bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 13: Vascular Chemerin, Particularly from PVAT, contributes to Norepinephrine and Serotonin-Induced Vasoconstriction and Vascular Stiffness in a Sex-Dependent Manner
Authors: Wabel Emma , Krieger-Burke Teresa , Watts Stephanie
Published: October 2024

The adipokine chemerin has been implicated in healthy blood pressure maintenance and adiposity-associated hypertension, evidenced by falls in mean arterial pressure after administration of an antisense oligonucleotide against chemerin in Dahl SS rats. Circulating levels of chemerin are positively associated, in humans, with hypertension and aortic stiffening—a blood pressure-independent risk factor of cardiovascular disease. While chemerin’s role in blood pressure is observed in whole animals, mechanisms of chemerin’s influence on vascular health and disease remain unknown. Chemerin causes direct vasoconstriction through its main receptor Chemerin1 and indirect vasoconstriction by amplifying electrical field stimulation-induced contraction. We identified chemerin production at the vasculature—the blood vessel and its perivascular adipose tissue (PVAT)—and are working to discover the mechanistic role of vascular chemerin in blood vessel function and disease. Using RNAScope®, QPCR, isometric contractility, western blot, and
in vivo
imaging, we test the hypothesis that vascular chemerin increases arterial contractility through Chemerin1 and plays a role in aortic stiffening. RNAScope® probes detected
CMKLR1
expression in the tunica media and PVAT of the thoracic aorta. QPCR revealed
Rarres2
expression was higher in the PVAT, and
CMKLR1
expression was higher in the media. Chemerin1 antagonism via the selective inhibitor CCX832 (1μM) significantly reduced maximal contraction to both norepinephrine (NE) and serotonin (5-HT) (see figure), but not angiotensin II, in the male rat +PVAT groups. This supports that PVAT-derived chemerin plays a role in sympathetic stimulation of the vasculature. Interestingly, in females, this change in contractile response to NE and 5-HT was not observed. Western blot showed that females express significantly lower levels of chemerin protein in PVAT, suggesting PVAT as the primary source of active chemerin. Finally, male, but not female, genetic chemerin knockout Dahl SS rats have lower aortic arch pulse wave velocity than wild types (M WT: 3.7 ± .7 M KO: 1.4 ± .3 F WT: 2.6 ± .5, F KO: 1.5 ± .3 m/s, N=4-6/group), highlighting a role of chemerin in aortic stiffening. Thus, chemerin, sourced by the PVAT, plays a significant role in vascular contractility and aortic stiffening in males. Future work will determine if chemerin’s influence is amplified in adiposity-associated hypertension, where chemerin levels are elevated in both sexes.
Abstract 24: Effects Of Intensive Blood Pressure Lowering on Brain Tissue Pulsatility in Hypertensive Patients
Authors: Vongpatanasin Wanpen , Giacona John , Murillo Ashley , Bates Brooke , Pittman Danielle , Tomlinson Anna , Zhang Song , Zhang Rong , Zhu David
Published: October 2024

Recent studies have shown an association between blood pressure (BP), particularly pulse pressure (PP), in increasing brain tissue pulsatility. However, these studies were conducted in a phantom model or in healthy normotensive adults. Effects of intensive BP lowering on brain tissue pulsatility in hypertensive patients remain unknown. Accordingly, we performed a randomized clinical trial to compare effects of intensive BP lowering to target 24-h ambulatory BP <120/70 mmHg (n=26) vs. target of <130/80 mmHg in the control arm (n =19) in hypertensive patients aged 55-79 with normal cognitive function. The brain tissue pulsatility was assessed by the total tissue motion over one cardiac cycle, using CINE phase contrast MRI, with the velocity encoded in all three directions. In each cardiac cycle, the velocity of the tissue was measured at 16 time points. Brain tissue pulsatility was assessed at baseline and after 1 year of follow up. We found that 24-h ambulatory systolic BP (SBP) was reduced from 134.3±9.8 to 112.1±7.2 mmHg in the intensive arm and from 138.5±11.3 to 122.4±7.8 mmHg in the control arm (both p<0.01). The magnitude of 24-h SBP reduction from baseline was greater in the intensive arm than control arm (23.6 vs. 13.1 mmHg, p=0.052) while 24-h diastolic BP was reduced similarly in both groups (11.6 vs. 9.6 mmHg, p=0.8). Similarly, PP based on 24-h BP was reduced from 57.5±11.7 to 45.1±12.1 mmHg in the intensive BP arm and from 62.2±10.6 to 55.4±10.5 mmHg in the control arm (both p<0.01). The magnitude of PP reduction appeared greater in the intensive compared to control arm but was not statistically different (12.4 vs. 6.8 mmHg, p=0.08). We found that the overall gray-white matter tissue pulsatility per cardiac cycle remained unchanged after 12 months in the intensive arm (0.98±0.18 mm to 0.95±0.17 mm) while the brain pulsatility tended to increase in the control arm (0.85±0.17 mm to 0.92±0.16 mm, p=0.09 for treatment group, interaction-p=0.04). Similarly, the white matter (WM) tissue motion remained unchanged in the intensive arm (0.91±0.16 mm to 0.88±0.15 mm) while the WM pulsatility tended to increase in the control arm (from 0.77±0.14 mm to 0.84±0.15 mm, p=0.06 for group, interaction p=0.03). In conclusion, our data suggested a novel effect of intensive BP lowering in preventing the rise in brain tissue pulsatility in hypertensive patients, which may have an implication in the prevention of an accelerated brain injury related to hypertension.
Abstract 28: A major effect of aprocitentan on albuminuria in patients with resistant hypertension
Authors: Schlaich Markus , Bakris George , Flack John , Gimona Alberto , Narkiewicz Krzysztof , Sassi-Sayadi Mouna , Wang Jiguang , Weber Michael
Published: October 2024

Background and Objectives:
Micro- and macroalbuminuria measured by urinary albumin-to-creatinine ratio (UACR) (30–300 mg/g and >300 mg/g, respectively), and high normal UACR (10–30 mg/g) are associated with higher risk of mortality, CV disease and CKD progression in patients with hypertension, diabetes, decreased renal function, or even the general population and reduction can lower these risks. The endothelin ETA/ETB receptor antagonist aprocitentan reduced albuminuria in patients with confirmed resistant hypertension (RHT). In the PRECISION trial, in addition to standard background therapy including valsartan, aprocitentan 12.5 mg reduced UACR by 30% compared to placebo (LS Geom Mean [95 CL] 0.70 [0.61, 0.80], p<0.0001) and 25 mg by 34% (0.66 [0.58,0.75], p<0.0001) at the end of double-blind part 1 (4 weeks) in the overall population. In this analysis, we evaluated the effect of aprocitentan on UACR at both doses according to the baseline (BL) albuminuria (30–300 mg/g and >300 mg/g).

