bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROGNOSTIC VALUE OF MICRORNA-126-3P FOR CARDIOVASCULAR EVENTS IN A GENERAL POPULATION
Authors: Martinez-Arroyo Olga , Ortega Ana , Flores-Chova Ana , Sanchez-Garcia Belen , Garcia-Garcia Ana B. , Chaves Felipe J. , Martin-Escudero Juan C , Redon Josep , Cortés Raquel 
Published: June 2023

Objective:
Endothelial dysfunction is a forerunner of atherosclerosis, leading to cardiovascular disease, and albuminuria is a marker of endothelial dysfunction. Measurement of circulating levels of microRNAs is emerging as potential biomarkers for cardiovascular disease. We aimed to estimate the predictive value of a plasma microRNAs signature associated with albuminuria in the incidence of cardiovascular events.

Design and method:
The first study phase was to identify the plasma miRNAs associated with albuminuria in patients with HTN and controls. In a second step, a predictive model of miRNAs to assess the risk to develop CV events was analyzed in a retrospective study of the general population (HORTEGA Follow-up Study), on those who did not have previous CVD and had complete basal information on relevant covariates. Plasma miRNAs quantified in hypertensive patients by next generation sequencing were validated in a cohort of patients and controls by real-time quantitative PCR. The microRNAs associated with albuminuria were tested and their prognostic value for cardiovascular event incidence were analyzed on a retrospective, population-based study using Cox proportional hazard models.

Results:
A plasma microRNA profile was identified in the discovery cohort (n = 48) associated with albuminuria and three microRNAs (miR-126-3p, miR-1260b and miR-374a-5p) were confirmed in the validation cohort (n = 98). The microRNA signature discriminates urinary albumin excretion at baseline (n = 1025), and predicts the incidence of cardiovascular events and coronary heart disease and stroke in a general population retrospective study within a 14-year follow-up (n = 926). Thus, high miR-126-3p levels were associated with a shorter time free of both cardiovascular events (HR = 1.48, (1.36–1.62), p < 0.0001), as well as coronary artery disease and stroke combined (HR = 2.49, (2.19–2.83), p < 0.0001) (Figure).

Conclusions:
An increased plasma microRNAs profile was identified in hypertensive patients with albuminuria. Increased miR-126-3p emerges as a prognostic marker for cardiovascular events in a long-term general population. Further studies will assess the potential role of miR-126-3p as a guide for the status of endothelial dysfunction.
PREDICTION OF CAROTID INTIMA MEDIA THICKNESS AND STIFFNESS IN ADOLESCENCE AND YOUNG ADULTHOOD FROM FOUR BLOOD PRESSURE PARAMETERS AND RESTING HEART RATE
Authors: Neuhauser Hannelore , Büschges Julia , Schmidt-Trucksäss Arno 
Published: June 2023

Objective:
Childhood blood pressure (BP) is associated with hard outcomes and intermediate markers of cardiovascular disease several decades later but studies on more short-termed outcomes are scarce and and it is unclear whether different BP parameters are all predictive. This study investigates the association of four BP parameters and resting heart rate (RHR) at age 3 - 17 years with three carotid markers one decade later with population-based data.

Design and method:
4,607 14- to 28-year old participants of the nationwide German pediatric cohort KiGGS had semi–automated sonography with measurements of carotid intima media thickness (CIMT), lumen diameter (LD) and distensibility coefficient (DC) at their 11-year follow–up. We investigated associations of both baseline and follow-up systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), pulse pressure (PP) and RHR, with CIMT and LD > = 90th percentile and DC > = 10th percentile in logistic regression models. Percentiles were computed by sex and age. Analyses were adjusted for a cardiovascular risk score from added z-scores of body mass index, triglycerides, total-/HDL-cholesterol-ratio and HbA1c.

Results:
In longitudinal analyses SBP, DBP, MAP and RHR were significantly associated with all measures of subclinical atherosclerosis 11 years later, with similar, however weak, effect estimates, e.g. an OR of 1.19 (CI 1.09 - 1.31) for a one standard deviation increase in SBP with elevated CIMT. Cross–sectionally, the strongest association was found for MAP with reduced DC (OR 1.76; CI 1.60 - 1.94). For PP not all of these associations were significant. RHR was associated with elevated LD and reduced DC and inversely associated with elevated CIMT. Associations were similar when adjusting for the composite cardiovascular risk score.

