's AUC(150) (prolactin r(2)=0.23, P0.0001; cortisol r(2)=0.3, P0.0001). Additionally, citalopram's AUC(150) was affected by between-subject differences in both the peripheral and central volume of distribution. However, the neuroendocrine responses to citalopram did not correlate with the responses to placebo.The parenteral citalopram challenge test is characterized by a modest concentration-response relationship, with concentration influenced by variable PK factors. Accounting for individual differences in drug distribution may improve the power of the citalopram challenge test, when used as an in vivo measure of central 5-HT function.

Statins are highly effective cholesterol-lowering drugs but may have broader effects on metabolism. This investigation examined effects of simvastatin on serum levels of n-6 and n-3 polyunsaturated fatty acids (PUFAs). Subjects were 106 healthy adults with hypercholesterolemia randomly assigned to receive placebo or 40 mg simvastatin daily for 24 weeks. Serum fatty acids were analyzed by gas chromatography. Total fatty acid concentration fell 22% in subjects receiving simvastatin (P

Dimensional personality characteristics (e.g. impulsivity) and related behaviors and psychiatric disorders are linked to abnormalities of central nervous system (CNS) serotonergic functioning. Although neuroendocrine [e.g. plasma prolactin (PRL)] responses to the serotonin agonist, fenfluramine, have been used widely to index CNS serotonergic responsivity, safety concerns constrain continued use of fenfluramine. Citalopram, which inhibits serotonin reuptake, may serve as an alternative pre-synaptic neuropharmacologic challenge agent, due to its high selectivity and absence of intrinsic activity at serotonin or other receptor families. Twenty-two healthy adults who had been administered a fenfluramine challenge before May 1996 completed a 5-h oral citalopram challenge 3-6 years later. PRL responsivity to citalopram correlated significantly with PRL response to fenfluramine for baseline-corrected maximal and area-under-the-curve (AUC) indices ( r's > or =0.49, P's< or =0.02). The magnitude of the correlations is notable given the length of time between challenges. The results support the use of citalopram as an alternate neuroendocrine challenge to index CNS serotonergic responsivity.

Daily experiences of demand and control were examined as correlates of carotid artery atherosclerosis among healthy adults (ages 50-70). Mediating effects of ambulatory blood pressure (ABP) were also explored. Participants (n=337) collected ABP and recorded daily experiences, using electronic diaries, over two 3-day periods. Carotid artery intima-medial thickness (IMT) was assessed using ultrasonography. Participants reporting higher task demands during daily life showed larger IMT, after adjustment for demographic covariates. This association was not limited to workplace ratings or to employed individuals. The association was mediated, in part, by daytime systolic blood pressure. Previous findings linking job stress with cardiovascular disease may reflect the broader impact of daily psychological demands, not necessarily associated with the workplace.

The metabolic syndrome, recognized by the co-occurrence of general or abdominal obesity, hypertension, dyslipidemia, insulin resistance, and dysglycemia, appears to involve disturbances in metabolism, autonomic function, and health-related behaviors. However, physiological processes linking the components of the metabolic syndrome remain obscure. The current study examined associations of central nervous system serotonergic function with each metabolic syndrome risk variable, the metabolic syndrome, and physical activity. The subjects were 270 adult volunteers who participated in a study of cardiovascular disease risk factors and neurobehavioral functioning. Central serotonergic responsivity was indexed as the prolactin (PRL) response evoked by the serotonin-releasing agent, fenfluramine. Across the sample, low PRL response was associated with greater body mass index, higher concentrations of triglycerides, glucose, and insulin, higher systolic and diastolic blood pressure, greater insulin resistance, and less physical activity (P < 0.03-0.001). There also existed an inverse linear relationship between PRL response and the number of metabolic syndrome risk factors individuals possessed (P for trend = 0.002). Finally, a 1 SD decline in PRL response was associated with an odds ratio for the metabolic syndrome of 2.05 (95% confidence interval, 1.10-3.83; P = 0.002) and 5.70 (95% confidence interval, 1.69-19.25; P = 0.005), according to the definitions of the National Cholesterol Education Program and the World Health Organization, respectively. These findings reveal a heretofore unrecognized association between reduced central serotonergic responsivity and the metabolic syndrome.

