Barry Elliot Hurwitz, Ph.D. - US grants

The recognition of alterations in cardiac autonomic function in asymptomatic Type I insulin-dependent diabetic (IDDM) individuals has been facilitated by the development of standardized cardiovascular reflex tests from which inferences about autonomic integrity are drawn. Recent experimental and clinical evidence points to the existence of a left ventricular structural and functional impairment associated with diabetes mellitus that raises the possibility that early in IDDM disease progression the cardiovascular dysfunction detected by standard diagnostic tests may be due to cardiac pathology rather than autonomic neuropathy. This revision of a proposed 4-year study will extend our previous NHLBI- funded work in evaluating autonomic mediation of dynamic cardiovascular function and noninvasive diagnostic approaches for assessing diabetic neuropathy. We will study healthy and IDDM (of more than 10 years duration) men and women (n=130 of 144 recruited), 18-55 years old. IDDM subjects with abnormal and normal autonomic function will be classified using a standard battery of autonomic integrity tests. Group assignment using the standard classification method will be compared with an alternative autonomic classification method that is based on a quantitative clustering technique. Echocardiographic evaluation of left ventricular structure and function will be performed. Then autonomic contribution to the cardiovascular response to orthostatic challenge will be noninvasively assessed using: l) selective pharmacologic blockade; 2) V-hat, a quantitative index of parasympathetic cardiac neural input; 3) systolic time interval estimates of sympathetic myocardial input; and 4) measures of hemodynamic function (heart rate, blood pressure, cardiac output, peripheral resistance). Subjects will be tested under four conditions: placebo, 13-sympathetic blockade, parasympathetic blockade, and combined 13-sympathetic and parasympathetic blockade. The comprehensive assessment of hemodynamic function during rest and postural adjustment (head-up and head-down tilt) in each of the pharmacologic blockade conditions will provide information about the autonomic contribution to hemodynamic regulation in IDDM individuals. The degree of autonomic blockade will be assessed pharmacologically. These data together with the information derived from the echocardiographic left ventricular assessment will yield information regarding IDDM disease progression in relation to the sensitivity and specificity of the standard and alternative IDDM classification methods.

This proposed 5 year project, which will examine acute stress responses in a total of 120 (of 144 recruited) HIV-infected symptomatic but not AIDS- defined men and women, is subdivided into three separate projects 4A-C. In our previous NIMH-funding studies, we have examined the impact of the CBSM intervention on immune reconstitution. To date, our findings are consistent with the contention that the CBSM intervention acts to modulate coping and normalize measures of immunologic status in asymptomatic HIV infected individuals. While the CBSM has been shown to decrease EBV antibody titers in asymptomatic HIV infected individuals. While the CBSM has been shown to decrease EBV antibody titers in asymptomatic HIV infected individuals, this finding was not replicated in symptomatic HIV infected individuals, although the symptomatic subjects did not display immunologic normalization of HSV-2 antibody titers following CBSM intervention. Because stressors and other psychosocial factors have been shown to impair certain aspects of cell-mediated immunity, and because interventions, such as CBSM, have been demonstrated to normalize some stress associated immunologic functional impairments, we propose in projects A and B to examine the impact of the CBSM intervention on resting immune functioning (CD4 and NK cell count, NK cytotoxicity, lymphoproliferative response to PHA) and surveillance of herpes viruses (EBV, HHV-6, HSV-2) in symptomatic HIV infected men and women on combination antiretroviral therapy compared with control subjects. In addition, projects A and B extend our previous NIMH-funded studies of acute stress responses in HIV seropositive men and women by moving the focus of the investigation from the laboratory manipulation to using the laboratory manipulation as a tool toward the examination of the effectiveness of the cognitive behavioral stress management (CBSM) intervention in enhancing immuno-cellular functioning. Two types of acute challenge, a psychological stressor (evaluate speech stress) and a physical stressor (bicycle exercise) will be used to probe for the impact, before and after the CBSM intervention on the autonomic (blood pressure, cardiac contractility indices, respiratory sinus arrhythmia), neuroendocrine plasma catecholamines, ACTH, cortisol), and immuno-cellular (lymphocytes with phenotypes, lymphocyte activation and adhesion markers, NK number with intracellular perforin assessment and NK cytotoxicity, and lymphocytic proliferation in response to mitogen) stress responses in the HIV symptomatic gay men enrolled in 0002 and the HIV symptomatic women enrolled in 0004. Equal numbers of subjects will either received CBSM plus standard-care treatment or a control procedure in which subjects will receive standard-care only. In previous research, we observed that HIV infected a symptomatic and symptomatic subjects displayed attenuated increased in NK cytotoxicity relative to seronegative subjects during speech stress. Thus in project C using in vitro methodology, we will examine in the 60 (of 72 recruited) men and women participating in projects A and B. 1) the influence of catecholamines cortisol and the type 1 cytokines, IFN-gamma and IL-2 on the NK cytotoxicity observed during speech: and 2) whether the impact of the CBSM intervention has a differential effect on these potential influences of NK cytotoxicity response during the psychologically stressful challenge.

