bluuebunny/crossref_metadata_2025 huggingface dataset:
IMPLEMENTATION OF THE NOVEL HYPERTENSION-SPECIFIC PATIENT-REPORTED OUTCOME MEASURE IN M-HEALTH. A SINGLE-CENTRE EXPERIENCE
Authors: Ionov Mikhail , Dubinina Elena , Khromov-Borisov Nikita , Tregubenko Ilya , Kurapeev Dmitry , Zvartau Nadezhda , Konradi Alexandra
Published: April 2021

Objective:

Telehealth techniques are hugely involved in management of hypertension (HTN). Despite much evidence of clinical efficacy, the quality of life (QoL) is still poorly addressed in m-Health studies. Furthermore, generic tools are often used for QoL assessment. The aim was to assess QoL of blood pressure telemonitoring (BPTM) with the brand new HTN-specific patient-reported outcome measure called HYpertension imPact questionnairE (HYPE).

Design and method:

Conceptual model of HYPE was designed and the item pool was created by an expert panel consisting of 4 cardiologists, 2 psychologists. Validation survey was conducted in a 400-cohort of ambulatory patients with HTN Grades 1–3. Exploratory and confirmatory factor analyses (EFA and CFA respectively) were undertaken to confirm validity. Reliability was confirmed with Cronbach's alpha. Free and secure m-Health app was developed for BPTM. 100 patients were enrolled and allocated to BPTM (mean age 48 y.o.) and control (mean age 49 y.o.) in 1:1 ratio. The 6-month program was developed with baseline and end of study clinic visits and HYPE polling.

Results:

There were 5 factors (“symptoms”, “emotions”, “social issues”, “treatment efficacy” and “treatment adherence”) retained with respect to Cattel scree test. Of 80 initial questions only 35 were eligible due to EFA (factor loadings >0.5). CFA indicated SRMR was 0.08, RMSEA was 0.07 (90% CI [0.07–0.08]) and CFI was 0.08. Cronbach's alpha was more 0.80 for each of the factors and 0.89 for the whole scale confirming its reliability. Six-month results reaffirmed the clinical efficacy of BPTM (141,2 ± 10,2 vs 149,5 ± 8,4 mm Hg, p < 0.003). The vast majority of patients in BPTM achieved target office BP instead of control group (50% vs 15%). HYPE score was markedly higher in BPTM group than in controls (+22,4 [+16%] vs +5,6 [4%], p < 0.0001) at the end of the study. Qualitative substudy showed 70% positive patient experience with using BPTM.

Conclusions:

Novel patient-reported outcome measure is a solid tool for assessing different patterns of QoL in patients with HTN. BPTM seems to be effective especially in a patient-centered manner and paves the way for future telehealth studies focusing on quality of life in hypertensive subjects.
RENAL OXIDATIVE STRESS IN A MODEL OF HYPERTENSION INDUCED BY SALINE OVERLOAD: ROLE OF CHLORIDE ANION
Authors: Puyó Ana María , Kouyoumdzian Nicolás Martín , Prince Paula Denise , Robbesaul Gabriel Damián , Kim Gabriel , Pandolfo Marcela , Fernández Belisario Enriqu , Galleano Mónica Liliana , Choi Marcelo Roberto
Published: April 2021

Objective:

A chronic saline overload in the diet induces a renal inflammatory response and oxidative stress, leading to hypertension development. Our aim was to demonstrate that chloride anion (Cl-), besides sodium cation (Na+), is involved in these inflammatory and oxidative responses. These alterations might be reduced if Cl- is replaced by other anion (like citrate), or if Na+ is replaced by other cations.

Design and method:

Male Wistar rats were divided into four groups (n = 8): control (C); NaCl 8%W/W; high Na+ without Cl- (Na: sodium citrate 11,8%); high Cl- without Na+ (Cl: CaCl2 3,80%; KCl 3,06% and MgCl2 1,30%). After three weeks, systolic blood pressure (SBP) was measured, and rats were housed in metabolic cages in order to collect 24-hour urine to assess renal function. Oxidative stress parameters were determined in renal cortex: TBARS production and antioxidant enzymes activities and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx).

Results:

In all groups we observed a significant increase of diuresis (∗p < 0,05 versus C) while SBP was increased only in those rats fed with Cl- (mmHg, C:125 ± 9; NaCl:164 ± 8∗; Na:133 ± 4; Cl:152 ± 7∗). These changes were accompanied by an increase in TBARS production in renal cortex (mol TBARS/mg protein) (x1012): C:1,30 ± 0,10; NaCl:1,82 ± 0,18∗; Na:2,01 ± 0,32∗; Cl:1,91 ± 0,34∗. No changes were observed on the activity or expression of SOD and CAT. Despite GPx expression being unaltered, its activity was increased in those groups with Cl- (micromol oxidized glutathione/mg protein.min, C:1,34 ± 0,14; NaCl:2,31 ± 0,37∗; Na:1,30 ± 0,14; Cl:2,77 ± 0,52∗).

Conclusions:

A high salt intake as sodium chloride increased SBP and water, sodium and chloride urinary excretion after 3 weeks of treatment. These changes were associated with an increase in oxidative stress parameters in renal cortex (mainly TBARS production and GPx activity). Only chloride salts could increase diuresis and induce an increase in SBP (compared with C) but reaching lower values than NaCl group. Additionally, chloride salts were able to increase oxidative stress parameters in renal cortex as NaCl group. These findings suggest that chloride component in the diets can be crucial to determine a higher prooxidant state in the kidney, rather than the sodium component in salt diets.
RENAL FUNCTIONAL RESERVE IS RELATED TO THE NON-DIPPING PHENOTYPE AND TO THE EXERCISE HEART RATE RESPONSE IN PATIENTS WITH ESSENTIAL HYPERTESION AND A PRESERVED RENAL FUNCTION
Authors: Damianaki Katerina , Burnier Michel , Tsioufis Constantinos , Dimitriadis Kyriakos , Vlahakos Demetrios , Petras Dimitrios
Published: April 2021

Objective:

Renal functional reserve (RFR) defined as the difference between stress and resting glomerular filtration rate (GFR) may constitute a diagnostic tool to identify patients at higher risk of developing acute kidney injury or chronic kidney disease. A blunted RFR has been demonstrated in early stages of hypertension and has been attributed to an impaired vascular reactivity due to an overactive sympathetic nervous system. The purpose of this study was to investigate whether RFR correlates with other phenotypes expressing an over-activity of the SNS in patients with essential hypertension and a preserved renal function.

