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Aims We recently reported five cases of vaccine-induced immune thrombotic thrombocytopenia (VITT) 7–10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against corona virus disease 2019 (COVID-19). We aimed to investigate the pathogenic immunological responses operating in these patients. Methods and results We assessed circulating inflammatory markers by immune assays and immune cell phenotyping by flow cytometry analyses and performed immunoprecipitation with anti-platelet factor (PF)4 antibody in plasma samples followed by mass spectrometry from all five patients. A thrombus was retrieved from the sinus sagittal superior of one patient and analysed by immunohistochemistry and flow cytometry. Precipitated immune complexes revealed multiple innate immune pathway triggers for platelet and leucocyte activation. Plasma contained increased levels of innate immune response cytokines and markers of systemic inflammation, extensive degranulation of neutrophils, and tissue and endothelial damage. Blood analyses showed activation of neutrophils and increased levels of circulating H3Cit, dsDNA, and myeloperoxidase–DNA complex. The thrombus had extensive infiltration of neutrophils, formation of neutrophil extracellular traps (NETs), and IgG deposits. Conclusions The results show that anti-PF4/polyanion IgG-mediated thrombus formation in VITT patients is accompanied by a massive innate immune activation and particularly the fulminant activation of neutrophils including NETosis. These results provide novel data on the immune response in this rare adenoviral vector-induced VITT., Graphical Abstract Graphical Abstract

Background The adipose tissue (AT) compartments surrounding the heart have been claimed to exert different pro-inflammatory properties with different associations with cardiovascular disease states. The epicardial AT (EAT), located close to the coronary arteries between the myocardium and the pericardial layer, seems to be associated with atherosclerosis and metabolic syndrome, whereas the pericardial AT (PAT), separated from the heart by the pericardium, is discussed to have less pro-inflammatory properties. Purpose The aim of the present study was to explore any differences in genetic regulation of pro-inflammatory markers included in the inflammasome related pathway in EAT, PAT and in subcutaneous AT (SAT). In addition, any relationship to the corresponding inflammatory markers in the circulation was explored. Materials and methods Biopsies from EAT, PAT and SAT, and arterial blood samples were collected from 52 patients with coronary heart disease (CHD) undergoing coronary by-pass surgery (aged 48–82 years, 70% male, median body mass index (BMI) 27.3 kg/m2). RNA was extracted by use of RNeasy Lipid Tissue Mini Kits. Gene expression of Interleukin (IL)-1β, IL-18, NLRP3, Caspase-1, toll-like receptor 4 (TLR4), IL-6, IL-6 receptor and gp130 in the different adipose tissue compartments were analyzed using RT-PCR. Circulating levels where possible, were measured in serum with ELISAs. Results We demonstrated that IL-18 and IL-6 were about 4-fold higher expressed in EAT compared to PAT (p Conclusions The results shows that only IL-18 and IL-6 were higher expressed in EAT, compared to the two other AT compartments in our non-obese CHD population. The results further show that the inflammasome related genes in pericardial AT associated strongly with subcutaneous AT, suggesting SAT to be more pro-inflammatory than previously expected. Funding Acknowledgement Type of funding sources: None.

Background In the OMEMI trial, elderly post-MI patients did not achieve reduction in cardiovascular events from supplementation of 1.8g n-3 polyunsaturated fatty acids (PUFA). In two recent trials of hypertriglyceridaemic patients the REDUCE-IT trial demonstrated an association between high levels of serum eicosapentaenoic acid (EPA) and reduced risk of CV events with 4 g/day icosapent ethyl supplements while in the STRENGTH trial no such association was present in patients treated with 4 g/day of EPA+ docosahexaenoic acid (DHA). Purpose To assess associations between changes in concentrations of EPA and DHA during two years supplementation with n-3 PUFA and incident cardiovascular events in the OMEMI trial. Methods In the randomized controlled OMEMI trial, 1014 elderly patients with a recent acute myocardial infarction (AMI) were treated with 1.8g/day of EPA and docosahexaenoic acid (DHA) or placebo for two years, and followed for the primary outcome of MACE (AMI, coronary revascularization, stroke or heart failure hospitalization) and secondary outcome of new-onset atrial fibrillation (AF). Serum concentrations of EPA and DHA were measured at inclusion and at study completion by gas chromatography, and reported as % weight of total FA (%wt) in serum phospholipids. Results Serial EPA and DHA measurements at study inclusion and completion were available in 881 patients (92% of survivors). At baseline EPA and DHA concentrations were (mean±SD) 2.84±1.41 and 5.71±1.35%wt, respectively. Higher baseline EPA and DHA concentrations were associated with previous n-3 PUFA supplementation, lower prevalence of current smoking and diabetes, lower levels of triglycerides and higher levels of HDL-cholesterol (all p Conclusion Patients treated with 1.8 g/day n-3 PUFA for two years experienced a doubling of serum EPA concentrations. Greater increases in EPA were associated with a lower risk of MACE, but also a higher risk of new-onset AF. Changes in DHA concentrations were not associated with outcomes, suggesting that EPA may be the more important n-3 PUFA with respect to risk of cardiovascular events. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Oslo University Hospital, Ullevål Figure 1

