bluuebunny/crossref_metadata_2025_split huggingface dataset:
EXPLORING THE BIDIRECTIONAL CAUSAL ASSOCIATION BETWEEN FRAILTY AND CARDIOVASCULAR DISEASES: INSIGHTS FROM A BIDIRECTIONAL MENDELIAN RANDOMIZATION STUDY
Authors: Yin Zheng , Miao Huanhuan , Yang Shijie , Zhou Zhanyang , Zhang Yuqing 
Published: May 2024

Objective:
Observational studies have consistently shown a robust association between frailty and cardiovascular diseases. However, it remains uncertain whether this association reflects causality. We performed a bidirectional Mendelian randomized (MR) study to assess the bidirectional causality between frailty, as measured by the frailty index (FI), and hypertension(HTN), atrial fibrillation(AF), coronary artery disease (CAD) and heart failure(HF).

Design and method:
Using the latest genome-wide association study (GWAS) summary data on individuals of European descent, we extracted independent single nucleotide polymorphisms (SNPs) for each phenotype at genome-wide significance levels as instrument variables, including FI (N=175,226), HTN (N=462,933), AF (N=138,994) and HF (N= 977,323). The inverse variance weighting method in two-sample MR analysis was primarily used, followed by various sensitivity and validation analyses such as MRPRESSO.

Results:
Higher FI significantly increased the risk of HTN (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.07-1.16 P<0.001) and CAD (OR 2.57, 95% CI 1.72-3.84 P<0.001). FI was suggestively associated with a higher risk of AF (OR 1.83 95%CI 1.11-3.01 P<0.05). No association between FI and HF was observed (OR 1.30, 95% CI 1.00-1.71 P>0.05). In the reverse analysis, genetic predisposition to HTN (OR 1.94 95% CI 1.71, 2.19 P<0.001) and CAD (OR 1.07 95% CI 1.05-1.09 P<0.001) was significantly associated with higher FI. A suggestive correlation between genetic susceptibility to HF (OR 1.09 95% CI 1.00-1.19 P<0.05) and higher FI was also observed. No association between AF and FI was observed (OR 1.01 95% CI 1.00-1.03 P>0.05). Results of sensitivity and validation analyses were stable.

Conclusions:
Our findings support a bidirectional causal association between frailty and HTN and CAD and a possible causal association between frailty and the development of AF and HF. A deeper exploration of this association is imperative to optimize the management of elderly patients.
A EUROPEAN SURVEY TO IDENTIFY CURRENT PRACTICES ON THE TREATMENT OF HYPERTENSION IN ADULTS >75 YEARS IN ESH EXCELLENCE CENTRES
Authors: Camafort Miguel , Bahat Gülistan , Bogaert Jonathan , Rojas Dhayana E. Dallmeier , De Backer Tine , Desideri Giovambattista , Kenny Rose , Protogerou Athanasios , Rajzer Marek , Ribeiro Heloise , Sheppard James , Ungar Andrea , Virdis Agostino , Labat Carlos , Weber Thomas , Persu Alexandre , Benetos Athanase 
Published: May 2024

Objective:
Treatment specificities of hypertension in older adults remains a matter of debate. We therefore investigated the clinical practices on the treatment of hypertension in adults >75 years in ESH Excellence Centres (EC).

Design and method:
A survey with 24 questions was developed by the Working Group Hypertension in Older Adults and addressed to ESH-EC. The survey was questioning therapeutic strategies in treating hypertension in 4 groups of frailty/functionality status: Group 1: Fit, Group 2: Frail and Independent, Group 3: Frail and Dependent Group 4: End of Life.

