| ABSTRACTS CURRENT AWARDS (as
Principal Investigator)
RO1 National Institutes on Aging 2001-2005 Aging is associated with alterations in left ventricular (LV) relaxation and compliance, even in the absence of manifest co-morbid conditions such as coronary artery disease or hypertension. This "diastolic dysfunction" may result in an elevation of LV filling pressure and cause signs and symptoms of congestive heart failure (CHF) despite the presence of preserved systolic function. This problem is critical for elderly CHF patients in whom nearly 1/2 may have predominantly diastolic dysfunction as the cause of their heart failure. The broad objective of this proposal is to determine the precise alterations of diastolic function associated with normal, healthy aging in humans, and compare these changes with those associated with CHF due to diastolic dysfunction. The hypotheses to be tested include: 1) Normal aging is associated with alterations in both relaxation and chamber compliance of the LV leading to impaired ventricular filling compared to healthy young adults. Moreover, such abnormalities will be substantially reduced in fit compared to sedentary healthy elderly subjects; 2) Patients with CHF and preserved LV systolic function have more pronounced abnormalities of LV chamber compliance and relaxation which contribute to the development of CHF; 3) Exercise training in both the healthy aged, as well as patients with CHF and diastolic dysfunction will improve abnormalities of diastolic function and will be an effective therapy for this disease. To test these hypotheses, we propose to accomplish the following specific aims: a) To measure the static component of diastole directly by constructing ventricular function (Starling) and LV pressure/volume curves in well, sedentary and fit elderly adults. The dynamic component of diastole will be assessed using state-of-the-art imaging techniques including: tissue Doppler imaging; color Doppler M-mode echo; and magnetic resonance imaging with myocardial tagging. b) To select a group of patients with CHF but preserved systolic function, and to quantify left ventricular relaxation and compliance using the same methods; c) To repeat the specific measures of diastolic function after a prolonged (one year) endurance exercise training program in both the sedentary elderly, and patients with CHF and diastolic dysfunction. These studies will result in a comprehensive understanding of the effect of normal aging and physical conditioning on LV diastolic function, and will identify the specific abnormalities of diastole which lead to CHF in the absence of contractile dysfunction. The precise dose of exercise necessary to restore normal diastolic function will be identified and will allow specific exercise prescription for these populations. Heat Intolerance in Elderly Patients with CHF Doris Duke Foundation 2000-2003 Congestive heart failure (CHF) in the elderly is a problem of great national importance, limiting the functional and adaptive capacity of the aging population and causing substantial morbidity and mortality. One complicating factor that may be particularly important, but is often ignored, is tolerance to heat stress. During exposure to a hyperthermic environment, systemic vascular resistance decreases due to cutaneous vasodilation. In order to maintain blood pressure, cardiac output must increase -- in normal subjects up to 12 liters/min during whole body heating. In a condition such as CHF where a cardiac output of 8-12 liters/ min may not be achievable, during a heat stress the patient will either not maintain blood pressure or will not perfuse the skin adequately for thermoregulation leading to grave risk for heat injury. Given the aging of the United States population, coupled with the increased prevalence of CHF in the elderly, there is a growing population of elderly patients with CHF who are at particular risk for complications related to heat injury. Despite the clinical importance of this problem, there are virtually no studies reported in the literature investigating the mechanisms of heat intolerance in patients with CHF. Therefore the global objective of this proposal is to test the overall hypothesis that altered hemodynamics, combined with abnormal neurohormonal control of the circulation in CHF patients leads to impaired thermoregulation and increased risk for heat injury. The following specific hypotheses will be tested: 1) Elderly patients with CHF have limited systolic and diastolic reserve, and thus are unable to increase cardiac output sufficiently to increase skin blood flow (SkBF) appropriately for thermoregulation during a heat stress; 2) Pre- and post-synaptic regulation of SkBF is altered in elderly patients with CHF independent of the magnitude of hemodynamic impairment; 3) Arterial and cardiopulmonary baroreflexes are impaired in elderly patients with CHF, leading to hypotension and impaired thermoregulation during heat stress. Upon completion of these studies, the mechanisms of a serious medical problem of growing significance, namely heat intolerance in the elderly with CHF, will be elucidated.Post-space flight orthostatic hypotension/intolerance occurs in 25 to 66% of crew members upon returning to a 1 G environment. The mechanism(s) causing this response are not completely understood. Identification of countermeasures to reduce the incidence of orthostatic intolerance associated with space flight is paramount to NASA's mission. One such countermeasure may be skin surface cooling. In light of this, three specific objectives will be accomplished by the proposal work: 1) Identify an optimal skin surface cooling paradigm that causes the largest increase in autonomic responses (i.e. stroke volume, blood pressure, sympathetic nerve activity, etc.) without causing shivering or altering motor function. 2) Identify the mechanisms by which skin surface cooling increases the aforementioned autonomic responses resulting in improved tolerance to orthostatic stress. 3) Identify whether skin surface cooling is an effective countermeasure to improve orthostatic tolerance in men and women following simulated microgravity exposure using the head-down tilt bed rest model. Upon completion of the proposed studies important information will be provided that will be beneficial for both operational and safety concerns for astronauts, as well as to individuals who suffer from idiopathic orthostatic intolerance.
