bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 067: Genome-wide Chromatin Conformation Map Of Human Induced Pluripotent Stem Cell-derived Vascular Endothelial Cells Reveals New Regulatory Insights
Authors: Liu Yong , Pandey Rajan , Therani Bhavika , Mishra Manoj , Rao Sridhar , Liu Pengyuan , Geurts Aron M , Cowley Allen W , Greene Andrew , Liang Mingyu
Published: September 2022

Chromatin conformation influences gene transcription by changing the spatial organization and accessibility of DNA regulatory elements. Endothelial cells (ECs) play an important role in the regulation of blood pressure. We have shown that human induced pluripotent stem cell (iPSC)-derived ECs (iECs) exhibit robust expression of a large panel of EC marker genes. In this study, we developed genome-wide maps of chromatin conformation in iECs using Hi-C and Micro-C techniques. With Hi-C, we identified 309 and 1,584 loops at 5,000 base pairs (bp) and 10,000 bp resolution, respectively, from a total of more than 171 million chromatin contacts. We also identified 62 and 582 contact domains at the two levels of resolution. From a total of more than 356 million contacts in the Micro-C map of iECs, we identified 3,259 and 6,497 loops and 1,262 and 3,542 contact domains at 5,000 bp and 10,000 bp resolution, respectively, including many identified by Hi-C. A subsample of the Micro-C data that was similar to the Hi-C map in size identified four fold more loops and six fold more domains at 5,000 bp resolution. Using approaches that we published recently, we identified 54 overlapping genes between 1,278 genes known to be relevant to ECs and 251 genes known to be involved in blood pressure regulation. We searched the 3,259 loops in the Micro-C map of iECs for the 54 genes and 26,585 single nucleotide polymorphisms (SNPs) in 1,071 haplotypes associated with blood pressure.
EDNRA
(endothelin receptor type A) and
SMAD3
(SMAD family member 3) were in the same loops as blood pressure-associated haplotypes, were the closest genes to the haplotype regions, and were expression quantitative trait locus (eQTL) genes for SNPs in the haplotypes.
GJA1
(connexin-43) was in the same loop as the rs6925750 haplotype and an eQTL gene for some SNPs in the haplotype, but
GJA1
was not the closest gene to the haplotype. In fact, the
GJA1
promoter was 498,217 bp away from the haplotype region, indicating possible long-range regulation of
GJA1
by SNPs in this blood pressure-associated haplotype. In summary, we have developed a genome-wide chromatin conformation map for human iECs, which may reveal new insights into the mechanisms underlying the regulation of endothelial gene expression and blood pressure.
Abstract 070: ONE UP-REGULATED NOVEL MICRORNA AND 4 DOWN-REGULATED MRNA TARGETS WERE IDENTIFIED IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF HYPERTENSIVE PATIENTS WITH METABOLIC SYNDROME
Authors: Berillo Olga , Huo Kugeng , Fraulob-Aquino Julio C , Richer Chantal , Li Na , Briet Marie B , Lipman Mark , sinnett daniel , Paradis Pierre , Schiffrin Ernesto L
Published: September 2022

Introduction:
Hypertension is associated with target organ damage such as kidney injury. The immune system plays a role in hypertension and target organ damage. Activation of T cells has been reported among peripheral blood mononuclear cells (PBMCs) of patients with HTN. MicroRNAs are crucial post-transcriptional regulators of immune cell development and function.

Hypothesis:
MicroRNAs play a role in the activation of immune cells in hypertension with target organ damage in humans.

Methods:
Normotensive subjects (NTN) and patients with hypertension (HTN) associated or not with at least 2 other features of the metabolic syndrome (MetS) or chronic kidney disease (CKD) were studied (n=15-16). PBMCs were isolated from blood, RNA extracted, small and total RNA sequencing (RNA-seq) using an Illumina HiSeq-2500 and data were analyzed using a systems biology approach. Differentially expressed (DE) microRNAs and mRNAs were identified with fold change (FC) >2 and >1.5, respectively, and
P
<0.005. DE miRNAs with RNA-seq count number (CN) >500, and predicted targets by TargetScan with CN>300 were validated by reverse transcription-quantitative PCR (RT-qPCR) in PBMCs.

Results:
RNA-seq identified DE microRNAs and mRNAs in HTN (22 and 19), MetS (57 and 401) and CKD (6 and 26) compared to NTN. RT-qPCR validated a novel miRNA (miR-pl-86 [2-fold up]) and 4 predicted mRNA targets (WD repeat domain 89 [
WDR89
, 51% down], Dmx like 1 [
DMXL1
, 52% down], zinc finger protein 600 [
ZNF600
, 63% down] and NOC3 like DNA replication regulator [
NOC3L
, 61% down]) in MetS vs NTN (
P
<0.05). RNA-seq results were correlated with RT-qPCR data for miR-pl-86 (R
2
=0.37,
P
<5.5E-07, n=56)
,
WDR89
(R
2
=0.29,
P
<1.4E-05, n=57)
, DMXL1
(R
2
=0.33,
P
<2.7E-06, n=57)
, ZNF600
(R
2
=0.25,
P
<7.9E-05, n=57)
,
and
NOC3L
(R
2
=0.27,
P
<3.5E-05, n=57).

