bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 409: Reproducibility of White Coat and Masked Hypertension Definitions One Year after the Diagnosis
Authors: DE LA SIERRA ALEJANDRO , BANEGAS JOSE R , VINYOLES ERNEST , GOROSTIDI MANUEL , SEGURA JULIAN , DE LA CRUZ JUAN J , RUILOPE LUIS M
Published: July 2021

A significant number of subjects present discordant results when BP is measured both at the clinic and by 24-hour ABPM. The aim of the study was to assess the reproducibility of a diagnosis of normotension (NT), white coat hypertension (WCH), masked hypertension (MH) and sustained hypertension (SH) in a cohort of untreated subjects who underwent a second ABPM without being treated with antihypertensive drugs.

From the Spanish ABPM Registry, we selected 843 untreated subjects who underwent at least 2 BP examinations (both at the clinic and by ABPM) separated by 2 months or more (median,IQR: 13; 6-28 months), and who did not receive antihypertensive drug treatment in the period lasting between the 2 examinations. The 4 above mentioned categories were defined by normal (<140/90 mmHg) or elevated BP at the clinic (mean of 2 measurements), and by normal (<130/80 mmHg) or elevated 24-hour BP.

At baseline, 140 (17%), 206 (25%), 78 (9%), and 414 (49%) had NT, WCH, MH, and SH, respectively. At the 2nd clinic and ABPM examination 52% of NT, 55% of WCH, 47% of MH, and 82% of SH fall into the same category. In both the WCH and MH categories, the most frequent switch was to SH (26% and 33%, respectively). When patients who changed or remained in the same category were compared, there were no differences in clinical variables, such as age, gender, or prevalence of obesity, diabetes, or previous cardiovascular disease. Both clinic and ambulatory BP were higher in patients who fall into the same category in both examinations, but this was driven by the higher reproducibility of SH. In the specific group of WCH (206 patients) there were no significant BP differences at baseline between the 114 who maintained such diagnosis, compared to the 54 patients who developed SH. Conversely, in the 78 patients with MH at baseline, those who developed SH at the 2nd examination (26) had higher levels of clinic diastolic BP (84±4 vs. 80±5 mmHg; p=0.006), compared with those who remained with MH (37).

In conclusion, the diagnosis of SH is highly reproducible after one year of the first diagnosis. However, a diagnosis of WCH or MH requires a close follow-up, as almost 50% of patients do not show the same diagnosis and develop SH. There is no a specific clinical pattern which can be of help to predict which patients will develop SH.
Abstract 412: A Unique Telemetric Method for Long-term Measurement of Blood Pressures and Core Body Temperature in Hypertensive and Normotensive Non-human Primates
Authors: Osborn Jeffrey L , Rhoads Megan K , Collett Jason A , Beierschmitt Amy , Dascanio John , Knot Harm J
Published: July 2021

A non-human primate model of essential hypertension has unequivocal potential for understanding mechanisms of disease but requires a unique method for telemetric blood pressure measurement in animals living within a habituated natural environment. We have now identified a unique non-human primate model of spontaneous, essential hypertension in Chlorocebus aethiops sabaeus, the African Green, or vervet, monkey. Using forearm plethysmography under light ketamine sedation (~15mg/kg), adult vervets were categorized as hypertensive (HT; SBP >140mmHg), borderline hypertensive (BHT; 120mmHg < SBP < 140mmHg), or normotensive (NT; SBP < 120 mmHg). Of the 168 males phenotyped, 32% (53 of 168) were HT (average SBP = 168.79±3.29mmHg), 27% (45 of 168) were BHT (average SBP = 129.58±0.88mmHg), and 41% (70 of 168) were NT (average SBP = 100.21±1.65mmHg). Stellar Telemetry solid-state pressure sensors were surgically implanted into the abdominal aorta of feral, male monkeys (Chlorocebus sabaeus aethiops). SBP, diastolic (DBP) and mean (MBP) arterial pressures, core body temperature and heart rate were determined using different data acquisition parameters to assess system precision and reliability in this physically active non-human primate with spontaneous essential hypertension. All animals were pre-phenotyped for blood pressure using forearm plethysmography under light ketamine anesthesia. Different recording parameters (n=4) yielded consistent BPs, in normotensive (MBP=104±4.35 mmHg) and hypertensive (MBP=126±7.57 mmHg) animals. Ultrasonographic examination documented effective sensor placement directly within the vessel lumen. Post implant necropsy revealed no sensor induced blood pathologies. Conscious, telemetered SBPs were consistent with those of monkeys measured using plethysmography. This model of hypertension in an Old World, non-human primate is translational to human essential hypertension and allows for new directions in a genetically similar species. The use of the Stellar Telemetry system is ideal for monitoring conscious blood pressure, heart rate and body temperature in active primates allowing for cardiovascular assessment during natural social interactions and species specific behaviors.
Abstract 423: Low Level Laser Therapy Stimulates Hypoxia-Inducible Factor Expression and Increases MicroRNA 210 Content after Rat Myocardial Infarction
Authors: Silva Jose A , Feliciano Regiane S , Serra Andrey J , Manchini Martha T , Santana Eduardo T , Pires Juliana , Brigidio Eduardo , Antonio Ednei L , Tucci Paulo J
Published: July 2021

