Karen A. Matthews - US grants

The overall objective of our research program is to identify the biopsychosocial origins of the Type A behavior pattern. During the next three years, we propose to assess the familial patterns of individual Type A behaviors, their associated cardiovascular reactivity, and their determinants including family history of CHD, sex, modes of coping with and experiencing anxiety and anger, and parental childrearing practices and attitudes. To achieve this objective, all children currently enrolled in the ongoing longitudinal cohort study begun in 1979, their siblings attending school in the same school district as the case children, and their parents (number of families = 187) will be asked to participate in an individually administered experimental session, during which they will perform a difficult cognitive task, a frustrating psychomotor task, and an isometric exercise while their blood pressure and heart rate are intermittently measured. Participants will be administered the Type A interview and several questionnaires on their modes of coping with anxiety and anger. Parents only will complete several questionnaires on their reactions to their children's achievement and attitudes toward childrearing. Family medical history and Framingham Type A scores were already obtained from the parents and MYTH Type A ratings of the children were already obtained from the children's classroom teachers. In addition, three substudies of children only are planned. The aims of these substudies are to assess (a) the generalizability of children's cardiovascular responses to laboratory stressors to those induced by a naturally occurring stressor -- making a speech in class; (b) the consistency across one year of children's task-induced cardiovascular responses and their Type A interview behavior; and (c) the consistency of children's Type A behaviors in the classroom and their determinants across the six years during which approximately 190 children have been enrolled in the longitudinal study of children's Type A behaviors.

Description (provided by applicant): This is a competing renewal application for the training grant, HL07560 Cardiovascular Behavioral Medicine Research Training, continuously funded since 1983. The purpose of our program is to provide advanced training in cardiovascular behavioral medicine research to postdoctoral and predoctoral trainees. Specifically, our training program is designed to foster proficiency in four distinct areas: 1) Research methods and statistics, whereby the basic skills necessary for conducting research and for drawing valid inferences from empirical data are developed; 2) Cardiovascular physiology and psychophysiology, through which an understanding is established of cardiovascular functioning in the healthy human, and the availability of new technological advances that allow measurement of function; 3) Cardiovascular diseases, including distributions in human populations and principles of pathophysiology and physiology as related to disorders of the heart and vasculature and new tools to image subclinical and clinical cardiovascular diseases; and, 4) Principles of behavior and behavioral change through which an understanding is developed of such topics as learning, motivation, attitude and behavior change in individuals. This program benefits from the participation of enthusiastic and committed faculty from the Departments of Psychiatry, Medicine, Psychology, and Epidemiology, who are involved in collaborative research programs in cardiovascular behavioral medicine; the availability of appropriate course offerings in the School of Medicine, Graduate School of Public Health, and Department of Psychology targeted to achieve competency in the four distinct areas of cardiovascular behavioral medicine; a history of multidisciplinary research and training efforts by the above departments and their faculty; and new training resources at the University of Pittsburgh. Postdoctoral trainees can be physicians who have completed their residency in relevant specialties or doctorates in psychology or a related academic field and predoctoral students are individuals with a four-year college degree. Support is requested for five postdoctoral, four predoctoral, and two short-term summer trainees.

We plan to study cardiovascular risk factors among 500 premenopausal women and the change in risk factors during and following the menopause. Three different approaches are planned. 1) A cross-sectional study of 500 women ages 42+ at entry to the study to determine the relationship between risk factors, behavioral, psychosocial, and other environmental determinants. 2) A five year longitudinal followup of these women to evaluate changes over time in risk factors related to both the perimenopausal and postmenopausal period. 3) A longitudinal followup of the women following the menopause to determine the relationship between behavioral, hormonal, habits and risk factor changes. If this phase of the study is successful, longer term followup beyond the five year period is anticipated. The study will include a selection of a population sample of 500 women in Allegheny County who are premenopausal and aged 42+. We estimate that over five years at least 200 of these women will become postmenopausal. The women will have home interviews, baseline examination, followup of their menstrual cycles, and a six month self-administered questionnaire will be included. Menopause will be defined as one year of amenorrhea, validated by hormonal studies. The perimenopausal period as the first three months of amenorrhea. A perimenopausal examination followed by a postmenopausal examination and suitable control examinations will be included. Postmenopausal women will be followed with annual examinations. Dependent and independent variables to be measured include behavioral factors, exercise, cigarette smoking, nutrition, lipoproteins, blood pressure and hormones. The study should determine whether there is a group of women who become high risk in relation to cardiovascular and other diseases around the time of the menopause because of changes in risk factors and whether this group can be classified by behavioral, hormonal or genetic characteristics.

DESCRIPTION: (adapted from the applicant's abstract) Epidemiological investigations are unable to explain sex differences in coronary heart disease (CHD). The applicants propose that to the extent that individual differences in cardiovascular, neuroendocrine, and metabolic responses to behavioral challenge are a risk factor for CHD, sex differences in stress responses may assist in explaining sex differences in CHD. The ongoing research program has documented differences in psychological responses to acute stress between men and women and among women who vary in reproductive hormone status. Building on these findings, but also departing from previous efforts in strategy and design, the continuation application proposes five studies. Study 1 will measure hemodynamic measures that underlie sex differences in cardiovascular responses to behavioral challenge. Using longitudinal designs, Study 2 will compare women's stress responses prior to and three months after surgical menopause, whereas Study 3 will compare healthy women's stress responses prior to and three months after a "temporary menopause" due to the administration of a GnRH agonist. In both studies, some women after the second testing will be administered estrogen replacement therapy and stress responses will again be measures. Thus, Studies 2 and 3 will also address the effects of estrogen replacement therapy on stress responses. These studies gain significance from the fact that surgical menopause is associated with heightened risk for CHD, whereas estrogen replacement therapy is associated with protection from CHD. Study 4 will describe the extent of sex differences in exposure to psychological stressors among men and women from two levels of social class. Social class is included in the design because it is a risk factor for psychological stress and for CHD. The final study will test the hypothesis that sex differences in stress responses will be attenuated during a task within a feminine area of competency and accentuated during a task within a masculine area of competency.

