bluuebunny/crossref_metadata_2025_split huggingface dataset:
THE EFFECT OF POTASSIUM SUPPLEMENTATION ON ALDOSTERONE AND BLOOD PRESSURE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: McNally Ryan , Chowienczyk Phil , Farukh Bushra , Faconti Luca 
Published: June 2023

Objective:
Increased potassium intake can reduce blood pressure (BP) particularly in subjects with hypertension by favouring sodium excretion and promoting vasorelaxation. However, potassium intake also stimulates the activity of the renin-angiotensin-aldosterone system (RAAS) which is one of the main homeostatic pathways for BP regulation. This interaction however has not been extensively investigated. Here we perform a systematic review and meta-analysis of clinical trials to assess the effect of subacute potassium supplementation on plasma aldosterone concentration (PAC) and BP in adult individuals.

Design and method:
This systematic review and meta-analysis was carried out in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Three databases were searched: MEDLINE, EMBASE and The Cochrane Central Register of Controlled Trials (CENTRAL). Medical subject headings (MeSH) and non-MeSH terms were used to search the databases for relevant publications. Titles were firstly screened by title and abstract for relevance before full-text articles were assessed for eligibility according to a pre-defined inclusion and exclusion criterion. The keywords used included “aldosterone”, “potassium” and “RAAS”. The review protocol was registered on the PROSPERO database.

Results:
A total of 6395 articles were retrieved (after removal of duplicates) and after title/abstract screening, 124 full-text articles were assessed for eligibility. 38 met the pre-specified inclusion/exclusion criteria of including potassium and PAC (of which 17/38 also reported systolic BP (SBP)). Potassium supplementation caused a significant decrease in SBP (mean difference [95% CI] -3.48mmHg [-4.8, -2.1], P < 0.001) and an increase in both urinary potassium excretion (75.5mEq/day [59.6, 65.5], P < 0.001) and serum potassium (+0.43 [0.22, 0.64] mmol/L, P < 0.001). There was also an increase in PAC (standardised 0.395 [0.271, 0.519], P < 0.001). Meta-regression showed a significant positive correlation between change in PAC and change in urinary potassium (P < 0.001) but not with SBP (P = 0.93).

Conclusions:
In adult individuals, potassium supplementation lead to decrease in BP and increase in serum/urinary potassium and PAC. There is no correlation between the BP-lowering effect and rise in aldosterone.
PROGNOSTIC SIGNIFICANCE OF THE WALL TO LUMEN RATIO OF RETINAL ARTERIOLES EVALUATED BY ADAPTIVE OPTICS IN HUMAN HYPERTENSION
Authors: Ciuceis Carolina De , Rosei Claudia Agabiti , Malerba Paolo , Brami Valeria , Chiarini Giulia , Fama’ Francesca , Rossini Claudia , Gaggero Andrea , Lemoli Matteo , Nardin Matteo , Petelca Alina , Bortoluzzi Chiara , Baresi Mattia , Porteri Enzo , Muiesan Maria Lorenza , Rosei Enrico Agabiti , Rizzoni Damiano 
Published: June 2023

Objective:
Structural alterations in the microcirculation may be considered an important mechanism of hypertension-mediated organ damage. An increased media to lumen ratio of subcutaneous small resistance arteries evaluated with locally invasive techniques (biopsies of subcutaneous fat, micromyography) may predict the subsequent development of cardiovascular events. However, it is not presently known whether structural alterations of retinal arterioles evaluated with a non-invasive approach (adaptive optics) may have a prognostic meaning.

Design and method:
Two-hundred and thirty-seven subjects were included in the present study. They were normotensive subjects (n = 65, 27,4%) and patients with essential hypertension (n = 163, 68,8%) or primary aldosteronism (n = 9, 3,8%). All subjects were submitted to a non-invasive evaluation or retinal arteriolar morphology (evaluation of the wall/lumen ratio: WLR) by adaptive optics. The subjects were re-evaluated after an average follow-up time of 5.5 years on order to assess the occurrence of death or cardio-cerebrovascular events.

Results:
Fifty-four total events occurred in the population enrolled, of which 29 were cardio-cerebrovascular event (ischemic or hemorragic stroke, atrial fibrillation, heart failure, coronary artery disease, peripheral artery disease, including aneurism requiring intervention, cardiac valvular disease) while the remaining were events or deaths for any cause, including neoplastic disease. The event-free survival was significantly less in those with a WLR above the median value of the population (0.28) according to Kaplan-Mayer survival curves and multivariate analysis (p < 0.001 by both the Mantel-Cox test and the Breslow test). Subjects with events had a WLR of retinal arterioles significantly greater than those without events. The evidence was confirmed after restricting the analysis to cardiovascular events, excluding events or deaths of neoplastic origin. The average follow-up time of our subjects was 4.6 ± 1.6 years for a total of 1090 patients-years. Patients with cardiovascular events were older and with more elevated levels of circulating glucose.