Methods:
730 patients with RHT on a standardized fixed-dose combination of amlodipine/ valsartan/hydrochlorothiazide were randomized to aprocitentan (12.5 mg or 25 mg) or placebo. Of these, 174 and 90 had BL microalbuminuria or macroalbuminuria, respectively. Changes from BL in UACR and office systolic blood pressure measured at trough (SBP, the primary endpoint in PRECISION) after 4 weeks of double-blind treatment.

Results:
In subjects with microalbuminuria, aprocitentan reduced UACR by 43% in the 12.5 mg group (0.57 [0.42, 0.78], p=0.0005) and by 45% in the 25 mg group (0.55 [0.40,0.77], p=0.0004) compared to placebo. In subjects with macroalbuminuria, aprocitentan reduced UACR by 48% with 12.5 mg (0.52 [0.37, 0.75], p=0.0006) and by 61% with 25 mg (0.39 [0.27,0.57], p<0.0001) compared to placebo. In contrast, placebo did not have any noticeable effect on albuminuria in any group. The effect of aprocitentan in lowering blood pressure, measured at trough, was independent of the level of albuminuria at baseline.

After 4 weeks, 53.3% and 60% of patients achieved a decrease of ≥10 mmHg from baseline with 12.5 mg aprocitentan, respectively in the microalbuminuria and macroalbuminuria groups, compared to 64% with aprocitentan 25 mg (both cohorts) and 48% and 29% in the placebo group.

Conclusion:
Aprocitentan produced a major decrease of albuminuria regardless of baseline level in patients with RHT. These findings suggest substantial clinical benefit of aprocitentan in CKD patients.
Abstract 31: Deacetylation Mimetic Mutation of Mitochondrial Superoxide Dismutase Attenuates Angiotensin II-Induced Hypertension by Protecting Against Oxidative Stress
Authors: Dikalova Anna , Ao Mingfang , Tkachuk Liliya , Dikalov Sergey
Published: October 2024

Almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite the use of multiple drugs, likely due to mechanisms that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. Hypertension is associated with inactivation of key intrinsic mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to hyperacetylation but the role of specific SOD2 lysine residues has not been defined. Hypertension is associated with SOD2 acetylation at Lysine 68 (Circ Res. 2020;126(4):439-452) and we suggested that deacetylation mimetic mutation of K68 to Arginine in SOD2 inhibits vascular oxidative stress and attenuates hypertension. To test this hypothesis, we have developed a new deacetylation mimic SOD2-K68R mice. We performed
in vivo
studies in SOD2-K68R mice using angiotensin II (AngII) model of vascular dysfunction and hypertension. AngII infusion in wild-type mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. SOD2-K68R mutation completely prevented increase in mitochondrial superoxide, abrogated vascular oxidative stress, preserved endothelial nitric oxide production, protected vasorelaxation, and attenuated AngII-induced hypertension. AngII and cytokines contribute to vascular oxidative stress and hypertension. Treatment of wild-type aortas with AngII and cytokines in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. Interestingly, ex vivo treatment of aortas isolated from hypertensive mice with Sirtuin activator resveratrol reduces SOD2 acetylation, inhibits mitochondrial superoxide, and rescues endothelial nitric oxide. These data support the important role of SOD2-K68 acetylation in vascular oxidative stress and pathogenesis of hypertension. We conclude that strategies to reduce SOD2 acetylation may have therapeutic potential in the treatment of vascular dysfunction and hypertension.
Abstract 33: CD4+ T Cell-Induced Renal Damage and Salt-Sensitive Hypertension is Not Modified by CD8+ T Cells
Authors: Walton Samuel , Abais-Battad Justine , Dasinger John Henry , Burns-Ray Emily , Baldwin Kaitlyn , Shaw Mary , Mattson David
Published: October 2024

Salt-Sensitive (SS) hypertension and renal damage in the Dahl SS rat mirrors human disease with T cell infiltration in the kidney accompanying the development of SS hypertension and renal damage. Deletion of T cells on the Dahl SS genetic background (SS
CD247-/-
) attenuates hypertension and renal damage, and subsequent replacement of CD4+ T cells alone restores the disease phenotype while the transfer of only CD8+ T cells had no significant effect on the disease phenotype. The present study tested the hypothesis that CD4+ and CD8+ T cells will synergistically act to enhance salt-sensitive hypertension and renal damage in the Dahl SS compared to the injection of only CD4+ T cells. This hypothesis was tested by adoptive transferring purified CD4+ T cells from Dahl SS (~5 million, CD4+ SS→), a combination of ~5 million CD4+ T cells with ~5 million CD8+ T cells from Dahl SS (CD4+CD8+ SS→) or PBS vehicle (PBS→) into the SS
CD247-/-
rat on postnatal day 5. Animals were instrumented with radiotelemeters at 8 weeks of age. After a week of recovery, baseline measurements of blood pressure and albumin excretion were obtained while rats were fed a low salt (LS, 0.4% NaCl) diet. Rats were then switched to a high salt (HS, 4.0% NaCl) diet for 21 days, with continuous blood pressure measurements and urine collections every 7 days. On day 21, the rats were euthanized, and their kidneys were perfused and collected for immune cell analysis by flow cytometry. During the LS baseline period there was no significant difference observed in mean arterial pressure (MAP) between the CD4+ SS→, CD4+CD8+ SS→, or PBS→ groups (121±2, 122±2, 119±1 mmHg; n=9, 10, 6, respectively). After three weeks of HS, both CD4+ SS→ and CD4+CD8+ SS→ rats demonstrated an equivalent amplification of SS hypertension (176±6 and 179±5 mmHg) and albuminuria (261±53 and 285±37 mg/day, respectively) which was significantly greater than the MAP (159±5 mmHg) and albuminuria (169±29 mg/day) in PBS→. Finally, a flow cytometric analysis at the end of the experiment confirmed the absence of CD3+ T cells in the PBS→ and documented the reconstitution of equal numbers of CD4+ cells in the blood and kidney of the rats receiving CD4+ cells or the combined CD4+ CD8+ cell transfer. We also confirmed the CD4+CD8+ was the only group that had reconstituted CD8+ T cells. These studies demonstrated that CD4+ T cells amplify salt-sensitive hypertension and renal damage in the Dahl SS independently from CD8+ T cells.
Abstract 39: Tryptophan contributes to the sex-dependent loss of diurnal sodium excretion in BMAL1 knockout rats.
Authors: Latimer Mary , Pollock David
Published: October 2024

