bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P1122: Sympathetic Vasodilation Improves Insulin-Mediated Microvascular Recruitment in the Forearm of Obese Subjects
Authors: Patel Jay N , Celedonio Jorge E , Smith Emily C , Lonce Suzanna , Paranjape Sachin , Okamoto Luis , Biaggioni Italo , Gamboa Alfredo
Published: September 2019

Background:
Obesity is associated with sympathetic activation which results in insulin resistance and a blunted insulin-mediated microvascular recruitment. We propose that removal of sympathetic vasoconstriction can result in improvement of insulin-mediated vasodilation and subsequently in sensitivity to insulin-mediated glucose uptake.

Methods:
We blocked sympathetic vasoconstriction in an isolated forearm model during a hyperinsulinemic euglycemic clamp to determine the effect of insulin recruitment on microvascular circulation using contrast-enhanced ultrasonography (CEU). We studied 9 obese human subjects (age 41±6 years, BMI 37±3 kg*m
-2
, SBP 125±6 mm Hg). We assessed the effects of insulin on microvascular recruitment and glucose uptake on two separate occasions, randomly assigned and at least one month apart, during an intrabrachial infusion of the alpha-adrenergic blocker phentolamine (PHE, 25 micrograms/min, blocked day) or saline (SAL, Control day). Subjects were studied at baseline (BSL) and at the end of the clamp (CLAMP).

Results:
As expected forearm blood flow increased after insulin alone (67±27%, p=0.016) and with alpha blockade and insulin (140± 22%, p=0.0011). Microvascular blood volume (MBV, index of microvascular recruitment), showed a significant increased during PHE compared to SAL (figure). Muscle glucose uptake trended towards increase with PHE but did not reach statistical significance (p=0.0558). There were no systemic effects due to sympathetic blockade.

Conclusions:
This data shows that sympathetic vasoconstriction contributes to the blunted insulin-mediated microvascular recruitment seen in obesity.
Abstract P120: Leukocyte and Lymphocyte-Derived Extracellular Vesicles are Elevated in Angiotensin-Induced Hypertension
Authors: La Salvia Sabrina , Musante Luca , Lannigan Joanne , Carey Robert M , Isakson Brant , Le Thu H , Erdbrügger Uta
Published: September 2019

Infiltration of macrophages and T cells in kidneys and vasculature may play a role in the development of hypertension (HTN) and extracellular vesicles (EVs) have emerged as novel cell-to-cell communicators in the pathogenesis HTN. Immune cell-derived EVs can reflect the pathophysiological activity of the parental cell and mediate immune stimulation or inhibition in paracrine fashion. We investigated subgroups of circulating leukocyte-derived EVs (LEVs) in angiotensin II (Ang II)-induced HTN with or without candesartan (C) or hydralazine, hydrochlorothiazide, and reserpine (HHR).

Ang II was delivered via osmotic mini pumps (500 ng/kg/min; n=15) and with C (10 mg/kg/day, n=5) or HHR (30 mg/kg/day, n=5) in drinking water for 4 weeks to 129S6 mice. Systolic blood pressure (SBP) was measured daily by tail-cuff manometry. After 4 weeks, mice were euthanized and citrated blood collected. EV isolation was performed by differential centrifugation, followed by EV phenotyping with imaging flow cytometry. We used EV surface markers for leukocyte (CD45), T- and B-cells (CD3,CD19), neutrophils (Ly6g+/CD11b-) and monocytes/macrophages (Ly6g-/CD11b+).

Ang II infused mice had significantly higher SBP compared to normotensive controls (NC) (n=5) (173.79 ± 4.9mmHg vs 129.8 ± 6.2mmHg, p <0.0001) and C/HHR treated mice (134.42 ± 7.5mmHg (C) and 138.21 ± 5.2mmHg (HHR), p = NS). Leukocyte-derived EV counts (CD45+ EVs for Ang II: 2.16E+06 particles/ml; NC: 6.15E+05 particles/mL; p=0.0001) and T cell-derived EV counts (CD3+) (Ang II: 2.14E+06 particles/ml, NC: 4.46E+05 particles/mL; p=0.0001] increased after 4 weeks in Ang II-infused mice compared to NC. In C and HHR treated groups, leukocyte- and T cell-derived EV concentrations were similar to NC, suggesting a BP effect rather than drug class effect. CD45+ and CD3+ EV concentrations correlated significantly with SBP [(r2=0.9343; p= 0.0004) and (r2= 0.8982; p= 0.0012), respectively]. In conclusion, leukocyte- and T cell-derived EVs were increased in Ang II-induced HTN and correlated significantly with SBP. Therefore, leukocyte- and T cell-derived EVs are potential bio-markers in HTN. Further studies are required to understand the functional role of leukocyte- and T cell-derived EVs in the pathogenesis of HTN.
Abstract P121: A Novel Delivery of Alpha-Calcitonin Gene Related Peptide (α-CGRP) Using Alginate Microcapsules Protects Against Pressure-Overload Induced Heart Failure
Authors: Kumar Ambrish , Belhaj Marwa , Dipette Donald J , Potts Jay D
Published: September 2019

