bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P646: Vascular AT1 Angiotensin Receptors Regulate Sodium Transporter Abundance in Kidney Epithelium
Authors: Sparks Matthew A , Ralph Donna L , Chen Daian , Azad Hooman A , Gurley Susan B , McDonough Alicia A , Coffman Thomas M
Published: July 2021

Vasoconstriction is a signature physiological action of angiotensin II (AngII) acting via AT1 receptors (AT1R). In order to define the contribution of AT1R in vascular smooth muscle cells (VSMCs) to BP control, we generated mice with cell-specific deletion of AT1AR from VSMCs (SMKOs) using Cre-loxp technology. Baseline BP was reduced by ~7 mmHg and responses to AngII-induced hypertension were significantly blunted by in SMKO mice compared to controls (16 vs. 30 mm Hg change in BP from baseline after 4 wks AngII, P<0.02). Baseline renal blood flow (RBF) was higher, and renal vasoconstriction after Ang II was impaired in SMKOs. Moreover, SMKO mice displayed Na+ sensitivity and exaggerated natriuresis during chronic AngII infusion. To investigate the mechanism of the lower baseline BP and the enhanced natriuresis during AngII infusion (1000ng/kg/min for 5 days), we measured a panel of key Na+ transporters in the kidney by immunoblot. Baseline measurements in SMKO vs. controls detected reductions in NKCC2 in both cortex (0.8±0.03 vs. 1±0.03; P=0.0002) and medulla (0.6±0.02 vs. 1±0.05; P<0.0001); medullary NHE3 was similarly reduced (0.6±0.07 vs. 1±0.07; P=0.002). In controls, AngII infusion was associated with reduced levels of cortical and medullary NHE3 and medullary NKCC, consistent with the pressure-natriuresis response, whereas cortical NKCC, NCC and ENaC were all significantly activated. By contrast, in SMKOs, there was no AngII infusion dependent depression in cortical or medullary NHE3, nor medullary NKCC. However, the extent of increase in activated (cleaved) αENaC was significantly less than controls (cortex: 1.46±0.16 vs. 2.58±0.17, P=0.002; medulla: 1.49±0.09 vs. 2.22±0.31, P=0.01). Yet, 24 hr urinary aldosterone excretion was not different between the groups (18.6±2.7 vs. 15.8±4.5 ng/24hrs). Our studies indicate that the lower baseline BP in SMKO mice is associated with reduced Na+ transporter abundance along the loop of Henle, and that attenuated hypertension and improved natriuresis during AngII infusion are associated with diminished ENaC activation. In conclusion, we suggest that vascular-epithelial cross-talk modulates renal Na+ handling and thereby contributes to control of BP at baseline and during hypertension.
Abstract 019: Effect of CPAP on Blood Pressure and Central Sympathetic Outflow in Diabetic Patients with OSA, Resistant HTN, and CKD
Authors: Ruzicka Marcel , Hiremath Swapnil , Leenens Frans H , Leech Judith , Aaron Shawn
Published: July 2021

Introduction:
Central sympathetic hyperactivity as assessed by muscle sympathetic nerve activity recordings is thought to play a crucial role in the development and maintenance of hypertension (HTN) in patients with obstructive sleep apnea (OSA). Decreases in daytime and nocturnal blood pressure (BP) in response to treatment with continuous positive airway pressure (CPAP) are paralleled by decreases in muscle sympathetic nerve activity (MSNA). Patients with chronic kidney disease (CKD) have high MSNA. Bilateral nephrectomy, but not renal transplantation normalizes MSNA indicating central sympathoexcitatory effects by renal afferents. The objective of this study was to assess to what extent is HTN driven by central sympathetic hyperactivity in patients with diabetic CKD, OSA, and resistant HTN. Thirteen patients (age 62.2±7.4 years) with diabetic CKD, resistant HTN defined as SBP on 24-hr ABPM above 135 mmHg while on 3 or more BP lowering drugs (including diuretic) with OSA, were randomized to therapeutic CPAP or non-therapeutic CPAP for one months. 24-hr ABPM, plasma catecholamines, aldosterone, and renin, and MSNA were assessed before and 1 months after randomization. Our results show (Table) that in contrast to sham CPAP, therapeutic CPAP decreased daytime and nighttime BP. In contrast, neither therapeutic nor sham CPAP caused any changes in MSNA and plasma catecholamines. In conclusion, decreases in BP in response to CPAP in patients with in diabetic CKD, despite maintained high MSNA, indicate other mechanism contributing to HTN in these patients as well as other central sympathoexcitatory pathways activated.
Abstract 022: mTORC1 is Required for the Cardiovascular but Not the Metabolic Actions of Leptin
Authors: Bell Balyssa , Morgan Donald , Rahmouni Kamal
Published: July 2021

Obesity represents a major risk factor for the development of hypertension, and inappropriate leptin action has been implicated as an essential mediator of obesity-associated hypertension. Leptin plays a critical role in energy homeostasis, acting through the brain to stimulate energy expenditure and suppress food intake. Leptin also increases sympathetic outflow to a variety of target organs, including those involved in blood pressure regulation. Here, we investigate the role of mTORC1 as a potential mediator of leptin’s cardiovascular and metabolic actions. For this, we generated conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb) expressing cells (LRb
Cre
/Rap
fl/fl
). LRb
Cre
/Rap
fl/fl
displayed similar body weight, food intake and body composition as compared to littermate controls when fed a normal chow diet (body weight=29.6±0.8 g vs 31.0±0.8g at 14 weeks of age). Control and LRb
Cre
/Rap
fl/fl
mice also developed diet-induced obesity to a similar extent when fed either a 45% high-fat (37.2±3.1g g vs 40.9±2.2) or high-fat/high-sucrose diet (35.4±1.1g vs 35.2±2.7g). Additionally, fasting blood glucose (77.3±6.7mg/dL vs. 71.8±4.3mg/dL) as well as insulin (AUC=7788 ±1013, n=3 vs. 8964±884, n=4) and glucose (AUC=39750±2075, n=3 vs. 44259±1948, n=4) tolerance in high fat/high-sucrose diet fed mice were not changed in LRb
Cre
/Rap
fl/fl
mice as compared to littermate controls. Conversely, while baseline mean arterial pressure (MAP) was comparable between LRb
Cre
/Rap
fl/fl
mice (108±9 mmHg) and controls (103±7 mmHg), intracerebroventricular administration of leptin significantly increased MAP in control mice (30±14 mmHg), but not in LRb
Cre
/Rap
fl/fl
mice (1±9 mmHg, P<0.05 vs controls). Consistent with this, LRb
Cre
/Rap
fl/fl
mice displayed a blunted renal sympathetic nerve response to leptin (-4±15%, n=9 vs. 127±16%, n=9, P<0.05) but a preserved increase in sympathetic outflow to brown adipose tissue (109±27%, n=5 vs. 173±52%, n=4). Together, our data indicate a critical role for mTORC1 in mediating the cardiovascular but not the metabolic effects of leptin.
Abstract 032: Acute Inhibition of HDACs After MI Leads to Suppression of Angiogenesis
Authors: Veeranki Sudhakar - , Tyagi Suresh C
Published: July 2021