Conclusions:
This study fills a gap between previous findings of an association between childhood BP and adverse effects in the vasculature in mid-adulthood, several decades later, by giving evidence for the association already after one decade. While individual risk prediction based of single BP measurements in this study is only weak, its robustness and consistency over five haemodynamic parameters and three subclinical atherosclerosis measures underscore the importance of preventing high blood pressure already early in the life course.
A PROOF-OF-PRINCIPLE EPIGENOME-WIDE ASSOCIATION STUDY OF PLASMA RENIN AND ALDOSTERONE CONCENTRATION IN A GHANAIAN POPULATION: THE RODAM STUDY
Authors: Linden Eva L. van der , Born Bert -Jan van den , Henneman Peter , Agyemang Charles 
Published: June 2023

Objective:
The epigenetic regulation of the renin-angiotensin-aldosterone system (RAAS) potentially plays a role in the pathophysiology underlying the high burden of hypertension in sub-Saharan Africans (SSA). In this first epigenome-wide association study (EWAS) of plasma renin and aldosterone concentrations, we explored the association between DNA methylation and concentrations of renin and aldosterone.

Design and method:
Epigenome-wide DNA methylation was measured using the Illumina 450k array on whole blood samples of 68 Ghanaian participants of the Research on Obesity and Diabetes among African Migrants Study (RODAM). Differentially methylated positions (DMPs) were assessed for plasma renin and aldosterone concentration using linear regression models adjusted for age, sex, body mass index, diabetes mellitus, hypertension, and technical covariates. Additionally, we extracted methylation loci previously associated with hypertension, kidney function, or that were annotated to RAAS-related genes, and associated these with renin and aldosterone concentration.

Results:
We identified one epigenome-wide significant DMP associated with renin, and ten DMPs associated with aldosterone. Top DMPs were annotated to the PTPRN2, SKIL, and KCNT1 genes, which have been reported in relation to cardiometabolic risk factors, atherosclerosis, and sodium-potassium handling. Moreover, EWAS loci previously associated with hypertension, kidney function, or RAAS-related genes, were also associated with renin and aldosterone concentration.

Conclusions:
In this first EWAS on RAAS hormones, we identified DMPs associated with renin and aldosterone in a SSA population. These findings are a first step in understanding the role of DNA methylation in regulation of the RAAS in general, and in a SSA population specifically. The results of this proof-of-principle study will inform new analyses including a larger sample size and a new methylation array (Illumina Infinium MethylationEPIC), which will we use to replicate these initial findings. This will help to further establish the role of DNA methylation and the RAAS system in the hypertension burden in SSA populations.
FOLLOW-UP OF VASCULAR LESIONS IN FIBROMUSCULAR DYSPLASIA. NO EVIDENCE FOR PROGRESSION YET
Authors: Leeuw Peter W. de , Zelis Piet , Kleijnen Bianca , Schutten Monica , Kroon Abraham 
Published: June 2023

Objective:
It is currently unknown whether the vascular lesions in patients with fibromuscular dysplasia (FMD) are progressive in time. Therefore, repeat CT-angiography (CTA) is often necessary to evaluate possible evolution of the abnormalites. It would be unjustified to frequently expose patients to this diagnostic modality with its drawbacks (radiation, contrast material) if the vascular lesions turn out to be stable.
The aim of our study was to explore whether vascular FMD lesions (unifocal or multifocal, with or without aneurysms) change in terms of extensiveness or localization over a period of a few years.

Design and method:
To qualify for the present study, patients had to be diagnosed with FMD in any vascular bed and both the diagnostic and the follow-up CTA had to be performed at the same institution using the same imaging protocol. Patients who had been referred by other hospitals and were followed in our own clinic were excluded from the analysis. On both the basal and the follow-up CTA, we assessed the number of lesions, the site of lesions, and the presence or absence of aneurysms.

Results:
A total of 161 patients had both a diagnostic and a follow-up CTA at our own clinic. Their mean age at diagnosis was 49 + 11 years (range 19-76) and 63% of the patients had been detected during a work-up for hypertension. On average, FMD was diagnosed nine years after the initial diagnosis of hypertension had been made. In the remainder of the patients, FMD was diagnosed after the patient had experienced a dissection (coronary, carotid).
Follow-up CTA after two years was available in 111 patients and after three years in 50 patients. In only three patients we found new vascular lesions after a period of two years. In all the others, the pattern of lesions remained constant.

