bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P139: Genetic Signature Of Accelerated Cardiac Fibrosis Due To Trpa1 Ablation
Authors: Ma Shuangtao , Wang Donna
Published: August 2021

While our previous study demonstrated that loss of transient receptor potential ankyrin 1 (
Trpa1
) accelerates age-related cardiac fibrosis in mice, the underlying mechanism of potential anti-fibrotic property of TRPA1 remains largely unknown. TRPA1 is a sensor of oxidative stress and may play a protective role in age-related diseases. In this study, we performed quantitative polymerase chain reaction array analyses of the mRNA expression of 84 fibrosis-related genes in the myocardial tissue of 12-month-old
Trpa1
-/-
mice with significant cardiac fibrosis and age-matched wild-type mice without cardiac fibrosis. The mRNA levels of
Col1a2
and
Col3a1
in the myocardial tissue were similar between
Trpa1
-/-
and wild-type mice, suggesting comparable cardiac collagen synthesis in the two strains. Matrix metalloproteinases are major enzymes responsible for degradation of collagen fibers. The results show that the mRNA levels of matrix metalloproteinases, including
Mmp1a
,
Mmp2
,
Mmp3
,
Mmp8
,
Mmp9
,
Mmp13
, and
Mmp14
, in the heart were similar between
Trpa1
-/-
and wild-type mice. Nevertheless, we identified 7 significantly changed genes in the heart between the two strains. The expression levels of
Acta2
,
Inhbe
,
Ifng
, and
Ccl11
were significantly increased with fold changes of 3.1, 1.9, 1.9, and 1.5 (all
P
< 0.05), respectively, while
Timp3
,
Stat6
, and
Ilk
were significantly decreased with fold changes of 0.3, 0.5, and 0.7 (all
P
< 0.05), respectively, in the heart of
Trpa1
-/-
mice compared with wild-type mice.
Acta2
, the most upregulated gene in
Trpa1
-/-
hearts, is a marker of myofibroblasts. Its upregulation indicates increased differentiation from fibroblasts into myofibroblasts in
Trpa1
-/-
hearts compared with wild-type hearts.
Timp3
, the most downregulated gene in
Trpa1
-/-
hearts, codes an extracellular matrix protein TIMP3, which not only inhibits matrix metalloproteinases but also regulate post-translational modification of collagen fibers. Taken together, these findings suggest that upregulation of
Acta2
and downregulation of
Timp3
may serve as genetic signature or play a role in accelerated age-related cardiac fibrosis due to TRPA1 ablation.
Abstract P144:
Local Signaling And Cardiac Hypertrophy:specificity In The Face Of Pleiotropy
Authors: Aslam Naveed
Published: August 2021

Rationale:
Most likely, the overall myocyte cell growth during the pathological state of cardiac hypertrophy is regulated by a local muscle A-kinase anchoring protein β (mAKAPβ) complex. The mAKAPβ may act as a significant coordinator of myocyte hypertrophic signals. It may critically integrate the hypertrophic signals due to β-adrenergic and leukemia inhibitory factor (LIF)/gp-130 receptor stimulation. Observations suggest that mAKAPβ signalosome may act as a gate-keeper for regulating nuclear factor of activated T cells (NFATc) activity and nuclear localization of this complex might be directly linked to the induction of cardiac hypertrophy. The mAKAPβ complex might function through modulating the profiles of a local cyclic adenosine 3’,5’ monophosphate (cAMP) microdomain at perinuclear region in cardiomyocytes. The acute stimulation of cAMP may be beneficial for the heart, whereas chronic stimulation might cause damage. The transition between the chronic and acute function of cAMP is probably modulated by the ability of myocytes to tightly regulate the cAMP levels in local microdomains across the cell. Any dysfunction in this process may lead to net accumulation and a global rise of cAMP levels, leading to deleterious effects on the heart.

Objective:
cAMP is a single messenger but delivers multiple messages in myocytes. How is this managed? Here, we aim to investigate a key question that how mAKAPβ signalosome might ensure the microdomain specificity despite the pleiotropic nature of the second messenger.

Methods and Results:
Our results may explain how, in the context of hypertrophy, mAKAPβ complex coordinates the interactions between two coupled cAMP-induced feedback loops and LIF-induced activation of the MAPK pathway. Our results may also explain that mAKAPβ complex functions through anchoring protein kinase A (PKA) and ERK5 in the signalosome thus, modulating the bidirectional regulation of phosphodiesterase and hence the control of localized cAMP metabolism as well as the shape and temporal profile of the second messenger in a specific domain.

Conclusion:
Here, we propose a mechanistic model which suggests that stress-induced reprofiling of cAMP flux at discrete cellular locations may lead to cardiovascular disease.
Abstract P146: Sex Differences In The Association Between Systolic Blood Pressure And Carotid Distensibility In Adults
Authors: Shah Mohammad , Tian Jing , BUSCOT Marie-Jeanne , Phan Hoang T , Marwick Thomas , Dwyer Terence , Venn Alison , Gall Seana L
Published: August 2021

Background and Aim:
We explored sex differences in the association between systolic and diastolic blood pressure (SBP), in early adulthood with carotid plaques, carotid IMT and carotid distensibility (CD) in mid-adulthood.

Methods:
Participants in the Childhood Determinants of Adult Health study at ages 26-36 years were followed-up at ages 39-49 years. Systolic BP and diastolic BP and carotid ultrasound measures (plaques, IMT and CD) were performed in clinics. We used log binomial and linear regression models with risk factor*gender interactions for predicting these carotid measures. Sex-stratified models adjusted for sociodemographic, health-related behavior and biomedical factors were fitted when likelihood ratio tests suggested the effect of risk factors on outcomes differed by sex.

Results:
Among 1,286 participants (53% women), men, compared to women, had higher prevalence of carotid plaques (17% vs. 10%), thicker carotid IMT (Mean 0.66 ± 0.09 vs. 0.61 ± 0.07) and lower CD (Mean 1.87 ± 0.60 vs. 2.37 ± 0.77). In women, greater SBP in early adulthood was sharply associated with significantly smaller CD (β -0.016 95%CI -0.023, -0.010 vs. β -0.006 95%CI -0.012, -0.001) than men in mid-adulthood adjusted for sociodemographic factors (Figure 1a). In analyses restricted to women, the effect of SBP on CD has decreased after adjusting for age, education, occupation, DBP and use of contraceptives (β -0.009 95%CI -0.019, 0.000) (Figure 1b).