Aim:
Although histone deacetylase inhibitors (HDACi) confer protection after myocardial injury (MI), the changes in the profiles of the angiogenic regulators are unknown after the usage of clinically approved HDAC inhibitors.

Methods:
All the mice underwent permanent LAD ligation. The mice were treated with Belinostat (PXD101), a clinically approved HDACi, for a period of 3 days at a dose of 100 mg/kg, I.P., daily after the creation of MI. Mice were sacrificed after 72 hrs of MI and the ischemic and non-ischemic portions of heart tissue were collected. Relative levels of 53 angiogenesis-related proteins were quantified by using angiogenic arrays. Heart function was evaluated before and after 72 hrs of MI injury. Markers of inflammatory cells (macrophages and neutrophils) and endothelial progenitor cells (EPCs) were assayed in the ischemic tissues. Levels of different cytokines were measured in the plasma.

Results:
Belinostat (PXD101) treatment failed to ameliorate heart function after the 72 hrs of treatment. There were specific changes in the levels of EPC chemokines such as CXCL1 and MCP1 after the treatment. Further assaying of various endothelial markers revealed diminished endothelial migration and differentiation in the ischemic tissues after the treatment, which was coincided with reduced macrophage presence. The transcriptional ability of the two major regulators of CXCL1 and MCP1, STAT3 and NFκB, was suppressed. Reduced IL-6 signaling was found to be the major cause behind the low inflammatory profile, diminished inflammatory cell presence and declined EPC presence.

Conclusions:
Acute inhibition of HDACs through Belinostat (PXD101) led to lower inflammatory profile and neoangiogenesis after MI. Our study underscored the complex role of HDACi in the regulation of myocardial angiogenic responses after MI injury and suggested careful reexamination before their translational use. It was also noted that the timing of HDACi use after the MI is crucial in the successful translation of HDACi into the clinic.
Abstract 043: Influence of Sex, Hormones and Age on Cerebrovascular Function: Role of Large Conductance Potassium Channel Subunits
Authors: Pabbidi Mallikarjuna R , Kuppusamy Maniselvan , Pareek Tanya , Alexander Barbara T , Newsome Ashley D
Published: July 2021

Although adult females are protected, the cerebrovascular disease is greater in aged post-menopause females than in age matched males, but the role of vascular function and large conductance potassium (BK) channel is not clear. We hypothesize that “compared to adult males, cerebral vasculature of intact adult female rats displays an attenuated myogenic response and greater intrinsic tone due to differential expression and function of BK channel subunits. Aging or menopause exaggerates myogenic response, diminishes intrinsic tone and thus, vasodilatory capacity in females more than males due to a reduction in the BK subunit function.” Our results suggest that middle cerebral arteries (MCA) of intact adult females had attenuated myogenic response compared to adult males and ovariectomy (OVX) females (% change in diameter: 16±8, -25±4 and -49±7). Development of intrinsic tone was greater in intact adult females than adult males and OVX females (% intrinsic tone: 47±5, 27±4 and 15±5). The ratio of BK β1 to α subunits was less in intact adult females than adult males and OVX females (0.4±0.07, 2±0.3 and 0.6±0.1). Spontaneous transient outward currents (STOC) were higher in smooth muscle cells of intact adult females compared to adult males (pA: 204±27 and 128±7). While aging exaggerated the myogenic response in females, it had no effect in males (fold change 4±1 Vs 0.8±0.5). However, intrinsic tone was decreased in aged females but increased in aged males (% change -43±9 Vs 37± 6). Aging decreased the amplitude of STOCs but with a greater magnitude of effect in females (fold change females: -4.9±1; males: -0.8±0.2). While aging increased BKα subunit, it decreased β1 subunit protein (β1 change: females -52±8; males -37±13). Acute activation of BKα subunit by NS1619, while had no effect in intact adult females (-5±3%), it dilated the MCA of adult males (32±9%). However, acute activation of BKβ1 by estradiol while relaxed MCA of adult females (35±7%) and males (22±2%), it had less effect in OVX females (-7±8%) and aged females (4±9%). In conclusion, a higher incidence of cerebrovascular disease in aged and menopause female may be due to sex-specific changes in vascular properties and BK channels that could result in diminished estradiol-mediated vasodilation.
Abstract 062: Vascular Dysfunction and Hypertension are Prevented by a Novel PPARγ Target Gene, RhoBTB1
Authors: Mukohda Masashi , Ibeawuchi Stella-Rita C , Hu Chunyan , Lu Ko-Ting , Nair Anand R , Agbor Larry N , Wu Jing , Quelle Frederick W , Sigmund Curt D
Published: July 2021