Design and method:

Thirty-six patients with untreated essential hypertension and a GFR >60 ml/min/1.73m2 were enrolled. The following parameters were measured: RFR, a 24 h ambulatory BP profile, a treadmill stress test and an echocardiographic examination. Urine and venous samples were obtained for the determination of clinical parameters and calculation of RFR after an acute oral protein load (1 g/kg).

Results:

Twenty-one patients had a RFR below 30 ml/min/1.73m2 and 15 had a RFR above this cut-off. A non-dipping pattern of 24 h BP was significantly more frequent in patients with low RFR (57.1% vs. 25.0%, p < 0.05 for systolic BP and 52.3% vs 10.0%, p < 0.02 for diastolic BP). Moreover, patients with lower RFR values showed a blunted heart rate response to exercise during treadmill test (r = 0.439, p < 0.05). None of the echocardiographic parameters differed between the two groups of patients.

Conclusions:

In hypertensive patients with a preserved GFR, a reduced RFR is related to non-dipping BP phenotype as well as with an attenuated exercise HR response. An overactivity of the sympathetic nervous may be a common pathway. Since a loss of RFR may represent a risk factor for acute or chronic kidney injury, hypertensive patients with a blunted RFR might need a more careful renal follow-up.
INITIAL EGFR DECLINE AND LONG-TERM RENAL FUNCTION DURING BLOOD PRESSURE LOWERING THERAPY: A PATIENT LEVEL META-ANALYSIS OF THE SPRINT AND ACCORD-BP RANDOMIZED CONTROLLED TRIALS
Authors: Collard Didier , Brouwer Tom , Engberink Rik Olde , Zwinderman Aeilko , Vogt Liffert , Van Den Born Bert-Jan
Published: April 2021

Objective:

Lowering blood pressure (BP) can lead to an initial decline in renal function. Guidelines recommend treatment adjustment when the estimated glomerular filtration rate (eGFR) decreases by more than 20%. However, there is ongoing debate how much can be accepted. We determined the relation between initial eGFR and BP decrease, and subsequent eGFR during follow-up in participants from ACCORD-BP and SPRINT.

Design and method:

Diabetic and non-diabetic patients at increased cardiovascular risk were randomized to intensive (<120) or standard (<140 mmHg) systolic BP-targets. We determined the relation between initial decline in mean arterial pressure (MAP) and eGFR. Subsequently, we stratified patients to BP-target and initial eGFR decrease and assessed the relation with annual eGFR-decline after 1 year.

Results:

In total 13266 patients, aged 66.2 year, 39% female and with mean eGFR 76.4 ml/min/1.73m2, with 41126 eGFR measurements were analyzed. The >20% stratum consisted of 669 (10%) in the intensive and 334 (5%) participants in the standard group. Up to 10 mmHg MAP decrease, there was no significant change in eGFR, with a lower bound of 26% based on 95% of the participants. Hereafter, there was a linear association between MAP and eGFR with an initial eGFR decrease of 3.4% (95%CI 2.9–3.9%) per 10 mmHg MAP decrease, with a lower eGFR bound increasing to 46% after 40 mmHg MAP decrease (figure 1). There was no significant difference in eGFR slope (p = 0.37) after stratification to treatment allocation and initial eGFR decline, with an annual eGFR decrease of 1.24 (95%CI 1.09–1.39), 1.20 (95%CI 0.97–1.43) and 1.14 (95%CI 0.77–1.50) in the 5, 5–20% and >20% stratum during intensive and 0.95 (95%CI 0.81–1.09), 1.23 (95%CI 0.97–1.49) and 1.17 (95%CI 0.65–1.69) ml/min/1.73m2/year during standard treatment.

Conclusions:

In patients at high cardiovascular risk, we found no association between initial eGFR and annual eGFR decline during BP-lowering treatment. The observed degree of initial eGFR decline was strongly dependent on the achieved BP decrease, suggesting that the achieved BP difference should be taking into account when interpreting the eGFR decline during antihypertensive therapy.
IN-HOSPITAL DIURETIC USE IS ASSOCIATED WITH WORSE OUTCOME IN PATIENTS WITH COVID-19
Authors: Pengo M. , Stefanini G , Pivato C , Soranna D , Zambra G , Zambon A , Torlasco C , Bilo G , Condorelli G , Parati G
Published: April 2021

Objective:

Background: Hypertension is associated with increased risk of severe COVID-19 and increased mortality. The knowledge about the impact of blood pressure lowering medications on outcomes is still incomplete: whilst studies about renin-angiotensin-aldosterone system inhibitors did not show association with increased mortality, less is known about the impact of other antihypertensive classes. Diuretics, in particular, are frequently used in patients with hypertension thus we aimed to investigate the association between diuretics and mortality in a cohort of COVID-19 patients hospitalized in two referral centers in the Lombardy region (Istituto Auxologico Italiano and Humanitas Research Hospital).

Methods:

Data of confirmed COVID-19 patients, with information available about drug treatment and outcomes, were pooled together. Socio-demographic, clinical features, and medications pre and during hospitalization were retrieved, patients were classified according to the use of diuretics before and/or during hospitalization. The effect of diuretic use before and during hospitalization on death was estimated by means of a multiple Poisson regression model with robust variance and reported as Relative Risk (RR) and 95% confidence interval (95% CI).

