bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 108: Altered Erk / Klf4-mediated Control Of Agrp And Metabolic Rate During Obesity
Authors: Ritter McKenzie L , Balapattabi Kirthikaa , Reho John J , Claflin Kristin E , Morselli Lisa L , Sigmund Curt D , Grobe Justin L
Published: September 2022

Resting metabolic rate (RMR) adaptation contributes to the maintenance of human obesity, yet mechanisms controlling RMR in lean vs obese states remain poorly defined. Leptin contributes to RMR control in part through suppression of inhibitory Agouti-related peptide (AgRP) neurotransmission in the hypothalamic arcuate nucleus (ARC). Within AgRP neurons, leptin activates the extracellular signal-regulated kinase (ERK) cascade, which is thought to interrupt
Agrp
transcription through interference with the Krüppel-like factor 4 (KLF4) transcription factor, and our published data support altered ARC ERK signaling during obesity. We therefore hypothesized a role for ERK/KLF4 signaling within AgRP neurons for the suppression of AgRP transcription and thereby stimulation of RMR in the lean state, and changes in this pathway during obesity. In the GT1-7 cell model of AgRP neurons, leptin increased the phosphorylated ERK (pERK)/ERK ratio (n=4, 1 uM, 15 min +89% p<0.05) and reduced
Agrp
mRNA (n=4, 1 uM, 1 hr -43.0% p<0.05); similarly, siRNA knockdown of
Klf4
reduced
Agrp
mRNA (n=4, -21.6% p<0.05). In lean adult C57BL/6J mice, leptin increased the ARC pERK/ERK ratio (n=8, 1 ug/g ip 16.5-fold p<0.05) and stimulated RMR (n=11, 2 ug/g ip 30 min +43.8% p<0.05). Lean transgenic mice with conditional deletion of KLF4 from AgRP neurons (
Agrp
-Cre x
Klf4
flox
) exhibited increased RMR (n=13 KO +13.48% vs controls n=22 p<0.05). These findings support the model that ERK inhibition of KLF4 within AgRP neurons mechanistically contributes to leptin-mediated control of
Agrp
and RMR in the lean state. Ten weeks of high fat feeding strongly increases endogenous plasma leptin in C57BL/6J mice, and this treatment increased the ARC pERK/ERK ratio (n=5 +54.4% p<0.05), yet ARC KLF4 was increased (n=6 +74.6% p<0.05) and
Agrp
mRNA was not suppressed (n=4 +1.6-fold, p=ns). Therefore, these data also support the concept that loss of ERK-mediated suppression of KLF4 within the AgRP neuron during obesity may contribute to the pathogenesis of RMR adaptation.
Abstract 116: Proof Of Biological Activity And Exploration Of Early Signaling Events Of Angiotensin-(1-5)
Authors: Silva Igor M , Peluso Augusto , Nawrocki Arkadiusz , Jakobsen Lene A , Jensen Pia , Ribeiro Lucas R , Mortensen Christina , Sumners Colin , Verano-Braga Thiago , Larsen Martin , Steckelings Ulrike M
Published: September 2022

Introduction:
Recombinant human ACE2 increases the circulating levels of angiotensin-(1-5) [Ang-(1-5)], a peptide thus far regarded as biologically inactive. Since ACE2 is a central component of the protective RAS, we hypothesized that Ang-(1-5) is a new biologically active peptide within this hormonal system.

Objective:
To investigate biological activity and signaling mechanisms of Ang-(1-5).

Methods:
In order to show a biological effect and to test whether Ang-(1-5) signals through the AT
2
-receptor (AT
2
R), nitric oxide (NO) release was measured by DAF-FM fluorescence in AT
2
R transfected (AT
2
R-CHO) or non-transfected (NT-CHO) CHO cells, treated with Ang-(1-5) or C21 (AT
2
R agonist, positive control) (0.1nM to 10μM) for 15 minutes. Vehicle (cell media) treated cells served as negative control. To investigate Ang-(1-5) signaling patterns, human aortic endothelial cells (HAEC) were treated with vehicle or Ang-(1-5) (1μM) for 1, 3, 5 or 20 minutes. Proteins were harvested, digested and labeled with TMTpro-16plex. Phosphopeptide enrichment was carried out by TiO
2
. Samples were subjected to LC-MS/MS analysis and the resulting mass spectra were searched against the human SwissProt database.

Results:
Ang-(1-5) induced a concentration-dependent increase in NO production in AT
2
-CHO cells (E
max
: 65.60 ± 14.02%), thus proving its biological activity. Ang-(1-5) had 69% higher efficacy than the established AT
2
R agonist C21 (E
max
: 38.76 ± 10.24%). Ang-(1-5) seems to signal through the AT
2
R, because effects on NO release were absent in NT-CHO cells. Treatment of HAEC with Ang-(1-5) significantly modified the phosphorylation status of 831 proteins at 1799 residues. The majority of residues (1079) were dephosphorylated while 729 residues were phosphorylated. Changes in protein phosphorylation in response to Ang-(1-5) occurred at all investigated time points, most of them after 20 minutes. Functional bioinformatic analysis revealed a cluster of proteins involved in cell cycle and cell division regulation.