Low-level laser therapy (LLLT) has been used as an anti-inflammatory alternative treatment in several disease conditions, even when inflammation is a secondary consequence, such as in myocardial infarction (MI). LLLT treatment effectively reduces MI size and attenuates the systolic dysfunction after MI. However, the mechanism by which LLLT is able to protect the remaining myocardium remains unclear. Here, we tested the hypothesis that LLLT might reduce the hypoxia effects generated by MI. To achieve this purpose, we evaluated, after laser irradiation, the modulation of hypoxia-inducible factor (HIF) and microRNA 210 expressions, which are consistently stimulated under hypoxic conditions. We observed that HIF content presented an up-regulation after MI, however, a significant augmented HIF expression was observed after LLLT. Accordingly, micro-RNA 210 expression in the MI remote area increased even further after laser irradiation. Our data suggest that LLLT stimulates HIF expression pathway, increasing hypoxia-induced microRNA 210 content after MI, therefore, highlighting a possible cardioprotective role of LLLT.
Abstract 426: Factors Associated With Multimorbidity And Its Link With Poor Blood Pressure Control Among 223,286 Hypertensive Patients
Authors: Wong Martin C , Wang Harry H , Kwan Mandy W , Cheung Clement S , Tong Ellen L , Sek Antonio C , Cheung Ngai Tseung , Yan Bryan P , Yu Cheuk Man , Griffiths Sian M , Coats Andrew J
Published: July 2021

Background:
Multimorbidity, defined as the presence of ≥ 2 chronic disorders, has become the norm in many countries as populations age. It remains, however, very infrequently researched. This study evaluated the factors associated with multimorbidity in a predominantly Chinese hypertensive population.

Methods:
We included all adult patients prescribed their first antihypertensive agents in the public sector of the entire Hong Kong population from a validated clinical database. Multinomial regression analyses were performed to explore factors independently associated with multimorbidity.

Results:
223,286 hypertensive patients (average age of 59.9 years, SD 17.6) were included. The prevalence of having 0, 1 and ≥2 additional chronic conditions was 59.6% [133,176/223,286], 32.8% [73,313/223,286] and 7.5% [16,797/223,286], respectively. Older age (>50 years), male sex, lower household income, receipt of comprehensive social security allowance and suboptimal blood pressure control (>140mmHg or >90mmHg; >130mmHg or >80mmHg for diabetes patients; AOR=3.38 to 4.49) were significantly associated with the presence of ≥2 additional conditions. There exists a synergistic effect among these variables as older (≥70 years), male patients receiving security allowance had substantially higher prevalence of ≥2 multimorbidity (19.9% vs 7.5% among all patients).

Conclusions:
Multimorbidity is very common in hypertensive patients and its prevalence increased markedly with the presence of risk factors identified in this study. Hypertensive patients with multimorbidities should receive more meticulous clinical care as their blood pressure control tends to be poorer.
Abstract 428: Shear Stress-Induced Mitochondrial Biogenesis: Implications for Salutary Effects of Aerobic Exercise on Endothelial Homeostasis
Authors: Kim Ji-Seok , Kim Boa , Lee Hojun , Thakkar Sunny , Babbitt Dianne M , Eguchi Satoru , Brown Michael D , Park Joon-Young
Published: July 2021

Enhancing structural/functional integrity of mitochondria in the vascular endothelium has emerged as a novel therapeutic approach for vascular disease. Aerobic exercise stimulates mitochondrial biogenesis via a shear stress (SS)-dependent mechanism in the vasculature. However, functional consequences of SS-induced mitochondrial remodeling in the vascular endothelium remain largely unknown. The purpose of this study was to examine effects of aerobic exercise on endothelial activation/apoptosis and to elucidate the underlying mechanism. In in vivo study, twenty-one prehypertensive individuals underwent a 6-month supervised aerobic exercise training (65% HRmax, 40 min/day, 3 days/week). In in vitro study, cultured Human Umbilical Vein Endothelial Cells (HUVECs) were exposed to SS using a cone-and-plate shear apparatus. Endothelial cells (ECs) were harvested for protein analysis and cell-culture media were collected to assess endothelial microparticle (EMP) production. Antimycin A, SIRT1 siRNA and PGC-1α siRNA were used for the disruption of mitochondrial functional/structural integrity. Protein expressions were analyzed by western-blotting. EMP productions were measured by flow cytometry. Circulating levels of activated (CD62E+) and apoptotic (CD31+/CD42a-) EMPs were significantly decreased (49±6 to 20±2 and 4.0 to 2.4 events/μL, respectively p<0.01) after 6-month aerobic exercise training in prehypertensives. In ECs, laminar SS attenuated productions of activated EMPs (3.18 to 1.43 events/μL) and apoptotic EMPs (0.24 to 0.07 events/μL), which were accompanied by an increase in mitochondrial content (7.8-fold increase). SIRT1 knockdown using siRNA completely abolished the protective effect of laminar SS. Disruption of mitochondrial integrity by either antimycin A or PGC-1α siRNA provoked the activated- (1.7-fold and 2.4-fold increase, respectively) and apoptotic- statuses (2.1-fold and 1.7-fold increase, respectively) and shear stress normalized these impairments. In conclusion, aerobic exercise attenuates endothelial activation and apoptosis by SS-induced mitochondrial biogenesis. This study expands the understanding of implications of mitochondrial biogenesis in endothelial cell homeostasis.
Abstract 431: A Novel Score System for Primary Aldosteronism Screening, PUK2 score: Combination of Urine pH and Serum Uric Acid and K+ Levels
Authors: Yamashita Tomohisa , Togashi Nobuhiko , Koyama Masayuki , Mita Tomohiro , Tobisawa Toshiyuki , Onuma Yoshito , Hasegawa Toru , Tsuchida Akihito , Endo Toshiaki , Ando Toshiaki , Yoshida Hideaki , Miura Tetsuji
Published: July 2021

Background:
Hypokalemia is not a sensitive marker of primary aldosteronism (PA) , and method for screening PA by routine clinical parameters has not yet been established.

Objective:
We examined whether serum uric acid (UA) or urine pH alone, or their combination with serum K+ level is usable for PA screening .

Design and Setting:
Cross-sectional analyses were retrospectively performed on consecutive patients who visited a single general hospital from April 2012 to September 2013.

Participants:
Entry criteria were age <75 years old, hypertension and presence of data on serum aldosterone (ng/dL) and renin activity (ng/mL/hr). Exclusion criteria were use of aldosterone blockers, ACE inhibitors, angiotensin receptor antagonists, diuretics, beta-adrenergic blockers, steroids or UA-lowering drugs and diagnosis of secondary hypertensions other than PA.

