bluuebunny/crossref_metadata_2025_split huggingface dataset:
AUGMENTED PROSTAGLANDIN E2 SIGNALING CAUSES PODOCYTE DAMAGE AND ALBUMINURIA-LIKE PHENOTYPE IN A ZEBRAFISH DISEASE MODEL OF GLOMERULAR HYPERFILTRATION
Authors: Kourpa Aikaterini , Mangelsen Eva , Bolbrinker Juliane , Schulz Angela Martina , Rothe Michael , Kreutz Reinhold , Panakova Daniela 
Published: June 2022

Objective:
Prostaglandins (PGs) are important active lipids synthesized from arachidonic acid with the participation of cyclooxygenases (COXs) and specific prostaglandin synthases. Prostaglandin E2 (PGE2), the most abundant prostaglandin in the kidney, plays a crucial role in renal homeostasis and the pathogenesis of chronic kidney diseases. Augmented PGE2 signaling that may occur in podocytes during increased fluid flow shear stress as observed during glomerular hyperfiltration, results in glomerular filtration barrier (GFB) permeability defects, ultimately leading to albuminuria. The cellular mechanisms that precede podocyte damage are not fully resolved. Here, we deploy a zebrafish model to study the role of PGE2 signaling in glomerulus and its effects on GFB integrity and function.

Design and method:
To model the outcome of increased PGE2 signaling in podocytes, zebrafish embryos were exposed to 16,16-dimethyl PGE2 (dmPGE2, 125 μM) or DMSO vehicle after the complete formation of GFB, i.e. from 72 hours post fertilization (hpf) to 96 hpf. To probe the PGE2 pathway, embryos were treated with the selective PGE2 receptor (EP) type 2 (EP2) and EP4 antagonists PF04418948 and ONO-AE3-208 or the COX inhibitor indomethacin. Zebrafish embryos of Tg(fabp10a:gc-EGFP) were used to evaluate the functional role of GFB integrity and albuminuria phenotype, while embryos of Tg(wt1b:EGFP) in combination with angiography using BSA-conjugated AlexaFluor555 allowed glomerular morphological analysis. In vivo stereomicroscopy, confocal laser scanning microscopy, and electron microscopy were used to analyze GFB at cellular as well as ultrastructural level. Statistical analysis was performed using GraphPad software.

Results:
Stimulation with dmPGE2 causes an albuminuria-like phenotype in zebrafish embryos, mimicking the suggested PGE2 effects during glomerular hyperfiltration in rodent models. The albuminuria-like phenotype could be significantly suppressed by the combined and separate inhibition of the EP2 and EP4 receptors as well as by indomethacin treatment. Although the glomerular ultrastructure appeared unaffected, high-resolution confocal imaging showed impaired podocyte intercalation around the glomerular capillaries after dmPGE2 exposure. Importantly, these specific podocyte defects were restored after blockage of EP2 and EP4.

Conclusions:
Our results support a role of augmented PGE2/EP2/EP4 signaling in the setting of glomerular hyperfiltration and albuminuria.
AWARENESS AND LIMITATIONS OF MEASURING VASCULAR AGEING IN EVERYDAY PRACTICE. A PILOT QUALITATIVE ANALYSIS FROM VASCAGENET(CA18216)
Authors: Triantafyllou Areti , Elia Stavria-Artemis , Park Chloe , Climie Rachel , Mayer Christopher C. , Weber Thomas , Panayiotou Andrie G. 
Published: June 2022

Objective:
Despite current evidence demonstrating the important role of Vascular ageing (VA) in cardiovascular risk assessment, its awareness and mostly implementation in everyday practice still lags significantly. To effectively assess the need for future target strategies for health providers, a qualitative questionnaire was developed. The aim of this analysis was to identify perceptions and factors associated with omitting VA assessment in a group of clinicians and researchers.

Design and method:
An online qualitative questionnaire based on intentionally left open-ended key questions identified by a Network for Research in Vascular Ageing (VascAgeNet) COST Action(CA18216) expert working group was developed and distributed to participants working in the field of VA, in order to globally assess knowledge and perceptions. Importance of VA was evaluated on a scale 0(least important)-5(very important).