Conclusion:
This study identified one up-regulated novel microRNA and 4 down-regulated mRNA targets in PBMCs of patients with HTN and MetS.
Abstract 074: Empagliflozin Improves Impaired Sensitivity Of Afferent Neurons With Renal Axons
Authors: Rodionova Kristina , Ditting Tilmann , Hilgers Karl F , Peter Linz , Schmieder Roland E , Ott Christian , Schiffer Mario , Amann Kerstin , Veelken Roland
Published: September 2022

Afferent renal nerve pathways likely play a role in salt sensitive hypertension. We recently reported that high salt diet (HS) impairs these afferent renal pathways in rats. Now we tested the hypothesis that during HS a decrease in sensitivity of renal afferent neurons is prevented by the SGLT2 inhibitor empagiflozin.Respective groups of rats were put on HS containing 8% NaCl or a normal diet. Two groups (HS, controls) received empagiflozin 20 mg/kg BW/day orally. Renal neurons were retrogradely labeled with DiI. In culture, labeled dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated electrophysiologically using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active (> 5 action potentials, AP) and phasic less active neurons (≤ 5 AP upon stimulation. )In neurons from rats on HS, the relation of tonic highly active neurons to less active phasic neurons shifted consistently towards phasic units (63,8% tonic neurons in controls vs. 42%* on HS, *p<0.05, z-test). However, continuous treatment with empagiflozin preserved the proportion of tonic neurons as in controls (67,9% on HS with concomitant administration of empagiflozin). In controls, empagiflozin did not affect the proportion of tonic to phasic neurons (63,8% tonic neurons in controls vs. 67,9% on HS & empagliflozin, p=0.7, z-test). Blood pressure and heart rate were not altered by HS and/or treatment with any chosen dose of empagiflozin.In rats, chronically elevated sodium intake (8% NaCl) reduced the sensitivity and stimulability of renal afferent DRG neurons. Under these circumstances, concomitant treatment with the SGLT2 inhibitor empagiflozin preserved the function of renal afferent DRG neurons. SGLT 2 inhibitors may help to treat dysfunction of renal innervation in cardiovascular disease.
Abstract 082: Association Of Age And Blood Pressure Severity With ICD-10 Diagnosis Codes For Hypertension Disorders Among Youth Referred For Hypertension: Interim Analysis Of Data From Three Sites Of The Study Of The Epidemiology Of Pediatric Hypertension (SUPERHERO) Registry
Authors: Weaver Donald J , Giammattei Victoria , Lucas Caroline , Sethna Christine , South Andrew M
Published: September 2022

Background:
Secondary HTN is thought to be the main cause of HTN in young children and those with more severe HTN. However, the rising incidence of primary HTN has called this into question. Our objective was to estimate risk of secondary HTN based on ICD-10 codes due to age and BP.

Methods:
The SUPERHERO Registry is a multicenter retrospective cohort of youth referred to subspecialty care for HTN. Inclusion criteria were initial visit for HTN disorder (per ICD-10) from 1/1/2016-12/31/2021 and age <19 years. Exclusion criteria were pregnancy, dialysis, or transplant per ICD-10. Exposures were age and BP, including z-scores, and outcomes were primary and secondary HTN by ICD-10, all at baseline. We used unadjusted generalized linear models to estimate risk of 1) secondary vs. primary HTN and 2) kidney vs. non-kidney secondary HTN.

Results:
Median age was 14.2 years [IQR 10.5, 16.4], 52% (1703/3295) had obesity, 58% (1927/3295) had primary HTN, 9% (283/3295) had non-kidney secondary HTN, and 5% (171/3295) had kidney secondary HTN. Compared to youth <13 years old, adolescents had 38% lower risk of secondary vs. primary HTN (95% CL 0.53-0.74) and 23% lower risk of kidney vs. non-kidney secondary HTN (95% CL 0.61-0.98) (Table). A 1-unit higher systolic BP z-score was associated with 23% lower risk of secondary vs. primary HTN (95% CL 0.71-0.85) and 19% lower risk of kidney vs. non-kidney secondary HTN (95% CL 0.72-0.91).

Conclusions:
Older age was associated with greater risk of primary HTN and lower risk of secondary HTN due to kidney disease. However, worse systolic BP was associated with lower risk of secondary HTN, including due to kidney disease. Ongoing analyses are validating these findings.
Abstract 088: Comparison Of 24-hour Blood Pressure Tracking Between A Commercially Available Cuffless Wearable Device And Standard Ambulatory Monitoring
Authors: Tan Isabella , Gnanenthiran Sonali R , Chan Justine , Kyriakoulis Konstantinos G , Schlaich Markus P , Stergiou George S , Schutte Aletta E
Published: September 2022

Introduction:
Cuffless blood pressure (BP) monitoring offers great potential in assessing 24-hour BP without user disturbance. Despite the myriad of commercially available cuffless BP devices, it is uncertain whether these devices can accurately track BP changes during usual daily activities and sleep as with standard 24-hour ambulatory BP monitoring (ABPM).

Hypothesis:
A commercially available cuffless wearable BP device, previously demonstrated to have good accuracy for seated BP, can track 24-hour BP changes as well as standard ABPM.

Methods:
We included 45 individuals (36 hypertensive, 15 female, age 58±14 years [mean±SD]) in two centres (Perth, Australia; Athens, Greece). Participants used a cuffless wearable BP device (Aktiia, Switzerland) continuously for 7-10 days and 24-hour ABPM (MicroLife WatchBP O3, Switzerland) on the first and the last day of cuffless BP monitoring. Daily 24-hour, daytime, and nighttime BP values were averaged across the total study days for the cuffless device and across the two ABPM days.

Results:
Compared to ABPM, the cuffless device reported higher 24-hour systolic BP (SBP) by 6.8 mmHg, 95% CI [3.7, 9.7], higher daytime SBP by 3.8 mmHg [1.0, 6.7], and higher nighttime SBP by 17.5 mmHg [13.6, 21.4] (all p≤0.01). Cuffless 24-hour diastolic BP (DBP) was comparable with ABPM (difference 1.2 mmHg, 95% CI [-1.0, 3.5]), as was daytime DBP (difference -0.8 mmHg, [-3.0, 1.3]) (both p≥0.27), but nighttime DBP was higher by 9.2 mmHg, [6.3, 12.2] (p<0.001). Nighttime dip in SBP (-5.1 mmHg, 95% CI [-13.7, 3.6]) and DBP (-3.8 mmHg, [-11.6, 4.2]) as measured by the cuffless device were substantially less than ABPM (SBP dip: -18.0 mmHg, [-35.5, -1.2]; DBP dip: -13.8 mmHg, [-27.2, -0.8]). The cuffless device identified 44 nighttime non-dippers (defined as a relative dip < 10%) for SBP and 42 non-dippers for DBP, compared to 10 non-dippers for both SBP and DBP as identified by ABPM (both comparisons p<0.001).

