bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROFILING CIRCULATING EXTRACELLULAR VESICLE SURFACE ANTIGENS IN PRIMARY ALDOSTERONISM
Authors: Burrello Jacopo , Tetti Martina , Forestiero Vittorio , Biemmi Vanessa , Bolis Sara , Pomatto Margherita , Amongero Martina , Di Silvestre Dario , Mauri Pierluigi , Vassalli Giuseppe , Camussi Giovanni , Williams Tracy Ann , Mulatero Paolo , Barile Lucio , Monticone Silvia 
Published: June 2022

Objective:
Primary aldosteronism (PA) is characterized by an inappropriate secretion of aldosterone. Chronic aldosterone excess exerts detrimental effects on cardiovascular system, including endothelial dysfunction and vascular inflammation. Circulating extracellular vesicles (EVs) are central players in the crosstalk between endothelium and inflammatory cells, and they may be involved in the development of organ damage in patients with PA. The aim of the present study was to assess the potential role of EVs in aldosterone-related vascular injury by evaluating a panel of 37 EV surface antigens through an innovative flow cytometry multiplex bead-based platform.

Design and method:
Serum EVs were isolated by immuno-capture from 32 patients with PA, 29 patients with essential hypertension (EH) and from 22 normotensive (NT) controls. EVs were characterized by nanoparticle tracking analysis, transmission electron microscopy, western blotting, and flow cytometry.

Results:
EV concentration was higher and diameter lower in patients with PA compared to patients with EH and NT controls and the number of particles decreased after unilateral adrenalectomy. Nineteen EV surface antigens were differentially expressed in patients with PA compared to patients with EH or NT controls, including markers from activated platelets, endothelial and immune/inflammatory cells. Supervised learning was used to combine the expression levels of EV surface markers in a specific molecular signature which discriminated patients with PA from controls (EH and NT), whereas after specific treatment the profile became similar to EH. Stimulation of human endothelial cells with PA patient-derived EVs, but not with EVs from EH, resulted in the overexpression of 5 selected genes (AKT1, CALR, CSNK2A1, FN1, and PIK3R1), previously identified by bioinformatics analysis as potential targets of differentially expressed EV antigens. Notably, the effect was specifically dependent on EV surface antigens, since it was abolished by removal of EV membrane associated proteins. The overexpression of CALR and FN1 was confirmed also at protein level.

Conclusions:
Our data suggest that EVs represent biomarkers of vascular inflammation and endothelial dysfunction in patients with PA, and also potential biovectors contributing to endothelial dysfunction, vascular inflammation, and accelerated organ damage by multiple signalling processes.
NOX5 EXPRESSION IN A VASCULAR SMOOTH MUSCLE CELL-SPECIFIC MANNER INDUCES FIBROBLAST PHENOTYPIC SWITCH AND PRO-FIBROTIC EFFECTS
Authors: Montezano Augusto , Rios Francisco , Blaikie Zachariel , Saad Tomador , Camargo Livia , Palacios-Ramirez Roberto , Tarjus Antoine , Sagan Agnieszka , Beattie Wendy , Guzik Tomasz , Jaisser Frederic , Graham Delyth , Touyz Rhian M. 
Published: June 2022

Objective:
Mice expressing human Nox5 (hNox5) in vascular smooth muscle cells (VSMC) exhibit redox-sensitive vascular dysfunction and cardio-renal fibrosis. Mechanisms underlying pro-fibrotic effects are unclear. Here we assessed whether hNox5 in VSMCs promotes fibroblast phenotypic changes leading to myofibroblast differentiation and pro-fibrotic/inflammatory responses.

Design and method:
Fibroblasts were cultured from wildtype (WT) and mice expressing hNOX5 in VSMC (Nox5+SM22+). Mice (20 weeks old) were infused with Ang II (600 ng/Kg/day) for 28 days and renal fibrosis/inflammation studied. Markers of myofibroblasts, pro-fibrotic and inflammatory phenotypes were assessed by qPCR and immunoblotting. Inflammatory infiltrate was assessed by FACS.