Conclusions:
Over a period of two to three years, vascular FMD lesions do not seem to progress in most patients. If repeat CTA scanning is considered, one should respect at least this time period.
AT1R BLOCKADE PROMOTES TRANSFER OF HYPERTENSION BY RENAL CD11C+F4/80+ MACROPHAGES
Authors: Araos Patricio , Cortés Sut’yam , Campos Rafael , Reyes Javier , Figueroa Steffany M. , Fuenzalida María José , Pacheco Rodrigo , Amador Cristián 
Published: June 2023

Objective:
The immune system participates in arterial hypertension (AHT) induced by Angiotensin II (AngII). dendritic cells (DCs)-CD11c+ and macrophages (Mo) are abundant in the kidney. However, new subpopulations of CD11c+ cells with Mo characteristics have been described, presenting an F4/80+ phenotype. Additionally, recent studies have shown a controversial role of the type 1 AngII receptor (AT1R) in CD11c+ cells. In this context, it is unknown whether Mo CD11c+-F4/80+ modifies their phenotype during AngII-induced inflammatory kidney damage, and whether this promotes AHT in an AT1R-dependent manner.
The goal was evaluate whether renal Mo CD11c+-F4/80+ (rMo) modify their phenotype in AHT by AngII and determine whether their transfer to normotensive animals promotes AHT in an AT1R-dependent manner.

Design and method:
Male C57BI/6 mice (8 - 10 weeks, n = 6) were infused with AngII (490 ng/kg/min), AngII+Losartan (LOS; 20mg/kg/day, in drinking water), or vehicle for 14 -days. Systolic blood pressure (SBP) was measured by photoplestimography, DCs-CD11c+-F4/80- and rMo infiltrate were evaluated in cortex and medulla by flow cytometry. These cells were isolated and transferred to normotensive recipients, whose SBP was measured for 7-days (n = 3 - 5). Finally, the rMo were stimulated in vitro with AngII (100nM-24h) to analyze the abundance of mRNAs (Nox2, Sgk1, ENaC and AT1R; qRT-PCR). The data correspond to the mean ± standard deviation.

Results:
AngII increased SBP (AngII 134.7 ± 6.9 vs. Vehicle (Vh) 114.5 ± 7.8mmHg;p < 0.001) and promoted DCs-CD11c+F4/80- (AngII = 45.6 ± 11.9% vs. Vh = 31.7 ± 6.7%; p < 0.05) and Mo-CD11c+F4/80+ (AngII = 66.1 ± 8.4% vs. Vh = 55.6 ± 5.1%; p < 0.05) infiltration in renal medulla, and that was prevented by LOS (p < 0.05). We did not observe statistical differences in cortex. Interestingly, rMo transfer from AngII animals did not induce AHT in healthy recipient animals after 24h (Basal = 106.8 ± 2.3 vs.112.4 ± 4.9 mmHg;ns), compared to DCs-CD11c+-F4/80- (Basal = 110.0 ± 8.3 vs.132.0 ± 14.3mmHg;p < 0.05). However, the rMo of AngII+LOS animals increased SBP healthy recipients with respect to their baseline (basal = 109 ± 5.6 vs. 123 ± 8.0mmHg;p < 0.05). The rMo and DCs of hypertensive animals showed an increase in the abundance of AT1R (p < 0.05) compared to vehicle rMo.

Conclusions:
Pharmacological blockade of AT1R in vivo would have a differential effect on rMo, transferring AHT to normotensive animals. These findings suggest that subpopulations of renal CD11c+ cells have a differential role in AHT.
SUBCLINICAL TARGET ORGAN DAMAGE IN A SAMPLE OF CHILDREN WITH SOLITARY FUNCTIONING KIDNEY. A PRELIMINARY OBSERVATIONAL STUDY
Authors: Tagetti Angela , Cattazzo Filippo , Marcon Denise , Romano Simone , Bortolotti Stefano , Minuz Pietro , Brugnara Milena , Fava Cristiano 
Published: June 2023

Objective:
Solitary Functioning Kidney (SFK) is a condition characterized by a single-functioning kidney. Children bearing this condition are exposed to an increased risk of subclinical organ damage (SOD) due to the compensatory hyperfiltration in the remaining kidney and increased peripheral blood pressure (pBP) values. The aim of the present study was to assess the impact of traditional (pBP) and novel (central systolic blood pressure, cSBP) cardiovascular risk factors on SOD in children and adolescents with solitary functional kidney.

