bluuebunny/crossref_metadata_2025 huggingface dataset:
RENIN-ANGIOTENSIN SYSTEM INHIBITORS AND COVID-19: A SYSTEMATIC REVIEW AND META-ANALYSIS EVIDENCE FOR SIGNIFICANT GEOGRAPHICAL DISPARITIES
Authors: Patoulias Dimitrios , Katsimardo Alexandra , Stavropoulo Konstantinos , Imprialos Konstantinos , Kalogirou Maria -Styliani , Doumas Michael
Published: April 2021

Objective:

While the COVID-19 pandemic is constantly evolving, it remains unclear whether the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) affects the clinical course of SARS-CoV-2 infection.

Design and method:

For this meta-analysis, PubMed, CENTRAL, and grey literature were searched from their inception to 19 May 2020 for randomized, controlled trials or observational studies that evaluate the association between the use of either ACE inhibitors or ARBs and the risk for major clinical endpoints (infection, hospitalization, admission to ICU, death) in adult patients during the COVID-19 pandemic. In addition, a subgroup geographical analysis of outcomes was performed. Studies including less than 100 subjects were excluded from our analysis.

Results:

In total, 25 observational studies were included. ACE inhibitors and ARBs were not associated with increased odds for SARS-CoV-2 infection, admission to hospital, severe or critical illness, admission to ICU, and SARS-CoV-2-related death. In Asian countries, the use of ACE inhibitors/ARBs decreased the odds for severe or critical illness and death (OR = 0.37, 95% CI 0.16–0.89, I2 = 83%, and OR = 0.62, 95% CI 0.39–0.99, I2 = 0%, respectively), whereas they increased the odds for ICU admission in North America and death in Europe (OR = 1.75, 95% CI 1.37–2.23, I2 = 0%, and OR = 1.68, 95% CI 1.05–2.70, I2 = 82%, respectively). ACE inhibitors might be marginally protective regarding SARS-CoV-2-related death compared with ARBs (OR = 0.86, 95% CI 0.74–1.00, I2 = 0%).

Conclusions:

Randomized controlled trials are needed to confirm the aforementioned associations between ACE inhibitors, ARBs, and SARS-CoV-2.
ANGIOTENSIN II-INDUCED ER STRESS RESPONSE CONTRIBUTES TO PROFIBROTIC VSMC PHENOTYPE AND SUBSEQUENT HYPERTENSIVE ARTERIAL STIFFNESS
Authors: Cicalese Stephanie , Cooper Hannah , Preston Kyle , Kawai Tatsuo , Scalia Rosario , Eguchi Satoru
Published: April 2021

Objective:

The renin-angiotensin-aldosterone system is known to play a pivotal role in human hypertension, and specifically angiotensin II (Ang II) is believed to mediate arterial stiffness through maladaptive responses from vascular smooth muscle cells (VSMCs). The objective of this study was to elucidate Ang II activation of the endoplasmic reticulum unfolded protein response (ER UPR) in VSMCs, how this contributes to hypertrophic and fibrotic responses, and how inhibition of ER UPR may mitigate increased aortic pulse propagation velocity (PPV, a surrogate measurement for aortic stiffness).

Design and method:

ApoE-/- mice were infused with 1 ug/kg/min angiotensin II for 14 days with or without 1 mg/mL 4-PBA For in vitro studies, rat VSMCs were explanted and used from P4-P8. 4-PBA 30 min pretreatment at 1 mM before Ang II 48 hr stimulation or adeno GRP78 infection used to assess chaperoning effect on sirius red collagen assay, THP-1 adhesion, and protein aggregate accumulation.

Results:

Chronic 14 day infusion of Ang II in apoE-/- mice leads to increased PPV from 0.06 m/s to 0.12 m/s, whereas supplementing drinking water with 1 mg/mL chemical ER chaperone 4-PBA mitigates this induction (PPV = 0.055 m/s), P = 0.039. Fibrosis of the heart, kidney and aorta were reduced with 4-PBA treatment as well. ER stress markers pIRE1a and XBP1S were activated in the thoracic aorta by Ang II infusion and inhibited by 4-PBA. Preamyloid oligomer accumulation induced by Ang II in the aorta was also reduced by 4-PBA. Rat VSMCs stimulated with Ang II were stained with aggregate dye Proteostat, which was increased with 48 hour Ang II treatment, and inhibited with 4-PBA pretreatment (P < 0.05). To evaluate VSMC stiffness promoting phenotype, collagen production and immune cell adhesion were assessed by Sirius Red assay and THP-1 adhesion, respectively. Both inductions by Ang II were decreased by 4-PBA. Overexpression of GRP78 significantly mitigated aggregate formation (P < 0.05) and immune cell infiltration (P < 0.05).

Conclusions:

Ang II induced pulse pressure and vascular amyloid deposition is decreased by chaperoning nascent protein folding. Targeting GRP78 to reduce ER UPR activation and subsequent disturbances in proteostasis may be a therapeutic strategy for aortic stiffness.
BLOOD PRESSURE PREVALENCE WITH STRATIFICATION AND ASSOCIATIONS: A COMMUNITY-BASED STUDY FROM LONGITUDINAL COHORT HOUSEHOLD SURVEY 2019
Authors: Chakaraborty Nilanjana , Chakraborty Kaushik , Mitra Ramendra Nath , Saha Angana , Chatterjee Papri , Manna Subhankar , Mitra Dipra
Published: April 2021

Objective:

For decades morbidity and mortality due to hypertension remains the major contributor of NCD burden worldwide. Objective is to assess the prevalence of a community cohort's Blood Pressure of all categories: measured hypertension (mHTN), self-reported doctor diagnosed hypertension (DDH), undiagnosed hypertension (UDH), also blood pressure stratification followed as per Joint National Committee-8 guideline. Associations with socio-demographic variables also reported. Aim being to use the study data with collated same cohort's past relevant information as primary tool to formulate burden minimisation intervention protocol of the ongoing population health Study.