Results:
Responses were received from 50 ESH excellence centres. The representatives of these centers who answered (one person per center) were mostly internists (42%), cardiologists (32%) and nephrologists (18%). A total of 48% of respondents stated that they always considered frailty status, whilst a further 48% said that they frequently consider frailty, usually based on general appearance of the patient (68%).
The preferable SBP range was considered for the 4 groups. A SBP range of 130-139 mm Hg for Groups 1 and 2 was considered as optimal by 56% of respondents whereas for Group 3, 48% considered a SBP range of 140-149 mmHg and for Group 4, 56% considered SBP 150 mmHg or more as optimal.
For Group 1, 46% and 48% of respondents respectively proposed combination therapy in all hypertensives and in grade 2-3 hypertensives. These percentages were respectively 8% and 66% for Group 2, 4%and 34% for Group 3, 2% and 12% for Group 4.
When considering a reduction in antihypertensive treatment, 57% did not specify any tool, and 34% used START/STOPP criteria. For Group 1, 42% proposed treatment reduction when SBP was between 100-120 mmHg whereas 40% of the respondents reduced treatment only if SBP <100mmHg. In the 3 other groups about 74-80% proposed to reduce treatment when SBP<120 mmHg.

Conclusions:
As frailty increases, higher SBP targets are considered optimal; Nevertheless the use of validated tools to improve frailty stratification, is still not standardized.
PLASMA EXOSOMES FROM HYPERTENSIVE PATIENTS WITH RENAL DYSFUNCTION ARE ENRICHED IN SPECIFIC REDOXIMIRS AND FIBROMIRS
Authors: Redon Josep , Martinez-arroyo Olga , Flores-chova Ana , Debacts Marta Mendez , Martinez-hervas Sergio , Forner Maria J , Ortega Ana , Cortes Raquel 
Published: May 2024

Objective:
Several microRNAs (miRNAs) have emerged as powerful regulators of fibrotic processes and have been termed “fibromiRs”. In addition, miRNAs can also influence the expression of genes responsible for the generation of reactive oxygen species and antioxidant defense and are termed “redoximiRs”. Both biological processes are present in the development and progression of renal damage. Frequently, miRNAs are enclosed inside exosomes, which have evolved as novel specific targets for pathogenic mechanisms and therapy search. We aimed to investigate whether plasma exosomes from hypertensive and diabetes patients are enriched in fibromiRs and redoximiRs using deep sequencing technology.

Design and method:
: In a cohort of hypertensive and diabetic patients with nephropathy (n=15) and a control group (n=20), we analyzed by next generation sequencing (RNA-Seq) the miRNA profile in plasma exosomes. Then, we validated miR-21-5p by RT-qPCR such as relevant “redoxifibromiR” and their target predictions and molecular pathways analysis were performed through GO terms and KEGG pathways.

Results:
RNA-Seq analysis from plasma exosomes identified 32 differentially expressed (DE) miRNAs in patients compared to controls, of which 75% are biofluid specific. In addition, the majority of the exosomal DE miRNAs were identified as fibromiRs (17 miRNAs, 53%) or redoximiRs (8 miRNAs, 25%). One of the most representative miRNAs identified was miR-21-5p, whose levels in plasma exosomes were increased 23.5 fold-change (p<0.05), validated by qPCR, and were highly associated with UAE/U-Creatinine (r Spearman=0.96, p<0.001). Bioinformatic analysis revealed that within the top 20 terms of this pro-fibrotic “redoximiR”, miR-21-5p is implicated in molecular functions such as growth factor and cytokine activity, and cytokine receptor binding and regulates key signalling pathways with specific relevance in the context of organ fibrosis, such as chemokine, Ras, Rap1, TNF and MAPK signalling pathways.

Conclusions:
Our study found an enrichment of fibromiRs and RedoximiRs in plasma exosomal biofluid from hypertensive/diabetic patients with renal dysfunction and are closely related with relevant signaling pathways implicated in fibrogenesis.
FUNDING: Health Institute Carlos III [PI19/01796; PI21/00249; PI23/01179 (National Health Research Projects); FI20/00096 FI22/00032 (PFIS Grants); CD00069 (Miguel Servet Contract)]; IJC2020-045308-I, by MCIN/AEI. European Regional Development Fund (ERDF).
HYPERTENSIVE EMERGENCIES AND URGENCIES: ADHERENCE TO GUIDELIENS AND RELATIONSHIP BETWEEN BLOOD PRESSURE MANAGEMENT AND IN-HOSPITAL MORTALITY
Authors: Maloberti Alessandro , Valobra Tommaso , Giani Valentina , Garofani Ilaria , De Censi Lorenzo , Galasso Michele , Colombo Valentina , Menna Alessandro , Annalisa Giacalone , Ferretti Cecilia , Sultana Andrea , Gheda Silvia , Capsoni Nicolò , Galbiati Filippo , Bombelli Michele , Giannattasio Cristina 
Published: May 2024