Main Outcome Measures:
Diagnosis of PA was made in accordance with the guideline of Japanese Society of Hypertension: patients with aldosterone-to-renin activity ratio (ARR) > 20 and one or more positive results in captopril challenge test, furosemide-upright test, saline infusion test and/or ACTH stimulation test.

Results:
We enrolled 103 patients (PA = 29, essential hypertension [eHT] = 74). PA has lower serum K+ (3.5±0.32 vs 3.8±0.23 mEq/L, p<0.001, mean ± S.D.), higher urine pH (6.6±0.83 vs 6.1±0.62, p<0.001) and lower UA (5.6±1.6 vs 6.5±1.2 mg/dL, p=0.004) compared with those in eHT. Urine pH≧ 7.0 and UA < 6.0 mg/dL were selected as optimum cutoffs for diagnosis of PA by ROC curve analysis. Multivariable logistic regression analysis indicated that high urine pH, low UA and hypokalemia (K < 3.5 mEq/L) were independently associated with PA. Using the cutoff values, we developed a score system, PUK2 score, which is derived from the sum of point values of PA predictor; 1 point was assigned to low UA and to high urine pH and 2 points were assigned to hypokalemia. The prevalence of PA in the patients with PUK2 score of 0, 1, 2 and 3~ was 5.0%, 31%, 37%, and 83%,respectively. Furthermore, the likelihood ratio in patients with PUK2 score of 0 was 0.13 (95%CI: 0.034-0.52).

Conclusions:
PUK2 score is easy to use and useful for screening PA in hypertensive patients.
Abstract 441: Sex Differences in Microglia Activation During Subpressor Dose of Angiotensin (Ang) II Sensitization of Subsequent Pressor Dose of Ang II
Authors: Hay Meredith , Samareh- Jahani Farmin , Xue Baojian , Johnson Alan K
Published: July 2021

In previous studies using the Induction-Delay-Expression (I-D-E) experimental design we have shown that there are sex differences in the effects of one-week Ang II pre-treatment to sensitize the brain to produce an enhanced hypertensive response to subsequent Ang II. In other studies, we have shown that females are protected from hypertension and brain infiltration of T lymphocytes during Ang II infusion. The purpose of the present study was to test whether there is a sex difference in brain microglia activation on the sensitizing effects of Ang II. The present studies followed an I-D-E experimental design. Three male and three female Sprague-Dawley rats were assigned to each of the following experimental groups: 1) Control ( I saline + D) ; 2) I-Ang II+D ( I with subpressor dose of Ang II, 10 ng/kg/min); 3) I-saline+D+E-Ang II (I with saline plus E with a pressor dose of Ang II, 120 ng/kg/min); 4) I-Ang II+D+E-Ang II (I with subpressor dose of Ang II plus E with pressor dose of Ang II). At the end of the experiment, animals were anesthetized and perfused with formalin. Thirty-micron frozen slices of the area postrema (AP), nucleus tractus solitarius (NTS), and subfornical organ (SFO) were processed for IHC staining with IBa-1 microglia antibody (WAKO, 1:200). The number of IBa-1+ activated microglia (MG) in each region were counted in an approx 3 consecutive brain slices from 3 separate animals. The subpressor dose of Ang II resulted in a significant increase in NTS activated microglia in males (MG 19.2 vs. 5.1) but not in females (MG 1.5 vs 2.3) when compared to control. In females, the pressor dose of Ang II did not increase the activated microglia in the NTS. The numbers of activated microglia in the AP was similar in males and females in the I-Ang II+D+E-Ang II group, but in the I-Sal+D+E-Ang II, males had greater number of MG in the AP as compared to females (21.5 vs 11.8, P=0.05). The number of MG in the SFO were low across all groups compared to the number of MG in other regions examined (males I-Ang II+D+E-Ang II group averaged 3.9 MG vs females averaged 2.3 MG). These results suggest that sex differences observed in the brain sensitization to Ang II may involve differential induction of microglia activation in selective brain regions important for Ang II generation of hypertension.
Abstract 454: Plgf Mediates A Neuroimmune Interaction In The Spleen To Allow The Onset Of Hypertension
Authors: Carnevale Daniela , Pallante Fabio , Fardella Valentina , De Lucia Massimiliano , Fardella Stefania , Iacobucci Roberta , Lembo Giuseppe
Published: July 2021

In the past several years, there has been mounting interest in the roles played by immunity in hypertension, an health problem affecting over 1 billion people worldwide. An emerging area of investigation revealed that adaptive immunity is a central player of hypertension, since mice devoid of T lymphocytes were protected from AngII-induced hypertension. However, how hypertensive stimuli like AngII can afford this, is still enigmatic.

Here we found an unprecedented splenic neuroimmune pathway driven by Placental Growth Factor (PlGF) during hypertension. The hypertensive response induced by chronic AngII infusion (28days) was completely prevented in PlGF KO mice (WT AngII 140±2 vs PlGF KO AngII 103±3 mmHg), as well as the typical end organ damage and immune cells infiltration. To determine whether the involvement of PlGF had a causal role or was merely a consequence of the failure in BP raise, we analyzed vessels and kidney early after AngII infusion (3days), before BP increase (WT AngII 108±3 vs PlGF KO AngII 105±1), finding that PlGF absence already protected from T cells infiltration. We also uncover that the splenic PlGF is essential for hypertension, through a noradrenergic drive mediated by the celiac ganglion. An intact neuroimmune interaction of the celiac ganglion on the spleen was needed to have PlGF release upon AngII and chimeric mice, generated by spleen transplantation, demonstrated that the ablation of PlGF in the spleen (KO spleen into WT mice) was sufficient to protect from hypertension. At the molecular level, we found that PlGF released in the spleen exerted a repression of the tissue protein of inflammation Timp3 through p53. In particular, while in WT splenocytes the Timp3 transcriptional repressor region was bound by its molecular repressor p53 upon AngII, PlGF KO splenocytes showed the Timp3 repressor region free from p53, as evidenced by ChIP. Finally, we demonstrated that this pathway is necessary to control T cells costimulation, through the regulation of CD86 expression, and allow their deployment toward classical organs involved in hypertension. Overall, we demonstrate that PlGF mediates the neuroimmune interaction in the spleen, organizing a unique and non redundant response that allows and is necessary for the onset of hypertension.
Abstract 460: IL-33 Treatment Prevents Cyclosporine A-Induced Hypertension, Endothelial Dysfunction, and Vascular Remodeling in Mice
Authors: Chiasson Valorie L , Manandhar Lochana , Roman Marcos H , Bounds Kelsey R , Mitchell Brett M
Published: July 2021

