bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE PREVALENCE AND IMPACT OF ISOLATED DIASTOLIC HYPERTENSION IN CHILDREN
Authors: Myette Robert , Obrycki Lukasz , Litwin Mieczyslaw , Seeman Tomas , Feber Janusz 
Published: June 2022

Objective:
Isolated systolic (iSH) and combined (SDH) hypertension is associated with increased left ventricular mass index (LVMi). Isolated diastolic hypertension (iDH) is less commonly observed and its impact on LVMi in children is less clear.
To analyze the prevalence of iDH in children (1–18 years), and associations between iDH and BMI Z-score (BMIz) and LVMi.

Design and method:
We enrolled 1971 pediatric patients from 3 academic centres: Ottawa, Canada; Warsaw, Poland; Prague, Czech Republic who were worked up/treated for hypertension. All patients had office and ambulatory blood pressure monitoring (ABPM). Office and ambulatory (daytime, nighttime, 24-hour) iDH was defined as diastolic blood pressure Z-score (DBPz)> 1.65, with systolic BP Z-score (SBPz) < = 1.65. 511/1971 had LVMi (g/m^2.7) adjusted to the 95th percentile (aLVMi) using Khoury et al.

Results:
The distributions of office BP were: iSH in 28.6%, SDH in 19.4%, iDH in 3.0% and normotension in 49.0%. Children with office iDH had lower aLVMi compared to those with iSH (p = 0.01) or SDH (p = 0.005). Those with iDH also had lower BMIz compared to iSH (p = 0.0004) and SDH (p = 0.007). The distributions of 24-hour ambulatory BP were: iSH in 24.0%, SDH in 15.0%, iDH in 5.0% and normotension in 56%. Daytime iDH was observed in 2.8% and nighttime iDH in 6.8%. Those with daytime (p = 0.003) and nighttime (p = 0.009) iDH had a lower BMIz compared to those with iSH, but there was no difference in BMIz between those with iDH and SDH. Primary hypertension patients with nighttime iDH had lower aLVMi compared to those with nighttime iSH (p = 0.04) or SDH (p = 0.03). There were no other differences in aLVMi between iDH, and iSH or SDH.

Conclusions:
In summary, the prevalence of office and ambulatory iDH is low (3–5%) in children. Those with iDH appear to have a lower BMIz and aLVMi compared to those with iSH and SDH.
SECULAR TRENDS OF BODY MASS INDEX AND BLOOD PRESSURE DURING 1977–2020; NATIONWIDE REGISTRY OF 2.8 MILLION ADOLESCENTS
Authors: Fishman Boris , Zloof Yair , Orr Omri , Tsur Avishai M , Furer Ariel , Omer Ma’Ayan , Chodick Gabriel , Leiba Adi , Derazne Estela , Tzur Dorit , Afek Arnon , Grossman Ehud , Twig Gilad 
Published: June 2022

Objective:
Adolescence elevated blood pressure is an emerging public health issue with growing evidence of its future deleterious cardiovascular and renal effects. Most data regarding systolic (SBP) and diastolic blood pressure (DBP) trajectories are based on surveys of selected adolescent populations within short periods of time. Our objective was to describe the secular trends of blood pressure and body mass index (BMI) throughout the years 1977-2020.

Design and method:
This nationwide population-based study comprised of 2,785,515 Israeli male and female (41.6%) adolescents (mean age 17.4 years) whose weight, height and blood pressure were routinely measured as part of comprehensive medical assessment prior to compulsory military service. Linear regression models were applied to calculate the P for trend along the study period separately for males and females. Predicted SBP and DBP adjusted for BMI, were calculated using the Analysis of Covariance.

