bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 116: Safety And Tolerability Of Zilebesiran, An RNA Interference Therapeutic Targeting Hepatic Angiotensinogen Synthesis, In Obese Patients With Hypertension
Authors: Taubel Jorg , Desai Akshay S , Lasko Maxwell , Zee Tiffany , Stiglitz Daniel , Rhyee Sean , Zappe Dion H , Bakris George L
Published: October 2023

Introduction:
Single subcutaneous (SC) doses of zilebesiran, an investigational RNA interference therapeutic targeting hepatic angiotensinogen (AGT) synthesis, have been shown to reduce serum AGT levels and blood pressure (BP) in patients with mild-moderate hypertension based on results from phase 1 studies. Limited data are available on the safety, pharmacodynamics, and efficacy of multiple dosing or administration of zilebesiran in patients with Class II/III obesity.

Methods:
Patients with hypertension (mean seated office systolic BP (SBP) of >130 and ≤165 mmHg after washout of antihypertensive medication) and Class II/III obesity (BMI >35 kg/m
2
and ≤50 kg/m
2
) without diabetes were randomized 2:1 to zilebesiran or irbesartan in a double-blind, double-dummy design. Patients received either sequential doses of zilebesiran 800 mg SC (Day 1 and 85) and daily oral placebo, or sequential SC doses of saline (Day 1 and 85) and daily 150mg oral irbesartan. Key endpoints included safety, change in AGT level from baseline to week 24 (using an enzyme-linked immunosorbent assay), and change in BP from baseline to week 24 (by 24-h ambulatory BP monitoring).

Results:
Twelve patients were enrolled (zilebesiran, N=8; irbesartan, N=4; median (range) age 56 (46-64) years, 67% female, mean ± SD BMI 40 ± 4 kg/m
2
, baseline 24-h mean ± SD [systolic/diastolic] BP 144 ± 10 / 88 ± 9 mmHg). At least one adverse event (AE) was reported in 6 zilebesiran patients and 4 irbesartan patients, most of which were mild or moderate; one serious AE occurred with zilebesiran and was considered unrelated. There were no episodes of hypotension requiring intervention in either arm. AGT levels did not change with irbesartan but were reduced with zilebesiran by 99% from week 4 to week 24. Change in SBP from baseline to week 24 was -27 ± 8 mmHg with zilebesiran versus -19 ± 6 mmHg with irbesartan.

Conclusions:
In this Phase 1 study of obese patients with hypertension, administration of two sequential doses of zilebesiran was associated with durable reductions in serum AGT levels and sustained reductions in BP persisting to 24 weeks. Zilebesiran was also generally well tolerated in this patient population. These data suggest that pharmacodynamics, efficacy, and safety of zilebesiran may not be influenced by BMI.
Abstract 117: The Impact Of De-escalating Antihypertensive Drugs: A Secondary Analysis Of The Systolic Blood Pressure Intervention Trial (sprint)
Authors: Du Fanxing , Smith Steven , Bress Adam P , Jiao Tianze
Published: October 2023

Introduction:
As a chronic disease, patients with hypertension typically receive more antihypertensive drugs. Though this rarely happens, patients may receive fewer antihypertensive drugs (de-escalation) when the SBP is well controlled. SPRINT is a uniquely designed trial to study this impact. In the trial, patients were randomly assigned to two groups where systolic blood pressure (SBP) targets: 1) <120 mmHg (intensive treatment group (IG)); 2) <140 mmHg (standard treatment group (SG)). In both groups, their antihypertensive drugs were continuously adjusted to achieve the SBP targets. Before randomization, physicians may adopt more intensive SBP targets than the above two given patients’ disease severity, and personal preference. This study aims to investigate the impact of de-escalation on cardiovascular outcomes, adverse events, and antihypertensive treatment patterns among hypertensive patients.

Methods:
By comparing the number of antihypertensives a patient received at the screening visit, and at randomization, we categorized patients into de-escalation (less medications) and normal groups. The primary outcome was a composite of myocardial infarction, acute coronary, heart failure, and cardiovascular death. Secondary outcomes included individual components of the primary outcome and all-cause mortality. Adverse events include hypotension, syncope, and acute kidney injury. Cox proportional-hazards regressions were applied.

Results:
In the IG, there were 427 and 4,007 patients in the de-escalation and normal groups, respectively. There were 794 and 3,733 patients in these two groups in the SG. The median follow-up time was 3.26 years. In both IG and SG, higher proportions of patients in the de-escalation used thiazide diuretics, ARA, or k-sparing diuretics. In the IG, patients in the de-escalation group were associated with a higher risk of heart failure (HR: 2.66, 95% CI: 1.39-5.09) than the normal group. A similar trend was identified in the de-escalation group for the primary outcome (HR: 1.34, 95% CI: 1.04-1.74).

Conclusion:
De-escalation is associated with an increased risk of cardiovascular events. It reassures the importance of intensive SBP on patients at high CVD risk and indicates a more intensive SBP target may be needed.
Abstract 124: Renin Cell Identity And Blood Pressure Homeostasis: Exploring The Role Of Endothelial Cell Cross-talk
Authors: Nagalakshmi Vidya K , Smith Jason P , Li Minghong , Watanabe Hirofumi , Medrano Silvia , Gomez Roberto A , Sequeira Lopez Maria
Published: October 2023