Kidney function is time-of-day-(TOD) dependent irrespective of light, sleep, activity, and meal timing. Recent discoveries reveal that diurnal (day/night) kidney function is maintained by an intrinsic molecular clock. We recently observed that loss of this transcriptional regulatory system impairs functional rhythms in electrolyte excretion in a novel rat model. When the core clock gene, brain and muscle ARNT-like protein 1 (BMAL1) is knocked out of Sprague-Dawley rats we now find that male, but not female, BMAL1 knockout (KO) rats no longer have diurnal changes in both glomerular filtration rate (GFR; Day:1.3±0.1 vs Night:1.2±0.1mL/min/100gBW;t-test p=0.919) along with sodium excretion (UNaV) (Day:819±58 vs Night:756±113 μmol/12h; t-test p=0.439) compared to littermate wildtype controls (CON; GFR Day:1.1±0.1 vs Night:1.6±0.1mL/min/100g; t-test p=0.044; UNaV Day: 849±138 vs Night:1423±102 μmol/12h; t-test p=0.003). LC/MS analysis of plasma from KO rats found that levels of tryptophan (trp) were significantly (2-way ANOVA p
Interaction
=0.847, pGenotype=0.041, p
TimeofDay
=0.952) lower in KO males during the day (KO:77±6, CON:99±7μM; Sidak post-hoc p=0.049) but not night (KO:78±5, CON:99±12μM; Sidak post-hoc p=0.084) with no differences in plasma trp seen in KO females (Day:110±26,107±14μM vs Night:96±8,96±12μM KO and CON respectively). Trp had recently been shown to both regulate and be regulated by the circadian clock as well as increase GFR similar to other aromatic amino acids. This led us to hypothesize that TOD trp availability may underlie the changes seen in both UNaV and GFR in male KO rats. Therefore, we gave a single dose of trp (100 mg/kg,PO) at either 7pm (lights off, ZT12) or 7am (lights on, ZT0). After a 1 wk washout period, rats were dosed again in a crossover design. Male KO rats receiving trp at ZT0 had no significant change from baseline in UNaV (818±58 vs 784±61 μmol/12h) over the following 12hrs; however, a significant increase in UNaV (756±114 vs 1152±146 μmol/12h) following ZT12 dosing was observed (2-Way ANOVA p
Interaction
=0.038, p
TrpTime
=0.087, p
TimeofDay
=0.210; Sidak Post-Hoc: baseline vs ZT12 trp p=0.003) with no significant change seen in female KO or either male or female CON rats. Taken together these results suggest that BMAL1 is necessary for maintaining kidney physiologic rhythms in sodium excretion potentially through changes in trp availability.
Abstract 44: Transcutaneous hydrogen sulfide measurement as a way to evaluate skin blood flow
Authors: Moghaddam Samuel , Neff Jessica , Shekarriz Reza , Fredrichson Debra , Clark Ross , Lew Eric , Kanagy Nancy
Published: October 2024

Hydrogen sulfide (H
2
S) generated in the endothelium of small arteries has been shown to contribute to vasodilation, angiogenesis, and antioxidant properties. We have developed a non-invasive way to measure H
2
S emitted by the skin (TAGS™) and have shown that the ratio of leg:arm emitted levels correlate with severity of microvascular impairment in subjects with diabetes. This study evaluated the correlation of transdermal H
2
S ratios with the current gold standard method of evaluating leg skin blood flow, transcutaneous oxygen pressures (tcpO
2
). TAGS™ measurements were made on the forearm and lower limbs in subjects to calculate the leg:arm ratio while tcpO
2
was recorded only from legs. Other measurements included ankle brachial index (ABI), fasting blood glucose, HbA1c, plasma lipids, blood pressure, and BMI. We observed that TAGS™ ratios correlated strongly with HbA1c (p = 0.0002) and with tcpO
2
(p = 0.0009). In addition, TAGS ratios were significantly lower in subjects with diabetes (0.69 +/- 0.18) compared to healthy controls (1.13 +/- 0.40) (p = <0.0001). These results suggest lower leg:arm ratios of transdermal H
2
S measurements are indicative of impaired microvascular function and that the TAGS™ measurements may be a simpler way than tcpO
2
to detect and monitor diminished skin blood flow that leads to PAD complications.
Abstract 51: Targeted Apoptosis of the Angiotensin AT
1
R-Expressing Subtype of Agouti-Related Peptide Neurons Increases Resting Metabolism and Blood Pressure
Authors: Pasos Jhonatan , Wagner Valerie , Lawton Samuel , Muskus Veitia Patricia , Grobe Connie , Brozoski Daniel , Reho John , Mathieu Natalia , Lu Ko-Ting , Segar Jeffrey , Sigmund Curt , Nakagawa Pablo , Grobe Justin
Published: October 2024