Results:
Throughout study period, the mean BMI increased in males by 2.1 and 1.6 kg/m2 in females (P for trend < 0.001 in both sexes). The mean DBP decreased by 3.6 and 2.9 mmHg among males and females, respectively. (P < 0.001 in both sexes). While the mean SBP blood increased by 1.6 mmHg among males and decreased by 1.9 mmHg among females. These trends were consistent in models assessing BMI adjusted SBP and DBP. The trend were consistent in sub analyses stratifying the population by immigration status and by health status (existence of additional significant comorbidities).

Conclusions:
DBP among adolescents decreased over the the last 44 years, despite the significant increase in BMI and obesity prevalence in both sexes. Meanwhile, SBP increased slightly in males and decreased in females.
IMPAIRED ACE2 GLYCOSYLATION AND PROTEASE ACTIVITY LOWERS SUSCEPTIBILITY TO SARS-COV-2 INFECTION IN GITELMAN/BARTTER SYNDROMES
Authors: Bertoldi Giovanni , Ravarotto Verdiana , Sgarabotto Luca , Gobbi Laura , Stefanelli Lucia Federica , Calò Lorenzo A. 
Published: June 2022

Objective:
ACE2, part of the counterregulatory arm of the ennin-angiotensin system, serves both as protective toward oxidative stress and cardiovascular enninling and as key entry for SARS-CoV-2. ACE2 has two isoforms, non-glycosylated and glycosylated, being this latter accountable for the binding with SARS-CoV-2. After the binding, viruses use proteases as cathepsin-L (Cat-L) to entry the cells. Both ACE2 glycosylation and Cat-L activity are pH-dependent. Gitelman and Bartter syndromes (GS/BS), rare genetic tubulopathies, are characterized by electrolytic alterations, activation of the ennin-angiotensin system, yet normo-hypotension, increased levels of ACE2 and metabolic alkalosis with likely increased intracellular pH. We reported that during the first wave of COVID-19 in early 2020 none of our cohort of 128 GS/BS patients from the major hotspots in Northern Italy had been infected or suffered any major COVID-19 symptoms and in a second survey on the same cohort in 2021 we reported only 8 positives, 4 asymptomatic and 4 with very light symptoms This study aims to investigate potential mechanisms as ACE2 glycosylation and Cat-L activity related to patients’ metabolic alkalosis and viral entry/infection.

Design and method:
Mononuclear cells ACE2 glycosylation (Western blot) and blood Cat-L activity (ELISA) from 20 GS/BS patients have been compared to those from 15 heathy subjects.

Results:
Non-glycosylated ACE2 was higher in GS/BS (0.82 ± 0.19 d.u. vs 0.67 ± 0.13 p = 0.01); glycosylated ACE2 was not different (0.85 ± 0.28 in GS/BS vs 0.73 ± 0.23 p = 0.19). Cat-L activity was lower in GS/BS (3.90 ± 1.13 r.f.u. vs 5.31 ± 0.8 p < 0.001) and inversely correlated with blood bicarbonate (HCO3-), while a negative correlation between glycosylated ACE2 and HCO3- approaches statistical significance (p = 0.08).

Conclusions:
GS/BS's metabolic alkalosis, likely by increasing intracellular pH, influences the glycosylation of ACE2 and the activity of Cat-L, providing a mechanistic explanation for the near complete absence of COVID-19 or its symptoms reported in our cohort. These findings provide a rationale for pursuing the identification and/or synthesis of new drugs that specifically target ACE2 glycosylation and/or proteases involved in SARS-CoV-2 infection.
DEVELOPMENT OF CLINICAL SCORING SYSTEM AND MACHINE LEARNING-BASED MODEL TO PREDICT DIAGNOSIS OF PRIMARY ALDOSTERONISM IN PATIENTS WITH HYPERTENSION
Authors: Buffolo Fabrizio , Burrello Jacopo , Burrello Alessio , Heinrich Daniel , Adolf Christian , Muller Lisa Marie , Chen Rusi , Forestiero Vittorio , Sconfienza Elisa , Tetti Martina , Veglio Franco , Williams Tracy Ann , Mulatero Paolo , Monticone Silvia 
Published: June 2022

Objective:
Current guidelines recommend screening for PA in patients with hypertension on the basis of individual factors, that considered together are present in more than 50% of patients. Recently, some experts proposed to further expand the screening for PA to all patients with hypertension, potentially increasing the burden and the costs on the health care system.

