James A. Blumenthal - US grants

The major aim of this project will be to test the hypothesis that the cardiovascular adaptations associated with increased levels of habitual physical activity in a sample of older adults will produce improvements in major quantifiable parameters, cognitive functioning, mood, and psychosocial functioning that have been previously noted to decline with advancing age. One hundred twenty old (60-69 years) healthy volunteers of both sexes will be randomly assigned either to a high intensity supervised aerobic exercise program (65-80% max VO-2), to a low intensity exercise program (less than 35% max VO-2) or to a no-exercise biweekly lecture series control group. At entry and after the completion of six months of exercise (or lecture series) subjects will undergo physiological and psychological testing. Cardiovascular function will be assessed by fatigue-limited exercise testing with expired gas analysis. Cognitive function will be assessed by two reaction time experiments that will examine potential changes in both the efficiency and attentional demands of short-term and long-term memory. In addition, subjects will complete a battery of neuropsychological tests, psychometric tests, and a semi-structured psychosocial interview. All subjects will also undergo a third follow-up assessment six months after the formal completion of the structured exercise program. We hypothesize that the cardiovascular adaptations associated with high intensity physical exercise training will be associated with significant improvements in cognitive abilities and psychosocial functioning. These improvements are expected to be greater than those observed for the low intensity exercise group, who will receive an equivalent amount of social stimulation but not cardiovascular conditioning. Data generated from this study will have important practical significance by determining the extent to which an intervention can improve the physical and psychological well-being of the elderly. The data will also have scientific significance through its potential to expand basic knowledge regarding (a) the cardiovascular physiology and cognitive functioning of normative aging, and (b) the extent to which the psychological and cardiovascular declines typically observed in normal aging may be modified through a program of aerobic conditioning.

Hypertension is a major cardiovascular disorder affecting 18% of the adult population in the United States. The goal of antihypertensive therapy is to minimize end-organ damage that can lead to kidney failure, stroke, and coronary heart disease. In addition, hypertension itself has been shown to be associated with impaired psychological functioning that may be reversed with blood pressure normalization. The present study is designed to test the hypothesis that chronic aerobic exercise will reduce blood pressure and improve quality of life in hypertensive men and women. One hundred twenty men and women with mild hypertension and 40 normotensive controls will serve as subjects for this study. First, the cognitive performance of hypertensives and normotensives will be compared. Second, hypertensive subjects will be randomly assigned to an aerobic exercise program, to a toning and flexibility group, or to a waiting list control group. Upon entry and after four months, subjects will undergo comprehensive evaluations including blood chemistries, symptom-limited treadmill testing, ambulatory blood pressure monitoring, and cognitive and psychometric testing. Subjects also will undergo a behavioral challenge to assess cardiovascular and neuroendocrine responsivity. We hypothesize that a program of regular exercise will attenuate cardiovascular and neuroendocrine responsivity, reduce blood pressure as measured in the laboratory and in the natural environment, and improve cognitive functioning. We will also examine the role of individual differences in responses to exercise training, including considerations of ethnicity and sympathetic nervous system tone. This project has important scientific significance by proposing to systematically evaluate the effects of aerobic exercise on blood pressure in patients with mild hypertension. The study also has important practical significance by evaluating the efficacy of non-pharmacologic management of hypertension. If successful, aerobic exercise could be implemented as a cost-effective strategy for reducing the physical, psychological, and economic costs associated with hypertension.

The purpose of this study is to determine if transient myocardial ischemia is related to the occurrence of stressful events in daily life and can be elicited in the laboratory, and to determine if behavioral interventions (stress management and aerobic exercise) can reduce this incidence.

