Graduate

Biobehavioral Bases of CHD Risk and Management

NHLBI-funded Program Project, 2001-2006

This program project consists of an integrated, multidisciplinary program including 3 closely related projects examining the progression of atherosclerosis and/or its amelioration, which is supported by 4 core units. Project 1, which is conducted upon adolescents with persistently elevated blood pressure, will examine the effects of a behavioral intervention involving diet, exercise and stress management counseling. This project will assess the impact of the intervention on cardiovascular risk factors (e.g., lipid profiles, adiposity, inflammatory markers) and putative subclinical markers of disease (e.g., left ventricular mass, endothelial function). Project 2 will examine the effects of individual and group based cognitive behavior therapy (CBT) in acute myocardial infarction (AMI) patients who are at increased risk for medical morbidity and mortality after AMI because they are clinically depressed. Participants randomized into a CBT or usual care condition will be assessed in terms of biological risk factors (e.g., lipids, adiposity, coagulation factors) and possible subclinical markers of disease (e.g., carotid intima-media thickness, coronary calcification). The third project, which will be conducted on Watanabe Heritable Hyperlipidemic Rabbits (WHHL) will assess the role of: (a) the sympathetic nervous system (SNS) in behaviorally-related atherosclerosis; (b) corticotropin-releasing hormone in regulating SNS activity and progression of atherosclerosis during chronic social stress; (c) oxytocin (OT) in the hypothalamus as a function of social environment; and (d) OT in the regulation of hypothalamic pituitary adrenocortical and SNS activity in relation to the progression of behaviorally-related atherosclerosis. These 3 projects will each be supported by Administrative (Core A), Endocrinology and Metabolism (Core B), Cardiovascular Management (Core C) and Statistics/Data Management (Core D) units.

Investigators:

Project 1 - Modifying Risk in Youth with Elevated Blood Pressure

During the past 4 years, this project has examined the aggregation of cardiovascular disease risk factors among adolescents having either elevated or normal blood pressure (BP). It was found that adolescents with elevated BP had greater body mass, a poorer lipid profile, elevated blood glucose, decreased insulin sensitivity, and increased left ventricular mass (LVM). In preliminary studies we have provided evidence that a program involving stress management, diet and exercise counseling can reduce body weight, enhance physical activity, and lower BP.

The purpose of this project is to examine the long-term effects of 3 intervention conditions: 1) a 3 month self-management intervention program partially completed as part of the currently funded supplement; 2) a 6 month augmented self-management skill acquisition intervention program; 3) and usual care. The self-management interventions are designed to increase physical activity, improve nutrition, and enhance stress management. The study has three primary objectives: 1) to determine the impact of the interventions on lifestyle behaviors, cardiovascular risk factors, and preclinical disease states as indexed by LVM, endothelial function, and carotid intima medial thickness; 2) to examine the maintenance of behavior change and treatment effects across conditions; and 3) to determine what factors are associated with maintenance. Adolescents with persistently elevated BP at or above the 90th percentile adjusted for age, gender, and height will be randomized to one of three intervention conditions after the pretreatment assessments. The 3 conditions vary in level of demand. The 3 month self-management condition involves 10 group sessions plus some parental involvement. The augmented self-management condition involves 12 group and 6 individual sessions over 6 months with active parental involvement. Both self-management interventions will be followed by 6 monthly maintenance phone calls. Usual care involves one session in which the participants are provided with a participant workbook (summarizing the content and recommendations of the self-management intervention) and are asked to follow the suggestions. Participants in the 3 month self-management condition and the usual care condition will be reassessed at post-treatment (corresponding to 3 months post randomization), at 3 month follow-up, and at 6 months post treatment. Similarly, participants in the augmented self-management condition will repeat assessments following 3 months and 6 months of treatment and at 3 and 6 months post treatment. This design permits examination of treatment effects, and both short-term and long-term maintenance.

Key personnel

• Patrice G. Saab, Ph.D. - Project Leader
• Ronald B. Goldberg, M.D.
• Judy McCalla, Ph.D.
• Arthur LaPerriere, Ph.D.

Project 2 - Cognitive Behavioral Therapy in Acute Post-MI Patients

Depression is considered a psychosocial risk factor for medical morbidity and morality after acute myocardial infarction (AMI). Previous research has examined the effectiveness of cognitive-behavioral treatment (CBT) for depression in post-AMI patients on all cause mortality.

