bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P126: Exercise-Induced Changes in Skeletal Muscle of Patients with Chronic Kidney Disease on Maintenance Hemodialysis
Authors: Demirci Mert , Peng Dungeng , DeMatteo Anthony , Norman Jennifer , Begue Gwenaelle , Roshanravan Baback , Ikizler Alp , Gamboa Jorge
Published: October 2024

Background:
Chronic kidney disease (CKD) patients on maintenance hemodialysis (MHD) often experience sarcopenia and functional decline. The impact of exercise and inactivity on sarcopenia in CKD is poorly understood. We aimed to identify exercise-responsive genes that are differentially expressed between controls and patients on MHD. We also aim to investigate the changes in gene expression in skeletal muscle following a resistance exercise program in patients on MHD.

Methods:
In a cross-sectional study, we performed RNA sequencing analysis in skeletal muscle biopsies from two groups (matched for age, gender, body mass index, and history of diabetes): controls (n=13) and patients on maintenance hemodialysis (MHD, n=10). In a separate cohort, we conducted a 12-week intradialytic resistance training in seven patients on MHD. Skeletal muscle biopsies were collected pre- and post-intervention to assess the acute (before and after a single bout of exercise) and chronic (after 12 weeks) effects of exercise. Total RNA was extracted and used to construct libraries for RNA sequencing using the Illumina NovaSeq 6000 system. Differentially expressed genes (DEGs) were identified based on a false discovery rate (FDR) of less than 0.05 and a fold change greater than 1.5. Exercise and inactivity-responsive genes in non-CKD populations identified in the MetaMEx (www.metamex.eu) were used as reference.

Results:
We found significant DEGs between the control and MHD that were affected by exercise or inactivity according to MetaMEx. These genes and fold changes between control and MHD groups are depicted in Table 1. In the exercise intervention cohort, we observed no significant differences in the expression of these genes either acutely (Figure 1A) or 12 weeks after the exercise intervention (Figure 1B).

Conclusion:
We found many DEGs related to exercise and inactivity between patients on MHD and controls; however, resistance training does not significantly alter skeletal muscle gene expression. Future studies should explore alternative exercise interventions, such as HIIT exercise, aerobic training, combined aerobic and resistance training, or longer duration programs, to determine if these approaches can effectively modulate gene expression and improve sarcopenia and frailty in this population.
Abstract P141: Salt tips the balance of tryptophan metabolism between host and gut microbiota in a sex specific manner
Authors: Bardhan Pritam , Mei Xue , Mell Blair , Tummala Ramakumar , Aryal Sachin , Manandhar Ishan , Li Ying , Li Hongbao , Joe Bina , Yang Tao
Published: October 2024

Introduction:
Tryptophan (Trp) diet attenuates hypertension in male Dahl salt sensitive (S) rats with unknown mechanisms. Kynurenine (a vasodilator) and serotonin (mixed effects on blood pressure) are host-derived Trp metabolites while indole is produced exclusively by the gut microbiota. We have previously shown that the gut microbiota of male, but not female, S rats is susceptible to salt, causing a higher indole level that elevated blood pressure. In this study, we reported the sex differences in all Trp metabolites with a focus on the impact of salt and the mechanisms by which female gut microbiota is more resilient.

Methodology:
S rats of both sexes (10–13-week-old, n = 4-7/group) were maintained on either a low-salt (0.3 % NaCl, LS) or high-salt (2 % NaCl, HS) diet for 3 weeks. Trp metabolites were analyzed in serum and cecum by LC-MS/MS. To investigate if estrogen shape gut microbiota, gonadectomy was performed on 7-week-old Spontaneously Hypertensive Rats (SHR) of both sexes (n=5/group). β-estradiol (2.8 mg/kg) was administered subcutaneously for 12 weeks before fecal 16S rRNA gene sequencing.

Results:
Females had elevated levels of kynurenine (Kyn) compared to male S rats on both LS (5.5 ± 1.4 vs. 2.1 ± 0.5 µM;
P
<0.05) and HS (7 ± 1.3 vs. 4.2 ± 1 µM;
P
<0.05). Kyn metabolites including kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid were elevated in the serum of females compared with males, and HS amplified this difference (all
P
<0.05). Further, HS significantly decreased the serum serotonin levels in both sexes (
P
<0.01 in females,
P
<0.0001 in males). Intriguingly, HS increased cecal indole levels in male (
P
<0.05), but not in female rats. Microbiota analysis of gonadectomized (GDX) SHR rats revealed (1) Significant differences in β-diversity between intact vs. GDX rats (
P
<0.01), and between GDX male vs. female rats (
P
=0.01); (2) Estrogen supplementation eliminates the gut microbiota differences between GDX females and males (
P
=0.18).

Conclusion:
We demonstrated sex differences in Trp metabolism in response to high salt. Further, estrogen masked the microbial differences between GDX male and female SHR rats. In summary, salt led to an elevated Trp-Kyn metabolism in female host, and an enhanced Trp-indole metabolism in male gut microbiota, which could be due to the estrogen’s effect on shaping gut microbiota. Thus, the Trp metabolism in salt-sensitive hypertension is regulated in a sex-specific manner.
Abstract P149: Sex-Specific Blood Pressure Thresholds in Middle-Aged Adults: Results from the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Williams Katherine , Col Hannah , Larbi Fredrick , Zhang Mingyu , Turkson-Ocran Ruth-Alma , Ngo Long , Grams Morgan , Coresh Josef , Lutsey Pamela , Selvin Elizabeth , Wagenknecht Lynne , Windham B Gwen , Juraschek Stephen
Published: October 2024

Background:
Recent studies reported higher coronary heart disease (CHD) risk at lower blood pressure (BP) in females than males, implying a need for sex-specific hypertension (HTN) thresholds. Whether these observations apply to diagnosis thresholds and/or treatment targets remains unclear.