Plasma prolactin (PRL) levels after acute administration of fenfluramine (FEN) have been used as a probe of brain serotonin activity. FEN-evoked increases in PRL levels inversely correlate with arterial blood pressure (ABP) in humans (Muldoon et al. Hypertension . 1998;32:972–975), thereby suggesting that brain serotonin activity may be reduced in hypertension. The present study sought to determine whether the relation between FEN-evoked PRL levels and ABP was present in two rat models of hypertension. Experiments were performed in awake male rats that were instrumented with femoral arterial and venous catheters 2 days before experiments. FEN (3.0 mg/kg IV) significantly increased plasma PRL levels in both spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY); however, FEN-evoked PRL levels were significantly lower in SHR compared with WKY, though baseline levels were similar between strains. Similar results were obtained in rats with chronic hypertension produced by figure-8 renal wrap plus contralateral nephrectomy. In contrast, the increase in PRL levels evoked by the serotonin receptor agonist m-CPP or the dopamine receptor antagonist eticlopride did not differ between SHR and WKY, indicating that PRL secretion is not generally blunted in chronic hypertensive rats. Furthermore, FEN-evoked PRL levels were not attenuated in rats made acutely hypertensive by an infusion of the α-adrenergic agonist phenylephrine. Thus, the present findings are consistent with the human data and suggest that chronic hypertension is associated with a presynaptic alteration in brain serotonin function.

To determine whether normative variability in aggressive behavior correlates negatively with central nervous system (CNS) serotonergic function among men, plasma prolactin (PRL) responses to a standard fenfluramine challenge (administered to assess central serotonergic responsivity) were examined in relation to interview-assessed aggression histories among 118 adult males derived from a nonpatient, community sample. Fenfluramine-induced, peak PRL rises were smaller in subjects whose 'aggression' scores fell above the sample median, compared to their less aggressive counterparts (P

A plethora of epidemiologic evidence links consumption of fish and n-3 fatty acids with reduced morbidity and mortality from atherosclerotic cardiovascular disease [1]. What is not at all clear is how such benefits accrue, how long diet must be changed, and what quantity of n-3 fatty acids confers disease protection. An important, randomized clinical trial recently found no reduction in major cardiovascular events from a margarine providing the relatively low dose of 400 mg daily of n-3 fatty acids for 40 months [2]. In the current issue, Skulas-Ray and colleagues report a clinical experiment examining the dose–response relationship between n-3 fatty acid supplementation and BP at rest and during acute mental stress [3]. BP was reduced comparably at rest and during stress by 3,400 mg/day for 8 weeks, whereas the lower dose of 850 mg had no effect. BP reduction was proportional to the increase in circulating n-3 fatty acids, corroborating the existence of a presumably linear, dose–response relationship. The authors further report a robust reduction in stroke volume, which in conjunction with a reduced heart rate (found in prior studies), yields a notable decline in resting cardiac output. Several caveats about the study design warrant mention. Subjects were normotensive, and the BP reduction of about 2 mmHg from high-dose supplementation may be larger in persons with high-normal or hypertensive BP. The duration of 8 weeks may be insufficient to fully characterize the effects of a diet change since tissue levels may require more than 4 months to plateau [4]. Finally, the use of a cross-over design has efficiencies at the cost of susceptibility to carry-over effects. The latter two issues could have conspired to produce null findings for the low dose but would not have biased the findings. In the context of extant literatures, Skulas-Ray's study indicates that BP declines with n-3 consumption in normotensives, extending the relatively robust evidence for such effects in persons with hypertension [5]. This suggests a role for fish and n-3 intake in hypertension prevention [6]. The manner in which BP falls could involve cardiovascular autonomic control or direct effects on the heart and vasculature. Research on n-3 fatty acids and heart rate variability, an index of cardiac autonomic control, is rather mixed, perhaps due to effect modification by concurrent health behaviors, such as exercise [7]. The current findings of reduced heart rate, stroke volume, and cardiac output, and lengthened pre-ejection period, all point to modulation of cardiac autonomic control. This collection of alterations in cardiovascular function at rest begs the question of how n-3 fatty acids affect cardiovascular responses, given our inconstant environmental stimuli and demands. The lack of a change in reactivity to mental stress reported here conflicts with the blunting of stress-induced BP elevation reported recently by Ginty and Conklin [8]. With respect to oxygen delivery at rest and during exercise, the decline in resting cardiac output implies a reduction in tissue oxygen demand, itself a provocative suggestion. Such may indeed be the case, as oxygen consumption during exercise has been reported to fall with fish oil supplementation [9]. Therefore, this paper adds evidence of multifaceted and dose-dependent changes in cardiovascular physiology from dietary n-3 fatty acids. It supports a role for increased fish and n-3 fatty acid consumption in hypertension prevention and should stimulate further research to untangle the various mechanisms of these micronutrients in human disease pathogenesis.

