bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 062: Lower Middle Cerebral Artery Resistance In A Transgenic Rat Model Of Preeclampsia: A Platform For Studying Long-term Preeclampsia Induced Cerebrovascular Disease
Authors: Ray Jonathan W , Sun Xuming , Shaltout Hossam , Yamaleyeva Liliya M
Published: October 2023

Preeclampsia (PE) is a pregnancy disorder characterized by new onset hypertension and end-organ dysfunction. PE patients have increased risk of cerebrovascular disease (CVD) later in life; however, the mechanisms are unclear. We determined whether exposure to a PE-like syndrome in transgenic rat (TGA-PE: female TG for angiotensinogen mated to male TG for renin) alters left middle cerebral artery (LMCA) or left internal carotid (LICA) artery hemodynamics at 2 or 5 months post-pregnancy. The analyses of systolic (SBP) and diastolic (DBP) blood pressures and heart rate (HR) (by tail cuff; NIBP-8 Columbus Instruments), and LMCA and LICA pulsatility index (PI) (by transcranial Doppler (TCD); Vevo 2100), were performed at late gestation, and at 2 and 5 months post-pregnancy. SBP and DBP were elevated in TGA-PE vs. Sprague-Dawley (SD) in late pregnancy (n=5-6), and at 2 (n=4-6), and 5 months (n=2-3) post-pregnancy (p<0.05). HR was elevated in TGA-PE vs. SD in late pregnancy (493.5±10.6 vs. 392.5±14.2, p<0.05, n=5-6), but not at 2 or 5 months post-pregnancy. However, LMCA PI was lower in TGA-PE vs. SD at 2 months post-pregnancy (p<0.05), and tended to decrease in late gestation and at 5 months post-pregnancy. LICA PI was lower in TGA-PE vs. SD during pregnancy (0.729 ± 0.086 vs 1.34 ± 0.095, p<0.05, n=4-5). In summary, PE-like syndrome in TGA-PE resulted in higher SBP and lower LMCA resistance versus SD at 2 months post-pregnancy, suggesting a dysfunctional autoregulation of cerebral blood flow. Since women with history of PE have lower MCA resistance, we conclude that TGA-PE model may provide a suitable platform to investigate the mechanistic link between PE and future development of CVD.
Abstract 067: Suppression Of The Renin Angiotensin Aldosterone System In Human Hypertensive Pregnancy
Authors: Shoemaker Robin C , Poglitsch Marko , Huang Hong , Vignes Katie , Bauer John A , Cockerham Cynthia , O'Brien John
Published: October 2023

In healthy pregnancy, elevated renin activity stimulates aldosterone release via angiotensin II (Ang II) signaling. Despite the known importance in blood volume expansion, mechanisms of aldosterone secretion during pregnancy are not well understood.
In vitro
/
in vivo
evidence that aldosterone concentrations are disproportionally elevated compared to renin activity suggest altered sensitivity to Ang II or nonangiotensin stimulation during pregnancy. We used a novel LC-MS/MS-based methodology to quantify serum biomarkers of the renin-angiotensin-aldosterone system (RAAS) in order to evaluate renin-aldosterone relationships in healthy and hypertensive human pregnancy. We recruited 73 pregnant individuals with no known hypertension and followed them prospectively for the development of gestational hypertension or pre-eclampsia outcomes (HYP, n=27), no adverse outcomes (No AO, n=27), or adverse outcomes that were non-hypertensive (AO, Non-HYP, n=20). Concentrations of Ang peptides I and II and aldosterone were quantified from first and third trimester serum. Blood pressure was elevated starting in the first trimester in women who developed HYP outcomes (P<0.01). Renin activity (calculated by [Ang I + Ang II]) and aldosterone concentrations significantly increased from first to third trimester in No AO and AO Non-HYP (renin activity, 30% and 37% increase; aldosterone, 230% and 238% increase, respectively, P<0.001). This was in contrast to HYP pregnancies, where renin activity and aldosterone increased by 19% and 70%, respectively, and were not significant(P=0.54). Further, third trimester aldosterone was significantly lower, median (interquartile range) = 492 (260 - 827) pmol/L compared to No AO = 828 (467-1778) and AO Non-HYP = 1046 (527 - 1368) pmol/L (P<0.01). There was a significant increase in the aldosterone to Ang II ratio over gestation in No AO and AO Non-HYP pregnancies(P<0.01), but not HYP. Taken together, we propose that activity of the RAAS is suppressed in pregnancies that develop hypertension, likely a compensatory response to already-elevated BP. Further, non-hypertensive pregnancy is characterized by a preferential increase in aldosterone, where mechanisms may be impaired in pregnancies that develop hypertension.
Abstract 071: Seated And Supine Blood Pressure And Risk Of Cardiovascular Disease And Mortality From The Atherosclerosis Risk In Communities Study
Authors: Giao Duc M , Col Hannah , Larbi Kwapong Fredrick , Turkson-Ocran Ruth-Alma , Ngo Long H , Cluett Jennifer , Wagenknecht Lynne , Windham B Gwen , Selvin Elizabeth , Lutsey Pamela L , Juraschek Stephen P
Published: October 2023

Background:
Hypertension (HTN) while asleep is strongly associated with cardiovascular disease (CVD) and death. Whether HTN while supine in clinic is a risk factor for CVD independent of seated BP remains unknown.

Objectives:
To determine the relationship between supine HTN and adverse CVD.

Methods:
The Atherosclerosis Risk in Communities (ARIC) Study measured supine and seated BP during visit 1 (1987-1989). Supine HTN was defined as a supine systolic BP (SBP) ≥130 or diastolic BP (DBP) ≥80 mm Hg and seated HTN was defined as a seated SBP ≥130 or DBP ≥80mm Hg. We excluded participants with a history of coronary heart disease (CHD), heart failure, or stroke and examined the association of supine HTN with incident CHD, heart failure, stroke, fatal CHD, and all-cause mortality using Cox models adjusted for seated HTN and CVD risk factors. Analyses were repeated in strata of HTN treatment.