Our previous studies using an Aortic Coarctation (AoCo) mouse model identified that renin-expressing juxta-glomerular (JG) cells respond to changes in perfusion pressure and Lamin A/C as a component of the renin cell baroreceptor. However, as the mechanisms for transmitting the extracellular pressure to the JG cells are unclear, we hypothesized that the endothelial cells (ECs) act as transducers of signals to the JG cells. Therefore in the current study, we aim 1) to identify the concurrent transcriptomic and epigenomic changes in JG cells and ECs in response to the changes in the perfusion pressure by single-nuclei multiomics approach 2) to define the contribution of EC-specific Lamin A/C (Lmna) in the EC-JG-cells cross-talk. We performed the AoCo surgeries on 3 months (M) old VE-Cad-Cre;Foxd1-Cre;mTmG mice where GFP is expressed simultaneously in
Foxd1
and EC-lineage cells. We compared the single-cell gene expression and chromatin accessibility between the left (LK) and the right kidneys (RK) at 72h post-surgeries. Our study revealed: 1) JG cells increased significantly in the LK along with renin gene expression 2) ECs significantly increased by 10.73% in LK with a higher expression for genes promoting EC proliferation, morphogenesis, and immune response 3) JGs of the LK showed enrichment for the motifs Mbd1, Smad1, Smad5 indicating epigenetic changes promoting transcriptional regulation and TgfB1 signaling. Enrichment of Mybl1, Myb, and E2f2 motifs in the ECs of the LK suggests positive regulation of EC proliferation in response to low blood pressure (BP). Furthermore, deletion of the Lmna gene in the EC-lineage affected the BP responses in 4M old Lmna
fl/fl
;VE-Cad.Cre mice. The difference between the carotid and femoral mean BP (MBP) measurements was more prominent in the wild type (WT) compared to the mutants at 72h post-AoCo [WT (n=7), Carotid MBP: 69.16±2.24 Femoral MBP: 63.28±2.33, P<0.00001 Mutants (n=4); Carotid MBP: 75.98±3.06 Femoral MBP: 69.75±3.10, P<0.05)]. Our current study shows that ECs undergo transcriptional and epigenetic alterations in response to changes in perfusion pressure. Deletion of
Lmna
in ECs reduces the differences in the BP between LK and RK, suggesting that it is important for sensing the changes in extracellular pressure.
Abstract 136: Unsupervised Learning Using EHR Data To Detect Distinct Subphenotypes Of Hypertension
Authors: Smith Steven M , Xu Jie , Hall Jaclyn , Walsh Marta G , Cho Hee Deok , Harrell Grant , Staras Stephanie A
Published: October 2023

Introduction:
Hypertension (HTN) is a complex condition with significant heterogeneity in presentation and treatment response. Identifying distinct subphenotypes of HTN may improve our understanding of its underlying mechanisms and guide more precise treatment or public health initiatives.

Methods:
Using EHR data from the OneFlorida+ research consortium (2012-2021), we identified a cohort of adult Floridians with newly-diagnosed HTN (first diagnosis following 2 outpatient BPs ≥140/90 mmHg & no prior antiHTN treatment). We extracted demographic and clinical data from the diagnosis visit and ≤1 year prior. We used hierarchical clustering to identify distinct subphenotypes within the HTN population.

Results:
A total of 40,741 patients were included (mean ± SD age, 61 ± 18 y; 55% women). Six subphenotypes (S1-6) were identified (Figure). For example, S1 was characterized by older age and higher BMI and T2DM prevalence, while S2 included younger individuals with lower BMI and more women, and S3 had low prevalence of HTN-related comorbidity. Distinctions in SDOH factors were also observed: despite lower comorbidity burden, the youngest subphenotype (S2) had high SDOH burden and presented with HTN 8-15 y earlier than higher income subphenotypes (e.g., S4 & S5).

Conclusions:
Unsupervised learning identified 6 HTN subphenotypes varying in demographic, socioeconomic and risk profiles. Further investigation into biological mechanisms of these subphenotypes and their relationships to social factors may enhance our ability to deliver targeted interventions that consider social policy implications in addition to the traditional behavioral and physiological interventions.
Abstract P107: High-throughput Screening Detects Thiazide-induced Prescribing Cascades.
Authors: Smith Kayla , Morris Earl , Ndai Asinamai , Keshwani Shailina , Kulkarni Priyanka , Schmidt Stephan , Pepine Carl , Vouri Scott , Smith Steven M
Published: October 2023

Introduction:
Thiazide diuretics are effective but can cause adverse effects that prompt the use of additional therapy, i.e., a prescribing cascade. We aimed to identify potential thiazide-induced prescribing cascades using high throughput sequence symmetry analysis.

Methods:
Using claims from 5% (2011-15) and 15% (2016-20) samples of Medicare fee-for-service beneficiaries we identified new thiazide users aged ≥66 years who had continuous enrollment for ≥360 days pre- and ≥180 days post-thiazide initiation. We screened for the initiation of 446 other ‘marker’ drug classes (based on WHO Anatomical Therapeutic Classification level 4 codes) within ±90 days of thiazide initiation, generating sequence ratios (SRs) representing the proportion of thiazide initiators starting the marker class after, compared to before, the thiazide. Adjusted SRs (aSRs), accounting for prescribing trends over time, were calculated with 95% CIs >1 suggesting a prescribing cascade signal.

Results:
We identified unique 189,971 thiazide initiators (mean ± SD age 76.2 ± 7.4 years, 66% women, 90% with hypertension). Among 446 ‘marker’ classes analyzed, we identified 21 statistically significant prescribing cascade signals (Figure). The 2 strongest prescribing cascade signals were carbohydrates and electrolyte solutions.

Conclusion:
Among 446 classes, we identified 21 possible prescribing cascades in our Medicare population, which may impact patient care outcomes. Further investigation is required to determine the biological plausibility of these signals.
Abstract P123: Patients With Arterial Hypertension And Hypertrophic Cardiomyopathy Affected By Non-alcoholic Fatty Liver Disease Have Worse Clinical Outcomes, Nation-wide Study
Authors: Khokhlov Leonid R , Rahima Kenan , Eshghabadi Amin , Mateo-Faxas Sila , Hijazi Mohamad , Hussain Fatima , Ali Mehnaaz , Shemisa Kamal
Published: October 2023

Background:
Hypertrophic cardiomyopathy is a predominantly genetic disorder affecting the cardiac muscle & its functionality. NAFLD is known to increase the risk of adverse outcomes. We aimed to investigate HCM population with HTN (as a surrogate for preserved contractility) affected by NAFLD.

