David S. Krantz, PhD - US grants

The beta-adrenergic blocking drugs, introduced clinically for the treatment of cardiovascular disorders, have a variety of behavioral and psychological effects. Despite the fact that these drugs are among the most widely prescribed in the U.S., the mechanisms and extent of these effects remain poorly understood. One part of the proposed research examines the effects of CNS-penetrating and non-CNS-penetrating beta-blockers on a) behavior pattern Type A which has been implicated as a risk factor for ischemic heart disease (IHD), b) motor and vigilance performance (reaction time), and c) other behavioral side effects (e.g., fatigue, impotence, mood changes, sleep disturbance, anxiety-reduction) which patients widely experience. Two small clinical trials will compare the effects of various beta-blockers in patients with mild to moderate essential hypertension. In these studies, two control groups will consist of patients on a diuretic or a placebo. The first study will compare the effects of chronic administration of propranolol with atenolol. A second study will examine the relationship of beta 1 selectivity to behavioral effects by comparing nadolol with atenolol treatments. A third study involves acute administration of a beta-blocker and a beta-agonist to healthy subjects and examines the role of sympathetic reactivity in potentiating Type A behavior. A fourth study compares the acute effects of propranolol with atenolol. The broad objectives of this research are to understand psychophysiological mechanisms responsible for the expression of Type A behavior (an established IHD risk factor), and behavioral and psychological effects of beta-blocking medications at clinically-administered dosages. In addition, this research will yield basic information of potential use in further developing applications of beta-blockers, in the control of anxiety, anger, and untoward side effects, and in elucidating a possible application of beta-blockers in the primary prevention of coronary disease.

Myocardial ischemia is an Important clinical marker of coronary artery disease (CAD) activity that results from an Imbalance of myocardial oxygen supply and demand. The presence of ischemia, both in- and out- of-hospital, confers significant prognostic risk of cardiac events for CAD patients. Thus, understanding of the pathophysiology and triggers of myocardial ischemia may provide a link between the asymptomatic development of CAD and the occurrence of health-damaging clinical events, and Is also potentially Important for effective efforts at prevention and risk factor stratification. The broad goal of this revised project is to assess the role of myocardial oxygen supply and demand mechanisms in interaction with mental stress triggers in accounting for individual differences In ischemic activity. Prior research indicates that mental stress and daily activities interact with the biology of CAD to trigger ischemia, and that mental stress-induced ischemia and out-of-hospital ischemia occur in a subset of patients with CAD. Similarities between characteristics of ambulant ischemia and mental stress-induced ischemia have been noted, suggesting--but not proving--that common pathophysiologic mechanisms are operative. To investigate these mechanisms, the general hypothesis is of this project Is that individual differences In ischemic activity may be accountable for by levels of mental stress and by myocardial supply and demand mechanisms that relate to dysfunction of the coronary endothelium and to cardiovascular responsiveness to stress. Using quantitative angiography during cardiac catheterization, and non-invasive techniques (echocardiography and ambulatory ECG monitoring) to quantity mental stress-induced ischemia and out-of-hospital ischemia in separate sessions' specific aims of this project are to test the following hypotheses: (1) that patients with ischemia inducible by mental stress in the lab have more severe coronary endothelial dysfunction and Increased hemodynamic responses to stress compared to patients with ischemia Inducible with exercise alone; (2) that patients with daily life ischemia also evidence more severe endothelial dysfunction and Increased cardiovascular responses to stress; (3) that mental stress Is an Important determinant of daily life ischemia in patients with endothelial dysfunction; and (4) that changes in ambulant ischemia over time will be predicted by: initial endothelial dysfunction, susceptibility to mental stress ischemia, and changes in levels of mental and physical stress. Using a combination of non-invasive and Invasive methodologies, this project will assess possible mechanisms that may link the asymptomatic development of CAD to the occurrence of health damaging clinical events.