Hypertension (HTN) is a major health problem in the United States placing some 58 million Americans at increased risk for stroke, myocardial infarction, kidney failure, and peripheral vascular disease. In addition, HTN is associated with subclinical changes in the heart (e.g., left ventricular hypertrophy) and in the brain (e.g., impairments of cognitive function). Although pharmacologic management of HTN is often effective, medications are not without complications and untoward side effects. Consequently, there has been a great deal of interest in the development and application of behavioral treatments for the management of HTN. The present study has three long term objectives. The first is to evaluate the efficacy of two behavioral interventions -- aerobic exercise and weight management -- in reducing blood pressure in men and women with mild HTN; the second is to examine the mechanisms by which blood pressure is reduced; and the third is to investigate the effects of behavioral treatments on cognitive performance and related aspects of quality of life. Two hundred unmedicated subjects with mild HTN will be randomly assigned to 6 months of mild-moderate aerobic exercise, moderate-intensive aerobic exercise, moderate exercise combined with weight management, intensive exercise combined with weight management, or a waiting list control group. Subjects will undergo comprehensive evaluations at baseline and at 6 months. Measurements of blood pressure will be obtained in the clinic, during everyday life using ambulatory blood pressure monitoring, and during physical exercise and mental stress testing. Blood pressures will also be obtained at 1 year follow-up. In order to examine potential mechanisms responsible for blood pressure changes, subjects will undergo glucose tolerance testing, studies of heart rate variability, and hemodynamic and neuroendocrine assessments. Because hypertension has been shown to be associated with measurable changes in cognitive function, which may be reversible when blood pressure is normalized, subjects will also complete a neuropsychological assessment battery along with psychometric testing. Finally, the clinical significance of the blood pressure changes will be determined by repeat cardiac echocardiography, as well as by repeated blood pressure testing at baseline, 6 months, and 1 year followup. The information obtained from this study will have important practical significance by determining the efficacy of exercise and weight reduction in lowering blood pressure in men and women with mild hypertension, and by assessing the clinical importance of these changes. Moreover, the study has important scientific significance by clarifying the mechanisms that may be responsible for the blood pressure reductions.

The purpose of this study is to determine the efficacy of exercise training relative to pharmacologic treatment in clinically depressed older adults aged 50 years and older. This study is a randomized controlled trial of exercise training and/or pharmacologic treatment (sertraline or Zoloft) in which subjects undergo comprehensive assessments including a clinical diagnostic evaluation, exercise treadmill testing, and medical examinations. Following this assessment, subjects are classified as mild/moderately or severely depressed and within these groups randomly assigned to one of three treatment groups: (a) medication (Zoloft); (b) aerobic exercise training; or (c) medication and exercise. Following the completion of the 4-month treatment program, subjects undergo a third evaluation at 6-month follow-up, and a fourth evaluation at 1 year follow-up. This study hypothesizes that: (1) an aerobic exercise program is feasible among older depressed patients, and the extent of improvement in cardiorespiratory function will be comparable to that of normal subjects; (2) an aerobic exercise program will be associated with comparable reductions in depression in mild-moderately depressed patients relative to mild-moderately depressed patients receiving medication alone; (3) drug therapy will be superior to exercise alone in the treatment of severely depressed patients; (4) aerobic exercises combined with medication will be superior to medication alone among severely depressed patients; (5) aerobic exercise training in mild-moderately depressed patients will be associated with less relapse at 6 months than patients receiving drug therapy alone; and (6) at 6 month and 1 year follow-ups, there will be greater relapse in the severely depressed patients receiving drug alone compared to patients who receive both drug and exercise training. This past year, we recruited 1 additional participant, a white male who was classified as severely depressed. This participant dropped out of the study following his Time 1 assessment. One hundred and fifty-six subjects have been enrolled during the past four years. Of these 156 subjects, 43 are male and 113 are female; 66 are classified as severe and 90 are classified as mild/moderate depressives. The ethnic breakdown of these 156 subjects is as follows: 133 Caucasions ( 39 male, 94 female); 18 African-Americans (3 male, 15 female); 3 Hispanic subjects ( 1 male, 2 female); 1 Native American female; and 1 Iranian female. Our protocol states that our ethnic breakdown will be 75% white and 25% minority, which we attempted to reach by participation in health fairs, contacting churches, and presentations. However, our total ethnic minority recruitment was 14.7%. In addition, our gender breakdown is currently 72% female and 28% male, which meets our protocol criteria (50% female and 50% male). In total, thirty-two (21%) subjects dropped out prematurely from the study (7 from medication only, 14 from exercise only, and 11 from exercise/medication). All active subjects (134 participants) have completed the four-month treatment and 6-month follow-up portions of the study. To date, 80 active subjects have completed the 18-month follow-up portions of the study. There are no plans to recruit further patients. Future plans include completing the 18-month follow-up assessments for all active participants, which is expected to continue through September, 1999. Additionally, we will be working on data analyses and manuscript publications and presentations. The information obtained from this study will have significant practical implications for the treatment of depression by clarifying the psychological benefits of exercise for older adults.

