bluuebunny/crossref_metadata_2025_split huggingface dataset:
IMPACT OF HYPERTENSION IN THE MORBIDITY AND MORTALITY IN DIABETES MELLITUS: A REAL-WORLD DATA
Authors: Sauri Inmaculada , Uso Ruth , Trillo Jose Luis , Fernandez Antonio , Holgado Jose Luis , Lopez Cristina , Vela Sara , Bea Carlos , Ruiz Adrian , Martinez Fernando , Redon Josep 
Published: April 2021

Objective:
To assess the impact of hypertension in the risk of cardiovascular events and mortality in a population of diabetic patients from a Mediterranean population based in Real World Evidence.

Design and method:
The sample was recruited from beneficiaries of the Valencian Health Agency's health care system, with a population of 3799884 people older than 25 years in 2012. The observational study was undertaken as part of routine clinical practice from January 2012 to December 2016. Diabetes was defined as a non-fasting glucose higher or equal to 200 mg/dl, a recorded physician diagnosis, medication use or an HbA1c higher or equal to 6.5%. Hypertension was defined by a recorded physician diagnosis or antihypertensive medication use. Estimated glomerular filtration rate (eGFR) was calculated from calibrated creatinine, age and sex using the CKD-EPI and CKD was defined when eGFR < 60 ml/min/1.73m2. Vital status was determined by matching records and death certificates from the Spanish National Death Index.

Results:
Among the total population of 3799884, DM was present in 510922 (13%) patients (12% in women and 15% in men), Average of HbA1c was 6.9% + 1.4%. Hypertension was recorded in 387590 (75%) with a rate of BP < 140/90 mmHg of 45% and CKD in 125441 (24%). The incidence rates for DM, with and without diagnostic of HTN, of acute myocardial infarction, heart failure and stroke, as well all-cause mortality by age and sex rates are in the figure, in which the times of increment of risk due to the presence of HTN is presented.

Conclusions:
Presence of HTN in patients of diabetes largely increases the risk of MI, stroke, HF and all-cause mortality. The impact even it is higher in more younger patients, it still until the last decade of life.
MODULATION OF SYMPATHETIC NERVE ACTIVITY BY SGLT2 INHIBITOR EMPAGLIFLOZIN IN DIABETIC RABBITS
Authors: Gueguen Cindy , Burke Sandra L. , Barzel Benjamin , Lim Kyungjoon , Eikelis Nina , Watson Anna Md , Jha Jay C. , Jackson Kristy L. , Sata Yusuke , Lambert Gavin W. , Jandeleit-Dahm Karin Am , Cooper Mark E. , Thomas Merlin C. , Head Geoffrey A. 
Published: April 2021

Objective:
Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in patients with type-2 diabetes is associated with 38% reduction in cardiovascular mortality. We explored the notion that the mechanisms underlying these benefits may involve an action on the sympathetic nervous system (SNS).

Design and method:
Diabetes was induced by alloxan in New-Zealand White rabbits. We determined the associated changes in blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) as well as baroreflex responses to changes in BP and norepinephrine spillover in conscious rabbits. The effects of one-week treatment with empagliflozin were compared to those of another blood glucose-lowering treatment insulin, the proximally-acting natriuretic acetazolamide, the ACE inhibitor perindopril, vehicle treatment and to an untreated diabetic group.

Results:
Diabetic rabbits were treated with daily insulin to maintain a stable elevation in blood glucose over 4 weeks (20.5 ± 0.4 mM vs 6.5 ± 0.4 mM in controls). BP was 9% greater in diabetic than non-diabetic rabbits (P = 0.02) but there were no differences in RSNA or HR. One-week treatment with empagliflozin (without insulin) lowered blood glucose by 43% but there was no difference in BP, HR or RSNA between these animals and untreated diabetic rabbits or those treated with acetazolamide. However, insulin treatment alone lowered blood glucose similarly to empagliflozin (32%) and increased HR (+10%) while perindopril lowered BP (-9%). In diabetic rabbits there was marked augmentation of the maximum RSNA response to baroreceptor unloading compared to non-diabetic (+69%, P < 0.01). Empagliflozin attenuated the baroreflex by 34% and there was a similar reduction after acetazolamide (-29%, both P < 0.05). Empagliflozin also attenuated the HR baroreflex (-8%) but insulin and perindopril had no effect on either baroreflex. Norepinephrine spillover to plasma was similar in diabetic and non-diabetic rabbits but was elevated after both empagliflozin and acetazolamide (+147% and + 134%, P < 0.05).

