bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P115: Increased Diastolic Blood Pressure Post-mild Exercise is Associated With Early Structural and Functional Cardiovascular Abnormalities
Authors: Tucker Susan , El Shahawy Mahfouz
Published: July 2021

Background:
Previous research has suggested that an increase in SBP post-mild exercise is correlated with early structural and functional cardiovascular abnormalities.

Purpose:
To determine if an increase in diastolic blood pressure post-mild exercise (DBP PME) is associated with early structural and functional cardiovascular abnormalities.

Methods:
1416 untreated, asymptomatic subjects were screened for early indicators of cardiovascular disease using the Early CVD Risk Score (ECVDRS), also known as Rasmussen Risk Score (RRS), which consists of a panel of 10 tests; large (C1) and small (C2) artery stiffness, resting BP and post mild exercise (PME), CIMT, abdominal aorta and left ventricle ultrasounds, retinal photography, microalbumuria, ECG, and pro-BNP. 267 subjects were normotensive. Of those subjects, 12 had a increase in DBP PME, 23 had no change in DBP PME, and 232 had a decline in DBP PME. Focus was placed on the three known tests recommended for early CVD assessment; C1, C2 and CIMT.

Results:
As seen in Figure 1.0, a rise in diastolic blood pressure PME is statistically evident for an increased risk of early structural and functional cardiovascular abnormalities. A significant increase in abnormalities was noted with C2 and CIMT with subjects whose DBP increased PME.

Conclusion:
Assessment of diastolic blood pressure PME is an easy, noninvasive, inexpensive test that can be performed by any health care practitioner to evaluate the risk of CVD in patients. Any increase in diastolic blood pressure PME should warrant physicians on the urgency to further investigate and treat patients to divert the progression of CVD.
Abstract P138: Alterations in Cardiac Structure and Function in Young Adults Born Extremely Preterm: Impact of Neonatal Bronchopulmonary Dysplasia
Authors: Mian Muhammad Oneeb Rehman , Bigras Jean-Luc , Fernandes Rafael , Bertagnolli Mariane , Xie Li Feng , Paquette Katryn , Wu Rong , Cloutier Anik , Orlando Valerie , Luu Thuy Mai , Nuyt Anne Monique
Published: July 2021

Objective:
Studies support a causal association between preterm birth and increased risk of cardiovascular diseases. Increased left and right ventricular mass and impaired systolic and diastolic function has been reported in young adults born preterm. However, the impact of extreme preterm birth and prematurity-specific complications on adult cardiac structure and function has not been evaluated. We assessed cardiac structure and function in young adults born extremely preterm (EPT) versus term, and correlated long term cardiac remodeling with neonatal bronchopulmonary dysplasia (BPD).

Methods:
Eighty five EPT (gest. age = 27.1±1.4 weeks) were recruited along with term-born controls matched for age, sex and socioeconomic status. Birth and neonatal data (gestational age, birth weight, BPD indicated by O
2
requirements at 36 weeks postmenstrual age) was collected. Ambulatory blood pressure (Spacelabs) and echocardiographic measurements (Phillips) were taken. Comparisons were performed using ANOVA or T-test.

Results:
EPT presented with increased systolic (119±9 vs 116±8 mmHg, P<0.05) and diastolic (68±5 vs 66±6 mmHg, P<0.05) blood pressures. EPT exhibited reduced septal thickness (IVS, 6.8±0.8 vs 7.1±1.1 mm, P<0.05), left ventricular internal dimension (LVID, 46±4 vs 48±5 mm, P<0.05), LV end-diastolic (98±20 vs 106±24 ml, P<0.05) and end-systolic (36±9 vs 40±11 ml, P<0.01) volumes, right ventricular internal dimension (RVID, 22±3 vs 24±4 mm, P<0.05), and LV mass (104±27 vs 115±30 g, P<0.05), but similar LV mass and volume indexes. EPT exhibited increased LV myocardial performance index (0.41±0.04 vs 0.39±0.04, P<0.01), reduced mitral lateral e’ (17.6±2.8 vs 19.1±2.6 cm/s, P<0.01), mitral s’ (10.7±2.3 vs 11.6±2.3 cm/s, P<0.01), tricuspid E’ (15.8±2.7 vs 16.8±2.1 cm/s, P<0.05), and tricuspid S’ (13.1±2.0 vs 14.0±2.0 cm/s, P<0.01) waves, and a trend in reduced mitral E wave (81±14 vs 85±15 cm/s, P=0.09). EPT with neonatal BPD exhibited greater reduction in IVS (6.5±0.8 mm, P<0.05 vs terms), LVID (45±4 mm, P<0.05), LV Mass (98±22 g, P<0.05), and RVID (20±3 mm, P<0.01).

Conclusions:
EPT exhibit cardiac structural and functional alterations compared to term-born individuals. Neonatal BPD in EPT is a key contributor to long term cardiac remodeling.
Abstract P145: Screening Rates for the Diagnostic Workup of Resistant Hypertension
Authors: Jaffe Gilad M , Krishnan Gomathi , Stedman Margaret , Chertow Glenn M , Leppert John T , Bhalla Vivek
Published: July 2021