Methods:
We queried NIS between 2017-2020 for adult patients who were hospitalized with HCM&HTN and had NAFLD. The primary outcome was inpatient mortality. The secondary outcomes were cardiogenic shock, cardiac arrest, GIB, invasive mechanical ventilation, length of stay (LOS) & total hospital cost. Multivariable logistic & Poisson regression analyses were used to estimate clinical outcomes.

Results:
There were 35,640 hospitalizations with HCM&HTN, of which 954 (2.6%) had NAFLD. NAFLD & non-NAFLD cohorts were with mean age of 62.6 vs. 65.6 yrs; males 49.2% vs 47.8%; Caucasians 67% vs 66%; HF 4.7% vs 4.8%; PH 5.7% vs 5.4%; PE 3.6% vs 3.5%; ACS 12% vs 13.6%; obesity 19.9% vs 21.2%; HLD 44.5% vs 57.8%; anemia 19.3% vs 12.9%, DM 42.4% vs 28.6%; AF 36.1% vs 33.1%; VF 4.1% vs 1%; CKD 1.5% both; stroke 4.7% vs 6.2%, COPD 19.3% vs 16.4%, respectively. NAFLD cohort had significantly higher mortality & worse clinical outcomes (Table 1).

Conclusion:
HCM patients with HTN & NAFLD demonstrated significantly worse clinical outcomes. They were younger, white females with more prevalent dHF, PH, PE, anemia, DM, AF, VF, VTachy, COPD. NAFLD is associated with increased rates of diastolic pathology, cardiac arrhythmias, pulmonary & endocrinological diseases. Detection & appropriate management of NAFLD in patients with cardiomyopathies may have clinical benefit & play a role in prognostication.
Abstract P125: Tissue Specific Regulation Of The Cardiac And Renal Endothelin System In A Lupus-prone Mouse Model
Authors: McCrorey Marice K , Hawkins Kennedy P , Colvert C. Alex , Abdul Yasir , Ergul Adviye , Cunningham Melissa A , Deleon-Pennell Kristine Y , Van Beusecum Justin P
Published: October 2023

Systemic Lupus Erythematosus (SLE), the most common form of lupus autoimmune disease, disproportionally affects women (9:1) with high prevalence in African Americans. Numerous studies report elevated endothelin-1 (ET-1) in the plasma of patients with lupus and demonstrate increased ET-1 contribution to various pathological cardiovascular complications including hypertension, cardiac hypertrophy, and heart failure in lupus patients. However, few studies explored the relative roles and regulation of the cardiac and renal ET systems in lupus-associated cardiovascular complications. We hypothesized that immune modulation and acceleration of lupus by a toll-like receptor 7/8 agonist, Resiquimod, would lead to tissue-specific regulation of the ET system in both the kidney and heart in lupus-prone mice. To investigate this, female lupus-prone B6.Nba2 mice were subjected to bi-weekly treatment with the Resiquimod (R848; 100ug/30ul; n=4) or vehicle control (Acetone; n=5) for one month and subsequently studied for 12 weeks. At 16 weeks post-treatment (30 weeks old), heart and kidneys were collected, and the ET system was analyzed by RT-PCR, immunoblotting, and immunohistochemistry. R848 treatment significantly increased cardiac but not kidney expression of ET-1 (19.90 ± 1.36 vs. 7.65 ± 0.54 pg/mg; p=0.02 compared to controls (6.10 ± 1.64 vs. 4.95 ± 0.55 pg/mg; p>0.05). Furthermore, R848 treated mice had no significant effect on cardiac endothelin receptor A (ET
A
) nor endothelin receptor B (ET
B
) expression at both the RNA and protein levels (p>0.05 for all). Interestingly, renal ET
B
RNA expression was reduced (0.08 vs. 1.62; p <0.05), while ET
A
expression was unchanged (p > 0.05) with R848. The same trend was observed at the protein level by immunoblotting and immunohistochemistry (p>0.05) Our results provide evidence that lupus acceleration with TLR7/8 activation in B6.Nba2 mice differentially regulates tissue-specific ET systems in the heart and kidney, potentially contributing to the tissue specific dysfunction found in lupus. These findings suggest that our model offers an opportunity to identify cardiac and renal contributions to lupus complications, and specifically determine the cell-specific regulation of ET biosynthesis and signaling.
Abstract P127: Protective Effects Of Protocatechuic Acid In Murine Model Of UUO-induced Renal Injury
Authors: Saad Karim M , Da Silva Lopes Salle Evila , Emami Naeini Sahar , Baban Babak , Elmarakby Ahmed A
Published: October 2023

Chronic kidney disease (CKD) is a global public health problem, affecting millions of people worldwide. CKD can result from obstructive nephropathy; a condition that arises from urinary flow obstruction in the kidneys, leading to renal inflammation and injury. Protocatechuic acid (PCA) is a natural phenolic compound that showed a promising protective effect in cardiovascular diseases. In the current study, we investigated the reno-protective effects of PCA in mice model of unilateral ureteral obstruction (UUO). Male C57BL/6J mice (10-12 weeks old) were divided into 4 groups (n=6-8/group). Sham control, Sham/P (sham plus PCA (50 mg/kg IP daily for two weeks), UUO, and UUO plus PCA. Induction of UUO significantly decreased creatinine clearance (CrCl) and increased pulse wave velocity (PWV), a marker of arterial stiffness, relative to sham control (CrCl; sham control: 60.6 ± 14 vs. UUO: 24.5 ± 6.0 ml/day and PWV; sham control: 1.58 ± 0.1 vs. UUO: 3.35 ± 0.22 m/s). Immuno-histochemical analysis revealed that KIM-1 expression, a marker of tubular injury, was elevated in UUO mice vs. sham control and PCA reduced this elevation, however there was no significance difference in urinary KIM-1 excretion. Moreover, UUO significantly increased renal oxidative stress and inflammation as evidenced by elevation in renal TBARs, IL-6, active caspase-1 and active MMP2 compared to sham control (TBARs; sham control: 8.3 ± 0.9 vs. UUO: 30.5 ± 3.33 nmol/mg protein, renal IL-6; sham control: 1 ± 0.07 vs. UUO: 24.35 ± 8.55 pg/mg protein, active caspase-1; sham control: 1.7 x 10
3
± 95 vs. UUO: 2.79 x 10
3
± 145 cpm/μg protein and MMP2; sham control: 1.6 ± 0.4 vs. UUO: 6 ± 0.6 ng/μg protein). PCA treatment significantly improved the UUO-induced decline in creatinine clearance (52.5 ± 10.2 ml/day) and attenuated UUO-induced elevation in renal PWV (1.95 ± 0.1 m/s). Furthermore, PCA treatment significantly decreased renal TBARs (5.2 ± 1.12 nmol/mg protein), IL-6 (5.39 ± 1.4 pg/mg protein) and active MMP2 (1.1 ± 0.3 ng/μg protein) in UUO-induced renal injury. Collectively, these data suggests that PCA provides renal protection in murine model of UUO via reduction of renal oxidative stress, inflammation and fibrosis.
Abstract P135: Effect Of A High Fat Western Diet On The Progression Of Diabetic Kidney Disease In Type 2 Diabetic Nephropathy (T2DN) Rats
Authors: Lowe Melissa , Bohovyk Ruslan , Klemens Christine A , Staruschenko Alexander
Published: October 2023

