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Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB1R and CB2R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB1- and CB2 receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)—CB1R agonist, rimonabant—CB1R antagonist, John W. Huffman (JWH133)—CB2R agonist and CB2R antagonist—6-Iodopravadoline (AM630). Treatment of cells with the CB2R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB1R inhibition with rimonabant showed similar protective properties as the CB2R agonist JWH133, but to a lesser extent. In conclusion, CB1R and CB2R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB2R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation.

The angiotensin AT2receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system and exerts for instance anti-inflammatory effects. The impact of AT2R stimulation on autoimmune diseases such as rheumatoid arthritis (RA) is not yet known. We investigated the therapeutic potential of AT2R-stimulation with the selective non-peptide AT2R agonist Compound 21 (C21) in collagen-induced arthritis (CIA), an animal model for inflammatory arthritis. Arthritis was induced by immunization of DBA/1J mice with collagen type II (CII). Prophylactic and therapeutic C21 treatment alleviates arthritis severity and incidence in CIA. Joint histology revealed significantly less infiltrates of IL-1 beta and IL-17A expressing cells and a well-preserved articular cartilage in C21- treated mice. In CIA, the number of CD4+CD25+FoxP3+regulatory T (Treg) cells significantly increased upon C21 treatment compared to vehicle. T cell differentiation experiments demonstrated increased expression of FoxP3 mRNA, whereas IL-17A, STAT3 and IFN-gamma mRNA expression were reduced upon C21 treatment. In accordance with the mRNA data, C21 upregulated the percentage of CD4+FoxP3+cells in Treg polarizing cultures compared to medium-treated controls, whereas the percentage of CD4+IL-17A+and CD4+IFN-gamma+T cells was suppressed. To conclude, C21 exerts beneficial effects on T cell-mediated experimental arthritis. We found that C21-induced AT2R-stimulation promotes the expansion of CD4+regulatory T cells and suppresses IL-17A production. Thus, AT2R-stimulation may represent an attractive treatment strategy for arthritis.

Rationale: Hypertension is a major risk factor for cerebral small vessel disease, the most prevalent cause of vascular cognitive impairment. As we have shown, hypertension induced by a prolonged Angiotensin II infusion is associated with increased permeability of the blood-brain barrier (BBB), chronic activation of microglia and myelin loss. In this study we therefore aim to determine the contribution of microglia to hypertension-induced cognitive impairment in an experimental hypertension model by a pharmacological depletion approach.Methods: For this study, adult Cx3Cr1gfp/wtxThy1yfp/0 reporter mice were infused for 12 weeks with Angiotensin II or saline and subgroups were treated with PLX5622, a highly selective CSF1R tyrosine kinase inhibitor. Systolic blood pressure (SBP) was measured via tail-cuff. Short- and long-term spatial memory was assessed during an Object Location task and a Morris Water Maze task (MWM). Microglia depletion efficacy was assessed by flow cytometry and immunohistochemistry. BBB leakages, microglia phenotype and myelin integrity were assessed by immunohistochemistry.Results: SBP, heart weight and carotid pulsatility were increased by Ang II and were not affected by PLX5622. Short-term memory was significantly impaired in Ang II hypertensive mice, and partly prevented in Ang II mice treated with PLX5622. Histological and flow cytometry analysis revealed almost complete ablation of microglia and a 60% depletion of brain resident perivascular macrophages upon CSF1R inhibition. Number and size of BBB leakages were increased in Ang II hypertensive mice, but not altered by PLX5622 treatment. Microglia acquired a pro-inflammatory phenotype at the site of BBB leakages in both Saline and Ang II mice and were successfully depleted by PLX5622. There was however no significant change in myelin integrity at the site of leakages.Conclusion: Our results show that depletion of microglia and PVMs, by CSF1R inhibition prevents short-term memory impairment in Ang II induced hypertensive mice. We suggest this beneficial effect is mediated by the major decrease of pro-inflammatory microglia within BBB leakages. This novel finding supports the critical role of brain immune cells in the pathogenesis of hypertension-related cognitive impairment. An adequate modulation of microglia/PVM density and phenotype may constitute a relevant approach to prevent and/or limit the progression of vascular cognitive impairment.

The frst May Measurement Month (MMM) campaign, a global blood pressure (BP) screening programme, began in 2017 as an initiative of the International Society of Hypertension.1 Two subsequent annual campaigns have also been completed in consecutive years2,3 and having had to defer activities due to the COVID-19 pandemic in 2020 the fourth campaign was run in 2021, the results of which are currently in press. Since its initiation in 2017, volunteers from more than 100 countries have participated. The aims of MMM have remained consistent from the start-to raise awareness of the importance of the measurement of BP at the individual and population level and to provide a temporary pragmatic solution to the shortfall in BP screening programmes in countries around the world.

The aim of the present study was to evaluate the effect of Compound 21 (C21), a selective AT2R agonist, on the prevention of endothelial dysfunction, extracellular matrix (ECM) remodeling and arterial stiffness associated with diet-induced obesity (DIO). Five-week-old male C57BL/6J mice were fed a standard (Chow) or high-fat diet (HF) for 6 weeks. Half of the animals of each group were simultaneously treated with C21 (1 mg/kg/day, in the drinking water), generating four groups: Chow C, Chow C21, HF C, and HF C21. Vascular function and mechanical properties were determined in the abdominal aorta. To evaluate ECM remodeling, collagen deposition and TGF-β1 concentrations were determined in the abdominal aorta and the activity of metalloproteinases (MMP) 2 and 9 was analyzed in the plasma. Abdominal aortas from HF C mice showed endothelial dysfunction as well as enhanced contractile but reduced relaxant responses to Ang II. This effect was abrogated with C21 treatment by preserving NO availability. A left-shift in the tension–stretch relationship, paralleled by an augmented β-index (marker of intrinsic arterial stiffness), and enhanced collagen deposition and MMP-2/-9 activities were also detected in HF mice. However, when treated with C21, HF mice exhibited lower TGF-β1 levels in abdominal aortas together with reduced MMP activities and collagen deposition compared with HF C mice. In conclusion, these data demonstrate that AT2R stimulation by C21 in obesity preserves NO availability and prevents unhealthy vascular remodeling, thus protecting the abdominal aorta in HF mice against the development of endothelial dysfunction, ECM remodeling and arterial stiffness.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Objective The receptor MAS, encoded by Mas1, is expressed in microglia and its activation has been linked to anti-inflammatory actions. However, microglia are involved in several different processes in the central nervous system, including the promotion of angiogenesis. We therefore hypothesized that the receptor MAS also plays a role in angiogenesis via microglia. Approach and results To assess the role of MAS on vascular network development, flat-mounted retinas from 3-day-old wild-type (WT) and -Mas1(-/-) mice were subjected to Isolectin B4 staining. The progression of the vascular front was reduced (- 24%, p < 0.0001) and vascular density decreased (- 38%, p < 0.001) in -Mas1(-/-) compared to WT mice with no change in the junction density. The number of filopodia and filopodia bursts were decreased in -Mas1(-/-) mice at the vascular front (- 21%, p < 0.05; - 29%, p < 0.0001, respectively). This was associated with a decreased number of vascular loops and decreased microglial density at the vascular front in -Mas1(-/-) mice (-32%, p < 0.001; - 26%, p < 0.05, respectively). As the front of the developing vasculature is characterized by reduced oxygen levels, we determined the expression of Mas1 following hypoxia in primary microglia from 3-day-old WT mice. Hypoxia induced a 14-fold increase of Mas1 mRNA expression (p < 0.01). Moreover, stimulation of primary microglia with a MAS agonist induced expression of Notch1 (+ 57%, p < 0.05), Dll4 (+ 220%, p < 0.001) and Jag1 (+ 137%, p < 0.001), genes previously described to mediate microglia/endothelial cell interaction during angiogenesis. Conclusions Our study demonstrates that the activation of MAS is important for microglia recruitment and vascular growth in the developing retina. Foulquier, S (reprint author), Maastricht Univ, Dept Pharmacol Toxicol, POB 616, NL-6200 MD Maastricht, Netherlands, CARIM, Cardiovasc Res Inst Maastricht, Maastricht, Netherlands, Maastricht Univ, Sch Mental Hlth & Neurosci, MH&NS, Maastricht, Netherlands. s.foulquier@maastrichtuniversity.nl