RhoBTB1 is a novel peroxisome proliferator-activated receptor gamma (PPARγ) target gene expressed in smooth muscle cells (SMC) which may mediate some of the vascular protective and antihypertensive benefits of PPARγ. Here, we tested the hypothesis that RhoBTB1 can prevent angiotensin II (ANG)-induced hypertension. RhoBTB1 expression in aorta from C57BL/6 mice was decreased by 54±9% (n=16) in response to ANG infusion (490 ng/min/kg, 2 weeks). To test if RhoBTB1 expression is protective, we generated double transgenic mice with tamoxifen-inducible, Cre-dependent overexpression of RhoBTB1 specifically in SMC (S-RhoBTB1). S-RhoBTB1 and non-transgenic (NT) mice were treated with tamoxifen (Tx; 75 mg/kg, ip, 5 days) or vehicle (corn oil) and then ANG was infused. Although RhoBTB1 expression was decreased in ANG-infused control mice (p<0.01, n=8-10), RhoBTB1 expression in Tx-treated S-RhoBTB1 mice infused with ANG was restored to a level similar to NT treated with saline (n=11). Overexpression of RhoBTB1 did not alter baseline blood pressure (BP) in the absence of ANG (n=7-8). However, the increase in BP induced by ANG was significantly attenuated by RhoBTB1 restoration in S-RhoBTB1 mice with Tx compared to ANG-infused control mice (either NT with Tx, NT with corn oil, or S-RhoBTB1 with corn oil) in which RhoBTB1 was not restored (Systolic BP, 159±5 in control mice vs 132±6 mmHg in S-RhoBTB1 mice with Tx, p<0.01, n=7-8). We also observed increased heart weight in ANG-infused control mice, which was prevented in S-RhoBTB1 mice treated with Tx (p<0.05, n=8). Thoracic aorta and basilar artery from ANG-infused control mice exhibited impaired acetylcholine-induced endothelial-dependent relaxation (Aorta, 48±2%, p<0.01, n=6-8), which was prevented by restoration of RhoBTB1 in SMC (Aorta, 76±5%, p<0.01, n=6-8). Thoracic aorta from ANG-infused control mice also displayed decreased sodium nitroprusside-induced endothelial-independent relaxation with a right-shifted dose-response (76±9%, p<0.01, n=8), which was also prevented in tamoxifen-treated S-RhoBTB1 mice (95±10%, p<0.01, n=8). We conclude that the novel PPARγ target gene, RhoBTB1, functions in SMC to specifically facilitate vasodilation and mediates a protective anti-hypertensive effect.
Abstract 065: Induction of Human Endothelin-1 Overexpression for 3 Months Causes Blood Pressure Rise and Renal Injury
Authors: Paradis Pierre , Coelho Suellen C , Berillo Olga , Ouerd Sofiane , Fraulob-Aquino Júlio C , Caillon Antoine , Barhoumi Tlili , Offermanns Stefan , Schiffrin Ernesto L
Published: July 2021

Introduction:
Endothelium-derived endothelin (ET)-1 has been implicated in hypertension and renal disease but the mechanisms are complex and remain unclear. We have shown that tamoxifen-inducible endothelium-restricted human ET-1 overexpressing (ieET-1) mice exhibited BP rise after 3 weeks of induction in an ET type A receptor (ET
A
R)-dependent manner, in absence of renal injury. It is unknown whether long-term exposure to ET-1 overexpression results in sustained BP elevation and renal injury.

Methods:
Adult male ieET-1 and control tamoxifen-inducible endothelium-restricted Cre recombinase (ieCre) mice were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and 2.5 months later were treated or not with an ET
A
R blocker, atrasentan (10 mg/kg/day, PO) for 2 weeks. Blood pressure (BP) by telemetry, renal artery flow (RAF) by ultrasonography, immune cell infiltration by flow cytometry, kidney injury molecule (KIM)-1 expression by immunofluorescence, 24h urinary albumin by ELISA and creatinine by alkaline picrate method were determined at the end of the study.

Results:
Induction of ET-1 overexpression for 3 months resulted in greater systolic BP (135±4 vs 114±2 mmHg,
P
<0.001) and reduced RAF (1.7±0.2 vs 3±0.3 mL/min,
P
<0.05). ieET-1 mice presented increased myeloid (21255±5294 vs 5146±1987 CD11b
+
cells/kidney,
P
<0.001) and myeloid-derived suppressor cells (5332±1463 vs 1126±507 CD11b
+
Gr-1
+
cells/kidney,
P
<0.01) renal infiltration associated with greater frequency of CD11b
+
(23.2±1.8 vs 7.5±1.6 % of CD45
+
cells,
P
<0.001) and non-immune renal cells (CD45
-
, 5.7±0.8 vs 3.2±0.6 % of CD45
-
cells,
P
<0.001) expressing a pro-inflammatory maker, CD36. Early renal injury was demonstrated in ieET-1 by increased KIM-1 expression in proximal tubules (4.0±0.7 vs 1.0±0.2 % of renal cortex,
P
<0.05) and unchanged albumin/creatinine ratio (327±74 vs 173±36 μg/mg, P=0.215). Atrasentan reversed or reduced all of the above except the decreased RAF (
P
<0.05).

Conclusions:
Long-term exposure to endothelial ET-1 overexpression caused sustained BP elevation and renal injury via ET
A
R.
Abstract 072: Paradoxical Blood Pressure Increase After Brief Patient Rest Period
Authors: Shofu Abimbola , Kennedy Timothy , Omar Bassam , Malozzi Christopher , Awan G. Mustafa
Published: July 2021

Background:
Office-based blood pressure (BP) measurement is subject to variations which may influence management.

Objective:
To assess the effect of rest period on repeat BP measurement.

Methods:
Clinic charts were review identified 200 encounters with BP re-measurement due to initial BP of > 130/80 mmHg. BP was measured initially by a nurse, with the patient in a sitting position and the arm resting at the level of the heart. If BP was > 130/80 mmHg, it was repeated by physician after resting the patient for 15 minutes. Mean age was 64 ± 12 years.

Results:
Among encounters with BP re-measurement, initial systolic BP (SBP) was 154 ± 25 mmHg, and diastolic BP 87 ± 15 mmHg. Upon re-measurement, 135 of 200 patients (68%) had lower SBP of 144 ± 21 mmHg compared with initial SBP of 161 ± 25 mmHg; a 17 mmHg drop (P < 0.01). However, 53 of 200 patients (27%) had higher SBP of 149 ± 17 mmHg compared with initial SBP of 138 ± 14 mmHg; an 11 mmHg increase (P < 0.01). Twelve patients (6%) had no BP change. In 47% (93/200) of encounters, BP re-measurement necessitated medication changes. Compared with the remaining patients, those with paradoxical increase in BP were younger (60 ± 9 years versus 66 ± 12 years; p < 0.01), and with lower initial SBP (138 ± 14 versus 161 ± 25, p < 0.01).