Background Inflammation has emerged as a new treatment target in patients with coronary artery disease, and inflammation seems to play an important role in the ischemia/reperfusion injury in ST-elevation myocardial infarction (STEMI). The pro-inflammatory cytokine interleukin-6 (IL-6) has been shown to be associated with myocardial injury and poor prognosis in patients with STEMI. Purpose The aim of the study was to further elucidate possible associations between the IL-6 trans-signalling system and final infarct size, myocardial function, adverse remodelling, and future cardiovascular events in patients with STEMI. Methods A total of 272 patients with first-time STEMI included in the POSTEMI study on ischaemic postconditioning, with symptom duration Results There was a significant increase in IL-6 levels from admission to day 1 with a subsequent decline from day 1 to 4 months (Figure 1A). No significant change in IL-6R levels were found from admission to day 1 (Figure 1B). There was no difference between patients treated by postconditioning compared to routine PCI. High levels of IL-6 (> median) at all sampling points were significantly associated with increased infarct size and reduced left ventricular ejection fraction (LVEF) measured by CMR. Additionally, high levels of IL-6 (> median) at day 1 were associated with lower myocardial salvage, more presence of microvascular obstruction and larger increase in indexed LV end diastolic volume (LVEDVi). IL-6R measured during hospitalisation was significantly associated with change in LVEDVi, but did not associate with infarct size, LVEF or myocardial salvage. High levels of IL-6 (>75th percentile) at all sampling points were associated with an increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure 2), whereas there was no association between IL-6R and adverse clinical events. Conclusion Patients with high IL-6 levels during the acute phase of STEMI had larger infarct size, reduced myocardial salvage, reduced LV function and worse clinical outcome than patients with lower levels of IL-6. High levels of IL-6 measured after 4 months were associated with larger infarct size, reduced LVEF and increased all-cause mortality. IL-6R was significantly associated with increase in LVEDVi. The results add important information to the role of IL-6 in myocardial injury in acute STEMI and the IL-6 pathway as a potential treatment target. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Stein Erik Hagen Foundation for Clinical Heart Research, Oslo, Norway. Figure 1Figure 2

Background A large proportion of patients with cryptogenic stroke or transitory ischemic attack (TIA) have underlying subclinical atrial fibrillation (SCAF) detected on follow up. It is not clear whether SCAF is the underlying primary entity in the pathogenesis of stroke in these patients, or merely a marker of atrial myopathy associated with left atrial remodeling, fibrosis and inflammation. Purpose As a hypothesis generating study, we investigated a panel of selected biomarkers involved in fibrosis, inflammation, and thrombosis: growth differentiation factor 15 (GDF-15), transforming growth factor b (TGFb), galectin-3, soluble suppressor of tumorgenicity2 (sST2), von Willebrand factor (vWF), Tissue metalloprotease1 (TIMP1), Matrix metalloprotease9 (MMP9), Emmprin, Interleukin6 (IL6), C-reactive protein (CRP), Tissue factor (TF), Plasminogen activator inhibitor (PAI1), and their relation to the occurrence of SCAF during follow-up in patients after cryptogenic stroke or TIA. We hypothized that biomarker levels were increased in patients with subclinical AF. Methods 236 patients, median age 71 years (range 21–94) of which 38% were women, with their first cryptogenic stroke or TIA were included 2–4 days after the index event and followed with an Implantable Cardiac Rhythm Monitor for >1 year. Echocardiography and blood sampling were performed at inclusion. ELISA methods were used. Results SCAF occurred in 84 patients (36%). Only GDF-15 was significantly increased in AF- vs no-AF patients: 1010 pg/mL (inter quartile range: 814–1416) vs 860 pg/mL (inter quartile range: 622–1197) (p=0.018), and correlated with the number of premature atrial contractions (PAC)/24h (by Holter ECG during index hospitalization) (rs=0.314, p Conclusion In patients with a cryptogenic stroke or TIA experiencing SCAF during follow up, only levels of GDF-15 were elevated and correlated with PAC/24h and AF-burden. However, GDF-15 was highly related to age and co-morbidities and did not add significantly to the prediction of AF in a multivariate analysis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Stiftelsen Dam, Norwegian Atrial Fibrillation Research Network

