Lung Foundation Research Articles

The power of music.

How music can so powerfully impact our bodies and minds defies rational explanation. Through our senses, music can mysteriously reach our deepest emotions without using language or images. Even if we do not understand it intellectually, music speaks to us, and can transform our experience. Music is often a communal experience. Anthony Storr, psychoanalyst and musician, writes that when a group of people sing together, ‘a culturally agreed upon pattern of rhythm and melody, i.e. a song, that is sung together, provides a shared form of emotion that, at least during the course of the song, carries along the participants so that they experience their bodies responding emotionally in very similar ways, sharing the emotions of the music’ (Music and the Mind, HarperCollins Publishers, 1992). But why are we talking about music here? Music is integral to healing practices in many indigenous cultures. In Western medicine, the impact of music on wellbeing is increasingly explored. The beneficial impact of music on reducing anxiety and stress responses, with possible resulting immune system modulation, has been observed in individuals with a range of nervous system conditions, from autism, depression, Parkinson's and schizophrenia. In patients with dementia, music and singing can reduce hallucinations and depression, increase social interactions and may even be associated with slower cognitive impairment. During the early phases of the COVID-19 outbreak, when most of the world was in lockdown and clinical staff were under severe psychological distress, an Italian hospital piloted a music therapy programme for healthcare staff assisting COVID-19 patients (https://doi.org/10.1016/j.aip.2020.101688). After listening to playlists prepared by trained music therapists and customized to individual preferences, clinical staff reported significantly reduced tiredness, sadness, fear and worry. Similarly, in a randomized controlled trial investigating mindfulness and music therapy in nurses caring for COVID-19 patients in Turkey, work-related strain was reduced in the intervention compared to control group. (https://doi.org/10.1097/hnp.0000000000000511). British Lung Foundation (BLF) commissioned Phoene to deliver a training programme for singing leaders entitled ‘Singing for Lung Health (SLH)’, with more than 100 groups established across the UK. Service evaluation has shown that SLH is associated with improved respiratory related quality of life and reduced health care utilization (https://journals.sagepub.com/doi/10.1177/1757913918774079). In the words of a SLH participant: ‘I feel as though my airways have really opened up and my natural breathing is more fluid. Singing has so many benefits: physical, emotional and pure enjoyment’. Group singing as a treatment for patients with chronic lung diseases is increasingly explored in Europe, North America, Australia and Africa, with research ongoing to study the physiological and psychosocial benefits for participants and how this intervention could best be implemented more widely (https://www.mdpi.com/2227-9059/10/9/2086#B14-biomedicines-10-02086). None declared.

A unique perfusion pattern with 15O-water PET as a risk marker for arrhythmias in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swedish Heart Lung Foundation. Background Myocardial ischemia in hypertrophic cardiomyopathy (HCM) is associated with an elevated risk of ventricular arrhythmia and sudden cardiac death. Fibrosis often occurs in subendocardial regions of the LV and the RV insertion in the interventricular septum. Globally lowered hyperemic myocardial blood flow (MBF) by 15O-water PET is known to indicate poor prognosis, but is mainly linked to late-stage "burn-out". Recent scanner and image analysis developments allow detailed 3D visualisation of quantitative biventricular 15O-water MBF. Purpose To investigate whether there is a visual myocardial perfusion pattern with 15O-water PET in patients with HCM which could indicate an increased risk of arrhythmias. Methods We reanalysed rest/adenosine stress 15O-water PET in 24 patients with high-risk HCM treated with implantable cardioverter-defibrillator from a previous study. Non-sustained ventricular tachycardia (NSVT) was noted in 10 patients during 1 year preceding PET. PET was used to determine the LV MBF subendocardial-subepicardial gradient (ml/g/min per mm). Parametric MBF images from 15O-water PET at rest and stress were visually analysed at a segmental level. The myocardial segment which visually had both the highest endocardial MBF at rest and the lowest endocardial MBF at stress was selected as the most affected segment for each patient. Results Reduced resting MBF with partial normalisation at stress was seen in the RV insertion in 15 patients, including all NSVT subjects. Sixteen patients, including all NSVT subjects, had a visual perfusion pattern in the septal wall or apex with enhanced subendocardial MBF at rest and reduced MBF at stress in the same segment. The MBF gradient at stress was 0.04±0.01 ml/g/min per mm for the patients with NSVT and 0.07±0.03 ml/g/min per mm for the patients without NSVT in the visually most affected segments (p = 0.01). Conclusions Using 3D visualisation of quantitative MBF we noted a distinct pattern with intramural redistribution of perfusion between rest and stress in HCM, significantly associated with NSVT. Reduced resting perfusion at RV insertion points has not been reported in other cardiomyopathies. Enhanced subendocardial resting perfusion in ischemic segments might indicate reactive postischemic hyperemia. Clinical use of 15O-water PET to predict ventricular arrhythmia requires prospective trials.

What determines who gets cardiac resynchronization therapy in europe?