Diet influences the growing rate of obesity, increasing the risk of developing metabolic syndrome, which leads to chronic illnesses such as diabetes. Diabetic Nephropathy (DN) is a complication of Type 2 Diabetes prevalent in about 1 in 3 diabetics and is the primary cause of End-Stage Renal Disease (ESRD). The aim of this study was to assess how a high-fat Western diet impacts diabetic severity and DN during ESRD. We used aged (38+ wks) T2DN rats, an established DN model which has chronic kidney disease at this age and placed them on a normal (NFD) or high fat (42%, HFD) diet for 12 weeks. Previous studies revealed that T2DN males have more severe kidney injury progression. Thus, male (N=5-6) and female (N=6) rats were used to test effects of HFD in both sexes. Total food intake did not vary between diets. Urine and glucose tolerance tests (GTT) were assessed at weeks 0, 3, 6, 9, and 12. Both male (404.0 ± 10.2 vs 431.0 ± 7.1 g, p=0.053) and female (305.0 ± 14.4 vs 334.5 ± 17.6 g, p=0.22) T2DN rats gained weight on the HFD; however, the total body weights were not significantly different by week 12. Throughout the study, there were no significant differences in GTT curves or fasting blood glucose levels in females on NFD or HFD (wk 12: 123.3 ± 10.7 vs 149.3 ± 12.3 mg/dL, p=0.14). In contrast, the HFD males’ fasting blood glucose levels increased progressively over the 12-week period and became significantly different between the two groups by week 9 (204.5 ± 10.8 vs 284.4 ± 15.8 mg/dL, p=0.003). Furthermore, at the 2 hr time point in the week 9 GTTs, male blood glucose concentrations were elevated compared to females (370.4 ± 25.1 vs 457.5 ± 10.4 mg/dL, p=0.01; and 222.7 ± 28.8 vs 205 ± 16.8 mg/dL, p=0.61, for male and female, respectively). The HFD did not affect urine volume output or kidney/total body weight ratios in males or females compared to their NFD counterparts. However, heart weight/total body weight ratios in females were significantly reduced on the HFD (3.7 ± 0.1 vs 3.4 ± 0.1, p=0.03). Ongoing studies will quantify renal fibrosis, glomerular damage, albuminuria, glucosuria, lipidemia, and liver damage resulting from the HFD. In conclusion, the HFD seems to have a more deleterious effect on glucose handling in males than females; however, further studies are warranted to validate this effect.
Abstract P136: Association Of Undernutrition Severity With Development Of Incident Hypertension In Youth.
Authors: McMillan Kayla , South Andrew
Published: October 2023

Cardiovascular disease (CVD) is a leading cause of death despite improved treatment, largely due to limitations in primordial prevention. Youth with chronic health conditions have higher risk of CVD and undernutrition, however it is unknown if undernutrition causes hypertension (HTN). Our goal was to investigate if undernutrition in youth is associated with incident HTN.

Interim analysis of electronic health record data from a bioinformatics-driven retrospective cohort study. Inclusion criteria were ages 6 months - 18 years with a first occurrence of undernutrition by ICD-10 code, weight-for-height z-score <-2, or BMI z-score <-2 in outpatient clinic or inpatient hospital encounters between 2015-2022. Exclusion criteria were premature birth, low birth weight, or diagnosis of heart disease, liver disease, or chronic kidney disease at index date. We created a Kaplan Meier curve and log-rank test.

Of 8,878 participants, 2,569 (58%) were males. We found that more severe undernutrition was associated with decreased risk of HTN.

More severe undernutrition was associated with decreased risk of HTN. However, only first instances of blood pressure in HTN range were included. Ongoing steps include refining the undernutrition population, building a Cox regression model, and developing a matched control population to compare the risk of HTN to. Concurrently, we have an animal study to further assess the impact of undernutrition on HTN development. Determining if undernutrition is a causal risk factor for HTN, which often leads to additional serious and life-threatening illnesses, will allow for earlier screening and intervention to prevent clinical diagnoses later in life.
Abstract P152: Chromatin Accessibility Landscape Of The Proximal Tubule And Thick Ascending Limb In Humans And Rats
Authors: Ray Atrayee , Stelloh Cary , Yang Chun , Liu Yong , Geurts Aron M , Cowley Allen W , Kwitek Anne E , Liu Pengyuan , Liang Mingyu , Greene Andrew , rao sridhar
Published: October 2023