Design and method:

From the pooled sample of 637 patients, a final sample of 502 patients with complete data was analyzed (mean age 67 years, 67% males, 54% patients with hypertension). Among hypertensive patients, 64% were not treated with diuretics either pre- or during hospitalization (Reference group), 15% had diuretic treatment only during hospitalization (Group A), 9% only pre-hospitalization (Group B) and 12% both pre- and during hospitalization (Group C).

After adjusting for confounders (age, sex, respiratory rate at admission, number of comorbidities, number of other drugs taken during hospitalization, orotracheal intubation), use of diuretics only during hospitalization was significantly associated with mortality (Figure 1).

Conclusion:

Our data show an association between diuretic use only during hospitalization and worse outcome in patients with COVID-19. Such association needs to be further investigated in order to possibly improve outcomes in patients admitted for COVID-19

Figure 1: Relative Risks and 95% confidence intervals of patients treated with diuretics only during hospitalization (Group A), only during pre-hospitalization (Group B) and during both pre- and hospitalization (Group C). The subgroup of patients not treated with diuretics neither pre- nor during hospitalization was taken as the reference group.
IMPACT OF COVID-19 LOCKDOWN ON VASCULAR STIFFNESS TRAJECTORIES IN FRANCE AND GERMANY
Authors: Bruno Rosa Maria , Pepin Jean-Louis , Empana Jean-Philippe , Yang Rui-Yi , Vercamer Vincent , Jouhaud Paul , Escorrou Pierre , Boutouyrie Pierre
Published: April 2021

Objective:

Aim of the study is to investigate the impact of COVID-19 lockdown on trajectories of vascular stiffness among a large population of users of a connected bathroom scale, allowing reliable measurements of pulse wave velocity (PWV).

Design and method:

Pulse wave velocity (PWV) recordings obtained by Withings Heart Health & Body Composition Wi-Fi Smart Scale users before and during lockdown were analyzed. We compared two demonstrative countries: France, who applied strict lockdown rules (n = 26,196) and Germany, who applied partial lockdown (n = 26,847). Subgroup analysis was conducted in users of activity trackers and home blood pressure monitors (HBPM). Linear growth curve modeling and clustering trajectories analyses were performed.

Results:

During lockdown a significant reduction in PWV, weight, BP and physical activity was observed in the overall population. PWV reduction was significantly greater in France than in Germany, corresponding to an improvement of 5.2 months in vascular age.

In the French population three clusters of PWV trajectories were identified: decreasing (21.1%), stable (60.6%) and increasing PWV (18.2%). Decreasing and increasing PWV clusters had both higher PWV and vascular age at baseline compared to stable PWV cluster. Only decreasing PWV cluster showed a significant weight reduction (-400 g), whereas living alone was associated with increasing PWV.

Conclusions:

Total lockdown induced a reduction in vascular stiffness in a significant proportion of French smart scale users. Impact on long term behaviors and cardiovascular health remains to be established.
DIFFERENTIAL PREVALENCE AND ASSOCIATIONS OF CHRONIC KIDNEY DISEASE BY FIVE ESTIMATORS IN A SOUTH AFRICAN POPULATION-BASED STUDY
Authors: Peer Nasheeta , George Jaya , Lombard Carl , Steyn Krisela , Levitt Naomi , Kengne Andre-Pascal
Published: April 2021

Objective:

The aim was to determine the prevalence, distribution, concordance and associations of chronic kidney disease (CKD) assessed by five glomerular filtration rate (GFR) formulae in urban black residents of Cape Town.

Design and method:

In this population-based cross-sectional study, stratified for age and gender, data collection included administered questionnaires, clinical measurements and biochemical analyses, including serum creatinine and cystatin C levels. GFR was based on the CKD Epidemiology Collaboration (CKD-EPI) equations (CKD-EPI creatinine (CKD-EPIcr), CKD-EPI cystatin C (CKD-EPIcys), CKD-EPI creatinine-cystatins (CKD-EPIcr-cys)), Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault formula (CGF). GFR <60 mL/min/1.73 m2 defined CKD.

Results:

Mean estimated GFR, among 392 men and 700 women, was between 114.0 (CKD-EPIcr) and 135.4 mL/min/1.73 m2 (CGF) in men, and between 107.5 (CKD-EPIcr-cys) and 173.4 mL/min/1.73 m2 (CGF) in women. CKD prevalence ranged from 2.3% (CKD-EPIcr and MDRD) to 5.1% (CKD-EPIcys) in men and 1.6% (CGF) to 6.7% (CKD-EPIcr-cys) in women. Correlations between different estimates of GFR were positive and significant, and there were no significant differences between any two coefficients. The kappa statistic was high between CKD-EPIcr and MDRD (0.934), and CKD-EPIcys and CKD-EPIcr-cys (0.815), but fair-to-moderate between the other equations (0.353–0.565). In the basic regressions, older age and body mass index >30 kg/m2, but not gender, were significantly associated with CKD-EPIcr-defined CKD. In the presence of these three variables, but in separate models, hypertension, heart rate >90 beats/minute, diabetes and increasing low-density lipoprotein cholesterol were significant predictors of prevalent CKD by CKD-EPIcr and MDRD (except for diabetes). Metabolic syndrome, in the model with age and gender only, was significantly associated with CKD-EPIcr- and MDRD-defined CKD. No cardio-metabolic variable was associated with CKD determined by CKD-EPIcys, CKD-EPIcr-cys or CGF.

Conclusions:

The varying CKD prevalence estimates, on account of different GFR equations used, underscores the need to improve accuracy of CKD diagnoses. Moreover, considering the significant associations of cardio-metabolic diseases with CKD-EPIcr- and MDRD-defined CKD, screening for CKD should be incorporated into the routine assessment of high-risk patients such as those with hypertension or diabetes.
PREVALENCE OF TYPE 2 DIABETES MELLITUS AMONG KNOWN HYPERTENSIVES AT THE REGIONAL HOSPITAL BAMENDA, CAMEROON
Authors: Ngeh Etienne , Atabon Fidelis Ako
Published: April 2021

Objective:

To evaluate the prevalence of type 2 diabetes mellitus (T2DM) and the associated risk factors among hypertensive patients with known and or unknown diabetes status. Secondly, to indirectly evaluate the impact of adopting diabetes screening in routine practice for all patients diagnosed with hypertension in the clinical settings.