Design and method:

Barrackpore Population Health Study, an urban household-based community cohort of 3030 households commenced in 2001. Third household survey enrolled 6632 participants (Male2576; Female 4056). Beside pre-tested structured questionnaire, real time anthropometric measurements for BMI assessment and Blood Pressure measurement termed as ‘Measured Hypertension (mHTN)’ also performed in the survey. All measurements were carried out at participants’ residence on a working day during working hours according to standard protocol.

Results:

Among total participants of mHTN (N6632) 31.48% were normotensive, 39.02% were prehypertensive, 20.73% were HTNstg1, 8.76% were HTNstg2. Prevalence of DDH (n = 1563) was 23.57%. Among DDH, prevalence of normotensive 12.35%, well controlled; prehypertensive 37.17%, moderately controlled; HTNstg1 33.21% and HTNstg2 17.27%, both uncontrolled. Undiagnosed HTN (n = 3174) 47.86%. of total population. Among UDH, prehypertensive 63.23%, moderately controlled; HTNstg1 26.97% and HTNstg2 9.79% not controlled. Increasing age was a higher odds of DDH [OR = 1.08, CI: 1.07,1.10; p < .0001]. Smokers were 27% [OR = 0.73, CI: 0.60, 0.89; P = 0.0019] and alcohol drinkers 47% [OR = 0.53, CI: 0.40, 0.71; p < .0001]. Compare to non-snorers, always snorers were two times [OR = 2.27, CI: 1.93,2.54; p < .0001] and diabetics were four times [OR = 4.885, CI: 4.20, 5.68; p < .0001] likely to be higher in DDH population.

Conclusions:

Almost half of the hypertensives remain undiagnosed. Among the diagnosed population, significant majority were not controlled. Association of age, alcohol consumption, smoking, snoring, diabetes and above normal BMI were confirmed. Monitoring of the efficacy of the burden reduction intervention program of the established longitudinal study cohort should be considered.
ASSOCIATION OF CHILDHOOD PHYSICAL EXAMINATION AND LABORATORY PARAMETERS WITH HIGH BLOOD PRESSURE IN JAPANESE YOUNG ADULTS
Authors: Azegami Tatsuhiko , Uchida Keiko , Arima Fujiyo , Sato Yasunori , Awazu Midori , Inokuchi Mikako , Takeda Ayano , Itoh Hiroshi , Tokumura Mitsuaki , Mori Masaaki
Published: April 2021

Objective:

We aimed to identify childhood risk factors for high blood pressure (BP) in young adults.

Design and method:

Childhood data were obtained from medical checkups of Japanese male and female junior high school students aged 12-13 years during the period from 2008 to 2009. Childhood variables were sex, body weight, body mass index (BMI), systolic BP, complete blood count, uric acid, total cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. The 1129 participants were followed up for average 8.6 years with a range of 6.0 to 9.0 years. High BP was defined as elevated BP and hypertension of ACC/AHA BP category (systolic BP 120 mmHg or more and/or diastolic BP 80 mmHg or more).

Results:

At the follow-up, the prevalence of high BP was 42.2% in male young adults and 7.7% in female young adults. The mean systolic/diastolic BP was 117.8 [SD, 10.1] / 63.6 [SD, 6.1] mmHg in men and 105.2 [SD, 9.6] / 59.6 [SD, 5.5] mmHg in women. Univariable logistic regression analysis showed that systolic BP (odds ratio 1.56), body weight (1.50), uric acid (1.38), and red blood cell (1.31) at childhood baseline were significantly associated with high BP in male young adult, whereas variables associated with high BP were not found in female young adults because few women developed high BP. A logistic regression analysis with the stepwise method indicated that the regression model including systolic BP, body weight, WBC, platelet count, and uric acid had a high prediction power for high BP in male young adults (Area under curve 0.660, p < 0.001).

Conclusions:

These results suggest that childhood medical checkup information including BP, anthropometric data, and laboratory parameter can contribute to the prediction of future high BP in young adults.
PHYSICIAN- AND PATIENT REPORTED ADHERENCE TO ANTIHYPERTENSIVE DRUGS VERIFIED BY SERUM DRUG CONCENTRATION
Authors: Bergland Ola Undrum , Søraas Camilla Lund , Halvorsen Lene Vernås , Rognstad Stine , Hjørnholm Ulla , Kjær Vibeke , Opdal Mimi Stokke , Rostrup Morten , Larstorp Anne Cecilie , Høieggen Aud , Fadl Elmula Fadl Elmula M.
Published: April 2021

Objective:

Non-adherence to drugs remains a challenge in hypertension treatment. Indirect assessments such as questionnaires and physician guessing have been the mainstay of such evaluation. Existing adherence questionnaires suffer from lack of both consensus and validation against objective methods. Recently, direct measurement of antihypertensive drugs in serum has become available. We aimed to compare both physician- and patient-reported adherence to antihypertensive treatment with serum drug concentration measurements.

Design and method:

We extracted data from 161 consecutive patients in an ongoing, national multicenter study, who were examined at a hypertension clinic. Patients were aged 18 years or older and used 2 or more antihypertensive drugs. All completed a medical history assessment, laboratory analyses and office- and ambulatory blood pressure (BP) measurements. Additionally, they filled out a five-item questionnaire designed to uncover both non-intended and intended non-adherence to antihypertensive drugs. Each item was scored 1–4, with the lowest obtainable total score of 5 indicating perfect adherence, and 20 points indicating absolute non-adherence. Investigators guessed patient adherence status prior to measuring BP and the results of serum drug concentrations became available. Adherence was objectively confirmed by serum drug concentration measurement using liquid chromatography tandem mass spectrometry, of which the patient was not informed. Patients were defined as non-adherent if serum concentration of at least one drug was below a pre-specified level.

Results:

We identified 149 (92%) adherent- and 12 (8%) non-adherent patients. Descriptives and results are listed in Table 1. Non-adherent patients were significantly younger and had lower diastolic BP and daytime ambulatory heart rate. Mean total adherence scores obtained from the questionnaire did not differ between groups (5.9 ± 1.7 vs. 5.9 ± 1.0, p = 0.84). Among the non-adherent patients, 33% had daytime ambulatory BP < 135 mmHg, and 58% stated that they never forgot to take their prescribed antihypertensive drugs compared to 44% in the adherent group. Only 17% were correctly classified as non-adherent by investigators, while 8% of adherent patients were erroneously classified as non-adherent.