Cardiovascular Collapse: Mechanisms of Individual Variability In Susceptibility to Syncope Wallace, Barbara and Kelly King Foundation Trust Cardiovascular collapse, or syncope, is a catastrophic event which may lead to sudden cardiac death. Syncope – the sudden loss of consciousness due to failure of the heart to pump enough blood to the brain – is responsible for approximately 2% of all emergency room visits in the United States, affecting more than 1 million individuals annually at a cost of more than $1 billion/year (source: Mayo Clinic). Approximately 1 in 4 people will have a transient, sudden loss of consciousness at some point in their lives. However whether this is a harbinger of sudden death, or a more benign "fainting spell" is not always clear. The ability to distinguish a potentially life threatening cause of syncope, from one which is more benign is the key goal of the evaluation of the patient with syncope. Under normal circumstances, the cardiovascular control system keeps the blood pressure relatively constant, both by increasing the pumping action of the heart, and by increasing the resistance to blood flow by constricting the small peripheral blood vessels. These compensatory mechanisms occur through the sympathetic nervous system which is responsible for stimulating the circulation during periods of stress. In brief, the cardiovascular control center in the brain stem receives information from higher order pathways in the cerebral cortex, as well as feed back from pressure sensors located within the blood vessels themselves ("baroreceptors"), as well as the heart (cardiac "mechanoreceptors"), and skeletal muscle (particularly important during exercise). These diverse signals are integrated and processed in the brain, which determines whether the circulation should be stimulated (via the sympathetic nervous system) or relaxed (via the parasympathetic nervous system). It is the delicate balance between these two arms of the autonomic cardiovascular control system that ensures adequate blood pressure and flow to the brain. Recent work from our laboratory and others, has demonstrated that there is a large variability among individuals in their responses to cardiovascular stresses. Some individuals have an extensive amount of "vasoconstrictive reserve" and therefore are able to stabilize the circulation, even in the face of severe stresses such has dehydration, heat, or exercise. In contrast, others appear to have a limited cardiovascular reserve, and are predisposed to syncope and collapse with even modest levels of stress. If such individuals develop heart disease, they have a much higher risk of cardiovascular collapse and sudden death, than patients with greater degrees of cardiovascular reserve. The purpose of this pilot proposal is to determine the mechanism of this wide individual variability in normal individuals, prior to the development of cardiovascular disease. We hypothesize that individuals susceptible to cardiovascular collapse have a blunted ability to increase the activity of the sympathetic nervous system under stress, and a reduced ability to constrict the blood vessels to maintain the blood pressure. To test this hypothesis, we propose to use a new technique called microneurography, which will allow us to directly measure the activity of the sympathetic signals to peripheral blood vessels. With the new knowledge gained from this pilot project, we plan to submit a larger, more comprehensive proposal to the National Institutes of Health, and/or the American Heart Association, to study mechanisms of syncope in a number of divergent patient populations, including those with a history of previous cardiovascular collapse, and those who complain of frequent fainting. This approach was very successful with the last King Foundation proposal. We were funded to acquire pilot data to evaluate cardiac function in the elderly, and we used this data to support a more comprehensive application to NIH which was just funded to Dr. Levine for $1.7 million over 4 years.
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