The cardioprotective role of α-calcitonin gene related peptide (α-CGRP), a 37-amino acid neuropeptide and potent vasodilator, in cardiac diseases has been established by our laboratory and others. Systemic delivery of α-CGRP decreases blood pressure in hypertensive humans, and improves hemodynamic variables in congestive heart failure (CHF) patients. However, the short half-life of the peptide (t
1/2
= ~5.5 min in serum) limits α-CGRP use in any long-term treatment regime. The present study utilized alginate-α-CGRP microcapsules for long-term continuous delivery of α-CGRP in a mouse CHF model. We used an electrospray method to prepare α-CGRP encapsulated alginate microcapsules approximately 200μm in size. The α-CGRP encapsulated microcapsules showed no cytotoxicity when incubated with the cardiac cell lines, HL-1 and H9c2 cells, for 7 days. Subcutaneous administration of microcapsules containing 150, 250, or 500μg α-CGRP lowered the systolic pressure up to 18 h, 3 days, and 7 days, respectively, in wild-type mice (measured by tail-cuff method), indicating that released α-CGRP remains biologically active. The cardioprotective effect of microcapsules released α-CGRP was examined using a transverse aortic constriction (TAC) induced pressure-overload mouse model of CHF. After two days of TAC, 500μl of alginate-α-CGRP microcapsules (containing 150μg α-CGRP) was administered in nine weeks old C57/BL6 mice on alternate days up to 28 days. Echocardiography data showed that microcapsule treatment of α-CGRP significantly preserved left ventricular fraction shortening (FS) and ejection fraction in the TAC mice (FS±SD: sham 47.2±1.5%, sham-alginate-α-CGRP 48.4±1.8%, TAC 29.5±1.4%, and TAC-alginate-α-CGRP 43.2±1.2%). α-CGRP delivery attenuated cardiac hypertrophy in TAC mice when reported as heart wt/tibia length (mg/mm±SD): sham 6.3±0.1, sham-alginate-α-CGRP 6.3±0.2, TAC 8.6±0.3, and TAC-alginate-α-CGRP 6.6±0.2. Alginate-only microcapsules did not affect these cardiac parameters. Our results show that α-CGRP delivery through alginate microcapsules protect hearts from cardiac failure. As alginate is immunologically inactive, the alginate microcapsules offer a new potential delivery paradigm for patients with heart failure.
Abstract P125: Determining Patient and Provider Acceptance of Therapeutic Drug Monitoring to Improve Medication Adherence
Authors: Schesing Kevin , Sharma Shishir , Lodhi Hamza , Wu Bryan , Das Sandeep R , Elwood Bryan , Smith Scott A , Halm Ethan A , Vongpatanasin Wanpen
Published: September 2019

Objective:
Therapeutic drug monitoring (TDM) is the assessment of medication adherence by detection of a drug or its metabolites in blood or urine samples. TDM-guided feedback has been shown to improve medication adherence and subsequent blood pressure (BP) control in patients with resistant hypertension. Herein, we sought to evaluate the attitudes of patients with uncontrolled hypertension as well as their providers towards incorporating TDM in clinical practice.

Methods:
We conducted a qualitative study consisting of in-depth, cognitive interviews in 10 patients seen in Parkland General Cardiology and Internal Medicine Clinics with uncontrolled hypertension. The patients were asked a series of 9 standardized questions to elicit their attitudes towards TDM use in the management of hypertension after informed consent. In addition, 10 providers, including faculty, trainees, and pharmacists, were also interviewed, using the same questionnaire to evaluate their attitudes of incorporating TDM in hypertension management.

Results:
Of the patients interviewed, 90% (9 of 10) were supportive of TDM use in clinical practice. Similarly, 100% (10 of 10) of providers thought TDM was a good idea and should be used regularly. On subsequent questioning, 78% (7 of 9) of patients who felt TDM was a good idea expressed reservation that TDM could negatively impact the physician-patient relationship. Nonetheless, 86% (6 of 7) of these patients felt TDM could be a useful tool to identifying and solving non-adherence of antihypertensive drugs, if providers are mindful of patients’ unique circumstances. Amongst providers, 90% (9 of 10) felt TDM may negatively impact the physician-patient relationship, yet felt TDM could still be useful in addressing non-adherence.

Conclusion:
TDM was found to be well accepted amongst patients and providers, though between 80-90% of patients and providers still had concerns that TDM could negatively impact the physician-patient relationship. However, the majority of patients and providers believed that TDM could be an effective tool in identifying and solving barriers to adherence, if the providers are sensitive to the patients’ specific needs. Our survey suggested feasibility of adopting TDM in improving medication adherence.
Abstract P131: A Selective Chymase Inhibitor, TEI-f00806, Eliminates the Ang II Production From Rat Ang-(1-12) in Bone Marrow Tissue
Authors: Yamashita Tomohisa , Ahmad Sarfaraz , Wright Kendra N , Roberts Drew J , VonCannon Jessica L , Varagic Jasmina , Sun Xuming , Wang Hao , Groban Leanne , Ferrario Carlos M
Published: September 2019

Background:
Rat bone marrow (BM)-chimeric experiments reveal a critical role of locally formed angiotensin II (Ang II) in mediating the oxidant-rich inflammatory milieu associated with cardiovascular disease pathogenesis. Extending our first demonstration of renin angiotensin system (RAS) components in the BM, we recently reported a primary role of chymase rather than angiotensin converting enzyme (ACE) in BM generation of Ang II from the novel substrate angiotensin-(1-12) [Ang-(1-12)]. To verify chymase contribution over other proteases such as cathepsins, Ang-(1-12) metabolism studies in rat BM were carried out in the absence and in the presence of a selective orally active chymase inhibitor (TEI-F00806).

Methods:
Plasma membrane (PM) of BM and left ventricle (LV) tissues were obtained from 12 week-old Sprague Dawley rats following systemic perfusion with phosphate buffered saline with or without the secondary addition of Zamboni’s fixative. PMs were incubated with
125
I-Ang-(1-12) and the metabolic products during incubation were determined by high-performance liquid chromatography. All data were analyzed using GraphPad PRISM 7.0 with P<0.05 to determine statistical significance.

Results:
Assessment of
125
I-Ang-(1-12) hydrolysis in the absence of the chymase inhibitor revealed that chymase activity in BM membranes was 280 fold higher than that in LV (4,531 ± 137 fmol/mg/min and 16.3 ± 0.3 fmol/mg/min, respectively, n = 6, P < 0.001). In the presence of TEI-F00806, 96% of the chymase-mediated Ang II production was inhibited in BM. Confocal microscopy showed chymase-positive but tryptase-negative cells as the most dominant in BM, indicating that stem/progenitor cells rather than mature mast cells might be the source of chymase in BM.

