bluuebunny/crossref_metadata_2025 huggingface dataset:
AMBULATORY BLOOD PRESSURE MONITORING: A NEW DIAGNOSTIC APPROACH FOR DETECTION OF HYPOTENSION IN REFLEX SYNCOPE (SYNABPM 1 STUDY)
Authors: Rivasi Giulia , Groppelli Antonella , Brignole Michele , Soranna Davide , Zambon Antonella , Bilo Grzegorz , Pengo Martino , Sharad Bashaaer , Hamrefors Viktor , Rafanelli Martina , Testa Giuseppe Dario , Rice Ciara , Kenny Rose Anne , Sutton Richard , Ungar Andrea , Fedorowski Artur , Parati Gianfranco
Published: June 2022

Objective:

Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. We hypothesized that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM.

Design and method:

We conducted a retrospective analysis comparing ABPM data from reflex syncope patients and controls, matched by average 24-hour SBP, age, sex and hypertension. Patients with constitutional hypotension, orthostatic hypotension, predominant cardioinhibition or competing causes of syncope were excluded. Daytime and night-time SBP drops (<110, 100, 90, 80 mmHg) were assessed. Hypotensive susceptibility was defined likely or possible for cut-offs achieving the highest sensitivity among those with specificity > 90% and 80–90%, respectively. Findings were validated in an independent sample.

Results:

In the Derivation cohort, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drop < 90 mmHg provided the best diagnostic yield (91% specificity, 32% sensitivity, Odds Ratio [OR] = 4.6, p = 0.001). Two or more-daytime drops < 100 mmHg achieved 84% specificity and 40% sensitivity (OR = 3.5, p = 0.001). Results were confirmed in the Validation cohort: one or more daytime SBP drop < 90 mmHg provided 94% specificity and 29% sensitivity (OR = 6.2, p < 0.001), while two or more daytime SBP drops < 100 mmHg achieved 83% specificity and 35% sensitivity (OR = 3.5, p < 0.001)

Conclusions:

SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.
PREVALENCE AND PREDICTORS OF NOCTURNAL BLOOD PRESSURE DIPPING IN CHRONIC KIDNEY DISEASE
Authors: Motiejunaite Justina , De Pinho Natalia Alencar , Arnoult Florence , Tabibzadeh Nahid , Vrtovsnik Francois , Flamant Martin , Vidal-Petiot Emmanuelle
Published: June 2022

Objective:

Management of blood pressure (BP) in chronic kidney disease (CKD) is critical for preventing cardio-renal complications. Information on nocturnal BP decrease patterns (dipping) in CKD is still scarce. We aimed at describing nocturnal BP dipping patterns and its predictors in patients with CKD.

Design and method:

We analysed data from patients with CKD stages 1 to 5 referred for kidney function testing from September 2006 to January 2022, including 24-hour urine collection, gold-standard measurement of glomerular filtration rate (GFR) using clearance of a radioisotopic tracer, as well as ambulatory BP measurement (ABPM) in a single tertiary hospital in Paris, France. A total of 1177 ABPM were available in 642 participants. The magnitude of dipping was calculated as the difference between day- and night-time systolic BP (SBP), in percentage of daytime SBP. Factors associated with a less than 10% dipping were analysed with adjusted logistic regression models including a random intercept to deal with clustering of measurements within patients.

Results:

Participants (mean age 56 ± 15 years; 35% female, mean GFR 49 ± 21 mL/min per 1.73 m2) consisted of 8% extreme-dippers (> = 20%), 37% dippers (10% to < 20%), 40% non-dippers (0% to < 10%), and 15% reverse-dippers (<0%). The prevalence of non- or reverse- dipping increased with CKD severity, from 36% in CKD stage 1 to 65% in CKD stages 4–5 (Figure). Non or reverse dipping was independently associated with measured GFR (odds ratio [OR, 95% confidence interval] per 10 ml/min/1.73m2 decrease = 1.16 [1.06 – 1.26], p = 0.001), daytime ambulatory SBP (OR per 10 mmHg decrease = 1.17 [1.06–1.28], p = 0.001), African origin (OR = 1.56 [1.04 – 2.34], p = 0.03) and 24 h Na/K (OR per 1-unit increase = 1.20 [1.06 – 1.37], p = 0.006).

