bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P163: Prevalence And Incidence Of Hypertension In 18-40-year-old Patients Referred For Palpitations With Normal Cardiac Monitor Findings
Authors: Wasco Christopher , Carter Cody , Kesari Aditya , Khan Zeryab , Kothari Shaili , Scheidemantel Andrew , Volio Andrew , Willett Aimee , Lockhart Marie , Chopra Nagesh
Published: October 2023

Background:
Among referred patients 16% have no known cause for palpitations. Studies show that hypertension (HTN) intricately influences ‘heart rate’ and ‘contractility’, the key components of ‘palpitation’. While prevalence of HTN is 22.4% in 18-39-year-olds, the relationship between palpitations and HTN remains unknown in this age group.

Objective:
To assess the incidence and prevalence of HTN in 18-40-year-olds referred for palpitations without a known arrhythmic cause.

Methods:
Data from 130 patients with repeated normal cardiac monitor findings referred for palpitations to an electrophysiology clinic between 1/1/2016, and 12/31/2017, were retrospectively analyzed over a 5-year follow-up period.

Results:
The study cohort comprised of 94 females, 114 of white race with a mean age of 28 years. A 16% (21/130) prevalence of HTN was noted at initial evaluation. Over a period of 2.2 years additional 56% (73/130) patients were diagnosed with HTN. At the end of study period the prevalence of HTN increased to 72% (93/130) (p<0.0001). Hypertensive patients were obese (BMI: 29 kg/m
2
versus
25 kg/m
2
; p=0.03), used NSAIDs regularly (81
versus
46; p=0.04), and had a stronger family history of HTN (72
versus
5; p<0.0001). Hypertensive patients exhibited higher systolic (124 mmHg
versus
112 mmHg; p<0.0001) and diastolic (80 mmHg
versus
72 mmHg; p<0.0001) blood pressures during the study period.

Conclusion:
Undiagnosed and hence under-treated HTN is common in 18-40-year-old patients without a known arrhythmic cause for palpitations. The possibility of untreated HTN causing palpitations needs further evaluation.
Abstract P165: Hypertension Increases Susceptibility To Experimental Malaria In Mice
Authors: Kandalgaonkar Mrunmayee R , Yeoh Beng San , Joe Bina , Vijay-Kumar Matam , Saha Piu
Published: October 2023

Despite available treatments, global prevalence of hypertension is on the rise and burdening healthcare, especially in under-developed countries where infectious diseases are also rampant. Previously we reported that hypertension is associated with abnormal red blood cell (RBC) physiology and anemia. Since RBCs are target host cells for malarial pathogen,
Plasmodium
, we hypothesized that hypertensive patients with abnormal RBC physiology are at an increased risk of susceptibility to Plasmodial infection.

Methods:
To test this hypothesis, eight weeks old hypertensive BPH/2J and normotensive BPN/3J female mice (n=6) were first characterized for their RBC physiology and subsequently infected with
Plasmodium yoelii (P. yoelii)
, a murine-specific non-lethal strain.

Results:
Compared to BPN mice, BPH mice displayed comparable RBC count, but lower hemoglobin (BPH 16.3±0.8,
vs
BPN 16.5±1.0 mg/dL; p<0.01); lower % hematocrit (BPH 59.6 ±2.4
vs
BPN 61.0 ± 2.7; p<0.01), and lower mean corpuscular volume (BPH 52.6±3.13
vs
BPN 54.2±1.6 fl; p<0.005), indicating microcystic anemia. Further, RBCs from BPH mice were resistant to osmotic hemolysis in hypotonic (0.42%) NaCl solution (% hemolysis BPH 43.2±1.6%
vs
97.3±1.8% BPN; p<0.001). Lower membrane fluidity was observed in the RBCs of BPH mice as noted through higher levels of the saturated fatty acid, stearate (BPH 16.2±0.1%
vs
BPN 13.9±0.16%; p<0.001), phospholipids (BPH 554±18.3
vs
BPN 496±6.2 μg/mg protein p=0.02) and lower polyunsaturated fatty acids like arachidonic acid (BPH 13.7±0.1%
vs
BPN 15.1±0.5%, BPN; p=0.03). Further, upon infection for 7 days with
P. yoelii
, BPH mice experienced severe body weight loss compared to minimal change in body weight noted in the BPN mice (BPH Day 0 18.53±0.32 g
vs
Day 7 16.43±0.71 g
vs
BPN Day 0 22.5±1.28 g
vs
Day 7 22.43±1.30 g; p<0.01). This was accompanied by a significantly decreased number of RBC compared to BPN mice (BPH 3.4±1.3х10
12
vs
BPN 5.5±1.2х10
12
cells/L; p=0.03), indicating that BPH mice were more susceptible to malaria infection.

Conclusion:
Collectively, these data demonstrate that aberrant RBC physiology observed in hypertensive mice contributes to an increased susceptibility to experimental malaria.
Abstract P171: Does Sleep Loss Affect Sympatho-excitatory Reactivity Of Blood Pressure In The Morning In People With Untreated Hypertension? A Preliminary Analysis.
Authors: Brito Leandro , Rice Sean P , Rope Robert , Emens Jonathan S , McHill Andrew W , Minson Christopher T , Shea Steven A , Thosar Saurabh S
Published: October 2023

Objective:
To determine the effect of sleep on the morning sympatho-excitatory reactivity of blood pressure (BP) in patients with untreated hypertension while controlling for the effects of the circadian system.

Methods:
Four participants (aged 50-63 y) underwent a randomized cross-over trial consisting of an 8-h overnight sleep opportunity and a night of 8-h supine rested wakefulness in dim light. After each trial, we measured beat-to-beat BP and heart rate (HR) at rest and during 2 min of the sympatho-excitatory stress, isometric handgrip exercise (IHG at 30% of maximal voluntary contraction), followed by 2 min of post-exercise ischemia (PEI). Sympathetic vasomotor modulation was analyzed at rest by the low-frequency band of systolic BP variability (LF
SBP
, mmHg
2
). The effect size (ES) for repeated measures (Cohen’s d
rm
) was used to compare absolute values at rest and the change in HR and mean BP during IHG and PEI as not meaningful (<0.2), small (0.2-0.49), moderate (0.50-0.79), or large (≥0.80).