Conclusion:
This study provides evidence that Ang-(1-5) is an endogenous AT
2
R agonist with high efficacy towards the AT
2
R. The early signaling phosphorylation pattern resembles those of other protective RAS agonists, such as C21 and Ang-(1-7).
Abstract 117: Interleukin-18 Is A Critical Mediator Of Cardiac Remodelling During Angiotensin II-induced Hypertension
Authors: Drummond Grant , Saini Narbada , Georgia-Sherriff Ashleigh , Diep Henry , Pinto Alexander , Dona Malathi , Sobey Christopher G , Jelinic Maria , Vinh Antony
Published: September 2022

Hypertensive heart failure is characterised by cardiomyocyte hypertrophy, inflammation and fibrosis, leading to stiffening and diastolic dysfunction. There are currently no effective treatments for hypertensive heart failure, in part reflecting our limited knowledge of the molecular mechanisms. Interleukin-18 (IL-18) is a pro-inflammatory, inflammasome-derived cytokine that is elevated in the circulation of hypertensive patients; however, its role in promoting cardiac remodelling and dysfunction is unknown. Thus, we examined if IL-18-deficient (
Il18
-/-
) mice were protected from hypertensive cardiac remodelling and, if so, whether this occurs independently of changes in blood pressure. Hypertension was induced in male wild-type (WT) and
Il18
-/-
mice by angiotensin II (Ang II; 1.44 mg/kg/d,
s.c.
) infusion for 28 d. Normotensive controls were saline-infused. Systolic blood pressure (SBP) was measured by tail cuff, gene expression was measured by single cell RNA sequencing (scRNA-seq), cardiac fibrosis by picrosirius red-staining, and cardiac hypertrophy/remodelling was assessed histologically and via heart weight:body weight. scRNAseq analysis of hearts isolated from Ang II-treated WT mice revealed that IL-18 was expressed by macrophages, granulocytes and epicardial cells. Baseline SBPs were not different between WT and
Il18
-/-
mice, and Ang II evoked a similar degree of hypertension in each genotype (160 ± 24 and 165 ± 16 mmHg in WT and
Il18
-/-
mice, respectively). Despite having no impact on pressor responses to Ang II, IL-18-deficiency provided marked protection against Ang II-induced cardiac hypertrophy (6.58 ± 0.53
cf.
7.87 ± 1.14 mg/g in
Il18
-/-
and WT, respectively; n≥7, P<0.01) and fibrosis (1.84 ± 0.18
cf.
4.06 ± 0.46 % in
Il18
-/-
and WT, respectively; n≥7, P<0.01). Furthermore, cardiac myocytes were enlarged, disorganised and displayed hyperchromatic nuclei in Ang II-treated WT mice, but not in Ang II-treated
Il18
-/-
mice. In conclusion, IL-18 deficiency protects against cardiac remodelling during hypertension, independent of an effect on SBP. These findings suggest that IL-18 is a driver of hypertensive cardiac remodelling and potential target for future therapies.
Abstract 120: Midgestation Eplerenone Treatment Ablates Leptin-induced Hypertension And Endothelial Dysfunction But Not Fetal Growth Restriction In Preeclamptic Mice
Authors: Mellott Elisabeth , Moronge Desmond , Ayulo Victor , Connor Gabrielle , Ogbi Safia , Faulkner Jessica L
Published: September 2022

Elevated leptin (lep) in pregnant women strongly associates with preeclampsia (PE), a hypertensive pregnancy disorder. Our lab established a mid-late gestation lep-infusion model of PE, which induces endothelial dysfunction, hypertension and fetal growth restriction (FGR); deletion of endothelial mineralocorticoid receptors (MR) ablated these PE characteristics in pregnant mice. Whether pharmacological MR antagonism ablates lep-induced PE, however, is unknown. We hypothesized that MR antagonism (eplerenone) ablates lep-induced PE characteristics in pregnant mice. We infused pregnant BALB/c mice with leptin (lep, 0.9mg/kg/day) or saline (sham) via osmotic minipump alongside eplerenone (Eplr, 200mg/kg/day) or vehicle in drinking water from gestation day (GD)11-18. We measured vascular function via wire myography of 2
nd
order mesenteric vessels and pup/placental weights on GD18 (n=5-7). We implanted radiotelemeters in separate mice (n=1-3) prior to mating and measured mean arterial pressure (BP) from GD11-18. Pre-pregnancy BP did not differ between treatment groups. Preliminary data indicates lep increased BP compared to sham from GD11-18 (112.7±4.5 lep vs 89.4 sham mmHg,) and Eplr decreased BP in lep pregnant mice (97.2±7.2 lep+Eplr mmHg, P=0.09 vs lep student’s t-test). Vascular relaxation to endothelial-dependent acetylcholine (ACh) decreased in lep+vehicle compared to sham+vehicle (*P<0.05, 2-Way ANOVA w/ RM). Eplr+lep restored ACh-mediated vascular relaxation (*P<0.05 vs lep+vehicle). LNAME pre-incubation did not ablate differences in ACh-mediated relaxation between lep+vehicle and lep+eplr (P>0.05) indicating that Eplr restored a non-NO mechanism to improve endothelial function. Lep as a variable decreased pup weight in both vehicle and Eplr pregnant mice, however, Eplr did not increase pup weight in either vehicle or lep mice (0.74±0.01sham+veh, 0.71±0.01 lep+veh, 0.70±0.01 sham+eplr, 0.67±0.01 lep+eplr (g), *P<0.05, 2-Way ANOVA). Collectively these data indicate that Eplr improves lep-induced endothelial dysfunction and hypertension, but may not prevent FGR when given from GD11-18. Therefore, further studies will determine whether MR antagonism promises therapeutic potential in lep-induced PE.
Abstract 121: The Selective Aldosterone Synthase Inhibitor PB6440 Normalizes Blood Pressure In A Human Aldosterone Synthase-Transgenic Mouse Model Of Hypertension
Authors: Lee John , Schotzinger Robert , Becherer David , Sparks Steven , Gu Huiying , Yu Yongqi , Du Yansheng
Published: September 2022

Introduction:
Aldosterone synthase inhibitors are emerging as important future treatment options for diseases associated with aldosterone signaling, such as resistant hypertension and chronic renal disease. PB6440 is a potent inhibitor of aldosterone synthase (CYP11B2) with high selectivity over the closely related enzyme CYP11B1. The goal of the current study was to determine whether PB6440 was capable of reducing aldosterone production and blood pressure in an established human aldosterone synthase-transgenic mouse strain (hAS
+/-
) that is associated with aldosterone excess and the development of hypertension under a 4% salt diet.

