PROJECT SUMMARY Neurogenic orthostatic hypotension (nOH) is a significant medical problem in the elderly; It not only causes substantial disability, but is also a regonized risk for falls and increased mortality. The main hemodynamic mechanism underlying the fall in upright blood pressure (BP) in nOH is an exagerated decrease in venous return due to splanchnic venous pooling that patients are unable to compensate for because of impaired autonomic reflexes. Developing therapies that reduce splanchnic capacitance and restore venous return would have the potential to selectively improve upright BP. However, the only approved treatments for nOH are pressor agents which do not target the underlying pathophysiology and increase supine BP as much or more than upright BP. Furthermore, their increase in supine hypertension leads to pressure diuresis and worsening of OH. We have developed an automated abdominal binder that uses a novel technological approach to overcome the limitations of current drug therapy. The device is triggered by an accelerometer that senses the patient's upright posture and inflates to a sustained a servo-controlled compression pressure of 40 mm Hg. The device automatically deflates when the patient is seated or supine and, therefore, will not have the negative effect of supine hypertension inherent to pressor agents. Our preliminary results showed not only that this device acutely improves orthostatic tolerance and upright BP in nOH patients, but also that it is as effective as midodrine, the current standard of care. Thus, this device has several potential advantages over current therapy: it targets the underlying pathophysiology of OH (unrestrained venous pooling), its effects are immediate compared to medications that usually require about an hour to reach peak effect; it is activated only when standing (it does not induce or worsen supine hypertension), and it does not rely on patient compliance or caregiver involvement. The purpose of this project is to investigate the mechanisms by which the automated abdominal binder improves upright BP and orthostatic tolerance in nOH patients, and the effects of abdominal compression on central hemodynamics and markers of cardiovascular risk. We propose 3 proof-of- concept clinical mechanistic studies to 1) test the hypothesis that the automated abdominal binder improves upright BP by decreasing splanchnic capacitance, venous pooling and the orthostatic drop in stroke volume compared to sham device and midodrine; 2) to determine the acute effects of the automated binder and midodrine on markers of cardiovascular risk such as augmentation index, pulse wave velocity and central BP, and 3) to test the hypothesis that the automated abdominal binder will be associated with lower 24-hr supine BP, reduced diuresis and improved upright BP in the morning after treatement compared to daytime use of midodrine (10 mg t.i.d). We believe the results of these studies will provide the mechanistic insight to foster the efforts currently under way to develop a novel therapy for nOH targeting splanchnic capacitance.

Project Narrative Public Health Relevance Statement Neurogenic orthostatic hypotension (nOH) is a significant clinical problem in the elderly and an unmet medical need. We have developed an automated abdominal binder that, unlike pressor agents, selectively improves upright blood pressure without inducing or worsening lying down high blood pressure. The results of these studies will provide the mechanistic insight to foster the efforts currently under way to develop more targeted treatments for nOH.