Results:
After wakefulness, resting mean BP and sympathetic vasomotor modulation were both higher than after sleep with large ES (151±21 vs. 137±17 mmHg: ES=0.9, 95%CI [+1.3, +0.4]) and (12±9 vs. 6±2 mmHg
2
; ES=0.9 95%CI [+1.7, +0.1]), respectively. BP reactivity was higher after wakefulness than after sleep with large ES at IHG min 2 and PEI min 1 and moderate ES at PEI min 2 (Figure 1), while HR was higher only at IHG min 2 with large ES.

Conclusion:
Our data suggest that sleep loss increases sympathetic vasomotor modulation and sympatho-excitatory reactivity of BP to morning physical stress in patients with untreated hypertension increasing their risk for adverse cardiovascular events.
Abstract P178: Role Of The C-C Motif Chemokine Receptor 5 (CCR5) Polymorphism In A Mouse Model Of Kawasaki Disease-Induced Vasculitis
Authors: Costa Rafael , Alves Juliano , Ayupe Marina , Awata Wanessa , Singh Shubhnita , Bruder-Nascimento Ariane , Hand Timothy , Bruder Thiago
Published: October 2023

Introduction:
Kawasaki disease (KD) is the most common form of vasculitis in young children. However, the etiology and the vulnerability of vasculitis are still enigmatic. In children, polymorphisms in CCR5 influence KD susceptibility and cardiovascular outcome, but the mechanisms are unclear. Therefore, the use of murine models is an attractive strategy to evaluate the interface between immune system and vasculitis in KD. We aimed to explore the mechanisms by which polymorphisms in CCR5 aggravates the vascular injury in KD by using the
Candida albicans
water soluble (CAWS) fraction model.

Methods:
Male (6-10-weeks-old) CCR5 deficient mice (CCR5
-/-
) and their counterpart (CCR5
+/+
) were used.

Results:
After 28 days of CAWS treatment, CCL5 and CCR5 levels were increased in plasma [(pg/mL) CCR5
+/+
: 5.01 ± 0.7 n=5
vs
. CCR5
+/+
CAWS: 18.71 ± 1.4* n=4, *p<0.05], and heart (14-fold changes) of CCR5
+/+
, which was associated with a clear vasculitis in coronary and AA, as well as cardiac senescence (p21 expression), cell death (caspase-3 levels), and higher contractility to norepinephrine (NA) in AA [(mN) CCR5
+/+
: 3.60 ± 0.3 n=4
vs
. CCR5
+/+
CAWS: 5.72 ± 0.2* n=4, *p<0.05]. Remarkably, CCR5
-/-
displayed a worse vasculitis level, further accumulation of cardiac p21 and caspase-3, and an exacerbated vascular response to NA (CCR5
-/-
-CAWS: 6.70 ± 0.4
#
n=5,
#
p<0.05
vs
. CCR5
+/+
CAWS). To understand the mechanisms, we performed a plasma proteome profile cytokine assay, which revealed that KD elevates the levels of various inflammatory mediators (IL-1β, IL-6, IL-17, and TNFα) and chemokines (CXCL2, 10, 11, 19, 12, and 13 and CCL2, 3, and 4), which were exacerbated in CCR5
-/-
. Yet, CAWS induced an increase in cardiac neutrophil infiltration in CCR5
+/+
[(% in relation to 10
^
6 leukocytes) CCR5
+/+
: 2.5 ± 1.7 n=4
vs
. CCR5
+/+
CAWS: 16.1 ± 3.2* n=4, *p<0.05], which was worsened in CCR5
-/-
(CCR5
-/-
-CAWS: 30.2 ± 7.4
#
n=4,
#
p<0.05
vs
. CCR5
+/+
CAWS).

Conclusion:
Deficiency in CCR5 aggravates the vasculitis levels and cardiovascular outcomes likely regulating neutrophil infiltration and cytokines production. Therefore, children with polymorphism in CCR5 might be more susceptible in developing a severe vasculitis during KD.
Abstract P179: Nano- And Microplastic-enriched Diets Affect Inflammation And Target Organ Damage In Hypertension
Authors: Fuckert Franziska , Rauch Ariana , Anandakumar Harithaa , Bartolomaeus Hendrik , Wilck Nicola
Published: October 2023

Plastic particle pollution is a major environmental challenge worldwide. Micro (MP)- and nanoplastic (NP) particles appear ubiquitously and have been detected in food, drinking water, human feces and blood. Once absorbed, plastic particles can alter the gut microbiome and induce inflammation. Current research primarily focuses on the impact on healthy organisms. Yet, a deeper understanding of the impact of MP and NP on health-to-disease transition and their impact on cardiovascular disease is missing. This project aims to investigate the impact of MP and NP in experimental hypertension.

Ten-week-old male NMRI mice were randomized to receive the following particle-enriched diets: a polystyrene MP (particle size 5 μm) (20 μg/g chow, 100 μg/l via drinking water), NP (particle size 100nm) (20 μg/g chow,100 μg/l via drinking water) or control (C) for four weeks. Subsequently, hypertension (HTN) was induced by Angiotensin II (AngII) infusion (1000 ng/kg*min s.c., osmotic minipump). Sham-treated non-hypertensive mice served as controls. During hypertension induction mice were continued on their respective diets. After 14 days, we assessed hypertensive organ damage and inflammation.

AngII-treated mice developed hypertension an increased cardiac hypertrophy index (Sham vs HTN: 10.1 vs 10.7 mg/mm tibia), and lower cardiac output (HTN vs Sham: 15.5 vs 19.9 ml/min, echocardiography). MP fed mice showed upregulated mRNA expression of marker genes for renal fibrosis (
Ctgf; Acta
) in both homeostasis (ddCT
-2
for MP: 2.7; 6.6) and HTN (ddCT
-2
3.2 (MP) vs. 2.3 (C); 14.2 (MP) vs 11.2 (C)), as well as enhanced proinflammatory gene expression (
Ccl2; IL1b
) in HTN (ddCT
-2
7.4 (MP) vs 4.0 (C); 5.8 (MP) vs 4.3 (C)). Similarly, NP fed mice showed altered mRNA expression for e.g.
IL1b
(ddCT
-2
for NP: 3.6). Flow cytometric analysis shows a proinflammatory immune response to MP and NP, e.g. an increase of circulating neutrophils (HTN C vs. MP: 24.7% vs 50.0% of CD45+) and Ly6C
hi
monocytes (Homeostasis C vs NP: 2.4 vs 3.2% of CD45+).