Conclusions:
A commercially available cuffless wearable BP device was unable to adequately track diurnal BP variation and considerably overestimated average SBP over 24 hours as compared to standard ABPM.
Abstract 091: Does Smooth Muscle Cullin-3 Regulate The Renin-angiotensin System?
Authors: Golosova Daria , Brozoski Daniel T , Muskus Veitia Patricia , Lu Ko-ting , Sigmund Curt D
Published: September 2022

Cullin-3 (CUL3) is a scaffold protein involved in the formation and function of the CUL3-RING E3 ubiquitin ligase complex. Loss of smooth muscle CUL3 promotes vascular dysfunction, arterial stiffness, and severe hypertension (HTN). We hypothesized that conditional deletion of CUL3 in smooth muscle cells causes severe HTN through a renin-angiotensin system (RAS)-dependent mechanism. Mice carrying a conditional allele of CUL3 were bred to mice expressing a tamoxifen-inducible CRE-recombinase driven by a smooth muscle promoter (ISM-CRE, control). Tamoxifen was administered to generate smooth muscle CUL3 knockout (S-CUL3KO). Three weeks after tamoxifen, mean arterial pressure (MAP) was 140±1 vs. 108±1 mmHg (S-CUL3KO vs. ISM-CRE). Aorta from S-CUL3KO mice exhibited impaired acetylcholine-induced vasorelaxation (ACh, max relaxation: 19±11% vs. 84±5%, p<0.05). S-CUL3KO mice also manifested impaired vasorelaxation to sodium nitroprusside (SNP, max relaxation: 15±12% vs. 96±2%, p<0.05). Captopril administration (7 days) markedly reduced MAP to 84±0.3 mmHg and improved vasorelaxation in response to both ACh (72±6%) and SNP (87±4%) in S-CUL3KO mice, suggesting RAS-dependency of the HTN. Q-PCR analyses and RNAScope showed no difference in renin expression in the kidney between the S-CUL3KO and control mice suggesting a blunting of the baroreceptor mechanism regulating renin. In preliminary studies, lamin A/C, a crucial component of the nuclear mechanotransducer controlling expression of renin, displayed a trend to increased protein expression in S-CUL3KO animals (6±2 vs. 2±1 normalized RFU, p=0.12). Similarly, expression of connexin 40, a component responsible renin signal transduction in the renin cells, was significantly higher in S-CUL3KO mice (8±1 vs. 3±1 normalized RFU, p<0.05). Our data suggest that CUL3 may play a vital role in baroreceptor mechanism in the renin cells via regulation of components of the baroreflex sensor (connexin 40) and transducer (lamin A/C) which are essential for responding to changes in perfusion pressure. Hence, understanding CUL3 target proteins and the mechanism of the impaired baroreceptor mechanism is beneficial in developing new treatments of hypertension.
Abstract 095: Obstructive Sleep Apnea Induced Gut Dysbiosis Stimulates A Proinflammatory Response In Gut And Brain That Contribute To Hypertension
Authors: Durgan David J , Ayyaswamy Sriram , Shi Huanan , Bryan Robert
Published: September 2022

Objective:
Obstructive sleep apnea (OSA) is an independent risk factor for the development of hypertension (HT). OSA induces gut dysbiosis, and a dysbiotic microbiota is causal in the development of HT. The mechanisms linking gut dysbiosis to blood pressure (BP) regulation remain unclear. Gut dysbiosis can induce a pro-inflammatory response of the host resulting in peripheral- and neuro-inflammation, key factors in the development of HT.
We hypothesized that OSA induced gut dysbiosis elicits a pro-inflammatory response that promotes neuroinflammation and HT.

Methods:
OSA was induced in 8-week-old male rats (60 apneas/hr for 8 hrs during sleep) by inflating a tracheal balloon. Sham rats underwent balloon implantation without inflations. After 2 weeks of apneas, lymphocytes were isolated from brain, cecum, ileum, mesenteric lymph node (MLN), and spleen for flow cytometry. The role of IL-17 was tested by treating rats with a monoclonal antibody to IL-17 to neutralize circulating IL-17. To track the distribution of lymphocytes originating from the gut, cells in the Peyer’s patches of the small intestine were labelled by injection of carboxyfluorescein succinimidyl ester (CFSE) dye.

Results:
Following 2 weeks of OSA we found a significant decrease in anti-inflammatory regulatory T (Treg) cells along with an increase in T
H
17 (IL-17+) in the brain, cecum, and ileum (n=7, p<0.05 for each). To examine the role of T
H
17, we injected an IL-17 neutralizing antibody or control IgG during the 2 weeks of OSA. Compared to OSA rats receiving IgG control, neutralization of IL-17 significantly reduced BP of OSA rats (n=6, p<0.05). IL-17 neutralization also resulted in a significantly increased Tregs and decreased Th1 cells in brain, cecum and ileum of OSA rats (n=6, p<0.01 for each). To examine the distribution of lymphocytes originating from the gut, cells in the Peyer’s patches were labelled with CFSE. We observed significant increases in CFSE+ Th1, Th2, and Th17 cells in the brain, MLN and spleen of OSA as compared to sham rats (n=6, p<0.05).

