Publications by authors named "Fernando Elijovich"

55 Publications

Immune Mechanisms of Dietary Salt-Induced Hypertension and Kidney Disease: Harry Goldblatt Award for Early Career Investigators 2020.

Hypertension 2021 Aug 7;78(2):252-260. Epub 2021 Jul 7.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (F.E., C.L.L., A.K.).

Salt sensitivity of blood pressure is an independent risk factor for cardiovascular mortality not only in hypertensive but also in normotensive adults. The diagnosis of salt sensitivity of blood pressure is not feasible in the clinic due to lack of a simple diagnostic test, making it difficult to investigate therapeutic strategies. Most research efforts to understand the mechanisms of salt sensitivity of blood pressure have focused on renal regulation of sodium. However, salt retention or plasma volume expansion is not different between salt-sensitive and salt-resistant individuals. In addition, over 70% of extracellular fluid is interstitial and, therefore, not directly controlled by renal salt and water excretion. We discuss in this review how the seminal work by Harry Goldblatt paved the way for our attempts at understanding the mechanisms that underlie immune activation by salt in hypertension. We describe our findings that sodium, entering antigen-presenting cells via an epithelial sodium channel, triggers a PKC (protein kinase C)- and SGK1 (serum/glucocorticoid kinase 1)-stimulated activation of nicotinamide adenine dinucleotide phosphate oxidase, which, in turn, enhances lipid oxidation with generation of highly reactive isolevuglandins. Isolevuglandins adduct to proteins, with the potential to generate degraded peptide neoantigens. Activated antigen-presenting cells increase production of the TH17 polarizing cytokines, IL (interleukin)-6, IL-1β, and IL-23, which leads to differentiation and proliferation of IL-17A producing T cells. Our laboratory and others have shown that this cytokine contributes to hypertension. We also discuss where this sodium activation of antigen-presenting cells may occur in vivo and describe the multiple experiments, with pharmacological antagonists and knockout mice that we used to unravel this sequence of events in rodents. Finally, we describe experiments in mononuclear cells obtained from normotensive or hypertensive volunteers, which confirm that analogous processes of salt-induced immunity take place in humans.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.16495DOI Listing
August 2021

Why is salt-sensitivity of blood pressure, a known cardiovascular risk factor, not treated?

Int J Cardiol Hypertens 2021 Jun 5;9:100096. Epub 2021 Jun 5.

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, USA.

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http://dx.doi.org/10.1016/j.ijchy.2021.100096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193348PMC
June 2021

CONNed in Pregnancy.

Hypertension 2021 Jul 1;78(1):241-249. Epub 2021 Jun 1.

Division of Experimental Medicine and Immuno-therapeutics, University of Cambridge, United Kingdom (I.B.W.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17021DOI Listing
July 2021

Hypertension: Do Inflammation and Immunity Hold the Key to Solving this Epidemic?

Circ Res 2021 Apr 1;128(7):908-933. Epub 2021 Apr 1.

Division of Clinical Pharmacology (M.S.M., F.E., M.R.A., A.P., J.I., J.P.V.B., D.M.P., C.D.S., C.L.L., A.K.), Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.

Elevated cardiovascular risk including stroke, heart failure, and heart attack is present even after normalization of blood pressure in patients with hypertension. Underlying immune cell activation is a likely culprit. Although immune cells are important for protection against invading pathogens, their chronic overactivation may lead to tissue damage and high blood pressure. Triggers that may initiate immune activation include viral infections, autoimmunity, and lifestyle factors such as excess dietary salt. These conditions activate the immune system either directly or through their impact on the gut microbiome, which ultimately produces chronic inflammation and hypertension. T cells are central to the immune responses contributing to hypertension. They are activated in part by binding specific antigens that are presented in major histocompatibility complex molecules on professional antigen-presenting cells, and they generate repertoires of rearranged T-cell receptors. Activated T cells infiltrate tissues and produce cytokines including interleukin 17A, which promote renal and vascular dysfunction and end-organ damage leading to hypertension. In this comprehensive review, we highlight environmental, genetic, and microbial associated mechanisms contributing to both innate and adaptive immune cell activation leading to hypertension. Targeting the underlying chronic immune cell activation in hypertension has the potential to mitigate the excess cardiovascular risk associated with this common and deadly disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.318052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023750PMC
April 2021

Renovascular Hypertension: One Size Does Not Fit All: Challenges in Diagnosis and Management.