Conclusion:
The current findings demonstrate that BM has tremendously higher chymase-mediated Ang II producing activity from Ang-(1-12) compared to heart tissue. The fact that TEI-00806 inhibited the Ang II producing activity of chymase underscores a tissue-selective enzymatic mechanism for Ang II formation from Ang-(1-12) contributing to the chronic inflammatory processes accompanying the pathogenesis of cardiovascular disease.
Abstract P139: Cytochrome B5 Reductase 3 Biases Activation of Soluble Guanylyl Cyclase in Resistance Arteries
Authors: Durgin Brittany G , Hahn Scott A , De Cabo Rafael , Straub Adam C
Published: September 2019

Soluble guanylyl cyclase (sGC) heme oxidation (Fe
3+
) leading to apo-sGC formation diminishes the ability of nitric oxide (NO) to bind sGC and generate intracellular cGMP levels needed for downstream protein kinase G activation and vessel relaxation. While several studies suggest that pathological oxidative stress drives sGC heme oxidation and apo-sGC formation, we report for the first time that resistance arteries, but not conduit arteries, contain a previously unrecognized pool of heme oxidized and/or apo-sGC in non-stressed conditions that can be activated independent of NO. Specifically, our vascular reactivity studies indicate that systemic resistance and pulmonary arteries are responsive to NO-independent sGC activator BAY 58-2667 at 2-3 log-fold lower concentrations than that of conduit aorta and renal arteries (n=4-5/ vascular bed). Further, mesenteric arteries treated with 1μM MitoTempol, a superoxide dismutase mimetic and mitochondrial anti-oxidant, show a decreased responsiveness to BAY 58-2667 (n=3-5/group). Notably, we have published evidence that cytochrome b5 reductase 3 (CYB5R3) acts as an sGC heme reductase (Fe
3+
-> Fe
2+
) in cultured vascular smooth muscle cells. We recently performed vasoreactivity studies in transgenic CYB5R3 overexpression (OE CYB5R3) mice and show these mice have a significantly decreased responsiveness to BAY 58-2667 compared to controls irrespective of vascular bed (n=4-6/ group). Additionally, OE CYB5R3 mice exhibit a ~7mmHg decrease in pulse pressure and impaired blood pressure reduction in response to an acute injection of BAY 58-2667 as compared to controls (n=5/ group). Combined, these data indicate that mitochondria derived-reactive oxygen species and expression of CYB5R3 serve as a rheostat for modulating sensitivity to sGC activator BAY 58-2667 and vascular responsiveness in resistance arteries. Importantly, these results provide valuable insight into sGC activator therapy for treatment of hypertension and other cardiovascular related diseases.
Abstract P156: Long-Term Blood Pressure Outcomes and Costs Associated With a Barber-Pharmacist Hypertension Intervention: 10-Year Simulation of the Los Angeles Barber Trial
Authors: Bryant Kelsey B , Kazi Dhruv S , Fontil Valy , Penko Joanne , Blyler Ciantel A , Lynch Kathleen , Ebinger Joseph , Moy Norma B , Rader Florian , Bibbins-Domingo Kirsten , Moran Andrew E , Bellows Brandon K
Published: September 2019

Background:
Barber-pharmacist blood pressure (BP) management reduced systolic BP >20 mm Hg compared to education alone over one year in Non-Hispanic (NH) black men with uncontrolled hypertension (HTN) in the Los Angeles BARBER (LA-BARBER) Trial. Long-term BP outcomes and costs of this intervention are unknown.

Objective:
Simulate 10-year BP outcomes and intervention and medication costs of a one-year barber-pharmacist HTN intervention followed by usual care compared to usual care alone.

Methods:
We simulated 1000 LA BARBER-eligible NH black men sampled from the National Health and Nutrition Examination Survey. We used a discrete event simulation version of the validated BP Control Model to predict BP outcomes over 10 years. Model inputs were derived from published literature, national sources, LA-BARBER individual participant data, and interviews with LA-BARBER intervention pharmacists. Medication and intervention (clinical care, travel, and administrative time) costs were calculated from a 2018 US payer perspective and discounted 3% annually. Primary outcomes were percent with BP <130/80 mm Hg, medication and intervention costs, and the cost per patient with BP controlled. We used 100 probabilistic model iterations to examine parameter uncertainty.

Results:
Our calibrated model accurately reproduced baseline characteristics and predicted 1-year BP outcomes of the LA-BARBER study (mean age 54 years, baseline BP 153/91 mm Hg, 69% predicted 1-year BP control with the barber-pharmacist HTN intervention). Over 10 years, 64% of patients (95% uncertainty interval [UI] 61%-67%) were predicted to achieve BP control with the barber-pharmacist HTN intervention compared to 38% (95% UI 26%-48%) with usual care. Projected intervention and medication costs were $8084 (95% UI $7664-$8598) with the barber-pharmacist intervention compared to $4183 ($3514-$4768) with usual care costing $15,000 per controlled patient gained.

Conclusions:
Medication and intervention costs for a barber-pharmacist HTN intervention were about double usual care, but it achieved substantially higher BP control rates. Ongoing research will examine if this strategy meets traditional cost-effectiveness thresholds (e.g.,<$100,000 per quality-adjusted life year).
Abstract P158: Preeminent Role of the Cardiorenal Axis in the Antihypertensive Response to an Arteriovenous Fistula: An
In Silico
Analysis
Authors: Clemmer John S , Pruett W. Andrew , Hester Robert L , Lohmeier Thomas E
Published: September 2019

Percutaneous creation of a small central arteriovenous (AV) fistula is currently being evaluated in clinical trials for the treatment of uncontrolled hypertension (HT). Although the mechanisms that contribute to the antihypertensive effects of the fistula are unclear, investigators have speculated that chronic blood pressure (BP) lowering may be due to: 1) reduced total peripheral resistance (TPR), 2) increased secretion of atrial natriuretic peptide (ANP), and 3) suppression of renal sympathetic nerve activity (RSNA). We used an established integrative mathematical model of human physiology to investigate these possibilities from baseline conditions that mimic sympathetic overactivity and impaired renal function in patients with resistant HT. After simulating a small fistula there were sustained increases in cardiac output, atrial pressures, and plasma ANP concentration (3-fold), without suppression of RSNA; at 8 weeks BP was reduced 14 mmHg along with a 32% fall in TPR. In contrast, when this simulation was repeated while clamping ANP at baseline BP decreased only 4 mmHg, despite a comparable fall in TPR. Further, when chronic resetting of atrial mechanoreceptors was prevented during the fistula RSNA decreased 7% and, along with the same 3-fold increase in ANP, BP fell 19 mmHg. This exaggerated fall in BP occurred with a similar decrease in TPR when compared to the above simulations. These findings suggest that ANP, but not TPR, is a key determinant of long-term BP lowering after an AV fistula and support a contribution of suppressed RSNA if resetting of the atrial-renal reflex is truly incomplete.
Abstract P160: Dual-Specificity Protein Phosphatase 5 Regulates Renal Vessel Myogenic Response via Direct Modulating Extracellular Signal-Related Kinase and Protein Kinase C
Authors: Gao Wenjun , Zhang Huawei , He Xiaochen , Wang Shaoxun , Ya Guo , Booz George W , Roman Richard J , Fan Fan
Published: September 2019