Methods:
hAS
+/-
mice were administered PB6440, positive controls and vehicle by oral gavage. In a single-dose study, plasma aldosterone levels were assessed 8 hours after the administration of PB6440 at 2, 10 and 30 mg/kg as well as the positive control fadrozole at 5 mg/kg. In a pilot study, blood pressure was assessed following 10 days of PB6440 once daily at 10 mg/kg as well as the positive control spironolactone at 50 mg/kg. In a definitive study, blood pressure was assessed following 8 weeks of PB6440 once daily at 30 mg/kg as well as spironolactone at 50 mg/kg. Blood pressure was assessed 4-6 hours after drug dosing using a tail-cuff system.

Results:
In the single-dose study, PB6440 markedly reduced plasma aldosterone with a similar potency to fadrozole (e.g., PB6440 10 mg/kg -96% compared to vehicle; fadrozole 5 mg/kg -96%). In the pilot study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice, with a somewhat greater effect on both parameters than spironolactone at day 10. In the definitive study, PB6440 normalized both systolic and diastolic blood pressures to that of wild-type mice through 8 weeks with an efficacy similar to spironolactone. The decreases in SBP were approximately 30 mm Hg and DBP approximately 20 mm Hg in both drug groups compared to vehicle-treated hAS
+/-
mice.

Conclusions:
PB6440 was shown to lower aldosterone levels and normalize blood pressure through 8 weeks in an established mouse model of aldosterone excess and hypertension. PB6440 is a promising potential therapy for the treatment of conditions associated with aldosterone signaling in humans.
Abstract 125: Modified Angiotensin II Has Lower Vasoconstrictive Effect Than Angiotensin II
Authors: Lellig Michaela , Muñoz-Castañeda Juan R , Hermann Juliane , Jankowski Vera
Published: September 2022

Introduction:
The renin-angiotensin-aldosterone system (RAAS) is involved in the regulation of the blood pressure, water- and electrolyte balance. Pathophysiologically, this system is essential for the development and pathogenesis of both cardiovascular and renal diseases. Angiotensin II, a component of the RAAS, is the best-known vasoconstrictive and hypertensive peptide in the human organism. This peptide consists of 8 amino acids (asp-arg-val-tyr-ile-his-pro-phe). The first amino acid, aspartic acid, is converted to pyruvamide in the presence of pyridoxal-5’-phosphate (PLP). The influence of pyruvamide-angiotensin II on the blood pressure is not yet clarified.

Hypothesis:
We assessed the hypothesis that the transformation of angiotensin II to pyruvamide-angiotensin II by PLP leads to lowering the blood pressure.

Methods:
To clarify the influence of pyruvamide-angiotensin II on blood pressure
ex vivo
experiments were performed. Angiotensin II as well as pyruvamide-angiotensin II was tested in isolated perfused rat kidney. Further,
in vivo
experiments were performed. Wistar Kyoto rats (WKY) and Spontaneously Hypertensive Rats (SHR) were treated with angiotensin II in the absence and presence of PLP. The blood pressure was measured at different time.

Results:
Pressure in isolated perfused rat kidney increases by 50.11 ± 4.57 mmHg after injecting angiotensin II, whereas pressure increases by 38.40 ± 4.31 mmHg after injecting pyruvamide-angiotensin II. Data are shown as mean ± SEM of triplicate measurements from three independent experiments. Further, blood pressure of SHR treated with PLP decreases from 171/139 ± 5 mmHg to 129/98 ± 2 mmHg after three days. Blood pressure of WKY treated with angiotensin II increases to 167/133 ± 3 mmHg, whereas blood pressure of WKY treated with angiotensin II and PLP decreases to 129/99 ± 2 mmHg. Data are shown as mean ± SEM from five independent experiments.

Conclusions:
In conclusion, pyruvamide-angiotensin II has a lower vasoconstrictive effect than angiotensin II. Furthermore, PLP decreases the blood pressure in SHR and WKY.
Abstract 126: Antigen Presenting Cell Isolevuglandins: A Potential Diagnostic Tool For Salt Sensitivity Of Blood Pressure In Humans
Authors: Ertuglu Lale A , Laffer Cheryl L , Elijovich Fernando , Sahinoz Melis , Pitzer Ashley , Ikizler Alp , Kirabo Annet
Published: September 2022

Salt sensitivity of blood pressure is an independent cardiovascular risk factor as powerful as hypertension, yet it goes untreated due to the lack of a feasible diagnostic tool. We previously found that sodium enters antigen-presenting cells (APCs) via ENaC, leading to the formation of isolevuglandins (IsoLGs). IsoLGs are highly reactive oxidative products of fatty acids and act as neoantigens to trigger inflammation in hypertension. We found that activation of APCs via IsoLG is highly variable in humans. Thus, we hypothesized that this variability in IsoLG-mediated APC activation contributes to the variability observed in human salt sensitivity of blood pressure and that IsoLGs can be used as a diagnostic tool. We measured systolic blood pressure (SBP) and IsoLG-containing APCs (dendritic cells [DC], classical, intermediate and non-classical monocytes) by flow cytometry in 14 hypertensive subjects who were off therapy for 2 weeks, before (B) and after in-patient 24 hr salt loading (HI, 460 mmol Na
+
) and salt depletion (LO, 10 mmol Na
+
and furosemide 40 mg x 3). Salt sensitivity was assessed by ΔSBP (LO minus HI). Median age was 49, with 5 females, median BMI (IQR) of 29.8 (25.2, 39.5) kg/m
2
and screening SBP of 135.1 (130, 144.9) mmHg. The median urinary Na
+
excretions (IQR) were 169.6 (125, 203.3), 360.9 (324.1, 421.2) and 54.8 (36.8, 76) mmol/24h at baseline, HI and LO days, respectively. Baseline percentages of classical and non-classical monocytes with IsoLGs were positively correlated with ΔSBP (r=0.64, p=0.01 and r=0.71, p<0.01 respectively). Changes in IsoLG-containing DCs and nonclassical monocytes positively correlated with ΔSBP (r=0.60, p=0.03 and r=0.69, p=0.01 respectively). Both the baseline levels and changes in IsoLG containing APCs associated with salt sensitivity. Greater decrease in IsoLG-containing APCs predicted greater decline in blood pressure in response to salt depletion, suggesting that oxidative stress in APCs is implicated in the pathogenesis of salt sensitivity. Our results further suggest that baseline percentage of IsoLG-containing APCs may be the first predictor of salt sensitivity that does not require a protocol of salt loading and depletion. This would enable the diagnosis of salt sensitivity in clinic practice.
Abstract 131: Interleukin-23 Receptor Deficiency Increased Interferon-gamma Producing T Cells And Potentiated Blood Pressure Elevation In Angiotensin II-infused Mice
Authors: Paradis Pierre , Shokoples Brandon , Comeau Kevin , Higaki Akinori , Ferreira Nathanne d , Caillon Antoine , Berillo Olga , Oukka Mohamed , Schiffrin Ernesto L
Published: September 2022