Resistant hypertension is a common clinical condition associated with higher rates of cardiovascular disease, kidney disease, and death. Among individuals with resistant hypertension, secondary causes of hypertension occur in about 20% of cases, but the rates of screening are unknown. We assessed the practice pattern of these guidelines in a major primary and tertiary care academic institution in Northern California. Using the electronic health record, we identified individuals between the years of 2008 and 2014 who were prescribed three separate classes of antihypertensive agents and had follow-up laboratory data within 24 months. We excluded individuals with known causes of secondary hypertension such as hyperaldosteronism, renal artery stenosis, fibromuscular dysplasia, adrenal disease, and end-stage renal disease. We also excluded individuals with diagnosed heart failure, who may have been prescribed selected medications for heart failure instead of hypertension. This cohort of 37,073 individuals with presumed resistant hypertension had a mean age of 58.5 years (SD 15.8), was 51.7% male, and 56.4% Caucasian, 6.3% Black, and 12.4% Asian. Among these individuals, only 520 had a serum aldosterone, and only 447 had both aldosterone and plasma renin activity levels measured. These data infer that the recommended initial screening tests for secondary causes of resistant hypertension - notably primary and secondary hyperaldosteronism - are conducted in only 1.2% of individuals. A detailed chart review of a representative sample of this cohort will be also be conducted. Thus far, these data suggest that there is significant under-screening of reversible causes of resistant hypertension. Furthermore, an electronic implementation strategy to prompt screening for secondary causes may be warranted to reduce blood pressure, optimize use of antihypertensive medications, and lower cardiovascular risk. A similar analysis will be performed in the Veterans Affairs database to evaluate screening rates in health-care delivery systems enriched with African Americans.
Abstract P153: Mineralocorticoid Receptor Inhibition Abolishes Sex-specific, Renin Angiotensin Aldosterone System-associated Salt Sensitivity in Female Mice
Authors: Faulkner Jessica L , Kennard Simone , Harwood Daisy , Antonova Galina , Morwitzer Jane , Belin de Chantemele Eric J
Published: July 2021

Up to half of essential hypertension cases in women are associated with salt sensitive blood pressure (BP) increases, however, the sex-specific mechanisms of salt sensitivity in women are unknown. Our lab has shown that female mice are more sensitive to the hypertensive effects of aldosterone than male mice but it is unknown if aldosterone plays a role in salt sensitivity in female mice. We hypothesized that increasing dietary sodium via a high salt diet would increase blood pressure in female mice which would be abrogated by mineralocorticoid receptor (MR) antagonism. To determine salt sensitivity male and female Balb/C mice were implanted with radiotelemeters for continuous recording of BP. BP was recorded during baseline (7 days) and throughout the administration of a high salt (4% NaCl, HS) diet for 7 days with or without concurrent eplerenone supplementation (daily 200 mg/kg/day). Plasma and kidneys were then harvested. Systolic (SBP) and diastolic (DBP) BP were increased in female mice, but not in males, on HS (7.8±3.3 SBP and 7.8±4.0 DBP Δ change in mmHg in female (P<0.05) vs -3.7±3.1 SBP and 3.1±2.1 DBP in male, respectively, n=7-8). Plasma aldosterone levels were decreased in HS male mice compared to control (224±57 vs 151±19 pg/ml, n=3-5), however, increased modestly in HS females (254±56 vs 394±158 pg/ml, n=3-6). Preliminary data indicated that MR antagonism with eplerenone ablated increases in SBP and DBP in HS female mice, while having no effect on blood pressure in HS males (-22.8 SBP and -23.9 DBP Δ change in mmHg in female vs 1.0 SBP and -1.5 DBP in male, n=2). In addition, and in association with an absence of aldosterone suppression with HS, renal mRNA expression of renin (1.4±0.1-fold, P<0.05, n=5), angiotensinogen (4.4±0.2-fold, P<0.05, n=5), AT1 receptor (52.9±0.9-fold, P<0.05, n=5), MR (1.6±0.2-fold, P<0.05, n=5) and α-ENAC (1.3±0.0-fold, P<0.05, n=5) were increased in HS female mice compared to control females. These data indicate that BP increases in HS female mice are associated with unexpected increases in plasma aldosterone as well as mRNA expression of proteins associated with renin angiotensin aldosterone system activation, which may be novel mechanisms via which females have increased risk for salt sensitive hypertension.
Abstract P159: MicroRNA Profiling in Small Resistance Arteries of Hypertensive Patients With or Without Chronic Kidney Disease
Authors: Huo Ku-Geng , Fraulob-Aquino Julio C , Richer Chantal , Rehman Asia , Briet Marie , Boutouyrie Pierre , Lipman Mark , Sinnett Daniel , Paradis Pierre , Schiffrin Ernesto L.
Published: July 2021

Background:
Hypertension (HTN) and chronic kidney disease (CKD) are global health disorders that are epidemiologically associated. Vascular injury is an early manifestation in HTN and contributes to CKD. It is characterized by endothelial dysfunction and vascular remodeling that are accompanied by gene expression changes. MicroRNAs (miRs) are important non-coding RNA regulators of gene expression. Dysregulation of miRs has been shown in HTN and CKD, but their implication in vascular injury remains unclear. We aimed to identify differentially expressed (DE) miRs in small arteries of HTN and CKD human subjects to get further insight into pathophysiological molecular mechanisms in these conditions.

Methods and Results:
Normotensive, HTN (systolic blood pressure (BP) > 135 mm Hg or diastolic BP of 85-115 mm Hg with BpTRU) and CKD subjects (estimated glomerular filtration rate <60mL/min/m
2
) (n=15-16) were studied. Small arteries were dissected from a subcutaneous gluteal biopsy under RNAse free condition and used for total RNA extraction with the mirVana miR isolation kit. cDNA libraries were prepared using the TruSeq small RNA prep kit and the TruSeq stranded total RNA prep kit, and sequenced by Illumina HiSeq 2500. DE miRs and DE mRNAs (
P
<0.05) were identified using EdgeR, which found 3 up- and 6 down-regulated miRs, as well as 134 up- and 149 down-regulated mRNAs uniquely associated with HTN, 42 up- and 39 down-regulated miRs, as well as 743 up- and 348 down-regulated mRNAs uniquely associated with CKD, while 2 up-regulated miRs and 101 up- and 75 down-regulated mRNAs were found in both groups. Target Scan was used to predict DE miR targets in the DE mRNAs. Enrichment analysis showed that the HTN-associated DE miR-targeting DE mRNAs were highly enriched in gene ontology (GO) terms involved in peptidase activity, mitochondrial activity and immune response (
q
<0.01), while the CKD-associated DE miR-targeting DE genes were highly enriched in GO terms involved in tube formation, fibroblast proliferation and EGF response (
q
<0.001).