Conclusions:
Structural alterations of retinal arterioles evaluated by adaptive optics may predict cardio-cerebral events and total mortality.
THE CLINICAL RELEVANCE OF ADOPTING DIFFERENT DEFINITIONS OF NIGHT-TIME WHEN ASSESSING NOCTURNAL BLOOD PRESSURE
Authors: Hofmann Elisabeth , Küchler Gert , Parati Gianfranco , Bothe Tomas L. , Patzak Andreas , Pilz Niklas 
Published: June 2023

Objective:
For hypertension diagnosis, the current European guidelines recommend to combine repeated office readings with use of out-of-office blood pressure (BP) measurements, like ambulatory blood pressure monitoring (ABPM). The drop of systolic BP during night (dipping behaviour) is one of the most important information offered by 24h ABPM. Night-time is most defined as the time period between 22 and 6 h. However, ambulatory sleep studies have shown that individual sleep behaviour is heterogenous. Shifted, shortened, or prolonged time-in-bed (TIB) may lead to changes in classification of dipping behaviour. Additionally, 20% of the population suffers from insomnia, meaning that during TIB patients are partially awake. We investigated nocturnal BP and dipping classification based on actual sleep time vs. individual TIB vs. 22 - 6 h.

Design and method:
Thirty adults (9 women, mean age 65.1 ± 9.5 years) underwent ABPM via a validated Boso TM- 2430 device. Simultaneously, motor activity and body position were recorded (SOMNOtouch™ NIBP, SOMNOmedics) allowing determination of individual TIB and actual sleep time.

Results:
In nine patients (30%), individual TIB was shifted by more than two hours, usually being shifted towards later hours. Mean duration of TIB was 7:18h (2:13h to 10:08h). Mean sleep efficiency in individual TIB was 85.6% compared to 72.4% in standard 22 - 6 h.
When defining TIB as 22 - 6 h, prevalence of non-dippers was 63% (n = 19). After analysing the corrected TIB, only 37% (n = 11) remained non-dippers. Individual adoption of TIB led to a change in dipping classification in 27% (n = 8) of patients (in all cases from non-dipper to dipper). Considering only BP values during actual sleep, dipping classification changed in another four patients, two patients changing from non-dipper to dipper while two patients changed from dipper to extreme dipper.

Conclusions:
In 12 out of 30 patients (40%), BP dipping classification changed when adjusting TIB individually and considering BP values during actual sleep. This study highlights that individually determined TIB and exclusion of wake phases during night is of critical importance for a correct assessment of dipping behaviour and may play an important role in optimizing the clinical management of arterial hypertension.
MONOCYTE DERIVED CYTOKINES INDUCE ENDOTHELIAL DYSFUNCTION IN PATIENTS WITH PRIMARY ALDOSTERONISM
Authors: Kantauskaite Marta , Wieners Rebecca , Knipping Anika , Rahman Masudur , Duvnjak Blanka , Schmidt Claudia , Srugies Fabian , Rump Lars C. , Stegbauer Johannes 
Published: June 2023

Objective:
Due to aldosterone excess and its pleotropic effects patients with primary aldosteronism (PA) are exposed to high rates of cardiovascular events. Endothelial dysfunction, as a part of vascular disease, is one of the earliest changes related to high cardiovascular risk and monocytes are the main immune cells participating in the development of vascular wall damage. Therefore, we ought to compare endothelial function between PA patients and healthy controls. Next, we wanted to estimate, if monocytes are able to induce endothelial dysfunction solely by their secretome.

Design and method:
13 healthy controls and 42 PA patients received flow mediated dilation measurements (FMD). Later, monocytes were isolated from 8 PA patients and 6 healthy individuals and placed in cell culture. 24 hours later supernatants were collected for cytokine measurements using Human Cytokine 17-plex Assay (Bio-rad). Effects of monocyte derived cytokines on endothelial function were assessed using wire Myograph (Danish Myo Technology). Pre-contraction was induced by norepinephrine (1μM) (Sigma) followed by cumulative concentration response curve to carbachol (0.3μM-300μM) (Sigma).