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Supported by Swedish Heart and Lung foundation and Stockholm County Council. Background/Introduction Cardiac resynchronization therapy (CRT) is a valuable treatment in selected patients with heart failure (HF) but is still underutilized. Aim We compared three informative data sources, which enrolled patients with HF at different organization setting and identified clinical, organizational, and level of care factors linked to CRT implantation in these cohorts. Methods Data from three large cohorts of patients with HF were compared. Patients with HF with reduced ejection fraction (HFrEF) in an ESC HF-Long Term Registry (ESC-HF-LT, n=25,621), a National HF Registry - Swede HF (n=156,621) and in the ESC-CRT Survey II (n=11088, all receiving CRT across 42 ESC countries), contributed data to the analysis. The ESC Survey II recruited patients at implanting centers, ESC-HF-LT at HF centers, whereas SwedeHF enrolled HF patients at different levels of care. Firstly, we compared patient characteristics, socio-economic and organizational factors between cohorts as well as between overlapping countries participating both in CRT Survey II and ESC HF LT. Secondly, we identified independent predictors of CRT use in the two registries using multivariable logistic regressions. Results Of the 1031 patients in ESC-HF-LT and the 5008 patients in Swede-HF, CRT was not used in 53-75 % of guideline- indicated patients. Women constituted 22% and median age ranged between 68-72 years. Guideline Directed Medical Therapy (GDMT), atrial fibrillation, previous myocardial infarction (SwedeHF) and HF hospitalization (ESC-HF-LT) was associated with more CRT use as was enrollment at university hospital and follow-up at HF center/Hospital. In Swede-HF above median income and higher education level were also independently associated with use of CRT. In the ESC-CRT Survey II (n=11.088) all patients received CRT with differences in the clinical indications between countries. Conclusion(s) CRT is an important treatment option for eligible patients with HF, which is still largely underused. The findings reported demonstrate that awareness of CRT indications as well as demographics, organizational and economic factors play an important role in CRT utilization.

Sustained inflammation and high cortisol reactivity following an coronary event

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Heart and lung foundation Sweden. Background Over the last decades, significant improvements have been made in medical and lifestyle managements of patients with coronary artery disease (CAD). Nonetheless, "residual inflammatory risk" for recurrent cardiovascular events is high in this patient group and remains a diagnostic and therapeutic challenge. Activation of the NLRP3 inflammasome, involving release of interleukin (IL)-1β and IL-18 followed by their downstream target IL-6, is considered a major component of the inflammatory process in atherosclerosis. One major immunomodulator is the hypothalamic–pituitary–adrenal (HPA) axis. Interestingly, there is increasing evidence that cortisol exerts proinflammatory effects through the induction of NLRP3 expression. Purpose We investigated whether sustained inflammation was associated with altered HPA stress reactivity in patients with CAD. From 4 weeks up to 6 months after a coronary event, we measured systemic inflammation, with focus on inflammasome-related cytokines, and HPA axis hormones (ACTH and cortisol) before and after acute physical stress. Method We included 81 patients (mean age 62 years, 77 % males) and 30 controls (mean age 69 years, 67 % males). Patients underwent a standardized submaximal exercise stress test at 4 weeks (visit A) and 3-6 months after the coronary event (visit B) while controls performed one test only. Free cortisol was measured in saliva before, directly and 30 min after exercise. IL-18, IL-Ra (as a surrogate for IL-1 β), IL-6, ACTH and total cortisol were measured in plasma before and 30 min after exercise. Results At visit A, plasma levels of CRP (baseline only) and IL-6 did not differ between patients and controls while IL-18 and IL-1Ra were significantly higher in patients both before and after exercise, 500 (391-632) vs 386 (295-493), p=0.002; and 179 (141-267) vs 147 (117- 182), p=0.005, respectively(table 1). At visit B, CRP decreased while IL-18 and IL-1Ra levels remained at higher levels than controls. At both visits, patients showed a heightened cortisol reactivity (i.e. significant increase directly after exercise) while this did not occur in controls (Figure 1). At visit B, the relative increase in cortisol directly after exercise was even higher than at visit A (p=0.024). At both visits, ACTH decreased significantly after exercise in patients (p<0.01), probably due to negative feedback, while no change in ACTH was observed in controls. Conclusion Sustained elevations in IL-18 and IL-1Ra in CAD patients following a coronary event may indicate enhanced activity of NLRP3 inflammasome. Furthermore, patients exhibited a heightened cortisol stress reactivity, a phenomenon which has been associated with atherosclerosis progression and sedentary lifestyle in the population. It may be speculated that HPA axis alteration is directly associated with NLRP3 inflammasome activation in CAD, thus opening doors to new insights in prevention. However, this remains to be further investigated.

Implementation of a primary care asthma management quality improvement programme across 68 general practice sites

Despite national and international guidelines, asthma is frequently misdiagnosed, control is poor and unnecessary deaths are far too common. Large scale asthma management programme such as that undertaken in Finland, can improve asthma outcomes. A primary care asthma management quality improvement programme was developed with the support of the British Lung Foundation (now Asthma + Lung UK) and Optimum Patient Care (OPC) Limited. It was delivered and cascaded to all relevant staff at participating practices in three Clinical Commissioning Groups. The programme focussed on improving diagnostic accuracy, management of risk and control, patient self-management and overall asthma control. Patient data were extracted by OPC for the 12 months before (baseline) and after (outcome) the intervention. In the three CCGs, 68 GP practices participated in the programme. Uptake from practices was higher in the CCG that included asthma in its incentivised quality improvement programme. Asthma outcome data were successfully extracted from 64 practices caring for 673,593 patients. Primary outcome (Royal College of Physicians Three Questions [RCP3Q]) data were available in both the baseline and outcome periods for 10,328 patients in whom good asthma control (RCP3Q = 0) increased from 36.0% to 39.2% (p < 0.001) after the intervention. The odds ratio of reporting good asthma control following the intervention was 1.15 (95% CI 1.09–1.22), p < 0.0001. This asthma management programme produced modest but highly statistically significant improvements in asthma outcomes. Key lessons learnt from this small-scale implementation will enable the methodology to be improved to maximise benefit in a larger scale role out.

Patients' acceptance of outcome and experience measurements during hospitalisation for COPD exacerbations: a CICERO Clinical Research Collaboration-European Lung Foundation online patient survey.