Background Relative blood volume (RBV) monitoring is widely used in hemodialysis (HD) patients, yet the association between intradialytic RBV and mortality is unknown. Methods Intradialytic RBV was recorded once/min during a 6-month baseline period; all-cause mortality was noted during follow-up. RBV at 1, 2 and 3 h into HD served as a predictor of all-cause mortality during follow-up. We employed Kaplan–Meier analysis, univariate and adjusted Cox proportional hazards models for survival analysis. Results We studied 842 patients. During follow-up (median 30.8 months), 249 patients (29.6%) died. The following hourly RBV ranges were associated with improved survival: first hour, 93–96% [hazard ratio (HR) 0.58 (95% confidence interval (CI) 0.42–0.79)]; second hour, 89–94% [HR 0.54 (95% CI 0.39–0.75)]; third hour, 86–92% [HR 0.46 (95% CI 0.33–0.65)]. In about one-third of patients the RBV was within these ranges and in two-thirds it was above. Subgroup analysis by median age (≤/> 61 years), sex, race (white/nonwhite), predialysis systolic blood pressure (SBP; ≤/> 130 mmHg) and median interdialytic weight gain (≤/> 2.3 kg) showed comparable favorable RBV ranges. Patients with a 3-h RBV between 86 and 92% were younger, had higher ultrafiltration volumes and rates, similar intradialytic average and nadir SBPs and hypotension rates, lower postdialysis SBP and a lower prevalence of congestive heart failure when compared with patients with an RBV >92%. In the multivariate Cox analysis, RBV ranges remained independent and significant outcome predictors. Conclusion Specific hourly intradialytic RBV ranges are associated with lower all-cause mortality in chronic HD patients.

BackgroundResidual renal function (RRF) affects sodium and fluid balance. The aim of this analysis was to examine the impact of RRF on the effect of a sodium-reduced peritoneal dialysis fluid (PDF) on blood pressure (BP).MethodsThis is a post-hoc analysis of a prospective, randomized, controlled double-blind clinical trial with 82 patients on continuous ambulatory PD (CAPD) treated with a low-sodium (125 mmol/L Na) or a standard-sodium (134 mmol/L Na) PDF. Subgroups according to glomerular filtration rate (GFR) at baseline (≤ / > 6 mL/min/1.73 m2) were analyzed for BP and antihypertensive medication.ResultsIn the low-GFR group on low-sodium PDF ( N = 26), systolic BP was reduced from 152 ± 24 mmHg at baseline to 137 ± 21 mmHg at week 12, diastolic BP from 90 ± 16 mmHg to 83 ± 11 mmHg. In the low-GFR group on standard-sodium PDF and in the high-GFR group on both PDF types, only minor changes were observed. For the low-GFR subgroup, the confounder-adjusted mean study group difference in systolic BP at week 12 between low-sodium and standard-sodium PDF was -16.9 (95% confidence interval [CI] -27.2 to -6.6) mmHg, for diastolic BP, it was -7.0 (95% CI -12.6 to -1.4) mmHg. In both GFR subgroups, more patients had a reduced daily dose of antihypertensive medication and fewer patients an increased daily dose in the low-sodium compared with the standard-sodium group at week 12.ConclusionsThe reduction of BP with a sodium-reduced PDF seems to be more effective in patients with no or low RRF than in patients with residual capacity of renal sodium and fluid control.

Dialysis patients manifest both an increased thrombotic risk and a haemorrhagic tendency. A great number of patients with chronic kidney disease requiring dialysis have cardiovascular comorbidities (coronary artery disease, atrial fibrillation or venous thromboembolism) and different indications for treatment with antithrombotics (primary or secondary prevention). Unfortunately, few randomized controlled trials deal with antiplatelet and/or anticoagulant therapy in dialysis. Therefore cardiology and nephrology guidelines offer ambiguous recommendations and often exclude or ignore these patients. In our opinion, there is a need for an expert consensus that provides physicians with useful information to make correct decisions in different situations requiring antithrombotics. Herein the European Dialysis Working Group presents up-to-date evidence about the topic and encourages practitioners to choose among alternatives in order to limit bleeding and minimize atherothrombotic and cardioembolic risks. In the absence of clear evidence, these clinical settings and consequent therapeutic strategies will be discussed by highlighting data from observational studies for and against the use of antiplatelet and anticoagulant drugs alone or in combination. Until new studies shed light on unclear clinical situations, one should keep in mind that the objective of treatment is to minimize thrombotic risk while reducing bleeding events.

Background: Low serum sodium (SNa) is associated with an increased mortality in chronic hemodialysis (HD) patients. Dialysis patients are thought to have an individual pre-dialysis SNa set-point, yet there is evidence for variability of pre-dialysis SNa in individual patient. In this study, we explored the association of several SNa variability metrics with all-cause mortality in a large patient population from the international MONitoring Dialysis Outcomes (MONDO) Initiative. Methods: All adult incident patients from the MONDO database with more than 5 SNa measurements during the first year on HD were included. All patients were required to survive the first year on HD (defined as the baseline). During the subsequent 2 years of follow-up, all-cause mortality was recorded. The following variability indicators were calculated during baseline: mean SNa and its SD; average real variability (ARV, average the absolute distance of the 2 consecutive SNa measurements), and average directional range (DR, the difference between minimum and maximum values). We used Cox Proportional hazard model with bivariate spline terms to analyze the joint association of SNa and SD, ARV and DR, respectively, with all-cause mortality. While conducting the multivariate Cox regression analyses, patients were stratified into 3 groups of DR (Negative DR: –20≤ DR ≤ –6, Null DR: –6< DR < 6 and Positive DR: 6≤ DR ≤20) with the Null DR as the reference group. Results: We included 20,216 patients in the study. A SNa ≤135 mEq/L was observed to be the strongest predictor of evaluated mortality risk. Higher SNa variability (quantified as SD, ARV, and DR) was also associated with an increased mortality irrespective of SNa levels. When compared with higher SD or ARV, greater DR showed a stronger association with an elevated risk of death. Controlling the Cox Proportional hazard models for additional parameters showed consistent results. Conclusion: Higher SNa variability associated with increased all-cause mortality at all levels of SNa. DR of SNa showed the strongest association with mortality and may constitute a Simple and novel prognostic indicator, easily applicable at the bedside.

