bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 237: Breastfeeding is Not Associated With Worse Outcomes for Women With Peripartum Cardiomyopathy
Authors: Kawamoto Kris , Langen Elizabeth , Jackson Elizabeth A , Davis Melinda
Published: June 2021

Background:
Women diagnosed with peripartum cardiomyopathy (PPCM) are frequently advised not to breastfeed their infants because of concern that the nursing hormone prolactin drives the pathogenesis of PPCM. However, this remains controversial. We sought to determine whether women with PPCM who breastfed had lower rates of recovery.

Methods:
Patients with PPCM at the University of Michigan (2000-2011) were retrospectively reviewed. Demographics, clinical data, and outcomes were collected. Questionnaires requesting information about breastfeeding status and duration were mailed to women with PPCM. This data was correlated with recovery status, defined as left ventricular ejection fraction ≥ 50% at 1 year after diagnosis.

Results:
Of 27 women with PPCM with known breastfeeding status, 13 women breastfed (48%) and 14 did not (52%). Among women who breastfed, 8 recovered (62%) and 5 did not (38%). Among women who did not breastfeed, 11 recovered (79%) and 3 did not (21%). This was not statistically different (p=0.29). There were no significant differences between breastfeeding and non-breastfeeding women related to their mean age or treatment with heart failure medications. Of the 16 patients who completed additional survey questionnaires, 11 (69%) reported their physician had instructed them not to breastfeed.

Conclusions:
Contrary to some expert opinions, breastfeeding was not associated with lack of recovery. While larger prospective studies are needed to clarify this conclusion, it appears that a diagnosis of PPCM should not be an absolute contraindication to breastfeeding.
Abstract 245: Demonstrating the Effectiveness of an Outpatient Occupational Therapy Program for Individuals with Heart Failure
Authors: Carroll Olivia , Nxumalo Kristin , Bennett Amber , Pike Whitney
Published: June 2021

Objective:
To demonstrate the effectiveness of an outpatient occupational therapy program on improving self-care for individuals with heart failure.

Background:
Hospitalizations for heart failure (HF) are the largest Medicare expenditure, and 12% of these admissions are considered preventable. Effective self-management of the debilitating symptoms associated with HF (shortness of breath, fatigue, fluid retention, cognitive decline) helps keep patients out of the hospital. Individuals often experience difficulty incorporating self-care management activities into their daily lives. Occupational therapy (OT) is well suited to address the self-care needs of people with HF by increasing patient self-efficacy and facilitating lifestyle modification through the incorporation of new habits, roles, and routines.

Methods:
Participants with HF (n=11, ages 40-86) enrolled in an outpatient OT program focusing on self-care management. Participants received weekly, bi-weekly or monthly one-hour treatments over a six-month period. Sessions addressed the following topics: low sodium diet adherence, medication management, activity tolerance, symptom monitoring and psychosocial coping strategies. The Self-Care of Heart Failure Index (SCHFI) was administered at evaluation and upon completion of the program. The SCHFI is a reliable and valid assessment tool that measures self-care maintenance, management and confidence in people with HF.

Results:
All participants who received two or more treatments demonstrated 33.33% (16.67 of 49.99) to 190.01% (63.33 of 33.33) improvement in maintenance of self-care routines based on pre and post SCHFI scores. Additionally, half of these participants demonstrated 28.47% (22.16 of 77.84) to 85.33% (38.4 of 45) improvement in confidence with self-care management based on pre and post SCHFI scores.

Conclusion:
Participation in an outpatient OT program that focused on incorporating lifestyle modifications into daily routines was effective at improving self-care for people with HF, specifically maintenance of self-care routines and confidence with ability to self-manage their chronic condition.
Abstract 248: Mortality and Readmission After Acute Myocardial Infarction in the Department of Veterans Affairs Health Care System
Authors: Hess Paul L , Gunzburger Elise C , Liu Chuan-Fen , Jones Jacqueline , Matlock Daniel D , Heidenreich Paul A , Levy Cari R , Maddox Thomas M , Grunwald Gary K , Ho P. Michael
Published: June 2021

Background:
Little contemporary data about the performance of Veterans Affairs (VA) hospitals related to mortality and readmission rates after an acute myocardial infarction (MI) are available. Accordingly, we sought to characterize the rates of in-hospital and 30-day mortality and 30-day unplanned readmission after an acute MI as well as associated site-level variation.

Methods:
Using data from the External Peer Review Program, which abstracts data from the records of all patients admitted with an acute MI, linked with administrative data from the Corporate Data Warehouse, we performed an observational analysis of patients admitted with an acute MI from January 1, 2011, to February 28, 2014.

Results:
A total of 16,024 patients were admitted with an acute MI; 806 (5.0%) patients died during hospitalization, 1299 (8.1%) died within 30 days of admission, and 2529 (16.9%) had an unplanned hospital readmission. The annual risk-standardized in-hospital mortality rate (Hazard Ratio (HR) 0.90, 95% Credible Interval (CI) 0.83-0.98) and the 30-day mortality rate (HR 0.94, 95% CI 0.88-1.00) but not the unplanned readmission rate (HR 1.00, 95% CI 0.96-1.04) decreased over time (
Figure
). Individual hospital rates for in-hospital mortality, 30-day mortality, and 30-day unplanned readmission were comparable to the system-wide rates, with little variation between hospitals.

Conclusions:
In Veterans Affairs hospitals from 2011 to 2014, in-hospital and 30-day mortality but not 30-day unplanned readmissions rates declined over time. Little site-level variation in mortality or readmission rates was observed.
Abstract 252: Trust in the Medical Profession is Associated with Medication Adherence and Health-Related Quality of Life in Hispanic Adults with Hypertension
Authors: Meltzer Lilia S , Hays Ron D
Published: June 2021

Background:
Nonadherence to blood pressure lowering medication is a main contributor to poor hypertension control. While trust in the medical profession has been found to be associated with health behaviors such as treatment adherence, it has rarely been examined in Hispanics with hypertension and its relationship with health-related quality of life (HRQOL) is unknown.

