bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
CLINICAL EVENT REDUCTIONS IN HIGH-RISK HYPERTENSION PATIENTS TREATED WITH RENAL DENERVATION: 10-YEAR PROJECTIONS BASED ON 3-YEAR FOLLOW-UP FROM THE GLOBAL SYMPLICITY REGISTRY
Authors: Esler Murray , Cao Khoa , Lobo Melvin , Sharp Andrew S. P. , Kandzari David E. , Mancia Giuseppe , Böhm Michael , Schmieder Roland E. , Pietzch Jan B. 
Published: June 2022

Objective:
Clinical event rates over 3 years have been published for patients with uncontrolled hypertension treated with radiofrequency renal denervation (RDN) in the Global SYMPLICITY Registry (GSR). We estimated 10-year clinical event reductions following RDN vs. a simulated control group without RDN, for two high-risk subgroups and the full GSR cohort.

Design and method:
A Markov model was used to compare projected 10-year clinical events [stroke, myocardial infarction (MI), cardiovascular death (CVD), heart failure (HF), all-cause death (ACD), and a composite of major adverse cardiac events (MACE, calculated as sum of stroke, MI, and CVD)] for RDN patients vs. a hypothetical control for the high atherosclerotic vascular disease risk (ASCVD) subgroup (n = 737; 69 ± 8 years), the type-2 diabetes mellitus (T2DM) subgroup (n = 1,007; 64 ± 10 years), and for all GSR patients (n = 2,651; 61 ± 12 years). The simulated control assumed maintenance of baseline office systolic blood pressure (oSBP) over time. The model was calibrated to 3-year stroke and MI events reported in the GSR and used published meta-regression data to calculate risk reduction based on cohort-specific changes in oSBP from baseline. Relative risks (RRs), events avoided, and numbers needed to treat (NNTs) were calculated at 3 and 10 years, along with the ratio of 10- vs. 3-year projected events avoided.

Results:
10-year MACE events were 35.8% vs. 48.5% (-12.7%, RR = 0.74) for RDN vs. control for all GSR patients, 37.8% vs. 52.4% (-14.6%, RR = 0.72) for the high ASCVD risk cohort, and 40.5% vs. 54.0% (-13.5%, RR = 0.75) for the T2DM cohort. Across all three cohorts, events avoided were highest for stroke and lowest for MI. 10-year NNTs for MACE were comparable between the three cohorts, estimated between 7 to 8. The ratio of model-projected MACE at 10- vs. 3-years was 5.20, 5.46, and 5.03 for the full GSR, high ASCVD risk, and T2DM cohorts, respectively.

Conclusions:
Model-based projections based on 3- year events observed in the GSR suggest meaningful event reductions after treatment with radiofrequency RDN at 10 years that might be up to 5-times higher than the projected events avoided at 3 years under the assumption of maintained treatment effect versus baseline.
PREDICTING LONG-TERM SURVIVAL AFTER AN ISCHEMIC STROKE. THE ESH-STROKE SURVEY
Authors: Wohlfahrt Peter , Krajcoviechova Alena , Jr Otto Mayer , Vanek Jiri , Hlinovsky David , Kielbergerova Lenka , Lanska Vera , Cifkova Renata 
Published: June 2022

Objective:
To identify factors influencing long-term survival after ischemic stroke is of utmost importance. The aim of the present study was to analyze long-term survival and to assess factors associated with increased mortality following ischemic stroke.

Design and method:
Consecutive patients enninlised between March 2009 and January 2012 for their first-ever ischemic stroke in 2 large tertiary hospitals in the Czech Republic were enrolled in this survey.

Results:
In total, 736 patients (mean age 66 ± 11 years; 58% men) were included in this analysis. The cumulative risk of death at 1, 3, 5 and 10 years was 13.6%, 20.8%, 29.3% and 48.3%, respectively. After adjusting for age and gender, patients with discharge systolic blood pressure between 120 and 140 mmHg showed the lowest mortality risk (Figure 1.) Higher age, higher NIHSS on admission and more severe functional impairment, diabetes and current smoking were associated with higher mortality risk, while the reperfusion therapy, and ennin-angiotensin system blockers were associated with a lower mortality (Figure 2).