Dual-specificity protein phosphatase 5 (DUSP5) is a serine-threonine phosphatase that regulates intracellular signal transduction by dephosphorylating extracellular signal-related kinase (ERK1/2) and protein kinase C (PKC). We previously reported that knockout (KO) of
Dusp5
enhanced the myogenic response and autoregulation of cerebral and renal circulation in association with increased levels of phosphorylated ERK1/2 (p-ERK1/2) and phosphorylated protein kinase C (p-PKC) in the vessels. However, the influence of increased levels of p-ERK1/2 and p-PKC on vascular function is unknown. This study investigated whether
Dusp5
regulates myogenic reactivity of freshly isolated middle cerebral arteries (MCA, ~140 um), cerebral penetrating arteries (PA, ~15 um), renal arcuate arterioles (AA, ~ 50 um), and interlobular arterioles (IA, ~25 um) of
Dusp5
KO and WT rats via inhibition of ERK1/2 and PKC. The myogenic reactivity of both cerebral and renal vasculature was compared at different perfusion pressure. The inner diameters of IA and AA decreased to 87.24 ± 0.76 % and 92.81 ± 2.90 %, respectively, in
Dusp5
KO rats (n=4), but only to 99.70 ± 2.76 % and 98.85 ± 2.79 %, respectively, in WT rats (n=4) when perfusion pressure was increased from 60 to 180 mmHg. Similar results were found in MCA and PA. Inhibition of ERK1/2 with FR 180204 (1 uM) or PKC with BIM III (300 nM) diminished myogenic reactivity to a greater extent in cerebral and renal vessels of
Dusp5
KO versus WT rats. These results indicate that downregulation of DUSP5 expression increases the myogenic reactivity of both cerebral and renal arteries (both large and small vessels) by increasing p-ERK1/2 and p-PKC levels. Targeting Dusp5 may offer a novel approach for preventing hypertension-induced end-organ damage.
Abstract P164: Sexual Dimorphic Role of CD14 in Dahl SS Hypertension
Authors: Fehrenbach Daniel J , Abais-Battad Justine M , Dasinger John Henry , Lund Hayley , Keppel Theodore , Zemaj Jeylan , Gundry Rebekah L , Geurts Aron M , Dwinell Melinda R , Mattson David L
Published: September 2019

Previous work has implicated the immune system in potentiating salt-sensitive (SS) hypertension and kidney damage in the Dahl SS rat model. The innate immunity protein Cluster of Differentiation 14 (CD14), normally involved in bacterial responses of macrophages, has been associated with hypertension in humans. The present study tests the hypothesis that CD14 influences the extent of high-salt diet induced renal damage and hypertension in the Dahl SS rat, by modulating activation of the innate immune system. CD14 was mutated in the Dahl SS background using CRISPR-Cas9 technology, leading to the loss of CD14 protein in peritoneal macrophages (pMacs) as evidenced by mass spectrometry-based parallel reaction monitoring. pMac stimulation
in vitro
demonstrated altered IL-1β production in CD14-/- animals. To monitor SS phenotypes
in vivo
, male and female CD14+/+ and CD14-/- animals maintained on a 0.4% NaCl diet underwent carotid catheter telemetry implantation at 7 weeks of age (n=12/14). After recovery and baseline recordings, animals were switched to a 4.0% NaCl diet for 21 days. There was no significant difference in the SS increase in blood pressure or albuminuria between genotypes of males. However, female CD14-/- animals demonstrated exacerbated salt-sensitivity of blood pressure (+45mmHg) compared to wild types (+31mmHg). To determine what may mediate this difference, immune cells were isolated from the kidneys of these animals. Accordingly, males showed no difference in immune cell infiltration; whereas, female CD14-/- animals showed an elevation in the infiltration of CD11b/c+ macrophages. To determine whether knockout of CD14 in immune cells specifically was responsible for this phenotypic difference, a lethal dose of total body irradiation (11Gy) of CD14+/+ recipient animals followed by either CD14-/- or CD14+/+ bone marrow transfer experiment was done in female animals (n=6/7). Remarkably, even though all host tissue cells were wildtype, transfer of CD14-/- bone marrow recapitulated the exacerbated SS phenotypes, including increased renal infiltration of macrophages. Together, these data demonstrate that CD14 signaling in hematopoietic cells of females modulates the full extent of the immune response and blunts SS hypertension.
Abstract P165: Vascular Endothelial Exosomes Propogate Inflammation in Vascular Smooth Muscle Cells Through Up-Regulation of HMGB1
Authors: Boyer Michael , Kimura Yayoi , Akiyama Tomoko , Eguchi Satoru , Rizzo Victor
Published: September 2019