The lack of standardised outcome assessments during hospitalisation and follow-up for acute COPD exacerbations has hampered scientific progress and clinical proficiency. The objective of the present study was to evaluate patients' acceptance of selected outcome and experience measurements during hospitalisations for COPD exacerbations and follow-up. An online survey was held amongst COPD patients in France, Belgium, The Netherlands, Germany and the UK. The European Lung Foundation COPD Patient Advisory Group was involved in the conceptualisation, development and dissemination of the survey. The survey was complementary to a previously obtained expert consensus. We assessed patients' views and acceptance of selected patient-reported outcomes or experiences and corresponding measurement instruments (for dyspnoea, frequent productive cough, health status and hospitalisation experience), and of selected clinical investigations (blood draw, pulmonary function test, 6-min walk test, chest computed tomography, echocardiography). 200 patients completed the survey. All selected outcomes and experiences were deemed important, and acceptance of their methods of assessment was high. The modified Medical Research Council scale and a numerical rating scale to address dyspnoea, the COPD Assessment Test for quality of life and frequent productive cough, and the Hospital Consumer Assessment of Healthcare Providers and Systems for hospital experiences were the instruments preferred by patients. Consensus on importance of blood draw and spirometry was higher compared with the other investigations. The survey results endorse the use of the selected outcome and experience measurements during hospitalisations for COPD exacerbations. They can be used to optimise standardised and patient-centred care and facilitate multicentric data collection.

Public support for smoke-free policies in outdoor areas and (semi-)private places: a systematic review and meta-analysis

Smoke-free policies are essential to protect people against tobacco smoke exposure. To successfully implement smoke-free policies that go beyond enclosed public places and workplaces, public support is important. We undertook a comprehensive systematic review of levels and determinants of public support for indoor (semi-)private and outdoor smoke-free policies. In this systematic review and meta-analysis, six electronic databases were searched for studies (published between 1 January 2004 and 19 January 2022) reporting support for (semi-)private and outdoor smoke-free policies in representative samples of at least 400 respondents aged 16 years and above. Two reviewers independently extracted data and assessed risk of bias of individual reports using the Mixed Methods Appraisal Tool. The primary outcome was proportion support for smoke-free policies, grouped according to location covered. Three-level meta-analyses, subgroup analyses and meta-regression were performed. 14,749 records were screened, of which 107 were included; 42 had low risk of bias and 65 were at moderate risk. 99 studies were included in the meta-analyses, reporting 326 measures of support from 896,016 individuals across 33 different countries. Support was pooled for indoor private areas (e.g., private cars, homes: 73%, 95% confidence interval (CI): 66-79), indoor semi-private areas (e.g., multi-unit housing: 70%, 95% CI: 48-86), outdoor hospitality areas (e.g., café and restaurant terraces: 50%, 95% CI: 43-56), outdoor non-hospitality areas (e.g., school grounds, playgrounds, parks, beaches: 69%, 95% CI: 64-73), outdoor semi-private areas (e.g., shared gardens: 67%, 95% CI: 53-79) and outdoor private areas (e.g., private balconies: 41%, 95% CI: 18-69). Subcategories showed highest support for smoke-free cars with children (86%, 95% CI: 81-89), playgrounds (80%, 95% CI: 74-86) and school grounds (76%, 95% CI: 69-83). Non-smokers and ex-smokers were more in favour of smoke-free policies compared to smokers. Support generally increased over time, and following implementation of each smoke-free policy. Our findings suggested that public support for novel smoke-free policies is high, especially in places frequented by children. Governments should be reassured about public support for implementation of novel smoke-free policies. Dutch Heart Foundation, Lung Foundation Netherlands, Dutch Cancer Society, Dutch Diabetes Research Foundation and Netherlands Thrombosis Foundation.

OA19 Incidence and management of inflammatory arthritis in England before and during the COVID-19 pandemic: a population-level cohort study using OpenSAFELY

Abstract Background/Aims The impact of the pandemic on the incidence and management of inflammatory arthritis (IA) is not understood. Routinely-captured data in secure platforms, such as OpenSAFELY, offer unique opportunities to understand how IA was impacted upon by the pandemic. Our objective was to use OpenSAFELY to assess the effects of the pandemic on diagnostic incidence and care delivery for IA in England, and replicate key metrics from the National Early Inflammatory Arthritis Audit. Methods With the approval of NHS England, we used primary care and hospital data for 17 million adults registered with general practices using TPP health record software, to explore the following outcomes between 1 April 2019 and 31 March 2022: 1) incidence of IA diagnoses (rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, undifferentiated IA) recorded in primary care; 2) time to first rheumatology assessment; 3) time to first prescription of a conventional synthetic DMARD (csDMARD) in primary care, and choice of first csDMARD. Results From 17,683,500 adults (representing 40% of the English population), there were 31,280 incident IA diagnoses recorded between April 2019 and March 2022. New IA diagnoses decreased by 39.7% in the early months of the pandemic. Overall, a 20.3% decrease in IA diagnoses was seen in the year commencing April 2020, relative to the preceding year (5.1 vs. 6.4 diagnoses per 10,000 adults, respectively). Further decreases coincided with rising COVID-19 numbers, before returning to pre-pandemic levels by the end of the study period. No rebound increase in IA incidence was observed as of April 2022. The median time from referral to first rheumatology assessment was shorter during the pandemic (18 days; IQR 8-35 days) than before (21 days; 9-41 days). The proportion of patients prescribed csDMARDs in primary care was comparable to before the pandemic; however, fewer people were prescribed methotrexate or leflunomide, and more were prescribed sulfasalazine or hydroxychloroquine. Conclusion IA diagnoses decreased markedly during the early phase of the pandemic; however, the impact on rheumatology assessment times and DMARD prescribing was less marked than might have been anticipated. This study demonstrates the feasibility of using routinely-captured, near real-time data in the secure OpenSAFELY platform to benchmark care quality on a national scale, without the need for manual data collection. Disclosure M.D. Russell: Honoraria; Lilly, Menarini, Biogen. Other; Lilly, Pfizer, Janssen, UCB. J.B. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi, UCB. C.D. Andrews: None. B. MacKenna: None. B. Goldacre: Grants/research support; Laura and John Arnold Foundation, NIHR, Mohn-Westlake Foundation, Wellcome Trust, Good Thinking Foundation, Health Data Research UK, Health Foundation, World Health Organisation, UKRI, Asthma UK, British Lung Foundation, and National Core Studies programme. A. Mehrkar: Other; Former employee and interim CMO of NHS Digital, and RCGP representative on GP Data Professional Advisory Group to NHS Digital. H.J. Curtis: None. B. Butler-Cole: None. T. O'Dwyer: None. S. Qureshi: Grants/research support; BMS. J.M. Ledingham: Other; Clinical director for NEIAA, Secretary for The Federation of Joint Royal Colleges of Physicians SCE Board, and trustee of the BSR. A. Mahto: Honoraria; Abbvie, Galapagos. Other; Lilly. A.I. Rutherford: Other; Lilly. M.A. Adas: None. E. Alveyn: None. S. Norton: None. A.P. Cope: Consultancies; BMS, Abbvie, GSK/Galvini. Member of speakers’ bureau; BMS, Abbvie. Grants/research support; BMS. Other; Executive committee of the EULAR research centre. K. Bechman: Grants/research support; Versus Arthritis and Pfizer Global Medical Grants.

