bluuebunny/crossref_metadata_2025_split huggingface dataset:
SALT SENSITIVITY AND HYPERTENSIVE NEPHROPATHY: A LINK TO BE DISCOVERED
Authors: Lanzani Chiara , Simonini Marco , Lorena Citterio , Laura Zagato , Garcia Luz Maria Gonzalez , Francesca Tunesi , Marianna Contursi , Paola Maiucchi , Paolo Manunta 
Published: June 2023

Objective:
Sodium sensitivity is defined as a change in blood pressure depending on sodium intake, which is present in about 30% of the adult population. According to blood pressure variation in salt load test we can classify the population in 3 categories: sodium sensitive (SS), sodium resistant (SR), inverse sodium sensitivity (ISS), based on, respectively, an increase, a non-significant variation or a decrease in the blood pressure values following the administration of sodium. It is reported that SS subjects have, independently from other risk factors, an increased risk of cardiovascular diseases. Moreover, SNPs located in genes related with Na+ metabolism, aldosterone synthesis and tubular sodium reabsorption in the kidney are related to salt sensitivity phenotype. The aim of this study is to analyze the relationship between sodium sensitivity and the development of hypertensive kidney damage in patients with primary hypertension.

Design and method:
A cohort of 712 naïve hypertensive patients were classified for salt-sensitivity using acute saline test (NaCl 308 mEq / 2h / iv).127 patients (follow-up > 5 years- median 11) were selected for the present analysis (SS, n = 40; 0 SR, n = 46; RSS, n = 41).
We analyzed annual decline of the eGFR (CDK-EPI) (Delta-eGFR) and development of microalbuminuria (MicrAlb) as renal outcome. Moreover, genetic polymorphism involved in salt sensitive hypertension has been investigated.

Results:
No differences in Delta-eGFR was observed among the groups. However, SR subjects develop earlier microalbuminuria (p = 0.002) even with an adequate pressure control. Genotypes analysis revealed: polymorphism in CYP11B2 and NEDD4L to be protective against decline in eGFR. For microalbuminuria HSD3B1 and ADD3 seem to be a risk factors, whereas KL, PKD and TRPC6 polymorphism result protective factors.

Conclusions:
Unexpectedly these finding suggests that SR patients are more at risk of developing hypertensive nephropathy than other groups of patients. Moreover genotypes associated with salt sensitivity play different and complex role in kidney damage in hypertension. Improvement in salt sensitivity testing and standardization will be needed to allow all this pathophysiological knowledge to be translated in a clinical setting
DISCREPANCIES BETWEEN DIETARY AND URINE NA/K RATIO CAN BE EXPLAINED BY ALDOSTERONE, CORTISOL AND URINE VOLUME
Authors: Vliet Myrthe van , Zwager Charlotte , Rauh Manfred , Titze Jens , Engberink Rik Olde 
Published: June 2023

Objective:
Increased urine sodium-to-potassium (Na/K) ratio is associated with hypertension and cardiovascular disease. However, we demonstrated that urine Na/K ratio does not accurately reflect dietary Na/K ratio. As rhythmic patterns of sodium storage and release are associated with aldosterone and cortisol levels and previous studies linked tissue sodium accumulation to water conservation, we investigated whether the discrepancy between urine and dietary Na/K ratio could be explained by these factors.

Design and method:
We performed a post-hoc analysis of the long-term sodium balance studies Mars105 and Mars520. Ten healthy participants consumed a diet with known sodium and potassium content. For 105 or 205 days 24-hour urine samples were collected. We calculated the difference between urine and dietary Na/K ratio. A linear mixed-effect model was used to determine whether this difference varied across salt intake levels. Furthermore, we fitted two linear mixed-effect models to explain discrepancies between urine and dietary Na/K ratio. In the first, sodium intake, potassium intake, urine aldosterone and urine cortisol were fixed effects and for each factor random slopes per participant were allowed. In the second, sodium intake, potassium intake and urine volume were fixed effects and for each factor random slopes per participant were allowed. We analysed the salt intake levels 6, 9 and 12 grams separately.

Results:
Urine Na/K ratio underestimated dietary Na/K ratio (median difference -0.21, IQR -0.47 to 0.09). The discrepancy was significantly larger at higher salt intake levels (mean difference -0.11, -0.22 and -0.36 for 6, 9 and 12 grams salt intake, respectively, P < 0.001). At all salt intake levels, higher aldosterone levels were associated with underestimation of the dietary Na/K ratio (Figure 1A). In contrast, higher urine cortisol and higher urine volume were associated with overestimation of the dietary Na/K ratio (Figure 1B and C respectively).