Conclusion:
CV health was worse in men than women. However, elevated SBP in women put them at greater risk of poorer CV health compared to men, which was partly explained by sociodemographic, biomedical and female-specific factors.
Abstract P149: Rural Residence And Blood Pressure Medication Use In United States Stroke Survivors, 2019 Behavioral Risk Factor Surveillance System Survey
Authors: Tran Phoebe , Tran Lam , Polyakova Inna
Published: August 2021

Background:
Over the last two decades, recurrent stroke rates and hypertension rates have increased significantly in rural US areas. Blood pressure medication use is associated with lower recurrent stroke risk, but information on blood pressure medication use after stroke in rural areas is limited. We sought to compare blood pressure medication use in US stroke survivors living in rural versus urban areas.

Methods:
We identified US stroke survivors with hypertension in the national 2019 Behavioral Risk Factor Surveillance System survey. The survey-weighted prevalence of current blood pressure medication use was determined by rural and urban residence status. Survey-weighted logistic regression was used to calculate unadjusted Odds Ratios (OR) of current blood pressure medication use as well as ORs adjusted for stroke/hypertension related sociodemographic factors. We further stratified blood pressure medication use by other lifestyle factors in rural and urban settings.

Results:
Our study included 51,161 people who had a stroke, of which 18,097 were rural residents (
Table
). In weighted analyses, medication use was comparable for rural and urban residents. Stroke survivors in rural areas had similar odds of medication use as those in urban areas before and after risk-adjustment. Medication use did not vary by smoking status, physical inactivity, and high cholesterol between rural and urban residents.

Conclusions:
Overall, post-stroke blood pressure medication use was high and did not differ by rural/urban status or lifestyle factors. Other factors such as post-discharge care may have a greater impact on recurrent stroke rates in US rural areas.
Abstract P154: Win Ratio Methodology Demonstrates Consistency Of Benefit Across Different Blood Pressure Reduction Thresholds Following Renal Denervation In The Spyral Htn-on Med Pilot Study
Authors: Kandzari David E , Pocock Stuart , Weber Michael A , Boehm Michael , Fahy Martin , Mahfoud Felix
Published: August 2021

Objective:
The win ratio is a statistical methodology to evaluate clinical trial outcomes using multiple hierarchical endpoints. We applied the win ratio to patients in SPYRAL HTN-ON MED pilot study to quantify potential differences in renal denervation (RDN) efficacy utilizing different blood pressure (BP) reduction thresholds.

Methods:
In the SPYRAL HTN-ON MED pilot study, patients were enrolled with office systolic BP (OSBP) ≥150 mmHg and <180 mmHg, office diastolic BP ≥90 mmHg, and mean 24-hour ambulatory systolic BP (ASBP) ≥140 mmHg and <170 mmHg despite 1 to 3 antihypertensive medications. Patients were randomized 1:1 to RDN or sham procedure. For the win ratio analysis, each RDN patient was compared with every sham control patient in the opposing group first according to ASBP to determine “win”, “lose” or “tie” with a threshold of 5 mmHg. Then, ties from the ASBP comparison underwent the comparison using OSBP with a threshold of 10 mmHg. Any tie for a pair comparing OSBP resulted in comparison of any reduction in anti-hypertensive medication burden. The win ratio analysis was repeated using thresholds of 3.5 mmHg for ASBP change, 5 mmHg for OSBP change and any net change in medication burden.

Results:
The calculated win ratio favored RDN: 2.78 (95% CI: 1.58, 5.48, p<0.001), using thresholds of 5 mmHg for ASBP change, 10 mmHg for OSBP change, and any net change in medication burden, all at 6 months. To test the sensitivity of the analysis, the BP thresholds were changed to 3.5 mmHg for ASBP and 5 mmHg for OSBP, and the win ratio analysis was repeated, resulting in a win ratio again in favor of RDN of 2.68 [1.58, 5.00], p<0.001.

Conclusions:
Win ratio methodology applied to the SPYRAL HTN-ON MED pilot study demonstrated that RDN was associated with a 2.6-2.8 times greater likelihood of BP or drug reduction compared with sham patients when evaluated across different BP reduction thresholds at 6 months.
Abstract P155: Etiology And Complications Associated With High-output Heart Failure; A National Readmission Database Study.
Authors: Uddin Mohammed M , Micho Ulbeh Tarec , Mir Tanveer , Sebastian Joseph , Jehangir Qasim , Dixit Priyadarshini , Qureshi Waqas , Soubani Ayman , Afonso Luis
Published: August 2021

Background:
The literature on the etiologies and complications of high-output heart failure (HOHF) is limited.

Objective:
To study the causes and complications related to HOHF in the United States (US).

Methods:
Data from the national readmissions database (NRD) sample that constitutes 49.1% of the stratified sample of all hospitals in the United States, representing more than 95% of the national population were analyzed for hospitalizations with primary diagnosis of HOHF for the years 2017-2018. Etiology associated with HOHF were extracted using ICD-10 codes.

Results:
A total of 2,107 index hospitalizations (mean age 62.2 ± 19.1) with primary diagnosis of HOHF were recorded in the NRD for the years 2017-2018. The most common causes of HOHF include sepsis 204 (9.7%), leukemia 53 (2.5%), arteriovenous fistula 13 (0.6%), liver cirrhosis 155 (7.4%), Hyperthyroidism 133 (6.3%), thalassemia 23 (1.14%), sickle cell disease 71 (3.35%), morbid obesity 188 (8.95%), COPD 406 (19.3%), myeloproliferative disorders 166 (7.87%). Among the HOHF group, major complications include acute ischemic stroke (42 or 2%), acute kidney injury (593 or 28.1%), hypertensive emergency (74 or 3.5%), atrial fibrillation (409 or 19.4%), ventricular tachycardia/fibrillation (77 or 3.7%), and conduction block (81 or 3.8%) and ST-Elevation myocardial infarction (11 or 0.5%). A total of 83 (3.9%) patients had died during the inpatient hospitalization. Out of the remaining 2,024 patients, a significant portion (62 or 3.1%) required readmission within 30 days.