Objective:
We evaluated a priori hypotheses positing that trust in the medical profession would be associated with greater medication adherence, resilience, and, in turn, better HRQOL in patients with hypertension. The three specific aims of this study were to: 1) examine the overall association (total effect) of trust in the medical profession and HRQOL (self-reported physical and mental health); 2) assess whether the association of trust with HRQOL is mediated by medication adherence and resilience; and 3) evaluate whether these associations vary by ethnicity (Hispanic vs. non-Hispanic).

Methods:
A cross-sectional survey that included the PROMIS® global physical and mental health scales and Morisky Medication Adherence Scale-8 was conducted with 201 adults (101 Hispanics and 100 non-Hispanics) under treatment for hypertension at a practice with seven cardiologists. A structural equation model was estimated to examine hypothesized associations (direct and indirect effects) among variables. Model fit was assessed via the chi-square statistic and three fit indices (Root Mean Square Error of Approximation; Comparative Fit Index; Non-Normed Fit Index).

Results:
The proposed model fit the data well and explained 37% of the variance in mental health and 15% of the variance in physical health. Trust was positively associated with physical health (β = 0.32,
P
< 0.001) and mental health (β = 0.43,
P
< 0.001). Trust was also positively associated with resilience (β = 0.18,
P
< 0.05), and medication adherence (β = 0.25,
P
< 0.05). Resilience was not significantly associated with physical health, but it was positively associated with mental health (β = 0.34,
P
< 0.001). Medication adherence was not significantly associated with either physical or mental health. Additionally, resilience partially mediated the relationship between trust and physical and mental health. And medication adherence partially mediated the relationship between trust and mental health, but did not significantly mediate the relationship between trust and physical health. A simultaneous group analysis indicated that Hispanic ethnicity did not moderate the associations between trust, medication adherence, resilience, and HRQOL.

Conclusions:
Findings suggest that trust in the medical profession serves as a protective mechanism for improving health in patients with hypertension by enhancing medication adherence, resilience, and global health irrespective of Hispanic ethnicity.
Abstract 259: Two Readily Obtainable Measures of Patient-reported Adherence and Their Association With Anticoagulation Control
Authors: Sevilla-Cazes Jonathan , Finkleman Brian S , Chen Jinbo , Brensinger Colleen M , Epstein Andrew E , Streiff Michael B , Kimmel Stephen E
Published: June 2021

Introduction:
Despite the emergence of new effective anticoagulation therapies, the prevention of thromboembolic events remains challenging in cases of poor medication adherence. Unfortunately, clinical prediction of future adherence has been suboptimal and electronic adherence measures are impractical. The inability of clinicians to easily and accurately identify poorly adherent patients has been an obstacle to the delivery of quality care. We examined two measures of real-time, self-reported adherence among warfarin treated patients to determine if these could be used to explain level of anticoagulation control.

Methods:
The IN-RANGE2 Cohort recruited patients initiating warfarin therapy in 3 urban anticoagulation clinics. At each study visit, participants reported adherence using a 100-point Visual Analogue Scale (VAS, marking % of pills taken since prior visit on a linear scale) and 7-day recall of pill taking behavior before their current INR was revealed. Anticoagulation control was measured by between visit time in therapeutic INR range (BVTR), dichotomized at the cohort median. The longitudinal association between these adherence measurements and anticoagulation control was estimated using generalized estimating equations, controlling for clinical and demographic characteristics, prior BVTR, and warfarin dose changes.

Results:
A total of 598 participants with 3204 (median 4) visits were studied. The median BVTR was 36.8% (interquartile range 0-73.9%). Mean VAS score was 96.6% (standard deviation 5.8), with participants reporting less than or equal to 80% adherence in 182 (5.7%) visits; missed pills in the past 7 days were reported in 308 (11.8%) visits. Multivariate regression analysis found poorer anticoagulation control (BVTR<36.8%) in those with a VAS score less than or equal to 80% (odds ratio [OR] 1.89, 95% confidence interval [CI] 1.12-3.18, p=0.02) and self-report of a change in adherence since last visit using 7-day recall (OR 1.55, 95% CI 1.20-2.01, p=0.001).

Conclusion:
Self-reported VAS medication adherence at a clinic visit and changes in reported adherence since the last visit are independently associated with BVTR. Incorporating information from both the VAS and changes in 7-day pill recall into clinical practice could improve the quality of anticoagulation management, by helping clinicians identify poorly adherent patients who might benefit from specialized interventions. Because the association is independent of knowing the prior BVTR, these findings may be translatable to direct oral anticoagulant, medications that are not easily monitored with laboratory testing.
Abstract 002: Adoptive Transfer of CD8 T Cells With Constitutively Active Pi3kγ Induces Hypertension in Mice
Authors: Carnevale Daniela , Piacenti Maria , Cifelli Giuseppe , Iacobucci Roberta , Lembo Giuseppe
Published: June 2021

In the field of research exploring the connection existing between hypertension and immune system, CD8 effector T cells emerge as the possible mediators of target organ colonization. In the absence of overt inflammation or pathogen response, naïve T cells circulate from the blood into secondary lymphoid organs, where, upon challenge, become activated. Then, they differentiate into effector T cells, which display typical activation patterns. However, less is known about the intracellular signaling pathways that are responsible for the acquisition of effectors functions in T cells. The p110γ isoform of the PI3K family has unique features, being crucially involved in the immune and cardiovascular systems. On this issue, we have described that PI3Kγ has a crucial role in blood pressure regulation, being KO mice protected from AngII-induced hypertension. Moreover, we found that mice with a constitutively active PI3Kγ isoform (CAAX mice) were spontaneously hypertensive (SBP: CAAX 135 ± 3 vs WT 105 ± 4 mmHg, p<0.001). Interestingly, PI3Kγ is known to play a selective role in regulating the migration of effector CD8 T cells, even though there was no effect of PI3Kγ in naïve T cells. Thus we explored the possible involvement of PI3Kγ in the crosstalk between hypertension and immunity. CAAX mice displayed a significant infiltration of activated CD8
+
CD69
+
T cells in kidney, as compared to WT mice (10.2 ± 2.1 vs 2.8 ± 0.6 *10
4
cells/kidney, p<0.01). At the functional level, this phenotype was associated with enlarged Bowman’s spaces and fibrosis in the kidney of CAAX mice, leading to disruption of renal function, as shown by later development of proteinuria. In the end, to demonstrate whether the CAAX hypertensive phenotype, associated to renal damage after CD8 colonization, could be ascribed to the overactivation of PI3Kγ signaling in this immune cell type, we performed an adoptive transfer of CD8 T cells isolated from CAAX mice in WT mice. Strikingly we found that CD8 T cells with constitutively active PI3Kγ were effective to induce hypertension in naïve mice. These data suggest that in the development of hypertension, PI3Kγ signaling in CD8 T cells is crucial for their accumulation in the kidney, likely contributing to increase in blood pressure by altering renal function.
Abstract 006: Let-7b Mirna Down-regulates Cytochrome P450 Epoxygenase Ii High Fat Diet-induced Obesity
Authors: Elmarakby Ahmed A , Katary Mohamed A , Ibrahim Ahmed S , Baban Babak , Al-Shabrawey Mohamed
Published: June 2021

