A pragmatic effectiveness-implementation study comparing trial evidence with routinely collected outcome data for patients receiving the REACH-HF home-based cardiac rehabilitation programme.

BACKGROUND: Cardiac rehabilitation for heart failure continues to be greatly underused worldwide despite being a Class I recommendation in international clinical guidelines and uptake is low in women and patients with mental health comorbidities. METHODS: Rehabilitation EnAblement in CHronic Heart Failure (REACH-HF) programme was implemented in four UK National Health Service early adopter sites ('Beacon Sites') between June 2019 and June 2020. Implementation and patient-reported outcome data were collected across sites as part of the National Audit of Cardiac Rehabilitation. The change in key outcomes before and after the supervised period of REACH-HF intervention across the Beacon Sites was assessed and compared to those of the intervention arm of the REACH-HF multicentre trial. RESULTS: Compared to the REACH-HF multicentre trial, patients treated at the Beacon Site were more likely to be female (33.8% vs 22.9%), older (75.6 vs 70.1), had a more severe classification of heart failure (26.5% vs 17.7%), had poorer baseline health-related quality of life (MLHFQ score 36.1 vs 31.4), were more depressed (HADS score 6.4 vs 4.1) and anxious (HADS score 7.2 vs 4.7), and had lower exercise capacity (ISWT distance 190 m vs 274.7 m). There appeared to be a substantial heterogeneity in the implementation process across the four Beacon Sites as evidenced by the variation in levels of patient recruitment, operationalisation of the REACH-HF intervention and patient outcomes. Overall lower improvements in patient-reported outcomes at the Beacon Sites compared to the trial may reflect differences in the population studied (having higher morbidity at baseline) as well as the marked challenges in intervention delivery during the COVID-19 pandemic. CONCLUSION: The results of this study illustrate the challenges in consistently implementing an intervention (shown to be clinically effective and cost-effective in a multicentre trial) into real-world practice, especially in the midst of a global pandemic. Further research is needed to establish the real-world effectiveness of the REACH-HF intervention in different populations.

A systematic review of provider-and system-level factors influencing the delivery of cardiac rehabilitation for heart failure.

BACKGROUND: There is a longstanding research-to-practice gap in the delivery of cardiac rehabilitation for patients with heart failure. Despite adequate evidence confirming that comprehensive cardiac rehabilitation can improve quality of life and decrease morbidity and mortality in heart failure patients, only a fraction of eligible patients receives it. Many studies and reviews have identified patient-level barriers that might contribute to this disparity, yet little is known about provider- and system-level influences. METHODS: A systematic review using narrative synthesis. The aims of the systematic review were to a) determine provider- and system-level barriers and enablers that affect the delivery of cardiac rehabilitation for heart failure and b) juxtapose identified barriers with possible solutions reported in the literature. A comprehensive search strategy was applied to the MEDLINE, Embase, PsycINFO, CINAHL Plus, EThoS and ProQuest databases. Articles were included if they were empirical, peer-reviewed, conducted in any setting, using any study design and describing factors influencing the delivery of cardiac rehabilitation for heart failure patients. Data were synthesised using inductive thematic analysis and a triangulation protocol to identify convergence/contradiction between different data sources. RESULTS: Seven eligible studies were identified. Thematic analysis identified nine overarching categories of barriers and enablers which were classified into 24 and 26 themes respectively. The most prevalent categories were 'the organisation of healthcare system', 'the organisation of cardiac rehabilitation programmes', 'healthcare professional' factors and 'guidelines'. The most frequent themes included 'lack of resources: time, staff, facilities and equipment' and 'professional's knowledge, awareness and attitude'. CONCLUSIONS: Our systematic review identified a wide range of provider- and system-level barriers impacting the delivery of cardiac rehabilitation for heart failure, along with a range of potential solutions. This information may be useful for healthcare professionals to deliver, plan or commission cardiac rehabilitation services, as well as future research.

Anti-TNFα therapy transiently improves high density lipoprotein cholesterol levels and microvascular endothelial function in patients with rheumatoid arthritis: a pilot study.

