bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 073: Blood Pressure Variability and Control by 24-hour Ambulatory Blood Pressure Monitoring Before and After Resection of Catecholamine-secreting Neuroendocrine Tumors
Authors: Cohen Jordana B , Ganguli Anirban , Bennett Bonita J , Townsend Raymond R , Cohen Debbie L
Published: March 2022

Background:
Measurements obtained by 24-hour ambulatory blood pressure monitoring (ABPM), such as nocturnal dipping and 24-hour blood pressure variability, are strongly associated with long-term renal and cardiovascular outcomes. Sparse data exist about how these parameters change after resection of catecholamine-secreting neuroendocrine tumors (NETs).

Methods:
We performed a prospective observational study of patients who underwent resection of catecholamine-secreting NETs at Penn between January 2014 and December 2016. Patients underwent 24-hour ABPM 1-3 weeks prior to and 6-8 weeks following resection.

Results:
Of the 32 patients who underwent resection, median age was 56 years, with 44% males (14 of 32), 78% Caucasians (25 of 32), and 84% (27 of 32) on at least one antihypertensive medication pre-operatively. Following resection, 50% (16 of 32) were on no antihypertensive medications and 74% (20 of 27) were on less medications than at baseline. There was a significant decline in clinic systolic blood pressure ([SBP] 134.6 vs. 122.5 mmHg, p<0.001), clinic pulse pressure (56.0 vs. 50.7 mmHg, p=0.037), clinic heart rate (80.8 vs. 75.5 mmHg, p=0.029), 24-hour mean SBP (133.1 vs. 127.4 mmHg, p=0.036), 24-hour SBP average real variability (10.0 vs. 9.0, p=0.031), 24-hour mean pulse pressure (54.5 vs. 51.6 mmHg, p=0.012), and 24-hour mean heart rate (78.5 vs. 74.0 bpm, p=0.023). Although the decline in nocturnal mean SBP (125.2 vs. 116.3 mmHg, p=0.007) was greater than the decline in daytime mean SBP (135.2 vs. 128.4, p=0.035), there was no reduction in non-dipping (38% vs. 44%, 12 vs. 14 of 32, p=0.854). Among patients who had masked (7 of 32), white coat (4 of 32), or sustained hypertension (9 of 32) at baseline, 60% (12 of 20, p=0.002) had controlled hypertension upon follow up.

Conclusion:
Following resection of catecholamine-secreting NETs, patients had a significant decline in 24-hour blood pressure variability and many experienced resolution of white coat, masked, and sustained hypertension, on less antihypertensive medications compared to baseline. There was no significant decline in non-dipping. NET resection may have greater prognostic significance than appreciated by changes in in-office blood pressure measurements and related parameters.
Abstract 081: Pathogenic Role of Ubiquitin Ligase Klhl3 in Diabetic Nephropathy
Authors: Ishizawa Kenichi , Uchida Shunya , Shibata Shigeru
Published: March 2022

Background and Aim:
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lyisne (WNK) kinases for degradation. Mutations and inactivation of KLHL3 cause hypertension resulting from increased Na-Cl cotransporter (NCC) activity in the kidney. Previously, we have reported that angiotensin II (Shibata et al. PNAS 2014) and potassium deficiency (Ishizawa et al. BBRC 2016) inactivate KLHL3 by protein kinase C (PKC)-mediated phosphorylation at S433 in the Kelch-domain, thereby contributing to increased blood pressure. Although clinical studies have shown that diabetic patients display salt-sensitive hypertension, its pathogenesis remains unclear. In this study, we examined the possible involvement of KLHL3 in the diabetic kidney, using a model of type 2 diabetes.

Methods:
We examined the expression levels of total KLHL3, KLHL3 phosphorylated at S433 (inactive form; KLHL3
S433-P
), and NCC in the kidney of Db/+ and Db/Db mice by Western blot. Distribution of KLHL3
S433-P
and NCC was analyzed by immunofluorescent microscopy. In some experiments, bisindolylmaleimide (BIM; the PKC inhibitor) was administered intraperitoneally.

Results:
We found that KLHL3
S433-P
levels were significantly increased in the kidneys of Db/Db mice (2.2-fold increase versus Db/+ mice; P < 0.01), which was associated with the increased levels of WNK1/4. Moreover, NCC levels in the membrane fraction were significantly higher in Db/Db mice than Db/+ mice
(
2.3-fold increase, P < 0.01
)
. Immunofluorescent study indicated that KLHL3
S433-P
is increased in the distal convoluted tubules (where NCC is present). Of note, active, phosphorylated PKC was increased in the kidney of Db/Db mice (1.8-fold increase; P <0.01), explaining the KLHL3
S433-P
induction in this model. To investigate the causal role of PKC and KLHL3
S433-P
, we administered BIM to Db/Db mice. Importantly, KLHL3
S433-P
levels were significantly decreased by BIM (29% decrease vs Db/Db mice; P < 0.05). Furthermore, the increased NCC at the plasma membrane in Db/Db mice was also ameliorated by the PKC inhibitor.

Conclusion:
These data indicate that the inactivation of KLHL3 is involved in the aberrant NCC activity in the kidney of Db/Db mice.
Abstract 103: Decreased Ability to Excrete a Na Load and Hypertension in the ALMS1 (Alstrom Syndrome 1) Knockout Rat
Authors: King-Medina Keyona N , Jaykumar Ankita B , Ortiz Pablo A
Published: March 2022