Conclusions:

Our results suggest that indirect methods of assessing antihypertensive drug adherence are inadequate when compared to direct serum drug concentration measurements.
TWO-DRUG FIXED-DOSE COMBINATION AS INITIAL ANTIHYPERTENSIVE TREATMENT STRATEGY CONFERS HIGHER MEDICATION ADHERENCE COMPARED TO MONOTHERAPY
Authors: Rea Federico , Savaré Laura , Corrao Giovanni , Mancia Giuseppe
Published: April 2021

Objective:

The recent European guidelines recommend to start treatment with two drugs in a single tablet in most hypertensive patients to improve on the low adherence to the treatment regimen that characterizes the hypertensive population. Evidence that this is the case is limited, however. Aim of our study was to compare adherence to antihypertensive drug therapy between newly treated patients who were prescribed initial monotherapy or a fixed-dose combination of two drugs.

Design and method:

The target population consisted of Lombardy residents (Italy), aged 40–80 years, who were beneficiaries of the National Health Service. 63,448 patients, newly treated with antihypertensive drugs during 2016, were followed for 1 year after the first prescription. Adherence to drug therapy was measured according to the “proportion of days covered” (PDC) criterion, i.e. the ratio between the number of days in which the drug was available from prescription and the days of follow-up. Patients who had a PDC greater than 75% were defined as adherent to drug therapy. Log-binomial regression models were fitted to estimate the risk (HR) or propensity to treatment adherence in relation to the initial therapeutic strategy. Adjustment was made for baseline demographic and clinical covariates.

Results:

47% of patients showed high adherence to treatment during the first year of drug therapy. Compared to patients under initial monotherapy, those who were initially treated with a fixed dose combination had a higher propensity to adhere to antihypertensive treatment (HR 1.19, 95%CI 1.17–1.22, p < 0.0001). This was the case in all strata, i.e. both genders, an age below or above 65 years, different clinical statuses, and no or previous cardiovascular event. It was also the case across the different initial fixed-dose-combinations, most of which promoted better adherence than the corresponding monotherapies.

Conclusions:

In a real-life setting, patients who were initially prescribed a fixed-dose combination of two antihypertensive drugs exhibited more frequently a good adherence to antihypertensive treatment than those starting with a single drug. This provides strong support to the initial fixed-dose-combination strategy as a means to improve adherence and favour blood pressure control.
ASSOCIATIONS OF RENALASE WITH BLOOD PRESSURE AND THE RISK OF HYPERTENSION IN CHINESE ADULTS
Authors: Wang Yang , Gao Ke , Chen Chen , Yan Yu , Yuan Yue , Wang Ke-Ke , Hu Jia-Wen , Chu Chao , Ma Qiong , Fu Bo-Wen , Liao Yue-Yuan , Li Min , Sun Yue , He Ming-Jun , Mu Jian-Jun
Published: April 2021

Objective:

Renalase, a novel secretory flavoprotein with amine oxidase activity, is secreted into the blood by the kidneys and is hypothesized to participate in catecholamine metabolism. The aim of the study was to investigate the associations of renalase with blood pressure (BP) and the risk of hypertension from three perspectives of genetic variations, serum and kidney levels in humans.

Design and method:

1. A total of 515 Chinese participants from 124 families were eligible for this study. We followed up this cohort in 2009, 2012 and 2018, respectively. 10 SNPs in renalase gene were genotyped to examine the associations with longitudinal BP changes and incident hypertension during 14 years of follow-up.

2. 2342 participants from the Hanzhong Adolescent Hypertension Study cohort who were followed up in 2017 were included. Cross-sectional analysis was used to examine the relationships between serum renalase and the risk of hypertension.

3. 204 patients undergoing renal biopsy were recruited from our hospital. Expression of renalase in renal biopsy specimens were measured by immunohistochemistry (IHC).

Results:

1. During 14 years of follow-up, 160 (53.9%) participants developed hypertension. renalase SNPs rs10887800, rs796945, rs1935582, rs2296545 and rs2576178 were significantly associated with 14-year change in DBP while SNP rs7922058 was associated with longitudinal SBP change. In addition, SNPs rs796945, rs1935582 and rs2576178 were significantly associated with hypertension incidence over 14 years. Gene-based analysis found that renalase was significantly associated with hypertension incidence over 14-year follow-up.

2. Hypertensive subjects have higher levels of serum renalase than in the normotensive subjects. Serum renalase showed a linear association with increased BP (24.8, 25.6, 27.1, and 27.7 ug/mL for subjects with normotension, prehypertension, stage 1 and stage 2 hypertension). In addition, serum renalase [1.018 (1.006–1.030)] was significantly associated with the risk of hypertension in 2392 Chinese subjects.

3. The levels of SBP and DBP were positively correlated with the level of renalase in renal tubular epithelial cells (RTEC). The RTEC renalase expression was decreased in hypertensive patients compared to non-hypertensive patients.

Conclusions:

These findings indicate that renalase may play an important role in BP progression and development of hypertension.
EARLY HYPERTENSION: EXPLORING THE VASCULAR PHENOTYPE
Authors: Murray Eleanor , Guzik Tomasz , Delles Christian
Published: April 2021

Objective:

Despite well-established demographic and lifestyle risk factors for hypertension, the early phenotypic features remain elusive. Understanding these characteristics could allow for early identification of disease phenotypes and tailoring of management.

Design and method:

Primary hypertension in treatment-naïve patients without co-morbidities (‘HTN’; n = 48) were comprehensively phenotyped. Blood pressure (BP) was analysed using ambulatory monitoring. Vascular assessment included flow mediated dilatation (FMD), pulse wave velocity (PWV); pulse wave analysis (PWA)-derived heart-rate-adjusted augmentation index (AI75), and central BP; and peripheral arterial tonometry (EndoPAT-2000) index (LnRH) and AI75. Data were entered into Principal Component Analysis, generating phenotypic clusters.