Conclusions:
DE miRs were identified in small arteries of HTN and CKD patients. Enrichment analysis in DE miR-targeting DE mRNAs revealed GO terms that could be linked to different degrees of vascular changes in HTN and CKD.
Abstract P161: Inhibition of Class I HDAC Enhances the Expression of
Npr1
and Repairs Renal Pathology in Gene-targeted Haplotype Mice
Authors: Kumar Prerna , Gogulamudi Venkateshwara R , Nguyen Christian , Samivel Ramachandran , Pandey Kailash N
Published: July 2021

The objective of the present study was to determine the effect of class I histone deacetylase (HDAC) inhibitor, mocetinostat (MGCD0103) on the expression of
Npr1
(coding for natriuretic peptide receptor-A; NPRA) and renal pathology in
Npr1
gene-disrupted haplotype (50% of normal) mice. Adult male
Npr1
haplotype (1-copy;
Npr1
+/-
), wild-type (2-copy;
Npr1
+/+
), and gene-duplicated (3-copy;
Npr1
++/+
) mice were injected intraperitonealy with MGCD0103 (2 mg/kg) at alternate days for 2-weeks. After MGCD0103 treatment, the renal
Npr1
mRNA was increased in
Npr1
+/-
mice by 7.3-fold (p < 0.01),
Npr1
+/+
mice by 4.4-fold (p < 0.05) and
Npr1
++/+
mice by 3.6-fold (p < 0.05) compared with vehicle-treated controls. The MGCD0103 also enhanced renal cGMP levels (pmol/mg protein) in
Npr1
+/-
(57 ± 7 vs. control, 12 ± 1; p < 0.01),
Npr1
+/+
(125 ± 9 vs. control, 66 ± 5; p < 0.01), and
Npr1
++/+
(202 ± 7 vs. control, 127 ± 15; p < 0.05) mice. An increased HDAC activity (ng/min/mg protein) was observed in
Npr1
+/-
mice (24.4 ± 2.8; p < 0.05); however,
Npr1
++/+
mice showed lower HDAC activity (6.4 ± 0.7; p < 0.05); compared with
Npr1
+/+
mice (15.9 ± 1.3). Treatment with MGCD0103 significantly attenuated HDAC activity by almost 50% (15.3 ± 1.2; p < 0.01) in
Npr1
haplotype mice. A significant decrease in systolic blood pressure was observed in MGCD0103-treated
Npr1
+/-
mice (106 ± 0.6 vs. control, 131 ± 1.9, p < 0.001). Significantly lower creatinine clearance (μl/min) was observed in
Npr1
+/-
(51 ± 11; p < 0.05) vs.
Npr1
+/+
mice (130 ± 14.0; p < 0.05) and treatment with MGCD0103 increased creatinine clearance in
Npr1
+/-
mice (105 ± 13; p < 0.05) vs. controls. Higher urinary albumin to creatinine ratio was detected in
Npr1
+/-
mice (0.7 ± 0.05) vs.
Npr1
+/+
animals (0.5 ± 0.05; p < 0.05) and a complete reversal was observed in drug-treated
Npr1
+/-
mice (0.4 ± 0.04). The present results provide direct evidence that class I HDAC inhibition upregulates NPRA expression
in vivo
and repairs the renal pathology in
Npr1
+/-
haplotype mice. The present findings will have important implications in the treatment and prevention of hypertension and renal pathophysiological conditions.
Abstract P174: Free Triiodothyronine Level Correlates with Statin Responsiveness in Acute Myocardial Infarction
Authors: Zhang Kuo , Wang Wenyao , Gerdes A. Martin , Tang Yi-Da
Published: July 2021

Background:
Although thyroid hormone (TH) has important effects on lipid metabolism, the relationship between TH and statin responsiveness has never been investigated. We hypothesized that TH plays an important role in statin responsiveness in AMI patients.

Methods:
Consecutive 1091 hospitalized AMI patients in Fuwai hospital were enrolled. The study population was divided into three groups based on the intensity of statin treatment: low (n=221), moderate (n=712) and high (n=158). Lipid levels were measured after statin therapy lasting for 10-14 days. We explored the association between TH, lipid levels and achievement of low density lipoprotein cholesterol (LDL-C) lowering goals in patients with acute myocardial infarction (AMI) on statin therapy.

Results:
By general linear analysis, a significant linear trend between FT3 and LDL-C level (linear coefficient=-0.082, P =0.001) and FT3 and total cholesterol (TC) level (linear coefficient=-0.105, P =0.031) was observed in the moderate-intensity statin group. A more apparent linear trend was detected in the high-intensity statin group (for LDL-C: linear coefficient=-0.113, P =0.005; for TC: linear coefficient=-0.172, P=0.029, respectively). However, no significant correlation was observed in the low-intensity statin group. Compared with the low-T3 group (defined as FT3<1.79 pg/ml), the OR (95% CI) for attaining a LDL-C<3.0mmol/L was found to be 2.217 (1.001-4.839) in the higher FT3 group (>2.95 pg/ml).The OR for attaining the more intensive goal (LDL-C<1.8mmol/L) (95% CI) was 2.836 (1.014-5.182).

