bluuebunny/crossref_metadata_2025 huggingface dataset:
ROSTAFUROXIN RESTORES THE INCREASED PERIVASCULAR INNERVATION IN RESISTANCE ARTERIES OF HYPERTENSIVE RATS
Authors: de Paula Ricardo Bernardino , Rossoni Luciana Venturini
Published: April 2021

Objective:

Ouabain (OUA) inhibiting Na+, K+-ATPase (NKA) activity modulates neurotransmitter release from perivascular innervation (PVI). However, the role of OUA on PVI through NKA/cSRC signalosome pathway is unknown. Thus, we investigated the role of rostafuroxin (ROSTA) treatment, an OUA signalosome pathway antagonist, on PVI of mesenteric resistance arteries (MRAs) from deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, mainly on sympathetic and nitrergic PVI participation.

Design and method:

Five-week after DOCA-salt treatment, rats were allocated into two groups: DOCA-salt treated with ROSTA (1 mg/kg per day gavage, 3 weeks) or vehicle. Male, Wistar rats uninephrectomized were used as normal control (NC). Systolic blood pressure (SBP) was measured weekly by tail-cuff method. Electric field stimulation (EFS), noradrenaline (NA) and sodium nitroprusside (SNP) response-curves were evaluated in isolated MRA without endothelium.

Results:

ROSTA treatment decreased SBP (42%) compared to DOCA-salt. EFS induced contractile response in MRAs of all groups, while this response was higher in DOCA-salt compared to NC or ROSTA group. EFS-induced contraction was reduced in the presence of alfa-adrenoceptor antagonist (phentolamine, PNT) in all groups, whereas this contractile response was blocked by the association between PNT and suramin (P2-purinergic receptor antagonist) only in NC and ROSTA groups. L-NAME enhanced the contraction induced by EFS; however, this effect was smaller in DOCA-salt rings compared to NC and ROSTA. EFS-induced contraction was abolished in MRAs preincubated with tetrodotoxin (voltage-dependent sodium channel blocker). On the other hand, concentration–response curves to exogenous NA and SNP were unmodified among groups.

Conclusions:

ROSTA treatment was able to reduce perivascular sympathetic innervation and to increase nitrergic innervation on the contractile response to EFS in MRAs of DOCA-salt rats. These modifications might contribute to the beneficial effects of OUA/NKA/cSRC pathway antagonism on volume-dependent hypertension.
HYPERTENSION, AUTONOMIC DYSFUNCTION AND SUDDEN DEATH RISK IN CADASIL DISEASE: NOVEL DATA
Authors: Kotliar Carol , Obregon Sebastian
Published: April 2021

Objective:

Sudden death (SD) is the first cause of mortality in CADASIL disease (CD)(Cerebral Autosomic Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). An early development of cardiac autonomic neuropathy (CAN) in the pathogenesis of CD was demonstrated by others. As we detected hypertension in members of 4 families of this rare condition we decided to explore the imbalance of the autonomic nervous system as a potential tool for the prediction of SD risk.

Aims:

to explore the relationship between hypertension and CAN in CD.

Design and method:

We included 10 hypertensive (officce and 24 hs ABPM) patients with CD. Autonomic function was evaluated by the study of heart rate variability (HRV) and Ewing test (handgrip, inspiration/espiration, valsalva manouver and orthostatism). CAN stages were determined as as subclinical, early and advanced.

Results:

CD patients were classified as hypertensives (n:5), or normotensives. Table 1 showed hypertensives subjects characteristics and the distribution of CAN. The control group was constituted with patients with CD and arterial normotension (n:5), the study of HRV and Ewing Test being normal in them. No association was observed between the number and extent of brain lessions, location, impact of white matter with the presence of hypertension. The prevalence of CVRF was similar between both groups.

Conclusions:

Autonomous alterationwas identified in 80% of hypertensive patients with CADASIL disease in our population sample. This association would be independent of traditional CVRF, and the evolutionary characteristics of brain lesions. Although hypertension has not been reported elsewhere as associated with CD, its identification could indicate the risk of autonomic nervous system involvement in these patients. The relevance of their suspicion would reside in the risk re-stratification of cardiovascular events with a focus on the risk of sudden death, linked to the NAC. The limitation of the reduced number of subjects requires the analysis of this hypothesis in a larger population sample, the present being a proof of concept that could justify the development of a survey work in other centers that report cases of this rare disease.
NEW STROKE RISK SCORE FOR PATIENTS WITH CORONARY ARTERY DISEASE
Authors: Minushkina Larisa , Brazhnik Victoria , Zubova Ekaterina , Chichkova Marina , Hasanov Nyaz , Kosmacheva Elena , Zateyshchikov Dmitry
Published: April 2021

Objective:

The study aimed to analyze the possible association of clinical factors with the development of strokes in patients after acute coronary syndrome (ACS).