Conclusions:

The prevalence of nocturnal non-or reverse dipping BP profiles increases substantially across the spectrum of CKD. Measured GFR, African origin, ambulatory daytime SBP and 24-hour urinary sodium to potassium ratio are independent predictors of abnormal nocturnal BP decrease and thus may help in cardiovascular risk stratification in this population. More research is needed on whether nocturnal dipping may be a treatment target to reduce cardiorenal complications.
ORTHOSTATIC HYPERREACTIVITY AND THE CARDIOVASCULAR RISK IN JUVENILE AND MIDDLE-AGE HYPERTENSION
Authors: Palatini Paolo , Mos Lucio , Rattazzi Marcello , Vriz Olga , Saladini Francesca
Published: June 2022

Objective:

The prognostic significance of orthostatic hypertension (BP) in young individuals is still controversial. This study aims to evaluate the association of hyperreactivity to standing with major adverse cardiovascular and renal events (MACE) in a cohort of young-to-middle-age subjects.

Design and method:

This investigation was performed in 1207 untreated stage 1 hypertensive subjects with a mean age of 33.1 ± 8.6 years. Supine and standing BPs were measured during two visits performed two weeks apart. At each visit, three supine BP measurements and three orthostatic measurements were taken at 1-minute intervals. The orthostatic BP response to standing was calculated as the average of the standing-lying BP differences obtained during the two visits. Hyperreactors to standing were defined people with a standing-supine systolic BP difference in the top decile (>6.5 mmHg). The mean difference in the whole group was -2.5 ± 7.3/4.6 ± 5.4 mmHg. In 630 participants 24 h urinary epinephrine was measured.

Results:

Hyperreactors to standing were more frequently smokers (p = 0.003) and coffee drinkers (p = 0.05), and had higher 24 h urinary epinephrine (118.4 ± 185.6 versus 77.0 ± 90.1 nmol/mol, p = 0.005). Hyperreactors also had a greater orthostatic response of diastolic BP (p < 0.001). Ambulatory hypertension evaluated with 24-hour recordings was more common in Hyperreactors than Normoreactors (90.8% versus 76.4%, p = 0.001). During a 17.2-year follow-up, 105 MACE were accrued. In multivariate Cox analysis adjusted for age, gender, parental history of cardiovascular disease, smoking, alcohol drinking, coffee use, physical activity habits, body mass index, office systolic and diastolic BP, postural diastolic BP change, office heart rate, serum glucose, and total cholesterol, Hyperreactors to standing had an almost doubled risk of MACE compared to Normoreactors with a hazard ratio of 1.97 (95%CI, 1.10–3.52). Hyperreactivity remained an independent predictor of MACE even when ambulatory BP data and incident hypertension during follow-up were included in the Cox model (hazard ratio: 1.94; 95%CI, 1.10–3.44).

Conclusions:

Our data indicate that in young-to-middle-age hypertensive subjects an exaggerated systolic BP response to standing is associated with sympatho-adrenergic hyperreactivity and is an independent predictor of MACE. Orthostatic BP assessment gives the advantage of simple acquisition and future guidelines should encourage measurement of BP on standing in young individuals.
PROGNOSTIC CUTOFF OF TRIGLYCERIDES PREDICTING CARDIOVASCULAR OUTCOME IN A LARGE REGIONAL-BASED ITALIAN DATABASE
Authors: Tikhonoff Valerie , Casiglia Edoardo , Virdis Agostino , Barbagallo Carlo , Cirillo Massimo , Desideri Giambattista , Ferri Claudio , Galletti Ferruccio , Grassi Guido , Giannattasio Cristina , Iaccarino Guido , Mazza Alberto , Muiesan Maria Lorenza , Palatini Paolo , Parati Gianfranco , Pontremoli Roberto , Verdecchia Paolo , Volpe Massimo , Ungar Andrea , Borghi Caludio
Published: June 2022

Objective:

Searching for a prognostic cut-off value of triglycerides (TG) in predicting cardiovascular (CV) outcome in a large regional-based Italian database of men and women.