Conclusions:
Variation in FT3 levels is related to the lipid-lowering responsiveness of statins in AMI patients.
Abstract P178: The Role of Lateral Hypothalamic Leptin Signaling in Metabolic and Cardiovascular Regulation
Authors: Cui Huxing , Rodriguez Cruz Eva
Published: July 2021

While neurons in the lateral hypothalamic area (LHA) are clearly involved in feeding, metabolism, and cardiovascular regulation, neurochemically and neuroanatomically heterogeneous nature of LHA neurons has been a challenge in understanding their function in physiological regulation. We have recently identified a unique subset of LHA GABAergic neurons, which are distinct from well-known orexin and MCH neurons, that co-express two metabolically important leptin receptor (LepR) and melanocortin-4 receptor (MC4R), suggesting that these neurons might be the important targets of leptin and melanocortin for metabolic and cardiovascular regulation. Here we show that LHA LepR-positive neurons innervate broadly to intra- and extra-hypothalamic brain regions important for feeding, sympathetic nervous activity, and cardiovascular function, including but not limited to arcuate nucleus, paraventricular nucleus of hypothalamus, parabrachial nucleus, and nucleus of the solitary tract. Stereotaxic microinfusion of leptin into the LHA increases renal sympathetic nerve activity (RSNA) (% changes from baseline at 4
th
hour: vehicle -25.03 ± 7.09 % vs leptin 100.23 ± 26.94 %, p<0.001); and specific deletion of LepR from LHA significantly increase body weight when fed high-fat diet (44.5 ± 1.9g vs 52.5 ± 2.5g, p<0.01); and selective chemogenetic activation of LHA LepR+ neurons decrease feeding and increase physical activity. Our findings identify the LHA as a novel brain site for leptin to integrate feeding, metabolism and sympathetic regulation. Further investigation of the role of LHA leptin signaling in blood pressure regulation is underway.
Abstract P181: Contrasting Effects of High Fat Diet and DOCA-salt on Primary Neuronal Cilia
Authors: Jiang Jingwei , Rahmouni Kamal
Published: July 2021

Virtually, every mammalian cell is equipped with an antenna like primary cilium, a cell surface protrusion that is thought to act as a sensory organelle. Many of the rare genetic disorders that cause shorter, absent or disrupted cilia are associated with obesity and cardiovascular dysfunction in humans and rodents, which suggest that cilia length contribute to energy balance and cardiovascular homeostasis. Here, we examined the length of the primary neuronal cilia in the brain nuclei that contribute to metabolic and cardiovascular regulation in high fat diet-induced obese (DIO) mice and DOCA-salt mice. Cilia length was examined by adenylate cyclase 3 (AC3) immunostaining, followed by confocal 3D reconstruction, and quantification by IMARIS imaging analysis software. Analysis of the cilia length and distribution showed reduced frequency of cilia that are over 10 μm in the brain of DIO mice compared to control mice fed normal diet fed mice (17.02±1.36% vs 23.78±1.15%, p=0.032). Interestingly, the most pronounced difference in cilia length was observed in the dorsomedial hypothalamus with the DIO mice displaying significantly shorter cilia (6.90±0.06 μm) relative to controls (7.32±0.14μm in controls, n=5/group p<0.05). Conversely, we found that average neuronal cilia length was elongated in 3-week DOCA-salt treated mice compared to sham group. The number of primary neuronal cilia that are over 10 μm was significantly increased in DOCA-salt mice by 8% (p=0.0114). On the other hand, the number of cilia that are 4-5 μm in length was significantly decreased in DOCA-salt mice compared to sham controls (11.73±1.70% vs 18.73±2.02%, p=0.0385). The supraoptic nucleus was the only nucleus that displayed difference in the length of cilia that are 5-10 μm in length (7.46±0.24 μm vs 6.76±0.15μm, n=5/group, p=0.0509). Our data demonstrate plasticity of neuronal cilia in response to high fat diet and DOCA-salt treatment in defined brain regions. Our results raise the possibility that primary neuronal cilia may function as part of environmental surveillance system in the brain that control energy homeostasis and cardiovascular function. Further analysis of the role of primary neuronal cilia in cardiovascular regulation is underway.
Abstract P186: Selective ET
A
Receptor Antagonism versus Dual ET
A
/ET
B
Receptor Blockade for Preventing Angiogenesis Inhibitor-induced Hypertension
Authors: Mirabito Colafella Katrina M , van Veghel Richard , de Vries Renè , Versmissen Jorie , van den Meiracker Anton H , Danser A. H. Jan
Published: July 2021

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET
A
receptor causes pro-hypertensive effects whereas stimulation of the ET
B
receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET
A
receptor blockade versus dual ET
A
/ET
B
blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET
A/B
receptor antagonist; 30 mg/kg/day) or sitaxentan (ET
A
receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, P<0.001). Co-treatment with macitentan blunted the pressor response to sunitinib, such that on day 6 of treatment the increase in MAP was 7±4 mmHg (P<0.01 versus sunitinib-treated). Similar results were observed for co-treatment with 30 mg/kg/day of sitaxentan. Conversely, co-treatment with 100 mg/kg/day sitaxentan, which has been shown to induce a depressor response in normotensive Wistar rats, completely abolished sunitinib-induced hypertension, with MAP actually decreasing before returning to near baseline level (-1±1 mmHg on day 6 of treatment, P<0.001 versus sunitinib-treated). Compared to vehicle treatment, ET
B
receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET
B
receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET
A
receptor blockade is sufficient to block this effect.
Abstract P214: Shotgun Metagenomic Analysis of Fecal Microbiome Reveals Profound Functional Differences in Patients with Hypertension
Authors: Kim Seungbum , Richards Elaine M , Qi Yanfei , Mohammed Mohammed , Handberg Eileen M , Pepine Carl J , Raizada Mohan K
Published: July 2021

Objectives:
Recent studies have implicated changes of the gut pathology and altered microbiome in the animals of various hypertension models. However, these relationships in human hypertension are poorly understood. Thus, our objectives in this study was to test the hypothesis that microbiome from hypertensive patients (HTN) would be taxonomically and functionally differ from those of normotensive subjects.

Design and Method:
Fecal samples were collected from HTN (n=22, mean SBP 155.8±3.4mmHg) and reference subjects without hypertension (REF) (n=18, mean SBP 121.1±1.5mmHg) (see ClinicalTrials.gov, NCT02188381 for detailed protocol). Gut microbiomes were analyzed using shotgun metagenomics and the USEARCH6.1 algorithm for OTU clustering. Taxonomy was assigned with Metaphlan. Qiime, Phyloseq and Galaxy web applications were used to further analyze the data.