Objectives:
To determine whether CHD risk differs by BP levels between males and females according to HTN treatment status.

Methods:
The ARIC Study measured seated BP during Visit 1 (1987-1989), averaging the second and third of three measurements. HTN treatment was determined based on pill-bottle review. We excluded participants with a history of CHD, heart failure, or stroke. Incident CHD events were adjudicated. We examined 10-year CHD risk scores using the PREVENT risk estimator, CHD incidence rates (IR), and the hazard ratios (HR) of CHD events via the Pooled Estimating Equation, Poisson regression, and Cox proportional hazard models, controlling for CHD risk factors (
Table Footnote
).

Results:
Of 13,426 participants (56% female, mean age [54±5.7 years]), 25% were treated for HTN. Males in both groups had higher average 10-year CHD risk scores across SBP categories than females (
P
comparing trends <0.001) (
Table
). While IRs were lower among females in the untreated group, they did not differ significantly from males in treated participants (
P
comparing trends > 0.05). Notably, while similar in untreated populations, treated females may experience higher risk (HR) of incidence CHD events than treated males across all SBP categories.

Conclusion:
While there were differences in absolute and relative risk of CHD between males and females, we did not find consistent evidence that untreated males and females experience different risk of CHD risk by SBP threshold. These findings do not support a sex-specific threshold for hypertension diagnosis or treatment.
Abstract P160: Sex Differences in Age-Dependent Hypertension and Cognitive Impairment in Sprague-Dawley Rats
Authors: Nist Kayla , Wainford Richard
Published: October 2024

Objective:
We previously found that male (M), but not female (F), Sprague-Dawley (SD) rats develop age-dependent hypertension (HTN) that is associated with cognitive impairment. We hypothesized that ovariectomy (OVRX) at midlife, to model human menopause, would induce hypertension and cognitive impairment with age.

Methods:
In M and F SD rats at 3-, 8-, and 16-months-old (MO), blood pressure (MAP; mmHg) and sympathetic tone to the vasculature (iv hexamethonium, PeakΔMAP; mmHg) was measured via femoral artery cannulation. Recognition memory was assessed using the novel object recognition task. Blood brain barrier (BBB) integrity in the PVN was assessed as FITC extravasation following carotid artery cannulation. In a separate group of female rats at 8 MO, sham procedure, OVRX, or OVRX with estradiol replacement for 8-months (s.c. estradiol valerate, 1.5 mg extended-release pellet) was performed and rats were aged to 16MO. At 16MO, the previously described procedures were carried out.

Results:
M, but not F, SD rats develop age-dependent HTN and increased sympathoexcitation that is associated with recognition memory deficits and BBB disruption. Following OVRX, female rats develop age-dependent HTN that is associated with recognition memory deficits and BBB disruption. Replacement of estrogen with 17β-estradiol prevented the development of HTN, cognitive impairment, and BBB disruption.

Conclusions:
In males, HTN induces BBB disruption and is associated with cognitive impairment. Our studies suggest midlife loss of estrogen likely contributes to the development of age-dependent HTN and cognitive impairment in females. We speculate estrogen supplementation may mitigate HTN-related changes in memory with age.
Abstract P166: Genetic Ablation of the Bile Acid Receptor- Takeda G-protein Coupled Receptor 5 (TGR5) Promotes Weight Gain but Lowers Hypertension
Authors: Aryal Sachin , Tummala Ramakumar , Manandhar Ishan , Mell Blair , Kumariya Sanjana , Kondapalli Narendra , Bardhan Pritam , Saha Piu , Yeoh Beng San , Osman Islam , Thodeti Charles , Yang Tao , Vijay-Kumar Matam , Joe Bina
Published: October 2024

Introduction:
TGR5 belongs to G-protein coupled receptor family, that mediates bile acid signaling. Activation of TGR5 by bile acids triggers intestinal glucagon-like peptide-1 secretion, whereby pharmacological activation of TGR5 constitutes a promising incretin-based strategy for the treatment of metabolic disorders. Hypertension is one of the hallmark features of metabolic disorders. We previously reported that hypertension is associated with lower conjugated bile acids, which are ligands for TGR5. Therefore, we hypothesized that lack of activation of TGR5-mediated bile acid signaling promotes not only body weight gain, but also hypertension.

Methods:
CRISPR/Cas9 technology was used to generate

Tgr5
-/-

rats from hypertensive Dahl Salt-sensitive (S) rats. Twenty-four-hour blood pressure (BP) readings of 8-weeks-old control female

Tgr5
+/+

S rats and age-matched female

Tgr5
-/-

S rats (n=7/group) were monitored by radiotelemetry for 4 weeks. Body weight, food intake, and water intake were recorded every week. At the end of the study, vascular function was examined using wire myography of dorsal and mesenteric resistance arteries, cardiac function was assessed by echocardiography, and microbiota profiling was conducted via fecal 16S rRNA gene sequencing using Miseq.

Results:
In support of our hypothesis, despite no difference in food and water intake, at 4 weeks, the body weights of
Tgr5
-/-
S rats were significantly higher compared to

Tgr5
+/+

S rats (236.3gm vs. 225.4gm; p<0.01). Surprisingly, in contrast to our hypothesis, at 4 weeks,
Tgr5
-/-
S rats had significantly lower systolic BP (151.8mmHg vs. 156.9mmHg, p<0.0001), diastolic BP (107.9mmHg vs. 115.5mmHg, p<0.0001), and mean arterial BP (128.8mmHg vs. 134.9mmHg, p<0.0001) compared to

Tgr5
+/+

S rats. However, no significant differences were observed either in vascular reactivity or cardiac function between the groups. Interestingly, fecal microbiota analysis revealed that
Tgr5
-/-
S rats presented with significant remodeling of gut microbiota with lower α-diversity (observed features; p=0.05), b-diversity (Bray-Curtis; p<0.05, Jaccard; p<0.01), and higher relative abundance of the BP-lowering genera
Akkermansia
.

