bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P114: Chemerin Leads to a Contraction of the Uterine Artery After Stimulation With Seretonin
Authors: Dela Justina Vanessa , Priviero Fernanda , V. Lima Victor , Giachini Fernanda , Webb Clinton
Published: September 2019

Chemerin circulating levels are augmented during preeclampsia. This adipokine has been shown to contract many vascular beds, however, its role on the uterine artery (UA) remains to be elucidated. This study tests the hypothesis that chemerin leads to a hypercontractile state of the uterine artery contributing to the development of preeclampsia-like symptoms. Also chemerin may interacts with serotonin, which is released by the placenta and increased in preeclampsia, to impair the circulation of uterine artery during preeclampsia. UA from pregnant Sprague Dawley rats (200-250g) were removed and mounted in wire myograph with or without PVAT. Concentration response-curves to thromboxane analogue [U-46619 (1 nM to 3μM)] and seretonin [5-HT (1 nM to 100 μM)] were performed in UA and repetead in the presence of chemerin (0.5 ng/ml and 5 ng/ml, 1 hour). Incubation with chemerin 5ng/ml led to contraction of the UA when administered after concentration-response curve to 5-HT (68% contraction; 17 of 25mN), but not U-46619. Neither the potency nor the maximal response of 5-HT and U-46619 were changed in the presence of chemerin. Contraction induced by chemerin (5ng/ml) was not seen in UA with PVAT. Chemerin 0.5ng/ml did not contract the UA and did not cause changes in agonist-induced contractions. Chemerin 5ng/ml leads to a contraction of the UA after stimulation with 5-HT which was prevented in the presence of PVAT. We conclude that signaling pathway stimulated by 5-HT unvel the contractile properties of the adipokine. These tow vasoactive agents may come together to elevate blood pressure in preeclampsia.
Abstract P115: Troponin I and Dystrophin Proteolysis by Matrix Metalloproteinase 2 Contribute to Chronic Cardiac Remodeling and Dysfunction in Renovascular Hypertension
Authors: Parente Juliana M , Mello Marcela M , Omoto Ana C , Fazan Rubens , Castro Michele M
Published: September 2019

Aim:
Increased MMP-2 activity contributes to hypertension-induced chronic cardiac morphological and functional changes by proteolyzing troponin I and dystrophin.

Methods:
Male Wistar rats were sham or two kidney-one clip (2K1C) operated and treated with water or doxycycline (15 mg/kg/day) by gavage for six weeks, starting from the tenth week. To establish this aim tail-cuff plethysmography, echocardiogram,
in situ
zymography, troponin I western blotting and dystrophin immunofluorescence were performed. Results were analyzed by Two-way ANOVA (Ethics Committee approval number: 023/2015-1).

Results:
Systolic blood pressure (SBP) of 2K1C rats was higher than sham after sixteen weeks of hypertension (215.7 ± 4.8 vs. 120.9 ± 4.4, p<0.05) and doxycycline did not decrease it (216.1 ± 6.1, p>0.05). After four months of hypertension, 25% (6 of 24) of 2K1C rats had left ventricular eccentric hypertrophic remodeling (LVEHR (2K1C-D)) while others remained at left ventricular concentric hypertrophic remodeling (LVCHR (2K1C-H)). Interestingly, 17.6% (3 of 17) of 2K1C rats treated with doxycycline had LVEHR while others 2K1C had LVCHR. Furthermore, 2K1C-D rats had reduced ejection fraction (EF: 39.8 ± 2.9 vs. 66.7 ± 1.7 and 66.2 ± 1.6, p<0.05) and shortening fraction (SF: 20.4 ± 1.6 vs. 38.7 ± 1.4 and 38.4 ± 1.3, p<0.05) when compared to 2K1C-H and Sham. Doxycycline preserved both EF and SF (66.4 ± 2.3 and 38.6 ± 1.8, p<0.05). MMP-2 activity was increased in both 2K1C rats (2K1C-H: 7.2 ± 0.5 and 2K1C-D: 6.5 ± 0.4 vs. 5.3 ± 0.3 Sham, p<0.05) and treatment with doxycycline decreased it (5.5 ± 0.3, p<0.05). Higher amounts of degradation products of troponin I were observed in 2K1C-D when compared to 2K1C-H and Sham (3.6x10
-8
± 7.9x10
-9
vs. 2.0x10
-8
± 2.3x10
-9
and 2.0x10
-8
± 3.4x10
-9
, p=0.06) and doxycycline prevented it (1.9x10
-8
± 3.0x10
-9
, p<0.05). The levels of dystrophin also decreased in 2K1C-H and -D when compared to Sham (13.5 ± 1.4 and 10.7 ± 2.1 vs. 15.6 ± 1.7) and doxycycline reversed it (16.9 ± 0.6, p<0.05).

Conclusion:
Increased MMP-2 activity contributes to diminish troponin I and dystrophin levels in 2K1C and this effect may lead to chronic cardiac remodeling and dysfunction.
Abstract P122: Downregulation and Inhibition of PKCα Causes Increased Ca
2+
-Sensing Receptor-Mediated Vascular Relaxation in Aged Dahl Salt-Sensitive Rats
Authors: Odutola Samuel O , Bridges Lakeesha E , Awumey Emmanuel M
Published: September 2019

The G protein-coupled Ca
2+
-Sensing Receptor (CaSR) mediates extracellular calcium (Ca
2+
e
) - induced relaxation of mesenteric arteries under tension and may therefore play a role in blood pressure regulation. This presents CaSR as promising target for therapeutic drug design for cardiovascular pathologies such as hypertension. Protein kinase Cα (PKCα) is an important regulator of CaSR signaling and can phosphorylate the receptor leading to desensitization. In this study, we investigated the effects of CaSR mutation and downregulation of PKCα in CaSR-mediated relaxation of phenylephrine (PE)-contracted mesenteric arteries from aged Dahl salt-sensitive rats, fed a low salt (0.1% NaCl) diet, using automated wire myography. We have observed in our laboratory, that there is significant decrease in relaxation response of PE-contracted mesenteric arteries to Ca
2+
e
. as animals get older. The results show minimal relaxation responses of arteries to Ca
2+
e
and that downregulation of CaSR expression had no significant effect. PKCα downregulation (siRNA) and inhibition of PKC (Gö 6976) showed greater than 80% increase in maximum Ca
2+
-induced relaxation, with significant decreases in EC
50
values compared to untreated controls. The results indicate that PKCα plays an important role in the regulation of CaSR -mediated relaxation of mesenteric arteries. Therefore, inhibition of PKC may lead to increased CaSR sensitivity to Ca
2+
indicating a possible therapeutic mechanism for intervention in age-related vascular dysfunction.
Abstract P124: Nlrp3 Activation by Endothelin-1 Mediates Neutrophil Recruitment in Cavernosal Tissue of DOCA/salt Mice
Authors: Fais Rafael S , Gomes Raphael F , Wanderley Carlos W , Tostes Rita d , Carneiro Fernando S
Published: September 2019