Conclusion:
OSA induced gut dysbiosis is associated with a pro-inflammatory response in the gut and brain that involves IL-17 signaling. Treatment strategies to prevent gut dysbiosis may prove useful in reducing neuroinflammation and HT.
Abstract 098: Double Deletion Of At
1a
Receptors And Na
+
/h
+
Exchanger 3 In The Proximal Tubules Attenuates Angiotensin Ii-induced And 2k1c Goldblatt Hypertension In Proximal Tubule-specific Pt-

Agtr1a
-/-

/
Nhe3
-/-
Mice
Authors: Li Xiao C , Hassan Rumana , Leite Ana , Zhuo Jia L
Published: September 2022

We have previously shown that genetic deletion of AT
1
(AT
1a
) receptors or Na
+
/H
+
exchanger 3 (NHE3) selectively in the proximal tubules attenuated the development of angiotensin II (Ang II)-induced hypertension in mice. The present study determined whether double deletion of AT
1a
receptors and NHE3 selectively in the proximal tubules further attenuates the development of Ang II-induced or 2-kidney, 1-clip (2K1C) Goldblatt Hypertension. Proximal tubule-specific AT
1a
receptor and NHE3 double knockout mice, PT-

Agtr1a
-/-

/
Nhe3
-/-
, were generated using the iL-
Sglt2-Cre
/
LoxP
approach. Adult male wild-type (WT), PT-

Agtr1a
-/-

, PT-
Nhe3
-/-
, and PT-

Agtr1a
-/-

/
Nhe3
-/-
double knockout mice were treated with vehicle (or sham as time-controls), a slow pressor dose of Ang II infusion for 2 weeks (500 μg/kg body wt./day, i.p.), or induction of 2K1C Goldblatt hypertension by placing a silver clip (0.12 mm) on the left renal artery for 4 weeks, respectively. In WT mice, control systolic blood pressure was 118 ± 3 mmHg (n=9), which increased to ~143 ± 5 mmHg in response to Ang II infusion (
P
<0.01, n=10) or to induction of 2K1C Goldblatt hypertension (n=12,
P
<0.01). By comparison, control systolic blood pressure was 15 ± 2 mmHg lower in age-matched PT-
Agtr1a
-/-
mice (
P
<0.01), or 13 ± 3 mmHg lower in PT-
Nhe3
-/-
mice than WT mice (
P
<0.01). Double deletion of AT
1a
receptors and NHE3 selectively in the proximal tubules further but only moderately decreased basal blood pressure to 98 ± 2 mmHg in PT-

Agtr1a
-/-

/
Nhe3
-/-
double knockout mice (
P
<0.05, n=10). In response to Ang II infusion, systolic blood pressure increased only to ~126 ± 3 mmHg in PT-
Agtr1a
-/-
or PT-
Nhe3
-/-
mice (
P
<0.01). Interestingly, 2K1C Goldblatt hypertension was markedly attenuated in PT-
Agtr1a
-/-
(108 ± 3 mmHg,
P
<0.01, n=10), PT-
Nhe3
-/-
(110 ± 2 mmHg,
P
<0.01, n=10), or PT-

Agtr1a
-/-

/
Nhe3
-/-
double knockout mice (103 ± 2 mmHg,
P
<0.01, n=8), respectively. Taken together, these data strongly support the hypothesis that the intratubular Ang II/AT
1a
receptor/NHE3 signaling plays a key role in maintaining basal blood pressure homeostasis and the full development of Ang II-induced or 2K1C Goldblatt hypertension.
Abstract 099: Role Of Nox-induced Oxidative Stress In Mitochondrial Bioenergetic Dysfunction In The Kidney Cortex And Outer Medulla Of Dahl Salt-sensitive Rats During The Development Of Hypertension
Authors: Dash Ranjan K. , Tomar Namrata , Sadri Shima , Yang Chun , Liang Mingyu , Cowley Allen W
Published: September 2022

Background:
Although renal mitochondrial dysfunction has been observed in various models of hypertension, the events leading to this dysfunction remain unclear. The present study focused on the role of salt (NaCl) intake upon renal mitochondrial bioenergetic function in Dahl salt-sensitive (SS) rats hypothesizing that a high salt (HS) diet would impair mitochondrial bioenergetics via stimulation of NOX-induced oxidative stress.

Method:
The HS induced progressive alteration of oxidative phosphorylation (OxPhos) and ATP synthesis in mitochondria obtained from renal cortex and outer medulla (OM) of male SS rats were compared to those of SS rats with dual knockout of NOX4 and p67
phox
subunit of NOX2 (NOX DKO). Mitochondria were isolated from the cortex and OM of groups of age matched rats fed a 0.4% NaCl (LS) diet since weaning and at days 3, 7, 14 & 21 of a 4.0% NaCl (HS) diet feeding. ADP-induced (state 3) O
2
consumption rates (OCR) were measured in mitochondria energized with pyruvate and malate as substrates using an Oroboros Oxygraph-2k Instrument.

Results:
In SS rats, a biphasic pattern in state 3 OCR was observed with progressive uncoupling of OxPhos occurring in both cortex and OM. In the early phase of hypertension (days 3 & 7), state 3 OCR was increased (155 ± 8.2 to 190 ± 12.2 to 203.4 ± 12.1 nmol/min/mg in cortex and 101.4 ± 5.1 to 121.8 ± 7.3 to 112.8 ± 6.8 nmol/min/mg in OM; n = 5). In the established phase of hypertension (days 14 & 21), this increase was not sustained as state 3 OCR was reduced to 153 ± 7.65 and 132 ± 6.6 nmol/min/mg in cortex and 105 ± 7.3 and 63.3 ± 6.5 nmol/min/mg in OM. In contrast, SS NOX DKO rats fed a HS diet showed no significant differences in state 3 OCR in both cortex and OM, as was also observed in a control group of age matched NOX DKO rats maintained on a LS diet throughout the study.

Conclusions:
In SS rats, a HS diet causes initial increase in the efficiency of OxPhos for ATP production followed by a progressive decrease in the efficiency of OxPhos for ATP production in the established phase of hypertension. This biphasic pattern with ultimate reduction in the efficiency of OxPhos for energy production was not observed in SS NOX DKO rats demonstrating the important causal role of NOX-induced oxidative stress in the renal mitochondrial bioenergetic dysfunction.
Abstract 119: P2Y12 Inhibitor With Or Without Aspirin In Patients With Hypertension Undergoing Percutaneous Coronary Intervention
Authors: Song Pil-Sang , CHOI SI WAN , Jeong Jin-Ok
Published: September 2022

Background:
P2Y12 inhibitor monotherapy after a brief period of dual antiplatelet therapy (DAPT) can reduce bleeding without increasing ischemic harm after percutaneous coronary intervention (PCI). We sought to examine the effect of P2Y12 inhibitor monotherapy vs. prolonged DAPT among patients with hypertension undergoing PCI.