Results:

Mean 24hr SBP was 143 ± 15.6; mean age 37 ± 8.6; 69% were male, and BMI was 28.2 ± 5.4 kg/m2. Analysis revealed 3 distinct phenotypic subgroups (see Figure). Age and BMI did not differ between the groups; other parameters are outlined below; statistically significant difference (P < 0.005) is indicated by ∗:

A) ‘Vascular HTN’, n = 19: Mean office BP 151/96 mmHg∗, though 24 hr mean 141/90 mmHg, with loss of nocturnal dip∗ (systolic 7.5%/ diastolic 11.6%); 53% were male∗, 84% were Caucasian; endothelial dysfunction by FMD and EndoPAT AI@75∗ (mean 16.1%); CIMT∗ was greater (0.67 mm); greater vascular stiffness by PWA (15.8), and elevated central pressures∗ (136.6/97.9 mmHg).

B) ‘Early HTN’, n = 15: Mean office BP 136/84 mmHg, 24hr BP similarly 135/82 mmHg, with intermediate nocturnal dip (mean 11.8/17.1%), but high variability in diastolic readings∗ (SD 10.6) and in HR overnight∗; 71% male, 93% Caucasian; endothelial function was normal (EndoPAT AI@75∗ –15.9%, FMD∗ 8%); central pressures were borderline, PWA was healthy range (-6.9).

C) ‘Physically Fit Dippers, HTN driver unknown’, n = 15: Mean office 140/90 mmHg, 24hr 139/85 mmHg, but pronounced nocturnal dip∗ (mean 14.0/18.4%) and variability in SBP∗ (SD 13.8 mmHg) and daytime HR∗ (mean range 33 bpm), though lower resting pulse∗ (61 bpm); intermediate PWV (mean 7.3m/s) and EndoPAT AI75 (mean 8.3%), and lowest central pressures∗ (122/84 mmHg). Physical activity scores higher∗.

Conclusions:

We identify different phenotypes in drug-naïve, incident patients with primary hypertension, with different vascular techniques associated, and potentially differing pathophysiology. This warrants further examination of these phenotypes in a larger population.
RELATIONSHIP BETWEEN DIURETIC RELATED HYPERURICEMIA AND CARDIOVASCULAR EVENTS: DATA FROM THE URRAH (URIC ACID RIGHT FOR HEART HEALTH) STUDY
Authors: Maloberti Alessandro , Bombelli M. , Facchetti R. , Virdis A. , Casiglia E. , Tikhonoff V. , Barbagallo C.m. , Cirillo M. , Desideri G. , Ferri C. , Galletti F. , Iaccarino G. , Mallamaci F. , Masi S. , Mazza A. , Muiesan M.l. , Salvetti M. , Palatini P. , Pontremoli R. , Verdecchia P. , Volpe M. , Grassi G. , Giannattasio C. , Borghi C.
Published: April 2021

Objective:

Hyperuricemia can be both determined by overproduction (due to xanthine oxidase hyperactivity) or renal hypoexcretion. In this latter case, also diuretic use (particularly hydrochlorotiazhide) can be involved. While the relationship between hyperuricemia and CardioVascular (CV) events has been definitively linked in many studies, data on diuretic related hyperuricemia are still lacking. The objective of this analysis is to assess the relationship between diuretic induced hyperuricemia and CV events.

Design and method:

The URic acid Right for heArt Health study is a nationwide, multicentre, observational cohort study involving data on individuals aged 18–95 years recruited on a regional community basis from all the territory of Italy under the patronage of the Italian Society of Hypertension with a mean follow-up period of 122 ± 66.9 months. Patients were classified into four groups accordingly to the diuretic use (yes vs no) and Uric Acid (UA) levels (higher or lower than the median value of 4.9 mg/dL). All cause death, CV deaths and CV events were consiedered as outcomes.

Results:

A total of 17747 individuals were included in the analysis. Mean age was 57.1 ± 15.2 years, males were 45.3%, SBP/DBP were 144.1/85.2 ± 24.6/13.2. 17.2% of the subjects use diuretic of whom 58% presents UA higher than median values. As showed in figure 1, patients with Hpeuricemia without diuretic use served as reference group. In multivariate adjusted analysis (for sex, age, SBP, BMI, glycemia, total cholesterol and creatinine) subjects without hyperuricemia and without diuretic show a significant lower risk for the three outcomes. Subjects without hyperuricemia with diuretic use have lower risk of all cause death but similar risk of CV death and events. Finally subjects with hyperuricemia and diuretic use exhibit a similar risk for the three outcomes as compared with the reference group.

Conclusions:

Our study showed that diuretic related hyperuricemia is related to CV events similarly to the subjects that present hyperuricemia without diuretics.
REFERENCE RANGES AND CUT-OFF VALUES FOR SIMULTANEOUS MONITORING OF RAS BLOCKER EFFICACY AND SCREENING FOR SECONDARY HYPERTENSION USING RAAS TRIPLE-A PROFILING
Authors: Poglitsch Marko , Foco Luisa , Gögele Martin , Pramstaller Peter Paul , Pattaro Cristian
Published: April 2021

Objective:

Uncontrolled hypertension is caused by various factors including compliance issues, patient specific drug uptake and elimination profiles or secondary forms of hypertension, resulting in blood pressure control rates of less that 50%. RAAS Triple-A profiling is based on a high-throughput mass-spectrometry assay for Angiotensin I (Ang I), Angiotensin II (Ang II) and Aldosterone in serum samples. Quantified hormone levels are used to calculate markers for plasma-renin-activity (PRA-S), plasma angiotensin-converting-enzyme activity (ACE-S) and adrenal aldosterone secretion (AA2-Ratio). The integrated analysis of these molecular markers together with drug prescription information allows to identify the underlying cause of uncontrolled hypertension, including primary aldosteronism and insufficiency in drug adherence or dosing for ACE inhibitors (ACEi) and angiotensin receptor blockers (ARBs).

Design and method:

500 participants with prescribed antihypertensive drugs were selected from the “Cooperative Health Research in South Tyrol” (CHRIS) study, a population-based study from an Alpine rural environment. Five age- and sex-matched groups (N = 100 each) selected were individuals on single therapy with ARBs, ACEi or beta blockers, and on single pill dual therapy of ACEi or ARBs in combination with diuretics. Three age and sex-matched control groups of 100 participants each were included, being normotensive, hypertensive (treated with non-antihypertensive drugs) and hypertensive participants without any prescribed medication.

