bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P395: A New Technique for Selective Denervation of the Aortic and Carotid Baroreceptors
Authors: Castania Jaci A , Katayama Pedro L , Brognara Fernanda , Sabino João P , Fazan Rubens , Salgado Helio C
Published: March 2022

The traditional sinoaortic denervation (SAD) technique in rats includes aortic and carotid baroreceptors denervation, but also leads to concomitant denervation of the carotid chemoreceptors. Here we report a new technique to denervate the carotid and aortic baroreceptors, selectively, preserving the carotid chemoreceptors intact. Wistar rats were subjected to selective aortic and carotid baroreceptor denervation sparing the carotid chemoreceptors intact (BAROS-X), or sham surgery (SHAM). The animals were also implanted with femoral arterial and venous catheter for arterial pressure recording and drug administration. In unanesthetized, freely moving rats, baroreflex or peripheral chemoreflex activation was elicited by intravenous injection of phenylephrine or potassium cyanide (KCN), respectively. Phenylephrine caused a significant hypertensive response in SHAM (Δ = 46 ± 3 mmHg, P<0.001) and BAROS-X (Δ = 38 ± 3 mmHg, P<0.001) combined with a reflex bradycardia in SHAM (Δ = -54 ± 11 bpm, P<0.001) but no change in heart rate in BAROS-X subjects (Δ = -5 ± 2 bpm, ns); confirming the absence of aortic and carotid baroreceptors in BAROS-X rats. KCN elicited significant hypertensive response in SHAM (44 ± 6 mmHg, P<0.001) and BAROS-X (39 ± 5 mmHg, P<0.001) subjects followed by bradycardic response in SHAM (-88 ± 17 bpm, P<0.001) and BAROX-S (-103 ± 23 bpm, P<0.01) rats; confirming that the carotid chemoreceptors were intact in both groups. These data provide support to a new surgical technique that allows working with conscious rats exhibiting selective inactivation of the aortic and carotid baroreceptors, combined with intact carotid chemoreceptors.
Abstract P398: Screening of Primary Aldosteronism by Clinical Features and Daily Laboratory Tests: Combination of Urine pH, Sex, and Serum K
+
Authors: Yamashita Tomohisa , Moniwa Norihito , Koyama Masayuki , Ohno Kohei , Yoshida Hideaki , Miura Tetsuji
Published: March 2022

Introduction:
There is a clinical need for an easy-to-use method to determine who should be screened for primary aldosteronism (PA).

Objective:
The aim of our study is to develop and validate a scoring system from clinical features and daily laboratory tests to select patients who should proceed to endocrinolgic examinations of PA from newly diagnosed hypertensives.

Methods:
A multivariate logistic regression analysis which entered possible PA markers, age < 40 years, female sex, moderate to severe hypertension, hypokalemia, serum Na
+
minus Cl
-
≥ 40 mmol/L, serum uric acid ≤ 237.92 μmol/L (4.0 mg/dL), and urine pH (U-pH) ≥ 7.0 were undertaken in consecutive outpatients newly diagnosed hypertension. The diagnosis of PA was made by plasma aldosterone concentration-to-plasma renin activity ratio (ARR) ≥ 20 and at least one positive result in challenge tests.

Results:
In derivation study, 24 of 130 patients were diagnosed PA. The area under the receiver operating characteristic curve (AUC) for a logistic model incorporating all possible PA markers was 0.73 (95% CI: 0.61-0.85). Removing high U-pH, female sex, and hypokalemia from the full model decreased the AUC by 0.059, 0.035, and 0.011, respectively. We devised the diagnostic score for predicting possible PA, in which one point each was assigned to high U-pH, female sex and hypokalemia, and named it PFK score. The prevalence of PA in patients with 0, 1, 2, and 3 points were 11% (6 of 50), 14% (7 of 50), 42% (8 of 19), and 60% (3 of 5), respectively. In external validation datasets including patients already treated, 23 of 106 patients were diagnosed PA. AUC of PFK score was 0.73 (95% CI: 0.63-0.83), significantly higher than that of hypokalemia alone (0.53, 95% CI: 0.44-0.63,
P
<0.01).

Conclusion:
We successfully developed the easy-to-use diagnostic score for predicting possible PA, PFK score which is superior to hypokalemia alone.
Abstract P401: The Progress of Carotid Atherosclerosis is Associated With Incident Stroke and Coronary Heart Disease: The Suita Study
Authors: Kokubo Yoshihiro , Watanabe Makoto , Higashiyama Aya , Nakao Yoko M , Nakamura Fumiaki , Miyamoto Yoshihiro
Published: March 2022

Background and Purpose:
We observed that the maximum of intima-media thickness (IMT) more than 1.1 mm in the common carotid artery (CCA), i.e. CIMT-plaque, is the best predictive marker for incident cardiovascular disease (CVD) in the Suita Study. There has been no study of the association between the progress of carotid atherosclerosis and CVD in a general population. We assessed our hypothesis that CIMT-plaque progression could predict the risk of new-onset CVD in a general population.

Methods:
We studied 3,722 men and women (mean age 59.8 years without CIMT-plaque or CVD at baseline) who completed a baseline survey and carotid ultrasonography. CIMT-plaque was defined as a maximum IMT in the CCA more than 1.1 mm. During the follow-up periods from April 1994 to March 2005, we observed 632 new CIMT-plaques. After new incident CIMT-plaque or as of April 2005, we conducted a prospective cohort study of the cases until the December 2013 endpoint. We compared the CVD risk by a Cox proportional hazards model after adjusting for age, sex, body mass index, prehypertension, hypertension (grades I and II+III), TC, HDL, antihypertensive drug and/or statin use, diabetes, impaired fasting glucose, chronic kidney disease, smoking, and excessive drinking (more than 4 units/day).