Results:
Of 11,369 participants (56% female, 25% Black, mean age [53.9±5.7 years]), 16% of those without seated HTN had supine HTN, while 74% of those with seated HTN had supine HTN. Over a median of 25-28 years of follow-up, despite adjustment for seated HTN, supine HTN was associated with incident CHD (HR 1.60; 95% CI: 1.45, 1.76), heart failure (1.83; 1.68,2.01), stroke (1.86; 1.63, 2.13), fatal CHD (2.18; 1.84, 2.59), and all-cause mortality (1.43; 1.35,1.52). Results did not differ by HTN medication use (
P
-interactions >0.05). Participants with supine HTN alone, had a risk similar to HTN in both positions (
Figure
).

Conclusion:
Participants with supine HTN had a significantly higher risk of adverse CVD events independent of seated HTN. Supine HTN screening should be further evaluated in a clinical trial.
Abstract 075: Ketone Bodies Rescue Mitochondrial Dysfunction And Improve Maladaptive Epigenetic Remodeling In Heart Failure
Authors: Varzideh Fahimeh , Jankauskas Stanislovas S , Kansakar Urna , Sidoli Simone , Gambardella Jessica , Santulli Gaetano
Published: October 2023

CATEGORY: Genetics, Epigenetics and Epidemiology

Ketone Bodies Rescue Mitochondrial Dysfunction and Improve Maladaptive Epigenetic Remodeling in Heart Failure

Fahimeh Varzideh
1
, Stanislovas S. Jankauskas
1
, Urna Kansakar
1
, Simone Sidoli
1
, Jessica Gambardella
1
, Gaetano Santulli
1
1
: Albert Einstein College of Medicine, 10461, New York, NY, USA

Background:
The exact molecular processes leading to the progression of post-ischemic heart failure (HF) are not fully understood.

Methods:
we carried out a comprehensive and coordinated set of
in vivo
and
in vitro
experiments using human cardiac specimens from patients with post-ischemic HF and healthy controls, a mouse model of HF, and mechanistic studies
in vitro
.

Results:
We identified, for the first time to our knowledge, a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and one methylation of lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF, murine HF, and
in vitro
models. To translate our findings
in vivo
, we used an established murine model of HF induced by myocardial infarction, obtained by permanent ligation of the left anterior descending coronary artery. After surgery, the mice were fed standard diet or diet supplemented with β-hydroxybutyrate (BHB), the most abundant ketone body in humans, for one month. Mechanistically, we demonstrate that the histone modification H3_K27me2K36me1 mediates the ischemia-induced transcriptional repression of PPARG Coactivator 1α (PGC1α), a master regulator of mitochondrial function and biogenesis. Strikingly, both the augmented H3_K27me2K36me1 and the PGC1α-mediated mitochondrial dysfunction were significantly attenuated by the treatment with BHB, revealing an unprecedented molecular pathway coupling metabolism to gene expression. The increased circulating levels of ketone bodies observed in HF patients treated with SGLT2 inhibitors further supports our preclinical results.

Conclusion:
Collectively, our findings establish maladaptive chromatin remodeling as a key mechanism in post-ischemic heart injury, functionally modulated by ketone bodies.
Abstract 080: The Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction In Preclinical Non-diabetic Chronic Kidney Disease
Authors: Lima Posada Ixchel , STEPHAN Yohan , Soulié Matthieu , Palacios-Ramirez Roberto , Bonnard Benjamin , Kolkhof Peter , Mulder paul , Jaisser Frederic
Published: October 2023

Background:
The mineralocorticoid receptor (MR) plays an important role in the development of Chronic Kidney Disease (CKD) and its overactivation contributes to the progression of cardiovascular complications. Antagonizing the overactivation of the MR with MR antagonists (MRA) is a therapeutic option. Finerenone, is a non-steroidal MRA recently studied in two large clinical trials showing the beneficial effects lowering the risks of CKD progression and cardiovascular events in stage 1 to 4 CKD patients with type 2 diabetes (T2D) (FIDELIO-DKD and FIGARO-DKD trials)

Aim:
To test whether finerenone improves renal and/or cardiac functions in preclinical non-diabetic CKD.

Methods:
non-diabetic CKD was induced by 5/6 nephrectomy in 6 weeks old Sprague Dawley rats. Finerenone (10 mg/kg/day) was administered as preventive or as curative treatment. Left ventricle (LV) function/hemodynamics, LV tissue perfusion and GFR were assessed in vivo at the age of 24 weeks.

Results:
12 weeks after 5/6 nephrectomy, the rats showed classical signs of CKD: reduced GFR and increased kidney weight; associated with LV diastolic dysfunction confirmed by increased in LV end-diastolic pressure (LVEDP), LV relaxation constant (Tau) and LV end-diastolic pressure volume-relation (LVEDPVR), while LV perfusion was reduced. Both prevention and curative treatment with finerenone reduced significantly both LVEDPVR and Tau; and increased LV tissue perfusion. Finerenone treatment did not impact reduced kidney GFR but reduced renal hypertrophy.