DESCRIPTION (provided by applicant): This revised application requests support for an interdisciplinary training program in cardiovascular behavioral medicine. The focal point of the program is the basic and/or clinical research training of predoctoral students and postdoctoral fellows around two programmatic themes: risk factors and prevention, and cardiac pathophysiology. This program builds on, and will become a part of a successful, longstanding, and widely recognized graduate research training program in Medical Psychology/Behavioral Medicine at the Uniformed Services University. Students in the proposed training program will receive a strong foundation in areas of behavioral science, cardiac physiology, and cardiovascular behavioral medicine that will have an important impact on improving cardiovascular health outcomes and reducing health disparities. All program faculty members have strong, well-established research programs, track records of significant multi-disciplinary research collaboration, and substantial commitments to biomedical and behavioral research training relevant to cardiovascular disease. Primary training for the pre-doctoral students in this program occurs in the research environment. This is richly supplemented with a formal educational curriculum that has trained outstanding graduate students and fellows for over twenty years. The postdoctoral program is also based on a research apprenticeship model. Journal clubs, seminars, and conferences will significantly contribute to the social and intellectual interactions of the trainees and faculty. The present focus on interdisciplinary training meets a need identified by the NHLBI (NHLBI Task Force on Behavioral Research on Cardiovascular Lung and Blood Disease, 1998). To ensure interdisciplinary preparation, this program will uniquely provide trainees with a strong background in basic biobehavioral methods and laboratory techniques, as well as clinical applications and interventions. This will prepare trainees to be leading biobehavioral investigators who are equipped to study the role of behavior in disease outcomes, to understand the social, behavioral, and biological bases of health disparities, and thereby help reduce cardiovascular morbidity and mortality.

[unreadable] DESCRIPTION (provided by applicant): Heart failure (HF) is an important clinical and public health problem in the U.S, and a major health care burden. Although advances in therapies for HF have improved survival, recurrent hospitalization rates, prevalence, and mortality remain high. The clinical course of HF includes repeated exacerbations that account for repeat hospitalizations and poor clinical outcomes. Precipitating factors for HF exacerbations such as uncontrolled hypertension and medication noncompliance have been identified, and emotional stress may also be an important precipitating factor. Knowledge of these factors has important implications for prevention and treatment. However, the prevalence, time trajectory, and interactions among these precipitating factors are poorly understood. The impact of mental stress in HF patients may be of clinical relevance since exercise capacity and activity levels are reduced in heart failure. Poor prognosis in CAD patients with HF is heightened by increased sympathetic activity and blood pressure, by decreases in LV function often associated with myocardial ischemia, and by malignant arrhythmias. Research demonstrates that emotional stress influences each of these mechanisms. Beta natriuretic peptide (BMP), secreted by cardiac myocytes in response to ventricular stretch and volume overload, is a biological marker of HF presence and severity. Recent advances provide the opportunity to utilize BMP as a more objective biomarker to study effects of emotional stress on HF exacerbations. The direct effects of emotional stress on markers of poor prognosis in HF (hemodynamic, cardiac function, ischemia, and electrophysiologic mechanisms) in CAD patients can also be studied in the laboratory. This project consists of a prospective study of HF precipitants in CAD patients, and a laboratory study of pathophysiologic mechanisms of emotional stress in the same population. Aims are: 1) to determine the prevalence and time trajectory of emotional stress as a precipitant of HF exacerbations as measured by >50% increases in the biomarker BMP. Secondary analyses will explore relationships between stress and measures of symptoms and functional status; (2) to determine the relationship of emotional stress to other precipitants (e.g., noncompliance with medications, uncontrolled hypertension, etc.) of HF exacerbations, and to determine if stress is a risk factor for HF worsening independent of other precipitants; and 3) to compare mental stress- induced changes in cardiac function, ischemia, and arrhythmic vulnerability in CAD patients with stress- related precipitants of HF exacerbations, to patients with non-stress precipitants, and to patients without exacerbations. This clinical research project will identify and enhanced understanding of the emotional stress and other precipitants of HF decompensation that will aid in preventive and treatment efforts. [unreadable] [unreadable] [unreadable]