Results:
Out of the 127 responses, 104 questionnaires were complete. The mean age of participants was 42.5 ± 10.5 years, 60.6% male. 43.3% were clinicians (mostly cardiologists, internists, and endocrinologists) and 56.7% were other scientists (mostly computer scientists and physiologists). Although participants were aware of the role of VA and scored median 5/5 (very important) on the evaluation scale, only 53.8% measured it in the research setting and only 16.3% in everyday clinical practice. Amongst the most frequently identified limiting factors regarding clinical setting were time(31.5%), lack of reimbursement of tests(22.3%), cost of equipment(16.7%), guidelines(13%),validation data(5.6%) and devices(9.4%). 15.6% considered that there was no clinical benefit. Participants who measured VA in clinical practice considered VA significantly more important than those who didn’t measure it (0% vs.3.3%(1–2), 17.6% vs.39.3%(3–4), 82.4% vs.57.4%(5), respectively, p = 0.029). Similar were the results in research setting (1.8% vs.4.5%(1–2), 28.6% vs. 50.0%(3–4), 69.6% vs. 45.5%(5), respectively, p = 0.053). Table 1 presents the main results, according to the participants’ status.

Conclusions:
Although aware of the importance of VA in cardiovascular risk assessment, participants are still unable to implement it in their clinical practice. Our results identify for the first time some important factors, which informed the construction of a quantitative questionnaire for confirmation in larger populations, and could constitute a small startup for future experts’ recommendations.
EXERCISE CAPACITY AND MORTALITY RISK IN A WIDE AGE SPECTRUM COHORT OF 750,302 VETERANS
Authors: Pittaras Andreas , Faselis Charles , Doumas Michael , Grassos Haralampos , Stavropoulos Konstantinos , Imprialos Konstantinos , Papavasiliou Maria , Manolis Athanasios , Myers Jonathan , Kokkinos Peter 
Published: June 2022

Objective:
Most studies that have evaluated the association between exercise capacity and the risk of all-cause mortality have focused on middle-aged Caucasian populations. We assessed mortality risk associated with fitness in male and females across a wide spectrum of age (30–95 years) and ethnicities.

Design and method:
In this retrospective cohort study, we included male and female Veterans who completed an exercise treadmill test (ETT) between 1999–2020. We assigned participants to one of ten age-specific fitness categories based on peak metabolic equivalents (METs) achieved during the ETT. The primary endpoint was all-cause mortality adjusted for age, body-mass index, ethnic origin, sex, cardiovascular disease, cardiovascular risk factors and medications. We assessed mortality from Veterans Affairs records up to Dec 31, 2020. We compared groups with Cox proportional hazard model.

Results:
We assessed 750,302 Veterans, ages 30–95 years (mean 61.3 years, SD 9.8 years). During a median follow-up of 9.8 years (IQR 5.6–14.0), 164,288 died with an average yearly mortality rate of 22 deaths per1,000 person-years. The exercise capacity-mortality risk association was independent, inverse, and graded for all ages, ethnicities, and men and women. Compared to the least fit group for each age decile, mortality risk was 50% lower at peak exercise capacities of approximately 10.0 METs for those 30–49 years, 8.0 METs for septuagenarians, and 7.0 METs for octogenarians. The lowest mortality risk was observed at approximately 14.0 METs with no additional decline or increase in risk beyond this level. Being unfit, defined having exercise capacity below the median (<8.5 METs), was associated with > 2 times higher mortality risk compared to fit (>8.5 METs), and was higher than the risk of the traditional cardiac risk factors examined.

Conclusions:
Higher Exercise Capacity is independently associated with lower mortality risk for all ages, ethnicities, and gender. An exercise capacity < 8.5 METs carried a greater risk than that of the traditional cardiac risk factors. Approximately 50% lower risk was noted in all age categories, commensurate to an exercise capacity achievable by most individuals within a given age category.
IMPACT OF BODY FAT DISTRIBUTION, ADIPOCYTOKINES AND VARIABILITY IN ASSOCIATED GENES ON KIDNEY TRANSPLANT OUTCOMES
Authors: Perez Roberto Nicolas Robles , Pino Guadalupe Garcia , Luna Enrique , Tormo Maria Angeles , Mota-Zamorano Sonia , Gonzalez Luz M. , Gervasini Guillermo 
Published: June 2022

Objective:
Adiposity distribution contributes to a number of pathologies. We aimed to assess whether this distribution was associated with clinical outcomes and to identify its relationship with leptin and adiponectin gene variants and plasma concentrations in renal transplant recipients (RTR).