Agouti-related peptide (AgRP) neurons in the hypothalamic arcuate nucleus (ARC) control feeding and resting metabolic rate (RMR) and may also contribute to blood pressure (BP) and heart rate (HR) control. Our recent studies demonstrate that three subtypes of ARC AgRP neurons can be distinguished by differential expression of angiotensin II (ANG) receptors and differential electrophysiological responses to ANG. The "Type 1" subtype of AgRP neurons in the ARC express the ANG type 1 receptor (AT
1
R), and application of ANG inhibits these cells via a Gi cascade, ultimately causing increased RMR. Other published data suggest that AT
1
R action in AgRP neurons may also stimulate BP. Thus, we hypothesized that cell-specific ablation of Type 1 AgRP neurons would disinhibit (increase) RMR and BP. Within the ARC, only Type 1 AgRP neurons express AT
1
R. Thus, cell-specific ablation of Type 1 AgRP neurons was achieved by injecting an Adeno-associated virus (AAV) encoding Cre-activatable Caspase3 into the ARC of adult AT
1
R
CRE
mice that express Cre-recombinase via the AT
1
R locus (n=10m+6f). Cre-deficient mice receiving AAV-Casp3 injection, mice receiving anesthesia but no virus, and AT
1
R
CRE
mice receiving an AAV vector encoding GFP were used as controls (n=21m+10f). Multiplexed metabolic phenotyping demonstrated that two weeks after injection, ablation of Type 1 cells grossly stimulated RMR (+11%: 0.331±0.007 vs. 0.366±0.008 kcal/h, p<0.01) without affecting activity-dependent expenditure; and paradoxically increased meal initiations (+10%, p<0.05) but reduced meal size (-14%, p<0.05), yielding no net change in total food intake after correction for body size and composition (+7%, p=0.24). Ablation of Type 1 neurons also increased preferred ambient temperature in a thermal gradient (29.4±0.3 vs 30.9±0.1 °C, p<0.01). In a separate cohort instrumented with radiotelemetric BP transducers (n=6m), HR progressively decreased (24h avg: -58±9 bpm, p<0.01) as systolic BP tended toward an increase (24h avg: +6±3 mmHg, p=0.10) through 5-7 weeks after ablation. We conclude that AT
1
R-expressing AgRP Type 1 neurons critically contribute to RMR control and appear to also influence BP/HR and feeding control. Therefore, we posit that altered function of these cells may mechanistically contribute to changes in RMR, BP/HR, and feeding control associated with obesity.
Abstract 60: Atlas of Distal Nephron Mineralocorticoid Receptor-Dependent Transcriptome Reveals Novel Aldosterone Actions
Authors: Welling Paul , Jung Hyun Jun , Su Xiao-Tong , Kim Boyoung , Alqusairi Lama , Fenton Robert , Ellison David
Published: October 2024

Aldosterone regulation of Na+ and K+ balance and blood pressure are mediated by the mineralocorticoid receptor (MR, Nr3c2). Although several aldosterone/MR-dependent genes have been identified, their regulation cannot fully explain how aldosterone activates electrogenic Na+- K+ exchange in the aldosterone-sensitive distal nephron (ASDN). Here, we apply RNA-Seq and comprehensive downstream analysis to define the complete inventory of MR-regulated genes. MRfl/fl/Pax8,rtTA/LC1 mice were used to knock out the Nr3c2 gene in an inducible and kidney-specific manner. RNA-Seq analysis was conducted in the micro-dissected connecting tubule and cortical collecting duct tubule segments, followed by multimodal bioinformatic analyses. Direct MR-dependent gene regulation was validated in vitro on immortalized collecting duct cells, ex vivo with isolated distal nephron segments and gene reporter assays. All known aldosterone-response genes, including Sgk1, Scnn1a, Ndrg2, Per3, Tsc22d3, Zbtb16, MLPH, and Atp1a1 were significantly decreased in MR KO mice. 1193 additional genes were down-regulated in the MR KO, and 526 of these have a Mineralocorticoid Responsive Element (MRE), revealing the MR-dependent transcriptome is much larger than previously imagined. MREs were found in most genes with closed chromatin regions, suggesting MR binding might pioneer transcription for most of its regulated genes. The architecture of some MR-regulated genes, highlighted by the co-regulation of 7 Kallikrein genes, points to a novel mechanism of MR-regulation involving epigenetic remodeling in topology-associated domains. Pathway enrichment analysis revealed that MR-regulated genes are highly enriched in mitochondria-associated metabolic processes, and direct MR regulation of Klf15 was identified as a key transcriptional driver. In summary, the inventory of MR-regulated genes in the ASDN is much larger than previously imagined, involving new mechanisms of gene regulation. In addition to pathways that directly up-regulate transport, the data suggest that aldosterone-MR may directly influence metabolism to make energy-consuming transport highly efficient.
Abstract 72: Genetic variance in heparan sulfation is associated with salt-sensitivity: a gene-environment analysis in EPIC-Norfolk, UK biobank, and HELIUS
Authors: Oppelaar Jetta , Romman Mohamed , Sahebdin Ghazalah , Zwinderman Aeilko , Galenkamp Henrike , Boekholdt S , Van den Born Bert-Jan , Olde Engberink Rik , Vogt Liffert
Published: October 2024

Background:
High heritability of salt sensitivity suggests an essential role for genetics in the relationship between sodium intake and blood pressure (BP). The role of glycosaminoglycan (GAG) genes, which are crucial for salinity tolerance througout evolution, remains to be elucidated.

Methods:
Interactions between 54,126 variants in 130 GAG genes and daily sodium excretion on BP were explored in 20,420 EPIC-Norfolk subjects. UK Biobank (n=414,132) and the multi-ethnic HELIUS study (n=2,239, comprising a balanced representation of people from European, Subsaharan, South Asian, Turkish, and Moroccan descent) were used for validation. Afterwards, urinary GAG composition was studied in HELIUS participants (n=57) stratified by genotype, and upon dietary sodium loading in a time-controlled crossover intervention study (n=12).

Results:
rs2892799 (NDST3) showed the strongest interaction with sodium on mean arterial pressure (MAP) (FDR 0.03), with higher MAP for the C-allele in high sodium conditions. Also, rs9654628 (HS3ST5) showed an interaction with sodium on systolic BP (FDR 0.03). These interactions were multi-ethnically validated (figures A and B, respectively). Stratifying for rs2892799 genotype, showed higher urinary expression of N-sulfated heparan sulfate epitope D0S0 for the T-allele. Conversely, upon dietary sodium loading, urinary D0S0 expression was higher in participants with stable BP after sodium loading, and sodium-induced effects on this epitope were opposite in individuals with and without BP response to sodium.