Design and method:

This cross-sectional study was conducted on a sample of 150 hypertensive patients attending the diabetes/hypertension clinic of the Regional Hospital Bamenda. Blood pressure and glycemic blood measurements were assessed in all participants. A complete clinical history and physical exam were conducted and a data collection tool was completed. Prevalence of T2DM was obtained from fasting blood sugar, health reports and diabetes medications. Data was entered and analyzed descriptively in the form of frequency and percentage tables with the aid of SPSS 23.0 software.

Results:

The prevalence of T2DM among hypertensive patients in the was 44.7% (n = 67/150) with gender prevalence rates of 20.6% and 24% among males and females respectively in the studied sample (P = 0.002). T2DM prevalence increases with age, body mass index and duration of being hypertensive. Base on age, the prevalence increases from 9% in those 30–39 years and peak at 31.3% in those over 70 years. T2DM prevalence were 25.3%, 22.4%, 23.4%, and 28.4%, for BMI<18.5 kg/m2, 18.5–24.9 kg/m2, 25.0–29.9 kg/m2, and >30 kg/m2. The prevalence of unrecognized DM was 32.8% in hypertensive patients. Also, more than half of the subjects (56.7%) suffering from DM (38 out of 67 persons) had poorly controlled hypertension, contrasted with only about one third 27.7% (23 out of 83) of the non-diabetic participants with poorly controlled hypertension.

Conclusions:

The prevalence of DM in patients with hypertension was more than 8times that of the general population. The prevalence of unrecognized DM was equally very high in hypertensive patients. These findings demonstrate that hypertensive patients should regularly submit to T2DM screening for timely DM diagnosis. Therefore, major recommendations would be to adopt strict strategies to improve diabetes screening among hypertensive patients to minimize both the health and economic burdens associated with undiagnosed T2DM.
COMBINATION THERAPY IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND HEART FAILURE WITH REDUCED EJECTION FRACTION
Authors: Gaman Mihnea-Alexandr , Dobrica Elena Codruta , Cozma Matei Alexandru , Diaconu Camelia Cristina
Published: April 2021

Objective:

According to practice guidelines, heart failure with reduced ejection fraction (HFrEF) patients should receive combination therapy. Diuretics, angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), beta-blockers (BB) and digoxin are employed in HFrEF treatment. In patients with type 2 diabetes mellitus (T2DM) and HFrEF, clinical guidelines are not always respected, since many physicians fear the adverse effects of ACEI (hyperkalemia) and BB (altered response to hypoglycemia). We aimed to investigate the use of combination therapy in patients with HFrEF and T2DM.

Design and method:

Retrospective, observational study on patients referred between January-June 2017 to the Internal Medicine Department of an emergency hospital in Romania. Patients were identified by a database search of diagnostic codes of discharge diagnoses. The patients’ characteristics/medical prescriptions were retrieved from their medical records.

Results:

The study group (70.81 ± 9.49 years, range 38–92 years) included 100 patients with HFrEF and T2DM: 47 women (47.00%), 53 men (53.00%); NYHA functional classification: 63 (63.00%) NYHA class II, 18 (18.00%) NYHA class III, 19 (19.00%) NYHA class IV. Patients were prescribed BB in 86 cases (86.00%), diuretics in 70 cases (70.00%), ACEI in 50 cases(50.00%), digoxin in 25 cases (25.00%) and ARB in 19 cases (19.00%). 19 patients (19%) received a combination of beta-blocker+diuretic+ACEI, 15 patients (15%) received a combination of beta-blocker+diuretic+ACEI+digoxin, 11 patients (11%) received a combination of beta-blocker+diuretic and 10 patients (10%) received a beta-blocker alone (Table 1).34 (34%) patients received a combination of 2 drugs, 27 (27%) patients received a combination of 4 drugs, 23 (23%) patients received a combination of 3 drugs and 16 patients (16%) were prescribed monotherapy. Combination therapy included a BB in 76 cases, an ACEI in 49 cases and BB+ACEI in 43 cases.

Conclusions:

In our study, almost two-thirds of patients with HFrEF and T2DM received combination therapy. The most prescribed combination was the association of a beta-blocker, a diuretic and anangiotensin-converting enzyme inhibitor. More than two-thirds of the patients with HFrEF and T2DM received a beta-blocker and a half received an angiotensin-converting enzyme inhibitor (in monotherapy or as part of the combination therapy).
CHOLECALCIFEROL SUPPLEMENTATION AMELIORATES IMMUNE DYSFUNCTION IN OBESE HYPERTENSIVE PATIENTS
Authors: Santos Catarina , Monteiro Andreia , Esgalhado Andre , Fonseca Mafalda , Castelo-Branco Miguel
Published: April 2021

Objective:

Reduction of T regulatory cells (Treg) and upregulation of T helper 17 cells (Th17) contributes to obesity-associated hypertension. Since vitamin D is a modulator of the immune system, we hypothesized that supplementation with cholecalciferol in hypertensive patients may lead to a shift to a more anti-inflammatory immune status.

Design and method:

a 24-week randomized, open, parallel groups clinical trial including 36 patients with hypertension and overweight or obesity was conducted to evaluate the effects of cholecalciferol in peripheral Treg and Th17 cells. Patients were randomized to receive cholecalciferol according serum vitamin D (VD) levels plus usual therapy or usual therapy alone. The levels of Treg and Th17 on week 0 and 24 were obtained as well as body mass index (BMI), waist circumference, serum free VD, lipids, HbA1c, T helper 1 (Th1) cells and monocytes.

