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OBJECTIVE: Long COVID can include impaired cognition ('brain fog'; a term encompassing multiple symptoms) and mental health conditions. We performed a systematic review and meta-analysis to estimate their prevalence and to explore relevant factors associated with the incidence of impaired cognition and mental health conditions. METHODS: Searches were conducted in Medline and PsycINFO to cover the start of the pandemic until August 2023. Included studies reported prevalence of mental health conditions and brain fog in adults with long COVID after clinically-diagnosed or PCR-confirmed SARS-CoV-2 infection. FINDINGS: 17 studies were included, reporting 41,249 long COVID patients. Across all timepoints (3-24 months), the combined prevalence of mental health conditions and brain fog was 20·4% (95% CI 11·1%-34·4%), being lower among those previously hospitalised than in community-managed patients(19·5 vs 29·7% respectively; p = 0·047). The odds of mental health conditions and brain fog increased over time and when validated instruments were used. Odds of brain fog significantly decreased with increasing vaccination rates (p = ·000). CONCLUSIONS: Given the increasing prevalence of mental health conditions and brain fog over time, preventive interventions and treatments are needed. Research is needed to explore underlying mechanisms that could inform further research in development of effective treatments. The reduced risk of brain fog associated with vaccination emphasizes the need for ongoing vaccination programs.

INTRODUCTION: Oxidative stress is one of many factors suspected to promote antinuclear autoantibody (ANA) formation. Reactive oxygen species can induce changes in the antigenic structure of macromolecules, causing the immune system to treat them as "neo-antigens" and start production of autoantibodies. This study was designed to evaluate the relationship between oxidative stress markers, lifestyle factors and the detection of ANA. MATERIAL AND METHODS: We examined measures of oxidative stress indices of free-radical damage to lipids and proteins, such as total oxidant status (TOS), concentration of protein thiol groups (PSH), and malondialdehyde (MDA), activity of superoxide dismutase (SOD) in 1731 serum samples. The parameters of the non-enzymatic antioxidant system, such as total antioxidant status (TAS) and uric acid (UA) concentration, were also measured and the oxidative stress index (OSI-index) was calculated. All samples were tested for the presence of ANA using an indirect immunofluorescence assay (IIFA). RESULTS: The presence of ANA in women was associated with lower physical activity (p = 0.036), less frequent smoking (p = 0.007) and drinking of alcohol (p = 0.024) accompanied by significant changes in SOD isoenzymes activity (p < 0.001) and a higher uric acid (UA) concentration (p < 0.001). In ANA positive males we observed lower concentrations of PSH (p = 0.046) and increased concentrations of MDA (p = 0.047). CONCLUSIONS: The results indicate that local oxidative stress may be associated with increased probability of ANA formation in a sex-specific manner.

Aim: To investigate the effectiveness of exercise and the most effective types of exercise for patients with atrial fibrillation (AF) to improve health-related quality of life (HRQoL) and exercise capacity, and reduce AF burden, AF recurrence and adverse events. Methods and results: Systematic search in PubMed, Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL Plus, and SPORTDiscus for randomized controlled trials (RCTs) and nonrandomized pre-post intervention studies investigating the effect of different types of exercise on AF patients. After exclusion, 12 studies (11 RCTs, 1 prepost) with a total of 670 participants were included. Exercise interventions consisted of aerobic exercise, aerobic interval training (AIT), Qigong, yoga, and exercise-based cardiac rehabilitation (CR). There were significant positive effects of exercise on general health {mean difference [MD] = 6.42 [95% confidence interval (CI): 2.90, 9.93]; P = 0.0003; I2 = 17%} and vitality [MD = 6.18 (95% CI: 1.94, 10.41); P = 0.004; I2 = 19%)] sub-scales of the Short Form 36-item questionnaire (SF-36). Qigong resulted in a significant improvement in the 6-min walk test [MD = 105.00m (95% CI: 19.53, 190.47)]. Exercise-based CR and AIT were associated with a significant increment in V̇O2peak, and AIT significantly reduced AF burden. Adverse events were few and one intervention-related serious adverse event was reported for exercise-based CR. Conclusion: Exercise led to improvements in HRQoL, exercise capacity, and reduced AF burden. The available exercise interventions for AF patients are few and heterogeneous. Future studies are needed for all types of exercise intervention in this patient group to (co-)develop an optimized exercise training intervention for AF patients.

The detection of antinuclear autoantibody (ANA) is dependent on many factors and varies between the populations. The aim of the study was first to assess the prevalence of ANA in the Polish adult population depending on age, sex and the cutoff threshold used for the results obtained. Second, we estimated the occurrence of individual types of ANA-staining patterns. We tested 1731 patient samples using commercially available IIFA using two cutoff thresholds of 1:100 and 1:160. We found ANA in 260 participants (15.0%), but the percentage of positive results strongly depended on the cutoff level. For a cutoff threshold 1:100, the positive population was 19.5% and for the 1:160 cutoff threshold, it was 11.7%. The most prevalent ANA-staining pattern was AC-2 Dense Fine speckled (50%), followed by AC-21 Reticular/AMA (14.38%) ANA more common in women (72%); 64% of ANA-positive patients were over 50 years of age. ANA prevalence in the Polish population is at a level observed in other highly developed countries and is more prevalent in women and elderly individuals. To reduce the number of positive results released, we suggest that Polish laboratories should set 1:160 as the cutoff threshold.