Introduction:
We previously demonstrated a role for γδ T cells in hypertension and vascular injury. In inflammatory conditions γδT17 are a prominent producer of IL-17A, which has been shown to contribute to hypertension. The development and expansion of γδT17 cells is regulated in part through IL-23 receptors (IL-23R).

Hypothesis:
We hypothesized that angiotensin (Ang) II-induced blood pressure (BP) elevation and vascular injury would be blunted in mice with dysfunctional IL-23R.

Methods:
Wild-type (WT) and
Il23r
knock-in (

Il23r
gfp/gfp

) mice were infused or not with Ang II (490ng/kg/min, SC) for 7 or 14 days. BP was monitored via telemetry, mesenteric artery function and remodeling using pressurized myography, and T cell profiling in mesenteric artery perivascular adipose tissue (PVAT) by flow cytometry.

Results:

Il-23r
gfp/gfp

mice exhibited a greater BP elevation in response to Ang II than WT by day 3 (152±5 vs 144±7 mm Hg,
P
<0.05), which was sustained through day 9 (169±2 vs 155±5 mm Hg,
P
<0.05), but eventually similar to that of WT mice by the end of the Ang II infusion (167±2 vs 167±4 mm Hg).

Il-23r
gfp/gfp

mice were not protected from vascular dysfunction and remodeling after 14 days of Ang II.

Il23r
gfp/gfp

mice had less γδT17 cells in PVAT than WT mice (40±8 vs 108±15 cells/PVAT,
P
<0.05). Ang II increased interferon-γ producing γδ T cells in WT (13±3 vs 5±1 cells/PVAT,
P
<0.05) and

Il23r
gfp/gfp

mice (14±3 vs 3±1 cells/PVAT,
P
<0.05), and interferon-γ producing CD4
+
(125±27 vs 38±13 cells/PVA,
P
<0.05) and CD8
+
T cells (76±13 vs 33±8 cells/PVA,
P
<0.05) only in

Il23r
gfp/gfp

mice.

Conclusion:
Functional IL-23R deficiency exaggerated BP elevation during the initiation of Ang II-induced hypertension, potentially due to the increased number of interferon-γ producing T cells.
Abstract 134: Blood Pressure Control And Hypertension Diagnosis Six Months After Completing Ambulatory Blood Pressure Diagnostic Testing
Authors: Green Beverly , Hall Yoshio , Anderson Melissa L , Margolis Karen L
Published: September 2022

Importance:
Undiagnosed hypertension contributes to excess morbidity and mortality.

Objective:
To examine the effect of hypertension diagnostic testing on hypertension diagnoses and blood pressure (BP) control months at 6 months.

Design, Setting, and Participants:
BP CHECK was a randomized diagnostic study of 510 adults aged 18-85 without diagnosed hypertension with elevated BP in clinic and at baseline, conducted from 2017 to 2019 in primary care centers of an integrated healthcare system. Participants were randomization to one of three diagnostic regimens: (1) Clinic BP, (2) Home BP, or (3) Kiosk BP. All participants completed 24-hour ambulatory blood pressure monitoring (ABPM) at 3 weeks. ABPM results were sent to participants and their primary care providers and uploaded into the electronic health records (EHR).

Main Outcomes and Measures:
The primary outcomes were BP control and receipt of a new hypertension diagnosis at 6 months. We further examined whether changes in patient-reported outcomes relating to health behaviors or 6-month health attitudes were associated with BP control or a new hypertension diagnosis.

Results:
Mean baseline BP was 150/88 mmHg. Among 467 study participants completing ABPM, 335 (72%) were confirmed to have hypertension. At 6 months, 47% (156/335) of participants with hypertension achieved BP <140/90 mmHg and 41% (137/335) had a new hypertension diagnosis recorded in the EHR with no differences by randomized group. Participants with a new hypertension diagnosis (n=137) experienced significantly greater reductions from baseline in systolic and diastolic BP (mean difference, -4.9 mmHg [95% CI: -7.8,-2.1]) and diastolic BP (-2.3 mmHg [-4.3, -0.4]) compared to individuals with undiagnosed hypertension (n=198). Significantly higher proportions of participants with adequate BP control and diagnosed hypertension felt sharing home BP readings with their provider was helpful or very helpful in managing their BP.

Conclusion and Relevance:
Most participants with high BP on screening and ABPM diagnostic testing did not achieve adequate BP control or receive a hypertension diagnosis within 6 months. New strategies are needed to increase diagnosis of hypertension in clinical practice
Abstract 136: Measured Blood Pressure, Genetically Predicted Blood Pressure, And Cardiovascular Disease Risk
Authors: Cho So Mi J , Koyama Satoshi , Ruan Yunfeng , Lannery Kim , Wong Megan , Ajufo Ezimamaka , Lee Hokyou , Khera Amit V , Honigberg Michael , Natarajan Pradeep
Published: September 2022

Introduction:
Hypertension remains the major cardiovascular disease (CVD) risk factor, but variability in blood pressure (BP) may result in suboptimal management. Whether genetic contributors to high BP complementarily inform CVD risk assessment is unknown. We examined CVD risk by BP polygenic risk score (PRS) independent of measured BPs and antihypertensives.

