Swedish Heart-Lung Foundation Research Articles

Dysglycaemia screening and its prognostic impact in patients with coronary artery disease: experiences from the EUROASPIRE IV and V cohort studies

Glucose perturbations can be detected by fasting plasma glucose (FPG), HbA1c, and the oral glucose tolerance test (OGTT). The highest yield is provided by OGTT. HbA1c is considered more practical. We compare the diagnostic and predictive performance of these glycaemic indicators based on combined data from the EUROASPIRE IV (EAIV) and V (EAV) studies. This cohort study was conducted in 79 centres in 24 European countries (EAIV) and 131 centres in 27 European countries (EAV). Eligible patients were aged 18-80 years, did not have diabetes, and were diagnosed with coronary artery disease 6-36 months (EAIV) or 6-24 months (EAV) before the investigation. Patients were investigated with OGTT (FPG and 2 h post-load glucose [2-hPG]) and HbA1c. Follow-up of subsequent cardiovascular events was done by means of a questionnaire at least 1 year after the baseline investigation. Analyses were done in patients with both OGTT and HbA1c data available. Outcome analysis in these patients was restricted to those with valid follow-up data available. 16 259 patients were interviewed in EAIV (2012-13) and EAV (2016-17). 8364 patients had both OGTT and HbA1C data and were included in the analysis population (3932 in EAIV and 4432 in EAV). Information on cardiovascular events was available in 7892 patients. Follow-up was for a median 1·6 years (IQR 1·2-2·0). The average patient age was 63·3 years (SD 9·8), and 6346 (75·9%) of 8364 patients were men. At baseline, 1856 (22·5%) of 8263 patients were determined to have newly detected type 2 diabetes using OGTT alone, compared with 346 (4·2%) using HbA1c alone. New dysglycaemia, defined as newly detected type 2 diabetes or impaired glucose tolerance (IGT), was present in 3896 (47·1%) of the patients according to 2hPG. 2hPG 9 mmol/L or greater (162 mg/dL, adjusted hazard ratio [aHR] 1·58; 95% CI 1·27-1·95, p<0·0001), and HbA1c 5·9% or greater (41 mmol/mol, aHR 1·48, 1·19-1·84; p=0·0010) were the strongest predictors of cardiovascular events, while FPG did not predict. A multivariable model showed that the effect of HbA1c on cardiovascular events was mainly explained by 2hPG (aHR for 1 unit increase in HbA1c 1·13, 0·98-1·30; p=0·11; and aHR for 1 unit increase in Ln[2hPG] 1·37, 1·08-1·74; p=0·0042). 2hPG appears better than HbA1c in detecting dysglycaemia and predicting its impact on future cardiovascular events in patients with coronary artery disease and should be recommended as the primary screening tool. Swedish Heart-Lung Foundation, Region Stockholm (ALF), the Erling Persson Foundation, the Baltic Child Foundation.

Sedentary lifestyle, physical activity, and gastrointestinal diseases: evidence from mendelian randomization analysis

The causal associations of physical activity and sedentary behavior with the risk of gastrointestinal disease are unclear. We performed a Mendelian randomization analysis to examine these associations. Genetic instruments associated with leisure screen time (LST, an indicator of a sedentary lifestyle) and moderate-to-vigorous intensity physical activity (MVPA) at the genome-wide significance (P<5×10-8) level were selected from a genome-wide association study. Summary statistics for gastrointestinal diseases were obtained from the UK Biobank study, the FinnGen study, and large consortia. Multivariable MR analyses were conducted for genetically determined LST with adjustment for MVPA and vice versa. We also performed multivariable MR with adjustment for genetically proxied smoking, body mass index (BMI), waist-to-hip ratio, type 2 diabetes, and fasting insulin for both exposures. Genetically proxied longer LST was associated with an increased risk of gastrointestinal reflux, gastric ulcer, duodenal ulcer, chronic gastritis, irritable bowel syndrome, diverticular disease, Crohn's disease, ulcerative colitis, non-alcoholic fatty liver disease, alcoholic liver disease, cholangitis, cholecystitis, cholelithiasis, acute pancreatitis, chronic pancreatitis, and acute appendicitis. Most associations remained after adjustment for genetic liability to MVPA. Genetic liability to MVPA was associated with decreased risk of gastroesophageal reflux, gastric ulcer, chronic gastritis, irritable bowel syndrome, cholecystitis, cholelithiasis, acute and chronic pancreatitis. The associations attenuated albeit directionally remained after adjusting for genetically predicted LST. Multivariable MR analysis found that BMI and type 2 diabetes mediated the associations of LST and MVPA with several gastrointestinal diseases. The study suggests that a sedentary lifestyle may play a causal role in the development of many gastrointestinal diseases. Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001), Natural Science Foundation of Hunan Province (2021JJ30999), Swedish Heart-Lung Foundation (Hjärt-Lungfonden, 20210351), Swedish Research Council (Vetenskapsrådet, 2019-00977), Swedish Cancer Society (Cancerfonden), the Wellcome Trust (225790/7/22/Z), United Kingdom Research and Innovation Medical Research Council (MC_UU_00002/7) and National Institute for Health Research Cambridge Biomedical Research Centre (NHIR203312).

Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke.

Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data. Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results. Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months.

CPAP may promote an endothelial inflammatory milieu in sleep apnoea after coronary revascularization

Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease. Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed. Patients with OSA (n=189; 84% men; age 66±8 years, BMI 28±3.5kg/m2, AHI 41±23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n=91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n=98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes. Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA. National Institutes of Health/National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.

Long-term incidence of haematological cancer after bariatric surgery or usual care in the Swedish Obese Subjects study: a prospective cohort study

Bariatric surgery in people with obesity is associated with a reduced overall cancer risk. Retrospective studies indicate that bariatric surgery specifically might reduce the risk of haematological cancers, but there is an absence of data from long-term, prospective studies. We therefore studied the association between bariatric surgery and haematological cancer in the Swedish Obese Subjects study. The prospective controlled Swedish Obese Subjects study was designed to compare overall mortality in people who underwent bariatric surgery (n=2007) and usual care (n=2040). Participants were recruited through campaigns in mass media and at 480 primary health-care centres all over Sweden. The inclusion criteria were an age of 37-60 years and a BMI of 34 kg/m2 or more in men and 38 kg/m2 or more in women before or at the time of the examination. Haematological cancer events, including malignant lymphoma, myeloma, myeloproliferative neoplasms, as well as acute and chronic leukaemias, were captured from the Swedish Cancer Registry. The main outcome of this study was haematological cancer incidence and mortality. This study is registered with ClinicalTrials.gov (NCT01479452) and is ongoing. A total of 4047 individuals with obesity were enrolled between Sept 1, 1987, and Jan 31, 2001. Overall, 34 participants in the surgery group and 51 participants in the usual care control group were diagnosed with haematological cancer during follow-up (hazard ratio [HR] 0·60; 95% CI 0·39-0·92; p=0·020). Moreover, there were three deaths by haematological cancer in the surgery group and 13 deaths in the control group (0·22; 0·06-0·76; p=0·017). Surgery was also associated with a reduced incidence of lymphoma (0·45; 0·23-0·88; p=0·020). A significant difference in treatment effect between men and women was found; bariatric surgery was associated with reduced incidence of haematological cancer in women (0·44; 0·26-0·74; p=0·002), but not in men (1·35; 0·58-3·17; p=0·489; interaction p=0·031). Bariatric surgery is associated with a reduced incidence of haematological cancer, specifically in women. Health-care providers and policy makers working in the field of cancer prevention should consider bariatric surgery a primary prevention resource for people with obesity. The Swedish Research Council, the Swedish State under the agreement between the Swedish Government and the county councils, the Avtal om Läkarutbildning och Forskning agreement, the Health & Medical Care Committee of the Region Västra Götaland, the Swedish Heart Lung Foundation, Gothenburg Medical Society, and the Adlerbert Research Foundation. For the Swedish translation of the abstract see Supplementary Material section.

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.

Assessment of primary mitral regurgitation and lung water content using 15O-water positron emission tomography