The pathogenesis of the chronic fatigue syndrome ( S) includes severe and debilitating fatigue, orthostatic intolerance, and the disruption of autonomic, hematological, and cardiovascular function. Plasma volume expansion is associated with a reduction or resolution of orthostatic hypotensive symptoms in some but not all CFS patients. Preliminary findings in our lab suggest that: 1) reduced red blood cell (RBC) mass is a critical hematological marker of CFS; and 2) RBC mass expansion improves orihostatic tolerance and fatigue beyond that ascribed to plasma volume expansion alone. However, the physiological mechanisms underlying these treatment effects and the relationship of such mechanisms to individual differences in treatment response have not been elucidated. This proposed 5-year study will extend our previous work in evaluating autonomic, hemodynamic, neuroendocrine, and adrenergic receptor function in individuals with CFS. We will study 90 (of 105 recruited) CDC-defined CFS patients before and after 3-month intervention in a randomized, double-blind, placebo-controlled study of pharmaco-therapy to expand plasma volume compared with combined treatment to expand RBC mass and plasma volume. Therefore, 30 CFS men and women will be randomized to each of three treatment conditions (plasma volume expansion; plasma volume and RBC mass expansion; and placebo) and tested pre- and post-treatment. Echocardiographic evaluation of left ventricular structure and function (left ventricular mass and wall thickness, compliance, and contractility) will be performed to examine whether the diminished cardiac function is a consequence of myocardial origin. Autonomic integrity will be assessed during response to a standardized battery of reflex tests (supine rest, paced respiration, Valsalva maneuver, lying-to standing, and sustained handgrip). Baroreceptor sensitivity and alpha- and beta-adrenoceptor sensitivity will be examined using adrenoceptor pharmacological challenge (phenylephrine, isoproterenol). A 70 degrees head-up tilt (HUT) test combined with beta-adrenergic agonist infusion at 2 microgram/min (and then again at 5 microgram/min if previous test failed to induce a orthostatic hypotension) will be performed to determine orthostatic susceptibility. During these HUT tests noninvasive measurement of parasympathetic cardiac neural input, sympathetic cardiac neural input, catecholamines and measures of hemodynamic function (heart rate, blood pressure, cardiac output, total peripheral resistance) will be derived to assess the autonomic mediation of cardiovascular response to the HUT challenge as a function of treatment. In addition, we will examine the effect of treatment on exertional fatigue in response to the HUT. Then we will examine the relation between the criterion (orthostatic hypotension susceptibility) and the predictors (hemodynamic, autonomic, cardiac structure/function and baroreceptor, alpha-adrenoceptor and beta- adrenoceptor sensitivities) in order to determine the extent to which the predictors are mediating the treatment effects on orthostatic hypotension susceptibility. Therefore, this project will further the investigation of pathophysiological mechanisms in CFS of a deficiency in plasma volume and red blood cell mass as a possible source for the pathophysiology of fatigue and cardiovascular dysfunction by comprehensively examining: a) autonomic and hemodynamic function; b) cardiac structure and function; and c) cardiac and vascular adrenoceptor sensitivity, before and after the pharmacological manipulation of plasma volume and RBC mass expansion.