Conclusion:
The C-allele of rs2892799 (NDST3) exhibits higher BP in high sodium conditions when compared to low sodium conditions, whereas no differences were detected for the T-allele. Concomitantly, both alleles demonstrate distinct expressions of D0S0, which, in turn, correlates with sodium-mediated BP elevation. These findings underscore the potential significance of genetic GAG variation in human BP regulation.
Abstract AW12: Hyperinnervation and Immune-endocrine Interactions in Renal Arteriolar Hypertrophy during Inhibition of The Renin-Angiotensin System
Authors: Yamaguchi Manako , Almeida Lucas , Yamaguchi Hiroki , Smith Jason , Medrano Silvia , Sequeira Maria Luisa , Gomez Ariel
Published: October 2024

Background:
Chronic stimulation of renin cells by long-term use of renin-angiotensin system (RAS) inhibitors or renin deletion leads to concentric renal arteriolar hypertrophy frequently surrounded by immune-inflammatory cells. The disease is caused by the renin cells which increase in number and adopt an embryonic-secretory phenotype and induce the accumulation of smooth muscle cells that obstruct the vessels leading to ischemia. Normally, renin cells are innervated but it is unclear whether innervation of the renal arterial tree is affected under RAS inhibition.

Hypothesis:
Long-term RAS inhibition increases renal arteriolar innervation.

Methods:
We used two models of RAS inhibition: 1)

Ren1
c-/-
; Ren1
c-Cre
; R26R
mTmG

mice studied at 3 months of age; 2)

SMMHC
CreERT2
; R26R
tdTomato
; Ren1
cYFP

mice were treated with captopril for 6 months. We performed tissue clearing and 3D staining with an anti-tubulin β3 antibody. The expression of neurogenesis-related genes in renin lineage cells was examined using our previous single-cell RNA sequencing (scRNA-seq) data from mouse kidneys. We compared RNA expression of nerve growth factor (NGF) between

Ren1
c−/−

mice and control mice by qPCR and in situ hybridization (ISH). T cell infiltration was observed by immunostaining with anti-CD3 antibody.

Results:
3-D imaging revealed that in both RAS inhibition models there was marked hyperinnervation. Renin cells expanded along and around the renal arterioles, and covered the glomeruli. Axons grew in numerous branches surrounding thickened afferent arterioles, bound tightly to renin cells and encasing the glomeruli. Our scRNA-seq data showed that
Ngf
, a gene important for neurogenesis and produced by immune cells, was highly expressed in renin cells. In

Ren1
c−/−

mice, expression of
Ngf
was significantly increased compared to controls (p=0.0054). ISH revealed that
Ngf
was highly expressed in

Ren1
c−/−

mice in the juxtaglomerular area and in the renal cortical stroma. Infiltration of T cells around affected arterioles was prominent in both models of RAS inhibition.

Conclusion:
Long-term inhibition of RAS leads to renal hyperinnervation, infiltration of immune cells and arteriolar hypertrophy. The identification of this neuro-immune-endocrine arterioles may help understand and treat vascular disease and hypertension.
Abstract MP01: Clinical Characteristics of Morning Blood Pressure Surge in Patients with Autonomic Failure
Authors: Okamoto Luis , Paranjape Sachin , Vance Yuliya , Black Bonnie , Diedrich Andre , Biaggioni Italo
Published: October 2024

Autonomic failure (AF) is characterized by orthostatic hypotension (OH), but most of these patients also have nocturnal supine hypertension (SH), which has been associated with end-organ damage, pressure natriuresis, and worsening of daytime OH. About 30% of patients with SH, however, have a preserved nocturnal BP dipping that is likely associated with a morning BP surge (MBPS). To determine the pattern of MBPS and its association with dipping, natriuresis, and morning OH, we studied 92 AF patients (67±1 yr, 59% males; 32 multiple system atrophy and 60 peripheral autonomic failure [pAF]). Patients were studied off BP medications and placed on a low monoamine, caffeine-free diet containing 150 mEq/d sodium and 70 mEq/d potassium. Nocturnal BP was assessed every 2 hours from 8pm-8am, followed by a 10-minute standing test. Urine was collected for 24 hours and divided into two 12-hour periods. As expected, we found that dipping (systolic BP [SBP] fall ≥10% during nighttime sleep [12am-6am] from baseline [8pm to 10pm]) occurred in 33% of patients, with an average decrease of 35±5 mmHg at 4am. The MBPS (SBP increase at 8am from the average of 3 nighttime SBPs centered on the lowest one) was 10±2 mmHg (range -83 to 77 mmHg; MBPS≥ 20 mmHg, 23%). MBPS was negatively correlated with the magnitude of dipping (r=-0.328, p<0.001; dippers 18±3 vs. nondippers 6±3 mmHg; p=0.010) and mean nighttime SBP (r=-0.230, p=0.028). The night-to-day ratio of sodium (r=-0.417, p=0.002) and urine (r=-0.292, p=0.037) excretion was also negatively correlated with MBPS, indicating that patients with greater MBPS had decreased natriuresis during the night compared to the day. In the morning, a greater MBPS was associated with a larger SBP drop on standing (r=-0.242, p=0.034). No associations were found between MBPS and age, sex, history of essential hypertension, or the underlying diagnosis of AF. To assess the hemodynamic mechanisms of the MBPS, we studied 17 AF patients (67±2 yr, 14 males, all pAF). We found that MBPS (13±5 mmHg, range -18 to 56 mmHg) was associated with an increase in systemic vascular resistance (SVR, r=0.777, p=0.01) and a higher augmentation index (Aix@75, r=0.516, p=0.049). In conclusion, a subset of AF patients had a preserved dipping pattern and an MBPS despite severe impairment of BP regulation. MBPS was associated with increased SVR, lower nighttime SBP, and lower night-to-day natriuresis, but the higher supine SBP in the morning was associated with worse OH.
Abstract MP18: Evidence for An Important Physiological Role of Bradykinin B
2
Receptors in The Renomedullary Interstitial cells of The Kidney in Angiotensin II-induced Hypertension in Mice
Authors: Li Xiao , Hassan Rumana , Katsurada Akemi , Sato Ryosuke , El-Dahr Samir , Zhang Ming-zhi , Harris Ramond , Zhuo Jia
Published: October 2024