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Swedish Heart-Lung Foundation, Stockholm, Sweden. Introduction Severe primary mitral valve regurgitation (MR) is associated with significant hemodynamic changes in the cardio-pulmonary system, eventually resulting in lung congestion. The gold standard for assessing the regurgitation volume and fraction (RegVol; RegFraction), and severity of MR is cardiac magnetic resonance (CMR). The PET-tracer 15O-water is considered the gold standard for non-invasive quantitation of myocardial blood flow, but techniques for performing other functional assessments are evolving: using first-pass imaging total LV stroke volume (SV) can be measured with ECG-gating, and cardiac output (CO), forward SV (FSV) and pulmonary transit time (PTT) can be measured with indicator dilution techniques. Purpose The purpose of this study was to evaluate the method for calculating RegVol and RegFraction with 15O-water PET compared to CMR, and to assess the correlation to PWV. Methods N=19 patients with asymptomatic or mildly symptomatic severe MR were imaged on the same day with CMR and 15O-water PET. The PET-examinations were conducted on a digital PET/CT scanner (Discovery MI, GE Healthcare). The scans were performed in resting state and a 4-lead ECG was connected during the procedure. 400 MBq 15O-water was injected as an automated intravenous bolus simultaneous to starting a 4 min PET-emission in list mode. The list mode data was reconstructed into a 4 min dynamic series, and 16 ECG-gated images using the first 50 s of the scan only. The reconstructions were analysed using a semi-automatic software developed in-house. We calculated RegVol=total SV- FSV, RegFraction=RegVol/total SV *100 and PWV=CO*PTT. PWV was indexed against body surface area. Bland-Altman and linear regression analyses were performed and P &amp;lt; 0.05 was considered statistically significant. Results PET-based RegVol and RegFraction correlated significantly with CMR (r=0.94 and 0.89, both p&amp;lt;0.001). Bland-Altman plots showed a systematic underestimation for RegVol and RegFraction calculated by PET compared to CMR, but no proportional bias was present. PET and CMR- based RegFraction correlated significantly with PWV (r=0.70 and 0.78, both p&amp;lt;0.001). Conclusions 15O-water PET can be used to measure the severity of primary mitral regurgitation and the backward impact of regurgitation on lung water accumulation.

Time for Routine Helicobacter pylori Screening in Coronary Artery Disease?

Time for Routine Helicobacter pylori Screening in Coronary Artery Disease?

Evolution of age-related mutation-driven clonal haematopoiesis over 20 years is associated with metabolic dysfunction in obesity

Haematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF) increase with age and are linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones (VAF<2%) are also associated with adverse outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes in individuals with obesity treated by usual care or bariatric surgery (a treatment that improves metabolic status), and to examine the expansion of clones in relation to age and metabolic dysregulation over up to 20 years. Clonal haematopoiesis-driver mutations (CHDMs) were identified in blood samples from participants of the Swedish Obese Subjects intervention study. Using an ultrasensitive assay, we analysed single-timepoint samples from 1050 individuals treated by usual care and 841 individuals who had undergone bariatric surgery, and multiple-timepoint samples taken over 20 years from a subset (n=40) of the individuals treated by usual care. In this explorative study, prevalence of CHDMs was similar in the single-timepoint usual care and bariatric surgery groups (20.6% and 22.5%, respectively, P=0.330), with VAF ranging from 0.01% to 31.15%. Clone sizes increased with age in individuals with obesity, but not in those who underwent bariatric surgery. In the multiple-timepoint analysis, VAF increased by on average 7% (range-4% to 24%) per year and rate of clone growth was negatively associated with HDL-cholesterol (R=-0.68, 1.74E-04). Low HDL-C was associated with growth of haematopoietic clones in individuals with obesity treated by usual care. The Swedish Research Council, The Swedish state under an agreement between the Swedish government and the county councils, the ALF (Avtal om Läkarutbildning och Forskning) agreement, The Swedish Heart-Lung Foundation, The Novo Nordisk Foundation, The European Research Council, The Netherlands Organisation for Scientific Research.

PD1 blockade promotes IFN-γ production by progenitor exhausted PD1-expressing T cells in atherosclerotic plaques

Abstract Objective: Interferon-γ (IFN-γ) is a key cytokine regulating the development of atherosclerosis, but little is known regarding the phenotype and regulation of T cells producing IFN-γ in plaques. Methods: To identify and characterize IFN-γ-producing T cells in the development atherosclerosis, we utilized IFN-γ-YFP and Nur77-GFP reporter mice crossed onto an atherosclerotic background (Apoe−/−IFN-γ YFP/YFP; Apoe−/−Nur77GFP/wt), adoptive transfer of transgenic ApoB-reactive T-cells into mice containing humanized ApoB100 (HuBL mice), and treatment with immune checkpoint inhibitors in atherosclerotic mice. Results: Aortic CD4 +and CD8 +T cells producing IFN-γ were a complex set of cells comprised predominantly of “progenitor exhausted” PD1-intermediate (PD1 int) SLAMF6 +IL7R +T cells and a minor population of “terminally exhausted” PD1 hiTOX +T cells. However, both PD1 intand PD1 hiplaque T cells were Ki67 +and displayed elevated levels of recent TCR signaling (Nur77-GFP +). ApoB-specific transgenic CD4 +T cells adoptively transferred to a hypercholesterolemic HuBL mice showed sign of early exhaustion, upregulating PD1, TOX, and Tim3. Finally, PD1 blockade in mice with advanced atherosclerosis resulted in increased levels of IFN-γ production of plaque-infiltrating CD4 +and CD8 +T cells. Conclusion: IFN-γ-producing T cells in the atherosclerotic plaque display markers classically associated with an exhausted T cell phenotype but still produce cytokines, proliferate, and are responsive to anti-PD1 treatment. Our study suggests that PD1 signaling regulates T cell IFN-γ production in plaques and reveals a potential mechanism by which immune checkpoint blockade therapy aggravates cardiovascular disease. Supported by grants from Swedish Heart-Lung Foundation (#20200522, #20190449) sourced by Daniel Engelbertsen.