Conclusions:
Sodium intake, aldosterone, cortisol and urine volume can explain the discrepancy between dietary and urine Na/K ratio. These data suggest that tissue sodium accumulation contributes to the inability to estimate dietary intake using the Na/K ratio in a single 24-hour urine collection.
TNF ALPHA INHIBITOR USE AFFECTS BIRTHWEIGHT INDEPENDENTLY OF THE SOLUBLE FMS-LIKE TYROSINE KINASE 1 / PLACENTAL GROWTH FACTOR RATIO IN PREGNANT WOMEN WITH RHEUMATOID
Authors: Kluivers Anna , Witte-Quaak Cornelia H. , Smeele Hieronymus T.W. , Neuman Rugina I. , Saleh Langeza , Visser Willy , Dolhain Radboud J.E.M. , Danser A.H. Jan 
Published: June 2023

Objective:
The use of tumor necrosis factor ↑ (TNF↑) inhibitors in pregnant women with rheumatoid arthritis (RA) improves birthweight, while in women with preeclampsia high levels of soluble fms-like tyrosine kinase 1 (sFlt-1) result in a reduction in birthweight, possibly because binding of placental growth factor (PlGF) to sFlt-1 reduces its activity. Here we studied whether the beneficial effect of TNF↑ inhibitors on birthweight involves a reduction in sFlt-1 and an improved sFlt-1/PlGF ratio.

Design and method:
Levels of sFlt-1 and PlGF were retrospectively determined in each trimester for 158 women enrolled in a prospective study on pregnancy and RA (Preconception Counseling in Active RA study) and treated according to a treatment protocol aimed at minimal disease activity.

Results:
Half (52.5%) of the women used TNF↑ inhibitors during (part of) their pregnancy. There was no significant difference in the levels of sFlt-1 and PlGF or their ratio between TNF↑ inhibitor users and non-users when comparing the biomarker values per trimester. Correction for parity, other drug use (sulfasalazine, prednisone, hydroxychloroquine), trimester, and disease activity score (DAS28CRP) did not alter this outcome. The well-known negative correlation between sFlt-1 and birthweight was observed in women not using TNF↑ inhibitors and became stronger in each subsequent trimester. Remarkably, this association was entirely absent in all trimesters in women using TNF↑ inhibitors.

Conclusions:
TNF↑ inhibitor use by pregnant women with RA does not alter the levels of sFlt-1 and PlGF or their ratio, although it did annihilate the negative correlation between sFlt-1 and birthweight. This indicates that TNF↑ inhibitor use improves birthweight independently of the sFlt-1/PlGF ratio.
EFFECTS OF THE DUAL ENDOTHELIN ANTAGONIST APROCITENTAN ON AMBULATORY BLOOD PRESSURE INDICES IN PATIENTS WITH RESISTANT HYPERTENSION. RESULTS FROM THE PRECISION STUDY
Authors: Schlaich Markus , Weber Michael A. , Bakris George L. , Flack John M. , Lu Wentao , Haskell Lloyd P. , Wang Ji -Guang , Narkiewicz Krzysztof 
Published: June 2023

Objective:
The phase-3 PRECISION trial demonstrated both the safety and the efficacy of aprocitentan to lower office blood pressure (BP) in patients with resistant hypertension. Here, we report on the effects on relevant indices of ambulatory BP measurements (ABPM).

Design and method:
A total of 730 patients with resistant hypertension were randomized to aprocitentan 12.5 mg (n = 243), 25 mg (n = 243), or placebo (n = 244). Paired ABPM results at baseline and week 4 of double-blind treatment were available for n = 174, n = 182, and n = 178 patients, respectively. Changes in 24h ABPM from baseline to week 4 were pre-defined as a secondary endpoint. Here, we analyzed effects on 24h average BP, daytime BP, night-time BP, nocturnal dipping, and BP load. Statistical significance was assessed using the Wilcoxon rank-sum test.