Conclusions:
Despite several advances in stroke management, the mortality remains high. Timely reperfusion therapy use together with ennin-angiotensin system blockers may decrease the risk of mortality.
INDIVIDUAL ANTIHYPERTENSIVE MEDICATION AND SKIN CANCER RISK: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Heisel Annalena , Vuurboom Mart D. , Daams Joost G. , De Rie Menno A. , Vogt Liffert , van den Born Bert-Jan , Engberink Rik H.G. Olde 
Published: June 2022

Objective:
The use of hydrochlorothiazide has recently been linked to skin cancer in observational studies. This may be explained by its enninnsitising properties, but photosensitivity has also been reported for other antihypertensive drugs. We conducted a systematic review and meta-analysis to compare skin cancer risk among antihypertensive drug classes and between individual blood pressure lowering drugs.

Design and method:
We searched Medline, Embase and the Web of Science and included studies that investigated the association between antihypertensive medication exposure and non-melanoma skin cancer (NMSC) or cutaneous malignant melanoma (CMM). We combined the extracted the adjusted odds ratios (OR) using a random effects model. We performed sensitivity analyses comparing study type, population and studies with and without correction for important covariates.

Results:
We included 37 studies. Diuretics (n = 16,625,573), in particular hydrochlorothiazide (n = 16,068,501), and calcium channel blockers (CCB, n = 13,176,689) were examined more frequently than beta-blockers (n = 94,872) or ennin-angiotensin system inhibitors (n = 2,014,579). Exposure to diuretics (OR 1.33, 95% CI [1.10–1.61]) and CCB (OR 1.06, 95% CI [1.04–1.09]) was associated with an increased risk for NMSC. No antihypertensive drug class was associated with an increased risk for CMM. Within every drug class, at least 1 individual drug was associated with an increased risk for NMSC: nifedipine, hydrochlorothiazide, sotalol, verapamil, enalapril and bendroflumethiazide. Increased NMSC risk was only observed in case-control studies, specific populations (such as non-Hispanic whites, patients with coronary heart disease or veterans) and studies that did not correct for important covariates. No increased NMSC risk was observed in cohort studies, the general population, and studies that did correct for the covariates sun exposure, skin phototype or smoking (Figure). Only 2 out of 37 studies provided information about antihypertensive co-medication. Egger's test revealed a significant publication bias for the subgroup of diuretics and hydrochlorothiazide concerning NMSC (both p < 0.0001).

Conclusions:
Of all antihypertensive drugs, diuretics and calcium channel blockers may be associated with an increased risk of NMSC, but causal inferences remain difficult to make because of substantiation limitation of the available data.
COST-EFFECTIVENESS OF INTENSIVE VERSUS STANDARD BLOOD-PRESSURE CONTROL IN OLDER PATIENTS WITH HYPERTENSION
Authors: Liao Chia-Te , Toh Han Siong , Yang Chun-Ting , Wei Dongmei , Melgarejo Jesus , Chen Zhih-Cherng , Shih Jhih-Yuan , Zhang Zhen-Yu 
Published: June 2022

Objective:
In the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial, Chinese patients aged 60 to 80 years who received intensive systolic blood-pressure control (target, 110 to 130 mmHg) had a significantly lower incidence rate of cardiovascular events than did those who received standard control (target 130 to 150 mmHg). Based on these data, we aimed to examine the lifetime cost-effectiveness of intensive versus standard blood-pressure control from the different healthcare providers’ perspectives.

Design and method:
A microsimulation model was employed to apply STEP treatment effects and medical costs and utility from national sources or published data to a hypothetical cohort of STEP-eligible patients in China. Incremental cost-effectiveness ratio (ICER) against willing-to-pay threshold was used to evaluate whether intensive versus standard blood-pressure control was a cost-effective option. A series of sensitivity, subgroup, and scenario analyses in other countries (the US and UK) were performed to account for the generalisability and uncertainties arising from study assumptions and parameters.