Obesity-induced vascular inflammation is an early pathological change for the development of diabetic nephropathy. Studies have previously demonstrated that high fat diet (HFD) treatment decreased cytochrome P450 epoxygenase-mediated epoxyeicosatrienoic acids (EETs) production which in turn triggers vascular dysfunction and renal inflammation. We hypothesize that HFD up-regulates let-7b miRNA to decrease epoxgenase-mediated EETs production triggering vascular dysfunction and renal injury. Injection of let-7b mimetic has let-7b (1 nmol/day i.v) into rats decreased renal and hepatic cyp2c23 and cyp2j epoxygenases expression (P< 0.05). To determine whether high fat diet up-regulates let-7b to decrease EETs production, we use sEH gene (Ephx2) knock-out mice (KO) as a model for high EETs availability as EETs are rapidly hydrolyzed by the soluble epoxide hydrolase (sEH) to less active metabolites. WT and Ephx2 (-/-) mice were fed normal (ND, 14% fat) or HFD (60 % fat) for 3 months. HFD treatment was associated with 2 fold up-regulation of renal let-7b miRNA and this effect was coincided with down-regulation of cyp2c44 and cyp2j epoxygenases and decreased EETs levels. Decreased EETs levels in HFD fed rats was also associated with significant podocyte loss and elevation in podocalyxin excretion (56±4 ng/day) when compared to rats fed ND (33±7 ng/day) and these changes were significantly reduced in Ephx2 (-/-) mice. Furthermore, HFD treatment markedly elevated T helper cells expressing inflammatory IL-17 (CD3+CD4+TH17+) and decreased anti-inflammatory regulatory T cells (Tregs, CD3+CD4+FOXP3+) when compared to ND and these changes were also significantly attenuated in Ephx2 (-/-) mice. In-vitro, treatment of cultured glomerular endothelial cells with palmitate (200 μM) for 48 hours increased let-7b miRNA expression and decreased cyp2J mRNA and the tight junction protein ZO-1 expression levels and these changes were significantly reduced by transfecting cells with let-7b inhibitor (50 nM). Our data suggest that up-regulation of let-7b miRNA decreases epoxygenase-mediated EETs production to trigger vascular dysfunction and inflammation in the kidney of obese mice via shifting T cells polarization to favor inflammatory Th17 cells activation.
Abstract 015: Immunosuppression Attenuates Intrarenal Angiotensinogen Augmentation in Angiotensin II Dependent Hypertension
Authors: Satou Ryousuke , Franco Martha G , Katsurada Akemi , Miyata Kayoko , Navar L G
Published: June 2021

Augmented intrarenal angiotensinogen (AGT) is a critical contributor to activation of intrarenal renin-angiotensin system (RAS) leading to the development of hypertension and associated kidney injury. It has been shown that treatment with mycophenolate mofetil (MMF), an immunosuppressive drug, mitigates the increased intrarenal angiotensin (Ang) II levels and blood pressure in hypertensive animal models, suggesting that an activated immune system mediates intrarenal RAS activation and consequent hypertension. Associated macrophage (MΦ) infiltration augments pro-inflammatory cytokine levels including interleukin-6 (IL-6), which plays a crucial role in augmentation of AGT expression in cultured renal proximal tubular cells. Accordingly, this study was performed to establish pathophysiological relevance for the effects of stimulated MΦ and IL-6 on intrarenal AGT augmentation in Ang II-dependent hypertension. Ang II (80 ng/min) was infused with/without daily MMF administration (50 ng/kg) to Sprague-Dawley rats for 2 weeks. Mean arterial pressure (MAP) in Ang II infused rats was slightly higher (169.7±6.1 mmHg) than MAP in Ang II+MMF group (154.7±2.0 mmHg) which was not statistically different than in control group. The augmentation of urinary AGT and urinary protein by Ang II infusion was attenuated by MMF treatment (AGT, control: 89.3±25.2, Ang II: 1,194±305.1, and Ang II+MMF: 389±192.0 ng/day). Importantly, the augmentation of urinary AGT by Ang II infusion was observed before the onset of proteinuria. Urinary 8-isoprostane levels were not altered by Ang II and/or MMF during the 2-week treatments. MMF treatment suppressed Ang II-induced renal MΦ infiltration and IL-6 elevation (IL-6 mRNA, Ang II: 32.4±7.5 and Ang II+MMF: 3.6±1.7, ratio to control). qRT-PCR, western blot and immunohistochemistry revealed elevated intrarenal AGT mRNA and protein levels in Ang II infused rats which were normalized by the MMF treatment (AGT mRNA, Ang II: 2.5±0.2 and Ang II+MMF: 1.5±0.1, ratio to control). These results indicate that stimulated IL-6 production in infiltrated MΦ contributes to intrarenal AGT augmentation in early stages of Ang II-dependent hypertension, which contributes to the development of kidney injury.
Abstract 018: Afferent-targeted Renal Denervation Attenuates Established Deoxycorticosterone-salt Hypertension: A Central Role for Renal Afferent Nerves in Hypertension?
Authors: Banek Christopher T , Van Helden Dusty , Asirvatham-Jeyaraj Ninitha , Osborn John W
Published: June 2021