Methods:
A total of 331,078 unrelated UK Biobank study participants without prior cardiovascular disease were studied. Exposures included measured BP and BP PRS stratified by normal BP (systolic BP [SBP] <130 & diastolic BP <80 mmHg without antihypertensives), untreated hypertension, and treated hypertension. The primary outcome was a composite of first incident myocardial infarction, stroke, heart failure, or CVD death.

Results:
Of the 331,078 study participants (mean [SD] age at enrollment, 56.9 [8.1] years, and female sex, 178,824 [54.0%]), 83,094 (25.1%) had normal BP, 197,597 (59.7%) had untreated hypertension, and 50,387 (15.2%) had treated hypertension. Over a median follow-up of 11.1 years (IQR, 10.4-11.8), CVD occurred in 15,293 participants. Among normal BP, untreated hypertension, and treated hypertension, a 10 mmHg higher measured SBP was associated with HRs of 1.05 (95% CI, 0.97-1.12), 1.12 (95% CI, 1.11-1.14), and 1.04 (95% CI, 1.02-1.06) for CVD. Among these same categories, a 10 mmHg higher genetically predicted SBP was associated with 1.31 (95% CI, 1.12-1.54), 1.09 (95% CI, 1.02-1.17), and 1.14 (95% CI, 1.05-1.25) increased HR for CVD independent of measured BPs.

Conclusions:
BP PRS may augment identification of individuals at heightened CVD risk, including those with both normal BP and hypertension.
Abstract P001: Repurposing A Drug Targeting Inflammatory Bowel Disease For Lowering Hypertension
Authors: Mei Xue , Mell Blair , Manandhar Ishan , Aryal Sachin , Tummala Ramakumar , Kyoung Jun , Yang Tao , Joe Bina
Published: September 2022

Both the gut
per se
and its residents, the gut microbiota are linked to blood pressure (BP) regulation, whereby, the gut can be recognized as a previously neglected target organ for hypertension. Hypertension and gut diseases such as inflammatory bowel disease (IBD) share commonalities of host inflammation in the gut and microbiota dysbiosis. Therefore, we reasoned that current treatments to remedy gut inflammation and dysbiosis in IBD could be repurposed to ameliorate hypertension. IBD is commonly treated with 5-Aminosalicylic acid (5-ASA, Mesalamine), which is a selective PPAR-γ agonist to prevent gut inflammation. Clinical use of 5-ASA is also reported to ameliorate gut dysbiosis in IBD. Based on this premise, in this study we chose to test our hypothesis that 5-ASA is an antihypertensive drug owing to its dual ability to enhance PPAR-γ in the gut and to correct gut dysbiosis. 2 groups of 11-12 weeks old male genetically hypertensive Dahl salt-sensitive (S) rats were radiotelemetrically monitored for BP, and orally gavaged with (n=9) or without (n=7) 5-ASA (150 mg/kg) for 4 weeks. PPAR-γ expression was assessed by RT-qPCR. Fecal microbiota were profiled by 16S gene sequencing. Lastly, for translational significance, F/B ratio of non-IBD (n=611) patients was compared with that of IBD (n=631) patients in the American Gut Project data for their Firmicutes/Bacteroidetes (F/B) ratio, elevation of which is a marker of gut dysbiosis. 5-ASA significantly lowered BP of the S rat (mean BP without 5-ASA, 153±1 mm Hg; mean BP with 5-ASA, 145±1 mm Hg,
P
<0.0001). PPAR-γ gene expression was significantly higher in proximal colon, but not in the heart or kidney. In addition, treatment with 5-ASA corrected gut dysbiosis as observed by a significant reduction in the F/B ratio compared to control. In accordance, humans without IBD had a similar lower F/B ratio, which was consistent with the data presented here comparing S rats with 5-ASA. Collectively, these data support our hypothesis that 5-ASA, an FDA-approved anti-IBD drug, could be repurposed to treat hypertension by specifically enhancing the gut PPAR-γ mediated anti-inflammatory effect while also correcting microbiota dysbiosis to lower BP.
Abstract P003: Chemerin Supports Basal Blood Pressure In Both Male And Female Dahl SS Rats
Authors: Wabel Emma A , Orr Alexis , Flood Emma D , Thompson Janice , Garver Hannah , Mullick Adam E , Fink Gregory D , Watts Stephanie W
Published: September 2022

Evidence supports that Antisense oligonucleotides (ASO) against the adipokine chemerin reduce the blood pressure of the normal male Sprague Dawley rat and, to a greater magnitude, the hypertensive Dahl SS rat fed a high fat diet. In the Dahl SS rat, chemerin protein concentration in white adipose tissue [mesenteric perivascular adipose tissue (Mes PVAT)] was significantly higher in females vs males. We hypothesized that female Dahl SS rats would be more dependent on chemerin for blood pressure maintenance than males because of the Mes PVAT’s proximity to blood vessels that control total peripheral resistance. Age-matched male and female Dahl SS rats on a standard chow (0.2% NaCl, 6.2% fat) diet were used. Radiotelemeters were implanted to measure blood pressure (MAP) and heart rate (bpm). Following a two-week recovery period after implantation, one week of baseline measures were collected. Knockdown of whole body chemerin was achieved by subcutaneous injections of scrambled control ASO or whole-body ASO against chemerin (both 25 mg/kg) on days 0, 7, 14, and 21. On day 23, the rats were euthanized, and samples were collected for western blot and qPCR of the chemerin gene
Rarres2
. Plasma chemerin was abolished in both male and female rats given the ASO against chemerin vs that of rats receiving the control ASO. In males and females, respectively, chemerin mRNA expression (2
-ΔCT
) was reduced from 0.53 to 0.001 ± 0.002 and 0.23 to 0.001 ± 0.02 in liver, 0.05 to 0.01 ± 0.005 and 0.07 to 0.005 ± 0.02 in RP fat, and 0.09 to 0.01 ± 0.003 and 0.05 to 0.001 ± 0.02 in epididymal/uterine fat. MAP in control ASO rats showed no significant change from baseline measurements (M:137.4 ± 3.0 /F: 130.6 ± 1.5 mmHg), while males and females treated with whole-body ASO dropped by 10.7 ± 1.6 and 10.9 ± 2.1 mmHg respectively after four injections, with no significant change in heart rate. Pulse pressure also decreased by 5.6 ± 1.3 and 6.8 ± 1.3 mmHg in whole-body ASO males and females, respectively, with no significant changes from baseline in the control animals. These data suggest, contrary to our hypothesis, that chemerin plays a similar role in basal blood pressure regulation in males and females. This indicates that males and females may be equally dependent on chemerin for high fat diet-induced hypertension.
Abstract P005: Treatment And Clinical Implications Of Vascular Endothelial Growth Factor (VEGF) Inhibitor-induced Blood Pressure Rise: A Clinical Cohort Study
Authors: Van Dorst Daan C , Kabadayi Sumeyye , Oomen-de Hoop Esther , Danser Jan H , Mathijssen Ron , Versmissen Jorie
Published: September 2022