Results:
Two beta diversity measures, principal coordinates analysis and partial least squares discriminant analysis, showed significantly different microbiome composition between the two groups (ANOSIM p=0.012). A heatmap based on significantly enriched functional genes from each cohort (P<0.05) also showed clustering of samples by group. Metagenomic analysis showed that the butyrate kinase gene and the abundance of butyrate producing bacteria were negatively correlated with SBP (R
2
=0.10 and P<0.05 for both). Additionally, functional analysis showed that HEME biosynthesis and hydroxyphenylacetate degradation were decreased in the HTN cohort (LDA score 2.15 and 1.95 respectively) suggesting inefficient nitric oxide synthesis and polyphenol digestion in HTN patients.

Conclusions:
1) Significant difference in taxa of HTN from REF was observed. 2) Microbial genes linked to butyrate, nitric oxide and polyphenol were significantly decreased in HTN. Gene products of all these were shown to have important implications in cardiovascular diseases. Thus, our observations suggest that targeting of gut and its microbiota can offer a novel strategy for hypertension control.
Abstract P225: Non-invasive Measurement of Renal Blood Flow (RBF) in Different Rat Models by Magnetic Resonance Imaging (MRI)
Authors: Romero Cesar A , Knight Robert , Cabral Glauber , Carretero Oscar A
Published: July 2021

Quantitative measure of RBF provides important information regarding renal physiology and pathology, in different animal’s models. Arterial Spin Labelling-MRI (ASL-MRI) is a non-invasive method to measure blood flow without exogenous contrast media, using arterial water protons labeled by radiofrequency as an endogenous tracer. However, the low signal/noise radio, and the motion artifacts are a challenge for the acquisition of RBF in small animals. Our objective is evaluated the feasibility and reproducibility of the RBF measure by ASL-MRI in different hypertensive rats models. ASL-MRI images were obtained in Sprague-Dawley (SD) rats (200-300g) under inhalation anesthesia using a 7 Tesla Varian MRI system with a spin echo imaging sequence. After 4 days the MRI studies was repeated to evaluate reproducibility, using paired sample T-test and the test-retest reliability (TR) equation. RBF was also measured in in Dahl SS rats on regular chow and spontaneous hypertensive rats (SHR). Additionally we measure the RBF in a set of animals under unilateral nephrectomy (UNx) and renal arterial stenosis (RS) before and after the surgery. Table 1 shows the mean cortical RBF in different rat strains and models. Re-test analysis showed no relevant differences, being the means of differences 9.4±35 ml/min/100g tissue (p=0.58) in SD rats. The TR was 92.4±6%. UNx increase the RBF in 69.1% in comparison with sham group. (p<0.01). After the RS the blood pressure increased and the RBF decrease 56% (p<0.01) in comparison with sham group. ASL-MRI performed with navigator correction and respiratory gating is a feasible and reproducible non-invasive method to measure RBF in several rat models.
Abstract P231: Offspring of Captopril Treated Spontaneously Hypertensive Rats Have Lower Angiotensin II Type 1 Receptor Expression Which is Associated With Lower Blood Pressure
Authors: Masjoan-Juncos J X , Liao Tang-Dong , Bordcoch Ginette , Romero Cesar A , Carretero Oscar A
Published: July 2021

It has been reported that SHR rats receiving angiotensin converting enzyme (ACE) inhibitor Captopril decrease blood pressure (BP) in at least two generation after the treatment was stopped. A decreased response to an intracerebroventricular infusion angiotensin I and angiotensin II in treated animals and their offspring was reported; however there is no reported mechanism that explains the changes observed in the untreated offspring of the Captopril treated animals. We hypothesize that captopril reduces angiotensin II type 1 receptor (AT1R) expression in CNS of the offspring of SHR rats treated with captopril. Animal groups are as follows: control animals, captopril treated animals, offspring of the control animals, offspring of the treated animals where the mother was removed from the treatment immediately after giving birth and Offspring of treated animals where the mother was removed from the treatment at weaning. BP was measured by intra-arterial method and Tail cuff. AT1R expression was measured in brain tissue using the posterior wall of the forth ventricle, as well as the top half of the brain stem. BP was different between treated groups and their offspring vs. control (Table 1). AT1R expression was significantly reduced in both offspring groups of the treated animals, when compared to control (Table 1). Therefore we conclude that captopril reduces blood pressure in the offspring of captopril treated SHR rats and that associates with a decrease in AT1R expression in CNS. Further research is necessary to determine the possible epigenetic mechanisms involved in AT1R reduction.
Abstract P242: Nicotinic Acetylcholine Receptor Subunit α7 is Protective Against Angiotensin II-induced Aneurysm and Hypertension
Authors: Khan Nayaab S , Mavropoulos Spyros , Ojamaa Kaie
Published: July 2021