Vascular homeostasis is predicated on the integral interaction between a myriad of cell types. Principle to homeostasis is the interaction between the endothelial cells (ECs) of the intima and the vascular smooth muscle cells (VSMCs) of the media. Disruption of the tightly controlled communication between these cell types can lead to development of pathophysiology. In the past decade, much study has been given to a novel means of intercellular communication in exosomes. Exosomes are nanovesicles derived from endosomal compartments capable of carrying functional proteins, small RNAs and lipids into extracellular space. Initially characterized in the field of immunology, little is known on exosomes within vascular biology. Therefore, we present a model through which EC exosomes initiate inflammatory signaling and remodeling within VSMC. Primary rat aortic EC and VSMC exosomes isolated in serum-free conditions displayed characteristic size, shape and protein content of exosomes as analyzed through nanoparticle tracking analysis, electron microscopy, and western blot. Proteomics identified differential expression between EC and VSMC exosomes suggesting altered cargo between the two populations. Incubation of EC exosomes with VSMC identified a dose- and time-dependent increase in the expression of vascular cell adhesion molecule 1 (VCAM1) in VSMC (2.6 fold, p<0.01) and functional increase in leukocyte adhesion (p<0.05), that was a one-way mechanism of EC-VSMC. EC exosomes increased the prevalence of senescence cells (1.62 fold, p<0.05) in VSMC with increases in cellular volume, suggesting a pro-inflammatory remodeling. Unbiased mass spectroscopy on VSMC incubated with EC exosomes derived with/without TNF stimulation identified pro-inflammatory mediator HMGB1 as significantly up-regulated in both conditions. Interestingly, use of HMGB1 inhibitor Glycyrrhizin was able to abolish increase in VCAM1 (p<0.05) and increases in THP-1 adhesion (p<0.05). Identification of HMGB1 was also present in unbiased proteomics performed on EC exosomes themselves. Taken together, this suggests that EC exosomes derived from nutrient-stressed conditions induce inflammatory remodeling and signaling in VSMC through an HMGB1-dependent mechanism.
Abstract P168: Drug-Drug Interactions in Hospitalized Cardiac Patients and It's Clinical Management
Authors: Reddy Kavya
Published: September 2019

Drug Interaction refers to modification of response to one drug by another when they are administered simultaneously or in quick succession, receiving multi drug therapy is a major concern. Polypharmacy is the administration of many drugs at the same time and several drug interactions are desirable and deliberately employed in therapeutics and the severity of drug interactions in most cases is highly unpredictable.

Aim and objectives:
The present study was to identify major DDI’s in patients with cardiovascular disease and assess the various organ systems affected by the DDI’s.

Discussion and Conclusion:
During the study period a total of 80 prescriptions were analysed and it was found that 35 patients had multiple major DDIs. The percentage of DDIs was higher in males 27.77% (25 of 90) than females 11.11% (10 of 90). Clopidogrel: aspirin 27.77% (25 of 90) was the most predominant DDI, followed by Aspirin : Furosemide 22.22% (20 of 90), Heparin : Aspirin 18.88% (17 of 90), Clopidogrel : Heparin 17.77% (16 of 90), Carvediloló Digoxin 3.33% (3 of 90), Ondansetron : Metronidazole 2.22% (2 of 90), Telmisartan : Digoxin 2.22% (2 of 90), Aspirin : Spironolactone 2.22% (2 of 90), Atorvastatin : Diltiazem 1.11% (1 of 90), Heparin : Nitroglycerin 1.11% (1 of 90), Aspirin : Torsemide 1.11% (1 of 90). Bleeding 65.83% (59 of 90) was the commonest clinical consequence followed by Urinary system disorder 25.55% (23 of 90), Heart rate and Rhythm disorders 7.77% (7 of 90), and musuloskeletal disorder 1.11% (1 of 90). There was an ADR identified during the study which was Aspirin : Furosemide induced Grade I renal parenchymal disease. On assessment of DDI’s majority of the cases were classified as major in severity. Atmost care must be taken to optimise the therapy, thereby we can improve the outcome.

Keywords:
Drug Interactions, Nitroglycerin, Heart Rate.
Abstract P172: Is the Elastin Receptor Complex a Bridge Between Perivascular Adipose Tissue and the Artery?
Authors: Weber Paul , Flood Emma , Thompson Janice , Watts Stephanie
Published: September 2019

Elastin is a metabolically stable structural protein with a half-life known to last nearly a lifetime. This supporting peptide is essential for the artery to withstand the repetitive forces of pulsation. Vascular pathology and remodeling cause damage to this critical support system releasing elastin-derived peptides known as elastokines. Elastokines stimulate the Elastin Receptor Complex (ERC) via an Elastin Binding Peptide(EBP). We investigate the hypothesis that the EBP is present within perivascular adipose tissue (PVAT), providing a form of vessel-to-PVAT communication. Immunohistochemistry techniques were used to identify EBP and Neuraminidase-1, components of the ERC, in rat arteries. Additionally, mesenteric resistance vessel PVAT was isolated into adipocytes and stromal vascular fraction for determining the presence of GLB1 mRNA, encoding the EBP. GLB1 mRNA was observed in adipocytes and stromal vascular fraction respectively 2
-delta Ct
0.0220±0.00130 and 0.0237±0.00192 (N=5). EBP and Neuraminidase-1 immunofluorescently colocalized in vasculature and surrounding PVAT (figure 1, representative of N=5, scale bar 50μm). The EBP agonist VGVAPG [10 μM] (N=7) relaxed the isolated aorta to 65.8±1.67% of a half-maximal phenylephrine contraction. These results support the presence of the ERC in arteries, that PVAT may not be necessary for ERC activation, and that elastin may have multiple functions.
Abstract P173: Trimethylamine N-Oxide (TMAO) Impairs Endothelium-Dependent Relaxation of the Mesenteric Artery in Lean and Db/db Mice
Authors: Priviero Fernanda , Dela Justina Vanessa , Arishe Olufunke , Webb Clinton
Published: September 2019