Discussion:
Hypertension is a major challenging public health problem. JNC 8 guidelines recommend that prior to BP measurement, patients should be seated quietly for at least 5 minutes in a chair, with feet on the floor, and arm supported at heart level; this may decrease initially elevated BP. However, 27% of our patients exhibited a paradoxical response, with elevation of the SBP after a 15 minute period of rest. The cause of this paradox is not clear, but may have resulted from white-coat hypertension during the rest period, which may be more common in younger patients, as noted in our study. This underscores the importance of ambulatory BP monitoring, especially in subsets of patients prone to having labile or white coat hypertension, to avoid the cost and side effects of BP overtreatment. Studying larger number of patients, and including patient with normal initial BP, may help clarify the mechanism and clinical significance of this observation.
Abstract 098: Augmenting Renal Lymphatic Vessel Density Prevents Salt-sensitive Hypertension in Mice
Authors: Balasubbramanian Dakshnapriya , Lopez Gelston Catalina A , Abouelkheir Gabriella R , Lopez Alexandra H , Hudson Kayla R , Johnson Eric R , Garza Victoria C , Daboul Reem A , Rutkowski Joseph M , Mitchell Brett M
Published: July 2021

Salt-sensitive hypertension (SSHTN) is associated with renal immune cell infiltration and interstitial inflammation. Lymphatic vessels drain the interstitial compartment and traffic immune cells to draining lymph nodes; however little is known about the role of lymphatics and immune cell trafficking in the kidney during SSHTN. Our hypotheses were that renal lymphatic vessel density is increased in mice with SSHTN and that further augmenting renal lymphatic vessels will prevent SSHTN. SSHTN mice were made by administering L-NAME for two weeks, followed by a two week washout, and then were fed a 4% high salt diet for three weeks. Compared to control mice, mice with SSHTN (SBP: 103±3 vs. 136±2 mmHg; p<0.05) had markedly increased renal lymphatic vessel density. Kidneys of SSHTN mice had significantly increased gene expression of the lymphatic vessel marker
Lyve1
, the macrophage marker
Adgre1
(F4/80), the Th1 cell marker
Tbx21
, and the pro-inflammatory cytokine
Il6
while expression of the immune cell-lymphatic chemokine receptor
Ccr7
was decreased significantly. Mice solely fed a 4% salt diet for three weeks did not exhibit hypertension or increased renal lymphatic vessel density. To determine whether augmenting renal lymphatic vessels prior to the high salt diet could prevent SSHTN, we used transgenic mice that overexpress the lymphangiogenic signal VEGF-D only in the kidney under the control of doxycycline (KidVD+ mice) and thus exhibit renal lymphangiogenesis. Doxycycline initiated one week prior to the high salt diet prevented SSHTN in KidVD+ mice while having no effect on blood pressure in KidVD- mice (SBP: 117±4 vs. 139±5 mmHg; p<0.05). Renal gene expression of
Tbx21
was decreased in KidVD+ mice while
Ccr7
gene expression was increased significantly. These data demonstrate that renal lymphatic vessel density is increased in SSHTN and that augmenting renal lymphatic vessel density prior to a high salt diet can prevent SSHTN by improving renal immune cell exfiltration.
Abstract 127: Disparities in Total Health Care Expenditure, and Payment Type Related to Hypertension Between Non Hispanics and Hispanics in the USA: Results From the Medical Expenditure Panel Survey (2013 - 2014)
Authors: Veledar Emir , Saxena Anshul , Osondu Emeka , Valero Elizondo Javier , Nasir Khurram
Published: July 2021

Background:
Each year in the USA, more than 75 million adults are diagnosed with hypertension (HTN), but less than 54% have this condition under control. Due to poor management, mortality due to HTN or related complications was 410,000 in 2014 and resulted in close to $50 billion spent. We sought to examine disparities in the proportion of events and related expenditure due to HTN between 54 million Hispanics, representing 17% in the USA population and non Hispanics.

Methods and Population:
We used data from the Medical Expenditure Panel Survey (MEPS), the most complete source of data on the cost and use of health care and health insurance coverage for 2013 and 2014. Cost was grouped as related to ambulatory, emergency room, inpatient, home visits and medications. By source, payments were grouped as paid by family, MEDICARE, MEDICAID, private insurance, VA, Tricare and other.

Results:
Overall, there were 61.2 and 61.9 million total events associated with HTN in 2013 and 2014 respectively; Hispanics accounted for 5.8 (9.5%) and 5.4 (8.7%) million events each year. On an average, HTN events involving Hispanics were costlier up to $90 - $300 more than non Hispanics ($1053 vs. $ 746 in 2013; and $890 vs. $804 in 2014). For Hispanics, payments were mainly covered by MEDICAID (42.1%) and MEDICARE (27.5%), compared to MEDICARE (39.3%) and private insurance (23.7%) for non-Hispanic population. Hispanics HTN expenditures were $6.1 billion (12.9%) in 2013 and 5.3 billion (10.3%) in 2014 and Hispanics had disproportionately fewer number of events than expected 17%, and the structure of their costs for those events was not different from non-Hispanics. In regression model, accounting for demographics and type of insurance, being Hispanic was a significant predictor of the total, ambulatory and inpatient cost, but not emergency room or medication cost.