Bradykinin is a potent vasoactive peptide of the kallikrein-kinin system and activates two different classes of G protein-coupled receptors, B
1
and B
2
, in the kidney. In the present study, we tested the hypothesis that deletion of B
2
receptors selectively in renomemdullary interstitial cells (RMICs) of the kidney medulla lowers basal blood pressure and attenuates angiotensin II (Ang II)-induced hypertension. To test the hypothesis, we generated a novel mouse model with deletion of B
2
receptors selectively in RMICs of the medulla (RMIC-
Bdkrb2
-/-
) using inducible

Tenascin-C-CreER2/Bdkrb2
fl/fl

recombination approach. Mice with deletion of B
2
receptors selectively in RMICs developed and grew normally without structural abnormalities in the kidney medulla. Basal telemetry systolic (SBP), diastolic, and mean arterial blood pressure were significantly lower in RMIC-
Bdkrb2
-/-
than WT mice (WT: 123 ± 3 mmHg vs. RMIC-
Bdkrb2
-/-
: 106 ± 3 mmHg,
P
<0.01) (n=12-15). The hypotensive phenotype in RMIC-
Bdkrb2
-/-
mice was associated with significant decreases in 24 h urine output (WT: 1.86 ± 0.15 mL/24 h vs. RMIC-
Bdkrb2
-/-
: 1.09 ± 0.15 mL/24 h,
P
<0.05) and urine osmolality (WT: 1893 ± 441 mOsm/Kg H
2
O vs. RMIC-
Bdkrb2
-/-
: 1311 ± 78 mOsm/Kg H
2
O,
P
<0.01) (n=12=15). Deletion of Bdkrb2 receptors in RMICs significantly decreases COX-2, eNOS, ENaC, and AQP2 mRNA expression (
P
<0.01 vs. WT), but not PGE
2
or prorenin receptor mRNA expression in the kidney medulla (n.s.) (n=6-10). In response to Ang II, SBP increased to 166 ± 6 mmHg in WT mice (
P
<0.01 vs. Basal), but it increased only to 139 ± 5 mmHg in RMIC-
Bdkrb2
-/-
mice (
P
<0.01 vs. WT+Ang II) (n=10-12). Ang II-induced hypertension was completely blocked by oral administration of AT
1
receptor blocker losartan (20 mg/kg/day, p.o.) in WT and RMIC-
Bdkrb2
-/-
mice (n=10). By comparison, infusion of DDAVP (1-deamino-8-D-arginine vasopressin, ~0.5 mg/kg/day, i.p., for 2 weeks) had no effect on blood pressure in WT and RMIC-
Bdkrb2
-/-
mice (n.s.) (n=8). Similarly, infusion of Ang II or DDAVP for 2 weeks significantly increased urine osmolality in WT mice (
P
<0.01), and restored urine osmolality in RMIC-
Bdkrb2
-/-
mice to the WT basal level (1995 ± 315 mOsm/Kg H
2
O,
P
<0.01) (n=8-12). In conclusion, the present study demonstrates for the 1
st
time that bradykinin B
2
receptors in RMICs of the kidney medulla plays an important role in maintaining basal blood pressure and urine osmolality homeostasis and the development of Ang II-induced hypertension.
Abstract MP20: Leveraging Electronic Health Records to Assess Neighborhood Advantages and Risk of Cardiovascular Outcomes Among Hypertensive Patients
Authors: Lu Yuan , Xin Xin , Kim Chungsoo , Asher Jordan , Krumholz Harlan , Brush John
Published: October 2024

Introduction:
Hypertension disproportionately impacts socially disadvantaged groups in the U.S. with increasing prevalence and suboptimal control rates. Our study aims to examine the association between neighborhood-level social vulnerability and hypertension outcomes using electronic health record (EHR) data from a large regional health system.

Methods:
We conducted a retrospective analysis of EHR data from the Sentara Health System, covering the period from January 1st, 2010, to December 31st, 2022. We assigned a Social Vulnerability Index (SVI) based on the residential census tract of each patient and established a longitudinal cohort of patients who consistently utilized healthcare services. To be included in the study, patients were required to have a minimum of five years of observational time and to have healthcare visits in at least 50% of the observed years. The study focused on patients diagnosed with hypertension—either through a hypertension diagnosis, a blood pressure measurement exceeding 140/90, or antihypertensive medication prescriptions. We utilized multivariate Cox Proportional Hazards models to analyze the associations of SVI with cardiovascular outcomes and blood pressure control (<140/90 mmHg).

Results:
The longitudinal cohort consisted of 55,060 patients, with an average age of 54 years (Interquartile range: 42-65), 30.0% of whom were Black adults and 60.0% were females. Compared to patients residing in the most advantaged neighborhoods (quartile 1 of SVI), those in more disadvantaged neighborhoods (quartiles 2, 3, and 4) had hazard ratios for composite cardiovascular endpoint (myocardial infarction, heart failure, and stroke) of 1.22 (95% CI, 1.19-1.25), 1.40 (95% CI, 1.37-1.44), and 1.64 (95% CI, 1.60-1.68), respectively, after adjustment for age and sex. Additionally, blood pressure control was significantly lower in higher SVI quartiles, with control rates in quartiles 1 through 4 at 78.4%, 76.5%, 75.2%, and 72.8%, respectively (P<0.001). Among the SVI themes, socioeconomic status (theme 1) and housing type and transportation (theme 4) were associated with the highest hazard ratios for cardiovascular outcomes.