Trimethylamine N-oxide (TMAO) is a gut microbiota-dependent metabolite produced from choline and phosphatidylcholine and it has recently been related to risk for cardiovascular diseases. This study tests the hypothesis that TMAO would contribute to impaired endothelium dependent relaxation in db/db mice. Sixteen week old male lean and db/db mice were euthanized and the small mesenteric arteries (SMA) were mounted in a wire myograph. Concentration response curves to phenylephrine (PE; 1 nM- 30 μM) and acetylcholine (ACh; 1 nM- 30 μM) were performed in the absence or in the presence of TMAO (100 μM - incubated for 30 min) in order to evaluate contraction and endothelium dependent relaxation of the SMA. PE induced similar contractions of the SMA in lean and db/db mice and neither the potency nor the maximal response (E
MAX
)

to PE was affected in the presence of TMAO in both strains. On the other hand, there was a decrease in the potency (pEC
50
: 7.61 ± 0.19 lean; 6.67 ± 0.25 db/db; n=6) and E
MAX
(9.73 ± 0.43 mN lean; 8.41 ± 0.62 mN db/db; n=6) to ACh in the SMA of db/db mice. TMAO led to a decrease the E
MAX
to ACh in both strains (7.52 ± 0.43 and 5.46 ± 0.46, for lean and db/db respectively) and the potency of ACh only in lean mice (pEC
50
: 6.01 ± 0.15 and 6.13 ± 0.24, for lean and db/db respectively) when compared to the respective control in the absence of TMAO. In conclusion, TMAO may contribute to the development of cardiovascular complications by impairing the vascular relaxation.
Abstract P177: The Dissociation of Heart Rate and Blood Pressure Masks the Regulatory Role of Heart Rate in Systemic Hemodynamics
Authors: Anwar Muhammad Absar , Elango Kalaimani , Elsayed Sherif , Ahmed Rahil , Osmond Peter , Izzo Joseph L
Published: September 2019

Blood pressure (BP) and heart rate (HR) are independent cardiovascular risk factors but there is little information about interactions among HR, BP, and systemic hemodynamics throughout the day. We performed 24-hour ambulatory pulse wave analysis (Mobil-O-Graph, IEM, Stolberg, DE) with measurements at 20 minute intervals. Variables measured were: systolic and diastolic BP (SBP and DBP), HR, oscillometric pulse wave velocity (oPWV), stroke volume index (SVI), and total vascular resistance index (TVRI). We also performed regression analyses within-subjects to determine the slopes of the SVI-HR and TVRI-HR relationships within individuals and for the group. We studied 89 individuals (mean age 61 years, weight 84 kg, BP 138/82 mm Hg (38 normal or controlled BP, 51 uncontrolled BP), resting HR 69 beats/min (bpm), 36% non-white, 64% female); 24-hour mean HR was not correlated with corresponding SBP or DBP values (r= -0.013 and r= 0.154, pNS, respectively) and this dissociation persisted in corresponding day-time vs. night-time comparisons and subgroup stratification by BP control status, age, and gender. In contrast, 24-hour mean HR was strongly correlated with 24-hour mean cardiac index (r=0.629, p<0.000) but strongly inversely related to mean 24-hour SVI and TVRI (r= -0.508 and r= -0.505, p<0.000 each); each 10 beat/min change in mean HR was associated with a 2.3 mL/m
2
(6%) change in SVI and a corresponding 6% change in TVRI. Analysis of individual 24-hour studies also revealed no correlations between HR and BP but the within-individual slopes and correlation coefficients between HR and SVI or TVRI were more variable; higher oPWV (which correlated with the SD of SBP, p=.01) was associated with a lesser sensitivity of SVI to HR change and a greater sensitivity of TVRI to HR change (p<0.001 each) independent of age, gender, or BP. We conclude that BP is normally independent of HR, which plays a hidden but important regulatory role in the underlying systemic hemodynamics between and within individuals. The clinical impact of differential sensitivity of systemic hemodynamics to HR change is not established but people with stiffer arteries display diminished SVI sensitivity and greater TVRI sensitivity to HR change, which may contribute to their greater SBP variability.
Abstract P179: Time Restricted Feeding Improves Blood Pressure and Heart Rate Rhythms as Well as Activation of NOS3 and AMP Kinase in Mice on a Chronic High Fat Diet
Authors: Pati Paramita , Zhang Dingguo , Colson Jackson , Sedaka Randee , Young Martin E , Gamble Karen L , Bailey Shannon M , Pollock David M , Pollock Jennifer S
Published: September 2019

Irregular timing of food intake increases cardiometabolic disease and hypertension risk. A chronic high fat diet (HFD) leads to loss of endothelial function and reduced activation of endothelial NO synthase (NOS3). We hypothesized that restricting food availability to the active period in mice on HFD will restore the blood pressure rhythm and NOS3 activation. Mice (male 8-week old, C57BL/6J) were given normal diet (ND; 10% fat) or HFD (45% fat) for 20 weeks ad lib. During the final 2 weeks, food availability was limited to the active phase (restricted feed, RF) in half the HFD mice. Mean arterial pressure (MAP), heart rate (HR), and locomotor activity were measured by telemetry. At the end of the study, 24 hr MAP, HR, and locomotor activity were similar in all groups. However, RF significantly increased the difference in MAP and HR between active and inactive periods in mice on HFD (MAP: ND: 16±0.7 mmHg, HFD: 15±0.8 mmHg, HFD+RF: 18±0.9 mmHg, n=6-8, p=0.01; HR: ND: 68±5.1 bpm, HFD: 69±6.5 bpm, HFD+RF: 113±7.9 bpm, n=6-8, p<0.01). The active-inactive difference in activity was similar in ND, HFD, and HFD+RF (p>0.05). At the end of the study, aorta (Ao) and renal vessels (RV) were isolated in the middle of the active period (ZT17). Western blotting revealed that diet or RF did not affect total NOS3, total Akt kinase (Akt), pAkt(S473), or total AMPK abundance in either vascular bed. pNOS3(S1177) abundance in Ao was improved by RF in HFD mice (ND: 8.5±4.7 rdu, HFD: 0.5±0.2 rdu, HFD+RF: 2.1±0.6 rdu, n=4, p=0.06). RF in HFD mice increased aortic pAMPK(T172) activation at ZT17 but not in renal vessels (Ao: ND: 0.2±0.1 rdu, HFD: 0.2±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=4-5, p=0.01; RV: ND: 0.8±0.2 rdu, HFD: 0.5±0.1 rdu, HFD+RF: 0.7±0.2 rdu, n=5-6, p=0.30). Plasma nitrite was significantly decreased in HFD and HFD+RF mice at ZT17 compared to ND mice (HFD: 0.6±0.04 μM; HFD+RF: 0.7±0.03 μM; ND: 1.4±0.3 μM; n=6, p=0.03). Our findings indicate that RF increases the differences in diurnal MAP and HR as well as increased activation of NOS3 and AMP kinase in mice on a chronic high fat diet. In conclusion, these results suggest that timing of food intake on a HFD improves MAP and HR rhythms possibly via increased activation of NOS3 and AMPK.
Abstract P183: Retinol Binding Protein 7, a PPARγ Target Gene Protects Against Endothelial Dysfunction Induced by Mitochondrial Uncoupling
Authors: Silva Junior Sebastiao D , Nair Anand R , Agbor Larry , Sigmund Curt D
Published: September 2019