Objective:
Data regarding prevalence and clinical management of hypertensive emergencies and urgencies are lacking and heterogeneous. Our goal is to characterize patients with hypertensive emergencies and urgencies admitted to the Emergency Department (ED) of Niguarda hospital and Pio XI Hospital of Desio. In this population we also want to evaluate factors associated with organ damage, adherence to guidelines and the impact of Blood Pressure (BP) management on in-hospital mortality.

Design and method:
We performed a multi-centre retrospective study collecting data about all adult patients with systolic BP > 180 mmHg and/or diastolic BP >120 mmHg admitted to our hospitals’ ED during 2017 and 2019.

Results:
Admission to ED for BP elevation were 1838 (0.95% of total admission to ED), of whom 38% were hypertensive emergencies and 62% were hypertensive urgencies. Patients with hypertensive emergencies were older, mainly male, with more comorbidities and more symptomatic at ED admission. In the emergencies group, we observe a SBP mean reduction of 39.50 mmHg (±26.35) and a DBP mean lowering of 16.28 mmHg (±17.57); the most used drugs were furosemide, nitroglycerin and parenteral labetalol. In the urgencies group, the mean reduction was 39.09 mmHg (±22.46) for SBP and 15.34 mmHg (±16.07) for DBP. The most used drug was short-acting nifedipine benzodiazepine and amlodipine in this group. Age, sex, clinical history of heart failure and chronic obstructive pulmonary disease, symptoms at ED admission ad eGFR have been recognised as factors associated with organ damage. Instead, BP at ED admission and its management didn’t appear to have a significant impact on outcomes.

Conclusions:
Our study demonstrated better adherence to guidelines in the treatment of hypertensive emergency than of hypertensive urgencies. Furthermore, no significant association were found between the BP management in the ED and in-hospital mortality
THE MEDICAL IMPACT OF EMERGENT BANNING OF N-NITROSODIMETHYLAMINE (NDMA)- CONTAMINATED ANTIHYPERTENSIVE DRUG: A NATIONWIDE LONGITUDINAL COHORT STUDY
Authors: Lee Hae -YOUNG , Cho Myung -Chan 
Published: May 2024

Objective:
Concerns exist regarding the potential carcinogenic effect of N-nitrosodimethylamine (NDMA) as a contaminant of the antihypertensive medication, valsartan. This study evaluated the association of NDMA-contaminated generic valsartan with cancer incidence.

Design and method:
Nationwide longitudinal observational cohort of 3,231,212 participants with satisfactory minimal adherence, followed up from January 1, 2013 until December 31, 2020 from the National Health Insurance Service of South Korea consisted. We performed 1:1:1 pairwise propensity score matching (PSM) of NDMA-uncontaminated original, NDMA-contaminated generic, and initially-suspended-but-finally confirmed as NDMA-uncontaminated generic valsartan user-groups. Time-dependent Cox models and dose-response evaluation were used to evaluate carcinogenicity. The primary outcome was any primary cancer incidence. The secondary outcome was the incidences of 12 organ-specific cancers. The risks of all-cause and cardiovascular deaths were estimated before and after the withdrawal of valsartan.

Results:
Among participants (mean age 59.5±13.1 years; male, 53.5%), valsartan new users had adjusted hazard ratios and 95% confidence intervals (CI) of 1.069 (1.054 to 1.085) and 1.172 (1.128 to 1.216) for any cancer in the NDMA-exposed period (versus NDMA-unexposed) before and after 1:1:1 PSM, respectively. Regardless of PSM, prostate cancer risk increased significantly during the NDMA-exposed period and did not increase in the eventually-NDMA-uncontaminated group in valsartan new users. All-cause and cardiovascular mortality did not differ significantly with NDMA exposure before and after emergent banning.