Methods:
This is a post-hoc analysis of the SMART-CHOICE trial, in which patients undergoing PCI were randomly assigned to either P2Y12 inhibitor monotherapy after 3-month DAPT (n=1495) or DAPT for 12 months or longer (n=1498). The primary endpoint was Bleeding Academic Research Consortium (BARC) 2~5 bleeding. The composite ischemic endpoint was all-cause death, myocardial infarction, or stroke. Treatment effects were estimated according to the presence of hypertension with formal interaction testing.

Results:
Patients with hypertension comprised 61.5% of the randomized cohort, and were characterized by more frequent comorbidities, a higher PRECISE-DAPT score, and a higher prevalence of the multivessel disease. At 3 years, patients with hypertension experienced higher rates of all-cause death (3.9% vs 2.5%; p=0.039), stroke (1.6% vs 0.6%; p=0.014), or a composite ischemic endpoint (6.8% vs 3.8%; p<0.001), but similar BARC 2~5 bleeding (5.4% vs 4.9%; p=0.601) compared with patients without hypertension. The incidence of BARC 2~5 bleeding was 2.9% and 7.8% among patients with hypertension randomized to P2Y12 inhibitor monotherapy versus DAPT [hazard ratio (HR), 0.382; 95% confidence interval (CI), 0.243 to 0.600; p<0.001]. However, P2Y12 inhibitor monotherapy was not associated with an increase in ischemic events compared with DAPT (7.2% vs. 6.5%; HR: 1.135; 95% CI: 0.767 to 1.679; p=0.527) in patients with hypertension. In the overall population, there was no significant interaction between hypertension and treatment for the primary bleeding (adjusted p for interaction 0.835) or ischemic endpoints (adjusted p for interaction 0.707).

Conclusions:
P2Y12 inhibitor monotherapy is associated with a significantly lower risk for bleeding events compared with DAPT, without any compromise in ischemic prevention, among patients with hypertension undergoing PCI.
Abstract 124: Angiotensin-(1-12) Immunoneutralization: A New Approach To Hypertension Treatment
Authors: Ferrario Carlos M , VonCannon Jessica L , Fearn Miles , Saha Amit , Cheng Heng-Jie J , Ahmad Sarfaraz
Published: September 2022

There is a critical need to identify new therapeutic targets and treatments, given emerging data documenting the limited effectiveness of current antihypertensive drugs to have a marked impact in preventing target organ damage and cardiovascular death. While monoclonal antibodies (mAb) are revolutionizing the treatment of human diseases, including severe hypercholesterolemia, their applicability to long-term hypertension control remains unexplored. Identification of angiotensin-(1-12) [Ang-(1–12)] as a non-renin-dependent substrate for Ang II generation in rodents and humans led us to engineer a mAb directed against the C-terminus of human Ang-(1–12) [h-Ang-(1-12)] sequence. We utilized a model of hypertension expressing the human angiotensinogen (AGT) gene in the rat genome [TGR(hAGT)L1623 rats] to address the effectiveness of endogenous h-Ang-(1–12) immunoneutralization in controlling the elevated blood pressure and reversing hypertension-induced target organ damage. Acute delivery of the h-Ang-(1–12) mAb (30 mg/Kg, i.v.) in anesthetized hypertensive transgenic rats induced a prompt arterial pressure fall (M ± SE: -18 ± 6/-16 ± 3 mm Hg, n=7; p< 0.001) in the absence of corresponding heart rate changes. The antihypertensive effect of the h-Ang-(1-12) mAb triggered a rise in plasma renin concentrations (from 107 ± 24 to 381 ± 260 ng/mL/h) that was inversely correlated with the fall in mean arterial pressure (r= -0.92, p< 0.001). Prior intravenous delivery of aliskiren fumarate (3-5 mg/Kg, i.v.) while inducing a fall in arterial pressure did not mask the antihypertensive action of the h-Ang-(1-12) mAb. Extension of these acute effects of the h-Ang-(1-12) mAb to awake instrumented transgenic hypertensive rats given consecutive daily doses of the mAb (30 mg/Kg, i.m. x 4 -5 days, n=7) documented a trend for significant statistical drops in daytime blood pressure and no changes in heart rate. We conclude that Ang-(1–12) is an endogenous Ang II forming substrate participating in the control of arterial pressure in a humanized model of high blood pressure and that selective immunoneutralization of this alternate substrate is a promising and novel therapeutic approach to treat hypertension and prevent its adverse cardiovascular sequelae.
Abstract 135: Contribution Of Maternal Age To Trends In Pre-pregnancy Hypertension Prevalence In The United States From 1995-2019: A Kitagawa Decomposition Analysis
Authors: Cameron Natalie A , Hughes Zachary H , Petito Lucia C , Lloyd-Jones Donald M , Bello Natalie A , Grobman William A , Khan Sadiya S
Published: September 2022

Introduction:
Prevalence of pre-pregnancy hypertension (HTN) has increased concurrently with maternal age in the US. We sought to understand the contribution of changes in maternal age vs. age-related HTN prevalence to trends in pre-pregnancy HTN.

Methods:
We included individuals aged 15-44 years old with a singleton first live birth in 1995-1999 and 2015-2019 from the National Vital Statistics System. We calculated the prevalence of pre-pregnancy HTN per 1,000 live births in 1995-1999 and 2015-2019, overall and in each 5-year age group. Using a Kitagawa analysis, we decomposed change in prevalence into two parts: (1) change in maternal age distribution and (2) change in age-specific prevalence of pre-pregnancy HTN (rate component). Analyses were repeated by self-identified race and ethnicity.

