bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 006: Blood Pressure Categories and Newly Progression of Carotid Artery Plaques in a Prospective Cohort Study: The Suita Study
Authors: Kokubo Yoshihiro , Watanabe Makoto , Higashiyama Aya , Miyamoto Yoshihiro
Published: September 2019

Purpose:
We have first reported that the new progression of carotid artery plaque (C-plaque) is a risk factor for incident cardiovascular disease (CVD), but there have been no reports on the risk factors associated with newly progression of C-plaque.

Methods:
We studied 4,724 Japanese men and women (mean age 59.7 years) without CVD whose intima-media thickness (IMT) was measured with carotid ultrasonography on both sides of the entire carotid artery areas as a baseline survey (April 1994 to August 2001). C-plaque was defined as a maximum IMT of the common carotid artery more than 1.1mm. We excluded subjects with carotid artery plaque at baseline (n=1,044), lost to follow-up (n=167), and missing data (n=2). Carotid ultrasonographic follow-ups for 3,511 subjects were performed every two years until March 2016. Blood pressures (BPs) were used the average of two measurements recorded more than 1 min apart. We analyzed multivariable-adjusted Cox proportional hazard regression models for incident C-plaque progression according to BP categories by the ESC/ESH 2018 guideline.

Results:
During 38,457 person-years of follow-up, 1,771 new progressions of C-plaque occurred. The incident new progression of C-plaque per 1000 person-years was 39.9, 4.8, 50.6, 56.3, and 60.6 for optimal, normal, and high normal systolic BPs, and grade I and II+III systolic hypertension, respectively. Compared to the optimal BP, the adjusted HRs (95% CIs) for incident progression of C-plaque were 1.14 (1.00-1.30), 1.18 (1.03-1.35), 1.18 (1.02-1.36), and 1.32 (1.06-1.64), respectively. The adjusted HRs (95% CIs) for incident C-plaque progression were 1.21 (1.06-1.39) and 1.27 (1.07-1.50) for pulse pressures 50-59 mm Hg and ≥60 mm Hg, based on the subjects with pulse pressure <40 mm Hg. Compared to subjects with optimal BP without antihypertensive medication, the adjusted HRs (95% CIs) for incident C-plaque progression were not significant in controlled BP but increased the risk of incident C-plaque in poor-controlled hypertension (HR=1.21, 95% CIs=1.05-1.38).

Conclusion:
A community-based cohort study showed for the first time that high BP levels lead to new progression of incident C-plaque. It is first shown that BP control contributes to the suppression of plaque development.
Abstract 007: Endothelial Mineralocorticoid Receptors are Increased by Pregnancy in Mice and Mediate Obesity-Associated, Leptin-Induced Endothelial Dysfunction in Pregnancy
Authors: Faulkner Jessica L , Kennard Simone , Jaffe Iris Z , Belin de Chantemele Eric J
Published: September 2019

Obesity is a risk factor for endothelial dysfunction and hypertension in pregnancy. Our lab has demonstrated that obesity-associated hypertension in female animal models develops via leptin-mediated, aldosterone-induced endothelial dysfunction (ED). We also showed that female mice are more sensitive to leptin-induced aldosterone activation of endothelial mineralocorticoid receptors (ECMR) due to an endogenous sex-specific upregulation of ECMR in females. Our previous data demonstrates that endothelial progesterone receptor activation increases ECMR expression and that ECMR deletion protects female mice from obesity-associated, leptin-mediated ED. However, whether ECMR play a role in ED in pregnancy is unknown. Therefore, we hypothesized that high progesterone levels increase ECMR expression in pregnant mice and that ECMR deletion protects pregnant mice from obesity-associated, leptin-mediated ED. Endothelial cells were isolated from aorta of timed-pregnant Balb/C mice (gestation day (GD) 17) and assessed for ECMR expression via RT-PCR. ECMR mRNA expression increased 9.2±0.2-fold (*P<0.05) in pregnant compared to nonpregnant mice in association with high plasma progesterone levels (24±6 ng/ml pregnant vs 2±2 nonpregnant, *P<0.05). Endothelial function was experimentally measured by wire myography concentration response curves to acetylcholine in mouse aorta analyzed by 2-way ANOVA of curves with repeated measures. No changes in endothelial-independent sodium nitroprusside responses were observed. Chronic leptin infusion in mid-pregnancy (GD11-17) induced ED in pregnant mice that was impaired both compared to sham-treated pregnant (*P<0.05) and non-pregnant leptin-infused females (*P<0.05), indicating that increased ECMR expression in pregnancy increases sensitivity to leptin-induced ED. Further evidence for this notion is provided in that ECMR deletion in pregnant mice protected them from leptin-mediated ED (*P<0.05). Collectively, these data indicate a role for ECMR in the pathogenesis of obesity-associated ED in pregnancy and indicate a potential role for MR antagonists for the treatment of hypertensive pregnancies such as preeclampsia.
Abstract 008: Aldosterone Contributes to the Blood Pressure Elevation, Endothelial Dysfunction, and Norepinephrine Sensitivity Caused by Endothelial Human Endothelin-1 Overexpression in Mice
Authors: Berillo Olga , Mahjoub Nada , Coelho Suellen C , Mahmoud Ahmad , Offermanns Stefan , Paradis Pierre , Schiffrin Ernesto L
Published: September 2019

Background:
The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells (ECs) are complex and remain unclear. Transgenic mice with tamoxifen-inducible EC-restricted human ET-1 overexpression (ieET-1) exhibited BP elevation 3 months after induction. ET-1 has been shown to stimulate the release of aldosterone from adrenal cortex (AC). Whether aldosterone plays a role in EC ET-1 overexpression-induced BP elevation and vascular injury is still unknown.