cocaine; dietary supplements; HIV infections; drug abuse; cardiovascular disorder prevention; selenium; disease /disorder proneness /risk; cardiovascular disorder; oxidative stress; insulin sensitivity /resistance; cardiovascular function; clinical research; human subject; nutrition related tag;

The pathogenesis of the chronic fatigue syndrome (CFS) includes severe and debilitating fatigue, orthostatic intolerance, and the disruption of hematological, autonomic, and cardiovascular function. Our preliminary findings suggest that: 1) reduced red blood cell (RBC) mass is a critical hematological marker of CFS; and 2) RBC mass expansion improves orthostatic tolerance and fatigue beyond that ascribed to plasma volume expansion alone. However, the physiologic mechanisms underlying the RBC mass treatment effect and the relationship of such mechanisms to individual differences in treatment response have not been elucidated. This proposed 5-year study will screen 150 CDC-defined CFS men and women and classify them into low and normal RBC mass groups. The CFS subjects (90 of 105 enrolled) will be studied before and after a 3-month intervention in a randomized double-blind, placebo-controlled study of pharmacotherapy to expand RBC mass; specifically, two CFS groups with low RBC (RBC-treated and placebo-treated) will be compared to another CFS group with normal RBC mass (standard and usual care). To assess whether the diminished cardiac function, characteristic of CFS orthostatic intolerance, is a consequence of myocardial origin, echocardiographic evaluation of left ventricular structure and function (left ventricular mass and wall thickness, compliance, and contractility) will be performed. In addition, autonomic integrity will be assessed during a standardized battery of tests (supine rest, paced respiration, Valsalva maneuver, lying-to standing, and sustained handgrip); baroreceptor sensitivity and alpha- and beta-adrenoceptor sensitivity will he tested using adrenoceptor pharmacologic challenge (phenylephrine, isoproterenol). To determine orthostatic susceptibility, a 70 head-up tilt (HUT) test combined with beta-adrenoceptor infusion at 2 mug/min (and then again at 5 mug/min, if the previous HUT failed to induce orthostatic hypotension) will be performed. We will further examine the treatment effect on exertional fatigue and hemodynamic and autonomic physiologic response to the HUT tests. Finally, the relation between the criterion (orthostatic hypotension susceptibility) and the predictors (hemodynamic, autonomic, cardiac structure/function and baroreceptor, alpha-adrenoceptor and beta-adrenoceptor sensitivities) will be evaluated to determine the extent to which the predictors are mediating the treatment effects on orthostatic hypotension susceptibility.

DESCRIPTION (provided by applicant): HAART medication has been implicated as a potential etiopathological source of the increased prevalence of cardiovascular disease (CVD) risk in HIV infected persons. Although recent reports indicate an increasing rate of Hepatitis C virus (HCV) coinfection in the HIV-infected, and HCV infection independently communicates increased cardiovascular risk, the literature has not adequately assessed the possible role of HCV coinfection in cardiovascular pathogenesis in HIV spectrum disease. Comorbid conditions known as dysmetabolic syndrome X are independently associated with both HIV and HCV infection; the syndrome includes alterations in fat deposition, cardiac structure and function, and vascular endothelial function, as well as dyslipidemia and insulin resistance. Two pathophysiological sources in HIV and HCV infected persons is increased pathogen burden and diminished infection surveillance, which result in an elevation of proinflammatory processes. These processes have been shown to induce greater reactive oxygen species formation, which has been linked to atherogenesis and alterations in cardiac and vascular structure and function. Oxidative stress has also been associated with insulin resistance. Because of the possible role of HCV infection and HAART medication in cardiovascular disease risk and because proinflammatory and oxidative factors are likely mediators of this risk, the primary objective of the proposed study is to systematically examine these factors in 420 (of 465 screened) men and women, as a function of HIV and HCV infection, and coinfection. The influence of HAART treatment regimen (anti-retrovirals plus protease inhibitors [PI+] vs. anti-retrovirals without protease inhibitors [PI-]) on these outcomes will be assessed by nesting HAART regimen within the HIV+ groups, thereby yielding a six group comparison (HIV+PI+/HCV+ vs. HIV+PI-/HCV+ vs. HIV+PI+/HCV- vs. HIV+PI-/HCV- vs. HIV-/HCV+ vs. HIV-/HCV-). The secondary objective is to determine whether the data collected is described by the proposed pathophysiological model, which postulates that the burden of exposure to multiple infectious sources is associated with greater levels of proinflammatory factors and oxidative stress, and consequently greater CVD risk and diminished cardiovascular function.