Eradication of Burkholderia cepacia complex in cystic fibrosis patients with inhalation of amiloride and tobramycin combined with oral cotrimoxazole.

This case series suggests that successful eradication therapy of BCC in cystic fibrosis can be done with a combination of inhaled and oral medication, which in many cases may eliminate the need for intensive treatment with intravenous antibiotics https://bit.ly/40oOMIn.

How philanthropy can make you healthy and happy.

When I came to Australia 40 years ago from the European headquarters of Time Magazine I fell in love with this wide brown land. And despite working my tail off as being a top executive, it did not’ matter with such friendly and caring people. I suffered from repeated bronchitis in Amsterdam (originally from USA) for the 10 years I lived there because I was not used to the dampness. So I was so excited about coming to a sunny and warm part of the universe. I have always loved to help needy causes, and as a new citizen, I embraced charity work. Yes, give with gratitude to my new country! And I threw my heart and soul into so many multifarious needy causes. Opera artists, Uni students, Olympics, Legacy, Cochlear Implant for Deaf Children; the list is long. My focus was to raise as much money as possible. My philosophy was and still is, why do people wait until they die and leave their donations to their favourite charities? Why not give whilst you are living, and you can smile knowing you have helped someone in an area, such as The Lung Foundation, or other passionate causes. Guess what? It makes you feel so good. I know it has helped me deal with my lung disease, Bronchiectasis. Yes, I was diagnosed in 2018 after years of chronic pneumonia. I started playing golf at 40 because I love sport. And many of the gentlemen I was dealing with in business went out, had lunch, played golf and did business deals! I was a weekend warrior, and became hooked. And guess what? As a female, I started doing business deals because I could play pretty good golf! Fast forward to 2023, and there are 26 girls who have been scholars and loving their golf. I joined the nascent Australian Golf Foundation in 2020, and presented to the board that if I went out and raised the money every year, I wanted to launch this across the country. Especially in rural and regional communities to young girls who could never even dream of playing golf. First nation, farming communities etc. The game has shrunk dramatically for women over the past 25 years. Today, we have nearly 2000 girls in the past 3 years who have had a scholarship. The fundraising is close to a million dollars, and I am so busy and having so much fun seeing these girls become friends for life with girls they never would have met before. And for the past 2 years, 8 young girls from the scholarship have been chosen to caddy for the lady Pro's on TV at an annual tournament called the Athena. Golf is brilliant exercise for lung diseases. Bonnie Boezeman provides an annual donation to The Lung Foundation for a new Peer To Peer program for Bronchiectasis.

FEV1 and pulmonary rehabilitation: Let's get the facts straight.

Pulmonary rehabilitation (PR) is a miracle intervention. Despite the lack of effect on resting lung function,1 symptomatic people with chronic obstructive pulmonary disease (COPD) generally have less symptoms (i.e., dyspnea, fatigue, anxiety and depression), better physical functioning and physiological exercise responses, less care dependency, an improved performance of activities of daily life, less healthcare use and an improved quality of life following a 8–12 weeks multidisciplinary PR program on top of the regular respiratory drug treatment.2-10 To date, post-bronchodilator forced expiratory volume in the first second (FEV1) is still often used as a selection criterion for referral for PR.11, 12 However, FEV1 is useless for this objective. Let us get the facts straight: Fact 1: Baseline FEV1 does not or only weakly correlate with physical, emotional and social functioning of people with COPD. Daily symptoms (such as dyspnea, fatigue, anxiety and depression), abnormal body composition, low exercise capacity, problematic activities of daily life, low physical activity and an impaired health status can occur in people with COPD, irrespective of the degree of airflow limitation.13-18 Moreover, FEV1 is only weakly correlated with the number of extra-pulmonary traits.18 So, FEV1 cannot be used to identify symptomatic people with limitations in daily functioning and extra-pulmonary traits, which can be addressed during a comprehensive PR program.2 Fact 2: Baseline FEV1 does not predict the likelihood of dropping out. PR programs report that 15%–40% of the participants drop out from the program.5, 19-25 Generally, people with COPD who drop out have similar baseline FEV1 compared to those who complete the PR program.19-22, 24 The presence of psychological factors (i.e., depressive symptoms, lack of motivation and/or distress arising from bodily perceptions), social factors (i.e., transportation difficulties, other duties or responsibilities, unsupportive remarks by staff or patients and/or conflict with other patients) and/or people's perception of insufficient improvements during the PR program, may partially explain why people with COPD drop out, irrespective of baseline FEV1.24, 26 So, baseline FEV1 cannot be used to identify people at risk of dropping out from a PR program. Fact 3: PR improves exercise capacity, symptoms and health status across all grades of COPD severity. Improvements in the abovementioned outcomes have been reported in people with a variety of baseline FEV1 values.27, 28 Moreover, baseline FEV1 (alone or in combination with other lung function attributes) does not predict whether or not people with COPD achieve the minimal important difference for exercise capacity, health status, fatigue, anxiety and/or depression following PR.5, 7, 29-31 So, baseline FEV1 cannot be used to identify responders or non-responders. To conclude, FEV1 has no added to value as selection criterion for PR in people with COPD. Therefore, the respiratory community needs to foster adequate referral to exercise-based interventions, including center-based pulmonary rehabilitation, without using FEV1 as a referral criterion.32 Consequently, an interdisciplinary assessment must go far beyond the regular lung function tests, and should include also patients' physical, emotional and social status.18, 33 Frits M. E. Franssen has received grants and personal fees from AstraZeneca, and personal fees from Boehringer Ingelheim, Chiesi, GSK and Novartis. Martijn A. Spruit received grant from Netherlands Lung Foundation, Stichting Astma Bestrijding, all paid to Ciro. Moreover, he received grants and/or personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi and Teva, all paid to Ciro.