Ambient air pollution exposure linked to long COVID among young adults: a nested survey in a population-based cohort inSweden.

Post COVID-19 conditions, also known as long COVID, are of public health concern, but little is known about their underlying risk factors. We aimed to investigate associations of air pollution exposure with long COVID among Swedish young adults. We used data from the BAMSE (Children, Allergy, Environment, Stockholm, Epidemiology [in Swedish]) cohort. From October 2021 to February 2022 participants answered a web-questionnaire focusing on persistent symptoms following acute SARS-CoV-2 infection. Long COVID was defined as symptoms after confirmed infection with SARS-CoV-2 lasting for two months or longer. Ambient air pollution levels (particulate matter ≤2.5μm [PM2.5], ≤10μm [PM10], black carbon [BC] and nitrogen oxides [NOx]) at individual-level addresses were estimated using dispersion modelling. A total of 753 participants with SARS-CoV-2 infection were included of whom 116 (15.4%) reported having long COVID. The most common symptoms were altered smell/taste (n=80, 10.6%), dyspnea (n=36, 4.8%) and fatigue (n=34, 4.5%). Median annual PM2.5 exposure in 2019 (pre-pandemic) was 6.39 (interquartile range [IQR] 6.06-6.71) μg/m3. Adjusted Odds Ratios (95% confidence intervals) of PM2.5 per IQR increase were 1.28 (1.02-1.60) for long COVID, 1.65 (1.09-2.50) for dyspnea symptoms and 1.29 (0.97-1.70) for altered smell/taste. Positive associations were found for the other air pollutants and remained consistent across sensitivity analyses. Associations tended to be stronger among participants with asthma, and those having had COVID during 2020 (versus 2021). Ambient long-term PM2.5 exposure may affect the risk of long COVID in young adults, supporting efforts for continuously improving air quality. The study received funding from the Swedish Research Council (grant no. 2020-01886, 2022-06340), the Swedish Research Council for Health, Working life and Welfare (FORTE grant no. 2017-01146), the Swedish Heart-Lung Foundation, Karolinska Institute (no. 2022-01807) and Region Stockholm (ALF project for cohort and database maintenance).

Difference in functional constituents of myocardial passive compliance renders BalbC/J mice sensitive to pulmonary edema compared to C57BL6/J mice