Results:
At week 4, after placebo correction, aprocitentan decreased 24-hour ambulatory SBP (-4.2 mmHg; 95% CI: –6.2, –2.1 for the 12.5-mg dose and –5.9 mmHg; 95% CI: –7.9, –3.8 for the 25-mg dose). The placebo-corrected SBP-lowering was more pronounced during night-time (–5·1 and –7·4 mmHg) compared with daytime (–3·8 and –5·3mmHg) for the 12.5 and 25mg doses, respectively. At baseline, non-dipper rates were 66%, 62%, and 60% for the 12.5mg, 25mg of aprocitentan, and placebo groups, respectively. Non-dippers had a particularly pronounced reduction in night-time systolic BP compared with dippers for both 12.5mg (-11.25 vs -2.79mmHg; p < 0.01) and 25mg of aprocitentan (-13.12 vs -6.29mmHg; p < 0.01). After 4 weeks of treatment, the proportion of non-dippers who had normalization of their dipping pattern was 44%, 40% and 31% for 12.5mg, 25mg of aprocitentan, and placebo, respectively. The change in BP load for both daytime and night-time was more pronounced with both doses of aprocitentan (-18.7/-24.5% for 12.5mg; -20.7/-21.1% for 25mg) compared to placebo (-9.2/-6.6 %; p < 0.001 for all comparisons).

Conclusions:
In patients with resistant hypertension, aprocitentan resulted in substantial ambulatory BP lowering, particularly during night-time. This was associated with reduction in non-dipping rates and BP load. These findings further support the likely clinical benefit of aprocitentan in resistant hypertension.
EFFECT OF BAROREFLEX ACTIVATION THERAPY ON BLOOD PRESSURE: THE BAT-STUDY – A RANDOMIZED SHAM CLINICAL PILOT TRIAL
Authors: Simonsen Rasmus , Vikatmaa Pirkka , Vikatmaa Leena , Groop Per -Henrik , Tikkanen Ilkka , Gordin Daniel 
Published: June 2023

Objective:
To explore the effects of baroreflex activation therapy (BAT) on blood pressure in individuals with refractory hypertension.

Design and method:
This investigator-initiated randomized, double-blinded sham-controlled pilot trial included five Finnish patients with refractory hypertension. Participants were found eligible if they were 18 - 70 years old with a daytime systolic ambulatory blood pressure (ABP) of 145 mmHg or higher, and/or a daytime diastolic ABP of 95 mm Hg or higher. Patients were on 3 or more antihypertensive drugs including a diuretic. A witnessed drug intake prior to ABPM was implemented. The Barostim Neo System was implanted for modulation of the autonomic nervous system by direct electrical stimulation of the carotid baroreceptors. After 1 month following implantation, all participants were randomized to either 8 months of baroreflex activation therapy (BAT-system on) or continuous pharmacotherapy (BAT-system off) followed by continuous BAT-therapy for all participants for 8 months. The complete design is outlined in the Figure. 24-hour ABP-measurements were performed per protocol. The primary outcome was defined as a change in ambulatory systolic blood pressure after 8 months of BAT, compared to pharmacotherapy.
Results and conclusions: After 8 months of follow-up BAT decreased mean systolic daytime blood pressure by 11.8 mmHg in three participants randomized to BAT, while in the two remaining participants randomized to continuous pharmacotherapy mean systolic daytime blood pressure increased by 8.7 mmHg. When pooling all daytime systolic 24-hour ABP-measurements across the entire follow-up, BAT-therapy was associated with a 9.2 mmHg lower mean blood pressure as compared to continuous pharmacotherapy (143.5 mmHg [95% CI:142.2 - 144.9] vs 152.7 mmHg [151.1 - 154.2], P < 0.0001). In linear mixed models with the BAT-system's status as a fixed effect, day-time systolic blood pressure recordings from 24-hour ABP-measurements at baseline and after 8 months of follow-up were compared between individuals on BAT and continuous pharmacotherapy. Here, BAT-therapy was associated with a reduction in mean systolic day-time blood pressure of -11.7 mmHg (P < 0.0001). In conclusion, BAT-therapy may be a promising tool in lowering systolic blood pressure in individuals with refractory hypertension.
Figure. Study design. ABPM = ambulatory blood pressure measurement. Device = Control of Device.
WORKLOAD-INDEXED HYPERTENSIVE RESPONSE TO EXERCISE ACROSS THE HEART FAILURE SPECTRUM
Authors: Pugliese Nicola Riccardo , Biase Nicolò De , Punta Lavinia Del , Balletti Alessio , Armenia Silvia , Buralli Simona , Mengozzi Alessandro , Taddei Stefano , Metra Marco , Pagnesi Matteo , Borlaug Barry A. , Williams Bryan , Masi Stefano 
Published: June 2023

Objective:
Limited evidence is available regarding the impact of workload-indexed hypertensive response to exercise (HRE) in patients at different stages of the heart failure (HF) spectrum.
We evaluated the prevalence, pathophysiologic and prognostic correlates of HRE, evaluated by the systolic blood pressure (SBP)/Workload slope, across the HF spectrum as defined by the American College of Cardiology/American Heart Association.