Cardiovascular disease (CVD) remains the most pervasive cause of death worldwide. High arterial pressure, or hypertension (HTN), is the highest risk factor for CVD morbidity and mortality. Increased peripheral and renal sympathetic nerve activity (SNA) is hypothesized to be a primary contributor to HTN etiology. Moreover, recent clinical and experimental studies show total renal denervation (T-RDNx), may reverse the HTN; however, the contribution of afferent and efferent renal nerves in this effect is unknown. We have recently reported T-RDNx and afferent-specific denervation (A-RDNx) identically attenuated the development of deoxycorticostereone acetate (DOCA)-salt hypertension. However, the efficacy of T-RDNx and A-RDNx to reverse the established phase of this model of HTN is unknown. Therefore, the present study tested the hypothesis that A-RDNx and T-RDNx would similarly decrease the mean arterial pressure (MAP) in DOCA-salt rats with established HTN. Twenty-four male Sprague Dawley rats (275-300g) instrumented with radiotelemeters were administered DOCA (100mg, s.c.) and 0.9% saline to drink
ad libitum
for 35 days. On day 21 of DOCA-salt, rats underwent T-RDNx (n=9), A-RDNx (n=9), or sham (n=6) treatments. MAP was monitored for an additional 14 days. Neurogenic pressor activity (NPA) was assessed 14 days after treatment by measuring the MAP response to acute ganglionic blockade (hexamethonium, 30mg/kg, i.p.). Data was analyzed with a one-way ANOVA with Bonferroni post-hoc test (α=0.05). Data presented as mean ± SEM. MAP was similar across all groups prior to treatment on Day 21 of DOCA-salt (Sham: 165±6; T-RDNx: 164±3; A-RDNx: 162±7mmHg). Whereas Sham had no effect (-2±3) on MAP 14 days after treatment, both RDNx treatments decreased MAP by approximately 20 mmHg (T-RDNx -18±8; A-RDNx -22±5). NPA 14 days after treatment in Sham rats was -97±12mmHg. This response was reduced by nearly half in both T-RDNx (-50±9mmHg) and A-RDNx (-48±4mmHg) groups. We conclude from these findings that: 1) RDNx is effective in treating the established phase of DOCA-salt hypertension, 2) the MAP response to RDNx is mediated by ablation of afferent renal nerves, and 3) the antihypertensive response to RDNx is mediated by a decrease global neurogenic pressor activity.
Abstract 022: Blood Pressure-Lowering Effect of Local Passive Heat in Autonomic Failure Patients with Supine Hypertension
Authors: Okamoto Luis E , Celedonio Jorge E , Gamboa Alfredo , Shibao Cyndya A , Raj Satish R , Diedrich Andre , Paranjape Sachin , Black Bonnie K , Robertson David , Crandall Craig C , Biaggioni Italo
Published: June 2021

Primary autonomic failure (AF) is characterized by disabling orthostatic hypotension that is acutely worsened by environmental heat. Given that about half of AF patients have paradoxical supine hypertension, we hypothesized that controlled local passive heat would lower supine blood pressure (BP) in these patients. Fourteen AF patients with supine hypertension (age 71±2 years, 9 men, systolic BP 172±6 mmHg) were randomized to receive passive heat (40-42°C, commercial heating pad over abdomen and pelvis) and sham control for up to 2 hours in a 2-day crossover study. Hemodynamic parameters and core body and skin temperatures were measured in the supine position. The heating pad increased abdominal skin temperature to 40.8±0.4°C and 40.1±0.3°C after 1 and 2 hours of passive heat (vs 35.2±0.2°C and 35.1±0.4°C in sham controls). Core body temperature increased after 1 hour (by 0.2±0.1°C [to 36.9±0.8°C] vs 0.0°C [36.7±0.1°C] in sham controls; P=0.04) and 2 hours (by 0.4±0.1°C [to 37.2±0.1°C] vs 0.1±0.03°C [to 36.8±0.1°C] in sham controls; P=0.04). Systolic BP decreased during heat stress compared to sham control (P<0.01 by mixed-effects model) with a maximal reduction at 1.7 hours of -26±5 mmHg (Figure). This BP drop was due to a decrease in cardiac output (-30±5% vs sham -5±3%; P=0.02) and stroke volume (-29±5% vs sham -6±3%; P<0.01). Systemic vascular resistance and heart rate were similar in both groups. In conclusion, low levels of local passive heat had a BP-lowering effect in AF patients with supine hypertension presumably due to an uncompensated decrease in central blood volume. The therapeutic application of this approach needs to be addressed in future studies.
Abstract 026: Role of Tank in the Regulation of Pathological Cardiac Hypertrophy
Authors: Li Hongliang , Zhang Peng
Published: June 2021

TRAF associated NF-κB activator (TANK) is adaptor protein which was identified as a negative regulator of TRAF-, TBK1- and IKKi-mediated signal transduction through its interaction with them. Besides its important roles in the regulation of immune response, it has been reported that TANK contributes to the development of autoimmune nephritis and osteoclastogenesis. However, its functions in cardiovascular diseases especially cardiac hypertrophy is largely unknown. In the present study, we interestingly observed that TNAK expression is increased by 240% in human hypertrophic cardiomyopathy(HCM)tissue and 320% in mouse hypertrophic heart after aortic banding (AB), indicating that TANK may be involved in the pathogenesis of this diseases. Subsequently, cardiac-specific TANK knockout (TANK-KO) and transgenic(TANK-TG)mice were generated and subjected to AB for 4 to 8 weeks. Our results demonstrated that TANK deficiency prevented against cardiac hypertrophy and fibrosis induced by pressure overload,as evidenced by that the cardiomyocytes enlargement and fibrosis formation was reduced by about 34% and 43% compared with WT mice, respectively. Conversely, TANK-TG mice showed an aggravated effect on cardiac hypertrophy in response to pressure overload with 36% and 47% increase of cardiomyocytes enlargement and fibrosis formation compared with non-transgenic mice. More importantly, in vitro experiments further revealed that TANK overexpression which was mediated by adenovirus in the cardiomyocytes dramatically increased the cell size and the expression of hypertrophic markers, whereas TANK knockdown had an opposite function. Mechanistically, we discovered that AKT signaling was activated (230%) in the hearts of TANK-TG mice, while being greatly reduced in TNAK-KO hearts after aortic banding. Moreover, blocking AKT/GSK3β signaling with a pharmacological AKT inhibitor reversed cardiac dysfunction of TANK-TG mice. Collectively, our data show that TNAK acts as a novel regulator of pathological cardiac hypertrophy and may be a promising therapeutic targets.
Abstract 036: Mitoprotection Preserves the Cytoskeleton and Alleviates Myocardial Injury in Early Swine Metabolic Syndrome
Authors: Yuan Fang , Woollard John R , Jordan Kyra L , Lerman Amir , Lerman Lilach O , Eirin Alfonso
Published: June 2021