Hypertension 2021 Apr 10;77(4):1022-1028. Epub 2021 Mar 10.

Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville (A.K., G.C., R.M.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.121.17022DOI Listing
April 2021

Hypothesis: Unrecognized actions of ENaC blockade in improving refractory-resistant hypertension and residual cardiovascular risk.

Int J Cardiol Hypertens 2020 Dec 12;7:100048. Epub 2020 Sep 12.

Division of Clinical Pharmacology. Department of Medicine. Vanderbilt University School of Medicine, 2220 Pierce Ave, 536 RRB, Nashville, TN, 37232, USA.

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http://dx.doi.org/10.1016/j.ijchy.2020.100048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803029PMC
December 2020

Sodium activates human monocytes via the NADPH oxidase and isolevuglandin formation.

Cardiovasc Res 2021 Apr;117(5):1358-1371

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Room 536 Robinson Research Building, Nashville, TN 37232-6602, USA.

Aims: Prior studies have focused on the role of the kidney and vasculature in salt-induced modulation of blood pressure; however, recent data indicate that sodium accumulates in tissues and can activate immune cells. We sought to examine mechanisms by which salt causes activation of human monocytes both in vivo and in vitro.

Methods And Results: To study the effect of salt in human monocytes, monocytes were isolated from volunteers to perform several in vitro experiments. Exposure of human monocytes to elevated Na+ex vivo caused a co-ordinated response involving isolevuglandin (IsoLG)-adduct formation, acquisition of a dendritic cell (DC)-like morphology, expression of activation markers CD83 and CD16, and increased production of pro-inflammatory cytokines tumour necrosis factor-α, interleukin (IL)-6, and IL-1β. High salt also caused a marked change in monocyte gene expression as detected by RNA sequencing and enhanced monocyte migration to the chemokine CC motif chemokine ligand 5. NADPH-oxidase inhibition attenuated monocyte activation and IsoLG-adduct formation. The increase in IsoLG-adducts correlated with risk factors including body mass index, pulse pressure. Monocytes exposed to high salt stimulated IL-17A production from autologous CD4+ and CD8+ T cells. In addition, to evaluate the effect of salt in vivo, monocytes and T cells isolated from humans were adoptively transferred to immunodeficient NSG mice. Salt feeding of humanized mice caused monocyte-dependent activation of human T cells reflected by proliferation and accumulation of T cells in the bone marrow. Moreover, we performed a cross-sectional study in 70 prehypertensive subjects. Blood was collected for flow cytometric analysis and 23Na magnetic resonance imaging was performed for tissue sodium measurements. Monocytes from humans with high skin Na+ exhibited increased IsoLG-adduct accumulation and CD83 expression.

Conclusion: Human monocytes exhibit co-ordinated increases in parameters of activation, conversion to a DC-like phenotype and ability to activate T cells upon both in vitro and in vivo sodium exposure. The ability of monocytes to be activated by sodium is related to in vivo cardiovascular disease risk factors. We therefore propose that in addition to the kidney and vasculature, immune cells like monocytes convey salt-induced cardiovascular risk in humans.
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http://dx.doi.org/10.1093/cvr/cvaa207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064439PMC
April 2021

Hypertension and Metabolic Syndrome in Persons with HIV.

Curr Hypertens Rep 2020 09 3;22(10):78. Epub 2020 Sep 3.

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Purpose Of Review: With the advent of highly active antiretroviral therapy (ART), the life span of persons with HIV (PWH) has been nearly normalized. With aging, prevalence of the metabolic syndrome (MetS), including hypertension, has increased in the HIV population and exceeds that in the general population in some studies. This is due to a combination of traditional risk factors in addition to the effects attributable to the virus and ART. We review recent findings on the mechanisms contributing to MetS and hypertension in PWH, particularly those specific to the viral infection and to ART.

Recent Findings: Activation of the renin-angiotensin-aldosterone system (RAAS) and chronic immune activation contribute to the development of MetS and hypertension in PWH. HIV proteins and some ART agents alter adipocyte health contributing to dyslipidemias, weight gain, and insulin resistance. HIV infection also contributes to hypertension by direct effects on the RAAS that intertwine with inflammation by the RAAS also contributing to T cell activation. Recent data suggest that in addition to current ART, therapeutic targeting of the MetS and hypertension in PWH, by interfering with the RAAS, treating insulin resistance directly or by use of immunomodulators that dampen inflammation, may be critical for preventing or treating these risk factors and to improve overall cardiovascular complications in the HIV-infected aging population.
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http://dx.doi.org/10.1007/s11906-020-01089-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467859PMC
September 2020

The Gut Microbiome, Inflammation, and Salt-Sensitive Hypertension.