Results:
After new incident CIMT-plaques in CCA, we observed 234 incident CVD events (139 strokes and 95 coronary heart disease [CHD]) during 38,243 person-years of follow-up. Age, men, hypertension grades I and II+III, diabetes, and hypercholesterolemia were associated with the progression of CIMT-plaque. After new incident CIMT-plaques, the adjusted hazard ratios (95% confidence intervals) for CVD, stroke, and IHD during follow-up were 1.58 (1.15 to 2.17), 1.54 (1.03 to 2.31), and 1.72 (1.03 to 2.88).

Conclusions:
The novel finding of this study is that CIMT-plaque progression could be a good predictor of new-onset CVD in a general population.
Abstract P406: Sleep Health as an Important Determinant of Elevated Blood Pressure: A Population Based Study
Authors: Khalid Sumaira
Published: March 2022

Introduction:
One mechanism elucidating the association between lack of sleep and elevated blood pressure includes over-activity of the sympathetic neurotransmitters which in turn raises the levels of adrenaline in the blood. Persistently raised adrenaline levels directly elevate heart rate, systolic blood pressure (SBP) and the diastolic blood pressure (DBP). We aimed at evaluating the association of sleep duration with blood pressure among the adult population in the United States after adjusting for the confounding effects of age, gender, BMI, income poverty ratio (IPR), and race.

Methods:
Our study was based on a population-based cross-sectional study design, comprising of a nationally representative sample of US adults derived from the National Health and Nutrition Examination Survey (NHANES) data cycle 2013-2014 (N=6266). Study population comprised of adults aged 16 years or above who had participated in both interview and medical examination components of the NHANES survey. Measurements on SBP, DBP, and BMI were obtained at the designated clinic by trained personnel, while age, gender, IPR, and race were recorded during the interview by self-report.

Results:
Of 6266 participants, aged between 16 to 80 years with a mean age of 45(
+
9.2) years, a total of 2302 (34%) reported short sleep duration (<6 hours per day) (Table 1). The outcome variables, SBP and DBP, were significantly different across short and normal sleep duration (p-value <0.05) (Table 1). SBP and DBP were also significantly different among males and females (p-value <0.0001) (Table 2). Both unadjusted and adjusted analyses showed a statistically significant association between sleep duration and DBP [b
adjusted
= -0.42, sd=0.16, 95%CI= -0.74, 0.08, p-value= 0.02]. When stratified by gender, the association was only significant for males [b
adjusted
= -0.50, sd=0.20, 95%CI= -0.90, -0.09, p-value = 0.02] (Table 3).

Conclusion:
Sleep health is a significant determinant of elevated blood pressure in our data even when BMI was held constant. Prospective studies are needed to augment the understanding of this association to seek early public health and behavioral interventions for the prevention of premature cardiovascular morbidity.
Abstract P410: Characterization of the Renin-angiotensin System in Induced Pluripotent Stem Cell-derived Human Kidney Organoids
Authors: Satou Ryousuke , Dugas Courtney M , Liu Jiao , El-Dahr Samir , Saifudeen Zubaida
Published: March 2022

Intrarenal renin-angiotensin system (RAS), including proximal tubular angiotensinogen (AGT), plays crucial roles in the progression of hypertension, kidney injury, and kidney development and has been investigated
in vivo
using animal models. For translational relevance, we sought to further our investigations in human tissue. This study investigated RAS expression and AGT regulation by histone deacetylase 9 (HDAC9), an epigenetic repressor of AGT, in human iPSC-derived kidney organoids. After pre-treatment of human iPSC with CHIR99201, a glycogen synthase kinase inhibitor, and fibroblast growth factor 9, cells were moved to transwell membranes. Cells were harvested on day 0, 5, 12 or 18 to determine mRNA copy numbers of developmental markers and RAS genes by digital PCR. Marker genes of renal structures were induced during the culture with concomitant decrease in progenitor markers including Cited1. Immunostaining revealed that the organoids contain podocytes, proximal tubules expressing AGT and distal tubules. Angiotensin II type 1 receptor (AT1R) levels were higher than other RAS components on day 0 and the expression was downregulated on day 5. AT2R induction peaked on day 5 and reduced until day 18. Renin expression was strongly induced on day 5 and sustained until day 18. Angiotensin-converting enzyme levels were moderately augmented during the culture. AGT levels were elevated on day 12 and remained until day 18 (7.6-fold, ratio to day 0). Conversely, HDAC9 levels decreased by day 18. On day 18, AGT and HDAC9 levels were inversely correlated in a CHIR99201 concentration-dependent manner. Moreover, an HDAC9 inhibitor increased AGT expression (2.25±0.21-fold, ratio to control). These results suggest that all RAS components are expressed and independently regulated during the development of iPSC-derived human kidney organoids. The existence of all RAS components including high renin expression, their regulation, and epigenetic regulation of AGT in the organoids support previous findings in rodent models. Concerted effort, including this study, to overcome technical challenges to generate complete nephrons will provide human kidney organoids to study development, pathophysiological mechanisms, novel drugs and clinical therapies.
Abstract P411: Angiotensin-(1-7) Preserves Mitochondrial Function in Doxorubicin-exposed Renal Epithelial Cells
Authors: Soto-Pantoja David , Cruz-Diaz Nildris , Chappell Mark C
Published: March 2022