Vascular endothelial growth factor inhibitors (VEGFI) are highly effective anti-cancer agents, but frequently induce a rise in blood pressure (BP). The optimal treatment of this BP rise is currently unknown, and risk factors for this rise and its association with survival remain unclear.

To this end, baseline characteristics and BP readings were collected from electronic medical records from oncology patients who received oral VEGFI treatment (sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib or cabozantinib) in the period of 2008 until 2020. Risk factors for a clinically relevant BP rise, defined as an increase of ≥20mmHg in systolic BP (SBP) and/or ≥10mmHg in diastolic BP (DBP), were investigated via logistic regression, and their association with survival via Cox regression analysis.

In total, 343 patients were included of whom 162 (47%) developed a clinically relevant rise in BP ≥ 7 days after VEGFI treatment initiation. Both calcium channel blockers (CCB) and renin-angiotensin system inhibitors (RASI) effectively reduced SBP (-24.1mmHg and -18,2mmHg, respectively) and DBP (-12.0mmHg and -11mmHg, respectively) when started during VEGFI therapy. Pazopanib therapy (OR: 2.67, 95% CI 1.33-5.34,
P
=0.006, compared to sorafenib) and eGFR < 60ml/min/1.73m
2
(OR: 1.77, 95% CI 1.00-3.11,
P
=0.049) were risk factors for a BP rise, whereas a baseline BP of >140/90mmHg was associated with a lower risk (OR: 0.39, 95% CI 0.25-0.62,
P
<0.001). Only for renal cell carcinoma (RCC) patients, BP rise was associated with substantially improved overall survival (OS) compared to patients without BP rise (median OS 45.4 versus 20.3 months, respectively,
P
=0.003). No significant difference in OS between patients with and without new antihypertensives during VEGFI therapy was found (median OS 21.9 vs. 18.5 months, respectively,
P
= 0.143). In conclusion, the VEGFI-induced BP rise is determined by the type of VEGFI, baseline BP, and baseline eGFR. Both CCB and RASI can be used as effective antihypertensive treatment without impairing OS. Our study identified unique risk factors for a VEGFI-induced BP rise and demonstrated that this rise is an indication of treatment efficacy in RCC patients.
Abstract P006: Systematic Identification Of Metabolites Associated With Manp, A Novel Anp Analog, In Human Hypertension With Metabolic Syndrome
Authors: Ma Xiao , Yu Yue , Sangaralingham Jeson , Chen Horng , Cannone Valentina , Burnett John
Published: September 2022

Introduction:
The atrial natriuretic peptide (ANP) regulates blood pressure (BP) and cardiorenal homeostasis via activation of guanylyl cyclase A (GC-A) receptor and second messenger cGMP. We recently demonstrated the safety, tolerability, and BP-lowering properties of MANP, an ANP analog and best-in-class GC-A activator, in subjects with essential hypertension (HTN). However, the effects of MANP on human metabolome during HTN remains undefined.

Hypothesis:
A single subcutaneous (SQ) administration of MANP can trigger metabolomic changes in humans.

Methods:
Twenty-two patients with HTN and metabolic syndrome (MetS) were randomized to receive placebo (N=5) or MANP (N=17, 2.5 μg/kg). Untargeted liquid chromatography mass spectrometry-based metabolomics and informatics were conducted on plasma of all subjects at baseline, 1 h post injection (hpi), and 6 hpi. Top circulating metabolites associated with MANP treatment were identified via a comparison of abundance between before and after MANP administration.

Results:
Compared to placebo, MANP resulted in the most prominent cGMP increase at 1 hpi and BP lowering effect at 6 hpi. With untargeted approach, we identified totally 1384 circulating metabolites. Principal component analysis supported distinct metabolic signatures at baseline, 1 hpi and 6 hpi in subjects receiving MANP. In MANP group, we found 31 metabolites at 1 hpi and 148 metabolites at 6 hpi showing significant change in abundance (adjusted
P
value < 0.05) compared to baseline. By contrast, <10 metabolites with difference in circulating abundance at either 1 hpi or 6 hpi compared to baseline were found in placebo group. Specifically, 8 annotated metabolites were identified with significant and progressive changes at both 1 and 6 hpi after treatment of MANP but not placebo, which included spisulosine, paecilaminol, quinine ethyl carbonate, thyrotropin releasing hormone, 3-epideoxycholic acid, hellicoside, pentanorvitamin D3, and tetracosanal.