DESCRIPTION (provided by applicant): The primary function of this Core is to perform the cardiovascular assessments for the projects within the Program Project that use human subjects. Using echocardiographic methodology, this core will provide assessments of resting cardiovascular function and measures of cardiac and common carotid artery structure. In addition, using this methodology during ischemic and pharmacological challenges, assessments of brachial artery endothelial-dependent and -independent vasodilatory function will be preformed. Using electron beam computed tomography (EBCT), the core will also provide assessments of coronary artery calcification.

ABSTRACT NOT PROVIDED

[unreadable] DESCRIPTION (provided by applicant): Individuals who are overweight or obese not only constitute a group who are at increased risk for coronary heart disease (CHD) but also display features of Metabolic Syndrome (MSX) and diminished endothelial vasodilatory function many years prior to their normal-weighted counterparts. In our studies of at-risk and healthy cohorts, we have observed that central obesity is a primary predictor of insulin and glucose metabolic dysregulation and is linked with diminished vasodilatory function, an early indicator of CHD risk. The literature has focused more on insulin resistance as the primary deficit in MSX but there is a growing body of evidence that suggests that glycemic dysregulation, as indexed by postprandial indicators, may be independently predictive of GHD risk and vascular dysfunction. Although methodology was previously unavailable, the development of a device to continuously measure glucose levels has now been introduced that would permit assessments of meal-related glycemic regulation over prolonged periods of time and under various conditions. The primary objective of the proposed research is to use this technology, systematically manipulate glucose content of meals over the course of a two-day in-patient visit, and then as function of CHD risk status examine indices of meal-related glycemic functioning and its impact on vascular functioning, in the context of postprandial metabolic mediators i.e., insulinemia, triglyceridemia and free fatty acids. The study will enroll 281 (of 400 screened) persons to obtain complete data on 184 subjects. We will compare 92 high risk men and women who meet MSX diagnostic criteria and have body mass > 25 kg/m2 with 92 low risk age-, sex- and ethnicity-matched individuals who do not have MSX (as per NCEP ATP III criteria) and whose body mass is [unreadable] 25 kg/m2. Subjects will be screened with an exercise stress test and will have no diagnosed cardiovascular conditions. The study will include two contiguous 24 hour periods of in-patient stay. Subjects will have an oral glucose tolerance test (OGTT) and 4 meals/day of equivalent caloric content but the glucose content will be manipulated such that on one day the glucose content will be 300 calories/meal (as in an OGTT) and the other day the glucose content will be 600 calories/meal. The order of low and high glucose load days will be counterbalanced across subjects. Measures of metabolic mediators will be derived following overnight fasts, OGTTs, and meals for the low and high caloric days. Echocardiographic measures of carotid intimal media thickness and cardiac structure and function will be obtained as well as measures of endothelial-dependent vasodilatory function and arterial stiffness (using the brachial artery reactive hyperemia test before and 1 hour after meals). A measure of insulin sensitivity will be derived using a euglycemic hyperinsulinemia clamp. Measures of central obesity (waist girth, and CT measures of visceral adipose mass, subcutaneous adipose mass) will also be obtained. In sum, the study postulates that high risk overweight and obese persons with MSX relative to low risk controls will exhibit greater meal-related glycemic dysregulation that worsens over the day and worsens with increasing glucose load; more corresponding meal-related decrease in vasodilatory function and enhancement of arterial stiffness will be predicted. This research is an essential step toward understanding in persons with MSX the role of postprandial glycemic regulation in accelerated CHD pathogenesis. [unreadable] [unreadable] [unreadable]