We recently identified components of an Angiotensin-(1-7) system (Ang7) within mitochondria (Mito) of the renal cortex, as well as angiotensinogen uptake and trafficking to the Mito and nucleus in proximal tubules. Although activation of the Ang II-AT1 receptor (AT1R) axis is deleterious to the Mito, the functional role of Ang7 is unknown. Thus, we evaluated the effects of Ang7 and its agonist AVE0991 (AVE) to attenuate doxorubicin (DOX)-induced Mito toxicity. NRK-52 renal epithelial cells were exposed to DOX (10 μM, 24 hours) and either saline, Ang7 (100 nM), AVE (100 nM), the MasR antagonist A779 (10 μM) or LNAME (1 mM). Mito function in NRK cells was evaluated by a Seahorse XF-96 analyzer; the OCR data were expressed as the mean ± SD. Both Ang7 and AVE attenuated the decline in Mito function by DOX exposure (Fig_A); the calculated maximal respiration (MR) rates for Ang7 and AVE treated DOX cells were similar to control cells without DOX [25.5 ± 4.4 and 26.7 ± 7.8 vs. 33.9 ± 11.4 pmol/min; p>0.05]. Preservation of Mito function by Ang7 and AVE in DOX cells was reversed by the A779 antagonist (Fig_B). Ang7 stimulation of the nitric oxide synthase (NOS)-NO pathway is a key signaling event in various cell types; however, the NOS inhibitor LNAME failed to block the Ang7 response in DOX exposed cells [MR: 32.2 ± 7.6 pmol/min; Fig_B]. DOX also increased phospho-ERK1/2 over 10-fold [1.12 ±. 0.27 vs. 0.08 ± 0.03], but Ang7 did not attenuate the MAPK response [1.19 ±. 0.34]. We conclude that Ang7 preserves mitochondrial function following DOX exposure in tubular epithelial cells. Moreover, the protective effect of the Ang7-MasR axis does not apparently reflect the contribution of the NOS-NO or MAPK pathways.
Abstract P417: The Elevation of Blood Pressure in Adipocyte Prorenin Receptor Deficient Female Mice is Mediated by a Local AngII Dependent Mechanism
Authors: Gatineau Eva , Cohn Diane , Gong Ming , Yiannikouris Frederique
Published: March 2022

Studies of acquired or genetic lipodystrophy are becoming increasingly significant because it may provide new insights to decode mechanisms leading to obesity related hypertension. The objective of the study was to determine the mechanism by which lipodystrophy contributes to hypertension in adipocyte-(pro)renin receptor (PRR) deficient female mice. Control (

PRR
fl/fl
)

and adipocyte-PRR deficient (

PRR
Adi

) female mice were fed a high fat diet (HF) for 31 weeks (n=7-8/groups) and blood pressure was recorded by radiotelemetry. As predicted, the deletion of adipocyte PRR prevented HF diet-induced obesity, decreased by 85% (8.5 of 10) the fat mass and increased significantly systolic blood pressure (SBP) in female mice. To determine the mechanism by which the deletion of adipocyte PRR led to an increase in blood pressure, female mice were injected with a β-adrenergic antagonist (propranolol), a parasympathetic agonist (atropine), a ganglionic blockade (hexamethonium) and an AT1R antagonist (Losartan, Los). The bradycardic response after propranolol injection, the tachycardic response induced by atropine or the sensitivity of ganglionic blockade to the elevated BP were similar in

PRR
fl/fl

and

PRR
Adi

female mice suggesting that hypertension was not para- or sympathetically mediated. However, the decrease of SBP induced by Los was more pronounced in

PRR
Adi

compared to control female mice (

PRR
Adi

, -14.2± 0.9 mmHg;

PRR
fl/fl

, -5.3±1.2 mmHg; P<0.05) whereas the decrease of SBP induced by Los was similar in

PRR
Adi/Y

and

PRR
fl/Y

male mice. Analyze of systemic and local angiotensin peptides revealed a local increase of AngII peptides in the cortex of the kidney of

PRR
Adi

compared to control female mice (

PRR
Adi

, 236 ± 24;

PRR
fl/fl

, 119± 16 pg/g; P<0.05). Urinary level of vasopressin was higher in

PRR
Adi

mice compared to control female mice (

PRR
Adi

, 19.4± 2.8;

PRR
fl/fl

, 7.3± 0.7 pg/mg of creatinine; P<0.05) and was positively correlated with plasma sPRR levels (P<0.05). Our results demonstrated that, elevation of blood pressure due to adipocyte PPR deficiency is driven by a local AngII dependent mechanism in female mice whereas this elevation might be mediated by the autonomic nervous system in male mice and suggest an important role of PRR in blood pressure control.
Abstract P436: Intrarenal Ghrelin Receptor Inhibition Prevents Sodium Retention and Reduces Blood Pressure in Angiotensin II-induced Hypertension
Authors: Kemp Brandon A , Howell Nancy L , Padia Shetal H
Published: March 2022

The renal ghrelin receptor (GR) is localized to collecting duct (CD) cells where it increases E
Na
C-dependent sodium (Na
+
) reabsorption. We have previously shown that in uninephrectomized Sprague-Dawley (SD) rats, systemic Ang II infusion induces hypertension after 1 day (129.2 ± 5 vs. 158.2 ± 2.6 mmHg; P<0.01), and this increase is sustained over a 6 day period (191.2 ± 4.0 mmHg; P<0.001). The increase in BP is attenuated with concomitant intrarenal (IR) GR siRNA infusion (F=28.9; P<0.001), but the mechanism is unknown. In this study, we tested whether the reduction in Ang II-induced hypertension in the presence of IR GR siRNA is the result of the prevention of antinatriuresis. Uninephrectomized SD rats (N=33) received a subcutaneous osmotic pump for chronic systemic delivery of Ang II (200 ng/kg/min) or 5% dextrose in water (D
5
W). Rats received IR bolus infusion of D
5
W, GR siRNA (15 μg x 3 over 6 days), or scrambled siRNA (SCR siRNA, 15 μg x 3 over 6 days). Systemic Ang II + SCR siRNA reduced 24 h U
Na
V from 0.90 ± 0.04 to 0.34 ± 0.08 μmol/min (P<0.001) and increased cumulative Na
+
balance from 0 to 0.54 mEq Na
+
(P<0.01) on day 1, with no significant differences for either group for the remainder of the study. IR GR siRNA infusion prevented Ang II-mediated Na
+
retention (0.86 ± 0.06 vs. 0.87 ± 0.06 μmol/min) and induced a decrease in cumulative Na
+
balance from 0 to -0.37 ± 0.08 mEq on day 1 with no significant differences for either group for the remainder of the study. At 24 h of Ang II + SCR siRNA infusion, IR GR expression was increased in whole cell kidney (0.55 ± 0.03 vs. 0.91 ± 0.08 DU; P<0.05) and major CD Na
+
transporter E
Na
C translocated from intracellular sites to apical plasma membranes to mediate Na
+
reabsorption (0.34 ± 0.05 vs. 0.51 ± 0.02 DU; P<0.05). In rats receiving IR GR siRNA infusion, however, Ang II failed to recruit E
Na
C to the apical plasma membranes of CD cells. There was no change in total whole cell E
Na
C for all conditions. These data demonstrate that chronic inhibition of IR GR activity significantly reduces E
Na
C-dependent Na
+
retention, resulting in a negative cumulative Na
+
balance, thereby preventing Ang II-induced hypertension in rats. Thus, renal GRs represent a novel therapeutic target for the treatment of hypertension and other Na
+
-retaining states.
Abstract P438: Cardio-Renal Anemia Syndrome in acute heart failure patients: An Observational data from “Gulf-CARE” Heart Failure Registry
Authors: Al Jarallah Mohammed , Rajan Rajesh , Al-Saber Ahmed R. , Dashti Raja , Bulbanat Bassam , Ridha Mustafa , Sulaiman Khadhim , Panduranga Prashanth , Alshekh-Ali Alawi , Al Habib Khalid , Al Suwaidi Jassim , Al Mahmeed Wael , Al Faleh Hussam , Elasfar Abdelfatah , Al Motarreb Ahmed , Bazargani Nooshin , Asaad Nidal , Amin Haitham
Published: March 2022