Principles of patient partnership: integrating patient perspectives into ERS Clinical Research Collaborations.

Patient and public involvement in research is increasingly considered a cornerstone of good research practice, and the research community recognises people with lived experience as valuable stakeholders within the research process. European Respiratory Society (ERS) strongly encourages patient input into its research programme and scientific activities, working in partnership with the European Lung Foundation (ELF) to facilitate this. Based on the ERS and ELF experience and best practice in the field of patient and public involvement, we developed a set of principles to which future ERS and ELF collaborations should adhere. These principles provide guidance on how to address key challenges when planning and conducting patient and public involvement in order to develop successful partnerships with patients and drive forward patient-centred research.

Smoking, alcohol consumption, and 24 gastrointestinal diseases: Mendelian randomization analysis.

Whether the positive associations of smoking and alcohol consumption with gastrointestinal diseases are causal is uncertain. We conducted this Mendelian randomization (MR) to comprehensively examine associations of smoking and alcohol consumption with common gastrointestinal diseases. Genetic variants associated with smoking initiation and alcohol consumption at the genome-wide significance level were selected as instrumental variables. Genetic associations with 24 gastrointestinal diseases were obtained from the UK Biobank, FinnGen study, and other large consortia. Univariable and multivariable MR analyses were conducted to estimate the overall and independent MR associations after mutual adjustment for genetic liability to smoking and alcohol consumption. Genetic predisposition to smoking initiation was associated with increased risk of 20 of 24 gastrointestinal diseases, including 7 upper gastrointestinal diseases (gastroesophageal reflux, esophageal cancer, gastric ulcer, duodenal ulcer, acute gastritis, chronic gastritis, and gastric cancer), 4 lower gastrointestinal diseases (irritable bowel syndrome, diverticular disease, Crohn's disease, and ulcerative colitis), 8 hepatobiliary and pancreatic diseases (non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis, liver cancer, cholecystitis, cholelithiasis, and acute and chronic pancreatitis), and acute appendicitis. Fifteen out of 20 associations persisted after adjusting for genetically predicted alcohol consumption. Genetically predicted higher alcohol consumption was associated with increased risk of duodenal ulcer, alcoholic liver disease, cirrhosis, and chronic pancreatitis; however, the association for duodenal ulcer did not remain statistically significant after adjustment for genetic predisposition to smoking initiation. This study provides MR evidence supporting causal associations of smoking with a broad range of gastrointestinal diseases, whereas alcohol consumption was associated with only a few gastrointestinal diseases. The Natural Science Fund for Distinguished Young Scholars of Zhejiang Province; National Natural Science Foundation of China; Key Project of Research and Development Plan of Hunan Province; the Swedish Heart Lung Foundation; the Swedish Research Council; the Swedish Cancer Society.

Dyspnea and perfusion defects (V/Q scan) are common after an acute pulmonary embolus whereas chronic thromboembolic pulmonary hypertension (CTEPH) is a rare sequele

Abstract Introduction Acute pulmonary embolism (PE), a common disease with substantial morbidity and mortality. Many previous studies have focused on the short-term consequences after an acute PE, but less attention has been directed to the long-term effects of a PE. The most feared complication is chronic thromboembolic pulmonary hypertension (CTEPH), with reported incidence rates ranging from 0.6 to 4.8%. Even though CTEPH is a rare complication after PE, dyspnea and functional impairment are common complaints, and a syndrome named PPES (post-PE-syndrome) has been suggested. The aim of this study was to follow a large national-wide cohort of post-PE-patients and to gather information regarding long-term symptoms and to determine the prevalence of CTEPH. Patients and methods We identified all patients diagnosed with acute PE in 2005 (ICD-10-SE: I26.0 and I26.9) that were registered in the Swedish National Patient Register (NPR), which has nearly 100% coverage. In 2007, all surviving individuals were invited to participate by letter. They were asked to complete a questionnaire regarding symptoms and risk factors for long-term sequele including CTEPH. Individuals who reported dyspnea or had known risk factors for CTEPH were invited to a follow-up with blood tests (NT-pro-BNP) and pulmonary scintigraphy. If any perfusion defects were detected, an echocardiography was performed. If signs of pulmonary hypertension, a referral was done to the regional PAH-center. Results In 2005, 5793 unique patients were admitted with a PE diagnosis in Sweden. Of those, 3510 were still alive in 2007, and 3226 individuals were contacted and asked to complete the questionnaire. Altogether 2105 (65%) individuals returned the questionnaire, and 53% reported dyspnea and 15% were asymptomatic but had risk factors for CTEPH. Altogether 944 individuals were referred for further follow-up including a recommendation to perform a V/Q-scan. Altogether 530 V/Q-scans were performed and 44% showed perfusion defects, whereof 85% had an echocardiography. Twenty-seven % of them registered a systolic right ventricular pressure of at least 30 mmHg. Referrals resulted in 6 cases with proved CTEPH. In parallel, 10 patients with CTEPH diagnosed before 2005 were detected, and 8 patients were diagnosed after 2005 and outside the study.Altogether 24 patients with CTEPH were thus identified and the cumulative incidence of CTEPH ranged between 0.7 and 1.2%. Conclusion Dyspnea is common after an acute PE and over 40% of them have perfusion defects on a V/Q scan, suggesting the presence of a post PE-syndrome (PPES). The incidence of CTEPH is however low. More research is needed to better define PPES. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Actelion PharamceuticalsSwedish Heart and Lung Foundation