Conclusion:
Both preventive and curative finerenone improves non-diabetic CKD related LV diastolic function, independently from changes in kidney function.
Abstract 081: Transactivation Of Brain ADAM17 In Angiotensin II-Induced Hypertension Can Be Prevented By Kinin B1 Receptor Blockade
Authors: Theobald Drew , Sriramula Srinivas
Published: October 2023

A disintegrin and metalloprotease 17 (ADAM17) has been implicated in mediating inflammation in several cardiovascular diseases. Targeting brain ADAM17 using siRNA revealed a reduction in blood pressure, confirming its role in hypertension. Previously, we reported that kinin B1 receptor (B1R) activation increases ADAM17 activity in primary hypothalamic neurons, while pretreatment with a B1R antagonist mitigated this effect. However, whether there is a direct interaction between ADAM17 and B1R in hypertension is unknown. In this study, we tested the hypothesis that B1R blockade will prevent the transactivation of ADAM17, thereby, preventing the development of angiotensin II-induced hypertension. Male and female C57BL/6NJ wild-type (WT) and B1R knockout mice (B1RKO) were administered Ang II (600 ng/kg/min; SC, 2 weeks) or saline via osmotic minipumps. Ang II infusion significantly increased mean arterial pressure (radiotelemetry) in WT mice (145 ±13 mmHg vs. 103 ±6, n=6, p<0.01), which was attenuated in B1RKO mice. Both male and female B1RKO mice showed similar attenuation of Ang II-induced hypertension. Ang II-infusion led to a significant upregulation of ADAM17 in the PVN of WT mice and was blunted in B1RKO mice (p<0.05, n=3). Proximity ligation assay (PLA) was used to examine close proximity (<40nm) interactions between two receptors. ADAM17-B1R interactions in the PVN of hypertensive mice were significantly increased (p<0.05, n=3). To further understand this correlation, primary neurons and microglia from the hypothalamus of neonatal WT mice were cultured and treated with Ang II (300 nM) for 24 hours. Ang II increased B1R and ADAM17 protein expression in both cell types and was prevented by a B1R antagonist SSR240612 (10 uM) (p<0.05, n=5). To supplement these findings, PLA was used on primary neurons and microglia and revealed an increase in ADAM17-B1R interactions following Ang II. Furthermore, B1R antagonism attenuated this ADAM17-B1R interaction in both neurons and microglia (p<0.05, n=5). Our data provides novel evidence that B1R blockade can attenuate Ang II-induced hypertension in the brain, possibly through a reduction in B1R-ADAM17 interactions, suggesting that B1R blockade may serve as a potential antihypertensive therapeutic agent.
Abstract 085: Monocytes-derived Cytokines Induce Endothelial Dysfunction In Primary Aldosteronism
Authors: Kantauskaite Marta , Wieners Rebecca , Rahman Masudur , Schmidt Claudia , Rump Lars Christian , Stegbauer Johannes
Published: October 2023

Due to aldosterone excess and its pleotropic effects, patients with primary aldosteronism (PA) are exposed to high rates of cardiovascular events. Endothelial dysfunction is the first step in the development of vascular disease and monocytes are an important immune cell type inducing vascular damage. Therefore, we measured endothelial function between PA patients and healthy controls and analyzed the impact of monocytes-derived cyctokines on the development of endothelial dysfunction. Endothelial function was measured in 13 healthy controls, 42 PA patients before and in 22 patients 6 months after initiation of a specific treatment using flow mediated dilation method (FMD). Monocytes were isolated from 6 healthy individuals as well as from 8 PA patients before and treatment. Cytokine profile was measured by a Human Cytokine 17-plex Assay (Bio-rad). The effects of monocyte-derived cytokines on endothelial function were studied by wire myography in pre-constricted thoracic aortic pieces of healthy mice. FMD was significantly lower among PA patients compared to controls. Surgical or pharmacological treatment significantly improved endothelial function in PA patients. Monocytes from untreated patients with PA secreted significantly higher concentrations of the following cytokines and growth factors than healthy controls: G-CSF, IFN-γ, TNF-α, IL-6, IL-10, IL-8, IL-17, and MCP-1. Especially concentrations of IL-6 (388 (351-580)pg/ml vs. 36(4-268)pg/ml, p<0.05) and TNF-α (95(48-135)pg/ml vs 17(5-41)pg/ml, p<0.05) were much higher among PA patients. In pre-constricted murine aortas, 24 hours incubation of the secretome from untreated patients with PA induced an impaired endothelial vasodilation compared to the secretome of the controls. Interestingly, in comparison to untreated patients, treatment of PA not only reduced monocytes-derived cytokine levels, but also improved endothelial dysfunction in pre-constricted aortas incubated with the corresponding secretome. Endothelial function is impaired in PA. This impairment seem to be in part mediated by an increased release of pro-inflammatory cytokines from monocytes. PA treatment reduced the pro-inflammatory activity of monocytes and improved endothelial function.
Abstract 091: Efficacy Of A Patient-engagement Platform In Reducing Uncontrolled Hypertension In Community Health Clinics
Authors: Yermilov Irina , Coatney Randall , Soza Harry , Anderson Kenneth
Published: October 2023

Introduction:
Hypertension affects 47% of US adults and can lead to serious sequelae such as myocardial infarction and stroke when uncontrolled. Over 37 million US adults have blood pressure (BP) higher than 140/90 mmHg. Medication to treat hypertension is effective, yet, approximately 50% of patients do not take medication as prescribed and non-adherence to cardioprotective medications increases a patient’s risk of death from 50% to 80%.

Objective:
To use a novel patient engagement platform to assist federally qualified health centers (FQHCs) in improving BP control.

Methods:
We enrolled patients treated at FQHCs in a digital hypertension management program. Patients were prompted to submit their BP and responses to questions about medication adherence and potential side effects of medication either daily or weekly in English or Spanish. The responses were prioritized by level of concern. The clinic reviewed these data, in real-time and provided coaching or treatment changes. We analyzed first and last systolic and diastolic BPs of patients who participated for ≥90 days (range 90-721 days) and considered BP <140/90 mmHg to be controlled.

Results:
The cohort included 2500 patients, 38.6% male, with a mean age of 53.9 years (range 14-100 years) from 43 FQHCs across the US. Of these patients, 30.7% (768 of 2500) had an initial controlled BP and 61.2% (1529 of 2500) demonstrated a final controlled BP measurement. In patients with an initial uncontrolled BP, 55.4% (959 of 1732) had a controlled final BP. The Spanish language version was used by 551 patients, and in this subgroup, 35.2% (194 of 551) and 70.4% (388 of 551) had controlled BPs on initial and final measurements, respectively, with 66.0% (235 of 356) of initially uncontrolled patients having a controlled final BP.