The purpose of this study is to determine the efficacy of a behavioral intervention, aerobic exercise, in lowering blood pressure in older Black men and women with mild hypertension and to investigate the mechanism of these effects. We will also determine if reductions in BP are associated with improvements in various aspects of quality of life, including cognitive gnat psychosocial functioning.

human therapy evaluation; social support network; isolation /deprivation; depression; myocardial infarction; psychosocial rehabilitation; quality of life; therapy compliance; health behavior; clinical trials; relapse /recurrence; health education; gender difference; psychosocial separation; racial /ethnic difference; psychological stressor; behavioral /social science research tag; human subject; electrocardiography;

DESCRIPTION (adapted from the applicant's abstract): The presence of transient myocardial ischemia is an important functional expression of coronary heart disease (CHD). Recent research has shown that mental stress can trigger ischemia in the laboratory and during daily life, and that mental stress-induced ischemia is associated with increased risk for coronary events over and above exercise-induced ischemia. The present study is designed to examine the extent to which a program of exercise or stress management training reduces ischemic activity measured in the laboratory using radionuclide ventriculography and during daily life using ambulatory monitoring. In addition, we propose to examine the bio-behavioral mechanisms by which mental stress triggers ischemia, and the mechanisms by which the inter-ventions reduce ischemic activity. Two hundred and ten patients with documented CHD and evidence of exercise-induced myocardial ischemia will serve as subjects for this study. Patients will be withdrawn from anti-ischemic medications and undergo comprehensive evaluations both in-hospital and out-of-hospital. In-hospital assessments will include provocative mental stress testing to elicit myocardial ischemia, ultrasound testing to assess endothelial function, and psychometric testing to assess underlying personality traits and behavioral dispositions. The out-of-hospital assessment will consist of 48-hour ischemia monitoring with concurrent blood pressure monitoring and behavioral diary recording. Following completion of the assessments, patients will resume their usual medications and will be randomly assigned to either Aerobic Exercise, Stress Management or Education/Routine Care. Patients will be re-evaluated after the four-month treatment program and thereafter followed for at least six months. It is hypothesized that exercise and stress management training will be associated with a reduction in ischemic activity, associated with reductions in blood pressure and systemic vascular resistance, and improved endothelial function. Data from this study will provide new scientific insights into the mechanisms of stress-induced myocardial ischemia, as well as important knowledge regarding the clinical benefits of exercise and stress management training in the treatment of CHD patients with myocardial ischemia.

The presence of transient myocardial ischemia is an important functional expression of coronary heart disease (CHD). Two hundred ten CHD patients will be recruited via local media and from surrounding area hospitals. All participants will have clinical evidence of CHD and evidence of transient myocardial ischemia on mental stress testing or ambulatory monitoring. After a comprehensive evaluation and baseline assessments, subjects will be randomly assigned to a Stress Management group, to an Exercise training group, or to a Usual Care control group. All intervention groups will last 16 weeks. The baseline and 16-week assessments include a physical examination; blood lipid and c-reactive protein assay (30 cc of blood); the completion of questionnaires; measures of hemodynamic response during mental and exercise stress testing via radionuclide ventriculography (RNV) testing; ambulatory ECG and blood pressure monitoring of myocardial ischemia; a non-invasive test of endothelial function; and a baroreflex assessment. The long-term clinical outcomes of these ischemic changes will be evaluated by obtaining patient medical records documenting cardiac events and by contacting patients annually after the second comprehensive assessment. We hypothesize that exercise and stress management training will be associated with a reduction in ischemic activity, associated with reductions in blood pressure and systemic vascular resistance, and improved endothelial function. Data from this study will provide new insights into the mechanisms of stress-induced myocardial ischemia, as well as important knowledge regarding the clinical benefits of exercise and stress management training in the treatment of CHD patients with myocardial ischemia.