Curr Hypertens Rep 2020 09 3;22(10):79. Epub 2020 Sep 3.

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Room 536 Robinson Research Building, Nashville, TN, 37232-6602, USA.

Purpose Of Review: Salt sensitivity of blood pressure (SSBP) is an independent predictor of death due to cardiovascular events and affects nearly 50% of the hypertensive and 25% of the normotensive population. Strong evidence indicates that reducing sodium (Na) intake decreases blood pressure (BP) and cardiovascular events. The precise mechanisms of how dietary Na contributes to elevation and cardiovascular disease remain unclear. The goal of this review is to discuss mechanisms of salt-induced cardiovascular disease and how the microbiome may play a role.

Recent Findings: The innate and adaptive immune systems are involved in the genesis of salt-induced hypertension. Mice fed a high-salt diet exhibit increased inflammation with a marked increase in dendritic cell (DC) production of interleukin (IL)-6 and formation of isolevuglandins (IsoLG)-protein adducts, which drive interferon-gamma (IFN-γ) and IL-17A production by T cells. While prior studies have mainly focused on the brain, kidney, and vasculature as playing a role in salt-induced hypertension, the gut is the first and largest location for Na absorption. Research from our group and others strongly suggests that the gut microbiome contributes to salt-induced inflammation and hypertension. Recent studies suggest that alterations in the gut microbiome contribute to salt-induced hypertension. However, the contribution of the microbiome to SSBP and its underlying mechanisms are not known. Targeting the microbiota and the associated immune cell activation could conceivably provide the much-needed therapy for SSBP.
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http://dx.doi.org/10.1007/s11906-020-01091-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471100PMC
September 2020

New Insights Into the Renin-Angiotensin System in Chronic Kidney Disease.

Circ Res 2020 08 13;127(5):607-609. Epub 2020 Aug 13.

From the Division of Clinical Pharmacology, Department of Medicine (C.L.L., F.E., A.P., A.K.), Vanderbilt University School of Medicine, Nashville, TN.

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http://dx.doi.org/10.1161/CIRCRESAHA.120.317624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430039PMC
August 2020

What Kind of Evidence Is Needed to Dictate Practice Regarding Inhibitors of the Renin-Angiotensin System in COVID-19?

Hypertension 2020 09 12;76(3):665-669. Epub 2020 Aug 12.

From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15712DOI Listing
September 2020

Elevated Eosinophils as a Feature of Inflammation Associated With Hypertension in Virally Suppressed People Living With HIV.

J Am Heart Assoc 2020 02 17;9(4):e011450. Epub 2020 Feb 17.

Division of Clinical Pharmacology Vanderbilt University Medical Center Nashville TN.

Background People living with HIV (PLWH) are at increased risk of cardiovascular disease, including hypertension, which persists despite effective plasma viral suppression on antiretroviral therapy. HIV infection is characterized by long-term alterations in immune function, but the contribution of immune factors to hypertension in PLWH is not fully understood. Prior studies have found that both innate and adaptive immune cell activation contributes to hypertension. Methods and Results We hypothesized that chronic inflammation may contribute to hypertension in PLWH. To test this hypothesis, we enrolled a cohort of 70 PLWH (44% hypertensive) on a long-term single antiretroviral therapy regimen for broad phenotyping of inflammation biomarkers. We found that hypertensive PLWH had higher levels of inflammatory cytokines, including tumor necrosis factor-α receptor 1, interleukin-6, interleukin-17, interleukin-5, intercellular adhesion molecule 1 and macrophage inflammatory protein-1α. After adjustment for age, sex, and fat mass index, the circulating eosinophils remained significantly associated with hypertension. On the basis of these results, we assessed the relationship of eosinophils and hypertension in 2 cohorts of 50 and 81 039 similar HIV-negative people; although eosinophil count was associated with prevalent hypertension, this relationship was abrogated by body mass index. Conclusions These findings may represent a unique linkage between immune status and cardiovascular physiological characteristics in HIV infection, which should be evaluated further.
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http://dx.doi.org/10.1161/JAHA.118.011450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070208PMC
February 2020

Measurement of sodium intake or measurement of the detrimental effects of sodium on health in individual subjects?