Design and method:
Carotid ultrasonography was performed to measure carotid Intima-Media Thickness (cIMT), an index of subclinical atherosclerosis. Arterial stiffness was assessed by measuring carotid Distensibility Coefficient (cDC) and carotid-femoral Pulse Wave Velocity (PWV). Cardiac mass and remodeling were analyzed using transthoracic echocardiography. Central and peripheral (both office and ambulatory) BP measurements, as well as biochemical data from blood and urine samples were collected.

Results:
Forty-eight SFK children and adolescents were included, of whom 45.5% were hypertensive at the Ambulatory Blood Pressure Monitoring. Twenty-four patients had increased cIMT and RWT while 8.4% and 8.9% demonstrated a reduction of cDC and an increase of PWV. Two patients had a left ventricular mass index (LVMi) above the 95th percentile. cSBP correlated with all vascular indices measured (cIMT r = 0.43; cDC r = -0.33; PWV r = 0.42, p < 0.05) and with LVMi (r = 0.41; p = 0.005). Office pSBP correlated with cDC (r = -0.31; p = 0.03), PWV (r = 0.42 and p = 0.004) and LVMi (r = 0.33; p = 0.02). Regarding ABPM measurements, daytime systolic BP correlated with all vascular indices (cIMT r = 0.34, cDC r = -0.31, PWV r = 0.39 p < 0.005) but not with echocardiographic ones. No correlation was found between cardiovascular parameters and the estimated glomerular filtration rate or the urinary albumin to creatinine ratio.

Conclusions:
Our data show a high prevalence of subclinical atherosclerosis and cardiac remodeling in children and adolescents with SFK. A lesser proportion of patients presented an increased arterial stiffening. cSBP more than pBP (office or ambulatory) associates with SOD. Children with SFK could bear a greater cardiovascular risk pointing out the importance of early preventive efforts.
PHARMACOLOGICAL AND INTERVENTIONAL TREATMENT OF RESISTANT HYPERTENSION. A NETWORK META-ANALYSIS
Authors: Schmidt Bernhard , Barbosa Clara Vollmer , Lang Hannah , Melk Anette , Tian Zhejia 
Published: June 2023

Objective:
Resistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease and mortality. Yet, its management is still challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis.

Design and method:
We systematically searched MEDLINE, Cochrane Register of Controlled Trials (CENTRAL) and Web of Science Core Collection in March 2022. Randomized controlled trials comparing treatment options as add-on therapy for management of resistant hypertension were included. Outcomes were blood pressure changes, measured in the office and in 24h ABPM. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator.

Results:
From 4771 records, 24 studies met our inclusion criteria with 3458 included patients in total. 12 active treatment alternatives were analyzed. Among all comparators, spironolactone had the highest-ranking probability and was considered as the most effective treatment to reduce office systolic blood pressure (-13.30 mmHg [-17.89; -8.72]; P < 0.0001) and 24h systolic blood pressure (-8.46 mmHg [-12.54; -4.38]; P < 0.0001) in patients with resistant hypertension.

Conclusions:
Among all pharmacologic and interventional treatments, spironolactone has been found to be most effective in reducing office and 24h systolic blood pressure as an add-on therapy for resistant hypertension. Our study provides an evidence-based and valid reference in clinical decision-making.
A HYPERADRENERGIC STATE IN HYPERTENSION IS ASSOCIATED WITH MOOD DISTURBANCE AND IMPAIRED STRESS-MODULATED VASOMOTOR RESPONSES
Authors: Farukh Bushra , Faconti Luca , McNally Ryan , Moulton Calum , Young Allan , Chowienczyk Phil 
Published: June 2023

Objective:
Increasing evidence suggests a high prevalence of affective disorders in hypertension, however, the physiological associations remain unclear. Noradrenergic activation in the central and peripheral nervous systems is a putative mechanism that may explain the link between both conditions. Here, we investigate whether these stress-sensitive co-morbidities may be dependent on basal noradrenergic activity and whether vascular responses to centrally acting stimuli vary according to noradrenergic activity.

Design and method:
We examined the relation of affective disorders and stress-mediated vascular responses to plasma concentrations of normetanephrine (NMN), a measure of noradrenergic activity, in subjects with primary hypertension. Subjects on antidepressant medication, alpha- and beta-blockers were excluded. The Patient Health Questionnaire (PHQ-9), the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDSSR-16), and Generalised Anxiety Disorder-7 (GAD-7) questionnaires were used for the evaluation of symptoms of depression and anxiety. Forearm blood flow (strain gauge plethysmography) was used to assess vascular responses to mental stress (Stroop colour-word test) and slow breathing (by biofeedback), interventions that respectively increase or decrease noradrenergic activity in the pre-frontal cortex and locus coeruleus.