DESCRIPTION: (adapted from the applicant's abstract) Epidemiological investigations are unable to explain sex differences in coronary heart disease (CHD). The applicants propose that to the extent that individual differences in cardiovascular, neuroendocrine, and metabolic responses to behavioral challenge are a risk factor for CHD, sex differences in stress responses may assist in explaining sex differences in CHD. The ongoing research program has documented differences in psychological responses to acute stress between men and women and among women who vary in reproductive hormone status. Building on these findings, but also departing from previous efforts in strategy and design, the continuation application proposes five studies. Study 1 will measure hemodynamic measures that underlie sex differences in cardiovascular responses to behavioral challenge. Using longitudinal designs, Study 2 will compare women's stress responses prior to and three months after surgical menopause, whereas Study 3 will compare healthy women's stress responses prior to and three months after a "temporary menopause" due to the administration of a GnRH agonist. In both studies, some women after the second testing will be administered estrogen replacement therapy and stress responses will again be measures. Thus, Studies 2 and 3 will also address the effects of estrogen replacement therapy on stress responses. These studies gain significance from the fact that surgical menopause is associated with heightened risk for CHD, whereas estrogen replacement therapy is associated with protection from CHD. Study 4 will describe the extent of sex differences in exposure to psychological stressors among men and women from two levels of social class. Social class is included in the design because it is a risk factor for psychological stress and for CHD. The final study will test the hypothesis that sex differences in stress responses will be attenuated during a task within a feminine area of competency and accentuated during a task within a masculine area of competency.

The major aims of our ongoing research have been: (a) to identify the early emergence and stability of children's hostile behaviors and their concomitant psychophysiological responses to stress, which may be risk factors for cardiovascular disease in adulthood; and (b) to specify their determinants. Our past studies examining the Type A behavior pattern, hostility, physiological responses and family interactive behaviors have primarily involved White, upper-middle class children and parents. We propose to extend our program of research to include the study of Black children and those from lower-middle to middle class families. This extension is important not only because these groups have been understudied, but also to examine developmental factors that may be important in accounting for the much higher incidence of hypertension and related disorders in Blacks and in lower and lower-middle class groups. However, we are adopting a somewhat different strategy of inquiry for the present proposal. Specifically, we will: (1) study the patterns of cardiovascular responses exhibited by Black and White children in order to better assess hemodynamic and autonomic nervous system mechanisms that underlie these responses; (b) examine how these hemodynamic patterns relate to cardiovascular risk factors such as body fat distribution, left ventricular geometry (via echocardiography), as well as insulin, glucose, and lipid levels; and (c) to explore a new conceptualization of hostility indices and cardiovascular risk factors. 160 Black and White children and adolescents of both genders will be recruited for participation, half being pre-pubescent (9-10 years old) and half being post-pubescent (15-16 years old). The first laboratory session will consist of a fasting venous blood draw, collection of anthropomorphic data, a psychophysiological stress protocol involving four tasks selected to elicit different autonomic nervous system responses, and completion of standardized questionnaires to assess hostility and social support. A second session will involve an echocardiographic assessment of left ventricular geometry and cardiac performance variables, the Type A Structured Interview, and an interview examining how subjects process information about hostile intentions and actions of others. The proposed project attempts to add significantly to the understanding of etiology of Black-White and social class differences in cardiovascular risk factors, and the role of hostility in this development.

This is an application for a Clinical Site in response to RFA AG-94-002. We have studied the menopausal transition in a sample of 541 initially healthy women, predominantly middle- and upper middle-class. Although the number of African American women and women with a high school education or less were in the minority in our sample, they had unique characteristics at study entry and experienced unique changes during the follow-up period. We now propose to recruit 450 premenopausal women of middle and lower class socioeconomic status into a longitudinal study of the menopausal transition; 150 of them will be African American. Women will be evaluated at study entry and at 4 (perimenopause) and 12 months (postmenopause) after the cessation of menses. Matched by age and race to peri- and post-menopausal women, premenopausal women will be evaluated at the same time to serve as controls for aging, seasonality, and repeat testing. With this study design, we will evaluate the hypotheses that independent of aging, change in reproductive hormones, marked by cessation of menses, leads to alterations in levels of lipids and lipoproteins, susceptibility to lipid peroxidation; cardiovascular responses to behavioral challenge; carotid artery vessel compliance and distensibility; endothelial function in the brachial artery; bone mass of the proximal femur, lumbar spine, and total body calcium; body composition; production of pro-inflammatory cytokines; health behaviors; and rates of clinical episodes of depression or anxiety and levels of depressive symptoms. We will compare the magnitude of changes in the above according to race and social class, as measured by educational attainment, and will test specific hypotheses about the interrelationships among the changes, e.g. changes in bone and correlated with changes in cytokines; changes in cardiovascular responses to stress are related to changes in compliance, distensibility, endothelial function, and LDL oxidative susceptibility. Little is known about the menopausal transition, especially in Africa American women and women of lower socioeconomic status, and this proposal aims to supply important missing information.