Results:
Fibroblasts isolated from Nox5+SM22+ mice exhibited increased mRNA expression of pro-fibrotic markers, such as Col1A1 (2-ddCt: 1.74 ± 0.16 vs. WT 0.67 ± 0.11), Col3A1 (2-ddCt: 1.74 ± 0.18 vs. WT 0.96 ± 0.24) and TIMP3 (2-ddCt: 2.65 ± 0.25 vs. WT 0.38 ± 0.07), p < 0.05. Myofibroblast phenotype (SMC) markers mRNA, aSMA (2-ddCt: 1.54 ± 0.05 vs. WT 0.78 ± 0.17) and Myocd (2-ddCt: 1.36 ± 0.17 vs. WT 0.39 ± 0.22) were also increased in fibroblasts from Nox5 mice, p < 0.05. In terms of inflammatory phenotype, we observed that mRNA expression of CD36 (2-ddCt: 1.37 ± 0.07 vs. WT 86 ± 0.24), TNFa (2-ddCt: 1.32 ± 0.2 vs. WT 0.71 ± 0.17) and TNFR1 (2-ddCt: 1.26 ± 0.04 vs. WT 1.02 ± 0.10) were increased, while CD68 expression was decreased (2-ddCt: 0.82 ± 0.11 vs. WT 1.36 ± 0.18) in fibroblasts from Nox5+SM22+ mice (p < 0.05). In Nox5 mice fibroblasts, key regulators of fibrosis such as ROS production and TGFb protein expression (AU: 1.8 ± 0.05 vs. WT 1.4 ± 0.06), as well as TGFbR2 gene expression (2-ddCt: 2.04 ± 0.17 vs. WT 0.57 ± 0.12), were increased (p < 0.05). Kidneys from Ang II-infused Nox5+SM22+ mice exhibited significant perivascular fibrosis and inflammatory cell infiltration compared to WT. Kidney expression of vimentin (AU: 1.01 ± 0.05 vs WT 0.85 ± 0.03) and aSMA (AU: 0.44 ± 0.03 vs WT 0.33 ± 0.01), markers of myofibroblast differentiation, were increased in Nox5 mice (p < 0.05). In kidneys from Nox5+SM22+ mice, increased frequencies of macrophage F4/80 + (%: 24 ± 2 vs WT 18 ± 1, p < 0.05).

Conclusions:
Our findings suggest that Nox5 in VSMCs influences fibroblast phenotypic switching to myofibroblasts that likely influences cardiovascular and renal fibrosis in hypertension.
THERAPEUTIC EFFECTS OF NEBULIZATION- BASED DELIVERY OF ANTI-MIR-146A IN EXPERIMENTAL PULMONARY ARTERIAL HYPERTENSION
Authors: Gomes Joana , Ferreira Pedro , Adão Rui , Rocha Carolina , Vasconcelos Inês , Rego Beatriz , Salvador Pedro , Moreira Adelino , Silva Carmén 
Published: June 2022

Objective:
Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH.
This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure.

Design and method:
Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a-/-) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx).

Results:
Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index), decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi).

Conclusions:
Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH.
AORTIC CALCIFICATION INCREASES CENTRAL BLOOD PRESSURE RELATIVE TO BRACHIAL BLOOD PRESSURE IN CKD PATIENTS – A STUDY IN PATIENTS UNDERGOING ELECTIVE CORONARY ANGIOGRAPHY
Authors: Nyvad Jakob , Christensen Kent Lodberg , Andersen Gratien , Reinhard Mark , Nielsen Sebastian , Thomsen Martin , Jensen Jesper M⊘ller , N⊘rgaard Bjarne Linde , Buus Niels Henrik 
Published: June 2022

Objective:
Chronic kidney disease (CKD) and arterial stiffness are associated with increased central (aortic) systolic blood pressure (cSBP) relative to brachial systolic blood pressure (bSBP). This study examined the impact of aortic calcification on cSBP relative to bSBP in patients with CKD.

Design and method:
Patients with or without CKD undergoing elective coronary angiography (CAG) at Aarhus University Hospital were considered for inclusion in this cross-sectional study. During CAG, cSBP was measured in the ascending aorta with a fluid-filled catheter while bSBP was measured simultaneously with an oscillometric device using a cuff. Furthermore, patients underwent a non-contrast computed tomography (CT) scan of the entire aorta with subsequent blinded Agatston-scoring of the aorta from (but excluding) the aortic valve to the aortic bifurcation. Carotid-femoral pulse wave velocity was measured in duplicate using a Sphygmocor device. Data are presented as mean ± standard deviation unless stated otherwise. Statistical comparisons were made using Wilcoxon rank sum test for differences between 2 groups and Bonferroni-adjusted Kruskal-Wallis test when testing for differences between > 2 groups.

Results:
149 patients were included in the study. Of these, 134 patients had a CT-scan of sufficient quality to allow analysis. Patient characteristics and measurements of BP and pulse wave velocity are presented in Table 1. Agatston-score was higher in CKD patients as compared to patients with normal kidney function (table 1, P < 0.001). bSBP was 6.5 ± 13.1 mmHg higher than cSBP in patients categorized into the first tertile of Agatston-scores. This difference was reduced to 3.3 ± 11.0 mmHg in the second tertile (p = 0.31, compared to first tertile) and -2.6 ± 16.8 mmHg in the third tertile (p < 0.01, compared to first tertile).