Conclusion:
MP and NP affect the inflammatory response and organ damage in hypertension. Our further investigations will help to shed light on the impact of this ubiquitous environmental influence on hypertension, associated organ damage and the microbiome.
Abstract P183: Porcupine Protects The Kidney By Suppressing Tubular Inflammation And Preserving Mitochondrial Integrity
Authors: Lu Xiaohan , Ren Jiafa , Wen Yi , Su Jiahui , Ali Saba , Chen Yanting , Madan Babita , Virshup David M , Yang Ting , Crowley Steven D
Published: October 2023

Chronic Kidney Disease (CKD) progression may be slowed or stopped with early diagnosis and intervention, so developing novel therapies is paramount. The Wnt acyl transferase porcupine (PORCN) regulates the secretion of all 19 Wnt ligand isoforms that propagate β-catenin signaling. We find that mice with deletion of PORCN from kidney epithelia (PORCN iKKO) had augmented kidney injury in the nephrotoxic serum nephritis (NTS) model of CKD, with higher BUNs (202 ± 12 vs. 101 ± 38, mg/dL; p<0.01), and renal mRNA levels for NGAL (6.1±1.14 vs. 1.0±0.35 au, p=0.0013), KIM-1(2.5±0.65 vs. 1.0±0.26 au, p=0.046), collagen I (2.4±0.31 vs. 1.0±0.38 au, p=0.025), and fibronectin (2.5±0.35 vs. 1.0±0.27 au, p=0.006) compared to wild-type (WT) controls. PORCN iKKOs also had upregulated renal protein levels for collagen I (1.5 ± 0.2 vs. 1.0 ± 0.1 au; p=0.01) and fibronectin (1.8 ± 0.3 vs. 1.0 ± 0.1 au; p<0.01), recapitulating the mRNA patterns. We also detected marked TNFα mRNA upregulation in the PORCN iKKO kidneys vs WTs during CKD (2.6±0.67 vs. 1.0±0.30 au, p=0.036). TNFα is a potent driver of renal injury and fibrosis, acting via TNFα receptor 1(TNFR1) to promote ROS generation. At day 14 of NTS, PORCN iKKO kidneys contained higher levels of the ROS metabolite, 8-isoprostane (2348 ± 718 vs. 486 ± 77, pg/mg kidney; p=0.02), and expressed higher levels of mitochondrial dysfunction markers, including Drp1 (1.26 ± 0.06 vs. 1.0 ± 0.04 au; p<0.01) and p62 (1.3 ± 0.09 vs. 1.0 ± 0.07 au; p=0.07). TNFR1 inhibition (R-7050, 12mg/kg, IP, every other day) reduced BUNs (94.13 ± 3 vs. 90.26 ± 4.1, mg/dL; p=0.46) and renal Drp1 protein levels (1.4 ± 0.17 vs. 1.0 ± 0.15 au; p=0.11) in the PORCN iKKO cohort to WT levels. In primary renal tubular cells (RTCs), TNFα treatment (50ng/ml, 12hrs) induced 8-isoprostane generation (387 ± 119 vs. 121 ± 39, pg/ml in medium; p=0.07), corroborating our
in vivo
studies. Moreover, treatment of the RTCs with the Drp1 inhibitor mdivi-1 (MD1, 10μm) for 12 hours attenuated TNFα-induced accumulation of fibronectin and collagen I. Our studies suggest that PORCN in renal epithelia protects against kidney damage by limiting TNFα induction, thereby diminishing Drp1-mediated mitochondrial dysfunction and ROS generation.
Abstract P184: Inducing Macrophages Towards A Regulatory Phenotype Reduces Blood Pressure And Testicular Proinflammatory Immune Cells In Hypertensive Mice
Authors: Navaneethabalakrishnan Shobana , Goodlett Bethany , Smith Hannah , Mitchell Brett M
Published: October 2023

Our laboratory has previously reported that salt-sensitive hypertension (SSHTN) induces proinflammatory macrophages, inflammation, and inflammation-associated lymphangiogenesis in the testes of mice. However, it is unknown whether altered macrophage polarization causes these changes leading to testicular dysfunction. We hypothesized that inducing macrophages towards a regulatory phenotype will lower blood pressure and reverse inflammation in the testes that is associated with SSHTN. Control (C) male C57BL6/J mice received tap water and normal diet. SSHTN mice were provided 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% high salt diet and mice in the third group received AVE0991 (0.58 nmol/g) through i.p injections (AVE) in the last 3 weeks. SSHTN mice had increased systolic blood pressure (146±2 mm Hg) when compared to C mice (96±2 mm Hg), but the blood pressure was reduced in AVE mice (136±1 mm Hg; p<0.05). Flow cytometry analysis revealed a significant reduction in M2 macrophages in the testes of SSHTN mice when compared to C mice but were increased in AVE mice when compared to SSHTN mice (% of CD45 cells: C: 19.3%±2, SSHTN: 7.7%±2, AVE: 15.7%±3; p<0.05). There was an increase in CD45+ F4/80- CD11c+ dendritic cells (C:3.3%±1, SSHTN:6.7%±1, AVE: 3.1%±1; p<0.05), CD4+ IL17+ Th17 cells (C:5.8%±1, SSHTN:28.5%±3, AVE: 10.6%±3; p<0.05), CD4+ TNFa+ Th1 cells (C:11.8%±2, SSHTN:38.8%±8, AVE: 15.2%±3; p<0.05), and gamma-delta T cells (C:2.9%±1, SSHTN:8.9%±2, AVE: 4.9%±1; p<0.05) in the testes of SSHTN mice when compared to C mice, but were decreased significantly in AVE mice. These data demonstrate that alteration in testicular macrophage phenotypes is a contributing factor to testicular inflammation resulting in reproductive dysfunction in SSHTN mice. Therapeutic strategies may be developed by targeting macrophage imbalance to improve testicular function that is associated with SSHTN.
Abstract P187: Comparative Analysis Of Covid-19 Vaccine Efficacy In Heart Transplant Recipients On Standardized Immunotherapy Regimens
Authors: Sharma Shriya , Ruiz Jose , Paghdar Smit , Desai Smruti , Goswami Rohan
Published: October 2023

Background:
International data on COVID-19 infection in immunosuppressed populations is limited. Heart transplant (OHT) recipients requiring immunotherapy are at risk for potentially increased complications with COVID-19 infection, including long-covid and oxidative stress during initial infection. The availability of vaccination and temporal trends in this population has not been well described. We report outcomes in immunosuppressed patients during the initial years of the COVID pandemic.