Background:
The mechanisms responsible for cardiac injury in the early stage of metabolic syndrome (MetS) remain unknown. Mitochondria are intimately associated with myofibrils, where the cytoskeleton functions as a linkage coordinator. We hypothesized that early MetS is characterized by cytoskeletal-mitochondrial disorganization, and that mitoprotection with mitochondria-targeted peptides (MTP) would preserve cytoskeletal-mitochondrial structure and attenuate myocardial injury in early swine MetS.

Methods:
Pigs were studied after 16wks of diet-induced MetS, MetS treated for the last 4wks with the MTP Elamipretide (0.1mg/kg SC q.d), and Lean controls (n=6 each). Cardiac function (multidetector CT) was assessed in-vivo, and mitochondrial structure (electron microscopy), the mitochondrial inner membrane phospholipid cardiolipin (mass spectrometry), cytoskeletal proteins, oxidative stress, and apoptosis ex-vivo.

Results:
MetS pigs developed hypertension and insulin resistance, yet cardiac function was preserved. MetS induced loss of desmin and tubulin that was paralleled by mitochondrial disorganization, decreased 18:2 cardiolipin, and increased oxidative stress and apoptosis. MTP slightly improved cardiolipin species profile, restored mitochondrial organization, and upregulated cytoskeletal proteins, attenuating apoptosis and oxidative stress.

Conclusion:
Early MetS leads to disorganization of the cardiomyocyte cytoskeletal- mitochondrial architecture and cardiac injury. MTP may provide a novel therapeutic potential for improving cardiac injury in early MetS, and potentially preventing future deterioration in cardiac function.
Abstract 039: Adipocyte (pro)renin-receptor is a Master Regulator of Adipocyte Differentiation
Authors: Yiannikouris Frederique B
Published: June 2021

Previous findings from our laboratory have demonstrated that adipocyte (pro)renin receptor deficiency induced profound metabolic disturbances leading to lipodystrophy, liver steatosis and increased in blood pressure. The purpose of the study was to determine whether adipocyte (pro)renin receptor (PRR) deficiency leads to similar physiological consequences when the deletion of adipocyte PRR is induced at adulthood. Male mice expressing an inducible adipocyte-specific Cre under the control of the adiponectin promotor (C57BL/6-Tg (Adipoq-cre/ERT2)1Soff/J, Jackson Laboratory, USA) were bred to female

PRR
fl/fl

mice (n=4-5 mice/ group). Control (

PRR
f/Y
)

and inducible adipocyte-PRR-deficient mice (

PRR
adi-CreERT/y

) were fed a standard diet. At 8 weeks of age, control and

PRR
adi-CreERT/y

mice were injected intraperitonally on 5 consecutive days with tamoxifen (40 mg/kg of tamoxifen in sunflower oil). The expression of PRR gene was significantly decreased in adipose tissue of

PRR
adi-CreERT/y

mice compared with control mice confirming the efficacy of the deletion. Preliminary data suggest that the body weights were slightly but not significantly decreased in

PRR
adi-CreERT/y

mice compared to control mice (

PRR
f/Y
:

29±3g;

PRR
adi-CreERT/y
: 27

±1g). White adipose tissue and fat masses were significantly reduced in

PRR
adi-CreERT/y

mice compared with control mice (

PRR
f/Y
:

0.97±0.12g;

PRR
adi-CreERT/y
:0.24

±0.07g). Brown adipose tissue (BAT) weights were not different between

PRR
adi-CreERT/y

and control mice (BAT:

PRR
f/Y
:

0.18±0.07g;

PRR
adi-CreERT/y
:0.13

±0.01g). Liver weights were not significantly different between

PRR
adi-CreERT/y

and control mice (Liver:

PRR
f/Y
::

1.6±0.2g;

PRR
adi-CreERT/y
:1.7

±0.1g) suggesting the absence of hepatic steatosis. Gene expression analysis in white adipose tissues revealed a downregulation of genes involved in adipocyte differentiation (CREB, PPARγ, CEBPα and CEBPβ) and lipid synthesis and trafficking (FAS and CD36) confirming the specificity of PRR to regulate adipocyte differentiation in white adipose tissue. Our data suggest that PRR is a master regulator of adipocyte differentiation. The expression of gene of the renin angiotensin system and blood pressure are currently under investigation.
Abstract 041: mTORC1 is Required for Leptin-induced Sympathetic Activation to the Kidney but Not Brown Adipose Tissue
Authors: Bell Balyssa B , Morgan Donald A , Rahmouni Kamal
Published: June 2021