J Clin Hypertens (Greenwich) 2020 02 8;22(2):303. Epub 2020 Jan 8.

Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.

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http://dx.doi.org/10.1111/jch.13786DOI Listing
February 2020

Critical role of Interleukin 21 and T follicular helper cells in hypertension and vascular dysfunction.

JCI Insight 2019 04 23;5. Epub 2019 Apr 23.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.

T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.
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http://dx.doi.org/10.1172/jci.insight.129278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629096PMC
April 2019

Urinary sodium excretion measures and health outcomes.

Lancet 2019 03;393(10178):1295

Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

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http://dx.doi.org/10.1016/S0140-6736(19)30695-6DOI Listing
March 2019

Of Cardiac Holes and Crew Leaders.

Am J Med 2018 10;131(10):e433

Vanderbilt University; Nashville, Tenn.

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http://dx.doi.org/10.1016/j.amjmed.2018.03.039DOI Listing
October 2018

Hypertension and increased endothelial mechanical stretch promote monocyte differentiation and activation: roles of STAT3, interleukin 6 and hydrogen peroxide.

Cardiovasc Res 2018 09;114(11):1547-1563

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Aims: Monocytes play an important role in hypertension. Circulating monocytes in humans exist as classical, intermediate, and non-classical forms. Monocyte differentiation can be influenced by the endothelium, which in turn is activated in hypertension by mechanical stretch. We sought to examine the role of increased endothelial stretch and hypertension on monocyte phenotype and function.

Methods And Results: Human monocytes were cultured with confluent human aortic endothelial cells undergoing either 5% or 10% cyclical stretch. We also characterized circulating monocytes in normotensive and hypertensive humans. In addition, we quantified accumulation of activated monocytes and monocyte-derived cells in aortas and kidneys of mice with Angiotensin II-induced hypertension. Increased endothelial stretch enhanced monocyte conversion to CD14++CD16+ intermediate monocytes and monocytes bearing the CD209 marker and markedly stimulated monocyte mRNA expression of interleukin (IL)-6, IL-1β, IL-23, chemokine (C-C motif) ligand 4, and tumour necrosis factor α. STAT3 in monocytes was activated by increased endothelial stretch. Inhibition of STAT3, neutralization of IL-6 and scavenging of hydrogen peroxide prevented formation of intermediate monocytes in response to increased endothelial stretch. We also found evidence that nitric oxide (NO) inhibits formation of intermediate monocytes and STAT3 activation. In vivo studies demonstrated that humans with hypertension have increased intermediate and non-classical monocytes and that intermediate monocytes demonstrate evidence of STAT3 activation. Mice with experimental hypertension exhibit increased aortic and renal infiltration of monocytes, dendritic cells, and macrophages with activated STAT3.

Conclusions: These findings provide insight into how monocytes are activated by the vascular endothelium during hypertension. This is likely in part due to a loss of NO signalling and increased release of IL-6 and hydrogen peroxide by the dysfunctional endothelium and a parallel increase in STAT activation in adjacent monocytes. Interventions to enhance bioavailable NO, reduce IL-6 or hydrogen peroxide production or to inhibit STAT3 may have anti-inflammatory roles in hypertension and related conditions.
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http://dx.doi.org/10.1093/cvr/cvy112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106108PMC
September 2018

Human monocyte transcriptional profiling identifies IL-18 receptor accessory protein and lactoferrin as novel immune targets in hypertension.

Br J Pharmacol 2019 06 21;176(12):2015-2027. Epub 2018 Jun 21.

Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Background And Purpose: Monocytes play a critical role in hypertension. The purpose of our study was to use an unbiased approach to determine whether hypertensive individuals on conventional therapy exhibit an altered monocyte gene expression profile and to perform validation studies of selected genes to identify novel therapeutic targets for hypertension.

Experimental Approach: Next generation RNA sequencing identified differentially expressed genes in a small discovery cohort of normotensive and hypertensive individuals. Several of these genes were further investigated for association with hypertension in multiple validation cohorts using qRT-PCR, regression analysis, phenome-wide association study and case-control analysis of a missense polymorphism.

