Pregnancy-induced hypertension affects up to 10% of pregnant women in the United States, and the most severe form, preeclampsia, is the leading cause of maternal and fetal death or morbidity. Although the mechanisms for such complications are unclear, it has been proposed that either pregnancy-induced hypertension or preeclampsia is associated with a hyperadrenergic state, which may contribute to the pathophysiology of these conditions. Sympathetic adrenergic control plays an important role in blood pressure maintenance in humans. Sympathetic activity was found to increase in normal pregnancy and to be even greater in women with pregnancy-induced hypertension or preeclampsia in late pregnancy. However, it is completely unknown whether sympathetic hyperactivity develops early in normal pregnancy, remaining high throughout the entire gestation, or whether this sympathetic activation only occurs at term, providing the substrate for pregnancy-induced hypertension or preeclampsia.

We found in 5 healthy Caucasian women that during early pregnancy, sympathetic activity was extremely high (similar to those of congestive heart failure patients), while paradoxically their blood pressure and peripheral vascular resistance were normal. This finding is counter to the prevailing wisdom regarding the neurohormonal adaptation to normal pregnancy, which suggests that sympathetic activation occurs only in late pregnancy, and to our knowledge, there are no published nerve recordings in early human pregnancy. Surprisingly, one Asian woman in early pregnancy had a much less prominent increase in sympathetic activity, raising the possibility that marked sympathetic activation may be race-dependent. These observations need to be verified in more pregnant women. Thus, the purpose of this research project is to determine whether marked sympathetic activation is a universal characteristic of early pregnancy (≤ 8 weeks of gestation) in humans and the role of sympathetic neural control in normal pregnancy.

To this end, the specific aim of this project will test the hypothesis that vasomotor sympathetic activity increases dramatically during early pregnancy despite a normal blood pressure in healthy Caucasian but not Asian women. This objective will be accomplished by utilizing the innovative technique of microneurography. If the results obtained are the same as in our pilot data, it would radically alter the understanding of how blood pressure is regulated in pregnancy as well as provide insights into the development of gestational hypertension and its most feared outcome, preeclampsia. 

Hypertension is a major public health problem worldwide affecting over 50 million Americans. It is a major risk factor for target organ damage resulting in coronary artery disease, heart failure, stroke, and kidney disease. Large epidemiological surveys have shown that more elderly women than men have hypertension. Whether this specific effect of sex is grounded in equally specific pathophysiology which could “personalize” the selection of antihypertensive therapy and improve the response to treatment is unknown. The primary goal of this research proposal is to determine the mechanisms underlying sex differences in hypertension in sedentary seniors (i.e., ≥65 years old), and to determine whether exercise training in combination with antihypertensive drug treatment is effective in elderly women.

Using the innovative techniques of microneurography, Doppler ultrasound, and tonometry, Specific Aim 1 will test the hypothesis that sympathetic neural activity is augmented in elderly hypertensive women. Autonomic function tests will be performed; sympathetic neural responses, vasoconstrictor capability, transduction of sympathetic traffic into vascular resistance, and baroreflex function will be compared in elderly normotensive and hypertensive men and women; Specific Aim 2 will test the hypothesis that ventricular-arterial stiffening is more prominent in elderly hypertensive women than men. Pulse wave velocity, dynamic systolic arterial elastance, aortic artery augmentation pressure and index, total arterial compliance, cardiac size, and aortic pulsative dimensions will be compared between normotensive and hypertensive men and women; Specific Aim 3 will test the hypothesis that a long-term exercise training program in combination with antihypertensive drug treatment is more effective than pharmacologic therapy alone in hypertensive seniors, and the responses to exercise training differ between sexes.

Patients enrolled in Specific Aim 1 and 2 studies will be assigned randomly either to drug treatment alone [a combination of losartan (AT1 receptor antagonist) and hydrochlorothiazide (diuretic), Hyzaar plus contact control] or to exercise training (Hyzaar and exercise training) for 6 months, the same protocols employed in Specific Aim 1 and 2 will be repeated after treatment, and results will be compared  among groups and between sexes. Upon completion of this project, we will have obtained novel and clinically important information regarding the nature of hypertension associated with aging and sex, the selection of antihypertensive therapy, and the responses to treatment in elderly hypertensive men and women. We will identify the mechanisms underlying sex differences in hypertension and antihypertensive therapy in seniors, which may lead to more effective therapies for this particularly patient population. 