Conclusion:
This novel hypertension control program, which used technology to gather and prioritize data, facilitating the clinic’s efficient response, improved BP control rates by over 30% in a real-world, underserved population. BP control was higher in the Spanish-speaking population. Remote digital monitoring with intervention improves clinical outcomes without increasing the overall cost of care, thereby promoting value-based care strategies for chronic diseases such as hypertension.
Abstract 099: Akr1b7

CreERT2

Mice, A New Time And Renin Cell-specific
Cre
Inducible Model
Authors: Medrano Silvia , Li Minghong , Liang Xiuyin , Sequeira Lopez Maria Luisa S , Gomez Roberto A
Published: October 2023

Gene targeting in renin cells has relied on either non-inducible
Cre
lines that can introduce developmental effects of gene deletion or BAC transgene-based inducible lines that may be prone to spurious and/or ectopic gene expression. To circumvent these problems, we generated an inducible mouse in which
CreERT2
is under the control of the
Akr1b7
locus.
Akr1b7
, an established marker of renin cells, is co-expressed with renin under different developmental, physiological, and pathological conditions. To study the pattern of
Cre
expression, we generated

Akr1b7
CreERT2/+

;

R26R
mTmG/+

mice in which
Cre
-expressing cells are labeled with GFP upon tamoxifen (Tmx) administration. At E18.5 and P5, GFP was found in Juxtaglomerular (JG) cells, along the arterioles, and in the glomerular mesangium. In adult kidneys, GFP expression was present mainly in JG cells. We did not observe any GFP
+
cells in vehicle-treated mice, indicating that Cre expression is tightly regulated in this model. In mice given 0.5 g/L captopril in the drinking water and a low-NaCl (0.1%) diet to induce recruitment of renin cells, GFP expression extended along the afferent arterioles and in the mesangium. To study the response to
Ren1
deletion in JG cells in the mice, we generated

Akr1b7
CreERT2/+
;Ren1
cFl/-
;R26R
mTmG/+

(

Ren1
c

cKO) mice. Compared to control mice,

Ren1
c

cKO mice exhibited a marked reduction in Ren1+ cells by immunostaining and a 80.1% reduction of
Ren1
mRNA levels by RT-qPCR (0.19 ± 0.04
vs
0.92 ± 0.26,
p=
0.0003). Plasma renin levels were significantly decreased in

Ren1
c

cKO versus control mice (12,5 ± 7,0 ng/ml
vs
53,7 ± 27,9 ng/ml,
p=
0.003). In addition,

Ren1
c

cKO mice had lower mean arterial pressures (68.91 ± 5.27 mmHg
vs
82.74 ± 2.63 mmHg,
p=
0.0001). When subjected to a low NaCl diet + captopril,

Ren1
c

cKO mice were able to recruit renin GFP+ cells along arterioles, mesangial cells, and large kidney arteries, suggesting that
Ren1
expression in JG cells is dispensable for recruitment. More importantly, the cells can be monitored/tracked by the expression of GFP even when they are unable to express renin.In summary,

Akr1b7
CreERT2

mice constitute a suitable model for the spatial and temporal control of gene expression in renin cells and the tracking of cells even when they are not expressing renin.
Abstract 106: Vascular Dysfunction In The Mesenteric Resistance Arteries Occurs Prior To The Occurrence Of Early-onset Alzheimer’S Disease In A Sex-dependent Manner
Authors: Waigi Emily W , Pernomian Laena , Townsend Paul , Wilson Emily W. , JA. McQuail , F. Hollis , McCarthy Cameron G. , Wenceslau Camilla F
Published: October 2023

Alzheimer’s Disease (AD) and cardiovascular diseases (CVDs) are a major cause ofdisability and death among the older population. Familial Alzheimer’s Disease (FAD) islinked with an early onset AD (EOAD) pathology (<65years) that manifests throughpathogenic mutations in the presenilin (PSEN)1 and PSEN2 genes, leading to theincreased production of central amyloid β (Aβ) peptides. There is increasing evidencethat elevated blood pressure and peripheral arterial stiffness contribute to thedevelopment and increase the risk of β-amyloid deposition in the brain leading to cognitivedecline later in life. We hypothesized that peripheral vascular remodeling and vasculardysfunction in the aorta and mesenteric resistance arteries (MRA) would be observedprior to the development of EOAD. The MRA of male and female C57Bl/6J (control) andAD mice (B6. CApptm1DboTg(APPswe,PSEN1dE9)85Dbo) at 9-weeks-old were isolatedprior to the onset of AD. Acetylcholine-induced relaxation (1pM-30μM) andphenylephrine-induced contraction (0.1nM-30μM) were evaluated using wire myography.Pulse wave velocity (PWV) and H&E staining were used to measure vascular stiffnessand morphology, respectively. Data were analyzed as non-linear curve regression andmaximum response (Rmax) using the Student
t
test (
p
<0.05*). MRA from AD miceshowed impaired relaxation in both males (Rmax: control 90±0.9
vs.
AD 59±6.4* %, n=3-4) and females (Rmax: control 90±2.8
vs.
AD 70±8.3*%, n=4-6). Interestingly,phenylephrine-induced contraction was reduced in arteries from males (Rmax: control11.7±0.9
vs
. AD 7.7±0.8* mN, n=3-4), but not in arteries from females (Rmax: control9.3±1.3
vs.
AD 8.1±0.6 mN, n=6-7). However, no differences were observed in the aortawall thickness in the male (control 51.8±2.9
vs.
AD 72±9.2 μm, n=3-4), or female (control63.7±9.8 vs. AD 54±4.8μm, n=2-3) AD mice, as well as the PWV analysis from male ADmice (control 2.41±0.44
vs.
AD 4.05±1.4 mm/ms, n=6). These data suggest that thechanges observed in the peripheral microvasculature prior to the onset of AD could laterhave direct effects on cerebral blood flow leading to areas of altered blood perfusion andmicrovascular damage, thus contributing to the genesis and maintenance of AD.
Abstract 110: Age-Dependent Hypertension-Induced Cognitive Impairment: Can We Prevent It?
Authors: Nist Kayla , Wainford Richard D
Published: October 2023

Aim:
We previously found age-dependent hypertension-induced cognitive impairment can be attenuated by losartan treatment for 3 weeks. We hypothesize that midlife administration of losartan will prevent the development of hypertension and hypertension-induced cognitive impairment.