Conclusions:
Empagliflozin normalised the maximal RSNA response to lowering BP, which was exaggerated in diabetic rabbits, without altering BP or resting RSNA. A similar action of the natriuretic acetazolamide suggests that the mechanism underlying the cardiovascular benefits of empagliflozin may involve increased sodium and water excretion.
SODIUM ACETATE AND EPLERENONE RESTORE RENAL GLUTATHIONE AND ADENOSINE CONTENT OF RATS EXPOSED TO TESTOSTERONE DURING LATE GESTATION
Authors: Usman Taofeek , Adeyanju Oluwaseun , Areola Emmanuel , Badmus Olufunto , Olaniyi Kehinde , Oyeyipo Ibukun , Olatunji Lawrenc 
Published: April 2021

Objective:
The kidney plays a critical role in human health and any alteration to its normal function can lead to severe morbidity and mortality. Prenatal exposure to elevated testosterone level has been linked to several disorders particularly kidney disorders by acting undoubtedly through androgen receptor (AR) whereas the involvement of mineralocorticoid receptor (MR) is unclear. The renal effect of sodium acetate (SAc) during late gestational testosterone exposure is not well known. We therefore hypothesized that SAc or MR blockade would protect the kidney of testosterone-exposed pregnant rats against glutathione and adenosine depletion.

Design and method:
Twenty-five pregnant Wistar rats were treated (sc) with olive oil, testosterone propionate (0.5 mg/kg) singly or in combination with SAc (200 mg/kg; p.o), androgen receptor (AR) blocker, flutamide (Flu; 7.5 mg/kg; p.o) or (MR) blocker, eplerenone (Eple; 0.5 mg/kg) between gestational days 14 and 19.

Results:
The results showed that in the kidney of rats exposed to gestational testosterone, there were decreased kidney glutathione and adenosine, increased uric acid (UA), xanthine oxidase (XO), malondialdehyde (MDA), lactate dehydrogenase, free fatty acids and decreased nitric oxide (NO). There was also elevated plasma urea and creatinine. However, SAc and Eple comparably reversed all these testosterone-induced effects on the kidney.

Conclusions:
The findings in the present study demonstrate that testosterone exposure during late gestation caused defective renal antioxidant defense that is mediated by AR and MR. The study also provides evidence that sodium acetate protects the kidneys of gestational testosterone-exposed rats against defective antioxidant defense in like manner as MR or AR antagonist.
NOVEL MIRNAS AS TARGETS OF MESENCHYMAL STEM CELLS-BASED THERAPY FOR TREATMENT OF PREECLAMPSIA
Authors: Alqudah Abdelrahim , Suvakov Sonja , Richards Claire , Todd Naomi , Eastwood Kelly-Ann , Hunter Alyson J. , Holmes Valerie A. , Mccance David R. , Young Ian S. , Furlong Fiona , Ali Ahlam , Krasnodembskaya Anna , Lopez-Campos Guillermo , Garovic Vesna D. , Mcclements Lana 
Published: April 2021

Objective:
Preeclampsia is a cardiovascular complication characterised by the new onset of hypertension and proteinuria or other end-organ dysfunction. Currently there are no effective treatments for preeclampsia except delivery of the placenta and the baby, often pre-term. Administration of mesenchymal stem cells (MSCs) has shown therapeutic potential in pre-clinical models of preeclampsia. In this study, we aimed to identify novel placental miRNAs in preeclampsia which could be targeted by MSCs or their extracellular vesicles (MSC-EVs).

Design and method:
Human MSCs were isolated from abdominal fat tissue during caesarean section and cultured for 48 h. Human umbilical cord endothelial cells (HUVEC) were co-cultured with MSCs from pregnancies with or without preeclampsia (n = 3) up to 90 h and angiogenesis assessed using tubule formation assay in IncuCyteu live cell imaging system. Using separate patient samples, miRNA was isolated from placentae from women with and without preeclampsia (n = 2) and miRNA next generation sequencing (miRNAseq) performed. The expression of two miRNAs identified in miRNAseq (miRNA-183–5p and miRNA-203a-3p) were measured in HUVEC cells exposed to 24 h hypoxia (1%) or normoxia (21%) in the presence of MSC conditioned medium (MSC-CM) or MSC-EVs.