Conclusion:
SQ administration of MANP triggers changes in a wide range of circulating metabolites beyond cGMP activation and BP reduction in humans. The biological outcome and clinical impact of these MANP-associated metabolites may help guide a precision medicine approach in HTN with MetS.
Abstract P007: Timing Of Orthostatic Hypotension And Its Relationship With Falls In Older Adults
Authors: Petriceks Aldis H , Appel Lawrence J , Miller Edgar R , Mitchell Christine , Schrack Jennifer , Mukamal Ken J , Lipsitz Lewis , Wanigatunga Amal , Plante Tim B , Michos Erin D , Cai Yurun , Juraschek Stephen P
Published: September 2022

Background:
There is inconsistent evidence on the optimal time after standing to assess orthostatic hypotension (OH).

Objectives:
To characterize the timing of OH after standing in older adults and the fall risk associated with OH at specific times.

Methods:
We performed a secondary analysis of the Study to Understand Fall Reduction and Vitamin D in You (STURDY). Blood pressure (BP) was measured in the supine position. Participants stood upright and underwent 6 standing BP measurements: 3 (M1-M3) immediately after standing, and 3 (M4-M6) after 3 minutes of standing. OH was defined as a decrease from supine systolic BP (SBP) of 20 or supine diastolic BP (DBP) of 10 mm Hg. We used generalized estimating equations to characterize changes in SBP, DBP, and OH over time. We used Cox models to examine the relationship between OH at each time point and subsequent falls.

Results:
There were 425 falls among 491 adults with 6,055 BP measurements and a median follow-up of 275 days. SBP/DBP decreased by a mean 9.5/2.6 mm Hg immediately after standing (M1) vs. 2.2/0.9 about 5 minutes after standing (M6). OH was observed in 32% of assessments at M1, and only 16% at M5 and M6 (
Table
). Only OH at M5 (Hazard Ratio = 1.84 [95% confidence interval = 1.17, 2.91]) and M6 (1.85 [1.03, 2.91]) predicted higher fall risk among individual time points. However, average OH from early (M1-3) and late (M4-6) measurements, respectively, also predicted higher fall risk (M1-3 = 1.65 [1.08, 2.52]; M4-6 = 1.73 [1.03, 2.91]).

Conclusions:
OH was most prevalent immediately after standing, but most informative for fall risk in late and average measurements. Multiple standing BP measurements may improve the clinical assessment of OH.
Abstract P008: Development And Implementation Of A Community-focused Blood Pressure Training Curriculum For Undergraduate Students
Authors: Visaria Aayush , Kandalgoankar Sneha , Wickramasinghe Kithmy , Lo David
Published: September 2022

Background:
Community-based health education curricula focused on BP screening and preventive counseling are currently lacking.

Methods:
We developed a preventive lifestyle medicine curriculum for students focused on 1) comprehensively and accurately measuring BP; 2) obtaining data on medication adherence, healthcare utilization, lifestyle habits, and self-monitoring; and 3) providing individualized preventive counseling. Students at a single university completed an in-person training, an online module, an in-person simulated patient assessment, and a supervised community screening. To assess improvement in student knowledge, we administered identical 10-question (1 subjective, 9 content-based) multiple-choice questionnaires pre-training and one-week post-training. Content-based questions were scored as number correct, for a max of 9 points, and analyzed using paired t-tests at the 0.05 level.

Results:
From 2015-2022, we trained approximately 1,140 (91%) pre-medical undergraduates. Of 128 students trained in 2021-2022, 104 (81%) passed assessments, and 58 (45%) attended at least 1 community health screening. Students contributed 495 volunteer hours across 57 health screenings in 18 locations. Among 29 students with complete data on pre- and post-training questionnaires, the mean (SD) BP-taking confidence increased 1.3 (1.2) points (on a 1-5 point Likert scale; p<0.001). Scores for knowledge-based questions increased by a mean (SD) 2.3 (1.7) points (p=0.002). This significant increase was present for all individual questions. Despite improvement in scores, only 22% correctly answered questions on treatment goals and BP modality post-training.

Conclusion:
Adoption of a community-focused BP training curriculum may not only lead to improvement in student knowledge and confidence, but also have tangible benefits on reducing healthcare disparities and improving BP control through community-based initiatives.
Abstract P009: Feasibility And Acceptability Of A Digitally-Based Blood Pressure Self-monitoring Program That Promotes Hypertension Self-management And Health Education Among Low-income Patients.
Authors: Poblete Jacqueline , Felisme Earl , Mohn Paloma , Shea Jennifer , Vawter Natalie , Northrup Adam , Liu Jie , Al-Rousan Tala , Godino Job G
Published: September 2022

Introduction:
According to evidence-based clinical guidelines, adults with hypertension should self-monitor their blood pressure regularly. We developed a remote patient monitoring (RPM) program that supports self-monitoring and promotes improved self-management among low-income patients.

Hypothesis:
We hypothesized that the program would have high feasibility and acceptability among patients with varying digital health literacy and at least 50% of patients would utilize their monitor at a rate required for reimbursement of the cost of the device (16 days of measurements in any 30-day period).

Methods:
Between 01/2022 and 05/2022, we deployed cellularly connected monitors to patients with hypertension at Family Health Centers of San Diego. Program elements included training on measurement, behavior change, SMS reminders, and physician communication. Data was monitored via a RPM platform provided by Withings. Participants completed a baseline and follow-up survey on digital health literacy and usability. We used descriptive statistics to quantify the utilization of the monitors over time and evaluate usability.

Results:
Patients who received blood pressure monitors (N=177) had a mean (SD) age of 55 (12.0) years and 57.6% (102 out of 177) were female. Most patients were Hispanic (71.8%, 127 out 177), spoke Spanish (62.7%, 111 out 177), and owned a smartphone (79.7%, 141 out 177). However, only 63.3% (112 out 177) had access to internet or Wi-Fi at home. The mean (SD) SBP was 136.45 mm Hg (20.5) and the mean (SD) DBP was 83.85 mm Hg (13.9). Only 20.9% (37 out of 177) of patients were able to comply with the measurement rate that would result in device cost reimbursement. This did not differ by levels of digital health literacy; with 86.2% (50 out of 58) participants having said they would recommend the monitor to others and 74.1% (43 out of 58) having said they would like to continue using the monitor in the future.