Design and method:
Anthropometric parameters were measured in 236 RTR by bioelectrical impedance analysis, allograft function and post-transplant complications were retrieved from records. Blood samples were drawn to measure plasma leptin/adiponectin levels and to seek for polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes. Logistic regression models were applied to identify associations.

Results:
The waist-to-height ratio (WHr) displayed a significant association with delayed graft function (DGF), acute rejection (AR) and post-transplant diabetes mellitus, with OR values of 2.04 (1.02–4.08) p = 0.045; 3.08 (1.22–7.79) p = 0.017 and 2.79 (1.16–6.74) p = 0.022, respectively. Waist circumference was linked to DGF [OR = 1.03 (1.01 – 1.053), p = 0.025] and AR [OR = 1.041 (1.01 – 1.073), p = 0.009]. Leptin levels were significantly higher in patients who experienced AR [19.91 ± 23.72 vs. 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01–1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs. 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs. 96.38 ± 14.65 for GG/GT genotypes; p = 0.021).

Conclusions:
We have shown that WC, and especially WHr, are associated with adverse outcomes in renal transplant and hence may be useful parameters in RTR monitoring. In turn, these anthropometric parameters were affected by variability in the ADIPOQ gene, suggesting this polymorphism could be a useful marker of transplanted patients at risk.
MATERNAL OBESITY AND GESTATIONAL DIABETES ARE ASSOCIATED WITH DNA METHYLATION ALTERATIONS IN THE OFFSPRING THROUGHOUT THE FIRST YEAR OF LIFE
Authors: Alba-Linares Juan José , Fernández-Pérez Raúl , Ponce-Zanon Francisco , García-Carbonell Nuria , Gomez-Zafra Rafael , Fernández-Fraga Mario , Lurbe-Ferrer Empar 
Published: June 2022

Objective:
Obesity is a chronic metabolic disease of increasing prevalence and health importance in modern societies, which represents an added risk for the development of multiple pathologies. Moreover, epidemiological studies have shown how maternal obesity or gestational diabetes during pregnancy constitutes an important risk factor related to the appearance of cardiovascular and metabolic diseases in the offspring. Furthermore, this period of life is especially sensitive to extrinsic and intrinsic influence, so epigenetic remodelling may help explain the molecular mechanisms that underlie epidemiological findings. The main objective of this work was to determine the DNA methylation landscape of children born to mothers with obesity and gestational diabetes across their first year of life.

Design and method:
We have characterized the methylome of blood samples from a paediatric cohort of 39 subjects consisting of children born to mothers who suffered from obesity or obesity with gestational diabetes during pregnancy and healthy controls. We performed longitudinal measurements throughout the first year of life (0, 6 and 12 months; total N = 92) using Illumina Infinium MethylationEPIC BeadChip arrays to profile more than 770,000 CpG sites. The design allowed us to carry out both cross-sectional and longitudinal analyses in order to derive DNA methylation alterations associated with developmental and pathological-related epigenomics.

Results:
We have identified abundant DNA methylation alterations during child development from birth to 6 months and, to a lesser extent, until 12 months of age. At the same time, using cross-sectional analyses, we have identified DNA methylation biomarkers that discriminate children born to mothers who suffered from obesity or obesity with gestational diabetes during pregnancy compared to their healthy counterparts. Moreover, our longitudinal design allowed us to determine that these alterations are at least maintained during the first year of life. In addition, gene enrichment analyses revealed that these DNA methylation alterations are associated with regions and genes related to feeding behaviour, appetite, metabolism and cell signalling.

Conclusions:
Our results support the existence of an intrauterine-mediated maternal obesity effect with an impact on the childhood methylome and possible functional implications.
PSYCHOLOGICAL DETERMINANTS OF DRUG ADHERENCE AND SEVERITY OF HYPERTENSION IN PATIENTS WITH RESISTANT VS. CONTROLLED HYPERTENSION
Authors: Persu Alexandre , Georges Coralie M.G. , Ritscher Sabrina , Pappaccogli Marco , Petit Géraldine , Lopez-Sublet Marilucy , Bapolisi Achille , Monaco Silvia Di , Wallemacq Pierre , Rabbia Franco , Toennes Stefan W. , De Timary Philippe 
Published: June 2022

Objective:
In a pilot study including 35 patients with resistant hypertension, we documented associations between psychological profile, drug adherence and severity of hypertension. The current study aims to confirm and expand our findings in a larger sample of patients with resistant hypertension, using controlled hypertensive patients as comparator.