INTRODUCTION: As mortality rates from COVID-19 disease fall, the high prevalence of long-term sequelae (Long COVID) is becoming increasingly widespread, challenging healthcare systems globally. Traditional pathways of care for Long Term Conditions (LTCs) have tended to be managed by disease-specific specialties, an approach that has been ineffective in delivering care for patients with multi-morbidity. The multi-system nature of Long COVID and its impact on physical and psychological health demands a more effective model of holistic, integrated care. The evolution of integrated care systems (ICSs) in the UK presents an important opportunity to explore areas of mutual benefit to LTC, multi-morbidity and Long COVID care. There may be benefits in comparing and contrasting ICPs for Long COVID with ICPs for other LTCs. METHODS AND ANALYSIS: This study aims to evaluate health services requirements for ICPs for Long COVID and their applicability to other LTCs including multi-morbidity and the overlap with medically not yet explained symptoms (MNYES). The study will follow a Delphi design and involve an expert panel of stakeholders including people with lived experience, as well as clinicians with expertise in Long COVID and other LTCs. Study processes will include expert panel and moderator panel meetings, surveys, and interviews. The Delphi process is part of the overall STIMULATE-ICP programme, aimed at improving integrated care for people with Long COVID. ETHICS AND DISSEMINATION: Ethical approval for this Delphi study has been obtained (Research Governance Board of the University of York) as have approvals for the other STIMULATE-ICP studies. Study outcomes are likely to inform policy for ICPs across LTCs. Results will be disseminated through scientific publication, conference presentation and communications with patients and stakeholders involved in care of other LTCs and Long COVID. REGISTRATION: Researchregistry: https://www.researchregistry.com/browse-the-registry#

© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation Background: Atrial fibrillation (AF) and hypertension are independently associated with impaired autonomic function determined using heart rate variability (HRV). As these conditions frequently co-exist, we sought to determine whether AF would worsen HRV in hypertensive patients. Design: We studied HRV in AF (and hypertension) (n = 61) and hypertension control group (n = 33). The AF (and hypertension) group was subdivided into permanent AF (n = 30) and paroxysmal AF (n = 31) and re-studied. Time-domain, frequency-domain and nonlinear measures of HRV were determined. Permanent AF group (n = 30) was followed up after 8 weeks following optimisation of their heart rate and blood pressure (BP). Results: Time-domain and nonlinear indices of HRV were higher in AF (and hypertension) group compared to hypertensive controls (P ≤.01). Time-domain and nonlinear indices of HRV were higher in permanent AF group compared to paroxysmal AF (P ≤.001). Permanent AF was an independent predictor of HRV on multivariable analysis (P =.006). Optimisation of heart rate and BP had no significant impact on HRV in permanent AF. Conclusions: AF, independent of hypertension, is characterised with marked HRV and is possibly related to vagal tone. HRV is higher in permanent AF compared to paroxysmal AF suggesting evident autonomic influence in the pathophysiology of permanent AF. Modulation of autonomic influence on cardiovascular system should be explored in future studies.

BACKGROUND: The RE-DUAL PCI trial demonstrated that in patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), dual therapy with dabigatran and a P2Y12 inhibitor, either clopidogrel or ticagrelor, reduced the risk of bleeding without an increased risk of thromboembolic events as compared to triple therapy with warfarin in addition to a P2Y12 inhibitor and aspirin. What remains unclear is whether this effect is consistent between males and females undergoing PCI. HYPOTHESIS: The reduction in risk of bleeding without increased risk of thromboembolic events with dual therapy with dabigatran and a P2Y12 inhibitor in comparison to triple therapy with warfarin, a P2Y12 inhibitor and aspirin is consistent in females and males. METHODS: The primary safety endpoint was the first International Society on Thrombosis and Hemostasis (ISTH) major bleeding event (MBE) or clinically relevant non-major bleeding event (CRNMBE). The efficacy endpoint was the composite of death, thromboembolic event (stroke, myocardial infarction, and systemic embolism) or unplanned revascularization. Cox proportional hazard regression analyses were applied to calculate corresponding hazard ratios and interaction p values for each endpoint. RESULTS: A total of 655 women and 2070 men were enrolled. The risk of major or CRNM bleeding was lower with both dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy compared with warfarin triple therapy in female and male patients (for 110 mg: females: HR 0.69, 95% CI 0.47-1.01, males: HR 0.46, 95% CI 0.37-0.59, interaction p value: 0.084 and for 150 mg: females HR 0.74, 95% CI 0.48-1.16, males HR 0.71, 95% CI 0.56-0.90, interaction p value: 0.83). There was also no detectable difference in the composite efficacy endpoint of death, thromboembolic events or unplanned revascularization between dabigatran dual therapy and warfarin triple therapy, with no statistically significant interaction between sex and

Acceptance and commitment therapy (ACT) is an adapted form of cognitive behavioural therapy. ACT focuses on how thinking affects behaviour and promotes psychological flexibility. The prevalence of psychological distress among people living with cardiovascular disease (CVD) and/or type 2 diabetes mellitus (T2DM) is high, and ACT may offer an alternative treatment approach. This scoping review explored the use of ACT as an intervention to support adults living with CVD and/or T2DM. A systematic search of the literature resulted in the inclusion of 15 studies. Studies were reviewed using the Joanna Briggs Institute approach to conducting scoping reviews. Most studies (n = 13) related to people living with T2DM, and most (n = 10) used a pre-post design, four studies were randomised controlled trials, and one was a qualitative study. Eight studies reported an improvement in the outcome(s) assessed post-intervention, suggesting that ACT was an acceptable and valid intervention to support people living with CVD or T2DM. However, studies were underpowered and only limited studies involved people living with CVD. ACT was assessed as a valuable approach to improve a range of patient-reported outcomes for those living with CVD or T2DM, and further research involving robust study designs and larger cohorts are warranted.