Conclusion and Discussion:
Hispanics participate disproportionately less in HTN events and costs compared to their proportion in population, even when age, demographic and socioeconomic factors are accounted for. They also have on average higher and more complex events compared with non Hispanics. Almost 70% of HTN expenditure for Hispanics in 2013-2014 was covered by MEDICAID and MEDICARE indicating socioeconomic disparities.
Abstract 138: Mas-related G-protein Coupled Receptor D Deficiency Leads to a Marked Dilated Cardiomyopathy in Mice
Authors: Oliveira Aline C , Melo Marcos B , Peluso Augusto A , Motta-Santos Daisy , Neto Fernando P , da Silva Rafaela F , Jesus Itamar C , Guatimosim Silvia , Alenina Natasha , Bader Michael , Campagnole-Santos Maria Jose , Santos Robson A
Published: July 2021

Recently, we described a new peptide of the RAS, the heptapeptide alamandine. Alamandine [Ala
1
-angiotensin-(1-7)] is formed from angiotensin-(1-7) by decarboxilation of the N-terminal Asp residue to Alanine or from the octapeptide angiotensin A (Ala
1
-Ang II) by removal of the Phe c-terminal residue by ACE2. Alamandine effects were independent of Angiotensin-(1-7) receptor Mas. The Mas-related G protein receptor member D (MrgD) was identified as the alamandine receptor. Although cardioprotective effects of alamandine similar to Ang-(1-7) have been described, the significance of this peptide in the heart function is still elusive.

Objective:
To evaluate the functional role of the alamandine receptor, MrgD, in the heart using MrgD-deficient mice.

Methods:
Primary cardiomyocytes were obtained from neonatal rats and mice with up to 72 hours of life. Cells were fixed, blocked, permeabilized and incubated with an anti-MrgD antibody, washed and incubated with a secondary antibody and Phalloidin. Slides were analysed using confocal microscopy. High-resolution echocardiography was performed in MrgD
+/+
and MrgD
-/-
mice (12 weeks old, n=5-6) under isoflurane anesthesia. Standard B-mode images were obtained in right and left parasternal long and short axis for morphological and functional assessment and evaluation of cardiac deformation (VevoStrain).

Results:
Immunofluorescence indicates that MrgD is present in cardiomyocytes, mainly in the perinuclear and nuclear region, with similar pattern in rats and mice. High resolution echocardiography showed left ventricular remodelling and dysfunction in MrgD-KO mice when compared to their controls. Strikingly, MrgD-deficient mice presented a pronounced dilated cardiomyopathy with a marked decrease in systolic function (EF: 34.39 ± 2.9 versus 66.49 ± 2.3 %; FS: 16.23 ± 0.6 versus 35.91 ± 1.8 %; EDV: WT = 46.47 ± 2.4 versus 81.15 ± 3.7; ESV: 15.41 ± 0.7 versus 53.21 ± 2.5).

Conclusion:
Alamandine MrgD receptor is expressed in cardiomyocytes and its deletion leads to a pronounced dilated cardiomyopathy indicating a major role for alamandine in the heart.
Abstract 143: Pregnancy Dependant Transcriptomic Changes in Uterine Arteries From Hypertensive and Normotensive Rat Models
Authors: Morgan Hannah L , Beattie Elisabeth , McBride Martin W , Graham Delyth
Published: July 2021

Background:
During normal pregnancy the uteroplacental vasculature remodels to accommodate for the increased blood flow to the placenta. In hypertensive pregnancies this remodelling is impaired. Stroke prone spontaneously hypertensive (SHRSP) rats exhibit a hypertensive pregnancy with impaired uteroplacental remodelling. This study investigated early gene expression changes in the uterine arteries (UA) of pregnant SHRSP and normotensive Wistar Kyoto (WKY) rats.

Methods:
SHRSP and WKY females were time mated and UA isolated at gestational day (GD)6 (n=3). Non-pregnant (NP) UA were isolated from virgin aged matched controls (n=3). UA RNAseq (Illumina platform) was performed. Transcript level gene changes were interpreted using Ingenuity Pathway Analysis (FDR < 0.05, FPKM>1.0). Quantitative RT-PCR was used to validate significantly differentially expressed genes.

Results:
There was a greater number of differentially expressed transcripts NP v GD6 in SHRSP compared to WKY (796 vs 535). 147 pregnancy dependant gene changes were common to SHRSP and WKY; which involved cellular movement and cell growth/proliferation pathways. Further analysis revealed calcium signalling genes involved in the α-adrenergic pathway were downregulated in WKY NP v GD6, e.g. inositol-1,4,5-trisphosphate receptor (Ip3r) (
FC 2.5; p<0.01)
, but were not different in SHRSP. Inflammatory response was increased over pregnancy, specifically phospholipase A2 (Pla2ga) expression (
FC -7.2 in WKY and FC -4.3 in SHRSP; FDR<0.0001
). Gene expression differences were also observed in nitric oxide and reactive oxygen species pathways. Nox2 subunits were downregulated in SHRSP NP v GD6 e.g. p40-phox (
FC -2.2; FDR<0.001
), but did not change in WKY. qPCR confirmed significantly increased UA Ip3r gene expression in GD6 SHRSP vs GD6 WKY (
27.1CT vs 28.3CT p<0.05
) and reduced Pla2ga expression in WKY vs SHRSP NP UA (
23.3CT vs 26.4CT; p<0.001
).

Conclusion:
We show that SHRSP UA have different gene expression profiles in response to pregnancy compared to WKY. These early transcript level changes occur prior to structural or functional changes, suggesting that the strains have pre-existing genetic differences that may ‘prime’ the UA to respond differently due to chronic hypertension in SHRSP rats.
Abstract P128: Intensive Blood Pressure Management in Chronic Kidney Disease Patients: An Analysis of the SPRINT Dataset
Authors: Mirzan Haares , Aggarwal Rahul , Chiu Nicholas , Han Sang Myung , Park Jason , Petrie Benjamin , Steinkamp Jackson , Lu Kimberly
Published: July 2021

Introduction:
Systolic Blood Pressure Intervention Trial (SPRINT) determined that among non-diabetic patients with increased CV risk, intensive management of systolic blood pressure (SBP) to a target of 120 mmHg resulted in lower rates of CV events and all-cause mortality, as opposed to the standard goal of 140 mmHg. Current management of BP in the CKD population shows conflicting evidence on target SBP. With the use of patient-level SPRINT data, our study investigates the risks and benefits of intensive BP management in patients with CKD at baseline and is the largest study of intensive BP management in CKD patients (n=2646).

Methods:
The similarity between CKD patients in standard and intensive blood pressure management groups with regard to age, race, gender, estimated GFR (eGFR), and baseline SBP were assessed and no differences were found between the two groups. Differences in mortality, adverse events, and rates of achieving BP targets in intensive and standard BP management groups were examined. Cox proportional-hazards models were used for the events analysis. Multiple linear regression was used to assess the differences in achieving BP targets.

