Stephen B. Manuck, Ph.D. - US grants

Essential hypertension is a major public health problem. As such, an extensive literature has developed concerning its etiology and development. The data have consistently implicated psychosocial factors, most notably problems in the expression of anger and hostility; yet, conceptual and methodological problems have left many unanswered questions. The principal purpose of the proposed project is to examine two hypotheses that bear on this issue: (a) the critical psychosocial dimension in hypertension is not an intrapsychic conflict, but is a specific, measurable deficit in assertiveness; and (b) psychosocial factors (i.e., assertiveness deficits) are of significance primarily among hypertensives who show evidence of increased autonomic activity. Two studies will be conducted to examine these hypotheses. In one, three borderline hypertensive groups which differ in extent of suspected autonomic involvement (as marked by plasma renin levels, in conjunction with other indices sensitive to sympathetic nervous system activity), normotensive individuals with ulcerative colitis, and normotensives without a chronic illness will be compared on a variety of behavioral, self-report, and "significant other" measures of assertiveness and anger. A second study will compare young adults who have a hypertensive parent with a matched group having normotensive parents on a similar battery of measures. In both studies, individual differences in behaviorally-induced cardiovascular reactivity will be assessed, and examined in relation to assertiveness deficits. The second study will also examine the combined influences of parental hypertension and individual differences also examine the combined influences of parental hypertension and individual differences in stress-related physiologic reactivity on resting blood pressure measurements. The results will have implications for our understanding of the nature of essential hypertension and may point to a new strategy for treatment (i.e., social skills training).

Essential hypertension is a major public health problem. Extensive literature has arisen concerning not only its etiology and development, but also its physiologic and behavioral consequences. Several recent investigations demonstrate behavioral correlates of even mild hypertension among young adults. These correlates include subtle disturbances in perceptual, cognitive and psychomotor performance, decreased assertiveness, and heightened cardiovascular responsivity to behavioral stimuli. Recent emphasis on the control of hypertension has also led to widespread (and potentially long term) use of various antihypertensive medications, many of which differ in the mechanisms of their pharmacologic action. However, little is yet known concerning the effects of such agents on behavior: whether they lead to restoration of hypertension-associated deficits and/or generate new areas of behavioral dysfunction. Our purpose is to examine effects of a variety of common-prescribed antihypertensive medications across a broad range of behavioral and social functioning in male, mild essential hypertensive patients. Within each of two treatment conditions, 42 patients will be placed, for consecutive six-week trials, on two medications that differ in the extent of their pharmacologic effects on the central nervous system (lipophilic versus hydrophilic beta-blockers; diuretic versus a centrally-acting sympatholytic (e.g., alpha-agonist)). Comparison conditions will include both placebo-treated hypertensive patients and matched normotensive controls. Behavioral measurements assessing the neurobehavioral, psychophysiologic, and interpersonal functioning of subjects will be obtained at repeated intervals, both before and during treatment. By studying patients prospectively, matching them for a variety of variables that may concomitantly influence behavior (e.g., age), and by using each patient as his own control while on drugs of different pharmacologic types, it will be possible to partition those behavioral consequences attributable to hypertensive disease from those which are due to medications used to treat the disease.

Aggression is a prominent feature of many clinical conditions (such as antisocial personality disorder), a common cause of criminal incarceration, and a frequent concomitant of alcohol and other substance abuse. The social costs associated with aggressive behavior also rank among the primary concerns of contemporary society. In addition to environmental determinants, genetic factors contribute to the etiology of aggressive temperament. Reduced central nervous system (CNS) serotonergic activity is also correlated with human aggression, as seen in clinical, forensic and non patient samples. We have previously found that among unrelated individuals in a non patient population, life history of aggression and anger-related personality traits, as well as CNS serotonergic responsivity, are associated with polymorphisms of two genes regulating elements of the serotonergic system: tryptophan hydroxylase and monoamine oxidase A. The purpose of the proposed research is to confirm and extend these observations by more definitive methodology, utilizing family-based controls in conjunction with transmission-disequilibrium (TDT) analysis of adult, community volunteers and their parents. The primary study sample will include 800 individuals comprising relative ends (quartiles) of the population distribution of aggressive phenotype, as assessed by standardized clinical interview. Additional polymorphisms in the serotonergic system will also be evaluated, and if alleles of non-functional polymorphisms are found to differentiate high and low aggressive subjects, detailed molecular analyses will be conducted to identify functional variation that may account for these associations. Psychiatric characterization of study participants will be made by structured diagnostic evaluation and group differences in aggressive behavior will be confirmed by additional interview, questionnaire and observational measures of antagonistic disposition and impulsivity. The findings of this project will advance understanding of the genetic correlates of an important dimension of human temperament germane to antisocial behavior, violence, interpersonal distress, and personality-related psychopathology. This application is the resubmission of a prior proposal of the same title.