Conclusion:
HOHF is an under-reported cardiovascular complication associated with non-cardiovascular disorders. HOHF is associated with significant 30-day readmissions and mortality rates. Proper management of the underlying etiology can prevent the development of HOHF and associated complications.

Keywords:
cirrhosis; hemodynamics; obesity, leukemia, myeloproliferative disorders, ST-Elevation myocardial infarction (STEMI).
Abstract P164: Risk Factors Of Undiagnosed Diabetes And Hypertension In Arkansas
Authors: Matich Eryn , Zohoori Namvar , Su L. Joseph , Hsu Ping-Ching
Published: August 2021

Introduction:
Hypertension and diabetes are issues in the US especially in the south. In Arkansas, an estimated 797,000 adults have prediabetes and are at risk for diabetes. We aimed to assess cardiometabolic risk factors and impact of nutrition-related indicators in self-identified diabetes and hypertension patients and those at risk.

Method:
Data were analyzed from the 2008 Arkansas Cardiovascular Health Examination Survey (n=1,383), which used probability sampling to obtain a representative sample of Arkansas residents. A self-report survey was administered on health history, socioeconomic status (SES), lifestyle, and diet. Blood biomarkers were measured and compared for those who self-reported diabetes or hypertension with those who were at risk.

Results:
We used t-tests for continuous variables and chi-square test for categorical variables with statistical significance at p<0.05. We hypothesized that participants with undiagnosed diabetes or hypertension had less access to care (SES as a surrogate) and worse health behavior than the diagnosed groups. Significant differences in SES, behaviors, nutrients, and biomarkers were observed between healthy vs. both diagnosed and undiagnosed groups. Surprisingly, we found that undiagnosed groups had higher average food security than the diagnosed groups. Also, some of the health behaviors including alcohol consumption were 5-6 fold higher among the undiagnosed and healthy groups as compared to currently diagnosed diabetes group. Moderate physical activity was about 2 fold higher among the healthy (5.5 hours/week) as compared to undiagnosed hypertension group (3 hours/week). In addition, the currently diagnosed groups seem to have some improved dietary habits based on higher levels of vegetable and fruit consumption and lower blood cholesterol. We have also found that both the healthy and undiagnosed diabetes groups had above normal or high triglyceride levels.

Conclusion:
Undiagnosed diabetes and hypertension do not have serious symptoms, but are dangerous health conditions. From our findings, targeted education should be implemented among all people, especially on access to food, vegetable and fruit consumption, alcohol use, physical activity, cholesterol and triglyceride levels.
Abstract P165: Urinary Amino Acid Profile And Cardiovascular Parameters In Overweight And Obese Brazilian Children
Authors: Passadore Mariana D , Cruz Nayara A , Bocato Mariana Z , Ferreira Leonardo A , Mill Jose Geraldo , Barbosa Fernando , Casarini Dulce E , Oliveira Lilian Caroline G
Published: August 2021

Despite being thoroughly studied, there isn’t complete elucidation of mechanisms underlying obesity, and especially regarding overweight in children. Small molecule metabolites are promising candidates for understanding obesity′s phenotypes. Recent metabolic studies have advanced in discovery of biomarkers for better knowledge of mechanisms related to obesity and its comorbidities. In this cross-sectional study it was evaluated the profile of urinary amino acids of 110 children that were classified in into groups of nutritional status according to their BMI/A (Body Mass Index/age), as normal weight (NW) (n=45), overweight (OW) (n=21) and obese (OB) (n=44). The 24h urine samples were submitted to LC-MS/MS for evaluation of 47 amino acids using
Amino Acids Analysis Kit
(Zivak®, Turkey), corrected by creatinine concentration. Biochemical profile, cardiovascular parameters and anthropometric measurements were assessed following standard protocols. Girls showed a higher heart rate (G:
82bpm vs B:79bpm, p=0,01
) than boys. Increased weight presented higher values of systolic blood pressure (
NW: 102.0, OW: 109.0, OB: 110.0; NW vs OW, p = 0.0001; NW vs OB, p = 0.0001
) and diastolic blood pressure (
NW: 60.0, OW: 67.0, OB: 66.75, NW vs OW, p < 0.0001; NW vs OB, p < 0.0001
). The following amino acids (expressed in nmol/mg of creatinine) were found in higher concentrations in children’s urine with overweight or obesity, when compared with NW group, glutamine (
NW: 1024.3 vs OW: 1309.2, p=0.05),
tryptophan
(NW: 85.65, OW:113.55, OB:109.36; NW vs OW p=0.01; OW vs OB p=0.004),
phenylalanine
(NW: 43.04, OW:49.66, OB:72.08; NW vs OB p=0.01; OW vs OB p=0.04),
and Tyrosine
(NW: 85.07, OW: 109.74, OB: 140.54; NW vs OB p<0.01; OW vs OB p=0.04).
In contrast, sarcosine had reduced concentrations for groups with weight excess
(OW: 78.7 vs OB: 62.3, p=0.04).
Urine levels of glutamine and aromatic amino acids were higher in OW and OB groups. Tyrosine also showed a positive association with systolic blood pressure values. Thus, there was a positive correlation between levels of glutamine and aromatics amino acids and excess weight, suggesting that they may be candidates to biomarkers for obesity in children. Furthermore, obesity was directly related to increase in blood pressure values.
Abstract P169: Effects Of
Saccharina Japonica
Intake On Blood Pressure In Normotensive Rats Fed A High-salt Diet
Authors: Maruyama Saki , Segawa Yukiko , Harui Ayaka , Hashimoto Hiroko , Osera Tomoko , Kurihara Nobutaka
Published: August 2021

Objectives:
One of foods used for Japanese cuisine “Washoku” is brown algae, including
Saccharina japonica
(SJ). The intake of SJ is reported to decrease blood pressure (BP) in spontaneously hypertensive rats in some studies, and in 2-kidney, 1-clip hypertensive (2K1C) rats in our studies. Several studies indicated that dietary fibers contained in SJ, such as alginate and fucoidan, may play an important role in reducing BP. We previously demonstrated that SJ intake did not decrease BP in normotensive rats fed a normal-salt (NS) diet. We also observed that the suppression of BP rise by SJ intake was stronger in 2K1C rats fed a high-salt (HS) diet than in 2K1C rats fed an NS diet. An HS diet may lead to the development of hypertension in both humans and rats. However, to our knowledge, it has not been reported that the effect of SJ intake on BP in normotensive rats fed an HS diet. In this study, we compared the effects of SJ intake on BP between in normotensive and hypertensive rats when fed an HS diet.