AIMS: Cardiovascular diseases (CVDs) increase mortality risk from coronavirus infection (COVID-19). There are also concerns that the pandemic has affected supply and demand of acute cardiovascular care. We estimated excess mortality in specific CVDs, both 'direct', through infection, and 'indirect', through changes in healthcare. METHODS AND RESULTS: We used (i) national mortality data for England and Wales to investigate trends in non-COVID-19 and CVD excess deaths; (ii) routine data from hospitals in England (n = 2), Italy (n = 1), and China (n = 5) to assess indirect pandemic effects on referral, diagnosis, and treatment services for CVD; and (iii) population-based electronic health records from 3 862 012 individuals in England to investigate pre- and post-COVID-19 mortality for people with incident and prevalent CVD. We incorporated pre-COVID-19 risk (by age, sex, and comorbidities), estimated population COVID-19 prevalence, and estimated relative risk (RR) of mortality in those with CVD and COVID-19 compared with CVD and non-infected (RR: 1.2, 1.5, 2.0, and 3.0).Mortality data suggest indirect effects on CVD will be delayed rather than contemporaneous (peak RR 1.14). CVD service activity decreased by 60-100% compared with pre-pandemic levels in eight hospitals across China, Italy, and England. In China, activity remained below pre-COVID-19 levels for 2-3 months even after easing lockdown and is still reduced in Italy and England. For total CVD (incident and prevalent), at 10% COVID-19 prevalence, we estimated direct impact of 31 205 and 62 410 excess deaths in England (RR 1.5 and 2.0, respectively), and indirect effect of 49 932 to 99 865 deaths. CONCLUSION: Supply and demand for CVD services have dramatically reduced across countries with potential for substantial, but avoidable, excess mortality during and after the pandemic.

A nationwide cross-sectional study, LIPIDOGRAM2015, was carried out in Poland in the years 2015 and 2016. A total of 438 primary care physicians enrolled 13,724 adult patients that sought medical care in primary health care practices. The prevalence of hypertension, diabetes mellitus, dyslipidaemia, and CVD were similar in urban and rural areas (49.5 vs. 49.4%; 13.7 vs. 13.1%; 84.2 vs. 85.2%; 14.4 vs. 14.2%, respectively). The prevalence of obesity (32.3 vs. 37.5%, p < 0.01) and excessive waist circumference (77.5 vs. 80.7%, p < 0.01), as well as abdominal obesity (43.2 vs. 46.4%, p < 0.01), were higher in rural areas in both genders. Mean levels of LDL-C (128 vs. 130 mg/dL, p = 0.04) and non-HDL-C (147 vs. 148 mg/dL, p = 0.03) were slightly higher in rural populations. Altogether, 14.3% of patients with CVD from urban areas and 11.3% from rural areas reached LDL <70 mg/dL (p = 0.04). There were no important differences in the prevalence of hypertension, diabetes, dyslipidaemia, and CVD, or in mean levels of blood pressure, cholesterol fractions, glucose, and HbA1c between Polish urban and rural primary care patient populations. A high proportion of patients in cities and an even-higher proportion in rural areas did not reach the recommended targets for blood pressure, LDL-C, and HbA1c, indicating the need for novel CVD-prevention programs.

BACKGROUND: The purpose of the study was to evaluate secondary stroke prevention in Poland and its association with sociodemographic factors, place of residence, and concomitant cardiovascular risk factors. MATERIAL AND METHODS: From all patients in LIPIDOGRAM2015 Study (n = 13,724), 268 subjects had a history of ischaemic stroke and were included. RESULTS: 165 subjects (61.6%) used at least one preventive medication. Oral antiplatelet and anticoagulation agents were used by 116 (43.3%) and 70 (26.1%) patients, respectively. Only 157 (58.6%) participants used lipid-lowering drugs, and 205 (76.5%) were treated with antihypertensive drugs. Coronary heart disease (CHD) and dyslipidaemia were associated with antiplatelet treatment (p = 0.047 and p = 0.012, respectively). A history of atrial fibrillation, CHD, and previous myocardial infarction correlated with anticoagulant treatment (p = 0.001, p = 0.011, and p < 0.0001, respectively). Age, gender, time from stroke onset, place of residence, and level of education were not associated with antiplatelet or anticoagulant treatment. Only 31.7% of patients were engaged in regular physical activity, 62% used appropriate diet, and 13.6% were current smokers. CONCLUSIONS: In Poland drugs and lifestyle modification for secondary stroke prevention are not commonly adhered to. Educational programmes for physicians and patients should be developed to improve application of effective secondary prevention of stroke.