Hypertension is a major risk factor for disease burden and mortality. A decrease in the kidney’sability to excrete sodium can lead to hypertension. Specifically, the proximal tubule (PT) and thickascending limb (TAL) of the nephron play crucial roles in the reabsorption of filtered sodium toregulate blood pressure (BP). Understanding the genetic and epigenetic factors that influence PTand TAL functions is essential for unraveling the molecular mechanisms underlying hypertension.GWAS identified over 1,000 BP-associated genomic loci comprising > 26,000 SNPs. Most (~90%)are in intronic and intergenic regions and may influence BP-relevant gene expression by yetunexplored epigenetic mechanisms. Better understanding of how non-coding genomic regionsregulate BP is critical to defining the genetic underpinnings of hypertension. To address this, weestablished chromatin state (open and closed chromatin) maps for PT and TAL from humans andinbred salt-sensitive rats (SS/JrHsdMcwi) using the Assay for Transposase-Accessible Chromatinwith Sequencing (ATAC-Seq). Linear dimensional reduction revealed that in both species, PT andTAL segments clearly separated, indicating their chromatin states were distinct. ATAC-seq “peaks”represent regions of open chromatin, and therefore likely to be within regulatory elements. Ahigher number of differential peaks was identified between human PT and TAL (65,823) comparedto rat (1,063). The number of PT and TAL enriched peaks also differs between species. Genomicdistribution of these differential peaks indicates the bulk fall within distal intergenic and intronicregions (human: 71.64%, rat: 88.81%) rather than the gene promoters or exonic regions for bothspecies. This indicates that the chromatin accessibility of regulatory regions is significantlydifferent between these two segments for both species. Our next steps are to identify upstreamregulators that differ between the kidney segments and species and integrate ATAC-Seq data withexpression data to define the association of non-coding regions with transcript levels. Our workhas generated chromatin state maps that may improve the understanding of the role of noncodinggenomic regions in the transcriptional regulation in PT and TAL in human and rat.
Abstract P153: Protein Kinase A Inhibition Epigenetically Silences
Ren1
Authors: Smith Jason P , Paxton Robert , Sequeira Lopez Maria Luisa S , Gomez Roberto A
Published: October 2023

Renin-expressing cells are myoendocrine cells crucial for survival which detect changes in blood pressure and release renin to maintain homeostasis. One of the pathways responsible for renin expression includes cAMP as a central factor. cAMP binds to subunits of protein kinase A (PKA), ultimately recruiting both CBP and p300. Binding to the cAMP-responsive element in the renin enhancer region thus amplifies renin transcription. To evaluate transcriptomic and epigenomic changes occurring at the renin locus via the cAMP pathway, we treated As4.1 cells (a tumoral cell line that constitutively expresses renin) with the PKA inhibitor H89 (treated) or DMSO (control).

Using scRNA-seq, we confirm that PKA inhibition leads to significant decreases in
Ren1
abundance (p=3.18e-25), and
Ccl8
,
Cilp
,
Cdkn1a
,
Lox
,
Ly6c1
,
Ccl7
,
Cryab
are all significantly increased. Analysis of bulk ATAC-seq of treated and control As4.1 cells revealed 527 significantly increased regions of accessible chromatin and 1523 significantly decreased. Within the increased accessibility regions, motifs for the transcription factors
Bach1
,
Fos
,
Fosb
,
Trp73
, and
Gli1
are overrepresented. Within the regions with decreased accessibility are enriched motifs for
Zfp161
,
Esr2
,
Zfa
,
Maz
,
Phf21a
,
Hlf
, and
Tcf7
.

We further identified a cluster of differentially accessible regions composed of 172 chromatin regions that shift concurrently in accessibility following PKA inhibition. Within these regions, the KLF (p= 7.5e-11) and AP-1 (p= 1.4e-5) families of transcription factors are overrepresented. Interestingly, open chromatin around the
Ren1
locus is not differentially accessible following H89 treatment.

To better understand the effect of PKA inhibition, we evaluated H3K27Ac and P300 binding via ChIP-seq. H3K27Ac is significantly reduced at the renin locus (p=1.99e-08), and P300 binding is also significantly reduced (p=1.79e-13).

Taken together, the data suggests that cAMP pathway inhibition controls renin expression through a reduction not in accessibility, but via a switch from an active to poised state of epigenetic control and the rise in immediate early genes regulating cellular gene expression.
Abstract P156: IMPACT OF CHRONIC KIDNEY DISEASE ON HYPERTENSIVE EMERGENCY OUTCOMES
Authors: Muhyieddeen Amer , ABDULLAH KHALED , SALEH KHALED , Ranasinghe Sachini , Chang Joseph , Nomigolzar Soroush , Rasheed Oune
Published: October 2023

Introduction:
In patients suffering from hypertension, the presence of concurrent chronic kidney disease (CKD) tends to escalate the risk of severe conditions and hospitalizations compared to those without such complications. This study, aimed to delve into the impact that a simultaneous diagnosis of CKD can have on patients admitted for hypertensive emergencies during the initial year of the COVID-19 pandemic.

Methods:
We examined data from the 2020 National Inpatient Sample to identify patients who were primarily admitted due to a hypertensive emergency. We used ICD-10 codes to distinguish between those with and without a concurrent CKD diagnosis. We employed logistic and linear regression analyses and accounted for potential confounders. We deemed the results as statistically significant when the 2-tailed p-value was less than 0.05.

Results:
During the calendar year of 2020, there were a total of 1,221,535 admissions, primarily for hypertensive emergencies. Notably, a significant proportion of these cases, amounting to 475,380 (38.9%), involved patients concurrently diagnosed with CKD. After adjusting for confounding variables, patients hospitalized for hypertensive emergencies, who were also diagnosed with CKD, demonstrated an elevated risk of in-hospital mortality (aOR 1.46, 95% CI 1.38-1.55), mechanical ventilation (aOR 1.12, 95% CI 1.09-1.15) and vasopressor therapy (aOR 1.27, 95% CI 1.15-1.40)

Conclusion:
Our findings suggest that CKD significantly impacts the hospital outcomes of patients admitted with hypertensive emergencies, often leading to less favorable results. As CKD prevalence is likely to rise in an aging population, the need to understand its pathophysiology and influence on severe hypertension cases is vital for future research.
Abstract P167: Hypertension And Diseases Associated With Gut Microbiome Alterations: Insights From The National Inpatient Sample (nis) From 2020
Authors: Umrani Rohan , Khallid Yaser , Dasu Neethi , Dasu Kirti
Published: October 2023

Introduction:
Hypertension (HTN) is a common condition at the focus of global health efforts. While great strides have been made towards the treatment and diagnosis of this condition, its relationship with the gut microbiome requires further investigation. We sought to assess the impact of HTN on various conditions associated with alterations of the gut microbiome.