Key Results: We identified 60 genes that were significantly differentially expressed in hypertensive monocytes, many of which are related to IL-1β. Uni- and multivariate regression analyses of the expression of these genes with mean arterial pressure (MAP) revealed four genes that significantly correlated with MAP in normotensive and/or hypertensive individuals. Of these, lactoferrin (LTF), peptidoglycan recognition protein 1 and IL-18 receptor accessory protein (IL18RAP) remained significantly elevated in peripheral monocytes of hypertensive individuals in a separate validation cohort. Interestingly, IL18RAP expression associated with MAP in a cohort of African Americans. Furthermore, homozygosity for a missense single nucleotide polymorphism in LTF that decreases antimicrobial function and increases protein levels (rs1126478) was over-represented in patients with hypertension relative to controls (odds ratio 1.16).

Conclusions And Implications: These data demonstrate that monocytes exhibit enhanced pro-inflammatory gene expression in hypertensive individuals and identify IL18RAP and LTF as potential novel mediators of human hypertension.

Linked Articles: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.
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http://dx.doi.org/10.1111/bph.14364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534784PMC
June 2019

Mechanisms of salt sensitivity of blood pressure: an unbiased approach to skinning a cat.

J Hypertens 2018 03;36(3):702-703

Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

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http://dx.doi.org/10.1097/HJH.0000000000001636DOI Listing
March 2018

Two Pools of Epoxyeicosatrienoic Acids in Humans: Alterations in Salt-Sensitive Normotensive Subjects.

Hypertension 2018 02 26;71(2):346-355. Epub 2017 Dec 26.

From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (F.E., G.L.M., N.J.B., C.L.L.); and Department of Pharmacology, New York Medical College, Valhalla (M.L.-S.).

We measured epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DHETs) in 21 normotensive subjects classified as salt resistant (13) or salt sensitive (8) with an inpatient protocol of salt loading (460 mEq Na/24 hours, HiNa) and depletion (10 mEq Na/24 hours+furosemide 40 mg×3, LoNa). No urine EETs were detected; hence, enzyme linked innumosorbent assay 14,15-DHETs (dihydroxyeicosatrienoic acids) were considered the total converted 14,15-urine pool. We report ultra-performance liquid chromatography/tandem mass spectrometry plasma EETs, DHETs, and their sum (plasma total pool) for the 3 regioisomers (8,9-, 11,12-, 14,15-) and their sum (08,15-). In salt-resistant subjects, urine total pool was unchanged by HiNa, decreased by LoNa, and correlated with urine sodium excretion, fractional excretion of Na, and Na/K ratio for the 3 days of the experiment combined (<0.03). In contrast, plasma total pool increased in LoNa and did not correlate with natriuresis or Na/K ratio but showed correlations between EETs, blood pressures, and catecholamines and between DHETs and aldosterone (<0.03). Urine total pool of salt-sensitive was lower than that of salt-resistant subjects in certain phases of the experiment, lacked responses to changes in salt balance, and exhibited limited correlations with natriuresis and Na/K ratio during LoNa only. Plasma total pool of salt-sensitive was lower than in salt-resistant subjects and did not correlate with blood pressures or aldosterone but did with catecholamines. We conclude that the urine total pool reflects a renal pool involved in regulation of natriuresis, whereas the plasma total pools are of systemic origin, uninvolved in Na excretion, perhaps contributing to regulation of vascular tone. Data suggest that abnormalities in EETs in salt-sensitive subjects participate in their renal or vascular dysfunction, which has potential therapeutic implications.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764817PMC
February 2018

Discontinuation of Therapy in Hypertension Research: Value, Ethics, Risk, and Role in Renal Denervation Trials.

Hypertension 2017 05 3;69(5):795-797. Epub 2017 Apr 3.

From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.08884DOI Listing
May 2017

Hypertension and Its Complications in a Young Man With Autoimmune Disease.

Hypertension 2017 04 27;69(4):536-544. Epub 2017 Feb 27.

From the University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, United Kingdom (E.M.-H., N.D.); Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, United Kingdom (A.F.D.); Baker IDI Heart and Diabetes Institute, Melbourne, Australia (G.L.R.J.); Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham (S.O.); Division of Nephrology and Hypertension, Northwestern University Feinberg School of Medicine, Chicago, IL (D.C.B.); Division of Clinical Pharmacology, Department of Medicine (F.E.) and Department of Medicine (C.L.L.), Vanderbilt University School of Medicine, Nashville, TN; Medical University of South Carolina, Charleston (J.N.B.); and Hypertension Unit, Nephrology Department, Hospital Universitari del Mar, Barcelona, Spain (A.O.).