PPARγ is a nuclear receptor that prevents oxidative stress in the endothelium. Endothelium specific PPARγ target gene, retinol binding protein 7 (RBP7) is required for the protective effects of PPARγ. In response to a cardiovascular stressor (high fat diet or Ang II), transgenic mice carrying a dominant-negative mutation in PPARγ in the endothelium (E-V290M) and RBP7 knockout mice (RBP7KO) exhibited increased oxidative stress and endothelial dysfunction. We hypothesize that RBP7 has a protective role against endothelial dysfunction induced by the pro-oxidant effects of mitochondrial uncoupling (MU). Acetylcholine (ACh) and sodium nitroprusside (SNP) induced vasodilation response were evaluated in carotid arteries from 4 and 8 month old RBP7KO mice, infused with either saline or a sub-pressor dose of Ang II (120ng/kg/min) for 2 weeks. Ang II infusion did not alter systolic blood pressure either in wild type (WT) (4 months old: 116.2±4.2 vs 113.9±4.1 mmHg; 8 months old: 111.3±3.8 vs 109.5±2.9 mmHg) or RBP7KO (4 months old: 112.9±1.1 vs 111.8±5.2 mmHg; 8 months old: 112.2±4.2 vs 113.9±4.1 mmHg). Endothelium-dependent relaxation to ACh was not affected by Ang II in either RBP7KO (4 month old: % relaxation - saline, 89.7±1.3 vs Ang II, 93.8±2.0; 8 months old: % relaxation - saline, 80.1±6.8 vs Ang II, 74.6±10.6) or WT littermates (4 months old: % relaxation - saline, 98.1±0.3 vs Ang II, 94.5±1.7; 8 months old: % relaxation - saline, 81.4±4.7 vs Ang II, 78.6±10.4). To test if RBP7 plays a role in MU, the vessels were pre-incubated with the MU carbonyl cyanide m-chlorophenyl hydrazone (CCCP; 1uM for 30 min). Pre-incubation with CCCP did not alter the relaxation responses to ACh in 4 month old mice in all groups. However, in 8 month old mice, there is a trend towards impaired endothelial function in the carotid artery from Ang II-infused RBP7KO compared with genotype-matched saline-treated mice (% relaxation: 51.9±3.8 vs 81.8±5.3, p=0.06) as well as Ang II-treated WT mice (% relaxation: 51.9±3.8 vs 77.1±2.0 p=0.08). In conclusion, Ang II alone was not able to impair vascular function, however, in 8 month old mice, Ang II increased the susceptibility to CCCP-dependent endothelial impairment, and RBP7 was required to mediate vascular protection against mitochondrial uncoupling.
Abstract P191: Greater Beat-To-Beat Blood Pressure Variability is Associated With Lower Cognitive Performance Independent of Mean Blood Pressure Among Cigarette Smokers
Authors: Luehrs Rachel E , Linkenmeyer Carinda J , Amaza Hannatu I , Wong Christina , Ward Ryan C , Phillips Gwyneth B , Comellas Alejandro P , Pierce Gary L , Hoth Karin F
Published: September 2019

Introduction:
Cigarette smoking is associated with increased cerebrovascular disease risk and reduced cognitive performance, particularly in domains sensitive to vascular insults, such as executive function and processing speed. Short-term blood pressure variability (BPV) is associated with cognitive decline among older adults with and without hypertension (HTN) and BPV is significantly greater among smokers than non-smokers. However, it is unknown if greater short-term BPV contributes to lower cognitive performance in smokers. We hypothesized that greater beat-to-beat BPV would be associated with lower cognitive performance in smokers and that this relation would be independent of mean blood pressure (BP).

Methods:
Twenty-three smokers (3 current/20 former; age 69 ± 9; pack-years 33 ± 17; systolic BP (SBP) 133 ± 18; diastolic BP (DBP) 71 ± 8; anti-HTN medication use 16Y/7N)), without chronic obstructive pulmonary disease, completed measurements of beat-to beat BPV by 10 minutes of finger plethysmography and electrocardiography, and neuropsychological testing. Age-adjusted neuropsychological test t-scores were grouped into four cognitive domains (executive function, processing speed, language and memory recall).

Results:
Greater systolic BPV was associated with lower cognitive performance in the executive function (r=-0.59, p<0.01), processing speed (r=-0.60, p<0.01) and language (r=-0.49, p<0.01) domains. The associations between systolic BPV with executive function and processing speed remained significant after adjusting for age, sex, pack-years, years of education, mean SBP and anti-HTN medication use (all p<0.05). Similarly, greater mean BPV was associated with lower executive function (r=-0.50 p=0.01), processing speed (r=-0.60, p<0.01) and language (r=-0.59, p<0.01). However, only the association between mean BPV and executive function remained significant after adjusting for age, sex, pack-years, years of education, mean SBP and anti-HTN medication use (p<0.05). There was no association between systolic or mean BPV and memory recall.

Conclusion:
These data suggest that greater beat-to-beat BP variability may contribute to lower cognitive performance in smokers and that this relation is independent of mean SBP.
Abstract P192: Implications of a Simplified Hypertension Screening Approach for Low-and Middle-Income Countries
Authors: Tang Olive , Miller Edgar R , Appel Lawrence , Neupane Dinesh , Lu Yifei , Brady Tammy , Moran Andrew , Dennison-Himmelfarb Cheryl , Matsushita Kunihiro
Published: September 2019

Background:
In low- and middle- income settings, standardized protocols that require triplicate blood pressure (BP) readings pose substantial logistical barriers to hypertension (HTN) screening. We assessed algorithms using fewer measurements.