Design and method:

1843 ACS pts from the 4 PCI centers were included in ORACLE II (ObseRvation after Acute Coronary syndrome for deveLopment of trEatment options) observational multicenter study (NCT04068909 ClinicalTrials.gov) in 2014–2017 years. Mean age 64,9 years, 1149 (61,9%) man. The primary end-point was all-cause death. Ischemic stroke was one of the secondary end-points. We collected data about unfavorable outcomes on 25, 90, 180 and 360 days after hospital discharge. We also control blood pressure (BP) on the day of discharge and at all follow-up visits.

Visit-to-visit BP variability was expressed as the CV (%) of mean BP across all visits during the follow-up.

Results:

We fixed 42 stokes during the follow-up (2,3%). 25 strokes were fatal. Patients with stroke during the follow up were older (70,9 ± 11,88 and 64,7 ± 12,72, p = 0,01), had higher blood pressure visit to visit variability (CV 25,3 ± 4,25 and 12.7 ± 3,67%, p = 0,019). These patients more frequently had arterial hypertension (100% and 88%, p = 0,017) and lower rate of achievement target blood pressure (35,7% and 62,7%). Patients with stroke had higher rate of atrial fibrillation (38,1% and 16,9%), heart failure (83,3% and 49,6%), peripheral atherosclerosis (47,6% and 25,4%), CKD (64,3% and 36,7%), IGT (17,1% vs 7,1%). Stroke patients were less likely to receive anticoagulant therapy (2,0% vs 5,8%, p = 0,003) and were less likely to receive PCI during index hospitalization (31,1% vs 50,5%, p = 0,01). These patients also had lower level of HDL (1,00 ± 0,266 vs 1,18 ± 0,503, p = 0,039). According to results of linear regression analysis we make simple stroke risk score: BP CV low than 12% (-1), atrial fibrillation (+3), heart failure (+2), IGT (+2), CKD (+1), HDL more than 1 mmol/l (-1), PCI (-1), anticoagulants treatment (-3). Score higher than 4 is associated with high store risk. Area under the ROC curve for this risk score was 0,780.

Conclusions:

BP variability and HDL levels, GFR, PCI, heart failure, atrial fibrillation, and anticoagulant treatment were associated with the risk of ischemic stroke.
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.
PROSPECTIVE OBSERVATIONAL STUDY ASSESSING AMBULATORY BLOOD PRESSURE IN PRIMARY ALDOSTERONISM AFTER SURGICAL AND MEDICAL TREATMENT
Authors: Puar Troy , Zhang Meifen , Khoo Joan , Chai Siang Chew
Published: April 2021

Objective:

Primary aldosteronism (PA) affects 5–10% of all patients with hypertension. Patients with PA can be treated with mineralocorticoid antagonists (medications), or curative adrenalectomy (surgery) if they have unilateral PA. Some studies have shown that surgery leads to greater improvement in blood pressure (BP) compared with medications.

Design and method:

We conducted a prospective study from 2016 - 2019 in patients with PA to assess for BP changes after both surgical and medical treatment. All patients had a 24hr ambulatory BP measurement done before treatment, and 12 months after. Daytime ambulatory systolic BP, diastolic BP, number of hypertension medications, and WHO defined daily dose (DDD) of hypertension medications were compared at baseline versus 12 months post-treatment.

Results:

32 patients with PA, mean age 56.0 ± 10.5 yr, 7 females (21.9%) completed both baseline and 12 months post-treatment ambulatory blood pressure. 13 patients (40.6%) were treated with surgery, and the remaining 19 patients were treated with medications. In the entire cohort, daytime systolic BP improved from 144.0 to 135.8 mmHg, P < 0.05, and diastolic BP from 87.3 to 84.8 mmHg, P = 0.18. In patients post-surgery, there was a trend towards improvement in systolic BP from 148.8 to 137.6 mmHg, P = 0.13, and diastolic BP from 92.1 to 85.7 mmHg, P = 0.09. In addition, there was a significant decrease in use of hypertension medications, from 2.1 to 0.7 medications, P < 0.01, and DDD from 3.6 to 0.8, P < 0.01. In patients post-medical treatment, systolic BP improved from 140.8 to 134.5, P = 0.035, diastolic BP did not change from 84.1 to 84.2, P = 0.93. There was an increase in number of hypertension medications from 1.9 to 2.7, P < 0.01, and DDD from 3.1 to 3.5, P = 0.24.