Design and method:
We prospectively enrolled 58 healthy controls, 201 subjects at risk of developing HF (HF Stages A-B), and 369 patients with a definite diagnosis of HF (Stage C) and either preserved (HFpEF) or reduced (HFrEF) left ventricular ejection fraction. All patients underwent a combined cardiopulmonary-exercise stress echocardiography test. We recorded two SBP measurements for each patient: the first within the first minute of exercise and the last at peak effort. The SBP/Workload slope was calculated as the difference in SBP over the corresponding increment in watts (W): (SBPpeak – SBPfirst)/(Wpeak – Wfirst). In each subgroup, we divided patients according to SBP/Workload slope tertiles, using sex-specific cut-off values; HRE was defined as the highest SBP/Workload slope tertile in each HF stage. A composite of all-cause mortality and hospitalization for cardiovascular reasons was chosen as the primary outcome.

Results:
The median SBP/Workload slope was 0.53 (interquartile range 0.36 - 0.72) mmHg/W and was steeper in women than men in all subgroups. After adjusting for age and sex, SBP/Workload slope in controls was similar to HFrEF but significantly lower than Stages A-B and HFpEF. In all HF stages, patients with HRE showed significantly lower peak oxygen consumption and peripheral oxygen extraction. After a median follow-up of 16 months, HRE was independently associated with adverse outcomes (Hazard Ratio 2.05, 95% confidence interval 1.81 - 5.18). Kaplan-Meier analysis confirmed a worse survival probability in Stages A-B and HFpEF, but not HFrEF. After adjusting for clinical and echocardiographic variables, patients in the highest SBP/Workload tertile had a 47% higher risk of the primary outcome than subjects in the lowest tertile.

Conclusions:
HRE is associated with peculiar pathophysiological features and possibly worse prognosis in patients in the earliest stages of cardiovascular disease and in those with HFpEF.
EMPAGLIFLOZIN IMPROVES IMPAIRED SENSITIVITY OF AFFERENT NEURONS WITH RENAL AXONS
Authors: Rodionova Kristina , Ditting Tilmann , Hilgers Karl F. , Linz Peter , Schmieder Roland E. , Ott Christian , Schiffer Mario , Amann Kerstin , Veelken Roland 
Published: June 2023

Objective:
Afferent renal nerve pathways likely play a role in salt sensitive hypertension. We recently reported that high salt diet (HS) impairs these afferent renal pathways in rats. Now we tested the hypothesis that during HS a decrease in sensitivity of renal afferent neurons is prevented by the SGLT2 inhibitor empagiflozin.

Design and method:
Respective groups of rats were put on HS containing 8% NaCl or a normal diet. Two groups (HS, controls) received empagiflozin 20 mg/kg BW/day orally. Renal neurons were retrogradely labeled with DiI. In culture, labeled dorsal root ganglion neurons (DRG Th11-L2) with renal afferents were investigated electrophysiologically using current clamp mode to assess action potential generation during current injection. Neurons were characterized as tonic highly active ( less than 5 action potentials, AP) and phasic less active neurons (more than 5 AP upon stimulation).

Results:
In neurons from rats on HS, the relation of tonic highly active neurons to less active phasic neurons shifted consistently towards phasic units (63,8% tonic neurons in controls vs. 42%* on HS, *p < 0.05, z-test). However, continuous treatment with empagiflozin preserved the proportion of tonic neurons as in controls (67,9% on HS with concomitant administration of empagiflozin). In controls, empagiflozin did not affect the proportion of tonic to phasic neurons (63,8% tonic neurons in controls vs. 67,9% on HS & empagliflozin, p = 0.7, z-test). Blood pressure and heart rate were not altered by HS and/or treatment with any chosen dose of empagiflozin.

Conclusions:
In rats, chronically elevated sodium intake (8% NaCl) reduced the sensitivity and stimulability of renal afferent DRG neurons. Under these circumstances, concomitant treatment with the SGLT2 inhibitor empagiflozin preserved the function of renal afferent DRG neurons. SGLT 2 inhibitors may help to treat dysfunction of renal innervation in cardiovascular disease.
LINEAR AND NON-LINEAR HEART RATE VARIABILITY INDICES AT REST AND IN RESPONSE TO PHYSICAL AND MENTAL STRESS: A COMPARATIVE STUDY BETWEEN HEMODIALYSIS AND PERITONEAL DIALYSIS PATIENT
Authors: Faitatzidou Danai , Dipla Konstantina , Theodorakopoulou Marieta , Koutlas Aggelos , Sampani Erasmia , Tsitouridis Alexandros , Dimitriadis Chrysostomos , Pateinakis Panagiotis , Zafeiridis Andreas , Papagianni Aikaterini , Sarafidis Pantelis 
Published: June 2023

Objective:
Cardiac arrhythmias and sudden death are the leading causes of cardiovascular mortality in end-stage-kidney-disease(ESKD). Autonomic dysfunction contributes to the arrhythmogenic background of ESKD patients. This is the first study to compare linear and non-linear heart-rate-variability(HRV) indices between hemodialysis(HD) and peritoneal(PD) patients, both at rest and in response to mental- and physical-stimulation maneuvers.