Circulating CD31 reflects endothelial activity and is associated with a lower risk for cardiovascular complications

Abstract Background CD31 is a membrane receptor expressed by leucocytes, platelets and endothelial cells. CD31 regulates endothelial leukocyte transmigration and is key in maintaining endothelial homeostasis. An increased endothelial activation is suggested to contribute to atherosclerotic plaque inflammation but studies focusing on CD31 in atherosclerosis have provided evidence for both pro- and anti-atherosclerotic effects. However, which biological processes that are reflected by circulating soluble CD31 (sCD31) in human atherosclerosis remain unknown. Purpose Here, we aimed to explore 1) which biological processes circulating sCD31 reflects in the human atherosclerotic plaque and circulation 2) if sCD31 levels predicts cardiovascular death in individuals with carotid atherosclerosis and 3) if circulating sCD31 is causally associated to coronary artery disease (CAD) and ischemic stroke, in order to investigate its role as a biomarker of atherosclerotic disease and complications. Methods Cardiovascular associated plasma proteins (n=543) and carotid plaque proteins (n=197) were assessed by a proximity extension assay (Olink, SciLife) in the Carotid Plaque Imaging Project biobank. Plaques were phenotyped by immunohistochemistry. CD31 was located by immunofluorescence. Human carotid artery endothelial cells (HCtAECs) were stimulated with IL-6 and TNF-α to assess sCD31 release. National registries were used to identify cardiovascular death during follow up. All patients gave written informed consent. The study was approved by the local ethical review board and followed the declaration of Helsinki. Causal effects for sCD31 on stroke and CAD were examined by Mendelian randomization (MR). Summary statistics for GWAS of circulating CD31, coronary artery disease and stroke were retrieved from the SCALLOP study, the CARDIoGRAMplusC4D and the MEGASTROKE consortia. Results Plasma sCD31 correlated to plaque sCD31, TNF-α, MMP-2, MMP-9 levels and CD68+ plaque area. Plasma sCD31 also correlated to plasma CSF-1, MCP-1 and IL-8 levels. Clustering and enrichment analyses revealed that plasma sCD31 was associated to angiogenesis, cell migration and inflammatory responses. CD31 was pre-dominantly expressed on the plaque endothelium. TNF-α and IL-6 induced HCtAECs sCD31 release in vitro. Furthermore, low levels of circulating sCD31 predicted cardiovascular death and our MR analyses suggested that low circulating sCD31 levels were causally associated with a higher risk of stroke and CAD. Conclusions The present study shows that circulating sCD31 is released from endothelial cells due to inflammatory stimuli and reflects plaque inflammation. However, our follow-up data and MR analyses suggest that circulating sCD31 is associated with a lower risk for cardiovascular complications. This indicates that circulating sCD31 is not only a marker of an inflammatory response but also a marker of a functional endothelium, able to maintain the endothelial homeostasis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Swedish Society for Medical Research, The Swedish Research Council, Crafoord foundation, The Swedish Society of Medicine, The Swedish Heart and Lung Foundation, The Knut and Alice Wallenberg foundation, the Medical Faculty at Lund University and Region Skåne.

The incremental value of exercise ECG to myocardial perfusion SPECT for prediction of cardiac events

Abstract Background Both myocardial perfusion SPECT (MPS) and exercise ECG (Ex-ECG) are known to carry prognostic information in patients with chronic coronary syndrome (CCS). However, it is not fully understood if combining MPS and Ex-ECG results improves risk prediction. Current guidelines no longer recommend Ex-ECG for diagnostic evaluation of CCS, but adding Ex-ECG results to MPS could be of incremental prognostic importance. Purpose The study aimed to assess the incremental prognostic value of Ex-ECG to MPS results in patients with CCS. Methods A single-center study of 908 consecutive patients with CCS (age 63±9 years, 49% male) who underwent a MPS with Ex-ECG. Subjects were followed for five years. The clinical endpoint was a composite of cardiovascular death (CV), acute myocardial infarction (AMI), unstable angina and unplanned PCI. National registry data and electronic medical charts were used for end point allocation. Results Combining the findings of MPS and Ex-ECG resulted in concordant evidence of ischemia in 72 patients (8%) or absence of ischemia in 634 patients (70%). Dis-concordant results were found in 202 patients (22%; MPS−/Ex-ECG+, n=126 and MPS+/Ex-ECG−, n=76). During follow-up 95 composite cardiac events occurred (CV deaths n=6, AMI n=27, unstable angina n=34 and unplanned PCI n=28). Kaplan-Meier curves display an increased risk of cardiac events in patients with any combination of abnormal stress test results (Figure 1). In a multivariable regression model (adjusting for age, sex, smoking, known IHD, diabetes, dyslipidaemia and exercise capacity) MPS was the strongest predictor of cardiac events regardless of Ex-ECG results (MPS+/Ex-ECG−, Hazard ratio (HR) = 3.0, p=0.001 or MPS+/Ex-ECG+, HR=4.0, p&amp;lt;0.001). However, an abnormal Ex-ECG almost doubled the risk of event in subjects with a normal MPS (MPS−/Ex-ECG+, HR=1.9, p=0.04). Conclusions Combining the results from MPS and Ex-ECG in patients with chronic coronary syndrome lead to an improved prediction of future cardiac events. Even though MPS is the stronger predictor, there is an incremental prognostic value of adding data from Ex-ECG to MPS, especially in patients with normal MPS findings. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Swedish Heart and Lung Foundation, Region of Scania