Conclusions:
Patients with CKD have a higher degree of aortic calcification. Furthermore, patients with a high degree of aortic calcification have a higher invasively measured cSBP as compared to the bSBP measured with an ordinary oscillometric BP device.
KIDNEY SUBCLINICAL LESIONS IN HYPERTENSION PHENOTYPES DEFINED BY HOME BLOOD PRESSURE MONITORING AMONG YOUNG ADULTS ENROLLED IN A FAMILY HEALTH STRATEGY UNIT
Authors: Pecly Inah Maria Drummond , Fernandes Ana Cristina Tenorio C. , Bica Rafael Barbosa Da S. , Flumingnan Vitoria Santa Marinha , Marinho Beatriz Deberaldini , Da Silva Luisa Leite Vaz , Boghossian Rodney Barberá , Falcão Michelle Felipe , Neto Valter Correa Branco , Bandeira Heito De O. M. Rego , Moura Carlos Augusto Parente M. , Ushijima Nathalia Rossilho , Muxfeldt Elizabeth Silaid 
Published: June 2022

Objective:
To assess kidney subclinical lesions among different hypertension (HTN) phenotypes identified by Home Blood Pressure Monitoring (HBPM) in an adult population enrolled in a Family Health Strategy unit

Design and method:
Cross-sectional, populational study with adults between 20–50 years old enrolled in a Family Health Strategy unit in a metropolis. Sociodemographic, anthropometric and CV risk factors were registered. Office blood pressure (BP) was the average of two consecutive measurements, and HBPM followed a 7-day protocol. HBPM < 135x85 mmHg and office BP < 140x90mmHg were considered normal, identifying four phenotypes: normotension (controlled office BP and HBPM); white-coat hypertension (uncontrolled office BP and controlled HBPM); masked hypertension (controlled office BP and uncontrolled HBPM) and sustained hypertension (uncontrolled office BP and HBPM). Albuminuria was dosed in an isolated urine sample whereas glomerular filtration rate was calculated by CKD Epi formula using serum creatinine.

Results:
A total of 483 individuals were evaluated (39% male; mean age: 37.6 ± 8.8 years). More often, individuals with white-coat hypertension (9.3%) are male, with greater neck circumference and higher prevalence of metabolic syndrome. Individuals with masked hypertension (10%) are more obese, with increased neck and waist circumferences whereas those who present sustained hypertension are predominantly male, more obese, with increased neck and waist circumferences and higher prevalence of diabetes and metabolic syndrome. Analyzing four phenotypes, a progressive albuminuria increase was observed among normotensive patients: white-coat hypertension 4.0 ± 2.2; masked hypertension 5.3 ± 3.4 and sustained hypertension 7.1 ± 1.4 mg/g creatinine. We also observed an increased serum creatinine and decreased GFR: white-coat hypertension 0.74 ± 0.16/132 ± 34; masked hypertension 0.79 ± 0.17/123 ± 28; sustained hypertension 0.81 ± 0.32/120 ± 59, respectively, although without statistical significance.

Conclusions:
The performance of HBPM refined HTN diagnosis and was able to early identify a progressive worsening of kidney function parameters in the different phenotypes.
IMPAIRED SKIN MICROCIRCULATION DYNAMICS IN PATIENTS WITH RHEUMATOID ARTHRITIS: ASSOCIATION WITH ARTERIAL STIFFNESS AND CORONARY MICROVASCULAR PERFUSION
Authors: Anyfanti Panagiota , Gavriilaki Eleni , Nikolaidou Barbara , Triantafyllou Areti , Dolgyras Panagiotis , Zarifis Hippokrates , Lazaridis Antonios , Koletsos Nikolaos , Douma Stella , Gkaliagkousi Eugenia 
Published: June 2022

Objective:
Rheumatoid arthritis (RA) is characterized by excess cardiovascular risk. Laser Speckle Contrast Imaging (LSCI) is a novel and highly reproducible technique for the real-time evaluation of skin microcirculation. However, relevant data using non-invasive laser techniques remain far too limited in RA, especially in patients free from cardiovascular risk factors with relatively suppressed inflammatory load.