Methods:
Male Sprague Dawley rats implanted with radiotelemetry probes at 8 months old (MO) were given losartan (10 mg/kg/day) or normal drinking water until 16 MO (N=4/gp) with 3 MO rats as controls. Ang II (36 μg/kg IP) was used to confirm AT
1
R antagonism. Chlorisondamine (5 mg/kg IP) assessed sympathetic tone to the vasculature. Novel object recognition (NOR) test was performed at baseline and end of study. Blood brain barrier (BBB) integrity in the paraventricular nucleus (PVN) was assessed using dextrans infusion. Immunofluorescence for microglia (Iba-1), astrocytes (GFAP), and interleukin-6 (IL-6), was used to assess inflammation.

Results:
Young, 3 MO rats were normotensive and lacked neuroinflammation, BBB disruption, and had normal cognition. Losartan prevented an age-dependent increase in BP, however sympathetic tone to the vasculature remained elevated. Further, losartan prevented the development of hypertension-induced neuroinflammation and BBB disruption in the PVN. Lastly, losartan prevented cognitive impairment.

Conclusions:
Our findings show losartan attenuates the development of age-dependent hypertension and prevents the development of hypertension-induced cognitive impairment and neuroinflammation in the PVN. We speculate losartan may represent a new therapeutic approach for the prevention and treatment of cognitive impairment in the aging population.
Abstract 111: Accelerated Biological Aging As An Early Pregnancy Predictor Of Preeclampsia
Authors: Anderson Cindy M , Gillespie Shannon , Lesniak John , Joseph Joshua , Lin Shili
Published: October 2023

Introduction:
Inability to predict risk for preeclampsia represents a major limitation in prenatal care.

Hypothesis:
We expect that accelerated biological aging in early pregnancy is an important predictor of preeclampsia.

Aim:
The aim of this study was to determine the clinical relevance of maternal characteristics and a blood-based biomarker of accelerated biological aging in early pregnancy as a predictor of preeclampsia.

Methods:
In the discovery phase, we analyzed data from a prospective cohort of pregnant, nulliparous women (n=54). Maternal peripheral blood (MPB) was collected during the first trimester and DNA methylation was quantified using the Illumina Infinium 450K array. Six women developed preeclampsia during the assessed pregnancy and 48 women served as controls. In the validation phase, we analyzed publicly available data from the Prenatal Exposures & Preeclampsia Prevention Project (PEPP3) cohort study. MPB was collected during the first trimester with DNA methylation quantified using the Illumina Infinium 850K array among 28 cases and 28 controls matched for race, pre-pregnancy BMI, smoking history, and gestational age at sampling. For both phases, biological aging was estimated using established epigenetic clocks. Predictors of preeclampsia were identified using lasso regularization and random forest, with final models produced using logistic regression.

Results:
In the discovery cohort, accelerated biological aging, as well higher chronological age and greater gestational weight gain, were identified as important predictors of preeclampsia. Interestingly, only Hannum’s epigenetic clock (and not Horvath nor Levine’s epigenetic clocks) showed predictive power for preeclampsia. In the validation cohort, accelerated biological aging per Hannum’s epigenetic clock and chronological age also arose as important predictors of preeclampsia. Though weight gain data was not available for further analysis.

Conclusions:
Among women who developed preeclampsia, accelerated biological aging during early pregnancy may represent a risk biomarker that can be leveraged in clinical care. Findings represent the potential for a key clinical indicator for preeclampsia risk, addressing an important gap in screening and early diagnosis.
Abstract 119: Exploring The Role Of Rho-related BTB Domain Containing 1(RhoBTB1) And Phosphodiesterase 5(PDE5) To Identify Potential Proteomic Targets In Cardiovascular Function
Authors: Kumar Gaurav , Golosova Daria , Lu Ko-Ting , Brozoski Daniel T , Vazirabad Ibrahim , Sigmund Curt D
Published: October 2023

The study of macromolecular (protein:protein) interactions has significantly enhanced our comprehension of human impairments, such as cardiovascular diseases (CVDs). We previously identified that RhoBTB1 acts as a key regulator of vascular tone by associating with Cullin-3 (CUL3) to control the activity of phosphodiesterase 5 (PDE5) through the ubiquitination-proteasomal pathway. PDE5 selectively hydrolyzes cGMP thus regulating NO-mediated vasodilation. We hypothesized that the PDE5 binding region on RhoBTB1 could be responsible for binding to other unknown partners in RhoBTB1-CUL3 pathway. We truncated RhoBTB1 into its component domains individually (GTPase, BTB1, BTB2, and CT) and in combination (B1B2C, PB1B2, and B2C) and studied their interaction with PDE5 by co-immunoprecipitation (co-IP) in HEK293 cells. These analyses revealed that the B1B2C domain of RhoBTB1 is the minimal region required to bind PDE5. Interestingly, the CT region is essential as the truncations lacking CT could not participate in PDE5 binding and its subsequent proteasomal degradation. The GTPase and Proline-rich (P) domains were dispensable for binding of RhoBTB1 to PDE5. We identified that Pro
353
and Ser
363
are key amino acid residues in the B1B2C region involved in CUL3 binding to RhoBTB1. Mutation of these amino acids resulted in hampered binding to CUL3. The mutants failed to degrade PDE5 despite their preserved binding to PDE5. We employed ascorbate peroxidase (APEX2) labeling using a B1B2C-APEX2 fusion construct as a bait to identify unknown RhoBTB1 binding partners. As a contemporaneous screen, we used B1B2-APEX2 since it does not bind to PDE5, and therefore is not expected to bind to those unknown partners. We “filtered” the captured proteome for its interaction with B1B2C better than B1B2 (without the CT). SET Domain Containing 2 (SETD2) was among several B1B2C binding partners identified and validated. SETD2 and RhoBTB1 directly interacted, and the level of SETD2 increased in response to RhoBTB1-inhibition with siRNA, inhibition of proteasomal machinery either by pharmacological means or CUL3 editing. This suggests that SETD2 is regulated by the RhoBTB1-CUL3 axis. Future studies may pave a way to determine if SETD2 is important for cardiovascular function.
Abstract 128: Saline Load Induces Acute Changes In Ventricular Extracellular Volume And Mass
Authors: Bagordo Domenico , Cabrelle Giulio , Crimì Filippo , Nervo Giona , Ruzza Luisa , Bertoldi Giovanni , Seccia Teresa M , Pepe Alessia , Rossi Gian P , Rossitto Giacomo
Published: October 2023