Methods:
Male Sprague Dawley rats (6 wks) were treated with sham operation (SHAM) or clipping the left renal artery (2K1C). After surgery, rats were received a control diet (CTL) or a diet contained 5.0% (5 of 100, w/w) SJ, with an NS (0.7% NaCl) or HS (6.0% NaCl) in diets for 6 weeks. Systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial pressure (MAP) was measured in each rat under anesthesia.

Results and Discussion:
Analysis of variance showed that SBP was significantly higher in 2K1C-HS-CTL than in SHAM-HS-CTL (P<0.001, 156±4 vs 131±2 mmHg at the 6th week), and that SBP was lower in 2K1C-HS-SJ (146±3 mmHg) than in 2K1C-HS-CTL (P<0.05). On the other hand, there were no significant differences in SBP among SHAM groups. MAP in 2K1C-HS-CTL rats was significantly higher than that in SHAM-HS-CTL rats (153±2 vs 132±4 mmHg, P<0.005). MAP in 2K1C-HS-SJ (140±5 mmHg) rats was significantly lower than that in 2K1C-HS-CTL rats (P<0.05). There were no significant differences in MAP among SHAM groups. These findings suggested that SJ intake has an antihypertensive effect in a hypertensive model of rats, but no effect of lowering BP in a normotensive model of rats, unlike antihypertensive drugs, which reduce BP in both hypertensive and normotensive model.
Abstract P180: Proximity To Telomeres Or A+t Content Suffices To Project Monogenic Hypertension At An 80 % Matching Rate
Authors: McKnight Ian , Raines Regan , White Hunter , Shim Joon W
Published: August 2021

Hypertension remains the single biggest risk factor contributing to the global burden of disease and mortality. Despite the prevalence of individuals with elevated blood pressure, the role of genetics in hypertension is poorly understood. We have recently demonstrated that mutations causative to the congenital disorder can be projected by a stochastic approach centered on chromosomal characteristics of proximity to telomeres (F(i)) and adenine and thymine (A+T) content (F(ii)). Here, we investigated the two chromosomal factors, F(i) and F(ii), to determine whether they are associated with high mutation rates in human genes related to essential and monogenic hypertension (MH). In essential hypertension, the mismatch of two factors and the disease as well as the correlation between the full-length size of the genes and A+T content was either unexpectedly low (~53%) or statistically insignificant. When we examined 79 genes susceptible to MH and contributing to the genetic architecture of hypertension focusing on the factor-disease matching rate, 64 of 79 genes exclusively satisfied either the F(i) or F(ii) condition. Unlike the previous study on essential hypertension, a quarter of these genes displayed high A+T content at higher than 59%. 16% of genes (13 of 79) associated with hypertension met neither F(i) nor F(ii). Furthermore, 2 of 79 genes met both F(i) and F(ii). Our analysis suggests that these two factors can explain the cause of genetic mutations in 79 loci proposed in MH roughly at an 80% rate. In comparison, these two factors proposed can only explain the cause of idiopathic disease such as essential hypertension at a rate comparable to flipping a coin (50 %). The proposed genomic analyses demonstrate an intermediate matching rate or a mediocre predictability (~75% or less) between the cause of genetic mutations and the disease in the cases of congenital heart disease, thoracic aortic aneurysm, and age-related degenerative disorder.
Abstract P184: Aging Male Offspring Of Polycystic Ovary Syndrome Rat Model Have Normal Blood Pressure And Exaggerated Pressor Response To Angiotensin II
Authors: Shawky Noha M , Reckelhoff Jane F
Published: August 2021

Background:
Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia and elevated blood pressure (BP). Male offspring of hyperandrogenemic female (HAF) rats, PCOS model, have low birth weight, with normal BP, but exaggerated pressor response to Angiotensin (Ang) II as adults. The present study tested the hypothesis that with aging, male HAF offspring are at increased risk of developing hypertension (HT).

Methods:
Hyperandrogenemia was induced in female SD rats (5α-dihydrotestosterone pellets 7.5 mg/90 d, s.c. at 4 wks of age and throughout life). HAF and controls (10-12 wks of age) were mated, allowed to deliver and lactate. HAF and control male offspring (F1
HAF
and F1
Contr.
) were left untreated until 16-20 mos of age. Body composition (echoMRI) and proteinuria were measured in aging offspring. BP was measured (baseline; 9 d, enalapril (25 mg/kg/d); 7d) by telemetry. Rats were then given Ang II (50 ng/kg/min, s.c. minipumps) or saline (No Ang II) for 13 d. High salt (4%) diet (HSD) was started for both Ang II and No Ang II groups on day 8 of Ang II.

Results:
Aging male F1
HAF
had similar fat mass, but lower lean mass (433.7 ± 6 vs 453.6 ± 7 g, p< 0.05) and body weight (552.3 ± 11 vs 590.4 ± 11 g, n = 8-16, p<0.05) than F1
Contr.
. Despite higher proteinuria in F1
HAF
(412 ± 42 mg/24h vs 292 ± 47 mg/24h, n = 11-13, p<0.05), baseline mean arterial pressure (MAP) was similar between F1
HAF
and F1
Contr.
(130 ± 1 mmHg vs 126 ± 4 mmHg, respectively, n = 8, p=NS). Enalapril decreased MAP similarly in both F1
HAF
and F1
Contr.
(110 ± 2 mmHg vs 107 ± 3 mmHg, respectively). On low salt, Ang II increased MAP to higher levels in F1
HAF
than F1
contr.,
saline-treated>F1
HAF
and F1
Contr.
(140 ± 11 mmHg vs 119 ± 10 mmHg, 105 ± 3 mmHg and 103 ± 4 mmHg, respectively, n = 4, p<0.05 F
1
HAF vs other grps). With 6 days of HSD, MAP was similar between F1
HAF
and F1
Contr.
not treated with Ang II (142 ± 6 mmHg and 132 ± 9 mmHg, respectively). MAP was also similar between F1
HAF
and F1
Contr.
with Ang II (169 ± 1 mmHg and 159 ± 9 mmHg, respectively). However, both Ang II-treated groups had significantly higher MAP compared to their respective No Ang II control groups.