Conclusion:
Providing a simple and low-cost method to monitor blood pressure was feasible and acceptable to patients. However, relatively few patients were able to use the monitors at a rate that would result in device cost reimbursement. While RPM programs show promise, plans for sustaining costs among low-income patients need to be further evaluated.
Abstract P010: Performance Of Home Blood Pressure Monitors In The Clinical Setting
Authors: Vyavahare Medha , Cluett Jennifer , Wood Julia , Turkson-Ocran Ruth-Alma , Mukamal Ken J , Juraschek Stephen P
Published: September 2022

Background:
Self-measured blood pressure (SMBP) monitoring is increasingly used for remote management of hypertension, but the real-world performance of home BP devices remains unsettled.

Objectives:
To determine the performance of home BP devices among patients with hypertension using the American Medical Association’s (AMA) Self-Measured Blood Pressure Device Accuracy Test protocol.

Methods:
Patients at a single hypertension clinic underwent up to five seated, same-arm BP readings using home monitors and an automated BP machine (Omron HEM-907XL). Following the AMA’s 3-step protocol, we used the home device for the first, second, and fourth measures and the office device for the third and fifth (if needed) measures. Device failure was defined as an absolute difference in systolic BP >10 mm Hg between the home and office monitors in either Step 2 or Step 3. Patient factors associated with failure were examined via logistic regression models adjusted for age, sex, and race.

Results:
We evaluated 152 patients (mean age 60 ± 15 years, 58% women, 31% Black) seen between October 2020 and November 2021. Device failure occurred in 21.7% (95% CI: 15.8, 29.0) of devices tested, including 18.1% among Omron devices and 27.6% among non-Omron devices (
P
= 0.08) (
Table
). Higher BMI was associated with higher odds of device failure (OR: 1.09; 95% CI: 1.01, 1.17) though age, sex, and race were not associated with device failure.

Conclusions:
Over one-fifth of home devices failed accuracy testing using the AMA SMBP protocol. Higher BMI was associated with device failure. These findings confirm the importance of office-based monitor verification to ensure the accuracy of home BP monitoring.
Abstract P014: A Pilot Study To Develop A Telehealth Program For Self-Measured Blood Pressure Education And Assessment Within A Veterans Affairs Clinic
Authors: Betcher Stephanie , Fayad Michael , GIUSTINO NINA , Kramer Holly , O'HALLORAN MEGHAN
Published: September 2022

Background:
Lack of education and assessment of self-measured blood pressure (BP) monitoring quality is a barrier to its widespread implementation.

Objective:
To develop a pilot Veterans Affairs (VA) Telehealth Program utilizing a tool to educate and assess competencies in self-measured BP technique.

Methods:
This pilot study was implemented in a single VA primary care clinic. Veterans aged 18 to 85 years old with an office-based BP measurement of ≥140/90 or ≥130/80 mmHg and high cardiovascular disease risk were eligible. Enrolled Veterans completed a four-week program whereby trained registered nurses (RNs) educated Veterans on self-measured BP techniques via video conferencing. At each visit, RNs conducted an 11-part assessment tool (Figure Top) adapted from the American Medical Association measurement skills assessment for patient self-measured BP technique.

Results:
Forty Veterans (mean age 66 years [SD 12.6], 100% male) were referred for enrollment and twenty completed the program. Veterans demonstrated overall high scores on self-BP measurement skills assessment at each time point (Figure Top), but most frequent skills with non-adherence included: avoiding stimulant use prior to BP measurement; emptying bladder; resting quietly for 3-5 minutes; and talking or using a personal device during measurement. Mean SBP and DBP generally declined over time from a baseline mean SBP and DBP of 147.9 and 81.7 mmHg at enrollment to a mean of 140.4 and 79.9 mmHg, respectively, at program completion (Figure Bottom).

Conclusions:
Education and assessment of self-measured BP technique may serve as a meaningful target for future education and quality improvement efforts.
Abstract P016: Blood Pressure Measurements Obtained By Community-dwelling Adults Are Similar To Clinician-obtained Measurements: The SMART-BP Validate Study
Authors: Liu Xiaoyue , Chen Yuling , Slone Sarah , Yeboah-Kordieh Yvette , Alharthi Abeer , Amihere Johnitta , Moyo-Songonuga Sharon , Lane Tynetta , Ostchega Yechiam , Brady Tammy M , Himmelfarb Cheryl D , Commodore-Mensah Yvonne
Published: September 2022

Background:
Home blood pressure (BP) monitoring is an effective strategy to diagnose and manage BP. However, uncertainty regarding patients’ ability to accurately measure their BP contributes to treatment inertia. Thus, we compared BP measurements with the Omron 9210T device obtained by clinicians and community-dwelling adults, after training.

Methods:
This cross-sectional study was conducted in a simulated home environment at an academic center in Maryland. After a 5-minute rest period, a trained clinician measured participants’ BP, twice at a 1-minute interval. Participants then ambulated at their usual pace for two minutes followed by a 5-minute rest. During the second rest period, the participant viewed a 3-minute video on how to measure their BP. They obtained two measurements at a 1-minute interval.

Results:
We included 90 adults with a mean age of 55 (±13.9) years, 58% were female, 88% were Black, 39% had annual income <$25,000, 64% had diagnosed hypertension, and 53% had BMI
>
30 kg/m
2
. About half (52%) had a home BP monitor. There were no significant differences between clinician- and participant-obtained systolic BP (mean difference [MD]: -1.22, 95% confidence interval [CI]: -2.98-0.54,
p
= 0.173) or diastolic BP (MD: -0.62, 95% CI: -1.35-0.12,
p
= 0.094). There was no difference in between the large or extra-large cuff sizes. All participants demonstrated satisfactory self-measured BP skills after the training.

Conclusions:
Community-dwelling adults can accurately measure BP after a brief training. Integration of BP training into patient encounters may result in reliable home BP measurements, and use of home BP measures may potentially reduce clinical inertia.