Aims:
Cardio renal anemia syndrome is a condition (CRAS) where heart failure, anemia and renal failure co-exist. The purpose of this article is to measure and analyze the role of CRAS in acute heart failure in terms of left ventricular (LV) systolic function.

Subjects & Methods:
Gulf aCute heArt failuRe rEgistry (Gulf-CARE) study analyzed 5005 consecutive patients admitted with AHF to 47 hospitals in middle-eastern Gulf countries between 14 February and 14 November 2012. Out of which we analyzed the data of patients with CRAS and divided into two groups. The first group G1 that consists of CRAS patient with ejection fraction (EF) less than 40%, where the second group G2 that consists of CRAS patient with ejection fraction (EF) more than 40%. Chi-square test of independence was utilized for G1 and G2.

Results:
Out of total study population of 5005 patients, 26.8 % (1343) were identified as CRAS patients. Anemia was observed in 54.5% (2728/5005) and chronic kidney disease (CKD) in 45.1% (2257/5005) patients. G1 had 743 patients, and G2 had 600 patients. It was overserved that in G1, around 40.4% (300) were in NYHA Class IV, where G2 has only 28.8 % (173) with a
p
value=0.001. Cardiogenic shock, Intubation, and major bleeding were reported almost same in both groups. In-hospital stroke was seen more in G1 1.6% (12) when compared to GII 0.8% (5) without any statistical significance (
p
=0.20). Out of total CRAS patients, 36.6% (491/1343) had dialysis. Mortality rates were almost similar in both groups 6.1% (45) in GI and 6.7% (40) in GII.

Conclusions:
In the setting of acute heart failure in CRAS patients LV function has no significant role in the incidence of in-hospital stroke, major bleeding and death.
Abstract P445: Sympathetic and Renal Mechanisms of Age-related Hypertension
Authors: Wainford Richard D , Frame Alissa A
Published: March 2022

Hypothesis:
Sympathoexcitation and sodium retention contribute to age-related hypertension (HTN).

Methods:
Three, 8, and 16 month old male SD rats underwent an IV volume expansion (VE; 5% BW) and MAP, HR, urine output and paraventricular nucleus (PVN) neuronal activation (c-Fos expression) were assessed. In separate groups of rats fed a 21 day normal (NS; 0.6% NaCl) or high salt (HS; 4% NaCl) diet, measures of 1) ex vivo afferent renal nerve (ARN) activity (norepinephrine (NE)-evoked substance P release) or 2) MAP, HR, NCC activity (ΔUNaV to IV HCTZ, 2mg/kg) and sympathetic tone (plasma and renal NE content, ΔMAP to IV hexamethonium) were assessed. Separate groups of rats underwent bilateral renal denervation (RDNX) or chronic NCC antagonism (SC HCTZ, 4mg/kg/d, 14d) and MAP was assessed (N=4/gp).

Results:
Acute VE-evoked natriuresis, diuresis, and PVN parvocellular neuronal activation were impaired in aged rats. Aged rats exhibited reduced ARN activity on a NS diet and failed to increase ARN activity during a HS diet. In aged rats, basal MAP, NCC activity and sympathetic tone were increased and HS-evoked suppression of NCC activity and sympathetic tone was impaired. Chronic NCC antagonism and RDNX attenuated age-related HTN (MAP [mmHg] 16mo 149±3 vs RDNX 139±1 vs SC HCTZ 136±5, P<0.05).

Conclusion:
Our data suggest that the ARN, which have been implicated in the regulation of sympathetic outflow and renal sodium excretion, are impaired in age-related HTN. We speculate that an age-related decrease in ARN activity promotes sympathoexcitation, perhaps in part via reduced activation of PVN sympathoinhibitory parvocellular neurons, resulting in NCC-mediated sodium retention and HTN.
Abstract P451: Cerebrovasuclular Events in Patients With Primary Aldosteronism: Results of the PA Sendai Study Registry
Authors: Kudo Masataka , Morimoto Ryo , Mugikura Syuji , Tezuka Yuta , Omata Kei , Nezu Mashiro , Igarashi Yasuhiro , Seiji Kazumasa , Takase Kei , Ito Sadayoshi , Satoh Fumitoshi
Published: March 2022

Background:
Hyperaldosteronism is associated with the risk of cardio-and cerebrovascular events (CVE) that is independent of blood pressure levels and Primary aldosteronism (PA) display a higher risk of CVE compared with essential hypertension (EH).