Conclusion:
Aging male HAF offspring do not develop hypertension, but are at increased risk of renal injury and cardiovascular disease due to enhanced pressor sensitivity to Ang II.
Abstract P186: Chemical And Mechanical Activation Of The Mechanosensor Piezo1 Alters Adipogenesis In Pvat Preadipocytes
Authors: Rendon Mora Cristian Javier , Flood Emma D , Chirivi Gonzales Miguel Leonardo , Thompson Janice , Watts Stephanie W , Contreras Genaro Andres
Published: August 2021

During hypertension, vascular remodeling allows the blood vessel to withstand high blood pressure (BP). This process is well characterized in the media and intima layers of the vessel. In the perivascular adipose tissue (PVAT) there is evidence for fibrosis development during hypertension; but PVAT remodeling is poorly understood. In stem cells (i.e., adipocyte progenitors) from non-PVAT depots, mechanical forces affect adipogenesis' commitment and lipogenic stages. The mechanism involves PIEZO1, a mechanosensor that boosts the differentiation of preadipocytes towards osteogenic and fibroblastic lineages. However, PVAT's particular anatomical location continuously exposes it to forces generated by blood flow that could affect adipogenesis during normotensive and hypertensive states. Our objective was to evaluate PIEZO1's role in the adipogenic potential of preadipocytes. We hypothesize that activation of PIEZO1 reduces Adipogenesis in PVAT preadipocytes. Aortic (APVAT) was collected from male SD rats at 10 weeks of age (n=15) to harvest preadipocytes by Liberase™ digestion. Nonselective cationic channel PIEZO1 activity was evaluated with Ca
2+
indicator Fluo-4AM.
Piezo1
was reduced with siRNA. Preadipocytes were differentiated for 4 d in adipogenic media containing PIEZO1 agonist Yoda1 (CON=0; YODA1=10μM). Mechanical strain (MS) was applied with FlexCell System at 12%, half-sine at 1 Hz for 4 d (MS+; MS-). Adipogenesis was evaluated by quantification of adipogenic gene network expression using PCR; lipid accumulation using lipophilic stains (Bodipy, siRNA experiments) or Oil Red O (FlexCell experiments). Adipogenesis efficiency is reported as Adipocyte/Total cells as measured in the IncuCyte Live-Cell
®
system. Yoda1 reduced adipogenesis by 33% compared with CON and as expected, increased cytoplasmic Ca
2+
. In si
Piezo1
cells, the anti-adipogenic effect of Yoda1 was reversed. MS+ reduced adipogenesis efficiency (0.15±0.06) compared with MS- (0.22±0.1). These data demonstrate that Piezo1 activation in PVAT may be an adaptive or pathogenic mechanism by which adipocyte populations are reduced, thus minimizing their secretion of vasoactive adipokines, and enhancing the deleterious impact of hypertension on PVAT function.
Abstract P188: Blood Pressure Control And Glaucoma Risk In Older Women
Authors: Haring Bernhard , Hovey Kathleen , La Monte Michael , Andrews Chris , Saquib Nazmus , Manson Joann , Shimbo Daichi , Ritch Robert , De Moraes C. Gustavo , Wassertheil-Smoller Sylvia
Published: August 2021

Objective:
Individuals with elevated systolic blood pressure (BP) or low diastolic BP, whether or not on antihypertensive treatment, may be at higher risk for developing glaucoma. We aimed to investigate BP levels in relation to risk of incident glaucoma in a large cohort of elderly women.

Methods:
Prospective follow-up of 101,447 postmenopausal women without prior history of glaucoma enrolled in the Women’s Health Initiative Study (WHI). Blood pressure was measured in-clinic at baseline and after 3 years using standardized procedures and average BP was calculated. Antihypertensive medication use was determined by drug inventory at baseline and year 3. Women self-reported incident newly diagnosed glaucoma annually. Hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards analyses adjusting for demographic, medical history, and lifestyle covariates.

Results:
During a mean follow-up of 4.7 years, we documented 7,514 glaucoma cases. Among women not on antihypertensive treatment, those with systolic BP ≥140 mmHg or diastolic BP ≥80 mmHg were not at higher risk of developing glaucoma (HR 0.97, 95% CI 0.88-1.08 and HR 1.00 [0.93-1.08], respectively), compared to women with a systolic BP <120 mmHg or a diastolic BP 60-<80 mmHg. Among women on antihypertensive treatment, neither systolic BP ≥140 mmHg nor diastolic BP ≥80 mmHg was associated with an increased risk of glaucoma (HR 0.91 [0.82-1.01] and HR 0.97 [0.90-1.05], respectively). A diastolic BP <60 mmHg was not associated with a higher risk compared to a diastolic BP 60-<80 mmHg.