Background: Calcium (Ca) is an essential element that plays a critical role in many biological processes. In dialysis patients, the regulation of Ca balance is highly complex, given the absence of kidney function, endocrine disturbances and the use of drugs such as phosphate binders, vitamin D analogues, and calcimimetics. Also, the use of different dialysate Ca (DCa) baths has profound effect on Ca balance, which depends both on the difference between the Ca concentration in the bath and the serum of the patients, as on the ultrafiltration volume. Summary: The choice of DCa may have important short- and long-term consequences. While lower DCa (especially < 2.5 mEq/L) concentrations have been associated with an increased risk of sudden cardiac death in observational studies, DCa in the higher ranges (3.0 mEq/L and above) may contribute to vascular pathology. Intra-dialytic hemodynamics may also be affected by the choice of DCa. In general, lower DCa concentrations are associated with an increase, and higher DCa concentrations with a decrease in parathyroid hormone (PTH) levels. Preliminary data has suggested that a DCa of 2.75 mEq/L may help in obtaining a net zero intradialytic Ca balance in individual patients, but clinical experience is still limited. Key Message: The optimal Ca balance depends on multiple parameters including blood Ca levels, PTH and the use of phosphate binders and vitamin D analogues, as well as on the risk of hemodynamic stability and cardiac arrhythmias. Therefore, DCa prescription should be individualised. A DCa of 2.75 mEq/L may be useful adjunct for dialysis providers.

Compound 21 (C21), a selective agonist of angiotensin II type 2 receptor (AT2R), induces vasodilation through NO release. Since AT2R seems to be overexpressed in obesity, we hypothesize that C21 prevents the development of obesity-related vascular alterations. The main goal of the present study was to assess the effect of C21 on thoracic aorta endothelial function in a model of diet-induced obesity (DIO) and to elucidate the potential cross-talk among AT2R, Mas receptor (MasR) and/or bradykinin type 2 receptor (B2R) in this response. Five-week-old male C57BL6J mice were fed a standard (CHOW) or a high-fat diet (HF) for 6 weeks and treated daily with C21 (1 mg/kg p.o) or vehicle, generating four groups: CHOW-C, CHOW-C21, HF-C, HF-C21. Vascular reactivity experiments were performed in thoracic aorta rings. Human endothelial cells (HECs; EA.hy926) were used to elucidate the signaling pathways, both at receptor and intracellular levels. Arteries from HF mice exhibited increased contractions to Ang II than CHOW mice, effect that was prevented by C21. PD123177, A779 and HOE-140 (AT2R, Mas and B2R antagonists) significantly enhanced Ang II-induced contractions in CHOW but not in HF-C rings, suggesting a lack of functionality of those receptors in obesity. C21 prevented those alterations and favored the formation of AT2R/MasR and MasR/B2R heterodimers. HF mice also exhibited impaired relaxations to acetylcholine (ACh) due to a reduced NO availability. C21 preserved NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways. In conclusion, C21 favors the interaction among AT2R, MasR and B2R and prevents the development of obesity-induced endothelial dysfunction by stimulating NO release through PKA/p-eNOS and AKT/p-eNOS signaling pathways.

There continues to be an inexorable rise in the death toll due to raised blood pressure (BP) which remains the biggest single contributor to global death and the global burden of disease.1 It is estimated that in 2019 about 19% of all deaths (10.8 million) were due to raised BP, having risen from 9.4 million deaths in 2014.2 Hypertension causes over 50% of cases of heart disease, stroke, and heart failure3 and it is estimated that about 10% of global healthcare spending arises from raised BP and its complications.4 Moreover, hypertension-mediated organ damage increases risk of severe infections from COVID-19, including risk of death.5 For any of these reasons, it is critical to prevent and, failing that, identify and manage raised BP that appears to differentially affect the most vulnerable groups in society. [...]

IntroductionWhether ACE inhibitors (ACEi) or angiotensin II receptor blocker (ARB) therapy should be continued, initiated or ceased in patients with COVID-19 is uncertain. Given the widespread use of ACEi/ARBs worldwide, guidance on the use of these drugs is urgently needed. This prospective meta-analysis aims to pool data from randomised controlled trials (RCTs) to assess the safety and efficacy of ACEi/ARB therapy in adults infected with SARS-CoV-2.Methods and analysisRCTs will be eligible if they compare patients with COVID-19 randomised to ACEi/ARB continuation or commencement versuss no ACEi/ARB therapy; study duration ≥14 days; recruitment completed between March 2020 and May 2021. The primary outcome will be all-cause mortality at ≤30 days. Secondary outcomes will include mechanical ventilation, admission to intensive care or cardiovascular events at short-term follow-up (≤30 days) and all-cause mortality at longer-term follow-up (>1 month). Prespecified subgroup analyses will assess the effect of sex; age; comorbidities; smoking status; ethnicity; country of origin on all-cause mortality. A search of ClinicalTrials.gov has been performed, which will be followed by a formal search of trial registers, preprint servers, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify RCTs that meet inclusion criteria. To date, a search of ClinicalTrials.gov identified 21 potentially eligible trials for this meta-analysis. We will request trial investigators/sponsors to contribute standardised grouped tabular outcome data.Ethics and disseminationEthics approval and informed consent will be the responsibility of the individual RCTs. Dissemination of results will occur by peer-reviewed publication. The results of our analysis can inform public health policy and clinical decision making regarding ACEi/ARB use in patients with COVID-19 on a global scale.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients.

Purpose:Hypertension is the most important risk factor for disease and premature death. Treatment strategies adjusted for cardiovascular risk have been proposed in guidelines, but real-life treatment strategies for patients with newly diagnosed hypertension in Germany are largely unknown. The aim of the study was to analyse initial drug treatment strategies and associated risk status in patients with newly diagnosed hypertension. Material and methods:In the representative research database of the public health insurance system in Germany (2077899 individuals) we identified patients with newly diagnosed hypertension in 2012 and analysed co-existing cardiovascular co-morbidities and hypertension-mediated organ damage by ICD-codes as qualifiers for high risk. Health insurance billing datasets for redeemed prescriptions were analysed at several time points using ATC-codes. Results:The incidence of hypertension was 2.6%, 33.6% of the patients were at high risk at diagnosis, mainly due to cardiovascular co-morbidities. Most patients initially received monotherapy (55.4%), of which ACE inhibitors (43.8%) or beta-blockers (32.4%) were the leading drug classes, while 21.7% of patients received no drug therapy during the first year. The treatment strategies of low and high-risk patients resembled each other - high-risk patients also received mostly monotherapy during the first year after diagnosis (53.4%), while 13.7% remained without drug therapy. Combination therapy was the most frequent treatment strategy one year after hypertension diagnosis (40.6%) and in the long term (68.4%). Conclusion:Initial treatment strategies may not always be stratified according to cardiovascular risk. The majority of patients with hypertension receives initial monotherapy independent of their individual risk. However, combination therapy represents the major form of therapy in the long-term.