DESCRIPTION (adapted from investigator's abstract): Lung transplantation is a relatively new procedure developed to increase life expectancy in selected individuals with irreversible end-stage lung disease. In the brief period since its inception, it appears that lung transplantation has achieved its initial aim of extending life. Despite these successes, lung transplantation remains fraught with difficult challenges for the patient and the medical community. The pre-surgical waiting period is a particularly stressful time. The long, uncertain wait for an organ, the marked decline in functional capacity, the tremendous financial burden, and the prospect of a complicated medical regimen after surgery, combine to exert a profound strain on patients' coping capacities. Not surprisingly, the rate of clinically significant psychological distress during this period is quite high, with rates of clinical depression, panic, anxiety and adjustment disorders far exceeding those observed in the general population. Although it is well established that brief, focused cognitive-behavioral therapy (CBT) can significantly improve psychological function in medically ill persons, the wide geographic distribution of transplant patients, along with their marked debilitation makes face-to-face delivery of such therapy extremely difficult. Recent pilot data have demonstrated the feasibility and short-term efficacy of a telephone-based psychological intervention with patients awaiting transplant. A larger, dual-site (Duke and Washington University), randomized trial using a relatively comprehensive set of outcome measures, over an extended follow-up period is proposed in which 600 pre-surgical lung transplant patients will be randomly assigned to either a telephone-based CBT intervention or to usual care. The study will examine the short- and longer-term impact of the intervention on psychological distress and quality of life as well as the effects of the intervention on morbidity, mortality, and medical costs during the pre- and post-operative periods. If the intervention is successful, it may serve as a model for the delivery of home-based, cost-effective treatment for seriously ill patients unable to benefit from more traditional face-to-face psychotherapy.

DESCRIPTION (provided by applicant): High Blood Pressure (HBP) is a major health problem in the United States, with most adults >35 years of age exhibiting BP above optimal levels. Persons with HBP exhibit subclinical vascular disease, which is associated with increased risk for cardiovascular and cerebrovascular morbidity and mortality. Although pharmacologic treatments have proven to be successful in reducing HBP in many patients, drug therapy is not always successful and may be associated with iatrogenic effects that compromise compliance and impair quality of life. Furthermore, abnormalities associated with HBP, including insulin resistance and dyslipidemia, may persist or may even be exacerbated by anti-hypertensive medications. Thus, there continues to be a need to develop behavioral treatments for reducing HBP. There is now good reason to believe that diet and exercise may be one such approach. The study proposed in this application will build upon our previous work in which we demonstrated that exercise, especially when combined with a behavioral weight loss program, resulted in clinically significant BP reductions. In addition, feeding studies have demonstrated that a diet high in low fat dairy products as well as fruits and vegetables (i.e., the DASH diet) may significantly reduce BP without weight loss. The present application seeks to extend these findings by (a) evaluating the efficacy of the DASH diet in a free-living situation; (b) considering the DASH diet alone and in combination with a cognitive-behavioral weight loss program including aerobic exercise; (c) examining the impact of diet and exercise on cardiac, metabolic, and vascular function, and (d) following patients for one year to determine the longer term impact of the interventions on BP, body weight, and cardiovascular function. One hundred twenty men and women with HBP will be randomly assigned to the DASH diet alone, the DASH diet combined with a behavioral weight loss program, or to a usual care control condition. Before and after 4 months of treatment, patients will undergo assessments of BP and measures of arterial stiffness, endothelial function, baroreflex control, body composition, insulin resistance, systemic hemodynamics, and left ventricular structure and function. Twelve month follow-up will assess maintenance of benefit. The data generated from this study will have important clinical significance by determining the extent to which the DASH diet, alone and combined with caloric restriction and exercise, may lower BP and improve associated risk factors.