The proposed study will examine biological risk factors (e.g., lipoproteins, lipids, glucose tolerance, adiposity, insulin, inflammatory markers, coagulation factors), possible subclinical markers of disease (e.g., coronary calcification, elevated intima-media thickness [IMT] of carotid artery, decreased brachial artery vasodilation, increased left ventricular mass) or putative mediators (e.g., cortisol, catecholamines) of increased coronary heart disease (CHD) risk or putative subclinical markers of disease, in two populations of post-AMI patients. The populations will include depressed and non-depressed post-AMI patients. The depressed patients will be randomized into a CBT condition and a usual care/control condition. The therapeutic intervention will include risk factor reduction counseling and medication adherence in addition to the CBT for depression. The intervention will begin with individual sessions and in most cases progress to a group based intervention. All three groups of 110 patients per group (i.e., non-depressed, depressed CBT, and depressed usual care) will be assessed one-month post-AMI and six months later. The intervention group will be assessed both before and after treatment. Assessments will be in terms of psychosocial variables (e.g., depression), putative biological mediators (e.g., elevated cortisol), risk factors (e.g., elevated triglycerides) and possible subclinical markers of disease (e.g., coronary calcification) as well as demographic and medical characteristics.

Key personnel

• Neil Schneiderman, Ph.D. - Project Leader
• Rafael Sequeira, M.D.
• Patrice G. Saab, Ph.D.
• Marc Gellman, Ph.D.
• Karen Esposito, M.D., Ph.D.

Project 3 - Environment CNS, and Atheroclerosis in WHHL Rabbits

Recent findings from our laboratory have demonstrated that social behavioral factors can influence the progression of atherosclerosis in an animal model genetically predisposed to the development of disease, the Watanabe Heritable Hyperlipidemic Rabbit (WHHL). Specifically, it was found that stable social conditions, accompanied by increased affiliative social behavior, slowed the progression of atherosclerotic lesions in these animals. In contrast, animals in unstable social conditions, which is accompanied by increased agonistic behavior, and animals housed singly in cages exhibited significant aortic pathology. These data could not be explained entirely by resting plasma glucocorticoids, gonadal steroids, lipid levels, nor resting cardiovascular measures. Because regulation of bodily functions during stressful behavior is likely to involve the sympathetic nervous system (SNS) and the hypothalamic pituitary adrenocortical system (HPA), the proposed research will focus on role of these regulatory systems, and their interaction, in the behaviorally-related changes in atherosclerosis using this animal model. It is hypothesized that chronic activation of the SNS accelerates the progression of atherosclerosis either through hemodynamics changes or through regulation of cellular activity and inflammatory mechanisms within the vessel wall. In addition, the proposed work will examine Central Nervous System (CNS) mechanisms underlying the regulation of the SNS and HPA, focusing primarily on the roles of central corticotropin-releasing hormone (CRH) and oxytocin (OT) in the control of SNS and HPA responses. It is hypothesized that CRH, released centrally during stressful behavior, stimulates the SNS and HPA, thereby accelerating the progression of disease. In contrast, central OT, which has been linked to increased affiliative behavior, may act to buffer the organism during stable social conditions from the effects of stress by inhibiting the HPA axis, and consequently decreasing SNS activity. Another component of the proposed research plan will examine the role of risk factors related to the insulin resistance syndrome. Animals housed singly exhibited low glucocorticoid levels and showed little stressful behavior, yet still developed significant atherosclerosis. Upon further examination it was found that these sedentary animals gained more body weight than the other groups and had developed profound hyperinsulinemia, suggesting that metabolic factors may be particular important for the progression of disease in this group of dyslipidemic animals.

In order to address these issues, the proposed work will: 1) assess the role of the SNS in behaviorally-related atherosclerosis, and through the use of selective adrenergic receptor antagonists, focus on the relative contribution of alpha2- versus beta1-adrenergic receptors to disease progression, 2) determine the role of central CRH in the regulation of SNS activity and the progression of atherosclerosis during chronic social stress through the use of a centrally administered CRH antagonist, 3) measure changes in the release of OT in the hypothalamic paraventricular and supraoptic nuclei as a function of social environment through the use of chronic microdialysis, 4) through the use of an centrally administered OT antagonist, determine the role of central OT in the regulation of HPA and SNS activity, and its relationship to the progression of behaviorally-related atherosclerosis, 5) assess the impact of dietary restriction or daily exercise on the progression of atherosclerosis and risk factors related to the insulin-resistance syndrome in Socially Isolated WHHLs, 6) examine the influence of social environment on the progression of atherosclerosis in the Heterozygous WHHL, in order to develop an alternative animal model that more closely parallels lipid status and disease progression in a large percentage of humans. Because Coronary Heart Disease, and its underlying atherosclerosis, is the leading cause of death in the U.S., the development of an animal model to study the social/behavioral influences on atherosclerosis is important to determine the underlying mechanisms by which chronic emotional stress may accelerate the disease process. Through the use of this animal model, an understanding of the CNS, autonomic, and hormonal mechanisms involved in the pathophysiology of atherosclerosis also may help to identify intervention strategies which can attenuate , or slow the disease process.

Key personnel

• Philip McCabe, Ph.D. - Project Leader
• Neil Schneiderman, Ph.D.
• Jon Levine, Ph.D.
• Alan Herron, D.V.M.
• Julia Zaias, D.V.M.