Design and method:
Patients with resistant hypertension were enrolled in hypertension centers from Brussels and Torino. Psychological profile was assessed using five validated questionnaires. Drug adherence was assessed by high-performance liquid chromatography-tandem mass spectrometry analysis of urine samples, and drug resistance by 24-hour ambulatory blood pressure adjusted for drug adherence.

Results:
The study sample otalised 144 patients, including 81 resistant and 63 controlled hypertensive patients. Mean adherence level was significantly lower in the resistant group (78.9% versus 92.7% in controlled patients, p-value = .022). In resistant hypertensive patients, independent predictors of drug adherence assessed by regression analysis were somatization, smoking status, acceptation and living with a partner, accounting for 46% of variability in drug adherence. Independent predictors of severity of hypertension were somatization, smoking status, admissions to emergency department and acceptation, accounting for 67% of variability in severity of hypertension. In contrast, in patients with controlled hypertension, the single predictors of either drug adherence or severity of hypertension were number of years of hypertension and, for severity of hypertension, alcohol consumption, accounting for only about 15–20% of variance.

Conclusions:
Psychological factors, mostly related to somatization and expression of emotions are strong, independent predictors of both drug adherence and severity of hypertension in resistant but not in controlled hypertensive patients.
IS BASAL NITRIC OXIDE ACTIVITY OF THE RENAL VASCULATURE ALTERED? ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL COMPARING TWO COMBINATION THERAPIES
Authors: Kannenkeril Dennis , Ott Christian , Bosch Agnes , Striepe Kristina , Pietschner Robert , Schiffer Mario , Schmieder Roland E. 
Published: June 2022

Objective:
Recently we demonstrated that a combination therapy with empagliflozin and linagliptin in patients with type 2 diabetes mellitus (T2DM) induce changes in renal hemodynamics. The purpose of this study was to analyze the influence of basal nitric oxide (NO) activity of the renal vasculature on the described changes of the renal hemodynamic profile.

Design and method:
In this study patients with T2DM were nalysing to receive either empagliflozin and linagliptin (E+L group, n = 50) or metformin and insulin glargine (M+I group, n = 46), for 3 months. Renal hemodynamics were assessed with constant-infusion input-clearance technique with p-aminohippuric acid for renal plasma flow (RPF) and inulin for glomerular filtration rate (GFR) at baseline and after treatment. Due to withdrawal of inulin from the market during the study, GFR and filtration fraction (FF) were measured only in a sub-group of patients (E+L: n = 34; M+I: n = 31). Intraglomerular hemodynamics were calculated according the model established by Gomez. The basal NO activity in the renal circulation has been assessed by nalysing change in RPF in response to intravenously administrated NG-monomethyl-l-arginine (NO inhibitor).

Results:
After 3 months of treatment, we did not observe any change in basal NO activity compared to baseline in either of the groups. In the E+L group, we found a correlation between basal NO activity of the renal vasculature after 3 months of treatment and change in RPF (r = -0.535, p < 0.001), renal blood flow (r = -0.468, p = 0.001) and renal vascular resistance (r = 0.377, p = 0.007) induced by treatment. Similar correlations with change in FF (r = 0.639, p < 0.001), preglomerular (r = 0.350, p = 0.046) and postglomerular resistance (r = 0.588, p < 0.001) have been found. No such relationships were found in the M+I group after 3 months and with basal NO activity at baseline in both treatment groups.

Conclusions:
Basal NO emerged as a determinant of the renal hemodynamic response in the combination therapy of empagliflozin and linagliptin, but not in the combination therapy of insulin and metformin.
ASSOCIATION BETWEEN ADMISSION BLOOD PRESSURE, INCIDENT CARDIOVASCULAR EVENTS AND EARLY MORTALITY IN PATIENTS WITH REVASCULARIZED CRITICAL LIMB ISCHEMIA
Authors: Gaisset Roxane , Lin Franck , Lazareth Isabelle , Mourad Jean-Jacques , Priollet Pascal , Emmerich Joseph , Yannoutsos Alexandra 
Published: June 2022

Objective:
Patients with critical limb ischemia (CLI) present a high-risk of cardiovascular events and death. Hypertension is one of the most prevalent risk factors in this population. This study investigated the association between blood pressure (BP) level at hospital admission, major cardiovascular events (MACE) and one-year mortality in patients undergoing percutaneous revascularization for CLI.