Statement of remit: To align with its mission to reduce the global burden of raised blood pressure (BP), the International Society of Hypertension (ISH) has developed worldwide practice guidelines for the management of hypertension in adults, aged 18 years and older. The ISH Guidelines Committee extracted evidence-based content presented in recently published extensively reviewed guidelines and tailored ESSENTIAL and OPTIMAL standards of care in a practical format that is easy-to-use particularly not only in low-resource settings but also in high-resource settings- by clinicians, but also nurses and community health workers, as appropriate. Although distinction between low-resource and high-resource settings often refers to high (HIC) and low-income and middle-income countries (LMIC), it is well established that in HIC, there are areas with low-resource settings, and vice versa. Herein optimal care refers to evidence-based standard-of-care articulated in recent guidelines [1,2] and summarized here, whereas essential standards recognize that optimal standards would not always be possible. Hence, essential standards refer to minimum standards of care. To allow specification of essential standards of care for low-resource settings, the Committee was often confronted with the limitation or absence in clinical evidence, and thus applied expert opinion. In the Guidelines, differentiation between optimal and essential standards were not always possible, and were made in sections where it was most practical and sensible. The Guidelines Committee is also aware that some recommended essential standards may not be feasible in low-resource settings, for example, out-of-office BP measurements, the requirement of multiple visits for the diagnosis of hypertension, or advising the use of single pill combination therapy. Although challenging to implement, these guidelines may aid in local initiatives to motivate policy changes and serve as an instrument to drive local improvements in standards of care. Every effort should be made to achieve essential standards of care to reduce hypertension-induced cardiovascular morbidity and mortality.

Elevated blood pressure remains the single biggest risk factor contributing to the global burden of disease and mortality. May Measurement Month is an annual global screening campaign aiming to improve awareness of blood pressure at the individual and population level. Adults ({greater than or equal to}18 years) recruited through opportunistic sampling were screened at sites in 92 countries during May 2019. Ideally three blood pressure readings were measured for each participant, and data on lifestyle factors and co-morbidities were collected. Hypertension was defined as a systolic BP {greater than or equal to} 140 mmHg, and/or a diastolic BP {greater than or equal to} 90 mmHg (mean of the second and third readings) or taking antihypertensive medication. When necessary, multiple imputation was used to estimate participants' mean blood pressure. Mixed-effects models were used to evaluate associations between blood pressure and participant characteristics. Of 1,508,130 screenees 482,273 (32.0%) had never had a blood pressure measurement before and 513,337 (34.0%) had hypertension, of whom 58.7% were aware and 54.7% were on antihypertensive medication. Of those on medication, 57.8% were controlled to

In May 2017, the International Society of Hypertension (ISH) introduced the first in a series of annual blood pressure (BP) screening programmes with the simple aim of raising awareness of the importance of raised BP as the single biggest contributor to the global burden of disease and to globalmortality. After the success of this initial May Measurement Month (MMM) campaign—which included over 1.2 million screenees from 80 countries,2 MMM expanded in 2018 and again in 2019. The global results of MMM17 and MMM18 have been published elsewhere2,3 and the national data from 39 of 40 countries who screened at least 2500 adults in 2017 were collated as a European Heart Journal (EHJ) Supplement. 4 Here, we present a second collation of data from 41 countries with the highest number of participants who took part in MMM18.

Introduction It is known that breast reconstruction improves quality of life (QoL) in women who underwent mastectomy. Previous studies showed that autologous immediate breast reconstruction is as safe as delayed breast reconstruction. However, there is not much known about the influence of the timing of the breast reconstruction on QoL. Therefore, this study aims to assess the effect of timing of the breast reconstruction on QoL, using the BREAST-Q questionnaire. Methods A total of 543 patients aged 18 years or older who underwent deep inferior epigastric perforator flap reconstruction after mastectomy (for prophylactic or oncological reasons) at least 12 months ago were selected in 3 hospitals in the Netherlands and invited to complete the BREAST-Q. Mean QoL outcomes were compared between patients who underwent immediate or delayed breast reconstruction. Furthermore, QoL outcomes were compared with recently published normative data of the BREAST-Q. Results Patients who underwent immediate reconstruction reported higher scores on satisfaction with psychosocial well-being, sexual well-being, physical well-being of the chest, and physical well-being of the abdomen. Patients who underwent delayed reconstruction reported higher scores on satisfaction with breasts, outcome, and nipples. However, after adjusting for potentially influencing factors, none of the differences were significant. Compared with the normative BREAST-Q data, both of our patient groups reported higher scores on satisfaction with breasts, psychological well-being, and sexual well-being, whereas they reported lower scores on satisfaction with physical well-being of the chest and the abdomen. Conclusions This study suggests that patients who underwent immediate or delayed deep inferior epigastric perforator flap breast reconstruction have comparable QoL more than 1 year after surgery, irrespective of the timing of the breast reconstruction.

The effects of the selective AT 2 R (angiotensin AT2 receptor) agonist, Compound 21 (C21), on abdominal aortic aneurysm formation were investigated in normotensive Wistar rats. Abdominal aortic aneurysm was induced by perfusion of isolated aortic segments with elastase. Treatment with C21 (0.03 mg/kg daily) was started after operation and continued for 14 days. Sham-operated animals and vehicle-treated animals after aneurysm induction served as controls. Aortic diameter, aortic wall distensibility, and pulse propagation velocity were measured via ultrasound. Hemodynamic parameters, aortic tissue protein expression, and serum cytokines were analyzed. On day 14 post aneurysm induction, aortic diameter of vehicle-treated animals was increased 1.6-fold compared with sham-operated rats (2.65±0.05 versus 1.70±0.06 mm; P P P P 2 R stimulation with C21 prevented extracellular matrix degradation, maintained vascular integrity of the aorta and prevented abdominal aortic aneurysm progression.

End-stage renal disease patients have insufficient renal clearance capacity left to adequately excrete metabolic waste products. Hemodialysis (HD) is often employed to partially replace renal clearance in these patients. However, skeletal muscle mass and strength start to decline at an accelerated rate after initiation of chronic HD therapy. An essential anabolic stimulus to allow muscle maintenance is dietary protein ingestion. Chronic HD patients generally fail to achieve recommended protein intake levels, in particular on dialysis days. Besides a low protein intake on dialysis days, the protein equivalent of a meal is extracted from the circulation during HD. Apart from protein ingestion, physical activity is essential to allow muscle maintenance. Unfortunately, most chronic HD patients have a sedentary lifestyle. Yet, physical activity and nutritional interventions to support muscle maintenance are generally not implemented in routine patient care. To support muscle maintenance in chronic HD patients, quantity and timing of protein intake should be optimized, in particular throughout dialysis days. Furthermore, implementing physical activity either during or between HD sessions may improve the muscle protein synthetic response to protein ingestion. A well-orchestrated combination of physical activity and nutritional interventions will be instrumental to preserve muscle mass in chronic HD patients.