Few genes involved in obesity are known to be involved in hypertension. The Alstrom Syndrome 1 protein (ALMS1) is involved in obesity in humans. We found it is expressed in the thick ascending limb (TAL) where it interacts with the Na/K/2Cl cotransporter (NKCC2). ALMS1 is also expressed in other nephron segments such as the proximal tubule and collecting ducts. We hypothesized that ALMS1 deletion leads to hypertension which is likely due to a decrease ability to excrete a salt load secondary to enhanced NaCl transport by the TAL and other nephron segments. To study the role of ALMS1 in renal function we generated ALMS1 knockout (KO) rats in a Dahl-salt sensitive genetic background via zinc-finger nuclease targeting by MCW gene targeting core. Using radio-telemetry we found the KO rats to have a higher baseline systolic blood pressure on normal Na chow compared to the Wild-type salt sensitive (WT) rats (KO:146±2 and WT:136±1 mmHg, *p=0.0012). To explore whether hypertension is related to increase renal Na reabsorption in KO rats we performed metabolic cage protocols to measure the acute excretion of a Na load (1% of body weight) in conscious rats. Our data show that it took longer for KO rats to excrete the Na load; cumulative or at individual time points (6, 9, 24 h) (cumulative Na, KO:4251±590 μmols/24h and WT:8788±994 μmols/24h, *p=0.0028). To test the role of different nephron segments in higher Na reabsorption we used a single dose of diuretics and measured urine Na and volume excretion. The NKCC2 inhibitor bumetanide (5mg/kg), induced a higher natriuretic response in KO rats (KO:485.2±37.1 μmols/8h, WT:221.8±32 μmols/8h, *p<0.05). The NCC inhibitor hydrochlorothiazide (HCTZ) 200mg/kg, caused a similar natriuretic effect in KO rats (KO:206.8±16 μmols/8h and WT:155.6±20 μmols/8h, p=0.0717). The ENaC inhibitor benzamil (10mg/kg), caused a similar natriuretic response in KO rats (KO:214.5±33 μmols/8h and WT:253.4±22 μmols/8h, p=0.3477). We conclude that ALMS1 KO have a decreased ability to excrete a salt load and this is primarily mediated by enhanced TAL-mediated Na reabsorption. Higher TAL Na absorption is likely involved in hypertension in ALMS1 KO rats. These data show that ALMS1 is important for blood pressure control and renal function.
Abstract 108: Imaging Renin Granule Exocytosis by Total Internal Reflection (TIRF) Microscopy in Mouse Juxtaglomerular Cells: Effect of cAMP and Beta Adrenergic Stimulation
Authors: Mendez Mariela
Published: March 2022

Renin is stored in dense core granules in juxtaglomerular (JG) cells. Renin release is highly regulated. However, the kinetics of renin release and mode of granule exocytosis remains unexplored. We developed a new method for real-time visualization of renin granule exocytosis by TIRF microcopy. We hypothesize that renin exocytosis is due to a kiss-and-run mode of exocytosis, where fusion of the granule with the plasma membrane is transient and granule integrity is maintained. To study this, we generated a new adenoviral construct encoding full length mouse renin tagged with Carboxyl-terminus yellow fluorescent protein (Ad-Renin-YFP). First, we characterized its expression and activity in an endocrine pituitary cell line that does not express endogenous renin (Att20 cells). By Western Blot, we observed a band at the expected molecular mass of renin-YFP (70 kDa)(n=4). Ad-Renin-YFP retains its enzymatic activity in Att20 cells since angiotensin I conversion from angiotensinogen was only detected in Att20 cells transduced with renin-YFP (n=3;
p
<0.01). To monitor exocytosis of renin-YFP, we transduced primary cultures of mouse JG cells and monitored granule movement and their changes in fluorescence intensity within 250 nm of the plasma membrane by TIRF microscopy. Under baseline conditions the average number of docked granules was 16±4 granules per cell (n=12). Translational movement (X-Y planes) of docked granules was negligible. The number of events per cell during 10 minutes was low and no full fusion was detected (1.5 ±0.5 total events per cell, n=4). After stimulation with cAMP, the number and frequency of events increased to 5.3±1.0 events per cell/10 min (n=8, p<0.05). Similarly the number of events increased to 4.25±0.9 when JG cells were stimulated with isoproterenol, without a decrease in the number of granules docked (n=9). While most (73.5%) of the exocytic events occurred from docked granules; only 36.5% of events were caused by recruitment of newcomer granules to the TIRF field. We conclude that in JG cells, full fusion of granules is not the main mechanism of renin exocytosis. The rapid bursts in fluorescence intensity of docked granules suggest that kiss-and-run is the main mechanism of stimulated-renin exocytosis, in a highly regulated process.
Abstract 114: Sympathetic Activity Increases With Obesity in Hypertensive Patients
Authors: Siddiqui Mohammed , Dudenbostel Tanja , Lin Chee P , Oparil Suzanne , Calhoun David A
Published: March 2022

Introduction:
Obesity is one of the most important risk factors for the development of hypertension; the mechanisms by which obesity raises BP are not fully understood. Obesity leads to ↑ sympathetic autonomic nervous system (SANS) activity by several mediators such as leptin, ↓ nitric oxide, ↑ angiotensin II, ↓adiponectin, ↓ ghrelin and baroreflex dysfunction. Unknown is the role of dopamine, catecholamines and metanephrines in hypertensive individuals with obesity indexed by body mass index (BMI).

Methods:
In this prospective evaluation, 195 hypertensive patients on medications were recruited after ≥3 clinic visits at University of Alabama at Birmingham Hypertension Clinic. All patients underwent measurement of clinic BP, BMI and 24-hr urine for dopamine, total catecholamines (epinephrine and norepinephrine) and total metanephrines (metanephrine and normetanephrine). WHO obesity classification was used to categorize patients based on BMI into normal weight (BMI 18.5 to 24.9, n=19); over-weight (BMI 25 to 29.9, n=45); Class 1 obesity (BMI 30 to 34.9, n=46); Class 2 obesity (BMI 35 to 39.9, n=44) and Class 3 obesity (BMI greater than 40, n=36).

Results:
Overall, patients were 50% females, 56.8% African Americans, 58.1 ± 11.0 years old, BMI was 34.1 ± 7.1 Kg/m
2
, BP was 126.5/79.9 ± 20.2/12.3 mmHg and heart rate of 73.5 ± 12.5 beats/min and total number of BP medications were 3.8 ± 1.4. 24-hr urinary dopamine, norepinephrine, total catecholamines, normetanephrine and total metanephrines increased with increasing BMI categories.