Introduction:
Endothelin-1 (ET-1) induces penile detumescence and acts as an important mediator of chronic inflammation. NACHT, leucine reach repeat (LRR) and PYD domain-containing protein 3 (NLRP3) releases the active form of IL-1β. This cytokine is involved in neutrophil recruitment from the circulation to the tissues. Increasing evidence shows that neutrophil infiltration is involved in the genesis and aggravation of various cardiovascular diseases.

Hypothesis:
NLRP3 activation by ET-1 mediates neutrophil infiltration in the corpora cavernosa (CC) of DOCA/salt hypertensive mice.

Methods:
All protocols were approved by the Animals Use Ethics Committee (CEUA 213/2016). Male C57BL/6 (WT) and NLRP3 deficient mice (NLRP3
-/-
) were either induced to DOCA/salt hypertension or SHAM and treated with bosentan or vehicle. Caspase-1 and IL-1β activities were determined in CC. NF-κB, ICAM-1 and VCAM-1 expressions in CC were determined by immunohistochemistry. Flow cytometry was performed to evaluate the infiltration of myeloid cells into CC.

Results:
DOCA/salt hypertension increased caspase-1 and IL-1β activities in CC. NF-κB, ICAM-1, VCAM-1 and neutrophil infiltration were increased in CC of DOCA/salt mice. The treatment with bosentan or the absence of NLRP3 prevented all these alterations in DOCA/salt mice.

Conclusion:
ET-1-induced NLRP3 activation is involved in neutrophil recruitment in CC of DOCA/salt hypertensive mice.
Abstract P128: Increasing Pressure to Lower Blood Pressure: Assessing Blood Pressure Goals at Resident Physician Clinic
Authors: Schultz Emily , Trieu Lien , Snyder Matthew , Lebrun Sandrine , Mazurkiewicz Rebecca
Published: September 2019

Introduction:
The 2017 ACC/AHA guidelines lowered the threshold for blood pressure goals and emphasized incorporation of cardiovascular risk assessment and lifestyle modifications. Due to this update, the prevalence of hypertension increased from 31.9% to 45.6% of Americans. We hypothesized that our patients were not being assessed and counseled in accordance with the 2017 ACC/AHA guidelines at our resident clinic in New York City.

Methods:
Patients with a diagnosis of hypertension who had at least one office visit between July to September of 2018 at our clinic were included. Patients not seen by a resident physician were excluded. Variables collected included lowest blood pressure reading from visit, comorbidities, and demographics (age, language, race, and gender). The most recent progress note was reviewed for the assessment of hypertension. Additionally, residents of all levels completed an electronic anonymous survey to assess knowledge of updated guidelines.

Results:
Of the 206 patients meeting inclusion and not exclusion criteria, 148 (71.8%) were above blood pressure goal. The average blood pressure was 137/82 (CI 95%, 134.7-139.3/80.6-83.4). Of those 148 patients not at goal, 108 (72.97%) were incorrectly identified as at goal or did not have hypertension assessed at all. Of the total 206 patients, only 16 (7.77%) had documented discussion of lifestyle modification and 1 patient (0.5%) had an atherosclerotic cardiovascular disease (ASCVD) score in the assessment. Patients with an established resident primary care physician (n=118) were not more likely to meet goal blood pressure (p=0.58) than those who did not. A total of 27 of 78 (34.6%) residents completed the survey, and only 15% (4 of 27) answered all questions correctly.

Conclusions:
Our hypertensive patients are not meeting their blood pressure goals and often the assessment is insufficient. We are not reliably identifying patients with elevated blood pressure per the 2017 ACC/AHA guidelines and missing opportunities for optimizing care. Enhancing resident understanding of guidelines and evaluation of hypertension is important for meeting blood pressure targets and reducing cardiovascular risk. An intervention to improve resident education and documentation is underway.
Abstract P142: Progression of Diabetic Kidney Disease in the Type 2 Diabetic Nephropathy Rat Model
Authors: Spires Denisha , Ilatovskaya Daria , Levchenko Vladislav , Palygin Oleg , Staruschenko Alexander
Published: September 2019