Methods and results:
Nine to 12-week-old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of EC-specific
Tie2
promoter were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and studied 3 months later. Plasma aldosterone levels measured by ELISA was increased in ieET-1 vs. ieCre mice (1.21±0.14 vs. 0.70±0.09 ng/mL,
P
<0.05). Reverse transcription-quantitative PCR (RT-qPCR) showed that aldosterone synthase (
Cyp11b2
) was decreased in AC of ieET-1 vs. ieCre mice (fold change: 0.52±0.06 vs. 1.00±0.16,
P
<0.01). CYP11B2 protein levels measured by Western Blotting was unchanged. Treatment with mineralocorticoid receptor antagonist eplerenone (100 mg/kg/day) during the last 2 weeks decreased daytime systolic BP determined by telemetry in ieET-1 vs. ieCre mice (Systolic after 14 days [mm Hg]: 128±1.6 vs. 137±1.8,
P
<0.01). The EC50 concentration for norepinephrine-induced MA contraction was reduced in ieET-1 vs. ieCre mice (EC50 [mol/L]: 5x10
-7
±6x10
-8
vs. 4x10
-6
±7x10
-7
,
P
<0.05), which was reversed by elplerenone (EC50 [mol/L]: 8x10
-6
±5x10
-6
,
P
<0.05). The MA relaxation response to acetylcholine was decreased in ieET-1 vs. ieCre mice (32.2±5.3% vs. 70.5±5.9%), effect that was reduced by eplerenone (43.1±5.5%). The MA endothelium-independent relaxation response to sodium nitroprusside (SNP) was similar in ieET-1 and ieCre mice. Eplerenone enhanced sensitivity to SNP in iET-1 mice (EC50 [mol/L]: 3x10
-8
±1x10
-8
vs. 1x10
-7
±2x10
-8
,
P
<0.05).

Conclusions:
Increased aldosterone production contributes to EC human ET-1 overexpression-induced daytime SBP elevation, enhanced contractile response to norepinephrine and endothelial dysfunction.
Abstract 009: Endothelial Epithelial Sodium Channel Promotes Intrinsic Cardiomyocyte Stiffness and Diastolic Dysfunction in Response to a Diet Induced Obesity in Female Mice
Authors: Aroor Annayya , DeMarco Vincent , Jia Guanghong , Habibi Javad , Yan Yang , Manrique Camila , Lastra Guido , Dongqing Chen , Zhe Sun , Hill Michael , Whaley-Connell Adam , Jaisser Frederic , Sowers James
Published: September 2019

Obesity is associated with a metabolic cardiomyopathy characterized by diastolic dysfunction with preserved systolic function. Although premenopausal non-obese women show relative protection against development of metabolic cardiomyopathy and cardiovascular disease compared to men, this relationship is lost in obese women. Diastolic dysfunction in such cardiomyopathy is caused not only by extrinsic extracellular remodeling and interstitial fibrosis but also through alterations in intrinsic stiffness of cardiomyocytes. One mechanism by which intrinsic cardiomyocyte stiffness is increased in obesity is decreased coronary endothelial cell production of nitric oxide. We have described a clinically relevant diet induced obesity murine model that exhibits increased vascular stiffness associated with cardiac dysfunction. In this model, female mice have high plasma aldosterone levels and increased mineralocorticoid receptor (MR) expression in both the vasculature and heart. One of the mechanisms by which MR activation promotes endothelial stiffness is through increased expression and activation of epithelial sodium channel (ENaC) in ECs (EnNaC). In this study, we tested the hypothesis that specific deletion of EnNaC ameliorates increases in endothelial stiffness and decreases diastolic dysfunction occurring during diet induced obesity (DIO) in female mice. To produce cell specific deletion of the EnNaC gene,”floxed” EnNaC mice were serially crossed with Tie 2-Cre transgene mice. This resulted in marked suppression of EnNaC expression in ECs. Female KO mice and littermate controls were fed a diet high in fat (46%) and fructose (17.5%) for 12 to 16 weeks. Compared to mice fed a control diet (CD), whole cell sodium currents in pulmonary ECs and aortic EC stiffness were significantly increased in DIO mice and this was prevented in EnNaC KO mice with DIO. Moreover, deletion of EnNaC also prevented DIO increases in stiffness of isolated cardiomyocytes (WD, 7.43 ± 1.21 kPA, WD-KO, 3.47 ± 0.14 kPA) as well as normalizing impaired diastolic relaxation. Collectively, these findings support the notion that DIO promotes coronary ECMR mediated activation of EnNaC and associated increases in intrinsic cardiomyocyte stiffness and diastolic dysfunction.
Abstract 014: Impact of Placental Ischemia on Hippocampal Asic2a and Glutamate Receptor Protein Expression in Mice
Authors: Jones-Muhammad Maria A , Thompson Rachael , Shao Qingmei , Warrington Junie P
Published: September 2019

Preeclampsia (PE) is a pregnancy condition occurring in the 3
rd
trimester with phenotypes such as hypertension, proteinuria, and seizures (in eclampsia). Our lab previously showed that placental ischemia, used to mimic PE, induces increased sensitivity to drug-induced seizures in rats; however, the underlying mechanisms are unknown. Acid sensing ion channels (ASICs), proton-gated ion channels, have been shown to reduce the prolonged effects of seizures and respond to pH changes within tissues. It is possible that reduced hippocampal ASIC, specifically ASIC2a, may contribute to increased seizure severity following placental ischemia. In this study, we investigated whether placental ischemia reduces ASIC2a, NMDAR1, and NMDAR2 protein expression in mouse hippocampal tissues. C57BL/6 female mice, aged 8-12wks, were randomly assigned to Sham (n=6) or reduced uterine perfusion pressure (RUPP, n=5) groups. At day 14 of pregnancy, mice underwent Sham or RUPP surgery (total ligation of uterine artery between ovary and first pup) or no ligation (Sham). Protein expression levels in placenta (ASIC2a) and hippocampus (ASIC2a, NMDAR1, and NMDAR2B) were assessed using Western blot and Image Lab software. Differences in expression were analyzed using unpaired t-tests. Placental ischemia led to reduced live pups (8±1 vs 5±1; p=0.0499) and increased hematocrit in surviving pups (30.3±1.5 vs 34.6±1.6%; p=0.0295). There was no difference in body weight (39.2±2.4 vs. 37.8±1.4g; p=0.52) or placental weight (0.09±0.01 vs. 0.10±0.004g; p=0.63) between groups. Placental ischemic mice had reduced ASIC2a levels in hippocampus (1.0±0.2 vs. 0.5±0.1; p=0.02) but not placenta (1.0±0.2 vs. 0.7±0.1; p=0.07) compared to Shams. There was no difference in expression of hippocampal NMDAR1 (1.0±0.3 vs. 1.1±0.1; p=0.84) or NMDAR2B (1.0±0.2 vs. 1.1±0.1 p=0.68) between groups. Our findings support the hypothesis that RUPP-induced increases in seizure susceptibility occurs through reduced hippocampal ASIC2a expression. Whether other ASIC subunits are decreased in the hippocampus following placental ischemia is not known. Additionally, studies assessing whether reduced ASIC2a contributes to increased seizure susceptibility are ongoing.
Abstract 016: Sex-Specific Effects of Neuropeptide Y2 Receptor (y2) Deletion in Adipose Tissue From Mice Exposed to Early Life Stress
Authors: Leachman Jacqueline R , Xu Xiu , Dalmasso Carolina , Taylor Bradley K , Loria Analia S
Published: September 2019