BACKGROUND: Cardiac rehabilitation (CR) is an essential component of long-term recovery following a cardiac event. Typical CR may not be optimal for patients presenting with sarcopenic obesity (SO) who present with reduced muscle mass and elevated adipose tissue, and may indicate greater cardiovascular disease (CVD) risk. Resistance exercise and high-protein diets are known to increase muscle mass, while Mediterranean-style diets have been shown to reduce CVD risk. A high-protein Mediterranean-style diet combined with resistance exercise intervention is yet to be trialled in cardiac rehabilitation populations. OBJECTIVES: Primary outcome: to determine the feasibility of such an intervention by investigating the perceptions, acceptance and adherence to a resistance exercise protocol and high-protein Mediterranean style diet in a UK cardiac rehabilitation population with SO. Secondary outcome: to trial this protocol ahead of a fully powered clinical study. METHODS: Eligible cardiac rehabilitation patients will be randomised to one of the following: 1) a control group (standard CR), 2) high-protein Mediterranean-style diet, 3) resistance exercise group, or 4) both high-protein Mediterranean-style diet and resistance exercise group. The pilot study will last 12 weeks. Measures of body composition (dual energy x-ray absorptiometry) grip strength, CVD risk (e.g., fasting triglycerides, glucose, cholesterol) and dietary adherence will be assessed at baseline and after 12 weeks. To compare groups, a mixed model ANOVA (time x intervention) will be performed. Patient participant involvement throughout the development of this project will be used to determine the feasibility of a future, fully powered, randomised control trial. A feasibility questionnaire will help establish the proportion of eligible participants, their willingness to be randomised, response rates, and ethical considerations. Furthermore, focus groups, food tasting and telephone interviews will be conducted t

BACKGROUND: Cardiac rehabilitation (CR) is an essential component of long-term recovery following a cardiac event. Typical CR may not be optimal for patients presenting with sarcopenic obesity (SO) who present with reduced muscle mass and elevated adipose tissue, and may indicate greater cardiovascular disease (CVD) risk. Resistance exercise and high-protein diets are known to increase muscle mass, while Mediterranean-style diets have been shown to reduce CVD risk. A high-protein Mediterranean-style diet combined with resistance exercise intervention is yet to be trialled in cardiac rehabilitation populations. OBJECTIVES: Primary outcome: to determine the feasibility of such an intervention by investigating the perceptions, acceptance and adherence to a resistance exercise protocol and high-protein Mediterranean style diet in a UK cardiac rehabilitation population with SO. Secondary outcome: to trial this protocol ahead of a fully powered clinical study. METHODS: Eligible cardiac rehabilitation patients will be randomised to one of the following: 1) a control group (standard CR), 2) high-protein Mediterranean-style diet, 3) resistance exercise group, or 4) both high-protein Mediterranean-style diet and resistance exercise group. The pilot study will last 12 weeks. Measures of body composition (dual energy x-ray absorptiometry) grip strength, CVD risk (e.g., fasting triglycerides, glucose, cholesterol) and dietary adherence will be assessed at baseline and after 12 weeks. To compare groups, a mixed model ANOVA (time x intervention) will be performed. Patient participant involvement throughout the development of this project will be used to determine the feasibility of a future, fully powered, randomised control trial. A feasibility questionnaire will help establish the proportion of eligible participants, their willingness to be randomised, response rates, and ethical considerations. Furthermore, focus groups, food tasting and telephone interviews will be conducted t

© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation Background: Atrial fibrillation (AF) and hypertension are independently associated with impaired autonomic function determined using heart rate variability (HRV). As these conditions frequently co-exist, we sought to determine whether AF would worsen HRV in hypertensive patients. Design: We studied HRV in AF (and hypertension) (n = 61) and hypertension control group (n = 33). The AF (and hypertension) group was subdivided into permanent AF (n = 30) and paroxysmal AF (n = 31) and re-studied. Time-domain, frequency-domain and nonlinear measures of HRV were determined. Permanent AF group (n = 30) was followed up after 8 weeks following optimisation of their heart rate and blood pressure (BP). Results: Time-domain and nonlinear indices of HRV were higher in AF (and hypertension) group compared to hypertensive controls (P ≤.01). Time-domain and nonlinear indices of HRV were higher in permanent AF group compared to paroxysmal AF (P ≤.001). Permanent AF was an independent predictor of HRV on multivariable analysis (P =.006). Optimisation of heart rate and BP had no significant impact on HRV in permanent AF. Conclusions: AF, independent of hypertension, is characterised with marked HRV and is possibly related to vagal tone. HRV is higher in permanent AF compared to paroxysmal AF suggesting evident autonomic influence in the pathophysiology of permanent AF. Modulation of autonomic influence on cardiovascular system should be explored in future studies.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Atrial fibrillation (AF) and hypertension often co-exist and both are associated with endothelial dysfunction. We hypothesised that AF would further worsen endothelium-dependent flow-mediated dilatation (FMD) in hypertension patients compared to those without AF. In a cross-sectional comparison, we measured brachial artery diameter at rest and during reactive hyperaemia following 5 min of arterial occlusion in two patient groups: AF (and hypertension) (n = 61) and hypertension control groups (n = 33). The AF (and hypertension) subgroups: permanent AF (n = 30) and paroxysmal AF (n = 31) were also assessed. The permanent AF patients received heart rate and blood pressure (BP) control optimisation and were then followed up after eight weeks for repeat FMD testing. There was no significant difference in FMD between AF (and hypertension) group and hypertension control group (4.6%, 95% CI [2.6–5.9%] vs 2.6%, 95% CI [1.9–5.3%]; p = 0.25). There was a significant difference in FMD between permanent AF and paroxysmal AF groups (3.1%, 95% CI [2.3–4.8%] vs 5.9%, 95% CI [4.0–8.1%]; p = 0.02). Endothelium-dependent FMD response showed a non-significant improvement trend following eight weeks of heart rate and BP optimisation (3.1%, 95% CI [2.3–4.8%] (baseline) vs 5.2%, 95% CI [3.9–6.5%] (follow up), p = 0.09). Presence of AF generally does not incrementally worsen endothelial dysfunction in hypertension patients, although the duration and frequency of AF (paroxysmal AF to permanent AF) does lead to worsening endothelial function. Eight weeks of BP optimisation did not significantly improve endothelial dysfunction as measured by FMD.