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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09036DOI Listing
April 2017

Hemodynamics and Salt-and-Water Balance Link Sodium Storage and Vascular Dysfunction in Salt-Sensitive Subjects.

Hypertension 2016 07 9;68(1):195-203. Epub 2016 May 9.

From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN (C.L.L., J.M.T., F.C.L., F.E.); Division of Cardiology, Scott and White Health Care, Texas A&M University, Temple (R.C.S.); and Experimental and Clinical Research Center, Max-Delbrück Center, and Charité Medical Faculty, Berlin, Germany (F.C.L.).

We investigated 24-hour hemodynamic changes produced by salt loading and depletion in 8 salt-sensitive (SS) and 13 salt-resistant (SR) normotensive volunteers. After salt loading, mean arterial pressure was higher in SS (96.5±2.8) than in SR (84.2±2.7 mm Hg), P<0.01, owing to higher total peripheral resistance in SS (1791±148) than in SR (1549±66 dyn*cm(-5)*s), P=0.05, whereas cardiac output was not different between groups (SS 4.5±0.3 versus SR 4.4±0.2 L/min, not significant). Following salt depletion, cardiac output was equally reduced in both groups. Total peripheral resistance increased 24±6% (P<0.001) in SR, whose mean arterial pressure remained unchanged. In contrast, total peripheral resistance did not change in SS (1±6%, not significant). Thus, their mean arterial pressure was reduced, abolishing the mean arterial pressure difference between groups. SS had higher E/e' ratios than SR in both phases of the protocol. In these 21 subjects and in 32 hypertensive patients, Na(+) balance was similar in SR and SS during salt loading or depletion. However, SR did not gain weight during salt retention (-158±250 g), whereas SS did (819±204), commensurate to iso-osmolar water retention. During salt depletion, SR lost the expected amount of weight for iso-osmolar Na(+) excretion, whereas SS lost a greater amount that failed to fully correct the fluid retention from the previous day. We conclude that SS are unable to modulate total peripheral resistance in response to salt depletion, mirroring their inability to vasodilate in response to salt loading. We suggest that differences in water balance between SS and SR indicate differences in salt-and-water storage in the interstitial compartment that may relate to vascular dysfunction in SS.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900938PMC
July 2016

Mineralocorticoid Receptor Activation Contributes to the Supine Hypertension of Autonomic Failure.

Hypertension 2016 Feb 7;67(2):424-9. Epub 2015 Dec 7.

From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.

Primary autonomic failure is characterized by disabling orthostatic hypotension, but at least half of these patients have paradoxical supine hypertension. Renin-angiotensin mechanisms were not initially thought to contribute to this hypertension because plasma renin activity is often undetectable in autonomic failure. Plasma aldosterone levels are normal, however, and we recently showed that plasma angiotensin II is elevated and acts at AT1 (angiotensin type 1) receptors to contribute to hypertension in these patients. Because aldosterone and angiotensin II can also bind mineralocorticoid receptors to elevate blood pressure, we hypothesized that mineralocorticoid receptor activation plays a role in the hypertension of autonomic failure. To test this hypothesis, we determined the acute effects of the mineralocorticoid receptor antagonist eplerenone (50 mg, oral) versus placebo on supine blood pressure in a randomized, double-blind, crossover study. Medications were given at 8:00 pm with blood pressure recorded every 2 hours for 12 hours. Ten primary autonomic failure patients with supine hypertension completed this study (7 pure autonomic failure, 2 multiple system atrophy, 1 parkinson's disease; 7 male; 70±2 years of age). Eplerenone maximally reduced supine systolic blood pressure by 32±6 mm Hg at 8 hours after administration (versus 8±10 mm Hg placebo, P=0.016), with no effect on nocturia (12-hour urine volume: 985±134 mL placebo versus 931±94 mL eplerenone, P=0.492; nocturnal weight loss: -1.19±0.15 kg placebo versus -1.18±0.15 kg eplerenone, P=0.766). These findings suggest that inappropriate mineralocorticoid receptor activation contributes to the hypertension of autonomic failure, likely independent of canonical mineralocorticoid effects, and provides rationale for use of eplerenone in these patients.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.115.06617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748950PMC
February 2016

Effects of carotid body tumor resection on the blood pressure of essential hypertensive patients.