Neuropeptide Y (NPY) plays a critical role in the regulation of energy homeostasis acting in the central nervous system as an orexigenic agent. Peripherally, NPY is co-released by catecholaminergic neurons and stimulates adipocyte precursor proliferation, differentiation, via NPY receptor 2 (Y2), and inhibit lipolysis, via the cAMP/PKA pathway. We have shown that female mice exposed to a model of early life stress, maternal separation and early weaning (MSEW), display greater increases in fat mass in response to high fat diet (HF). Thus, we hypothesized that Y2 deletion in adipose tissue could prevent fat expansion in female MSEW mice. MSEW was performed by separating pups from the dam during postnatal days 2 to 16, and weaned early on day 17. Control (C) mice remained undisturbed and were weaned on day 21. Genotyping was completed to determine WT (Y2 fl/fl) and Y2 KO (Y2 fl/fl) littermates. All groups were placed on a HF (60% kcal from fat) for 18 weeks. Following, mice were subjected to 6-weeks of chronic restraint stress (1 hr/day) combined with high fat/high sucrose diet (RS+HFS). No differences in fat mass were found between male WT MSEW and C mice (37.5±2.0 vs. 41.9±2.3 % body fat, respectively), although Y2 KO reduced fat mass in both groups (23.2±2.3 vs. 38.1±2.9 % body fat, p MSEW=0.084, p genotype=0.011, p interaction=0.401). Conversely, female WT MSEW mice displayed increased fat mass compared to C (26.4±2.6 vs. 19.1±2.6 % body fat), and Y2 KO further increased fat deposition in MSEW female mice compared to C (36.1±4.3 vs. 15.8±1.2 % body fat, p MSEW=0.0001, p genotype=0.047, p interaction=0.007). In addition, female WT MSEW mice displayed reduced free fatty acid release in response to an
in vivo
lipolysis test in compared to C (101±21 vs. 167±12 uM/ml, p=0.066). After RS+HFS, MSEW increased fat mass in male WT mice more than in female WT mice, while Y2 KO attenuated this effect in both sexes. These data suggests that Y2 in adipose tissue may contribute to reduced lipolysis in HF-fed female mice exposed to MSEW. However, Y2-mediated effects of chronic stress on fat expansion in adult life are greater in male than in female MSEW mice. Overall, our data shows that there is possibly a sex-specific imbalance between adipogenesis and lipolysis in response to different stressors.
Abstract 020: PLGF VEGFB Neuropilin1 a Neuroimmune Mechanism Necessary for the Initiation of the Adaptive Immune Response Recruited by Angiotensin II to Induce Hypertension and Target Organ Damage
Authors: Carnevale Daniela , Iodice Daniele , Perrotta Sara , Carnevale Lorenzo , Iacobucci Roberta , Perrotta Marialuisa , Pallante Fabio , Cifelli Giuseppe , Lembo Giuseppe
Published: September 2019

Vascular endothelial growth factors (VEGFs) are mainly known as angiogenic factors but they also play less explored immune-modulating functions. In the past years we found that one of the VEGF family members, Placental Growth Factor (PlGF), is critical for hypertension. PlGF is recruited in the spleen by Angiotensin II (AngII) to prime T cell costimulation through the expression of CD86 in antigen presenting cells (APCs). Here we show that AngII also recruits VEGF-B, PlGF homolog, in the spleen and its selective splenic ablation, obtained by transplanting VEGF-B KO spleen in WT mice, protects from immune activation and hypertension. In the search for a downstream common mediator of PlGF/VEGF-B, we analyzed the splenic expression of VEGFR1, a major candidate receptor, which was activated by AngII. However, mice genetically defective of VEGFR1 signaling (Flt1-TK) become hypertensive as WT when subjected to AngII (SBP: Flt1-TK 139±2; WT 138±2; ***p< 0.001), thus ruling out its role. Since the expression of PlGF/VEGF-B was confined to the stromal and marginal zone (MZ), where lymphoid and innate zones are entangled with noradrenergic fibers, we analyzed Neuropilin1 (Nrp1), a secondary receptor for PlGF/VEGF-B, functioning in neuronal guidance and dendritic cell maturation. Immunofluorescence revealed that AngII increases Nrp1 expression and flow cytometry indicated a localization of the receptor on myeloid APCs. Splenic denervation reduced Nrp1 expression on APCs (from 29 ± 3% to 14 ± 2%), further supporting that it mediates PlGF/VEGF-B signaling. In the end, we selectively deleted the receptor in myeloid lineage, generating Nrp1
myeloidKO
mice, thus blocking the effect of PlGF/VEGF-B on the APCs. The in vitro induction of DC maturation in monocytes isolated from Nrp1
myeloidKO
mice failed to produce mature APC, thus indicating the requirement of this pathway for the initiation of the adaptive immune response. AngII fails to induce T cell costimulation and egression from the spleen, and ultimately increase BP (SBP: Nrp1
myeloidWT
mice 140±3; Nrp1
myeloidKO
mice 105±2; ***p< 0.001). Overall we demonstrate that PlGF/VEGF-B/Nrp1 is a critical neuroimmune mechanism responsible for initiation of the adaptive immune response in hypertension.
Abstract 024: Melatonin Abolishes Renal Infiltration of T Lymphocytes in a High Salt Diet Induced Hypertension Model
Authors: Bier Ariel , Khashab Rawan , Grossman Ehud , Liebowitz Avshalom
Published: September 2019