Design and method:
Thirty-four HD and 34 PD patients matched for age, sex, and dialysis-vintage, as well as 17 age- and sex-matched controls were studied. Autonomic function was examined by linear and non-linear-HRV indices. Heart-rate was recorded continuously with Finometer-PRO at rest and during orthostatic, mental-arithmetic, sit-to-stand, and handgrip-exercise tests.

Results:
No significant between-group differences were observed in resting HRV indices(RMSSD: HD:57.1 ± 81.1 vs PD:69.6 ± 113.4ms; p = 0.792) except for DFA-a1 index(HD:0.87 ± 0.40 vs PD:0.70 ± 0.20, p = 0.047). All HRV indices during the mental arithmetic test (RMSSD HD:128.2 ± 346.0 vs PD:87.5 ± 150.0ms; p = 0.893) and the physical stress tests were similar between HD and PD patients. Both dialysis groups presented similar patterns of HRV responses to orthostatic and handgrip exercise tests; however, after the sit-to-stand test RMSSD, SD1, SD2 and DFA-a2 indices were higher compared to rest only in HD patients(RMSSD: 57.1 ± 81.1 vs 126.7 ± 185.7ms, p = 0.028), suggesting a greater difficulty of HD patients in recovering normal ANS function following a physical stress-test.

Conclusions:
HRV indices at rest and after mental and physical stimulation did not differ between HD and PD patients, however the ANS response following the sit-to-stand test was more impaired in HD. These findings suggest that ANS dysfunction is not largely affected by dialysis modality but small differences in normal ANS recovery may exist.
PATIENT PREFERENCES IN PHARMACEUTICAL AND DEVICE-BASED TREATMENTS FOR UNCONTROLLED HYPERTENSION
Authors: Kandzari David , Weber Michael A. , Poulos Christine , Cohen Sidney , Debruin Vanessa , Pathak Atul 
Published: June 2023

Objective:
Radiofrequency renal denervation (RDN) safely reduces high blood pressure (BP) in hypertensive (HTN) patients. Patient preference regarding such a treatment over antihypertensive (AH) drugs for uncontrolled HTN is poorly understood.

Design and method:
A recent discrete choice experiment (DCE) study in patients with uncontrolled HTN identified the reduction in systolic BP as the most important driver of patient preference between interventional treatments (e.g. RDN) or drugs. Using a predictive model consisting of the preference weights for safety and efficacy attributes from the DCE study, we calculated patients’ treatment preferences in 3 typical clinical scenarios in HTN management. Each scenario presented a choice to either initiate/increase AH drugs, or to have interventional treatment such as RDN: (1) AH drug naïve: initiate AH drugs vs. interventional treatment (2) mild-moderate HTN, 1-3 AH drugs: increasing AH drugs vs. intervention with no drug changes, (3) severe HTN (systolic BP >150mmHg, >3 AH drugs): increasing AH drugs vs. intervention with no drug changes.
In each scenario, the average predicted probability of choosing one treatment over the other was calculated based on a benefit-risk profile from the sum of preference-weighted treatment attributes (type of treatment, changes in AH drugs, office systolic BP reducing efficacy, effect duration, risk of drug side effects, interventional treatment adverse events). Values of the treatment attributes were derived from the literature, expert opinion, and published RDN studies (SPYRAL HTN OFF-MED, ON-MED, Global SYMPLICITY Registry).

Results:
In (1), 17% preferred interventional treatment without drugs vs 83% preferred initiation of drugs. In (2), 24% preferred interventional treatment without increasing drugs vs 76% preferred increasing drugs. In (3), 45% preferred interventional treatment without increasing drugs vs 55% preferred increasing drugs. Preference differences were driven by the magnitude of office systolic BP reductions with each treatment. Risks of treatment-related adverse events were less important to treatment choices.

Conclusions:
Preference for RDN ranged from one-fifth to one-half of patients depending on clinical scenario. The increase mirrored the extent of prior treatment with AH drugs and HTN severity on drugs. Patient preference was driven predominantly by efficacy and minimally by safety of treatment.