Alpha7 nicotinic acetylcholine receptor (α7 nAChR), an integral component of the cholinergic nervous system is known to mediate cholinergic anti-inflammatory activity in various disease models such as sepsis, stroke and neurocognitive disorders. We report for the first time that the α7 nAChR
-/-
deficient mouse serves as a novel model of hypertension and aneurysm formation. Seven month old male WT and α7 nAChR
-/-
mice weighing 28-33g were infused with low dose Ang II (350 ng/kg/min) or high dose (700 ng/kg/min) or vehicle for 15 days using mini-osmotic pumps (Alzet, model 2004) implanted subcutaneously. Blood pressure (BP) was recorded on day 0,3,7,10 and 14. Mice were euthanized on day 15. Heart and body weights were measured, histological analysis was performed on the aortas and immune profile of peripheral blood was analyzed by flow cytometry. High dose Ang II resulted in 70% mortality from aneurysm rupture in α7 nAChR
-/-
mice starting as early as the 4
th
day of infusion. While cardiac hypertrophy was not observed, low dose Ang II resulted in a sharp rise in blood pressure in α7 nAChR
-/-
beginning on the 3
rd
day to 167±3.7 mmHg compared to 138±3.3 mmHg in WT treated mice. On day14 of low dose treatment, BP in α7 nAChR
-/-
rose to 171±4.2 vs.135±3.1 in WT mice. No changes were observed in BP of untreated WT or α7 nAChR
-/-
animals. Histological analysis revealed high grade aneurysm in aortas of α7 nAChR
-/-
mice treated with low dose Ang II, demonstrating a prominent germinal center within the false lumen and fibrous desmoplastic stroma. Increased infiltration of CD11B
+
monocytes, and myeloperoxidase
+
stained neutrophils were observed in these aortas but not in the aortas of similarly treated WT mice. Flow cytometric analysis showed 27% ± 3.9 CD11B
+
/CD45
+
circulating monocytes and 48% ± 0.8 Ly6G
+
/CD45
+
neutrophils in α7 nAChR
-/-
vs. 19% ± 3 monocytes and 11.85% ± 2.9 neutrophils in WT mice. No differences in the levels of circulating immune cells were observed in untreated mice of either genotype. These data support a protective role of α7 nAChR in hypertension and aneurysm, potentially acting through its cholinergic anti-inflammatory activity. The α7 nAChR
-/-
mouse may serve as a new genetic model of aneurysm relevant in studies of the human disease.
Abstract P251: Relationship Between Reactive Hyperemia Index in Patients with Coronary Artery Disease With the Cardiac Function and Prognosis
Authors: Tianhu Liu , Chaoping Yu , Fengcheng Xu
Published: July 2021

Objective:
To investigate the relationship between reactive hyperemia index(RHI) in patients with coronary heart disease (CHD) with the cardiac function and prognosis, intervention so as to provide guidance for coronary heart disease severity and prognosis assessment.

Methods:
500 cases of volunteers had coronary artery angiography by Judkins method in our hospital. coronary angiography showing one or more quarantine branch of coronary artery stenosis lower than 50% or more were taken as the standard for coronary heart disease diagnosis, and the volunteers were divided into CHD group (n=81) and health group (n=419). RHI and left ventricular ejection fraction (LVEF) of two groups were detected. The CHD group were followed up for 1 year and survival prognosis and cardiovascular events prognosis of the patients were statistically analyzed and the relationship between RHI and LVEF, cardiovascular events rate and mortality were analyzed.

Results:
Compared with health group, RHI and LVEF of CHD group were lower (
P
<0. 05). RHI of patient in CHD group with LVEF ≥ 50% were higher than that of patient with LVEF < 50% (
P
<0. 05). Pearson correlation analysis results showed that RHI and LVEF of CHD patients were positively correlated (r=0.827,
P
<0. 05). Coronary heart disease group were followed up for 1 year and the cardiovascular events rates and mortality rates were 28.40% and 9.88% respectively, and RHI and LVEF of patient with cardiovascular events were lower than that of patients without coronary heart disease, and RHI and LVEF of death patients were also lower than that of survived patients (
P
<0. 05). Spearman unconditionally correlation analysis results showed that the RHI and cardiovascular events and mortality in patients with CHD are negatively correlated (r=-0.794, -0.762,
P
<0. 05).

Conclusion:
RHI in CHD patients is lower and closely related to the cardiac function and prognosis, this may be related to RHI reflecting endothelial function and endothelial function damage of CHD associating with disease development, therefore, RHI may be reference indicators of disease severity and prognosis assessment of CHD.
Abstract P256: Vasopressin Infusion During Pregnancy in Mice Induces Early Histological Placental Phenotypes of Preeclampsia
Authors: Sandgren Jeremy A , Gibson-Corley Katherine N , Linggonegoro Danny W , Perschbacher Katherine J , Zhang Shao Yang , Scroggins Sabrina M , Deng Guorui , Pearson Nicole A , Santillan Donna A , Pierce Gary L , Santillan Mark K , Sigmund Curt D , Grobe Justin L
Published: July 2021

Human preeclampsia (PE) is associated with elevated secretion of arginine vasopressin (AVP), and chronic infusion of AVP into pregnant mice is sufficient to model PE by causing hypertension, renal glomerular endotheliosis, proteinuria, fetal placental hypoxia, and growth restriction. Early stages of PE are associated with defective trophoblast invasion of maternal spiral arteries, leading to decreased artery diameter and placental oxygenation. AVP infusion (24 ng/hr, sc) into pregnant mice caused placental hypoxia (chromatin-bound HIF1α on gestational day (GD)17.5; saline n=5, 0.31±0.01; AVP n=5, 0.34±0.01 AU, p<0.05) and reduced placental growth factor mRNA (n=18, 1.0 (0.7-1.3) vs n=21, 0.3 (0.2-0.4) fold (1 se), p<0.05). Therefore, we performed histological analyses of placentas collected from mice at GD12.5 infused with saline or AVP, with the hypothesis that AVP leads to early placental PE phenotypes. Similar to effects on GD17.5, this preliminary cohort demonstrated increased urine protein content (n=7, 27±3 vs n=13, 44±3, g/L p<0.05) and mid-gestational systolic blood pressure (-7.6±3.1 vs +3.5±2.2, mmHg p<0.05), similar fetal (75±7 vs 78±4 mg, p=0.75) and placental (83±10 vs 81±4 mg, p=0.80) masses, and similar changes in heart rate (+37±16 vs +39±12 bpm, p=0.93). GD12.5 placentas were then stained with haemotoxylin and eosin or immunostained for cytokeratin-8 to examine morphological changes induced by AVP. AVP infusion had no significant effects on labyrinth (saline n=3, 647±25 vs AVP n=7, 602±35 um, p=0.45), spongiotrophoblast (342±19 vs 363±24 um, p=0.61), or decidua (622±47 vs 520±47 um, p=0.24) layer thicknesses. AVP caused a reduction in average maximum spiral artery diameter (171±28 vs 121±8 um, p<0.05) and a trend toward reduced total spiral artery number (8.4±2.9 vs 4.9±0.7, p=0.13), but no difference in the maximum invasion depth of CK8-positive trophoblasts (310±50 vs 286±37 um, p=0.72). We conclude that AVP infusion is sufficient to induce cardinal mid-gestational features of PE in pregnant mice, including reduced spiral artery diameter. Such morphological changes may be associated with the placental hypoxia and reduced placental growth factor expression in model.
Abstract P259: Characterization of Hyperandrogenemic Female Rats With History of Pregnancy
Authors: Patil Chetan N , Dalmasso Carolina , Maranon Rodrigo O , Reckelhoff Jane F
Published: July 2021

