bluuebunny/crossref_metadata_2025_split huggingface dataset:
DEVELOPMENT OF AN ADRENOCORTICAL CELL MODEL OF CALCIUM SIGNALING MODULATION TO DECIPHER THE MOLECULAR MECHANISMS RESPONSIBLE FOR PRIMARY ALDOSTERONISM
Authors: Fedlaoui Bakhta , Cosentino Teresa , Sayed Zeina Al , Giscos-Douriez Isabelle , Fernandes-Rosa Fabio L. , Hulot Jean-Sebastien , Magnus Chris , Sternson Scott M. , Zennaro Maria-Christina , Boulkroun Sheerazed 
Published: June 2022

Objective:
Primary aldosteronism (PA) is the most frequent form of secondary hypertension. The identification of germline or somatic mutations in different genes coding for ion channels (KCNJ5, CACNA1D, CACNA1H and CLCN2) and ATPases (ATP1A1 and ATP2B3) defines PA as a channelopathy. These mutations promote activation of calcium signaling, the main trigger for aldosterone biosynthesis.
The objective of our work was to elucidate, using chemogenetic tools, the molecular mechanisms underlying the development of PA by modulating sodium entry into the cells, mimicking some of known mutations identified in PA.

Design and method:
We have developed an adrenocortical H295R_S2 cell line stably expressing a chimeric ion channel receptor formed by the extracellular ligand-binding domain of the α7 nicotinic acetylcholine receptor fused to the ion pore domain of the serotonin receptor 5HT3α and named α7–5HT3. Mutations have been introduced in the ligand binding domain to allow only synthetic drugs to activate this channel receptor. Activation of α7–5HT3 by a specific drug, PSEM-817 leads to sodium entry into the cells. This cell line was characterized in terms of intracellular calcium concentrations, cell proliferation, aldosterone production, steroidogenic expression and electrophysiological properties.

Results:
Treatment of α7–5HT3 expressing cells with increasing concentration of PSEM-817 (from 10–9 to 10–5 M) induced a significant increase in intracellular calcium concentrations, similarly to potassium (12 mM) or angiotensin II (10–8 M). This stimulation of calcium signaling did not affect cell proliferation, but was responsible for an increase in CYP11B2 expression and aldosterone production after 24 h of treatment. However, while increased intracellular calcium concentrations were observed starting from 10–8 M of PSEM-817, CYP11B2 expression and aldosterone production were only affected starting from 10–7 M, suggesting a dose dependent effect. Finally, whereas cells were hyperpolarized in absence of stimulation (around -60 mV), PSEM-817 induced a strong depolarization, cells rising to a membrane potential around -10 mV.

Conclusions:
This cell line, in which we can modulate the intracellular calcium concentration “on demand”, is a useful tool for a better understanding of the alterations of intracellular ion balance and calcium signaling in the pathophysiology of PA.
PRELIMINARY REPORT: BLOOD PRESSURE TRAJECTORIES OVER TIME IN A MULTI-ETHNIC POPULATION
Authors: Vriend Esther Martha Ca , Bouwmeester Thomas Adriaan , Galenkamp Henrike , Collard Didier , van den Born Bert-Jan Hendrik 
Published: June 2022

Objective:
Objective: Hypertension remains the leading cause of cardiovascular diseases worldwide. Major interethnic differences in the prevalence of hypertension exist. Exploring blood pressure (BP) levels in a large prospective multi-ethnic population provides insight in interethnic differences in blood pressure trajectories across the life course.

Design and method:
Design and method: We examined BP course over time in participants from the HEalthy Life in an Urban Setting (HELIUS) study. Participants aged 18–70 years from Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin with BP data at baseline and follow-up were included. BP levels were corrected for the use of antihypertensive medication. BP change over time was expressed as delta systolic blood pressure (delta SBP) and delta diastolic blood pressure (delta DBP). Multivariate regression analyses were performed to assess the association between ethnicity and BP levels at follow-up, with correction for sex, age, follow-up time, change of BMI and blood pressure levels at baseline.