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased morbidity and mortality from cardiovascular disease (CVD). This can be only partially attributed to traditional CVD risk factors such as dyslipidaemia and their downstream effects on endothelial function. The most common lipid abnormality in RA is reduced levels of high-density lipoprotein (HDL) cholesterol, probably due to active inflammation. In this longitudinal study we hypothesised that anti-tumor necrosis factor-α (anti-TNFα) therapy in patients with active RA improves HDL cholesterol, microvascular and macrovascular endothelial function. METHODS: Twenty-three RA patients starting on anti-TNFα treatment were assessed for HDL cholesterol level, and endothelial-dependent and -independent function of microvessels and macrovessels at baseline, 2-weeks and 3 months of treatment. RESULTS: Disease activity (CRP, fibrinogen, DAS28) significantly decreased during the follow-up period. There was an increase in HDL cholesterol levels at 2 weeks (p < 0.05) which was paralleled by a significant increase in microvascular endothelial-dependent function (p < 0.05). However, both parameters returned towards baseline at 12 weeks. CONCLUSION: Anti-TNFα therapy in RA patients appears to be accompanied by transient but significant improvements in HDL cholesterol levels, which coexists with an improvement in microvascular endothelial-dependent function.

Cognitive ability in early adulthood is associated with systemic inflammation in middle age: the Vietnam experience study.

We examined the prospective association between cognitive ability in early adulthood and erythrocyte sedimentation rate, a marker of inflammation, in middle age. Participants were 4256 male Vietnam era US veterans. Data on cognitive ability, assessed by the Army General Technical Test, ethnicity, and place of service were extracted from enlistment files. Smoking behaviour, alcohol consumption, basic socio-demographics, and whether participants suffered from a physician diagnosed chronic disease were determined by telephone interview in middle-age in 1985. Erythrocyte sedimentation rate, cholesterol, blood pressure, height, and weight were measured at a 3-day medical examination in 1986. In linear regression models that adjusted for age and then additionally for circumstantial, socio-demographic, lifestyle, and health factors, poor cognitive ability in early adulthood was associated with greater erythrocyte sedimentation rate in middle age, ß=-.09. Thus, it would appear that not only does systemic inflammation influence cognition, but also that poor cognitive ability earlier in life is associated with inflammation in middle-age.

Position Statement on Exercise Dosage in Rheumatic and Musculoskeletal Diseases: The Role of the IMPACT-RMD Toolkit.

There is convincing evidence to suggest that exercise interventions can significantly improve disease-related outcomes as well as comorbidities in rheumatic and musculoskeletal diseases (RMDs). All exercise interventions should be appropriately defined by their dose, which comprises of two components: a) the FITT (frequency, intensity, time and type) and b) the training (ie, specificity, overload, progression, initial values, reversibility, and diminishing returns) principles. In the published RMD literature, exercise dosage is often misreported, which in "pharmaceutical treatment terms", this would be the equivalent of receiving the wrong medication dosage. Lack of appropriately reporting exercise dosage in RMDs, therefore, results in limited clarity on the effects of exercise interventions on different outcomes while it also hinders reproducibility, generalisability and accuracy of research findings. Based on the collective but limited current knowledge, the main purpose of the present Position Statement is to provide specific guidance for RMD researchers to help improve the reporting of exercise dosage and help advance research into this important field of investigation. We also propose the use of the IMPACT-RMD toolkit, a tool that can be used in the design and reporting phase of every trial.

Mental Health and Psychological Wellbeing in Rheumatoid Arthritis during COVID-19 - Can Physical Activity Help?

In response to the COVID-19 pandemic, many countries have adopted community containment to manage COVID-19. These measures to reduce human contact, such as social distancing, are deemed necessary to contain the spread of the virus and protect those at increased risk of developing complications following infection with COVID-19. People with rheumatoid arthritis (RA) are advised to adhere to even more stringent restrictions compared to the general population, and avoid any social contact with people outside their household. This social isolation combined with the anxiety and stress associated with the pandemic, is likely to particularly have an impact on mental health and psychological wellbeing in people with RA. Increasing physical activity and reducing sedentary behaviour can improve mental health and psychological wellbeing in RA. However, COVID-19 restrictions make it more difficult for people with RA to be physically active and facilitate a more sedentary lifestyle. Therefore, guidance is necessary for people with RA to adopt a healthy lifestyle within the constraints of COVID-19 restrictions to support their mental health and psychological wellbeing during and after the COVID-19 pandemic.

