bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 050: TLR4 Antagonism Prevents Early Left Ventricular Hypertrophy and Dysfunction Associated With Neonatal Hyperoxia Exposure
Authors: Mian Muhammad Oneeb Rehman , He Ying , Fernandes Rafael , Bertagnolli Mariane , Cloutier Anik , Luu Thuy Mai , Nuyt Anne Monique
Published: March 2022

Objective:
Preterm birth is associated with proinflammatory conditions early in life. Our lab has shown in rats that transient neonatal exposure to high O
2
, an established model of prematurity-related conditions, leads to early CV inflammation and remodeling. TLR4 signaling is a critical link between inflammation and the pathogenesis of CVD. Whether programmed innate immune activation, via TLR4 signaling, impacts long term CVD is unknown. In our rat model of prematurity we investigated whether neonatal TLR4 antagonism will prevent the development of CV dysfunction.

Methods:
Male Sprague-Dawley pups were kept with their mother in 80% O
2
or room-air from day (P)3 to 10 of life. At P10, cardiac TLR4 protein expression was assessed. In other experiments, pups were treated i.p. with TLR4 antagonist LPSRS (100 μg/kg) or vehicle (0.9% NaCl) at P3, P6 and P9 (concomitant to O
2
exposure; n=6-9/group, max 3 animals/group/liter). At 4, 7 and 12 wks, body weights were measured and left ventricular (LV) echocardiography was performed under isoflurane using VEVO 3100 (VisualSonics). At 12 wks, central mean BP was measured under isoflurane by catheterism (BIOPAC, n=4-6). Comparisons were made using T-test or one-way ANOVA.

Results:
At P10, cardiac TLR4 protein expression was increased ~2 fold in O
2
-exposed pups compared to room-air controls (P<0.05). At 4 wks, body weight in vehicle- or LPSRS-treated O
2
-exposed animals (101±2 g and 106±2 g) was lower compared to room-air vehicles (117±2 g, P<0.01). Compared to room-air vehicles, vehicle- but not LPSRS-treated O
2
-exposed animals exhibited increased LV mass index (3.8±0.1 and 3.4±0.1 vs 3.3±0.1 mg/g, P<0.05 for O
2
-exposed vehicles vs controls), reduced ejection fraction (74±2 and 79±2 vs 82±1 %, P<0.05) and fractional shortening (43±2 and 48±2 vs 52±2 %, P<0.01), reduced cardiac output index (0.43±0.02 and 0.48±0.02 vs 0.56±0.03 ml/min/g, P<0.01), and decreased mitral E/A ratio (1.3±0.1 and 1.7±0.1 vs 1.7±0.1 mg/g, P<0.01). Findings were similar at 7 and 12 wks. At 12 wks, mean BP was higher in vehicle- but not LPSRS-treated O
2
-exposed animals, compared to controls (95±4 and 89±4 vs 81±4 mmHg, P<0.05).

Conclusion:
TLR4 antagonism prevents BP rise and LV hypertrophy and dysfunction associated to neonatal exposure to hyperoxia.
Abstract 054: Visinin Like Protein 1 Regulation of Aldosterone Biosynthesis
Authors: Kuppusamy Maniselvan , Ishimwe Jeanne , Williams Tracy A , Mulatero Paolo , Gomez-Sanchez Elise P , Gomez-Sanchez Celso E
Published: March 2022

Visinin-Like Protein-1(Vsnl1) is a member of the EF-hand calcium sensor proteins. Its mRNA was found to be upregulated in aldosterone-producing adenomas and to be expressed in the zona glomerulosa (ZG) of the rat and human adrenal. We studied the expression pattern of Vsnl1 and its co-localization with the CYP11B2 enzyme and ZG marker Dlk1 (ZOG) using double and triple immunofluorescence in adrenal glands of rats on normal, high and low sodium diets and the effect of Vsnl1 on calcium mobilization and aldosterone biosynthesis in the human adrenocarcinoma cell line, the HAC15 cell. In rat adrenals, Vsnl1 was expressed only in ZG, in the same cells as Dlk1, in both functional and undifferentiated ZG cells. CYP11B2 co-localized with Vsnl1 in nearly all ZG cells of rats on a low sodium diet. Co-expression of CYP11B2 with Vsnl1 in adrenals of rats on normal and high sodium diets was significantly less. HAC15 were transduced with a lentivirus carrying Vsnl1 or an empty virus. Three days later cells were incubated with vehicle, A-II 10 nM, Forskolin 10μM, or potassium 16 mM. Aldosterone and cortisol were measured after 24 hr. Basal secretion of aldosterone was not increased; cortisol was. Aldosterone and cortisol secretion were greater after A-II, forskolin or potassium stimulation in cells overexpressing Vsnl1. Intracellular calcium measured by Fluo-4 AM dye and proliferation were increased by Vsnl1 overexpression. HAC15 cells were transduced with 2 different shRNA for Vsnl1. Aldosterone synthesis was reduced in HAC15 cells transduced with the shRNA for Vsnl1 stimulated with A-II. Vsnl1 has a myristoylation consensus sequence at the N-terminal domain. Site directed mutagenesis of Vsnl1 at the 2 position (G2A) resulted in a significant decrease in the aldosterone response to A-II. In summary, the calcium sensor protein Vsnl1 is ZG specific and detected in both steroidogenically active and inactive cells, as well as undifferentiated cells in the subcapsular area of the rat adrenal. Vsnl1 expression and activity in HAC15 cell correlate positively with calcium mobilization, proliferation and aldosterone synthesis.
Abstract 063: Mechanical Stretch on Endothelial Cells Promotes Monocyte Activation and Differentiation into Immunogenic Dendritic Cells via STAT3
Authors: Loperena Roxana , Itani Hana A , Gomez Jose A , Engel Noah , Kirabo Annet , Harrison David G
Published: March 2022