Erythrocytes from patients with ST-elevation myocardial infarction induce cardioprotection via the purinergic P2Y13 receptor and nitric oxide signalling

Abstract Background Red blood cells (RBC) are suggested to act as important mediators in the regulation of cardiovascular function by exporting nitric oxide (NO) bioactivity and ATP under hypoxic/ischemic conditions. In addition, RBCs are known to protect from ischemia-reperfusion injury via the export of NO bioactivity in experimental settings. However, it remains unknown if such beneficial effects of RBCs are protective in patients with acute myocardial infarction. Purpose To investigate whether RBCs from patients with ST-elevation myocardial infarction (STEMI) protect against myocardial ischemia-reperfusion injury and whether such effect involves activation of purinergic and NO signalling in the RBCs. Methods RBCs were collected from patients with STEMI undergoing primary percutaneous coronary intervention and age- and gender-matched healthy controls. The RBCs were administered into the coronary circulation of isolated Langendorff-perfused rat hearts at the onset of global ischemia for 25 min followed by reperfusion of 60 min. Recovery of left ventricular developed pressure (LVDP) during reperfusion and infarct size were determined. All animal experiments and procedures were performed according to the guidelines by the U.S National Institutes of Health (NIH publication no 85–23, revised 1996). The present study was performed following The Code of Ethics of the World Medical Association outlined in the Declaration of Helsinki of 1975 and revised in 1983 for experiments that involve human subjects. Results Administration of RBCs from STEMI patients improved recovery of LVDP and reduced infarct size in hearts subjected to ischemia-reperfusion in comparison with RBCs from healthy controls (Figure 1A, B). Pre-incubation of the RBCs with the NO synthase (NOS) inhibitor L-NAME (Figure 1C, D) and the inhibitor of the NO receptor soluble guanylyl cyclase (sGC) ODQ abolished the cardioprotective effect of RBCs from STEMI patients. The cardioprotective effect was also attenuated by inhibition of cardiac cGMP-dependent protein kinase (PKG). Further, the purinergic P2Y13 receptor antagonist MRS2211 (Figure 1E, F), but not the P1 receptor antagonist 8PT applied to RBCs, attenuated the cardioprotection induced by RBCs from STEMI patients. Moreover, administration of RBCs from healthy subjects pre-incubated with a cell permeable ATP analogue improved post-ischemic recovery of LVDP and reduced infarct size. This cardioprotective effect was abolished by co-incubation of the RBCs with ODQ (Figure 2) and MRS2211. Conclusion Our findings demonstrate a novel function of RBCs in patients with STEMI that provides protection against myocardial ischemia-reperfusion injury via the activation of P2Y13 receptor and the NO-sGC pathway in RBCs and cardiac PKG. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung Foundation; Swedish Research Council

Endothelial-specific deletion of methyltransferase Set7 protects mice from obesity-induced endothelial dysfunction

Abstract Background The prevalence and incidence of obesity is alarmingly increasing worldwide. Among the constellation of weight-related comorbidities, cardiovascular disease (CVD) carries the largest burden. A large body of evidence supports the notion that endothelial dysfunction contributes to the pathogenesis of obesity-related CVD. Seminal work has revealed that oxidative stress is a key event preceding the development of endothelial dysfunction in this setting. Epigenetic connections underpinning oxidative stress and vascular dysfunction in experimental and human obesity are emerging. We and others have previously demonstrated that histone methyltransferase Set7 may participate to adverse vascular phenotypes in elevated cardiometabolic risk. Purpose To investigate whether Set7 contributes to endothelial dysfunction in a mouse model of diet-induced obesity. Methods Aortas were isolated from obese mice fed with high fat diet (HFD, 15.5% fat) for 12 weeks and control littermates fed with standard diet (STD, regular unrestricted diet). To specifically investigate Set7 role in obesity-driven endothelial dysfunction, endothelium-dependent (EDR) and independent relaxations were assessed in aortas isolated from control and obese mice, with or without endothelium-specific conditional genetic deletion of Set7. Endothelium-specific Set7 conditional knockout (mice have been generated in our facilities. Conditional Set7flox/flox mice were crossed with TekCre mice to generate E-Set7−/− mice. Set7 deletion was induced by tamoxifen. Body weight, glucose/insulin and lipid plasma levels were measured in all experimental groups. Set7 expression in endothelial cells isolated from mice aorta was assessed by RT-PCR and confocal microscopy. Reactive oxygen species (ROS) production was determined by electron spin resonance spectroscopy. Results Set7 was upregulated in endothelial cells isolated from aortas of obese WT mice as compared to lean controls. Confocal microscopy and RT-PCR of aortic tissue confirmed selective endothelial deletion of Set7 in the E-Set7−/− mice. Both WT and E-Set7−/− animals fed with HFD had similarly elevated body weight and plasma lipids (triglycerides, total and LDL cholesterol), as well as decreased HDL cholesterol. EDR to acetylcholine were impaired in aortas isolated from WT mice fed with HFD as compared to STD. Higher production of superoxide anion (O2-) was observed in aortas isolated from WT, but not in E-Set7−/−, HFD fed mice. Accordingly, apocynin and free radical scavenger TEMPOL rescued HFD-induced EDR in WT mice. Interestingly enough, E-Set7−/− HFD fed mice were protected against obesity-induced endothelial dysfunction. Conclusions Our findings demonstrate that chromatin-modifying enzyme Set7 is upregulated in obesity and involved in oxidative stress, and endothelial dysfunction. Targeting Set7 might represent a promising option to dampen oxidative stress and to prevent atherosclerotic vascular disease in this setting. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Research Council, the Swedish Heart &amp; Lung Foundation, and King Gustav V and Queen Victoria Foundation.