Conclusions:
NDMA-contaminated valsartan increased cancer risk, especially of prostate cancer. All-cause and cardiovascular mortality did not evidently increase following banning. This supports emergent health-policy action against potentially carcinogenic drugs.
BLOOD PRESSURE AND RENAL FUNCTION RESPONSES IN WORKERS EXPOSED TO LEAD FOR UP TO SIX YEARS
Authors: Yu Yuling , An Dewei , Yang Wenyi , Verhamme Peter , Allegaert Karel , Nawrot Tim , Staessen Jan 
Published: May 2024

Objective:
As the contemporary environmental lead exposure is comparable to the pre-industry levels in developed countries, whether lead exposure still contributes to the hypertension and renal impairment is controversial. We aimed to assess the association between blood pressure, renal function and lead exposure at contemporary low level in a longitudinal occupational cohort.

Design and method:
The Study for Promotion of Health in Recycling Lead assessed the blood pressure (BP) including the incidence of hypertension and renal function (RF) responses for up to six years in the workers without previous occupational exposure. BP averaged by 5 consecutive readings and the estimated glomerular filtration rate (eGFR) derived from serum creatinine and cystatin C (eGFRcrt and eGFRcys). Blood lead (BL) was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 mg/dL). The statistical methods included multivariable-adjusted mixed models and interval-censored Cox regression analysis.

Results:
The 234 workers analysed were on average 28.5 years old and included 91.9% men. The baseline BL concentration was 4.35 microgram/dL and increased 3.17-fold over follow-up (median: 2.03 years; range: 0.92-6.45 years). The changes in BP and RF were not significantly correlated with the follow-up-to-baseline BL ratio (p >= 0.51 and p >= 0.18, respectively). The fully-adjusted changes in systolic/diastolic BP associated with a doubling of BL were -0.25/-0.12 mm Hg (CI: -0.94 to 0.44/-0.66 to 0.42 mm Hg). Accordingly, the incidence of stage-1 or stage-2 hypertension was not associated with the BL change (p >= 0.063). Similarly, the changes in eGFRcrt and eGFRcys associated with a 2 fold BL increment were not significant, amounting to -0.70 mL/min/1.73 m2 (CI: -1.70 to 0.30 mL/min/1.73 m2) and 1.06 ml/min/1.73 m2 (-2.16 to 0.03 mL/min/1.73 m2).

Conclusions:
The BP and RF responses to an over 3-fold BL increment were small and not significant confirming the safety of modern lead-handing facilities operating under current safety rules.
CALCIUM INTAKE IS INVERSELY ASSOCIATED WITH PERIPHERAL BLOOD PRESSURE: POSSIBLE INTERACTION WITH SERUM CALCIUM
Authors: Pont Chiara Dal , Giontella Alice , Sartorio Andrea , Minuz Pietro , Ericson Ulrika , Melander Olle , Fava Cristiano 
Published: May 2024

Objective:
Serum calcium has been directly associated with blood pressure (BP) level or the presence of hypertension in different observational studies, but the association between dietary calcium intake and BP remains unclear. The objective of this study is to investigate the relationship between calcium intake and BP in two large population-based studies.

Design and method:
Calcium intake and BP were evaluated in the Malmö Diet and Cancer (MDC) study (n∼28,000) in Sweden and the UK Biobank (n∼330,000) in the United Kingdom. Calcium intake in the MDC study was determined using a 7-day menu book for recording of meals that varies from day to day (usually lunch and dinner meals) and a 168-item diet questionnaire (“Kosthistoria”), combined with a 45–60 min diet history interview. In the UK Biobank food frequency was assessed using a dietary questionnaire based on a 24-hour dietary recall of the previous day.