Background Venous insufficiency of the lower extremity affects up to 40–60% of general adult population in the Western population, of which around 25% has varicose veins mostly treated by ablation of the incompetent great saphenous vein. Although endovenous options are available, the majority is still treated with stripping of the great saphenous vein for which there is no consensus regarding postoperative compressive therapy. The objective of this prospective randomised controlled trial was to evaluate 4 h compared to 72 h of leg compression after great saphenous vein stripping. Method Patients in the Zuyderland Medical Centre with an indication for stripping of the great saphenous vein were eligible for inclusion in this study. Patients were randomised to 4 or 72 h of leg compression (standard elastic bandaging) after stripping of the great saphenous vein. Primary outcome was change in leg volume after 14 days. Secondary outcomes were post-operative pain scores, complications and time to full recovery. Results A total of 78 patients were randomised, 36 patients enrolled the intervention (4 h) group and 42 patients the control group (72 h). The intervention group (4 h) showed a 57 mL reduction in leg volume after 14 days, compared to 6 mL of the control group (72 h) ( p = 0.11). Post-operative pain, complications and time to full recovery did not statistically differ. Conclusion Wearing leg compression four hours after stripping is non-inferior in preventing leg oedema compared with 72 h compression therapy. No statistically significant difference in pain and time to full recovery was shown.

Objectives Stent grafts for endovascular repair of infrarenal aneurysms are commercially available for aortic necks up to 32 mm in diameter. The aim of this study was to evaluate the feasibility of endovascular repair with large thoracic stent grafts in the infrarenal position to obtain adequate proximal seal in wider necks. Methods All patients who underwent endovascular aneurysm repair using thoracic stent grafts with diameters greater than 36 mm between 2012 and 2016 were included. Follow-up consisted of CT angiography after six weeks and annual duplex thereafter. Results Eleven patients with wide infrarenal aortic necks received endovascular repair with thoracic stent grafts. The median diameter of the aneurysms was 60 mm (range 52–78 mm) and the median aortic neck diameter was 37 mm (range 28–43 mm). Thoracic stent grafts were oversized by a median of 14% (range 2–43%). On completion angiography, one type I and two type II endoleaks were observed but did not require reintervention. One patient experienced graft migration with aneurysm sac expansion and needed conversion to open repair. Median follow-up time was 14 months (range 2–53 months), during which three patients died, including one aneurysm-related death. Conclusions Endovascular repair using thoracic stent grafts for patients with wide aortic necks is feasible. In these patients, the technique may be a reasonable alternative to complex endovascular repair with fenestrated, branched, or chimney grafts. However, more experience and longer follow-up are required to determine its position within the endovascular armamentarium.

The angiotensin II (Ang II) type 2 receptor (AT2R) and the angiotensin-(1–7) (Ang-(1–7)) receptor (MasR) play a cardiovascular protective role by counter-regulating Ang II type 1 receptor (AT1R)-mediated effects, but whether this involves blunting of adrenocortical hormone secretion is unknown. We investigated the presence of AT1R, AT2R, and MasR in aldosterone-producing adenoma (APA), a condition featuring hyperaldosteronism, and in APA-adjacent tissue. The effect of Compound 21 (C21), an AT2R agonist, on CYP11B1 (cortisol synthase) and CYP11B2 (aldosterone synthase) gene expression in NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, was also assessed using the AT1R antagonist irbesartan to ascertain the specificity of C21 effect. We found that the AT1R, AT2R, and MasR were expressed in APA and APA-adjacent tissue, albeit heterogeneously. The gene expression of AT1R and AT2R was lower, and that of the MasR higher in APAs than in APA-adjacent tissue. In steroid-producing NCI-H295R and HAC15 cell lines, and in APA and APA-adjacent tissue, C21 was ineffective at nanomolar concentrations, but increased CYP11B1 and CYP11B2 gene expression at micromolar concentrations through AT1R, as this effect was blunted by irbesartan. The scant expression of the AT2R, along with the lack of any effect of C21 at low concentrations on CYP11B2, do not support the contention that the protective arm of renin–angiotensin system (RAS) blunts aldosterone synthase in the normal adrenal cortex and primary aldosteronism.

Background The meaning of high‐sensitivity troponin I (hsTnI) concentrations in patients without acute myocardial infarction ( MI ) requires clarity. We hypothesized that among patients referred for diagnostic coronary angiography without acute MI , hsTnI concentrations would correlate with prevalent coronary artery disease ( CAD ) and predict incident cardiovascular events and mortality. Methods and Results We measured hsTnI using a single‐molecule counting assay (99th percentile, 6 ng/L) in samples from 991 patients obtained at the time of angiography. Concentrations of hsTnI were assessed relative to the severity of CAD and prognosis during mean follow‐up of 3.7 years. Median hsTnI concentration was 4.19 ng/L; 38% of patients had hsTnI concentrations ≥99th percentile. Across increasing hsTnI quartiles, patients had higher prevalence of angiographic CAD ; in multivariate models, hsTnI ≥99th percentile independently predicted obstructive CAD (odds ratio: 2.57; P MI (hazard ratio [ HR ]: 2.68; P HR: 2.29; P =0.001), and all‐cause death ( HR: 1.84; P =0.004). In those with >70% coronary stenosis, hsTnI ≥99th percentile independently predicted incident MI ( HR: 1.87; P =0.01), cardiovascular mortality ( HR: 2.74; P =0.001), and the composite end point of MI and all‐cause death ( HR: 2.06; P MI ( HR : 8.41; P HR : 3.60; P =0.03), and the composite end point of MI and all‐cause death ( HR: 3.62; P Conclusions In a large prospective cohort of patients who were free of prevalent MI and undergoing diagnostic coronary angiography, hsTnI concentrations were associated with higher prevalence of CAD and predicted incident MI , cardiovascular death, and all‐cause death. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 00842868.

Purpose The number of breast cancer survivors continues to grow. Due to refinements in operating techniques, autologous breast reconstruction has become part of standard care. Impaired sensation remains a debilitating side effect with a significant impact on the quality of life. Microsurgical nerve coaptation of a sensory nerve has the potential to improve sensation of the reconstructed breast. This study investigates the effect of improved sensation of the reconstructed breast on the quality of life in breast cancer survivors. Methods A retrospective cohort study was performed in the Maastricht University Medical Center. Patients undergoing a DIEP flap breast reconstruction between January 2015 and January 2016 were included. The primary outcome was quality of life (BREAST-Q domain ‘physical well-being of the chest’). The Semmes–Weinstein monofilaments were used for objective sensation measurement of the reconstructed breast(s). Results Eighteen patients with and 14 patients without nerve coaptation responded. Nipple reconstruction was the only characteristic that differed statistically significant between both groups (p = 0.04). The BREAST-Q score for the domain physical well-being of the chest was 77.89 ± 18.89 on average in patients with nerve coaptation and 66.21 ± 18.26 in patients without nerve coaptation (p = 0.09). Linear regression showed a statistically significant relation between objectively measured sensation and BREAST-Q score for the domain physical well-being of the chest with a regression coefficient of − 13.17 ± 3.61 (p

