Request for Funding

Medical Student Research Fellowship for Summer 2004

Mentor: Benjamin D. Levine, M.D.
Department: Institute for Exercise and Environmental Medicine, Presbyterian Hospital of Dallas
Room number: Suite 435 (7232 Greenville Ave., Dallas, Texas 75231)
Mail Code: 9034 (Dr. Levine)
Phone number: 214-345-4620
E-mail: BenjaminLevine@TexasHeatlh.org
Project title: Gender & Orthostatic Intolerance: Mechanisms and Therapy

Human subjects IRB approved project number (where applicable): #012004-017

Animal subjects IRB approved project number (where applicable): None

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects): Patient-based research

Brief Description of Project:
The primary objective of this project is to determine the mechanisms underlying gender differences in orthostatic tolerance including neurohumoral influences on cardiovascular control processes and physical characteristics (primarily cardiac size and function) that determine orthostatic distribution of central blood volume. Menstrual cycle variability in young women, and differences among men, women, and women with Postural Orthostatic Tachycardia Syndrome (POTS, also called Chronic Orthostatic Intolerance, in which patients are unable to stand or remain upright for prolonged periods of time due to intolerable light headedness, weakness, and near-syncope) will be examined. Finally, "optimized" exercise training will be studied as a specific therapy for patients with POTS and compared with standard pharmacologic therapies.
To accomplish these objectives, we propose to test the following hypotheses. Hypothesis 1: Autonomic neural control of cardiovascular and sympathetic responses to orthostatic challenges is affected by the normal menstrual cycle in healthy young women. Hypothesis 2: Autonomic regulation of hemodynamic and neurohumoral responses to orthostasis is different in healthy young men and women. Hypothesis 3: Autonomic neural control of cardiovascular and sympathetic responses to orthostatic stress is impaired in women with POTS, and this difference will be an exaggeration of the gender differences between normal men and women. Hypothesis 4: A short-term "optimized" physical exercise training program can increase orthostatic tolerance in patients with POTS, and this non-pharmacologic therapy is more effective than standard pharmacologic therapies.
To test our hypotheses, we propose to accomplish the following specific aims. Specific Aim 1: To compare the magnitude of sympathetic neural responses, vasoconstrictor capability, transduction of sympathetic traffic into vascular resistance, sympathetic baroreflex sensitivity, orthostatic tolerance, and neurohumoral responses to prolonged orthostatic challenges in healthy young women during the early follicular (days 1 4 after the onset of menstruation) and luteal (days 17 20 after the onset of menstruation) phases of their menstrual cycles. Specific Aim 2: To compare the hemodynamic and sympathetic responses, baroreflex function, orthostatic tolerance, and neurohumoral responsiveness to orthostatic challenges in healthy young men and women. Specific Aim 3: To compare the cardiovascular responses, sympathetic neural activity, vasoconstrictor capability, vascular transduction, sympathetic baroreflex sensitivity, orthostatic tolerance, and neurohumoral responses to orthostatic challenges in female patients with POTS and in healthy young women. Specific Aim 4: To evaluate the effects of a 3-month mild to moderate physical exercise training program (including both endurance and strength training) on orthostatic tolerance, and neurohumoral responses to orthostatic stress in female patients with POTS; and to compare the effectiveness of this non-pharmacologic therapy with standard pharmacologic therapies such as -blockers and volume expanders.
Protocols: After recruitment and informed consent, 10 healthy young women and 10 female patients with POTS will undergo a two-day testing twice: once during early follicular phase and once during luteal phase of the menstrual cycle (the order will be counterbalanced). However, 10 healthy men will undergo the 2-day testing once. Day 1 testing the venoarteriolar response to leg venous congestion and neurohumoral responses to prolonged orthostatic stress; and Day 2 testing autonomic function tests including hemodynamic and sympathetic responses to a Valsalva maneuver, static handgrip to fatigue, a cold pressor test, graded (30º and 60º) head-up tilt, and a continuous positive airway pressure in the upright position. On Day 1, we will measure arm cuff blood pressure, heart rate, and skin blood flow by laser-Doppler flowmetry. We will also take blood samples to measure plasma catecholamines, plasma rennin activity, angiotensin II, and aldosterone. On Day 2, we will measure heart rate, cuff and beat-by-beat finger arterial blood pressure, muscle sympathetic nerve activity from the peroneal nerve using microneurographic technique, cardiac output with a modification of the acetylene rebreathing technique, forearm blood flow using venous occlusion plethysmography, and left ventricular end-diastolic volume with two-dimensional echocardiography. Plasma measurements will also be made on Day 2. At least 1 week after completion of all the studies, left and right ventricular mass, end-diastolic volume, and mean wall thickness will be assessed using MRI in all subjects.
Patients with POTS (all females) will be assigned randomly into the following four groups: 1) exercise training group; 2) ß-blocker treatment group; 3) volume expander treatment group; and 4) control group. The same protocols performed on Day 1 and Day 2 will be carried out before and after non-pharmacologic (exercise training) or pharmacologic (ß-blocker and volume expander) therapy in all patients, with ~4 months separation. Patients will be required to come for the experiments in the luteal phase of the menstrual cycle. For each patient, an overall level of well-being and percentage of functional capacity will be assessed before and after 3 months of therapy. Measures of Quality of Life will be made by all patients between the score of 0 (worst) and 100 (perfect). An exercise test will be performed 2 to 3 days after the above 2-day testing to assess the peak exercise capacity and peak oxygen consumption in all patients before and after non-pharmacologic or pharmacologic therapy. Heart rate and blood pressure will be monitored continuously. A modified Astrand-Saltin incremental treadmill protocol will be used. Measures of ventilatory gas exchange will be observed during the Douglas bag technique. At least 1 week after the experiments, left and right ventricular mass, end-diastolic volume, and mean wall thickness will be measured using MRI in all patients before and after 3 months of therapy. Non-pharmacologic therapy (exercise training): we will use the method of Banister et al, for the calculation of the training impulse (TRIMP). In addition to the endurance training, strength/resistance training using weight lifting will also be undertaken. Patients will be required to increase their dietary salt and water intake, and elevate the head of the bed during sleeping at night. Pharmacologic therapy: patients in the ß-blocker treatment group will be given a non-selective ß-adrenoceptor blocker propranolol LA 80 mg qd (oral) for 3 months. Patients in the volume expander treatment will be given fludrocortisone beginning from 0.1 mg, and then increasing to 0.2 mg qhs (oral) for 3 month. Additionally, these patients will be required to do "Yoga" as a control for increased health care contact in the exercise group. Patients in control group will be given "placebo" for 3 months, and they will also be required to do "Yoga".

Previous Research Activities or Publications with Medical Students: None.

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