Diabetic kidney disease (DKD) is a condition of hyperglycemia-induced renal injury that is one of the chief causes of end-stage renal disease (ESRD). Hypertension often affects people with type 2 diabetes and the combination of diabetes and hypertension is associated with high morbidity and mortality. Here we assessed the progression of DKD in the T2DN rat and tested if this model develops age dependent DKD similar to human patients. Sex difference in the development of DKD was further defined. For the assessment of disease progression, we used 12 weeks old (early stage) and >40 weeks old (late stage) male Wistar (non-diabetic control), Goto-Kakizaki (GK) and Type 2 Diabetic Nephropathy (T2DN) rats. At 12 weeks, male rats of type 2 diabetes background showed significant increases in blood glucose (374 ± 96 and 329 ± 45 vs. 280 ± 24 mg/dL, respectively for T2DN, GK vs. Wistar) and kidney to body weight ratio (10.05 ± 1.19 and 9.39 ± 0.78 vs. 7.31 ± 1.13, respectively). Aged male T2DN rats had significant increases in progressive albuminuria from 8 to 12 to >40 weeks of age (0.44 ± 0.16 vs 0.34 ± 0.17 vs 11.80 ± 5.67, respectively). T2DN rats also show significant reductions in the blood of the components of the renin-angiotensin-aldosterone system. There were significant changes in renal damage such as increases in percent of medullary protein casts and glomerulosclerosis (probability based; 1.2% vs 27.5%, respectively compared to age matched GK males). To explore the sexual dimorphisms in the development of DKD, we compared T2DN male and female rats when animals had the late stage of the disease (> 48 weeks old). Aged males had a significant impairment in their body’s response to sugar load compared to the females as assessed by both IP and oral gavage glucose tolerance tests. Aged male T2DN rats had increases in nephrin shedding in their urine (10,357 ± 4,866 vs 3,227 ± 2,918, respectively), which correlates with the dramatic differences in albuminuria (11.8 ± 5.7 vs. 0.98 ± 0.64 Alb/Cre ratio, respectively). In contrast, serum albumin levels were elevated in female T2DN rats. Therefore, we report here that T2DN rat develops renal and physiological lesions similar to those seen in patients with type 2 diabetes, and there is a dramatic sex difference in the progression of renal damage.
Abstract P143: Multifaceted Roles of Gut Microbiome and Bacterial Metabolites in Pulmonary Arterial Hypertension
Authors: Kim Seungbum S , Walejko Jacquelyn M , Rigatto Katya , Ray Jordan , Gazzana Marcelo B , Knorst Marli M , Richards Elaine M , Shapiro Brian , Pepine Carl J , Raizada Mohan K
Published: September 2019

Objectives:
Pulmonary arterial hypertension (PAH) is a deadly disease without any effective cure. Identification of the PAH-associated gut microbiome may shift conceptual paradigms of the disease that could lead to new therapeutic advancement. We tested the hypothesis that PAH patients have distinct gut microbiome composition contributing to PAH that predicts the disease.

Methods:
A total of 71 participants were recruited. Fecal microbiomes of 18 type 1 PAH patients (mean pulmonary arterial pressure [mPAP] 57.4±16.7 mmHg) and 13 reference subjects were compared by shotgun metagenomics methods. Plasma from 22 PAH patients (mPAP 48.3± 18.4 mmHg) and 18 reference subjects was used in untargeted metabolomic analysis.

Results:
Significant taxonomic and functional changes in the microbiome of the PAH cohort were observed. PAH patients had increased gut barrier dysfunction and inflammation as evidenced by plasma markers and metagenomics. A random forest model predicted PAH from gut microbiome composition with 82.6% accuracy. Changes in the gut microbiome were associated with purine metabolism, arginine biosynthesis, trimethylamine production and tryptophan biosynthesis, all previously associated with PAH. Area under the curve of the multi-variate receiver operating characteristics (ROC) plot for metabolites of these pathways had a predictive accuracy of 0.965.

Conclusions:
The gut microbiome/metabolites of PAH patients predict disease in random forest models and ROC analyses. The unique PAH gut microbiome influences carnitine, arginine and purine metabolisms contributing to pathophysiology. These highlight previously unknown roles of gut bacteria and their metabolites in PAH that could lead to new therapeutic or management paradigms.
Abstract P145: Notch3 Mutation is Involved in Pulmonary Vascular Dysfunction and Development of Pulmonary Arterial Hypertension
Authors: Morris Hannah E , Neves Karla B , Nilsen Margaret , Montezano Augusto C , Joutel Anne , MacLean Mandy R , Touyz Rhian M
Published: September 2019

Notch3 is implicated in CADASIL and pulmonary arterial hypertension (PAH), two diseases characterized by vascular dysfunction and remodelling. Mice harbouring the CADASIL-causing Notch3 mutation (TgNotch3
R169C
) exhibit gain-of-function Notch3 signalling. As increased Notch3 signalling has been demonstrated in several PAH models, we investigated the contribution of R169C mutation to pulmonary vascular dysfunction and PAH development. Briefly, vascular reactivity was studied by wire myography using pulmonary intralobar arteries from 24-week male mice overexpressing either a WT or R169C mutant Notch3 gene. Further mice were exposed to 2 weeks of normoxia or chronic hypobaric hypoxia (10% O
2
) before assessing PAH development by in vivo haemodynamic measurements. Notch3 effector gene Hes5, implicated in PAH development, was significantly increased in R169C but not WT lung (8.7 fold change vs WT) suggesting increased pulmonary Notch3 activation. Hypercontractility of R169C pulmonary arteries to both 5HT (Emax R169C 146 ± 10% vs WT 92 ± 6%) and ET-1 (Emax R169C 211 ± 15% vs WT 154 ± 32%) was observed; an effect attenuated by ROCK inhibitor Fasudil (5HT Emax R169C + Fas. 117% ± 20%, ET-1 R169C + Fas. 154 ± 11%) (p<0.05). In addition, gene expression for Rho-guanine nucleotide exchange factors LARG and PDZ, which can activate RhoA/ROCK signalling, was upregulated in R169C lung (R169C 33.5 fold vs WT, R169C 18.7 fold vs WT respectively), with no changes to ROCK gene or protein expression. Reduced endothelial-dependent (ACh Emax WT 43 ± 3% vs R169C 36 ± 3%) and -independent relaxation (SNP Emax WT 62 ± 4% vs R169C 57 ± 4%) were also observed in R169C vessels (p<0.05). Chronic hypoxia did not affect systemic haemodynamic parameters. RV systolic pressure increased in hypoxic animals vs normoxic; this was exacerbated in R169C hypoxic animals (WT hypoxic 27.46 ± 0.97 vs WT normoxic 22.76 ± 2.17mmHg, R169C hypoxic 32.18 ± 1.13 mmHg vs R169C normoxic 23.60 ± 1.44) (p<0.05). R169C hypoxic animals also exhibited RV hypertrophy (RV/LV+S) (hypoxic 0.26 ± 0.033 vs normoxic 0.16 ± 0.012). These data demonstrate Notch3 R169C mutation may contribute to pulmonary vascular hypercontractility and PAH susceptibility, and highlight ROCK as a potential mechanism.
Abstract P147: Changes in Renal Function Precede the Development of Hypertension in Female Mice With Systemic Lupus Erythematosus
Authors: Dent Elena , Ryan Michael
Published: September 2019