Background The NLRP3-inflammasome and the IL-6-pathways, i.e. the inflammasome signaling axis, seems to be central mechanisms in the inflammatory response related to myocardial reperfusion injury after revascularization. The beneficial results shown by treating MI-patients with canakunimab, an antibody blocking IL1-β, in the CANTOS trial*, and by treatment of NSTEMI patients with the IL6-receptor antagonist tocilizumab**, are looked upon as proof of concept for inflammasome inhibition. Purpose To study whether genes encoding inflammasome-related proteins are present in coronary thrombi and in circulating cells from STEMI patients, and whether these are related to the degree of myocardial injury as measured by troponin T, and time from symptoms to PCI. Methods Intracoronary thrombi were aspirated from 33 patients with STEMI treated with primary PCI. The thrombi were snap-frozen in RNA-later solution for gene expression analyses. Peripheral blood samples with Pax-gene tubes were drawn at end of the PCI-procedure. mRNA of NLRP3, caspase1, IL1-β, IL18, IL6, IL6-receptor (IL6-R) and gp130 were isolated from the thrombi and leukocytes in peripheral blood, and relatively quantified by RT PCR. Peak troponin was collected from clinical records. Results Genes coding for the 7 different markers were present in 76–100% of the thrombi. The expression of NLRP3 in thrombi significantly correlated to peak troponin T (r=0.468, p=0.024). Dividing peak troponin T values into quartiles, the median value of NLRP3 mRNA in Q4 was 2.0-fold higher compared to Q1–3 (p=0.012). Peak troponin T also correlated with the expression in circulating leukocytes of NLRP3 (r=0.420, p=0.0149) and IL1-β (r=0.394, p=0.023), and borderline to caspase1 (r=0.321, p=0.069) and IL18 (r=0.310, p=0.079). IL6-R expression in thrombi correlated significantly to peak troponin T (r=0.434, p=0.019), with a 2.5-fold higher median level in Q4 vs Q1–3 of troponin T (p=0.017). gp130 expression in thrombi correlated inversely with peak troponin T (r=−0.398, p=0.050), as did IL6-R expression in circulating leukocytes (r=−0.421, p=0.015). There were no significant correlations between genes expressed in the thrombi and time from symptom to PCI (median 152 minutes), whereas genes for IL6 in circulating leukocytes correlated inversely (r=−0.385, p=0.027). Conclusion The inflammasome signaling pathway was actively regulated in coronary thrombi and in circulating leukocytes from patients with STEMI. Genes encoding NLRP3 and IL6-R were increasingly expressed in thrombi from patients with increased myocardial damage, measured by troponin T, supporting the beneficial effects of medically targeting this pathway. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Stein Erik Hagens Foundation for Clinical Heart Research

Background Soluble ST2, a member of the IL-1 receptor family, seems to be associated with adverse outcome in acute myocardial infarction and heart failure (HF), and is suggested to be involved in left ventricular (LV) remodelling. Purpose To elucidate a possible role of ST2 in LV injury, remodelling and prognosis in ST-elevation myocardial infarction (STEMI) patients. The main objectives of the study were to investigate whether circulating ST2 levels were associated with infarct size, LV function, adverse remodeling and clinical outcome in a cohort of patients with STEMI. Methods 270 patients with clinically stable first-time STEMI treated with primary percutaneous coronary intervention (PCI) were included. Blood samples were drawn before and immediately after the PCI procedure, at day 1 (median 18.3 hours after PCI) and after 4 months. Cardiac magnetic resonance (CMR) was performed in the acute phase and after 4 months. Clinical events and all-cause mortality were registered during 12 months' and 70 months' follow-up, respectively. A composite endpoint was defined as death, MI, unscheduled revascularisation >3 months after the index infarction, rehospitalisation for HF or stroke. Associations between ST2 and CMR parameters and clinical events were evaluated with linear regression and logistic regression, respectively. Results There was a significant increase in ST2 levels from the PCI procedure to day 1 with a subsequent decline from day 1 to 4 months in the POSTEMI cohort. Patients with high ST2 levels (>median) at all sampling points during hospitalisation had significantly larger infarct size, lower myocardial salvage, lower LVEF, larger increase in EDV and higher frequency of MVO. After adjustment for relevant clinical variables, peak CRP and peak troponin T, ST2 measured at day 1 remained associated with infarct size (β 2.0 per SD of ST2, p75th percentile) were associated with increased risk of having an adverse clinical event during the first year and with long-term all-cause mortality (Figure). High levels of ST2 measured in a stable phase 4 months after STEMI were also associated with an increased risk of all-cause mortality (Figure). Figure 1 Conclusions High levels of ST2 in STEMI patients were associated with large infarct size, impaired recovery of LV function, and adverse clinical outcome in patients with STEMI. ST2 measured 4 months after STEMI remained associated with all-cause mortality.