Mechanical stretch activates the endothelium to produce reactive oxygen species and expression of adhesion molecules and cytokines. Human monocytes that traverse the endothelium differentiate into dendritic cells (DCs) upon exposure to a pro-inflammatory state. We hypothesized that human endothelial cells exposed to mechanical stretch will promote conversion of human monocytes into activated DCs. We co-cultured human aortic endothelial cells (HAECs) with monocytes from normotensive human donors and exposed the endothelial cells to either normal (5%) or hypertensive (10%) uniaxial cyclical stretch for 48 hours. Co-culturing monocytes with HAECs exposed to 10% stretch showed a marked increase in pro-inflammatory cytokines such as IL-6, IL-23A and IL-1β compared to 5% stretch. HAECs exposed to 10% stretch promoted monocytes in culture to differentiate into DCs. We have shown that DCs from hypertensive mice accumulate isolevuglandins (IsoLGs) that adduct to proteins and promote T cell activation. Thus, we performed intracellular staining and flow cytometry and found that these monocytes significantly accumulate higher levels of IsoLG-adducted proteins compared to 5% stretch (69.7 ± 5.8 vs 10.8 ± 1.85, respectively). In addition, monocytes co-cultured with endothelial cells exposed to 10% stretch expressed phosphorylated STAT3 (pSTAT3), which was blocked by stattic, a STAT3 inhibitor. Similarly, monocytes co-cultured with HAECs exposed to 10% stretch induced a 1,500-fold and a 1,300-fold increase in CD4
+
and CD8
+
T cell proliferation; while, inhibition of STAT3 prevented this T cell proliferation. To test if this is due to cell-cell contact, we seeded monocytes in a transwell with endothelial cells exposed to either 5% or 10% stretch. We found that these monocytes expressed DC markers, pSTAT3, and accumulated IsoLG-peptides when exposed to hypertensive mechanical stretch. In addition, angiotensin II (490ng/kg/min) infusion of C57Bl/6 mice increased pSTAT3 in monocytes, macrophages, and DCs in the renal and vascular tissue compared to sham controls. Thus, our data indicate that endothelial cells exposed to mechanical stretch cross-talk with monocytes to promote differentiation into DCs known to be immunogenic via STAT3.
Abstract 069: Increased Stretch-induced O
2
-
Production in Dahl Salt-sensitive Rats is Mediated by TRPV4
Authors: Saez Fara , Hong Nancy J , Garvin Jeffrey L
Published: March 2022

Medullary O
2
-
production is elevated in Dahl salt-sensitive (SS) when compared to Dahl salt-resistant rats (SR), and this is one of the main contributors to salt-sensitive hypertension in this model. In thick ascending limbs (TALs), flow-induced O
2
-
is caused by elevated ion delivery and cellular stretch. Mechanical stimulation by cellular stretch, in turn, leads to increases in intracellular calcium (Cai). We hypothesized that the elevated O
2
-
production by SS TALs is due to greater stretch-induced increases in Cai mediated by Transient Receptor Potential Vanilloid (TRPV4). To test our hypothesis, we measured O
2
-
and Cai in isolated, perfused TALs using the ratiometric dyes dihydroethidium and Fura2, respectively. Stretch led to a greater increase in Cai in SS (243±51 nM; n=9) compared to SR (124±27 nM; n=10; p<0.05 vs. SS). The increase in Cai and the difference between strains were blunted when tubules were treated with RN1734, a TRPV4 inhibitor (SS: 59±10 nM; SR: 24±3 nM; n=5 in each group). TRPV4 facilitates Ca influx into the cell. Thus we tested the effect of removing extracellular Ca on the response to stretch. When tubules were perfused and bathed with in Ca-free solutions stretch-induced increases in Cai and the difference between SS and SR TALs were completed eliminated (SS: 10±6 nM; SR: 8±4 nM; n=5 in each group). Transfecting SS TALs with an adenovirus expressing a TRPV4-small hairpin RNA abolished the difference in the stretch-induced Cai response between SS and SR tubules (SS: 75±15nM; SR: 56±28 nM; n=4 for each group). Stretch-induced O
2
-
production was greater in SS TALs compared to SR tubules (SS: 59±10 AU/min; SR: 24±3 AU/min; p<0.02; n=5 for each group). The increase in O
2
-
production caused by stretch and the difference between SS and SR TALs were eliminated when tubules were treated with the TRPV4 inhibitor RN1734 (SS: 15±7 AU/min; SR: 10±4 AU/min). Our results indicate that: 1) stretch increases Cai in SS and SR TALs and this is mediated by activation of TRPV4; 2) stretch raises Cai more in SS than SR tubules; 3) stretch-induced O
2
-
production is elevated in SS TALs compared to those from SR and this is due to greater increases in Cai; and 4) differences in TRPV4 activation likely explain, in part, both the differences in stretch-induced Cai and O
2
-
production.
Abstract 075: Seasonal Variation and Day-by-day Variability in Nocturnal Blood Pressure Fall: The Nagahama Study
Authors: Tabara Yasuharu , Matsumoto Takeshi , Murase Kimihiko , Nagashima Shunsuke , Hirai Toyohiro , Kosugi Shinji , Nakayama Takeo , Wakamura Tomoko , Chin Kazuo , Matsuda Fumihiko
Published: March 2022

Backgrounds:
Abnormalities in circadian blood pressure (BP) variation have been suggested to be associated with cardiovascular diseases and mortality. Factors affecting the variability need to be clarified to precisely evaluate the risk of circadian BP abnormalities. Given the seasonal differences in casual BP, it was hypothesized that nocturnal BP may also differ by season. Here we aimed to clarify seasonal and day-by-day variability of circadian BP variation in a large-scale general population.

Methods:
We analyzed a dataset describing in the Nagahama study. Study participants were 4,792 community residents. Evening, sleep, and morning BP values were measured for 5 days at home using an automatic cuff-oscillometric device (HEM-7080IC). Participants were required to sleep with putting a cuff on the upper arm. The BP monitor was programmed to automatically measure BP at 0, 2, and 4 o’clock, and all readings were recorded in a built-in memory of the device. Sleeping period was objectively defined by actigraphy.