Mobilization of gammadelta T lymphocytes in response to psychological stress, exercise, and beta-agonist infusion.

The mobilization of cytotoxic lymphocytes, such Natural Killer (NK) cells and CD8(+) T cells, during stress and exercise is well documented in humans. However, humans have another cytotoxic lymphocyte subset that has not been studied in this context: the Gamma Delta (gammadelta) T lymphocyte. These cells play key roles in immune processes including the elimination of bacterial infection, wound repair and delayed-type hypersensitivity reactions. The current study investigated the effects of stress, exercise, and beta-agonist infusion on the mobilization of gammadelta T lymphocytes. Three separate studies compared lymphocytosis in response to an acute speech stress task (n=29), high (85%W(max)) and low (35%W(max)) intensity concentric exercise (n=11), and isoproterenol infusion at 20 and 40 ng/kg/min (n=12). Flow cytometric analysis was used to examine lymphocyte subsets. gammadelta T lymphocytes were mobilized in response to all three tasks in a dose-dependent manner; the extent of mobilization during the speech task correlated with concomitant cardiac activation, and was greater during higher intensity exercise and increased dose of beta-agonist infusion. The mobilization of gammadelta T lymphocytes was greater (in terms of % change from baseline) than that of CD8(+) T lymphocytes and less than NK cells. This study is the first to demonstrate that gammadelta T cells are stress-responsive lymphocytes which are mobilized during psychological stress, exercise, and beta-agonist infusion. The mobilization of these versatile cytotoxic cells may provide protection in the context of situations in which antigen exposure is more likely to occur.

Acute exercise mobilises CD8+ T lymphocytes exhibiting an effector-memory phenotype.

An acute bout of exercise evokes mobilisation of lymphocytes into the bloodstream, which can be largely attributed to increases in CD8+ T lymphocytes (CD8TLs) and natural killer (NK) cells. Evidence further suggests that, even within these lymphocyte subsets, there is preferential mobilisation of cells that share certain functional and phenotypic characteristics, such as high cytotoxicity, low proliferative ability, and high tissue-migrating potential. These features are characteristic of effector-memory CD8TL subsets. The current study therefore investigated the effect of exercise on these newly-identified subsets. Thirteen healthy and physically active males (mean+/-SD: age 20.9+/-1.5 yr) attended three sessions: a control session (no exercise); cycling at 35% Watt(max) (low intensity exercise); and 85% Watt(max) (high intensity exercise). Each bout lasted 20 min. Blood samples were obtained before exercise, during the final min of exercise, and +15, and +60 min post-exercise. CD8TLs were classified into naïve, central memory (CM), effector-memory (EM), and CD45RA+ effector-memory (RAEM) using combinations of the cell surface markers CCR7, CD27, CD62L, CD57, and CD45RA. In parallel, the phenotypically distinct CD56(bright) 'regulatory' and CD56(dim) 'cytotoxic' NK subsets were quantified. The results show a strong differential mobilisation of CD8TL subsets (RAEM>EM>CM>naïve); during high intensity exercise the greatest increase was observed for RAEM CD8Tls (+450%) and the smallest for naïve cells (+84%). Similarly, CD56(dim) NK cells (+995%) were mobilised to a greater extent than CD56(bright) (+153%) NK cells. In conclusion, memory CD8TL that exhibit a high effector and tissue-migrating potential are preferentially mobilised during exercise. This finding unifies a range of independent observations regarding exercise-induced phenotypic and functional changes in circulating lymphocytes. The selective mobilisation of cytotoxic tissue-migrating subsets, both within the NK and CD8TL population, may enhance immune-surveillance during exercise.

Inflammation and vascular responses to acute mental stress: implications for the triggering of myocardial infarction.