Conclusions:
Neighborhood-level social vulnerability is significantly associated with worse hypertension control and adverse cardiovascular outcomes. Health systems can employ tailored interventions targeting high-risk neighborhoods to reduce disparities and enhance health outcomes for vulnerable populations.
Abstract MP34: Muscle Sodium Content and Isolevuglandin Formation in Antigen Presenting Cells in Human Salt Sensitive Hypertension
Authors: Demirci Mert , Ertuglu Lale , Sahinoz Melis , Mutchler Ashley , Haynes Alexandria , Yasmin Sharia , Saleem Mohammad , Ahmad Taseer , Crescenzi Rachelle , Pridmore Michael , Laffer Cheryl , Ikizler Alp , Kirabo Annet
Published: October 2024

Background:
Salt sensitivity of blood pressure (SSBP) is an independent risk factor for cardiovascular mortality. However, the mechanisms by which salt exposure affects blood pressure in SSBP are still unclear. We have shown that under high sodium (Na
+
) concentrations, Na
+
enters antigen-presenting cells (APCs) via epithelial Na
+
channel (ENaC), which leads to isolevuglandin (IsoLG) production and hypertension. Baseline %IsoLG+ APC correlates with SSBP. While the exact location where APCs are activated by salt and trigger an inflammatory response remains to be elucidated, muscle and skin are proposed as potential sites. We hypothesize that muscle and skin Na
+
levels are associated with SSBP.

Methods:
We assessed SSBP in 30 hypertensive subjects using an inpatient salt loading and depletion protocol. Flow cytometry was used to identify IsoLG-containing APCs; dendritic cells (DCs), classic (CD14+16-), non-classic (CD14-16+), and intermediate (CD14+16+) monocytes. Salt loading was achieved through saline infusion and a high-salt diet (460mmol/24 hours), while salt depletion was achieved via diuretic administration (furosemide 40mg x3) and a low-salt diet (10mmol/24hours). Baseline muscle and skin Na
+
levels were assessed with the
23
Na MRI technique. Spearman's correlation was used to analyze the associations. Demographic data are presented with mean and standard error of the mean.

Results:
Participants’ age was 53 ± 1.34 years, 53% female, baseline blood pressure was 140.2 ± 2.62 / 87.30 ± 1.77 mmHg, and salt sensitivity index was 3.72 ± 1.4 mmHg. We found an inverse correlation between baseline muscle Na
+
levels and the decrease in IsoLGs from salt loading to depletion (ΔIsoLGs) in DCs (r=-0.50, p=0.007), intermediate (r=-0.42 p=0.0284) and non-classic monocytes (r=-0.39 p=0.0432), but not in classical monocytes. Skin Na
+
levels were not correlated with any of these measures. There was a decreasing trend of salt sensitivity index with increasing muscle Na
+
, although this correlation did not reach statistical significance (r=-0.35 p=0.0686)

Conclusion:
This highlights the potential importance of muscle Na
+
in SSBP, such that patients with lower muscle Na
+
exhibited a higher trend of salt sensitivity index and increased variability in IsoLG+ APCs. Moreover, baseline tissue Na
+
assessment may emerge as a potential tool for evaluating the degree of salt sensitivity and IsoLG activation in SSBP.
Abstract MP36: Excessive ATP Promotes Hypertension Via Stimulating T cells
Authors: Liu Yunmeng
Published: October 2024

While CD8+ T cells (CD8Ts) have recently emerged as key players in hypertension, the precise mechanisms underlying their involvement remain incompletely understood. We reported previously that CD8T-activation is critical in initiating their direct interaction with renal tubules. Here, we discovered that CD8T activation in hypertension occurs in an antigen-independent manner. In this study, we delve into the contribution of the P2X7 receptor to CD8T activation and its subsequent promotion of hypertension.

To investigate whether CD8T activation in hypertension necessitates T cell receptor (TCR) stimulation, we employed Rag2/OT1 mice, which exclusively harbor transgenic OT1 CD8Ts, recognizing only ovalbumin peptides but no other antigens. These mice, without any exposure to ovalbumin, were induced hypertension through the DOCA + salt (DOCA) model. Blood pressure was monitored using biotelemetry, and CD8T activation was confirmed using flow cytometry. In our in-vitro studies, CD8Ts were obtained from WT or P2X7-KO mice and stimulated with ATP. The endpoints include calcium influx and cytokine production as indicators of activation. Moreover, we measured the activation profiles of CD8Ts obtained from WT or P2X7-KO mice subjected to sham or DOCA treatment using RT-PCR and flow cytometry. Additionally, we conducted an adoptive transfer experiment, transferring naive WT CD8Ts to P2X7-KO mice undergoing DOCA treatment.

We found that CD8Ts from Rag2/OT1 mice become activated in response to the DOCA pressor, leading to increased IFNγ production and contributing to salt-sensitive hypertension, even in the absence of TCR-mediated antigen stimulation. Furthermore, ATP elicited calcium influx in CD8Ts via P2X7, thereby upregulated IFNγ production. In addition, CD8Ts pre-treated with ATP exhibited a higher ability to stimulate sodium retention in co-cultured renal tubule epithelial cells compared to those co-cultured with naive CD8Ts. Notably, DOCA-treated P2X7 KO CD8Ts were unable to induce an increase in blood pressure in our adoptive transfer model. However, transferring sham WT CD8Ts to DOCA-treated P2X7 KO mice successfully restored hypertension to WT levels.

Our findings reveal a novel mechanism by which ATP/P2X7 signaling leads to activation of CD8Ts as the culprit to the pathogenesis of hypertension. As such, the CD8T P2X7 receptor presents itself as a promising target for improving blood pressure management.
Abstract P105: Comparative Effectiveness between Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors on Mortality: a Nationwide, Population-based, Prospective Cohort Study in China
Authors: Wang Yunfeng , Guo Weihong , Hao Yang , Zheng Xin , Zhang Haibo , Yang Yang , Chen Bowang , zhang xiaoyan , cui jianlan , Xu Wei , Song Lijuan , Wang Chunqi , Wu Yi , Krumholz Harlan , li xi , Hu Shengshou
Published: October 2024

Background:
Contemporary evidence comparing the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) versus angiotensin II receptor blockers (ARBs) on long-term outcomes in patients with hypertension is sparse and inconsistent. The aim is to compare the effectiveness of ACEI monotherapy versus ARB monotherapy on all-cause death and cardiovascular death.