Objective:
Low grade inflammation and oxidative stress play a role in the pathogenesis of cardiovascular diseases, including hypertension (HTN). There is emerging evidence that the immune system, and particularly the adaptive immune response, may be involved in the triggering of these processes. In a previous study we demonstrated that melatonin prevents kidney damage in salt induced HTN model by decreasing oxidative stress. We hypothesized that this effect is involving the immunomodulation properties of melatonin.

Design and method:
Dahl salt sensitive (DSS) rats were fed normal chow [control (Ctrl)], or high salt diet (HSD) or HSD and melatonin (Mel) (30/mg/kg/day) in their water for 8 weeks (n=8 each group). By the end of the treatment or when rats were considered ill with less than 24 hours survival, rats were sacrificed and kidneys were harvested for immediate lymphocytes isolation and characterization by FACS (CD3+CD4+ and CD3+CD8+) and for chemoatractants (vcam-1, cxcl1, cxcl9, cxcl10, cxcl11, cxcl12, cxcl16, cx3cl1,ccl3, ccl4, ccl7, ccl12, ccl17,ccl 19, ccl21) gene expression studies.

Results:
HSD was associated with significant renal infiltration of CD4+ and CD8+ T lymphocytes compare to control (0.16±0.02 vs. 5.18±1.6 and 0.95±0.15 vs. 4.6±0.75, % of CD3+ cell , Ctrl vs. HSD, CD4+ and CD8+ respectively, p<0.05). Melatonin treatment significantly reduced renal lymphocytes infiltration (0.7±0.2 and 1.37±0.45 % of CD3+ cells, CD4+ and CD8+ respectively, p<0.05 vs. HSD). HSD increased significantly mRNA expression of renal vcam-1, cxcl1, cxcl9, cxcl10, cxcl11, cxcl16, ccl3, ccl7, ccl21 (2±0.2, 3.1±0.1, 5.2±1.2, 2.4±0.3, 6.3±1, 1.9±0.08, 3±0.4, 3±0.7, 4.8±0.7, time fold, respectively, HSD vs. Ctrl, p<0.05). Adding melatonin to HSD prevented the increase in mRNA expression of cxcl1, cxcl9, cxcl10, cxcl11, cxcl16, ccl7 and ccl21, which are lymphocytes attractants.

Conclusion:
Treating HSD fed rats with melatonin decreased renal lymphocytes chemoatractants mRNA expression and is associated with significant reduction of renal T lymphocytes infiltration.
Abstract 025: Potential Implications of Simplified Blood Pressure Measurement Approaches: The Atherosclerosis Risk in Communities Study
Authors: Lu Yifei , Tang Olive , Miller Edger , Heiss Gerardo , Moran Andrew , Appel Lawrence J , Matsushita Kunihiro
Published: September 2019

Background:
Taking a mean of blood pressure (BP) measurements is recommended but impractical in resource-constrained settings. The implications of fewer BP measurements on BP classification and cardiovascular disease (CVD) risk are uncertain.

Methods:
In 15107 participants aged 45-64, with the mean of 2
nd
and 3
rd
BP as the standard, we quantified missed and misdiagnosed hypertension (HTN) by simpler BP approaches (e.g., single 1
st
, single 2
nd
BP, mainly 1
st
but 2
nd
BP if 1
st
in a certain range). We also assessed CVD risk related to HTN status by simpler vs. standard approach. Considering resource-constrained settings, HTN was defined as BP ≥140/90.

Results:
Of 8905 participants without diagnosed HTN, 823 were classified as HTN by the standard approach. With single 1
st
BP, 18.3% of HTN were missed and 2.8% of non-HTN were misdiagnosed as HTN (Figure). The corresponding estimates with single 2
nd
BP were 6.4% and 2.1%. Similar estimates were seen when 2
nd
BP was used if 1
st
BP ≥130/80 (8.1% and 1.9%), with only 27.8% needing 2
nd
BP. In general, HTN in either of simpler or standard approach showed higher CVD risk vs. consistent non-HTN by both approaches. Individuals with diagnosed HTN (n=6202) showed more misclassification than those without, with elevated CVD risk only in consistent BP ≥140/90. Results were similar with averaged 3 BPs as a standard.

Conclusions:
Simpler approaches can identify HTN with little misclassification (<5-8%) in those without diagnosed HTN. CVD risk was elevated in HTN by any approach, potentially justifying HTN treatment in misdiagnosed HTN and indicating the need to capture missed HTN. Multiple BP measures appear especially important in those with diagnosed HTN.
Abstract 028: Remote Health Monitoring Platform Reduces Blood Pressure and Crisis Hypertension
Authors: Shah Nirav , Fonner Clifford , Manders Noah , Aysola Rama , Sutton Sarah , Sanchez Jorge
Published: September 2019

Introduction:
We assessed the efficacy of mobile health hypertension monitoring for patients enrolled in Medicare’s Remote Physiologic Monitoring program.

Hypothesis:
Uncontrolled hypertension is an increasing epidemic associated with cardiovascular disease. Despite many available treatments, the average time to blood pressure control is slow. We hypothesized that mobile health monitoring and communication with clinicians in a Medicare cohort would decrease the hypertension burden and mitigate crisis blood pressure in patients.