Contains fulltext : 190533.pdf (Publisher’s version ) (Open Access) BACKGROUND: Red cell distribution width (RDW) is a standard component of the automated blood count, and is of prognostic value in heart failure and coronary heart disease. We investigated the association between RDW and cardiovascular events in patients with adult congenital heart disease (ACHD). METHODS AND RESULTS: In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. RDW was measured in fresh venous blood samples at inclusion in 592 patients (median age 33 [IQR 25-41] years, 58% male, 90% NYHA I) and at four annual follow-up visits. During 4.3 [IQR 3.8-4.7] years of follow-up, the primary endpoint (death, heart failure, hospitalization, arrhythmia, thromboembolic events, cardiac intervention) occurred in 196 patients (33%). Median RDW was 13.4 (12.8-14.1)% versus 12.9 (12.5-13.4)% in patients with and without the primary endpoint (P

Background Surgical management in laryngeal carcinoma remains a challenge with countless unexpected complications. Great vessel anomalies such as anomaly of the innominate artery carry high risk of morbidity and mortality if not managed properly. Methods We present our first experience with an aberrant innominate artery during total laryngectomy which complicated the whole surgical procedure and tracheostoma placement. Results We decided to place a pectoralis major muscle flap to separate and cover up the aberrant vessel from the trachea and end-stoma which ultimately did not lead to major complications postoperatively and postradiation therapy. Conclusion Aberrant innominate artery is an extremely rare entity and failure of recognizance can lead to hazardous complications. Preoperative angiography needs to be done if there are high suspicions of aberrant vessels in the operative field. Careful dissection of the head and neck region, and prompt decision making are mandatory to manage such cases. Levels of evidence Case Report.

Die multifaktorielle Genese kardiovaskularer Erkrankungen hat in der Primar- und Sekundarprophylaxe zur Polypharmazie mit evidenzbasierten Therapeutika wie Statinen, Antihypertensiva und Thrombozytenhemmern gefuhrt. Die Anzahl verschriebener Phamaka korreliert umgekehrt mit der Adharenz, was die Effektivitat der Therapie beeintrachtigen kann. Fixe Kombinationspraparate („Polypill“) konnten die Adharenz der Patienten steigern und damit kardiovaskularen Ereignissen vorbeugen. Literaturrecherche in Medline (via PubMed) und The Cochrane Library sowie der Studiendatenbank ClinicalTrials.gov. In den bisher durchgefuhrten Studien zur kardiovaskularen Primarpravention zeigt die Polypill eine uberlegene Kontrolle der Risikofaktoren (Hypertonie, „Low-density-lipoprotein“-Cholesterin [LDL-C]) gegenuber Placebo und gegenuber einer Standardtherapie aus Einzelpraparaten mindestens eine Nichtunterlegenheit. In der Sekundarpravention zeigen Kombinationspraparate vorwiegend Vorteile bei nichtadharenten Patienten bezuglich Blutdruckkontrolle und Reduktion der LDL-C-Konzentration. Der Nachweis, dass die Polypill die kardiovaskulare Morbiditat und Mortalitat gegenuber einer Standardtherapie absenkt, steht aus. Kombinationspraparate sind nach Risiko-Nutzen-Einschatzung als Alternative zur Polypharmazie, insbesondere bei nichtadharenten Patienten in Erwagung zu ziehen. Inwieweit durch die erwiesene Senkung der Risikofaktoren kardiovaskulare Ereignisse verhindert werden konnen, ist Gegenstand laufender Untersuchungen. Limitiert sind die gegenwartigen Polypills durch eine zu geringe Auswahl an Dosierungen der Einzelwirkstoffe, um eine Uber- und Untertherapie in der individuellen Behandlung zu vermeiden.

Purpose Lymphedema is a chronic and disabling sequel of breast cancer treatment that can be treated by lymphatico-venous anastomosis (LVA). Artificial connections between the venous and lymphatic system are performed supermicrosurgically. This prospective study analyses the effect of LVA on quality of life. Methods A prospective study was performed between November 2015 and July 2016 on consecutive patients in the Maastricht University Medical Centre. Quality of life was considered as the primary outcome, and the Lymphedema International Classification of Functioning (Lymph-ICF) questionnaire was used. Discontinuation of compressive stockings and arm volume, using the Upper Extremity Lymphedema index (UEL-index), were the secondary outcomes. Results Twenty women with early-stage breast cancer-related lymphedema (BCRL) were included. The mean age was 55.9 ± 4 years and the median BMI was 25.1 [21–30] kg/m2. The mean follow-up was 7.8 ± 1.5 months. Statistically significant improvement in quality of life was achieved in the total score and for all the quality of life domains after one year of follow-up (p

The title of the recent editorial by Prof. Kjeldsen et al. [1] suggests that the latest guidelines of the International Society of Hypertension (ISH) [2] have introduced a drug treatment recommenda...

Purpose TNM classification of solitary internal mammary lymph node metastases (IMLNMs) in breast cancer varies depending on their method of detection: sentinel lymph node biopsy (pN1b) or clinical examination including radiological and/or physical examination (pN2b). This study aimed to evaluate whether there is a difference in prognosis between both groups. Methods Data of all patients diagnosed with primary invasive epithelial breast cancer between 2005 and 2008 were obtained from the Netherlands Cancer Registry. Patients with IMLNMs were divided in groups according to their pN1b and pN2b status. The main outcome measures disease-free survival (DFS) after 5 years and overall survival (OS) after 8 years were analyzed using Kaplan–Meier survival analysis. Cox regression analysis was used to determine independent predictors for DFS and OS. Results A total of 73 patients with pN1b status and 28 patients with pN2b status were included. DFS rate was 74.1% in the pN1b group compared to 85.0% in the pN2b group (p = 0.211). Regarding OS, 20.5% (pN1b) and 25.0% (pN2b) of the patients deceased within 8 years of follow-up (p = 0.589). In multivariable cox regression analysis, nodal status was not statistically significant for DFS (HR 0.29 [95% CI 0.04–2.33], p = 0.244) or OS (HR 1.04 [95% CI 0.37–2.89], p = 0.947). Conclusions Although the TNM classification considers pN1b and pN2b to be distinct prognostic entities, we did not observe any prognostic differences between these groups. Therefore, solitary IMLNMs may be regarded as a single category in the future and revision of TNM classification should be considered.

IntroductionEnd-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce.MethodsWe compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology.ResultsIn linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter.ConclusionsLevels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation.

Brown adipose tissue (BAT) is known to secrete regulatory factors in response to thermogenic stimuli. Components of the BAT secretome may exert local effects that contribute to BAT recruitment and activation. Here, we found that a thermogenic stimulus leads to enhanced secretion of kininogen (Kng) by BAT, owing to induction of kininogen 2 (Kng2) gene expression. Noradrenergic, cAMP-mediated signals induce KNG2 expression and release in brown adipocytes. Conversely, the expression of kinin receptors, that are activated by the Kng products bradykinin and [Des-Arg9]-bradykinin, are repressed by thermogenic activation of BAT in vivo and of brown adipocytes in vitro. Loss-of-function models for Kng (the circulating-Kng-deficient BN/Ka rat) and bradykinin (pharmacological inhibition of kinin receptors, kinin receptor-null mice) signaling were coincident in showing abnormal overactivation of BAT. Studies in vitro indicated that Kng and bradykinin exert repressive effects on brown adipocyte thermogenic activity by interfering the PKA/p38 MAPK pathway of control of Ucp1 gene transcription, whereas impaired kinin receptor expression enhances it. Our findings identify the kallikrein–kinin system as a relevant component of BAT thermogenic regulation that provides auto-regulatory inhibitory signaling to BAT., Brown adipose tissue, known produce heat by metabolizing fat, is also secretes molecules capable of communicating with other organs. Here the authors show that brown adipose tissue secretes kininogen, a component of heat system regulation, that provides auto-regulatory inhibitory signaling in brown adipose tissue.