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation, hypertension, renal injury, and cardiovascular disease. Kidney involvement is common to patients with SLE and renal hemodynamic dysfunction is evident in patients with active renal disease. However, little is known about early changes in renal hemodynamic function that may contribute to the pathogenesis of hypertension during SLE. We hypothesize that the loss of immunological tolerance and subsequent production of autoantibodies in SLE leads to impaired renal hemodynamic function that precedes the development hypertension. Female NZBWF1 (SLE) and female NZW (control) mice were instrumented with carotid artery and jugular vein catheters to determine MAP and glomerular filtration rate (GFR) respectively at ages 15, 20, 24, 28, 31, and 34 weeks. MAP was measured in conscious, freely-moving mice. GFR was measured by the clearance of fluorescein isothiocyanate-inulin (FITC-inulin) after achieving steady state through continuous infusion for five hours. GFR increases at 28 weeks of age followed by a significant decline by 34 weeks of age (P = 0.0127, P = 0.0001) compared to 34 and 15 weeks of age respectively, in the mice with SLE. GFR is increased in control mice by 28 weeks of age (P = 0.002) and remains unchanged at other time points. Compared with control mice, female mice with SLE have higher MAP by 34 weeks of age (P = <0.0001). These data suggest that changes in renal hemodynamic function occur in female SLE mice prior to changes in MAP suggesting an important mechanistic role for autoimmunity to directly impair renal hemodynamic function and promote the development of hypertension.
Abstract P149: Factors Associated With Future Cardiovascular Disease in Women With Hypertensive Disorders of Pregnancy and Gestational Diabetes
Authors: Ukah Ugochinyere Vivian , Dayan Natalie , Auger Nathalie , Platt Robert
Published: September 2019

Background and aim:
Hypertensive disorders of pregnancy (HDP) and gestational diabetes (GDM) are common complications in pregnancy. The risk of developing premature cardiovascular disease (CVD) is increased in women with a history of these disorders. However, more nuanced risk stratification is needed to identify women who would derive the greatest benefit from early risk reduction. We investigated demographic and clinical factors associated with future CVD in women with a history of HDP or GDM.

Method:
Women who were aged 15 to 45 years at the time of delivery were identified from among all hospital deliveries in Quebec between 1989 and 2016. Criteria for inclusion in the study were HDP, defined as pre-existing hypertension, gestational hypertension, pre-eclampsia, and superimposed pre-eclampsia, or GDM. Women with HDP or GDM were followed until age 60 years for CVD events, death, or loss to follow-up. CVD events included heart disease, cerebrovascular disease, heart and blood vessel procedures, coronary care unit admission, or mortality prior to age 60 years. We examined the association (hazard ratio, HR; 95% confidence interval, CI) between potential predictor variables and future CVD using Cox proportional hazard regression models. Risk factor variables included sociodemographic, pregnancy-related and perinatal factors recorded at the time of delivery.

Results:
Hypertension in pregnancy or gestational diabetes occurred in 173,430 (14%) of 1,229,278 women admitted for hospital delivery during the study. CVD events occurred in 3.3% of women with hypertensive disorders of pregnancy or gestational diabetes, of which death occurred in 903 (0.5%) women. The median time to event was 12 years. Neonatal death and stillbirth had the strongest associations with CVD. HRs for CVD were 2.29 (95% CI: 1.62-3.25) for neonatal death vs none, and 2.01 (95% CI: 1.556-2.60) for stillbirth vs none. Maternal age, substance use, low socioeconomic status, tobacco use, and obesity were also associated with increased risk of CVD (Table 1).

Conclusion:
Future studies should investigate whether these identified factors can reliably predict the risk of CVD and mortality in women with a history of hypertensive disorders of pregnancy and gestational diabetes.
Abstract P151: Cardiac Outcome in Offspring of Diabetic Pregnancy
Authors: Schuette Till , Kraeker Kristin , Haase Nadine , Herse Florian , Alenina Natalia , Mueller Dominik N , Bader Michael , Schupp Michael , Golic Michaela , Dechend Ralf
Published: September 2019

Introduction:
Obesity and associated pathologies like insulin resistance and diabetes reach epidemic proportions worldwide. Parental diabetes has been acknowledged as a risk factor for cardiovascular disease in offspring.

Objective:
We investigated the influence of a diabetic pregnancy on the heart in offspring using a transgenic rat model of diabetes.

Methods:
We elicited pre-gestational hyperglycemia and hyperinsulinemia in transgenic Tet29 rats by application of doxycycline, which induces a knock down of the insulin receptor via RNA interference. Wild-type Sprague-Dawley (SD) rats served as controls receiving doxycycline as well. Heart analysis was performed in fetuses and adult groups at the age of 8 months challenged by a high fat diet lasting over 12 weeks. Cardiac function was evaluated by speckle tracking echocardiography and gene expression levels were measured by qRT-PCR.

Results:
Tet29 mothers had higher blood glucose levels throughout and at the end of pregnancy (blood glucose 153.9±22.2 vs. 93.3±4.2 mg/dl). The quantity of pups was unaffected. Fetuses from diabetic mothers were growth restricted (brain-liver-ratio 0.554±0.011 vs. 0.515±0.009) and they had lower blood glucose levels at birth (63.3±3.0 vs. 91.2±3.2 mg/dl). Fetal heart-body-ratio remained unchanged. After 8 months of normal chow, no difference in cardiac performance was detectable. However, after feeding a high fat diet, the male offspring of diabetic mothers showed a reduced cardiac function revealed by echocardiography (ejection fraction 50.4±2.7 vs. 57.0±1.9 %, global longitudinal strain -16.2±0.5 vs. -18.0±0.5 %, left ventricular mass 1242.3±32.9 vs. 989.4±65.1 mg) and gene expression analysis (Myh-6/Myh-7 1.1±0.1 vs. 1.7±0.2).