Methods:
337 patients who had contributed ≥ 20 blood pressure readings in a remote monitoring program were included in the study population, spanning clinics in Florida, Tennessee, and Arizona. Eligible patients carried a diagnosis of hypertension and had been seen by their doctor within the year they were referred. The mobile health platform was utilized to aggregate blood pressure data, which was analyzed by a remote care team and provided to clinicians on a monthly basis. Patients’ doctors and their teams reviewed and managed the patients based on the data provided by the mobile-cloud platform. The remote monitoring program provided alerts to clinic staff for patients who had blood pressures greater than 180mm Hg systolic (crisis hypertension) for expedited decision making.

Results:
337 patients who provided >20 BP readings from October 2018 to April 2019 were included in the study. A total of 51,125 blood pressure readings were included in this analysis. Patient readings were stratified by epoch chronologically. The first epoch (E1), represented the first 25% of readings in the remote monitoring system, and the fourth epoch (E4) represented the final 25% of readings. From E1 to E4, patients saw an average decrease of 4.7 mmHg in systolic blood pressure (133.0 vs. 128.3; p<0.001). The proportion of readings in crisis hypertension range decreased from 3.3% to 1.9% (p<0.001), while the amount of hypotensive readings did not substantially change (1.4 vs. 1.6%; p=0.14).

Conclusions:
In agreement with our hypothesis, patients in a Medicare cohort achieved a significant reduction in blood pressure via remote monitoring as well as a significant reduction in crisis blood pressure readings.
Abstract 029: Antihypertensive Treatment and Short-Term Blood Pressure Variability
Authors: De La Sierra Alejandro , Banegas Jose R , de la Cruz Juan J , Gorostidi Manuel , Vinyoles Ernest , Segura Julian , Ruilope Luis M
Published: September 2019

Blood pressure variability (BPV) is recognized as an important prognostic contributor in hypertension. We asseseds differences in short-term BPV in treated patients depending on the number of drugs, drug-classes and combinations, and individual compounds. From the Spanish ABPM Registry, we selected 38188 treated patiens. BPV estimates were obtained from ABPM records, and included weighted, daytime and nighttime SD and average real variability (ARV). Comparisons (general linear models adjusted for age, gender, diabetes, dyslipidemia and CV disease) were carried out depending on the number of drugs (1, 2, 3, and more). In patients treated with monotherapy (13765), BPV estimates were compared depending on the drug classes, as well as on individual compounds inside each class. Additional comparisons were performed depending on the type of combination in patients treated with 2 (12716) and 3 drugs (7888). Systolic BPV increased from monotherapy to treatment with 4 or more drugs (p<0.001 for weighted, daytime, and nighttime SD, and ARV). Among those treated with monotherapy, BPV was increased in those treated with beta blockers, ACEi and ARB, when compared to diuretics or CCB. No differences were observed among diuretics (chlorthalidone, hydrochlorothiazide, indapamide, or loop diuretics). Among betablockers, BPV was increased in those treated with carvedilol, compared to bisoprolol and nevibolol. Among CCB, BPV was lower in treated with amlodipine, with respect to other dihydropyridines. No differences were observed among most frequent used ACEi or ARB. In patients treated with 2-drug combinations, BPV was lower in those treated with diuretic/CCB combinations, compared with other types. Moreover, in those treated with 3-drug combinations, those which included a CCB resulted in a lower BPV in comparison to those which did not include a CCB. Results regarding diastolic BPV were consistent with those observed with systolic BPV. We conclude that antihypertensive treatment is associated with differences in BPV. CCB, specifically amlodipine, used in monotherapy or in combination with other drugs, especially diuretics, is associated with lower short-term BPV. These results may help to explain some benefits of amlodipine observed in clinical trials.
Abstract 035: Unique Associations of DNA Methylation With 24-Hour Blood Pressure Phenotypes in African Americans
Authors: Kidambi Srividya , Pan Xiaoqing , Li Yingchuan , Roberts Michelle , Yang Chun , Liu Pengyuan , Wang Tao , Laud Purushottam , Chelius Thomas , Munyura Yannick , Mattson David , liu Yong , Cowley Allen , Kotchen Theodore , Liang Mingyu
Published: September 2019

Blood pressure (BP) levels are influenced by genetic and environmental factors. Epigenome is the result of interactions between the DNA and the environment. Methylation is a naturally occurring epigenetic modification of genomic DNA and may influence BP levels. We examined the association of DNA methylation in whole blood with 24-hour and clinic BP phenotypes in 281 African Americans; fifty percent were women and fifty percent were hypertensive. Mean age of the participants was 44±7 years and mean body mass index (BMI) was 28±5 kg/m
2
. Clinic BP was obtained in duplicate from both arms and averaged using a standardized protocol as part of screening procedures for a 3-day inpatient clinical study. Blood was obtained for DNA at the time of screening visit. BP medications were discontinued for 1-week after the screening visit and prior to inpatient study. Detailed phenotyping and 24-hour BP measurements were performed during the in-patient study. DNA methylation profiles of these 281 subjects with 24-hour BP measurements were analyzed at single-base resolution with a modified reduced representation bisulfite sequencing (RRBS) method. Analysis of 38,216 DNA methylation regions, representing 1,549,368 CpG sites across the genome, identified up to 72 regions that were significantly associated with 24-hour, daytime or nighttime BPs. Considered jointly, these methylation regions explained up to 66.6% of the BP variance. Methylation regions associated with 24-hour, daytime or nighttime BPs or systolic, diastolic or mean arterial pressure or pulse pressure overlapped partially. No methylation region was significantly associated with clinic BP. Two to three methylation regions were significantly associated with 24-hour BP after adjustment for age, sex, and body mass index. These methylation regions, jointly, explained up to 16.5% of the variance of 24-hour BP, while age, sex and body mass index explained up to 11.0% of the variance. In summary, we have identified several DNA methylation regions in the whole blood that are associated with 24-hour, daytime or nighttime BPs, but not with clinic BP measured at a single point in time. DNA methylation appears to be an excellent marker for the cumulative effect of factors that influence 24-hour, daytime or nighttime BPs
Abstract 038: The Arg16 / Gln27 Diplotype of the Beta-2 Adrenergic Receptor: Cardiovascular Insights from a Novel Transgenic Mouse Model
Authors: Treesaranuwattana Thitinan , Maris Stephen , Garza Amanda E , Brooks Danielle , Pojoga Luminita H
Published: September 2019