Conclusion:
Our study revealed that deletion of TGR5 resulted in weight gain but lowered BP. It implies that activation of TGR5 may be a risk factor for raising BP. The mechanism by which TGR5 regulates BP seem independent of changes in vascular or cardiac function but is likely mediated by gut microbiota.
Abstract P174: The endogenous circadian system modulates blood pressure reduction after an aerobic exercise session in healthy adults
Authors: Brito Leandro , Jones Megan , Chaudhary Nicole , Giraud George , Shea Steven , Thosar Saurabh
Published: October 2024

Objective:
To determine the role of the circadian system on blood pressure (BP) reduction promoted by exercise.

Methods:
Nine (4 male/5 female) healthy adults (aged 23±2 y) completed a 30-hour circadian protocol in a dim light laboratory (<8 lux), where all behaviors and measurements were evenly distributed across the 24-hour cycle. Participants underwent five recurring 6-hour day-cycles of 2-hour sleep opportunities and 4-hour standardized wake episodes. Systolic, diastolic, and mean BPs, cardiac output (CO), and stroke volume were derived from beat-to-beat BP waveform (plethysmography). Heart rate (HR) was determined from an electrocardiogram (ECG), and systemic vascular resistance (SVR) was calculated (SVR = Mean BP/CO). Data were recorded for 10 minutes in supine at rest, before and after 30 minutes of moderate aerobic exercise (cycle ergometer, 30 min, 40% HR reserve). Circadian phases were calculated based on individual dim-light melatonin onsets. Mixed-model cosinor analyses tested if changes between before and postexercise had systematic rhythmicity with an underlying sinusoidal profile.

Results:
Systolic and mean BP change had a circadian rhythm (p<0.05) with the greatest decrease (-12 and -9 mmHg) at ~1pm and an amplitude of 11 and 8 mmHg, respectively, from its blunted response at ~1am. SVR change had a circadian rhythm with a greater decrease ~10am (see figure). No other variables displayed a circadian variation.

Conclusion:
In young healthy adults, the circadian system potentiates the hypotensive effect of exercise in the afternoon. However, the absence of this ability during the night may represent cardiovascular vulnerability in those who stay awake at that time (e.g., shift workers).
Abstract P177: High salt modulates Antigen Presenting Cell TNF-alpha production in an Isolevuglandin-dependent manner in Hypertensive Humans
Authors: Afolabi Jeremiah , Ertuglu Lale , Mutchler Ashley , Demirci Mert , Ahmad Taseer , Saleem Mohammad , Sheng Quanhu , Kirabo Annet
Published: October 2024

Salt intake is a predisposing factor to high blood pressure in people with salt sensitivity, but the mechanisms are not fully understood. Previously, we found that the epithelial sodium channel facilitates sodium entry into antigen-presenting cells (APCs), leading to the production of Isolevuglandins (IsoLGs) and hypertension via proinflammatory cytokines. TNF-alpha is a major proinflammatory cytokine that is produced in response to oxidative stress. We hypothesize that high salt intake-associated increased production of IsoLGs activates TNF-alpha-dependent mechanisms to contribute to salt-sensitive hypertension. To test this hypothesis, we conducted bulk RNA sequencing on isolated human monocytes with and without high salt. We also performed in vivo studies on humans living with hypertension using the rigorous Weinberger salt loading and depletion protocol at baseline (B), salt loading (SL), and salt depletion (SD) timepoints. We found that in vitro high salt treatment increased human monocyte expression of TNF-α, TNFRSF1A and TNFRSF1B (117.09 ± 23.71 vs 357.82 ± 59.62, p=0.001; 4560 ± 430.02 vs 6189 ± 461.11, p=0.0014 and 43824.73 ± 6462.55 vs 54585.64 ± 5383.58, p=0.0336 respectively, [n=11]) when compared to normal salt. In vivo studies on 16 hypertensive subjects reveal mean blood pressures as baseline (SBP: 137.7 ± 3.1, DBP: 85±2.2, MAP 104.7±2.1 [mmHg]), salt-loading (SBP: 141.3 ± 2.9, DBP: 86.1±2.3, MAP 105.6±2.2 [mmHg]), and salt-depletion (SBP: 138.7 ± 2.9, DBP: 87±2.4, MAP 104.7±2.1 [mmHg]). Using flow cytometry, we determined the buildup of Isolevuglandin adducts in APCs as follows: B: 57.6±6.4, SL: 59.8±4.6, SD: 46.0±7.1 (dendritic cells); B: 78.6±5.8, SL: 77.3±5.7, SD: 61.0±6.9 (CD14
+
cells); B: 83.2±4.9, SL: 74.0±6.4, SD: 63.3±8.2 (CD14
+
16
+
cells) and B: 63.3± 5.7, SL: 54.2±6.1, SD: 46.8±7.9 (CD16+ cells). In response to salt loading, patient plasma levels of TNF-α were B: 13.8±0.5 pg/mL, SL: 14.1±0.6 pg/mL, and SD: 15.3±1.2 pg/mL respectively. Finally, in vivo single-cell transcriptomic analysis in peripheral blood mononuclear cells revealed that in response to high salt treatment, TNF expression changes dynamically with blood pressure in salt-sensitive, but not salt-resistant patients. These preliminary findings suggest that TNF-α plays a role in salt-sensitive hypertension, possibly following IsoLG-driven reactive oxygen species generation. Further studies are needed to delineate specific dependent mechanisms by which this occurs.
Abstract P187: Obesity predicts left ventricular mass in youth undergoing ambulatory blood pressure monitoring
Authors: Murphy Maggie , Schadler Aric , Huang Hong , Valdez Lucrecia , Kiessling Stefan , Chishti Aftab , Clark Sarah E , Alsiraj Yasir , Shoemaker Robin , Clasey Jody , Collins Ronnie , Bauer John
Published: October 2024

Background:
Left ventricular hypertrophy (LVH) is a risk factor for cardiovascular disease in adults. In youth, elevated blood pressure (BP) is associated with LVH, but independent effects of adiposity and hypertension on LVH are not well defined. The purpose of our study was to investigate relationships among LVH, LV mass, BMI, and other clinical parameters in pediatric patients referred for elevated BP. We hypothesized both BP and BMI to be associated with LV mass.