It was reported recently that exposure to an adverse rearing environment lowers central nervous system (CNS) serotonergic activity in a nonhuman primate (rhesus monkeys), but only among animals having the shorter variant of a functional, biallelic repeat polymorphism in the regulatory region of the serotonin transporter (5-HTT) gene. Because repeat variants of the same core sequence affect transcriptional efficiency of the 5-HTT gene in humans, we examined whether biallelic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) acts analogously to modulate a previously described association between socio-economic status (SES) and CNS serotonergic function. The 5-HTTLPR was genotyped in 139 adult men and women (n = 75 and 64) who were administered a standard neuroendocrine challenge to assess central serotonergic responsivity (plasma prolactin (PRL) response to the serotonin releasing agent, fenfluramine). Socio-economic status was estimated from reported income and years of education. Hierarchical linear regression showed serotonergic responsivity to be predicted by the interaction of 5-HTTLPR genotype and SES (p = 0.018). Individuals of lower income and less education had lower peak PRL concentrations following administration of fenfluramine than did subjects ranking higher on these dimensions, but only among persons possessing at least one 5-HTTLPR short allele. Within genotype, SES covaried moderately with the PRL response to fenfluramine among subjects who were homozygous for the short allele (r18 = 0.50, p < 0.03). A similar association was present at lesser magnitude in heterozygotes (r70 = 0.24, p < 0.05) and absent among subjects homozygous for the long allele (r45 = -0.04, n.s.). Findings were comparable for men and women and persisted on re-analysis restricted to persons without current Axis I psychopathology. We conclude that allelic variation at 5-HTTLPR moderates the influence of social position on CNS serotonergic responsivity.

The aim of this study was to evaluate the association between resting baroreflex sensitivity (BRS) and carotid intima–media thickness (IMT), a putative marker of subclinical atherosclerosis. Participants were 64 men and 18 women (median age, 57 years; range, 40 to 70 years), who did not have a previous history of coronary artery disease or treatment for hypertension. Resting BRS was measured during a 9-min baseline period using the noninvasive sequence technique; carotid IMT was subsequently determined using ultrasonography. Hierarchical multiple regression analyses showed that greater IMT in the carotid bulb (an area with a high density of baroreceptors) was associated with reduced BRS. These findings remained after adjusting BRS for resting mean arterial pressure, age, body mass index, gender, and smoking history, R2 = 0.06, P = .03. In contrast, IMT in the common and internal carotid regions (areas with presumably lower baroreceptor densities) did not account for a significant proportion of the variance in BRS. These results suggest that subclinical atherosclerosis, specifically in a region with high baroreceptor density, is associated with a reduced sensitivity of the baroreflex.