Results:
The ICER values of intensive versus standard blood-pressure control were approximate ¥ 48,000, $32,300, £10,055 per QALY gained from the perspective of healthcare providers in China, the US and the UK. Simulation results indicated that intensive treatment would be cost-effective (54.6% and 70.1% below the willing-to-pay thresholds of ¥ 80,000 and ¥240,000). The scenario analyses presented that intensive treatment would be cost-effective in the US and UK settings (63.9% and 80.4% below the willing-to-pay thresholds of $50,000 and $150,000 in the US; 75% and 82.1% below the willing-to-pay thresholds of £30,000 and £90,000 in the UK)

Conclusions:
In this simulation study, intensive blood-pressure control in the older Chinese population produced fewer cardiovascular events and acceptable costs per QALY gained, commonly below the willing-to-pay threshold. Given the STEP treatment effects in other populations, the cost-effectiveness of intensive blood-pressure control in older patients was likely consistent across different countries.
BALKAN ENDEMIC NEPHROPATHY, PULSE WAVE VELOCITY AND INCREASED TELOMERE LENGTH-ASSOCIATED CARDIOVASCULAR MORTALITY IN PATIENTS UNDERGOING CHRONIC HEMODIALYSIS
Authors: Premuzic Vedran , Toupance Simon , Stipancic Zelimir , Bukal Nikolina , Jelakovic Ana , Brzic Ivan , Benetos Athanase , Jelakovic Bojan 
Published: June 2022

Objective:
Balkan endemic nephropathy (BEN) is characterized with later onset, milder forms of hypertension and lower pulse wave velocity (PWV)). We hypothesized that telomere length (TL) would be longer in BEN patients and associated with lower PWV and less cardiovascular (CV) mortality.

Design and method:
On total 124 hemodialysed (HD) patients (68 BEN, 56 non-BEN; 48.4% men; 65 ± 14 years) were enrolled and followed-up for 25 months. Blood pressure and PWV were determined before mid-week dialysis. TL was determined by telomere restriction fragment analysis.

Results:
Age-sex adjusted TL was significantly longer in the BEN group (7.19 vs 6.79; p < 0.001) despite being significantly older. In the BEN group TL was associated with PWV (beta = -0.373, p < 0.05), and in the non-BEN group with age (beta = -0.680, p < 0.01). In the full-adjusted model of multivariate linear regression analyses significant predictors of TL were systolic BP/PWV, and age in the BEN and the non-BEN group, respectively. BEN patients died significantly less frequently from CV events than non-BEN patients (p < 0.001) and lived significantly longer (log-rank p = 0.04). Patients who died had significantly shorter TL than survivors (p < 0.001). In the Cox Regression analysis older age, diagnosis of non-BEN and shorter TL were determinants of shorter survival in the entire cohort. In the BEN group shorter TL was the only determinant of shorter survival (HR 0.11 [95% CI 0.03, 0.35]). To analyze the diagnostic value of TL for CV mortality we used ROC analysis that revealed TL < 6.21 Kb to be useful for prediction of CV mortality in patients undergoing chronic HD.

Conclusions:
Shorter TL is associated with CV mortality in patients undergoing chronic HD. BEN patients had longer TL and longer survival than other ESKD patients. PWV was significant predictor of TL in BEN patients. This study confirmed our hypothesis that BEN is associated with slower vascular aging.
EPISODES OF HYPOTENSION AND DEGREE OF HBP CONTROL IN THE ELDERLY WITH ANTIHYPERTENSIVE DRUG TREATMENT
Authors: Carbonell Ana M. Piera , Anton Pilar Rodriguez , Carrasco Rodrigo Orellana , Suarez M. Jesus Campomanes , Robert M. Angeles Gavalda , Diaz Miguel Angel Prieto , Lozano Juan Eugenio Forcada , Sanchez Vicente Martín , Rodriguez Angel Diaz , Garrote Juan Antonio Divison , Valdés Ana Patricia Niembre , Carratala Vicente Pallarés 
Published: June 2022

Objective:
To determine the prevalence of episodes of hypotension in the elderly receiving antihypertensive treatment and its relationship with the number of drugs and associated symptoms, during 24-hour blood pressure monitoring.

