bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P246: Increased Urinary Prorenin and sPRR Excretion in Early Type 1 Diabetes
Authors: Ramkumar Nirupama , Stuart Deborah , Kohan Donald E
Published: December 2018

Activation of the intra-renal, rather than systemic renin angiotensin system (RAS) has been suggested to play a role in the development of diabetic kidney disease. In this study, we examined plasma and urinary prorenin/renin levels and urinary soluble prorenin receptor (sPRR) levels in a murine model of Type 1 diabetes. Male C57BL/6 mice were injected with streptozotocin (STZ) 50mg/kg at 3 months of age and metabolic balance studies conducted at 6 and 10 weeks post-injection. STZ injected mice developed hyperglycemia within 4 weeks of injection (STZ: 335 ± 35 vs control: 145 ± 22 mg/dL) and remained hyperglycemic at 10 weeks. At 10 weeks post-injection, STZ injected mice had significant polyuria (STZ: 20.9 ± 5.9 vs controls 1.8 ± 0.4 ml/day), increased water intake (STZ: 26.2 ± 5.9 vs controls: 6.2 ± 0.9 ml/day) and lower body weight (STZ: 28.3 ± 1.3 vs controls: 23.6 ± 1.4 grams) despite similar food intake. Compared to controls, urinary angiotensinogen, total prorenin/renin and sPRR levels were increased in STZ injected mice; these increases were proportionally greater than the trend in increased urinary microalbumin excretion (Table 1). In particular, urinary sPRR excretion was markedly increased in STZ injected mice compared to controls. In a separate experiment, 10 week old male Akita mice bearing a mutated
Ins2
gene, demonstrated a 4.8 fold increase in renal medullary renin mRNA expression and a 1.5-fold increase in renal medullary PRR expression. Taken together, these results demonstrate early activation of the intra-renal RAS in Type 1 diabetes. These changes occur independent of the systemic RAS.
Abstract P247: ACE2/ACE Imbalance in the Placental Circulation in an Ovine Model of Intrauterine Growth Restriction
Authors: Joshi Shrinidh , Lemley Caleb O , Vonnahme Kimberly A , Jarajapu Yagna P
Published: December 2018

Intrauterine growth restriction (IUGR) has been linked to the development of cardiovascular complications in the offspring. We have previously shown that in an ovine model of IUGR placental blood flow, in both umbilical and uterine artery, was decreased in diet-restricted dams. Angiotensin-converting enzyme (ACE), its metabolite Ang II and the receptor AT1 constitute the vascular-detrimental axis or renin angiotensin system, while ACE2, its metabolite Ang-(1-7) and Mas receptor constitute vasoprotective axis. This study tested the hypothesis that IUGR induces ACE2/ACE imbalance in the placental circulation. In ewe lambs, IUGR was accomplished by providing 60% of the nutrient requirement (RES) while the control group received adequate nutrients (CON) from day 50 to day 130 of gestation. At day 130, plasma samples were collected from umbilical artery (Um-A) and vein (Um-V), uterine artery (Ut-A) and vein (Ut-V), and jugular vein (J-V). ACE and ACE2 enzyme activities were determined by using enzyme-specific fluorogenic substrates, and enzyme-selective inhibitors, captopril and MLN-4760, respectively. Activities were expressed as percent inhibition by the respective inhibitors. ACE2 activity is decreased in the plasma obtained from Um-A (16±2), Um-V (29±4) and Ut-V (31±3) but not in Ut-A of RES group, compared to the CON group (Um-A 25±3, Um-V 42±2 and Ut-V 43±2, P<0.05, P<0.02 and P<.01, respectively, n=5). This resulted in decreased ACE2/ACE (CON: Um-A 0.43±0.03, Um-V 0.84±0.08 and Ut-V 0.82±0.05, and RES: Um-A 0.26±0.02, Um-V 0.46±0.05 and Ut-V 0.5±0.03, P<0.002, P<0.004, P<0.001, respectively). ACE activity was unchanged (n=5) in all four samples of placental circulation. In the J-V plasma ACE2 was decreased (24±2 vs 31±6, NS) and ACE was increased (68±4 vs 54±6, P<0.05) in RES group compared to CON (n=5). This resulted in decreased ACE2/ACE (CON: 0.58±0.04 and RES: 0.3±0.02). These observations suggest that IUGR induces ACE2/ACE imbalance. In the maternal systemic circulation it is largely due to increased ACE, while in the placental circulation it is due to decreased ACE2. Hyperactivity of ACE/Ang II/AT1 receptor pathway due attenuated opposing activity of ACE2 may restrict blood flow to the placental tissues during development.
Abstract P251: Angiotensin Based Biomarkers for Molecular Profiling and Drug Efficacy Monitoring in Hypertension
Authors: Poglitsch Marko , Ahmed Ashraf H , Stoller Andrea , Domenig Oliver , Haschke Manuel , Stowasser Michael
Published: December 2018