oronary heart disease (CHD) is the leading cause of death in the United States, affecting 1 million people each year. The term "cardiovascular vulnerable patient" has been used to describe patients susceptible to acute coronary events based upon plaque, blood, or myocardial characteristics. Recent evidence also has suggested that depression is a significant and independent risk factor for patients with CHD, and also may be associated with increased cardiovascular vulnerability. This evidence has provided a rationale for developing interventional strategies for treating depression in cardiac patients. Antidepressant medications, especially selective serotonin reuptake inhibitors, have been particularly effective in this regard. However, for many patients medication fails to adequately relieve depressive symptoms or does so at the cost of unwanted side ffects. Thus, there is a need to identify alternative approaches for treating depression, particularly in patients with CHD. There is now good reason to believe that exercise may be one such approach. To date, however, the therapeutic potential of exercise has remained unfulfilled due to a paucity of data from well-designed clinical studies of depressed patients, and virtually no randomized controlled trials of depressed CHD patients. The study proposed in this application will build upon our previous work in which we demonstrated the feasibility and efficacy of exercise as a treatment for depression. Specifically, we propose to (a) evaluate the effectiveness of exercise training in reducing depression in vulnerable cardiac patients;(b) examine changes in intermediate endpoints, including measures of autonomic nervous system dysregulation, endothelial dysfunction, chronic inflammation, and platelet activation, which also serve as physiologic markers of cardiac vulnerability to arrhythmias, plaque rupture, and thrombosis;and (c) explore possible mechanisms by which the interventionsreduce depression. Two hundred men and women with CHD and elevated symptoms of depression will be randomly assigned to Exercise, Medication, or Placebo. Before and after 3 months of treatment, patients will undergo clinical assessments of depression and measures of heart ratevariability, baroreflex control, endothelial function, C-reactive protein, and platelet activity. A six month follow-up will assess maintenance of benefit and evaluate cardiac events and medical cost utilization. The data generated from this study will have important clinical significance by determining the extent to which exercise may reduce depression and improve intermediate markers of CHD risk in vulnerable cardiac patients.

DESCRIPTION (provided by applicant): This revised competing renewal application seeks to extend our previous work among patients with end stage lung disease to evaluate the effectiveness of a novel, enhanced coping skills training (CST) protocol for patients with chronic obstructive pulmonary disease (COPD). COPD is an obstructive airway disease marked by symptoms of dyspnea, paroxysmal coughing, pain, fatigue, and insomnia. Approximately 12.1 million Americans have been diagnosed with COPD and 70 percent of these cases represent individuals under the age of 65. COPD patients who are at an early stage of their disease often experience a progressive worsening of symptoms, while the advanced stages of the disease may be marked by frequent visits to the emergency department or inpatient hospitalizations for acute COPD exacerbations. Importantly, COPD also is a fatal condition for many patients, and is the fourth leading cause of preventable death for both men and women in the United States, with over 120,000 deaths reported in 2002. Although COPD is preventable (i.e., by not smoking), there is no cure for the disease and therefore the symptoms must be managed effectively. It has been well-established that brief, focused cognitive-behavioral therapy can significantly improve psychological function in medically ill persons, the wide geographic distribution of patients with COPD, along with their chronic exacerbations of illness, make face-to-face delivery of such therapy extremely difficult. Our previous work demonstrated that a telephone-based coping skills intervention (CST) with patients awaiting lung transplantation was effective in improving quality of life but did not improve physical functioning or survival. In that study, patients with COPD at an earlier stage of their disease process appeared to benefit most from CST. Thus, the present application proposes a larger, dual-site (Duke and Ohio State University), randomized trial among patients with COPD, using a comprehensive set of outcome measures over an extended follow-up period. Six hundred COPD patients will be randomly assigned to either a telephone-based enhanced, caregiver-assisted CST intervention or to a Usual care plus education and symptom monitoring Control group. Patients and their self-identified caregivers will undergo comprehensive assessments of physical and psychosocial functioning before and after a 16-week intervention. The study will examine the short- and longer- term impact of CST on psychological distress and quality of life as well as the effects of the intervention on morbidity, mortality, and medical costs over a follow-up period of up to 4 years. The ultimate goal of this research program is to develop more effective ways to help patients with chronic lung disease and their caregivers cope more effectively with problematic symptoms, reduce distress, improve quality of life, enhance physical functioning, and increase survival. Public Health Relevance: Chronic Obstructive Pulmonary Disease (COPD) is a significant health problem in the United States and throughout the world, and is considered the fourth leading cause of death in the US. This study will examine the effects of an enhanced coping skills training program for COPD patients and their caregivers, delivered by telephone, on patients'psychosocial and physical functioning and long-term survival.