The immunosuppressive drug cyclosporine A (CsA) causes systemic and renal vascular remodeling, endothelial dysfunction, and hypertension and this is associated with decreased anti-inflammatory regulatory T cells (Tregs). Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature granulocytes, macrophages, and dendritic cells, play a central regulatory role in immune responses by inhibiting various pro-inflammatory innate and adaptive immune cells as well as stimulating Treg expansion. We hypothesized that CsA causes vascular remodeling, endothelial dysfunction, and hypertension in part by decreasing MDSCs and that augmentation of MDSCs in vivo with IL-33 treatment can prevent these effects. Daily treatment of male C57BL6/J mice for 1 week with CsA (50 mg/kg/day, ip) and IL-33 (0.5 ug/day, ip) prevented the CsA-induced decrease in splenic MDSC levels (Day 7 % of lymphocytes: Con=3.7±0.9, CsA=2.1±0.5*, CsA+IL-33=3.2±0.3; *p<0.05 vs. Con), increase in SBP (Day 7 SBP in mmHg: Con=94±3, CsA=148±4*, CsA+IL-33=100±3; *p<0.05 vs. Con), and decrease in maximal aortic endothelium-dependent relaxation responses (Con=78±2%, CsA=29±6%*, CsA+IL-33=74±2%; *p<0.05 vs. Con). Additionally, CsA treatment increased fibronectin protein levels in aortas and kidneys and caused renal intraglomerular mesangial expansion and congestion, all of which were ameliorated by co-treatment with IL-33. Together, these data suggest that the hypertension, endothelial dysfunction, and vascular remodeling caused by CsA is mediated in part by decreased MDSCs and that IL-33 treatment may have beneficial cardiovascular effects in CsA-treated patients.
Abstract 461: Effects Of Energy Restriction On Sleep Apnea, Blood Pressure, Sympathetic Activity, Oxidative Stress, Inflammatory Biomarkers, Endothelial Function And Metabolic Profile In Obese Patients With Obstructive Sleep Apnea
Authors: Fernandes Julia F , Araújo Luciene S , Rodrigues Maria de Lourdes G , Valença Debora C , Neto José Firmino N , Gaspar Bernardo B , Gomes Nathalia F , Carvalho Hadassa G , Klein Marcia R , Sanjuliani Antonio F
Published: July 2021

Introduction:
Weight loss is one of the treatment options for obstructive sleep apnea (OSA) in patients with excess body adiposity. However, the effects of moderate energy restriction on OSA are not known.

Objective:
To evaluate the effects of moderate energy restriction on severity of OSA, blood pressure (BP), sympathetic activity, oxidative stress, inflammation, body adiposity, metabolic profile and endothelial function in obese patients with OSA.

Methods:
A 16-week randomized clinical trial, involving 21 obese subjects aged 20-55y with apnea/hipopnea index (AHI) ≥ 5 events/h. Subjects were randomized in 2 groups: 11 in energy restriction group (ERG) and 10 in control group (CG). ERG was instructed to follow an energy-restricted diet (-800 kcal/day) and CG was advised not to change food intake. At the beginning and at the end of the study, participants underwent evaluation of: OSA with Watch- PAT200® including the determination of OSA severity parameters, body adiposity, BP, plasma catecholamines, c-reactive protein (CRP), adiponectin, malondialdehyde, metabolism of glucose, lipid profile and endothelial function (Endo PAT 2000®).

Results:
ERG, compared to CG, presented significantly greater reduction in body weight (-5.6±1.8 vs. 0.4±1.2kg, p<0.001) and in all parameters of body adiposity; AHI (-7.2±2.8 vs. 0.1±1.9 events/h, p=0.04); number of O2 desaturation >4% (-33.7±15.6 vs. 1.8±7.9, p=0.04); plasma adrenaline (-12.7±3.0 vs. -1.3±3.9pg/mL, p=0.04); and significantly greater increase in minimum O2 saturation (4.6±1.6 vs. -0.6±1.4%, p=0.03). ERG showed greater decrease, however without statistical significance, in systolic BP (-4.2±1.9 vs. 2.3±1.4mmHg, p=0.05), insulin (-5.1±1.9 vs. -0.7±1.3μU/mL, p=0.07) and HOMA-IR (-1.2±0.5 vs. -0.08±0.3, p=0.09). During the study period, changes in body adiposity presented significant correlation with changes in parameters of OSA severity, BP, insulin, HOMA-IR, norepinephrine and adiponectin. Changes in parameters of OSA severity presented significant association with changes in CRP.

Conclusions:
This study suggests that in obese patients with OSA moderate energy restriction is able to reduce body adiposity, parameters of OSA severity and sympathetic nervous system activity.
Abstract 473: Weight Loss Improved Hyperuricemia, and Cardiac and Renal Functions in Obese Individuals
Authors: Masuo Kazuko
Published: July 2021

Background:
Hyperuricemia (hyperUA) is a cardiovascular risk and UA levels might predict future hypertension. In this study, we evaluated the effects of chronic weight loss (WL) on UA levels, renal and cardiac functions.