This application proposed to test the hypothesis that high levels of hostility, depressive symptoms, and stressful life events will be associated with all cause and cardiovascular disease (CVD) mortality after 16 years of follow-up in the Multiple Risk Factor Intervention Trial (MRFIT). MRFIT was a randomized, multicenter primary prevention trial designed to determine whether a special intervention consisting of smoking cessation, cholesterol reduction and control of high blood pressure, would result in a significant reduction in coronary heart disease (CHD) mortality, compared to usual care. The sample is composed of 12,866 men who at the time of study entry were in the top 15 percent of a risk score distribution based on the Framingham Heart Study data, but had no clinical evidence of CHD. During the trial, annual measurements were taken, which included some health behaviors, stressful life events, feelings of anger and hostility. A subset of 3,110 men also were administered once the Type A Structured Interview from which Potential for Hostility can be rated and all men who survived until the sixth year of the trial were administered the CES-Depression scale. After approximately 7 years of the active phase of the trial, the men have been followed for an additional 9 years for mortality and cause of death. To test the major study hypotheses, we will code all Type A Structured Interview tapes for Potential for Hostility, and components of hostility (Style, Intensity, Content) and we will construct and validate a self-report measure of hostility from items administered to all participants. Cox proportional hazard regression techniques will be used to test the association of hostility, depression, and stressful life events with all cause and CVD mortality. If the major study hypotheses are confirmed, then educational attainment, baseline risk factors, change in risk factors, and adherence indicators will be included in subsequent analyses. The proposed project presents a unique opportunity to test in a cost-efficient manner the association of psychosocial factors and mortality in a large, well characterized sample of middle-aged men.

This is an application for a Clinical Site in response to RFA AG-94-002. We have studied the menopausal transition in a sample of 541 initially healthy women, predominantly middle- and upper middle-class. Although the number of African American women and women with a high school education or less were in the minority in our sample, they had unique characteristics at study entry and experienced unique changes during the follow-up period. We now propose to recruit 450 premenopausal women of middle and lower class socioeconomic status into a longitudinal study of the menopausal transition; 150 of them will be African American. Women will be evaluated at study entry and at 4 (perimenopause) and 12 months (postmenopause) after the cessation of menses. Matched by age and race to peri- and post-menopausal women, premenopausal women will be evaluated at the same time to serve as controls for aging, seasonality, and repeat testing. With this study design, we will evaluate the hypotheses that independent of aging, change in reproductive hormones, marked by cessation of menses, leads to alterations in levels of lipids and lipoproteins, susceptibility to lipid peroxidation; cardiovascular responses to behavioral challenge; carotid artery vessel compliance and distensibility; endothelial function in the brachial artery; bone mass of the proximal femur, lumbar spine, and total body calcium; body composition; production of pro-inflammatory cytokines; health behaviors; and rates of clinical episodes of depression or anxiety and levels of depressive symptoms. We will compare the magnitude of changes in the above according to race and social class, as measured by educational attainment, and will test specific hypotheses about the interrelationships among the changes, e.g. changes in bone and correlated with changes in cytokines; changes in cardiovascular responses to stress are related to changes in compliance, distensibility, endothelial function, and LDL oxidative susceptibility. Little is known about the menopausal transition, especially in Africa American women and women of lower socioeconomic status, and this proposal aims to supply important missing information.

behavioral /social science research tag

DESCRIPTION (adapted from investigator's abstract): The primary aims of Project 3: Psychobiological Pathways: Risks for Subclinical CVD are to evaluate the influence of chronic burdens and resources, cardiovascular responses to acute stressors, and neuroendocrine activation on subclinical cardiovascular disease (CVD) in middle-aged women. Noninvasive measures of subclinical CVD can now be made reliably, are related to clinical events, and can be used to investigate new putative risk factors or to test models of the influences of risk factors. We are proposing to test the Center's shared pathways model in the context of the Healthy Women Study's current objectives to determine the risk factors for subclinical CVD. This is an ongoing epidemiological study of initially healthy women begun in 1983. Very detailed measurements of cardiovascular risk factors and psychosocial characteristics, including some measures of chronic burdens and resources similar to those proposed to be used in the Center. Recently ultrasound measures of carotid disease and coronary and aortic calcification measured by electron beam computed tomography (EBCT) have been added to the protocol and these measures will be administered twice three years apart over the next 5 years in 350 women. In the present Center project, we propose to conduct the following as well: a) administration of Center psychosocial measures; b) thorough evaluation of cardiovascular reactivity to psychological stress via impedance cardiography; c) 24 hour urine collection for catecholamine assays; and d) salivary cortisol measured periodically throughout one day. Understanding the development of subclinical CVD and the associated psychological, behavioral, and biological processes should lead to prevention or reduction of clinical cardiovascular disease among women. This study will be the first to track progression of calcification by EBCT and carotid plaque in younger postmenopausal women in relation to psychobiological pathways.

DESCRIPTION (provided by applicant): The Pittsburgh Mind-Body Center (PMBC) was established in 1999 to conduct research and training on the effects of beliefs, attitudes, values, and stress on multiple diseases, in accord with the NIH requirements for five newly funded "Centers for Mind/Body Interactions and Health." One of PMBC's specific aims relevant to its training mission is to hold week long Summer Institutes on mind-body interactions and health, with alternate years concentrating on behavioral antecedents of disease and disability, and on psychosocial interventions. To our knowledge, there is no other summer institute on these topics available at a national or international level. PMBC faculty have already conducted two Summer Institutes and gained valuable information and experience for the design and conduct of future Summer Institutes. This application requests three years of funding to partially support the costs of these Institutes and to defray the travel expenses of the attendees that were not budgeted as part of the original Center application. The specific goals of the Summer Institutes are to provide information about basic pathways linking behavioral, psychological, and biological connections between environmental factors and physical illness; to evaluate the importance of state-of-the-art psychosocial interventions in preventing disease and disability; and to enhance research skills, including problems solving, design of studies, and communication of ideas. The overall goal is to foster the development of a cadre of new investigators in mind-body science and health. We anticipate that 25 scientists will attend the Summer Institute each year, with 20 from outside Western Pennsylvania.