Coronary heart disease (CHD) is the leading cause of death in the United States, affecting 1 million people each year. The term cardiovascular vulnerable patient has been used to describe patients susceptible to acute coronary events based upon plaque, blood, or myocardial characteristics. Epidemiological studies have shown that stress is a significant and independent risk factor for patients with CHD, and also may be associated with increased cardiovascular vulnerability. This evidence has provided a rationale for developing stress management training (SMT) interventions for CHD patients. Although cardiac rehabilitation (CR) is regarded as integral to the care of patients with CHD, SMT is currently not an essential component of most CR programs. We believe that the therapeutic potential of SMT has remained unfulfilled due to a paucity of well- designed clinical studies in CHD patients. Because randomized clinical trials (RCTs) employing hard endpoints-death or myocardial infarction-require large samples followed over long time intervals, such approaches are generally not feasible for most psychosocial RCTs. This application was developed in response to Program Announcement (PA-07-322), which invited proposals to examine the efficacy of SMT in improving intermediate outcomes, defined by biomarkers of cardiovascular risk purported to be in the pathway through which mental stress is thought to influence clinical events. The study proposed in this application will build upon our previous work in which we demonstrated the feasibility and efficacy of SMT in cardiovascular patients with stable CHD. Specifically, we propose to (a) evaluate the effectiveness of SMT combined with exercise-based CR in reducing stress in vulnerable cardiac patients; (b) examine changes in intermediate endpoints, including measures of cardiac vagal control, vascular endothelial dysfunction, inflammation, platelet function, and mental stress-induced myocardial ischemia, which are recognized biomarkers of cardiac vulnerability to clinical CHD events; (c) explore potential moderators and mediators by which SMT may improve biomarkers of risk; and (d) determine the impact of SMT on clinical endpoints over a mean follow-up period of 30 months. One hundred fifty men and women with CHD will be randomly assigned to exercise- based CR or to SMT-enhanced CR. Before and after 3 months of treatment, patients will undergo clinical assessments of stress and biomarkers of cardiovascular risk. Follow-up assessments will determine the maintenance of benefit and document cardiac events. The data generated from this study will have important clinical significance by determining the extent to which SMT combined with exercise-based CR reduces stress and improves prognosis in vulnerable cardiac patients.