Results:

RAAS Triple-A analysis was performed in all individuals and reference values for Ang I, Ang II, Aldosterone, PRA-S, ACE-S and AA2-Ratio were established in appropriate sub-populations. Drug monitoring by LC-MS/MS based quantification of anti-hypertensive drugs in serum was used as a gold standard to determine cut-off values for compliance with ARB and ACEi therapy and ROC analysis was performed using angiotensin-based biomarkers.

Conclusions:

RAAS Triple-A profiling for the first time provides an interpretation of blood pressure regulating effector hormone levels under consideration of individual drug prescriptions and its dynamic molecular impact on a patient's physiology. The resulting model for patient stratification paves the way for personalized treatment of hypertension, simultaneously screening for secondary hypertension and drug adherence/dosing based on a single high throughput routine blood test applied to patients while being on their standard therapy.
F-18 FDG PET/CT CAN BE USED AS AN IMAGING BIOMARKER FOR REFLECTING SYNTHETIC VASCULAR SMOOTH MUSCLE CELL ACTIVITY IN THE ANIMAL MODEL OF VASCULAR REMODELING DISORDER
Authors: Pahk Kisoo , Joung Chanmin , Kim Sungeun , Kim Won-Ki
Published: April 2021

Objective:

Synthetic vascular smooth muscle cells (VSMCs) play important roles in vascular remodeling disorders including atherosclerosis, restenosis, and transplant vasculopathy. 18F-fluorodeoxyglucose positron emission tomography (F-18 FDG PET/CT) is a non-invasive molecular imaging modality widely used in clinical practice for reflecting glucose metabolism. The aim of this study was to demonstrate the feasibility of measuring the activity of synthetic VSMCs using F-18 FDG PET/CT in an atherosclerotic rat model of partial carotid artery ligation.

Design and method:

Using Sprague-Dawley rats, neointimal hyperplasia was made by right partial carotid ligation method. After 1 month, all animal models undertook F-18 FDG PET/CT images. Then the vessels were harvested and analyzed with autoradiography and histomolecular approaches.

Results:

The affected carotid artery exhibited prominent neointinal hyperplasia region with a narrowed lumen. Known surrogate marker of synthetic VSMCs including matrix metallopeptidase-9, cyclophilin A, and collagen type III were increased in neointimal hyperplasia region. There were no immune cells such as macrophages or neutrophils. F-18 FDG PET/CT and autoradiography showed increased tracer uptake along the same affected arteries. Glucose transporter-1 was also increased in neointimal hyperplasia region.

Conclusions:

It is feasible to use F-18 FDG PET/CT as an imaging surrogate-marker for reflecting synthetic VSMC activities in vascular remodeling disorders.
ISOLATED SYSTOLIC HYPERTENSION VERSUS COMBINED SYSTOLIC-DIASTOLIC HYPERTENSION AS PREDICTOR OF ATRIAL FIBRILATION: DATA FROM AN 8-YEAR-FOLLOW-UP STUDY
Authors: Konstantinidis D. , Tsioufis K. , Liatakis I. , Koutra E. , Leontsinis I. , Kouremeti M. , Iliakis P. , Karaminas N. , Tatakis F. , Papakonstantinou P. , Anastasiou A. , Mourtzoukou D. , Siafi E. , Kakouri N. , Dimitriadi M. , Tousoulis D.
Published: April 2021

Objective:

Isolated systolic hypertension (ISH) and combined systolic-diastolic hypertension (CH) are related with increased cardiovascular risk. To compare the predictive role of ISH and CH for the incidence of atrial fibrillation (AF) in a cohort of essential hypertensive patients.

Design and method:

We followed up 1605 essential hypertensives with office systolic blood pressure (BP)> or = 140 mmHg (mean age 58.1 years, 842 males, office BP = 153/92 mmHg) for a mean period of 8 years. All subjects had at least one annual visit and at baseline underwent echocardiographic study and blood sampling for estimation of metabolic profile. Patients with baseline ISH exhibited office systolic BP > or = 140 mmHg and office diastolic BP <90 mmHg, while those with CH had office systolic BP > or = 140 mmHg and office diastolic BP > or = 90 mmHg. Moreover, new-onset AF was defined as hospitalization for AF or compatible electrocardiographic tracings.

Results:

The incidence of new-onset AF over the follow-up period was 3.4% (n = 55). Patients with ISH (n = 510) compared to those with CH (n = 1095) were older (65 ± 10 vs 55 ± 11 years, p < 0.0001), had at baseline lower waist circumference (95.5 ± 12 vs 98 ± 12 cm, p < 0.0001), office systolic BP (149 ± 10 vs 155 ± 13 mmHg, p < 0.0001), office diastolic BP (80 ± 5 vs 98 ± 7 mmHg, p < 0.0001), while did not differ regarding left ventricular mass index and lipid levels (p = NS for all). Univariate Cox regression analysis revealed that baseline ISH (hazard ratio = 4.612, p = 0.013) and CH (hazard ratio = 1.794, p = 0.036) predicted new-onset AF. However, in multivariate Cox regression model, age (hazard ratio = 1.078, p < 0.001), left ventricular mass index (hazard ratio 1.012, p = 0.014), left atrium diameter (hazard ratio = 1.102, p < 0.001) and ISH (hazard ratio = 1.551, p = 0.035) but not CH turned out to be independent predictors of new-onset AF episodes.

Conclusions:

In essential hypertensive patients, ISH but not CH exhibits independent prognostic value for AF. These findings support that ISH constitutes a hypertensive phenotype of particularly increased arrhythmia risk needing careful evaluation and treatment.
OBSTRUCTIVE SLEEP APNEA IS AN INDEPENDENT PREDICTOR OF ARTERIAL STIFFNESS IN HYPERTENSIVE PATIENTS
Authors: Rietz Hermine , Hellqvist Henrik , Kahan Thomas , Sommermeyer Dirk , Hedner Jan , Grote Ludger , Spaak Jonas
Published: April 2021

Objective:

Studies have suggested an association between obstructive sleep apnea (OSA) and arterial stiffness. We aimed to further assess this relationship in hypertensive patients.