Methods:
All patients who underwent heart transplantation at Mayo Clinic in Florida were reviewed from March 2019 to October 2021. Patients were divided into two groups: those diagnosed with COVID-19 (based on a positive SARS-CoV-2 RT-PCR) and those not. A p value of 0.05 was considered significant using the Chi-squared test.

Results:
A total of 98 patients were reviewed. Of these, 49 were COVID-19-positive (CP), and 49 were negative (CN). The cohort was well matched, with a median age of 58 years (49 - 65) in both groups. 20 females in the CP group and 9 in the CN group. Diabetic status (p = .07), history of hypertension (p=.5), BMI (p=.41), GFR (p=.19), and ejection fraction (p=.29) were not significantly different between the two groups. Immunosuppression was not significantly different for CP or CN patients, with a median trough tacrolimus level of 7.68 vs. 8.70 (p = .26). The median time from transplant to CP was 384 days (237 - 677). The CN group’s median follow-up after transplant was 947 days (737 - 1191). CP hospitalization rate was 24% (5 Pfizer, 3 unvaccinated, 4 Moderna) with only 1 death. Hospitalized patients’ markers of inflammation were: IL6 19.2 (12-48), D-dimer 1408 (763 - 2227), and CRP 54 (20 - 90). The CP group was more vaccinated than the CN group (92% vs. 78%, p = .025). More CP patients received the Pfizer vaccine compared to Moderna (p = .018).

Conclusion:
We found that patients after OHT on similar immunotherapy regimens did not carry the same risk of contracting Covid-19 despite being vaccinated. CP patients were generally infected in the first 1.5 years after OHT. This may indicate an increased infection rate due to a weakened immune system or lack of bivalent boosters before 2022. Vaccine efficacy in this population should be evaluated in larger studies.
Abstract P188: Hypertensive Stimuli Increase Pro-Inflammatory Bone Marrow Derived Macrophages In Vitro
Authors: Smith Hannah L , Goodlett Bethany , Navaneethabalakrishnan Shobana , Mitchell Brett M
Published: October 2023

Renal macrophage infiltration and inflammation is a hallmark of hypertension (HTN). An imbalance in macrophages has been observed in murine salt-sensitive and angiotensin II (AngII)-induced models of HTN. We have identified increased activated macrophages (CD45+ CD11b+ F4/80+ CD38+), pro-inflammatory M1 macrophages (CD45+ CD11b+ F4/80+ CD11c+ CD206-), and activated M1 macrophage (CD45+ CD11b+ F4/80+ CD11c+ CD206- CD38+) in the kidneys of these mice. In this study, we hypothesized that salt and AngII directly induce macrophages to become activated and pro-inflammatory. We exposed bone marrow derived macrophages (BMDMs) grown in GM-CSF to salt (190 μm) and AngII (0.01 μm) and found that there were significant increases in renal activated macrophages (% of CD45 cells: Con: 31 ± 1; AngII: 37 ± 1; Salt: 56 ± 1), pro-inflammatory M1 macrophages (Con: 27 ± 1; AngII: 37 ± 1; Salt: 56 ± 1), and activated M1 macrophages (Con: 22 ± 1; AngII: 28 ± 1; Salt: 43 ± 1) as determined by flow cytometry. However, the cultivation of BMDMs in M-CSF, the more traditional growth factor present in culturing BMDMs, did not produce the same significant results. Next, we will identify renal pro-inflammatory cytokines, chemokines, growth factors, and levels of GM-CSF present in these mouse models of HTN. Currently, these findings suggest that GM-CSF increases macrophage responsiveness to HTN stimuli and induces activated and pro-inflammatory macrophages which may contribute to the development and progression of HTN. Targeting activated renal macrophages or renal GM-CSF may provide a new therapeutic option for the treatment of HTN.
Abstract P190: Management Of Patients With Hypertension: Challenges From A Student-Run Free Clinic
Authors: Ahmed Sanya , Zhu Michelle , Behzadi Cyrus , Kuster Max , Laskar Thaif
Published: October 2023

Background/Objectives:
The Anne Kastor Brooklyn Free Clinic (BFC) is a student-run free clinic affiliated with the SUNY Downstate Health Sciences University which provides healthcare to the uninsured and represents patients from all five boroughs of New York City. Through this research, we were able to identify improvements for the management and care of a prevalent condition in a community which is both disadvantaged and underserved.

Methods:
De-identified data on patient visits were aggregated from the electronic health record of the BFC from 2020-2022 and organized into a database using Redcap. We analyzed chief complaints, prescriptions, symptoms, comorbidities, and demographics for patients with hypertension at the BFC during this time period.

Results:
Our analysis included 121 patients in 311 total visits. The average blood pressure for patients with hypertension was 144/83 (stage 2 hypertension). 18.9% of patients were obese, with an average BMI of 33.1 (SD: 9.76). Most patients presented for a general check-up (67.5%) or for cardiovascular concerns (15.1%) at an in-person visit (67.8%). Patients were predominantly female (63.6%), black (38.0%), non-smokers (69.1%) with a history of diabetes (24.6%) and alcohol use (26.4%). Patients frequently had hypertension (49.6%) and type II diabetes (38.0%) within the family. Physicians noted a common physical exam finding of lower extremity edema (15.1%) and frequently ordered HbA1c (30.4%) and lipid panel (29.2%) labs. 42.2% of patients were on medications to control their hypertension, and 25.3% of visits included a prescription of antihypertensive medications. 86.5% of visits included lifestyle counseling. Most patients were scheduled for a follow-up (80.6%).