RAAS Triple-A testing is a novel mass spectrometry based approach providing a comprehensive biochemical evaluation of the circulating renin-angiotensin-system (RAS) on the basis of equilibrium angiotensin levels and circulating aldosterone levels. In contrast to previous technologies involving complex sampling procedures, RAS-Equilibrium-Analysis combines the robustness and accuracy of LC-MS/MS based quantification with the versatility of serum sampling to generate a highly accurate readout containing multiple layers of information regarding the biochemical features of the circulating RAAS. Equilibrium Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone were simultaneously quantified in 500μl of standard collected serum samples from healthy volunteers or hypertensive patients receiving different anti-hypertensive first-line therapies. Stable-isotope labeled internal standards were used to control for analyte recovery. Following analyte extraction, samples were subjected to UPLC-MS/MS analysis and diagnostic ratios were calculated. ACE inhibitor therapy resulted in a significant reduction of the Ang II-to-Ang I-Ratio in equilibrium analysis, which was accompanied by an up-regulation of renin, as expected. Surprisingly, PRA showed a high correlation with the sum of equilibrium Ang I and Ang II, which was independent of ACE inhibitor treatment. While the ARR was strongly suppressed in the presence of ACE inhibitor treatment, the Aldosterone-to-Angiotensin II-Ratio (AA2-Ratio) was not affected, suggesting superior applicability in screening for primary aldosteronism (PA). RAAS Triple-A testing is a mass spectrometry based multiplex assay combining Ang I, Ang II and Aldosterone to diagnostic values that draw a comprehensive picture of a patient’s "RAAS Status". While the sum of Ang I and Ang II serves as a strong PRA surrogate marker, ACE activity and ACE inhibitor therapy efficacy can be monitored using the Ang II/Ang I-Ratio. On top, the AA2-Ratio serves as an advanced diagnostic marker for PA that might pave the way for patient screening without the need of withdrawing anti-hypertensive therapies.
Abstract P252: Angiotensin II Type 1 Receptor Autoantibody Inhibited Bk Channels In Vascular Smooth Muscle Cells
Authors: Yin Xiaochen , Zhang Suli , Wang Meili , Qu Yue , Liu Huirong
Published: December 2018

Aims:
The angiotensin II type 1 receptor autoantibody (AT1-AA) leads pathological sustainable vasoconstriction. Large-conductance Ca
2+
-and voltage-activated potassium (BK) channel, mainly consist by functional α subunits and modulatory β1 subunits in vascular smooth muscle cells (SMCs), plays a vital role on vascular relaxation. Recently, it has been found that AT1-AA inhibited BK channel’s function. However, the specific mechanisms remain unclear. In this study, we further investigated the open probability, Ca
2+
sensitivity and β1 subunits of BK channel after AT1-AA stimulation.

Methods and Results:
BKα subunit has several splicing variants. Immunofluorescence and PCR results showed that BK channels widely distributed among mesenteric artery (MA), most of them belong to zero-type. SMCs from MA were isolated freshly and used for patch clamp within 6 hours. AT1-AA downregulated the open probability of BK channel to 57.41±21.36% (the corresponding data of baseline was considered as 100%), specifically reduced the number of simultaneous opened channels (level 4 to level 2) instead of dwell time (T
1
=0.45 ms, T
2
= 3.39 ms to T
1
=0.58 ms, T
2
=4.99 ms) and amplitude (187.4 ±16.23 to 187.3 ±13.80 pS). This phenomenon could be reversed by BK channel agonist (NS1619) (enhanced to 124%). Noteworthy, different from Ang II, AT1-AA suppressed BK channel’s open probability consistently even after 15min (Ang II: recovered to 164.8%; AT1-AA, kept at 66.0%). The activated effect of Ca
2+
on BK channel nearly disappeared after bathing with AT1-AA in inside-out recording mode (vehicle: 100% to 471.6%; AT1-AA: 100% to 163.9%). Furthermore, to explore whether AT1-AA’s inhibitory effect on BK channel was independent from β1 subunit, only ZERO-BKα-GFP subunits were transfected into HEK293T cells. AT1-AA still diminished BK channels’ function to 57.35±5.4%. However, the inhibition of AT1-AA on BK channels was almost non-existent (to 92.1±12.81%) in AT1 receptor knock out rats.

Conclusion:
These results demonstrated that AT1-AA sustainably decreased open probability and Ca
2+
sensitivity of BK channels even if β1 subunit were absence. This effect was AT1 receptor dependent. It remains us that BK channel may become a novel target for improving AT1-AA related hypertension.
Abstract P253: Forty-Two Year Followup in a Patient With Conn's Syndrome
Authors: Grim Clarence E
Published: December 2018

This case report relies on detailed hospital and clinic records from the UK provided by the patient for review and synthesis. In 1977 a 24 y/o M college student in the UK was found to have asymptomatic HTN (245/125) during a routine exam and was admitted one day later for evaluation. He had no FH of HTN or low K. FH + for CAD before age 60. A renal arteriogram was normal. Hypokalemic alkalosis was noted as was an elevated plasma aldosterone (PALDO), but normal urine Aldo. Adrenal CT showed a normal L adrenal but the R was not seen. Adrenal venography was negative but the R adrenal could not be cannulated. The interpretation was bilateral disease. Spironolactone (S) was started at 300 mg/d. Admitted for surgery 2 months later the BP 160/100 and K was normal. At surgery, the L adrenal was estimated to be 2x normal size and was excised as was 1/2 of the R adrenal. Adrenal steroid coverage was used for 2 months, then ACTH gel was given for 2 months and stopped. BP was lowered for about 2 months but then returned to 200/110. S was started at 400 mg/d with good control but gynecomastia developed. BP control was attempted with S and hydrazine (H) for several years but despite being normal at home was always high in the office. Age 33 was noted to have a K or 3.2 and muscle “fascillcuations”. Age 51, atrial fibrillation developed/converted with Amiodarone. BP continued to be difficult to control until he began DASH eating plan at age 56 when he joined the Yahoo Group
hyp
e
raldostreronism@yahoogroups.com
which I have managed for 16 years. He retired from teaching math at age 58 early to care for his wife. Age 62 PALDO was 1300 and Renin was 10 on S and DASH diet (ENa 55, EK 139 mM/d) and then 600/1 off S and on high salt intake (ENa, 125 EK 100 mM/d). Age 60 MRI showed adenoma L adrenal. Rx with S and enalapril continued with home BPs 122/84. At age 65 non-ST MI was diagnosed and PTA and stenting was performed. BP has been stable for last year with home BP 120/80 on DASH Diet, Spiro 100 mg/d and enalapril 30 mg/d. Statin myalgia has prevented their use but lipids have improved on DASH. This case illustrates that long-term survival after 3/4 adrenalectomy for Conn’s syndrome is possible but that BP management can be difficult.
Abstract P258: What Clinic Blood Pressure Best Protects Renal Function in Children With Chronic Kidney Disease?
Authors: Flynn Joseph T , Carroll Megan , Ng Derek , Warady Brad , Furth Susan
Published: December 2018

Background:
No data are available regarding what office blood pressure (BP) is protective against progression of chronic kidney disease (CKD) in children. In this study, we examined the association between achieved office BP and CKD outcomes among 688 hypertensive children in the Chronic Kidney Disease in Children Cohort study.