Results:
Results: In total 8.053 participants (mean age 46.2 (12.4) years, 43.8% female) were included. Median follow-up time was 6.2 (5.3–7.1) years. Overall there was a slight increase in SBP over time (129.41 mmHg at baseline vs. 129.87 at follow-up), while diastolic blood pressure levels tended to decrease (delta DBP = -0.59 mmHg) (Figure 1). The highest SBP increase was found in the Ghanaian population (+1.84 mmHg), while the largest decrease was observed in in the Dutch population (-0.28 mmHg). The lowest DBP decrease was found in the Ghanaian population (-0.02 mmHg) and the highest decrease in the South-Asian Surinamese population (-1.31 mmHg). Multivariable regression analysis showed a strong association between ethnicity and SBP at follow-up, especially for the Ghanaian population (β = 5.51 (95%CI 4.42 – 6.61), p = 2.2e-16) compared to the Dutch reference population. For DBP these interethnic differences were also present, but less pronounced.

Conclusions:
Conclusions: Major interethnic differences in the course of blood pressure over time were found, with substantially higher SBP levels in the Ghanaian population compared to the reference Dutch population.
HIGHER SYSTOLIC BLOOD PRESSURE IN FEMALE PATIENTS WITH MITOCHONDRIAL DISEASE
Authors: Deinum Jaap , Viering Daan , Van Borselen Marjolein D , Bindels René , De Baaij Jeroen , Janssen Mirian Ch 
Published: June 2022

Objective:
Previous research suggests that hypertension is more prevalent among patients with mitochondrial diseases. Blood pressure (BP) is linearly related to increased cardiovascular risk, and this relationship is strongest for systolic blood pressure; nevertheless, studies on systolic and diastolic blood pressure in mitochondrial diseases have not yet been performed.

Design and method:
In a retrospective case-control study design, BP in mitochondrial disease patients was compared to BP in a population cohort. Secondly, using multiple linear regression, we examined blood pressure differences in various genetic mitochondrial diseases. Lastly, we explored additional predictors of BP in a subgroup with the m.3243A>G variant.

Results:
286 genetically confirmed mitochondrial disease patients were included. Of these patients 180 carried the m.3243A>G mitochondrial DNA variant. Systolic BP (SBP) was 9 mmHg higher in female mitochondrial disease patients than in the general female population (95% CI: 4.4 - 13.3 mmHg, p < 0.001), while male patients had similar BP compared to controls. BP was not significantly different in patients with (1) m.8344A>G and m.8363G>A, (2) a mtDNA deletion or (3) a nuclear mutation compared to m.3243A>G patients. Higher SBP was a predictor of left ventricular hypertrophy in the m.3243A>G subgroup (p = 0.04).

Conclusions:
Novel aspects of the role of mitochondrial dysfunction in blood pressure regulation are exposed in this study. Compared to the general population, female mitochondrial disease patients have a higher SBP. Left ventricular hypertrophy is more prevalent in patients with higher SBP. Clinicians should be aware of this to prevent hypertensive complications in mitochondrial disease patients.
THROMBOXANE-DEPENDENT CORONARY VASOCONSTRICTION IN OBESE MICE: ROLE OF PEROXYNITRITE
Authors: Villa Elisa , Rios Amelia , Escalante Bruno 
Published: June 2022

Objective:
Obesity leads to chronic oxidative stress promoting the development of cardiovascular diseases including endothelial dysfunction, which might occur through the cyclooxygenase (COX) pathway. This study aimed to investigate the role of peroxynitrite in the generation of COX-derived products and its role in coronary vascular responses.

Design and method:
We evaluated arachidonic acid (AA)-dependent coronary vascular responses in isolated hearts from control and obese C57BL/6 mice and explored COX metabolism using the COX-2 inhibitor indomethacin and 1-benzylimidazole, inhibitor of thromboxane synthase (TXS). COX, TXS, and TXA2 receptor (TP) protein expression was assessed in heart homogenates. The release of TXA2 in the coronary circulation was also evaluated. In addition, the possible involvement of peroxynitrite on increased coronary response was explored by detecting peroxynitrite by coumarin boronic acid (CBA) and 3-nitrotyrosine protein expression. Alterations in TXS, and TP receptor protein expression were also evaluated in heart homogenates from obese mice treated with the peroxynitrite scavenger FeTMPyP.

Results:
Arachidonic acid (AA) dependent coronary vasoconstriction in isolated hearts, increased from 31.06 ± 2.67 mmHg in control mice to 88.99 ± 6.09 mmHg in obese mice. Both, indomethacin and 1-benzylimidazole reduced the vasoconstriction response in control and obese mice. TXA2 released during AA-induced vasoconstriction phase was increased in heart perfusates from 76.1 ± 18.42 pg/mL in control mice to 203.6 ± 29.8 pg/mL in obese mice. COX- 2, TXS and TP receptor protein expression was increased in hearts from obese mice (1.96 ± 0.25, 0.70 ± 0.07, 1.22 ± 0.19 arbitrary units, respectively) compared with control mice (0.17 ± 0.02; 0.06 ± 0.02; and 0.29 ± 0.06 arbitrary units, respectively). Moreover, nitrotyrosine and peroxynitrite levels were higher in obese mice, compared with control mice. Increase in coronary vasoconstriction, TXA2 release as well as protein expression was prevented with FeTMPyP treatment in obese mice.