Results:
FMD was significantly lower among PA patients (6.3(3.8-8.1)% vs 10.5 ± 3%, p < 0.05). Furthermore, monocytes from patients with PA secreted significantly higher concentrations of following cytokines and growth factors than healthy controls: G-CSF, IFN-gamma, TNF-alfa, IL-6, IL-10, IL-8, IL-17, and MCP-1. Especially concentrations of IL-6 (388 (351-580)pg/ml vs 36(4-268)pg/ml, p < 0.05) and TNF-alfa (95(48-135)pg/ml vs 17(5-41)pg/ml, p < 0.05) were much higher among PA patients. Incubation of mouse thoracic aorta with this monocyte secretome for 24 hours revealed stronger vascular contraction than using supernatant from healthy controls. In pre-constricted murine aortas, maximal dilation of 87.9 ± 11% was reached using aortas incubated in PA monocyte secretome whereas a dilation of 90.9 ± 9.1% was reached in controls. Indeed, carbachol EC50 for aortas incubated in monocyte secretome derived from healthy controls was 1.0mkM and 1.9mkM for PA patients.

Conclusions:
PA patients demonstrate endothelial dysfunction measured by FMD. Moreover, monocytes isolated from these patients are characterized by high secretion of pro-inflammatory cytokines which induce endothelial dysfunction, one of mechanisms triggering vascular dysfunction among these patients.
GENETIC DELETION OR PHARMACOLOGICAL INHIBITION OF THE SODIUM AND HYDROGEN EXCHANGER 3 IN THE PROXIMAL TUBULES OF THE KIDNEY ATTENUATES ANGIOTENSIN II AND SALT-INDUCED HYPERTENSION
Authors: Zhuo Jia Long , Li Xiao 
Published: June 2023

Objective:
According to American Heart Association, ∼46% of American adults have hypertension and ∼13 of these patients develop poorly controlled hypertension even treated with >3 - 4 different classes of antihypertensive drugs. The mechanisms underlying poorly controlled hypertension remain incompletely understood. The present study tested the proof of concept hypothesis that the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubules of the kidney may be a therapeutic target of angiotensin II (Ang II) and salt-induced hypertension in mice.

Design and method:
To test the hypothesis, we generated a new mouse model with deletion of NHE3 selectively in the proximal tubules of the kidney using the iL-Sglt2-Cre and Nhe3-floxed approach (PT-Nhe3-/-). Adult male wildtype (WT) and PT-Nhe3-/- mice were infused without or with a low dose of Ang II (0.5 mg/kg/day, i.p., via minipump) and maintained on 2% high salt diet for 2 weeks to induce Ang II- and salt-dependent hypertension. Animals were then treated without or with an absorbable NHE3 inhibitor AVE-0657 for 2 weeks (20 mg/kg/day, p.o., a gift of Sanofi-Aventis).

Results:
Under basal conditions, deletion of NHE3 selectively in the proximal tubules of the kidney decreased basal systolic and mean blood pressure by ∼13 ± 3 mmHg in PT-Nhe3-/- mice (P < 0.01 vs. WT), whereas inhibition of NHE3 primarily in the proximal tubules with AVE-0657 lowered basal blood pressure by ∼7 ± 2 mmHg in WT mice (P < 0.05 vs. control WT). Ang II and high salt treatment significantly increased blood pressure by 26 ± 5 mmHg in WT mice (P < 0.01), which was significantly attenuated in PT-Nhe3-/- mice (P < 0.01). Ang II and salt-induced hypertension in WT mice was also significantly attenuated by NHE3 inhibition in the kidney proximal tubules with AVE-0657 (P < 0.01). Concurrent treatment with losartan, an AT1 receptor blocker (20 mg/kg/day, p.o.), completely lowered blood pressure to control level in WT mice (P < 0.05). AVE-0657 had no further effect on blood pressure in PT-Nhe3-/- mice.

Conclusions:
In conclusion, our results support the proof of concept hypothesis that NHE3 in the proximal tubules of the kidney may be a therapeutic target of Ang II and salt-induced hypertension.
PROGNOSIS OF RESISTANT HYPERTENSION, WHITE-COAT RESISTANT HYPERTENSION, AND REFRACTORY HYPERTENSION
Authors: Sierra Alejandro De La , Ruilope Luis , Gorostidi Manuel , Vinyoles Ernest , Segura Julian , Armario Pedro , Oliveras Anna , Williams Bryan 
Published: June 2023

Objective:
To evaluate total and cardiovascular mortality in different forms of Resistant Hypertension (RH).