[unreadable] DESCRIPTION (provided by applicant): The Study of Women's Health Across the Nation (SWAN) is a multicenter, multiethnic, community based, longitudinal study designed to characterize the biological and psychosocial changes that occur during the menopausal transition and to assess their effect on women's health. Current and past funding (SWAN I and II) support six years of follow-up, at the end of which 60% of observable transitions to postmenopause will have occurred. Together, this competitive renewal application (SWAN HI) and a separate competitive supplement application request funding to complete a total of 10 cohort follow-up visits, allowing us to capture 91% of observable transitions to postmenopause and thus providing a more representative sample. The additional data will permit a focus on the late perimenopausal and early postmenopausal periods that have not been well studied in the literature. As women reach the end of early postmenopause (two years following the final menstrual period), we will shift from an annual to a bi-annual follow-up schedule with mail and telephone contact in the alternating years. This will set the stage for cost-effective and less intensive follow-up beyond SWAN lB. We will continue our current observations as well as undertake new science in each of the four scientific project areas (ovarian aging; symptoms, risk factors, functioning and aging; cardiovascular risk factors; and determinants and outcomes of bone mass). The new science includes measurement of vascular stiffness to assess early cardiovascular disease, salivary cortisol levels, vertebral morphometry using newly developed DEXA technology, and circulating androgens and total bioactive estrogens using an assay system developed by SWAN investigators. In addition, we will focus on linking the menopause and midlife experiences to age-related outcomes and chronic diseases, including physical and cognitive function. The additional follow-up will contribute to and expand the SWAN biological specimen repository (annual blood and urine samples as well as DNA and immortalized cells), a separately funded component that broadens the opportunities to address future hypotheses about health, disease and aging. With SWAN llI, many of the original goals of SWAN will be brought to fruition. We will build upon the rich foundation developed during SWAN I and II, and ultimately, link these data to subsequent age-related health outcomes. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This supplement to the Study of Women's Health Across the Nation (SWAN) II is designed to provide funds for the on time fielding of the seventh follow-up clinic visit for the SWAN cohort. SWAN is a multicenter, multiethnic, community based, longitudinal study to characterize the biological and psychosocial changes that occur during the menopausal transition and to assess their effect on women's health. Current and past funding (SWAN I and II) support six years of follow-up, at the end of which 60% of observable transitions to postmenopause will have occurred. This application requests funding for 10 months, for the timely initiation of the seventh follow-up clinical visit. A separate SWAN Iii application requests funds to finish the seventh follow-up and complete a total of 10 follow-up visits, so that the study can capture 91% of observable transitions to postmenopause and thus provide a more representative sample. The additional data will permit a focus on the late perimenopausal and early postmenopausal periods that have not been well studied in the literature. As women reach the end of early postmenopause (two years following the final menstrual period), we will shift from an annual to a bi-annual clinic visit with mail and telephone contact in the alternating years. This will set the stage for cost-effective and less intensive follow-up beyond SWAN Iii. We will continue our current observations as well as undertake new science in each of the four scientific project areas (ovarian aging; symptoms, risk factors, functioning, and aging; cardiovascular risk factors; and determinants and outcomes of bone mass). The new science includes measurement of: vascular stiffness to assess early cardiovascular disease, salivary cortisol levels, vertebral morphometry using newly developed DEXA technology, and circulating androgens and total bioactive estrogens using an assay system developed by SWAN investigators. In addition, we will focus on linking the midlife experience to age-related outcomes and chronic diseases, including physical and cognitive function. The additional follow-up will also contribute to and expand the SWAN biological specimen repository (annual blood and urine samples as well as DNA and immortalized cells), a separately funded component that broadens the opportunities to address future hypotheses about health, disease, and aging. With SWAN Iii, many of the original goals of SWAN will be brought to fruition. We will build upon the rich foundation developed during SWAN I and II, and ultimately, link these data to subsequent age-related health outcomes. [unreadable] [unreadable] INTEGRATIVE SCIENCE AND THE NEXUS TO AGING (OVERVIEW AND INTEGRATIVE). [unreadable] [unreadable] DESCRIPTION (provided by applicant): SWAN is exceptional in the breadth of data that are being collected across scientific areas. In the scientific projects that are encompassed in the subsequent 100 pages of this application, specific study hypotheses relating to each of the primary scientific areas are presented. However, by approaching scientific areas individually, we are in danger of over-simplifying the biological and social processes involved. A great strength of SWAN is our ability to approach the study of women at mid-life from a multi-disciplinary perspective. An Integrative Committee has been formed and charged with fostering the development of multidisciplinary lines of investigation. The Integrative Committee will also link the data collected in SWAN to the larger body of knowledge related to aging. At the outset of SWAN III, the mean age of the cohort will be almost 53 years of age and 884 women will have transitioned to postmenopause. This maturation of the study population invites explicit consideration of the nexus between the menopausal transition and chronological aging. The Integrative Committee will focus on the interface between menopause and aging, taking advantage of the unique cohort and breadth of data being collected. [unreadable] [unreadable] While a number of integrative lines of investigation will be pursued, in the following brief section, we preview one integrative approach to aging and menopause from conceptualization through data collection and analysis. As will be described in this preview, to gain a more comprehensive perspective of the biology and implications of the menopausal transition, ultimately we must move beyond the simplistic concept of estrogen deficiency. This will require a shift to a new paradigm. As an illustration of how this can be accomplished in SWAN, the following section develops an exploratory approach that represents a new way to pull together information across scientific disciplines. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Starting May 2000 we have been functioning as the Pittsburgh Mind-Body Center (PMBC-I) dedicated to: a) understanding shared psychological, behavioral, and psychobiological pathways that contribute to the onset of and recovery from diverse physical illnesses; and b) providing a training resource locally and nationally regarding mind-body relationships and health. We are now proposing to continue PMBC-II for an additional five years through the "Mind-Body Interactions and Health: Research Infrastructure Program (RFA OB-03- 004)". Based upon our accumulated research experience and accomplishments of the last 3 years, we intend to evaluate further the shared pathways model guiding our PMBC-I work in three ways: 1) unpacking key relevant concepts in the model, decomposing them and subjecting them to more micro-level analysis; 2) testing the influence of the life course on the pathways; and 3) extending the shared pathways model to diseases not already studied in PMBC-I. To carry out this work, we will have 5 research cores that will function in an orchestrated fashion: (A) Data Management and Statistical Resources; (B) Psychosocial and Health Behavior Assessment; (C) Sleep Assessment and Resources; and (D) Biological and Biomedical Measurement. To continue our research development and training mission, we will establish three infrastructure components: Innovative Pilot Research; Faculty Development; and Summer Institutes. Addressing the first aim of PMBC-II, an R01-like project (Stress and Brain Pathways to Reactivity) examines the central nervous system underpinning of cardiovascular reactivity to acute stress. The significance of PMBC-II rests upon the realization that many of the key mind-body concepts may be similar across diseases; that there is no home in mainstream health research for cross-disease research because of the specificity of most funding agencies; and that there is a potential for a multiplier effect from understanding shared pathways for explicating other diseases not directly part of the PMBC work. The infrastructure provided by PMBC-II will serve to integrate and promote research on the themes and research questions that the Center is designed to address. Support-in-kind from the host institutions will enable us to leverage the funds provided by the RFA to expand Center activities that would not otherwise be possible.