Conclusion:
Many patients presented with poorly-treated chronic illnesses, leading to an increase in cardiovascular complications like hypertension. A minority of patients were taking medications to control their hypertension, and fewer were prescribed antihypertensives at their visit, suggesting the need for improved pharmacologic management of hypertension in addition to lifestyle counseling. Patients should also be encouraged to present in-person to assess for pitting edema and other cardiovascular concerns.
Abstract P193: Time To First Follow-up Visit For Patients With Newly Treated Hypertension Among Florida Medicaid And Medicare Recipients
Authors: Smith Kayla , Winterstein Almut , Gurka Matthew , Walsh Marta , Keshwani Shailina , Libby Anne , Hogan William , Pepine Carl , Cooper-Dehoff Rhonda M , Smith Steven M
Published: October 2023

Introduction:
Routine follow-up (f/u) leads to better BP control and CV outcomes in individuals with hypertension (HTN). Guidelines suggest newly treated patients f/u within 1-2 months after initiating treatment. Few real-world studies have assessed the timing of actual f/u care and concordance with guidelines.

Methods:
We performed a cohort study of adult Florida Medicaid (2012-2021) or Medicare (2012-2017) recipients with newly treated HTN in the OneFlorida+ Consortium. Patients were aged ≥18 y, diagnosed with HTN, who filled ≥1 first-line antiHTN drug with no evidence of antiHTN use in the year prior, and had ≥1-year of continuous insurance enrollment prior to first antiHTN fill (index date). Occurrence and timing of f/u were determined by identifying post-index outpatient encounters with a HTN diagnosis. Cox regression models were used to assess association of age-adjusted sex and race with time-to-first f/u, separately in Medicaid and Medicare recipients.

Results:
We identified 52,712 new antiHTN users in the Medicare population (mean ± SD age, 72 ± 19.4 y; 53.4% women; 15.4% Black). Among the 14,608 (27.7%) patients who had a f/u visit, median time-to-f/u was 100 (IQR: 21, 145) days. Among 64,586 new antiHTN users who were Medicaid recipients (age, 47 ± 14.3 y; 59.9% women; 30.4% Black), 28,304 (43.8%) had a f/u visit with median time of 56 (IQR: 32, 231) days. Among Medicare-insured, Whites were 11% (HR 1.11; 95% CI, 1.07-1.16) more likely to have a f/u visit than Black individuals, and among Medicaid-insured, Whites were 5% (HR 1.05; 95% CI, 1.02-1.08) more likely; sex was not associated with likelihood of f/u in either cohort after age-adjustment.

Conclusions:
Few patients had a f/u within 1 year of initiating antiHTN therapy, and, of those with a visit, fewer than half did so within 2 months, even when using a liberal definition of f/u (i.e., any outpatient encounter with HTN diagnosis). Such delays in care may prevent rapid BP control and expose individuals to higher CVD risk. We also observed small, but significant disparities among White and Black individuals. These findings may help explain well-known disparities in BP control and related adverse sequelae of uncontrolled HTN.
Abstract P197: The Total And Direct Effects Of Cardiovascular Risk Factors On Target Organ Injury And The Indirect Effect Mediated Through Blood Pressure Severity: Modifying Effect Of Chronic Kidney Disease
Authors: Vincent Carol , Campbell Jessica F , Londeree Jackson , Misurac Jason , Murphy Maggie , Onugha Elizabeth , Riar Sandeep , Sethna Christine , Siddiqui Sahar , Weaver Donald J , Yamaguchi Ikuyo , South Andrew
Published: October 2023

Youth-onset chronic kidney disease (CKD) is associated with early development of increased cardiovascular (CV) disease risk. CV health factors (CVHF) such as obesity, dyslipidemia, and hyperglycemia contribute to CV risk, but their specific role in target organ injury (TOI) development in youth with CKD is not well understood. Our objective was to determine the modifying effect of CKD on the total and direct effects of CVHF on TOI and the indirect effect mediated through blood pressure (BP) severity in youth with HTN disorders, hypothesizing that CKD would increase the mediating role of BP. Interim cross-sectional analysis of baseline data from the SUPERHERO Registry, a multisite retrospective registry of EHR data from youth referred for HTN disorders. Diagnoses were defined by ICD-10 codes unless otherwise specified. Inclusion criteria were age <19 years and HTN disorder from 1/1/2015-12/31/2022 at initial subspecialty clinic visit. Exclusion criteria were dialysis, kidney transplantation, or pregnancy. Presence of 0-3 CVHF defined our exposure: any combination of obesity (by BMI %ile), dyslipidemia, or hyperglycemia. Outcome was TOI (kidney and/or heart). Mediator was BP by HTN severity (defined by U.S. pediatric guidelines). Total and direct effects of CVHF on TOI and indirect effect mediated via HTN were analyzed using generalized linear models and causal mediation analysis adjusted for unmet social needs and participant home region, stratified by CKD. Of 11580 participants, 488 (4%) had a CKD diagnosis. Presence of only 1 CVHF was associated with lower odds of TOI overall in youth without CKD (OR 0.69, 95% CL 0.59, 0.81) but higher odds in youth with CKD (OR 1.7, 95% CL 0.98, 2.8), interaction term
p
<0.05. Presence of 2 CVHF was associated with higher odds of overall TOI (OR 1.53; 95% CL 1.14, 2.04) and heart-/kidney-specific TOI (OR 1.45 to 1.92). We found low prevalence of 3 CVHF and heart-specific TOI. We found no evidence of BP mediation or interaction for overall or organ-specific TOI. Our findings may be due to differences in kidney TOI between youth with and without CKD, reliance on ICD-10 codes, or different practices for TOI surveillance in youth with CKD. Future ongoing steps include analyzing laboratory and echocardiogram results for precision.
Abstract P203: Microvascular Imaging As Early Predictor For Cardiac Dysfunction After Preeclampsia
Authors: Kraeker Kristin , Haase Nadine , Kedziora Sarah , Frolova Alina , Schuette Till , Herse Florian , Mueller Dominik N , Dechend Ralf
Published: October 2023