Results:

18 men, average age 57.1 ± 5.5 years, BMI 34.5 ± 5.1 Kg/m2 and waist circumference 113.8 ± 10.7 cm. Sixteen patients (44.4%) had grade 1 obesity, seven (19.4%) grade 2 and six (1.6%) grade 3 obesity. The remaining had 7 had 25 < BMI < 30 Kg/m2. All patients were on antihypertensive drugs and mean value of vitamin D at the beginning of the trial was 15.7 ± 5.1 ng/mL. After supplementation serum VD levels rose to 26.9 ± 5.6 ng/mL (p = 0.000) and serum free VD levels from 5.2 ± 1.2 to 6.2 ± 3.3 ng/mL (p = 0.044). At 24 weeks the average ± SD values of the different cells between active and control groups were: Tregs 6.1 ± 1.5 and 6.8 ± 1.8; p = 0.226, respectively, Th17 cells 1.8 ± 0.8 and 2.7 ± 1.2; p = 0.017, Th1 cells 35.4 ± 18.1 and 30.3 ± 9.2; p = 0.299 and monocytes 5.7 ± 1.3 and 6.4 ± 2; p = 0.215.

Conclusions:

in overweight and obese hypertensive patients supplementation with cholecalciferol at regular doses reduces the levels of Th17 cells. Although statistically non-significant a decrease in monocytes was also observed. The reduction of Treg was unexpected, the significance of which should be clarified in future studies.
ANGIOTENSIN II INCREASES FORMATION OF NEUTROPHIL EXTRACELLULAR TRAPS: ROLE IN HYPERTENSION AND DIABETES
Authors: Landry Chloé , Thibodeau Jean -François , Gutsol Alexey , Kennedy Christopher Rj , Burger Dylan
Published: April 2021

Objective:

Endothelial dysfunction plays a central mechanistic role in the pathogenesis of hypertension and diabetes. However, the molecular determinants of endothelial dysfunction are not fully understood. Peptidylarginine deiminases (PADs) irreversibly convert arginine to citrulline in protein, generating neoantigens that are unrecognizable to the immune system. PAD4, an isoform predominantly expressed in neutrophils is upregulated in autoimmune and coronary artery disease. PAD4 activation, in turn, promotes vascular injury through the formation of neutrophil extracellular traps (NETs), networks of chromatin and protein-containing extracellular fibres released to fight infection. Whether PAD4 activity is altered in hypertension and diabetes and whether this contributes to disease pathogenesis is not known. The objective of the present study was to examine the effect of angiotensin II on formation of neutrophil extracellular traps in vitro and in an animal model of hypertension and diabetes.

Design and method:

Neutrophil-like cells were generated from differentiation of the HL-60 cell line and then treated with angiotensin II (10-7 M) for 24 hours. NET formation was assessed by Western blot analysis of citrullinated histone H3 (a primary component of NETs). We further assessed NET formation in mice expressing human renin under the control of the transthyretin promoter (TTRhRen) intercrossed with OVE26 diabetic mice [i.e. hypertensive-diabetic, HD mice] and compared with wild-type (WT) FVBN/J mice. We examined levels of citrullinated histone H3, neutrophil elastase, and PAD4 expression in the kidney of HD and WT mice by immunohistochemistry.

Results:

Treatment of neutrophil-like cells with angiotensin-II increased levels of citrullinated histone H3 by ∼2-fold. Similarly, in HD mice we observed a significant increase in citrullinated histone H3 (P < 0.0001), in neutrophil elastase (P < 0.0001), and in PAD4 protein levels (P < 0.0001) compared with WT. Increased PAD4 activity was associated with the presence of albuminuria, renal interstitial fibrosis and reduced glomerular filtration rate.

Conclusions:

Taken together these data suggest that angiotensin II induces NET formation leading to renal accumulation in hypertension and diabetes. PAD4 may therefore play a role in target organ injury in hypertension and diabetes.
CLINICAL IMPLICATION OF ASSESSING QUANTITATIVE PLASMA CONCENTRATIONS OF ANTIHYPERTENSIVE DRUGS
Authors: Peeters-Kalicharan Laura , Feyz Lida , Daemen Joost , Van Gelder Teun , Koch Birgit , Versmissen Jorie
Published: April 2021

Objective:

Dried blood spot (DBS) analysis is a novel analytical method for therapeutic drug monitoring (TDM) to identify non-adherence to antihypertensive drugs. This study was conducted to evaluate the clinical applicability of measuring drug concentrations of eight antihypertensive drugs, using DBS and venipuncture. Furthermore, this study aimed to provide more insight into the between-patient variability in drug concentrations.

Design and method:

In a previous study a TDM method for eight antihypertensive drugs and four of their metabolites (table 1) was validated in patients assumed to be adherent. The present data was retrieved from this validation study. False negative values from DBS compared to a venipuncture were determined to assess drug adherence. A Generalized Estimating Equation (GEE) was used to assess the influence of covariates including gender, dose, age, weight, and the time interval between drug intake and sampling on the Cplasma (drug concentration in plasma).

Results:

A total of 135 patients (mean age of 59 ± 12 years, 59% male) were included. The number of samples per drug ranged from 38 (enalaprilate) to 85 (hydrochlorothiazide). When drug concentrations from DBS and plasma were compared, no real false negative values were found. A high variability in Cplasma between patients was observed, especially at peak concentrations with a fold change reaching from 2.3 (canrenone) to 35.2 (losartan-carboxylic acid) (table 1). The time of intake was significantly related to the height of the Cplasma in 7 of the 8 measured drugs with a p-value < 0.05 with the exception of hydrochlorothiazide, but the influence of dose, weight, age and sex on drug levels differed largely between the measured drugs.

Conclusions:

DBS is a reliable and convenient method to assess non-adherence to antihypertensive drugs in clinical practice. The Cplasma of the eight antihypertensive drugs in this study show a large inter-individual difference and therefore low plasma concentrations do not necessarily mean non-adherence. Non-adherence can only be confirmed if drug levels are undetectable, i.e. values below the lower limit of detection.
ANTIHYPERTENSIVE EFFECTS AND SAFETY OF ESAXERENONE IN HYPERTENSIVE PATIENTS WITH MODERATE KIDNEY DYSFUNCTION
Authors: Ito Sadayoshi , Itoh Hiroshi , Rakugi Hiromi , Okuda Yasuyuki , Iijima Setsuko
Published: April 2021

Objective:

Mineralocorticoid receptor blockers (MRB) adding to renin–angiotensin system (RAS) inhibitors should be an effective treatment option for the strict blood pressure (BP) control of the hypertensive patients with moderate kidney dysfunction. Esaxerenone is a novel, first non-steroidal MRB with a dose-dependent antihypertensive effect and renal protective potential. We investigated the efficacy and safety of esaxerenone in Japanese hypertensive patients with moderate kidney dysfunction.