Discussion:
We hypothesize that a diabetic pregnancy per se, has no acute effect on cardiovascular health in offspring in our model. However, challenges like a high fat diet, may unravel an increased susceptibility of these rats.
Abstract P154: Plasma and Placental (Pro)Renin and Soluble (Pro)Renin Receptor are Upregulated in Preeclamptic Pregnancy
Authors: Pantho Ahmed F , Afroze Syeda H , Sprague David C , Kuehl Thomas J , Amaral Lorena , Ibrahim Tarik , LaMarca Babbette , Nakagawa Tsutumu , Zawieja David C , Uddin Mohammad N
Published: September 2019

Objective:
Preeclampsia (preE), a syndrome of hypertension, and end organ damage, is a leading cause of maternal and fetal morbidity and mortality. Recently, we and other researchers have shown that circulating (pro)renin, soluble (pro)renin receptor (s(P)RR) and placental (P)RR were significantly higher during preE compared to normal pregnancy (NP). In this study, placental expression of (P)RR and serum s(P)RR were evaluated in preE human patients and various rat models of preE.

Study Design:
(1) Placenta and blood samples were collected from 40 NP and 30 consented preE patients; (2) expression of (P)RR in placenta and soluble (P)RR were evaluated in two established preE rat models: reduced uterine perfusion pressure (RUPP) and deoxycorticosterone acetate (DOCA; PDS) models of preE and were compared to normal pregnant (NP) (SD) rats (n=8). We measured the expression of (P)RR by western blotting (WB) and immunohistochemistry. Plasma (pro)renin and s(P)RR were detected using a commercially available ELISA Kit.

Results:
The placental expression of (P)RR was higher (p*<0.05) in human preE patients compared to normal pregnant women as evaluated by WB and IHC. The s(P)RR was significantly (p*<0.05) higher in human patients with preE (preE: 31.2 ± 3.15 vs NP:19.6 ± 2.9 ng/mL) . Plasma levels of pro(renin) (normalized to angiotensin I, AngI) (preE: 49.2 ± 10 vs NP: 22.7 ± 4.3 ng/AngI/mL/h) and s(P)RR (preE: 31.2 ± 3.15 vs NP:19.6 ± 2.9 ng/mL) are significantly (p*<0.05; in each case) higher in DOCA rats (PDS) compared to normal pregnant (NP) (*p<0.05). Plasma s(P)RR is significantly (p*<0.05) elevated in RUPP rats (20.06 ± 2.17 ng/mL) compared to NP rats (11.2 ± 2.1 ng/mL). Similarly, plasma (pro)renin is significantly (p*<0.05) elevated in the RUPP group (38.1 + 3.86 (ng/AngI/mL/h) compared to NP rats (21.2 + 3.25 (ng/AngI/mL/h). In the RUPP and DOCA models, both PRR and s(P)RR are approximately doubled compared to controls.

Conclusions:
These data suggest that increased expression of (P)RR in the placenta and s(P)RR are associated with placental ischemia related to the occurrence of preE in both human patients and animal models of disease.
Abstract P155: Chronic Muscadine Grape Extract Intake Improves Diastolic Function Associated With Lower Circulating Aldosterone in Hannover Sprague Dawley Male Rats
Authors: Ryalat Fatima , Yamaleyeva Liliya M , Cruz-Diaz Nildris , Tallant E A , Gallagher Patricia E , Diz Debra I
Published: September 2019

Muscadine grapes are rich sources of polyphenols, which are natural anti-oxidants linked to cardiovascular health. Circulating aldosterone may contribute to cardiac diastolic dysfunction via pro-oxidant and pro-fibrotic effects. We investigated the effect of chronic treatment with a muscadine grape extract (MGE) on circulating aldosterone and cardiac function in Hannover Sprague Dawley (SD) rats, since we previously showed that male rats develop diastolic dysfunction by 60 weeks of age. MGE (Piedmont Research & Development Corp.) was administered in the drinking water (0.2 mg polyphenolics /mL) starting at 15 weeks of age. Control animals were given regular water. Animals were assessed after 15 and 30 weeks of treatment. At 30 weeks of age, male SD rats have higher systolic blood pressure (SBP, measured by tail-cuff plethysmography: 139 ± 5 vs. 124 ± 2, n = 7-8, p < 0.05), higher E/e’ (measured by Vevo LAZR ultrasound: 12.9 ± 0.7 vs. 10.9 ± 0.2, n = 5-8, p < 0.05), and lower ejection fraction (77 ± 2 vs. 82 ± 1, n = 5-8, p < 0.05) than females at 30 weeks of age. SBP was lower in MGE treated males (126 ± 2 vs. 139 ± 5, n=7-8, p < 0.05) but not in females at 30 weeks of age. At 45 weeks of age, MGE treated male rats had improved (lower) E/e’ ratio than control male rats (E/e’: 10.7 ± 0.6 vs. 13.4 ± 0.4, n = 7, p < 0.05). This effect was accompanied by lower serum aldosterone (15 ± 3 vs. 28 ± 3 ng/dL, n = 7, p < 0.05) at 45 weeks of age. The MGE effects were independent of differences in SBP, ejection fraction, cardiac output or LV mass at this time point in male rats. For the female SD rats, there were no differences in SBP, cardiac systolic or diastolic function comparing values at 30 and 45 weeks of age, and no effect of MGE treatment at either time point. Serum aldosterone was not lower in the female rats at 45 weeks of age relative to control females. Our data demonstrate sex differences in cardiac function in response to chronic MGE consumption in aging rats. The MGE-induced improvement in diastolic cardiac function in males is consistent with lower circulating aldosterone. Our results suggest a protective role for MGE in age-related cardiac dysfunction in males.
Abstract P167: Trends in Hypertension Prevalence, Awareness, and Control Based on the New Definition of Hypertension; A National Health and Nutrition Examination Survey-Based Study
Authors: Buhari Olajide , Atanda Adebayo , Onyekwelu Chioma , Gershon Adam , Faillace Robert
Published: September 2019

Introduction:
Hypertension is a significant risk factor for cardiovascular morbidity and mortality. According to the recent guideline, the criteria for diagnosing hypertension is now 130/80mmhg. This study seeks to gain a better understanding of the prevalence of hypertension, its awareness, and control in the United States population over the last 10 years using the new criteria for hypertension.

Methods:
NHANES is a stratified multistage probability sampling of the civilian noninstitutionalized population of the United States. We used the last five cycles available (2007-2016) to conduct a prevalence study applying statistical methods to account for the survey technique and non-response.