Preeclampsia (PE), the most common pregnancy disease, is the main cause for maternal and fetal mortality and morbidity worldwide. The disease is characterized by a sudden increase in blood pressure in combination with signs of end organ damage, e.g. proteinuria and the underlying mechanisms are poorly understood. Immune dysregulation and endothelial dysfunction are important pathomechanisms leading to PE, we hypothesize that anti-angiogenesis and dysregulation of microvascular perfusion postpartum lead to the increased cardiovascular risk in later life. In addition, we will test if the examination of retinal vessels can be used as a diagnostic window for early risk prediction of cardiovascular alterations. In a well-established transgenic rat model for PE, we performed speckle tracking echocardiography, immunostaining, RNA sequencing and small vessel imaging by micro-computed tomography of the heart and the eyes in former preeclamptic rats (PEpp) and healthy controls (WTpp). A reduction of cardiac vessels (AUC 0-200 μm: WTpp 77.19±4.64 vs. PEpp 62.59±2.72) in combination with an increase of small vessels in the retina (AUC 0-50 μm: WTpp 52.89±1.47 vs. PEpp 59.54±1.09) is shown postpartum. Data from echocardiography (Global longitudinal strain: WTpp -22.03±2.47 % vs. PEpp -14.50±1.80 %) and histological staining (CD31: WTpp 292.7±30.9 per fov vs. PEpp 219.0±10.5 per fov) support the hypothesis of persistent cardiovascular alterations after PE. Performing RNAseq, 65 genes were found to be permanently altered in the left ventricle of the heart of preeclamptic rats compared to 4 genes in controls. In the retinal tissue, 39 genes in PEpp and no genes in WTpp were identified postpartum compared to never pregnant animals (adjusted p-value < 0.05,
Abstract P207: Pravastatin Mitigates Hyperglycemia- Induced Cytotrophoblast Dysfunction
Authors: Rane Riddhi , Pantho Ahmed , Vora Niraj , Afroze Syeda , Ehrig Jessica , Kuehl Thomas , Zawieja David C , Uddin Mohammad N
Published: October 2023

Objective:
Despite advancements in our understanding of preeclampsia (preE), there are currently no effective therapies to prevent the disease. Pravastatin shows promise by attenuating pathophysiologic processes associated with preE such as decreased cytotrophoblast (CTB) migration, aberrant angiogenesis, and increased oxidative stress. This study assesses the effects of pravastatin on hyperglycemia-induced CTB dysfunction and its use as a potential drug for the prevention of preE.

Methods:
Human CTB cells were treated with 100, 150, 200, 300, or 400 mg/dL glucose for 48 hours. Some cells were pretreated with pravastatin (1ug/mL), while others were cotreated with pravastatin and glucose. Expression of urokinase plasminogen activator (
uPA
), plasminogen activator inhibitor 1 (
PAI-1
), proliferating cell nuclear antigen (
PCNA
), and
p38 MAPK
phosphorylation were measured by western blot.
uPA
and
PAI-1
mRNA was measured by quantitative PCR. Angiogenic (vascular endothelial growth factor [
VEGF
], placenta growth factor [
PlGF
]) and antiangiogenic factors (soluble fms-like tyrosine kinase-1 [
sFlt-1
], soluble endoglin [
sEng
]) were measured by enzyme-linked immunosorbent assay (ELISA) kits. Statistical comparisons were performed using analysis of variance with Duncan’s post-hoc test.

Results:
The hyperglycemia-induced downregulation of
uPA
was attenuated in CTB cells pretreated with pravastatin at glucose levels >200 mg/dL, and cotreated at glucose levels >300 mg/dL (p<0.05). The hyperglycemia-induced downregulation of
PAI-1
,
PCNA, VEGF, and PlGF
and the upregulation of
p38
phosphorylation,
sENG
, and
sFlt-1
were also attenuated in both pretreatment and cotreatment samples in all groups regardless of glucose dose (p<0.05).

Conclusions:
Pravastatin mitigates the CTB cell dysfunction initiated by hyperglycemic conditions by attenuating the glucose-induced down-regulation of
uPA
,
PAI-1
, and
PCNA
expression, up-regulation of
p38
phosphorylation, downregulation of
VEGF
and PlGF, and upregulation of
sFLT-1
and
sEng,
thereby decreasing the stress signaling response that normally leads to abnormal placentation, and is associated with the development of preE in pregnancy.

Key words:
Preeclampsia; Diabetes; Pregnancy
Abstract P209: Six Weeks Oral Losartan Treatment Improves Endothelium-dependent Dilation In Normotensive Women With A History Of Preeclampsia
Authors: Schwartz Kelsey S , Jalal Diana I , Stanhewicz Anna E
Published: October 2023

Women with a history of preeclampsia have a 4-fold increased risk of cardiovascular disease compared to women who had a healthy pregnancy. These women demonstrate microvascular endothelial dysfunction, mediated by reduced nitric oxide (NO)-dependent dilation and increased sensitivity to angiotensin II. We hypothesized that systemic angiotensin II type 1 receptor (AT
1
R) inhibition would improve endothelium- and NO-dependent dilation in the microvasculature of women with a history of preeclampsia. Seven normotensive (seated SBP 118±6; DBP 78±6 mmHg) women (33±6 years of age, 11±7 months postpartum) with a history of preeclampsia participated in a double-blind placebo-controlled crossover study. Following 6 weeks of placebo and losartan treatment (50 mg/day), participants wore a 24-hour blood pressure monitor and completed 1 study visit in which 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusions of acetylcholine (ACh, 10
-7
-10
2
mM) or ACh + 15 mM N
G
nitro L-arginine methyl ester (L-NAME; NO synthase inhibitor) to assess endothelium- and NO-dependent dilation, respectively. Red blood cell flux was measured over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=Doppler flux/mean arterial pressure) and normalized to maximum (%max; 28 mM SNP + 43°C). Systemic losartan treatment augmented endothelium-dependent (losartan: 96±4 vs placebo: 70±14%max;
P
<0.001) and NO-dependent (losartan: 35±14 vs placebo: 23±8%;
P
<0.001) dilation. There was no effect of treatment on 24-hour systolic blood pressure (losartan: 117±4 vs placebo: 117±8 mmHg), diastolic blood pressure (losartan: 72±5 vs placebo: 71±5 mmHg) or mean arterial pressure (losartan: 92±4 vs placebo: 92±6 mmHg; all
P>0.05
). Losartan treatment increased endothelium-dependent vasodilation via NO-mediated pathways in the absence of changes in blood pressure in women with a history of preeclampsia. These data suggest that systemic AT
1
R inhibition may be a viable therapeutic approach to treat persistent microvascular dysfunction in otherwise healthy women who have had preeclampsia.
Abstract P210: Sex Specific Changes In Cerebral Proinflammatory Cytokines In Intrauterine Growth Restricted Offspring
Authors: Smith Savanna , Smith Jonna , Jones Kylie , Castillo Angie , Cunningham Mark W
Published: October 2023