Conclusions:
Peroxynitrite-dependent induction of COX-2 and TXS protein expression in heart tissue from obese mice may lead to increased TXA2 coronary circulation, thereby increasing coronary vasoconstriction.
ENDOTHELIUM-SPECIFIC DEFICIENCY OF POLYCYSTIN-1 PROMOTES HYPERTENSION AND CARDIOVASCULAR DISORDERS
Authors: Guerrot Dominique , Hamzaoui Mouad , Groussard Deborah , Nezam Dorian , Mulder Paul , Richard Vincent , Bellien Jeremy 
Published: June 2022

Objective:
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary kidney disease and is generally due to mutations in PKD1 and PKD2, encoding polycystins 1 and 2. In ADPKD, hypertension and cardiovascular (CV) disorders are highly prevalent but their mechanisms are partially understood. The objective of this study was to determine whether hypertension and the CV disorders of ADPKD are a consequence of the endothelial deficiency in the polycystin complex, rather than to the kidney disease, as is currently believed.

Design and method:
Since endothelial cells express the polycystin complex, where it plays a central role in the mechanotransduction of blood flow, we generated a murine model with inducible deletion of Pkd1 in endothelial cells (Cdh5-CreERT2;Pkd1fl/fl) to specifically determine the role of endothelial polycystin-1 in ADPKD. We nalysed the endothelial phenotype associated with Pkd1 deficiency, invasive and non-invasive blood pressure, vascular function on isolated vessels, and echocardiography. The impact on the development of a model of aorto-cava arterio-venous fistula and on the CV consequences of superimposed chronic kidney disease were nalysed to further establish the clinical relevance of our results.

Results:
As expected, transgenic mice presented normal kidney structure and function. Endothelial deletion of Pkd1 induced endothelial dysfunction, as demonstrated by impaired flow-mediated dilatation of resistance arteries and impaired relaxation to acetylcholine, increased blood pressure and prevented the normal development of arterio-venous fistula. In experimental chronic kidney disease induced by subtotal nephrectomy, endothelial deletion of Pkd1 further aggravated endothelial dysfunction, vascular remodelling and heart hypertrophy.

Conclusions:
Altogether, this study provides the first in vivo demonstration that specific deletion of Pkd1 in endothelial cells promotes endothelial dysfunction and hypertension independently of kidney cysts and of impaired kidney function, impairs arterio-venous fistula development and potentiates the cardiovascular alterations associated with chronic kidney disease. It establishes the endothelium as a significant contributor to cardiovascular disease in ADPKD.
DISENTANGLING THE SHARED HERITABILITY OF THE PREDISPOSITION TO HYPERTENSION AND TYPE 2 DIABETES
Authors: Timasheva Yanina , Balkhiyarova Zhanna , Prokopenko Inga 
Published: June 2022

Objective:
Genome-wide association studies (GWAS) identified over 900 genetic loci for blood pressure traits and over 200 for type 2 diabetes (T2D). Hypertension and T2D often manifest in the shared setting of metabolic syndrome, which also includes obesity, hyperlipidemia, and increased coagulability. We aimed to dissect shared genetic factors contributing to the comorbidity of these conditions using multi-phenotype approach.

Design and method:
Using GWAS summary statistics, we defined 1,855 single nucleotide variants (SNVs) associated with 17 endophenotypes related to blood pressure, T2D, and glycaemic traits. We identified 242 T2D association signals represented by 561 T2D/glycaemic SNVs overlapping with 1189 SNVs associated with blood pressure trats and located within 100 kb distance. Using hierarchical clustering, we defined groups of shared loci affecting circadian rhythm (MTNR1B), cell-mediated autoimmunity (CDKAL1 and G6PC2), insulin signalling and cell metabolism (KCNJ11), cell cycle regulation and apoptosis (BCL2), inflammation, calcium ignalling and regulation of eating behavior (NUCB2).