Methods:
We evaluated the efficiency, % HTN missed and % misdiagnosed as HTN associated with algorithms based on the 1st and/or 2nd measurements. For reference, we defined HTN as recommended by the WHO, i.e. average of 2nd and 3rd BP ≥ 140/90. We focused on 11,999 and 7,382 adults without anti-HTN medication use in Nepal and India, respectively, from May Measurement Month 2017-2018 and contrasted them with 21,751 from the US National Health and Nutrition Examination Survey 1999-2014.

Results:
The prevalence of HTN was 18.8% in Nepal, 27.0% in India, and 10.2% in the US. Using only the 1st BP, 7.8%, 11.7%, and 10.1% of cases would be missed in each country respectively. The % of misdiagnosed HTN would be 9.9%, 9.4%, and 4.2%, respectively. Using a 2nd BP among those with a 1
st
BP ≥ 135/85 (“Two-Step Simple”) missed fewer cases (4.7%, 9.4%, and 7.7%), and misdiagnosed fewer people (2.8%, 3.5%, and 1.6%). Under this approach, 36.3%, 44.1%, and 18.7% would receive a 2
nd
BP reading. Alternative, more complex, algorithms were able to further minimize misclassification and improve efficiency (
Table
).

Conclusions:
Using screening data from Nepal, India, and the US, we found several algorithms based on <3 BP readings had low misclassification rates. These algorithms reduce the total number of measurements by more than half from the standard triplicate protocol and appear to be practical for large-scale screening in resource-constrained settings.
Abstract P195: Overexpression of ACE2 Boosts the Therapeutic Effects of Endothelial Progenitor Cells Derived Exosomes on Hemorrhagic Stroke
Authors: Wang Jinju , Pan Qunwen , Zhao Bin , Ma Xiaotang , Bihl Ji C
Published: September 2019

We have previously demonstrated that angiotensin converting enzyme 2 (ACE2) could boost the therapeutic effects of endothelial progenitor cell (EPCs) on ischemic stroke. Here, we tested whether ACE2 could enhance the effects of EPC derived exosomes (EXs) on intracerebral hemorrhagic stroke (ICH). A bolus of EPC-EXs or ACE2-EPC-EXs (1 x 10
11
EXs/100 ul) labeled with PKH26 was intravenously administrated to ICH mice (C57BL/6) 24 hrs after collagenase (VII-S; 0.075 U/0.5 μl) injection. ACE2 blocker, DCX 600 was used to verify the effects of ACE2. The neurological deficit score (NDS), hemorrhage volume, brain water content, and blood brain barrier (BBB) permeability were measured at day 24 hrs after injection. The levels of ACE2, inflammatory factors in the brain were measured. We found (table): 1) Both EPC-EXs and ACE2-EPC-EXs were dominantly uptaken by the brain endothelial cells, neurons and astrocytes in peri-infarct area; 2) ACE2-EPC-EXswere more effective than EPC-EXs in decreasing hemorrhage volume, brain edema, BBB permeability and improving NDS; 3) As compared to EPC-EXs, ACE2-EPC-EXs resulted in an up-regulation of ACE2, and more down-regulated TNF-α, NFкB, IκBα expressions. 4) DCX 600 could block the protective effects of ACE2-EPC-EXs. The data suggest that infusion of ACE2-EPC-EXsexhibited protective role for anti-inflammatory effect of ACE2 mediating TNF-α/NFкB in mice after ICH.
Abstract P2005: Antioxidant Resveratrol Attenuates Cardiac Fibrosis and Reduces Matrix Metalloproteinase-2 Activity in Heart Failure Rats
Authors: Durand Marina T , Orlandin Caisa B , Bonácio Giselle F , Sanchez Elen R , Durão Marilia P , Lataro Renata M , Ramalho Leandra N , Silva Carlos A , Amaral Jefferson H , Restini Carol B , Salgado Helio C
Published: September 2019

Increased reactive oxygen species activate matrix metalloproteinases (MMP) playing a critical role in cardiovascular remodeling after myocardial infarction (MI). We evaluated the antioxidant effect of resveratrol (RESV) on cardiac remodeling and MMP-2 activity in heart failure (HF) rats. Wistar rats were divided into the following groups: Control; Control+RESV; HF; HF+RESV (10mg/kg/day, p.o., 4 wk). The MI was elicited by ligation of the coronary artery. After four weeks, the animals were anesthetized to evaluate the cardiac function and to collect the hearts and blood samples. Heart weight/body weight (HW/BW, mg/g) ratio and the infarct size were calculated. Histological assessment of the left ventricle was carried out with hematoxylin/eosin, and fibrosis was quantified with Masson trichrome-staining. Cardiac and plasma MMP-2 activities were determined by gel zymography. The oxidative stress was assessed measuring the thiobarbituric acid reactive substances (TBARS) from plasma. HF and HF+RESV showed similar infarct size. The HW/BW ratio increased (3.7±0.2 vs 3.8±0.2 vs 3.0±0.05). RESV improved the maximal slope of the systolic increment of left ventricular pressure in HF animals (9004±1120 vs 5849±595 vs 7181±533 mmHg/s) and reduced the end diastolic pressure (4±1 vs 18±4 vs 7±1 mmHg). HF increased TBARS, whereas RESV produced an antioxidant effect in HF+RESV group (11.2±0.9 vs 21.7±3 vs 8.2±1.4 μmol/L). HF augmented cardiac fibrosis (30,8±1,3 vs 8,8±0,5%) and myocyte hypertrophy (12,2±0,7 vs 8,8±0,3μm). RESV reduced collagen deposition in HF hearts (22,7±1,9%), but did not reduce the myocyte hypertrophy (11,7±0,6 μm). Cardiac and plasma MMP-2 activity were higher in HF animals (plasma: 1344±39 vs. 1164±47; heart: 536±54 vs. 262±18). RESV decreased plasma MMP-2 activity in control (992±27) and HF animals (1200±49) and reduced cardiac MMP-2 activity only in HF+RESV group (426±42). In conclusion, the antioxidant effect of RESV improved cardiac function and fibrosis and reduced MMP-2 levels in the heart and plasma from HF rats.