There is evidence that mental stress can trigger myocardial infarction. Even though the underlying mechanisms remain to be determined, both inflammation and vascular responses to mental stress have been implicated as contributing factors. This review explores the effects of inflammation on the vascular responses to mental stress. First, the associations between inflammation and resting vascular function are discussed. It is known that increases in inflammation are associated with endothelial dysfunction, with a reduction in nitric oxide a common pathway through which inflammation can influence endothelial function. Second, the effects of mental stress on vascular responses are reviewed. There is ample evidence that in healthy participants, mental stress induces increases in forearm blood flow, which is impaired in those at risk for cardiovascular disease. Even though several mechanisms are discussed, there is evidence that nitric oxide plays an important role in stress-induced vasodilation. Finally, the influences of inflammation on the vascular responses are described. It is hypothesised that inflammation can alter vascular responses to mental stress, most likely due to lower levels of nitric oxide as a result of the inflammation. This poorer vascular response is thought to be an underlying factor through which mental stress can trigger myocardial infarction.

The endothelium and its role in regulating vascular tone.

The endothelium forms an important part of the vasculature and is involved in promoting an atheroprotective environment via the complementary actions of endothelial cell-derived vasoactive factors. Disruption of vascular homeostasis can lead to the development of endothelial dysfunction which in turn contributes to the early and late stages of atherosclerosis. In recent years an increasing number of non-invasive vascular tests have been developed to assess vascular structure and function in different clinical populations. The present review aims to provide an insight into the anatomy of the vasculature as well as the underlying endothelial cell physiology. In addition, an in-depth overview of the current methods used to assess vascular function and structure is provided as well as their link to certain clinical populations.

Vascular function and inflammation in rheumatoid arthritis: the role of physical activity.

Inflammation disturbs biochemical pathways involved in homeostasis of the endothelium. Research has established clear links between inflammatory mediators, particularly C-reactive protein and tumour necrosis factor alpha, endothelial dysfunction, and atherosclerosis. Endothelial dysfunction and atherosclerosis may be subclinical at early stages, and thus the ability to detect them with non-invasive techniques is crucially important, particularly in populations at increased risk for cardiovascular disease, such as those with rheumatoid arthritis. This may allow the identification of interventions that may reverse these processes early on. One of the best non-pharmacological interventions that may achieve this is physical activity. This review explores the associations between inflammation, endothelial dysfunction, and atherosclerosis and discusses the role of exercise in blocking specific pathways in the inflammation, endothelial dysfunction - atherosclerosis network.

Redefining overweight and obesity in rheumatoid arthritis patients.

OBJECTIVES: To assess whether body mass index (BMI) and body fat (BF) differ between rheumatoid arthritis (RA) patients, patients with non-inflammatory arthritis (osteoarthritis, OA) and healthy individuals, and whether disease specific measures of adiposity are required to accurately reflect BF in these groups. METHODS: 641 individuals were assessed for BMI (kg/m(2)) and BF (bioelectrical impedance). Of them, 299 (174 RA, 43 OA and 82 healthy controls (HC)) formed the observation group and 342 (all RA) the validation group. RA disease characteristics were collected. RESULTS: ANOVA revealed significant differences between disease groups for BMI (p<0.05) and BF (p<0.001). ANCOVA showed that age accounted for the differences in BMI (F(1,294) = 5.10, p<0.05); age (F(1,293) = 22.43, p<0.001), sex (F(1,293) = 380.90, p<0.001) and disease (F(2, 293) = 18.7, p<0.001) accounted for the differences in BF. For a given BF, patients with RA exhibited BMI levels reduced by 1.83 kg/m(2) (p<0.001) compared to HC; there were no significant differences between OA and HC. A predictive model for BF was developed (R(2) = 0.769, p<0.001) and validated using limits of agreement Analysis against measured BF in the validation group (95%LIM(AG) = 6.17; CV = 8.94). CONCLUSIONS: In individuals with RA, BMI cut-off points should be reduced by 2 kg/m(2) (that is, to 23 kg/m(2) for overweight and 28 kg/m(2) for obesity). The equation developed can be used to accurately predict BF from BMI in RA patients. These findings may be important in the context of the cardiovascular comorbidity of RA.