Neuropharmacologic probes to assess central nervous system (CNS) serotonergic responsivity (e.g., dl-fenfluramine) stimulate serotonergic neurotransmission, thereby causing proportional release of pituitary-derived hormones into the circulation. Individual differences in these hormonal responses are thus thought to reflect dimensional variability in central serotonergic activity, which may, in turn, underlie variation in serotonin-related traits of personality (e.g., impulsivity, behavioral inhibition, harm avoidance). However, the long-term temporal stability of neuropharmacologic indices of CNS serotonergic responsivity has not previously been tested in nonpsychiatric patients. dl-Fenfluramine was administered here to 57 adults, aged 24-60 years, on two occasions 6 months apart, to examine the retest reliability of fenfluramine-induced prolactin [PRL] response to fenfluramine. Baseline PRL concentration (i.e., before administration of fenfluramine) was highly stable over the 6 months (r = 0.88). Variability in serotonergic responsivity, adjusted for baseline PRL concentration, age, sex, and drug concentration during the challenge, was moderately reproducible (r = 0.50 for peak DeltaPRL and 0.57 for PRL "area under the curve," p.0001). These findings are consistent with speculation that variability in indices of central serotonergic function reflects a temporally stable dimension of individual differences.

The cardiovascular system, composed of the heart and vasculature, is responsible for supplying blood transporting oxygen, glucose, and other essential nutrients to all cells of the body. The brain is particularly dependent on the cardiovascular system for a constant supply of blood because it is relatively unable to store nutrients for utilization during interruptions of blood flow. Indeed, approximately one fifth of the cardiac output, or 1 liter of blood, is provided to the brain each minute; cessation of this blood supply for even a few minutes can be damaging to the brain. More subtle reductions in cerebral blood flow also may have deleterious short- or long-term consequences for the brain. For instance, Meyer, Rogers, and Mortel (1984) reported that decreased cerebral blood flow preceded signs and symptoms of cerebrovascular disease (i.e., diseases involving alterations in the brain’s blood supply) by up to 2 years. Alterations in blood flow can occur as a result of multiple diseases of the heart and vasculature that affect the ability of or efficiency with which the cardiovascular system pumps or distributes blood.

This study presents preliminary evidence of an association between polymorphic variation in the gene for monoamine oxidase-A (MAOA) and interindividual variability in aggressiveness, impulsivity and central nervous system (CNS) serotonergic responsivity. An apparently functional 30-bp VNTR in the promoter region of the X-chromosomal MAOA gene (MAOA-uVNTR), as well as a dinucleotide repeat in intron 2 (MAOA-CAn), was genotyped in a community sample of 110 men. All participants had completed standard interview and questionnaire measures of impulsivity, hostility and lifetime aggression history; in a majority of subjects (n=75), central serotonergic activity was also assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). The four repeat variants of the MAOA-uVNTR polymorphism were grouped for analysis (alleles '1+ 4' vs. '2+3') based on prior evidence of enhanced transcriptional activity in MAOA promoter constructs with alleles 2 and 3 (repeats of intermediate length). Men in the 1/4 allele group scored significantly lower on a composite measure of dispositional aggressiveness and impulsivity (P

Background Blood pressure (BP) measurements obtained in the clinic have long served as the basis for determining risk of hypertensive vascular disease, yet many patients with high BP in the physician's office are normotensive elsewhere. It remains unclear whether such patients with "white coat" hypertension elude the risk of atherosclerosis. Methods Community residents 40 to 70 years of age and not receiving any cardiovascular medications were recruited to participate in a study of cardiovascular risk factors. On the basis of clinic and daytime ambulatory BP and a threshold criterion of 140/90 mm Hg, subjects were classified as having persistent hypertension, white-coat hypertension, or persistent normotension. One-to-one matching was conducted in male participants on the basis of race and BP. Subjects with persistent hypertension and white-coat hypertension were matched on clinic BP, and those with white-coat hypertension and normotension were matched on daytime ambulatory BP. Results The 3 matched groups of men (n=40 in each group) were similar in age, smoking status, and fasting glucose and lipid levels. Compared with the normotensive subjects, subjects with either persistent or white-coat hypertension had greater mean body mass index, waist-hip ratio, and fasting insulin concentration. On the basis of standardized duplex ultrasound examination of the carotid arteries, mean maximal intimal-medial thickness and plaque index in subjects with white-coat hypertension were greater than among normotensive subjects and equal to that of the subjects with persistent hypertension. Conclusion When compared with unmedicated individuals with comparable elevations in clinic BP, individuals with white-coat hypertension appear not to be protected from the atherosclerotic sequelae of hypertension.