Study objective: We have found different survival rates in response to a 4-day angiotensin II (AngII) and high salt diet - treatment in two mouse strains, BalbC/J and C57BL6/J. The mortality is increased in BalbC/J mice alongside increased lung weight but the reason is unknown. Hypothesis: We hypothesize the increased mortality is due to differences in myocardial compliance. Methodology: Male mice were treated with AngII by osmotic mini-pump infusion and fed a high salt-diet (3%) for 4 days. At the end of the treatment the lungs were weighed. Left ventricle (LV) passive compliance was assessed by Langendorff, and collagen and non-collagen functional fractions using demembranated trabecular strips. A commercial assay was used to determine total collagen of the myocardium. All procedures were approved by the local ethics committee. Comparisons were carried out using unpaired t-test. All intervals reflect standard error of the mean. Data: Lung weights of animals before treatment were similar in BalbC/J (148 ± 8.8 mg (n=5)) and C57BL6/J (155 ± 12 mg (n=5)) mice (p&gt;0.05). After treatment they were higher in BalbC/J (255 ± 24 mg (n=7)) than C57BL6/J (166 ± 5.1 mg (n=6)) (p&lt;0.01). LV passive strain was higher in BalbC/J (62.4 ± 11.9 mN/mm2 (n=9)) than C57BL6/J (28.2 ± 2.3 mN/mm2 (n=7)) (p&lt;0.05), at 36 μl LV inflation past 5 mmHg end-diastolic pressure. In demembranated trabeculae, passive stiffness was higher in BalbC/J (38.7 ± 5.5 mN/mm2 (n=6)) than C57BL6/J (22.5 ± 2.0 mN/mm2 (n=6)) (p&lt;0.05) at baseline, as measured by passive tension at 15 % stretch from sarcomere length 2.0 μm. This was derived from the non-collagen fraction which was higher in BalbC (23.4 ± 2.8 mN/mm2 (n=6)) than C57BL6/J (12.4 ± 1.3 mN/mm2 (n=6)) (p&lt;0.01), unlike the collagen fraction that was the same (BalbC/J 15.3 ± 3.8 mN/mm2 (n=6), C57BL6/J 10.1 ± 1.5 mN/mm2 (n=6) (p&gt;0.05)). There was no difference in myocardial collagen content (BalbC/J 0.20 ± 0.01 μg/μl (n=7), C57BL6/J 0.18 ± 0.01 μg/μl (n=9) (p&gt;0.05)). Summary of results: Gross organ evaluation by Langendorff indicates higher myocardial stiffness in BalbC/J than C57BL6/. This renders the heart susceptible to backward failure. This is supported by findings in demembranated tissue bundles. The origin of this appears to lie in the non-collagen fraction of passive stiffness, as indicated by functional and biochemical assays. Conclusion: An acute lung weight increase indicates pulmonary edema. The most common reason for this is backwards failure of the LV. Our investigations into myocardial function suggest that BalbC/J mice has a propensity for this due to lower compliance secondary to increased non-collagen fraction, compared to C57BL6/J. This is likely caused by titin-derived stiffness. Therapies to modulate titin-derived stiffness may be useful to avoid backward failure. These findings also represent important knowledge for the research community modeling human heart disease on the backbone of two common mouse strains. The study was funded with grants from the Swedish Society of Medical Research and Åke Wiberg Foundation to HI, Swedish Heart-Lung Foundation to MH, and from Uppsala University Hospital to HI and MH. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

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.

Mental health outcomes in parents of children with a cancer diagnosis in Sweden: A nationwide cohort study.

The diagnosis of paediatric cancer is a crisis for the parents who are the primary caregivers of the affected child. A comprehensive assessment of the longitudinal impact of childhood cancer on parental mental health and the potential sex differences between the parents is lacking. Thus, we aimed to explore the subsequent short- and long-term mental health outcomes among the parents of children with cancer and examine whether the outcomes vary between the mother and father. By combining several Swedish registers, parents of a child (ages 0-14 years) with a cancer diagnosis between Jan 1, 2006, and Dec 31, 2016 were identified. For each parent of children with cancer, up to five mothers or fathers of cancer-free children were randomly selected and matched, respectively. Hospital contacts for any mental health disorders between 5 years before and 7 years after the diagnosis of childhood cancer were retrieved. An interrupted time series negative binomial regression was performed to assess the short- and long-term impact of a childhood cancer diagnosis on the parents' subsequent mental health outcomes. 16,199 mothers (2852 with a child with cancer and 13,347 without) and 15,708 fathers (2769 with a child with cancer and 12,939 without) were included in this study. Compared with mothers of children without cancer, mothers of children with cancer had higher risks of mental health disorders in the first year after diagnosis (rate ratio [RR] and 95% Confidence Interval [CI], 1.17 (1.03-1.32)), and notably, the adverse impact became more severe over time (RR and 95% CI, 1.36 (1.07-1.74), in the seventh year). For fathers of children with cancer, the risk of mental health disorders was continuously higher compared to matched comparisons (RR and 95% CI, 1.31 (1.01-1.71)). Our findings suggested that parental mental health was affected continuously by a diagnosis of childhood cancer in their children. In particular, the mother's mental health was affected more severely. Customised psychological services or interventions are highly needed for the parents of children with cancer. Swedish Research Council, Allmänna Sjukhusets i Malmö Stiftelsen för bekämpande av cancer, Swedish Heart-Lung Foundation, ALF funding from Region Skåne and China Scholarship Council.

Low Apgar score and asphyxia complications at birth andriskof longer-term cardiovascular disease: a nationwide population-based study of term infants.