Results:
Overall frequency of extreme-dipper, dipper, non-dipper, and riser were 6.5, 34.9, 45.1, and 13.5%, respectively. Nocturnal systolic BP fall was significantly smaller in individuals whose BP was measured during the summer season (summer, –5.8 ± 7.8%; middle, –8.2 ± 7.5%; winter, –11.1 ± 7.7%;
p
<0.001), resulting in higher frequencies of riser (summer, 19.9; middle, 12.8; winter, 7.5%) and non-dipper (summer, 51.5; middle, 46.2; winter, 36.7%) in summer season (
p
<0.001). The mean ambient temperature showed significant association with nocturnal SBP dipping level (r = 0.259, p <0.001). Results of linear regression analysis identified middle (beta = 0.156,
p
<0.001) and summer season (beta = 0.263,
p
<0.001) as strong positive determinants for decreasing nocturnal SBP fall, independently of other possible covariates. No marked seasonality was observed in day-by-day variability of the dipping pattern (Kendall’s coefficient: winter, 0.590; middle, 0.602; summer, 0.581).

Conclusion:
Nocturnal BP fall was largely different by season with higher frequency of riser and non-dipper in summer. The seasonality might not be due to the seasonal difference in day-by-day variability of nocturnal BP changes.
Abstract 078: Ox-LDL Leads to Increases of Endothelial Lysine Acetylation Linking Metabolic Memory to Diabetic Vascular Dysfunction
Authors: Carrillo-Sepulveda Maria Alicia
Published: March 2022

Around 70% of type 2 diabetic (T2DM) patients will die due to sustained vascular complications, including hypertension. Evidence from clinical trials has shown that even under proper glycemic control, diabetic patients exhibit persistent vascular dysfunction. This phenomenon referred as “metabolic memory” (MM) is a major problem in treating diabetic patients. A current gap in knowledge of how MM contributes to diabetic vascular dysfunction needs to be addressed. Elevated serum ox-LDL levels are frequently found in T2DM. Whether ox-LDL is linked with MM remains undefined. We hypothesize that transient ox-LDL exposure increases endothelial lysine acetylation which in turn may contribute to persistent vascular dysfunction. Using a model of MM in cultured primary human aortic endothelial cells (HAEC), we found that 16h stimulation with ox-LDL (40 μg/mL) significantly increased lysine acetylation in the total cellular proteins (2.2 fold of increase vs unstimulated cells, p<0.01, n=4). Moreover, ox-LDL increased vascular cellular adhesion molecule-1 protein (VCAM-1, 1.8-fold increase, p<0.05, n=3), and superoxide production detected by dihydroethidium (2.5-fold increase, p<0.001, n=4) in comparison to unstimulated HAEC. When HAEC stimulated with ox-LDL were returned to a regular medium for 48h, VCAM-1 expression markedly decreased, whereas superoxide and lysine acetylation levels remained unchanged, suggesting that transient ox-LDL exposure generates MM. To determine whether increased endothelial lysine acetylation correlates with vascular dysfunction, we assessed endothelium-depend relaxation through concentration-dependent responses to acetylcholine using wire myograph in freshly isolated mice superior mesenteric arteries in organ culture. Vasorelaxation was impaired in vessels incubated with 40 μg/mL ox-LDL for 8h (66.3 ± 3.4 vs 90.1 ± 2.2 % control, p<0.05, n=4). This impairment was ameliorated when vessels exposed to ox-LDL were returned to regular medium for 12h (75.5 ± 2.0 vs 66.3 ± 2.4 %, p<0.01, n=4). These results indicate that transient ox-LDL causes persistent endothelial dysfunction and augmented endothelial lysine acetylation which may be an epigenetic modification driving MM and diabetic vascular dysfunction.
Abstract 082: On the Significance of Urinary Renin in Diabetic Kidney Disease: A Critical Role of Impaired Proximal Tubular Reabsorption
Authors: Tang Jeannette , Wysocki Jan , Rein Johannes , Ye Minghao , Afkarian Maryam , Batlle Daniel
Published: March 2022

Increased expression of renin in the kidney collecting tubule of rodents made diabetic by streptozotocin (STZ) has been well demonstrated but whether this site is the main source of urinary renin is unknown. We wanted to examine the origin and significance of urinary renin in diabetic kidney disease (DKD).

Total and active renin was evaluated in urines from people with longstanding type 1 diabetes of more than 25 years, with (n=36) or without DKD (n=38) (eGFR 101 vs. 39 mL/min/1.73m
2
; p<0.001). Mice given STZ (n=15) or vehicle (n=8) 20 weeks prior to study were also studied. In people with DKD, total renin was markedly increased compared to people without DKD (82 vs. 49 pg/mg Cr; p=0.023). Active renin was also significantly increased in people with DKD compared to people without DKD (3.2 vs. 1.3 pg/mg Cr; p<0.001). In mice with STZ-induced DKD a significant increase in renin was found compared to controls (1093±319 vs. 64±18 pg/mg Cr; p=0.0001). To examine the role of filtration and tubular reabsorption on urinary renin, human active renin was measured in urines from non-diabetic mice infused with human recombinant renin (hrRenin) (n=8), a combination of lysine and hrRenin (n=5) and non-infused controls (n=15). Urines of mice infused with a combination of lysine (a blocker of proximal tubular protein reabsorption) and hrRenin had markedly higher urinary human active renin than those of controls (179±129 vs. 1.6±0.4 pg/mg Cr; p=0.001). The values were also markedly higher than those of mice infused with hrRenin only (4.4±1.1 pg/mg Cr; p=0.003). The effect of lysine was also evaluated in regard to endogenous mouse renin. Urinary mouse renin in mice infused with lysine (n=5) was markedly increased compared to non-infused controls (n=18) (22360±8673 vs. 346±82 pg/mg Cr; p=0.001).