Results:
MSCs isolated from women with preeclampsia demonstrated impaired pro-angiogenic profile compared to MSCs derived from normotensive pregnancies measured by the network length (mm/m2) of HUVECs following 66 h, 72 h, 78 h, 84 h and 90 h of exposure to MSC-CM (n = 3, p = 0.001). The results of miRNAseq identified a number of aberrantly expressed miRNAs including mir-183–5p (logFC = -2.8, p = 0.001) and mir-203a-3p (logFC = -6.7, p = 0.001). Following exposure of HUVECs to hypoxia, mir-183–5p was significantly increased by approximately 8-fold (p = 0.001) whereas mir-203a-3p showed no change in expression. MSC-CM and MSC-EVs were both capable of ameliorating this increase in mir-183–5p as a result of hypoxia (p = 0.01, MSC-CM; p = 0.001, MSC-EVs).

Conclusions:
In patients with preeclampsia, MSCs show impaired angiogenic function, potentially leading to inappropriate placental development and angiogenesis in pregnancy. Administration of healthy MSCs or associated MSC-EVs could have a therapeutic potential in the treatment of preeclampsia and the mechanism could involve novel mir-183–5p as a treatment target.
MODULATION OF ANGIOGENIC BALANCE DURING PREGNANCY BY EXOGENOUS HEPARIN
Authors: Moore Kyle , Chapman Heather , George Eric 
Published: April 2021

Objective:
Preeclampsia is a pregnancy-specific hypertensive disorder, commonly believed to result from placental dysfunction. Increased soluble vascular endothelial growth factor receptor-1 (sFlt-1) is consistently observed, and is believed to be pathogenic. sFlt-1 contains a binding site for the extracellular matrix (ECM) component heparan sulfate and, therefore, the anticoagulant heparin. Here we hypothesized that infusion of unfractionated heparin during pregnancy in rodents would displace and solubilize ECM-bound sFlt-1, cause maternal angiogenic imbalance, and maternal hypertension.

Design and method:
To determine the effects of heparin on sFlt-1 release in vitro. BeWo cytotrophoblasts and rodent placental explants were cultured at normoxic (8%) or hypoxic (1%) oxygen with or without exogenous heparin (10U/ml). Media sFlt-1 was measured by commercial ELISA, membrane-bound sFlt-1 was determined by quantitative immunofluorescence, and mRNA levels of Flt-1, sFlt-1, and heparanase were monitored by qRT-PCR. Pregnant rats were treated from GD14–19 with i.p. unfractionated heparin (300U/kg/day) or saline. MAP was monitored by carotid catheter on GD19, when tissues were collected and morphometrics noted. Placental and plasma sFlt-1 and VEGF were determined by commercial ELISA.

Results:
In BeWo cells, heparin increased media sFlt-1 in both normoxic (p = 0.0002) and hypoxic samples (p = 0.0066) compared to controls. Total Flt-1 and sFlt-1 was significantly decreased in heparin treated cells compared to controls (p = 0.0063) by immunofluorescence. In placental explants, 10U/mL heparin for 30 minutes significantly increased media sFlt-1 levels (p = 0.0005). Flt-1 mRNA was significantly decreased (p = 0.003) in heparin treated samples, while sFlt-1 and HPSE showed trends towards reduction. Infusion of unfractionated heparin increased MAP in pregnant rats compared to controls (110 ± 2.6 mmHg vs. 99.6 ± 1.3 mmHg, respectively; p = 0.0038). Placental mass (p = 0.0116) and pup weight (p = 0.0075) decreased with heparin treatment. Placental sFlt-1 levels were reduced with heparin (761.8 ± 48.4 pg/mg vs. 913.8 ± 33 pg/mg; p = 0.0178), while placental VEGF levels trended toward reduction. Heparin treatment reduced plasma bioavailable VEGF levels compared to controls (1174 ± 38.5 pg/mL vs. 1492 ± 62.2 pg/mL, respectively; p = 0.0006).