Design and method:

A nationwide multicentre database collects data on subjects aged 18 to 95 years recruited on a regional community basis from all the territory of Italy with at least 1 measure of TG and a mean follow-up of 110.1 ± 64.3 months. A total of 18,784 subjects were included in the analysis. CV outcome was defined on the basis of ICD10 codes and double-checked with general practitioners and hospital files. Multivariate dichotomic Cox regression models having CV outcome as dependent variable, adjusted for age, sex, serum uric acid, body mass index, total and HDL-cholesterol, arterial hypertension, diabetes, chronic renal disease, smoking habit, use of antihypertensive and lipid lowering drugs were preliminarily used to search for an association between TG log-transformed as a continuous variable and CV event. The conventional cut-off value of TG (150 mg/d) and the prognostic cut-off value of TG identified by means of receiver operating characteristics (ROC) curves, both able to discriminate between subjects developing a CV event, were used as independent predictors in further multivariate Cox models adjusted for the confounders listed above.

Results:

During 172,329 person-years of follow-up, 1910 participants experienced CV events (11.1 per 1000 age-adjusted person-years). In Cox analysis, TG as a continuous variable was a significant predictor of CV event [odds ratio, OR, 1.189 (1.060–1.334), p = 0.003]. ROC curve showed that > 105 mg/dl (95%CI 75.8–129.3, sensitivity 61.7, specificity 48.8, p < 0.0001) was the prognostic cut-off value for CV event. The conventional cut-off (150 mg/dl) and that identified by ROC curve (105 mg/dl) were both accepted as multivariate predictors in separate Cox analyses, the hazard ratios being 1.157 (95%CI 1.037–1.290, p = 0.009) and 1.137 (95%CI 1.023–1.263, p = 0.016), respectively. Nevertheless, we observed that cut-offs of TG between 89 and 105 mg/dl, when played in the multivariate Cox analyses, seems to be protective as well.

Conclusions:

In conclusion, lower than expected prognostic cut-off value of TG for CV event do exist.
ASSOCIATION OF CEREBRAL OXYGENATION DURING EXERCISE WITH TARGET ORGAN DAMAGE IN HYPERTENSIVE AND NORMOTENSIVE INDIVIDUALS
Authors: Triantafyllou Georgios , Triantafyllou Areti , Dipla Konstantina , Zafeiridis Alexandros , Koletsos Nikolaos , Zafeiridis Andreas , Gkaliagkousi Eugenia , Douma Stella
Published: June 2022

Objective:

To investigate whether indices of cerebral oxygenation during exercise correlate with subclinical markers of target organ damage (TOD), namely carotid intima-media thickness (cIMT), arterial stiffness, and retinal vessel diameter in newly diagnosed hypertensives and healthy individuals.

Design and method:

Hypertension was diagnosed using 24-hour ambulatory blood pressure (BP) monitoring. Patients with white coat or masked hypertension were excluded. Cerebral oxygenation was measured continuously during a three-minute isometric hand grip exercise at 30% of maximal voluntary contraction using near infrared spectroscopy. The average response during exercise in oxygenated-hemoglobin (O2Hb), deoxygenated-hemoglobin (HHb), and total-hemoglobin (tHb, reflecting changes in regional blood volume) were examined. CIMT was measured using ultrasound, arterial stiffness was estimated with augmentation index and pulse wave velocity, and retinal vessel diameters were estimated by the central retinal arteriolar (CRAE) and vein (CRVE) equivalent and retinal arteriovenous ratio (AVR). Univariate analyses were performed and partial correlation was used to account for traditional cardiovascular risk factors to identify independent associations between cerebral oxygenation indices and TOD.

Results:

Fifty-two newly-diagnosed, never treated hypertensives and 41 healthy normotensive individuals with no known medical history of any other disease were included in our study. There were no differences in anthropometric and laboratory variables between groups except for their BP levels, as expected by study design. Mean cIMT was negatively correlated with the average exercise response in cerebral oxygenation (rhoO2Hb = -0.348, pO2Hb = 0.001; rhotHb = -0.253, ptHb = 0.02). Augmentation index was negatively correlated with cerebral-oxygenation during exercise (rhoO2Hb = -0.374, p < 0.001; rhotHb = -0.332, p = 0.02), whereas no significant correlation was observed between pulse wave velocity and cerebral oxygenation indices. In the adjusted analysis, cerebral oxygenation was correlated with central retinal arteriolar diameter (CRAE rO2Hb = 0.233, pO2Hb = 0.043).