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) is the leading cause of death and disability in the United States, affecting more than 81 million American adults. It is well established that risk factors such as hypertension, diabetes, and hyperlipidemia not only place individuals at risk for CVD, but also place them at risk for neurocognitive impairment and dementia. CVD risk factors have been shown to be associated with a cascade of neurophysiologic and neuroanatomic changes (e.g., narrowing of the small arteries in the subcortical regions of the brain, reduced cerebral blood flow, disruption of the blood-brain barrier), resulting in cognitive impairment and dementia. Patients with CVD risk factors who exhibit cognitive impairment without dementia (CIND) are considered to be in a transition stage between normal aging and early dementia. There is great interest in CIND because longitudinal studies have documented that such individuals are highly vulnerable to developing dementia. Exercise and diet have been shown to improve CVD risk factors and also appear particularly promising lifestyle approaches for preventing dementia. In this application, we propose a randomized clinical trial of patients with CVD risk factors who also are characterized by subjective cognitive complaints and objective evidence of neurocognitive deficits without dementia (CIND). A 2 by 2 design is proposed to examine the independent and combined effects of diet and exercise on neurocognition. Participants will be randomly assigned to 6 months of aerobic exercise, dietary modification using the DASH diet, or a combination of both exercise and diet; a fourth (control) group will receive health education but otherwise will maintain their usual dietary and activity habits. The study will aim to (a) evaluate the effectiveness of aerobic exercise and the DASH diet in improving neurocognitive functioning in patients with CVD risk factors and CIND; (b) examine possible mechanisms by which exercise and diet improve neurocognition; and (c) consider potential moderators of treatment, including subclinical CVD. These data will have important clinical significance by determining the extent to which lifestyle may improve neurocognition in patients vulnerable to neurocognitive decline and will identify key vascular and related biomarkers that may account for improved neurocognition among persons with CIND.

? DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the leading cause of death in the United States, affecting 600,000 Americans each year. The term cardiovascular vulnerable patient has been used to describe patients susceptible to acute coronary events based upon plaque, blood, or myocardial characteristics. Recent evidence has suggested that anxiety, which is common in CHD patients, may be a significant and independent prognostic factor that also increases cardiovascular vulnerability. This evidence has provided a rationale for reducing anxiety in cardiac patients. Anxiolytic medications, especially selective serotonin reuptake inhibitors (SSRIs), may be effective in this regard, although the value of these medications in reducing anxiety has not been widely studied in cardiac patients and their value in improving clinical outcomes is not known. Exercise also may be effective in reducing anxiety, although the therapeutic potential of exercise has remained unfulfilled due to a paucity of data from well-designed clinical studies. The study proposed in this application will (a) evaluate the effectiveness of exercise training and anxiolytic medication in reducing anxiety in vulnerable cardiac patients; (b) examine changes in intermediate endpoints, including measures of autonomic nervous system dysregulation, vascular endothelial dysfunction, and chronic inflammation, which also serve as physiologic markers of vulnerability to adverse cardiac events; (c) follow participants for up to 4 years to assess clinical events including fatal and non fatal cardiac events, hospitalizations, and medical costs; and (d) explore possible mechanisms by which the interventions improve outcomes. One hundred fifty men and women with CHD and an anxiety disorder or elevated symptoms of anxiety will be randomly assigned to Exercise, Medication (escitalopram), or Placebo. Before and after 3 months of treatment, patients will undergo clinical assessments of anxiety and measures of autonomic nervous system regulation, vascular endothelial function, and inflammation. A six month follow-up will assess maintenance of psychological benefit and clinical outcomes will be monitored for up to 4 years. The data generated from this study will have important clinical significance by determining the extent to which exercise and medication may reduce anxiety, improve intermediate markers of CHD risk, and improve medical outcomes including clinical events and CHD-related hospitalizations.