Methods:
A retrospective analysis was completed utilizing the NIS. Patients were identified based on ICD-10 codes corresponding to those with essential hypertension (HTN) alone vs those with HTN and a gut microbiome disease (GMD). These included ulcerative colitis (UC), gastroparesis, clostridium difficile (C. diff), irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO). Primary outcomes were mortality, (mean length of stay (LOS) and total hospital charge (TOTCHG).

Results:
Of 8,667,791 patients with HTN, 39,280 had UC, 81,085 had gastroparesis, 9,285 had C. diff, 110,320 had IBS, and 12,295 had SIBO. Patients with HTN and GMD had an OR of 0.65 (CI 0.63-0.67, p = 0.00). Native Americans with concurrent HTN and GMD had an OR of 1.56 (CI 1.33-1.83, p = 0.00). LOS was increased in patients with HTN and concurrent gastroparesis and C. diff (Table 1). Having Medicare, Medicaid, being admitted with UC, gastroparesis or C. diff and being of asian or hispanic heritage were significantly associated with higher costs.

Conclusion:
HTN in the presence of a disease associated with alteration of the gut microbiome does not demonstrate a negative effect on mortality. It does, however, demonstrate increased mortality in Native American populations as well as increased LOS in gastroparesis and C. diff.
Abstract P170: Beta-arrestin-2 Sustains Experience-dependent Plasticity Of Sodium Ingestive Behavior
Authors: Hamilton Autumn J , Grobe Connie , Segar Jeffrey , Grobe Justin L , Sigmund Curt D
Published: October 2023

Elevated sodium (Na) intake is a risk factor for hypertension. Na “appetite” is defined by the persistence of Na consumption despite adverse conditions and is commonly assessed through ingestion of aversive NaCl solutions. β-arrestins interact with many G Protein-Coupled Receptors (GPCR), including the Angiotensin II Type 1 Receptor (AT
1
R). β-arrestins play roles in many physiological processes including regulation of cardiovascular function, sensory processing, and energy metabolism. Recent work published by our group concluded that β-arrestin-2 deficient (Arrb2
KO
) mice exhibited increased ingestion of NaCl solutions even in the absence of physiological need. Thus, we hypothesize that β-arrestin-2 plays a role in experience-based Na seeking behavior and elevated NaCl consumption. To explore this question, mice were first presented with a 2-bottle choice of water and 0.15 NaCl.; then exposed to aversive 0.3 M NaCl exclusively for 24h; followed by the same 2-bottle choice as at baseline. Usually, this manipulation would yield a reduction in preference for previously preferred concentrations of NaCl, demonstrating experience-based plasticity of NaCl preference. At baseline, male Arrb2
KO
mice exhibited the expected increase in preference for 0.15 M NaCl vs water (control n=14, 34±5%; Arrb2
KO
n=10, 55±7%, p<0.01). Following 24h hypertonic (0.3 M) saline exposure, both groups displayed a decrease in 0.15 M NaCl solution intake and preference (days 1+2 after exposure: 10±2% vs 21±4%, p<0.01 vs baseline within each group, and p=0.15 between groups). While control mice maintained this significant suppression of preference for 0.15 M NaCl beyond one week after 24h 0.3 M NaCl exposure (e.g., days 7+8 after exposure: controls 22±3% p=0.01 vs baseline), preference of Arrb2
KO
mice for 0.15 M NaCl returned to baseline levels within days (e.g., days 7+8 Arrb2
KO
45±9%, p=0.08 vs baseline, and p<0.01 vs control). This supports the idea that Arrb2 is implicated in Na ingestive behaviors, potentially influencing memory maintenance and retrieval. Future studies aim to characterize the role of Arrb2 downstream of the AT
1
R within specific brain regions in Na consummatory behaviors.
Abstract P173: Impact Of Treatment Stage And Blood Pressure Severity On Preference For Drug And/or Device-based Treatments In Patients With Uncontrolled Hypertension
Authors: Kandzari David E , Poulos Christine , Cohen Sidney A , DeBruin Vanessa , Hettrick Doug , Pathak Atul
Published: October 2023

Background:
Patient non-adherence to antihypertensive (AH) drugs impacts achieving treatment goals, highlighting the need for adjunctive therapies such as radiofrequency renal denervation (RDN). Patient preference for an intervention vs. drug therapy is poorly understood. We assessed patient treatment preferences at different stages of HTN management using a calculator derived from a discrete choice experiment (DCE) study.

Methods:
Preferences in 3 different clinical scenarios in the natural course of HTN management were evaluated: (1) initiating AH drugs vs. interventional treatment in untreated patients with mild-moderate HTN; (2) increasing drugs vs. interventional treatment with no drug change in patients with mild-moderate HTN; (3) increasing drugs vs. interventional treatment with no drug change in patients with severe resistant HTN. The predicted probability of choosing one treatment vs. the other was calculated based on preference-weighted treatment attributes (type of treatment, changes in AH drugs, BP reduction, effect duration, risk of drug side effects, intervention related adverse events). The values chosen for each scenario were derived from published RDN studies, the literature, and expert opinion.

Results:
Comparing scenario 1 to 2 to 3, the preference to select an intervention without drugs or change in drugs increased from 17% to 24% to 45%. Conversely, the preference to select either initiation or an increase in drugs decreased from 83% to 76% to 55%. The magnitude of BP reduction was the major driver of calculated patient preferences while drug and interventional treatment-related adverse events had a smaller impact on calculated patient preferences.