Raised blood pressure is the biggest single risk factor responsible for mortality worldwide. Despite this, the majority of people with hypertension are unaware of having it, are untreated, or are on treatment but uncontrolled. May Measurement Month is a global campaign initiated by the International Society of Hypertension with the aim of raising awareness of high blood pressure. In the first year of the campaign in 2017, over 1.2 million people were screened in 80 countries across the world, finding over 100 000 people with hypertension who were not on treatment and over 150 000 people on anti-hypertensive treatment who were not controlled. The individual national results from 39 countries are presented in this supplement. In this article, we discuss the background to the campaign, along with some of the logistical and methodological challenges that were faced in setting up the campaign, and in collecting and analysing the data from such a large cross-sectional study. With the lessons learned from the 2017 campaign, the campaign was repeated in 2018 and is to be repeated again in 2019.

BackgroundCardiovascular disease (CVD) related mortality and morbidity are high in end-stage renal disease (ESRD). The pathophysiology of CVD in ESRD may involve non-traditional CVD risk factors, such as accumulation of advanced glycation endproducts (AGEs), dicarbonyls, endothelial dysfunction (ED) and low-grade inflammation (LGI). However, detailed data on the relation of AGEs and dicarbonyls with ED and LGI in ESRD are limited.MethodsWe examined cross-sectional Spearman's rank correlations of AGEs and dicarbonyls with serum biomarkers of ED and LGI in 43 individuals with chronic kidney disease (CKD) stage 5 not on dialysis (CKD5-ND). Free and protein-bound serum AGEs (N-is an element of-(carboxymethyl) lysine (CML), N-is an element of-(carboxyethyl) lysine (CEL), N-delta-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)) and serum dicarbonyls (glyoxal, methylglyoxal, 3-deoxyglucosone) were analyzed with tandem mass spectrometry, and tissue AGE accumulation was estimated by skin autofluorescence (SAF). Further, serum biomarkers of ED and LGI included sVCAM-1, sE-selectin, sP-selectin, sThrombomodulin, sICAM-1, sICAM-3, hs-CRP, SAA, IL-6, IL-8 and TNF-alpha.ResultsAfter adjustment for age, sex and diabetes status, protein-bound CML was positively correlated with sVCAM-1; free CEL with sVCAM-1 and sThrombomodulin; glyoxal with sThrombomodulin; and methylglyoxal with sVCAM-1 (correlation coefficients ranged from 0.36 to 0.44). In addition, free CML was positively correlated with SAA; protein-bound CML with IL-6; free CEL with hs-CRP, SAA and IL-6; free MG-H1 with SAA; protein-bound MG-H1 with IL-6; and MGO with hs-CRP and IL-6 (correlation coefficients ranged from 0.33 to 0.38). Additional adjustment for eGFR attenuated partial correlations of serum AGEs and serum dicarbonyls with biomarkers of ED and LGI.ConclusionsIn individuals with CKD5-ND, higher levels of serum AGEs and serum dicarbonyls were related to biomarkers of ED and LGI after adjustment for age, sex and diabetes mellitus. Correlations were attenuated by eGFR, suggesting that eGFR confounds and/or mediates the relation of serum AGEs and dicarbonyls with ED and LGI.

INTRODUCTION: The concentration of dialysate calcium (dCa) has been suggested to affect vascular calcification, but evidence is scarce. Calcification propensity reflects the intrinsic capacity of serum to prevent calcium and phosphate to precipitate. The use of citric-acid dialysate may have a beneficial effect on the calcification propensity due to the chelating effect on calcium and magnesium. The aim of this study was to compare the intradialytic and short-term effects of haemodialysis with either standard acetic-acid dialysate with dCa1.50 (A1.5) or dCa1.25 (A1.25), as well as citric-acid dialysate with dCa1.50 (C1.5) in bicarbonate dialysis on the calcification propensity of serum.METHODS: Chronic stable hemodialysis patients were included. This multicenter randomized cross-over study consisted out of a baseline week (A1.5), followed by the randomized sequence of A1.25 or C1.5 for one week after which the alternate treatment was provided after a washout week with A1.5. Calcification propensity of serum was assessed by time-resolved nephelometry where the T50 reflects the transition time between formation of primary and secondary calciprotein particles.RESULTS: Eighteen patients (median age 70 years) completed the study. Intradialytic change in T50 was increased with C1.5 (121 [90-152]min) compared to A1.25 (83 [43-108]min, pCONCLUSION: Calcification propensity, as measured by the change in T50, improved significantly during treatment in C1.5 compared to A1.25 and A1.5. Long-term studies are needed to investigate the effects of different dialysate compositions concentrations on vascular calcification and bone mineral disorders.

Background Health-related quality of life (HrQoL) varies among dialysis patients. However, little is known about the association of dialysis modality with HrQoL over time. We describe longitudinal patterns of HrQoL among chronic dialysis patients by treatment modality. Methods National retrospective cohort study of adult patients who initiated in-center dialysis or a home modality (peritoneal or home hemodialysis) between 1/2013 and 6/2015. Patients remained on the same modality for the first 120 days of the first two years. HrQoL was assessed by the Kidney Disease and Quality of Life-36 (KDQOL) survey in the first 120 days of the first two years after dialysis initiation. Home modality patients were matched to in-center patients in a 1:5 fashion. Results In-center (n=4234) and home modality (n=880) patients had similar demographic and clinical characteristics. In-center dialysis patients had lower mean KDQOL scores across several domains compared to home modality patients. For patients who remained on the same modality, there was no change in HrQoL. However, there were trends towards clinically meaningful changes in several aspects of HrQoL for patients who switched modalities. Specifically, physical functioning decreased for patients who switched from home to in-center dialysis (p< 0.05). Conclusions Among a national cohort of chronic dialysis patients, there was a trend towards different patterns of HrQoL life that were only observed among patients who changed modality. Patients who switched from home to in-center modalities had significant lower physical functioning over time. Providers and patients should be mindful of HrQoL changes that may occur with dialysis modality change. Electronic supplementary material The online version of this article (10.1186/s12882-018-1198-5) contains supplementary material, which is available to authorized users.