Design and method:
A total of 35129 treated patients were included from the Spanish ABPM Registry. Mean follow-up was 10 years. Total and cardiovascular mortality were compared in Cox models adjusted for clinical confounders. The following groups were compared:
- Controlled Hypertension (CH; N = 8146; 23.2%): normal office BP treated with 3 or less antihypertensive drugs vs. RH (N = 9408; 26.8%): elevated office BP treated with 3 or more drugs or normal office BP treated with 4 or more drugs.
- Controlled RH (CRH; N = 831; 8.8%): normal office BP treated with 4 or more drugs vs. Uncontrolled RH (UCRH; 8577; 91.2%): elevated office BP treated with 3 or more drugs.
- Among patients with UCRH, the following groups were compared: True RH (TRH; 5288; 61.7%): elevated (>130/80 mmHg) 24-h BP vs. White-coat RH (WCRH; 3289; 38.3%): normal 24-h BP.
- Refractory hypertension (RefrH; 823; 8.7%): elevated office BP while treated with 5 or more drugs vs. Non-refractory RH (the remaining RH patients).

Results:
Compared to CH, RH was associated with an increased risk in total mortality (HR: 1.22; 95%CI: 1.13 - 1.31) and cardiovascular mortality (1.37; 1.21 - 1.55). Compared with CRH, UCRH was not associated with a significant increased risk in total or cardiovascular mortality. Compared to WCRH, TRH increased the risk of mortality (1.45; 1.32 - 1.60) and cardiovascular mortality (1.68 (1.43 - 1.98). Finally, RefrH also increased the risk of total mortality (1.16; 1.01 - 1.34) and cardiovascular mortality (1.30; 1.05 - 1.62) in comparison to non-refractory RH. Either total or cardiovascular mortality was not increased in WCRH, compared to CH.

Conclusions:
RH increased the risk of total and mortality with respect to CH. Among RH, office BP control does not modify such prognosis, while 24-h BP is a powerful determinant, with a clear increased risk in those with elevated 24-h BP (TRH), compared to those with normal 24-h BP (WCRH). The study confirms the clinical importance of RH, as well as the usefulness of ABPM in stratifying those patients, in order to improve therapeutical efforts to reduce the global risk.
AVERAGE ACHIEVED BP <130/80 MMHG IN HIGH-RISK MIDDLE-AGED AND OLDER HYPERTENSIVE PATIENTS PROVIDES STRONG CARDIOVASCULAR PROTECTION EXCEPT IN LEFT VENTRICULAR HYPERTROPHY
Authors: Heimark Sondre , Mehlum Maria H. , Mancia Giuseppe , Søraas Camilla L. , Liestöl Knut , Kjeldsen Sverre E. , Larstorp Anne C. K. , Rostrup Morten , Mariampillai Julian E. , Wachtell Kristian , Julius Stevo , Weber Michael A. 
Published: June 2023

Objective:
Evidence that reducing blood pressure (BP) to <130/80 mmHg rather than to <140/90 mmHg by antihypertensive treatment in hypertensive patients is conflicting. Left ventricular hypertrophy (LVH) is common in hypertension, and low perfusion pressure may result in ischemia in patients with LVH. We investigated whether average achieved BP <130/80 mmHg implied cardiovascular benefits in high-risk middle-aged and older hypertensive patients who participated in the VALUE Trial. Considering a previous report of excess mortality in LVH patients with in-treatment systolic BP (SBP) <130 mmHg, we paid special attention to whether the average achieved SBP <130 mmHg may cause harm in similar patients with LVH.

Design and method:
Of the 15,245 participants, we identified 13,803 patients without cardiovascular events during the first six months after randomization during which previous medications were discontinued and study drugs up-titrated. Of these, 2,458 patients had LVH on an electrocardiogram (ECG). Cox analyses adjusted for age, gender, and baseline variables compared cardiac and all-cause mortality and other pre-specified endpoints for patients who achieved average SBP 130 - 139 mmHg (No LVH group n = 4,863, ECG LVH group n = 929) and <130 mmHg (No LVH group n = 2,107, ECG LVH group n = 305). Reference groups were patients who achieved an average SBP > = 140 mmHg following the first excluded six months (No LVH group n = 4,375, ECG LVH group n = 1,224).

Results:
The No LVH group with average achieved BP <130/80 mmHg had a significantly lower incidence of all endpoints except for myocardial infarction. The ECG LVH group with average achieved SBP <130 mmHg had increased cardiac mortality (HR = 1.98, p = 0.032) and all-cause mortality (HR = 1.74, p = 0.007), and SBP <130 mmHg was not associated with a reduction in any endpoint. However, as in those without LVH, the ECG-LVH group had fewer strokes and heart failure with an average achieved diastolic BP <80 mmHg.