Design and method:
We designed a study to build and validate prediction models based on supervised learning and a conventional scoring system to define the risk of PA in arterial hypertension and tailor the diagnostic workup to the individual risk of each patient.
We developed a clinical score and supervised machine learning algorithms in a retrospective internal cohort of 4059 patients with hypertension, and an external cohort of 584 patients with hypertension. Primary aldosteronism was confirmed by confirmatory tests, in agreement with major international recommendations, and subtype diagnosis was achieved by computed tomography and adrenal vein sampling.

Results:
On the basis of 6 widely available parameters (male sex, systolic blood pressure, antihypertensive treatment, body mass index, lowest potassium, and organ damage) we developed a numerical scoring system (SToP-PA score) and 308 machine learning based models, selecting the one with the highest predicting performances. At internal validation we obtained high predictive performance with SToP-PA score (ptimised sensitivity of 90.7% for PA and 92.3% for unilateral PA) and even higher with machine learning based model (ptimised sensitivity of 96.6% for PA, and 100.0% for unilateral PA). The application of these models allowed the identification of a subgroup of patients with very low probability of having PA (0.6% with both models) and null probability of having unilateral PA. Finally, we validated our models within an independent external cohort, with performance not significantly different from internal validation.

Conclusions:
The SToP-PA score and the machine learning model accurately predict the individual pretest probability of PA in patients with hypertension, avoiding the screening for PA in up to 32.7% of patients using a machine learning algorithm, without omitting patients with unilateral UPA.
7-DAYS HIGH-SALT DIET AFFECTS NO-MEDIATED MICROVASCULAR ENDOTHELIAL VASODILATION IN YOUNG HEALTHY INDIVIDUALS
Authors: Peric Leon , Drenjancevic Ines , Kolar Mihael , Susnjara Petar , Stupin Ana 
Published: June 2022

Objective:
We have previously reported that short-term (7-days) high-salt (HS) loading impairs microvascular endothelial function in young healthy individuals, independently of blood pressure (BP) or body composition and fluid status changes. This study aimed to functionally assess specifically nitric-oxide (NO) mediated endothelial vasodilation of skin microcirculation in response to 7-day HS diet in healthy salt-resistant individuals.

Design and method:
20 young healthy individuals (10 women and 10 men), age ranged between 19–24 years, participated in the present study. All subjects adhered to a 7-day low-salt (LS) diet (3.5 g salt/day) followed by a 7-day high-salt (HS) diet (∼14.7 g salt/day) protocol. To confirm that subjects conformed to the diet protocol, daily salt intake based on 24-h urinary sodium excretion was calculated using appropriate formula before and after HS diet protocol. Blood pressure (BP) was measured before and after respective diet protocols and salt resistance was defined as a < 5 mmHg change in mean arterial pressure (MAP) determined on LS versus HS diet. NO-mediated microvascular endothelial vasodilation in response to local heating (42°C) was functionally assessed using laser Doppler Flowmetry (LDF) (moorVMS-LDF, Moor Instruments, UK) and skin heater controller (moorVMS-HEAT, Moor Instruments, UK).

Results:
24-hour sodium excretion significantly increased following HS diet compared to LS conditions (salt/g LS 6.6 ± 2.6 vs. HS 14.3 ± 2.5, P < 0.001). Salt resistance was confirmed in all subjects undergoing study (MAP/mmHg LS 87 ± 7 vs. HS 86 ± 9, P = 0.829). 7-day HS diet significantly reduced skin microvascular flow increase in response to local heating compared to LS conditions (LDF HEAT LS 14.16 ± 6.01 vs. HS 10.67 ± 3.27, P = 0.006).