The principle objective of this Project is to establish whether psychosocial, socio-environmental and lifestyle-related risk factors for cardiovascular disease are associated, individually and in aggregate, with interindividual variability in central nervous system serotonergic (5-HT) responsivity. Behavioral risk factors of interest include hostility, depression, low socio-economic status, social isolation (low social support), contemporaneous stress, smoking, imprudent diet, physical inactivity, and excessive consumption of alcohol. A second aim is to determine whether individual differences in central serotonergic responsivity also covary with preclinical indicators of vascular disease and cumulative risk factor exposure (viz., endothelium-mediated dilation of the branchial artery, carotid artery intimal-medial thickness and atherosclerotic plaque). A third aim is to determine whether population variability in central serotonergic function may be predicted, in part, by polymorphic variation in candidate genes of the 5-HT system. We propose to recruit a community sample of 600 men and women, 30-50 years of age and without clinical history of atherosclerotic cardiovascular disease. Subjects will be administered a neuropsychopharmacologic challenge to evaluate central serotonergic responsivity (plasma prolactin and ACTH responses to the 5-HT re-uptake inhibitor, citalopram) and data will be collected in each of the foregoing domains of behavioral risk for cardiovascular disease. The latter will include a batter of diagnostic and assessment interviews, as well as standardized questionnaires. Ultrasound evaluations of vascular reactivity and carotid artery disease will be obtained on 300 subjects, derived from the upper and lower tertiles on the distribution of central 5-HT responsivity (as indexed by subjects' citalopram-induced prolactin responses). In addition, blood for DNA analysis will be obtained from all study participants. Project 1 will provide a first systematic test of the hypothesis that diverse sources of behavior risk for cardiovascular disease aggregate, in part, under the influence of a common neurobiologic mechanism involving altered central serotonergic function. Support for this hypothesis will further our understanding of the origins of behavioral influences on heart disease and provide clues to possible commonalities of etiology and pathogenicity.

The principal objective of Project 1 is to establish whether psychosocial and lifestyle-related risk factors for cardiovascular disease are associated with individual differences in the reactivity of key neural structures underlying emotional processing and appetitive motivation. It is hypothesized that heightened reactivity of the amygdala to emotionally-relevant stimuli will covary with traits of neuroticism (or negative affectivity and affect- specific indicators of depression symptomatology, anxiety, and antagonistic disposition;autonomic, neuroendocrine and hemodynamic indices of potential relevance to cardiovascular risk;and to biomarkers of preclinical vascular disease and cumulative risk factor exposure. It is also hypothesized that heightened reactivity of the ventral striatum to reward-related stimuli will covary with psychometric indices of low conscientiousness, impulsivity, and intertemporal choice;with health risk behaviors (e.g., cigarette smoking, physical inactivity);metabolic syndrome and component risk factors, and carotid artery atherosclerosis. An additional aim is to identify genetic and environmental correlates of these two neural dimensions of individual differences. We propose to recruit a community sample of 530 men and women, 30-55 years of age and without clinical history of atherosclerotic cardiovascular disease. Subjects will participate in an fMRI neuroimaging protocol to assess amygdala and ventral striatal reactivities to behavioral stimuli, and data will be collected in each of the foregoing domains of behavioral and biological risk for cardiovascular disease. The latter will include a battery of diagnostic and assessment interviews and questionnaires, ambulatory physiological and behavioral monitoring, biological risk assessments, and ultrasound evaluations of carotid artery disease. In addition, blood for DNA analysis will be obtained from all study participants. Project 1 will provide the first systematic test of the hypothesis that individual differences in behavioral risk for cardiovascular disease may stem from functional variation in the reactivity of neural structures contributing to negative affect (threat sensitivity) and impulsive decision-making "reward sensitivity"). Support for this hypothesis will further our understanding of the origins of behavioral influences on heart disease and provide clues to possible commonalities of etiology and pathogenicity.

Abstract This document describes a proposed research program for studying dispositional (personality) differences among individuals as predictors of changes in key indicators of healthy aging and disease risk over the middle years of life. The program aims to re-evaluate up to 875 men and women who previously participated in the Adult Health and Behavior (AHAB) project (conducted between 2001 and 2005) in the second wave of a proposed longitudinal study of aging. This work was submitted for funding consideration as part of a P01 (Program Project) grant to the National Institute on Aging (NIA) in May, 2015. The P01 application included two other projects, as well as Core facilities for centralized administration, program-wide data collection, and data management and biostatics. When the application appeared unlikely to meet the P01 pay line at NIA this year despite receiving a commendable priority score (19), we were invited to forward a plan for converting the highest scoring individual project into an R01 scope of funding. On offer was the possibility of moving this one project directly into the R01 funding pool without further scientific review. To do so required absorbing certain Core functions from the P01 application into the single project prospectus, which is accomplished in this document, along with a modified budget request.