Conclusions:
Our data suggest that target SBP <130 mmHg may cause harm and needs further investigation in middle-aged and older patients with LVH detected by ECG. Otherwise, the average achieved BP <130/80 mmHg prevents most cardiovascular endpoints in middle-aged and older hypertensive patients with high cardiovascular risk but without LVH.
ROLE OF NATRIURESIS AND FRAILTY IN BLOOD PRESSURE REGULATION IN ELDERLY PEOPLE
Authors: Zagato Laura , Citterio Lorena , Simonini Marco , Tunesi Francesca , Rovere-Querini Patrizia , Manfredi Angelo , Concas Maria Pina , Manunta Paolo , Lanzani Chiara 
Published: June 2023

Objective:
The objective of the study is to investigate, in elderly people, the relationship between natriuresis, frailty and blood pressure (BP).

Design and method:
The FRASNET geriatric population (1204 subjects) is an Italian observational cohort that includes frail (35%), pre-frail (37.3%) and robust (27.7%) subjects. They have been characterised for BP, renal function, sodium intake (by Kawasaki formula), anthropometric data, cognitive status, quality of life, comorbidities, and chronic therapies.
ANOVA and conditional inference tree analyses have been carried out.

Results:
745 participants out of 1203 (60%) were under anti-hypertensive treatment. Increased visceral fat, male sex and lower number of medications taken are risk factors for suboptimal control of BP (71.4%).
An inferential analysis evidenced (Fig. 1) a first node between male and female, a second one according to age (75 y), a third with natriuresis (217 mEq/24h).
Non-frail subjects presented the highest values for both systolic and diastolic BP; the frail group presents systolic BP values below the threshold of 140 mmHg. BPs are negatively correlated with frailty status (systolic p = 0.048, diastolic p <0.001, Figure 2).

Conclusions:
Frailty and blood pressure follow an inverse tendency: the higher the severity of the frail status, the lower the blood pressure.
The relationship between BP and natriuresis is preserved only in young women whereas in very old people (>75 y) is no more present.
This evidence is supported by physiological explanations and suggest to be cautious in salt reduction intake in elderly people.
STABILIZATION OF TELOMERE BY THE ANTI-AGING PROPERTY OF METFORMIN MITIGATES OLEIC ACID-INDUCED ATHEROSCLEROTIC PATHOGENESIS
Authors: Sung Jin Young , Kim Seul Gi , Kang Young Jin , Choi Hyoung Chul 
Published: June 2023

Objective:
Factors associated with the atherosclerotic process, including inflammation, senescence-associated secretory phenotypes and telomere dysfunction are closely linked to senescence in VSMCs. However, whether senescent VSMCs are sufficient to cause atherosclerotic process and whether the phenotypes and risk factors of senescent VSMCs affect atherosclerotic pathogenesis are unclear. We investigated the mechanism of inhibition of atherosclerosis by the anti-aging agent metformin and whether attenuating risk factors senescent VSMCs affects atherogenesis.

Design and method:
We performed in vitro studies including western blot, immunoprecipitation, RT-PCR, flow cytometry, immunofluorescence, FISH analysis, MMP zymography, and transfection of TERT siRNA. In vivo, to test the effect metformin on atherosclerotic lesion formation in ApoE-/- mice, male mice were divided into three groups (each, n = 5). After feeding the high-fat diet for 16 weeks, mice were sacrificed and the formation of atherosclerotic lesions in the aortas and the aortic sinuses were analyzed.

Results:
Oleic acid (OA)-induced atherosclerotic pathogenesis in normal VSMCs showed marked senescence-associated features, manifested as increased b-gal positive cells and phenotypic switching of VSMCs in vitro; however, these phenomena were shown to be reversed by metformin. To determine what mechanism by metformin alleviates atherogenesis and senescent VSMC, we studied in the enhancement of telomere function by phosphorylating AMPK (Ser485) and PGC1 alpha. In our results, metformin showed increased the expression of p-AMPK (Ser485) as well as the phosphorylation of PGC1 alpha-dependent TERT expression and telomerase activity. Importantly, the depletion of TERT did not reduce risk factors for atherosclerosis and aged VSMCs despites metformin treatment in OA-induced atherosclerotic pathogenesis. We also found in the aortas of high-fat diet ApoE-/- mice, metformin treatment significantly attenuated atherosclerotic plaques and senescent VSMCs, and upregulated the expression of p-AMPK (Ser485)/p-PGC1 alpha and the enhancement of telomere function.

Conclusions:
The reduction of atherosclerotic pathogenesis in VSMCs and ApoE-/- mice is associated with significantly inhibited senescent phenotypes and risk factors. Increasing p-AMPK (Ser485)/p-PGC1 alpha by metformin the enhancement of telomere function mitigates senescent risk factors and may be a promising therapeutic strategy in atherosclerosis.