In conclusion, in humans with DKD, urine concentrations of both total and active renin are increased. In mice with STZ-induced DKD, urine total renin is also markedly increased. The data further demonstrate that 1) renin is both filterable and reabsorbable in normal mice and 2) the increase of urinary renin in DKD can be attributed largely to impaired reabsorption mainly in the proximal tubule.
Abstract 086: Knockdown of the Neuronal (Pro)renin Receptor in the Paraventricular Nucleus of the Hypothalamus Attenuates ERK1/2 Activation and the Development of Salt Sensitive Hypertension
Authors: Jensen Dane D , Li Wencheng , Feng Yumei
Published: March 2022

The (Pro)renin (PRR) receptor is a key player of the brain renin-angiotensin system. We previously reported that neuron-specific knockout of the PRR attenuated the development of salt-sensitive hypertension (SSH). However, the brain region responsible for this effect is unknown. To test our hypothesis that PRR plays a regulatory role in the paraventricular nucleus of the hypothalamus (PVN) during SSH development, we knocked down PRR using adeno-associated virus (AAV2)-mediated Cre recombinase micro-injection into the PVN of PRR-LoxP mice. Blood pressure (BP, mmHg), heart rate (HR, bpm), and autonomic function were monitored with radio telemetry. Immunofluorescence was used to determine cell localization of AAV2 in the PVN and ERK1/2 activation (pERK1/2). We found that AAV2-eGFP positive cells co-localized with the neuronal marker NeuN, but not with astrocytes (GFAP) or microglia (IBa1). PRR-LoxP mice were injected with either AAV2-eGPF (GFP) or AAV2-Cre-eGFP (Cre) bilaterally into the PVN (1.8x10
8
Vg). Three days post viral injection, mice received either DOCA-salt (50mg DOCA pellet + 0.9%NaCl drinking solution) or sham (sham pellet + tap water) treatment for 21 days. PVN injection of Cre or GFP had no effect on baseline BP. After 21 days of DOCA-salt treatment, the BP (119 ± 3 vs. 139 ± 7) was significantly lower in mice that received Cre compared with GFP. The cardiac sympathetic tone (ΔHR to propranolol: -123 ± 46 vs. -181 ± 16) and vasomotor sympathetic tone (ΔBP to chlorisondamine: -47 ± 9 vs. -69 ± 5) were also lowered in Cre compared GFP treated mice following DOCA-salt treatment. The pERK1/2 levels in the PVN were increased in the DOCA-salt compared to sham (fold change: 3.29 ± 0.62, P<0.0001) treated mice. Importantly, the pERK1/2 elevation in the PVN was blocked by Cre (0.98 ± 0.15) compared with GFP with DOCA-salt treatment. PVN-targeted PRR knockdown had not effect on pERK1/2 in the subfornical organ compared to GFP (0.74 ± 0.05 vs. 1.0 ± 0.14); while, it reduced pERK1/2 in the rostral ventrolateral medulla (RVLM) (0.77 ± 0.06 vs. 1.23 ± 0.11, P<0.001). In summary, PVN-targeted PRR deletion attenuates SSH and ERK1/2 activation in the PVN and RVLM, and is associated with reduction in sympathetic tone in mice indicating an important role of PVN PRR in BP regulation.
Abstract 089: A Simple Algorithm Identifies Hypertensive Patients Who Benefit From Intensive Blood Pressure Lowering
Authors: Wang Shidan , Khera Rohan , Das Sandeep , Vigen Rebecca , Wang Tao , Luo Xin , Lu Rong , Zhan Xiaowei , Xiao Guanghua , Vongpatanasin Wanpen , Xie Yang
Published: March 2022

Background:
Large randomized trials have provided inconsistent evidence regarding the benefit of intensive BP lowering in hypertensive patients. Identifying which patients derive a higher net benefit is essential in informing clinical decision-making.

Objectives:
To assess whether stratification by cardiovascular disease (CVD) risk will identify patients with a more favorable risk/benefit profile for intensive BP lowering.

Methods:
We used patient-level data from two trials that tested intensive vs. standard BP lowering: SPRINT and ACCORD. Within SPRINT, we selected a subset of patients at extremes of major adverse cardiovascular event (MACE) rates to develop a decision-tree using recursive partitioning modeling. We then validated its predictive effects in the remaining ‘intermediate’ SPRINT subset (n=8,357) and externally in ACCORD (n=2,258).

Results:
Recursive partitioning produced a three-variable decision-tree model consisting of age≥74 years, urinary albumin/creatinine ratio (UACR) ≥34, and history of clinical CVD. It classified 48.6% of SPRINT and 55.3% of ACCORD patients as “high-risk”. Compared with standard treatment, intensive BP lowering was associated with lower rates of MACE in this high-risk population in both SPRINT cross-validation data (HR=0.66, 95% CI 0.52-0.85) and ACCORD (HR=0.67, 95% CI 0.50-0.90), but not in the remaining low-risk patients (SPRINT: HR=0.83, 95% CI 0.56-1.25; ACCORD: HR=1.09, 95% CI 0.64-1.83). Additionally, intensive BP lowering did not confer an excess risk of serious adverse events in the high-risk group.

Conclusions:
A simple risk prediction model consisting of age, UACR, and clinical CVD history successfully identified a subset of hypertensive patients who derived a more favorable risk/benefit profile for intensive BP lowering.
Abstract 093: Can Hypertension Control be Improved Within a Short Time Frame? - Results From Implementing the Measure Accurately, Act Rapidly and Partner With Patients (MAP) Program
Authors: Egan Brent , Rakotz Michael , Hanlin R. Bruce , Asif Irfan , Yang Jianing , Sutherland Susan , Davis Robert , Wozniak Gregory
Published: March 2022

Objective:
Evaluate a multifaceted quality improvement program with evidenced-based interventions for Measuring blood pressure (BP, mm Hg) accurately, Acting rapidly to manage uncontrolled BP, and Partnering with patients to promote BP self-management (MAP) in primary care.

Methods:
Study design
: Quasi-experimental, pre-post intervention, design. BP control and BPs of uncontrolled patients were compared at baseline, February 2015[A1] to May 2016, at the last visit of the next 6 months.. Measure accurately included training staff in BP measurement. If attended BP was ≥140/90, unattended, automated office (AO) BP was obtained. Act rapidly included intensification of BP meds when unattended AOBP was ≥140/90 assessed by percent of visits with uncontrolled BP and no treatment change (therapeutic inertia). Partner with patients including BP self-monitoring and using low-priced generic BP meds assessed indirectly by the fall in systolic BP (SBP) per therapeutic intensification.
Population Studied:
Hypertensive patients (21,035) from 16 practices who had a visit during the baseline period and either no visit (4,691) or at least one visit (16,344) during the program.