Results and Discussion:
We highlight three key findings. First, the average post-management SBP was higher in CKD patients than in non-CKD patients in both standard (
p
= 0.017) and intensive (
p
< .001) groups, controlling for age, race, gender, eGFR, and baseline SBP, possibly indicating greater difficulty in controlling BP in CKD patients . Second, intensively-treated CKD patients had increased risks for intervention-related adverse events, including events that resulted in disability, hospitalization, or harm that may have required medical or surgical intervention (p < .001). They also experienced higher rates of AKI related adverse events (p<.008). Third, intensive management showed a mortality benefit (HR: .725; 95% CI, .532 to .987), a finding that may help clarify conflicting reports in current literature.

In conclusion, we present an analysis of CKD-specific SPRINT data in order to elucidate the clinical benefits and risks of intensive BP management in the CKD population.
Abstract P132: Increased Cardiovascular Parasympathetic Tone in African Americans With CD36 Partial Deficiency
Authors: Ejtemaei Mehr Shahram
Published: July 2021

Cardiovascular disease is the leading cause of death among African Americans (AA). Reduced parasympathetic tone as measured by high frequency heart rate variability (HF
RRI
) predicts cardiovascular mortality. HF
RRI
is reduced after a high fat meal through caveolar sequestration of muscarinic M2 receptors. The fatty acid translocase CD36 is a protein abundant in the myocardium and important for heart function and lipid metabolism. CD36 plasma membrane localization and function in fatty acid uptake is modulated by its interaction with caveolin. One in four AAs are G-allele carriers for CD36 SNP rs3211938 resulting in ~50% decreased CD36 expression. CD36 deficiency also reduces fat taste perception, which might lead to higher fat intake to reach taste saturation. We tested the hypothesis that obese AAs with partial CD36 deficiency have altered parasympathetic tone during fasting and after a high-fat meal. We recruited 13 G-allele carriers and 39 non-carriers. Subjects were matched by age (P=0.820), BMI (P=0.751), and blood pressure (P=0.701). There was a trend towards reduction in heart rate in carriers (P=0.07). Baseline HF
RRI
was elevated in G carriers (557.1 [251 to 942] vs. 224 [95 to 655] ms
2
, P=0.046). Eleven subjects received a high-fat meal (700 Cal/m
2
BSA, 80% fat). HF
RRI
was measured at baseline and 30, 60, 120, 240 minutes after meal. Non-carriers (n=4) showed a time-dependent decline in the percent change in HF
RRI
(-23, -32, -70, -84, respectively). In G-allele carriers (N=6), the decline in HF
RRI
(21, -11, -61, -70 min) was attenuated.

Conclusion:
AAs with partial CD36 deficiency have enhanced fasting parasympathetic tone and a blunted response to a high fat meal.
Abstract P137: Intrauterine Growth Restriction Programs a Greater Age-related Decline in Renal Function Associated With Increased Susceptibility to Chronic Renal Injury
Authors: Newsome Ashley D , Davis Gwendolyn K , Ojeda Norma B , Alexander Barbara T
Published: July 2021

Epidemiological studies indicate that low birth weight (
LBW
) is associated with a reduction in nephron number, hyperfiltration, hypertension, and accelerated loss of renal function. Yet, the mechanisms involved are not understood. Our laboratory uses a rodent model of LBW that results in hypertension but no change in glomerular filtration rate (
GFR
) in male intrauterine growth restricted (
IUGR
) offspring in early adulthood. The aim of this study was to test the hypothesis that IUGR programs a greater decline in GFR with aging and that it enhances susceptibility to a chronic renal insult. Male rats underwent sham (
S
) or uni-nephrectomy (
UNI-X
) with measurement of GFR two months post-surgery at 6 (young adult) and 14 months, or one month post-surgery at 19 months of age. GFR (mL/min/100 g body weight), determined by transcutaneous FITC-sinistrin clearance, was significantly decreased with age in IUGR S and IUGR UNI-X (**
P
<0.001 and *
P
<0.05 vs 6-month-old counterparts, respectively; Table). Although not significant, IUGR S had a higher mean GFR than Control S in young adulthood suggesting baseline hyperfiltration as a potential contributor to the greater age-related decline in GFR in IUGR offspring. In IUGR UNI-X at 19 months: GFR was significantly reduced (
†
P<0.05 vs IUGR S), urinary NGAL was increased (59872 vs 11620 ng/day in IUGR S; P<0.05), and renal TNF-α and TGF-β mRNA expression were elevated (9- and 3-fold greater than both Control UNI-X and IUGR S; P<0.05). Thus, these data indicate that IUGR programs a greater age-related decline in GFR and increased susceptibility to chronic renal injury in later life that is associated with an enhanced renal inflammatory response to injury.
Abstract P142: The CKD273 Urinary Peptidomic Biomarker is Associated with Mortality in People at Early Stages of Diabetic Nephropathy Independent of Traditional Risk Factors
Authors: Currie Gemma E , Mary Sheon , von Scholten Bernt J , Lindhardt Morten , Mischak Harald , Mullen William , Rossing Peter , Delles Christian
Published: July 2021

Background:
Mortality in type 2 diabetes (T2D) is primarily driven by cardiovascular disease. This is amplified in diabetic nephropathy (DN), even in early ‘pre-clinical’ stages. A urinary peptidomic classifier (CKD273) has been found to predict DN development in advance of detectable microalbuminuria. Whether it is also a determinant of mortality and cardiovascular disease in patients with established albuminuria is unknown.

Methods:
We studied 155 subjects with T2D, albuminuria (geometrical mean [IQR]: 85 [34;194] mg/24hrs), controlled blood pressure (129±16/74±11 mmHg) and preserved renal function (eGFR 88±17 ml/min/1.73m
2
). Blood and urine samples were collected for measurement of estimated glomerular filtration rate (eGFR), urine albumin excretion (UAE), N-terminal pro-brain natriuretic peptide (NT-proBNP; ELISA) and urinary proteomics (capillary electrophoresis coupled to mass spectrometry). Computed tomography imaging was performed to assess coronary artery calcium (CAC) score. Outcome data were collected through national disease registries over a 6 year follow up period.