Result:
The mean age was 47.33 years (95%CI, 46.82-29.09), females constituted 51.9% of the population(n=28147), non-Hispanic white 66.63%, non-Hispanic black, 11.40%, Mexican American 8.55%. About 39% of the population studied were obese (BMI greater than or equal to 30). The crude ten years prevalence of hypertension was 38.85%, there was an increasing trend from 37.58% in the 2007-2008 cycle to 41.12% in the 2015-2016 cycle; this increase is statistically significant<0.001. In subgroup analysis, 40.12% of non-Hispanic whites were hypertensive compared 48.61% of the black population and 28.65% of Mexican Americans. The age-adjusted prevalence rate of hypertension using the new guideline is 37%, ranging from 12.68% in age 20-39 years to 73.81% in people above 60 years. Non-Hispanic white had an adjusted 10 years prevalence of 35.66%, a minimal trend of 36.02 to 37.14% from 2005-2006 cycle to 2015-2016 cycle while Non-Hispanic black had a trend from 46.88-51.34%,p<0.0001. Awareness of being hypertensive went down from 64.02% in 2005-2006 cycle to 59.90% in the 2015-2016 cycle and control went down from 64.01% to 59.91%.

Conclusion:
We were able to demonstrate the significant increase in hypertension prevalence with an increasing trend based on the new guidelines. Also, there is a downward trend in awareness and control; we have demonstrated again, the significant racial disparities in hypertension with about half of the black population being hypertensive. Our study showed that there is a need to intensify effort to combat this epidemic.
Abstract P170: Cytochrome P450 1b1-Dependent Sex Differences in Norepinephrine-Induced Hypertension
Authors: Singh Purnima , Dutta Shubha R , Malik Kafait U
Published: September 2019

Females exhibit a lower pressor response to norepinephrine (NE) than the males. Previously we reported that cytochrome P450 (CYP) 1B1 contributes to the sex difference in angiotensin II-induced hypertension by metabolizing the sex steroids testosterone into 6β-hydroxytestosterone, and estradiol into 2-hydroestradiol which is further metabolized to 2-methoxyestradiol (2-ME) by catechol-O-methyl transferase (COMT). This study was conducted to determine the contribution of CYP1B1 to NE-induced hypertension. Eight weeks old wild-type (
Cyp1b1
+/+
) and CYP1B1 gene disrupted (
Cyp1b1
-/-
) intact, castrated (Cas) male, and ovariectomized (OVX) female mice were infused with NE (7μg/kg/min, s.c.) or its vehicle (saline) using mini-osmotic pumps for 2 weeks. The systolic blood pressure (SBP, mmHg) was measured by tail-cuff. At the end of 2 weeks, NE increased SBP to a higher level (P<0.05, n=5) in the intact
Cyp1b1
+/+
male (159±3 vs. 117±5) than in the female (137±2 vs. 120±5) mice. NE-induced increase in SBP was minimized (P<0.05, n=4) in the Cas
Cyp1b1
+/+
(127±6 vs. 116±3), and the intact
Cyp1b1
-/-
male mice (134±2 vs. 119±3). The increase in SBP by NE was enhanced in the
Cyp1b1
+/+
OVX (154±3 vs. 118±4) and
Cyp1b1
-/-
intact female mice (155±4 vs. 122±4) compared to the intact female
Cyp1b1
+/+
mice (p<0.05, n=4-5). The COMT inhibitor, Ro-041-0960 (25 mg/kg, s.c., every 2
nd
day) enhanced the NE-induced increase in SBP in
Cyp1b1
+/+
intact female (151±2, Δ14) (P<0.05, n=4-5) but not in the OVX (160±5, Δ6) or the intact
Cyp1b1
-/-
female mice (158±5, Δ3) (n=3-4). Treatment with 2-ME (1.5 mg/kg, i.p., every 3
rd
day) minimized the NE-induced increase in SBP in the intact
Cyp1b1
-/-
female mice (131±1, Δ24) (P<0.05, n=4). These data suggest that sex difference in NE-induced hypertension is dependent on CYP1B1, and the protective effect of E2 in female mice against NE-induced hypertension is mediated via the formation of 2-ME. Therefore, 2-ME could be useful to treat hypertension associated with increased sympathetic activity in postmenopausal females, hypoestrogenemic premenopausal women, and pre- and post-menopausal women with ovarian failure. Moreover, NE used to treat acute hypotensive states could produce deleterious cardiovascular effects in the above conditions.
Abstract P175: Resistance Hypertension and Achievement of Target Blood Pressure
Authors: Rekovets Oksana , Torbas Olena , Kushnir Svitlana , Primak Galina , Krushinska Nina , Sirenko Yuriy
Published: September 2019

Aim:
To evaluate the characteristics of patients with resistant arterial hypertension (RAH) and assessed the prevalence of true resistant hypertension in patients who takes 3 and more antihypertensive agents.

Materials and methods:
The study included 1146 patients with AH who received 3 or more antihypertensive drugs. The average level of systolic (SBP) / diastolic (DBP) blood pressure was (174,60 ± 0,64) / (100,50 ± 0,38) mm Hg.

Results:
Our data showed that in patients who received 3 or more drugs in (31%) goal blood pressure was not reached, it means true resistant hypertension. 3 drugs were received (51.4%) patients, 4 drugs - (37.1%), 5 drugs - (9.1%), and 6 drugs - (2.4%) of patients. ACE inhibitors were prescribed in 65.5%, calcium antagonists - in 69.9%, diuretics - in 91.8%. Beta-blockers - 75.5%, AT II blockers - 33.5%, aldosterone receptor blockers - 12.8%. Fixed combinations - 71.9%. Patients who did not achieve targeted SBP (31%) had higher cortisol (155.0 ± 44.0 vs 35.9 ± 20.8 ng/l), left ventricular mass index (147.5 ± 3.46 vs 135.3 ± 1.74 g/m
2
), obesity (42.9% vs 37.5%), kidney abnormality (2.7% vs 0.8%), nephropathy (1.3% vs 0.2%), and heart failure (16.9% vs 8.5%). Patients taking 4 and more drugs had higher glucose levels - (6.20 ± 0.09) mmol/l vs (5.90 ± 0.14) mmol/l (p <0.05) and the lower renin (31.10 ± 5.91) ng/l vs (218.30 ± 15.73) ng/l (p <0.05).