Conclusions:
Results of the present study have functionally demonstrated that 7-days HS diet alters specifically NO-mediated endothelium-dependent of skin microcirculation in salt-resistant young healthy individuals.
FINERENONE PREVENTS RENAL AND VASCULAR DAMAGE IN A NOVEL MODEL OF TYPE 1 DIABETES MELLITUS
Authors: Sanz-Gómez Marta , Vega-Martín Elena , González-Moreno Daniel , Pizzamiglio Chiara , Manzano-Lista Francisco J. , Kolkhof Peter , Kreutz Reinhold , Fernández-Alfonso María S. 
Published: June 2022

Objective:
The non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone (FIN) improves renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effects of FIN in a novel model of CKD in type 1 diabetes (T1D).

Design and method:
We employed the Munich Wistar Frömter (MWF) rat model of non-diabetic CKD with mild hypertension and albuminuria to generate a novel model of CKD with T1D. This was achieved by an intra-peritoneal injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (MWF-DKD-FIN) was compared to a group of diabetic rats receiving no treatment (MWF-DKD-Control) and a group of non-diabetic untreated MWF rats (MWF). Dietary exposure with or without pharmacological treatment was maintained for 6 weeks (n = 7–10 animals per group).

Results:
After 6 weeks, MWF-DKD-Control and MWF-DKD-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to MWF (110.3 ± 4.4 mg/dl; p < 0.05). MWF-DKD-Control showed a 10-fold higher expression of renal damage markers Kim-1 and Ngal compared to MWF. This upregulation was significantly suppressed in MWF-DKD-FIN. FIN treatment resulted in a significant reduction of blood pressure and pulse wave velocity compared to MWF-DKD-Control (p < 0.05). Vascular function studies showed an improvement in endothelial function in MWF-DKD-FIN compared to MWF-DKD-Control due to a reduction in pro-contractile prostaglandins, oxidative stress, and inflammatory cytokines (including IL-1, IL-6, TNFalpha and TGFbeta). FIN induced no changes in blood glucose levels, glucose tolerance or the increase in HOMA index compared to MWF-DKD-Control.

Conclusions:
Our data show that treatment with FIN improves renal and vascular damage in a new rat model of CKD with T1D. These beneficial effects associated with a reduction in inflammation and oxidative stress and was independent from changes in glucose homeostasis.
THE CAUSAL ROLE OF SERUM CALCIUM, PTH AND FGF23 ON BLOOD PRESSURE: A TWO-SAMPLE MENDELIAN RANDOMIZATION
Authors: Giontella Alice , Lotta Luca A. , Overton John D. , Baras Aris , Center Regeneron Genetics , Minuz Pietro , Melander Olle , Fava Cristiano 
Published: June 2022

Objective:
Parathyroid hormone (PTH) and Fibroblast Growth Factor 23 (FGF23) are among the calciotropic hormones involved in the regulation of blood calcium levels among the intestine, kidney, and bone through a tight endocrine feedback loop system. Altered levels of each of them could affect blood pressure either independently or not by the calcium, but the exact mechanisms remain unclear. To evaluate whether a causal relationship exists between serum calcium level and its homeostasis’ regulatory hormones with blood pressure traits, we performed a Two-Sample Mendelian Randomization.

Design and method:
From three large genome-wide association studies (GWAS) we obtained independent (r2 < 0.001) and GWAS-significant (p < 5X10-8) single nucleotide polymorphisms (SNPs) associated with serum calcium level (120 SNPs), PTH (5 SNPs), and FGF23 (5 SNPs), to investigate through MR their association with Systolic (SBP) and Diastolic (DBP) blood pressure in a Swedish large-scale cohort study, the Malmö Diet and Cancer (n = 29,298). Causality was evaluated with the Inverse Variance Weighted Method (IVW), and sensitivity analyses through MR-Egger.