Conclusions:

Our novel findings suggest that indices of cerebral oxygenation during a submaximal physical task are associated with markers of early, subclinical target organ damage, namely increased carotid intima-media thickness, arterial stiffness and retinal arteriolar narrowing in a population of newly diagnosed hypertensive individuals.
IMPACT OF SEX AND ANTIHYPERTENSIVE MEDICATION ON GLOBAL COGNITION IN PRIMARY CARE OLDER ADULTS
Authors: De La Colina Adrian Noriega , Vasiliadis Helen-Maria , Berbiche Djamal , Bherer Louis , Kaushal Navin , Girouard Hélène
Published: June 2022

Objective:

The goal of this study is to determine the impact of sex on the effects of different antihypertensive drugs classes, whether in monotherapy or in combination therapy, on the global cognition scores of older adults to identify the most appropriate medication regime in men and women.

Design and method:

This study used the ESA - Services study, consisting of a sample of 1811 older adults (>65 years) recruited in primary care practices in Quebec-Canada. Participants were examined for the Mini-Mental State Examination (MMSE), at three-time points: baseline, + 3 years, and + 4 years. Participants granted access to their provincial health record to assess: hypertension status, time since diagnosis, list of medications, and ptimisesations. Antihypertensives consumed by participants were divided into six categories: Diuretics, angiotensin II receptor blockers, beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, and others. We assessed the changes in MMSE scores during the 4-year follow-up on the six antihypertensive groups per sex. Results were adjusted for age, years of education, and the Carlson Comorbidity Index.

Results:

Women had higher mean MMSE scores than men regardless of their blood pressure status, even though men had more years of formal education (10.65 vs 11.74 years, p < .001). Compared to normotensive individuals, hypertensive women had the highest mean MMSE score at each time point (T1 28.591 (SE .064); T2 28.282 (SE .118); T3 28.524 (SE .119)), while hypertensive men had the worst (T1 28.038 (SE .070); T2 27.694 (SE .125); 27.809 (SE .128)). Women taking angiotensin II receptor antagonists showed the highest MMSE scores (p < .003), and men taking diuretics had the lowest MMSE scores (p < .001) after a 3-year follow-up. Combination therapy of two or three antihypertensives drugs was associated with higher scores in women at T1 and T2 (p < .001). In men, the use of three antihypertensives showed a sharp decrease in MMSE scores from T1 to T3 (p < .001).

Conclusions:

Sex differences in global cognition outcomes in older adults are related to the type and number of antihypertensive drugs used. Effective antihypertensive treatment should consider the impact of sex to ptimise the effect of pharmacological interventions on cognition.
EXCESSIVE PULSATILE POWER IN CAROTID ARTERIES IS ASSOCIATED REDUCED COGNITIVE FUNCTION: PULSATILE AND STEADY STATE ARTERIAL HEMODYNAMICS IN TWO COMMUNITY-BASED COHORTS
Authors: Chuang Shao-Yuan , Wang Jiun-Jr Wang , Lin Chen-Hua , Pan Wen-Harn , Chen Liang-Kung , Wang Pei-Ning , Chen Chen-Huan , Cheng Hao-Min
Published: June 2022

Objective:

Increased pressure and/or flow pulsatility in the carotid arteries have been adversely associated with cerebral structure and function. We postulated that increased power(product of pressure and flow) pulsatility is even harmful to the microcirculation of high-flow organs. We aimed to investigate the associations of carotid pressure, flow, and power pulsatility with cognitive function and pulsatile and steady state hemodynamics in proximal aorta and carotid arteries.