Results:
From 1995-1999 to 2015-2019, the proportion of first births decreased from 53% to 39% in 15-24 year olds and increased from 47% to 61% in 25-44 year olds. Pre-pregnancy HTN prevalence increased from 6.4 in 1995-1999 to 16.7 in 2015-2019 per 1,000 live births (
TABLE
). Changes in maternal age distribution and age-specific prevalence were associated with 16% and 84% of the increase in pre-pregnancy HTN, respectively. While prevalence differed by race and ethnicity, changes in age-specific prevalence accounted for the majority of changes in pre-pregnancy HTN in each group.

Conclusions:
Adverse trends in pre-pregnancy HTN were driven primarily by increasing age-specific prevalence overall, and in all race and ethnicity groups. Public health efforts are needed to identify and target the cardiovascular risk factors driving these age-specific trends and improve maternal health.
Abstract 137: Projected Impact Of Non-pharmacologic Management Of Stage 1 Hypertension Among Lower-risk U.s Adults
Authors: Sims Kendra D , Wei Pengxiao , Bellows Brandon K , Penko Joanne , Hennessy Susan , Kazi Dhruv S , Boylan Ross , Moran Andrew E , Bibbins-Domingo Kirsten
Published: September 2022

Introduction:
The 2017 ACC/AHA guidelines lowered the diagnostic blood pressure (BP) threshold, resulting in a new hypertension diagnosis for millions of younger, lower-risk U.S adults. Clinicians are encouraged to counsel these patients on health behavior modification. However, the potential population-level benefits from these non-pharmacologic interventions have not been assessed.

Methods:
We used the Cardiovascular Disease (CVD) Policy Model to simulate CVD events, mortality, and healthcare costs between 2018 and 2027. Simulations targeted US adults aged 35-64 years with untreated systolic BP 130-139 mmHg. Based on 2015-2018 NHANES estimates, we defined individuals as lower-risk based on not having diabetes, chronic kidney disease, or CVD and a predicted <10% 10-year CVD risk. Inputs for effects of dietary modification, sustained weight loss, physical activity, smoking cessation, and alcohol moderation on SBP were from published meta-analyses and trial data.

Results:
Of the estimated 8.7 million U.S. adults (50.6% women) aged 35-64 with lower-risk stage 1 hypertension, 5.5 million (61%) had regular healthcare access. Controlling BP to <130 mmHg in the full target population could prevent 27,000 CVD events, avoid 2800 deaths, and save an associated $16 million healthcare costs. We would see the largest benefit from adoption of the Dietary Approaches to Stop Hypertension (DASH) diet, with an estimated 16,000 CVD events prevented among men and 11,000 among women (Figure).

Conclusion:
Substantial health and economic benefits could result from widespread adoption of non-pharmacologic interventions in lower-risk U.S. adults with Stage 1 hypertension.
Abstract A1: Sglt2 Inhibition Via Empagliflozin Improves Endothelial Function And Reduces Mitochondrial Oxidative Stress: Insights From Hypertensive And Diabetic Frail Elders
Authors: Mone Pasquale , Varzideh Fahimeh , Jankauskas Stanislovas , Pansini Antonella , Lombardi Angela , Santulli Gaetano
Published: September 2022

Background:
Frailty is a multidimensional condition very common in older adults that leads to physical impairment. Frail older adults have an increased risk of adverse outcomes such as disability, hospitalization, and mortality. Hypertension and diabetes are prevailing comorbidities in frail elders.

Methods:
We studied consecutive frail older patients presenting at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to January 2021. Exclusion criteria were: absence of frailty, hypertension, and diabetes; age <65 years; left ventricular ejection fraction <50%; previous myocardial infarction. In all patients we assessed blood samples for glycemia, HbA1c and creatinine; a physical frailty evaluation was performed following the Fried Criteria.

Results:
We evaluated 407 patients; 325 frail elders with diabetes and hypertension successfully completed the study. We propensity-score matched 75 patients treated with empagliflozin and 75 with no empagliflozin. We observed a strong correlation between glycemia and Montreal Cognitive Assessment (MoCA) Score (r
2
: 0.91; p<0.001) and between glycemia and 5 meters gait speed (5mGS) (r
2
: 0.79; p<0.001). We tested the differences in MoCA Score at baseline and at 3-month follow-up in empagliflozin treated and non-treated groups (20.32
vs.
22.41, p<0.01; 20.34
vs
. 20.71). Moreover, we measured the differences in 5mGS (0.60
vs
. 0.64, p<0.05; 0.58
vs
. 0.59). We evaluated how many patients had frailty; the empagliflozin-treated group, at 3-month follow-up, only showed 25.3% of patients with frailty (n: 19), while the non-treated group had 73.3% of patients with frailty (n: 55) (p<0.001). Our results were confirmed by regression analyses with basal MoCA Score or 5mGS as the dependent variables, after adjusting for several covariates. Mechanistically, we found that Empagliflozin significantly reduced mitochondrial ROS production and leakage triggered by high glucose conditions in human endothelial cells.

Conclusions:
Taken together, our data indicate that empagliflozin treatment reduced frailty in diabetic and hypertensive patients, by reducing mitochondrial oxidative stress in endothelial cells.
Abstract P013: Hypertension Is Associated With High Risk Of Heart Failure Mortality
Authors: Iqbal Aqsa , Sulley Sannie , Egolum Ugochukwu
Published: September 2022

Introduction:
Heart failure is a growing public health issue with an estimated prevalence of 4-5million in the United States. Despite significant advances in heart failure management, the mortality rates remain high. This study investigates the risk factors that are associated with higher mortality rates in hospitalized patients with heart failure.

Methods:
We utilized the 2019 National Inpatient Sample (NIS) dataset sponsored by the Agency for Healthcare Research and Quality (AHRQ). Patients with heart failure (HF) were identified by using Clinical Classifications Software Refined (CCSR) for International Classification of Diseases, Tenth Revision, and Clinical Modification (ICD-10-CM). Variables of interest included complicated diabetes, complicated hypertension, peripheral vascular disease (PAD), intra-cardiac thrombi, and long term use of anticoagulation. Clinical outcomes included HF hospitalizations and effect of the different variables on HF mortality.