Design and method:

Two multicenter, open-label, non-randomized, dose-escalation studies were conducted to assess the efficacy and safety of esaxerenone monotherapy and add-on therapy to RAS inhibitor. Esaxerenone therapy started from 1.25 mg/day, titrated to 5 mg/day and continued until 12 weeks. Primary endpoint was change from baseline in sitting BP. Safety, pharmacokinetics, and urinary albumin-to-creatinine ratios were also evaluated.

Results:

Of 91 patients, 33 received monotherapy and 58 received add-on therapy; mean baseline estimated glomerular filtration rates were 52 and 51 mL/min/1.73m2, respectively. The esaxerenone dose was increased to 2.5 mg/day and above in 100% (n = 33) and 93% (n = 54) of patients receiving monotherapy and add-on therapy, respectively. After the initiation of treatment, significant reduction in sitting SBP/DBP at the end of treatment was observed in both studies (monotherapy: 19/9 mmHg; add-on therapy: 18/8 mmHg; both P < 0.001); 64% and 48% of patients achieved target blood pressure (<140/90 mmHg). The antihypertensive effects were consistent across patient subgroups by age, BMI, and eGFR. The UACR decreased significantly from baseline to Week 12: by 26% in the monotherapy study (P < 0.01) and 29% in the add-on therapy study (P < 0.001). An increased serum K+ level of 5.5 mEq/L and above occurred in 7 patients (12%) receiving add-on therapy, but in none receiving monotherapy. All increases in serum K+ were transient and no patient met predefined serum K+ level criteria for dose reduction or therapy discontinuation. No patient discontinued treatment due to kidney function decline.

Conclusions:

Esaxerenone demonstrated sufficient antihypertensive effects and was well tolerated in hypertensive patients with moderate kidney dysfunction, both as monotherapy and add-on therapy to a RAS inhibitor.
AGE-SPECIFIC ACUTE CHANGES IN CAROTID-FEMORAL PULSE WAVE VELOCITY DURING HEAD-UP TILTING
Authors: Pucci Giacomo , Avolio Alberto , Spronk Bart , Tap Lisanne , Vaudo Gaetano , Anastasio Fabio , Van De Meiracker Anton , Mattace-Raso Francesco
Published: April 2021

Objective:

Hydrostatic blood pressure (BP) gradient following changes in body posture may generate concomitant, age-dependent, increases in aortic stiffness. We analyzed the relationship between BP gradient, measured during head-up body tilting, and related changes in carotid-femoral pulse wave velocity (cf-PWV) at different age ranges, with the aim to separate the BP-dependent and BP-independent components of cf-PWV.

Design and method:

cf-PWV and other hemodynamic parameters were measured in 30 healthy individuals during head-up tilting at 0°, 30° and 60°. BP was taken at the upper arm, constantly kept at heart level. Aortic BP was reconstructed from radial tonometry (SphygmoCor). Stiffness index β0 was estimated at 0° (Spronck et al, J Hypertens 2017;35:98–104). We assumed that: from MRI studies (Sugawara et al, Am J Hypertens. 2016;29:1237–1244), the effective cf-PWV travel distance (ETD, 80% of straight carotid-to-femoral distance) begins at heart level; the change in DBP along the aorta is predictable from the hydrostatic pressure gradient (0.73 mmHg/cm, Gavish et al, J Hypertens. 2011;29:2099–2104); cf-PWV and hydrostatic pressure relate linearly, hence predicted cf-PWV can be calculated as the average of aortic (using β0 and aortic DBP) and femoral (using β0 and femoral DBP, corresponding to aortic DBP + (ETD x sin(α)∗0.73)) PWVs.

Results:

cf-PWV and peripheral SBP increases during head-up body tilting were different between age groups, being more pronounced in the “old” (>45 years) vs “young” group (both p for interaction <0.05), whereas both central and peripheral DBP changes were not influenced by age (Figure, panel left). Central SBP was not affected by tilt angles. When cf-PWV gradient measured by applanation tonometry (observed), was compared with that predicted from estimated DBP gradient (predicted), the difference in observed-vs-predicted PWV gradient increased non-linearly as a function of age (R2 for quadratic trend=0.38, p < 0.01, p vs linear=0.04, Figure panel right).

Conclusions:

Under a hydrostatic pressor gradient, the pulse wave travelling along the aorta undergoes positive acceleration which, for any given pressor change, increases non-linearly as a function of age. The evaluation of aortic pulse wave acceleration induced by pressor gradient may be of clinical relevance as a marker of vascular ageing.
A HIGH ALDOSTERONE TO RENIN RATIO MEDIATES MICROVASCULAR AND MACROVASCULAR DAMAGE IN NEWLY-DIAGNOSED, TREATMENT-NAÏVE ESSENTIAL HYPERTENSION
Authors: Mahmud Azra , Barhoumi Tlili , Aklabi Ali A. , Feely(Late) John , Silke Bernard
Published: April 2021

Objective:

The role of aldosterone in hypertension was generally considered in the context of primary hyperaldosteronism, an uncommon condition (less than 2% in the hypertensive population). However, based on an increased ambulant aldosterone-to-renin ratio (ARR), a marker of inappropriate aldosterone activity, the prevalence of primary hyperaldosteronism in the hypertensive population may be as high as 10% to 15%. There is increasing evidence to suggest a BP-independent effect of aldosterone on left ventricular structure, increased collagen deposition with fibrosis, diastolic dysfunction and arterial stiffness. We hypothesized that aldosterone and renin will be associated with microvascular and macrovascular alterations in never treated essential hypertension.