Results:
Serum calcium level was found to be associated with DBP (IWV: beta = 11.9, SE = 4.2, p = 0.004). Surprisingly PTH didn’t show any association with the traits, while FGF23 was inversely associated with the SBP (IWV: beta = -5.0, SE = 2.0, P = 0.01) even if the association lost its significance at sensitivity analysis with MR-Egger.

Conclusions:
Our study shows a strong direct association between serum calcium level, described by its genetic component, with diastolic blood pressure. These results underline the importance of understanding the target genes that could alter calcium homeostasis and that could bring harmful implications later in life, moreover, it will be relevant for improving personalized intervention strategies. Despite not showing a strong association as the one shown by serum calcium level, the genetically predicted FGF23 level confirms its involvement in the regulation of blood pressure. Further an alyses deserve to be performed to clarify involved gene pathways.
BURDEN OF DISEASE OF HYPERTENSION IN THE PHILIPPINES PROJECTED IN 2050
Authors: Mercado-Asis Leilani , Ona Deborah Ignacia , Bonzon Dolores , Vilela Gilbert , Diaz Alejandro , Balmores Benjamin , Co Marlon , Mina Arnold Benjamin , Cabral Esperanza , Aquino Abdias , Abelardo Nelson , Gomez Lynn , Valdez Les Paul , Castillo Rafael 
Published: June 2022

Objective:
The burden of disease attributable to hypertension in the Philippines has continuously increased over the last three (3) decades. In spite of this, the burden accounted for by hypertension is investigated to a lesser extent in the Philippine context. This study was carried out to ascertain the economic impact of hypertension if people within the productive years are affected and the results projected in the next 30 years.

Design and method:
Accordingly, data triangulation using interviews from 806 patients, vis-à-vis sources such as Philippine Statistics Authority (PSA), Family Income and Expenditure Survey (FIES), National Demographic and Health Survey (NDHS), National Nutrition Survey, Institute for Health Metrics and Evaluation (IHME), United Nations World Population Prospects, World Health Organization (WHO) and Labor Force Survey were employed. Consequently, cost of illness (COI) was calculated using the direct costs, morbidity costs, and mortality costs.

Results:
In 2020, about 70% of total economic burden are accounted for direct & indirect care. In the next 30 years (2020 - 2050), the economic cost of hypertension in present value is expected to increase from Php52.6. billion in 2020 to Php97.3 billion by 2050. The productivity of majority of the patients (60 - 78%) was affected most especially in household and missing work. The productivity loss due to premature mortality accounts for about 17% of total economic burden in 2020 and this is expected to increase to 20% by 2050.

Conclusions:
The economic cost of hypertension will almost double in the next 30 years. Both productivity loss and premature mortality will have a significant impact on the Philippine economy by 2050. This calls for a robust collaborative and cooperative participation of both governmental and nongovernmental agencies to thwart the looming effect of a controllable disease like hypertension on the ocio-economic status of the country and on public health in general.
IMPORTANCE OF URIC ACID THRESHOLD IN ITS CORRELATION WITH METABOLIC SYNDROME
Authors: Maloberti Alessandro , Garofani Ilaria , Fumagalli Stefano , Ciampi Claudio Mario , Ossola Paolo , Carbonaro Marco , Monticelli Massimiliano , Tavecchia Giovanni , Bombelli Michele , Giannattasio Cristina 
Published: June 2022

Objective:
The relationship between Hyperuricemia and Cardiovascular risk has been established but whether or not a correlation between Serum Uric Acid (SUA) and Metabolic Syndrome (MS) exists is still a matter of debate. Indeed whether SUA level is part of MS diagnosis or just a pure marker of an unfavourable metabolic profile has not been demonstrated. Besides it's unknown whether SUA's addition to MS definition makes a difference in terms of prognosis. In our study we focused on evaluating in a group of hypertensive patients, the correlation between MS diagnosis and SUA defined with two different cut-off: 1) > 6 mg/dL for women and > 7 for men (classic cut-off); 2) > 5.6 mg/dL for both sexes (recently proposed by the URRAH Project).

