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Hemodynamic Effects of Positive Airway Pressure to Treat Supine Hypertension and Improve Neurogenic Orthostatic Hypotension

Award Number: R01HL161095
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Hemodynamic Effects of Positive Airway Pressure to Treat Supine Hypertension and Improve Neurogenic Orthostatic Hypotension - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $604,522 )
2025	2025	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	4	12/5/2024	NON-COMPETING CONTINUATION	$604,522
														Subtotal = $604,522

Issue Date FY: 2024 ( Subtotal = $660,375 )
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	3	6/13/2024	NON-COMPETING CONTINUATION	$53,908
2024	2024	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	3	11/14/2023	NON-COMPETING CONTINUATION	$606,467
														Subtotal = $660,375

Issue Date FY: 2023 ( Subtotal = $671,588 )
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	001	2	2/11/2023	NON-COMPETING CONTINUATION	$67,158
2023	2023	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	2	11/11/2022	NON-COMPETING CONTINUATION	$604,430
														Subtotal = $671,588

Issue Date FY: 2022 ( Subtotal = $617,084 )
2022	2022	VANDERBILT UNIVERSITY MEDICAL CENTER	1161 21ST AVE S STE D3300 MCN	NASHVILLE	TN	37232	DAVIDSON	USA	Cardiovascular Diseases Research	000	1	11/25/2021	NEW	$617,084
														Subtotal = $617,084

Grand Total All Awards = $2,553,569

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Hemodynamic Effects of Positive Airway Pressure to Treat Supine Hypertension and Improve Neurogenic Orthostatic Hypotension

Award Number: R01HL161095

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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