Design and method:

In all, 199 patients with hypertension (mean age 57 ± 11 years, 73 females, body mass index 27.9 ± 4.4 kg/m2, office blood pressure (BP) 147 ± 19/89 ± 11 mm Hg) referred for 24-h ambulatory blood pressure monitoring (ABPM, recordings every 20 min throughout) underwent simultaneous over-night polygraphic sleep recording (nasal airflow and finger pulse-oximetry). The number of apneas and hypopneas during sleep per hour were measured (apnea hypopnea index, AHI) as well as the burden of desaturation (oxygen desaturation index, ODI). From ABPM the ambulatory arterial stiffness index (AASI) was calculated as 1 - the regression slope of diastolic on systolic BP. Patients were divided into three groups according to their AHI; AHI <5 (no OSA, n = 75), AHI 5<15 (mild OSA, n = 69) and AHI >15 (moderate/severe OSA, n = 44/11). Also 24-h pulse pressure (PP) was assessed as an indirect marker of arterial stiffness.

Results:

AASI increased with AHI severity: 0.39 ± 0.14, 0.44 ± 0.13, and 0.46 ± 0.13 in AHI<5, 5<15, and AHI >15, respectively (p = 0.011, by ANOVA). In a multivariate regression model including age, sex, triglycerides (TG), AHI, 24-h systolic BP, 24-h mean heart rate (HR) and diabetes, all but sex, HR and diabetes remained independent predictors for AASI (age p < 0.001, sex p = 0.086, TG p = 0.029, AHI p = 0.015, 24-h systolic BP p = 0.003, 24-h mean HR p = 0.064, diabetes p = 0.070 with R = 0.52, p < 0.001 for full model). Using ODI instead of AHI yielded similar results, though HR was significant (p = 0.022), not TG (p = 0.057). In a similar regression model for describing 24-h PP (replacing 24-h systolic BP with 24-h mean arterial BP), neither AHI, nor ODI, remained independent predictors for 24-h PP.

Conclusions:

AASI, but not 24-h PP, is independently associated with both AHI and ODI in hypertensive patients together with 24-h systolic BP and age. TG also seems to be of importance in predicting AASI, probably through its association to glucose control. Ongoing work aims to further reveal the potential influence of OSA on arterial function in hypertensive patients.
ARTERIAL STIFFNESS AND WAVE REFLECTIONS IN PATIENTS WITH SERONEGATIVE SPONDYLOARTHROPATHIES TREATED WITH TUMOR NECROSIS ALPHA BLOCKERS
Authors: Bozzao Francesco , Colapietro Nina , Xodo Carlotta , Grillo Andrea , Rovina Matteo , Magazzino Olga , Smitova Kristina Giraldi , Carretta Renzo , Bernardi Stella , Tomietto Paola , Fischetti Fabio , Fabris Bruno
Published: April 2021

Objective:

The seronegative spondyloarthropathies (SpA) are a group of rheumatic disorders characterized by oligoarticular arthritis, enthesitis and axial involvement. Cardiovascular manifestations play a pivotal role in determining the excess mortality in SpA, owing to the linkage between systemic inflammation and accelerated atherogenesis. Arterial stiffness measured as carotid-femoral pulse-wave velocity (PWV) and wave reflections are validated markers of cardiovascular disease. Anti-inflammatory therapy with anti-tumor necrosis factor-α (TNFα) agents may have a role in reducing arterial stiffening in some disease models but data in patients with SpA are inconclusive.

Design and method:

Twenty-three patients with a short duration and high disease activity SpA (8 males, 15 females, mean age 53.9 ± 11.5 years) and without overt cardiovascular disease were enrolled. PWV and augmentation index (AIx, as a measure of wave reflections) were measured by a validated arterial tonometer (PulsePen, DiaTecne, Milan). Patients were compared with 23 controls matched for age, gender, blood pressure and heart rate. Arterial tonometry was repeated in 10 patients after 16 weeks of treatment with an anti-TNFα agent (Adalimumab, in 9 patients; Certolizumab, in 1 patient).

Results:

Of the patients enrolled, 14 had ankylosing spondylitis, 8 psoriatic SpA, 1 Crohn's disease-associated SpA. The median duration of the disease from diagnosis was 2 years (2–11 years). In the comparison with matched controls, no significant differences in PWV or AIx were found (PWV: SpA 8.9 ± 2.0 m/s, controls 9.2 ± 3.8m/s, p = 0.80; AIx: SpA 18.3 ± 14.7, controls 19.5 ± 12.0, P = 0.77). During the 16-weeks follow-up of patients treated with anti-TNFα therapy, despite significant improvement in disease activity parameters (ASDAS-CRP: 2.75 ± 0.8 to 1.67 ± 0.4, P < 0.01; BASDAI: 5.05 ± 1.9 to 3,0 ± 1.2, P 0.05), no significant change was found in the hemodynamic parameters (PWV: 8.5 ± 1.8 to 9.7 ± 3.5 m/s, p = 0.11; AIx 16.6 ± 15.5 to 13.7 ± 10.0, p = 0.47).

Conclusions:

In patients with a short duration SpA, arterial stiffness and wave reflections are not significantly impaired. Anti-TNFα agents have no effects on arterial stiffness parameters in the short term, despite control of clinical and inflammatory burden. Forthcoming studies should explore the cardiovascular effects of novel therapeutics opportunities (anti-IL12/23 and anti-IL17) in patients with SpA.
RELATIONSHIPS BETWEEN ANTI-HYPERTENSIVE DRUGS AND NOCTURIA: A SYSTEMATIC REVIEW
Authors: Akasaki Yuichi , Kubozono Takuro , Higuchi Koji , Ohishi Mitsuru
Published: April 2021

Objective:

Nocturia frequently occurs with age in both men and women, and it is the worst symptom among the lower urinary tract symptoms which deteriorate the quality of life. The cause is an increase in urine volume at night or day and night, and a decrease in bladder capacity.

Hypertension is one of the diseases to cause nocturia. However, no systematic review has been performed to collate the evidence on the relationships between antihypertensive drugs and nocturia.

The objective of this systematic review is to synthesize the research evidence on relationships between antihypertensive drugs and nocturia.

