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Sympathetic-Vascular Dysfunction in Obesity-Related Hypertension

Award Number: R01HL159370
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Sympathetic-Vascular Dysfunction in Obesity-Related Hypertension - PROJECT SUMMARY Obesity is highly prevalent in the U.S. and has significant consequences for mortality and quality of life. Obesity is the primary gateway to additional cardiovascular disease (CVD) risk factors such as increased insulin resistance, dyslipidemia, and hypertension. Prospective studies have estimated that nearly 75% of cases of hypertension can be attributed to obesity. Hallmarks of obesity-related hypertension are oxidative stress, chronic inflammation, and vascular dysfunction. However, our understanding of the precise mechanisms underlying the development of hypertension in obesity and insulin resistance remains incomplete. We hypothesize that hyperglycemia and hyperlipidemia augment vascular sensitivity to single bursts of sympathetic nerve activity (SNA) via oxidative stress to heighten blood pressure variability in obesity and insulin resistance. Using a double- blinded, placebo-controlled, randomized approach, we will determine the extent to which sympathetic-vascular transduction is elevated by hyperglycemia and hyperlipidemia and resultant oxidative stress and the extent to which suppression of oxidative stress via ascorbic acid attenuates the exaggerated increase in vascular sensitivity to single bursts of SNA. Given our innovative approach, these studies provide direct insight into the ability of single bursts of SNA to dynamically regulate vascular tone and blood pressure. We will also test the novel hypothesis that sympathetic blockade mitigates the pro-inflammatory phenotype of obesity. Obesity is also characterized by chronic inflammation, which is mediated in part by the sympathetic nervous system. Expression of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) can be regulated by norepinephrine. The urgency to mitigate inflammation in obesity has recently been accelerated by the increased risk of poor outcomes following infection by SARS-CoV-2. Indeed, recent data show that circulating concentrations of pro- inflammatory cytokines such as interleukin 6 (IL-6) are positively correlated with poor outcomes in patients with SARS-CoV-2. We propose sympathetic blockade as a novel approach to mitigating the pro-inflammatory phenotype of obesity and hypertension. To demonstrate feasibility of our hypothesis, we have performed pilot studies using a randomized, double-blinded, parallel study design in a small group of overweight/obese adults using 4 weeks of oral clonidine to reduce central sympathetic outflow and observed significant reductions in MSNA and circulating TNF-α but no change in MSNA and circulating TNF-α following 4 weeks of placebo or hydrochlorothiazide (HCTZ) as a BP-lowering control condition. We plan to extend these preliminary data in our outlined studies to achieve sufficient power to observe signficant and clinically meaningful group differences in circulating and endothelial cell pro-inflammatory cytokines. The long-term goal of our research is to identify unique mechanisms that can be targeted to limit increases in vascular dysfunction in obesity and insulin resistance and reduce the excessively high prevalence of hypertension and risk for CVD.


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 = $370,080 )
2025	2025	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cardiovascular Diseases Research	000	5	8/6/2025	NON-COMPETING CONTINUATION	$370,080
														Subtotal = $370,080

Issue Date FY: 2024 ( Subtotal = $362,678 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cardiovascular Diseases Research	000	4	7/24/2024	NON-COMPETING CONTINUATION	$362,678
														Subtotal = $362,678

Issue Date FY: 2023 ( Subtotal = $369,110 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cardiovascular Diseases Research	001	3	7/19/2023	NON-COMPETING CONTINUATION	$358,647
2023	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cardiovascular Diseases Research	000	2	10/27/2022	NON-COMPETING CONTINUATION	$10,463
														Subtotal = $369,110

Issue Date FY: 2022 ( Subtotal = $347,409 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cardiovascular Diseases Research	000	2	7/20/2022	NON-COMPETING CONTINUATION	$347,409
														Subtotal = $347,409

Issue Date FY: 2021 ( Subtotal = $460,624 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Cardiovascular Diseases Research	000	1	7/23/2021	NEW	$460,624
														Subtotal = $460,624

Grand Total All Awards = $1,909,901

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Sympathetic-Vascular Dysfunction in Obesity-Related Hypertension

Award Number: R01HL159370

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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