Methods:
BP categories were defined as the maximum systolic/diastolic BP percentile (<50th, 50th to 75th, 75th to 90th and ≥90th percentile) with time-updated classifications corresponding to annual study visits. The outcome was time to renal replacement therapy or a 30% decline in estimated glomerular filtration rate from first visit with HTN or high BP. Cox hazard models described the putative protective effect of each lower BP category compared to those with BP ≥90th percentile as non-proportional relative hazards.

Results:
Median age was 11.3 years, 62% were male, median duration of CKD was 8y; 213 had glomerular [G] CKD and 475 had nonglomerular [NG] CKD. For both G and NG groups, the highest risk of CKD progression was observed for those with BP ≥90th percentile, and BP 50 to 75th percentile was associated with the lowest risk from 0 to 2 years for G (time-varying RH between 0.09 to 0.24, p<0.001) and over 8 years for NG (RH= 0.45, p<0.001); figure. Those with BP <50th had lower risk than those with BP between the 75th to 90th percentiles (time-varying RH between 0.16 and 0.26 from 0 to 2 years for G and 0.67 for NG), but not as low as in the 50th to 75th percentile group.

Conclusion:
Achieved office BP between the 50th-75th percentiles appeared to offer the greatest protection against CKD progression in this cohort. This observation should be confirmed prospectively.
Abstract P265: Early Renal Hyperfiltration In Obese Dahl Salt-Sensitive Leptin Receptor Mutant Rats is Associated With Glomerular Leukocyte Extravasation and Renal Disease
Authors: Williams Jan M , McPherson Kasi C , Shields Corbin A , Poudel Bibek , Cornelius Denise C , Garrett Michael R
Published: December 2018

Hypertension and diabetes are the major causes of chronic kidney disease (CKD). However, epidemiological studies within the last few decades have revealed obesity as an independent risk factor for CKD. Recently, we reported that the obese Dahl salt-sensitive leptin receptor mutant (SS
LepR
mutant) strain displays proteinuria and podocyte injury by 6 weeks of age independent of hyperglycemia and elevations in arterial pressure. The current study examined whether the development of renal injury in the SS
LepR
mutant strain is associated with elevations in glomerular filtration rate (GFR). During the study, the SS
LepR
mutant strain developed hyperinsulinemia and dyslipidemia but not hyperglycemia. Baseline MAP (via carotid catheter) at 6 weeks of age was similar between SS
WT
(n=8) and SS
LepR
mutant (n=8) rats and averaged 124 mmHg. However, by 18 weeks of age, MAP increased significantly in the SS
LepR
mutant strain compared to the values measured in SS
WT
rats (192±4 vs 149±6 mmHg, respectively). At baseline, protein excretion was 4-fold higher in the SS
LepR
mutant strain compared to SS
WT
rats and remained elevated over the course of the study (778±96 vs 137±25 mg/day, respectively). At 6 weeks of age, GFR was 34% higher in the SS
LepR
mutant strain compared to age-matched SS
WT
rats indicating renal hyperfiltration (2.92±0.23 vs 2.18±0.25 mL/min/kwt, respectively). While we observed only a 40% reduction in GFR in SS
WT
rats (1.30±0.07 mL/min/kwt), GFR markedly decreased by 70% in the SS
LepR
mutant strain (0.87±0.08 mL/min/kwt). Over time, kidneys from the SS
LepR
mutant strain displayed more glomerulosclerosis, mesangial expansion, and renal fibrosis in comparison to SS
WT
rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 weeks of age and RNA sequencing was performed to identify genes and pathways driving glomerular injury. The major, most consistent signaling pathways that changed at 6 and 18 weeks of age were involved in leukocyte extravasation. In conclusion, these data provide evidence that renal hyperfiltration may contribute to glomerular capillary leukocyte extravasation leading to the early development of proteinuria during obesity in the absence of hypertension and hyperglycemia.
Abstract P273: Association Between Arterial Stiffness and Vascular Related Diseases- Arterial Stiffness Increases in Participants Exposing in Combined Vascular Related Diseases: The Best Study
Authors: Wang Hongyu , Liu Huan , Liu Jinbo , Zhao Hongwei
Published: December 2018

Background:
Arterial stiffness has been confirmed the predictive value on first cardiovascular diseases, and many parameters could reflect arteriosclerosis. However, few studies evaluated the condition of artery in patients with various cardiovascular diseases and the combined influences on vascular function. The present study was designed to explore the association of arterial stiffening reflected by two different parameters in participants exposing in combined vascular related diseases from China.

Methods:
A total of 12576 participants were enrolled into the study from year 2010 to 2016, with males 6041 females 6535, mean age 58.75±13.23 years. All participants were analyzed according to the exposing and number of hypertension, diabetes mellitus (DM), coronary artery disease (CAD), stroke and peripheral artery disease (PAD). Arterial stiffness was assessed by carotid femoral pulse wave velocity (CF-PWV) and cardio-ankle vascular index (CAVI). Age- and sex-adjusted analyses by covariance and regressions were used.

Results:
Arterial stiffness reflected by CF-PWV and CAVI was significantly higher, and ankle brachial index (ABI) was lower in patients with hypertension, DM, CAD, stroke and PAD compared with no these diseases (all p<0.05). CF-PWV and mean CAVI increased, mean ABI decreased gradually with the increase of the number of combined diseases, the β for each 1 increase were 0.404 m/s, 0.106 and -0.022 respectively (all p<0.001). With the increase of the number of diseases, the proportion for arterial stiffness reflected by CF-PWV>12m/s, RCAVI>9 or LCAVI>9 all increased, with a β for each 1 increase were 1.40, 1.26 and 1.22 (p<0.001).