Methods:
Obese, mild hypertensive men (n=154) on no medications were measured BMI, total body fat-mass, blood pressures (BP), UA, serum creatinine (Crn), creatinine clearance (CCr), plasma norepinephrine (NE), glucose, insulin (INS), HOMA-IR and ECG before and every 6 month after 2 yrs with WL regimens achieved with mild calorie restriction and exercise. Significant WL was defined as ≥10% WL of entry BMI at 2 yrs. LVH determined by ECG was used as an index or cardiac function parameter.

Results:
Significant WL (≥10%) were observed 47.8% at 1 yr and 61.8% at 2 yrs, and hyperUA were 64.3% at baseline, 43.3% at 1 yr, and 29.9% at 2 yrs. UA levels, LVH parameters, plasma NE, BMI, fat-mass, and BP levels at entry were greater and CCr was smaller in the non-WL group (<10%) at 2 yrs compared to the WL group, whereas HOMA at entry and changes in HOMA-IR over 2 yrs were similar between WL and non-WL groups. UA, Crn, NE, HOMA, BMI, fat-mass, BP significantly decreased with WL in all subjects, but the decreases in those parameters were greater in the WL group compared to non-WL group. All parameters except CCr at entry were greater in subjects with hyper UA at 2 yrs than those with normal UA at 2 yrs. Changes in NE, HOMA, Crn, CCr, and LVH parameters over 2 yrs in subjects with normal UA at 2 yrs were greater than those with hyper UA at 2 yrs. Changes in UA over 2 yrs significantly correlated with changes in NE, BMI, systolic BP, and fasting glucose (all, P<0.05). UA levels at entry correlated with changes in BMI, changes in CCr and changes in LVH parameters (all, P<0.05).

Conclusions:
These results demonstrate that chronic WL over 2 yrs is effective to decrease UA levels in obese subjects. Reducing UA levels by WL might link to improving glucose metabolisms, renal function (observed in CCr) and cardiac function (measured by LVH parameters). UA levels could predict the effects of WL on renal and cardiac functions. Suppression of sympathetic nervous activation by WL, but not insulin resistance, might be related to UA reduction associated with WL.
Abstract 502: Cost-effectiveness Of Therapeutic Drug Monitoring In Patients With Resistant Hypertension
Authors: Chung Oliver , BONAVENTURA Klaus , Sohns Christian , Haverkamp Wilhelm , Haverkamp Wilhelm , Dorenkamp Marc , Vongpatanasin Wanpen
Published: July 2021

Background:
Non-adherence to anti-hypertensive medications poses a significant problem in the treatment of patients with presumed resistant hypertension (RH). Our recent study has shown that therapeutic drug monitoring (TDM) is a useful tool not only for detecting medication non-adherence but also exploring the barrier to antihypertensive drug therapy, resulting effective BP control. However, the cost effectiveness of TDM in the management of resistant hypertension has not been investigated.

Method:
A Markov model was used to evaluate life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios in RH patients receiving either TDM optimized therapy or standard best medical therapy (BMT). The model ran from the age of 30 to 100 years or death, using a cycle length of 1 year. Efficacy of TDM was modeled by reducing risk of hypertension-related morbidity and mortality.

Results:
In the age group of 60-year olds, TDM gained 1.07 QALYs in men and 0.97 QALYs in women at additional costs of є3,854 and є3,922, respectively. Given a willingness-to-pay threshold of є35,000 per QALY gained, the probability of TDM being cost-effective compared to BMT was ≥95% in all age groups from 30 to 90 years. Incremental cost-effectiveness ratios were influenced mostly by the annual frequency of TDM testing, the rate of non-responders to TDM, and the magnitude of effect of TDM on systolic blood pressure (Figure).

Conclusion:
Therapeutic drug monitoring presents a potential cost-effective health care intervention in patients diagnosed with RH. Importantly, this finding is valid for a wide range of patients, independent of gender and age.
Abstract 531: Regulation of Plasma 20-HETE and Soluble Epoxide Hydrolase by Salt Balance in Normotensive Subjects
Authors: Elijovich Fernando , Brown Nancy J , Milne Ginger L , Laffer Cheryl L
Published: July 2021

The tissue sources of circulating and urinary 20-HETE and EETs are not well known. We have previously shown urine 20-HETE abnormalities in salt-sensitive (SS) hypertension. We studied plasma 20-HETE and EETs in normotensive volunteers classified as SS or salt resistant (SR) with an acute protocol of salt loading (HS, 460 mmol diet and iv) and depletion (LS, 10 mmol and furosemide). Plasma 20-HETE and total (EET+DHET) or active EET did not differ between SR and SS during baseline (B, UNaV 146±17 mmol/24hr), HS (422±20) or LS (24±6). In normal SR subjects, HS did not affect the levels of either eicosanoid but reduced degradation of EETs into DHETs by decreasing the activity of soluble epoxide hydrolase (sEH or DHET/[EET+DHET]). No major clinical or biochemical correlates for plasma 20-HETE were identified in B, HS or LS. In SR but not SS, EET+DHET (r=0.57, p<0.003) and DHET (r=0.45, p<0.03) correlated with aldosterone during B and HS. LS stimulated 20-HETE in both SS and SR and also unexpectedly increased EET+DHET in SR subjects. This did not lead to increased EETs because of concomitant stimulation of sEH with increased degradation into DHETs. In SR, stimulation of 20-HETE by LS correlated with greater natriuresis (r=0.71, p<0.02), greater reduction of MAP (r=0.66, p<0.03) and lesser stimulation of aldosterone (r=0.64, p<0.04), relationships not observed in SS. Finally, in SR subjects only, during B and HS, plasma 20-HETE correlated with the activity of sEH (r=0.56, p<0.005) and levels of DHET (r=0.63, p<0.001), but not with total or active EETs. Our data on stimulation of plasma 20-HETE by LS and its correlates (markers of severity of sodium depletion) suggest recruitment of systemic vasoconstrictor 20-HETE for maintenance of BP. Plasma EET responses to HS and LS are not consistent with its renal natriuretic role but correlate with aldosterone responses to salt balance, perhaps reflecting modulation of aldosterone actions on extrarenal ENaC. Although no significant correlations were detected between blood pressure and EETs, there was a direct relationship between plasma 20-HETE, sEH activity and degradation of EETs into DHETs. This suggests coordinated vasoconstriction and vasodilation by these eicosanoids in normal SR humans, which is disrupted in normotensive SS.
Abstract 536: Myeloid Nox2 Mediates Vitamin D-induced Vascular Healing
Authors: Schröder Katrin , Wong SzeKa , Leisegang Matthias , Shah Ajay M. , Brandes Ralf P.
Published: July 2021