[unreadable] DESCRIPTION (provided by applicant): Growing evidence suggests that cardiovascular disease (CVD) morbidity and mortality may be predicted not only by established risk factors such as cholesterol level, hypertension, cigarette smoking, and hyperglycemia, but also by a set of emerging risk factors. These include the inflammatory markers, C reactive protein and interleukin 6, metabolic syndrome, and mild renal insufficiency. A project called HeartSCORE funded by the Commonwealth of Pennsylvania (Steven Reis, PI) is evaluating these emerging risk factors as well as coronary calcification, and brachial artery diameter in a population-based sample of 1000 African Americans and 1000 Caucasians. Our proposed project will build on this invaluable resource by examining another set of novel risk factors for CVD thought to be upstream from the more proximal, emerging risk factors: sleep disordered breathing (SDB) and psychosocial stress. Our project will evaluate whether links of both SDB and psychosocial stress with CVD risk may be due to their effects on nocturnal physiology, namely altered nonSDB sleep characteristics, nighttime elevation in blood pressure relative to daytime BP (termed nondipping), elevated urinary catecholamines and cortisol, and impaired autonomic tone. Thus, the general aim of this study is to understand the nocturnal psychophysiological underpinnings of cardiovascular morbidity and mortality. To address this general aim, we will study a multi-ethnic sample of 225 individuals drawn from two of the groups in the larger HeartSCORE design: (1) those who have high/moderate (hereafter labeled high) or (2) low Framingham risk equation scores, with no history of stroke, myocardial infarction, or interventional cardiology procedures in either group. The two groups will be matched on gender, race, and age. The proposed study will include two nights of polysomnography (PSG) conducted in participants' homes, two 24-hour periods of ambulatory blood pressure (ABP) monitoring, overnight urine collections on PSG night 2 and ABP night 2, wrist actigraghy on 10 nights, and assessment of self-report and other physiological indices. The study will provide novel data testing the relationships of daytime stressful events, SDB, and other nocturnal physiological measures with the emerging risk factors and subclinical CVD measured in HeartSCORE. [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The Study of Women's Health Across the Nation (SWAN) is a multicenter, multiethnic, community based longitudinal study designed to characterize the biological, symptomatic and psychosocial changes that occur during the menopausal transition and the effects of these changes on women's health during and after the transition. Current and prior funding (SWAN I and II) has supported a baseline and six annual follow-up examinations during which 895 (48%) women will have transitioned to postmenopause. This application requests funding to complete four additional follow-up visits (SWAN III) to allow an adequate evaluation of the late perimenopause and early postmenopause, a period that has not been well studied, particularly among non-white women. We will continue our current tracking of changes in reproductive hormones, bleeding patterns, symptoms, bone loss, cardiovascular (CV) risk factors blood pressure, body size, and other related characteristics and will undertake new scientific endeavors in targeted areas. These include measurement of vascular stiffness to assess early CV disease, assessment of vertebral morphometry at four sites using DEXA technology, and the addition of one cognitive function test. In addition, we will focus on linking the midlife experience to age-related outcomes (e.g. cognitive function, urinary incontinence) and chronic diseases (e.g. fractures, diabetes and hypertension). Specimens from the additional follow-up visits will continue to contribute to the SWAN biological specimen repository (annual blood and urine samples as well as DNA and immortalized cells). This is a separately funded component that broadens the opportunities to address future hypotheses about health and disease in aging women. As women reach the end of early postmenopause (two years following the final menstrual period), we will shift from an annual to a bi-annual follow-up examination schedule with mail and telephone contact in the alternating years. This will permit cost-effective and less intensive follow-up. SWAN's organization and operations have been modified to enhance productivity and we are poised to publish important biological, symptom and behavioral results pertaining to the menopause transition. With SWAN III, many of the original goals of SWAN will be brought to fruition. We will build upon the rich foundation developed during SWAN I and II and link these data to important menopause-related and health outcomes in SWAN III.