Conclusions:
Heparin infusion released ECM-bound sFlt-1, altered the angiogenic balance in the placenta and circulation of pregnant rats, and elevated their mean arterial pressure.
AFTER 20 YEARS OF SUSTAINED REDUCTION, RECENT TRENDS IN CARDIOVASCULAR DISEASE BURDEN HAVE STAGNATED OR REVERSED TO INCREASE IN THE REGION OF THE AMERICAS
Authors: Martinez Ramon , Soliz Patricia , Mujica Oscar , Reveiz Ludovic , Moran Andrew , Campbell Norm , Ordunez Pedro 
Published: April 2021

Objective:
To assess the levels, trends, and socio-demographic inequalities of the Cardiovascular diseases (CVD) burden in countries of the Americas, with the ultimate purpose of providing evidence to guide programmatic interventions and health system responses in the context of the World Health Organization's HEARTS Initiative, and the Resolve To Save Life's Global Cardiovascular Health Program.

Design and method:
This descriptive population-based study used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We examined disability-adjusted life-years (DALYs), years lived with disabilities (YLDs), years of life lost (YLLs) due to premature mortality from all-CVDs, and cause-specific CVDs using crude, age-specific, and age-standardized rates per 100,000 population by sex in 37 countries of the Americas. We assessed trends of outcome measures by estimating the average annual percentage change from 1990 to 2017 and quantified cross-country social-demographic inequalities in CVD burden.

Results:
In the Region of the Americas, age-standardized DALYs due to CVD decreased by -1.9% per year (95% UI -2.0 to -1.7) from 5,263.7 years (95% UI 5,143.1–5,390.0) per 100,000 population in 1990 to 3,159.4 years (3,047.1–3,280.4) in 2017. YLLs accounted for 87% of DALYs. Despite this progress, reduction rates decelerated in 2007–2013 and stagnated to -0.1% per year (95% UI -0.5 to 0.3) in 2013–2017. Ischemic heart disease (IHD) and stroke accounted for 80% of all-CVD DALYs. IHD exhibited similar trend patterns, but stroke showed an increasing trend since 2015. In 2017, CVD burden varied across countries from 1,812 years/100 000 (1,594–2,033) in Peru to 8,662 years/100 000 (7,404–10,029) in Haiti. From 2010 to 2017, reduction rates decelerated in all countries but Peru, trends stagnated in 8 countries and reversed to upward in 10 countries.

Conclusions:
The deceleration of decreasing trends in CVD burden in 18 countries, and the stagnation and reversed to increasing trends in 18 out of 37 countries of the Americas in recent years, indicates the need for reinvigorated efforts to reduce the CVD burden. The socio-demographic inequalities across countries pose challenges to these efforts. Countries with less favorable progress should be targeted for strengthening their national programs.
CHARACTERIZATION OF GLUCOSE UPTAKE METABOLISM IN VISCERAL FAT BY 18F-FDG PET/CT REFLECTS INFLAMMATORY STATUS IN METABOLIC SYNDROME
Authors: Pahk Kisoo , Kim Eung Ju , Lee Yong -Jik , Kim Sungeun , Seo Hong Seog 
Published: April 2021

Objective:
The inflammatory activity of visceral adipose tissue (VAT) is elevated in metabolic syndrome (MS), and associated with vulnerability to atherosclerosis. Inflammation can be assessed by glucose uptake in atherosclerotic plaques.

Design and method:
We investigated glucose uptake of VAT using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in 203 participants: 59 without MS component; M(0), 92 with one or two MS components; M(1-2), and 52 with MS. Glucose uptake in VAT was evaluated using the mean standardized uptake value (SUVmean) and the maximum SUV (SUVmax). Glucose uptakes of immune-related organs such as the spleen and bone marrow (BM) were evaluated using the SUVmax.

Results:
VAT SUVmax correlated with high-sensitivity C-reactive protein (hsCRP) and the SUVmax of spleen and BM, which reflect the status of systemic inflammation. Both hsCRP and the SUVmax of the spleen and BM were higher in the MS group than in the M(1-2) or M(0) groups. In VAT, SUVmax increased with increasing number of MS components, while SUVmean decreased.