Background:
Maladaptive left ventricular hypertrophy (LVH) in hypertension is generally regarded as a result of myocardial fibrosis. However, salt loading induces a systemic and isotonic expansion of the extracellular (EC) volume in tissues, which could affect myocardial structure independent of fibrosis.

Methods:
Cardiac MRI, including cine-images and native T1 and T2 mapping as surrogates for EC volume and myocardial water content, was performed immediately before and after a saline infusion test (SIT; 2L NaCL 0.9% in 4h) in patients with primary aldosteronism (PA), a prototypic sodium-retentive form of hypertension.

Results:
We enrolled 13 consecutive patients with PA (5F; 50±12 yo; BP=140/88±14/7 mmHg; sK
+
=3.7±0.4 mmol/L on KCl supplements; renin=2.5[2.0-4.8] mIU/L, aldosterone=568[368-737] pmol/L), lacking aldosterone suppression after SIT (562 [262-776] pmol/L, p=0.127). SIT induced a small but significant increase in wall thickness (septum: 9.0±1.5 vs 9.5±1.0 mm, p=0.027) and, overall, in left ventricular mass (56.3±9.1 vs 58.0±9.2 g/m
2
, p=0.026), paralleled by an increase in myocardial T1 (1012±29 vs 1027±25 ms, p<0.001) and T2 (49.9±2.0 vs 51.2±2.7 ms, p=0.012). After saline the left ventricular ejection fraction was mildly reduced (56[55-62] vs 53[51-59]%, p=0.023), reflecting an increase in end-systolic (ES) volume (38±10 vs 43±10 ml/m
2
, p=0.030) without significant changes in the end-diastolic (ED) volume (88±18 vs 91±16 ml/m
2
, p=0.114).

Conclusions:
Within a timeframe inconsistent with EC matrix remodeling, saline load induced an increase in ventricular mass and an expansion of the EC volume, i.e. edema, in a human model of salt-related disease.
Abstract 134: Role Of Epigenetic Mechanisms Regulating Renal Pathology And Disorders In Global
Npr1
Gene-targeted Mutant Mice In Sex-dependent Manner
Authors: Kumar Prerna , Neelamegam Kandasamy , Ramasamy Chandramohan , Pandey Kailash N
Published: October 2023

The objective of this study was to investigate the effect of class I-specific histone deacetylase inhibitor, mocetinostat (MGCD0103; MGCD) in the regulation of epigenetic mechanisms and renal pathology and disorders in
Npr1
(coding for natriuretic peptide receptor A; NPRA) gene-disrupted haplotype mice. Male and female
Npr1
gene-disrupted (1-copy;
+/-
), wild-type (2-copy;
+/+
) and gene-duplicated (3-copy; ++/+) mice were administrated with MGCD (2 mg/kg) by intraperitoneal injection at alternate days for 2-weeks. The renal NPRA protein levels and guanylyl cyclase (GC) activity were significantly lower in 1-copy mice and higher in 3-copy than in 2-copy mice; however, MGCD increased NPRA protein levels and GC activity. The vehicle-treated females showed lower SBP than male mice, whereas both sexes of 1-copy mice had higher SBPs, and 3-copy mice had lower SBPs as compared with 2-copy mice. Treatment with MGCD distinctly reduced SBP in male (1-copy, Δ-21±2.0 mmHg, p<0.001; 2-copy, Δ-5±0.6 mmHg, p<0.01; and 3-copy, Δ-4±0.5 mmHg, p<0.05) and female mice (1-copy, Δ-17±2.1 mmHg, p<0.01; 2-copy, Δ-3±0.5 mmHg, p<0.01; and 3-copy, Δ-3±0.8 mmHg). Hematoxylin and eosin staining showed pronounced renal morphological damages in 1-copy male than female mice as compared to 2-copy and 3-copy mice. One-copy male mice exhibited a greater degree of mesangial matrix expansion and interstitial nephritis as compared with 2-copy and 3-copy mice, which was significantly (p<0.1) decreased with MGCD treatment as compared with vehicle-treated mice. Creatinine clearance was significantly reduced in 1-copy male mice (52%; p<0.05) than female mice (35%; p<0.05) compared with 2-copy mice. The renal HDAC activity and HDAC1 and 2 protein levels in 1-copy male mice were significantly (p<0.05) higher than female mice as compared with 2-copy mice. MGCD markedly increased acetylation of histone marks (H3-K9, H3-K27, and H3-K18) and greatly reduced the renal pathologies as compared with controls. The present results demonstrate that MGCD upregulates NPRA activity and repairs renal pathology epigenetically in 1-copy haplotype mice. These findings will have important implications for treatment of hypertension and renal injury in humans in both sexes.
Abstract 138: Treatment Initiation During The First Month Following Hypertension Diagnosis Improves Blood Pressure Control Up To 30 Months
Authors: Barrett Robert B , Riesser Benjamin , Martin Ben , Sutherland Susan E , Rakotz Michael , Sachdev Neha , Egan Brent M
Published: October 2023

Background:
Adults with hypertension (HTN) have fewer cardiovascular events if controlled within the first 6 months after diagnosis, during which time they are excluded from many HTN control metrics. We compared BP control rates (BP <140/90) from 6 to 42 months in adults with HTN who did or did not have treatment initiated during the first month following diagnosis, irrespective of subsequent treatment initiation or intensification (TI).