Design and method:

A comprehensive search was conducted of the following electronic databases in English and Japanese: PubMed, MEDLINE, The Cochrane Central Register Controlled Trials (CENTRAL), NPO Japan Medical Abstracts Society's Ichushi - Web database, in March 2019. The title and abstracts of the studies were reviewed by two independent reviewers against the inclusion/exclusion criteria. The keywords were as follows: [hypertensive medications], [calcium channel blockers], [angiotensin converting enzyme inhibitors], [angiotensin receptor blockers], [diuretics], [beta blockers] AND [nocturia].

Results:

132 studies were screened (46 articles were about calcium channel blockers. 6 articles were about angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. 70 articles were about diuretics. 10 articles were about beta blockers), 24 (14 retrospective studies, 8 case control studies, and 2 reviews) were included in the systematic review. Hypertensive drugs had showed close relationships with nocturia. Calcium channel blockers worsened symptoms of nocturia. Lower urinary tract symptoms(LUTS) should be evaluated before and after calcium channel blockers administration. While thiazide diuretics worsened urination symptoms, loop diuretics worsened nocturia. People without gender, the use of diuretics was significantly correlated with the number of urinations at least 3 times / night and the rate of increased urinations was especially high in women.

Conclusions:

Hypertension is a risk factor of nocturia. When we treat hypertensive patients with nocturia, we need to consider antihypertensive drugs may worsen the symptoms of LUTS and select drugs which can improve those symptoms.
RENALASE PROTECTS AGAINST SALT-INDUCED KIDNEY INJURY AND INFLAMMATION BY INHIBITING THE ACTIVATION OF THE AKT-1 SIGNALING PATHWAYS
Authors: Wang Keke , Wang Yang , Yuan Yue , Ma Qiong , Yan Yu , Liao Yueyuan , Mu Jianjun
Published: April 2021

Objective:

An excess of dietary salt is the most common environmental factor that contributes to the development of hypertension leading to renal pathologies. Renalase (RNLS), a novel secreted flavoprotein with oxidoreductase activity, functions as a survival factor and promotes cell and organ survival. Previous evidence showed that recombinant renalase exerts powerful hypotensive effects and ameliorates renal interstitial fibrosis in rodents. In this study, we evaluated the potential protective role of renalase and underlying mechanisms in salt-induced kidney injury and inflammation.

Design and method:

In vitro, human proximal renal tubular epithelial (HK-2) cells were treated with normal salt or high salt (40 mM NaCl) for 24 hours, receiving recombinant renalase (25ug/mL) or vehicle. In vivo, Dahl salt-sensitive (DS) rats and renalase knockout mice were placed on normal (0.8% NaCl) or high salt (8% NaCl) diet with or without renalase (1 mg/kg) for 4 weeks.

Results:

In vitro, renalase decreased the phosphorylation levels of protein kinase B (Akt-1), leading to a reduction in the mRNA expression of pro-inflammatory cytokines and oxidative stress induced by high salt. And when knockdown the channel plasma membrane calcium ATPase (PMCA4b) in HK-2 cells, the inflammation and oxidative stress levels induced by high-salt decreased.

In DS rats, high salt diet significantly increased the blood pressure and the 24 h urinary sodium excretion. Furthermore, renal inflammation and fibrosis of high salt group were more severe compared to normal salt diet group. Administration of recombinant human renalase reduced kidney inflammation through inhibition of Akt-1 pathway.

Similarly, genetic depletion of renalase in mice (renalase knockout) exacerbated kidney injury in animals with high salt diet. Treatment with recombinant renalase significantly decreased the kidney inflammation through inhibition Akt-1 expression.

Conclusions:

Our study provides the first evidence that renalase can ameliorate kidney injury and inflammation through inhibition of the Akt-1 pathway. These results suggest that renalase has potential renoprotective effects in renal injury and inflammation and may be an effective agent for slowing kidney damage.
ASSOCIATION OF CARDIOVASCULAR ENDPOINTS AND MORTALITY WITH CENTRAL AND PERIPHERAL PULSATILE BLOOD PRESSURE COMPONENTS
Authors: Huang Qifang , Aparicio Lucas , Thijs Lutgarde , Wei Fang -Fei , Melgarejo Jesus , Cheng Yi -Bang , Sheng Chang -Sheng , Yang Wen -Yi , Gilis-Malinowska Natasza , Boggia José , Niiranen Teemu , Wojciechowska Wiktoria , Stolarz-Skrzype Katarzyna , Barochiner Jessica , Tikhonoff Valérie , Casiglia Edoardo , Narkiewicz Krzysztof , Filipovský Jan , Czarnecka Danuta , Kawecka-Jaszcz Kalina , Jula Antti , Vanassche Thomas , Verhamme Peter , Struijker-Bouder Harry , Wang Ji -Guang , Zhang Zhen -Yu , Li Yan , Staessen Jan
Published: April 2021

Objective:

Pulsatile blood pressure (pBP) confers cardiovascular risk. Whether associations of cardiovascular endpoints are tighter for central than peripheral systolic or pulse pressure (cSBP, pSBP, cPP, pPP) is uncertain.

Design and method:

We constructed the International Database of Central Arterial Properties for Risk Stratification (IDCARS), allowing a subject-level meta-analysis. IDCARS cohorts qualified for inclusion in the present analysis, if peripheral and central BP and cardiovascular risk factors had been measured at baseline, and if follow-up included both fatal and non-fatal outcomes.

Results:

Among 5608 participants (54.1% women; mean age, 54.2 years) enrolled in nine studies, median follow-up was 4.1 years. pSBP and pPP averaged 134.1 and 53.9 mmHg, and cSBP and cPP, estimated tonometrically from the radial waveform, 123.7 and 42.5 mmHg. The primary composite cardiovascular endpoint occurred in 317 participants (5.7%). Across fourths of the cPP distribution, rates increased exponentially (2.9, 5.7, 9.7, and 26.1 per 1000 person-years) with comparable estimates for cSBP, pSBP and pPP. The multivariable-adjusted hazard ratios, expressing the risk per 1-SD increment in blood pressure (HR), were 1.33 (95% confidence interval, 1.19–1.50) for cPP, 1.47 (1.31–1.64) for cSBP, 1.31 (1.17–1.46) for pPP, and 1.45 (1.30–1.62) for pSBP (P < 0.001). Further adjustment of cPP and cSBP, respectively for pPP and pSBP, and vice versa, removed the significance of all HRs. Adding cPP, cSBP, pSBP, pPP to a base model including covariables increased model fit (P < 0.001) with generalised R2 increments ranging from 0.40 to 0.77%, but adding a second pBP to a model including already one did not. Analyses of total mortality (204 deaths) and 106 cerebrovascular endpoints and sensitivity analyses across various subgroups produced consistent results.