The adipocyte-derived hormone leptin plays a critical role in the regulation of energy homeostasis through its action in the brain to decrease food intake and promote energy expenditure by increasing sympathetic nerve activity (SNA) to the thermogenic brown adipose tissue (BAT). Leptin also increases SNA to cardiovascular organs including the kidney and raises arterial pressure. However, it is unclear whether leptin controls regional SNA via conserved or distinct molecular mechanisms. Multiple intracellular pathways have been associated with leptin signaling including the mechanistic target of rapamycin complex 1 (mTORC1), which has been proposed as a critical determinant of leptin action. Here, we assessed the contribution of mTORC1 signaling to leptin-evoked regional sympathetic activation. Simultaneous multifiber recording of renal and BAT SNA in anesthetized C57BL/6J mice showed that intracerebroventricular (ICV) administration of leptin (2μg, n=5) increased both renal (170±34%) and BAT (208±37%) SNA. Interestingly, ICV pre-treatment with the mTORC1 inhibitor (rapamycin, 5ng, n=6) abolished the leptin-induced increase in renal (10±6%, P<0.05 vs controls) but not BAT (226±31%) SNA. Next, we used conditional knockout mice that lack the critical mTORC1 subunit, Raptor, specifically in leptin receptor (LRb)-expressing cells (LRb
Cre
/Raptor
fl/fl
) to determine the long-term effects of disrupting mTORC1 signaling on leptin-evoked increase in regional SNA. We confirmed the inability of leptin to activate mTORC1 signaling in LRb-expressing cells of LRb
Cre
/Raptor
fl/fl
mice relative to controls using immunohistochemical staining of phosphorylated ribosomal S6, a downstream target of mTORC1. We observed a significant increase in renal SNA in response to ICV leptin in control mice (127±16%, n=9), but not in LRb
Cre
/Raptor
fl/fl
mice (-4±15%, n=9, P<0.05 vs controls). Conversely, ICV leptin-induced increase in BAT SNA was not different in LRb
Cre
/Raptor
fl/fl
mice (109±27%, n=5) vs. littermate controls (173±52%, n=4). Our data suggest a critical role for mTORC1 signaling in selectively mediating the cardiovascular sympathetic but not the thermogenic actions of leptin, with important implications for obesity-associated hypertension.
Abstract 052: Direct Correlation Between Blood Pressure and Nephron Endowment in a Genetic Mouse Model of Hypertension
Authors: Didion Sean P , Wang Xuexiang , Garrett Michael R
Published: June 2021

Blood pressure high (BPH2) mice represent a novel genetic mouse model of hypertension that was derived from an 8-way cross of common inbred strains of mice. Mice derived from the original cross were segregated by blood pressure and then inbred to establish distinct mouse lines including the BPH2 line, a normotensive genetic control (blood pressure normal; BPN3) as well as a blood pressure low (BPL1) line. The goal of the present study was to test the hypothesis that the level of blood pressure in BPH2, BPN3, BPL1, and C57Bl/6 (normotensive inbred control) mice correlates with nephron endowment. Systolic blood pressure (SBP) was measured in male BPH2, BPN3, BPL1, and C57BL/6 mice (n=6/group) using tail-cuff plethysmography. SBP in BPH2, BPN3, BPL1, and C57BL/6 mice averaged 152±2, 117±1; 105±4; and 107±3 mm Hg, respectively. SBP was significantly greater (P<0.05) in BPH2 mice compared to the other three groups of mice. In contrast, SBP was found to be similar (P>0.05) between BPL1 and C57BL/6 mice and significantly (P<0.05) lower than that in either BPH2 or BPN3 mice. Total kidney weight/body weight ratios were found to be similar (P>0.05) in BPH2 and BPN3 mice and significantly (P<0.05) higher than that in BPL1 and C57BL/6 mice. Nephron number as assessed by the acid maceration technique revealed that total nephron number in BPH2, BPN3, BPL1, and C57Bl/6 averaged 10,409±285, 25,333±478, 27,300±445 and 22,533±668 nephrons per kidney, respectively. There was an extremely significant correlation (R2=0.779; P<0.0001) between nephron number and systolic blood pressure. These data provide evidence that blood pressure in a genetic mouse model of hypertension correlates with total nephron number. These findings are consistent with the emerging concept that nephron endowment at birth or progressive loss of nephrons with age or disease directly impacts blood pressure. Thus, we suggest that the BPH2 mouse can serve as an important experimental model to investigate the intrinsic relationship between nephron endowment and blood pressure.
Abstract 058: Transforming Growth Factor β1 Antagonizes
Npr1
Expression and Vascular Signaling: Role of Transcription Factor δEF1 Transforming Growth Factor β1 Antagonizes
Npr1
Expression and Vascular Signaling: Role of Transcription Factor δEF1
Authors: Sen Anagha , Kumar Prerna , Lindsey Sarah H , Katakam Prasad V , Bloodworth Meaghan , Pandey Kailash N
Published: June 2021

The objective of the present study was to examine the repressive effect of transforming growth factor beta 1 (TGF-β1) in the regulation of
Npr1
(coding for guanylyl cyclase/natriuretic peptide receptor-A; GC-A/NPRA) gene expression and vascular signaling. The rat thoracic aortic vascular smooth muscle cells (RTASMC) and denuded aortic rings were cultured in Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum and treated with TGF-β1 in a time-and dose-dependent manner. Treatment with TGF-β1 decreased NPRA mRNA and protein levels by 62% (0.42 ± 0.05 vs. control, 0.9 ± 0.02, p < 0.01) and 55% (9603 ± 860 vs. control, 22211 ± 1449, p < 0.01), respectively. TGF-β1 treatment significantly increased delta EF1 (δEF1) protein expression by 2.4-fold (907.9 ± 36.5. vs. control, 378.5 ± 10.3; p < 0.001) and enhanced its recruitment to
Npr1
promoter. TGF-β1-treated RTASMCs and denuded aortic rings showed significant increases in α-smooth muscle actin (α-SMA) and collagen type 1 alpha 2 (COL1A2) protein expression, which were markedly attenuated by ANP treatments. The TGF-β1-pretreated cells showed 2.6-fold increase in α-SMA (control, 1523 ± 143, TGF-β1, 3997 ± 182 and TGF-β1 + ANP, 2172 ± 135) and 3.4-fold increase in COL1A2 (control, 1250 ± 77, TGF-β1, 4234 ± 110 and TGF-β1 + ANP, 1546 ± 57), respectively. In
ex vivo
experiments of denuded-aortic rings, TGF-β1 decreased
Npr1
mRNA and protein levels by 62% (0.39 ± 0.06 vs. control 1.10 ± 0.01) and 70% (2609 ± 69 vs. control 5775 ± 123), respectively, and significantly (p < 0.0) increased the expression of TGF-β1-responsive proteins, namely α-SMA (2.6-fold) and COL1A2 (3.1-fold). Treatment with increasing concentrations of ANP (IC50=6x10
-9
M), relaxed denuded aortic rings contracted with prostaglandin F2α (PGF2α); however, pretreatment with TGF-β1 significantly attenuated ANP-mediated vascular relaxation after PFG2α contraction (ANP-treated, 68.68 ± 9.4 vs. TGF-β1 + ANP-treated 88.85 ± 4.7). The endothelium-intact vessels were not affected by TGF-β1 incubation. Together, the present results suggest that an antagonistic cascade exists between TGF-β1 pathways and ANP/NPRA signaling, which might be critical in the vascular remodeling and regulation of hypertension and cardiovascular homeostasis.
Abstract 060: Tauroursodeoxycholic Acid (TUDCA) Prevents High Salt-Induced Renal Damage in ET
B
Deficient Rats in a Blood Pressure-Independent Manner
Authors: De Miguel Carmen , Sedaka Randee , Abad Andrew , Hobbs Janet L , Pollock David M , Pollock Jennifer S
Published: June 2021