Design and method:
We enrolled 473 Hypertensive patients followed by the Hypertension Unit of San Gerardo Hospital (Monza, Italy), in which SUA was measured. Patients with Hyperuricemia were identified according to the two different thresholds. NCEP-ATP-III criteria were used for diagnosis of MS.

Results:
MS was diagnosed in 33.6% while Hyperuricemia was found in 14.8% of subjects according to the traditional cut-off and 35.9% according to URRAH study's cut-off. Hyperuricemia and MS coexist in 9.7% (traditional cut-off) and 17.3% (URRAH's threshold) of the population. Hyperuricemia was more frequent in MS than in non-MS subjects (29 vs 7.6%, p-value < 0.0001 for cut-off 6/7 mg/dL and 51.6 vs 28.0%, p-value < 0.0001 for cut-off 5.6 mg/dL). Linear regression models showed that SUA is related to MS diagnosis (β = 1.597, p-value < 0.0001). At logistic analysis Hyperuricemia was strongly related to MS when defined by the HURRAH's cut-off (OR = 0.303, p-value < 0.0001). The same relation is weak, although significan, when Hyperuricemia was defined by the classic cut-off (OR = 0.182, p-value < 0.0001).

Conclusions:
Hyperuricemia is related with MS diagnosis especially when defined by the recently defined cut-off of 5.6 mg/dL.
ASSOCIATIONS OF LONG-TERM VISIT-TO-VISIT BLOOD PRESSURE VARIABILITY WITH SUBCLINICAL RENAL DAMAGE AND ALBUMINURIA IN ADULTHOOD: A 30-YEAR PROSPECTIVE COHORT STUDY
Authors: Wang Yang , Mu Jian-Jun , Zhao Peng , Chu Chao , Du Ming-Fei , Zou Ting , Hu Gui-Lin , Liao Yue-Yuan , Chen Chen , Ma Qiong , Wang Dan , Wang Ke-Ke , Chen Fang-Yao 
Published: June 2022

Objective:
To determine the potential associations of long-term BPV from childhood to middle age with subclinical renal damage (SRD) and albuminuria in adulthood, independently of mean BP and cumulative exposure to BP.

Design and method:
Using data from the ongoing cohort of Hanzhong Adolescent Hypertension study, which recruited children and young adults aged 6 to 18 years at baseline, we assessed BP variability by standard deviation (SD) and average real variability (ARV) for 30 years (6 visits).

Results:
During a follow-up of 30 years, of the 1115 participants, 146 SRD events occurred. After adjustment for demographic, clinical characteristics and mean BP during 30 years, higher SDSBP, ARVSBP, SDDBP, ARVDBP, SDMAP and ARVMAP were significantly associated with higher risk of SRD [ORs (95% CIs) were 1.06(1.03–1.10), 1.12(1.06–1.19), 1.17(1.11–1.23), 1.22(1.13–1.32), 1.13(1.08,1.19) and 1.21(1.12–1.31), respectively]. When we used cumulative exposure to BP from childhood to adulthood instead of mean BP as adjustment factors, results were similar. In addition, greater long-term BPV was also associated with the risk of albuminuria [ORs (95% CIs) were 1.06(1.12–1.10) for SDSBP, 1.12(1.06–1.19) for ARVSBP, 1.14(1.08–1.21) for SDDBP, 1.19(1.10–1.30) for ARVDBP, 1.13(1.07–1.19) for SDMAP, and 1.20(1.11–1.32) for ARVMAP] adjusting for demographic, clinical characteristics, mean BP or cumulative exposure to BP during 30 years.

Conclusions:
Long-term BP variability for 30 years from childhood to middle age was associated with higher risk of subclinical renal damage and albuminuria in adulthood, independent of mean BP or cumulative exposure to BP during follow-up. Identifying long-term BP variability from early age may assist in predicting renal disease and cardiovascular disease in later life.