Results:
BP control rose from 65.6% (13,790 of 21,035) to 74.8% (12,234 of 16,344) (p<.001); 12 of 16 practices had significant increases in BP control. In uncontrolled patients at baseline, mean SBP/DBP fell from 149/85 to 139/80 (p<.001/p<.001). Measure accurately lowered SBP 12.8 mm Hg (p<.001) in uncontrolled patients with better technique in attended BP reducing SBP ≥6.5 mm Hg per practice; while unattended AOBP lowered SBP 8.6 mm Hg (p<.001). Therapeutic inertia was unchanged (50.2% vs. 48.4%; p=.10); the mean fall in SBP per therapeutic change increased from 5.4 to 14.0 mm Hg (p<.001).

Conclusions:
MAP was associated with significant improvement in hypertension control in primary care during a six-month period. The decrease in SBP and improved control were largely explained by Measure accurately and Partner with patients as therapeutic inertia (Act rapidly) did not change. Evidence-based strategies in MAP provide opportunities for primary care practices to quickly improve hypertension control toward the national goals of 80%, and importantly to reduce cardiovascular risk.
Abstract 119: Norepinephrine (NE) Resides in Renal Perivascular Adipose Tissue: Form and Function
Authors: Restini Carolina B , Ismail Alex , Burnett Robert , Fink Gregory D , Watts Stephanie W
Published: March 2022

Perivascular adipose tissue (PVAT) is gaining importance as its ability to secrete and take up substances that modify vascular tone, and thus blood pressure. The kidney is inarguably important to blood pressure regulation, but little is known about renal arterial PVAT (RP) relative to its adipogenic profile or its function to modify arterial contraction as specifically conducted by a resident adrenergic system. We hypothesized that NE was present in RP, that RP had a mixture of both brown and white adipocyte gene signatures and that the NE in RP could promote renal artery contraction. Our model was the isolated renal artery +/- PVAT of the male Sprague Dawley rat, with thoracic aortic PVAT (TAP) and mesenteric PVAT (MP) as brown-like and white fat comparators, respectively. HPLC and immunohistochemistry (IHC) were used to detect NE; RT-PCR to construct an adipogenic/adrenergic profile; and myography to measure contraction. All PVATs contained NE (ng/g tissue, n=4-6): RP:524±68, TAP:740±16, MP:96±24. In RP, NE, visualized by IHC, was clearly present in adipose tissue resembling both brown and white fat. The identification of brown fat was validated by positive uncoupling protein-1 (UCP-1) staining in the RP; this made up some but not all of the RP. RT-PCR measures (2-ddCt values, n=4) supported expression of both brown-like (UCP-1: RP: 1.0±0.1, MP 3.2e-05±2.94e-05, TAP: 1.3±0.1; Cidea: RP: 1.0±0.1, MP: 0.01±0.002, TAP: 0.9±0.1) and white adipogenic genes (Tcf21: RP: 1.0±0.2, MP: 5.9±1.0, TAP: 0.3±0.1). The existence of a functional adrenergic system in the RP was supported by two findings. First, the efficacy of the indirect sympathomimetic tyramine to cause contraction was greater in isolated renal artery (n=11) +PVAT (14.4+1.8mN) vs -PVAT (7.6+1.2mN). Second, tyramine-induced contraction in +PVAT tissues was reduced by the α1-adrenoceptor antagonist prazosin (100 nM; 90+5%, n=6) and NE transporter inhibitor nisoxetine (1 uM; -logEC50 [M]- Veh: -5.0+0.4; nisoxetine = 3.7+0.2 n=4). Collectively, these data support the existence of a functional adrenergic system in a PVAT that has a profound potential to change renal arterial function. Knowledge about this fat depot may increase our ability to modify renal function in the treatment of hypertension.
Abstract 121: Longitudinal Associations of Childhood Hemodynamic and Metabolic Traits to Adult Aortic Stiffness Vary by Race: The Bogalusa Heart Study
Authors: Zachariah Justin P , Fernandez Camilo , Barshop Rupert , Harvill Emily , Chen Wei , Bazzano Lydia
Published: March 2022

Background:
Aortic stiffness predicts future hypertension and cardiovascular disease (CVD) events. CVD predictors like metabolic traits and arterial stiffness vary by race. We hypothesized that in longitudinal analyses, metabolic traits since childhood would be associated with adulthood aortic stiffness, and that these associations vary by race in the biracial (black vs. white) Bogalusa Heart Study cohort.

Methods:
Included participants had ultrasound as young adults for aorta-femoral pulse wave velocity (afPWV) and at least three Study visits over the life course. Sampled participants (n=1081) were 24-44 years old, 31% black, 57% female, and mean follow-up was 27 years. Demographic, anthropometric, blood pressure, lipid, glucose and tobacco exposure data were extracted from each visit. Given variable visit intervals and numbers, growth mixed models were used to compute total area under the curve for risk factors on the primary outcome of interest, young adult afPWV. Childhood versus cumulative risk factors to afPWV associations were examined with multivariable adjusted linear regression. Significant race by risk factor interaction terms (p<0.001) led to race-specific reporting.

Results:
Adult afPWV was higher in black (5.4+/-1.2 m/s) than white (5.2+/-1.1 m/s) participants (p=0.01). Overall, afPWV was associated with childhood and cumulative low density lipoprotein cholesterol (LDL-C, β=0.13; p<0.001 and β=0.08; p<0.01, respectively) and mean arterial pressure (MAP, β=0.1; p=0.02 and β=0.18; p<0.001) and cumulative glucose (β=0.13; p<0.001). For blacks and whites, higher afPWV was associated with childhood LDL-C (β=0.17; p<0.01 and β=0.1; p<0.01) and cumulative glucose (β=0.14; p=0.02 and β=0.15; p<0.001). Only in whites were childhood and cumulative MAP (β=0.08; p=0.04 and β=0.22; p<0.001) and cumulative LDL-C (β=0.1; p<0.01) associated.

Conclusions:
Young adult aortic stiffness was associated with childhood metabolic and hemodynamic traits even after accounting for cumulative levels of these traits. The associations appear to vary by race and by child versus adult life stage. Future work may examine the mechanisms of these race-specific differences and implications for CVD event risk.
Abstract 123: Subtle Changes in Mechanical Properties of Carotid Artery in Overweight and Obese Children
Authors: Kim Sung-ai , Seo Young Kyun , Park Kyung-Hee
Published: March 2022

Objective:
Obesity in childhood has also been associated with the development of cardiovascular abnormalities. The aim of this study was to investigate the subtle changes of mechanical properties of carotid artery in overweight and obese children.