The molecular mechanisms by which the vasoactive peptide endothelin-1 (ET-1) leads to high salt-induced renal damage remain uncertain. These studies were designed to determine if the ET system induces renal damage by increasing renal cellular stress. ET
B
deficient (ET
B
def) and transgenic (TG) control rats were placed on normal (NSD, 1% NaCl) or high salt (HSD, 8% NaCl) diet for 3 weeks, and received daily i.p. injections of the cellular stress reliever tauroursodeoxycholic acid (TUDCA, 400 mg/kg/day) or vehicle. Blood pressure was monitored by telemetry. At the end of the study, renal inflammation, apoptosis and markers of kidney damage were assessed. In ET
B
def rats, HSD significantly increased blood pressure (NSD vs. HSD: 131.2±1.1 vs. 153.9±5.9 mmHg, p<0.05), albuminuria, excretion of cortical tubular injury markers (NSD vs. HSD: KIM-1: 14.2±3.4 vs. 104.1±20.6 pg/day; NGAL: 43.6±17.6 vs. 215.6±27.7 pg/day; n=4-7/group; p<0.05), cortical T cell infiltration (5.7±0.3 vs. 17.4±4.5 CD3
+
cells/field; p<0.05) and cortical apoptosis (4.0±1.0 vs. 18.0±4.2 TUNEL+ cells/field; n=3/group; p<0.05). No changes were seen in TG controls on HSD. TUDCA treatment prevented HSD-induced cortical damage in ET
B
def rats, as indicated by reduced excretion of kidney injury markers (albumin: 2.3±1.5 ng/day; KIM-1: 55.7±13.8 pg/day; NGAL: 114.2±18 pg/day; p<0.05), cortical T cell infiltration (10.8±0.5 CD3
+
cells/field; p<0.05) and cortical tubular apoptosis (1.9±0.3 TUNEL+ cells/field; p<0.05). TUDCA had no effect on renal medullary apoptosis or blood pressure. Nephrin excretion remained elevated in both genotypes despite TUDCA treatment. In conclusion, loss of ET
B
receptor leads to exaggerated salt-mediated renal cortical damage that is attenuated by treatment with TUDCA. These results highlight the protective role of ET
B
receptors against the development of renal damage, especially in renal cortex. Funded by NIH T32 DK007545 to CDM and P01 HL95499 and P01 HL69999 to DMP and JSP.
Abstract 068: Endothelin-1 Exaggerates Type-1 Diabetes-accelerated Atherosclerosis Through NADPH Oxidases 1 and 4
Authors: Ouerd Sofiane , Idris-Khodja Noureddine , Trindade Michelle , Coelho Suellen C , Neves Mario F , Jandeleit-Dahm Karin A , Paradis Pierre , Schiffrin Ernesto L
Published: June 2021

Objective:
NADPH oxidase (NOX) 1 but not NOX4-dependent oxidative stress plays a role in diabetic vascular disease, including atherosclerosis. Endothelin (ET)-1 has been implicated in diabetes-induced vascular complications. We showed that crossing mice overexpressing ET-1 selectively in endothelium (eET-1) with apolipoprotein E knockout (

Apoe
-/-

) mice exaggerated high-fat diet-induced atherosclerosis in part by increasing oxidative stress. We hypothesized that ET-1 overexpression in the endothelium would exaggerate diabetes-accelerated atherosclerosis through a mechanism involving NOX1 but not NOX4.

Methods:
Six-week-old male

Apoe
-/-

mice, eET-1/

Apoe
-/-

and eET-1/

Apoe
-/-

mice deficient in
Nox1
(eET-1/

Apoe
-/-

/

Nox1
y/-

) or
Nox4
(eET-1/

Apoe
-/-

/

Nox4
-/-

) were rendered diabetic with 55 mg/kg/day streptozotocin (STZ) IP injections for 5 days and studied 14 weeks later. Endothelial function and vascular remodeling were assessed in mesenteric arteries (MA) using pressurized myography. Aortic atherosclerotic lesions were quantified using Oil Red O staining. Plasma cholesterol, HDL and triglycerides were measured.

Results:
Diabetic

Apoe
-/-

mice presented an impaired endothelium-dependent vasodilatory response to acetylcholine, which was not observed in diabetic eET-1/

Apoe
-/-

, eET-1/

Apoe
-/-

/

Nox1
y/-

or eET-1/

Apoe
-/-

/

Nox4
-/-

mice (E
max
: 20±6 vs 99±1, 98±1 and 100±0%). ET-1 overexpression caused a 1.8-fold increase in MA media/lumen of diabetic

Apoe
-/-

mice (5.3±0.3 vs 2.9±0.2%), which was further increased 1.2-fold by
Nox4
(6.4±0.3%) but not
Nox1
knockout (5.5±0.3%). ET-1 overexpression exaggerated >2-fold the atherosclerotic lesion area in the aortic sinus in diabetic

Apoe
-/-

mice (plaque area [x10
5
μm
2
]: 5.3±0.5 vs 2.9±0.6), which was reduced ~40% by
Nox1
and
Nox4
knockout (plaque area [x10
5
μm
2
]: 3.3±0.6 and 3.6±0.6). Plasma triglycerides were unaffected by ET-1 overexpression but reduced by
Nox1
(2.2±0.4 vs 3.4±0.3 mmol/L) and
Nox4
knockout (1.8±0.4 mmol/L). Plasma HDL and cholesterol were similar between groups.