Background:
Vitamin D deficiency in humans is frequent and has been associated with inflammation. The role of the active hormone, 1,25-dihydroxy-vitamin D3 (1,25-VitD3) in the cardiovascular system is controversial; high doses induce vascular calcification whereas deficiency has been linked to cardiovascular disease. We hypothesized that treatment with 1,25-VitD3 promotes vascular regeneration.

Methods and Results:
The effects of 1,25-VitD3 in mice and of its precursor, VitD3, in healthy volunteers were studied. In mice, a 1,25-VitD3 (100ng/kg/d) enhanced carotid artery reendothelialization and increased the number of circulating CD45-CD117+Sca1+Flk1+ angiogenic myeloid cells (AMC). Importantly, in streptozotocin-diabetic mice, 1,25-VitD3 also promoted reendothelialization and restored the massively impaired angiogenesis in the femoral artery ligation model. As revealed my conditional knockout mice of the vitamin D receptor (VDR), 1,25-VitD3 increased the production of SDF1 in myeloid, but not endothelial or smooth muscle cells, which then promoted healing and attracted AMCs. This pathway was dependent on Nox2: 1,25-VitD3-induced healing was not affected by genetic deletion of Nox1 or Nox4 but absent in Nox2 knockout mice. Moreover, Nox2 but not Nox1 or Nox4 was induced in the course of healing. 1,25-VitD3 also increased the ROS formation of AMCs as determined by Amplex red / HRP assay. Conditional Nox2 knockout revealed that the effect of 1,25-VitD3 on healing and SDF1 production was mediated by LysM-positive cells but not through the endothelium. Accordingly, in cultured monocytes, stimulation with the combination of cytokines and vitamin D3 increased SDF1 production and this effect was blocked after knockdown of Nox2 or inhibition of the enzyme by gp91-ds-TAT. To determine the clinical relevance of this finding, healthy volunteers were treated with VitD3 (4000 I.E. cholecalciferol/day). Similarly as in mice, also in humans, VitD3 increased the number of circulating AMCs.

Conclusions:
By inducing SDF1 and enhancing AMCs, VitD3 through a pathway involving Nox2 is a novel approach to promote vascular repair.
Abstract 546: Arterial Stiffness And Pulse Pressure Predict Kidney Disease Progression In Chronic Kidney Disease
Authors: Townsend Raymond , Bansal Nisha , Chirinos Julio , Cuevas Magdalena , Ford Virginia , Grunwald Juan , Hsu Chi-yuan , Roy Jason , Kallem Krishan , Rahman Mahboob , Chai Boyang , Weir Matthew , Wright Jackson , Feldman Harold I
Published: July 2021

Brachial pulse pressure (bPP) predicts kidney function in CKD. Pulse wave velocity (PWV) may provide additional prediction of CKD progression, and was evaluated longitudinally in CKD patients enrolled in the CRIC cohort. bPP was used because it shows superior CKD progression prediction in humans.

There were 2821 participants in CRIC who underwent an assessment of PWV most of whom were studied at their second year follow-up visit. Of these 43 % were women, 48% diabetic, mean age 60 years and mean estimated GFR of 44.6 mL/min/1.73m2. Blacks were 40%, whites 44%, and Hispanics 12%. Mean blood pressure was 127/70 mmHg; mean bPP was 54 mmHg. The interaction of PWV with bPP on the occurrence of ESRD (dialysis or a transplant) [left panel of figure] and a combined endpoint of halving of the eGFR or ESRD [right panel], was analyzed used Cox regression. Events by tertiles of PWV (<7.9 msec; 7.9-10.3 m/sec; >10.3m/sec) and bPP (<46 mmHg, 46-62 mmHg, >62 mmHg) are shown in the figure.

There were significant interactions between PWV and bPP for both outcomes. For ESRD the hazard ratio of the highest tertiles of PWV/bPP compared with the lowest was 3.18 (p<0.001). For the combined ESRD or halving of eGFR the HR was 2.65 (p<0.001). In multivariable regression important predictors of CKD progression in this model were age, male gender, non-white race/ethnicity, initial eGFR, and proteinuria.PWV showed a strong and graded interaction with bPP in the prediction of ESRD and the combined outcome of halving of GFR or ESRD. A greater appreciation of the role of arterial stiffness in CKD is an important step towards pursuing the mechanisms underlying how this measure may influence the course of kidney disease progression.
Abstract 552: Vitamin D in Chronic Kidney Disease is Aassociated with Total or Central Body Adiposity?
Authors: BARRETO SILVA MARIA INES , VICENTE VANESSA , LEMOS CARLA , KLEIN MARCIA R , BREGMAN RACHEL
Published: July 2021

Introduction:
Obesity is reported as an important contributor for vitamin D (VitD) deficiency. Nevertheless, most of the studies use body mass index (BMI) to evaluate this relationship and results are not clear. In CKD, obesity and VitD deficiency are common conditions, however the association of body adiposity and VitD in nondialyzed CKD patients is not known.

Objective:
Determine the association of VitD with total and central body adiposity in nondialyzed CKD patients.