Methods:
We conducted an IRB-approved retrospective chart review of all patients ages 6-18 years who underwent 24-hour ambulatory BP monitoring via the pediatric nephrology clinic at Kentucky Children’s Hospital from August 2012-December 2023 (excluding those with secondary HTN). Obesity was defined by BMI and weight-for-length percentiles according to CDC guidelines. LV mass was assessed by standard echocardiography. We compared LVMI and BP measures among groups stratified by obesity stage. Associations among BP, obesity, and LVMI were determined using descriptive statistics, correlational analyses, and multivariable logistic modeling using a backwards elimination variables selection criteria with α=0.05.

Results:
Of the 520 patients, 66% (n=342) were male, 76% (n=395) were obese, and 46% (n=238) had LVH. LVMI was strongly correlated with 24-hr systolic BP, however there was no difference in mean LVMI across BP severity category. In contrast, there was a near stepwise increase in LVMI across obesity stage with the strongest effect in girls – Normal: 29.7 ± 5.3 (girls) v. 34.8 ± 11.4 (boys) g/m
2.7
; OB-1: 36.5 ± 6.6 (girls) v. 43.2 ± 10.3 (boys) g/m
2.7
; OB-2: 41 ± 11.6 (girls) v. 44.2 ± 9.2 (boys) g/m
2.7
; OB 3: 48 ± 11.6 (girls) v. 43.5 ± 9.4 (boys) g/m
2.7
. LVMI was positively correlated with TSH, creatinine, uric acid, cystatin, and inversely correlated with HDL. Multivariable logistic modeling revealed obesity stage and HDL cholesterol, but not BP or laboratory variables, as significant independent predictors of LVH.

Conclusions:
We report a high incidence of LVH in youth with obesity and demonstrate a strong association between obesity and LVMI. Our data, in agreement with previous studies, indicate that adiposity is a significant determinant of left ventricular mass, and suggest the need for cardiac screening of youth with obesity even in the absence of elevated blood pressure.
Abstract P198: Computational analysis of the proteome in circulating extracellular vesicles reveals hypertension induces diabetic cardiomyopathy signaling pathway.
Authors: Tarhriz Vahideh , Eivazi Morteza , Xia Huijing , Lazartigues Eric
Published: October 2024

Alterations in the composition of extracellular vesicles (EV) offer promising insights into identifying critical molecules as potential biomarkers for early diagnostic or novel therapeutic targets in the treatment of hypertension. In this study, we investigated the protein composition of circulating EV from DOCA+Salt hypertensive mice (fold change <0.71 or >2.3; P<0.05). Additionally, Ingenuity Pathway Analysis highlighted 257 altered pathways in male mice, with only 17 pathways specific to this sex. Among the 235 independent proteins identified, 132 demonstrated differential expression in hypertensive males in comparison to hypertensive female mice. Additionally, 72 proteins were exclusively detected in hypertensive male mice, and 4 were common across the 6 major pathways associated with hypertension, notably Gnai2 which was uniquely expressed in hypertensive male mice. Diabetic cardiomyopathy emerged as one of the top ten signaling pathways based on the enrichment scores for each pathway. Furthermore, our findings suggest that the Renin-Angiotensin System is significantly overexpressed in males compared to females (q-values: 1.4E-05 vs. 5.0E-4). This was evidenced by the upregulation of Leucyl/cystinyl aminopeptidase (IRAP) and aminopeptidase N which are involved in Ang-IV formation and signaling, respectively. Among other differentially expressed proteins, cyclin B1 (CCNB1) was upregulated, consistent with previous studies showing an increase in CCNB1 in rats with pulmonary arterial hypertension and our recent findings showing a significant decrease in miR-410-3p in plasma samples of hypertensive mice, a miRNA known to target CCNB1. These results support a negative correlation between miR-410-3p and CCNB1 in hypertension. Conversely, we noted a significant decrease in laminin levels, which are known to regulate blood pressure by modulating the expression of contractile proteins. Surprisingly, while it was observed that the hypertrophic cardiomyopathy pathway was significantly elevated, this increase was more prominent in females than males. Together, the Ingenuity Pathway Analysis revealed enrichment in proteins associated with diabetic cardiomyopathy signaling, the complement system, and NADH-ubiquinone oxidoreductase in extracellular vesicles from hypertensive mice. Further exploration of these alterations may enhance our understanding of salt sensitive hypertension.
Abstract P202: Excess of anything is detrimental - unraveling role of multiple accessory renal arteries in Pickering syndrome.
Authors: Harris Liliia , Zahid Zaid , Bains Nimrat
Published: October 2024

Flash pulmonary edema (FPE) appears to be more common in patients with bilateral renal artery stenosis (RAS) as compared to those with unilateral disease. The combination of bilateral RAS and recurrent FEP has been named the Pickering syndrome. Here, we present a case of Pickering syndrome caused by unilateral RAS in combination with multiple accessory renal arteries (ARA). To our knowledge, this case marks the inaugural report within the literature.

A 68-year-old woman presented to ER with her third episode of FPE in two months, accompanied by hypertensive emergency, BP 232/127 mmHg.