Conclusions:
Using preference-weights derived from a discrete choice experiment, a model predicting patient choice for drug vs. interventional treatment was applied to clinical scenarios derived from the natural course of management of patients with uncontrolled HTN. Preference for an interventional treatment increased from 17% in treatment naïve patients to 45% in patients with severe resistant HTN. Patient preference was driven predominantly by efficacy outcomes and minimally by safety concerns.
Abstract P185: Hydralazine Treatment Does Not Fully Reduce Proinflammatory Immune Cells In The Ovaries Of Mice With Salt-sensitive Hypertension
Authors: Navaneethabalakrishnan Shobana , Goodlett Bethany , Smith Hannah , Mitchell Brett M
Published: October 2023

Salt-sensitive hypertension (SSHTN) is associated with altered macrophage polarization, inflammation, and inflammation-associated lymphangiogenesis in the ovaries of mice, and this is associated with reproductive dysfunction. However, it is unknown whether high pressure or salt or both are involved in these adverse effects. We hypothesized that lowering of blood pressure will not reduce proinflammatory immune cells and inflammation in the ovaries of mice with SSHTN. Female C57BL6/J mice were divided into 3 groups: Control (C) mice received tap water and normal diet; SSHTN mice received L-NAME (0.5 mg/mL) in the drinking water for 2 weeks, followed by a 2-week washout period, and a subsequent 3-week 4% salt diet; and the third group were SSHTN and received hydralazine (250 mg/L) in their drinking water (HYD) during the last 3 weeks of salt diet. There was a significant increase in systolic blood pressure in SSHTN mice (143±2 mm Hg) when compared to control (99±2 mm Hg) but was reduced significantly in HYD mice (119±1 mm Hg). Flow cytometry analysis revealed a significant increase in M1 macrophages in the ovaries of SSHTN and HYD mice when compared to C mice (% of CD45 cells: C: 25%±2, SSHTN: 37.8%±2, HYD: 36.2%±3; p<0.05). There was an increase in CD4+TNFa+IFNg+ Th1 cells in the ovaries of SSHTN and HYD mice when compared to C mice (C: 0.33%±0.06, SSHTN: 0.8%±0.07, HYD: 0.7%±0.1; p<0.05), whereas CD4+ T cells (C: 26.5%±2, SSHTN: 51.5%±4, HYD: 14.7%±3; p<0.05) and CD4+IL17a+ Th17 cells (C: 2.9%±0.2, SSHTN: 5.4%±1, HYD: 3.1%±0.6; p<0.05) significantly increased in SSHTN mice but were reduced in HYD mice. Increased gene expression of IL-17 and iNOS was observed in the ovaries of SSHTN and HYD mice. Together, these data demonstrate that both high blood pressure and salt exert their effect on immune cells differentially contributing to the ovarian dysfunction in SSHTN mice. Further studies are needed to investigate whether manipulating macrophage polarization could reverse these adverse effects in the ovaries of mice with SSHTN.
Abstract P194: Unmet Social Needs In Youth Referred For Hypertension Disorders Across U.s. Geographic Regions: A Superhero Interim Analysis
Authors: Narvaez Estefania , Bagley Kiri , Chen Ashton , South Andrew , Vincent Carol
Published: October 2023

Objective:
Investigate the relationship between geographic region and unmet social needs in youth referred for hypertension disorders.Youth facing health disparities often experience substantial challenges due to adverse social determinants of health, such as those related to the geographic area in which they reside. Understanding the prevalence of unmet social needs by geographic region is vital to advocating for underserved patient populations. Interim cross-sectional analysis of baseline data from The Study of the Epidemiology of Pediatric Hypertension (SUPERHERO), a multisite retrospective Registry using electronic health record data. Inclusion criteria were initial visit for hypertension disorder (identified by ICD-10 code) between 1/1/2015 and 12/31/2022 and age <19 years. Exclusion criteria were ICD-10 code-identified kidney failure on dialysis, kidney transplant, or pregnancy. We recorded U.S. Census geographic Region based on participants’ home address. Our outcome was at least one ICD-10 code for an unmet social need. We used unadjusted generalized linear models.Of the 9,416 participants, mean age was 12 yrs. (SD 5.0) and 29 (0.3%) had at least one unmet social need (Table). Compared to the South, youth from the Northeast had 3.17 times higher risk of unmet social needs (1.08-9.32) and those from the Midwest had 4.71 times higher risk (95% CL 1.76-12.62).We found that youth referred for hypertension disorders from the Northeast and Midwest were more likely to have an unmet social need compared to youth from the South. Ongoing steps include acquiring geocoded data to investigate neighborhood-level metrics and more rigorous unmet social needs data.
Abstract P200: Tnf-α Blockade During Pregnancy Does Not Impact Offspring Development In A Rat Model Of Preeclampsia
Authors: Campbell Nathan , Solise Dylan , Ashraf Usman , Herrock Owen , Deer Evangeline M , Turner Ty , Zheng Baoying , Cockrell Kathy , Alexander Barbara T , Lamarca Babbette B
Published: October 2023