Conclusions:
Increased levels of ET-1 exaggerate diabetes-accelerated atherosclerosis through NOX1 and NOX4, despite paradoxically improving endothelium-dependent relaxation in small arteries.
Abstract 070: Discovery of a Novel Class of Endogenous, Small-molecule, Potent, Efficacious and Potassium-sparing Diuretics/Natriuretics with Antihypertensive and Glucosuric Activity
Authors: Jackson Edwin K , Gillespie Delbert G , Mi Zaichuan
Published: June 2021

In vivo, guanine moieties in DNA, RNA, guanine nucleotides or guanosine can undergo nitration (e.g., by peroxynitrite) or hydroxylation (e.g., by superoxide anion) on position 8 of the purine ring. Catabolism of these biomolecules leads to the in vivo production of a diverse group of 8-nitro, 8-amino and 8-hydroxy guanosine and guanine compounds. Since the renal effects of these compounds are entirely unknown, we examined in rats the effects of guanosine, guanine, 8-nitroguanosine, 8-nitroguanine, 8-hydroxyguanosine, 8-hydroxyguanine, 8-hydroxy-2-deoxyguanosine, 8-aminoguanosine and 8-aminoguanine (33 μmoles/kg/min; intravenous infusion for 115 minutes) on excretion of Na
+
, K
+
and glucose. Guanosine, 8-nitroguanosine and 8-hydroxy-2-deoxyguanosine had minimal activity. Guanine, 8-nitroguanine, 8-hydroxyguanosine and 8-hydroxyguanine had moderate natriuretic activity (increased sodium excretion by 9.4-fold, 7.8-fold, 7.1-fold and 8.6-fold, respectively). In contrast, 8-aminoguanosine (n=6) and 8-aminoguanine (n=6) were highly efficacious and increased Na
+
excretion by 26.6-fold (from 5.13 ± 2.16 to 136.44 ± 20.14 μmoles/30 min) and 17.2-fold (from 4.38 ± 2.00 to 75.28 ± 23.37 μmoles/30 min), respectively. 8-Aminoguanosine and 8-aminoguanine also increased glucose excretion by 12.1-fold (from 36.68 ± 11.22 to 445.11 ± 63.78 μg/30 min) and 12.2-fold (from 31.40 ± 16.70 to 382.68 ± 97.81 μg/30 min), respectively, and decreased K
+
excretion by 69.1% (from 51.11 ± 11.37 to 15.78 ± 2.74 μmoles/30 min) and 71.0% (from 28.57 ± 6.62 to 8.28 ± 2.14 μmoles/30 min), respectively. Radiotelemetry studies demonstrated that 8-aminoguanosine (n=3) and 8-aminoguanine (n=3) in drinking water (5 mg/kg/day) suppressed deoxycorticosterone/salt-induced (DOCA/salt) hypertension. For example, in untreated DOCA/salt rats, MABP increased from 103 ± 4 to 184 ± 9 mm Hg after 65 days of DOCA/salt; whereas in 8-aminoguanosine-treated DOCA/salt rats, MABP increased from 98 ± 2 to 148 ± 9 mm Hg during the same time period. We conclude that 8-aminoguanosine and 8-aminoguanine are endogenous, potent and efficacious K
+
-sparing diuretics/natriuretics that may regulate renal function and blood pressure and may represent a new class of antihypertensive drugs.
Abstract 076: Brain-targeted Bradykinin B1 Receptor Blockade Prevents DOCA-salt Hypertension by Oxidative Stress and ERK1/2 Phosphorylation Mediated Signaling Mechanisms
Authors: Sriramula Srinivas , Lazartigues Eric
Published: June 2021

DOCA-salt hypertension is associated with increased expression of the pro-inflammatory bradykinin B1 receptor (B1R) in the brain. We previously reported that DOCA-salt hypertension is attenuated in global B1R knockout mice. In this study, we further examined the role of B1R within the central nervous system, on hypertension and cardiac hypertrophy, and explored the contribution of downstream signaling mechanisms. DOCA-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of C57Bl6/J male mice produced a significant rise in mean arterial pressure (MAP; telemetry) in these animals (145 ±3 mmHg, n=8, p<0.01). Intracerebroventricular (ICV) infusion of R715 (70 μg/kg/day, 3 weeks), a specific B1R antagonist, attenuated the DOCA-salt-induced hypertension (125 ±3 mmHg, n=8, p<0.01). Moreover, DOCA-salt treatment resulted in cardiac hypertrophy in C57 compared to sham-treated mice (heart weight/tibia length; 9.2 ±0.3
vs.
7.2 ±0.2 mg/mm), which was prevented by B1R blockade with R715 (7.4 ±0.3 mg/mm;
P
<0.01
vs.
DOCA). DOCA-salt-treated mice had increased inflammation (qRT-PCR), as shown by elevated gene expression of TNF, IL-1β and IL-6 (3-, 8- and 5-fold, respectively, n=9, p<0.01
vs.
sham) in the hypothalamic paraventricular nucleus (PVN), which was attenuated in R715-treated mice. C57 mice treated with DOCA-salt showed increased oxidative stress, as indicated by increased gene expression of Nox-2 and iNOS (5- and 15-fold increase, respectively, n=4, p<0.01
vs.
sham) in the PVN which was prevented by central B1R blockade with R715 (1.9- and 4.4-fold increase, respectively, n=4, p<0.01
vs.
DOCA). DOCA-salt-induced increase in PVN Nox-2 protein expression was also prevented by central B1R blockade (2.2
vs.
1.1-fold change, p<0.01). Furthermore, phosphorylation of ERK1/2 was increased in the PVN of DOCA-salt-treated mice (66 ±3 % increase, n=4, p<0.05
vs.
sham), which was blunted in R715 treated mice. Taken together, these data provide evidence that blockade of brain B1R attenuates DOCA-salt-induced hypertensive and hypertrophic effects via oxidative stress and ERK1/2 phosphorylation-mediated signaling mechanisms. (Funding: AHA 15SDG25720021 (SS), NIH/NHLBI (HL093178) (EL), and P30GM106392).