Conclusions:

Treatment of PA leads to improvement of blood pressure. In patients with unilateral PA who undergo surgery, this is also accompanied with a significant reduction in use of antihypertensive medications.
INFLAMMATION AND SALT IN YOUNG ADULTS: THE AFRICAN-PREDICT STUDY
Authors: Crouch Simone , Roux Shani Botha-Le , Delles Christian , Graham Lesley A. , Schutte Aletta E.
Published: April 2021

Objective:

Low-grade inflammation and a diet high in salt (sodium) are both established risk factors for cardiovascular disease. High potassium intake attenuates increases in blood pressure in response to high salt intake and may have a similar protective effect on the modulation of inflammation. To better understand these interactions under normal physiological conditions, we investigated the relationships between 22 inflammatory mediators with 24hr urinary potassium in young healthy adults stratified by low, middle and high salt intake (sodium tertiles). We additionally stratified by ethnicity due to salt-sensitivity seen in black populations.

Design and method:

We included 991 healthy black (N = 457) and white (N = 534) adults, aged 20–30 years with complete data for 24hr urinary sodium and potassium. Blood samples were analysed for 22 inflammatory mediators.

Results:

Differences between plasma concentrations of inflammatory mediators between the low, middle and high sodium tertiles were not seen in either the black or white groups. In multivariable-adjusted regression analyses in white adults, we found only in the lowest sodium tertile that potassium associated negatively with the pro-inflammatory mediators interferon gamma, interleukin-7, interleukin -12, interleukin -17A, interleukin -23 and tumor necrosis factor alpha (all p greater than or equal to 0.046). In the black population, we found no independent associations between potassium and any inflammatory mediator were found.

Conclusions:

In young white adults 24 h potassium associated independently and negatively with specific pro-inflammatory mediators, but only in those with a daily salt intake less than 6.31 grams, suggesting potassium to play a protective, anti-inflammatory role in a low-sodium environment. No similar associations were found in young healthy black adults.
LONG-TERM ADHERENCE TO ANTIHYPERTENSIVE TREATMENT BY URINARY/PLASMA DETECTION IN PATIENTS WITH RESISTANT HYPERTENSION IN THE RENAL DENERVATION FOR HYPERTENSION (DENERHTN) TRIAL
Authors: Kably Benjamin , Fouassier David , Lorthioir Aurélien , Gosse Philippe , Delsart Pascal , Courand Pierre-Yves , Denolle Thierry , Pereira Helena , Billaud Eliane , Azizi Michel
Published: April 2021

Objective:

The DENERHTN trial reported the BP–lowering efficacy of renal denervation (RD) in addition to a standardized stepped-care antihypertensive treatment (SSAHT) in patients with resistant hypertension (RHTN) vs. SSAHT alone at 6 months despite a similar (around 50%) prevalence of partial+complete nonadherence (NA) to antihypertensive drugs (AHD). We report here adherence to AHD at 12 months.

Design and method:

106 patients with RHTN to indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to RD+SSAHT or SSAHT alone. For SSAHT, spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were sequentially added from 2 to 5 months if home BP was greater than or equal to 135/85 mmHg. From 6 to 12 months, patients received AHD at physician's discretion. At 6 and 12 months, urine/plasma AHD screening with ultrahigh performance LC-MS/MS was performed on available samples.

Results:

From 6 to 12 months, 25/44 (56.8%) RD+SSAHT patients and 26/53 (49.1%) SSAHT patients had a change in their antihypertensive treatment by their physician (p = 0.446). The percentage of NA decreased between 6 and 12 months from 50.0% (n = 20/40) to 42.9% (n = 15/35) in the RD+SSAHT group and from 53.3% (n = 24/45; p = 0.759) to 41.7% (n = 15/36; p = 0.919) in the SSAHT group. Among patients with samples at both 6 and 12 months, 10/33 (30.3%) RD+SSAHT patients and 7/33 (21.2%) SSAHT patients had a change in adherence (p = 0.398). A total of 5/18 (27.7%) RD+SSAHT and 0/13 (0/0%) SSAHT patients who were adherent at 6 months became NA at 12 months (p = 0.0580). Conversely, the same proportion of patients who were NA at 6 months became adherent at 12 (RD+SSAHT: n = 5/15, 33.3% vs. SSAHT: n = 7/20, 35%).