Methods:
Cross-sectional study conducted in nondialyzed CKD outpatients under regular treatment. Inclusion criteria: clinically stable; age≥18 years; estimated glomerular filtration rate (CKD-EPI) (eGFR)≤ 60 ml/min. Body adiposity: BMI (classified by WHO criteria; 1998); waist circumference (WC); waist-to-height ratio (WheiR); waist-to-hip ratio (WHR); total body adiposity (TBA) by dual-energy X-ray absorptiometry (DXA) and by body adiposity index (BAI). VitD[25(OH)D] analysed by Passing-Bablok method and leptin, used as TBA marker, by radioimmunoassay. Participants were stratified as: VitD-deficient (<20 ng/ml; 23%/n=40; VitD=16±3 ng/ml) and VitD-no-deficient (≥20 ng/ml; 77%/n=135; VitD=31±8 ng/ml).

Results:
We studied 175 nondialyzed CKD (57.7% men/n=101), 66±13 years, eGFR=29±13ml/min., BMI=26±5 kg/m2, VitD=27±9.7 ng/ml. CKD stages (CKD-s) profile was (%/n): 3A-15%/26; 3B-32%/56; 4-39%/68; 5-14%/25. VitD-deficient patients compared with VitD-no-deficient showed higher TBA evaluated by DXA (38±7 vs. 33±9%,p=0.003), BAI (32±7 vs. 29±5%,p=0.009) and leptin (median; interquartil interval=6.2; 5-10 vs. 11; 10-19 ng/dl,p=0,01), but showed no differences (p≥0.05) for BMI and central adiposity parameters (WC;WheiR;WHR). Serum 25(OH)D values were negatively associated with TBA (DXA: r= -0.3; p=0.0008; BAI: r= -0.22; p=0.008), but was not associated with BMI and with WC, WheiR, WHR. In multiple regression analysis TBA (by DXA and by BAI), but not BMI, was independently associated with VitD (p=0.001) after adjusted by age, gender, eGFR.

Conclusion:
Total body adiposity, but not BMI or central adiposity, was independently associated with vitamin D levels in this population with CKD.
Abstract 559: Augmented Urinary Angiotensinogen in Young Type-1 Diabetic Subjects Correlates with Hemoglobin A1c and Urinary 8-Isoprostane
Authors: Navar L Gabriel , Katsurada Akemi , Fonseca Vivian , Prieto Minolfa C , Chalew Stuart , Kobori Hiroyuki
Published: July 2021

Previous studies indicate that the intrarenal renin-angiotensin system (RAS) is activated in type-1 diabetes mellitus (T1DM) experimental animal models and human subjects, and is reflected by augmentation of urinary angiotensinogen (uAGT) excretion rate. Studies were performed to evaluate uAGT in young patients with short duration diabetes mellitus (DM) and its relationships with HbA1c and urinary 8-isoprostane excretion rate. Blood and urine samples were collected from 77 young (15±1 years) patients (44 male, 33 female) with short duration T1DM treated only with insulin and 36 (17 male, 19 female) control subjects. Serum glucose levels were 85±4 mg/dl in control subjects and 192±11 mg/dl in DM patients. Urinary Alb/Cr and uPro/Cr ratios were not significantly different in DM patients compared to control (8.6±.9 vs 9.7±.6 and 51±8 vs 62±14 mg/g). However, the uAGT/Cr ratios were significantly elevated in the DM patients (6.8±.8 vs 16.5±1.5 ug/g). Correlation analysis demonstrated highly significant relationships (P<.0001) between uAGT/Cr and HbA1c (R=.44) and urinary 8-isoprostane excretion rate (R=.52) in the DM patients. These results indicate that, even in young non-albuminuric patients with relatively short duration of DM, uAGT excretion rates are increased, suggesting early activation of the intrarenal RAS, and are correlated with HbA1c and urinary 8-isoprostane levels indicative of increased reactive oxygen species. Accordingly, uAGT levels may serve as an early marker of an activated intrarenal RAS and provide a specific index of renal RAS status potentially useful in monitoring clinical response to therapy.
Abstract 565: Genome-wide miRNA Expression Profiling and OPLS Discriminant Analysis in Hypertension and Cardiac Disease
Authors: Pinho Maria João , Vaz-da-Silva Manuel , Cabral José M , Afonso Joana , Serrão Paula , Bonifácio Maria João , Palma Nuno , Soares-da-Silva Patricio
Published: July 2021

MicroRNAs (miRNAs) are regulators of gene expression and play a key role in the pathophysiology of various disease processes, namely cardiovascular disease. This study aimed at the identification of the miRNA expression pattern of peripheral blood mononuclear cells derived from hypertensive subjects (HT) and non-hypertensive subjects with cardiac disease (CD) using a genome-wide approach. Furthermore, we explored the potential of orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze miRNA expression data. The homogeneity of the population was assessed with Principal Component Analysis (PCA) and verified by the clear separation of the three groups on the basis of the miRNA expression levels. Moreover, local PCA of HT group indicates the splitting of this group in two distinct subgroups. This distinction correlates with two subject’s characteristics (smoking habits and history of myocardial infarction) that are closest to the CD group. OPLS-DA analysis confirms the separation of three groups and identified the most important miRNA to discrimination between groups. Among the most influential miRNA to the positive differentiation of HT from CD and control, several of them are relevant to endothelial dysfunction. On the other hand, miRNAs associated with angiogenesis positively differentiate CD from HT and control. Mir-186, a regulator of myogenin, is the most important miRNA to discriminate HT from CD. These results provide evidence of altered miRNA profile in hypertensives and cardiac disease and demonstrate that PCA and OPLS-DA are very useful and robust tools to analyze how different miRNAs contribute to the separations of groups and to find interesting patterns within the multidimensional data.
Abstract 568: Congenic Mapping of Hypertension in the Nephrectomy Model of Chronic Kidney Disease.
Authors: Cechova Sylvia , Chan Rosa , Rudy Christine , Le Thu H
Published: July 2021