Conclusions:
BP control is not associated with an increased or decreased glaucoma risk in elderly women.
Abstract P193: Effect Of Nitroglycerin And Sympathetic Withdrawal On Splanchnic Capacitance And Cardiac Blood Volumes
Authors: Okamoto Luis E , Dupont William D , Paranjape Sachin Y , Celedonio Jorge E , Smith Emily C , Kronenberg Marvin W , Biaggioni Italo
Published: August 2021

The splanchnic vasculature is the largest blood volume reservoir in the human body. Reduced capacitance of this vascular bed, in part due to sympathetic venoconstriction, is proposed to play a role in hypertension and heart failure. Thus, interventions that increase splanchnic capacitance or decrease sympathetic activity may be beneficial in these conditions. In a proof-of-concept study in healthy and hypertensive subjects, we evaluated whether venodilation with nitroglycerin (NTG; Study 1) or sympathetic withdrawal with trimethaphan (Study 2) increase splanchnic capacitance and reduce cardiac and stroke volumes. In Study 1 (n=10, 36±4 yrs, BMI 26.1±1.7, 4 men), abdominal and chest scintigrams, to measure regional blood volumes, were obtained before and after 0.6 mg sublingual NTG. Splanchnic capacitance (volume-pressure relationships, VPR) and compliance (VPR slope) were estimated by recording abdominal scintigrams during progressive escalation of intrathoracic pressure using continuous positive airway pressure (CPAP) at 0, 4, 8, 12, and 16 cm H
2
O, each for ≤2 min. We found that NTG increased splanchnic blood volume at rest (4%, IQR 1.81-9.95; P<0.01) resulting in a rightward parallel shift in splanchnic VPR (P
slope
=0.46 and P
intercept
=0.01), indicating an increase in splanchnic capacitance. This was associated with a decrease in cardiac blood volume (-9%, IQR 2.2-10.3; P<0.01). In Study 2, we measured blood pressure (BP) and stroke volume, used as a surrogate of venous return, during the same CPAP protocol before and during autonomic blockade with trimethaphan in 12 hypertensive subjects (49±2 yrs, BMI 29.9±1.7, 5 men). Sympathetic withdrawal decreased systolic BP (-27±14 mmHg) and produced a leftward parallel shift in VPR (i.e. reduced stroke volume; P
slope
=0.12 and P
intercept
<0.01), indicating a reduction in venous return likely due to an increase in splanchnic capacitance. In conclusion, venodilation with NTG increased splanchnic capacitance and decreased cardiac volume. Sympathetic withdrawal had similar hemodynamic effects. These findings highlight the importance of splanchnic capacitance in cardiovascular regulation.
Abstract P195: No Functional Nerve Recovery To 6 Months Post Renal Denervation With Rf Energy In A Normotensive Pig Model
Authors: Sharp Andrew , Tunev Stefan , Schlaich Markus P , LEE David P , Finn Aloke , TRUDEL Julie , Kandzari David E
Published: August 2021

Background:
The safety and efficacy of catheter-based radio frequency (RF) renal denervation (RDN) have been demonstrated in randomized, sham-controlled trials. Long-term durability of blood pressure reduction following RDN has also been demonstrated by all-comer registries, although published pre-clinical reports of functional renal nerve regrowth are not consistent. We quantified the processes that support RDN procedural durability utilizing animal models.

Methods:
Animal studies were conducted in accordance with published guidelines. RDN was performed (4 lesions in the main renal artery) in normotensive swine using the Symplicity Spyral™ RDN system (Medtronic, Santa Rosa, CA, USA). Two additional groups not undergoing RDN served as control. Serial histological tissue samples were obtained in separate groups at 7 (n=12/group) and 180 (N=16/group) days post-procedure in all animals followed by bioanalytical quantification of cortical norepinephrine (NE) levels and immunohistochemical analysis of renal cortical axon density in matched samples.

Results:
Renal cortical axon density and NE levels were significantly reduced at 7 days and persisted through 180 days following RDN compared with control (
Figure
). Nerve fibrosis and necrosis were observed in the region of ablation, while nerve body atrophy was apparent distal to ablation location at 180 days.

Conclusions:
Reductions in both NE and renal cortical axon density were sustained at 7 and 180 days post-RDN procedure using RF renal denervation in a normotensive swine model. These data confirm and extend other pre-clinical and clinical evidence of long-term durability of the RDN procedure using RF energy.
Abstract P196: Exacerbation Of Postural Tachycardia Syndrome After An Oral Glucose Challenge: Role Of Incretins
Authors: Breier Nicholas , Diedrich Andre , Okamoto Luis E , Mehr Shahram E , Flynn Charles R , Shibao Cyndya A
Published: August 2021

Postural Tachycardia Syndrome (POTS) is characterized by excessive upright tachycardia and disabling pre-syncopal symptoms, which are exacerbated after consuming a high-carbohydrate meal. The purpose of this study is to investigate the effect of oral glucose on orthostatic hemodynamic changes and gastrointestinal hormone secretion in POTS. We studied 12 women with POTS and 13 age-matched controls, all subjects received 75-gr oral glucose and 20 mg/kg acetaminophen for nutrient absorption measurement. Hemodynamic, GI hormone secretion and acetaminophen levels were measured at different time-points up to 120-min post-ingestion and while supine and standing. POTS patients had significant upright tachycardia ( delta HR: 48.7 ± 11.2 vs. 23.3 ± 8.1 bpm, P=0.012) and norepinephrine levels (835.2 ± 368.4 vs. 356.9 ± 156.7 pg/mL, P= 0.004). After oral glucose, upright HR significantly increased in POTS (92±15.5 vs. 112± 26 bpm, P=0.002) with a concomitant decline in upright stroke volume (P=0.027); total peripheral resistance, blood pressure and cardiac output remained unaltered. Acetaminophen rate of appearance was similar between groups (P=0.707). POTS patients had increased secretion of C-peptide (P=0.001), Glucose Dependent Insulinotropic Peptide (GIP) (P=0.001), peptide YY (P=0.016) and pancreatic polypeptide (P=0.04), but not GLP-1 (p=0.658) or Glucagon (P=0.836). Only GIP had a time-dependent association with the worsening upright tachycardia and SV fall, figure.