The overall objective of this proposal is to test the central hypothesis that cerebrovasular function is impaired with aging, and these changes are exacerbated in patients in the early stage of Alzheimer’s disease (AD). Specific Aim 1 will test the hypothesis that cerebral autoregulation is impaired with aging and that these changes are exacerbated in patients with early AD. Cerebral autoregulation will be assessed by measuring changes in cerebral blood flow (CBF) velocity using transcranial Doppler during both steady-state and transient changes in arterial pressure. Specific Aim 2 will test the hypothesis that brain oxygen-extraction reserve is reduced with aging and that these changes are exacerbated in patients with early AD. 

To quantify brain oxygen-extraction reserve, regional CBF and brain metabolism will be measured using positron emission tomography (PET) under resting conditions and during carefully controlled acute brain hypoperfusion. Specific Aim 3 will test the hypothesis that the brain neuronal activation-CBF coupling (magnitude of the CBF response to visual stimulation) is attenuated with aging and to a greater extent in patients with early AD and that these changes are mediated primarily by a vascular mechanism. Specific Aim 4 will test the hypothesis that the rate of progression of AD is related to the rate of changes in cerebrovascular function.  In these studies, rate of progression in AD will be determined using the Clinical Dementia Rating (CDR) score and Mini-mental State Examination (MMSE) score. Changes in cerebrovascular function in AD will be correlated with the rate of progression of AD before and after a 2 year follow-up period. Alzheimer’s disease is a devastating brain disorder imposing heavy burdens on our aging society. The mechanism of AD still is not clear and effective treatment for AD is desperately needed. The outcome of this project will provide in-depth insight regarding the changes in brain vascular function with aging and in patients with AD. 

In addition, the new knowledge obtained will answer the fundamental question whether changes in brain vascular function with aging and in patients with AD play an important role in the disease course of AD. Eventually, this research may lead to new treatments to prevent and delay the onset of Alzheimer’s disease through specific vascular mechanisms.     

However, findings from the principal investigator and others show that vasodilatory and sweating responses in grafted skin are impaired or absent regardless of the maturity of the graft.  Thus, patients with large areas of grafted skin may have reduced thermal tolerance.  This important question has not been adequately addressed as it remains unknown to what extent skin grafting impairs the regulation of internal temperature, or whether heightened vasodilator and sweating responses from non-injured skin can compensate for reduced heat dissipating capacity of grafted skin. Thus, the first objective of this project is to test the hypothesis that subjects with 20-35% of BSA grafted skin will have normal thermoregulatory responses, subjects with 40-55% BSA grafted skin will have moderately impaired thermoregulatory responses, and subjects with >60% BSA grafted skin will have severely impaired thermoregulatory responses when compared to non-grafted subjects.  It is unknown whether individuals with substantial BSA of grafted skin can adapt to elevated temperature climates and thereby reduce their risk of a heat-related injury.  Heat acclimation is a widely accepted approach to improve temperature regulation in individuals required to work (i.e., firefighters or military personnel), or who choose to exercise, in hot environmental conditions.  It may be that heat acclimation is effective in improving temperature regulation of individuals with skin grafts over large portions of their body.  

To this end, the second objective of this project is to test the hypothesis that heat acclimation improves temperature regulation of individuals with varying BSA of grafted skin.  Answers to the proposed questions, as well as related mechanisms, will be pursued using novel techniques to assess both central and peripheral control of thermoregulatory efferent variables.  The academic environment in which this work will be conducted is unique in that surgeons and rehabilitation physicians, who treat skin graft patients, will collaborate with investigative physiologists to address these important questions.  The information gained from the proposed studies will be valuable to clinicians, patients, and the military towards an understanding of the effects of serious burn injuries and subsequent skin grafting on human temperature regulation, and whether heat acclimation will allow these individuals to better tolerate a hyperthermic challenge and thus improve thermal safety and comfort.