Objective:
Our objective was to elucidate the prevalence of symptomatic stroke in PA patients and to characterize their clinical features.

Design and Setting:
This was a retrospective cross-sectional single center study (PA Sendai Study registry) between 2007 and 2016 in Japan.

Patient:
807 patients with PA were registered and analyzed. The all patients were performed adrenal venous sampling(AVS) to make the diagnosis of PA subtypes.

Results:
Of 807 patients (male/female:395/412, age:53.3±11.8), 357 patients (44.2%) with alsosterone producing adenoma underwent adrenalectomy. The other patients were treated by medical therapy mostly administrating MR antagonists. Around the same time performed AVS, 698 patients were also performed MRI brain scans. Unruptured cerebral aneurysms were detected in about 4%, and Silent Brain Infarction were detected mainly around subcortical and basal ganglia region in about 30%. 27 patients (3.35%) suffered symptomatic stroke before the confirmed diagnosis of PA. The ratio of elderly and male was significantly high in stroke patients with PA. These patients had a higher rate of cerebral hemorrhage (thalamus or putaminal hemorrhage) rather than cerebellar infarction (63% vs 37%, p< 0.05). 457/807 patients (56.65%) were follow-up continually (period of observation: mean 1907 days) in our medical center. During this follow-up period, 6 patients died (malignant disease: 1, advanced heart failure: 2, cerebellar infarction: 1, unknown: 1). Eventually, the only 6 patients had new onset of cerebrovascular events (cerebral infarction: 4, cerebellar hemorrhage: 2). Over all, the prevalence of new-onset CVE was 1.8% in the patients treated for PA subtypes specific.

Conclusion:
This study suggests that the aldosterone excess in untreated PA patients particularly damages cerebral small vessels around subcortical and basal ganglia region. By extension, PA subtypes specific treatment and early diagnosis are useful in preventing CVE.
Abstract P463: Deterioration of Vasomotor Regulation of Perivascular Adipose Tissue at Later Stage of Metabolic Syndrome
Authors: Kagota Satomi , Maruyama Kana , Koyanagi Shiori , Iwata Saki , Shinozuka Kazumasa
Published: March 2022

Obesity is a critical risk factor for metabolic syndrome, which increases development of cardiovascular complications. Perivascular adipose tissue (PVAT) is known to modulate vascular tone. We reported that PVAT increases vasodilation via enhancing endothelial nitric oxide production in mesenteric arteries of SHRSP.Z-

Lepr
fa

/IzmDmcr rats (SHRSP.ZF) with metabolic syndrome (at 20 weeks of age; wks). However, the enhancing effects disappear at later stage (30 wks). We therefore investigated mechanisms underlying deterioration of the compensatory effects of PVAT in metabolic syndrome. Mesenteric arteries were isolated from male 20 and 30-week-old SHRSP.ZF, and vasodilation in response to nitroprusside was examined using bath bioassay techniques. Coexistence of PVAT from SHRSP.ZF at 20 wks increased vasodilation in arteries without PVAT from SHRSP.ZF at 20 wks, but the effects of PVAT were not substituted by replacement with PVAT from rats at 30 wks. Cyclic GMP levels in response to nitroprusside in arteries were increased by the presence of PVAT at 20 wks, but it was not altered by the presence of PVAT at 30 wks. In the presence or absence of vaspin, visfatin omentin, and apelin, vasodilation in response to nitroprusside was unchanged in SHRSP.ZF arteries at 20 wks. These results indicated that the production/release of diffusible vasodilator(s) from PVAT decreases with ageing. Vaspin, visfatin omentin, and apelin could be excluded from potential candidates of vasodilator(s). The deterioration of PVAT’s compensatory effects under the conditions of impaired vasodilations may induce cardiovascular complications at later stages of metabolic syndrome.
Abstract P469: CRISPR-Cas9 Gene Editing Yields Genetic Regulation of Obesity and Metabolism in Female LH-derived Rats
Authors: Clark Karen C , Grobe Justin L , Kwitek Anne E
Published: March 2022

Despite strong evidence that the Metabolic Syndrome (MetS) and its defining features (central obesity, dyslipidemia, hypertension, hyperglycemia) are highly heritable, the genetic etiology is complex and relatively few causative genes are known. For this reason, we employ the Lyon Hypertensive (LH) rat, a well-characterized genetic model of MetS.

Previously, we identified a novel gene (
RGD1562963
) on LH rat chromosome 17 (RNO17) that affects components of MetS, using a combination of genetic mapping and gene network analyses. In this study, frameshift mutations (by CRISPR-Cas9) in exon 2 of
RGD1562963
is shown to change resting metabolic rate (RMR) and body composition in LH-derived female rats, measured at 8 and 11 weeks of age, despite no differences in either total body weight or food consumption.

RGD1562963
-/-

(

RGD
-/-

) females have significantly more body fat mass than their wild-type control at 8 weeks of age, measured by nuclear magnetic resonance (NMR) as a percentage of total body weight (

#

8 weeks: WT = 5.08±0.099, n=5;

RGD
-/-

= 6.52±0.260, n=8; *p<.001), and this difference increases by 11 weeks of age (WT = 5.39±0.140, n=5;

RGD
-/-

= 7.81±0.293, n=8, *p<.0001). RMR measurements at 8 weeks showed that both genotypes had identical resting energy expenditure (WT: 0.721±0.033 kcal/hr, n=5;

RGD
-/-

: 0.721±0.021 kcal/hr, n=6) and body weights (WT = 160.5g±6.884, n=5;

RGD
-/-

= 160.7g±4.246, n=8). Though no body weight differences appear by 11 weeks (WT: 196.5g±7.226, n=5;

RGD
-/-

: 196.1g±3.765, n=8), the wild-type females have an unexpected decrease in RMR, while the RMR of

RGD
-/-

females remains high (WT: 0.654±0.005 kcal/hr, n=4;

RGD
-/-

: 0.759±0.014 kcal/hr, n=7, *p<.01).