Conclusions:

In patients with RHTN of the DENERHTN trial, the prevalence of NA to AHD drugs at 12 months remained high >40% but not different in the RD+SSAHT and SSAHT groups. About 1/3 of the patients became adherent at 12 months in both groups. However, numerically more patients became NA in the RD+SSAHT group than in the SSAHT group, which may impact the BP response to RD.
GROWTH DIFFERENTIATION FACTOR-15 IS AN INDEPENDENT PREDICTOR OF CARDIOVASCULAR DISEASE IN JAPANESE PATIENTS WITH CARDIOVASCULAR RISK FACTORS: THE J-HOP STUDY
Authors: Negishi Keita , Hoshide Satoshi , Ishiyama Yusuke , Shimizu Hayato , Shinpo Masahisa , Kario Kazuomi
Published: April 2021

Objective:

Growth differentiation factor-15 (GDF-15) is emerged as a novel biomarker to predict adverse outcomes in community-dwelling individuals and patients with cardiovascular (CV) disease. However, there is a paucity of information on the association between blood GDF-15 levels and adverse outcomes in outpatients with CV risk factors. In this study, we evaluated the prognostic value of GDF-15 in outpatients with CV risk factors and compared with those of other prognostic biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT).

Design and method:

We collected blood samples from 3,562 patients with CV risk factors in the J-HOP (Japan Morning Surge-Home Blood Pressure) study. Blood GDF-15 levels were determined by immunoassay analysis. During a mean follow-up period of 6.6 years, we recorded the incidence of adverse outcomes as follows: 1) cardiac events defined as ischemic heart disease and heart failure, 2) stroke events defined as ischemic stroke and cerebral hemorrhage, 3) all-cause death, and 4) cancer death. Patients were stratified according to tertiles of GDF-15. The association between GDF-15 and each outcome was evaluated by Cox-proportional hazard models adjusting for established risk factors and other biomarkers (hs-TnT and NT-proBNP).

Results:

We observed 141 (4.0%) cardiac events, 81 (2.3%) stroke events, and 155 (4.4%) death including 63 (1.8%) cancer death. Multivariate Cox regression model showed that patients in highest tertile of GDF-15 were independently and significantly associated with increased risk of stroke and death except for cardiac events [stroke events, hazard ratio (HR) 2.87, p = 0.008; all-cause death, HR 2.38, p = 0.007; cancer death, HR 2.48, p = 0.049; cardiac events; HR 1.07, p = 0.805, respectively] compared with lowest tertile after adjustment for established risk factors and other biomarkers. Furthermore, adding GDF-15 to the predictive models for stroke and death improved discrimination and reclassification more than adding other biomarkers to the models.

Conclusions:

In this study, GDF-15 predicts death and stroke except for cardiac events. Information of GDF-15 might be helpful when assessing the risk of death and stroke events in Japanese patients with CV risk factors.
PLASMA FATTY ACIDS AND THE RISK OF VASCULAR AND MORTALITY OUTCOMES IN INDIVIDUALS WITH TYPE 2 DIABETES: RESULTS FROM THE ADVANCE STUDY
Authors: Harris Katie , Oshima Megumi , Sattar Naveed , Wurtz Peter , Jun Min , Welsh Paul , Chalmers John , Woodward Mark
Published: April 2021

Objective:

This study aimed to quantify the association of essential and other plasma fatty acids biomarkers with macrovascular disease, microvascular disease and death in individuals with type 2 diabetes.

Design and method:

A case cohort study (N = 3,576), including 654 macrovascular events, 341 microvascular events and 631 deaths during 5 years of median follow-up was undertaken in participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study.

The fatty acids measured from baseline plasma samples, by proton nuclear magnetic resonance (NMR) analysis, were omega-3, docosahexaenoic acid (DHA), omega-6, linoleic acid (LA), polyunsaturated (PUFA), monounsaturated (MUFA) and saturated fatty acids (SFA). Hazard ratios (HRs) were modelled per standard deviation higher percentage fatty acid. C-statistics and net reclassification improvement were used to test the added value of fatty acids for risk prediction.

Results:

After adjustment for traditional cardiovascular risk factors, an inverse association was observed for omega-3 fatty acids and DHA (HR [95%CI]: 0.87 [0.80, 0.95] and 0.88 [0.81, 0.96], respectively per 1SD higher percentage) with the risk of macrovascular events, and for omega-3 fatty acids (HR [95%CI]: 0.91 [0.84, 0.99] per 1SD higher percentage) with death. Such associations were also evident when investigating absolute levels of fatty acids. There were no statistically significant associations between any fatty acids and microvascular disease after adjustment. However, there was limited improvement in predictive ability of models when any fatty acid was added.