Lower stress perfusion in patients with myocardial infarction with non-obstructive coronary arteries compared to controls in long-term follow-up with quantitative perfusion mapping

Abstract Introduction Myocardial infarction with non-obstructive coronary arteries (MINOCA) constitutes a heterogenous condition with different coronary, cardiac and non-cardiac etiologies. Cardiovascular magnetic resonance imaging (CMR) has emerged as an important diagnostic tool in recent years and is now recommended in patients with MINOCA as a working diagnosis. However, despite early CMR following admission for MINOCA, no cause can be found in around 25% of all patients. A pathophysiological mechanism may be diffuse global coronary microvascular dysfunction (CMD) which has emerged as an important cause of myocardial ischemia. Quantitative adenosine stress CMR perfusion mapping allows for absolute quantification of myocardial perfusion, reflecting CMD in the absence of obstructive coronary disease in MINOCA patients. Purpose To study the presence of CMD in MINOCA patients with an initial normal CMR scan compared to healthy controls. Methods Patients from the multicenter myocardial infarction in our city with normal Coronaries 2 (SMINC-2) study, with a normal CMR scan 2–4 days after hospitalization, and healthy age- and sex-matched controls underwent stress perfusion at 1.5T (MAGNETOM Aera). Native rest T1 and T2 short-axis maps were acquired. Quantitative perfusion maps were acquired during adenosine stress (140 micrograms/kg/min) and at rest following an intravenous contrast bolus (0.05 mmol/kg of gadoteric acid, Gd-DOTA). Post contrast T1 maps were acquired after intravenous contrast (total dose 0.2 mmol/kg) rendering extracellular volume (ECV) maps. Global native T1, T2, ECV and rest and stress perfusion values were acquired by averaging segmental values per patient. Myocardial perfusion reserve (MPR) was calculated as perfusion in stress divided by rest. Values were presented as mean±standard deviation and compared with the independent t-test in normally distributed data, and with the Mann-Whitney U test in non-normally distributed data. Clinical data regarding cardiovascular risk factors, smoking and medications were presented as numbers (percentages) and compared with Fisher's exact test. Rate pressure product (RPP) was calculated as systolic blood pressure multiplied by heart rate in rest and stress. Results In total, 15 patients (59±16 years old, 60% female), and 15 healthy age- and sex-matched controls, were included. There was a trend towards higher incidence of hypertension in patients compared to controls, however no difference in other risk factors (Table 1). Compared to controls, MINOCA patients had lower perfusion in stress (Figure 1). There was no difference in global native T1, T2, ECV, rest perfusion, MPR or hemodynamic parameters between the MINOCA patients and the controls (p&amp;gt;0.05 for all, Table 1). Conclusions Myocardial stress perfusion is lower in MINOCA patients with a normal initial CMR scan compared to age- and sex-matched controls suggesting CMD as a possible pathophysiological mechanism in MINOCA. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart and Lung Foundation

Polygenic risk scores for mood disorders predict future strokes in women: a Mendelian randomization study

Abstract Objectives Mood disorders and strokes are often comorbid, and their health toll worldwide is huge. This study characterizes prognostic and etiological roles of mood disorders in stroke. Methods We tested if genetic susceptibilities for mood disorders could predict future strokes using the Malmö Diet and Cancer cohort (24 631 individuals). Additionally, Mendelian randomization was employed to further examine the causality using summary statistics from large genome wide association studies (mood disorders: up to 287,932 individuals; strokes: up to 446,696 individuals). Results Among 24,366 stroke-free participants at baseline, 2,632 individuals developed strokes, 2,172 of them ischemic, during a follow-up of up to 25 years. After all adjustments, participants in the highest quintile (5th quintile) of polygenic risk scores (PRS) for mood disorders had 1.46x (95% confidence interval (CI): 1.22–1.74) higher risk of strokes and 1.45x (95% CI: 1.19–1.77) higher risk of ischemic strokes compared to the lowest quintile (1st quintile) of PRS in women. Univariable and multivariable Mendelian randomization analyses showed that mood disorders had causal effect on smoking (odds ratio (OR) = 1.19, 95% CI: 1.07–1.31), type 2 diabetes mellitus (T2D, OR=1.22, 95% CI: 1.04–1.43) and women's body mass index (BMI, coefficient = 0.11, 95% CI: 0.01–0.21), whereas causal effects for smoking, T2D and BMI on stroke/ischemic stroke were consistently observed. Conclusion Our results suggest that mood disorders can cause stroke through smoking, T2D and BMI. Using PRS, women, who benefit from prevention and treatment of smoking, T2D and BMI, could possibly be early identified to prevent mood disorders and strokes. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Swedish Research Council, Swedish Heart and Lung Foundation, Skåne University Hospital Foundations, Lund University Diabetes Center - Industrial Research Center from the Swedish Foundation of Strategic Research, Region Skåne Grants, Swedish Stroke Foundation, Swedish society of medicine, Söderström König Foundation, Emil and Wera Cornell Foundation, Hjelt Foundation, and Diabetes Research and Wellness Foundation Sweden.