Women with polycystic ovarian syndrome (PCOS) experience hyperandrogenemia, elevated MAP, irregular menses, and difficulty becoming pregnant. As a result many PCOS women undergo assisted fertilization. The long-term cardiovascular consequences of pregnancy in PCOS women are not clear. We tested the hypothesis that a single pregnancy attenuates cardio-renal parameters in hyperandrogenemic female rats, a model of PCOS. Female SD rats were implanted with Dihydrotestosterone (DHT, 7.5mg/90d; replaced every 85 d) or placebo pellets, beginning at 6 wks of age. At 3 months females were paired with SD males. After delivery and lactation, females were divided into placebo (PL) or DHT rats with (P) or without pregnancy (NP) and allowed to age to 10 mos (still estrous cycling) or 16 mos (post cycling) (n=5-8/grp). At 10 mos, body weight (BW), proteinuria (UPrV), and MAP were higher in DHT than PL rats, and pregnancy history had little effect. At 16 mos, BW was higher in DHT than PL rats, and was similar in NP and P groups. UPrV and MAP were also higher in DHT groups than PL, but were significantly attenuated in DHT-P vs DHT-NP. These data suggest that pregnancy in women with PCOS may be cardiovascular protective with aging. The mechanisms remain to be determined.

a, p<0.05 vs PL-NP; b, p<0.05 vs PL-P; c, p<0.05 vs DHT-NP, mean ± SEM, two-way ANOVA.

Supported by NIH-R01HL66072, PO1HL51971 (JFR).
Abstract P264: Endothelial-specific Interference With PPARγ Activity in Offspring Born From AVP-induced Preeclamptic Pregnancies Has Cardio-renal and Metabolic Consequences
Authors: Nair Anand R , Mukohda Masashi , Agbor Larry N , Lu Ko-Ting , Wu Jing , Sandgren Jeremy A , Grobe Justin L , Sigmund Curt D
Published: July 2021

Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor known to regulate metabolic and vascular function. Mutations in PPARγ result in hypertension, and synthetic agonists of PPARγ reduce blood pressure. Previously we found that mice expressing dominant-negative (DN) PPARγ driven by an endothelium-specific promoter (E-DN) exhibit vascular dysfunction. Preeclampsia (PE) is a hypertensive disorder of pregnancy which carries cardiovascular and metabolic risk to offspring. PE is associated with vascular dysfunction, and we therefore hypothesized a role for endothelial PPARγ in the pathogenesis of PE and its sequelae. C57BL/6J dams were bred with E-DN sires, and symptoms of PE were induced by the infusion of vasopressin (AVP, 24 ng/hr sc) throughout gestation. We assessed phenotypes of PE first in pregnant dams, and then in offspring as adults. Compared to saline infusion (SAL), AVP elevated maternal blood pressure (SBP: 116±3 vs 107±3, p<0.05) at gestational day (GD) 14-15 and urine protein (70±6 vs 27±4 mg/mL, p<0.05) at GD17. Offspring from these pregnancies were phenotyped in adulthood to assess cardiovascular and metabolic function. Data were stratified to sex, genotype, and maternal exposure to AVP vs SAL. Systolic blood pressure in adult male and female offspring born to AVP-infused pregnancies was similar to mice born to SAL pregnancies. At 20 weeks of age, vasorelaxation responses to acetylcholine were not different in offspring exposed to PE compared to mice born from SAL pregnancies. However, urinary protein levels were significantly elevated in both male (58±13 vs 32±5 mg/ml, p<0.05) and female (38±3 vs 25±2 mg/ml, p<0.05) adult E-DN born to PE pregnancies compared to E-DN controls born from SAL pregnancies. Male E-DN offspring exposed to PE showed significantly increased gain in body weight over time compared to male NT exposed to PE (ΔBW: 20±8 vs 14±2 g). These data highlight the impact of
in utero
exposure to elevated AVP upon cardiovascular function in the mother, and the adverse renal and metabolic consequences of PE upon offspring. Moreover, our data suggests that interference with endothelial PPARγ in pups born from PE pregnancies increases the risk for renal and metabolic dysfunction.
Abstract P269: Circulating Factors in Response to Placental Ischemia Cause Vascular Endothelial Mitochondrial Oxidative Stress
Authors: Vaka Venkata Ramana , McMaster Kristen M , Cunningham Mark W , Ibrahim Tarek , Amaral Lorena M , Cornelius Denise , LaMarca Babbette
Published: July 2021

Introduction:
Preeclampsia (PE) is associated with placental ischemia, new onset hypertension, oxidative stress and endothelial dysfunction. Factors linking placental ischemia with endothelial dysfunction and hypertension are not completely understood. Mitochondrial (mt) dysfunction (dys) is a major source of reactive oxygen species (ROS) and we have shown that placental ischemia causes oxidative stress in RUPP rats. We hypothesize that circulating factors in RUPP rats cause vascular endothelial mt dys and mt ROS as a contributor to endothelial dysfunction and hypertension during pregnancy.