Methods:
Based on a nationwide, population-based prospective cohort project, which covered 318 study sites from 2014 to 2021 in China. Detailed information was collected by questionnaire, physical measurement, and blood test. Participants aged 35-75 years with hypertension and taking ACEI or ARB monotherapy once daily, and with good medication adherence at baseline were included. Information on mortality was followed up until 31 December 2021. Stabilized inverse probability treatment weighting (IPTW) was applied to compare the effectiveness.

Results:
68 771 (49326 ARB, 19445 ACEI) participants were finally included, with a mean age of 59.9±8.3 years and 40.2% being female. During a median follow-up time of 44 months, 785 cardiovascular deaths and 1657 deaths were recorded. Compared with ACEI monotherapy, ARB monotherapy was associated with a quarter relative risk reduction of cardiovascular death (IPTW rates: 0.95 %
Vs
1.43%,
HR
=0.73 [
95%CI
, 0.62-0.87]) and one-fifth relative risk reduction of all-cause death (IPTW rates: 2.13%
Vs
2.84%,
HR
=0.80 [
95%CI
, 0.71-0.89]). These differences remained consistent after further adjusting for blood pressure and with differences more pronounced in patients with controlled and newly onset hypertension. Sensitive analysis and subgroup analysis yielded consistent results.

Conclusions:
Attention should be paid that ARB can be preferred to ACEI in patients with hypertension in terms of long-term health outcomes.

Funding:
This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Science (2021-I2M-1-011), and the National High Level Hospital Clinical Research Funding (2022-GSP-GG-4, NCRCSZ-2023-016).

Keywords:
Hypertension, Angiotensin receptor blocker, Angiotensin-converting enzyme inhibitor, Mortality, Comparative effectiveness
Abstract P107: Training for home blood pressure monitoring among women with a diagnosis or risk factors for hypertensive disorders of pregnancy
Authors: Denu Mawulorm , Shankara Sravya , Shao Cassie , Tak Katherine , Do Kelton , Kovell Lara
Published: October 2024

Introduction:
Hypertensive disorders of pregnancy (HDP) are leading causes of morbidity and mortality among pregnant women. Despite the potential benefits of home blood pressure monitoring (HBPM) for early diagnosis and monitoring of patients with HDP, its utilization is limited by inconsistent training by healthcare providers. This study sought to examine the use of and training for HBPM in those at risk for HDP.

Methods:
Pregnant women, aged 20-50 (N = 103), diagnosed with either hypertension, HDP, or risk factors for HDP, were recruited from a large academic medical center to complete a survey on HBPM practices from June 2020 to January 2024. Thisincluded questions about HBPM, frequency of HBPM, and prior HBPM training provision by providers. Statistical analysis was performed using STATA/BE 18.0.

Results:
Of the 103 participants, 41 (39.8%) did HBPM and the most common frequency was daily (70.7%). Of those who did HBPM, 36.6% had received training from their healthcare providers and 31.7% had their BP monitors calibrated in the clinic. There was a trend towards Hispanic women being less likely to receive training compared to white women (
p
=0.07). There were no significant differences in training across categories of education and location of residence.

Conclusion:
In this sample where nearly 40% of pregnant women used HBPM, we observed that only 1 in 3 received training for HBPM with little difference observed across demographic categories. Given the time constraints in clinic visits hindering appropriate training for HBPM, exploring alternative methods of HBPM training such as leveraging mobile health applications may be beneficial to ensure that pregnant women receive necessary training to effectively conduct HBPM.
Abstract P116: Hypertension Treatment and Control in Canadians with Diabetes
Authors: Pasricha Sachin Vidur , Dubrofsky Lisa , Goldman Bailey , Tobe Sheldon
Published: October 2024

Introduction:
3 million Canadians and 23 million Americans have concurrent hypertension and diabetes. Blood pressure (BP) control reduces the risk of heart attacks, strokes, retinopathy, and kidney disease. We investigated hypertension control rates in patients with diabetes, responses to uncontrolled BP measurements, and use of antihypertensive drug classes.

Methods:
We performed an observational study of adults with diabetes and hypertension drawing from the IQIVA primary care database (contains data on 1.2 million Canadians). Our first outcome was mean BP at 3, 6, 12, and 24 months after inclusion. Our second outcome was the number of uncontrolled BP measurements (≥130/80) followed by a physician BP check, medication dose/frequency increase, or new medication in the subsequent 6 weeks. Our third outcome (for a subset of individuals with medication data available) was the number of individuals prescribed renin-angiotensin-aldosterone-system inhibitors (RAASi), dihydropyridine calcium channel blockers (DHP-CCBs), or thiazide/thiazide-like diuretics.

Results:
We identified 10,814 individuals identified with both diabetes and hypertension. Mean BP (in mmHg) remained largely unchanged over 24 months: 136.7/78.6 at 3 months, 135.5/82.2 at 6 months, 137.2/82.8 at 12 months, and 136.6/82.3 at 24 months. Over the two years of follow-up there were 55,381 uncontrolled BP events, and in the subsequent 6 weeks only 27,877 (50.3%) were followed by ≥1 physician BP checks. Among individuals with medication data, there were 16,364 uncontrolled BP events, 33.4% followed by a new antihypertensive medication and 18.2% followed by an antihypertensive dose/frequency change. Of the 6,919 individuals for whom we had medication data, 6,216 (89.8%) were prescribed a RAASi, 2,371 (34.3%) were prescribed a DHP-CCB, and 1,672 (24.2%) were prescribed thiazide/thiazide like diuretic.

Conclusion:
Over two-thirds (68.8%) of people with diabetes and hypertension had uncontrolled blood pressure that persisted over 2 years during which half of uncontrolled BPs were followed by a physician BP check in 6 weeks, and one-fifth by a antihypertensive dose/frequency change. While almost 90% were treated with RAASi, over a third were on a DHP-CCB and less than one quarter were treated with a thiazide/thiazide like diuretic. Therapeutic inertia and under-prescribing of dual and triple therapy contribute to persistently high BP thus represent opportunities for improvement.