© Copyright © 2020 Junejo, Lip and Fisher. It is now well established that besides being the most common sustained arrhythmia, atrial fibrillation (AF) is a major healthcare burden. Risk of debilitating stroke is increased in AF patients, but even in the absence of stroke, this population is at heightened risk of cognitive decline, depression, and dementia. The reasons for this are complex, multifactorial, and incompletely understood. One potential contributing mechanism is cerebrovascular dysfunction. Cerebral blood flow is regulated by chemical, metabolic, autoregulatory, neurogenic, and systemic factors. The dysfunction in one or more of these mechanisms may contribute to the elevated risk of cognitive decline and cerebrovascular events in AF. This short review presents the evidence for diminished cerebral blood flow, cerebrovascular carbon dioxide reactivity (i.e., cerebrovascular vasodilatory reserve), cerebral autoregulation, and neurovascular coupling in AF patients when compared to control participants in sinus rhythm. Further work is needed to understand the physiological mechanisms underpinning these observations and their clinical significance in atrial fibrillation patients.

INTRODUCTION: Cardiovascular disease (CVD) is a major cause of morbidity and mortality throughout the world. The LIPIDOGRAM2015 study was performed to estimate the prevalence of risk factors for atherosclerotic diseases as well as cardiovascular and related disorders in the primary care setting in Poland. The LIPIDOGEN2015 sub-study was designed to include a random cohort of patients in order to analyse parameters related to lipid metabolism, oxidative stress, inflammatory responses, autoimmune disorders, and gene variants that confer susceptibility to cardiometabolic and atherosclerotic diseases. MATERIAL AND METHODS: The recruitment was carried out by 438 primary care physicians in Poland. The expected number of patients recruited for the LIPIDOGRAM2015 study was 13,000-14,000 with 13-15% (1700-2000) also participating in the LIPIDOGEN2015 sub-study. Each patient had to complete a questionnaire concerning medical and family history, concomitant diseases, and pharmacotherapy. Anthropometric measurements were performed at the doctor's office. For the LIPIDOGEN2015 sub-study, saliva samples for DNA isolation and blood samples for measurement of glycated haemoglobin, oxidative stress parameters, autoantibody levels, and inflammatory cytokine profile and apolipoprotein profile were collected. Follow-up data will be obtained from the National Health Fund in Poland. RESULTS: The LIPIDOGRAM2015 and LIPIDOGEN2015 study cohort reflects the prevalence of cardiovascular risk factors and concomitant diseases, markers of oxidative stress, the presence of autoantibodies, inflammatory cytokine profile, and apolipoprotein profile, as well as genetic variants potentially conferring susceptibility to cardiometabolic and atherosclerotic diseases. CONCLUSIONS: This study presents the prevalence of different CV risk factors, with special emphasis on lipid disorders, and it assesses the relationship between inflammation, oxidative stress, and mutations in genes encoding proteins regulat

© Copyright © 2020 Junejo, Lip and Fisher. It is now well established that besides being the most common sustained arrhythmia, atrial fibrillation (AF) is a major healthcare burden. Risk of debilitating stroke is increased in AF patients, but even in the absence of stroke, this population is at heightened risk of cognitive decline, depression, and dementia. The reasons for this are complex, multifactorial, and incompletely understood. One potential contributing mechanism is cerebrovascular dysfunction. Cerebral blood flow is regulated by chemical, metabolic, autoregulatory, neurogenic, and systemic factors. The dysfunction in one or more of these mechanisms may contribute to the elevated risk of cognitive decline and cerebrovascular events in AF. This short review presents the evidence for diminished cerebral blood flow, cerebrovascular carbon dioxide reactivity (i.e., cerebrovascular vasodilatory reserve), cerebral autoregulation, and neurovascular coupling in AF patients when compared to control participants in sinus rhythm. Further work is needed to understand the physiological mechanisms underpinning these observations and their clinical significance in atrial fibrillation patients.