Conclusions:
Participants with hypertension, DM, CAD, stroke or PAD, the degree and proportion of arterial stiffness were higher. With the increase of the combined number of diseases, the degree and proportion for arterial stiffness all increased. CAVI showed a similar effect to CF-PWV in various vascular related diseases.
Abstract P277: Ceramide Modulates GPCR And TK Receptor Signaling To Impact Endothelial Functions And Blood Pressure
Authors: Cantalupo Anna , Gargiulo Antonella , Sasset Linda , Rubinelli Luisa , Del Gaudio Ilaria , Bucci Maria Rosaria , Di Lorenzo Annarita
Published: December 2018

Ceramides are sphingolipids that modulate a variety of cellular processes, via two major modes of actions: by functioning as second messengers and by regulating the formation of lipid raft, important signaling platform. Receptor-mediated signaling orchestrates multiple pathophysiological processes, hence more than 50% of drugs clinically prescribed target mainly GPCRs. Alterations of ceramide levels are implicated in endothelial dysfunction, a key event in many cardiovascular diseases, including hypertension and atherosclerosis. However, specific molecular mechanisms of how ceramides modulate the structure and the function of GPCRs and TK receptors to impact endothelial functions remains unknown and unexplored. Thus, we generated mice lacking the endothelial sphingolipid
de novo
biosynthesis, by deleting the serine palmitoyltransferase long subunit 2, of the first enzyme of the pathway, named ECKO-Sptlc2. Systolic blood pressure was markedly increased in ECKO-Sptlc2 vs. control mice (122.1± 1.9 vs. 103.6±0.7 mmHg, n=9). Vasodilation of mesenteric arteries to acetylcholine and histamine (Gq-coupled receptors) and the NO-signaling downstream was preserved suggesting that altered membrane sphingolipid levels did not affect Gq-coupled receptor activation. On the contrary, vasodilation induced by the activation of tyrosine kinase receptors, i.e. VEGFR2 (Emax 32.8±3.5 vs. 55.7±3.6 % vasodilation, n=5), Gi-coupled GPCRs, i.e. S1PR1 (Emax 9.0±11.0 vs. 58.7 ±3.5 % vasodilation, n=5) and flow were markedly reduced. C16-, C24- and C24:1-ceramide are the most abundant ceramides in the endothelium and were markedly reduced by the loss of Sptlc2. Interestingly, the treatment of the mice and endothelial cells in culture with C16-, C24- and C24:1-ceramides, showed that C16-ceramide play a specific role in VEGFR2, IR, S1PR1 and flow mediated vasodilation. Mechanistically, C16-ceramide modulates VEGFR2 phosphorylation and downstream signaling in a concentration-dependent manner. The finding that C16-ceramide affects specific the function of Gi-coupled, TK but not Gq-coupled receptor is of great significance considering that alterations in C16-ceramide strongly correlate with CV conditions, such as CAD and heart failure.
Abstract P278: Flow-Induced NO Deficiency in Thick Ascending Limbs of Dahl Salt-Sensitive Rats Fed a High Salt Diet is Due to Decreased NOS3 Expression
Authors: Saez Fara , Gonzalez-Vicente Agustin , Hong Nancy J , Garvin Jeffrey L
Published: December 2018

The effects of medullary NO on Na excretion are reduced in Dahl salt-sensitive (SS) compared to salt-resistant rats (SR). We have shown that flow-induced NO production by thick ascending limbs (THALs) of SS is reduced when rats are on a normal salt diet although NO synthase 3 protein expression was the same. In Sprague-Dawley rats a high-salt diet markedly increase NOS3 expression. It is unknown whether this is also the case for both SS and SR fed a high-salt diet. We hypothesized that flow-induced NO production by SS THALs is blunted in part due to a failure to increase NOS3 expression in response to dietary salt. SS and SR were fed normal and high-salt diets for 7-9 days. We measured systolic blood pressure (SBP); flow-induced NO in isolated THALs; and NOS3 protein expression in renal medullary lysates. SBP was 164.5±3.2 mm Hg (
n
= 9) in SS and 130.1±4.8 in SR when fed a high-salt diet (
n =
7
; p
< 0.0001
)
. Flow-induced NO production by SS THALs from rats fed high salt was 9 ± 2 arbitrary units (AU)/min (
n =
6) while it was 44 ± 10 AU/min by SR tubules (
n
= 6), significantly greater (
p
< 0.005). NOS3 expression was 0.74 ± 0.08 AU (
n
= 5) in THALs from SS on high salt while it was 1.26 ± 0.08 AU in tubules from SR (
n
= 5), significantly greater (
p
< 0.003). THAL NOS3 expression was unchanged by a high-salt diet in SS (1.01 ± 0.08 vs 1.11 ± 0.11;
n
= 5) but increased in SR. We conclude that decreased flow-induced NO production in high-salt-fed SS is at least partially due to failure to increase NOS3 expression.
Abstract P280: Type V Collagen is a Lung-Associated Self-Antigen Uncovered by Chronic Hypoxia
Authors: Gonzalez Bosc Laura V , Morales-Loredo Juan H , Maston Levi , Howard Tamara , Jankowska-Gan Ewa , Arvedson Matthew P , Sullivan Jeremy A , Burlingham William J
Published: December 2018