OBJECTIVE We tested whether low SES was associated with reduced central serotonergic responsivity in a community sample of adult men and women and the extent to which standardized measures of aggression and impulsivity mediate the association. METHODS A total of 270 adults who were enrolled in a clinical trial on the neurobehavioral effects of lipid lowering were given a neuropharmacologic challenge (plasma prolactin response to orally administered fenfluramine) to measure serotonergic responsivity. Measures of family income and educational attainment were standardized and summed to derive an overall index of SES. Scores from the Brown-Goodwin Life History of Aggression interview, the Barratt Impulsiveness Scale, and the Angry Hostility subscale from the NEO Personality Inventory were also standardized and summed to form an aggression/impulsivity score. RESULTS Low SES was correlated with low prolactin responses to the fenfluramine challenge in the full sample (r = .15) as well as in whites, men, and women evaluated separately. Although the standardized SES score was correlated inversely with aggression/impulsivity measure (r = -.19, p < .01), the association between SES and prolactin responses remained significant when statistical adjustments were made for age, gender, body mass index, and aggression/impulsivity scores. CONCLUSIONS Blunted serotonergic responsivity is associated with low social class as measured by annual family income and educational attainment.

Background: Central nervous system (CNS) serotonergic activity correlates inversely with human aggressive behavior, and individual differences in aggressive disposition are at least partially heritable. This study was conducted to evaluate the possible association between measures of antagonistic behavior and an intronic polymorphism of the gene coding for tryptophan hydroxylase (TPH), the rate-limiting enzyme in serotonin biosynthesis. Methods: Locally recruited men and women ( n = 251) were genotyped for the A218C polymorphism located in intron 7 of the TPH gene. All subjects were administered standard interview and questionnaire indices of aggression and anger-related traits of personality; in a portion of subjects, CNS serotonergic activity was assessed by neuropsychopharmacologic challenge (prolactin response to fenfluramine hydrochloride). Results: Persons having any TPH U allele scored significantly higher on measures of aggression and tendency to experience unprovoked anger and were more likely to report expressing their anger outwardly than individuals homozygous for the alternate L allele. In men, but not women, peak prolactin response to fenfluramine was also attenuated among subjects having any U allele, relative to LL homozygotes. Conclusions: Individual differences in aggressive disposition are associated with an intronic polymorphism of the TPH gene in a nonpatient sample of community-derived volunteers.

To test the hypothesis that traits of aggression and impulsivity correlate negatively with central serotonergic system function in a nonpatient population, a standard fenfluramine challenge (for assessment of serotonergic responsivity) and behavioral measurements germane to aggression/impulsivity were administered to a community-derived sample of 119 men and women. In men, peak prolactin responses to fenfluramine correlated significantly with an interview-assessed life history of aggression (r = −.40, p < .002) , the Barratt Impulsiveness Scale (r = −.30, p < .03) , and traits of Conscientiousness (r = +.30, p < .03) , Neuroticism (r = −.31, p < .02) and Angry Hostility (r = −.35, p < .01) on the NEO-Personality Inventory. No significant relationships were observed across all women, although subanalyses restricted to postmenopausal subjects (in whom ovarian influences on prolactin secretion may be mitigated because of diminished estrogen) showed a pattern of behavioral associations somewhat similar to that seen in men. By extending documented relationships between an index of central serotonergic system function and traits of aggression and impulsivity to a more normative range of population variability than is represented in prior literature, this study supports speculation that these associations reflect a basic neurobehavioral dimension of individual differences.