Coronavirus disease 2019 (COVID-19), currently a worldwide pandemic, is a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The suspected contribution of thrombotic events to morbidity and mortality in COVID-19 patients has prompted a search for novel potential options for preventing COVID-19-associated thrombotic disease. In this article by the Global COVID-19 Thrombosis Collaborative Group, we describe novel dosing approaches for commonly used antithrombotic agents (especially heparin-based regimens) and the potential use of less widely used antithrombotic drugs in the absence of confirmed thrombosis. Although these therapies may have direct antithrombotic effects, other mechanisms of action, including anti-inflammatory or antiviral effects, have been postulated. Based on survey results from this group of authors, we suggest research priorities for specific agents and subgroups of patients with COVID-19. Further, we review other agents, including immunomodulators, that may have antithrombotic properties. It is our hope that the present document will encourage and stimulate future prospective studies and randomized trials to study the safety, efficacy, and optimal use of these agents for prevention or management of thrombosis in COVID-19.

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.

Objective We report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation. Design We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2). Setting Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands. Participants Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation. Main outcome measures Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA2DS2-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF. Results Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA2DS2-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA2DS2-VASc, other risk factors and demographics were similar. Conclusions About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation.

Background: The precise age distribution and calculated stroke risk of screen-detected atrial fibrillation (AF) is not known. Therefore, it is not possible to determine the number needed to screen (NNS) to identify one treatable new AF case (NNS-Rx) (i.e., Class-1 oral anticoagulation [OAC] treatment recommendation) in each age stratum. If the NNS-Rx is known for each age stratum, precise cost-effectiveness and sensitivity simulations can be performed based on the age distribution of the population/region to be screened. Such calculations are required by national authorities and organisations responsible for health system budgets to determine the best age cutoffs for screening programs and decide whether programs of screening should be funded. Therefore, we aimed to determine the exact yield and calculated stroke-risk profile of screen-detected AF and NNS-Rx in 5-year age strata. Methods and findings: A systematic review of Medline, Pubmed, and Embase was performed (January 2007 to February 2018), and AF-SCREEN international collaboration members were contacted to identify additional studies. Twenty-four eligible studies were identified that performed a single time point screen for AF in a general ambulant population, including people ≥65 years. Authors from eligible studies were invited to collaborate and share patient-level data. Statistical analysis was performed using random effects logistic regression for AF detection rate, and Poisson regression modelling for CHA2DS2-VASc scores. Nineteen studies (14 countries from a mix of low- to middle- and high-income countries) collaborated, with 141,220 participants screened and 1,539 new AF cases. Pooled yield of screening was greater in males across all age strata. The age/sex-adjusted detection rate for screen-detected AF in ≥65-year-olds was 1.44% (95% CI, 1.13%-1.82%) and 0.41% (95% CI, 0.31%-0.53%) for <65-year-olds. New AF detection rate increased progressively with age from 0.34% (<60 years) to 2.73% (≥85 years).

© The Author(s) 2019. The risk of cognitive decline and stroke is increased by atrial fibrillation (AF). We sought to determine whether neurovascular coupling and cerebral autoregulation are blunted in people with AF in comparison with age-matched, patients with hypertension and healthy controls. Neurovascular coupling was assessed using five cycles of visual stimulation for 30 s followed by 30 s with both eyes-closed. Cerebral autoregulation was examined using a sit–stand test, and a repeated squat-to-stand (0.1 Hz) manoeuvre with transfer function analysis of mean arterial pressure (MAP; input) and middle cerebral artery mean blood flow velocity (MCA Vm; output) relationships at 0.1 Hz. Visual stimulation increased posterior cerebral artery conductance, but the magnitude of the response was blunted in patients with AF (18 [8] %; mean [SD]) and hypertension (17 [8] %), in comparison with healthy controls (26 [9] %) (P < 0.05). In contrast, transmission of MAP to MCA Vm was greater in AF patients compared to hypertension and healthy controls, indicating diminished cerebral autoregulation. We have shown for the first time that AF patients have impaired neurovascular coupling responses to visual stimulation and diminished cerebral autoregulation. Such deficits in cerebrovascular regulation may contribute to the increased risk of cerebral dysfunction in people with AF.

BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intr

The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.

Objective We report on: (1) the proportion of patients with known atrial fibrillation (AF); and (2) demographic, clinical or radiological differences between patients with known AF (and not treated) and patients with newly diagnosed AF, in a cohort of patients who presented with ischaemic stroke or transient ischaemic attack (TIA) not previously treated with anticoagulation. Design We reviewed cross-sectional baseline demographic and clinical data from a prospective observational cohort study, (CROMIS-2). Setting Patients were recruited from 79 hospital stroke centres throughout the UK and one centre in the Netherlands. Participants Patients were eligible if they were adults who presented with ischaemic stroke or TIA and AF and had not been previously treated with oral anticoagulation. Main outcome measures Proportion of patients with known AF before index ischaemic stroke or TIA from a cohort of patients who have not been previously treated with oral anticoagulation. Secondary analysis includes the comparison of CHA2DS2-VASc and HAS-BLED scores and other demographics and risk factors between those with newly diagnosed AF and those with previously known AF. Results Of 1470 patients included in the analysis (mean age 76 years (SD 10)), 622 (42%) were female; 999 (68%) patients had newly diagnosed AF and 471 (32%) patients had known AF. Of the 471 patients with known AF, 68% had a strong indication for anticoagulation and 89% should have been considered for anticoagulation based upon CHA2DS2-VASc score. Patients with known AF were more likely to have a prior history of dementia (4% vs 2%, p=0.02) and had higher HAS-BLED scores (median 3 vs 2). CHA2DS2-VASc, other risk factors and demographics were similar. Conclusions About 1/3 of patients who present with stroke and have AF who have not been treated with oral anticoagulation have previously known AF. Of these patients, at least 68% were not adequately treated with oral anticoagulation.