Increasing prevalence of cardiovascular disease and new evidence on the effects of antithrombotic therapies have expanded the use of antiplatelet and anticoagulant drugs. In addition, extremely low and high body weights have become more common due to frailty associated with ageing and to the global epidemic of obesity, ‘globesity’, respectively. These extreme body weights affect cardiovascular risk, including mortality, as well as the pharmacokinetics and safety profiles of antithrombotic drugs, some of which have a relatively narrow therapeutic window. The ESC Working Group on Thrombosis therefore assembled a task group to examine the key issues related to this topic and to address the question of whether modified antithrombotic management strategies are required for patients at the extremes of body weight. Greater focus is directed toward to obesity, given its higher prevalence among patients with cardiovascular disease and its associated complexities in terms of pharmacology and pathophysiology. Further research is warranted to optimize antithrombotic therapy in underweight as well as in different classes of obese patients, to guide dosing, dose-adjustment and/or reference intervals, and to establish whether the balance of benefits and risks of antithrombotic drugs can be improved.

Aim The present study was undertaken to assess the effect of balloon inflation during percutaneous transluminal coronary angioplasty on markers of myocardial damage. Methods and results Seventy-five patients undergoing elective percutaneous transluminal coronary angioplasty were evaluated with serum creatine kinase MB and cardio-specific troponin T before and 1 and 4 days after the procedure. On day 1, 28% of the patients had increased cardiospecific troponin T values and 18% had increased creatine kinase MB values. On day 4, 24% had increased cardiospecific troponin T values, whereas all creatine kinase MB values were normal. A high degree of correlation between creatine kinase MB and cardiospecific troponin T on day 1, as well as between both markers on day 1 and cardiospecific troponin T on day 4 were found. The increased levels of cardiospecific troponin T on day 4 was significantly correlated with the total balloon inflation time ( P

Background: Pentraxin 3 (PTX 3) is an acute phase protein in the same superfamily as C-reactive protein (CRP) and is synthesized and released by endothelial cells, macrophages and smooth muscle cells, and also by circulating neutrophils by different stimuli. High levels of PTX3 have been found in patients with acute myocardial infarction (AMI). Aim: We have investigated the time profile of PTX3 in patients with acute myocardial infarction (AMI) and in patients with stable angina pectoris (AP) undergoing percutaneous coronary intervention (PCI) and stent implantation, to 1) compare the groups 2) to elucidate any influence of the PCI procedure. Methods: Ten patients with stable AP and 20 patients with AMI, all treated with PCI and stent implantation in a central coronary artery, were included. Blood samples were drawn immediately before PCI (in the AP group only), and after 3 and 12 hours, days 1, 3, 5, 7, and 14 in both groups. EDTA plasma was used for analyses of PTX3, determined by an ELISA-method. Degree of myocardial necrosis was assessed by Troponin T (max) and infarct size in the AMI patients was determined by MRI (gadolinium late contrast enhancement technique) after 6 weeks. Results: PTX3 levels at 3 and 12 hours after the procedure were significantly higher in the AMI group compared to the AP group (median levels: 2.36 vs 1.36 ng/mL, p

Background: We hypothesized that COPD leads to alterations in systemic vascular structure and that systemic arterial compliance (SAC) would have impact on the LV function even in a population free of clinical cardiovascular disease. Methods: Patients with COPD (GOLD stage I-IV) and matched healthy controls were included. Those with LV disease were excluded. Coronary heart disease was excluded by exercise ECG. The following TDI based indices for LV function were performed: LV acceleration during isovolumic contraction (LVIVA), myocardial performance-index (LVMPI) and peak systolic velocity (LVSm). SAC was calculated as stroke volume (ml)/systemic pulse pressure (mmHg). Inflammatory markers (Table) were measured. Results: Consistent with reduced SAC, a significant increase in systolic blood pressure was observed in the patient group (Table). Stroke volume did not differ between the groups. Significantly higher levels of the biomarkers were found (all p