Results:
In the MDC study, calcium intake demonstrated an inverse association with systolic (-0.564, 95% CI -0.784/-0.343) and diastolic BP (-0.326, 95% CI -0.444/-0.209) only when the values were not adjusted for total caloric intake. In the UK Biobank, higher calcium intake was associated with lower systolic and diastolic BP when adjusted for caloric intake, but only with diastolic BP when unadjusted for caloric intake. In the MDC, in the subsample of patients with measured serum calcium levels (n=4,095), we observed a positive association between serum calcium level and systolic BP. Upon comparing the association across quartiles of calcium intake, this association was evident only in the three lowest quartiles, while it became negative in the highest quartile.

Conclusions:
Calcium intake from diet tends to be linked with lower BP and appears to mitigate the positive association between serum calcium and BP. Further studies are required to confirm these associations and to explore whether there is an interaction with hormones that regulate calcium distribution in the body.
CLINICAL CHARACTERISTICS OF PATIENTS WITH FIBROMUSCULAR DYSPLASIA WITH AND WITHOUT SPONTANEOUS CERVICAL ARTERY DISSECTION IN THE ARCADIA-POL STUDY
Authors: Sterlinski Ignacy , Talarowska Paulina , Kolodziejczyk-kruk Sylwia , Szwench-pietrasz Elzbieta , Florczak Elzbieta , Kadziela Jacek , Michalowska Ilona , Michalowska Anna , Januszewicz Andrzej , Persu Alexandre , Januszewicz Magdalena 
Published: May 2024

Objective:
Fibromuscular dysplasia (FMD) is idiopathic, segmental, non-inflammatory, non-atherosclerotic disease affecting small and medium-sized arteries. FMD causes artery stenosis, although it may also lead to aneurysm, dissection, or arterial tortuosity. The aim of the study was to evaluate clinical characteristics of patients with spontaneous cervical artery dissection (SCeAD) and to assess prevalence of SCeAD among patients with FMD.

Design and method:
The ARCADIA-Pol is an ongoing study, initiated in 2015 at the Department of Hypertension, National Institute of Cardiology in Warsaw, Poland. Patients enrolled in the study met the inclusion criteria: presence or suspicion of FMD and/or radiologically documented episode of spontaneous dissection of any artery. Each patient underwent: clinical and 24h ambulatory blood pressure monitoring, biochemical tests, echocardiography, US Doppler of renal and carotid arteries and whole body angio-CT. We present data of 435 currently enrolled patients.

Results:
Among 435 patients included in the analysis SCeAD was confirmed in 77 subjects, most often in internal carotid arteries (68.8%). Mean age was 43,9 ± 9,6 years, majority of patients were women (64.9%). Hypertension (HT) was present in 59.7% patients, hypercholesterolemia in 44,2%.
Among 77 subjects with SCeAD, the presence of typical FMD changes was confirmed in 35.1% cases. Patients with SCeAD and FMD were older and more often female as compared to those with SCeAD and without FMD. There were no differences in biochemical parameters or target organ damage parameters between SCeAD patients with and without FMD.
Among 281 subjects with FMD, an episode of SCeAD was documented in 9.6% patients. Patients with FMD and SCeAD less often had HT. Women with FMD and SCeAD had more often a history of contraceptive pills use than those without SCeAD. No other differences were found between compared groups.

Conclusions:
FMD changes often coexist in patients with SCeAD (35.1%). In FMD patients complication of SCeAD occur relatively often (9.6%), which leads to conclusion that FMD is generalized arteriopathy. It is recommended to perform radiological screening in FMD patients to look for arterial complications in other vascular beds.
THE RELATION OF CIRCULATING VASCULAR BIOMARKERS TO ENDOTHELIAL FUNCTION AND SKIN MICROVASCULAR REACTIVITY IN PATIENTS WITH HYPERTENSION AND DECLINING KIDNEY FUNCTION
Authors: Jekell Andreas , Lundwall Kristina , Kahan Thomas 
Published: May 2024

Objective:
Adhesion molecules and glycocalyx (GC) shedding are believed to reflect endothelial dysfunction but few studies have compared circulating vascular biomarkers and measures of peripheral endothelial function and microvascular function in patients with hypertension over a wider range of renal function.