Introduction:
We previously reported a locus on mouse chromosome 11 (chrom 11) linked to development of hypertension (HTN) after sub-total nephrectomy (Nx). To begin fine mapping, we used the 129S6 (129) susceptible strain and the C57BL/6 (B6) resistant strain to generate 4 reciprocal congenic lines carrying ~ 2-LOD intervals of the linked locus for recombinant progeny testing. The intervals are defined by microsatellite markers 1-5 and markers 1-6, corresponding to regions defined by markers D11Mit2 and D11Mit177, and D11Mit2 and D11Mit285, respectively. Through brother-sister matings, the 4 lines are as follows: 1) 129 background, homozygous for B6 segment defined by markers 1-5 (129
Chrom11:1-5ofB6
), 2) 129 background, homozygous for 129 segment defined by markers 1-5 (129
Chrom11:1-5of129
), 3) B6 background, homozygous for 129 segment defined by markers 1-6 (B6
Chrom11:1-6of129
) and 4) B6 background, homozygous for B6 segment defined by markers 1-6 (B6
Chrom11:1-6ofB6
).

Methods:
Sub-total Nx was performed on male and female congenic mice at ~ 8 weeks of age. Beginning 4 weeks after surgery, using tail cuff manometer, mice were trained for 2 weeks, after which systolic blood pressure (SBP) was recorded daily for 2 weeks.

Results:
Table 1 summarizes the average SBP of the congenic lines.

Conclusion:
These findings confirm the effect of this chrom 11 region is dependent on the 129 genetic background, and suggest that interactions between this 129 locus and other loci in the 129 genome are necessary for the development of HTN after nephron mass reduction. Moreover, the influence of this region on chrom 11 appears to be dependent on sex.
Abstract 569: Distinct Metabolomic Features in Dahl salt-sensitive rats and consomic SS.13BN rats
Authors: Wang Le , Hou Entai , Wang Zhengjun , Sun Na , He Liqing , Chen Lan , Jia Pu , Zheng Xiaohui , Liang Mingyu , Tian Zhongmin
Published: July 2021

Our previous proteomic study revealed substantial differences in several proteins between Dahl salt-sensitive (SS) rats and salt-insensitive consomic SS.13BN rats. Subsequent studies indicated a role of fumarase insufficiency in the development of hypertension in SS rats. A global metabolic profiling study using gas chromatography/mass spectrometry (GC/MS) was performed in plasma of SS rats (n=9) and SS.13BN rats (n=8) on a 0.4% NaCl diet to gain further insights into the relationship between alterations in cellular intermediary metabolism and predisposition to hypertension. Principal component analysis of the data revealed a clear clustering and separation of metabolic profiles between SS rats and SS.13BN rats. 23 differential metabolites were identified (P<0.05). Levels of five TCA cycle-related metabolites, fumarate, cis-aconitate, isocitrate, citrate and succinate, were higher in SS rats. Pyruvate, which connects TCA cycle and glycolysis, was also increased in SS rats. Moreover, enzymatic activities of fumarase, aconitase, α-ketoglutarate dehydrogenase and succinyl-CoA synthetase were lower in the heart, liver or skeletal muscles of SS rats. The distinct metabolic features in SS and SS.13BN rats supports a role of abnormal TCA cycle in predisposing SS rats to developing salt-sensitive hypertension.
Abstract 578: Depletion Of Natural Killer Cells Is Associated With Deterioration Of Fetal Outcome In A Transgenic Rat Model For Preeclampsia
Authors: Golic Michaela , Haase Nadine , Herse Florian , Przybyl Lukasz , Verlohren Stefan , Henrich Wolfgang , Müller Dominik N , Dechend Ralf
Published: July 2021

Introduction:
Preeclampsia is defined by maternal hypertension and proteinuria developed during pregnancy. It is associated with fetal growth restriction and diminished trophoblast cell invasion into uterus. Uterine natural killer cells are the most abundant leukocytes during early pregnancy. They are considered as regulators of placentation and remodeling of spiral arteries. However, their precise function remains still unclear and is contradictory. It has been shown that depletion of natural killer cells increases number of invasive trophoblast cells in healthy pregnant rats. We tested the hypothesis whether depletion of natural killer cells improves maternal symptoms and fetal outcome in preeclamptic rats.

Material and Methods:
We have developed and characterized a transgenic rat model for preeclampsia. After a female rat expressing the human angiotensinogen has been mated with a male transgenic for the human renin, the female develops hypertension and proteinuria during pregnancy. Its fetuses are growth restricted. Within this rat model, we depleted natural killer cells with the antibody anti-asialo GM1 according to a published protocol (intraperitoneal injections on day 5 and day 10 of pregnancy). We analyzed 7 preeclamptic rats with in total 72 fetuses receiving anti-asialo GM1 and 5 control rats with in total 54 fetuses receiving rabbit serum. Rats were culled at end of pregnancy (day 21).

Results:
Successful depletion of natural killer cells was shown by flow cytometry of the spleen and mRNA analysis of the uterus. Application of anti-asialo GM1 had no influence on blood pressure (158±8mmHg control group vs. 155±8mmHg anti-asialo GM1 group, mean arterial pressure on day 17, measured by telemetry), proteinuria (7.0±5.1mg/24hrs control group vs. 16.2±10.0mg/24hrs anti-asialo GM1 group), and fetal weight (2.9±0.6g control group vs. 2.7±0.5g anti-asialo GM1 group). However, fetal brain/liver weight ratio as a marker of intrauterine growth retardation was increased by 22% in fetuses of the anti-asialo GM1 group (0.9±0.2 control group vs. 1.1±0.4 anti-asialo GM1 group, p=0.02).

Conclusion:
Depletion of natural killer cells is not associated with altered maternal symptoms of the preeclamptic phenotype, but with deterioration of fetal outcome.