Substantial epidemiologic evidence indicates that relative hypocholesterolemia in apparently healthy individuals is associated with increased subsequent mortality from cancer and other nonatherosclerotic causes of death. To test a hypothesis potentially underlying these unexplained associations, we evaluated whether individuals with hypo- and hypercholesterolemia differ in various enumerative and functional indices of the immune system. Nineteen healthy adult men with a mean age of 46 years and a mean total cholesterol concentration of 151 mg/dl constituted a low cholesterol group and were compared with 39 men of a similar age whose total cholesterol averaged 261 mg/dl. Relative to the high cholesterol group, hypocholesterolemic men had significantly fewer circulating lymphocytes, fewer total T cells, and fewer CD8+ cells (P's < 0.05). Trends toward fewer CD4+ cells and less IL-2 release in response to PHA were also noted in the low, compared to the high, cholesterol group. The low and high cholesterol groups did not differ in number of B lymphocytes, level of PHA-induced proliferation, number of natural killer (NK) cells, or degree of NK cytotoxicity. These data provide preliminary evidence of immune system differences in healthy individuals with hypo- and hypercholesterolemia.

OBJECTIVE The current investigation sought to determine whether intellectual performance is related to serum lipid concentrations. METHODS Subjects were 177 healthy, Caucasian adult males and females, aged 25 to 60 years, with widely varying total cholesterol concentrations. Crystallized intelligence was estimated from the Information and Vocabulary subtests of the Wechsler Adult Intelligence Scale, Revised (WAIS-R). Fluid intelligence was estimated from the WAIS-R Block Design subtest, and from a computerized version of the Letter Rotation test. RESULTS Controlling for age, better performance on both Information and Vocabulary subtests was associated with lower total and low-density lipoprotein (LDL) cholesterol and triglyceride concentrations (r's = -.24 to -.35, p's < .005). In contrast, better performance on Block Design was correlated with higher total and LDL cholesterol (r's = .22 to .23, p's < .005). Letter rotation response latency was unrelated to serum lipids. CONCLUSION These opposing relationships between serum cholesterol and different dimensions of intellectual performance, on the one hand, may reflect the propensity of knowledgeable individuals to consume low fat diets, and on the other hand, suggest that serum cholesterol concentration may be a correlate of brain nutrients important to mental efficiency.

Acute psychological stress is known to alter the distribution of circulating lymphocyte subsets and also to cause a reduction of plasma volume. Data were reanalyzed from 4 previously reported studies (E. A. Bachen et al., 1995; T. B. Herbert et al., 1994; A. L. Marsland, S. B. Manuck, T. V. Fazzari, C. J. Stewart, & B. S. Rabin, 1995; A. L. Marsland, S. B. Manuck, P. Wood, et al., 1995) to determine the extent to which changes in the concentration of lymphocyte subsets are attributable to such hemoconcentmtion. Meta-analytic procedures showed circulating concentrations of T-suppressor/cytotoxic (CD8) and natural killer (NK) cells to increase following acute laboratory challenge, whereas T-helper (CD4) and B- (CD19) cell populations did not change. Adjustments for concomitant hemoconcentmtion reduced the magnitude of stress-related increases in CD8 and NK cells significantly and revealed a decrease in CD4 and CD19 cell concentrations from baseline to stress measurements. These data provide evidence (a) that increases in circulating numbers of CD8 and NK cells following acute stress are partially attributable to hemoconcentration and Co)that CD4 and CD19 cell concentrations decrease during acute stress when hemoconcentration is taken into account.

To determine whether offspring of hypertensives show enhanced sympathetic nervous system activity, we evaluated several indices of sympathoadrenal activation and cardiovascular responsiveness to behavioral stimuli among 90 normotensive, young adult men having either one or two hypertensive parents (PH+(-), PH++) or normotensive parents only (PH--) (n = 30/group). Measurements included heart rate (HR) and blood pressure (BP) reactions to three mental stressors (the Stroop test, mental arithmetic, mirror tracing), a cold pressor test, postural adjustment (60 degrees upright tilt), isometric exercise and bicycle ergometry, as well as the 24-h excretion of catecholamines (epinephrine [E], norepinephrine [NE]) and venous plasma catecholamine concentrations, both at rest (seated and supine) and in response to the Stroop test and upright tilt. The three groups did not differ in age, education, body mass index (BMI), estimated aerobic fitness, resting HR, cardiac preejection period (PEP) and PEP:LVET (left ventricular ejection time) ratio, 24-h Na or K excretion, or fasting lipids, insulin or plasma renin activity. Resting systolic and diastolic BP varied as a function of parental hypertension, and were significantly higher in PH++ than among PH-- subjects (P.05). No significant group difference was observed on any measure of plasma or urinary catecholamines, nor did offspring of hypertensives (PH++ or PH+-) showed greater HR or BP reactions than PH-- subjects to any of the several laboratory challenges. In sum, we find no evidence of enhanced sympathetic activity or heightened cardiovascular responsiveness among normotensive young adults who are familially predisposed to essential hypertension.