Results:
We identified 35 signals associated with two or more cardiometabolic phenotypes, including rs560887 in G6PC2 gene related to higher fasting glucose levels pulse pressure (PP); rs7756992 in CDKAL1 leading to elevated systolic blood pressure (SBP), increased T2D risk, but lower body mass index (BMI); rs635634 in ABO influencing many metabolic endophenotypes, most notably leading to increased risk of T2D and stroke; rs5219 in KCNJ11 increasing risk of T2D, related to elevated SBP and PP; and rs12454712 in BCL2 related to higher SBP and abdominal obesity, and to lower T2D susceptibility and lower BMI.
Using functional enrichment analysis, we identified pathways significantly associated with hypertension, T2D, and glycaemic traits. Top associated pathways included detection of stimulus involved in sensory perception (GO:0050906), sensory perception of chemical stimulus (GO:0007606), detection of chemical stimulus involved in sensory perception (GO:0050907), sensory perception of smell (GO:0007608), detection of chemical stimulus involved in sensory perception of smell (GO:0050911), and detection of chemical stimulus (GO:0009593).

Conclusions:
Our results highlight the shared pathways involved in blood pressure and glucose metabolism regulation and the development of T2D, suggesting common biological mechanisms.
The study was supported by the megagrant from the Government of Russian Federation No. 075-15-2021-595
ASSESSING THE IMPACT OF IMMUNOSUPPRESSIVE THERAPIES ON INCIDENCE OF HYPERTENSION IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OTHER AUTOIMMUNE DISEASES: A SYSTEMATIC REVIEW
Authors: Alosaimi Hani , Maffia Pasquale , Padmanabhan Sandosh , Guzik Tomasz 
Published: June 2022

Objective:
To compare the effects of different classes of immunosuppressant therapies and anti-cytokine therapies on risk of hypertension in patients with Rheumatoid Arthritis and other Autoimmune diseases.

Design and method:
Meta-analysis and systematic reviews of randomised-control trials (RCTs) were identified using relevant electronic databases to assess current approaches towards the analysis of the effects of anti-interleukin-6, anti-interleukin-17, and methotrexate therapies in adult with regard to hypertension on all available RCTs.

Results:
In the studies where anti-IL6 was compared with placebos, the pooled estimates from the meta-In the studies where anti-IL6 was compared with placebos, the pooled estimates from the meta-analysis showed no statistically significant difference in the risk of hypertension between anti-IL6 and a placebo (RR = 1.2, 95% CI 0.82; 1.73, P = 0.35)). when anti-IL6 was compared to other active drugs, no statistically significant difference was observed in the risk of hypertension between groups (RR = 1.48, 95% CI 0.97; 2.25, P = 0.07)
In the anti-IL17 studies, the pooled estimates from the meta-analysis showed that the risk of hypertension with anti-IL17 and the placebo drugs was also not significantly different (RR = 1.23, 95% CI 0.92, 1.65, P = 0.16)
Where methotrexate was compared to a placebo, there was no significant difference in the risk of hypertension (RR = 1.09, 95% CI 0.65; 1.84, P = 0.73), and only low and non-statistically significant heterogeneity was observed between such studies (I2 = 42%, P = 0.14). However, when methotrexate was compared to other active drugs, a statistically significant difference was observed in terms of the risk of hypertension between groups (RR = 0.45, 95% CI 0.34; 0.61, P < 0.001) in favour of methotrexate.

Conclusions:
Anti-Interlukin-6 agents and anti-Interlukin-17 agents do not seem to affect the risk of occurrence of hypertension when compared to either placebo or other active drugs, while methotrexate appears to reduce the risk of high blood pressure in comparison other anti-inflammatory treatments.
THE EFFECT OF BIOFEEDBACK ON HYPERTENSION AND DIABETES: PRELIMINARY RESULTS FROM A SYSTEMATIC REVIEW
Authors: Jenkins S. , Gupta P. , Khunti K. , Cross A. 
Published: June 2022

Objective:
Biofeedback is a mind-body intervention that uses a device to provide feedback on physiological responses, such as heart rate variability. Through training and practice, participants can learn to exert an element of control over autonomic responses. There is a wealth of research on biofeedback in a range of health conditions, this review focuses on hypertension and diabetes.

Methods:
The systematic review aimed to evaluate the effectiveness of biofeedback on systolic and diastolic blood pressure and psychological wellbeing in patients with hypertension and/or diabetes. The review was preregistered on PROSPERO and followed the PICO search strategy. The following databases were searched: MEDLINE, PsycINFO, CINHAL, PubMed, Embase and Cochrane Central Register of Controlled Trials. Selection criteria included randomised control trials, diagnosis of hypertension/diabetes, inclusion of pre and post intervention measurements and recordings of blood pressure, Hba1c or blood glucose.