Initial evaluation, including laboratory tests and RA ultrasound, showed no abnormalities. However, a CTA of the abdomen revealed a single heavily calcified L main RA with severe atherosclerosis extending into the lumen of the aorta and the proximal L main RA. Three RAs supply R kidney with questionable stenosis of superior, smaller R RA. Atherosclerotic plaque is present at the origin of the inferior R RA, but no definitive significant stenosis is detected.

Unilateral RAS and multiple ARAs were suspected to cause HTN and FPE. An aortogram with possible RA stenting was recommended by vascular surgery. It confirmed > 75% stenosis in the L RA, prompting stent deployment. However, no significant stenosis was observed in R ARAs.

Post-procedure BP control was achieved with a single agent.

FPE is a life-threatening syndrome. Cardiac systolic or diastolic dysfunctions usually accompany it. Recurrent FPE due to bilateral RAS was described by Pickering et al. in 1988. Although its exact mechanism is not completely understood, it is believed to result from excessive fluid volume due to decreased sodium excretion. A similar mechanism was proposed in RAS in a single functional kidney.

Could the presence of an ARA mimic the pathophysiology of RAS?

It has been theorized that an ARA may lead to HTN due to reduced blood flow to the kidney, caused by its longer and narrower caliber, which increases resistance and may lead to stenosis. The Poiseuille equation, rearranged to R=8μL/ΔPπR4 (where R=resistance, μ=viscosity, L=vessel's length, P=pressure, R=vessel's radius), suggests that both the radius and the length of ARAs may play a role in our patient's condition. In summary, ARAs are a common anatomical variation, and depending on their specific characteristics, they may contribute to resistant HTN and FPE through renin-dependent hyperaldosteronism.
Abstract P213: Mechanisms of Renin-Angiotensin System-Mediated Nitric Oxide Signaling in Podocytes
Authors: Semenikhina Marharyta , Bohovyk Ruslan , Stefanenko Mariia , Fedoriuk Mykhailo , Klemens Christine , Ilatovskaya Daria , Oates Jim , Staruschenko Alexander , Palygin Oleg
Published: October 2024

Introduction:
The renin-angiotensin system (RAS) is a crucial cardiovascular and renal function regulator. Podocytes, glomerular epithelial cells that play a pivotal role in maintaining the renal filtration barrier, are key targets for RAS peptides. Our findings showed that RAS can promote calcium (Ca
2+
) and nitric oxide (NO) signaling in podocytes. Moreover, a decrease in NO bioavailability directly correlates with glomerular filtration barrier damage, Ca
2+
overload, and the development of salt-sensitive hypertension. We hypothesized that RAS-mediated NO production is crucial for Ca
2+
control and cytoskeletal rearrangements in podocytes, contributing to glomerular filtration regulation.

Methods:
We performed live confocal imaging on human podocytes and freshly isolated rat glomeruli to detect the production of NO (DAF-FM) and Ca
2+
(Fluo-8). RAS peptides (Ang II, III, IV, 1-7, 1-9, and TRV120027) were used to stimulate cells, and NO and Ca
2+
production were measured. Blockers for Ang II Type 1 (AT1R), Ang II Type 2 (AT2R), and MAS receptors were used to identify the pathways involved in NO production. The dynamic changes in podocyte cytoskeleton mediated by RAS-NO intracellular signaling were detected using rhodamine-phalloidin staining and scanning ion microscopy. The NOS isoform-specific blockers were used to determine the source of NO in podocytes. ANOVA with post-hoc was used for comparisons.

Results:
Angiotensins II and III generate the most profound increases in NO levels in podocytes. Ang II, Ang III, and Ang 1-7 promote NO production by activating AT2R (n ≥ 20, p < 0.01). Interestingly, the increase in NO modulates AT1R- and β-arrestin-mediated Ca
2+
signaling (n ≥ 20, p < 0.05), suggesting the role of the NO/AT2R axis in Ca
2+
control in podocytes. NO production correlates with podocyte volume increase, and scanning ion microscopy experiments further confirmed that AT2R activation and corresponding NO elevation are responsible for the protrusion of podocyte's lamellipodia. Finally, we found that in podocytes, NOS1 is responsible for NO bioavailability, accounting for 69±5% of the total NO response, while the remaining NO levels are generated by NOS2 (39±5%).

Conclusion:
Our data show that RAS activation promotes NO production in podocytes, mainly via the AT2R pathway. NO is crucial for Ca
2+
control in podocytes and lamellipodia formation, suggesting the essential role of NO in glomerular filtration barrier function.
Abstract P215: The reninness score: integrative analysis of multi-omic data to define renin cell identity.
Authors: xue bingjie , Medrano Silvia , Smith Jason , Martini Alexandre , Sequeira Maria Luisa , Sheffield Nathan , Gomez Ariel
Published: October 2024

Renin cell
(RC)
descendants regain the endocrine renin phenotype to overcome homeostatic threats, a process known as recruitment. The determinants that control the identity, fate, and recruitment of RCs are not well understood.
We aim to 1) define the chromatin pattern that determines RC identity; and 2) develop a computational tool to score samples by similarity to that pattern.

We compared open chromatin regions (ATAC-seq) between non-renin-expressing (n = 184) and renin-expressing samples (n = 19) from three different sources and stimulation states: 1) primary RCs in basal state (WT); 2) primary RCs chronically stimulated to produce renin (Recruited); and 3) constitutively renin-expressing tumoral cells. Differential analyses between the three types of RCs and the non-RCs revealed 1,525 unique open chromatin regions shared in at least two RC groups, including regions associated with RC-specific genes:
Ren1
and
Akr1b7.
Increased accessibility regions in RC groups are cell type specific and enriched in renin-related GO terms (
e.g.,
cAMP and Notch signaling pathway). The bZip family (
e.g.
, Atf3, p < 10
-2147
) was the most enriched motifs in tumoral cells, and MEF2 family (
e.g.
, MEF2a, p < 10
-91
) in primary cells. We did not find a unique set of TFs specific to the Recruited group, indicating that renin recruitment may not be regulated by a recruitment-specific factor family, but could instead be driven by post-translational modification, differential co-factors, or epigenetic modifications.