Conclusions:
Increase in BMI is associated with increasing dopamine, catecholamines and metanephrines indicative of progressive SANS activation.
Abstract 134: Proximal Tubule-mediated Control of Albumin Balance During the Development of Salt-sensitive Hypertension
Authors: Palygin Oleg , Levchenko Vladislav , El-Meanawy Ashraf , Staruschenko Alexander
Published: March 2022

Salt-induced hypertension and the associated renal and cardiovascular complications affect a large population and are one of the leading causes of CKD. It is widely accepted that albuminuria is a strong predictor of kidney injury and cardiovascular outcome. Despite the indisputable significance of albuminuria as one of the most important factors for predicting morbidity and mortality in patients with cardiovascular diseases, the events leading to the excessive filtration of albumin into the urine are not well understood. The goal of the current study was to determine the mechanisms contributing to albuminuria in the kidney of the Dahl salt-sensitive (SS) rat, a widely used model of salt-induced hypertension. The SS rats when fed a high salt (HS) diet develop progressive elevations in urinary albumin and mean arterial blood pressure (MAP). Intravital imaging analyses of the kidneys indicate increased loading of proximal tubules (PT) with filtered albumin at the early stage of the development of hypertension. Further progression of the disease strongly correlated with significant PT damage as indicated by the impaired albumin reabsorption, increased prevalence of granular casts, and necrosis of PT epithelial cells. To prevent PT albumin overload and further development of kidney damage PT reabsorption blocker L-Lysine (17 mg/ml) was added to the drinking water offered ad libitum, and the measurements of MAP repeated continuously on HS. Treatment of SS rats with L-lysine significantly reduced the progression of salt-induced hypertension (165±4 vs 133±2 mmHg at 14D on HS, control vs L-Lysine). L-lysine significantly attenuated the development of progressively increased albuminuria and restored serum albumin balance in hypertensive animals (1.5±0.25 vs 13.28±2.14 and 6.91±1.07 24 hrs Alb/Cre; 2.98±0.07 vs 2.46±0.08 and 2.86±0.05 g/dL of serum Alb at low salt vs 14D on HS, control, and L-Lysine treated, respectively). We conclude that salt-induced increase of albumin load at the PT results in loss of albumin reuptake, reduction of albumin serum concentrations and progression of albuminuria in SS hypertensive rats. The protection of PT against extensive albumin load can significantly reduce renal damage and development of high blood pressure.
Abstract P107: Hypertensive Patients Health Beliefs and Management Behaviors in a Tertiary Health Institution in Nigeria
Authors: Eze Chinwe E , Mohammed Oriyomi M
Published: March 2022

Background/Objective:
Hypertension remains a major global public health concern. Despite available effective therapies and lifestyle interventions, optimal control of blood pressure remains a very serious health challenge to healthcare professionals especially in most developing countries like Nigeria. Studies done among African Americans suggest that beliefs play important role in hypertension control or management behaviors. We therefore carried out a study to assess hypertensive patients’ knowledge and beliefs about hypertension and how they affect their management behaviors.

Method:
The study was centered at the outpatient cardiology clinic of Lagos University Teaching Hospital(LUTH). It was a cross sectional descriptive study with the use of interviewer-administered validated structured questionnaires. The Hypertension Knowledge-Level Scale was used to assess knowledge about hypertension. A questionnaire based on Health Belief Model was used to assess patients’ beliefs and management behaviors. Ethical clearance was obtained from the Research and Ethics committee of LUTH and patients consent sought prior commencement of the study. The data obtained was analyzed using SPSS version 20.0 using descriptive and inferential statistics.

Result:
A total ninety patients (52 males & 38 females) were interviewed. The level of knowledge of hypertension among the respondents was above average, 57.8%( 52 of 90) had good knowledge while 42.2% (38 of 90) had poor knowledge. Majority of the respondents had poor management behaviors (65.6%, 59 of 90). This could be attributed to poor cues to action (56.7%, 51 of 90) and high positive response (70%, 63 of 90) to perceived barriers in adopting lifestyle modification and medication adherence. However, high positive response was recorded for perceived susceptibility (74.4%, 67 of 90), severity (88.9%, 80 of 90), benefits (93.3%, 84 of 90), and self-efficacy (75.6%, 68 of 90).

Conclusion:
The study shows that high knowledge of hypertension as seen among the respondents did not translate into good management behavior which could be as a result of their beliefs or poor response to cues to action.
Abstract P112: Bmal1 in Perivascular Adipose Tissues Regulates Blood Pressure Rhythmicity via Angiotensinogen
Authors: Chang Lin , Xiong Wenhao , Zhao Xiangjie , Fan Yanbo , Guo Yanhong , Garcia-Barria Minerva , Zhang Jifeng , Jiang Zhisheng , Chen Yuqing
Published: March 2022

Background:
the perivascular adipose tissue (PVAT), surrounding vessel walls, constitutes a distinct functional integral layer of the vascular wall. Presence of a functional PVAT is beneficial for the regulation of vascular tone under physiological conditions while dysfunctional PVAT may promote damage of the vessel wall and development of cardiovascular diseases. However, there is little mechanistic information regarding the relationship between PVAT and blood pressure regulation.

Methods:
We investigated the vasoactivity of mouse vessel rings in response to homogenized PVAT and how Bmal1 and angiotensinogen in PVAT regulate the rhythmicity of blood pressure in mice.