Conclusions:
Oral glucose exacerbated upright tachycardia in POTS, which was associated with a decline in SV; these changes occurred while GIP, a splanchnic vasodilator, is being maximally secreted.
Abstract P197: Increased Serotonin In Visceral Adipose Tissue May Contribute To Stimulate Sensory Neurons Mediating Obesity Hypertension In Mice Exposed To Early Life Stress
Authors: Dalmasso Carolina , Leachman Jacqueline , Ghuneim Sundus , Ahmed Nermin , Giani Jorge F , Cassis Lisa A , Loria Analia S
Published: August 2021

Male C57BL/6J mice exposed to maternal separation and early weaning (MSEW), a mouse model of early life stress, display increased blood pressure (BP) and sympathetic activation compared to obese controls when fed a high fat diet (HF). Moreover, HF-fed MSEW males display exacerbated BP responses to the acute stimulation of the adipose afferent reflex (AAR) in epididymal white adipose tissue (eWAT). The aim of this study was to investigate the contribution of endogenous factors that could stimulate fat sensory neurons. MSEW and control (C) mice (n=8/group) were placed on a LF or HF (10% and 60% Kcal from fat, respectively) for 16 weeks. Then, serum obtained by decapitation and adipose tissue samples were collected to measure mRNA and protein expression of 15 factors and receptors known to activate sensory neurons. No differences were found across measurements on LF. Plasma AGT and AngII were decreased in HF-fed MSEW compared to C (AGT: 760±48 vs. 1267±161 ng/ml, p<0.05; AngII; 413±57 vs. 1082±340 pmol/l, p<0.07, Attoquant) and no differences were found in leptin (103±6 vs. 104±4 ng/ml, p<0.87). In eWAT, MSEW and C showed similar AGT (2.1±0.4 vs. 1.9±0.3 ng/ml per g tissue), AngII (1.7±0.2 vs. 2.3±0.5 pg AngII/mg tissue), ACE 1 activity (21.5±1.2 vs. 20.0±0.9 RFU/min/μg protein, p<0.33) and leptin (102.8±6.1 vs. 104.5±6.8 ng/mg of tissue, p<0.87). However, HF-fed MSEW showed increased eWAT mRNA expression of tryptophan hydroxylase 1 (Tph1), the rate limiting enzyme in serotonin (5-HT) synthesis (10.2±2.9 vs. 1.6±0.3 2
-ΔΔct
, p<0.03). SERT-Tph1-MAO signaling pathway protein expression was activated, and fat serotonin concentration was also increased in eWAT from obese MSEW mice compared to C (16.58±1.5 vs. 8.5±2.1 ug/mg of tissue, p<0.01). Acute stimulation of eWAT with serotonin (10-6 M, 4 sites, 2 ul/site) tend to increase pressor response in MSEW mice (p<0.066, n=2-3). Unlike in female MSEW mice, our study demonstrates that MSEW does not increase circulating and tissue AGT, Ang II and leptin in male mice. Taken together, these data suggest that increased local serotonin could be endogenously sensitizing the sensory neurons in obese MSEW mice contributing to chronic AAR stimulation, directly via TRPV1 channels, or indirectly, via acid-sensing ion channels.
Abstract P204: Sinusoidal Galvanic Stimulation Improves Orthostatic Symptoms In Patients With Postural Tachycardia.
Authors: Urechie Vasile , Smith Emily , Ogorodnikov Dmitri , Biaggioni Italo , Diedrich Andre
Published: August 2021

Postural Tachycardia Syndrome (POTS) is characterized by frequent orthostatic symptoms and excessive heart rate increase (>= 30 bpm) on standing in the absence of orthostatic hypotension for more than 6 months. We and others have described a vestibulo-sympathetic reflex that can be engaged by galvanic vestibular stimulation to modulate sympathetic activity (Biaggioni et al., 2000; Kaufmann et al., 2002; Monahan & Ray, 2002; Ray & Carter, 2003, Bent, Macefield et al. 2006). We hypothesize that habituation to sinusoidal galvanic vestibular stimulation will improve orthostatic tolerance. We studied 6 patients with POTS (30.5+/6.0 years, BMI 22.8+/-2.9 kg/m
2
) in two sessions using sinusoidal galvanic vestibular stimulation (sGVS 0.025 Hz, 2mA) or sham (0.01 mA). Stimulation was applied near mastoid process for 30 min in semi-recumbent position before orthostatic challenge. Patient were upright for a maximum of 15 minutes after each stimulation. Orthostatic change in Vanderbilt Orthostatic Symptom Score (dVOSS), orthostatic heart rate increase (dHR) and blood pressure response were recorded. Non-parametric Wilcoxon test for paired measures with significance level p<0.05 was used. sGVS stimulation reduced overall orthostatic symptom score (dVOSS sham: 32.5+/-9.3 bpm vs dVOSS sGVS: 10.5+/-5.5, p=0.03) and tended to reduce orthostatic HR increase (dHR sham: 65.83+/-11.5 vs dHR sGVS: 46.5+/-10.7 bpm, p=0.06). Blood pressure and tilt time did not change. This pilot study suggests that habituation to sinusoidal vestibular could be used to improve orthostatic symptoms and orthostatic tolerance.
Abstract P205: Use Of A Noninvasive, Closed-loop, Allostatic, Neurotechnology Reduced Blood Pressure And Improved Sleep In Heterogeneous Cohort
Authors: Shaltout Hossam A , Tegeler Catherine , Howard Lindsay , Brown Kenzie , Asif-Fraz Faiza , Kellar Dawn , Tegeler Charles H
Published: August 2021

Introduction:
Elevated blood pressure is a major modifiable risk for cardiovascular disease. Disturbed central control of cardiovascular regulation due to trauma, stress, anxiety or other causes can lead to rise in blood pressure. High-resolution, relational, resonance-based, electroencephalic mirroring (HIRREM®) is a noninvasive, closed-loop, allostatic, acoustic stimulation neurotechnology using software algorithms to identify specific brain frequencies, and translate them in real time into audible tones, to support self-optimization of brain rhythms.

Objective:
To evaluate the benefits of adding this nontraditional therapy on BP and symptoms of insomnia in subjects with normal or controlled BP, who are enrolled in an IRB-approved open label feasibility study evaluating HIRREM for diverse neuropsychological disorders.

Methods:
236 participants (105 female), mean (SD) age 43.1 (16.5), received 15.7 (4.8) HIRREM sessions over 22.6 (18.2) days, (9.3 (3.4) days with sessions). Brachial BP and insomnia score (ISI) were collected before, and 14.0 (14.0) days after HIRREM completion. Paired t-tests were performed.