Results:
100 subjects (53% male) with (mean ± SD) age 43.4 ± 10.9 years were recruited. 88% of subjects were treated with anti-hypertensive medications and 4% had type 2 diabetes. 31% and 34% of the study population scored moderate to severe depression for PHQ-9 and QIDSSR-16 respectively indicating significant mood disturbance. Scores representing low mood and high anxiety were 2-3-fold higher for hypertensive subjects in the highest compared to lowest NMN tertiles (PHQ-9: 9.2 ± 5.8 vs 3.8 ± 2.7, P < 0.001; QIDSSR-16: 12.3 ± 4.9 vs 4.5 ± 3.5, P = 0.003; GAD-7: 9.0 ± 5.5 vs 4.6 ± 3.8, P = 0.003). Forearm vasodilator responses to mental stress and vasoconstrictor responses to slow breathing were attenuated in those with high compared to low NMN (28.3 ± 21% vs. 47.1 ± 30% increases for mental stress and 3.7 ± 21% vs. 18.6 ± 15% decreases for slow breathing for highest vs. lowest tertiles of NMN, both P < 0.01).

Conclusions:
A hyperadrenergic state in hypertension is associated with mood disturbance and impaired stress-modulated vasomotor responses. This association may be mediated by chronic stress impinging on pathways regulating central arousal and peripheral sympathetic nerve activity.
CAN SERUM CONSENTRATION MEASUREMENTS OF ANTIHYPERTENSIVE DRUGS IMPROVE BLOOD PRESSURE CONTROL? A MULTICENTER DOUBLE BLINDED RANDOMIZED CONTROLLED TRIAL
Authors: Halvorsen Lene Vernås , Søraas Camilla Lund , Larstorp Anne Cecilie K. , Bergland Ola Undrum , Brobak Karl Marius , Aune Arleen , Olsen Eirik , Rognstad Stine , Heimark Sondre , Aarskog Nikolai Ravn , Hjørnholm Ulla , Kjær Vibeke Nordheim , Elmula Fadl Elmula M. Fadl , Solbu Marit Dahl , Gerdts Eva , Mo Rune , Opdal Mimi Stokke , Rostrup Morten , Kjeldsen Sverre Erik , Høieggen Aud 
Published: June 2023

Objective:
Drug concentration in urine or serum using liquid chromatography coupled to mass-spectrometry (UHPLC-MS/MS) may disclose non-adherence. Whether this direct method will improve adherence is still unknown. In this multicenter randomized controlled trial with a double-blinded approach, we aimed to investigate if measurements and standardized information about serum concentrations of antihypertensive drugs (therapeutic drug monitoring (TDM)), could improve blood pressure (BP) control in documented non-adherent hypertensive patients.

Design and method:
Patients were > = 18 years old with eGFR >30 mL/min/1.73m2, prescribed > = 2 antihypertensive agents and on a stable treatment regimen for at least 4 weeks. Experienced pharmacologists assessed adherence status based on serum drug concentrations, dose and patient-reported time since last intake of the drugs. Patients received no information regarding use of blood samples to screen for non-adherence. The ethics committee approved the study. All patients signed written informed consent.
Non-adherent patients with a systolic daytime ambulatory BP (ABPM) > = 135 mmHg were randomized 1:1 to TDM-intervention or not. The number of visits during 6 months follow-up were equal in both groups and antihypertensive medication regimens remained unchanged. Standardized TDM-information was given to the intervention-group at baseline and after 1 and 3 months. The control group remained uninformed about serum drug measurements until after completion of the study. Life style advice and information on necessity of BP treatment, how to remember to take medications and potential hypertension mediated end-organ damage were given to both groups.
Investigators and patients were masked for BPs, and separate personnel measuring BPs were blinded to randomization group.

Results:
From 2017 to 2022, 606 patients (52.3%) of 1159 patients investigated had uncontrolled HT. The non-adherent patients were younger (57.8 vs 64.0 years, p < 0.001), duration of hypertension was shorter (12 vs 16 years, p = 0.024) and daytime diastolic ABPM (90 vs 84 mmHg, p < 0.001) and heart rate (76 vs 70 bpm, p < 0.001) were higher. Uncontrolled and non-adherent patients were enrolled into the subsequent randomized study performed with a double-blinded approach.

Conclusions:
There was no difference in the primary end-point, daytime systolic ABPM at 3 months, between TDM and control group (-6.7 vs -7.3 mmHg, p = 0.897).