Results:
Our results demonstrate that loss of Bmal1 in PVAT reduces blood pressure of mice during the rest phase. PVAT extracts significantly induce contractility of isolated blood vessel rings
in vit
ro in an endothelium independent manner, and the PVAT extracts from brown adipocyte selective Bmal1 deficient mice result in reduced vessel contractility. The capability of PVAT to stimulate vessel constriction is mediated by angiotensin II (Ang II) signaling present in PVAT evidenced by angiotensinogen being highly expressed in PVAT and the blockage of angiotensin II type 1 receptors in the isolated vessels significantly repressing the pro-contractile effect of PVAT extracts. Consistently, the angiotensinogen mRNA and Ang II levels in PVAT of Bmal1 deficient mice are significantly reduced. Deletion of angiotensinogen in PVAT results in reduced blood pressure in the rest phase as well, and vessel contractility of the PVAT extracts from angiotensinogen deficient mice is significantly reduced. Furthermore, Ang II infusion reduces Bmal1 expression in PVAT. Deletion of angiotensinogen in PVAT decreases expression and phosphorylation of casein kinase -2 alpha and -2 beta (CK2α and CD2β), in turn, enhancing Bmal1 phosphorylation.

Conclusions:
these data indicate that local Bmal1 in PVAT regulates angiotensinogen expression and secrets Ang II that acts on smooth muscle cells (SMCs) in the vessel walls to regulate vasoactivity and blood pressure.
Abstract P113: Pairing the Mobile Device: Does the Engagement of Student Health Coaches Help Patients Use Smart-phone Enabled Devices for Blood Pressure Monitoring?
Authors: Vasti Elena , Pletcher Mark , Faulkner Madelaine
Published: March 2022

Research Question:
Does pairing of health coaches with smartphone-enabled blood pressure cuffs improve hypertension control and self-monitoring in a medically underserved area (MUA)?

Introduction/Context:
This pilot study aims to assess whether infusing tech-savvy youths trained as health technology coaches would (1) be a feasible approach in an MUA and (2) improve the frequency of self-monitoring, patient satisfaction, and blood pressure control of Stockton residents.

Methods:
Patients with hypertension were randomly assigned to 1 of 3 intervention arms. The “Cuff Alone" (CA) group was provided a QardioArm cuff only, and was encouraged to use the cuff at their convenience. The “Student Alone" (SA) group was instructed to meet for 30 minutes once a week for 5 weeks with a student health coach who had completed a 3-day health coach training. The third group “Student Plus Cuff" (SPC) group received both a QardioArm cuff and student coach. Student coaches and patients were surveyed about their experience in the project.

Results:
Participants (n=27) were randomly assigned (9:9:9). All 15 students completed training and 6/15 students (40%) completed all 5 meetings with their assigned patient. Barriers to feasibility included transportation and patient response drop-off at the end of the study. There was a statistically significant difference in frequency of cuff use (SPC vs CA groups, 37v17, p<0.01). The initial blood pressures for SPC, SA and CA groups were 139/78, 142/84, and 149/85 mmHg, respectively. Final BP readings were 128/69, 150/85, and 145/85 mmHg, respectively. The SPC group was the only group that reached adequate BP control, though it was not statistically significant (p=0.89). 77% of the SPC group rated the project overall as excellent, compared to CA and SA (77% vs 55% vs 44%). 78% of SPC participants reported their blood pressure to be well controlled most days of the week, compared to CA (32%) and SA (22%).

Conclusions:
This pilot trial demonstrated feasibility of pairing technology with that young student coaches, though challenges existed. The SPC group used their cuff more than twice the frequency of the CA group. Patients were more engaged in the SPC group, resulting in better blood pressure control by both self-reported and objective measures.
Abstract P134: Increased Gut Permeability and Dysbiosis in Patients With Pulmonary Arterial Hypertension
Authors: Goel Ruby , Kim Seungbum , Rigatto Katya , Shapiro Brian , Ray Jordan , Qi Yanfei , Gazzana Marcelo B , Knorst Marli M , Richards Elaine M , Sharma Ravindra K , Pepine Carl J , Raizada Mohan K
Published: March 2022

Introduction:
Pulmonary arterial hypertension (PAH) is a fatal disease and vasodilators are the mainstay for its therapy. However, they offer restricted advancement opportunities for the control and treatment of PAH. Thus, the PAH field needs a paradigm-shifting strategy for its successful management and control.

Objective:
To test the hypothesis that gut microbial dysbiosis and its increased permeability are associated with PAH.

Methods:
Healthy control subjects and patients with PAH were recruited from two hospitals in the Americas to ascertain the wider applicability of our hypothesis. Fecal samples of PAH patients (n=19) and control, reference subjects (n=16) were obtained at the Hospital de Clinicas de Porto Alegre, Brazil, for microbiota analysis. Plasma/serum samples were collected from PAH patients (n=22) and control, reference subjects (n=19) at the Mayo Clinic, Jacksonville, Florida, USA, for analysis of gut leakiness and inflammatory biomarkers.

Results:
In PAH patients, a significant decrease in abundance, diversity and evenness of gut microbial population was observed as measured by 16S ribosomal DNA analyses of fecal samples. Analysis of fecal bacteria populations also demonstrated significant increases in gram-positive, facultative-anaerobic genera, such as
Actinomyces, Bifidobacterium Slackia,
and
Streptococcus
in PAH patients. Further, plasma zonulin and iFABP, the biomarkers for gut leakiness increased by 40.3% (p=0.0018) and 81% (p=0.0012), respectively in PAH patients. High plasma LPS, HMGB1, and TIMP1 levels are involved in increased gut inflammation and gut mucosal injury. We also observed LPS, HMGB1, and TIMP1 levels were increased by 363% (p=0.0096), 20.5% (p=0.0027), and 213% (p<0.0001), respectively in PAH patients.

Conclusions:
PAH patients demonstrate profound gut microbial dysbiosis and increased permeability and inflammation. Further characterization of PAH specific microbial species holds novel management potential with the use of pre- and probiotics, designer antibiotics, appropriate fecal/bacterial transplantation, on top of background proven therapies.
Abstract P136: Ischemic Evaluation in Patients With Hypertensive Emergency / Urgency and Acute Systolic Heart Failure: Is Coronary Angiography Required for All?
Authors: Davis Jared W , Almubarak Muhannad , McElwee Samuel K , Mukherjee Amrita , Al-Solaiman Firas , Sasse Mark F , Leesar Massoud A , Chatterjee Arka
Published: March 2022

Aim:
Patients presenting with hypertensive urgency / emergency (HU/E) often have systolic heart failure(S-HF). Coronary angiography is routinely done for these patients to rule out obstructive coronary artery disease (O-CAD). We performed a retrospective study to investigate predictors of O-CAD in this population.

