Optimal outcomes from cardiac rehabilitation are associated with longer-term follow-up and risk factor status at 12 months : An observational registry-based study

AIM: The purpose of Cardiac Rehabilitation (CR) is to promote and reduce risk factors in the short and long term, however, the latter has, to date, been poorly evaluated. We explored characteristics associated with provision and outcomes of a long-term assessment in CR. METHOD: Data from the UK National Audit of CR between April 2015 and March 2020 was used. Programmes were selected if they had an established mechanism and routine methodology to collect the 12-month assessments. Risk factors pre and post phase II CR and at the 12-month assessment were explored; BMI ≤30, ≥150 min of physical activity per week, hospital anxiety and depression scale (HADS) scores <8. The data came from 32 programmes, 24,644 patients with coronary heart disease. Patients being in at least one optimal risk factor stage throughout phase II CR (OR = 1.43 95% CI 1.28 to 1.59) or successfully reaching an optimal stage during phase II CR (OR = 1.61 95% CI 1.44 to 1.80) had an increased likelihood of being assessed at 12 months compared to those who did not. Patients being in the optimal stage upon completion of phase II CR had an increased likelihood of still being in the optimal stage at 12 months. Most prominent was BMI; (OR = 14.6 (95% CI 11.1 to 19.2) for patients reaching an optimal stage throughout phase II CR. CONCLUSION: Being in an optimal stage upon routine CR completion could be an overlooked predictor in the provision of a long-term CR service and prediction of longer-term risk factor status

Factors Associated with Objectively Assessed Physical Activity Levels of Heart Failure Patients

This is the final version. Available on open access from Longdom Publishing via the DOI in this recordAim: To determine the level of objectively measured moderate-to-vigorous physical activity (MVPA) in patients with heart failure (HF), and to assess the association between MVPA and patient sociodemographic, exercise capacity, and health status factors. Methods: Baseline MVPA data was available in 247 HF patients with 7-day wrist-worn accelerometry from two randomized controlled trials. Associations between MVPA and patient sociodemographic, exercise capacity, and health status factors were assessed using univariate and multivariable linear regression models. Results: 247 patients (28% female, mean age 71 ± 10 years) with HF with reduced ejection fraction (n=198) and preserved ejection fraction (n=49) were included in the analysis. Average MVPA was 283. 3 min/week and ranged widely from a minimum of 0 mins/week to maximum of 2626. 7 mins/week (standard deviation: 404. 1 mins/week). 111 (45%) of patients had a level of PA that met current guidelines of at least 150 minutes/week of MVPA. Multivariable regression showed patient’s age, body mass index, employment status, smoking status, New York Heart Association class, NT-proBNP and exercise capacity to be strongly associated (p<0. 001) with the level of MVPA (p<0. 001). Conclusion: Whilst 45% of HF patients had objectively measured levels of MVPA that met current PA recommendations, we observed a wide range in the level of MVPA across this patient sample. As a number of factors were found to be associated with MVPA our findings provide important information for future interventions aiming to increase MVPA in HF patients.University of ExeterNational Institute for Health Research (NIHR

Preconditioned extracellular vesicles from hypoxic microglia reduce poststroke AQP4 depolarization, disturbed cerebrospinal fluid flow, astrogliosis, and neuroinflammation