Hypoxic pulmonary hypertension (PH) is a progressive and often fatal consequence of chronic hypoxia (CH) exposure (chronic lung diseases, high altitude and sleep apnea). We recently demonstrated that T helper 17 (T
H
17) cells are localized in the perivascular region of pulmonary arteries and contribute to CH-induced PH, at least in part, by causing pulmonary arterial (PA) remodeling. Naturally occurring “nT
H
17” cells, can be detected as early as week 17 of fetal life in humans, and are in homeostatic equilibrium with natural T regulatory (nTregs) cells. nT
H
17 cells are specific for a limited range of self-antigens, including type V collagen (colV). ColV is normally sequestered within type I col in the extracellular matrix of the lungs hidden from the immune system. Activation of matrix metalloproteinase-2, which is induced by CH, can expose colV. Therefore, we tested the hypothesis that ColV is a lung-associated self-antigen uncovered by CH. We found colV immunoreactivity only in lungs from mice exposed to hypobaric CH for 5 days vs. controls and colV mRNA expression is significantly increased in isolated PA (log fold change mean±SEM, normoxia= 0.22±0.08 vs. CH=0.48±0.02, n=3, p=0.02) suggesting that CH uncovers hidden colV. We then, determined cellular autoimmunity to colV using a trans-vivo delayed-type hypersensitivity assay (TV-DTH). Splenocytes obtained from 5 days CH-exposed mice displayed a TV-DTH colV response significantly higher than that from normoxic mice (footpad swelling [10
-4
”] normoxia=11.8±1.1 vs. CH= 35.6±3.0, n=14, p=0.0001), while there was minimal response to col I. To determine that reactivity to colV contributes to CH-induced PH, we induced peripheral tolerance to colV by administering 25 μl of 0.08 μg/μl of bovine colV (Sigma) in PBS in each nare or PBS every two days for two weeks prior and during CH (21 days). Right ventricular systolic pressure (RVSP) was higher in vehicle-treated compared to colV-treated mice (mmHg CH vehicle= 32.4±0.3 vs. CH colV= 27.8±0.9, n=4, p=0.0085) suggesting that oral tolerance to col V attenuated PH.

These results are ground-breaking suggesting that acute autoreactivity to colV develops after exposure to hypoxia. Next, we will determine whether a disrupted balance of nTh17/nTreg mediates this response.
Abstract P286: (Pro)renin Receptor Mediates Inflammation Induced by Renal Injury
Authors: Culver Silas A , McDevitt Rebecca , Akhtar Safia , Li Caixia , Siragy Helmy
Published: December 2018

(Pro)renin Receptor (PRR) expression in the kidney is reported to increase during injury from diabetic nephropathy, and ischemia. PRR is also reported to play a role in promoting renal inflammation. Aristolochic acid (AA) is a nephrotoxin which is known to target the proximal tubule. However, it is not known whether PRR plays a role in cortical inflammation caused by AA. We hypothesized that PRR promotes renal cortical inflammation in the setting of AA induced injury. This study utilized an inducible nephron specific PRR knockout (KO) mouse with KO induced at 6 weeks of age. Ten week old wild type and KO mice received intraperitoneal injection with 10mg/kg AA or vehicle. At baseline and two weeks after injection, glomerular filtration rate (GFR) was measured by FITC-sinistrin contrast injection. Two weeks after injection, kidneys were harvested, and RNA extracted from cortical tissue. PRR and IL-6 mRNA expression was measured by RT-PCR. Two weeks after injection, GFR was reduced in the Control +AA (1436 vs. 948 ul/min/100g body weight p<0.05) and KO + AA (1181 vs. 697 ul/min/100g body weight p<0.05) groups but not in control + vehicle group (1407 vs. 1186 ul/min/100g body weight). Renal cortical PRR expression increased by 157% in the Control + AA group compared to Control + vehicle (2.57 vs. 1) but was not increased in the KO + AA group (0.54). IL-6 expression similarly increased in the Control + AA group compared to Control + vehicle 1643% (16.43 vs. 1) and this response was attenuated in the KO compared to Control + vehicle (2.15 vs. 1). PRR promotes the inflammation of the renal cortex in response to AA injury. Further studies are needed to determine the long term role of PRR in renal injury.
Abstract P287: Time Course of Hemodynamic Responses to Different Doses of Lipopolysaccharide Administration in Unanesthetized Rats
Authors: Brognara Fernanda , Castania Jaci A , Dias Daniel P , Kanashiro Alexandre , Salgado Helio C
Published: December 2018

Introduction:
Intravenous administration of lipopolysaccharide (LPS) from
Escherichia coli
is an experimental model of systemic inflammation that has been widely used for investigating new therapeutic strategies for sepsis, which is characterized by clinical manifestations such as hypo or hyperthermia, tachycardia, hypotension and tachypnea. However, there is a number of doses of LPS used in several studies, and the hemodynamic responses were not well characterized. Thus, the aim of the present study was to evaluate the hemodynamic (arterial pressure and heart rate) responses from unanesthetized rats to different doses of LPS over time.

Methods and Results:
Femoral artery and vein catheters were inserted into anaesthetized Wistar Hannover male rats for arterial pressure recording and LPS administration, respectively. On the next day, the arterial pressure was recorded before (baseline) and after (90, 180 and 360 min) LPS injection in the unanesthetized subjects. Four different doses of LPS were tested: 0.06 mg/kg (n = 8), 20 mg/kg (n = 4), 30 mg/kg (n = 4), and 40 mg/kg (n = 5). As compared to baseline, the dose of 0.06 mg/kg of LPS decreased the mean arterial pressure at 360 min after its administration (113 ± 4 vs. 103 ± 7 mmHg,
p
= 0.007). However, the doses of 20, 30 and 40 mg/kg increased the mean arterial pressure at 360 min after LPS, compared to baseline values (
20 mg/kg:
101 ± 2 vs. 121 ± 4 mmHg,
p
< 0.001;
30 mg/kg:
115 ± 6 vs. 130 ± 0.4 mmHg,
p
= 0.023;
40 mg/kg:
92 ± 2 vs. 107 ± 3 mmHg,
p
= 0.005). In addition, all doses tested increased the heart rate at 360 min after LPS administration (
0.06 mg/kg:
342 ± 19 vs. 435 ± 11 bpm,
p
< 0.001;
20 mg/kg:
388 ± 6 vs. 588 ± 24 bpm,
p
< 0.001;
30 mg/kg:
366 ± 15 vs. 569 ± 8 bpm
p
< 0.001;
40 mg/kg:
426 ± 27 vs. 606 ± 24 bpm,
p
< 0.001). Nevertheless, the dose of 0.06 mg/kg promoted a smaller tachycardia as compared to the other doses evaluated (
0.06 mg/kg:
435 ± 11 bpm;
20 mg/kg:
588 ± 24 bpm;
30 mg/kg:
569 ± 8 bpm;
40 mg/kg:
606 ± 24 bpm,
p
< 0.001).