Methods:
Consecutive patients who underwent angiography to investigate S-HF and had hospital admissions for HU/E in the preceding 6 months were included in the study. Chart review was performed to obtain demographic, clinical and imaging / angiographic data. Statistical analysis was performed using SAS 9.4 software.

Results:
205 patients [age 58.9 ± 14.4 years; 62.4 % male; 39.5% diabetic; median EF 25% (Inter Quartile Range: 11)] were included in the study. 33.1% patients (n=68) had O-CAD. Age > 60 years (Odds Ratio: 2.3; 95% Confidence intervals: 1.3-4.3) , Diabetes (OR: 2.1; 95% CI: 1.2-3.8), history of stroke (OR: 2.7; 95% CI: 1.1-7.0) and presence of regional wall motion abnormalities (RWMA; OR: 7.4; 95% CI: 3.4-16.1) and abnormal perfusion study (OR: 7.6; 95% CI: 1.5-39.6) were significantly associated with O-CAD while African American (AA) race was a protective factor (OR: 0.4; 95% CI: 0.2-0.8). ROC curves constructed using an age cut off of 60 years along with non AA race, diabetes and RWMA yielded a good fit with a c statistic of 0.75.

Conclusions:
Our results suggest that only a minority of patients with HU/E and S-HF have obstructive CAD. It may be possible to stratify patients using demographic and non-invasive tests to direct only those with high likelihood of O-CAD for coronary angiography. These results should be validated in large registry populations.
Abstract P160: A Genome-spanning Map of Chromatin Structure Near the Renin Proximal Promoter
Authors: Stodola Timothy , Liu Pengyuan , Liu Yong , Vallejos Andrew , Geurts Aron , Greene Andrew , Liang Mingyu
Published: March 2022

Chromatin conformation capture technologies (3C, 4C-seq) allow mapping of the three dimensional spatial structure of the genome. Physical proximity mapping, which captures these 3 dimensional interactions, fills an important gap in our understanding of enhancer-gene relationship by linking possible regulatory regions to specific genes that may be distant from the enhancer by thousands or millions of base pairs or even located on different chromosomes. The goal of the current study was to expand our understanding of renin regulation by identifying regions containing potential regulatory elements of renin more than a few kilobases from the renin proximal promoter, using 4C-seq technology, in isolated SS/JrHrdMcwi cardiac microvascular endothelial cells. Three replicates of ten million cells were fixed, digested with EcoRI, ligated, and then decrosslinked. Secondary digestion with NlaIII followed by a second ligation captured an unknown sequence surrounded by the sequence of the renin promoter. A sequencing library was prepared using primers specific to the renin promoter to identify the captured sequences. Sequence reads were mapped to rat genome (Rn 5) divided into fragments cut by EcoRI. Reads were verified to contain the renin proximal promoter sequence and a uniquely mapped captured sequence. The read counts were binarized and Z-scores were calculated based on a windowed average reads relative to background, and Z-scores corresponding to FDR < 0.01 were considered significant. We found 62 loci spanning the genome in contact with the renin proximal promoter. Clusters of interactions were found on Chr13 at 39.6-40.5Mpb and at 53.9-56.3Mbp where the Renin gene is located. Additional contacting loci were found on all chromosomes except X. Quantitative PCR in newly isolated endothelial cells processed as 3C samples (fixed, digested, ligated, decrosslinked) were used to test 9 of the interactions, of which 8 were validated. These loci are enriched with genes whose expression is correlated with renin (53 of 268 genes,
p
= 7x10
-10
) in humans, rats and mice. The present study generated a genome-wide map of segments physically interacting with the renin proximal promoter producing the first such map for a gene that is essential for cardiovascular physiology.
Abstract P168: Prevalence of Spontaneous Hypertension in African Green Monkeys is Age-related
Authors: Rhoads Megan K , Osborn Jeffrey
Published: March 2022

Chlorocebus aethiops sabaeus
, the African Green Monkey (AGM), is a novel translational model of hypertension and cardiovascular disease. The AGM is a diurnal, primarily bipedal nonhuman primate, in which ~ 1/3 of the population exhibits spontaneous hypertension (systolic blood pressure > 140mmHg). Since age and sex are related to the development of human hypertension, we hypothesized that age and sex may be crucial to the development of hypertension in this primate species. Hypertension prevalence was compared in animals with known ages or highly confident age estimates. Age estimates were performed by staff with over 50 years combined experience working with AGMs. Behavior, weight, incisor length, fur coarseness, tail stiffness, and troop hierarchy were used to reasonably estimate an animal’s age. Animals were binned into 1 of 4 age categories: juvenile, 0-4 years; young adult, 5-10 years; adult, 11-15 years; or mature adult, ≥ 16 years. Overall, hypertensive (HT) AGMs comprised 31.3±22.8 % (mean± 95%CI) of the juvenile group, n=16; 31.9±6.6% of the young adult group, n=244; 48.3±12.6% of the adult group, n=60; and 61±18.1% of the mature adult group, n=28. The prevalence of HT is greater in the adult and mature adult groups (Z = -2.3, p<0.05; Z = -2.9, p<0.05, respectively) compared to the young adult age group. No significant differences in prevalence were found between sexes within the same age (p>0.05). In males, HT animals comprised: 30±28.4% of the juvenile group, n=10; 28.9±8.1% of the young adult group, n=121; 50±13.6% of the adult group, n=52; and 61.5±18.7% of the mature adult group, n=26. In females, HT animals comprised: 33.3±38.1% of the juvenile group, n=6; 36.9±11.1% of the young adult group, n=73; 37.5±33.5% of the adult group, n=8; and 50±50% of the mature adult group, n=2. In males, the prevalence of HT is increased in the adult (Z = -2.6, p<0.05) and the mature adult age groups (Z = -3.1, p<0.05) compared to the young adult group. No differences were found in female age groups. Similar to humans, age is a strong contributor to the development of spontaneous hypertension in the AGM. Sex may contribute to the development of AGM spontaneous hypertension and future studies will assess the impact of age, sex hormones, and hypertension in female AGMs.
Abstract P171: Smaller Body Mass Index is Associated With Mild Cognitive Impairment in Elderly Hypertensive Patients
Authors: Saito Yoshihiro , Ishikawa Joji , Toba Ayumi , Suzuki Ayumi , Tamura Yoshiaki , Araki Atsushi , Harada Kazumasa
Published: March 2022

Backgrounds:
In elderly hypertensive patients, it might be important to pay attention to cognitive function when achieving aggressive blood pressure goal; therefore we evaluated factors associated with cognitive impairment in elderly hypertensive patients.