Design and method:
We assessed skin microvascular function in a well-characterized sample of RA patients free from hypertension and cardiovascular diseases with low levels of systemic inflammation, compared to non-RA individuals. Microvascular function was dynamically evaluated using LSCI coupled with a post-occlusive reactive hyperaemia protocol. Applanation tonometry with the Sphygmocor device was applied to assess a) subendocardial viability ratio (SEVR) or Buckberg index as a functional marker of microvascular myocardial perfusion, b) carotid-femoral pulse wave velocity (PWV) as a marker of macrovascular dysfunction.

Results:
We studied 35 patients with RA at remission or low disease activity, and 35 controls matched for cardiovascular risk factors. Skin microvascular responses were impaired in RA patients compared to controls, specifically baseline flux [46.8(18.9) vs 36.4(13.9) LSPUs, p < 0.001], occlusion flux [12.4(13.5) vs 7.0(3.6) LSPUs, p = 0.001], time-to-peak [7.0(0.4) vs 11.0(8) sec, p < 0.001], peak magnitude [113.1(25.4) vs 99.1(32.5) LSPUs, p = 0.017], peak-to-baseline magnitude [136.5(75.2) vs 172.1(65.9) %, p = 0.014], baseline cutaneous vascular conductance (CVC) (0.54 ± 0.15 vs 0.44 ± 0.14 LSPUs/mmHg, p = 0.006), and percentage increase in CVC [139.5(75.3) vs 172.1(67.3) %, p = 0.011]. Moreover, SEVR was lower in RA patients compared to controls (140.6 ± 21.8 vs 157.2 ± 25.2%, p = 0.046), whereas PWV did not significantly differ. SEVR strongly and significantly correlated with nearly all LSCI indices (baseline and occlusion flux, peak magnitude, peak-to-baseline magnitude, baseline CVC, and percentage CVC increase). PWV significantly correlated only with baseline flux, occlusion flux, and time-to-peak.

Conclusions:
Microcirculation dynamics appear impaired even in RA patients with relatively low inflammatory load, regardless of cardiovascular risk factors. Importantly, we showed for the first time an association between impaired skin microvascular dynamics assessed with LSCI and microvascular myocardial perfusion using SEVR. Further studies need to evaluate the prognostic potential of LSCI in terms of cardiovascular risk in RA.
TIME DOSING OF ANTIHYPERTENSIVE TREATMENT AND PROGNOSIS
Authors: de la Sierra Alejandro , Ruilope Luis , Martinez-Camblor Pablo , Vinyoles Ernest , Gorostidi Manuel , Segura Julian , Williams Bryan 
Published: June 2022

Objective:
Night BP is the most powerful estimate of cardiovascular prognosis. It has been suggested that bedtime administration of antihypertensive therapy may favour night BP reduction and prognosis. We aimed to evaluate the risk of total and cardiovascular mortality in a large cohort of treated hypertensives, depending on the schedule of treatment administration (entirely in the morning, entirely at bedtime, or combined morning and evening) at the time ABPM was performed.

Design and method:
Vital status and death due to cardiovascular causes were obtained from death certificates in 26751 treated hypertensives (mean age 62, 60% males), enrolled in the Spanish ABPM Registry between 2004 and 2014, and having a valid 24-h ABPM at entry. Cox-models adjusted for clinical confounders and 24-hour systolic BP were used for HR calculation in groups depending on treatment administration.

Results:
Among the 26751 evaluable patients, most (76.7%) received their medication exclusively in the morning; 13% exclusively in the evening, and 10.3% in a multiple schedule both in the morning and in the evening. Mortality incidence in these 3 groups were 13.7, 17.8 and 21.8 per 1000 patients/year, respectively. Compared to patients receiving their antihypertensive medication entirely in the morning (reference group), those receiving their medication entirely in the evening did not show a significant increase in the HR for total mortality (1.06; 95%CI: 0.93–1.21) or in cardiovascular mortality (1.15; 0.93–1.41) after adjustment for clinical confounders and 24-hour systolic BP. Patients receiving their antihypertensive medication both in the morning and at bedtime had an increased risk for mortality (1.29; 1.14–1.48) and for cardiovascular mortality (1.46; 1.18–1.80). Additional analyses using double-robust propensity score yielded similar results.