Results:
A total of 1189 papers were retrieved, 32 papers met the inclusion criteria. Sample sizes ranged from 10 to 301 with a total of 1425 participants, 48% female and mean age 50.16 (±8.16) and 48.71 (±9.19) in experimental and control group respectively. Of the 32 papers, 28 investigated hypertension and 4 papers looked at diabetes. Of the 28 hypertension studies, 13 showed significant findings in favour of biofeedback. The analysis excluded 11 papers due to incomplete data. Biofeedback was significantly associated with reduced systolic blood pressure (-3.62 mmHg, [-6.33, -0.90], p value < 0.0001; Figure 1) and diastolic blood pressure (-4.15 mmHg, [-6.04, -2.26], p value < 0.0001). Biofeedback modalities included galvanic skin response, heart rate variability, thermal, electromyography, blood pressure and heart rate. Intervention length ranged from 10 days to 4 months, and follow up ranged from 1 week to 12 months. Of the 4 diabetes papers, 2 showed significant findings in favour of biofeedback. A total of 7 papers recorded psychological wellbeing measurements (i.e. depression and anxiety). However, only two reported incorporation of psychological/wellbeing targeted intervention components.

Conclusions:
The preliminary findings highlight the high heterogeneity between existing trials in biofeedback modality, intervention length, follow up and details reported. The results show biofeedback had a significant effect on systolic and diastolic blood pressure. There is limited research on biofeedback and diabetes. This systematic review will inform the protocol development of a biofeedback feasibility trial in patients with hypertension and anxiety. A key finding is the limited use of psychological wellbeing based intervention components, despite study measurements and correlating hypotheses. This is an important element we will integrate within our biofeedback intervention.
CEREBRAL OXYGENATION DURING EXERCISE ACROSS DIFFERENT STAGES OF CHRONIC KIDNEY DISEASE
Authors: Theodorakopoulou Marieta , Zafeiridis Andreas , Dipla Konstantina , Faitatzidou Danai , Koutlas Aggelos , Alexandrou Maria-Eleni , Polychronidou Georgia , Chalkidis Georgios , Papagianni Aikaterini , Sarafidis Pantelis 
Published: June 2022

Objective:
Cognitive impairment and reduced exercise tolerance are common in patients with chronic kidney disease (CKD), in part due to reduced brain function. Proper brain function relies on sufficient blood flow and oxygen supply by the cerebral vasculature. A reduction in cerebral oxygenation of more than 10% may deteriorate brain function and influence the decision to continue exercise. This study aims to examine the cerebral oxygenation and blood volume during a mild physical stress as an index of brain activation in patients at different stages of CKD and controls without CKD.

Design and method:
This is a preliminary analysis of an observational study enrolling patients with CKD stage 2–4 (matched for age and sex within the different stages) and controls without CKD. All participants underwent a 3-min intermittent handgrip exercise (HG) at 35% of their maximal voluntary contraction. Changes in prefrontal oxygenation (oxyhemoglobin-O2Hb) and deoxyhemoglobin-HHb) and total blood volume (total hemoglobin-tHb) were continuously recorded during HG-exercise by near-infrared spectroscopy (NIRS).

Results:
A total of 59 participants are included in this preliminary analyses (n = 11 controls, n = 15 stage 2 CKD, n = 18 stage 3 CKD and n = 15 stage 4 CKD patients). During HG-exercise, O2Hb significantly increased (p < 0.001) and HHb remained relatively unchanged in all groups compared to pre-exercise values. However, this O2Hb increase was progressively lower with advancing CKD Stages (controls: 2,58 ± 1,43 stage 2: 1,51 ± 1,31 stage 3: 1,29 ± 0,97 stage 4: 0,95 ± 0,92, p = 0.006) (Figure). During HG, tHb (an index of microvascular blood volume) increased significantly in controls, stage 2, and 3 CKD patients (p < 0.05) but not in stage 4 CKD patients (p = 0.100). As before this tHb increase was progressively lower with advancing CKD stages (p = 0.030). Controlling for age differences between groups did not alter the above observations.

Conclusions:
Brain activation/response during a mild physical task appears to decrease with advancing CKD as suggested by the smaller rise in cerebral oxygenation and blood volume. This may contribute both impaired cognitive function and reduced exercise tolerance with advancing CKD.