© The Author(s) 2019. The risk of cognitive decline and stroke is increased by atrial fibrillation (AF). We sought to determine whether neurovascular coupling and cerebral autoregulation are blunted in people with AF in comparison with age-matched, patients with hypertension and healthy controls. Neurovascular coupling was assessed using five cycles of visual stimulation for 30 s followed by 30 s with both eyes-closed. Cerebral autoregulation was examined using a sit–stand test, and a repeated squat-to-stand (0.1 Hz) manoeuvre with transfer function analysis of mean arterial pressure (MAP; input) and middle cerebral artery mean blood flow velocity (MCA Vm; output) relationships at 0.1 Hz. Visual stimulation increased posterior cerebral artery conductance, but the magnitude of the response was blunted in patients with AF (18 [8] %; mean [SD]) and hypertension (17 [8] %), in comparison with healthy controls (26 [9] %) (P < 0.05). In contrast, transmission of MAP to MCA Vm was greater in AF patients compared to hypertension and healthy controls, indicating diminished cerebral autoregulation. We have shown for the first time that AF patients have impaired neurovascular coupling responses to visual stimulation and diminished cerebral autoregulation. Such deficits in cerebrovascular regulation may contribute to the increased risk of cerebral dysfunction in people with AF.

Background: Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme might be associated with increased activation of platelets. We aimed to assess the relationship between PCSK9 levels, platelet reactivity and ischemic outcomes.Methods: Consecutive ACS patients receiving prasugrel or ticagrelor and undergoing percutaneous coronary intervention (PCI) were enrolled in a prospective, observational study. Adenosine diphosphate (ADP)-induced platelet aggregation was determined by Multiplate Analyzer in the maintenance phase of treatment with prasugrel or ticagrelor. Major adverse cardiovascular events (MACEs) defined as composite of cardiovascular death, myocardial infarction, unstable angina, stent thrombosis, repeat revascularization, ischemic stroke were evaluated at 12 months.Results: A direct association was found between increased PCSK9 scrum levels and platelet reactivity (r = 030; p = 0.004). When assessed according to tertile values of PCSK9, there was a significant increase in platelet reactivity in the upper vs lower Wade (p = 0.02). Clinical outcome was available at follow-up in 178 subjects. In the upper PCSK9 Wade 13/59 (22.03%) patients experienced a clinical MACE at one year, vs 2/59 (3.39%) patients in the lower PCSK9 tertile. At one-year follow-up, PCSK9 was independently associated with increased ischemic. MACEs: hazard ratio for upper vs lower PCSK9-level tertile was 2.62 (95% confidence interval 1.24-5.52; p = 0.01).Conclusions: These findings suggest that increased PCSK9 levels are associated with higher platelet reactivity and are a possible predictor of ischemic events in ACS patients undergoing PCI. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Guidelines summarize and evaluate all available evidence on a particular issue at the time of the writing process, with the aim of assisting health professionals in selecting the best management strategies for an individual patient with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines and recommendations should help health professionals to make decisions in their daily practice. However, the final decisions concerning an individual patient must be made by the responsible health professional(s) in consultation with the patient and caregiver as appropriate.

Contemporary medicine is shifting towards person rather than disease-oriented care.1With increasing life expectancy and the ageing of baby boomers, the proportion over 60 years is growing faster than the overall population, with worldwide estimates reaching 2 billion by 2050 (http://www.un.org/esa/population/publications/ worldageing19502050).2 In parallel, acute coronary syndromes (ACS) and atrial fibrillation (AF)—the most frequent indications for dual platelet inhibition or anticoagulation—occur mostly in older patients.2 – 6 There is general agreement that people ≥75 years can be defined ‘elderly’; however, cutoffs as low as 65 years have been applied to important clinical datasets and risk scores.3,7 – 10

OBJECTIVE To assess the benefits and risks of short term (<12 months) or extended (>12 months) dual antiplatelet therapy (DAPT) versus standard 12 month therapy, following percutaneous coronary intervention with drug eluting stents. DESIGN Meta-analysis of randomised controlled trials. DATA SOURCES PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Scopus, Web of Science, Cochrane Library, and major congress proceedings, searched from 1 January 2002 to 16 February 2015. REVIEW METHODS Trials comparing short term (<12 months) or extended (>12 months) DAPT regimens with standard 12 month duration of therapy. Primary outcomes were cardiovascular mortality, myocardial infarction, stent thrombosis, major bleeding, and all cause mortality. RESULTS 10 randomised controlled trials (n=32 287) were included. Compared to 12 month DAPT, a short term course of therapy was associated with a significant reduction in major bleeding (odds ratio 0.58 (95% confidence interval 0.36 to 0.92); P=0.02) with no significant differences in ischaemic or thrombotic outcomes. Extended versus 12 month DAPT yielded a significant reduction in the odds of myocardial infarction (0.53 (0.42 to 0.66); P<0.001) and stent thrombosis (0.33 (0.21 to 0.51); P<0.001), but more major bleeding (1.62 (1.26 to 2.09); P<0.001). All cause but not cardiovascular death was also significantly increased (1.30 (1.02 to 1.66); P=0.03). CONCLUSIONS Compared with a standard 12 month duration, short term DAPT (<12 months) after drug eluting stent implementation yields reduced bleeding with no apparent increase in ischaemic complications, and could be considered for most patients. In selected patients with low bleeding risk and very high ischaemic risk, extended DAPT (>12 months) could be considered. The increase in all cause but not cardiovascular death with extended DAPT requires further investigation.