Methods:
We performed Mini Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) in 209 elderly hypertensive patients who were evaluated frailty (Aged
>
65 years, Male 38.3 %). Dementia was diagnosed as MMSE scores
<
23 and/or anti-dementia drug use; mild cognitive impairment (MCI), MoCA<24 points and MMSE
>
24 points.

Results:
Mean age was 78.6±6.2 years. There were 84.2 % of patients who were taking antihypertensive drug. Clinic blood pressure was 133.2±17.6 / 74.3±11.9 mmHg and body mass index (BMI) was 23.7±7.6 kg/m
2
. MMSE score was 27.0±3.8 and MoCA was 21.1±4.9 points. There were 53.0 % of patients with MCI; 12.9 % with dementia. Patients with MCI and dementia had lower BMI than those without (MCI group, BMI=23.2±3.5 kg/m
2
; dementia group, 23.4±2.7 kg/m
2
; no MCI or dementia group, 24.8±3.9 kg/m
2
; P=0.012). The risk of MCI increased by 13.2 % per smaller BMI of 1 kg/m
2
(P=0.006); that of dementia increased by 18.6 % per smaller BMI of 1 kg/m
2
(P=0.055) after adjustment for age, gender, antihypertensive drugs use, diabetes, dyslipidemia, smoking habit, alcohol drinking, history of stroke, and systolic and diastolic blood pressure. Patients with the lowest quartile of BMI (< 21.34 kg/m2) had 3.82 (95%CI 1.42-10.27) times greater risk of MCI and had 7.59 (95%CI 1.22-47.27) times greater risk of dementia than those with highest quartile of BMI (> 25.69 kg/m2).

Conclusion:
In elderly hypertensive outpatients who were suspected of frailty, smaller BMI was associated with presence of MCI and dementia, suggested that we needed to decide optimal blood pressure level carefully in lean hypertensive patients.
Abstract P197: Vitamin D, Paratohormone and Cardiovascular Risk: The Good, the Bad and the Ugly
Authors: Giannotti Rocco , Pascale Valeria , Finelli Rosa , Visco Valeria , Matula Ida , Ragosa Nicola , massari Angelo , Di Sevo Maria G , Ciccarelli Michele , Iaccarino Guido
Published: March 2022

25OH Vitamin D (VitD) insufficiency and increased cardiovascular risk (CVR) association is still debated. The VitD dependendent paratohormone (PTH), is considered as the possible actuator of VitD effects on CVR. In an overall population observational study, we assessed the role of PTH in predicting CVR. We recruited 412 persons during the World Hypertension Day, in the area of Salerno, Southern Italy. Through means of dedicated questionnaires, blood pressure measurements and a blood draught, we collected dietary habits, anamnestic, clinical and metabolic data. CVR was calculated according to the Framingham CVR charts. The overall population mean age±SD was 49.9±20 yrs, and female sex was slightly prevalent (53.2%). VitD deficiency (<20 uMol/ml) was most frequent (65.4%). In this population VitD and CVR did not correlate. VitD and PTH inversely correlated (r=-0.236, p<0.001) as expected. PTH was in direct linear regression with CVR (F=14,982, p<0.0001).

Elevated PTH (>=56 mg/dl) levels identify a population with higher CVR (11.9±6.2 vs 9.2±7.1, p<0.01) and larger prevalence of cardiovascular events (10,2 vs 4.1, p<0,04). Since PTH increases with age and kidney function, we selected a 41-60 years old population (N=150). Also in this homogenous group, people with elevated PTH present a larger cardiovascular risk (8.4±10.5 vs 4.1±4.8, p<0,01) due to higher systolic blood pressure (137.2±20.4 vs 130.1±16.0, p<0.05). In conclusion, VitD deficiency causes PTH elevation that in the overall population increases the CVR. Our data let hypothesize that VitD supplementation may represent a major presidium to reduce PTH level and consequently CVR.
Abstract P201: Prevalence of Metabolic Syndrome in Hypertensive Patients
Authors: Singh Neki Nirankar , Singh Jaswinder
Published: March 2022

Introduction and Objectives:
Metabolic syndrome (MS) is strongly predictive of developing diabetes mellitus, stroke and cardiovascular diseases. This study was done to find out the prevalence of metabolic syndrome among newly diagnosed hypertensive patients in a tertiary care hospital of northern India, Guru Nanak Dev hospital, attached to Government Medical College, Amritsar, India.

Methods:
It is a hospital based cross sectional study involving one hundred newly diagnosed subjects with hypertension above the age 20 years. High blood pressure was defined according to Joint National committe-7 (JNC-7) guidelines, taking systolic BP> 140 and diastolic BP>90 as hypertension. Exclusion criteria included secondary hypertension, secondary cause of obesity, pregnancy, acute illness, or on steroids or any other medications known to elevate plasma glucose. The diagnosis of MS was defined as per Modified Cholesterol Education Program- Adult treatment Panel -III (MCEP-ATP III) criteria.

Statistical analysis was done using student’s t-test and chi- square test, and p value of less than 0.05 was considered significant.