Conclusions:
Morning or bedtime dosing of the antihypertensive medication has no effect on prognosis. We have found that patients receiving their medication in a multiple schedule, including morning and evening dosing have an increased risk of mortality and cardiovascular mortality, even after adjustment for confounders. However, we cannot exclude other aspects, such as a poorer treatment adherence, being the responsible of this worse prognosis.
INITIATION OF EMPAGLIFLOZIN THERAPY IS ASSOCIATED WITH A CLINICALLY RELEVANT DECREASE IN BLOOD PRESSURE IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND UNCONTROLLED HYPERTENSION
Authors: Kuzior Agnieszka , Hernandez-Lazaro Alba , De Leon-Durango Ricardo , Rios-Gomez Carlos , Arnas-Leon Claudia , Acosta-Calero Carmen , Fernandeztrujillo-Comenge Paula Maria , Santana-Suarez Ana Delia , Gonzalez-Diaz Paula , Martin Francisco Javier Martinez 
Published: June 2022

Objective:
In published clinical trials, initiation of empagliflozin is associated with modest BP reductions (around 2–3 mmHg vs. placebo, with doubtful clinical relevance). However, the patients who enter andomised clinical trials are receiving standard-of-care therapy with intensive antihypertensive medication when needed, and their baseline BP values are near-normal (typically around 135/75 mmHg). On the other hand, real-life patients who start empagliflozin therapy are often living with uncontrolled hypertension. Empagliflozin has well-known natriuretic and diuretic effects which might conceivably lower BP more powerfully in those subjects with a higher baseline BP.

Design and method:
Retrospective analysis of the BP data in patients with type 2 diabetes and office BP > 140/90 mmHg. Data were obtained from the patient's clinical records, and consent for their anonymous analysis and reporting was obtained from included subjects. Patients who changed their antihypertensive medication simultaneously with empagliflozin initiation were excluded.

Results:
We obtained SBP, height and body weight data from 158 patients (59.5% female, age 64 ± 9 years) in the visit in which empagliflozin was started and the following one (3–4 months afterwards typically). Dosages were 5, 10, 12.5 and 25 mg/day in 8, 126, 10 and 14 patients, respectively. Baseline BMI was 31.5 ± 8.4 Kg/m2. Baseline SBP was 164 ± 18 mmHg, with 141–160 mmHg in 52 patients (Grade 1), 161–180 mmHg in 75 (Grade 2), and > 180 mmHg in 31 (Grade 3). The reduction in SBP was 7.1 ± 5.8 mmHg, clinically and statistically significant (p = 0.014, paired t-test). In Grade 1 patients it was 4.9 ± 3.2 mmHg; 7.5 ± 5.1 mmHg in Grade 2, and 9.7 ± 6.8 mmHg in Grade 3. SBP reduction was strongly correlated with baseline SBP (Pearson's r = 0.39, p < 0.001) and weakly with body weight loss (Pearson's r = 0.318, p = 0.032) but not with gender, age, empagliflozin dosage and baseline BMI.

Conclusions:
In patients with type 2 diabetes and uncontrolled hypertension, empagliflozin initiation is associated with a reduction in SBP pressure which is both statistically and clinically significant, nearing the effect of classic antihypertensive drugs.
CARDIOVASCULAR EVENTS ACCORDING TO FOLLOW-UP INTERVAL IN HYPERTENSIVE PATIENTS
Authors: Lee Hae-Young , Cho Myeong-Chan 
Published: June 2022

Objective:
Hypertension is a chronic disease that requires long-term follow-up in many patients. Although the European hypertension guideline recommended that once the BP target is reached, a visit interval of a few months is reasonable, and there might be no difference in BP control between 3-month and 6-month intervals, there was limited evidence regarding shorter intervals of follow-up.
This study sought to evaluate the incidences of cardiovascular events and death according to the visit intervals.

Design and method:
This Korean Hypertension Cohort (KHC) enrolled 11,043 hypertensive patients and followed up for more than ten years. We evaluated the incidences of cardiovascular events and death according to the visit intervals after stabilization.

Results:
In this cohort, 28% of patients visited the clinic with intervals of 3 months, followed by visits with intervals of 4 months (23%), 4–6 months (20%), 2 months (18%), more than 6 months (9%), and less than 1 week (2%). Male, lower SBP and low risk patients had larger visit intervals than female, higher SBP, and high-risk patients. Surprisingly, shorter visit intervals of 34–66 days (about 2 months) showed a relatively larger visit-to-visit variation of 13.6 days, suggesting that shorter visit intervals do not always accompany better treatment adherence. The large visit-to-visit variation reaching 89 days of standard deviation in patients with visit interval of more than 6 months also support the decrease in treatment adherence. In the Cox proportional hazards model for cardiovascular events or death according to visit intervals, with adjustment of age, gender, and cardiovascular risk, showed that hypertensive patients with visit intervals of 3–4 months had fewer cardiovascular events than those either with more extended or shorter visit intervals.

Conclusions:
Hypertensive patients with visit intervals of 3–4 months had fewer cardiovascular events than those with longer or shorter visit intervals. Although we did not present a possible explanation for this, the increased standard deviation in the more extended interval group suggests that reduced treatment adherence may play a role.