Design and method:
This retrospective analysis of an ongoing cohort study included 285 consecutive patients ospitalised from November 2013 to December 2018. Major cardiovascular events, defined as heart failure, acute coronary syndrome, ischemic stroke and sudden death, were collected during the first year following revascularization. Multivariate analysis identified factors independently associated with MACE occurrence and one-year mortality. A p < = 0.05 was considered statistically significant.

Results:
The study included 157 men (55%) and 128 women (45%), mean age of 77.8 ± 12 years. Treated hypertension was present in 222 (78%) patients (admission systolic BP 132 (±18.2) mmHg, diastolic BP 69.9 (±7.79) mmHg, pulse pressure 62.3 (±15.8) mmHg and mean BP 90.7 (±9.77) mmHg); diabetes was present in 137 (48%) patients; 112 (39%) patients had known coronary heart disease (CHD) and 20 (7%) patients were dialysis dependent.
During one-year follow-up after revascularization, 75 (26.3%) patients presented a MACE. Peri-operative mortality rate was 4% (12 patients, of whom 6 patients died from MACE).
At one-year, cumulative mortality rate was 26.7% (76 patients) mostly from MACE.
Twenty-three patients (8%) experienced major limb amputation.
In multivariate analysis, the occurrence of MACE was associated with an increased mortality risk (HR 7.06 (2.99–17.51), p<0.001). Of the four BP indexes, systolic BP (p = 0.01), mean BP (p = 0.02), pulse pressure (p = 0.02), but not diastolic BP, were significantly and inversely correlated with 1-year mortality. Decompensated heart failure and CHD were both associated with incident MACE in multivariate analysis, independently of confounders.

Conclusions:
Incident MACE were prevalent in the year following endovascular procedure in patients with CLI and were associated with an increased risk of mortality. There is an inverse association between admission BP and one-year mortality, independently of the occurrence of MACE. Decompensated heart failure and CHD are important contributors for the occurrence of MACE.
PREVALENCE AND CLINICAL CORRELATES OF FRAILTY IN HYPERTENSIVE OLDER ADULTS
Authors: Rivasi Giulia , Tortu Virginia , D’Andria Maria Flora , Turrin Giada , Ceolin Ludovica , Capacci Marco , Mossello Enrico , Ungar Andrea 
Published: June 2022

Objective:
To assess the prevalence of frailty among hypertensive older adults according to the most widely used frailty measure tools and to investigate the clinical correlates of frailty.

Design and method:
A prospective observational study was conducted involving consecutive hypertensive patients aged 75 or older referred to a Hypertension clinic or a Memory clinic in Florence, Italy. The following frailty measure tools were applied: Fried Frailty Phenotype (FFP), Frailty Index, Clinical Frailty Scale (CFS), Frailty Postal Score (FPS), Short Physical Performance Battery (SPPB), gait velocity. The Cohen’s kappa coefficient was calculated to assess the agreement among measures. Multiple logistic regression was used to identify clinical variables independently associated with frailty (“correlates of frailty’’).

Results:
The study sample included 121 participants (mean age 81, 60% female). Frailty prevalence varied according to the definition used, ranging from 33% according to the FPS up to 50% according to the CFS. The Cohen’s kappa coefficient indicated moderate agreement of the FFP with the Frailty Index and the SPPB, and of the Frailty Index with the CFS and the SPPB (K = 0.60–0.79). Agreement was minimal or weak among the remaining measures (K < 0.60). At multivariable analysis, using a walking aid and reporting depressive symptoms at the Geriatric Depression Scale were independently associated with frailty, regardless of the frailty measure used. Correlates of frailty also included dementia, disability in instrumental activities of daily living (Frailty Index, CFS, gait velocity) and the comorbidity burden (Frailty Index, gait velocity). Regular physical activity was inversely associated with frailty when defined according to the FFP, the Frailty Index and the FPS.

Conclusions:
Frailty is common among older adults with hypertension, although prevalence varies depending on the definition used. Agreement among different frailty measures was moderate-to-weak. Multiple correlates of frailty were identified, including factors that are not routinely assessed in hypertensive patients, such as depressive symptoms and disability. Depressive symptoms and walking aids could represent frailty markers in hypertensive older adults, irrespective of how frailty is defined.