Design and method:

A total 1855 adult aged > = 30 years old were recruited for measurements of echocardiography and carotid sonography. We obtained hemodynamic parameters including pressure, flows, and power at proximal aorta and both carotid arteries. Proximal aortic pressure was determined by the tonometry waveform measured at common carotid arteries, calibrated by mean and diastolic pressure of brachial pressure. Pulsatility indexes(PIs) of pressure, flow and power in the proximal aorta and carotid arteries were calculated as the pulsatile value divided by mean value. We modelled the aorta-carotid interface with a large parent vessel(proximal aorta) branching into small (carotid) and large(distal aorta) daughter vessels and calculated the reflection coefficient and transmitting coefficient from aortic and carotid characteristic impedances. Cognitive function was evaluated by the Montreal Cognitive Assessment (MoCA) score.

Results:

The pulsatile component was 10.3%(105/996mW) and 4.2%(11/268mW) of total aortic and carotid power, respectively. PIs of aortic pressure(r = -0.048,p = 0.0417), aortic flow(r = 0.060,p = 0.0101), aortic power(r = -0.080,p = 0.006), carotid flow(r = -0.085,p = 0.003), and carotid power(r = -0.097,p < 0.0001) were all significantly associated with cognitive function, independent of age, sex, and education. Carotid power PI was significantly better than other PIs in the association with cognitive function. In the multivariable model, MoCA score was positively and negatively associated with carotid mean power (beta = 0.005,p < .0001) and carotid pulsatile power(beta = -0.048,p < .0001), respectively. With increasing aortic characteristic impedance and transmitting coefficient, and decreasing reflection coefficient, there was a significantly increased transmitting aortic power into carotid arteries(all p value < 0.0001).

Conclusions:

Among all ascending aorta and carotid hemodynamics, carotid power PI was the hemodynamic parameter with the best correlation with cognitive function. Increased proximal aortic stiffness, and increased transmission and decreased reflection of the aortic power at the aorta-carotid interface were closely associated with increased carotid pulsatile power.
THE PREVALENCE AND IMPACT OF ISOLATED DIASTOLIC HYPERTENSION IN CHILDREN
Authors: Myette Robert , Obrycki Lukasz , Litwin Mieczyslaw , Seeman Tomas , Feber Janusz
Published: June 2022

Objective:

Isolated systolic (iSH) and combined (SDH) hypertension is associated with increased left ventricular mass index (LVMi). Isolated diastolic hypertension (iDH) is less commonly observed and its impact on LVMi in children is less clear.

To analyze the prevalence of iDH in children (1–18 years), and associations between iDH and BMI Z-score (BMIz) and LVMi.

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

We designed a study to build and validate prediction models based on supervised learning and a conventional scoring system to define the risk of PA in arterial hypertension and tailor the diagnostic workup to the individual risk of each patient.

We developed a clinical score and supervised machine learning algorithms in a retrospective internal cohort of 4059 patients with hypertension, and an external cohort of 584 patients with hypertension. Primary aldosteronism was confirmed by confirmatory tests, in agreement with major international recommendations, and subtype diagnosis was achieved by computed tomography and adrenal vein sampling.

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

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

Objective:

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

Design and method:

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

Results:

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

Conclusions:

Long-term BP variability for 30 years from childhood to middle age was associated with higher risk of subclinical renal damage and albuminuria in adulthood, independent of mean BP or cumulative exposure to BP during follow-up. Identifying long-term BP variability from early age may assist in predicting renal disease and cardiovascular disease in later life.
VARIABILITY OF 24-HOUR URINE SODIUM EXCRETION AND LONG-TERM CARDIOVASCULAR AND RENAL OUTCOME
Authors: Van Maaren Jolan , Esseghir Malik , van den Born Bert-Jan , Vogt Liffert , Engberink Rik Olde
Published: June 2022

Objective:

High sodium intake is an important risk factor for cardiovascular disease, and is often monitored by measuring 24-hour urine sodium excretion. Besides sodium intake, the variability in 24-hour urine sodium excretion has been shown to be mediated by infradian aldosterone and cortisol rhythms. Considering the detrimental cardiovascular and renal effects of aldosterone excess, one may hypothesize that 24-hour urine sodium excretion variability may be associated with long-term cardiovascular and renal disease.