Next, we used a machine-learning approach to calculate a "reninness" score by training a genomic region model with renin and non-renin bulkATAC-seq data. We identified a cluster of regions (n = 112,992) around the trained renin label, which included 89% (21,820 of 24,612) of the regions with increased accessibility from the differential analyses. We calculated the reninness score based on the distance between the trained label and the predicted bulkATA sample embeddings using the trained model. Homogeneous WT RCs had the highest score, followed by renin-expressing tumoral and primary cells. Non-RCs had the lowest scores. We also adapted bulkATAC region-embedding models to pseudo-bulk ATAC- and scATAC-seq data. The observed reninness scores show that the model can also capture differences in renin recruitment potential.

In conclusion, we identified the chromatin configurations defining the identity and recruitment of RCs and developed a computational score to quantify it.
Abstract P220: Abdominal Aortic Perivascular Adipose Tissue Lipolysis Is Activated In Hypertensive Dahl SS Rats Fed a High-Fat Diet
Authors: Chirivi Miguel , Rendon Javier , Lauver Adam , Fink Gregory , Watts Stephanie , Contreras Andres
Published: October 2024

Perivascular adipose tissues (PVAT) possess anti-contractile functions that are lost during hypertension (HTN). PVAT stores fatty acids (FA) and releases them through lipolysis upon adrenergic or inflammatory stimuli. Visceral AT lipolysis in humans with high abdominal adiposity and hypertension elevates FA release, promoting HTN via lipotoxicity and increased oxylipin synthesis. We hypothesize that lipolytic activity in abdominal aortic PVAT (aaPVAT) is increased during HTN. Plasma and aaPVAT were harvested from Dahl SS rats fed a high-fat (HF) or a control (CON) diet for 8 (♂=20, ♀=20), 16 (♂=10, ♀=10) and 24 (♂=14, ♀=14) wks. Mean arterial pressure (MAP±SEM; mmHg) was measured with sphyngomanometry. Free FA (FFA), β-hydroxybutyrate (BHB), glucose, and triglycerides were quantified with the CataChemWell-T analyzer, and individual FA using HPLC–MS/MS (reported as ng/dL). Adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and phosphorylated pHSL(Ser563) were quantified in the Abby Western Blot. HF increased MAP compared to CON by 8 (131.5 vs 119.51±2.52), 16 (139.34 vs 118.26±5.7), and 24 wks (168.56 vs 121.94±3.93). HF at 24 wks had higher MAP compared to 8 and 16 wks. HF increased FFA and BHB at all time points and glucose at 24 wks. Plasma triglycerides were increased in HF vs. CON, and ♂ had higher levels than ♀ at all time points. ATGL, basal lipolysis rate-limiting enzyme, increased in aaPVAT from HF ♂ by 2.2, 2.53, and 1.82-fold at 8, 16, and 24 wks, respectively, compared to CON. In HF ♀, ATGL increased (1.95-fold change) at 16 wks vs. 8 wks. HSL content increased in HF vs. CON at 16 wks (2.1-fold change) but not at 24 wks. In contrast, pHSL abundance and the pHSL:HSL ratio were not affected by diet at 16 wks; however, both were reduced by 35.2% at 24 wks in HF ♂ and ♀. Lipolytic activity in HF coincided with higher plasma arachidonic (AA) and linoleic acid (LA) at 8 (AA HF=19.93, CON= 16.13±1.3; LA HF=29.22, CON=21.74±2.7) and 16 wks (AA HF=14.83, CON=11.61±1.34; LA HF=22.84, CON=11.66±2.9). Sex had no effect on AA or LA concentrations. Our results provide evidence that hypertensive Dahl SS rats fed HF exhibit higher aaPVAT basal lipolysis that may be driven by ATGL. In contrast, demand lipolysis, controlled by HSL activity, is reduced. Dysregulated basal lipolysis may lead to alterations in PVAT FA trafficking, enhance AA availability, and promote the biosynthesis of inflammatory oxylipins, thus impairing its vasoactive functions.
Abstract P301: A Meta-Analysis of Randomized Controlled Trials: Aldosterone Synthase Inhibitors as a Therapeutic Strategy for Hypertension
Authors: Marzano Luigi , Merlo Matteo , Pizzolo Francesca , Friso Simonetta
Published: October 2024

Introduction:
Hypertension is a widespread health concern globally, often associated with excessive aldosterone production. Aldosterone synthase inhibitors (ASIs) have been proposed as potential therapeutic agents. Yet, their effectiveness and safety in managing blood pressure in hypertensive adults are not definitively established. This study aims to elucidate this matter through a comprehensive systematic review and meta-analysis of Randomized Controlled Trials (RCTs).

Hypothesis:
We hypothesize that ASIs could be a safe and effective strategy for managing blood pressure in adults diagnosed with hypertension.

Methods:
A systematic review and meta-analysis of seven RCTs were conducted to assess the impact of ASIs versus placebo in hypertensive patients. The studies were systematically sourced from MEDLINE and EMBASE until March 30
th
, 2024. Continuous outcomes were pooled using the mean difference (MD), and dichotomous outcomes were pooled using the risk ratio (RR), both with their respective confidence intervals (CI).