The beta-2 adrenergic receptor (B2AR) is an established regulator of vascular tone and cardiac contractility. Two polymorphisms of the B2AR (Gly16Arg and Glu27Gln) have been associated with cardiovascular phenotypes, including hypertension, salt sensitivity of BP, cardiovascular disease and responses to antihypertensives. These same variants are associated with changes in receptor downregulation and desensitization in pulmonary tissues; however, there is no information on the effect of these polymorphisms on B2AR expression/function in cardiovascular tissues. To investigate the effect of these variants on cardiovascular function, we used the CRISPR/Cas9 approach to generate transgenic mice that carry the diplotype Arg16/Gln27 on 2, 1 or 0 alleles, i. e. mutant (Mut), heterozygous (Het) and wild-type (WT). Both male and female mice displayed significantly higher body weights with the increase in number of mutated alleles (P<0.05). Systolic and diastolic BP showed a similar positive dose-response relationship with the number of mutated alleles, irrespective of the gender (P(trend) < 0.001). In contrast, pulse pressure and heart rates were not significantly affected by the diplotype. Urine and plasma aldosterone levels (but not plasma renin activity) were progressively downregulated in the male but not female carriers of the diplotype (P<0.01). Cardiac ultrasound measurements revealed that male diplotype carriers displayed a decrease in left ventricular wall thickness, especially during systole (P<0.05), with a corresponding increase in internal diameter and volume, decreased stroke volume and fractional shortening (P<0.05); however, there were no significant effects of diplotype in the females. Cardiac B2AR transcript levels were significantly decreased in male but not female diplotype carriers versus WT. Our study provides strong support for a direct sex-dependent effect of the Arg16/Gln27 diplotype on cardiovascular function and supports the translational value of our novel animal model.
Abstract 045: Attenuated Natriuretic Response to Saline Loading in Sheep With Hypertensive Kidney Disease Following Radiofrequency Catheter-Based Renal Denervation
Authors: Denton Kate M , McCardle Zoe , Singh Harshil , Booth Lindsea , May Clive , Head Geoffrey , Moritz Karen , Schlaich Markus , Singh Reetu
Published: September 2019

In the present study, we examined the chronic effect of renal denervation (RDN) on the blood pressure (BP) and renal function in response to a slow-infused isotonic saline load. Normotensive (control) and hypertensive chronic kidney disease (CKD) sheep at 10 months of age underwent either a sham (control-intact; N=6, CKD-intact; N=7) or radiofrequency catheter-based RDN (control-RDN; N=7, CKD-RDN, N=7) procedure using the
Symplicity
catheter system. BP and renal function were measured during 3-h saline loading (0.9% NaCl, 0.13ml/kg/min) and 3-h recovery periods in animals at 2 and 11 months post-procedure. In this cohort of sheep, as previously reported, BP was reduced and GFR increased at 11 months in the CKD-RDN group. In response to saline loading, BP increased 3-5 mmHg in all groups. In response to saline loading sodium excretion increased in all groups. At 2 months post-procedure, the control-intact group excreted 66±7% of the sodium load over the 6-h period, whereas the response was exaggerated in the CKD-intact group (92±9%; P<0.001 vs. control-intact) but blunted in the RDN groups (control-RDN 32±5%; CKD-RDN 63±5%; both P<0.01 vs. intact). However, by 11 months post-procedure, the % excretion of the sodium load was similar in the intact (53±4%) and RDN (65±5%) control groups, but remained attenuated in the CKD-RDN group (33±6% P<0.001 vs. CKD-intact, 63±14%). Together these data indicate that (1) the normal suppression of RSNA activity during saline loading contributes to the rapid elimination of excess sodium and water, (2) following RDN the excretion of a saline load is attenuated and (3) this effect was maintained for 11 months in the CKD-RDN group indicating nerve regrowth is not complete. In conclusion, RDN in patients with hypertensive CKD may slow the return of extracellular fluid homeostasis in response to physiological challenges such as volume expansion.
Abstract 047: Mode of Orthostatic Hypotension Assessment and Dizziness in Older Adults
Authors: Juraschek Stephen P , Miller Edgar R , Michos Erin D , Appel Lawrence J
Published: September 2019

Background:
Orthostatic hypotension (OH) is an important predictor of dizziness, falls, and death. However, there is substantial uncertainty regarding the most clinically meaningful way to assess OH.

Methods:
The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a randomized trial (2015-2019), comparing the effect of vitamin D dose on fall risk in adults, 70 yrs or older. At baseline, seated blood pressure (BP) was measured after 5 minutes of rest. Then, after standing for 1 minute, a series of 3 BP measurements were performed, each separated by 30 seconds. Participants were asked about dizziness during the seated-to-standing protocol. OH was defined at 3 different times based on the consensus definition (a drop in systolic BP [SBP] of 20 or diastolic BP [DBP] of 10 mm Hg) and by its individual BP components. We used logistic regression to determine the association of OH definitions with dizziness.

Results:
Among 660 participants (mean age 76.4 ± 5.3 yrs, 44% women, 18% black), 52 (8%) reported dizziness and 19 (3%) had consensus OH. While all 3 assessments of consensus and systolic OH were associated with dizziness, associations based on average measurements were strongest (OR 6.8 [2.4, 19.6] and OR 11.7 [3.7, 36.7], respectively) (
Table
). Only diastolic OH measurements at or after 3 minutes were associated with dizziness. In contrast, the last measurement of postural change in SBP and none of DBP were associated with dizziness.