A growing proportion of the general population is being prescribed antihypertensive medications for the long-term treatment of essential hypertension. Untreated hypertensive individuals exhibit some neuropsychological performance decrements, and numerous researchers have sought to determine whether drug therapy for hypertension worsens, improves, or leaves unaltered objectively measured cognitive skills. These issues may be especially important in the elderly, among whom both high blood pressure and compromised cognitive function are common. In this review, we collate the findings of more than 50 clinical studies according to class of antihypertensive medication studied and domains of neuropsychological performance assessed. Special attention is given to investigations of elderly subjects, and a critical summary is provided.

The current study evaluates the hypothesis, derived from previous investigations, that alterations in dietary fat and cholesterol influence the social behavior of monkeys. Subjects were 62 adult male, cynomolgus macaques (Macaca fascicularis) assigned originally to an investigation of atherosclerosis regression. This study thus involves a secondary analysis of data derived from an investigation conducted for another purpose. Animals were housed for 14 months' in social groups of five individuals each and initially fed a diet very high in saturated fat and cholesterol to induce coronary artery atherosclerosis. Monkeys were then exposed for 28 months to one of three conditions; (1) a moderately high-fat, high-cholesterol diet and an unstable social environment (in which monkeys were switched among groups monthly); (2) a low-fat, low-cholesterol diet and an unstable social environment; and (3) a low-fat, low-cholesterol diet and a stable social environment. A comparison of animals living in unstable groups revealed that those consuming the low-fat diet exhibited more overt aggression (P0.001) and overt submission (P0.01) than did monkeys eating the high-fat diet. A second comparison involved only those animals living in stable social units. These monkeys, while consuming the low-fat diet, engaged in more aggression and submission (P

In this study we evaluated effects of an acute experimental stressor on β2-adrenoceptor density and examined the relationships of baseline receptor density to cardiovascular reactions induced by stress. In addition, we investigated whether any observed alterations in receptor density were associated with concomitant redistribution of circulating lymphocyte populations. Receptor density and lymphocyte subsets were determined before and immediately following performance of a frustrating laboratory task in 22 male volunteers. Blood pressure, heart rate (HR), and plasma catecholamine concentrations were also assessed at baseline and during task performance. Parallel measurements were obtained among 11 unstressed control subjects. Receptor density increased significantly between baseline and posttask measurements, but equally so in experimental and control subjects. Numbers of T suppressor/cytotoxic and natural killer cells increased selectively among subjects assigned to the experimental (stress) condition. However, there was no association between lymphocyte subset distribution and receptor density. Interindividual variability in pretask receptor density correlated significantly with heart rate and systolic blood pressure (SBP) reactivity during the initial 3 min of mental stress, but not over the entire task period. In addition, baseline receptor density correlated with SBP (but not HR) reactivity after covariance adjustment for the concomitant change in plasma catecholamine concentrations.

Allostatic load is a commonly used metric of health risk based on the hypothesis that recurrent exposure to environmental demands (e.g., stress) engenders a progressive dysregulation of multiple physiological systems. Prominent indicators of response to environmental challenges, such as stress-related hormones, sympatho-vagal balance, or inflammatory cytokines, comprise primary allostatic mediators. Secondary mediators reflect ensuing biological alterations that accumulate over time and confer risk for clinical disease but overlap substantially with a second metric of health risk, the metabolic syndrome. Whether allostatic load mediators covary and thus warrant treatment as a unitary construct remains to be established and, in particular, the relation of allostatic load parameters to the metabolic syndrome requires elucidation. Here, we employ confirmatory factor analysis to test: 1) whether a single common factor underlies variation in physiological systems associated with allostatic load; and 2) whether allostatic load parameters continue to load on a single common factor if a second factor representing the metabolic syndrome is also modeled. Participants were 645 adults from Allegheny County, PA (30-54 years old, 82% non-Hispanic white, 52% female) who were free of confounding medications. Model fitting supported a single, second-order factor underlying variance in the allostatic load components available in this study (metabolic, inflammatory and vagal measures). Further, this common factor reflecting covariation among allostatic load components persisted when a latent factor representing metabolic syndrome facets was conjointly modeled. Overall, this study provides novel evidence that the modeled allostatic load components do share common variance as hypothesized. Moreover, the common variance suggests the existence of statistical coherence above and beyond that attributable to the metabolic syndrome.