Methods:
Female Sprague Dawley rats were dived into two groups; normal pregnant (NP) and RUPP rats. On gestational day (GD) 14, RUPP surgery was performed, GD18 carotid catheters were inserted, and GD19 conscious blood pressure (MAP) was measured. GD 19 placentas were collected and mitochondria were isolated for respiration and ROS measurements. Mt ROS was measured spectrophotometrically in HUVECs incubated with 10% serum from NP or RUPP rats using MitoSox Red.

Results:
MAP was elevated in RUPP (n=9) compared to NP rats (n=9) (122±2 vs. 104±2 mmHg, p<0.05). State 3 (313±16 vs 423±15 pmol/sec/mg, p<0.05) and maximal (244±13 vs 300±11 pmol/sec/mg, p<0.05) respiration rates were significantly reduced in placental mitochondria from RUPP (n=7) vs NP (n=8) rats. RUPP placental mitochondria show 35-fold increase in ROS production compared NP mitochondria (p<0.05). HUVECs incubated with RUPP (n=7) serum showed significantly increased ROS vs NP (n=7) serum (9±3 vs 3±1, % gated, p=0.05).

Conclusion:
Reduced placental mitochondrial respiration and increased mt ROS support the hypothesis that mt dys and mt ROS occurs in response to placental ischemia. Importantly, increased ROS from endothelial cells in response to RUPP serum indicate the importance of circulating factors to cause vascular mt dyst and mt ROS.
Abstract P279: Mapping of Chromosome 2 Differentially Expressed Aortic Genes Linked to Vascular Inflammation Using Congenic Rats Fed a High-salt Diet
Authors: Berillo Olga , Ouerd Sofiane , Huo Ku-Geng , Richer Chantal , Sinnett Daniel , Kwitek Anne E , Paradis Pierre , Schiffrin Ernesto L
Published: July 2021

Background:
Three congenic rat strains (SB2a, SB2b and SB2e) were created by chromosome (Chr) 2 fragment introgression from normotensive Brown Norway (BN) rats into hypertensive Dahl salt sensitive (SS) background. SB2a and SB2b rats fed a normal-salt diet presented reduced blood pressure (BP) and inflammation when compared to SS rats. We hypothesized that BN-Chr2 contains antihypertensive and anti-inflammatory genes that could prevent high-salt diet (HSD)-induced BP elevation and vascular injury in SB2a and SB2b rats. These genes will be identified using microRNA (miRNA) and total RNA expression profiling analysis in aorta of congenic rats fed a HSD.

Methods and Results:
Four-to-6 week-old male SS, SS, SB2a and SB2b rats were fed a HSD (4% NaCl) for 8 weeks or until they developed a stroke as manifested by seizures. Systolic blood pressure (SBP) was measured by telemetry. Systolic BP was higher in SB2b but not SB2a when compared to SS (185±8, 167±7 vs 168±5 mm Hg). Total RNA was extracted from aorta and used to construct libraries for small and total RNA sequencing using Illumina HiSeq-2500. The bioinformatics pipeline included: FastQC for quality control, STAR for genome (Rattus norvegicus, release-86) alignment, mirdeep2 for miRNA annotation and counting, Htseq-count for mRNA and long non-coding RNA annotation and counting; R for differential expression analysis. Differentially expressed miRNAs and genes (mRNAs and non-coding RNAs) were identified in SB2a vs SS (miRNAs: 11 up and 10 down; genes: 92 up and 91 down) and in SB2b vs SS (miRNAs: 3 up and 2 down; genes: 10 up and 13 down) with FDR<0.05. Differentially expressed genes encoded within different BN-Chr2 congenic portions were identified in SB2a vs SS (genes: 7 up and 2 down) and SB2b vs SS (genes: 6 up and 4 down).

Conclusions and Perspectives:
Differentially expressed BN-Chr2 encoded genes were identified in aorta of congenic SB2a and SB2b rats fed HSD. Whether these genes play a role in HSD-induced BP elevation and vascular inflammation remains to be determined.
Abstract P282: Low Dose LNAME Causes Salt Sensitive Hypertension via Activation of NCC
Authors: Wang Conghui , Latapati Reheman , Ogura Sayoko , Koid Suangsuang , Mori Fumiko , Shimosawa Tastuo
Published: July 2021

Background:
Blood pressure is regulated both by vascular resistance and blood volume. Our group recently clarified norepinephrine activates sodium channel (sodium chloride cotransporter: NCC) via epigenetic modulation (Nat Med 2011). The accumulating data strongly suggest that vasoactive substances are not only act on vasculature but also effect on sodium homeostasis. We hypothesized that blockade of nitric oxide synthesis by L-NAME has a direct effect on sodium channels in the kidney.

Method:
C57BL/6J Mice were treated with 8%NaCl (high salt; HS) or 8%NaCl +L-NAME (0.7mg/10ml). Blood pressure was measured by telemetry. After 4 weeks’ treatment, the function of sodium channel was monitored by pharmacologically and molecular biologically. mDCT cell was used to observe the direct effect of L-NAME on NCC.

Result:
Low dose L-NAME or high salt loading alone did not change blood pressure in the C57BL/6J mouse, but L-NAME shifted the pressure natriuresis curve toward the right and induced salt-sensitive hypertension in HS group. No significant changes were observed in morphological changes in the kidney. However, significant changes of sodium and chloride excretion were observed after hydrochlorothiazide challenge test but not in amiloride test, which was consistent with increases in membrane NCC. This highly suggested NCC, not ENaC was activated by L-NAME to cause salt-sensitive hypertension. To determine whether L-NAME active NCC directly or not, we treated mDCT cells with L-NAME. The membrane NCC expression was increased in a time and dose depended manner.

Conclusion:
Low dose L-NAME inappropriately and directly activate NCC in both vivo and vitro, and finally induces salt-sensitive hypertension.