Conclusions:
These findings indicate that it is important to choose the correct dose of LPS, depending on the aim of the study. The current data indicate that each dose of LPS may promote different hemodynamic (mean arterial pressure and heart rate) responses, affecting the therapeutic strategy, for instance, for sepsis.
Abstract P289: Effect of Abaptacept on Blood Pressure in Essential Hypertensive Subjects with Rheumatological Disorders
Authors: Laffer Cheryl L , Shuey Megan M , Mosley Jonathan D , Madhur Meenakshi S , Harrison David G , Elijovich Fernando
Published: December 2018

We previously showed that abatacept, an inhibitor of T cell co-stimulation, prevents and reverses experimental hypertension. We now investigated whether it lowers blood pressure (BP) in humans. Of 1624 subjects receiving this drug in our de-identified electronic health record, 320 had hypertension and adequate baseline and follow up data (1 month to 3 years). Use of glucocorticoids (GC), non-steroidal antiinflammatory agents (NSAIDs), and antihypertensive drugs (HTND) was scored with the WHO system. ΔBPs at 1, 3 and 6 months and 1, 2 and 3 years after abatacept were adjusted for concomitant changes in medications and weights (Wt) by multivariate regression. Subjects were 80.6% female, 88.4% white, age 62±1 y, BMI 30.9±0.4 Kg/m
2
and BP 128.2±0.8/74.6±0.5 mmHg. Significant changes in confounders over time included decreases in GC, NSAID and HTND over the initial months followed by rebound beyond baseline at 2 and 3 years, and increases in Wt in these late periods. Changes in adjusted BP were limited to an increase in systolic BP at 2 years (1.75±1.04, p<0.05) and a decrease in diastolic BP at 3 years (-1.67±0.80, p<0.02). 91 subjects (28.4%) had a decrease of MAP ≥5 mmHg in at least half of the periods. ΔBP in these “responders” vs all other subjects was -10.8±0.7/-7.6±0.4, MAP -8.6±0.4 vs +5.0±0.4/+2.3±0.2, MAP +3.2±0.2, but these groups did not differ in sex, age, race, obesity, use of concomitant immunomodulators, pressors or blockers of the renin-angiotensin system (RASB). However, pooled adjusted ΔBP differed between women and men (diastolic -0.72±0.26 vs +1.48±0.48, p=0.0002; MAP -0.29±0.26 vs +1.58±0.55, p=0.003); between subjects younger and older than 65 y (systolic -0.05±0.48 vs +1.88±0.58, p=0.021; MAP -0.39±0.33 vs +0.64±0.37, p=0.037); and between those with BMI≤25 and >25 Kg/m
2
(systolic -1.31±0.79 vs +1.37±0.42, p<0.008). Finally, Δsystolic BP was -0.15±0.53 in subjects not taking and +1.42±0.50 in those taking RASB, p=0.037. In summary, long term use of abatacept mildly reduces BP in lean women with essential hypertension and rheumatological disorders. The effect is attenuated by obesity and perhaps also by aging and treatment with RASB. Further studies of abatacept in resistant essential hypertension are warranted, particularly in women.
Abstract P293: Chronic Pressure Overload Impacts Cardiac Endothelial Cell and Macrophage Gene Expression
Authors: Lother Achim , Deng Lisa , Hilgendorf Ingo , Kehl Theresa , Bode Christoph , Hein Lutz
Published: December 2018

Introduction:
The heart is composed of various different cell types that show distinct differences in gene expression. Inflammation is a key driver of adverse cardiac remodeling and endothelial cells and macrophages are crucially involved in that process. Thus, the aim of this study was to investigate cell type-specific changes in gene expression in cardiac endothelial cells and macrophages after left ventricular pressure overload.

Methods and Results:
Wildtype mice underwent transverse aortic constriction (TAC) to induce cardiac remodeling. After pressure overload, the number of macrophages in the heart increased about 3-fold (TAC 1755 ± 214 vs. CTRL 533 ± 76 macrophages / mg tissue, P < 0.001) as determined by flow cytometry. Lectin
+
endothelial cells and CD45
+
CD11b
+
F4/80
high
Ly6C
low
macrophages from CTRL and pressure overloaded hearts were isolated by fluorescence-assisted cell sorting. Cell type-specific gene expression was determined by RNAseq. We found 207 genes differentially expressed in cardiac endothelial cells isolated from pressure overloaded vs. CTRL hearts (n = 3-4 per group, q < 0.05). Approximately 25 % (52 genes) of these genes were highly enriched in endothelial cells vs. heart tissue (> 8-fold, q < 0.05). In cardiac macrophages, 1.359 genes were differentially expressed after pressure overload (n = 4-5 per group, q < 0.05). Bioinformatics analysis were performed to identify affected gene networks and putative key transcription factors involved in the regulation of these genes during cardiac remodeling. Integration of these datasets allowed to determine common, distinct and potentially interacting features of gene expression in both cell types.