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.

This study evaluated the temporal nature of cellular immune responses, as well as the effects of cardiovascular reactivity on immune responses after exposure to an acute psychological stressor. Lymphocyte subsets and lymphocyte proliferative response to phytohemagglutinin were assessed at baseline and at 5 and 21 minutes after stressor onset in the experimental group and at the same time points in a nonstressor control group. By 5 minutes after stressor onset, the number of CD8 suppressor/cytotoxic T and CD16/56 natural killer cells increased and proliferative response to phytohemagglutinin decreased. These changes were maintained at 21 minutes. Those subjects showing the greatest cardiovascular reactivity had the largest immune alterations. These data did not indicate that gender significantly moderated immune responses. Results are consistent with the hypothesis that sympathetic activation mediates stressor-induced quantitative alterations of peripheral blood lymphocyte subpopulations and nonspecific mitogen stimulated proliferation.

Serum cholesterol lowering is associated with elevated rates of death from violent or "unnatural" causes (including suicides, accidents, and homicide) (Muldoon et al 1990), and monkeys fed a low-fat diet are more aggressive than those receiving a diet rich in cholesterol and saturated fat. The low-fat diet derived 30% of calories from fat and had 0.03 mg cholesterol/Cal of diet, compared with 42% fat and 0.34 mg cholest.erol/Cal in the high-fat diet (Kaplan et ai 1992). However, the biological plausibility of a causal relationship between cholesterol lowering and destructive behavior cannot be evaluated due to the lack of research on the central nervous system (CNS) effects of serum lipidreducing treatments. Both suicidal behavior and impulsive aggression have been associated with low levels of CNS serotonergic activity (Mann et al 1989; Coccaro 1989). The present investigation, therefore, examines the hypothesis that the association between cholesterol reduction and de

Although the primary prevention of atherosclerotic disease events by the use of statins is both widely promoted and commonly prescribed, Mills et al. ([1][1]) astutely note that the clinical trial evidence for this clinical practice is inconsistent. There has been a lack of compelling evidence that

Although millions of hypertensive individuals receive chronic treatment with antihypertensive medication, the effect on the central nervous system by these drugs is poorly understood. Such treatment, while generally well tolerated, frequently produces symptoms of drowsiness, weakness, altered memory and impaired concentration. In addition to subjective evidence derived from patient reports, a large number of investigations have now been published which attempt to objectively assess the influence of antihypertensive medication on behavioral or cognitive performance. This paper summarizes and critically evaluates experimental studies of the effect of antihypertensive medication on subjects' performance of neuropsychological tasks and reviews the pharmacologic mechanisms by which these drugs may affect behavior. The literature is incomplete in its assessment of all domains of neuropsychological performance and all drug classes, and methodologic deficiencies are common. Nonetheless, the consensus of all studies and the findings of well-designed studies in particular do not identify any notable areas of performance impairment in patients receiving antihypertensive medication. Moreover, results suggest that, in certain instances, drug treatment may even enhance performance. In light of the limitations of the literature, however, an adequate understanding of the effects of antihypertensive therapy on behavioral functioning awaits completion of large, well-designed investigations including all major drug classes and thorough neurobehavioral assessments.

OBJECTIVE--To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials. DESIGN--Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years). PATIENTS--24,847 Male participants; mean age 47.5 years. MAIN OUTCOME MEASURES--Total and cause specific mortalities. RESULTS--Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04). CONCLUSIONS--The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.