Methods:
We prospectively recruited a cohort of overweight (n=25) and obese (n=176) children aged 7 - 17 years and non-obese children with same age and gender (controls, n=31). Overweight is defined as a body mass index (BMI) at or above the 85th percentile and below the 95th percentile and obesity as a BMI at or above the 95th percentile for children of the same age and gender. The mechanical properties of carotid artery were directly measured in a cross-sectional image of common carotid artery using a velocity-vector imaging (VVI) analysis including instantaneous vessel area and deformation parameters as fractional area change (FAC), circumferential strain, and strain rate (SR).

Results:
Compared to controls, obese children had higher blood pressures and serum glucose and worse lipid profiles than controls, whereas overweight children showed no any difference in blood pressure and laboratory findings. Among vascular properties, there were no differences in carotid intima-media thickness between the three groups. However, obese children showed larger vessel area and higher arterial stiffness as lower FAC, circumferential strain and SR than controls, whereas overweight children showed no difference in vascular properties with obese children and with controls except for circumferential SR. Circumferential SR in overweight children was significantly reduced than controls (0.47±0.19 cm/s, 0.75±0.22 cm/s, respectively, p<0.001) and was the only vascular parameter distinguishing overweight children from controls. In linear regression analysis, age (β=-0.13, p=0.03), BMI (β=- 0.37, p<0.001), and serum triglycerides (β=-0.14, p=0.01) were independent determinants predicting the circumferential SR of carotid artery in this population.

Conclusion:
A decrease in circumferential SR of carotid artery precedes the changes of other vascular properties as well as blood pressure and laboratory findings in overweight and obese children.
Abstract 124: RhoBTB1, a Novel PPARγ Target Gene, Rescues Hypertension and Vascular Dysfunction Caused by PPARγ Dysfunction
Authors: Mukohda Masashi , Ibeawuchi Stella-Rita C , Hu Chunyan , Wu Jing , Lu Ko-Ting , Davis Debbie R , Guo Deng-Fu , Rahmouni Kamal , Quelle Frederick W , Sigmund Curt D
Published: March 2022

We reported that mice (S-DN) expressing dominant-negative peroxisome proliferator-activated receptor gamma (PPARγ) in smooth muscle cells (SMC) are hypertensive and exhibit impaired vascular relaxation due to increased RhoA/Rho kinase (ROCK) activity, and display reduced expression of a novel PPARγ target gene, RhoBTB1. We hypothesize that RhoBTB1 plays a protective role in vascular function and that the function of RhoBTB1 is disrupted in S-DN mice. To test this, we generated double transgenic mice (termed S-RhoBTB1) with tamoxifen-inducible, Cre-dependent expression of RhoBTB1 in SMC. S-RhoBTB1 mice were crossed with S-DN to produce mice (S-DN/S-RhoBTB1) in which tamoxifen-treatment (75 mg/kg, ip, 5 days) restored RhoBTB1 expression in aorta to normal. Thoracic aorta and basilar artery from S-DN showed severely impaired vasodilation to acetylcholine (ACh) and sodium nitroprusside, which was reversed by restoration of RhoBTB1 in SMC (Aorta, 46±5 vs 80±2% ACh-induced relaxation, p<0.01, n=6-9). Replacement of RhoBTB1 also reversed the hypertensive phenotype and aortic stiffness observed in S-DN mice within 1 week of treatment (Radiotelemetry SBP, 141±6 vs 124±3 mmHg, p<0.01, n=8-10; Aortic Pulse Wave Velocity, 3.8±0.2 vs 2.5±0.1 mm/ms, p<0.01, n=11-13). Increased phosphorylation of myosin phosphatase targeting protein was preserved in both S-DN and S-DN/S-RhoBTB1 aorta, suggesting that restoration of RhoBTB1 did not affect increased RhoA/ROCK activity (p<0.01, n=6). A phosphodiesterase (PDE) 5 inhibitor, Zaprinast improved vasodilation in S-DN (p<0.01, n=8). Consistent with this, a cGMP analog that is resistant to PDE hydrolysis, 8-pCPT-cGMP, induced equivalent relaxation in S-DN and non-transgenic mice (n=4), while S-DN exhibited impaired relaxation induced by PDE-sensitive 8-Bromo-cGMP (p<0.01, n=7). PDE activity was increased in S-DN aorta and was reduced to normal levels in S-DN/S-RhoBTB1 (p<0.01, n=6). We conclude: a) loss of RhoBTB1 function explains the vascular dysfunction and hypertension observed in response to interference with PPARγ in smooth muscle, b) DN PPARγ in SMC causes vascular dysfunction via promoting PDE activity, and c) restoration of RhoBTB1 in SMC facilitates vasodilatation by normalizing PDE activity.
Abstract 129: In Defense of Clinic Blood Pressure
Authors: Kidambi Srividya , Chelius Thomas , Nunuk Irene , Ding Yue , Obi Brittaney , Jain Sumeet , Mattson David , Cowley Allen , Laud Purushottam , Wang Tao , Kotchen Jane , Liang Mingyu , Kotchen Theodore
Published: March 2022