Conclusion:
patients who received 3 or more antihypertensive drugs in 31% had true resistant hypertension. They had higher blood cortisol level, left ventricular mass index, obesity, kidney abnormality and more often heart failure.
Abstract P178: Mineralocorticoid Receptor Antagonism Improved the Metabolic Function in a Mouse Model With Chronic Kidney Disease and Obesity
Authors: Palacios Ramirez Roberto , Bonnard Benjamin , Jaisser Frederic
Published: September 2019

Introduction:
Chronic kidney disease (CKD) is associated to cardiovascular and metabolic comorbidities. Several studies reported beneficial effects of mineralocorticoid receptor antagonists (MRA) in CKD.

Objective:
We investigated the metabolic alterations associated to CKD in a context of obesity and explored the effect of MR antagonism.

Methods:
5/6 nephrectomy was applied to C57BL6j mice to induce CKD . One month later they were randomized in 3 groups with similar renal failure: CKD + chow diet (CKD), CKD + High Fat Diet (CKD HFD) and CKD HFD treated with canrenoate (30mg/kg/day) (CKD HFD CAN). Analysis was done one month later. Glucose tolerance test (ipGTT) and insulin tolerance test (ipITT) were performed. Gene expression in Epididymal Visceral Adipose Tissue (EVAT) was analyzed by RT-PCR: Adipokines and markers of fibrosis and inflammation were evaluated. The comparison was performed by one way ANOVA (n=7-9) and two way ANOVA for the insulin and glucose tests (n=7-9). Results were considered significant with p<0.05.

Results:
The CKD HFD mice showed body and EVAT weight higher than the CKD, these effects were prevented by canrenoate (eith no improvement of renal function). Glucose tolerance was impaired in CKD HFD mice and canrenoate improved it. The MRA also improved insulin sensitivity. The adipokine leptin was increased by HFD and canrenoate normalized its levels while the expression of PPARα were reduced in both CKD HFD and CKD HFD CAN. The expression of the pro-fibrotic marker TGFβ as well as the pro-inflammatory marker TLR4 was reduced in CKD HFD CAN compared to CKD HFD.

Conclusion:
MRA might be useful in the management of metabolic comorbidities associated to CKD.
Abstract P181: Optimizing Precision of Hypertension Care to Maximize Blood Pressure Control (OPTI-BP): A Pilot Study Utilizing a Smartphone App
Authors: Mehanna Mai , Chen Yiqing E , Gong Yan , Handberg Eileen M , Roth Brittney , De Leon Jessica , Smith Steven M , Paulson Helen , Montilla-Crespo Jose , Harrell Jonathan G , Cooper-Dehoff Rhonda M
Published: September 2019

Background:
About half of patients with hypertension (HTN) respond to any given antihypertensive drug. Discordance in pathophysiologic pathways underlying HTN and anti-HTN mechanism of action are major contributors. Personalizing anti-HTN therapy could optimize blood pressure (BP) control. The objective of OPTI-BP was to assess the pragmatic implementation of a smartphone app used to guide physiologically optimal HTN treatment based on plasma renin activity (PRA).

Methods:
The smartphone app (PRA-HTN) and PRA testing was implemented in three primary care clinics. Patients with untreated or treated but uncontrolled HTN, aged 18-65 years, were recruited. BP and PRA were measured at baseline (and again as often as needed) with final BP measured at 6 months. PRA level and current anti-HTN meds are entered into the app and recommendations to optimize volume- and RAS blocking meds returned. Providers were at liberty to follow or disregard app recommendations. The primary outcome was BP change from baseline to 6 months. Independent t-test was used to compare BP responses of patients whose clinicians followed the app recommendations vs. those who did not. A multivariable linear regression analysis adjusting for baseline BP, age and sex was also conducted.

Results:
This analysis includes 29 white patients, including 11 (37.9%) women, with a mean age of 52 ± 9 years and a median baseline PRA of 1.3 ng/mL/hr (IQR 0.5-3.1 ng/mL/hr). Mean baseline BP between patients whose clinicians followed the app recommendations (n=16, 55%) vs. those who did not (n=13, 45%) was not statistically different (
P
>0.05). After 6 months, the average BP change among patients whose clinicians followed the app recommendations was -14 ± 20/-7 ± 9 mmHg vs. -5 ± 21/-2 ± 9 mmHg among those who did not. In regression analysis, use of app recommended therapy was associated with greater mean BP difference of -13±8/-9±4 mmHg (
P
=0.1/0.02).

Conclusion:
This pilot study demonstrates that PRA testing and implementation of recommendations from a smartphone app that utilizes PRA to optimize anti-HTN therapy was associated with good BP lowering among a relatively small cohort of patients. Future studies using larger sample sizes are warranted to confirm these preliminary findings.
Abstract P188: Electrical Stimulation of Sub-Diaphragmatic Vagal Trunk Alleviates Hypertension in the SHR
Authors: Dirr Elliott W , Jiracek Ladan G , Baekey David M , Otto Kevin J , Zubcevic Jasenka
Published: September 2019

Introduction:
The vagus facilitates a bidirectional gut-brain communication. Low vagal tone is shown in conditions marked by inflammation and dysbiosis, including hypertension (HTN). However, the role of gut-projecting vagal nerve branches in blood pressure (BP) control is unexplored. Supplementing the potentially impaired gut vagal tone using electrical vagal nerve stimulation (vns) may restore homeostasis of the microbiota-gut-brain axis in HTN.