Conclusions:

Plasma omega-3 fatty acids and DHA were found to be inversely associated with macrovascular disease, whilst omega-3 fatty acids was also inversely associated with death. These results provide additional support for regular consumption of food rich in omega-3 fatty acids in type 2 diabetes.
IDENTIFICATION OF CANDIDATE BIOMARKERS FOR SALT SENSITIVITY OF BLOOD PRESSURE BY INTEGRATED BIOINFORMATICS ANALYSIS
Authors: Chen Chen , Liu Guanzhi , Chu Chao , Zheng Wenling , Hu Jiawen , Wang Yang , Ma Qiong , Yan Yu , Yuan Yue , Liao Yueyuan , Mu Jianjun
Published: April 2021

Objective:

In the current study, we aimed to identify potential biomarkers for salt sensitivity of blood pressure (SSBP), which may provide a novel insight into the pathogenic mechanisms of salt-sensitive hypertension. Firstly, we conducted weighted gene coexpression network analysis (WGCNA) and selected a gene module and 60 hub genes significantly correlated to SSBP. Then, GO function and KEGG signaling pathway enrichment analysis and protein-protein interaction (PPI) network analysis were performed. Furthermore, we identified a five-gene signature with high connectivity degree in the PPI network and high AUC of ROC curves, which may have high diagnosis value for SSBP. Moreover, through combining two gene screening methods, we identified 23 differentially expressed circRNAs and selected the top 5% circRNAs (1 circRNA) with the highest connectivity degree in the coexpression network as hub circRNA highly associated with SSBP. Finally, we carried out RT-qPCR to validate the expression of five hub genes, and our results showed that the expression of HECTD1 (P = 0.017), SRSF5 (P = 0.003), SRSF1 (P = 0.006), HERC2 (P = 0.004), and TNPO1 (P = 0.002) was significantly upregulated in the renal tissue in salt-sensitive rats compared to salt-resistant rats, indicating that these five hub genes can serve as potential biomarkers for SSBP.
ASSESSMENT OF URODYNAMICS AND CONCENTRATION FUNCTION OF PARENCHYMA IN PATIENTS WITH ARTERIAL HYPERTENSION AND GOUT
Authors: Gromova Margarita , Kislyak Oxana , Tsurko Vladimir , Kashkadayeva Anna , Averinova Svetlana , Aliokhin Andrei
Published: April 2021

Objective:

To assess the urodynamics and concentration function of the parenchyma in patients with arterial hypertension and gout.

Design and method:

We examined 87 patients with arterial hypertension and gout. 83% were men (mean age 55.4 ± 12.3 years). Grade 1 of arterial hypertension was detected in 43.7%, grade 2 - in 36.9%, grade 3 - in 19.3%. All the patients had chronic gouty arthritis, 30% of the patients had tophi. Markers for kidney damage, urine sediment, GFR calculation were evaluated in all the patients. All the patients were given a systemic examination of their nephro-urological condition based on complex renal scintigraphy (SENS-CRS) with the in-depth differential analysis of the impaired renal parenchyma function, upper and lower urinary tract (fig.1).

Results:

According to the standard method of GFR calculation using the CKD-EPI formula, we found that 10 patients (11.3%) had no CKD symptoms; stage I-II CKD was observed in 56 patients (64.5%), stage III-IV in 21 patients (24.2%). 16 patients with arterial hypertension and serum creatinin level >125 μmol/l were allocated to a subgroup of patients in the category of increased risk of developing high stages of CKD. According to the CKD-EPI formula, those 16 patients had CKD stage I-II and one patient had stage III CKD with a high risk of transition it to stage IV. The reliable difference (p < 0.05) was established only by the D (%) indicator that is by the radiopharmaceutical removal rate from the renal parenchyma when we compared the analyses of complex renal scintigraphy data in the 16 specified patients and in the remaining 71 patients with arterial hypertension (tab.1).

Conclusions:

Patients with arterial hypertension from the time of gout diagnosis must be included in the nephro-urological control system. It is important to control the risk factors related to the probability of CKD progression. The renocortical parameter D (%) used in the SENS-CRS technology is a prognostically important preclinical marker of intrarenal congestion when the latent development of serious morphological and functional disorders in the renal parenchyma occurs that leads to the CKD development or aggravation of the existing CKD stage.