Conclusions:
OH based on an average of 3 SBP measurements between 1-5 minutes was the most strongly associated with dizziness, suggesting that precision is more important than timing. These findings are useful for the clinical assessment of dizziness.
Abstract 048: Association of Central Arterial Stiffness With Hippocampal Blood Flow, N-Acetyl Aspartate and Anxiety in Hypertensive Dahl Salt Sensitive Rats
Authors: Ajamu Samuel , Fenner Rachel , Grigorova Yulia , Bouhrara Mustapha , Lakatta Edward , Spencer Richard , Fishbein Kenneth , Fedorova Olga
Published: September 2019

Background:
Hypertension and cardiovascular disease may be significant contributors to dementia and Alzheimer’s disease. However, the mechanism of this process is poorly understood. Central arterial stiffness (CAS) is accelerated by systemic hypertension and may be accompanied by increased stiffness in the cerebral arteries.

Methods & Results:
We used Dahl salt sensitive rats (Dahl-S) which develop CAS and hippocampal memory decline as they develop variable degrees of hypertension on a 0.5% salt diet with age. At 22 weeks, systolic blood pressure (SBP), pulse wave velocity (PWV), open field tests (OFT), hippocampal N-acetylaspartate (NAA) concentrations and blood flow (BF) data were all collected. The rats displayed moderate hypertension as compared to a 3 months baseline (SBP: 165±16 vs. 142±5 mmHg; P<0.01, t-test). SBP and PWV are positively correlated (a). PWV was negatively correlated with hippocampal BF (b), and positively correlated with hippocampal NAA (c). Ratio of central rearing duration to total rearing duration in the OFT, a negative measure of anxiety, positively correlated with hippocampal BF (d).

Conclusion:
In the Dahl-S model of hypertension, greater PWV, a marker for CAS, was associated with decreased hippocampal perfusion. Relationship between CAS and hippocampal BF was as hypothesized. Likewise, hippocampal BF correlates with hippocampal NAA concentration as expected. The positive correlation between hippocampal BF and increased central rearing duration suggests that higher cerebral BF is associated with a lower anxiety level. Supported entirely by the Intramural research Program of the NIH, National institute on Aging.
Abstract 049: Intracranial Atherosclerosis and Stage 1 Hypertension Defined by the 2017 ACC and AHA Guideline
Authors: Kwon Hyung-Min , Nam Ki-Woong , Park Jin-Ho
Published: September 2019

Background and aims:
In 2017, the American College of Cardiology (ACC) and American Heart Association (AHA) released a new, stricter definition of stage 1 hypertension which was previously considered prehypertension. However, impacts of the novel stage 1 hypertension on deleterious target organ outcomes are still controversial. In this study, we evaluated the relationship between this newly defined stage 1 hypertension and the presence of intracranial atherosclerosis (ICAS) lesions in neurologically healthy participants.

Methods:
We assessed consecutive participants in routine health check-ups between January 2006 and December 2013. BP was classified according to the 2017 ACC/AHA hypertension guideline, and ICAS was defined as occlusion or ≥ 50% stenosis of intracranial vessels on flight magnetic resonance angiography.

Results:
Among 3,111 healthy participants (mean age: 56 years, sex: 54% men), 85 (3%) had ICAS lesions. In multivariate analysis, stage 1 hypertension (adjusted odds ratio: 2.46, 95% confidence interval: 1.10-5.51,
P
= 0.029) remained an independent predictor of ICAS after adjustment for confounders. Stage 2 hypertension showed a higher odds ratio and a lower
P
value, indicating a dose-response effect. Age and HbA1c level were also significantly associated with ICAS, independent of the BP categories. The ICAS lesion burden showed a dose-response effect across the BP categories (
P
for trend < 0.001), while ICAS lesion location did not (
P
for trend = 0.699).

Conclusions:
We demonstrated that stage 1 hypertension, defined according to the 2017 ACC/AHA guideline, was associated with a higher prevalence and burden of ICAS lesions in a neurologically healthy population.
Abstract 058: High Sodium Intake Induces a Catabolic State via Glomerular Hyperfiltration and Enhanced Glomerulotubular Balance in Essential Hypertension
Authors: Rossitto Giacomo , Maiolino Giuseppe , Lerco Silvia , Ceolotto Giulio , Blackburn Gavin , Mary Sheon , Antonelli Giorgia , Berton Chiara , Bisogni Valeria , Cesari Maurizio , Seccia Teresa M , Lenzini Livia , Pinato Alessio , Montezano Augusto , Touyz Rhian M , Petrie Mark C , Welsh Paul , Plebani Mario , Rossi Gian Paolo , Delles Christian
Published: September 2019

Background:
A metabolic shift in energy expenditure toward a catabolic state upon high sodium (Na
+
) diet, ultimately favouring endogenous water accrual and body fluid preservation, has recently been described in a rodent model.

Objective:
To investigate the impact of high Na
+
intake on renal Na
+
/water handling and metabolic signatures in a large real-life cohort of patients.

Methods and Results:
We analysed biochemical data from 767 hypertensive patients (429 males, 55.9%; age 47 ± 13 years; BMI 25.6 [23.0-29.0] kg/m
2
) in washout from drugs affecting the renin-angiotensin-aldosterone system at the time of screening for secondary causes and with a conclusive diagnosis of essential hypertension (2012-2017). Classes of Na
+
intake (
L
ow ≤2.3g/d;
M
edium 2.3-5g/d;
H
igh >5g/d) were defined based on urinary 24h Na
+
excretion (uNaV). The fractional excretion (FE) of Na
+
increased with increasing Na
+
intake (L: 0.39% [0.30-0.47] vs H: 0.81% [0.73-0.98], p < 0.001), while FE of free water decreased (L: 1.13% [0.73-1.72] vs H: 0.89% [0.69-1.12], p = 0.015). uNaV was an independent predictor of glomerular filtration rate (GFR, estimated by creatinine clearance; H: 130 ± 33 vs M: 111 ± 52 and L: 96 ± 39 ml/min/1.73m
2
; p < 0.001 for comparisons) after correction for age, sex, BMI, renin, aldosterone and uKV (p = 0.001). This resulted in a marked increase in the 24h tubular Na
+
reabsorption and, accordingly, in the estimated energy expenditure (Δ H vs L= 18 [12-24] kcal/d, p < 0.001). At non-targeted LC/MS metabolomics (n = 67), metabolites increased (p < 0.05) in H vs L Na
+
intake mostly entailed intermediates or end products of the urea cycle and products of protein catabolism. Urinary 24h cortisol excretion, as a potential determinant of catabolism, increased with Na
+
intake (n = 137; L: 63 [36-72] nmol, M: 60 [47-86] nmol, H: 86 [75-139] nmol; p < 0.001), but its strongest predictor at multivariate regression analysis was GFR (p = 0.001).