Results:
Table1 Hypertensive MS patients Vs hypertensive patients without MS
Table 1

Discussion:
The increased prevalence of MS in our study shows the impact of life style changes, low socioeconomic status etc. High prevalence of MS in females is possibly because of sedentary habits and staying at home. In our study, high body mass index and central obesity and hypertriglyceridemia were shown to be strongly linked to MS.
Abstract P206: Anti-hyperglycemic Effects of Angiotensin-II Type 2 Receptor Activation by C21 in High Sodium Diet Fed Obese Zucker Rats
Authors: Patel Sanket N , Ali Quaisar , Hussain Tahir
Published: March 2022

Intake of high sodium diet (HSD) has been implicated in development of insulin resistance and obese subjects are salt-sensitive. Recently, we reported that stimulation of angiotensin-II type 2 receptor (AT
2
R) by selective non-peptide agonist C21 prevents salt-sensitive hypertension and oxidative stress, however effect of AT
2
R activation on insulin resistance and circulating lipids in obese animals fed HSD is unknown. Therefore, we investigated effects of AT
2
R activation by C21 (1 mg/kg/day, s.c. by Alzet osmotic pump) on insulin resistance and circulating lipids in obese Zucker rats (OZR) fed HSD (4%) for 14 days. High-salt diet feeding significantly increased fasting plasma glucose (p<0.05) and insulin (p<0.05), and caused glucose intolerance as evident by oral glucose tolerance test (p<0.05). Concurrent treatment with C21 reduced plasma glucose (p<0.05) and insulin (p<0.05) and improved glucose tolerance (p<0.05). Circulating plasma free fatty acids (FFA) and triglycerides were unchanged in OZRs fed normal diet or HSD. Interestingly, however, C21 treatment lowered plasma FFA (p<0.05), but not triglycerides. Results suggest that AT
2
R activation may prevent onset of hyperglycemia in obese animals fed HSD by improving insulin sensitivity, however, target organ involved in AT
2
R-mediated effects remains to be explored.
Abstract P208: N-acetyl-seryl-aspartyl-lysyl-proline (acsdkp) Reduces High Salt- induced Hypertension and Kidney Damage in Obesity
Authors: Maheshwari Mani , Monu Sumit , Romero Cesar , Kumar Nitin , Liao Tang-Dong , Peterson ED , Carretero Oscar A
Published: March 2022

Introduction:
Obesity increases the risk of salt sensitive hypertension and kidney damage. AcSDKP is a natural tetrapeptide with anti-inflammatory and antifibrotic properties but its effect on obesity-related salt sensitive hypertension and renal damage is unknown.

Hypothesis:
AcSDKP prevents high-sodium diet (HSD) induced hypertension and kidney damage in obese rats.

Methods:
Eight-week-old Zucker obese rats (ZOR) and Zucker lean rats (ZLR) were treated with AcSDKP (1.6 mg/kg/day infused via osmotic minipumps) while maintained on either normal-sodium diet (NSD; 0.4%) or high-sodium diet (HSD; 4%) for 8 wk. Rats were divided into following six groups: ZOR+vehicle, ZOR+HSD, ZOR+HSD+AcSDKP, ZLR+vehicle, ZLR+ HSD, and ZLR+HSD+AcSDKP. Systolic blood pressure (SBP) was measured by tail cuff method. 24-hour urine collection was done to measure albuminuria as a marker of renal damage. Renal fibrosis (collagen content in the kidney) was measured by hydroxyproline assay. Medullary and cortical interstitial fibrosis was measured by picrosirius red staining.

Results:
are summarized in Table 1. HSD increased SBP in ZOR but not in ZLR. AcSDKP treatment prevented HSD induced increase in BP in ZOR. HSD increased renal collagen content both in ZOR and ZLR and AcSDKP treatment decreased it. Increased interstitial fibrosis induced by high salt diet was confirmed by PSR staining in both cortical and medullary region and AcSDKP prevented this increase. Albuminuria in ZOR was significantly higher than ZLR, however neither high salt nor AcSDKP treatment was unable to normalize it.

Conclusion:
Chronic treatment with AcSDKP prevents high salt-induced hypertension and renal fibrosis in ZOR.
Abstract P239: (Pro)Renin Receptor Contributes to Albumin Overload Nephropathy: Role of Site-1 Protease-Derived Soluble (Pro) Renin Receptor
Authors: Fang Hui , Xu Chuanming , Lu Aihua , Zou Chang-Jiang , Xie Shiying , Chen Yanting , Zhou Li , Liu Mi , Wang Lei , Wang Weidong , Yang Tianxin
Published: March 2022

(Pro) renin receptor (PRR) is a new member of the renin-angiotensin system (RAS) and its role in chronic kidney disease largely remains elusive. We tested the role of PRR in albumin overload (OA) nephropathy. Uninephretomized Sprague-Dawley rats were treated for 7 weeks with vehicle, bovine serum albumin (BSA) (5 g/kg/d via a single i.p. injection) or in combination with PRO20 (500 μg/kg/d via i.p. 3 times a day). The OA rat exhibited severe proteinuria (23-fold), interstitial fibrosis, and oxidative stress, accompanied with increases in urinary renin activity (3.6-fold), urinary angiotensinogen (AGT, 3.6-fold), urinary AngII(7.8-fold), renal ACE mRNA (2.4-fold), all of which were significantly attenuated by PRO20. Urinary soluble PRR (sPRR) as assessed by ELISA was increased 13.6-fold in the OA model. In cultured HK-2 cells, BSA treatment for 24 h decreased full-length PRR (76% reduction) and increased sPRR (8-fold). BSA also increased medium renin activity (3.0-fold), IL6 (2.9-fold for mRNA and 4.1-fold for medium protein) and IL8 (5.5-fold for mRNA and 2.6-fold for medium protein), all of which were attenuated by PRO20 or PRR siRNA. Although furin or ADAM19 was previously shown to mediate the generation of sPRR, inhibition of either one of these had no effect on BSA-induced cleavage of PRR. In contrast, a serine protease inhibitor AEBSF significantly suppressed the production of sPRR. Of serine proteases, proprotein convertases (PCs) mediates post-translational processing of proprotein to active protein and are of particular interest. Screening of 9 PCs led to the identification of site-1 protease (S1P) as the predominant cleavage enzyme. S1P inhibition with siRNA or PF-429242 reduced the sPRR production by 47% and 87%, respectively. PF-429242 also reduced renin activity by 40%, in parallel with suppressed IL6 and IL8 levels. Administration of a recombinant sPRR reversed all the effects of S1P inhibition. Mutagenesis of the S1P but not furin cleavage site in PRR blocked the cleavage. Together, these results suggest that PRR mediates OA-induced renal injury at least in part through S1P-derived sPRR.
Abstract P260: Placental Ischemia-stimulated TH17 Cells Induce Preeclampsia-associated Cytolytic Natural Killer Cells During Pregnancy
Authors: Cornelius Denise C , Shields Corbin A , McCalmon Maggie L , Ibrahim Tarek , LaMarca Babbette
Published: March 2022