Results:
CKD273 correlated with UAE (r=0.481, p=<0.001), age (r=0.238, p=0.003), CAC score (r=0.236, p=0.003), NT-proBNP (r=0.190, p=0.018) and eGFR (r=0.265, p=0.001). On multiple regression only UAE (β=0.402, p<0.001) and eGFR (β=-0.184, p=0.039) were statistically significant determinants. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p=0.004), and retained significance (p=0.050) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. Neither eGFR nor UAE were determinants of mortality in this cohort.

Conclusions:
A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the peptidomics-based classifier CKD273 is associated with mortality in albuminuric people with T2D in even when adjusted for other established cardiovascular and renal biomarkers.
Abstract P156: Estrogen Regulation of Endothelin-B Receptor Mediated Vasodilation
Authors: Haigh Katherine , Feinberg Ronald F , Taylor Hugh S , Wenner Megan M
Published: July 2021

Our laboratory has recently demonstrated that a loss of endothelin-B (ETB) receptor mediated dilation contributes to impaired vasodilatory function in postmenopausal women. It is unclear if these changes are due to aging, or alterations in ovarian hormones that occur after menopause. The purpose of this study was to test the hypothesis that in a low estradiol state, there is a loss of ETB mediated dilation, and that estradiol administration reverses these responses and mediates dilation.

Methods:
We tested 8 young women (YW: 24±2 years, 23±1 kg/m
2
, mean arterial BP 84±2mHg) and 6 postmenopausal women (PMW: 56±1 years, 24±1 kg/m
2
, mean arterial BP 94±2mHg). In YW, we suppressed endogenous ovarian hormone production with daily gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix) administration for 10 days, adding estradiol (E2, 0.1 mg/day, Vivelle dot patch) on days 4-10. PMW were tested at baseline and after 1-week E2 administration (0.1 mg/day, Vivelle dot patch). We measured nitric-oxide mediated vasodilation in the cutaneous circulation during local heating (42°C) via laser Doppler flowmetry, followed by microdialysis perfusions of sodium nitroprusside (28mM) with local heating to 43°C to elicit maximal dilation. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flow/mean arterial blood pressure, and expressed as a percent of maximal dilation.

Results:
ETB receptor blockade increased vasodilation in YW during hormone suppression with GnRHant (control: 88±3 vs. BQ-788: 94±2 CVC %max,
P
<0.05). However, ETB receptor blockaded tended to reduce vaodilation during E2 administration (control: 88±3 vs. BQ-788: 82±2 CVC %max,
P
=0.12). In PMW, ETB receptor blockade had no significant effect on vasodilatory responses (control: 90±4 vs. BQ-788: 95±2 CVC %max,
P
=0.20). Similarly, ETB receptor blockade did not alter vasodilation after E2 administration (control: 88±7 vs. BQ-788: 88±4 CVC %max).

Conclusions:
These preliminary data suggest that suppression of endogenous ovarian hormone production alters ETB receptor responses in young women, which is partially mediated by E2. Additional data are needed to determine ETB receptor sensitivity to E2 after menopause.
Abstract P167: Aging Exacerbates Increased MAP and Proteinuria in Male Rat Offspring of Hyperandrogenemic Mothers
Authors: Dalmasso Carolina , Maranon Rodrigo O , Patil Chetan N , Reckelhoff Jane F
Published: July 2021

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 6-10 % of women, and is associated with hyperandrogenemia, oligo/anovulation and polycystic ovaries. Many women with PCOS have difficulty getting pregnant and, when they do, the infants are predisposed to preterm birth, metabolic disorders during childhood, and potential risk for the daughters to develop PCOS. The mechanisms by which the offspring of women with PCOS develop negative health outcomes are unknown. Our lab has already characterized the phenotype of young PCOS offspring showing an increased MAP and proteinuria in the males. In this study we tested the hypothesis that aging will exacerbate the negative health outcomes observed in the offspring of PCOS dams. Twelve months old female (F) and male (M) offspring of control (C) and PCOS (P) dams (SD; DHT 7.5mg/90d) were divided into 4 groups: F-C, F-P, M-C and M-P. At 12 months old, there is a significant decrease in body weight in F-P and M-P, compared to F-C and M-C, respectively (F-P: 284±4 vs. F-C: 301±5; M-P: 533±8 vs. M-C: 575±8 mg/24h, p<0.001) and the body weight remains lower until 18 months of age. Body composition analysis showed that there is a decrease in lean mass in F-P and M-P, compared to F-C and M-C, respectively (F-P: 284±4 vs. F-C: 301±5; M-P: 533±8 vs. M-C: 575±8 mg/24h, p<0.01). Proteinuria at 12 months, is higher in F-P and M-P, compared to F-C and M-C, respectively (F-P: 18±2 vs. F-C: 9±1; M-P: 169±8 vs. M-C: 108±6 mg/24h, p<0.001). This increased proteinuria is still observed at 15 months (F-P: 33±5 vs. F-C: 5±1; M-P: 143±7 vs. M-C: 103±4 mg/24h, p<0.001). Baseline mean arterial pressure (MAP, telemetry, 17 months old) was similar F-P vs. F-C (F-C: 109±2 mmHg vs. F-P: 107±1 mmHg; p=NS). However, in males, MAP was significantly higher in M-P than M-C (M-C: 114±1 mmHg vs. M-P: 127±1 mmHg; p<0.05). These results showed that aging exacerbates the increased MAP and proteinuria in males. Female offspring do not develop a PCOS phenotype with aging. Future studies will be necessary to determine the exact mechanisms responsible for the increase in blood pressure and renal injury.
Abstract P169: Difference of Risk Factors for Controlled Blood Pressure in Three Types of Heart Failure
Authors: Lee Hong Seok , Belen Nunez , Cativo Hans , Savadkar Amrut , Ferdinand Visco , Mushiyev Savi , Pekler Gerald
Published: July 2021

Background:
Hypertension is the most important modifiable risk factor for worsening heart failure (HF) because hypertension increases cardiac work, which results in worsening left ventricular hypertrophy and development of coronary artery disease. We will determine risk fctors of BP control in different types of heart failure according to JNC 8 guideline.