Conclusions:

In this subject-level meta-analysis, the primary endpoint, mortality and cerebrovascular events were similarly associated with central than peripheral pBP.
RELATIONSHIP BETWEEN ARTERIAL STIFFNESS, PHYSICAL ACTIVITY & SEDENTARY TIME IN A YOUNG MIDDLE-EASTERN POPULATION
Authors: Mahmud Azra , Dalton Teigh , Nalin Jay , Nalin M. , Merrigan Orla , Saud Anas , Hamadah Randah
Published: April 2021

Objective:

Arterial stiffness (AS) and physical activity are independent cardiovascular(CV) risk factors and predict outcome. We and others have shown that PA is associated with AS; however, the data is largely derived from older, Caucasian populations assessing PA with questionaires. The aim of this study was to explore the relationship between AS and PA using actigraphy in a young Middle-Eastern population, hitherto not studied.

Design and method:

Four-hundred and two apparently healthy subjects (mean age 20.7 ± 3 years, 52% females) were enrolled in this cross-sectional study. Anthropometric measurements performed included weight, height, waist and hip, total body fat, visceral fat and muscle mass.

Participants received an accelerometer (ActiGraph™) to wear on the wrist for 7 consecutive days. The average minutes/day spent at different PA intensities (min/day) was determined according to established cut-points as well as metabolic equivalents (METS). Arterial stiffness was measured using the SphygmoCor™ and Mibilograph® as pulse wave velocity (PWV), central BP and augmentation index(AIx), after fifteen minutes of supine rest. The data was analysed using JMP Pro version 13 (SAS for Windows, NC, USA).

Results:

30% of the population met the AHA Guidelines for PA with no gender difference. None of the subjects achieved moderate-vigorous or very vigorous activity with almost 50% of the time spent in being sedentary. There was a significant association between daily step count and body fat and body muscle content (p < 0.001). PWV was associated with age (r = 0.25, p < 0.001), brachial systolic BP(r = 0.57, p < 0.0001), aortic systolic BP(r = 0.65, p < 0.0001), cardiac output(r = 0.39, p < 0.0001), METS achieved(r = -0.42, p < 0.0001), light activity (r = -0.25, p < 0.001), moderate-to-vigorous (r = -0.29, p < 0.001), sedentary time (r = 0.45, P < 0.0001), waist(r = 0.47, p < 0.0001), visceral fat(r = 0.39, p < 0.001) and muscle mass(r = -0.31, p < 0.01). In a stepwise regression model with PWV as the dependent variable, age, MAP, gender, METS achieved and sedentary time emerged as independent determinants of PWV (R2 = 0.39, p < 0.0001).

Conclusions:

Unhealthy life-style is a strong risk factor for CVD, partly through the development of premature arterial stiffening. Our results highlight the deleterious effects of sedentary time on vascular function, independent of physical activity and energy consumption in a young, healthy population.
EARLY DETERMINANTS OF CHILDHOOD BLOOD PRESSURE AT AGE 6: THE GECKO DRENTHE AND ABCD BIRTH COHORTS
Authors: Xie Tian , Falahi Fahimeh , Schmidt-Ott Tabea , Vrijkotte Tanja , Corpeleijn Eva , Snieder Harold
Published: April 2021

Objective:

The study aimed to explore the association between early determinants and childhood blood pressure at age 6.

Design and method:

From the population-based GECKO Drenthe birth cohort, 1663 Dutch children were included in the analyses. Birth weight was standardized (std-BW) for sex and gestational age, blood pressure was measured, and prenatal factors, pregnancy outcome and participants characteristics were derived from gynecologist/midwives or from parents by questionnaire. Hierarchical multiple linear regression models were used to test whether prenatal factors, std-BW, gestational age, breastfeeding independently contribute to childhood blood pressure at age 6. The models were further replicated in 2052 Dutch children from the Amsterdam Born Children and their Development (ABCD) study, and meta-analyses were performed to combine the results of the two cohorts. Next the effect of child's postnatal weight gain (the weight for age z-score change from age 2 to 6) on childhood BP was evaluated after adjustment for covariates only in the GECKO Drenthe cohort.

Results:

In the meta-analyses results of multiple linear regression, maternal prepregnancy BMI was positively associated with SBP (beta=0.09 mmHg; 95% confidence interval (CI), 0.02–0.15) and DBP (beta=0.11 mmHg; 95% CI, 0.05–0.17) at age 6. Children of women with hypertension during pregnancy had higher SBP (beta=0.91 mmHg, 95% CI, 0.14–1.68) and DBP (beta=0.71 mmHg, 95% CI, 0.04–1.39). Higher std-BW was associated with lower SBP (Per unit std BW, beta=-7.20 mmHg, 95% CI, -9.41--4.99) and lower DBP (beta=-4.00 mmHg, 95% CI, -5.94--2.07). Longer gestational age was not associated with DBP, only with lower SBP (per extra gestational week, beta=-0.23 mmHg, 95% CI, -0.43--0.02). The direction of effect sizes of these perinatal factors on childhood blood pressure were consistent in the two cohorts. Furthermore in the GECKO Drenthe cohort, higher postnatal weight gain was associated with higher SBP (beta=0.78 mmHg, 95% CI, 0.24–1.32) and higher DBP (beta=0.57 mmHg, 95% CI, 0.08–1.05).

Conclusions:

Higher maternal prepregnancy BMI, maternal pregnancy hypertension, a relatively lower birth weight for gestational age, shorter gestational age and faster postnatal weight gain independently contribute to higher childhood blood pressure at age 6.