Design and method:
Multicenter cross-sectional descriptive study in hypertensive patients aged 75 or over. It was designed for a sample of 117 people, calculated for 8% hypotensive episodes, with a 95% confidence interval, 5% precision, and 25% losses.
Non-proportional stratified random sampling was performed, excluding patients with modified antihypertensive treatment in the last month and/or arrhythmias.
Through 24-hour ambulatory blood pressure monitoring, the incidence of hypotensive episodes was observed.
Associated comorbidities, antihypertensive treatment, and sleep quality during ABPM were recorded from the interview and clinical history.
Percentages, means, confidence intervals were obtained and the chi square test was performed in the bivariate analysis.

Results:
Of 117 monitored patients, 100 completed the study, with a mean age of 79.2 years (SD 3.9 years) and 59% women. 91.5% of women and 58.6% of men were overweight or obese. Some type of heart disease was associated with 31% of patients, and 33% had DM2, 38% anxiety-depressive disorder, and vertigo, 16%. 50.8% of the women and 61% of the men did not have good control of the mean TAS figures in the 24-h ABPM. However, DBP was controlled in 84.7% and 80.5% of women and men, respectively. 34% of the patients presented a dipper pattern.
76% of the patients presented at least one episode of hypotension, which was accompanied by symptoms in 11.8% of the cases, with headache and dizziness being the most frequent. No significant association has been observed between the number of antihypertensive drugs and the occurrence of hypotensive episodes.

Conclusions:
Most of the patients presented at least 1 episode of hypotension, rarely being symptomatic and not related to the number of antihypertensives. the low frequency of the dipper pattern, the high prevalence of obesity, and the poor control of systolic blood pressure require greater control of cardiovascular risk in the study population.
META-ANALYSIS OF DEDICATED HEART FAILURE TRIALS EVALUATING THE EFFECT OF SACUBITRIL/VALSARTAN ON MAJOR CARDIAC RHYTHM DISORDERS
Authors: Patoulias Dimitrios , Kassimis George , Katsimardou Alexandra , Imprialos Konstantinos , Stavropoulos Konstantinos , Koutsampasopoulos Konstantinos , Toumpourleka Maria , Siskos Fotios , Papadopoulos Christodoulos , Doumas Michael 
Published: June 2022

Objective:
The important role of major cardiac rhythm disorders in the prognosis of subjects with heart failure (HF) has been discussed extensively. Sacubitril/valsartan has revolutionized treatment strategy for patients with HF with reduced left ventricular ejection fraction (HFrEF), while it is cardiovascular safe -but not efficacious- in patients with HF with preserved ejection fraction (HFpEF). Anti-arrhythmogenic effect of sacubitril/valsartan has been demonstrated in several, recent experimental studies, however the clinical implications of that observations remain largely unknown.

Design and method:
We sought to determine the effect of sacubitril/valsartan compared to active comparator on major cardiac rhythm disorders in patients with HF, pooling data from the dedicated HF outcome trials. We evaluated the following outcomes of interest: atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation and cardiac arrest. The latter outcome was assessed in the light of recent evidence that arrhythmias account for almost 7% of cardiac arrest cases, both in in-hospital and out-of-hospital settings.

Results:
We pooled data from 3 trials in a total of 14,128 enrolled subjects with HF regardless of LVEF, assigned either to sacubitril/valsartan or valsartan.Sacubitril/valsartan compared to valsartan alone did not result in a significant risk reduction for atrial fibrillation (RR = 1.05, 95% CI; 0.89–1.24, I2 = 0%), atrial flutter (RR = 1.01, 95% CI; 0.55–1.86, I2 = 34%), ventricular tachycardia (RR = 0.92, 95% CI; 0.53–1.58, I2 = 32%) and ventricular fibrillation (RR = 0.79, 95% CI; 0.47–1.32, I2 = 0%). However, we demonstrated that sacubitril/valsartan compared to valsartan conferred a significant risk reduction in cardiac arrest by 47% (RR = 0.53, 95% CI; 0.38–0.76, I2 = 0%).

Conclusions:
Therefore, despite the cardiovascular efficacy and safety of sacubitril/valsartan among patients with HF, and its established role in the treatment of patients with HFrEF, it does not prevent major cardiac arrhythmias. However, its preventive role against cardiac arrest is of utmost importance and should be assessed in future randomized controlled trials as a surrogate outcome.