Design and method:

In a retrospective cohort study, we included adult subjects with an estimated glomerular filtration rate (eGFR) > 60 ml/min/1.73 m2 who collected an outpatient 24-hour urine sample between 1998 and 2000, and had collected at least 6 additional 24-hour urine collections during follow-up. We quantified the proportional variability among 7 consecutive 24-hour sodium excretion measurements by calculating the coefficient of variation (CV). We assessed the association between 24-hour sodium excretion variability and cardiovascular (coronary, cerebrovascular event, ospitalised heart failure or mortality) and renal (60% eGFR reduction, dialysis, kidney transplantation or mortality) outcome, using Cox regression analyses with correction for traditional cardiorenal risk factors.

Results:

We included 316 subjects with an average age of 44 years and a mean eGFR of 90 ml/min/1.73 m2. 46% were male, 50% had hypertension and 30% had diabetes. Median follow-up was 16.4 years during which 85 cardiovascular and 131 renal endpoints occurred. The CV for 24-hour urine sodium excretion was 8.3% (SD 1.6). Subjects with a high variability in 24-hour sodium excretion were more often female, had less often diabetes and a lower 24-hour urine sodium-to-potassium ratio. High 24-hour urine sodium excretion variability was associated with worse long-term renal outcome (p = 0.03), which was observed in the female subgroup (p = 0.02) but not in males (p = 0.65) (Figure). No linear association was found for cardiovascular outcome (p = 0.89), but the middle tertile was associated with an increased risk (OR 2.29, 95% CI 1.24–4.25).

Conclusions:

High 24-hour urine sodium excretion variability is associated with an increased risk for long-term renal disease.
TARGETING SIRT1 RESCUES AGE- AND OBESITY-INDUCED HUMAN MICROVASCULAR DYSFUNCTION
Authors: Mengozzi Alessandro , Costantino Sarah , Paneni Francesco , Duranti Emiliano , Taddei Stefano , Virdis Agostino , Masi Stefano
Published: June 2022

Objective:

Experimental evidence suggests a relevant role of SIRT1 in age- and metabolic-related vascular dysfunction. Whether these effects hold true in the human microvasculature is unknown. We aimed to investigate the role of SIRT1 in age- and obesity-related microvascular dysfunction in humans.

Design and method:

Individuals (n = 95) undergoing laparoscopic surgery were stratified by BMI status (above or below 30 Kg/m2) and age (above or below 40 years) and classified as young control (YC), young obese (YO), old control (OC) and old obese (OO). Endothelial function was assessed in small resistance arteries by pressurized micromyography, before and after incubation with a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). We assessed vascular levels of mtROS and nitric oxide availability by confocal microscopy and vascular gene expression of SIRT1 and mitochondrial proteins by qPCR. ChIP assay was employed to investigate SIRT1-dependent epigenetic regulation of mitochondrial proteins.

Results:

Endothelial function showed a graded decrease from YC to OO, with reduced nitric oxide availability and increased mtROS levels. Similarly, SIRT1 and mitochondrial antioxidant proteins (FOXO3 and SOD2) expression levels were reduced while there was a higher expression of pro-oxidant and ageing mitochondria proteins p66Shc and Arginase II. OO, YO and OC endothelial function was rescued by SRT1720 (Figure). The improvement in endothelial function showed a linear relationship with age, BMI and vascular emodelling. The restoration was comparable to the one obtained with mitoTEMPO in the same groups. These effects were explained by SIRT1-dependent chromatin changes leading to reduced p66Shc expression and upregulation of proteins involved in mitochondria respiratory chain: ATP synthase 6, cytochrome B, NADH dehydrogenase 2, NADH dehydrogenase 5.

Conclusions:

Restoring SIRT1 activity rescues obesity and age-related endothelial dysfunction. Its epigenetic control on mitochondrial pathways influences mtROS levels, NO availability, and the expression of the mitochondria respiratory chain proteins. SIRT1 is a novel central regulator of a homeostatic axis connecting vascular phenotype to systemic metabolism and ageing and to exposure to external adverse stimuli. Early targeting of SIRT1 might represent a crucial strategy to prevent the microvascular dysfunction related to age and obesity.