For genetic studies of hypertension, between 1994 and 2006, we established a cohort of 2,639 African Americans (53% female), 51% of whom were hypertensive (H). The purpose of this report is twofold: a) to evaluate the relationship of baseline hypertension status and blood pressure (BP) level with subsequent mortality in this cohort; and b) to compare the relationship of clinic and 24-hour BPs with the subsequent incidence of fatal and non-fatal cardiovascular (CV) events in a subset of the original cohort. Clinic BP was obtained in triplicate in all 2,369 subjects as part of screening procedures for a 3-day inpatient clinical study of a sub-sample (n=266). BP medications were discontinued for 1-week after the screening visit and prior to inpatient study. Detailed phenotyping along with 24-hour BPs were obtained during the 3-day study. Compared to normotensives (N) at baseline, H had higher standardized clinic BP (145 ± 20 [SD] / 94 ± 13 vs 118 ± 10/ 76 ± 8 mm Hg), were slightly older (45 ± 7 vs 42 ± 7 years; p<0.0001), and had higher BMI (29 ± 6 vs 27 ± 5 kg/m
2
; p<0.0001) in the overall cohort. Mortality data were obtained from the National Death Index. Average time from baseline to mortality was 12 ± 3 years. All-cause mortality was related to clinic systolic BP (p<0.03) and was greater in H than N (176 vs 70 deaths; p< 0.0002) after adjustment for age, sex, BMI, and duration of follow-up. CV mortality was also greater in H than N (52 vs 19 deaths; p<0.01). During a follow-up of 14 ± 4 years of the in-patient cohort, 49 subjects had a fatal (n=11) or non-fatal (n=38) CV event. After adjustment for covariates, clinic systolic and diastolic BPs were strongly associated with CV events (p<0.0001). The association of clinic BPs with CV events was as robust as the associations with overall 24-hour BP, day BP, and night BP. Average difference between day and night BP was 7 ± 8/5 ± 6 mm Hg (p< 0.0001), but day-night BP difference was not associated with CV events (p=0.45). In conclusion, in middle-aged African Americans, 24-hour BPs were no more predictive of CV events than BPs measured during a single outpatient visit. In addition, both all-cause mortality and CV mortality were related to the clinic BP. These results will require confirmation with larger sample sizes.
Abstract 141: Adipocyte Deficiency of Angiotensin Converting Enzyme 2 Increases Systolic Blood Pressures of Obese Female Mice
Authors: Shoemaker Robin C , Su Wen , Gong Ming , Gurley Susan , Cassis Lisa
Published: March 2022

Background:
We demonstrated that sexual dimorphism of obesity-hypertension was associated with differential activity of adipocyte angiotensin-converting enzyme 2 (ACE2) in male
versus
(
vs
) female mice. These data suggest that adipocyte ACE2 regulates blood pressure by influencing the balance of angiotensin II (AngII, a substrate of ACE2)
vs
angiotensin-(1-7) (Ang-(1-7)), which differs in male and female mice. We hypothesized that deficiency of ACE2 in adipocytes increases blood pressure of HF-fed female mice.

Methods/Results:
Mice with adipocyte ACE2 deficiency were developed from breeding

Ace2
fl/fl

mice to transgenic C57BL/6 mice with heterozygous transgenic expression of Cre recombinase driven by the adiponectin promoter (

Ace2
Adipo

). Female or male

Ace2
fl/fl

and

Ace2
Adipo

mice (8 weeks old) were fed a HF (60% kcal as fat) or low fat (LF; 10% kcal from fat) diet for 16 weeks, after which blood pressure was quantified by radiotelemetry. Systolic blood pressures (SBP) were not different in LF-fed female mice of either genotype (24 hr average SBP [mmHg]:

Ace2
fl./fl

: 121
+
1;

Ace2
Adipo

: 121
+
1; p>0.05). However, SBP was significantly increased in HF-fed female

Ace2
Adipo

vs

Ace2
fl/fl

mice (

Ace2
fl/fl

: 127
+
2;

Ace2
Adipo

: 133
+
3; p<0.05). As AngII is an ACE2 substrate, we quantified blood pressure responses of female mice to an acute challenge of AngII (20μg/kg body weight, sc). AngII administration increased SBPs of LF and HF-fed female mice of both genotypes. However, SBP responses to AngII were augmented in HF-fed

Ace2
Adipo

female mice compared to HF-fed

Ace2
fl/fl

controls (baseline
vs
AngII SBP [mmHg]: LF

Ace2
fl/fl

: 122
+
8
vs
180
+
4; LF

Ace2
Adipo

: 127
+
5
vs
173
+
7; HF

Ace2
fl/fl

: 121
+
3
vs
183
+
3; HF

Ace2
Adipo

: 138
+
7
vs
197
+
43; p<0.05). In contrast to females, HF-fed

Ace2
Adipo

male mice had similar SBPs compared to HF-fed

Ace2
fl/fl

males (24 hour SBP [mmHg]:

Ace2
fl/fl

: 127±2;

Ace2
Adipo

: 133±3; p>0.05).

Conclusions:
Deficiency of ACE2 in adipocytes promoted the development of obesity-induced hypertension in female mice. Moreover, female adipocyte ACE2 deficient mice exhibited augmented blood pressure responses to AngII. These data support the hypothesis that adipocyte ACE2 contributes to sex differences in obesity-induced hypertension.
Abstract 146: MicroRNA-216a Promotes M1 Macrophages Polarization Through the Activation of Telomerase
Authors: Yang Shujun , Li Jian , Chen Yu , Hui Rutai , Zhang Weili
Published: March 2022

Background:
Macrophages display significant phenotypic heterogeneity and plasticity. Two subtypes exist in atherosclerotic plaques: M1 pro-inflammatory subtype and M2 anti-inflammatory subtype, which can be converted to each other under certain conditions and therefore contribute to the plaque progression. But the underlying mechanisms remain unclear. Our previous work showed that m
iR-216a
mediates the activation of telomerase in macrophages differentiation via the Smad3/NF-κB pathway
in vitro
. In the present study, we aimed to examine the role of
miR-216a
in macrophages polarization and atherosclerosis
in vivo
.

Methods and Results:
We applied a tandem stenosis to the right carotid artery of apolipoprotein E-deficient mice model according to doctor Chen’s method (Circ Res. 2013;113(3):252-65.), with local infiltration of the
miR-216a
lentivirus. At 4 weeks postoperatively, the significant effect of
miR-216a
on plaque area was not observed; however, the results showed that
miR-216a
in the carotid atherosclerotic plaques markedly increased the numbers of M1 subtype by 1.8-fold whereas simultaneously decreased M2 subtype by 2.1-fold by applying CD16/32 and Arg1 immuno-fluorescent staining. In addition, we found that
miR-216a
significantly reduced the amounts of collagen III by Sirius-Red staining and downregulated the mRNA expression of collagen type III alpha 1 chain (COL3A1) by 70%. Furthermore, the THP-1 macrophages were used to explore the mechanism of
miR-216a
on macrophages polarization, and the results showed that
miR-216a
and telomerase reverse transcriptase (TERT) expression were only increased in M1 macrophages. Next, TERT lentivirus and siRNA were transfected, and the results showed that TERT overexpression promoted M1 polarization; on the contrary, silencing TERT inhibited M1 polarization and suppressed M2 to M1 conversion.