Conclusion:
Chronic pressure overload induces distinct changes in gene expression in isolated cardiac endothelial cells and macrophages. Ongoing epigenetic analysis will provide insight into mechanisms of cell type-specific transcriptional regulation in these cells during cardiac remodeling.
Abstract P295: Ambulatory Blood Pressure And Heart Rate Variability In Dietary Sodium And Weight Intervention
Authors: LEE John S , Lee Mary S , Lee Jong Y , Gillum Richard , Halberg Franz
Published: December 2018

Blood pressure (BP) fluctuates due to complex interactions between genetic factors and environmental stimulation. BP variability (BPV) is a physiological phenomenon, as a measure of hemodynamic conditions reflected in the autonomic nervous system. Daily (circadian) rhythms as biological time structures are considered essential parameters for recognizing and treating BP risk factors. Thus, ambulatory BP and heart rate (HR) were monitored (ABPM) in 11 normotensive (NT) in a free living, and 13 borderline hypertensive (BH) adults with Na and weight (WT, Kg) interventions in a freely moving lab environments, around the clock at 30-minute to hourly intervals. In the intervention study, circadian BP, HR, urinary aldosterone (Aldo, μg/h), creatinine (Cr), Na, K in mEq/h and Na/K ratio were compared. Data was analyzed by the linear least square rhythmometry method. All subjects showed significant circadian fluctuations in BP (mm Hg) and HR (beats/min). The circadian response peaked in the noon to late afternoon hours in the NT and in the reference stage of the intervention study. In NT, SBP: 111±2 with variability 14.6% and peak hr at 16:00; DBP: 74.0±1 with variability 16.0% and peak hr at 15:40; and HR: 64.3±2 with peak hr at 16:96 (-254°). In the intervention study with reference (I), Na restriction (II) and weight (WT) reduction (III) stages, SBP: 130±3.7; 130±1.7; 116±1.7 with variability (SBPV), 27.5, 31.4, and 25.4%; peak hrs at 16:26, 13:52; 12:24, respectively; DBP: 85±2.3; 83±2.2; 77±1.9 with variability (DBPV), 21.1, 26.4, 33.5%; peak hrs at 16:15, 18:29, 07:52, respectively; and HR: 64±2.1; 61±2.1; 66±2.3 with HRV, 30.2, 34.6, 28.3%; peak hrs at 15:07; 14:64, 14:55, respectively. Circadian UAldo: 0.63, 0.73, 0.58; UNa: 6.3, 2.9, 3.5; UK: 3.1, 3.1, 2.9; and WT: 89.9, 87.8, 83.2 in I, II, and III study stages, respectively. Thus, BP and HR, and their variabilities are the factors readjusted in the Na and WT reductions, and the peak shifted to earlier hours in the intervention. The variability, in the reference stage already higher than the NT levels, was not favorably changed with Na and WT interventions, although BP was normalized, especially following the WT reduction. Increased or shallow amplitudes may be predictive risk factors of vascular disease.
Abstract P302: Prevalence of refractory hypertension in the United States from 1999-2014
Authors: Buhnerkempe Michael , Botchway Albert , Nolasco Morales Carlos E , Prakash Vivek , Flack John M
Published: December 2018

Background:
Refractory hypertension has been defined as uncontrolled blood pressure (BP at or above 140/90 mmHg) when taking five or more classes of antihypertensive medication. Unbiased estimates of the prevalence of refractory hypertension in the United States are lacking.

Methods:
Refractory hypertension was assessed in the National Health and Nutrition Examination Survey. Eight cycles of NHANES surveys (1999-2014) representing 41,552 patients were included. Patients younger than 18 and who were pregnant were excluded. Prevalence of refractory hypertension was estimated in the hypertensive population (systolic BP ≥140 or diastolic BP ≥90 or taking an antihypertensive medication) after adjusting for the complex survey design and standardizing for age. Logistic regression was used to test for temporal trends and to compare prevalence across age classes (18-39, 40-59, 60+), genders, races, and chronic kidney disease status.

Results:
Refractory hypertension was found in 0.30% of all hypertensive individuals. Although prevalence of refractory hypertension peaked at 0.54% of hypertensive individuals in the 2005-2006 cycle, there was no significant trend in prevalence through time (p = 0.29). No individuals under 40 years old were observed with refractory hypertension, and refractory hypertension was more common in individuals 60 and older than in individuals 40-60 years old (odds ratio = 4.55, p = 0.004). There was no difference in the prevalence of refractory hypertension between males and females (p = 0.24), but white and black individuals were more likely to have refractory hypertension than individuals of Hispanic or other descent (OR = 4.63, p = 0.002). Finally, individuals with chronic kidney disease were significantly more likely to have refractory hypertension (OR = 9.88, p < 0.001).

Conclusions:
We provided the first nationally representative estimate of the prevalence of refractory hypertension in the U.S. Recently lowered BP targets, an aging population, and increased incidence of co-morbidities like chronic kidney disease all create the potential for increases in this hypertensive phenotype in the future.
Abstract P313: Isolated Central Hypertension and Features of the Pregnancy Courseisolated Central Hypertension and Features of the Pregnancy Course
Authors: Evsevyeva Maria , Oksana Sergeeva , Shchetinin Evgeniy , Frantseva Victoria , Bondar Tatiana
Published: December 2018

Background:
Physiological features of hemodynamic changes in pregnant Women seem to be important for the implementation of personalized prevention and effective prediction of the upcoming vascular events of Women itself and its offspring too. The problem of hypertension in pregnant women (PW) is a subject of many studies. However, to question of isolated increasing of aortic pressure during pregnancy was given much less attention. We aimed to evaluate the indices of vascular stiffness in pregnant women in the presence of isolated central hypertension (ICH) in correlation with some complications of pregnancy.

Methods:
The study included 89 women in the first trimester of pregnancy. Evaluated the signs of pre-eclampsia (PE) and syndrome of delayed fetal growth (SDFG). Determining of central pressure (CP) was performed using diagnostic system BPLab (Petr Telegin, Russia) on software Vasotens Office. Inclusion criteria - level of systolic pressure on shoulder in the range of 110-129 mm Hg. Among these women were identified bearers of CP on the level above 90th percentile for the relevant age group in accordance with established reference indicators by Herbert A. e.a. (2014). These women were included in first group with ICH (27 persons). The rest ones with normal pressure on shoulder and in the aorta constituted the second control group (62 persons). The groups did not differ by age. Data were processed using software package "Statistica 10.0" (StatSoft Inc, USA).