Preeclampsia (PE), a hypertensive disorder of pregnancy, is associated with increased circulating T
H
17 cells (T
H
17s), IL-17 and cytolytic Natural Killer cells (cNKs). Although the stimulus for cNKs in PE is currently unknown, recent
in vitro
studies suggest that IL-17 induces proliferation and cytotoxic activity in human NK cells. We have previously demonstrated that placental ischemia (PI)-stimulated T
H
17s mediate pathophysiology in pregnant rats similar to that seen in PE. In this study we tested the hypothesis that PI-stimulated T
H
17s induce cNKs and their associated cytokines, IFNγ and TNFα, and cytolytic proteins, perforin and granzyme B. T
H
17s were injected i.p. into NP rats on gestation day (GD) 12. Total NK cells (tNKs) and cNKs in blood and placental lymphocytes were quantified via flow cytometry. MAP, pup and placental weight, tissue ROS, cytokines, perforin and granzyme B were measured. As previously shown circulating T
H
17s and IL-17, MAP, IUGR, and placental and renal ROS were significantly increased after T
H
17 adoptive transfer. MAP was 100.6±1.7 mmHg (n=7) in NP rats and 119.4±2.6 mmHg (n=7) in NP recipients of T
H
17s (NP+T
H
17, p< 0.05). Placental tNKs (% gated) were significantly increased in NP+T
H
17 (19.7±4.6%) compared to NP rats (5.4±2.0%; p< 0.05). Importantly, placental cNKs were significantly increased in response to T
H
17s (NP: 2.9±0.9% vs NP+T
H
17: 14.9 ±4.0%, p< 0.05). Serum and placental IFNγ significantly increased from 5.8±3.3 pg/mL and 1.1±0.6 pg/mL/mg, respectively in NP to 193±26.12 pg/mL and 3.9±0.6 pg/mL/mg in NP+T
H
17 (p< 0.05). Serum and placental TNFα increased from 0.9 pg/mL and 0.1 pg/mL/mg in NP to 4.5 pg/mL and 0.2 pg/mL/mg in NP+T
H
17 (p< 0.05). Placental perforin was significantly increased from 0.3 pg/mL/mg in NP to 1.6 pg/mL/mg in NP+T
H
17 (p< 0.05). Serum perforin, and serum and placental granzyme B were comparable between NP vs NP+T
H
17. These data suggest a role for PI-stimulated T
H
17s to induce a cytotoxic phenotype in NKs during pregnancy and identifies stimulation of cNKs as a new mechanism by which the T
H
17/IL-17 pathway may mediate pathophysiology during PE. Further investigation into this innovative pathway may identify novel targets with therapeutic potential to improve outcomes associated with PE.
Abstract P265: Placental Ischemia Causes Renal Mitochondrial Impairment in Reduced Uterine Perfusion Pressure Rats
Authors: Vaka Venkata Ramana , McMaster Kristen M , Cunningham Mark W , Ibrahim Tarek , Amaral Lorena M , Usry Nathan E , LaMarca Babbette
Published: March 2022

Introduction:
Preeclampsia (PE) is characterized by new onset hypertension in pregnancy and is associated with renal dysfunction, proteinuria and is believed to be initiated by placental ischemia. Mitochondrial dysfunction is an important source of reactive oxygen species (ROS) generation. To better understand the role of mitochondrial dysfunction in hypertension during PE we examined renal mitochondrial expression in the kidney of RUPP rats.

Methods:
Female Sprague Dawley rats were dived into two groups; normal pregnant (NP) and RUPP rats. On gestational day (GD) 14, RUPP surgery was performed, GD18 carotid catheters were inserted, and GD19 conscious blood pressure (MAP) was measured, renal mitochondria were isolated for respiration and analysis. Respiration measurements were performed on intact isolated mitochondria under glutamate/malate as complex I substrate using Oroboros Oxygraph-2K. Oxidative phosphorylation was analyzed by western blot using total Oxphos cocktail antibody and VDAC.

Results:
MAP was elevated in RUPP (n=8) vs NP rats (n=10) (125±6 vs. 99±2 mmHg, p<0.05). RUPP (n=3) renal mitochondria show reduced expression of Complex I (0.5±0.02 vs 0.8±0.09, p<0.05) and Complex II (0.7±0.03 vs 1±0.08, p<0.05) compared to NP mitochondria. State 3 (624±112 vs 878±9 pmol/sec/mg, p=0.22) and maximal (496±87vs 748±75 pmol/sec/mg, p=0.14) respiration rates trended towards reduction in RUPPs (n=4) compared to NP (n=2).

Conclusion:
Reduced expression of Complex I and II expression with reduced respiratory rates indicate mitochondrial impairment in the RUPP kidneys. Although, renal mitochondrial mediated oxidative stress may be one mechanism of hypertension in the RUPP rat model of PE, further exploration of oxidative stress in the kidney is necessary to fully understand the contribution of mitochondrial mediated oxidative stress to pathology of PE.