Conclusions:
Our data indicated that
miR-216a
promotes M1 macrophages polarization through the activation of telomerase and reduces collagen III in mice carotid lesions, and ultimately accelerates the development of atherosclerosis.
Abstract P104: Oxygen Drastically Increases Cardiac Output Without Changing Mean Pulmonary Arterial Pressure in a Patient With Severe, Progressive Pulmonary Hypertension
Authors: Zheng Dan , Roe Thomas
Published: March 2022

Background:
The diagnosis of PH requires a high degree of clinical suspicion and is defined as a mean pulmonary artery (mPAP) greater than or equal to 25 mmHg. Systolic pulmonary artery pressure (sPAP) can be estimated by transthoracic echocardiolography (TTE) and mPAP directly measured by right heart catheterization (RHC). The hemodynamic data obtained from RHC provide diagnostic, therapeutic, and prognostic information important for the complete assessment of PH. We present a case of severe, progressive PH evidenced by serial TTE over a 6-year period. RHC confirmed severe mPAP elevation and showed a marked increase in cardiac output (CO) after giving 100% oxygen, observed with no significant change in mPAP, but decrease in heart rate (HR) and therefore increased right ventricular (RV) stroke volume (SV) in response to oxygen-induced decrease in pulmonary vascular resistance (PVR). Method A 68 year old female presented with exertional dyspnea, severe PH, but class 1 exercise capacity. Data was retrieved from serial TTE and RHC performed at rest on room air and after giving 100% oxygen.

Results:
Serial TTE conducted over a 6-year period showed a steady progression of sPAP at a rate of 10% annually, reaching 67 mmHg at the time of the RHC, which recorded mPAP at 51 mmHg on room air (RA) and 47 mmHg with 100% oxygen. CO was at 5.84 L/min on RA and increased by 33% to 7.79 L/min with oxygen. HR was at 99 bpm on RA and at 88 with oxygen meanwhile stroke volume (SV) showed a 50% increase from 59 ml to 88 ml.

Discussion/Conclusion:
Our patient had no significant change in mPAP facing oxygen-induced decrease in PVR. Instead, there was a marked increase in RV CO explainable only by an increase in RV SV facing decreased RV afterload, as HR decreased with oxygen. These findings are consistent with the patient’s class 1 exercise capacity despite having severe PH, indicating an ability to increase CO with activity and suggesting a positive response to medications and better prognosis. Our case shows the importance of assessing hemodynamic data in the workup and management of PH. We propose using TTE assessment of CO coupled with 100% oxygen administration in addition to sPAP estimation as a noninvasive, readily available means of obtaining this critical and underutilized information.
Abstract P108: Standardised and Interdisciplinary Management of Hypertensive Urgency Improve Patients Medicalcare and Follow Up
Authors: Duarte Mariano , Coyle Javier , Aquieri Analia , Yaryour Claudio , Savio Galimberti Eleonora
Published: March 2022

Acute severe hypertension (ASH) includes low risk to life threatening events and is defined as sustained blood pressure (BP) > 180/100 mmHg. There are 2 types of ASH: hypertensive emergency (HE), and hypertensive urgency (HU). The difference is the presence (HE) or absence (HU) of acute target organ damage (TOD). Unassisted HU can evolve to HE. More than 80 % of ASH was HU with inadequate managment. The aim of the present study was to standardize the HU management based on interdisciplinary team work and to differenciate low from high risk HU. We studied 193 patients with ASH (64±12,6 years old, 117 women and 76 men). HU evaluation consisted of physical exam, ECG, chest X-Ray, full blood and urine work, retinal exam. Patient education and patient’s follow-up inmediately after acute presentation were also included. We identified 2 HU populations: High-risk HU (previous hypertensive patients or with chronic TOD), and low-risk HU (no TOD). The latter would rest for 1 h until BP <160/100 mmHg. High-risk HU typically present 4
th
sound, ventricular hypertrophy, creatinine>1.5 mg/dL or “arterial-venous” crosses in retinal exam, and will receive pharmacological treatment (orally labetalol 200 mg). We monitored patients for 2 h after the drug was administered, and if BP <160/100, patients were sent home, to keep rest, follow a low-sodium diet and be reevaluated 24 h later. If BP >160/100 mmHg patients will receive a 2
nd
dose of labetalol. The study revealed that 41 of 193 pacients (22%) were not diagnosed with high BP before, and chronic TOD was identified in 19 of them. From 152 hypertensive patients, only 31 (20%) were adequately managed and treated. The most frequent cause that triggered HU was the dietary transgression (excessive salt ingestion). In conclusion, standardized assessment and management of HU revealed that a high percentage of patients with high BP lack adequate diagnosis and/or management, and end up developing HU. Implementation of resting allowed us to achieve the goal of BP<160/100 in low-risk HU patients. High-risk HU patients were best and safe treated with orally labetalol. The new guideline also secured a medical follow-up of all HU patients, decreasing their fall-off of the medical system (<10%) and improving their long-term medical management.
Abstract P111: Target Organ Damage in Hypertensive Patients: A Comparison Using 24h-ABPM
Authors: Dinamarco Nelson , Ibiapino Mateus K , Sampaio Bernardo P , Monteiro Gabriela T , Carvalho Barbara E , Couto Vanessa B , Dinamarco Marileide , Plavnik Frida L
Published: March 2022

Introduction:
BP assessed by ABPM is better related to TOD than office measurement. Evaluate TOD patients presented at a Hypertension Lab for first screening.

Methods:
353 hypertensive (188 Female, aged 19-89) by 24h-ABPM (SpaceLabs 90307), lab. tests, LVMIU by Echo (Terason, M3000), Divided in two groups: Controlled [C] by 24h-BP (<130x80 mmHg) and Not controlled [NC] (>130/80 mmHg), albuminuria (ALB).

Results:
Table shows no difference detected in lab panel, except Glu, Trygl, ALB and LVMI.

Discussion:
Expected Higher, Glu, trygl, ALB levels and LVMI, in NC group, with significant statistical differences comparing C group. Expected because the high blood pressure are the trigger to TOD.

Conclusion:
Screening with 24-h ABPM is a valuable tool to hypertensives patients and should be used more frequently to prevent TOD progression.