Our studies suggest
RGD1562963
is an obesity susceptibility gene. Furthermore, inhibition of this gene at the whole body level is tolerated, and unexpectedly induced increased resting metabolic rate despite increased adiposity, possibly as a protective mechanism. The continued study of this rat model of Metabolic Syndrome has the potential to functionally validate an uncharacterized regulatory gene, and provide novel targets for pharmacological intervention in the treatment of obesity.
#
all measures are presented as mean±SEM, * RM 2-WAY ANOVA, Sidak’s correction
Abstract P471: Increased Salt Intake Reduces Diet-induced Thermogenesis in Healthy Men
Authors: Wilck Nicola , Mähler Anja , Klug Lars , Klamer Samuel , Marko Lajos , Haase Nadine , Steiniger Jochen , Balogh Andras , Boschmann Michael , Müller Dominik N
Published: March 2022

Objective:
High salt intake is a potential risk factor for obesity independent of energy intake, though underlying mechanisms remain unclear. Excessive body fat accumulation is caused by a positive energy balance over an extended period of time. Food intake causes a postprandial increase in energy expenditure. This postprandial effect represents approximately 10% of the total energy ingested over 24h. A decrease in diet-induced thermogenesis (DIT) contributes to a positive energy balance and weight gain over time. The present study investigated the effect of a 14-day high salt intake on DIT in healthy men.

Methods:
We enrolled eight healthy men (34 ± 7 years, BMI 24 ± 2 kg/m
2
) in an exploratory, longitudinal study (Clincaltrials.gov identifier: NCT02509962). Probands received 6 g salt daily using sodium chloride tablets (Slow Sodium tablets, HK Pharma Ltd.) over 14 days on top of their habitual diet. Measurements were taken at baseline (V1), on day 3 (V2) and day 14 (V3) during and on day 9 (V4) after the salt challenge, respectively. At these time points, nocturnal ambulatory blood pressure monitoring, bioelectrical impedance analysis (BIA), food intake from 3-day food records, and resting and postprandial energy expenditure were obtained. Energy expenditure was measured by indirect calorimetry in a respiratory chamber after a 12h overnight fast and a standardized 440 kcal, high-protein meal.

Results:
Nocturnal systolic blood pressure increased after salt challenge (V1: 105.8 ± 8.5, V3: 111.2 ± 9.1 mmHg,
P
= 0.02). There was a trend towards higher energy intakes (V1: 2296 ± 752 kcal, V3: 2866 ± 831 kcal,
P
= 0.1). However, DIT was significantly decreased at all time points during and after salt challenge compared to baseline (V1: 17.3 ± 2.7%; V2: 11.3 ± 2.3%,
P
= 0.01; V3: 10.7 ± 3.6 %,
P
= 0.03; V4: 14.4 ± 2.5%,
P
= 0.04; all vs. V1). After 14 days of high salt, subjects expended 30 kcal less for metabolic processes after meal challenge. Assuming a total energy intake of 2300 kcal/d, this accounts for a 150 kcal positive energy balance.

Conclusion:
A moderate short-term increase of salt intake decreased the thermic effect of a high-protein meal. This could contribute to the observed weight gain in populations consuming a Western diet high in salt.
Abstract P475: What’s in a Letter: N vs. J Determines Responses to Ang II/DOCA and DPP4 Gene Deletion
Authors: An Jianzhong , Meuth Alex , Bender Shawn , Aroor Annayya , Nistala Ravi
Published: March 2022

Activation of the renin-angiotensin-aldosterone system (RAAS) drives blood pressure (BP) responses and kidney injury in humans and rodent models. Previously, we reported activation of dipeptidyl peptidase 4 (DPP4) by RAAS which may play an important role in BP responses and kidney injury. Classically, either angiotensin II (Ang II) or deoxycorticosterone (DOCA)-salt administration to mice, raises their BP over a period of hours to days. Recently, the two have been combined to elicit more robust kidney injury and proteinuria. Although there are not many head to head comparison studies, it is known through historical association that different strains of mice have different baseline BPs and vary in their response to vasoconstrictor agents for BP peaks as well as associated kidney injury. In this regard, the C57Bl/6J and C57Bl/6N mice are genetically very similar although they differ with respect to their responses to circadian rhythm on salt sensitivity to BP. Therefore, we hypothesized that J versus N strain will have differential BP responses to Ang II/DOCA and kidney injury susceptibility. C57Bl/6 J and N mice (
DPP4
+/+
and
DPP4
-/-
) were subjected to Ang II/DOCA salt infusion for 2 weeks (Ang II 1000ng/kg/min via miniosmotic pumps, DOCA 50mg pellet, 0.9% saline in drinking water) and compared to mice receiving saline only (osmotic pumps). BP was measured by Millar catheter. Kidney injury was quantified via albuminuria and histology. While the Ang II/DOCA treated J strain had mean BP (MBP) of 135mmHg, the Ang II/DOCA treated N strain had MBP of 125mmHg. There was no effect of
DPP4
gene deletion on BP in either strain. The J strain treated with Ang II/DOCA salt had higher albuminuria when compared to the N strain (180ug/ml vs. 60ug/ml).
DPP4
-/-
mice on the J strain receiving Ang II/DOCA had a relative improvement in albuminuria (120ug/ml vs. 180ug/ml). Surprisingly, the
DPP4
-/-
mice on the N strain had higher albuminuria when compared to the
DPP4
+/+
mice receiving Ang II/DOCA (143ug/ml vs. 60ug/ml). Taken together, our results suggest that mice strain plays an important role in BP and kidney injury responses to Ang II/DOCA and
DPP4
gene deletion. These results highlight the importance of selecting patient populations carefully to maximize the benefit of DPP4 inhibitors.
Abstract P477: Effect of Zamicastat on Blood Pressure and Heart Rate - Comparison Between Acute and Repeated Dosing in the SHR
Authors: Igreja Bruno , Pires Nuno , Moser Paul , Soares-da-Silva Patricio
Published: March 2022