Background: Stroke stimulates reactive astrogliosis, aquaporin 4 (AQP4) depolarization and neuroinflammation. Preconditioned extracellular vesicles (EVs) from microglia exposed to hypoxia, in turn, reduce poststroke brain injury. Nevertheless, the underlying mechanisms of such effects are elusive, especially with regards to inflammation, AQP4 polarization, and cerebrospinal fluid (CSF) flow. Methods: Primary microglia and astrocytes were exposed to oxygen-glucose deprivation (OGD) injury. For analyzing the role of AQP4 expression patterns under hypoxic conditions, a co-culture model of astrocytes and microglia was established. Further studies applied a stroke model, where some mice also received an intracisternal tracer infusion of rhodamine B. As such, these in vivo studies involved the analysis of AQP4 polarization, CSF flow, astrogliosis, and neuroinflammation as well as ischemia-induced brain injury. Results: Preconditioned EVs decreased periinfarct AQP4 depolarization, brain edema, astrogliosis, and inflammation in stroke mice. Likewise, EVs promoted postischemic CSF flow and cerebral blood perfusion, and neurological recovery. Under in vitro conditions, hypoxia stimulated M2 microglia polarization, whereas EVs augmented M2 microglia polarization and repressed M1 microglia polarization even further. In line with this, astrocytes displayed upregulated AQP4 clustering and proinflammatory cytokine levels when exposed to OGD, which was reversed by preconditioned EVs. Reduced AQP4 depolarization due to EVs, however, was not a consequence of unspecific inflammatory regulation, since LPS-induced inflammation in co-culture models of astrocytes and microglia did not result in altered AQP4 expression patterns in astrocytes. Conclusions: These findings show that hypoxic microglia may participate in protecting against stroke-induced brain damage by regulating poststroke inflammation, astrogliosis, AQP4 depolarization, and CSF flow due to EV release

An insulin hypersecretion phenotype precedes pancreatic β cell failure in MODY3 patient-specific cells

MODY3 is a monogenic hereditary form of diabetes caused by mutations in the transcription factor HNF1A. The patients progressively develop hyperglycemia due to perturbed insulin secretion, but the pathogenesis is unknown. Using patient-specific hiPSCs, we recapitulate the insulin secretion sensitivity to the membrane depolarizing agent sulfonylurea commonly observed in MODY3 patients. Unexpectedly, MODY3 patient-specific HNF1A+/R272C β cells hypersecrete insulin both in vitro and in vivo after transplantation into mice. Consistently, we identified a trend of increased birth weight in human HNF1A mutation carriers compared with healthy siblings. Reduced expression of potassium channels, specifically the KATP channel, in MODY3 β cells, increased calcium signaling, and rescue of the insulin hypersecretion phenotype by pharmacological targeting ATP-sensitive potassium channels or low-voltage-activated calcium channels suggest that more efficient membrane depolarization underlies the hypersecretion of insulin in MODY3 β cells. Our findings identify a pathogenic mechanism leading to β cell failure in MODY3.Peer reviewe

Long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for 603 838 individuals

Background Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. Methods We identifi ed published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-eff ects meta-analysis to combine eff ect estimates from published and unpublished data. Findings We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5·1 million person-years (mean 8·5 years), in which 4768 events were recorded, and for stroke was 3·8 million person-years (mean 7·2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35–40 h per week), working long hours (≥55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1·13, 95% CI 1·02–1·26; p=0·02) and incident stroke (1·33, 1·11–1·61; p=0·002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and diff erent methods of stroke ascertainment (range of RR estimates 1·30–1·42). We recorded a dose–response association for stroke, with RR estimates of 1·10 (95% CI 0·94–1·28; p=0·24) for 41–48 working hours, 1·27 (1·03–1·56; p=0·03) for 49–54 working hours, and 1·33 (1·11–1·61; p=0·002) for 55 working hours or more per week compared with standard working hours (ptrend<0·0001). Interpretation Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours

METIS - the Mid-infrared E-ELT Imager and Spectrograph

METIS, the Mid-infrared ELT Imager and Spectrograph (formerly called MIDIR), is a proposed instrument for the European Extremely Large Telescope (E-ELT), currently undergoing a phase-A study. The study is carried out within the framework of the ESO-sponsored E-ELT instrumentation studies. METIS will be designed to cover the E-ELT science needs at wavelengths longward of 3um, where the thermal background requires different operating schemes. In this paper we discuss the main science drivers from which the instrument baseline has been derived. Specific emphasis has been given to observations that require very high spatial and spectral resolution, which can only be achieved with a ground-based ELT. We also discuss the challenging aspects of background suppression techniques, adaptive optics in the mid-IR, and telescope site considerations. The METIS instrument baseline includes imaging and spectroscopy at the atmospheric L, M, and N bands with a possible extension to Q band imaging. Both coronagraphy and polarimetry are also being considered. However, we note that the concept is still not yet fully consolidated. The METIS studies are being performed by an international consortium with institutes from the Netherlands, Germany, France, United Kingdom, and Belgium.Comment: 15 pages, to be published in Proc SPIE 7014: Ground-based & Airborne Instrumentation for Astronomy I

Long working hours and risk of 50 health conditions and mortality outcomes : a multicohort study in four European countries

Background: Studies on the association between long working hours and health have captured only a narrow range of outcomes (mainly cardiometabolic diseases and depression) and no outcome-wide studies on this topic are available. To achieve wider scope of potential harm, we examined long working hours as a risk factor for a wide range of disease and mortality endpoints. Methods: The data of this multicohort study were from two population cohorts from Finland (primary analysis, n=59 599) and nine cohorts (replication analysis, n=44 262) from Sweden, Denmark, and the UK, all part of the Individual-participant Meta-analysis in Working Populations (IPD-Work) consortium. Baseline assessed long working hours (>55 hours per week) were compared to standard working hours (35-40 h). Outcome measures with follow-up until age 65 years were 46 diseases that required hospital treatment or continuous pharmacotherapy, all-cause, and three cause-specific mortality endpoints, ascertained via linkage to national health and mortality registers. Findings: 2747 (4.6%) participants in the primary cohorts and 3027 (6.8%) in the replication cohorts worked long hours. After adjustment for age, sex, and socioeconomic status, working long hours was associated with increased risk of cardiovascular death (hazard ratio 1.68; 95% confidence interval 1.08-2.61 in primary analysis and 1.52; 0.90-2.58 in replication analysis), infections (1.37; 1.13-1.67 and 1.45; 1.13-1.87), diabetes (1.18; 1.01-1.38 and 1.41; 0.98-2.02), injuries (1.22; 1.00-1.50 and 1.18; 0.98-1.18) and musculoskeletal disorders (1.15; 1.06-1.26 and 1.13; 1.00-1.27). Working long hours was not associated with all-cause mortality. Interpretation: Follow-up of 50 health outcomes in four European countries suggests that working long hours is associated with an elevated risk of early cardiovascular death and hospital-treated infections before age 65. Associations, albeit weak, were also observed with diabetes, musculoskeletal disorders and injuries. In these data working long hours was not related to elevated overall mortality. (C) 2021 The Authors. Published by Elsevier Ltd.Peer reviewe

Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease

<p>Abstract</p> <p>Background</p> <p>Endothelin-1 and angiotensin II are strong vasoconstrictors. Patients with ischemic heart disease have elevated plasma levels of endothelin-1 and angiotensin II and show increased vascular tone. The aim of the present study was to examine the endothelin and angiotensin II receptor expression in subcutaneous arteries from patients with different degrees of ischemic heart disease.</p> <p>Methods</p> <p>Subcutaneous arteries were obtained, by biopsy from the abdomen, from patients undergoing coronary artery bypass graft (CABG) surgery because of ischemic heart disease (n = 15), patients with angina pectoris without established myocardial infarction (n = 15) and matched cardiovascular healthy controls (n = 15). Endothelin type A (ET_A) and type B (ET_B), and angiotensin type 1 (AT₁) and type 2 (AT₂) receptors expression and function were examined using immunohistochemistry, Western blot and <it>in vitro </it>pharmacology.</p> <p>Results</p> <p>ET_Aand, to a lesser extent, ET_Breceptor staining was observed in the healthy vascular smooth muscle cells. The level of ET_Breceptor expression was higher in patients undergoing CABG surgery (250% ± 23%; P < 0.05) and in the patients with angina pectoris (199% ± 6%; P < 0.05), than in the healthy controls (100% ± 28%). The data was confirmed by Western blotting. Arteries from CABG patients showed increased vasoconstriction upon administration of the selective ET_Breceptor agonist sarafotoxin S6c, compared to healthy controls (P < 0.05). No such difference was found for the ET_Areceptors. AT₁and, to a lesser extent, AT₂receptor immunostaining was seen in the vascular smooth muscle cells. The level of AT₁receptor expression was higher in both the angina pectoris (128% ± 25%; P < 0.05) and in the CABG patients (203% ± 41%; P < 0.05), as compared to the healthy controls (100% ± 25%). The increased AT₁receptor expression was confirmed by Western blotting. Myograph experiment did however not show any change in vasoconstriction to angiotensin II in CABG patients compared to healthy controls (P = n.s).</p> <p>Conclusion</p> <p>The results demonstrate, for the first time, upregulation of ET_Band AT₁receptors in vascular smooth muscle cells in ischemic heart disease. These receptors may play a role in the pathophysiology of ischemic heart disease and could provide important targets for pharmaceutical interventions.</p

IL-33 Induces IL-9 Production in Human CD4+ T Cells and Basophils

IL-33, an IL-1 family member and ligand for the IL-1 receptor-related protein ST2, has been associated with induction of Th2 cytokines such as IL-4, IL-5, and IL-13. Here, we report that IL-33 can initiate IL-9 protein secretion in vitro in human CD4+ T cells and basophils isolated from peripheral blood. TGF-β has been described as a critical factor for IL-9 induction in Th2 cells; however, we found that TGF-β also induces co-production of IL-9 in purified, naïve (>99%) CD4+CD45RA+CD45RO−CD25− T cells differentiated towards a Th1 profile. Subsequently, it was demonstrated that TGF-β is important, although not an absolute requirement, for IL-9 production in CD4+ T cells. IL-9 production by purified (>95%) human basophils, cultured for 24 h with IL-3 or IL-33, was found, with a strong synergy between the two, likely to be explained by the IL-3 upregulated ST2 expression. Collectively, these data indicate that barrier functioning cells are important for the regulation of IL-9 production by immune cells in inflamed tissue

Job Strain as a Risk Factor for Peripheral Artery Disease : A Multi-Cohort Study

Background Job strain is implicated in many atherosclerotic diseases, but its role in peripheral artery disease (PAD) is unclear. We investigated the association of job strain with hospital records of PAD, using individual-level data from 11 prospective cohort studies from Finland, Sweden, Denmark, and the United Kingdom. Methods and Results Job strain (high demands and low control at work) was self-reported at baseline (1985-2008). PAD records were ascertained from national hospitalization data. We used Cox regression to examine the associations of job strain with PAD in each study, and combined the study-specific estimates in random effects meta-analyses. We used tau(2), I-2, and subgroup analyses to examine heterogeneity. Of the 139 132 participants with no previous hospitalization with PAD, 32 489 (23.4%) reported job strain at baseline. During 1 718 132 person-years at risk (mean follow-up 12.8 years), 667 individuals had a hospital record of PAD (3.88 per 10 000 person-years). Job strain was associated with a 1.41-fold (95% CI, 1.11-1.80) increased average risk of hospitalization with PAD. The study-specific estimates were moderately heterogeneous (tau(2)=0.0427, I-2: 26.9%). Despite variation in their magnitude, the estimates were consistent in both sexes, across the socioeconomic hierarchy and by baseline smoking status. Additional adjustment for baseline diabetes mellitus did not change the direction or magnitude of the observed associations. Conclusions Job strain was associated with small but consistent increase in the risk of hospitalization with PAD, with the relative risks on par with those for coronary heart disease and ischemic stroke.Peer reviewe