Conclusions:
Kidneys can effectively dissociate Na
+
and water handling upon high Na
+
diet, at the cost of glomerular hyperfiltration, enhanced glomerulotubular balance, increased tubular energy expenditure and, ultimately, protein catabolism from endogenous or excess exogenous sources. This has broad implications on global cardiovascular risk.
Abstract 060: Increased Urinary Potassium Excretion Does Not Associate With Reduced Systolic Blood Pressure in the Dietary Approaches to Stop Hypertension Sodium Trial
Authors: Chaudhary Parul , Wainford Richard D
Published: September 2019

Aim:
The 2019 National Academy of Science, Engineering and Medicine Dietary Reference Intakes (DRI) for Sodium (Na) and Potassium (K) Report concluded there remains insufficient evidence to establish potassium DRIs. This study investigated the association between Na and K excretion and blood pressure in salt sensitive (SS) vs. salt resistant (SR) subjects in the Dietary Approaches to Stop Hypertension Sodium (DASH-Na) Trial.

Methods:
Via the NHLBI BioLINCC we accessed the DASH-Na dataset containing data on systolic blood pressure (SBP), 24-h urinary Na and K excretion at screening (regular diet [no dietary intervention]; 186 SS and 222 SR adults) and post 1-month DASH diet (increased K intake; 72 SS and 123 SR adults). The relationships between SBP, urinary Na and K excretion and Na:K ratio were assessed via linear regression with SS vs. SR as a categorical factor.

Results:
At screening, on a regular diet, urinary Na excretion (adjusted for gender) positively correlated with increased SBP in SS but not SR individuals (SS - 1g increase in Na excretion increases SBP 1.1±0.3mmHg - up to 5g Na excretion/day). In contrast, despite urinary K excretion of <1g/day correlating with increased SBP in both SS and SS subjects, increased urinary K excretion (range 1-4g/day) did not correlate with changes in SBP in either SS or SR individuals. The urinary Na to K ratio (Na:K) was not significantly associated with SBP in SS or SR subjects. At the urinary Na excretion range 3-5g/day, equivalent to US Na intake, increased urinary K excretion had no effect on SBP in either SS or SR individuals. On the DASH diet; SBP was reduced in SS (-4.5±1.3mmHg) and SR (-8.3±0.8mmHg, P<0.05) subjects. However, no correlation was observed between the reduction in SBP and urinary K excretion or urinary Na:K ratio in either in SS or SR individuals on the DASH diet.

Conclusion:
These data show in the DASH-Na trial population increased urinary K excretion does not correlate with reductions in SBP irrespective of the salt sensitivity of blood pressure. Our data support the recent DRI recommendation not to propose K intake guidelines and suggest that further evidence is required to support the establishment of a Na:K intake ratio to reduce SBP.
Abstract 063: Evaluation of a Combination Therapy of Bone Marrow-Derived Stem Cells and Serelaxin Against Established Renal Fibrosis in Normotensive and Hypertensive Models of Disease
Authors: Samuel Chrishan S , Nguyen Jordan , Li Yifang , Shen Matthew , Ferens Dorota , Pinar Anita A , Ricardo Sharon D
Published: September 2019

Fibrosis significantly impairs the viability and therapeutic efficacy of stem cell-based therapies. To overcome this, we demonstrated that the anti-fibrotic drug, serelaxin (recombinant human relaxin; RLX), could prevent renal fibrosis progression in a unilateral ureteric obstruction (UUO)-induced murine model of interstitial renal disease and improve the ability of injected human bone marrow-derived mesenchymal stem cells (BM-MSCs) to attenuate renal injury. To advance the therapeutic potential of this combination therapy, we have now investigated its effects as an intervention therapy in the UUO model, and in a uninephrectomised/deoxycorticosterone acetate/drinking saline water (1K/DOCA/salt) model of hypertension. 7-8 week old male C57B6J mice were subjected to UUO or 1K/DOCA/salt (2.4mg/day, s.c; 21 days). Sub-groups of injured mice (n=6/group) were administered RLX (0.5mg/kg/day; s.c) alone, BM-MSCs (1x10
6
/mouse; i.v) alone or both combined 3-days post-UUO or 14 days post-1K/DOCA/salt-treatment. Untreated injured mice and sham-operated or 1K-mice were included as respective controls. Mice were killed 10 days post-UUO or 21 days post-1K/DOCA/salt treatment (7 days post-intervention) for tissue collection and analysis. UUO- and 1K/DOCA/salt-injured mice underwent significant renal damage, inflammation and (interstitial and total collagen-induced) fibrosis at the time-points studied, as determined by histological and biochemical analyses (all p<0.01 vs respective uninjured controls). All 1K/DOCA/salt-treated mice had systolic blood pressure levels of 140-150mmHg over the experimental period, compared to 1K-mice having 115-120mmHg (as measured by tail cuff plethysmography; p<0.01). Unlike BM-MSCs alone, the combined effects of BM-MSCs and RLX significantly reduced established UUO-induced renal damage and fibrosis, primarily by reducing myofibroblast-induced collagen deposition (all p<0.05 vs BM-MSCs alone). Treatment-induced effects of the hypertensive model are currently being evaluated and will be presented. These findings confirm that agents that can effectively reduce established fibrosis can enhance the therapeutic potential of BM-MSCs in treating kidney diseases, when added in combination.