The sympathetic nervous system (SNS) can alter blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalyses the conversion of dopamine to NE in sympathetic nerves. Zamicastat is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS. In order to compare the effect of zamicastat on blood pressure and heart rate after acute and repeated dosing in spontaneously hypertensive rats (SHR), male adult SHR were implanted with telemetry devices (TA11PA-C40, DSI). Zamicastat (30 mg/kg p.o.) was given either as a single dose (n=8) or once a day for five days (n=6). On day 1, the maximal effect (E
max
) of zamicastat on systolic blood pressure (SBP) was attained 15h after dosing. E
max
was similar in the acute and repeated dosing groups: -21.1±3.9 and -22.0±8.2 mmHg, respectively. In the acute treatment group, a gradual return of the SBP to the high baseline levels was observed over time. On the other hand, in the repeat dosing group the E
max
were consistent across the five administrations -22.0±8.2, -25.2±7.9, -22.0±7.5, -20.0±6.0 and -16.1±2.8 mmHg, respectively day 1 to 5. On day 5, after reaching E
max
a gradual return of SBP to baseline levels was also observed. The effect of zamicastat on diastolic blood pressure was similar with an E
max
of -18.4±3.5 mmHg in the acute dosing group and -18.8±8.7, -19.2±7.2, -18.2±6.6, -19.6±6.6 and -15.7±4.7 mmHg over the five days of administration in the repeated dosing group. Zamicastat did not affect heart rate under each dosing regimen. In conclusion, there is no tachyphylaxis or sensitization to the cardiovascular effects of zamicastat in this model and blood pressure returns to basal levels after zamicastat treatment discontinuation.
Abstract P478: Barriers to Health Care Access and Hypertension Treatment Among Us Adults With Self-reported Hypertension
Authors: Fang Jing , Wang Guijing , Ayala Carma , Lucido Sal , Loustatol Fleetwood
Published: March 2022

Background:
Hypertension is a major risk factor for heart disease and stroke. Previous studies have shown that access to health care affects hypertension management. The objective of this study was to examine the association between different measures of barriers to health care access and hypertension treatment among US adults with self-reported hypertension.

Methods:
Participants from the National Health Interview Survey in 2014 and 2015, who reported a diagnosis of hypertension were included in the study. Six indicators of barriers to health care access were assessed: 1) no place to see a doctor when needed, 2) cannot afford prescribed medicine, 3) did not see doctor in past 12 months, 4) delayed care due to cost, 5) did not get care due to cost and 6) no health insurance. We compared age-standardized percentages of antihypertension medication use among those with/without barriers to health care access and the odds ratios of using medication after adjusting for age, sex, race/ethnicity, and education.

Results:
Among 21,050 participants with self-reported hypertension (26.7%), 83.2% reported antihypertensive medication use. Antihypertensive medication use was significantly lower among those with barriers to health care access compared to those without (Table). Logistic regression models showed that those with barriers to health care access were significantly less likely to report medication use than those without (Table).

Conclusion:
Although antihypertensive medication use is common among those with hypertension, this study found lower levels of reported antihypertensive medication use among those with perceived barriers to health care access.
Abstract P488: Antihypertensive Effects of Lactotripeptides on Unattended Office and Abulatory Blood Pressure. A Randomized, Double-blind, Placebo-controlled Study
Authors: Crippa Giuseppe , Rossi Filippo , Bravi Elena , Fontana Manuela , Zabzuni Dorjan
Published: March 2022

Milk fermentation by Lactobacillus helveticus produces some tripeptides (VPP and IVP) with sustained ACE-inhibitor activity that have shown to lower blood pressure (BP) in experimental animals and in humans. Grana Padano DOP, an Italian cheese, has shown a potent in vitro ACE-inhibitory effect due to its high concentration of such tripeptides. Present data refer to a randomized, double-blind, placebo controlled, study in which 30 mild-moderate hypertensive patients received a dietary integration with Grana Padano DOP. At base-line all patients had BP not on target (>140 and/or 90 mmHg) after their usual treatment and received a dietary integration with Grana Padano (1 ounce per day) and placebo, in cross over fashion.BP was evaluated at baseline and at the end of the active and placebo treatment (2 months each) by Office and unattended Office BP (using the BpTRU, average of 5 consecutive BP readings) and by ambulatory BP monitoring (ABPM).

Results:
dietary integration with Grana Padano resulted in a significant decreased in systolic and diastolic office and unattended office BP (-6 mmHg for systolic and - 5 mmHg for diastolic BP). ABPM confirmed a sustained antihypertensive effect of such integration (see table).

In conclusion, the diaily integration with 1 ounce of Grana Padano DOP cheese caused a significant decrease in systolic and diastolic BP pressure in hypertensive patients. No changes in BMI, total and HDL cholesterol, triglycerides, glucose, serum sodium and potassium levels were observed. The statistically significant drop in BP may be considered also clinically significant since the majority (67%) of the patients reached normal BP levels at the end of active treatment.
Abstract P493: Multiple-ascending-dose Study of IW-1973, a Soluble Guanylate Cyclase Stimulator
Authors: Hanrahan John , Wakefield James , Wilson Phebe , Mihova Marina , Chickering Jennifer , Ruff Dennis , Hall Michael , Milne Todd , Currie Mark , Profy Albert
Published: March 2022

Background:
Soluble guanylate cyclase (sGC), an enzyme that catalyzes the formation of cyclic guanosine monophosphate (cGMP) in response to nitric oxide (NO) binding, is a key mediator of local blood flow, inflammation, and fibrosis. IW-1973 is an orally available sGC stimulator that enhances NOsGC-cGMP signaling and reduces blood pressure (BP) in animal models of hypertension, both alone and in combination with other antihypertensive agents.