Background Peritoneal dialysis (PD) starters generally have a better outcome compared with hemodialysis (HD) starters, perhaps related to treatment characteristics or case mix. We previously showed that pre- and post-dialysis start clinical parameter trajectories are related to outcomes. The aim of this study was to investigate these trajectories in PD and HD starters. Methods This retrospective observational study analyzing data from the Fresenius Medical Care–chronic kidney disease (CKD) Registry from January 2009 to March 2018 examines trends in key clinical parameters through the transition period covering 12 months before to 12 months after dialysis start in 8,088 HD and 1,015 PD starters. Results Hemodialysis starters differed from PD starters by a significantly greater decline in estimated glomerular filtration rate (eGFR) slope (-0.64 vs -0.45 mL/min/1.73 m2/month) before and higher eGFR (9.85 vs 7.84 mL/min/1.73 m2) at dialysis start. Relatedly, differences in phosphorus (0.07 vs 0.05 mg/dL/month) and hemoglobin (-0.08 vs -0.01 g/dL/month) slopes before the transition to dialysis therapy were observed. After dialysis start, HD starters experienced a greater increase in albumin (0.01 vs 0 g/dL/month) whereas PD starters experienced a decline in serum sodium and higher white blood cell counts compared with HD starters. Conclusion For nephrology practice CKD patients, HD and PD starters appear clinically comparable in the year before dialysis start although HD starters exhibit a more rapid pre-dialytic eGFR decline. Ideally, studies comparing incident HD and PD outcomes should also consider CKD eGFR trajectories. In the first dialysis year, divergence occurs in albumin, white blood cell count, sodium and hemoglobin trends, which may be partly treatment-related.

Background: Central venous oxygen saturation (ScvO2) is correlated with cardiac output. In most patients, ScvO2 declines during hemodialysis (HD) due to factors such as reduced preload, myocardial stunning, and intermittent arrhythmias. Previous research has shown that low ScvO2 is associated with higher mortality in chronic HD patients. In this research, we tested the hypothesis that ScvO2 variability is associated with all-cause mortality. Methods: We conducted a retrospective study in 232 chronic HD patients with central venous catheter as vascular access. ScvO2 was recorded 1× per minute during dialysis using the Crit-Line monitor. A 6-month baseline comprising at least 10 dialysis treatments with ScvO2 recordings preceded a follow-up period of up to 3 years. The coefficient of variation (CV) of ScvO2 (100 times the ratio of the standard deviation and mean of ScvO2) served as a measure of ScvO2 stability during baseline. Patients were stratified by median population CV of ScvO2 during baseline, and survival during follow-up was compared between the 2 groups by Kaplan Meier and multivariate Cox analysis. The association between CV of ScvO2 and all-cause mortality during follow-up was further assessed by Cox analysis with a spline term for CV of ScvO2. Results: The mean CV ± standard deviation of ScvO2 in our population was 6.1 ± 2.7% and the median was 5.3%. Univariate Kaplan-Meier analysis (p = 0.043) and multivariate Cox analysis (hazard ratio [HR] 1.16; p = 0.0005) indicated that a CV of ScvO2 > 5.3% was significantly associated with increased mortality. In Cox analysis with spline term, a CV of ScvO2 > 11% was associated with a significantly increased HR for all-cause mortality. Conclusion: High ScvO2 variability during dialysis is associated with increased all-cause mortality.

The causal relation between hypertension and cerebral small vessel disease (cSVD) remains elusive, and appropriate animal models are scarce. We aimed to assess the relevance of prolonged angiotensin II-induced hypertension in mice for the study of cSVD.Adult male C57BL/6 mice were continuously infused for 3 months with Angiotensin II (Ang II; 2 mu g/kg/min, sc) or saline (control) via osmotic minipumps. Blood pressure, neurological function, locomotor activity, and working memory (Y-maze alternation task) were assessed throughout the study. Short-term memory performance (object location task) was measured after 3 months of infusion. Blood-brain barrier (BBB) function was assessed by the presence of IgG leakage and quantified in each brain area of interest. Microglial activation and myelin loss were studied in the areas of leakage.Systolic blood pressure increased and remained elevated over the 3 months of Ang II infusion, while neurological scores and locomotor activity did not change. Working memory performance was also not changed, yet short-term memory performance was impaired in Ang II-treated mice compared to controls. While BBB leakages were present in both groups, mainly in the neocortex, hippocampus, and cerebral nuclei, Ang II-treated mice showed greater leakage than control mice, along with greater microglial density and soma size. Myelin loss was observed for the largest leaks.Prolonged Ang II-induced hypertension is associated with large BBB leaks, microglial activation, myelin loss, and memory dysfunction in the absence of stroke.

Purpose As more breast cancer patients opt for immediate breast reconstruction, the incidence of complications should be evaluated. The aim of this study was to analyze the recipient-site complications and flap re-explorations of immediate compared to delayed deep inferior epigastric artery perforator (DIEP) flap breast reconstructions. Methods For this multicenter retrospective cohort study, the medical records of all patients who underwent DIEP flap breast reconstruction in three hospitals in the Netherlands between January 2010 and June 2017 were reviewed. Patient demographics, risk factors, timing of reconstruction, recipient-site complications, and flap re-explorations were recorded. Results A total of 910 DIEP flap breast reconstructions (n = 397 immediate and n = 513 delayed reconstructions) in 737 patients were included. There were no significant differences in major complications or flap re-explorations between immediate and delayed reconstructions. The total flap failure rate was 1.5 and 2.5% in the immediate and delayed group, respectively. Significantly more hematomas (OR 2.91; 95% CI 1.59–5.30; p = 0.001) and seromas (OR 3.60; 95% CI 1.14–11.4; p = 0.029) occurred in immediate reconstructions, whereas wound problems were more frequently observed in delayed reconstructions (OR 1.99; 95% CI 1.27–3.11; p = 0.003). Correction for potential confounders still showed significant differences for hematoma and seroma, but no longer for wound problems (p = 0.052). Conclusions This study demonstrated similar incidences of major recipient-site complications and flap re-explorations between immediate and delayed DIEP flap breast reconstructions. However, hematoma and seroma occurred significantly more often in immediate reconstructions, while wound problems were more frequently observed in delayed reconstructions. Electronic supplementary material The online version of this article (10.1007/s10549-018-4695-0) contains supplementary material, which is available to authorized users.

Background Restoring the body as normal as possible increases quality of life. Aesthetically, almost perfect breast reconstructions can be created. However, these reconstructed breasts have almost no sensation. Our hypothesis is that if we succeed in restoring sensation, this will increase quality of life. So far, little is written about the phenomenon of breast sensation, which makes it difficult to evaluate whether the quality of life increases after restored sensation. Therefore, the primary goal of this study is to determine what the importance and meaning is of breast sensation among healthy women. Methods A qualitative, descriptive phenomenological study was performed in an academic hospital between October 2016 and March 2017. A total of 10 semi-structured in-depth interviews were conducted in healthy women who did not undergo prior breast surgery. The sample size was based upon ‘saturation’. The interviews were tape-recorded, transcribed verbatim, coded and analysed according to phenomenology keeping in mind the research question ‘what is the importance and meaning of sensation of the breast?’ Results Seven interrelated themes on how sensation of the breast is experienced were found: the absent breast (1), the present breast (2), the well-functioning breast (2a), the feminine breast (2b), the sensual breast (2c), the alien breast (2d), the safe breast (2d). Conclusions The seven interrelated themes can form the basis to develop a quantitative research tool to evaluate quality of life after innervated breast reconstruction and can be implemented in counselling before breast reconstructive surgery in the form of shared treatment decisions.

Aims Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions. Methods and results From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow‐up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow‐up, 177 (18%) developed new‐onset HF. Independent predictors of new‐onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino‐terminal pro‐B type natriuretic peptide and ST2). The c‐statistic for the model without biomarkers was 0.69; including biomarkers increased the c‐statistic to 0.76 (P