Methods:
Male 8 week-old Wistar-Kyoto (WKY, N=6) and spontaneously hypertensive rats (SHR, N=10) were used. Rats were implanted with radiotelemetric BP transducers. WKY rats received either a unilateral surgical vagotomy of the ventral sub-diaphragmatic vagal trunk (vgnx, N=3) or sham surgery (SHAM, N=3). SHR were implanted with either a silicone cuff electrode (500μm, Microprobes for Life Sciences, Gaithersburg, MD) (vns, N=5) or a sham cuff (SHAM, N=5) on same vagal trunk. SHR were connected to an IZ2H current controlled stimulus generator (Tucker-Davis Technologies, Alachua, FL), and subjected to biphasic, 600μA, 0.5s/phase, 25Hz vns for 10 minutes per session, three sessions per day, 5 days per week. 24-hour BP recordings were made once per week for seven weeks in all rats. Relative abundance of gut bacterial phyla (
Firmicutes, Bacteriodetes, Actinobacteria
) was determined in fecal DNA of all rats using qPCR.

Results:
Compared with SHAM, WKY vgnx showed a significant elevation in systolic BP (SBP) at week 7 post-vgnx (WKY SHAM: 148±4 mm Hg vs. WKY vgnx: 177±4 mm Hg;
p
<0.05). After 7 weeks of vns, SHR STIM group exhibited a significant dampening in SBP rise from baseline (SHR SHAM: ΔSBP=44±5 mm Hg vs. SHR vns: 22±3 mm Hg;
p
<0.05) and in mean BP (MBP) rise from baseline (SHR SHAM: ΔMBP=38±4 mm Hg vs. SHR vns: 14±3 mm Hg;
p
<0.05) compared to SHAM. No difference was observed in relative abundance of major bacterial phyla between the WKY vgnx and SHR vns rats and their respective controls.

Conclusions:
Bioelectric restoration of gut vagal tone is beneficial in restitution of neural gut-brain axis in control of BP in HTN. Considering no changes were observed in major gut bacterial phyla following WKY vgnx and SHR vns, the observed BP responses may be due to perturbations in gut vagal afferent rather than efferent signaling.
Abstract P190: Transcriptomic Data Analysis Reveals Sex-Related Differences in the Interplay Between Toll-Like Receptor 4 and Heat-Shock Protein 70 in the Aorta of Type 2 Diabetic Donors
Authors: Almeida De Oliveira Amanda , Faustino Josemar , Pedrosa Nunes Kenia
Published: September 2019

Background:
Emerging evidence highlights distinct mechanisms driving cardiovascular diseases in males and females. Particularly important in this context are the actions of the Heat Shock Protein 70 (HSP70) family, which are molecular chaperones that, under pathological conditions, modulate innate immune receptors such as Toll-like receptor 4 (TLR4). Activation of TLR4 triggers oxidative stress and inflammation, key elements of vascular diseases. However, it is still unknown if HSP70 stimulates TLR4 in smooth muscle cells (SMCs) as well as how the expression of HSP70 family members relate to TLR4 in the vasculature of type 2 diabetic (T2D) donors.

Methods and Results:
We used a proximity ligation assay to investigate the association between TLR4 and HSP70 in SMCs, and fluorescent spots were observed indicating both target proteins within interacting range. Additionally, we exposed SMCs to high glucose (25 mM) in presence or absence of an HSP70 inhibitor (VER155008, 10
-5
M), and we evaluated TLR4 levels, which showed that HSP70 blockade attenuates TLR4 expression (-3.3-fold
vs
. high glucose). Next, we analyzed a human transcriptomic dataset of T2D donors from the GTEx database, which contains 46 samples from aorta (30 males and 16 females). To reduce the effects of confounders, we matched two covariates (age and race), and we excluded donors with T1D or unknown T1D status. The
statsmodels
Python package was used to compute the Pearson correlation among the transcripts per million values of RNA for TLR4 and HSP70 family genes [cognate (HSPA8) and inducible (HSPA1A, HSPA1B, HSPA6)] in T2D donors (n=14 samples for each sex). We observed a positive correlation between HSPA6 and TLR4 in males (r = 0.58; p<0.05), but not in females (r = -0.097; p>0.05). On the other hand, the levels of HSPA8 inversely correlate with TLR4 in females (r = -0.55; p<0.05), but not in males (p>0.05). It appears that in males, an increase in the expression of TLR4 induces HSPA6 without affecting the levels of HSPA8 while in females an increase in TLR4 levels does not associate with the inducible genes, but it impairs HSPA8. No association was found in the other analyzed genes.

Conclusion:
Our results suggest that sex plays a role in the interplay between TLR4 and HSP70 family members in aortic tissue.
Abstract P194: Endothelin as a Persistent Biomarker of Hypoxia
Authors: Morales-Loredo Juan H , Jones David T , Resta Thomas L , Kanagy Nancy L , Gonzalez Bosc Laura V
Published: September 2019

Rationale:
Hypoxic symptoms at moderate altitude are not well characterized. Hypoxia can cause cognitive impairment, temporarily affecting the performance of aircrew, ground soldiers or other critical workers. Therefore, there is a need to determine if an individual has experienced asymptomatic hypoxemia after exposure to high altitude.

Goal:
To identify reliable blood biomarkers that are quickly modified by hypoxia which correlate with blood gases and cardiac-hemodynamic parameters. Plasma endothelin-1 [ET-1]p was initially investigated as a potential biomarker due to its upregulation by hypoxia.

Methods:
Mean arterial pressure (MAP), heart rate (HR) and electrocardiogram (ECG) were wirelessly recorded in conscious rats during exposure. Blood was obtained from rats exposed to normoxia (21% O
2
) or hypoxia (12% O
2
) after 0.5, 1, 6, or 24 hours. [ET-1]
p
level was assessed by ELISA.

Results:
MAP and HR increased after 6 hrs of hypoxia. PR interval of the ECG progressively increased in hypoxic rats correlating with the decrease in HR. Low frequency/high frequency (LF/HF) component of HR variability (HRV) decreased only after 30 min of hypoxia suggesting early parasympathetic effects. [ET-1]
p
increased after 1-24 hrs of hypoxia. [ET-1]
p
negatively correlated with Pa
O2
, Pa
CO2
, HCO
3
-
, MAP and HR, but positively with LF (baroreceptor band) and HF (respiratory band). These results suggest hypoxia rapidly increases [ET-1]
p
, which may contribute to restoration of MAP.

Conclusions:
Our data suggest that ET-1 is a reliable hypoxia biomarker. Future studies will determine other potential biomarkers and for how long ET-1 remains elevated after returning to normoxia.