Methods:
A Phase 1b placebo-controlled, randomized, multiple-ascending-dose study was conducted to assess safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (BP, heart rate, platelet function, and plasma biomarkers) of IW-1973 in healthy subjects. Four successive cohorts of 11 subjects each (8 active and 3 placebo) were enrolled. Subjects received a starting dose once daily (QD) for 14 days followed by an up-titrated QD dose for 7 days.

Results:
IW-1973 doses ranging from 15 to 40 mg were tolerated. There were no serious adverse events (AEs), severe AEs, or discontinuations due to AEs. Among the 32 subjects who received IW-1973, the most common AEs (which occurred mainly at doses ≥30 mg) were headache (15 subjects), dizziness/postural dizziness (6) and orthostatic hypotension/BP decreased (4). AEs tended to resolve with continued dosing. The AE profile of higher doses was not clearly improved by up-titration from a lower starting dose. PK was dose proportional, both for C
max
and AUC, with a T
max
of 2-4 hours and an effective half-life of 24-37 hours. After 14 days of treatment, least squares mean change from baseline in 24-h ambulatory systolic BP (±SE) was -0.85±1.32 (placebo), -7.29±1.62 (15 mg), -3.27±1.61 (20 mg), -6.75±1.62 (30 mg), and -5.23±1.61 mmHg (≤40 mg, ≤0.5 mg/kg). After 21 days, the change from baseline was -4.81±1.19 (placebo), -8.21±1.46 (15 to 30 mg), -6.29±1.45 (20 to 40 mg), -9.05±1.56 (30 to 40 mg), and -6.58±1.45 mmHg (≤40 to ≥40 mg). IW-1973 produced a dose-related increase in plasma cGMP indicating target engagement. There was no clear effect of IW-1973 administration on platelet function as assessed by the PFA-100
®
system.

Conclusion:
Further clinical investigation of IW-1973 is ongoing or planned in multiple indications, including resistant hypertension.
Abstract P516: Arterial Stiffness is a Mediator of Uric Acid-related Development of Hypertension
Authors: Tomiyama Hirofumi , Shiina Kazuki , Matsumoto Chisa , Chikamori Taishiro , Yamashina Akira , Fujii Shogen
Published: March 2022

Objectives:
Uric acid (UA) is a risk for the development of hypertension, but the underlying mechanisms of this development has not been fully clarified. On the other hand, arterial stiffness is also noted as a risk for the development of hypertension. Then, the present prospective observational study examined whether UA is associated with the development of hypertension mediated by the increase of arterial stiffness.

Methods and Results:
In 3274 middle-aged Japanese men (aged 42 ± 9 years old) without hypertension at the study baseline, the brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), systolic and diastolic blood pressure (SBP/DBP) and serum UA level were measured annually over a 9-year period. During this study period, 474 subjects (14.5%) developed hypertension. Binary logistic regression analysis demonstrated that serum UA levels has a significant odds ratio for the development of hypertension even after the adjustment [1.3 (1.1-1.5), p<0.01]. Multivariate linear regression analysis also demonstrated that serum UA levels at the baseline of study period had a significant association with delta changes of SBP (beta=0.10 p<0.01), DBP (beta = 0.13, p<0.01) and baPWV (beta=1.12 p<0.01), but not that of rAI, during the study period. Mixed model linear regression analysis in repeated measurement data revealed the following: 1) At each annual measurement, higher serum UA levels were associated with a higher annual increase of the SBP (estimate=0.63 p<0.01), DBP (estimate=0.63 p<0.01) and baPWV (estimate=6.70 p<0.01). Mediation analysis demonstrated that baPWV had a significant indirect effect on the association of UA at the baseline with the delta change of SBP (indirect effect = 0.03 p<0.01).

Conclusion:
UA is a risk for the development of hypertension. In there, UA may elevate blood pressure via increase in arterial stiffness, at least in parts.
Abstract P518: Abnormal Pressure Wave Reflection Accelerates the Development of Hypertension via the Increase of Arterial Stiffness
Authors: Tomiyama Hirofumi , Matsumoto Chisa , Shiina Kazuki , Chikamori Taishiro , yamashina Akira , Fujii Shogen
Published: March 2022

Objectives:
Arterial stiffness (macrovascular damage) and peripheral vascular damage (microvascular damage) affect pressure wave reflection, and several prospective studies have demonstrated that not only arterial stiffness but also abnormal pressure wave reflection are risks for the development of hypertension. However, the association between arterial stiffness and pressure wave reflection in the development of hypertension has not been fully clarified. The present study was conducted to examine whether the abnormal pressure wave reflection accelerates the development of hypertension via the increase of arterial stiffness.

Methods:
In 3102 middle-aged healthy Japanese men without hypertension at baseline, systolic/diastolic blood pressures, brachial-ankle pulse wave velocity (baPWV), and radial augmentation index (rAI) were annually measured during a 9-year study period.

Results:
In multivariate linear regression analysis and in mixed model linear regression analysis, baPWV was not longitudinally associated with rAI. Linear regression analysis demonstrated that the higher rAI at the baseline was associated with the larger longitudinal increase of baPWV (beta = 0.17, p<0.01). At the end of study period, 404 subjects were developed to hypertension. Binary logistic regression analysis demonstrated that baPWV (per SD increase = 1.43; 1.25 – 1.62, p<0.01) and rAI (per SD increase = 1.56; 1.33 – 1.82, p<0.01) at the baseline had significant odds ratio for the prediction of the development of hypertension. The prevalence rate of the development of hypertension during the study period was higher in subjects with higher baPWV and higher rAI at the baseline (220 in 939 subjects: 23 %) than that in other 3 groups classified by the status of baPWV and rAI at the baseline (e.g. 52 in 942 subjects with low baPWV combined with low rAI: 6%, p<0.01).

Conclusion:
The abnormal pressure wave reflection, which may be derived from both arterial stiffness and peripheral vascular damages, may be an accelerator for the development of hypertension via the increase of arterial stiffness. In there, the combination of macro- and micro-vascular damages may accelerate the development of hypertension.