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Principal Investigator: SETH WILLIAM HOLWERDA
Organization: UNIVERSITY OF KANSAS MEDICAL CENTER
Fiscal Year: 2024
Award: $362,678
Funding agency: National Heart Lung and Blood Institute
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.
Terms: <(TNF)-α><Acceleration><Active Oxygen><Apoptosis><Apoptosis Pathway><Ascorbic Acid><Attenuated><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BP reduction><BSF-2><BSF2><Blood Pressure><Blood Serum><Blood Vessels><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID19 patient><COVID19 positive patient><Cachectin><Cardiovascular Diseases><Chronic><Clinical><Clinical Research><Clinical Study><Clonidine><D-Glucose><Data><Development><Dextrose><Dichlothiazide><Dihydrochlorothiazide><Diuretics><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dyslipidemias><Endothelial Cells><Glucose><Goals><HCTZ><HPGF><Hepatocyte-Stimulating Factor><High Prevalence><Human><Humulin R><Hybridoma Growth Factor><Hydrochlorothiazide><Hydrodiuril><Hyperglycemia><Hyperinsulinemia><Hyperinsulinism><Hyperlipemia><Hyperlipidemia><Hypertension><IFN-beta 2><IFNB2><IL-6><IL6 Protein><IV Infusion><Impairment><Individual><Inflammation><Inflammatory><Infusion><Infusion procedures><Insulin><Insulin Resistance><Interleukin-6><Intravenous infusion procedures><Klofenil><Leanness><Leiomyocyte><Levarterenol><Levonorepinephrine><Lipids><MGI-2><Macrophage><Macrophage-Derived TNF><Measures><Mediating><Modern Man><Monocyte-Derived TNF><Muscle><Muscle Tissue><Myeloid Differentiation-Inducing Protein><Mφ><Nerve><Noradrenaline><Norepinephrine><Novolin R><Obesity><Obesity Related Hypertension><Oral><Outcome><Over weight><Overweight><Oxidative Stress><Oxygen Radicals><Participant><Phenotype><Pilot Projects><Placebo Control><Placebos><Plasmacytoma Growth Factor><Population><Pro-Oxidants><Programmed Cell Death><Prospective Studies><QOL><Quality of life><Randomized><Reactive Oxygen Species><Regular Insulin><Research><Research Design><Resolution><Risk><Risk Factors><Role><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><Serum><Sham Treatment><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Source><Study Type><Sympathetic Nervous System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Thinness><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><VIT C><Vascular Diseases><Vascular Disorder><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Smooth Muscle><Vitamin C><adiposity><adult adiposity><adult obesity><adults with obesity><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><attenuate><attenuates><blood pressure reduction><blood pressure variability><blood vessel disorder><cardiovascular disease risk><cardiovascular disorder><cardiovascular disorder risk><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><corpulence><cytokine><design><designing><developmental><effective therapy><effective treatment><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><glucose uptake><high blood pressure><hyperglycemic><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><inflammation marker><inflammatory marker><infusions><innovate><innovation><innovative><insight><insulin resistant><insulin tolerance><interferon beta 2><intravenous infusion><lower BP><lower blood pressure><lowers blood pressure><mortality><muscular><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><obesity development><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><pharmacologic><pilot study><placebo controlled><post SARS-CoV-2 infection><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><randomisation><randomization><randomly assigned><reduce BP><reduce blood pressure><reduction in BP><reduction in blood pressure><resolutions><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><sham therapy><social role><study design><translational study><vascular><vascular constriction><vascular dysfunction><vascular smooth muscle cell proliferation><vasculopathy><vasoconstriction>