Method:
Based on ACC/AHA guidelines, heart failure is classified as a reduced ejection fraction(HFrEF, EF <40), preserved ejection fraction (HFpEF, EF>50) and heart failure with an improved ejection fraction(HFpEF(i),EF≥40). 732 patients enrolled in our heart failure program were analyzed retrospectively. And 672 patients who had been followed from Jan 1
st
,2013 to June 30st 2015 were included. Multiple logistic regression analysis was performed to determine the relationship between hypertension and heart failure after adjusting for potential confounders.

Results:
Patients with three types of heart failure had different BP control rate. It was 67.5% (308/456) ,76.5%(104/136), 77.5%(62/80) in HFrEF, HFrEF, and HFpEF(i) based on JNC 8 guideline, respectively. Mean systolic BP was 127.1±17 mmHg in HFrEF, 129.0±21 mmHg in HFpEF and 124.4±18 mmHg in HFpEF(i). Obesity [Odds ratio (OR): 0.12,95% Confidence Interval(CI): 0.048-0.284] , ACE inhibitor or ARB [OR: 2.66, CI: 1.50-3.42] and lasix [OR: 1.90,CI: 1.07-3.40] and aspirin [OR 0.53, CI: 0.37-0.96] were noted to be related to controlled BP in HFrEF. Aspirin [OR 0.17, CI: 0.05-0.60] was significantly associated with controlled BP in HFpEF. And beta-blocker [OR: 0.07, CI: 0.01-0.62] and anti-lipid medication [OR: 4.76, CI: 1.73-5.89] were associated with BP control in HFpEF(i).

Conclusion:
In each type of heart failure, there was difference of risk factors related to BP control. Different medications were associated with control of BP in different types of heart failure. Patients may need to modify risk factors including types of medication to control BP according to types of heart failure. It might be leading to better heart failure management.
Abstract P175: Chronic Exercise Attenuates Blood Pressure Elevation and Albuminuria With Improvement of Renal Lipid Metabolism in High Fructose-fed Rats
Authors: Hu Gaizun , Ito Osamu , Xu Lusi
Published: July 2021

High fructose diet (HFr) can lead to metabolic disorder, hypertension, and renal disease. Although chronic exercise (Ex) provides various beneficial effects on hypertension and kidney disease, the precise mechanism is not fully clarified. Thus, present study examined the effects of Ex on the blood pressure, renal function and renal lipid metabolism in rats fed with HFr. Sprague-Dawley rats were allocated to 3 groups. The HFr and Ex groups were fed with HFr (60%, w/w), the control group was fed with the diet in which fructose was replaced by starch. The Ex group underwent treadmill exercise at aerobic intensity. After 12 weeks, renal triglyceride (TG) content were measured, and expression of enzymes and regulators of fatty acid metabolism were analyzed by Western blot. HFr increased systolic blood pressure (SBP) and albuminuria and Ex decreased the HFr-increased SBP and albuminuria (85±4 vs. 122±9 vs. 91±4 mmHg, P<0.01, 326±67 vs. 534±79 vs. 176±54 mg/day, P<0.01). HFr increased plasma TG and uric acid (UA) and Ex decreased the HFr-increased TG and UA (124±20 vs. 474±35 vs. 238±23 mg/dL, P<0.01, 1.15±0.10 vs. 2.14±0.10 vs. 1.50±0.13 mg/dL, P<0.01), whereas HFr or Ex did not affect plasma creatinine. HFr increased renal TG content and Ex decreased the HFr-increased TG content (12.2±0.5 vs. 14.1±0.5 vs. 10.3±1.1 mg/100mg tissue, P<0.01). Among enzymes of fatty acid synthesis, HFr increased the renal expression of fatty acid synthase (FAS), and Ex decrease the expression of FAS (P<0.01). Among enzymes and regulators of fatty acid oxidation, HFr decreased the renal expression of PPARα, carnitine palmitoyltransferase I (CPTI), medium-chain acyl-CoA dehydrogenase (MCAD) (P<0.05), and Ex increased the expression of PPARα, CPTI, MCAD, and acyl-coenzyme A oxidase (ACOX). These results indicated that Ex attenuates blood pressure elevation, albuminuria with an improvement of renal lipid metabolism in the HFr-fed rats. These effects of Ex may relate to an improvement of the renal lipid metabolism.
Abstract P191: Improved Systolic and Diastolic Blood Pressure After Enhanced External Counterpulsation Therapy Combined With a Lifestyle Modification Program
Authors: Bharmal Murtaza , Share Michael , Soulati Sara , Chiaro Dean , Weaver Ronald , Victor Ronald , Henry Timothy
Published: July 2021

Background:
Enhanced external counterpulsation (EECP) is a noninvasive, FDA approved therapy for refractory angina. Because EECP increases nitric oxide release, it may have an ancillary benefit on blood pressure (BP).

Methods:
We measured changes in BP at baseline over 35 sessions of EECP, which included lifestyle coaching. Supine blood pressure was measured before and after every EECP session by trained healthcare technicians with calibrated manual sphygmomanometers.

Results:
404 patients (age 67.2 ± 10.0, 50% male - 200/404, 77% African American - 311/404) completed the program. Hypertensive subjects at baseline (37% - 150/404) showed an improvement in both systolic and diastolic BP (Table). Notably, there was a marked reduction in BP after the first EECP session, with a further, more modest reduction by the end of the 35 sessions. Weight decreased by a mean 3.0 lbs (p<0.001) and there was no significant difference in the number of patients receiving antihypertensive medications before or after completing EECP (46% - 184/404 vs. 47% - 189/404, p=0.62).

Conclusions:
EECP therapy leads to a reduction in both systolic and diastolic blood pressure, which is most prominent in patients with baseline hypertension. These results maintain throughout the 35 sessions. These results reflect observational data from one highly experienced clinic in which EECP is routinely combined with daily coaching on vegan plant-based lifestyle modifications and exercise. Further studies are indicated to investigate this observed phenomenon to both confirm these findings as well as assess for the length and durability of the effect.