Methods:
A patient cohort from 5 diverse healthcare organizations, engaged in a quality improvement program, was identified with previously undiagnosed and untreated HTN. TI and BP control were assessed by measuring the period prevalence of visit BP control and TI on uncontrolled visits, then compared with the time since diagnosis (TSD) up to 42 months. Groups were stratified by treatment initiation status during the first month.

Results:
A prospective cohort of 14,328 newly diagnosed and untreated persons with HTN was identified, mean age 56.2±14.7 years. Patients with TI during the first month had higher rates of BP control at 6 (56.2% vs 46.2%, p<0.001) through 30 months (65.9% vs 61.4%, p<0.001) than those initially untreated. Patients initiated during the first month were less likely to receive additional intensifications (OR 0.68, 95% CI [0.63-0.74]).

Conclusion:
TI in the first month after diagnosis results in better BP control at 6 months, which has prognostic importance and coincides with the time when these individuals impact standard HTN control metrics. Of concern, TI during the first month after diagnosis was insufficient to achieve control rates ≥70% and lowered the probability of subsequent TI.
Abstract P100: Paradoxical Increase In Post-Captopril Aldosterone
Authors: Cajina Aguirre Carmen L , Bhalla Vivek
Published: October 2023

Hypertension remains one of the strongest risk factors for cardiovascular disease. Primary aldosteronism, the most common form of secondary hypertension, can be confirmed using the captopril challenge test. This study aims to investigate a subset of patients who exhibit a paradoxical increase in aldosterone levels after the administration of captopril, despite the expected decrease in aldosterone production. A retrospective design was employed to evaluate patients who exhibited atypical captopril suppression test results. The cohort consisted of 120 patients who underwent the captopril suppression test as part of their diagnostic evaluation for resistant hypertension. Demographic data and clinical parameters were collected for each patient.Among the patients who tested positive on the captopril suppression test based on a post-aldosterone level criterion of >12 mg/dL, one-third exhibited an increase equal to or greater than 50% in aldosterone levels (9 out of 27).We proposed different theories to explain this phenomenon. Intraindividual variability, which has been previously reported with a laboratory coefficient of variation between 2.7% and 4.4%, was ruled out using a cut-off ≥ 50%. Another possibility is the presence of extraadrenal aldosterone production independent of the regulation provided by captopril or ATII. This could be attributed to unrecognized compensation of aldosterone production by extra-adrenal tissues in response to a decrease in adrenal aldosterone levels. Additionally, conditions such as preeclampsia, post-transplant acute rejection, autoimmune diseases, lupus, and primary hyperaldosteronism have been associated with increased aldosterone production by zona glomerulosa cells due to the presence of activating antibodies.There are certain limitations to this study. Other biochemical tests were not performed, and the sample size was relatively small, making it challenging to draw definitive conclusions. In conclusion, this study aims to contribute to our understanding of the pathogenesis of primary aldosteronism. The findings highlight the utility of the captopril suppression test as a biochemical confirmation test for the diagnosis of primary aldosteronism and resistant hypertension.
Abstract P102: Gender-based Stroke Risk In Patients With Afib And Heart Failure Treated With Mineralocorticoid Receptor Antagonists
Authors: Sharma Shriya , Paghdar Smit , Desai Smruti , Ruiz Jose , Goswami Rohan
Published: October 2023

Background:
Atrial fibrillation (AF) is the most common cardiac arrhythmia detected in hospitalized patients. It is independently associated with an increased risk of stroke. Anti-fibrotic properties of mineralocorticoid receptor antagonists (MRA) have been proposed to modulate AF burden. Gender differences in patients with AF exist within the epidemiology and causative mechanisms to outcomes and complications. We compared men and women with known AF while treated with MRA to assess potential differences in stroke rate.

Method:
After IRB approval, we performed a retrospective chart review of all patients with confirmed HF and AF diagnoses. Patient data were extracted from electronic medical records. Patients with AF and HF treated with MRA were included in this study.

Results:
64 patients with HF and AF treated with MRA were reviewed between January 2021 and September 2022. 34 were male, and 30 were female. Females were younger, 66 years (57 -74) compared to males, 73 years (60 - 78), p=.13. The median ejection fraction was similar among women, 42% (31 - 50) compared to men, 41% (33 - 49), p = .43. A significantly higher incidence of atrial fibrillation was found in our male group (59%) compared to the female group (30%), p=.02. There was no significant difference in MRA or anticoagulation use between male and female patients (p = .11, p = .12 respectively). More men had strokes compared to females (16% vs. 26% p = .17). Men were also more likely to be hypertensive compared to females (47% vs. 25%, p<.01).