Most follow-up studies have focused on the long-term consequences of asphyxia at birth on the brain. The aim of this study was to investigate associations between low Apgar score and asphyxia-related complications and subsequent risks of cardiovascular diseases (CVD) in childhood and early adulthood. This population-based cohort study included 2,826,424 non-malformed singleton births, born at term (≥37weeks' gestation) between 1988 and 2018 in Sweden. Primary exposure was a composite of asphyxia-related complications, defined as a) Apgar score 0-3at 1-min; or b) Apgar score 0-3at 5-min; or c) neonatal seizures (including hypoxic ischemic encephalopathy). Using Cox regression, we estimated the risk of CVD after 1 year of age, defined as stroke, coronary heart disease, heart failure, and atrial fibrillation. Overall, there were 4165 cases with cardiovascular diseases. Individuals with asphyxia-related complications had adjusted hazard ratios (95% confidence intervals) of 1.90 (1.54 to 2.34) for cardiovascular disease, 2.29 (1.74 to 3.03) for stroke, 2.17 (1.37 to 3.42) for heart failure, and 1.38 (0.87 to 2.17) for atrial fibrillation. Hazard ratios for CVD were elevated among individuals with Apgar score 0-3at 1 and 5min, and those with neonatal seizures. Compared with unexposed individuals, neonatal seizures were associated with 5 times higher rates of stroke and heart failure, respectively. Asphyxia-related complications and its neonatal complications, especially low Apgar score and neonatal seizures, are associated with increased risks of CVD in childhood and early adulthood, although the absolute risk of CVD is low in young age. Swedish Research Council and the Swedish Heart-Lung Foundation.

Incidence of spontaneous coronary artery dissection during pregnancy in Swedish women between 1997 to 2019, a retrospective observational cohort study based on national Swedish health-registers

Abstract Background/Introduction Spontaneous coronary artery dissection (SCAD) is an acute myocardial event. Previous studies suggest female predominance. It is an unusual underlying cause of myocardial infarction. However, it is thought to be the most common cause of myocardial infarction associated with pregnancy. Purpose The aim of the study was to collect data on all women of reproductive age that had been diagnosed with SCAD in Sweden, including both pregnant and non-pregnant women, using the national Swedish health registers of the last two decades to describe the cohort and compare clinical characteristics. Methods Retrospective data on individuals with a diagnosis of SCAD (ICD-I25.4) occurring before fifty years of age were collected from four Swedish registers; the national patient register, the national medical birth register, the national cause of death register and the LISA register. Women diagnosed with SCAD between the years 1997 and 2019 and &amp;lt;50 years of age at diagnosis were included. SCAD during pregnancy or within 14 weeks post-partum was considered pregnancy-associated. Results A total of 75 women comprised the final cohort, seven of which met the criteria for pregnancy-associated SCAD. Nine percent of all women that had SCAD in Sweden before 50 years of age had it in association with pregnancy and in SCAD that occurred before 40 years of age, 28% arose in association with pregnancy. There were no clinically significant differences in height between women with pregnancy-associated SCAD and those with SCAD not associated with pregnancy. History of smoking, diabetes mellitus, hyperthyroidism, hypothyroidism and hyperlipidemia were not prominent in the cohort (9.3, 4, 1.3, 2.7 and 2.7% respectively). Seventeen percent of patients had had no pregnancies prior to first event of SCAD. Two patients (2.6%) were deceased due to ischemic heart disease, one had had SCAD associated with pregnancy. Conclusion Spontaneous coronary artery dissections are uncommon. However, when they do occur in women under forty years of age more than one in four (28%) is associated with pregnancy. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish heart lung foundation.

Left ventricular dysfunction in a cohort of new onset idiopathic inflammatory myopathy without known heart disease