Results:
A weighted total of 5,675,784 HF related hospitalizations were recorded in 2019. A total of 753,994 (68.9%) had hypertension, 37,450 (0.66%) were on long term anticoagulation use, 651,035 (11%) had PAD, 36,575 (0.67%) had an intra-cardiac thrombi, and 2,080,710 (36%) had complicated diabetes. The mortality rate per 10,000 HF hospitalizations were analyzed. There were 4,707 deaths due to complicated hypertension as compared to 2,953 in the non-hypertensive population. 2,853 deaths due to intra-cardiac thrombi were found as compared to 2,208 deaths in patients without intra-cardiac thrombi. Mortality rate was found to be 1,649 in patients with long term anticoagulant as compared to 2,252 in patients not on anticoagulant. PAD lead to 2,432 deaths per 10,000 as compared to 2,183 deaths in patients without PAD. The mortality rate due to complicated diabetes was 2,368 as compared to 2,122 deaths in non-diabetic patients.

Conclusion:
Heart failure leads to a significant number of hospitalizations in the United States annually, as seen in 2019. Among all the factors studied, hypertension was found to be associated with highest risk of mortality. This study emphasizes the importance of strict blood pressure control in decreasing mortality associated with heart failure.
Abstract P022: The Geographic Variations In Hypertension Medication Adherence
Authors: Schoenl Samantha A , Hyder Syed A , Kesiena Onoriode
Published: September 2022

Objective:
Hypertension (HTN) affects 47% of adults in the United States (US). Medication adherence is difficult to achieve due to its benign course. This study aims to characterize the difference in HTN medication adherence between major regions of the US and the incongruity between urban and rural areas.

Methods:
This is a cross-sectional study consisting of 11,494 persons, representing over 71 million adults in the US, with a diagnosis of HTN. Data was obtained from the National Health Interview Survey in 2020. Variables include HTN medication adherence, access to regular care, household region, and urban-rural classification as defined by the National Center for Health Statistics. Chi-square test and logistic regression was used to compare the study groups.

Results:
HTN medication adherence was 75.6% in large urban (LU), 81.5% in large fringe urban (FU), 81.1% in medium urban (MU), and 83.3% in nonmetro (NM) areas [p < 0.001]. Using urban as the baseline comparison for a logistic regression model, a statistically significant difference was observed between LU and each individual group [p < 0.001] . This association remained significant when adjusting for covariates of BMI, marital status, insurance status, race, and age [p < 0.001]. Also, patients in LU were least likely to have a regular healthcare provider at 94.7% followed by 95.9% in FU, and 97.0% in MU and NM [p < 0.01].

Adherence across U.S. regions, defined as Northeast, South, Midwest, and West was statistically significant [p <0.01]. On logistic regression, West had a significantly lower adherence rate at 76.6% when compared to other regions [OR 0.69; 95% CI 0.56, 0.85; p < 0.05]. The odds increased further when adjusting for covariates of BMI, marital status, insurance status, race, and age [AOR 0.74; 95% CI 0.58, 0.95; p < 0.05].

Conclusion:
Urban areas are associated with lower rates of HTN medication adherence with increasing adherence in smaller communities. Additionally, Western US is correlated with a lower adherence rate compared to other regions. Further investigation into sources for this discrepancy is warranted, including potential differences in public health campaigns, prescribing practices, and follow up care. This knowledge could assist in the development of targeted solutions.
Abstract P024: Longer Acting Antihypertensives Improve Blood Pressure Control
Authors: Bhikadiya Brisha , McManus Nicole , Rahner Erik , Heppenstall William , Pham Hung , Bedi Angad , Memon Rahat Ahmed , Penza Brian
Published: September 2022

Introduction:
Hypertension is a modifiable risk factor for cardiovascular and renal disease. It has been noted that blood pressure control has been decreasing over the past years throughout the US. In a quality improvement study, we are evaluating the effectiveness of longer acting antihypertensives in combination therapy with thiazide diuretic on blood pressure control in patients not sufficiently controlled.

Methods:
Participants included all clinic patients with diagnosed hypertension currently uncontrolled with BP >140/90. Their medications were modified to include a longer acting angiotensin II receptor blocker (ARB) and thiazide diuretic. Follow up visits were requested for 1 month and 3 months.

Results:
A total of 60 patients were started on longer acting ARB-thiazide therapy, of which 17 patients were included in analysis as follow up results were available. On follow-up visit, there was a mean decrease in blood pressure of 43.8 mmHg (95% CI 34.8 to 52.8, p <0.05) systolic and 18.9 mmHg (95% CI 11.9 to 25.9, p <0.05) diastolic. Of the 17 patients, 11 patients were switched from an ARB or an ARB-thiazide to a longer acting ARB-thiazide with a mean decrease in blood pressure of 41.0 mmHg (95% CI 30.5 to 51.5, p <0.05) systolic and 13.9 mmHg (95% CI 8.1 to 19.7, p <0.05) diastolic. Of the 11 patients, 7 were previously on an ARB-thiazide and switched to longer acting ARB-thiazide with a mean decrease in blood pressure of 33.5 mmHg (95% CI 24.7 to 46.2, p <0.05) systolic and 11.4 mmHg (95% CI 4.2 to 18.7, p <0.05).