Background:
Intrauterine growth restriction (IUGR) often times results from placental ischemia, which restricts the distribution of nutrients and oxygen to meet the metabolic demand of the growing fetus. IUGR offspring (OS) have an increased risk for developing cerebrovascular diseases (CVD) later in life. Factors for development of CVDs are HTN and inflammation. Our lab has shown 17 week IUGR male rats from preeclamptic pregnancies have HTN and elevated inflammation via systemic IL-17, while our females show no change. The role of inflammation to cause HTN in IUGR offspring in a sex specific manner is unknown and the major focus of this study which examines the changes in cerebral inflammation IUGR offspring at 12 weeks. We hypothesize that cerebral inflammation in IUGR males will be elevated, while no change in female IUGR offspring will be observed.

Methods:
IUGR offspring originate from preeclamptic Sprague Dawley dams. OS weaned for 3 weeks and were separated by sex and IUGR status. At 12 weeks, the rats underwent carotid catheterization to measure BP. Brains were collected to measure pro-inflammatory cytokines, such as TNF-α and IL-17 via ELISAs.

Results:
At 12 weeks, all OS were normotensive. Brain TNF-α increased in female IUGR (17,366± 1,500 vs 8,116± 1,341 pg/mL, p<0.05) and was elevated in male IUGR (20,845±7571 vs 8,516±1712 pg/mL, ns). Brain IL-17 increased in male IUGR (13,580± 945 vs 9,620± 945 pg/mL, p<0.05) and was elevated in female IUGR (13,143± 1613 vs 10,930± 696 pg/mL, ns). Systemic IL-17 was increased in IUGR male OS (112±16.8vs100±3.9 IU/Protein/CON %, ns).

Conclusion:
At 12 weeks, brain TNF-α and IL-17 were elevated in IUGR males and females. The differences in expression of each cytokine between the sexes suggest that IL-17 contributes to the increase in BP, especially in males. Understanding the timing of these developments could help to elucidate the role of inflammation in the development of CVD with or without HTN. This study is clinically relevant as it provides a sex specific inflammatory target for therapeutics, to help prevent hypertension and CVD in IUGR offspring. In the future, we will evaluate the role of inflammation in IUGR offspring in a sex specific manner.
Abstract P211: Expedited Versus Standard Postpartum Discharge In Patients With Hypertensive Disorders Of Pregnancy
Authors: Palatnik Anna , Tvina Alina
Published: October 2023

Background:
A hospital stay after an uncomplicated delivery is ~2 days for vaginal birth and ~3 days for cesarean birth. Hospitals and third-party payers have encouraged shorter maternity stays. The safety of earlier discharge is unclear particularly when it comes to patients with hypertensive disorders of pregnancy (HDP). Our aim was to examine whether expedited discharge (1 day after vaginal and 2 days after cesarean birth) has a negative effect on postpartum course and BP after HDP.

Methods:
A retrospective cohort study of patients with HDP (gestational hypertension, preeclampsia, chronic hypertension) during 2 epochs: 2015-2018, prior to implementation of expedited discharge, and 2019-2020, after implementation of expedited postpartum discharge. The primary outcome was unplanned health care utilization postpartum, defined as emergency room (ER) visits, clinic visits, and hospital readmission. Secondary outcomes were planned postpartum visit attendance and BP control during the 1st year. Bivariate and multiple logistic and linear regressions were run to evaluate the association between expedited discharge and study outcomes.

Results:
A total of 1441 patients were analyzed. There were no differences in ER or clinic visits or readmission for BP between expedited and standard postpartum discharge (table). Systolic and diastolic BP at 1-2 weeks, 6 weeks, and 1 year postpartum were similar in both groups. Expedited discharge was associated with higher likelihood of attending BP check at 1-2 weeks postpartum (aOR 1.33, 95% CI 1.08-1.77).

Conclusion:
Expedited discharge after HDP was not associated with BP complications or unplanned healthcare utilization postpartum.
Abstract P213: Multi-omic Analysis Of The Effect Of SGLT2 Inhibition On Blood Pressure In Dahl SS Rats
Authors: Kravtsova Olha , Billing Anja M , Upadhyay Gunjan , Levchenko Vladislav , Liu Ruisheng , Rieg Timo , Rinschen Markus M , Halade Ganesh V , Staruschenko Alexander
Published: October 2023

SGLT2 inhibitors (SGLT2i) have demonstrated efficacy in reducing heart failure, lowering blood pressure, and mitigating kidney diseases in both diabetic and non-diabetic conditions. Previously, we demonstrated the preventive effects of the SGLT2i dapagliflozin (Dapa) on salt-sensitive hypertension (SS HTN) in male Dahl SS rats (Dapa vs. vehicle: 136±3 vs. 156±6 mmHg) (Kravtsova
et al
., AJP Renal 2022). In the current study, we aimed to assess whether Dapa has similar outcomes in female rats. Our findings reveal that Dapa administration (2 mg/kg/day in drinking water for 3 weeks) resulted in a comparable effect on blood pressure in female rats (Dapa vs. vehicle: 140±5 vs. 160±9 mmHg). We further performed transcriptomic and proteomic analyses of the kidney cortex and medulla in both male and female rats fed a high salt (HS) diet, with or without Dapa. Both analyses revealed that the top biological functions affected by Dapa were related to lipid and amino acid metabolism, molecular transport, and cell function. The enrichment analysis of biological functions highlighted altered genes primarily associated with fatty acid oxidation, lipid transport and oxidation, and ion homeostasis primarily in the medulla. Notably,
Plin1
,
Plin4
,
Ucp1
, Ucp3 and
Adrb3
, which are involved in lipid metabolism, were the highest expressed genes in the kidney medulla of both sexes. Based on previous studies suggesting the involvement of oxidized phospholipids and metabolites of linoleic and arachidonic acids in the pathogenesis of SS HTN, we conducted preliminary experiments with males to assess the levels of lipid mediators in the kidneys of Dapa-treated rats. HS diet in Dahl SS rats led to elevated levels of several pro-inflammatory mediators, which were significantly reduced in Dapa-treated rats. These reductions were observed for prostaglandins (PGD2 [fold change (FC)=0.28], PGF2a [FC=0.14], 8-iso-PGF2a [FC=0.14]), 12-HHT [FC=0.31], TXB2 [FC=0.18], and 20-OH-LTB4 (FC=0.10). Our results indicated that SGLT2i altered various genes in the kidneys of Dahl SS rats independent of sex. This information provides novel insight on the pleiotropic effects of SGLT2i. Further studies are necessary to validate the predicted targeted pathways and subsequent biological functions.
Abstract P214: Impact Of NADPH Oxidase 4 Knockout On Renal O
2
Consumption In Dahl Salt-sensitive Rats
Authors: Shimada Satoshi , Dash Ranjan K , Cowley Allen W
Published: October 2023