J Am Soc Hypertens 2015 Jun 19;9(6):435-42. Epub 2015 Mar 19.

Division of Clinical Pharmacology, Department of Medicine, The Vanderbilt Comprehensive Hypertension Center, Vanderbilt University School of Medicine, Nashville, TN, USA.

Removal of carotid body (CB) improves animal models of hypertension (HTN) and heart failure, via withdrawal of chemoreflex-induced sympathetic activation. Effect of CB tumor (CBT) resection on blood pressure (BP) in subjects with HTN is unknown. A retrospective analysis of 20 subjects with HTN (BP≥140/90 mmHg or anti-hypertensives use) out of 134 with CBT resection. Short-term (30 days from surgery) and long-term (slope of regressions on time over the entire follow-up) changes in BP and heart rate were adjusted for covariates (interval between readings, total follow-up, number of readings and changes in therapy). Age and duration of HTN were 56±4 and 9±5 years. Adjusted short-term decreases in systolic (SBP: -9.9±3.1, p<0.001) and pulse pressures (PP: -7.9±2.7, p<0.002) were significant and correlated with their respective long-term changes (SBP: r=0.47, p=0.047; PP: r=0.54, p=0.019). There was a strong relationship between adjusted short-term changes in SBP and PP (r=0.64, p<0.004). Six (50% of responders or 33% of the total) had short-term falls of SBP ≥10 mmHg and of PP ≥ 5 mmHg. First study to show that unilateral CBT resection is associated with sustained reduction of BP in hypertensive patients. Targeted CB chemoreflex removal could play a role in the therapy of human HTN.
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http://dx.doi.org/10.1016/j.jash.2015.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785596PMC
June 2015

Effect of a siRNA on the cost and quality of American medicine.

Am J Med 2014 Oct;127(10):e29

Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenn.

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http://dx.doi.org/10.1016/j.amjmed.2014.06.021DOI Listing
October 2014

DC isoketal-modified proteins activate T cells and promote hypertension.

J Clin Invest 2014 Oct 17;124(10):4642-56. Epub 2014 Sep 17.

Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.
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http://dx.doi.org/10.1172/JCI74084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220659PMC
October 2014

Genetic variation in CYP4A11 and blood pressure response to mineralocorticoid receptor antagonism or ENaC inhibition: an exploratory pilot study in African Americans.

J Am Soc Hypertens 2014 Jul 9;8(7):475-80. Epub 2014 May 9.

The Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.

An rs3890011 variant of CYP4A11, which is in linkage disequilibrium with the loss-of-function variant rs1126742, is associated with hypertension in humans. In mice, Cyp4a deficiency results in salt-sensitive hypertension through activation of ENaC. We tested the hypothesis that the rs3890011 variant is associated with blood pressure response to drugs acting via the ENaC pathway. African Americans with volume-dependent, resistant hypertension were randomized to treatment with placebo, spironolactone, amiloride, or combination. Blood pressure responses were analyzed by CYP4A11 genotypes. Rs3890011 (GG:GC:CC = 20:35:28) and rs1126742 (TT:TC:CC = 45:31:7) were in linkage disequilibrium (D' = 1, r = 0.561). Expected small number of rs1126742 CC homozygotes precluded analysis of the effect of this genotype on treatment responses. Spironolactone reduced blood pressure in rs3890011 GG and GC individuals, but not in CC homozygotes (P = .002), whereas amiloride reduced blood pressure similarly in all rs3890011 genotypes. The antihypertensive effects of spironolactone and amiloride were comparable in GG and GC participants, but only amiloride reduced pressure in CC homozygotes (-6.3 ± 7.3/-3.2 ± 4.0 vs. +6.8 ± 7.9/+4.8 ± 8.6 mm Hg, P < .01/<.05). The aldosterone response to spironolactone was also blunted in the CC genotype. In individuals homozygous for the CYP4A11 rs3890011 C allele, blood pressure is resistant to mineralocorticoid receptor antagonism, but sensitive to ENaC inhibition, consistent with ENaC activation. Studies in a larger population are needed to replicate these findings.
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http://dx.doi.org/10.1016/j.jash.2014.04.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115247PMC
July 2014
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