Results:
It turned out that carriers of ICH had higher parameters of vascular stiffness compared with women in the control group. Particularly significant difference is revealed from the side of the aortic augmentation index - 5,4±1,1 vs 2,1±0,8. All cases of complications of pregnancy were identified only in the first group. So the frequency of PE and SDFG amounted to 11,1%.The average weight of newborns of the first group also differed from the control in direction of its decrease - 3338±99,6g vs 3487±125,3g.

Conclusions:
The presented results reflect the approach to the formation of new and more effective system of health care of pregnant women that is focused on predictive diagnostics of personalized threat profile for implementation targeted preventive measures in subsequent.
Abstract P315: Progesterone Supplementation Abolishes Sflt-1 Induced Hypertension In Pregnant Rats
Authors: Amaral Lorena M , Cunningham Mark W , Vaka Venkata R , Ibrahim Tarek , LaMarca Babbette
Published: December 2018

Preeclampsia (PE) affects 7% of pregnancies in the United States and is characterized by new onset hypertension in association with elevated soluble fms-like tyrosine kinase-1 (sFlt-1). We and others have shown that infusion of sFlt-1 into pregnant rodents causes hypertension, indicating an important role for sFlt-1 in mediating the pathophysiology of the disease. Currently, there is no effective treatment for PE except for early delivery of the fetal placental unit, making PE the leading cause for premature births worldwide. Administration of 17-hydroxyprogesterone caproate (17-OHPC, Makena) is used for prevention of recurrent preterm birth, but not for treatment of PE. This study was designed to test the hypothesis that 17-OHPC improves clinical characteristics of PE such as hypertension in response to sFlt-1 in pregnant rats. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg
–1
·day
–1
for 6 days, gestation day
13-19
) in the presence or absence of 17-OHPC (3.32mg/kg) administered via intraperitoneal injection on gestational days 15 and 18. Infusion of sFlt-1 into NP rats elevated mean arterial pressure (MAP) compared with control NP rats: 112
+
2 (n=11) vs. 98
+
2 mmHg (n=15, p<0.05). Administration of 17-OHPC attenuated this hypertension reducing MAP to 99
+
4 mmHg in sFlt-1 treated pregnant rats (n=8). Neither pup nor placental weight was affected by sFlt-1 or 17-OHPC. In conclusion, administration of 17-OHPC improves hypertension in response to elevated sFlt-1 during pregnancy and should be considered for merit further study to the management of PE
Abstract P317: Nocturnal Blood Pressure Variability is associated with hs-CRP in Hypertensive Patients
Authors: Valaiyapathi Badhma , Siddiqui Mohammed , El Hachem Maria , Judd Eric , Dudenbostel Tanja , Oparil Suzanne , Calhoun David A
Published: December 2018

Background:
24-hr Blood pressure (BP) variability and high sensitivity C-reactive protein (hs-CRP) have been found to be independently associated with increased cardiovascular diseases (CVD). Studies have shown a positive association between hs-CRP and BP variability in hypertensive population. In particular, nocturnal BP variability is associated with increased risk for CVD. However, the relationship between inflammation and nocturnal BP variability has not been examined in hypertensive patients.

Methods:
In this prospective study, 237 hypertensive patients were recruited from University of Alabama at Birmingham Hypertension clinic. As part of the study protocol, hs-CRP and 24-hr ambulatory blood pressure monitoring (ABPM) was performed at same visit. Patients with chronic kidney disease and those who did not have complete ABPM and hs-CRP values were excluded. Nocturnal BP variability was assessed using standard deviation.

Results:
Out of 202 patients who were included, 49.0% were women and 55.9% were African American. The mean age was 58.2 ± 10.9 years, mean nighttime BP (Systolic BP 132.4 ± 22.9 mmHg and diastolic BP 71.9 ± 14.0 mmHg), mean nighttime BP variability (systolic BP 13.4 ± 5.3 and diastolic BP 9.9 ± 4.2) and mean hs-CRP was 5.9 ± 7.0 mg/L. Regression analysis showed significant positive association (p-value = 0.033) between nocturnal BP variability and hs-CRP.

Conclusion:
In this study, we demonstrated that hs-CRP is strongly correlated with nocturnal BP variability in hypertensive patients, suggesting a likely mechanistic role of inflammation in the pathogenesis of nocturnal BP variability and a possible additive role in adverse cardiovascular outcomes.
Abstract P318: Cardiac and Vascular Changes in Patients With Morbid Obesity at 12 Months After Bariatric Surgery
Authors: Oliveras Anna , Granados Ana M , Molina Lluís , Goday Albert , Vazquez Susana , Sans Laia , Vera Maria , Xargay Berta , Pascual Julio
Published: December 2018

Aim:
To analyze changes in echocardiographic parameters and vascular stiffness in patients with morbid obesity, with either normal or high blood pressure, at 12 months after BS.

Methods:
We prospectively studied 62 patients (61% normotensive) with morbid obesity (BMI 42.7 ± 5.6 Kg/m
2
) before and 12 months post-BS. Pulse wave velocity (PWV) was determined, as well as different morphological and functional echocardiographic parameters.

Results:
generalized estimation equations showed a decrease in PWV at 6 months [mean (95% CI): -0.13 (-0.25 to -0.02), p=0.021], losing statistical significance at 12 months. Regarding cardiac involvement, the Table shows the changes in the different parameters at 12 months post-BS. Significant decreases were observed in the left ventricular mass (LVM), thickness of the interventricular septum (IST) and posterior wall (PWT), and relative wall thickness (RWT), as well as in the index E/e 'of ventricular filling, but not in the left ventricular mass index (LVMI). These changes were especially significant in normotensive patients (p=0.005 for RWT and IST, p=0.001 for the PWT and p = 0.004 for the LVM). In the adjusted analyzes, it was found that the changes observed in the LVM were determined by changes in weight (p <0.001) and changes in 24h-systolic BP(p=0.011).

Conclusion:
patients with morbid obesity experience 12 months after BS a significant reduction of the structural parameters of the left ventricle, especially when they are assessed with the RWT but not by LVMI. These changes are also significant in normotensive people, suggesting that factors other than obesity
per se
determine structural cardiac changes in them.