DESCRIPTION (provided by applicant): Hypertension (HTN) is considered to be the single most important risk factor for adverse cardiovascular events, including stroke, myocardial infarction and death. It has been estimated that 70% of the 68 million American adults with HTN receive pharmacological treatment, but only 46% have their blood pressure (BP) adequately controlled. Patients with BP that remains above goal (systolic blood pressure >140 mm Hg and/or diastolic blood pressure >90 mm Hg) despite the concurrent use of 3 or more classes of antihypertensive medications, including a diuretic, are considered to have resistant hypertension (RH). With the growing prevalence of HTN in this country, RH is a major public health concern, affecting more than 7.5 million Americans. Patients with RH are at high risk for CVD-related events, and there is a need to develop effective management strategies to help lower BP and reduce risk in these individuals. Surprisingly, there have been no randomized clinical trials (RCTs) evaluating whether an adjunctive lifestyle intervention that combines exercise, weight loss, and optimal nutrition featuring the DASH diet may help control BP and reduce CVD risk in patients with RH. This proposed RCT is designed to evaluate whether RH patients can achieve clinically significant BP lowering and improve other biomarkers of CVD risk through a lifestyle intervention delivered in a center-based cardiac rehabilitation facility (C-LIF) compared to a standardized education and physician advice control condition (SEPA). One hundred fifty men and women with RH will be randomized in a 2:1 design to C-LIFE or SEPA. We hypothesize that C-LIFE participants will (1) exhibit greater improvements in aerobic fitness, greater adherence to the DASH diet, and greater weight loss after 4 months compared to SEPA controls; (2) exhibit lower clinic BP and ambulatory BP after 4 months compared to SEPA controls; (3) exhibit greater regression of LV hypertrophy and greater improvements in CVD risk biomarkers including arterial stiffness, baroreceptor reflex sensitivity, insulin resistance, and inflammatory markers after 4 months compared to SEPA controls; (4) exhibit lower clinic BP and ABP, and improved CVD biomarkers at 1 year follow-up compared to SEPA controls. We also hypothesize that greater aerobic fitness, better adherence to the DASH diet, and greater weight loss will be associated with greater reductions in clinic BP at 4 months and at 1 year follow-up. I successful, the lifestyle intervention described in this application could be adopted by cardiac rehabilitation programs nationwide, and provide a viable non-pharmacologic treatment for managing patients with RH.

ABSTRACT For many patients with advanced lung disease, lung transplantation is the last viable treatment option to improve their quality of life (QoL) and extend their survival. With the growing number of individuals suffering from end-stage lung diseases, the frequency of lung transplantation has increased exponentially over the past two decades; more than 2,500 patients have been transplanted in the United States in 2016, a number that is expected to increase in the coming years. Despite advances in surgical techniques and medical management, median long term survival has plateaued at about 6 years, and, surprisingly, mental health QoL may not improve significantly after transplant. Developing treatments to extend life and improve QoL among individuals with advanced lung disease is a public health priority. Low functional capacity, physical inactivity, and heightened emotional distress are common following lung transplantation and are associated with increased risk of mortality and re-hospitalizations. Therefore we hypothesize that improving psychological well-being and functional capacity will further translate into improved QoL and better medical outcomes among lung transplant recipients. Prior research has shown that coping skills training (CST), designed both to teach patients self- management skills and to cope more effectively with psychological stress associated with chronic illness, is effective for a number of chronic conditions including diabetes, ischemic heart disease, arthritis, and heart failure. However, CST has not yet been evaluated as an intervention to facilitate self-management of lung transplant recipients, an even more complex condition in which patient self-management, regular exercise, and medication adherence are critical to successful outcomes. We propose a randomized clinical trial comparing a 12-week combined coping skills training and exercise (CSTEX) intervention with standard of care plus transplant education (SOC-ED) in a study sample of 150 lung transplant outpatients recruited from Duke University Medical Center and Washington University School of Medicine. The proposed CSTEX intervention, delivered by respiratory therapists using mHealth technology, is designed to reduce distress and depression and to improve key health behaviors, including physical activity, monitoring of pulmonary function, and adherence to medication, which have been shown to be related to medical outcomes in transplant recipients. Before and following treatment, overall distress and QoL indicated by both physical and mental health functioning, will be assessed. Effects of CSTEX on clinical outcomes also will be evaluated over a median follow-up period of 2.5 years. Findings from this trial could lead to the incorporation of coping skills training and exercise promotion into routine self-management interventions as cost-effective approaches to enhance disease management, QoL and medical outcomes in lung transplant patients and provide a basis for extending studies to other populations of patients with advanced lung disease.