Conclusions:
The SUVmax and SUVmean of VAT assessed by 18F-FDG PET/CT reflected inflammation-driven unique glucose metabolism in the VAT of MS patients, distinct from that of atherosclerotic plaques.
PENDRIN REDUCTION IS ASSOCIATED WITH ACUTE INTRAVENOUS SODIUM CHLORIDE LOADING IN PATIENTS WITH PRIMARY ALDOSTERONISM
Authors: Wu Aihua , Wolley Martin J. , Wu Qi , Cowley Diane , Gordon Richard D. , Fenton Robert A. , Stowasser Michael 
Published: April 2021

Objective:
Primary aldosteronism (PA) is a common, potentially curable form of hypertension characterised by excessive, autonomous aldosterone production. In the distal renal tubule, aldosterone is involved in volume homeostasis by modulation of NaCl reabsorption via the epithelial Na+ channel (ENaC), the NaCl cotransporter (NCC) and the Cl-/HCO3- exchanger (pendrin). Na+ loading suppresses plasma aldosterone but its effects on these proteins in humans remain unclear.

Design and method:
Urine samples were collected before and 1 h after a 4 h 2L 0.9% saline infusion from 13 (F9/M5) subjects including 10 confirmed with PA and 3 in which PA was excluded [herein designated low renin hypertension (LRH)]. Urinary exosomes were harvested by ultracentrifugation and analysed by LC-MS/MS.

Results:
Plasma aldosterone decreased (P < 0.05) from 623 [312, 2210] (median [range]) to 338 [197, 2330] pmol/L in confirmed PA and from 223 [180, 256] to 117 [110, 133] pmol/L in LRH. There were no changes in plasma K+ (pre 3.4 [2.6, 4.3] vs post 3.6 [2.6, 3.9] mmol/L in PA; pre 4.1 [3.6, 4.1] vs post 4.0 [3.9, 4.0] mmol/L in LRH). LC-MS/MS demonstrated decreases in abundance of pendrin (21.5%, P < 0.01) and aquaporin-2 (AQP2) (42.9%, P < 0.01) in urinary exosomes and a trend towards a decrease in NCC (20%, P = 0.07) in patients with PA. No changes were seen in those with LRH. PA patients had higher baseline pendrin abundance (1.2 [1.0, 2.1]) than LRH patients (0.7 [0.5, 1.0]) (P < 0.05), but there was no difference in baseline AQP2. In all 13 subjects combined, baseline pendrin correlated positively with plasma aldosterone (P = 0.02, r2 = 0.32) and negatively with plasma K+ (P = 0.02, r2 = 0.35), whilst no correlations were observed between AQP2 and aldosterone or K+. Delta Pendrin (P = 0.04, r2 = 0.3) and delta AQP2 (P = 0.01, r2 = 0.58) positively correlated with delta plasma aldosterone.

Conclusions:
In PA, reduction in pendrin during saline infusion may be due to falling plasma aldosterone in response to NaCl loading. Although also correlating with reduction in aldosterone, a more likely explanation for the reduction in AQP2 may be a fall in plasma vasopressin induced by water loading. Different observations in LRH require validation with larger numbers.
TUBULOINTERSTITIAL INJURY WAS SUPPRESSED BY INHIBITION OF PLATELET-DERIVED GROWTH FACTOR PATHWAY IN RAT RENAL VENOUS CONGESTION MODEL
Authors: Hirose Takuo , Matsuki Takuma , Takahashi Chika , Oba-Yabana Ikuko , Kato Toshiko , Tajima Ryo , Seki Takayuki , Kinugasa Satoshi , Nakamura Hannah , Tani Junichi , Mori Takefumi 
Published: April 2021

Objective:
Increased central venous pressure in congestive heart failure is responsible for renal dysfunction. Pericytes contribute to the renal myofibroblast pool in renal fibrogenesis via pericyte-myofibroblast transition (PMT), and their detachment of from capillaries might trigger capillary rarefaction. We recently created a novel rat renal congestion model by ligation of the inferior vena cava (IVC) between the renal veins, resulting high renal interstitial hydrostatic pressure, tubulointerstitial injury and PMT. In this model, platelet-derived growth factor receptors (PDGFRs), which are PMT indicators, were upregulated. Thus we examined the effect of imatinib, a PDGFR inhibitor, for renal injury.