Abstract Impaired myocardial function is linked to inflammatory mechanisms. Indeed, many systemic inflammatory diseases are associated to risk of developing heart disease. Idiopathic inflammatory myopathy (IIM; here Dermato- or polymyositis) are rare systemic inflammatory diseases, characterised by immune infiltration in muscle, presence of autoantibodies and cytokines in circulation leading to weakness and disability. IIM can involve extra-muscular tissues, e.g. heart, and is associ-ated with elevated risk for cardiovascular disease. Heart function in IIM is little investigated and has mostly been studied in patients at a chronic IIM stage or with a concomitant heart disease. To our knowledge, heart function has not been characterized at the early stage in IIM when the risk of inflammatory associated cardiomyopathy may be high. Our hypothesis is that patients at early-stage IIM may present with subclinical myocardial dysfunction that can be detected by echocardiography. We used echocardiography (echo) following clinical standards to investigate heart function in a cohort of 18 patients (61% females; age 46±12 years) with recent onset IIM (mean diagnosis time 5 month). Patients were recruited from the rheumatology clinic at Karolinska University Hospital, Stockholm, and had given written consent. None had previous heart disease. Echo parameters were compared to normal reference limits as established by the American Society for Echocardiography. Heart failure association (HFA)-PEFF score (≥2 p) was used to define left ventricular diastolic dysfunction (LVDD). Ejection fraction (EF) was generally preserved in the cohort with no patient displaying EF&amp;lt;55% (Table 1). Yet, 4 patients (22%) displayed reduced global strain (LVGLS; &amp;gt;−20%) suggesting presence of impaired myocardial contraction. In contrast, diastolic dysfunction was seen in several patients as indicated by one or more diastolic parameters outside normal rage (table 1). Moreover, when calculating HAVA-PEFF score 9 patients (50%) fulfilled criteria for LVDD. None of the patients displayed hypertension (&amp;gt;140/90 mmHg), or left ventricular hypertrophy. In a cohort of patients with recent onset IIM without known heart disease, we have found that diastolic dysfunction is prevalent with 50% of the patients fulfilling criteria for LVDD according to the HFA-PEFF score. This gives a high likelihood of fulfilling criteria for the diagnosis heart failure with preserved EF (HFpEF). We conclude that clinical echocardiography is important in the initial work up of IIM to screen for LVDD as the risk of heart failure is likely to be high. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart Lung Foundation

Invasive validation of pressure-volume loops derived from cardiovascular magnetic resonance imaging and brachial blood pressure in heart failure patients

Abstract Introduction Left ventricular (LV) pressure-volume (PV) loops provide gold-standard physiological information but require invasive measurements of ventricular intracavity pressure, limiting clinical and research applications. Recent development has seen the introduction of non-invasively computed PV loops from cardiovascular magnetic resonance (CMR) volumetry and a brachial blood pressure measurement. The approach combines LV volumes with a time-varying elastance function to compute time-resolved LV pressures and was validated on invasive pressure data from a porcine model. The method is readily implemented using standard CMR sequences and provides measures of hemodynamic parameters including stroke work, myocardial efficiency, and contractile state. However, the method remains to be validated in patients using invasive left ventricular pressure recordings. Purpose To validate for the first time in human patients the performance of non-invasively computed PV loops against invasive measures. Methods Four heart failure patients underwent two subsequent sessions of CMR cine imaging and simultaneous brachial blood pressure measurement, with intravenous administration of two different vasoactive drugs, resulting in two different haemodynamic states for each patient. LV catheterization was then conducted with repeat administration of the same infusions. Pressure-volume loops were computed from CMR volumes combined with 1) a time-varying elastance function scaled to brachial blood pressure and temporally stretched to match volume data, and 2) invasive pressures averaged from multiple sampled beats. Method comparison was conducted using linear regression and Bland-Altman analysis. Results Figure 1 shows non-invasively derived PV loop parameters compared to invasive data. The non-invasive method demonstrated strong correlations and low bias for stroke work (R2=0.97, bias 4.6%, p&amp;lt;0.0001), potential energy (R2=0.83, bias 1.5%, p=0.001), end-systolic pressure-volume relationship (R2=0.90, bias 5.4%, p=0.0003), energy per ejected volume (R2=0.93, bias 3.5%, p=0.0001), ventricular efficiency (R2=0.99, bias 1.1%, p&amp;lt;0.0001), arterial elastance (R2=0.87, bias −7.8%, p=0.0006), and mean external power (R2=0.89, bias 4.6%, p=0.0005). Conclusions Pressure-volume loops can be precisely and accurately computed from cardiovascular magnetic resonance imaging and brachial cuff blood pressure in humans, and is ready for use in research applications. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Swedish Heart Lung Foundation

Long-term survival in patients with univentricular heart: a nationwide, register-based cohort study