DESCRIPTION (provided by applicant): This application is a competing renewal application of T15 HL71805, Pittsburgh Mind-Body Summer Institutes, to partially support the Pittsburgh Mind-Body Center (PMBC-II) annual Summer Institutes. PMBC-I was established in 2000 to conduct research and training on mind-body relationships in the context of understanding multiple physical illnesses and will continue its educational mission under a R24 infrastructure support mechanism through 2009 (NIH RFA #06-03-004). One of the key specific aims of PMBC-I and II is to conduct annually a Summer Institute on mind-body interactions and health, with alternate years concentrating on behavioral antecedents of disease and disability, and on psychosocial interventions for physical illness. PMBC faculty have conducted 5 Summer Institutes and have had increasing success in recruiting and training talented young scientists or more senior scientists new to mind-body sciences. Evaluations of the Summer Institute encourage us to continue to provide this unique training experience, unavailable elsewhere. The specific goals of the Summer Institutes are to provide information about basic pathways linking psychological, behavioral, and biological connections between environmental factors and physical illness;to evaluate the efficacy and importance of state-of-the-art behavioral interventions in preventing disease and disability;and to enhance research skills, including problem solving, design of studies, and communication of ideas. The overall goal of the Summer Institutes is to foster the development of a cadre of new investigators in mind-body science and health. We anticipate that 30 scientists will attend the Summer Institute each year, with 20 from outside Western Pennsylvania.

DESCRIPTION (provided by applicant): This amended competing renewal application 2 R01 HL25767-28 proposes to continue our investigations of the psychobiological pathways connecting socioeconomic status (SES) with cardiovascular risk disease (CVD) factors in adolescence. In our most recent work, we have concentrated on understanding pathways leading to vascular stiffness and high blood pressure (BP). Because of the emerging epidemic of obesity and pre-clinical Type II diabetes in adolescence, we are changing the focus in the next stage of the research program to the metabolic syndrome and its component risk factors, especially central adiposity, elevated glucose (and insulin), and overall BP burden, as estimated by average daytime and nighttime BP and their ratio. Our most recent research suggests that several behavioral risk factors may have spillover effects onto nighttime physiology. Therefore, we are also planning to evaluate sleep disturbance in two ways: as a potential consequence of behavioral risk factors;and as a factor contributing to the metabolic syndrome and to elevated nighttime BP. Our proposed project will use the Reserve Capacity Model as an organizational framework. We plan to enroll into Project Pressure 250 adolescents (14 to 16 years of age), half high and half low SES families based on parental education and occupation. The sample will be composed of half African American and European American, and half male and half female adolescents. Each teenager will participate in two days and nights of ambulatory BP monitoring accompanied by diary ratings of positive and negative circumstances at the time of each daytime BP assessment. For one week, they will wear a wrist actigraph to measure sleep duration and fragmentation during school and weekend nights;and they will complete a short diary each morning and evening regarding key positive and negative experiences that day and quality of sleep. A blood draw and measurement of waist and hip circumference will allow calculation of the metabolic syndrome. The Reserve Capacity Model will be evaluated in a cross-sectional manner in the proposed project period. Should the Reserve Capacity model prove consistent with our cross-sectional data, we will propose in a later grant application to follow the sample for the predictors of change in CVD risk. PUBLIC HEALTH RELEVANCE: We propose to test if adolescents from low socioeconomic status (SES) backgrounds are at elevated risk for the metabolic syndrome, high nighttime blood pressure and sleep disturbance. To the extent SES is related to these precursors of diabetes and heart disease, we also will identify key psychobiological pathways connecting early SES to later health. The research has the potential of understanding the basis of adolescent health disparities.

DESCRIPTION (provided by applicant): We propose to continue the long term follow up of the Healthy Women Study that began in 1983-84 as the first study of the determinants of risk factors changes among women during the peri- to postmenopause. The HWS originally sampled 541 premenopausal women in 1983-84. This study has pioneered the use of new technologies for evaluating subclinical cardiovascular disease (CVD);first, carotid intimal medial thickness (IMT) in 1994 and then the addition of coronary and aortic calcium measurements using electron beam tomography (EBT) in 1997-98 (n=363). The subclinical vascular disease measurements were repeated twice, 3 years apart (2002-3 and 2004-7). At the 1st EBT study, the women had a mean age of 62;57% of the women had 0 coronary artery calcium (CAC) and by the 3rd EBT 37% of the women with 0 CAC had developed new CAC, an estimated 6% per year. We determined that premenopausal risk factors were the primary determinant of CAC. The extent of peripheral atherosclerosis, aorta and carotid measured at the time of the 1st EBT was an important determinant of the risk of developing new CAC among women with 0 CAC score at the 1st EBT by time of 3rd EBT examination 6 years later. In this application, we plan to repeat the coronary and aortic calcium studies and carotid ultrasound and vascular stiffness. We propose to add maximal exercise testing to determine functional capacity, and to measure cognitive function, history of clinical depression, physical functioning, and sleep quality and duration. We hypothesize that a small number of women, estimated to be 25% (N=75), will continue to have 0 CAC scores at age 73, that premenopausal risk factors will remain the primary determinants of CAC, even to the age of 73. We hypothesize that (a) measures of subclinical disease in other vascular beds, i.e. carotid and aorta, will be a primary determinant of the conversion from no CAC at 1st EBT to subsequent CAC over the 4 EBT measurements;(b) pulse wave velocity will be a predictor of the development of new CAC;and (c) women who have 0 CAC will have better functional capacity, cognitive function, and better sleep, and less depression and functional loss than those who have higher CAC scores, even in the absence of clinical coronary heart disease. We suggest that risk of vascular disease and healthy aging among postmenopausal women is primarily determined by premenopausal lifestyles and risk factors. PUBLIC HEALTH RELEVANCE: In the next phase of the Pittsburgh Healthy Women Study, we propose to test the hypotheses that (a) premenopausal cardiovascular risk factors are strong predictors of progression of coronary and aortic calcification and carotid intima media thickness measured 25 years later;and (b) postmenopausal women with no or low levels of subclinical atherosclerosis have concurrently better functional capacity, cognitive function, and sleep, and less depression and disability than those with higher levels.