Results:
Our meta-analysis incorporated data from seven randomized studies, averaging 7.7 ± 2.4 weeks in duration, and involving a total of 1440 patients. Compared to placebo, ASIs showed effectiveness in controlling systolic blood pressure (MD: -6.12 mm Hg; 95% CI [−4.32, −7.92];
p
< 0.0001;
I
2 = 0%) and diastolic blood pressure (MD: −2.71; 95% CI [−1.07, −4.36];
p
= 0.001;
I
2 = 0%). Notably, the incidence of adverse events did not significantly differ from that observed with placebo (RR: 1.11; 95% CI 0.95 to 1.29;
p
= 0.18;
I
2 = 0%).

Conclusions:
Our findings suggest that ASIs could be a safe and effective approach for managing blood pressure in hypertensive adults, with no significant difference in the incidence of adverse events compared to placebo. These results advocate for further investigation of ASIs in larger, long-term trials to confirm their safety and efficacy, and to explore any additional therapeutic benefits over mineralocorticoid receptor antagonists. Future research should also thoroughly examine the potential benefits of these inhibitors in diverse patient populations, including those with obesity-associated hypertension and suppressed plasma renin activity.
Abstract P309: Vasodilating Effects of Macrolides: ex vivo and in vivo study
Authors: Byiringiro Clement , Briones Ana , Garcia Ana , Caroccia Brasilina , Seccia Teresa , ROSSI Gian Paolo
Published: October 2024

Background:
Anecdotal reports showed a decrease in blood pressure (BP) values in subjects assuming macrolide antibiotics when co-administered with calcium channel blockers. Recently, in the MAPA study, in patients with primary hypertension given a single dose of macrolide a decrease in BP was observed. However, whether macrolides induce
per se
vasorelaxation remains unknown.

Aim: To investigate if macrolides induce vasorelaxation and to identify the underlying mechanisms.

Methods:
The effects of 3 macrolides (roxithromycin, azithromycin, clarithromycin) were investigated in a wire myograph in aortas isolated from C57BL/6J mice, following standard protocols. Relaxation/contraction was evaluated in phenylephrine pre-contracted aorta segments exposed to different macrolide concentrations [10
-10
M to 10
-5
M]. Longer-term effects of azithromycin (50 mg/Kg/d intraperitoneally for 14 days) were investigated in vivo in a mouse model of Ang II-induced hypertension. BP was measured with the tail-cuff method; functional and structural/mechanical properties of the aorta and mesenteric arteries were evaluated with wire or pressure myograph, as appropriate.

Results:
After exposure to macrolides, phenylephrine pre-contracted mice aorta segments showed relaxation (maximum effect: -15-20% vs DMSO). The vasodilating effect was abolished by the removal of the endothelium, and was blunted by L-NAME. In the vivo studies treatment with azithromycin lowered BP values and prevented Ang II-induced endothelial dysfunction.

Conclusions:
Macrolides exert a vasodilatory action that involves endothelium-dependent NO release. In a model of Ang II-mediated hypertension, azithromycin exerted a BP-lowering effect.
Abstract P311: Revisiting unattended vs attended automated office blood pressure measurements: A systematic review and meta-analysis
Authors: Deragon Valerie , Baati Youssef , Trudelle Laurence , Merabtine Amel , Picone Dean , Goupil Remi
Published: October 2024

Background:
Standardized automated office blood pressure (AOBP) measurement is now widely accepted as the preferred method for monitoring blood pressure (BP). However, disagreements persist amongst expert societies as to the need to perform AOBP in an unattended manner, where the patient is left alone in a quiet room. In 2019, two meta-analyses aiming to quantify the differences between unattended and attended BP showed opposite results. prompting the publication of several more studies on this subject. Our objective was thus to reassess the BP differences between unattended and attended AOBP when performed with the same device and an identical measurement protocol.

Methods:
This systematic review with meta-analysis was conducted according to the PRISMA guidelines and is registered on PROSPERO. Studies were included if both unattended and attended AOBP were measured on the same participants in a randomized or alternating sequence manner during a single visit with the same device and an identical measurement protocol apart from attendance status. Four databases were searched (Embase, Medline, Web of Science, Google Scholar). The primary outcome was the difference between unattended and attended systolic (SBP) and diastolic (DBP) BP, expressed as weighted mean differences (95% confidence interval) using random-effects models.

Results:
From 8,088 screened studies, data was extracted from 15 studies which met the inclusion criteria (n=1,747 participants). In the pooled analysis, the attended compared with unattended BP was higher for SBP by 2.7 mmHg (95%CI 0.6 to 4.7) and DBP by 0.9 mmHg (95%CI 0.1 to 1.8). In leave-one out analyses, results were similar except when excluding the study with the most extreme BP difference (Chotruangnapa 2023) where the difference became non-significant.

Conclusion:
Standardized attended AOBP measurements result in slightly higher readings than unattended AOBP. Whether such small differences translate into clinically significant changes in management of BP remains uncertain. Therefore, standardized attended AOBP could be viewed as a reasonable option for BP measurement in a real-life clinical setting.
Abstract P316: Beyond the Cuff: Revolutionizing Hypertension Care through Human-Centered Design and Tech-Driven Solutions in an Urban Community Health Center
Authors: Khan Aisha , McAuliff Kathleen , Govindarajan Geetha
Published: October 2024

Community Health Centers serve populations burdened with cardiovascular disease due to social determinants of health, necessitating innovative solutions in resource-limited environments. Wi-Fi/Bluetooth-enabled home blood pressure monitors have emerged as clinical tools for diagnosing, monitoring, and managing hypertension. The real time data enables timely interventions by care teams of patients being monitored. A multifaceted approach beyond clinic settings, supported by digital tools, can help reduce healthcare costs by preventing avoidable emergency room visits.

We posited that implementing a self-monitored blood pressure (SMBP) program, supplemented by holistic, human-centered patient coaching and feedback, in a community health center setting would enhance patient engagement, medication adherence, and hypertension control.