Conclusion:
Men were more likely to have AF and stroke compared to females with HF on MRA therapy. Males were more likely to be hypertensive, which may relate to increased stroke rate in this patient population. Increased awareness of the gender-based prevalence of stroke rate in patients with HF and AF may allow for earlier recognition and reduction in stroke events.
Abstract P108: A Novel Target For CVD Treatment: The Adipokine Chemerin Drives Hypertensive Blood Pressure And Potentially Aortic Stiffening In Female Dahl SS Rats
Authors: Wabel Emma A , McClintock Dillon , Garver Hannah , Mullick Adam E , Fink Gregory D , Watts Stephanie W
Published: October 2023

Chemerin, an inflammatory adipokine, supports basal blood pressure in male and female Dahl SS rats and, to a greater degree, adiposity-associated hypertensive blood pressure in the male rat, evidenced by falls in mean arterial pressure following an antisense oligonucleotide (ASO)-mediated loss of chemerin protein. Liver-specific ASOs that abolished hepatic-derived chemerin yielded no change in blood pressure; thus, it must be extra-hepatic chemerin that supports blood pressure. Our current focus is investigating the role of vascular chemerin—that produced by the blood vessel and its perivascular adipose tissue (PVAT)—in adiposity-associated hypertension and cardiovascular disease (CVD) development. We hypothesized that male Dahl SS rats would be more dependent on chemerin for hypertensive blood pressure because male rats gain more visceral fat (and likely more PVAT) than females on a high-fat diet. Age-matched female Dahl SS rats on a control or high fat (60%) diet from weaning were used. Radiotelemeters were implanted to measure blood pressure (MAP). Acute knockout of chemerin was achieved by subcutaneous injection of whole-body ASO against chemerin or PBS (25 mg/kg) on days 0, 7, 14, and 21. On day 23, the rats were euthanized, and tensile tests were performed on isolated thoracic aortae. Chemerin mRNA (2
-
ΔCT
) was significantly reduced in the liver (C: 0.56 ± 0.07, ASO: 0.00 ± 0.00) and thoracic aorta (C: 0.03 ± 0.01, ASO: 0.00 ± 0.00). MAP in PBS rats had no significant change from baseline measurements (C:159.0 ± 7.5, HF: 170.2 ± 3.4 mmHg), while control and HF-diet females treated with ASO dropped 14.0 ± 1.2 and 28.5 ± 4.2 mmHg, respectively, after four injections. Pulse pressure also decreased 3.4 ± 1.1 and 6.8 ± 0.8 mmHg in ASO-treated control and HF females, respectively. Interestingly, localized vessel stiffness was modestly lower in ASO-treated vs PBS animals on control diet (PBS: 174.2 ± 14.2 ASO: 151.4 ± 24.2 kPa; N=4/group). These data suggest that chemerin plays a similar role in driving adiposity-associated hypertensive blood pressure in males and females; additionally, chemerin may be a blood pressure-independent risk factor for aortic stiffness. Future work aims to further uncover chemerin’s potential as a therapeutic target for CVD treatment.
Abstract P109: Antigen Presenting Cell Activator Protein 1 Mediates Salt-sensitive Hypertension In Humans
Authors: Ahmad Taseer , Saleem Mohammad , Pitzer Mutchler Ashley , Ertuglu Lale , Kirabo Annet
Published: October 2023

Salt-sensitivity of blood pressure (SSBP) is defined by the changes in blood pressure according to dietary sodium loading/depletion and is a major independent risk factor for morbidity and mortality due to cardiovascular disease, even in normotensive individuals. We previously found that SSBP is associated with activation of antigen presenting cells (APCs), but the underlying mechanisms are unknown. The activator protein 1 (AP-1) (Fos/Jun) has been implicated in mediating inflammation but its role in SSBP is not known. We hypothesized that AP-1 in APCs senses elevated sodium and contributes to SSBP. Using bulk RNA-sequencing in human monocytes, we found elevated sodium increases expression of the AP-1 gene family when compared to normal sodium concentration, including FOS (2378.18 ± 480.7 vs 6494.09 ± 945.55, p= 0.0009), FOSB (47.63 ± 17. 55 vs 56.06 ± 10.30, p= 0.5320), JUN (7313.90 ± 984.93 vs 11370.09 ± 1286.35, p= 0.2563) JUNB (4745.36 ± 599. 17 vs 5955.45 ± 600.91, p= 0.7620) and JUND (3309. 63 ± 270.64 vs 8057.90 ± 1043.05, p= 0.00006). In additional experiments, we enrolled people with hypertension and phenotype them for SSBP using an established in-patient protocol of salt-loading/depletion and performed single-cell transcriptomic analyses
in vivo
on PBMCs. We found that expression of the FOS and JUN genes change in concert with blood pressure after salt-loading and depletion in salt-sensitive but not salt-resistant humans. Our findings reveal a role for immune cell AP-1 signaling in salt-sensitive hypertension and may provide a potential target for treatment and diagnosis.
Keywords:
Activator protein 1 (AP-1), FOS, JUN, Salt-sensitive hypertension, Humans
Abstract P110: Appropriateness Of Online Resources For Home Blood Pressure Measurement: Alignment With Guideline Recommendations, Readability, And End-user Involvement.
Authors: Clapham Eleanor , Picone Dean , Carmichael Samuel , Sharman James , Chapman Niamh
Published: October 2023

Home blood pressure measurement (HBPM) is recommended for BP management. HBPM must be accompanied by patient education, which may be achieved via online resources. These HBPM-resources should provide information that aligns with guideline recommendations, communicate at the recommended grade-eight reading level, and involve end-users in development. Using these criteria, this study aimed to determine the appropriateness of online HBPM-resources. Online HBPM-resources were identified on Google using seven search terms developed with end-users and included if in English and freely accessible (n=24). HBPM-resource appropriateness was appraised by 1) alignment with 13 guideline recommendations encompassing core HBPM activities, 2) grade reading level as calculated by a validated health-literacy-assessment software, and 3) evidence of end-user involvement in HBPM-resource development. Thirteen of twenty-four (54%) HBPM-resources aligned with ≤6 of the 13 guideline recommendations. Only two of twenty-four (8%) resources aligned with all 13 recommendations. Very few HBPM-resources included recommendations to use a validated BP device (n=9 of 24, 38%); fit the BP cuff within the indicated range (n=3 of 24, 13%) or report average BP readings (n=6 of 24, 25%). None of the HBPM-resources were at a grade-eight reading level (mean 11.8, range 8.8 to 17) or reported that patient end-users were involved in resource development. Most online HBPM-resources do not fully align with guideline recommendations, and all exceed the recommended reading level for adults. These findings indicate a need to improve the appropriateness of online HBPM-resources, and involving end-users in development may be a means to achieve this.