Conclusion:
Including long-acting ARB and thiazide in antihypertensive regimen provided a statistically significant decrease in blood pressure.
Abstract P025: Cite-seq And Predixcan Analyses Identify Galectin-1 As A Potential Novel Mediator Of Heart Failure With Preserved Ejection Fraction In Mice And Humans
Authors: Wassenaar Jean W , Smart Charles D , Fehrenbach Daniel J , Dungan Matthew , Amanda C Doran , Shuey Megan M , Madhur Meena S
Published: September 2022

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome where patients, despite having a normal left ventricular systolic function, present with symptoms of volume overload. Recent data have shown that HFpEF is associated with elevation of inflammatory biomarkers. In a well-known rodent hypertensive model (DOCA-salt), we isolated CD45+ leukocytes from the heart and then performed CITE-Seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, on a total of 4,359 and 7,600 cells from four sham and four DOCA-salt left ventricles, respectively. Analysis showed significant differential gene expression in the myeloid (macrophage/monocytic) population. We then took the top 20 genes that were differentially expressed between DOCA-salt vs sham treated myeloid cells and performed a genetic analysis called PrediXcan in Vanderbilt’s DNA databank, BioVU. Our analysis used gene expression prediction models built from the GTEx Project and tested its association with the HFpEF phenotype, which was derived on ICD-9 and 10 codes and natural language programming. From BioVU, 88,660 subjects were included in the association analysis. Of the 20 genes, 8 did not meet prediction model criteria for PrediXcan. In the remaining 12 genes, genetically predicted expression of only 2 (
Lgals1
and
Ctsl
) are associated with a HFpEF phenotype. Of these, the gene encoding galectin 1,
Lgals1
, had the lowest p-value (0.02) and highest beta coefficient (0.32) corresponding to an odds ratio for HFpEF of 1.38. Galectin-1 is a well known mediator of inflammation resolution in infection and tumor biology, however its role in heart failure is unknown. We are currently exploring the role of galectin-1 in the pathophysiology of HFpEF through Lgals1
-/-
and

LysM-Cre x Lgals1
fl/fl

mice. In conclusion, using two different approaches in mice and humans, we identified galectin-1 as a new potential mediator in HFpEF development.
Abstract P030: Racial Difference In The Association Of Albuminuria With Blood Pressure: Analysis Of The National Health And Nutrition Examination Survey 2017 - 2020
Authors: Tantisattamo Ekamol , Wattanachayakul Phuuwadith , Thimphitthaya Chanattha , Lopimpisuth Chawin , Lalitnithi Pakin , Pangkanon Watsachon , Chaisrimaneepan Nattanicha , Wannaphut Chalothorn , Naunsilp Piengpitch
Published: September 2022

Background:
Black is among the higher risk of albuminuria, the association between albuminuria and BP in different racial populations with relatively normal kidney function is unclear.

Methods:
A cross-sectional study including participants (>/= 18 years old) in the 2017 - 2020 NHANES was examined for the association between urinary albumin/ creatinine ratio (ACR) and BP by multiple linear regression.

Results:
Of 11,137 participants, the mean±SD age was 50±19 y/o and 51% were female. White accounts for 35% followed by Black (26%), Asian (12%), Mexican American (12%), Hispanic (10%), and others (5%). Median (IQR) serum creatinine (SCr) was 0.82 (0.68 - 0.98) mg/dL and median ACR was 7.59 (4.86 - 14.90) mg/g of Cr. Three-average measured SBP and DBP were 124±19 and 74±12 mmHg, respectively (Figure 1A and 1B). There was 1.1 and 0.2 mmHg increase in SBP and DBP, respectively for every 100 mg/g of Cr increase in ACR (β
SBP
0.011, 95%CI 0.009, 0.012 and β
DBP
0.002, 95%CI 0.001, 0.003). After adjusting for age, gender, race, BMI, SCr, dietary sodium and potassium intakes, and the interaction term between ACR and race, every 100 mg/g of Cr increase in ACR was associated with 16 mmHg greater SBP; while only 5 mmHg increase in DBP with no statistical significance (β
SBP
0.162, 95%CI 0.020, 0.305 and β
DBP
0.050, 95%CI -0.040, 0.140). Race was found to modify the SBP - ACR association with a stronger inverse association among Black (P
interaction Black
0.042) but not an effect modifier of the association between DBP and ACR.

Conclusions:
Albuminuria was associated with higher SBP and DBP, but this association for SBP was attenuated in Back. Studies are required to elucidate the relationship in long-term outcomes.
Abstract P033: Effect Of Acetaminophen On Blood Pressure: A Systematic Review And Meta-analysis Of Randomized Controlled Trials
Authors: Gupta Rahul , Behnoush Amir Hossein , Egeler David , Aronow Wilbert S
Published: September 2022

Introduction:
Acetaminophen is one of the most widely used over the counter medications, used for its analgesic and antipyretic properties. NSAIDs have been known to raise blood pressure, but there have been limited studies looking at the effect of acetaminophen on blood pressure. Observational studies have shown contradictory results regarding the effect of acetaminophen on blood pressure.

Purpose:
We aimed to perform a systematic review and meta-analysis of the randomized controlled trials (RCTs) to compare the effect of acetaminophen vs placebo on systolic and diastolic ambulatory blood pressure.

Methods:
A systematic comprehensive search using Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement was done in PubMed, Embase and Cochrane library for the RCTs investigating the effect of acetaminophen on blood pressure in patients compared to placebo. Standardized mean difference (SMD) and 95% confidence interval was used to compare the changes in blood pressure and p-values of <0.05 was considered as statistically significant. Finally, subgroup analysis was performed when possible.

Results:
Systematic search through April 2022 resulted in 3 relevant trials. The analysis showed that the patients receiving acetaminophen had significantly higher systolic blood pressure compared to those having placebo (SMD = 0.35, 95% CI = 0.08-0.63, p-value = 0.01). Moreover, subgroup analysis of the effect on hypertensive patients showed the significant change in systolic blood pressure as well (SMD = 0.38, 95% CI = 0.05-0.71, p-value = 0.02). In terms of diastolic pressure, our analysis showed that there is not any significant change in blood pressure when comparing acetaminophen and placebo (SMD = 0.18, 95% CI = -0.09-0.45, p-value = 0.19). This effect remains insignificant even after subgroup analyzing for hypertensive patients with SMD of 0.09 (95% CI = -0.34-0.52, p-value = 0.68).

Conclusion:
Our study demonstrated a significant correlation between the use of acetaminophen and elevated systolic blood pressure. This adds to concern regarding the safety of regular acetaminophen use, particular in patients with pre-existing hypertension or cardiovascular risk factors.