DESCRIPTION (provided by applicant): The Study of Women's Health Across the Nation (SWAN) is a multi-center, multi-ethnic longitudinal study designed to characterize the physiological and psychosocial changes that occur during the menopausal transition and to observe their effects on subsequent health and risk factors for age-related diseases. The goals of the original RFA were to answer the following questions: How do hormones change with the menopausal transition? What factors affect the timing of the transition? What are the symptoms that accompany menopause and who is at risk? How do cardiovascular risk factors change with the transition and is there ethnic variation? What are the rates of bone loss with the transition? When does bone loss begin and what are the risk factors? What are the health consequences of menopause and who is at risk? SWAN is compiling the most comprehensive characterization to date of the health and the physiologic and psychosocial changes of women from pre- to postmenopause in community based samples. SWAN is now poised to study the effects of these menopause-related changes on subsequent healthy aging and on age-related diseases in the post-reproductive period. SWAN I was first funded in September 1994 by the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR), and the Office of Research on Women's Health (ORWH) in response to RFA AG-94-002, Menopause and Health in Aging Women. The first competing continuation of SWAN (SWAN II) was funded in 1999 and the second (SWAN III) in 2004. SWAN I, II and III have been supported by a cooperative agreement mechanism, with 9 funded components: 7 clinical centers, a central reproductive hormone laboratory (CLASS), and a coordinating center. A second central laboratory (MRL) was originally funded as a subcontract to the Coordinating Center (CC). In addition, a Core Repository of serum, plasma, and urine specimens and a DNA Repository were established in June 2000 under separate funding (U01 AG 17719, PI: Dr. MaryFran Sowers). For non-study-related reasons, site operations at New Jersey Medical School stopped in April 2004. The basis of this action was allegations made by two study employees who resigned abruptly. The SWAN PI and study coordinator were subsequently exonerated from these allegations. Please see Appendix 12 for a more complete report. The grant was transferred to the Albert Einstein College of Medicine in 2005. Since that time, the New Jersey PI and project director have worked tirelessly to overcome the obstacles to re-implement the study. As of June 1, 2008, a total of 155 women have successfully completed their clinic visit and five more visits are scheduled. We project that by the end of SWAN III, data will be available for 250 women. This has been very encouraging and thus Nanette Santoro, PI of the New Jersey SWAN site has been approved by the NIA to prepare a U01 application to cover further contacts for the Hispanic women. Please note that the SWAN IVproject applications pertain to the remaining six sites only. Information relative to the New Jersey site is covered in the separate application submitted by Dr. Nanette Santoro. From over 16,000 women aged 40-55 years who were screened during 1995-1997, 3302 women aged 42-52 years were enrolled in SWAN's longitudinal cohort (approximately 450 at each of 7 clinical centers). They completed their baseline clinic visit during 1996-1997. Of the 3302 women enrolled, 1550 were Caucasian, 935 African American, 286 Hispanic, 250 Chinese, and 281 Japanese. A subset of 880 menstruating women was enrolled in the Daily Hormone Study (DHS) started in 1997, which is designed to examine cyclical daily hormone and symptom patterns during the menopausal transition.

DESCRIPTION (provided by applicant): Black men suffer disproportionately from premature mortality and cardiovascular disease (CVD) compared to their white counterparts, perhaps in part due to blacks' greater exposure to social and economic adversity across the life span as suggested by the weathering hypothesis. This application suggests that (a) black-white differences in CVD in adulthood stem from cumulative adversity correlated with race much earlier in life; and (b) early life exposures at the individual, family, and neighborhood level mus be considered simultaneously. Not emphasized in the weathering hypothesis is that intra- and inter-personal and cultural resources also may accumulate over the life course (labeled reserve capacity) and moderate effects of early life adversity; and that there may also be a critical perio exposure to adverse life events. Sleep may be an important factor here because of its likely relation to race and socioeconomic status (SES), and possibly to CVD events. This application focuses on the developmental antecedents of sleep, optimal cardiovascular (CV) health (defined by AHA criteria), and CVD risk in a population-based study of middle-aged black and white men who have been followed since they were enrolled in the first grade. They have been assessed repeatedly for health behaviors and academic and social competence; parent health behaviors, parenting practices, and household SES; and neighborhood characteristics, including census track SES, violence exposure, and community cohesiveness and involvement; these measures have been summarized into developmentally appropriate periods. In 300 men now in their late thirties, we propose to collect measures of CV biomarkers and psychosocial risk factors and sleep to test the following: 1) the extent of black/white differences in sleep, optimal CV health, and CVD risk, and sleep; 2) whether early adverse family and neighborhood environments, particularly during adolescence, predict adult optimal CV health, CVD risk, and sleep; and 3) if reserve capacity reduces the impact of early adverse environments. Knowledge gained from this project may identify the early life experiences and their timing that render black men particularly vulnerable to later CVD.