Abstract Background Univentricular heart (UVH) is a broad term that covers various cardiac structural abnormalities in which one ventricle is severely underdeveloped, or a ventricular septal wall did not form, leading to a functional single-ventricle physiology. Patients with UVH have a very limited life expectancy if not surgically treated. While the outcome in children with UVH have been extensively studied, data regarding the long-term outcomes in an unselected, nationwide cohort is still lacking. Purpose The aim of the present study was to determine long-term survival in patients with UVH compared to an age- and sex-matched control population without congenital heart disease in Sweden. Methods We linked data from the Swedish Patient and Cause of Death Register to identify patients with UVH that were born between 1970 and 2017. Each patient with UVH was matched with ten individuals without congenital heart disease for year of birth and sex. The mortality risk in patients with UVH compared with matched controls was analyzed using Cox proportional regression models and Kaplan-Meier survival analysis. Results Of a total of 5,075 patients with UVH and 50,620 matched controls, 1,992 (37.9%) and 485 (1.0%) died, respectively. The mean follow-up (standard deviation) was 15.7 (± 14.2) years. A total of 758 patients (14.9%) of the UVH population were diagnosed with hypoplastic left heart syndrome (HLHS). The mortality risk was 53.01 (95% CI, 48.0–58.6) times higher in UVH and 163.5 (95% CI, 124.3–215.2) times higher in HLHS compared to controls. According to birth period, highest mortality was found at the earliest UVH cohort (1970–1981) 59.8%, and decreased by later birth periods. The lowest mortality was in the latest birth period, 2006–2017 (16.3%). Conclusions In this nationwide, register-based cohort study, the overall risk of mortality was more than 50 times higher in patients with UVH compared to matched controls. However, an increased survival was observed over time and by later birth periods. Quadragenarians with UVH is still a rare group but are expected to increase during the next decades. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish heart lung foundation

Longitudinal assessment of myocardial edema following experimental acute myocardial infarction using a comprehensive CMR protocol

Abstract Background Preclinical and clinical data following acute myocardial infarction (MI) and reperfusion have shown a bimodal pattern of edematous myocardium at risk (MaR) on cardiovascular magnetic resonance (CMR) imaging during the first week [1,2]. In contrary, there have also been data demonstrating that MaR is stable during the first week in patients using contrast-enhanced steady-state free precession (CE-SSFP) imaging [3]. Purpose To use a comprehensive CMR protocol to assess the dynamics of edematous MaR during the first week following acute experimental MI. Methods Acute myocardial ischemia was induced in seven pigs by endovascular balloon occlusion in the left anterior descending artery with reperfusion after 40 minutes. CMR was performed at baseline, at 120 minutes, 24 hours and seven days post-reperfusion on a 1.5T scanner. The CMR protocol comprised of a prototype T2-SSFP sequence where two experiments with 16 echo times (T2 mapping16) and with 10 echo times (T2 mapping10) [1] were performed. After contrast administration, a short-axis CE-SSFP stack and late gadolinium enhancement (LGE) images were acquired. T2-maps were acquired in a mid-apical ventricular short-axis slice corresponding to the same anatomical level at all time points. All image analysis was performed using designated software. Severity of MaR was measured by placing a region of interest in the ischemic area on T2 maps and extent of MaR was assessed by delineating hyperintense areas in CE-SSFP short-axis stacks. Data is presented as mean ± SD and one-way ANOVA was used followed by Tukey's multiple comparison test. Results An example of all acquired CMR sequences is shown in Figure 1, with red arrows depicting the extent of edematous MaR. Figure 2 shows the severity of MaR by T2 values from T2 mapping16 where T2 values were significantly lower at 24 hours compared to 120 minutes post-reperfusion (P&amp;lt;0.05). However, no significant difference was seen at 120 minutes or at 24 hours compared to T2 values at seven days (P=0.46 and P=0.35). No difference at baseline (47±3 ms vs 49±3 ms, P=0.10) was observed when comparing T2 mapping16 against T2 mapping10 but a significant difference between the time points 120 min (80±8 ms vs 69±7 ms, P=0.02), 24 h, (69±9 ms vs 54±4 ms, P=0.03), and seven days (76±10 ms vs 67±5 ms, P=0.04) post-reperfusion. There was no statistically significant difference between T2 values post-reperfusion using T2 mapping10 (P=ns). The extent of myocardium at risk assessed by CE-SSFP did not show a bimodal pattern of edema, but rather a significantly lower extent at seven days compared to the extent at 120 minutes and 24 hours (P&amp;lt;0.05). Conclusion The severity and extent of edematous myocardium at risk does not follow a bimodal pattern over the course of one week. However, absolute T2 values differ between T2 mapping sequences and therefore a standardization of a CMR protocol for the assessment of MaR is of importance. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): The Swedish Heart-Lung Foundation and The Medical Faculty of Lund University (ALF)