Results:
Before HIRREM, participants were divided in the following groups based on ACC/AHA 2017 BP guidelines, normal n=78, elevated n=36, stage 1 n=50, stage 2 n=57, stage 3 n=14 and crisis n=2. There were no changes in medications throughout the study duration. The use of HIRREM was associated with significant reduction in systolic BP (from 126.1 (19.0) to 123.5 (17.0) mmHg, p=0.007), and diastolic BP (from 75.3 (10.6) to 73.0 (9.0) mmHg, p<0.001), with no change in heart rate. Many participants moved to lower BP stage after V2 with the number of participants within normal BP at V2 increasing from 78 to 88. ISI score decreased from 13.2 (7.2) to 6.7 (5.6), p<0.0001. This change met the clinically meaningful drop in ISI of 6 points or more.

Conclusion:
These data provide evidence of significant benefits of adding a closed-loop therapy for blood pressure reduction and improving sleep. Further studies are indicated to better define the role of this promising intervention to improve sleep, depression, anxiety, and cardiovascular outcomes.
Abstract P210: Central Blockade Of Tumor Necrosis Factor-Á-Converting Enzyme (tace) Ameliorates Neuroinflammation, Sympathetic Excitation And Cardiac Dysfunction In Heart Failure Rat
Authors: Yu Yang , Xue Baojian , Li Hanzeng , Chen Qing , Li Mingxuan , beltz terry , Weiss Robert M , Johnson Alan K , Wei Shunguang
Published: August 2021

TACE is a key metalloprotease involved in ectodomain shedding of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-α. We previously reported that TACE-mediated production of TNF-α in the hypothalamic paraventricular nucleus (PVN) contributes to the sympathetic excitation in heart failure (HF). Additionally, the upregulated TGF-α in the PVN transactivates the epidermal growth factor receptor (EGFR) to activate extracellular signal-regulated kinase (ERK) 1/2 in HF. Here we sought to determine whether central inhibition of TACE attenuates neuroinflammation and prevents the progress of HF. Male rats underwent coronary artery ligation to induce HF or sham surgery (Sham). These rats were treated with bilateral PVN microinjection of a TACE siRNA or control siRNA while some rats received a 4-week intracerebroventricular (ICV) infusion of TACE inhibitor TAPI-0 or vehicle. Compared with Sham rats, HF rats treated with control siRNA, had higher (*P<0.05) levels of TNF-α (7.88±1.32* vs 2.77±0.98 pg/mL) and TGF-α (28.27±2.76* vs 11.62±2.48 pg/mL) in cerebrospinal fluid, and increased mRNA expression of TACE (2.53±0.30* vs 1.04±0.12), TNF-α (3.43±0.55* vs 1.03±0.11), TNF-α receptor 1 (2.32±0.27* vs 1.07±0.19), cyclooxygenase-2 (2.96±0.31* vs 1.10±0.19) and TGF-α (2.68±0.41* vs 1.06±0.14) in the PVN, but these levels were markedly reduced (39-54%*) in TACE siRNA-treated HF rats. Compared with control HF rats, HF rats treated with TACE siRNA had reduced expression of phosphorylated (p-) NF-κB p65 (1.27±0.14 vs 0.84±0.07*), p-EGFR (0.52±0.05 vs 0.37±0.04*) and p-ERK1/2 (1.06±0.10 vs 0.62±0.09*) in the PVN. Moreover, the elevated plasma norepinephrine levels, lung/body weight, heart/body weight and left ventricular (LV) end-diastolic pressure along with decreased LV dP/dt
max
in HF rats-treated with control siRNA were significantly attenuated in HF rats treated with TACE siRNA. Treatments with TACE siRNA in the PVN also improved the indicators of cardiac hypertrophy and fibrosis of HF. ICV infusion of TAPI-0 had the similar effects with PVN TACE siRNA on these variables in HF. These data indicate that central interventions suppressing TACE activity ameliorate neuroinflammation, sympathetic activation and cardiac dysfunction in HF.
Abstract P216: Cholinergic-mediated Salt-Sensitive Hypertension In A Genetic Model Of Essential Hypertension
Authors: Raikwar Nandita , Hohmann Holly , Maiers Trever , Ryan Alan , Snyder Peter , Harwani Sailesh
Published: August 2021

Inflammation plays a key role in the pathogenesis of hypertension. High dietary sodium intake has been associated with inflammation in patients suffering from high blood pressure & atherosclerosis. Our lab has shown that development of hypertension in a genetic model of human essential hypertension, the Spontaneously Hypertensive Rat (SHR), is dependent on nicotinic acetylcholine receptor (nAChR) mediated renal inflammation, which leads to enhanced expression of the renal sodium-potassium chloride cotransporter (NKCC2). Based on these findings we hypothesized that sodium sensitivity may play a role in the development of cholinergic hypertension. To investigate this hypothesis, we infused young pre-hypertensive SHR and Wistar Kyoto (WKY, normotensive control) rats with either saline or nicotine (15mg/kg/day) and placed them on either low-salt (LSD, 0.01% NaCl) or high-salt (HSD, 4% NaCl) diet for 2 wks. There was no change in systolic blood pressure (SBP) in saline or nicotine infused WKY with either LSD or HSD. Similarly, there was no difference between the SBP of saline infused SHR with either LSD or HSD. Interestingly, nicotine infusion did not change SBP in LSD fed SHR, but did result in ~20% increase in SBP in HSD fed SHR (122.0 ± 0.7 vs. 146.2 ± 0.2mmHg, p= 0.01). HSD alone induced a 2.25-fold increase in renal NKCC2 expression compared to LSD in saline infused SHR (p=0.006). In comparison to saline, nicotine infusion further induced a 58% increase in renal NKCC2 expression in SHR fed HSD (p=0.004). Renal NKCC2 expression did not change in WKY with either diet or nicotine infusion. Nicotine infused SHR on a HSD also manifested a 16% sodium retention compared to saline infused SHR (2.1 ± 0.1 mM/gBW vs. 2.5 ± 0.1 mM/gBW, p = 0.017). Nicotine infused SHR had 1.7 times more renal IL-6 than saline-infused SHR (1442. ± 212 vs 826 ± 103 pg/25mg total protein, p=0.04) and 9 times more renal IL-6 than nicotine-infused WKY controls (1442. ± 212 vs 148. ± 71 pg/25mg total protein, p=0.0041) under HSD conditions. Taken together with our previously published data, we conclude that NKCC2 likely plays a role in cholinergic-mediated renal inflammation and hypertension.