It has been generally thought that in normal Sprague-Dawley (SD) rats, a high salt diet has minimal impact on blood pressure and kidney function. However, as we have recently reported, the kidneys of SD rats fed a 4.0% NaCl diet (HS) exhibit enhanced O
2
consumption (VO
2
) and marked changes in the metabolic pathways responsible for the generation of ATP and reactive oxygen species (ROS). In the current study, we examined the level of renal VO
2
in Dahl salt-sensitive (SS) rats and those in which the NADPH Oxidase 4 (NOX4) gene was globally knocked out (SS

Nox4

-/-
). Male SS (n=9) and SS

Nox4

-/-
(n=10) rats were fed a 0.4% NaCl (LS) diet. At 7-8 weeks of age, the rats were implanted with a renal artery ultrasonic flow probe (Transonic) together with a femoral arterial catheter and a renal venous catheter. Renal blood flow (RBF) and mean arterial pressure (MAP) were measured continuously (24/7) and arterial (A) and renal venous (Vr) blood was sampled intermittently when rats were fed a LS and on days 7, 14, and 21 after switching to a HS diet. Blood O
2
content was immediately measured by a radiometer. The average 24-hour MAP of SS rats rose after switching to a HS diet from 122 ± 2 on the LS to 140 ± 2 on HS7, and to 164 ± 5 by HS21. In contrast, MAP in SS

Nox4

-/-
rats increased from 121 ± 2 mmHg at LS to 132 ± 1 mmHg at HS7 and 152 ± 3 mmHg at HS21 (p<0.05). RBF was not significantly changed but tended to progressively rise in both strains of rats with 24-hr flows averaging 7.8 ± 0.7 ml/min when fed LS and 8.9 ± 1.0 ml/min at HS21, and SS

Nox4

-/-
from 6.9 ± 0.7 to 8.2 ± 0.9. Normalized by changes of kidney weights obtained in another group of SS and SS

Nox4

-/-
rats, RBF was significantly reduced over the 3 weeks of the HS diet given the increase of kidney weights (SS LS 7.0 ± 0.6, HS7 5.7 ± 0.5, HS21 4.9 ± 0.6; SS

Nox4

-/-
LS 6.4 ± 0.7, HS7 6.2 ± 0.7, HS21 5.4 ± 0.7). Most importantly, the O
2
extraction ratio at LS was lower in SS

Nox4

-/-
(10.5 ± 1.0%) compared to SS (14.6 ± 1.0%) (p<0.05). When switched to the HS diet, this was further reduced in the SS

Nox4

-/-
rats reaching 7.6 ± 0.9% at HS21 (p<0.05), while it did not change significantly in SS (13.3 ± 1.4%) at HS21. We conclude that the elevated levels of renal O
2
consumption observed in SS rats are at least in part a consequence of increased oxidative stress associated with NOX4.
Abstract P218: Ubr1 And Nedd4-2 Synergistically Modulate Ace2 Ubiquitination In Hypertensive Male Mice
Authors: Elgazzaz Mona , Restivo Luke , Moles Karl , Martinez Alexa , Filipeanu Catalin , Lazartigues Eric D
Published: October 2023

Angiotensin-converting enzyme 2 (ACE2) is a counter-regulatory player in the renin-angiotensin system (RAS). Downregulation of ACE2 in hypertension results in vasoconstriction, sympathetic over-activation, and hypertension. Recently, we identified UBR1, an E3 ubiquitin-protein ligase, as a potential ubiquitinase modulating ACE2 expression, notably in hypertensive male mice where UBR1 is upregulated in the hypothalamus and peripheral organs. Here, we aim to understand the role of UBR1 in hypertension and its crosstalk with Nedd4-2, another E3 ligase regulating ACE2. C57BI/6J male mice (3 month-old, n=18) were implanted with telemetry probes for weekly 24 h BP recording. One week following baseline BP recording, mice were implanted with subcutaneous osmotic pumps containing Ang-II (600 ng/kg/min). After confirming hypertension, mice were divided into 4 treatment groups (n=6/group); 1) peripheral UBR1 siRNA via osmotic pump (50 μg/day/2 weeks), 2) central UBR1 siRNA via intracerebroventricular infusion (ICV) (50 μg/day/2 weeks) 3) scrambled shRNA + Ang-II, and 4) no treatment. After 6 weeks of BP recording, mice were euthanized, and hypothalami were harvested for protein analysis (Capillary Western). BP was transiently reduced during the resting phase after 3 weeks of ICV UBR1 siRNA infusion compared to the Ang-II group (MAP: 114±7
vs
. 135±3 mmHg). Ang-II infusion enhanced UBR1 protein levels versus no treatment (Fold Change:1.6±0.1
vs
. 1.0±0.04; p<0.05) which was prevented by peripheral and central UBR1 siRNA infusion, respectively (0.7±0.08, 1.3±0.08
vs.
1.6±0.1, p<0.05). Interestingly, while UBR1 siRNA infusion increased ACE2 expression (1.7±0.1, 2±0.2, p<0.01, respectively), it was also associated with increased Nedd4-2 levels ( 2.9±0.1, 3.5±0.2, p<0.0001, respectively), and pNedd4-2 (4.1±0.4, 3.8±0.5, p<0.001, respectively). Together, these data suggest that while prevention of UBR1 upregulation in hypertension is associated with an increase in ACE2 expression, it is not sufficient to permanently reduce BP as other E3 ligases, like Nedd4-2, appear to compensate for the knockdown.