Background The CHA2DS2-VASc and HAS-BLED are well-validated stroke risk prediction scores for atrial fibrillation (AF), but their role in risk stratification of major adverse cardiac events (MACEs) and major bleeding for non-AF patients undergoing percutaneous coronary intervention (PCI) is unknown. Methods Consecutive patients without AF undergoing PCI at two Italian centers were analyzed with different measures of discrimination, net reclassification improvement and net prognostic benefit. MACE included all-cause death, myocardial infarction, destabilizing symptoms leading to hospitalization, and nonfatal stroke. Major bleeding was defined according to the TIMI classification. Results Of 1437 subjects undergoing PCI, 1330 (mean age 63.6 ± 10.9 years, 75.7% male) fulfilled the inclusion criteria. During 2.7 ± 1.2 years of follow-up representing 3539 patient-years at risk, 187 patients had a MACE (5.3%/year) and 48 had a major bleeding (1.4%/year). The cumulative incidences of MACE were significantly stratified by both high CHA2DS2-VASc (P = 0.020) or HAS-BLED (P < 0.001) scores, whereas major bleeding episodes were not. The CHA2DS2-VASc and the HAS-BLED scores had similar C-statistics for MACE (0.56 vs 0.60; P = 0.52) and major bleeding (0.63 vs 0.60; P = 0.63). Compared with CHA2DS2-VASc, the HAS-BLED score more accurately reclassified events and no events both for MACE (NRI 8.21%) and major bleeding (NRI 6.85%). Conclusions In patients without AF undergoing PCI and discharged on dual antiplatelet therapy, the HAS-BLED score performed better than the CHA2DS2-VASc for the prediction of MACE. Although both scores predict MACE, their discrimination was modest. Conversely, both scores did not significantly predict major bleeding in non-AF patients undergoing PCI.

Hypertension is the most common cardiovascular disorder and atrial fibrillation is the most common clinically significant arrhythmia. Both these conditions frequently coexist and their prevalence increases rapidly with aging. There are different risk factors and clinical conditions predisposing to the development of atrial fibrillation, but due its high prevalence, hypertension is still the main risk factor for the development of atrial fibrillation. Several pathophysiologic mechanisms (such as structural changes, neurohormonal activation, fibrosis, atherosclerosis, etc.) have been advocated to explain the onset of atrial fibrillation. The presence of atrial fibrillation per se increases the risk of stroke but its coexistence with high blood pressure leads to an abrupt increase of cardiovascular complications. Different risk models are available for the risk stratification and the prevention of thromboembolism in patients with atrial fibrillation. In all of them hypertension is present and is an important risk factor. Antihypertensive treatment may contribute to reduce this risk, and it seems some classes are superior to others in the prevention of new-onset atrial fibrillation and prevention of stroke. Antithrombotic treatment with warfarin is effective in the prevention of thromboembolic events, although quite recently, new classes of anticoagulants that do not require international normalized ratio monitoring have been introduced with promising results.

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed.

Despite the clear net clinical benefit of oral anticoagulation (OAC) in atrial fibrillation (AF) patients at risk for stroke, major bleeding events (especially intra-cranial bleeds) may be devastating events when they do occur. The decision for OAC is often based on a careful assessment of both stroke risk and bleeding risk, but clinical scores for bleeding risk estimation are much less well validated than stroke risk scales. Also, the estimation of bleeding risk is rendered difficult since many of the known factors that increase bleeding risk overlap with stroke risk factors. As well as this, many factors that increase bleeding risk are transient, such as variable international normalized ratio values, operations, vascular procedures, or drug-drug and food-drug interactions. In this Position Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in AF patients, with a view to summarizing 'best practice' when approaching antithrombotic therapy in AF patients. We address the epidemiology and size of the problem of bleeding risk in AF and review established bleeding risk factors. We also summarize definitions of bleeding in the published literature. Patient values and preferences balancing the risk of bleeding against thrombo-embolism is reviewed, and the prognostic implications of bleeding are discussed. We also review bleeding risk stratification and currently published bleeding risk schema. A brief discussion of special situations [e.g. peri-ablation, peri-devices (implantable cardioverter-defibrillator, pacemakers) and presentation with acute coronary syndromes and/or requiring percutaneous coronary interventions/stents and bridging therapy], as well as a discussion of prevention of bleeds and managing bleeding complications, is made. Finally, this document also puts forwards consensus statements that may help to define evidence gaps and assist in everyday clinical practice. Bleeding risk is almost inevitabl