DESCRIPTION (provided by applicant): This is the amended competing renewal application of the Study of Women's Health Across the Nation (SWAN), a 7-site longitudinal cohort study initiated in 1994 in response to RFA AG-94-002. SWAN was mandated to characterize the chronology of the biological and psychosocial antecedents and sequelae of the menopausal transition (MT) and the effect of this transition on subsequent health and risk factors for age- related disease, and to extend this information from White women to ...the range of peri-menopausal experiences in women of other racial/ethnic background(s). A total of 3302 Black, Chinese, Japanese, Hispanic and White women were enrolled, with 78% completing up to 13 visits spanning the premenopause to early post-menopause (PM). Thus far, SWAN has described the natural history of the MT -- its timing, patterns of hormonal changes, and symptoms and factors related to them - and their relation to disease risk indicators. During SWAN V, we will extend observations through the late PM, a necessary step to assess the impact of the MT on age-related diseases. Our specific aims are to: 1) complete the characterization of the natural history of reproductive aging through the late PM; 2) evaluate the impact of reproductive aging through the late PM on health outcomes clinically relevant to women in their 60s and 70s, including: cognitive and physical function, psychological well-being, sleep, bone and cardiometabolic health, urogenital symptoms, sexual function and vaginal health; and 3) identify potential underlying mechanisms linking reproductive aging and health by assessing the relation of inflammation, hemostasis and adipokines to the occurrence and progression of biological, functional and clinical outcomes and delineating the interrelationships of body size and composition, race/ethnicity and socioeconomic status with these outcomes. The SWAN V Core protocol will be completed at 7 study sites, with bone and cardiovascular studies at 4 sites and actigraphy studies in a subset of women at all sites. Longitudinal specimens from the SWAN Repository will enable characterization of skeletal markers, adrenal hormones, hemostasis, inflammation, and adipokines across the MT into PM. The Coordinating Center will provide the necessary organizational infrastructure, statistical resources, and timely dissemination of high quality SWAN data. The CLIA-certified Central Laboratory will perform or coordinate with other laboratories to provide accurate, high volume assays, adopting new methods as needed to provide state- of-the-art data. SWAN is uniquely positioned to fill important scientific gaps in understanding of the impact of the MT on women's health in their 60s and 70s and to facilitate the application of new knowledge to clinical practice. With 1.5 decades of both calendar time and menopause time, SWAN V can disaggregate the contributions of aging and the MT to women's health, address difficult and critical questions about the temporal nature of MT-disease associations, assess differences by race/ethnicity, and provide insights into modifiable factors relevant to the design of innovative prevention and treatment programs for aging women.

DESCRIPTION (provided by applicant): In this revised application, we addressed the IRG's concerns: we clarified the number/type of assessments on the 3 subject groups; proposed a further Hypothesis that mirrors better the use of childhood archival data about probands and their sibs; added ICAM-1 to our biological markers; and responded to various other concerns. Our study focuses on depression and coronary heart disease (CHD), which are enormous public health problems across the world. Depression not only predicts new onset CHD, and morbidity, and mortality in those with existing CHD but also is associated with behavioral risk factors (e.g. smoking, being sedentary) for eventual CHD. Although the depression-CHD link is well established, the causal role of depression is still being debated, and its most cardiotoxic features are yet to be confirmed. Notably, although both depression and CHD often originate in the pre-adult years, few studies have examined their association with behavioral CHD risk factors in a developmental context. We propose to assess 3 established samples of young adults in Hungary: a) probands (n=325), whom we have followed since childhood, when they had their first episode of major depression around the mean age of 9 years, b) never-depressed siblings of probands (n=325), and c) normal peer controls (n=155). We recently reported that: a) proband families have elevated rates of parental CV disease, b) by adolescence (mean age=17 years), being a proband predicted increased rates of behavioral risk factors for CHD (e.g., smoking, being sedentary), and c) rates of behavioral risk factors were highest among probands, lowest among controls, and intermediate among never depressed siblings of probands. The goal of the proposed study is to assess, for the first time, traditional biological risk factors (e.g., LDL cholesterol, blood pressure), along with behavioral risk factors, and several markers of CHD risk: pulse wave velocity, interleukin-6 and C-reactive protein (inflammation), ICAM-1 (endothelial function), and the metabolic syndrome. Our hypotheses address the levels of CHD risk markers as a function of subject group, the role of behavioral risk factors in adolescence in the link between depression and preclinical physiological outcomes, the impact of developmental trajectories of stress and risk variables on physiological outcomes among probands-sibs, and the most cardiotoxic clinical features of depression. Our extensive archival data on subjects' psychiatric history, family stress events, parental history of cardiovascular disease, socio-demographic variables, and various behavioral risk factors for CHD will yield a unique characterization of the unfolding relationships among depression, behavioral risk factors, and early markers of CHD risk. The sibling design will help isolate the contribution of depression to early markers of CHD risk by controlling for the adverse health impact of several family-based variables. Given the public health burden posed by depression and CHD, their study in young adults is particularly warranted, because risk factors and/or preclinical signs of CHD risk may be easier to modify earlier, rather than later, in the lifespan.