Design and method:

We prospectively studied newly diagnosed, untreated essential hypertensive and normotensive subjects (n = 1482, 47% females, mean age 51 ± 0.77, SEM). Pulse wave velocity (PWV), augmentation index (AIx), aortic systolic BP and pulse pressure amplification were measured with applanation tonometry(SphygmoCor). Albumin-creatinine ratio, urine sodium and potassium concentrations were determined from spot urine samples. Laboratory tests included serum creatinine and clearance, plasma renin activity, serum aldosterone, and high-sensitivity C-reactive protein(hs-CRP). Aldosterone to renin ratio(ARR) was divided into tertiles. Results were analysed using JMP Pro(Version 13, SAS for Windows). The patients gave informed consent and the study had Institutional ethics committee permission.

Results:

The top ARR tertile was associated with the highest levels of brachial BP, aortic systolic BP, AIx, pulse pressure amplification and PWV(P < 0.001 for all). Stepwise regression analysis showed that the positive association between PWV and increasing ARR tertiles remained significant after adjustment for BP, age and other potential confounders(R2 = 0.39, p < 0.05). The top ARR tertile was also associated with high potassium and low sodium urinary excretion, high ACR, low creatinine clearance and high hs-CRP (All p < 0.01).

Conclusions:

In untreated hypertensive subjects with mild to moderate hypertension, there are significant interactions between ARR and indices of microvascular and macrovascular damage. Our findings indicate that aldosterone and renin adversely modulate microvascular and macrovascular function very early in the evolution of hypertension. While aldosterone antagonism is recommended currently for treatment-resistant hypertension, our findings suggest that it should be initiated early in hypertension.
KEEP THE FIRST READING: AN ARGUMENT FOR THE IMPORTANCE OF THE FIRST OFFICE BLOOD PRESSURE READING IN CHILDREN
Authors: Myette Robert , Feber Janusz
Published: April 2021

Objective:

Lately, clinicians are using oscillometric devices with repeated blood pressure (BP) measurements (on the same occasion) to diagnose hypertension in children. It is unclear which of these measurements, or which combination of measurements, is the most predictive of ambulatory hypertension. Our objective was to determine which measurements of office BP correlate best with the 24-hour automated BP (ABPM).

Design and method:

We consecutively enrolled all pediatric patients, aged 1–18 years, who underwent ABPM in the last 3 years at The Children's Hospital of Eastern Ontario; all patients also had 3 consecutive oscillometric office blood pressure readings at the same time. We compared the first, second, and third and the average of all three measurements as well as the average of the last 2 readings with daytime BP from ABPM. All BP readings were converted to Z-scores based on published, normative paediatric data for office and ABPM.

Results:

Two-hundred and forty-five children (male=133) were included in the study. The median [IQR] of first, second and third systolic BP Z-scores (SBPz) were 2.29[1.44,3.21], 1.91[1.13,2.72] and 1.65[0.82, 2.47], respectively, and all were significantly different from one another (p < 0.001). The largest difference/effect size was noted between the first and third measurement of SBPz (Cohen-d 0.51). Similar differences were observed in diastolic blood pressure Z-scores (DBPz), with medians [IQR] of 0.97[0.00, 1.87], 0.77[-0.19, 1.75] and 0.55[-0.37, 1.54] respectively (p < 0.001, Cohen-d between first and third reading 0.32). On multivariate analysis, the only significant predictor of systolic daytime BP was the first office systolic BP reading (p = 0.001, relative importance 43%). Similarly, the only significant predictor of diastolic daytime BP was the first office diastolic BP reading (p < 0.001, relative importance 43%). The first office SBPz and DBPz were also the best predictors of daytime systolic (ABPM SBPz > 1.65) and diastolic (ABPM DBPz > 1.65) hypertension on ROC with area under the curve (AUC) analysis (SBPz AUC = 0.69, DBPz AUC = 0.81).

Conclusions:

We observed significant differences between first, second and third office BP measurements. The first office systolic and diastolic BP readings appear to be the best predictors of ABPM daytime systolic and diastolic BP.
HYPERTENSION PHENOTYPES IN YOUNG INDIVIDUALS DEFINED BY OFFICE, AMBULATORY AND HOME BLOOD PRESSURE MEASUREMENT: PREVALENCE AND ASSOCIATION WITH TARGET ORGAN DAMAGE
Authors: Zeniodi Maria Elena , Ntineri Angeliki , Kollias Anastasios , Servos George , Moyssakis Ioannis , Destounis Antonios , Vazeou Andriani , Stergiou George
Published: April 2021

Objective:

To assess the prevalence of hypertension phenotypes in young individuals defined by combined use of office (OBP), ambulatory (ABP), and home blood pressure (HBP) measurements and their association with target organ damage.

Design and method:

Subjects referred for suspected hypertension and healthy volunteers aged 6-25 years were evaluated with OBP (2–3 visits), 7-day HBP and 24 h ABP monitoring and classified as normotensives (NT), white-coat (WC), masked (MH) and sustained hypertensives (SH). Organ damage was assessed by echocardiographic left ventricular mass index (LVMI), carotid ultrasonography (intima-media thickness [IMT]) and pulse wave velocity (PWV; piezo-electronic principle).

Results:

233 individuals were included (mean age 14.1 ± 4.0 years, 72% males, BMI 23.8 ± 4.6 kg/m2, 31.8% children, 53.2% adolescents, 15% young adults) of whom 189 had LVMI, 123 IMT and 73 PWV measurements. NT/WC/MH/SH were diagnosed in 60.5/14.2/9.9/15.5% of the participants with HBP and 57.9/14.2/12.4/15.5% with ABP (84.9% agreement, kappa 0.74). HBP and ABP gave comparable stratification for preclinical target organ damage according to BP phenotypes, with SH having higher LVMI and PWV than NT (P < 0.01) and a similar trend for IMT (P = 0.07) (Figure).