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with increased tumor necrosis factor alpha (TNF-α), agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA), and low birth weight babies. We have previously shown that Etanercept (
E
), a TNF-α inhibitor, improves PE features in the reduced uterine perfusion pressure (RUPP) rat. However, the long-term effect of
E
on offspring health and immune competency has not been studied. Therefore, we hypothesize that
E
will improve maternal health without affecting offspring outcomes in a rat model of PE. To test this hypothesis,
E
(0.4 mg/kg) was injected on gestation day 18 into sham and RUPP dams which were allowed to deliver. Weights were recorded at birth and 16 weeks of age when mean arterial pressure (MAP) was measured. Whole blood was collected to measure immune cells by flow cytometry. AT1-AA was measured using a cardiomyocyte bioassay. A student’s t-test was used to compare differences among male and female RUPP offspring with and without
E
. RUPP male and female offspring were smaller (5.21±0.19 g, n=7; 5.24±0.10 g, n=7) than sham offspring (5.94±0.14 g, n=7, p<0.05; 5.86±0.16 g, n=9, p<0.01) while RUPP male offspring were larger and female offspring were unchanged following perinatal
E
(6.01±0.29 g, n=9, p<0.05; 5.28±0.14, n=9). MAP was comparable between sham (133±4 mmHg) and RUPP (132±4 mmHg) male offspring with no change seen following perinatal
E
(133±4 mmHg). Perinatal
E
did not impact adult male circulating B cells. Circulating AT1-AA was elevated in male RUPP offspring (16±2 ΔBPM, p<0.01) compared to sham and was not improved with
E
(13±2 ΔBPM). MAP was comparable in sham (131±5 mmHg) and RUPP (130±5 mmHg) female offspring but trended downward with perinatal
E
(123±4 mmHg). RUPP female offspring had reduced circulating B cells (4.24±0.81 % gated, p=0.066) compared to sham females (9.56±2.07 % gated) which was normalized following perinatal
E
(9.04±1.42 % gated, p<0.05). AT1-AA trended lower following perinatal
E
(7±2 ΔBPM, p=0.0888) compared to RUPP female offspring (16±3 ΔBPM). Our findings indicate that
E
does not worsen fetal outcomes. Moreover, E improves male birth weight and reduces adult female AT1-AA without compromising offspring immune competency.
Abstract P201: First Trimester Anxiety Is Associated With Increased Arterial Stiffness In High-risk Pregnant Women
Authors: Forrest Mekayla , Matossian Maria , Papacostas-Quintanilla Helena , Montreuil Tina , Daskalopoulou Stella S
Published: October 2023

Preeclampsia is a leading pregnancy complication characterized by vascular dysfunction, leading to hypertension and organ damage. Evidence suggests positive associations between higher arterial stiffness and preeclampsia, as well as anxiety and preeclampsia. Anxiety, a transdiagnostic factor, is also associated with increased arterial stiffness in the general population, but no reports exist in pregnant women. Moreover, the association between anxiety and arterial stiffness in pregnancy and the risk of developing preeclampsia has not yet been explored. To address this gap, we aimed to evaluate the role of anxiety in arterial stiffness measurements and the development of preeclampsia in high-risk pregnant women. In this prospective study, women with high-risk singleton pregnancies before 14 weeks gestation were recruited at two tertiary care obstetric clinics in Montreal, Canada, and followed throughout pregnancy. Arterial stiffness parameters (carotid-femoral pulse wave velocity [cfPWV]) were measured at baseline (10-13 weeks gestation) and at four-week intervals throughout pregnancy. Self-reported anxiety symptoms were recorded using the Beck Anxiety Inventory, and participants’ scores were ranked as having minimal, mild, moderate, or severe anxiety. After excluding incomplete questionnaires, the total study sample comprised 156 women, of whom 10 (6.4%) developed preeclampsia. There was no difference in anxiety scores between groups based on baseline characteristics (i.e., age, BMI, and race). First trimester anxiety scores were associated with increased cfPWV in the early and late second trimester time points (p=0.02, p= 0.04, respectively). Higher baseline anxiety was also associated with a greater increase in cfPWV from baseline to 18 weeks gestation (p=0.04). A trend was also observed between baseline anxiety scores and the development of preeclampsia (p=0.07). Anxiety in the first trimester of pregnancy is associated with higher cfPWV values and a greater increase from the first to the second trimester, as well as potentially a higher risk for preeclampsia. Our ongoing study will further explore these findings as they can have important implications for patient prenatal care.
Abstract P208: Cardiovascular Effects Of Antihypertensive Agents In A Rat Model Of Preeclampsia.
Authors: Haase Nadine , Schuette Till , Kedziora Sarah , Kraeker Kristin , Dechend Ralf , Palmrich Pilar , Sugulle Meryam , Binder Julia
Published: October 2023

Introduction:
Hypertensive disorders of pregnancy are a leading cause of maternal and neonatal morbidity and mortality. The placental origin of preeclampsia, characterized by hypertension and proteinuria after 20 weeks of gestation, is currently on the test bench. A number of studies reported a cardiovascular origin for preeclampsia, with increased long-term cardiovascular risk for affected women. Despite new insights into pathophysiology, there is a lack of evidence supporting improvement in maternal and neonatal outcomes with current antihypertensive therapy. This study aims to investigate maternal hemodynamics and cardiovascular parameters in a preeclamptic rat model, focusing on changes induced by antihypertensive treatment.

Purpose:
This study challenges blood pressure as the sole target for antihypertensive therapy in preeclampsia, seeking new insights into the disease's pathophysiology through invasive procedures and assessment of cardiac morphology in a rat model for preeclampsia.

Methods:
Maternal hemodynamics were invasively measured, and cardiac compliance was assessed via echocardiography. Cardiac phenotyping was performed combining the evaluation of physiology and structural changes. Maternal hearts were investigated at the end of pregnancy and postpartum. Blood pressure was continuously monitored using telemetry. The antihypertensive agents used in the study were methyldopa, nifedipine, and labetalol, which represent standard therapy for women with preeclampsia.

Results:
In the transgenic rat model for preeclampsia (PE), treatment with methyldopa and nifedipine led to a reduction of blood pressure during gestation whereas labetalol had no effect on the blood pressure (mean arterial pressure: PE 160.80±3.85 mmHg; PE+methyldopa 145.01±3.71 mmHg; PE+nifedipine 122.08±5.62 mmHg; PE+labetalol 163.12±3.12 mmHg). Despite the antihypertensive effects of methyldopa and nifedipine, the maternal hemodynamics as well as the cardiac compliance were unimproved during and after pregnancy.

Conclusion:
The results showed that standard therapy for women with preeclampsia does not seem to be sufficient to prevent the cardiovascular changes and therefore to reduce the CDV risk.