Orthostatic hypotension (OH) is a common disabling condition in the elderly, particularly in those with impaired
autonomic reflexes. Supine hypertension is the most common comorbidity; it not only increases the risk for target
organ damage but also induces pressure natriuresis during nighttime causing nocturia and volume depletion that
contributes to OH. Thus, nocturnal hypertension worsens daytime OH. Unfortunately, there is reluctance to
treat supine hypertension for fear of worsening OH. Sleeping in a head-up tilt (HUT) position can improve
nocturnal hypertension by reducing venous return, stroke volume and cardiac output, but tilt levels needed to
produce these effects are difficult to achieve clinically. In this application, we propose that increasing intrathoracic
pressure with continuous positive airway pressure (CPAP), at levels used clinically, will produce similar
hemodynamic effects as HUT, by inducing venous pooling into the splanchnic circulation. Indeed, our preliminary
studies show that CPAP, at levels used clinically, induces an acute and reversible decrease in blood pressure
in autonomic failure patients without obstructive sleep apnea (OSA) by a direct hemodynamic mechanism, and
this effect is sustained during the night and associated with decreased nocturia. In normal subjects this effect is
masked by compensatory sympathetic activation. The overall goal of this application is to test the hypothesis
that increasing intrathoracic pressure with CPAP is an effective treatment for nocturnal hypertension in patients
with autonomic failure and that, by reducing pressure diuresis, it will improve daytime OH. In Specific Aim 1,
we will characterize the hemodynamic mechanisms of CPAP in autonomic failure patients, determine its effects
on volume shifts from the thoracic to abdominal segments, on hormones that regulate natriuresis, and on central
blood pressure and indices of arterial stiffness. These indices are better predictors of negative cardiovascular
outcomes than brachial blood pressure, and this unique patient population will allow us to determine the effects
of CPAP unencumbered by sympathetic modulation. We also propose overnight proof-of-concept studies to test
the hypotheses that CPAP is effective in controlling nocturnal supine hypertension (Specific Aim 2) and reduces
nighttime diuresis, resulting in improvement of daytime orthostatic tolerance (Specific Aim 3). For these initial
proof-of-concept mechanistic studies we exclude patients with OSA because our focus is on the novel
hemodynamic effects of CPAP rather than suppression of apneic episodes. We believe the proposed studies
will lead to a clinically significant and innovative approach for the management of nocturnal hypertension in
patients with autonomic failure, changing the way we manage patients, and eliminating the controversy of
whether to treat, or not to treat, supine hypertension. If successful, lowering nighttime blood pressure will reduce
nocturia, which not only impairs sleep but also exposes patients to falls. More importantly, it will improve daytime
orthostatic tolerance and improve the quality of life of our patients. Our studies will also improve our basic
knowledge about the effects of CPAP on cardiovascular regulation, that can then be applied to other conditions.