Conclusions:

HBP and ABP identified similar proportions of BP phenotypes among young individuals. More importantly, SH identified by both methods was associated with more severe organ damage than NT.
GLUCO- AND MINERALOCORTICOIDS SYNERGISTICALLY DOWNREGULATE BKCA CHANNEL TRANSCRIPTION IN VASCULAR SMOOTH MUSCLE CELLS BUT DO NOT AFFECT THE EPOXYEICOSATRIENOIC ACID PATHWAY
Authors: Schneider Holger , Fruehbuss Laura , Sun Jing , Meng Yao , Marques Jair Gonzales , Koletzko Berthold , Schnitzler Michael Mederos Y. , Gudermann Thomas , Beuschlein Felix , Williams Tracy Ann , Reincke Martin
Published: April 2021

Objective:

A major driver of cardiovascular morbidity and mortality in primary aldosteronism (PA) is endothelial dysfunction. Endothelial dysfunction in PA is well established, but the precise mechanism underlying this phenomenon is incompletely investigated. Specifically, the cytochrome P450 monoxygenase (CYP)-dependent epoxyeicosatrienoic (EET) acid pathway has not been studied comprehensively. Promiscuity of mineralocorticoid receptors due to activation by glucocorticoids further complicates understanding of mechanisms.

Design and method:

Primary human coronary artery smooth muscle and endothelial cells were challenged with aldosterone concentrations typically found in primary aldosteronism (1 nM) in a background of physiological cortisol levels (140 nM). In both cell types, we analysed expression levels of transcripts which are vital for the generation and inactivation of EETs as well as their proposed mode of action. Smooth muscle cell responses to EETs were assessed by calcium imaging with Fura2. Release of EETs by aldosterone and cortisol-treated endothelial cells were measured by high-pressure liquid chromatography followed by tandem mass spectrometry.

Results:

Glucocorticoids and mineralocorticoids synergistically reduced BKCa potassium channel transcription in smooth muscle cells. Antagonist studies demonstrated that this effect was predominantly related to glucocorticoid receptor stimulation. The aldosterone-mediated decrease in BKCa mRNA levels was not reflected at the protein level. In line with preserved BKCa protein expression, aldosterone treatment did not affect the calcium response of smooth muscle cells to 14,15 EET stimulation. Endothelial cells challenged with aldosterone showed unchanged mRNA levels of the CYP monoxygenases and epoxide hydrolases, which are relevant for the synthesis and degradation of EETs, respectively. Mass spectrometry of supernatants from acetylcholine-stimulated endothelial cells did not reveal significant differences in concentrations of any of the 4 EET regioisomeres or their respective degradation products (dihydroxyeicosatrienoic acids).

Conclusions:

In endothelial dysfunction related to mineralocorticoid excess, targeting the EET pathway may be a promising therapeutic approach because all constituents of EET signalling appear to be expressed and functionally intact. Soluble epoxide hydrolase inhibition may thus represent a feasible specific therapy of endothelial dysfunction in PA. The effects of glucocorticoids on BKCa channel expression warrant further investigation under conditions such as glucocorticoid co-secretion in PA and Cushing syndrome.
DISTRIBUTION OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) BIOMARKERS IN TREATED HYPERTENSIVE INDIVIDUALS FROM THE GENERAL POPULATION: THE CHRIS STUDY
Authors: Foco Luisa , Poglitsch Marko , Gögele Martin , Pramstaller Peter Paul , Pattaro Cristian
Published: April 2021

Objective:

Renin-Angiotensin-Aldosterone System (RAAS) is a critical target in hypertension management. However, direct quantification of angiotensin I (AngI) and II (AngII) is challenging due to compound instability, and was never attempted in large population-based cohorts before. Recently, a novel high throughput approach for molecular profiling of the circulating RAAS became available. We aimed at assessing AngI, AngII and aldosterone's distributions in individuals under anti-hypertensive drugs (AHDs) in a real-world setting.

Design and method:

We selected 500 participants under AHDs and 300 controls from the Cooperative Health Research in South Tyrol (CHRIS) study, a population-based study from an Alpine rural environment, defining age- and sex-matched groups (N = 100 each). Five groups included individuals under AHDs: (i) plain AngI-converting enzyme inhibitor (ACEi); (ii) ACEi+diuretic; (iii) plain AngII type 1 receptor blocker (ARB); (iv) ARB+diuretic; and (v) plain beta-blocker. Three were control groups: (vi) hypertensive without medication (vii) under non-AHDs, (viii) normotensive. Using RAAS Triple-A testing, a novel liquid chromatography combined with tandem mass spectrometry analysis, we simultaneously quantified aldosterone and equilibrium AngI and AngII, and used them to estimate markers of plasma renin activity (PRA-S pmol/L), ace-activity (ACE-S, [pmol/L]/[pmol/L]) and adrenal function (AA2-Ratio, [pmol/L]/[pmol/L]).

Results:

An evaluation of the first 240 analysed samples revealed specific molecular effects of AHDs, proving the performance of the approach. ACEi and ARB result in compensatory renin up-regulation: PRA-S median (interquartile range) was 54.6 (29.6–86.6) in the pooled controls, 77.4 (49.7–186.4) in ACEi, and 154.6 (55.2–600.4) in ARB (Kruskal-Wallis test p = 0.0001). Using ACEi was associated with suppression of ACE-S, whose median was 5.0 (4.2–6.4) in the pooled controls and 0.3 (0.1–0.6) in ACEi (p < 0.0001). Using ARBs resulted in AA2-Ratio suppression, with a median of 2.3 (1.4–3.9) and 0.7 (0.2–1.7) in the no-medication and ARB groups (p = 0.0001). Combining ACEi or ARB with diuretics was associated with further increase of PRA-S. Data did not support the hypothesis of different aldosterone levels (median = 101.7 pmol/L pooled sample) across groups (p = 0.179).

Conclusions:

Results point to a potential application of angiotensin-based biomarkers in class-specific drug monitoring, and will be further evaluated in the context of personalized treatment and therapeutic biomarkers.