Design and method:
107 patients (58±13 years, 32% women) with hypertension (149±17/87±10 mmHg) and a wide range of renal function (mean eGFR 74, range 130–21 ml/min x 1.73 m2) were included. Skin microvascular function was assessed by laser Doppler fluxmetry and iontophoresis (acetylcholine, ACh, and sodium nitroprusside, SNP); resistance artery endothelial function by the reflection index change (RI%) before and after beta 2-adrenoceptor-agonist stimulation, assessed by pulse wave analysis (SphygmoCor, AtCor Medical); large artery endothelium dependent and independent vasodilatation by post-ischemic flow-mediated vasodilatation (FMD) and glyceryl trinitrate (GTN), respectively. Vascular circulating biomarkers assessed (by ELISA) were GC glycoproteins hyaluronan (HA) and syndecan-1 (syn-1), and the adhesion molecules ICAM-1, VCAM-1, and E-selectin.

Results:
For bivariate significant (p<0.05) correlations multivariate linear regression analyses including age, sex, body mass index, and eGFR, were performed. There were independent inverse relations between syn-1 (β= –0.27, p=0.042) and e-selectin (β= –0.26, p=0.051) to skin microvascular reactivity evaluated by ACh peak flux, while syn-1, and e-selectin were unrelated to SNP peak flux. HA, ICAM-1 and VCAM-1 did not relate to skin microvascular reactivity. Only syn-1 (β= 0.29, p=0.026) related to RI %. No biomarkers were related to FMD or GTN.

Conclusions:
Increased levels of circulating syn-1 and e-selectin reflect skin microvascular dysfunction and endothelial dysfunction of smaller resistance arteries, independently of eGFR. However, none of the circulating vascular biomarkers reflected large artery endothelial function. The lack of relations between the investigated circulating biomarkers and indices of endothelial function suggests that the investigated biomarkers are less suitable to assess large artery endothelial function in hypertensive patients independent of kidney function.
DEFINITION, VALIDATION AND CALIBRATION OF AN OUTCOME-DRIVEN THRESHOLD FOR PULSE PRESSURE AMPLIFICATION
Authors: Huang Qi -FANG , An De -Wei , Aparicio Lucas , Cheng Yi -Bang , Li Yan , Staessen Jan 
Published: May 2024

Objective:
Pulse pressure amplification (PPA) is the ratio of brachial-to-aortic pulse pressure and decreases with age and cardiovascular risk factors. In an individual-participant meta-analysis, we aimed to define, calibrate and validate an outcome-driven threshold for PPA in the general population.

Design and method:
Incidence rates and standardized multivariable-adjusted hazard ratios (HRs) of cardiovascular and coronary endpoints associated with PPA, as assessed by the SphygmoCor software, were evaluated in the International Database of Central Arterial Properties for Risk Stratification (n=5608). Model refinement was assessed by the integrated discrimination (IDI) and net reclassification (NRI) improvement.

Results:
Over 4.1 years (median), 255 and 109 participants experienced a cardiovascular or coronary endpoint. In a randomly defined discovery subset of 3945 individuals, the rounded risk-carrying PPA thresholds converged at 1.3. The HRs for cardiovascular and coronary endpoints contrasting PPA <1.3 vs >=1.3 were 1.54 (95% confidence interval: 1.00-2.36) and 2.45 (1.20-5.01), respectively. Models were well calibrated, findings were replicated in the remaining 1663 individuals analyzed as test dataset, and NRI was significant for both endpoints. The HRs associating cardiovascular and coronary endpoints per PPA threshold in individuals <60 vs >=60 years were 3.86 vs 1.19 and 6.21 vs 1.77, respectively. Of the younger high-risk individuals, 1107 (67.7%) were women.

Conclusions:
Over and beyond common risk factors, low PPA defined as a brachial-to-central PP ratio of <1.3 is a forerunner of cardiovascular and coronary complications, in particular in women younger than 60 years. Our study supports pulse wave analysis for risk stratification.