Design and method:
The inferior vena cava (IVC) between the renal veins was ligated by suture in male Sprague-Dawley rats to increase upstream IVC pressure and induce congestion only in the left kidney. Imatinib mesylate (20 mg/kg) or saline were injected intraperitoneally every day from one day before the operation. Both the right control kidney and the left congested kidney were obtained 3 days after the surgery and were weighted. The expression of renal injury marker and PDGFRs were assessed by quantitative reverse transcription-polymerase chain reaction, western blot and immunohistochemistry. The vascular structure of the kidneys was observed using micro-computed tomography (μCT) and low-vacuum scanning electron microscopy (LV-SEM).

Results:
Kidney weight was significantly increased in the left congested kidneys, and ameliorated by imatinib administration. However, μCT and LV-SEM results showed the maintained congestive state even in imatinib administration. Renal injury and fibrosis were observed in the congested kidneys, and imatinib significantly suppressed renal injury and fibrosis around the vasa recta.

Conclusions:
These results suggest that the inhibition of the PDGFRs pathway could suppress the renal fibrosis after PMT in heart failure-derived renal congestion. This mechanism could be a candidate therapeutic target for renoprotection against heart failure.
ROLE OF ACE2 GLYCOSYLATION AND RHO KINASE INHIBITION IN THE INFECTIOUS/THERAPEUTIC PROCESS OF COVID-19. INSIGHTS FROM GITELMAN'S AND BARTTER'S SYNDROMES PATIENTS
Authors: Bertoldi Giovanni , Gianesello Lisa , Rigato Matteo , Sgarabotto Luca , Calò Lorenzo 
Published: April 2021

Objective:
ACE2 in addition to be the counterregulatory enzyme in RAS system, is the entry point of SARS-CoV-2. Several studies have reported its protective role in SARS-CoV-2-induced Acute Distress Syndrome (ARDS) and a relationship between Rho kinase (ROCK), ARDS and increased ACE2 levels induced by ROCK inhibitors. Cells’ ACE2 expression is in two different immunoreactive forms, glycosylated and unglycosylated, but only the glycosylated is associated with viral binding. ACE2-glycosylation is driven by the acidic pH of intracellular endosomes/lysosomes/Golgi vesicles and this represents the rational to the prophylactic/therapeutic use of antimalarial drugs as hydroxychloroquine/chloroquine, weak bases that increase the pH of vesicles, which leads to the production of unglycosylated ACE2 and therefore reduction/inhibition of viral binding. Gitelman's and Bartter's syndrome patients (GS/BS) (rare genetic tubulopathies) have activated RAS, high Ang II yet normotension/hypotension, metabolic alkalosis, increased and related ACE2 and its product Ang 1–7 levels, reduced ROCK activity therefore may provide information on the protective role of increased ACE2 levels and ROCK inhibition. This study has assessesed the impact of COVID-19 on GS/BS

Design and method:
We performed a telephone survey on more than 100 GS/BS from the hotspots of COVID-19 pandemic in Northern Italy (Veneto, Lombardia, Emilia Romagna). COVID-19 prevalence in the general population was obtained from Civil Protection's official data and the estimated prevalence from published data. 95% CI values processed with Clopper-Pearson method using R-software

Results:
None of GS/BS reported infection/symptoms of COVID-19, which was statistically not significant vs the prevalence of COVID-19 in the general population in the Italian hotspots due to the low prevalence of GS/ BS (rare diseases) (95% CI 0.0 -3.0% vs 0.65%, 95% CI 0.6–0.7%). It becomes significant vs the estimated prevalence in the general population in the hotspot regions (8.7%, 95% CI 8.7–8.8%, (C2), p = 0.004)

Conclusions:
GS/BS might serve as a human model of increased ACE2 for ex-vivo mechanistic investigation on viral binding; provide additional evidence on the absence of high ACE2 levels-increased risk of COVID-19; demonstrate that suspension of treatments with ACE inhibitors/ARBs, which increase ACE2 expression, to reduce the risk of infection is not rationale.