We designed and piloted a small SMBP program using Bluetooth-enabled blood pressure devices, targeting adult patients with documented uncontrolled blood pressure seen in our health centers in a 6- month window. This was further augmented by a holistic, human-centered individual and group-level coaching session. Patients enrolled in the SMBP program received comprehensive education on hypertension, including medication management and lifestyle changes, as well as data-driven feedback on their blood pressure profiles during virtual group and individual outreach sessions. The program's goals were to increase patient engagement in their care, adherence to interventions, leading to better blood pressure control.

Results were significant: 22 of 32 participants graduated, achieving improved blood pressure control with medication and lifestyle changes. Average reductions of 17 mmHg in systolic and 6 mmHg in diastolic blood pressure were noted after being in the program for an average of three months. Among the graduates, 50% required medication intensification, and 60% adopted lifestyle changes, indicating the program's effectiveness.

Our pilot affirmed the efficacy of utilizing digital solutions and integrated strategies to improve hypertension control and empower patients to make timely changes with data feedback. The key findings from our pilot led to the expansion of the SMBP program to serve a larger cohort of patients in our clinic. This underscores the critical role of patient engagement, technology integration, and an integrated approach to care in improving hypertension management, particularly in underserved communities.
Abstract P322: Assessing the causal associations of obstructive sleep apnea syndrome and hypertension: a bidirectional two-sample Mendelian randomization study
Authors: Tao Jing
Published: October 2024

Background:
Obstructive sleep apnea syndrome (OSA) frequently coexists with hypertension, with 30% to 70% of OSA patients also having hypertension. Conversely, the incidence of OSA in hypertensive patients ranges from 30% to 50%. This study designs a bidirectional Mendelian randomization trial to explore the causal relationship between OSA and hypertension.

Methods:
The summary data for OSA were sourced from a recent large-scale genome-wide association study (GWAS) meta-analysis, which included 16,761 OSA patients and 201,194 European-ancestry controls from the Finnish biobank. Five SNPs were selected as instrumental variables (IVs) for OSA. The summary data for hypertension were obtained from the UK Biobank GWAS, which included 124,227 hypertension patients and 337,653 European-ancestry controls, making it the largest hypertension dataset in GWAS. From this dataset, 214 SNPs were selected as IVs for hypertension. Multiple MR methods, primarily the inverse variance weighted (IVW) method, were used for analysis. Sensitivity analyses of the MR results were performed using methods such as MR-Egger, and the F-statistic was used to evaluate the IVs.

Results:
OSA was associated with an increased risk of hypertension (OR=1.053, 95%CI 1.019-1.089, P<0.01), and hypertension was significantly associated with an increased risk of OSA (OR=1.812, 95%CI 1.354-2.425, P<0.001). There was heterogeneity in the bidirectional results (OSA → hypertension, P<0.001; hypertension → OSA, P<0.001), but no horizontal pleiotropy (OSA → hypertension, P=0.666; hypertension → OSA, P=0.556). The selected IVs for OSA and hypertension were strong (OSA-IVs F=14.695; hypertension-IVs F=39.624).

Conclusion:
This bidirectional MR analysis confirms the causal relationship between OSA and hypertension, with hypertension having a more pronounced effect on the incidence of OSA. OSA patients should regularly monitor their blood pressure and undergo routine physical examinations to detect hypertension early.
Abstract P324: Masked Hypertension Mimicking Migraine: A Case Report with Diagnostic Odyssey
Authors: Chitrala Sruthi , Mantripragada Nishanth , Suvvari Tarun Kumar , Tummala Nayanika , Menda Jaideep , Akthar Ahmed Aasim
Published: October 2024

Introduction:
Masked hypertension (MH) involves normal office blood pressure but elevated readings outside clinical settings, increasing cardiovascular and neurological risks. About 10-30% of the population may have MH, often undiagnosed. This case highlights the importance of considering MH.

Case Presentation:
A 42-year-old woman had recurrent headaches for six months: bilateral, pulsating pain in the temples, with dizziness and occasional vomiting, lasting 2-4 hours, worsening after work. Diagnosed with migraines and treated with sumatriptan without relief. Medical history included a caesarean section; otherwise, she was healthy.

Physical exam showed normal vital signs, including blood pressure at 130/80 mmHg. Neurological and ophthalmological evaluations were normal. Lab investigations were unremarkable. The patient had a normal BMI of 21.3. Further workup, including ECG, MRI, CT scan, and neck radiography, all normal.

Ambulatory blood pressure monitoring (ABPM) revealed elevated blood pressure during evening hours (post work), starting around 4 pm and rising until 8-9 pm. Thereafter, blood pressure normalized to 110-130 mmHg systolic and 70-80 mmHg diastolic.

To rule out nephrogenic hypertension, an ultrasound of the kidneys, renal function tests, urinalysis, and plasma metanephrine tests were negative. Following the exclusion of other causes, a diagnosis of MH was established. The patient started on Telmisartan 20 mg daily, with lifestyle modifications. Follow-up ABPM showed normalized blood pressure, and the patient reported no further headaches.

Discussion:
MH affects many but often remains undiagnosed due to normal clinic readings. Ambulatory or home blood pressure monitoring is essential for diagnosis. Timely diagnosis of MH is crucial, given its association with heightened risks of stroke and cardiovascular disease. Studies have revealed significantly elevated left ventricular mass index, maximal intima-media thickness, and urinary albumin levels. Consequences include left ventricular hypertrophy, carotid atherosclerosis, and albuminuria.

Conclusion:
Early recognition and management of MH are vital for preventing complications. Diagnosis can be achieved by home blood pressure monitoring (HBPM) or 24-hour ambulatory blood pressure. This case stresses considering MH in patients with normal office readings but persistent symptoms, advocating for regular monitoring and patient education for optimal health outcomes.