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Aims Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population. Methods and results Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient −3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography −0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P Conclusion Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management.

Background Current ESC guidelines on management of non-ST-elevation myocardial infarction (NSTEMI) recommend rapid diagnostic protocols using validated high-sensitivity cardiac troponin (hs-cTn) assays (1). While established protocols are available for several hs-cTn assays, data on the diagnostic performance of the Siemens Atellica IM High-Sensitivity Cardiac Troponin I assay is limited. Methods In a cohort study including 1,800 patients presenting with suspected acute MI. Final diagnosis of MI was adjudicated by two cardiologists separately in accordance with the fourth universal definition of MI (2). We developed and validated a 0/1h diagnostic algorithm using the Siemens Atellica assay. The algorithm was established in the first 928 patients and validated in the following 872 patients. Results ROC analyses for the diagnosis of NSTEMI revealed high discriminatory ability of the Siemens hs-cTnI assay with an area under the curve of 0.88 (95% confidence interval (CI): 0.86–0.90) at 0h, 0.93 (CI: 0.91–0.94) after 1h and 0.95 (CI: 0.93–0.96) after 3h (Figure 1). The derived algorithm consisted of a baseline rule-out of non-ST elevation MI using a cutoff Conclusion The Siemens hs-cTnI assay is well-suited for application in rapid diagnostic stratification of patients with suspected MI and showed similar performance when compared with an established hs-cTnI assay using an algorithm recommended by recent ESC guidelines. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): German Heart foundation Figure 1

Background Ejection time (ET) and Acceleration time (AT) have been described as echocardiographic markers for aortic stenosis (AS).1 Moreover, in a recent study time between invasively measured left ventricular and aortic systolic pressure peaks (T-LVAo) was associated with anatomic AS severity.2 However, the diagnostic value of these parameters has not been validated in a larger patient cohort and their prognostic impact in AS patients undergoing transcatheter aortic valve implantation (TAVI) remains unknown. Purpose We aimed to assess the diagnostic value and prognostic impact of ET, AT, and T-LVAo as assessed by invasive measurements in patients undergoing TAVI for severe AS. Methods This retrospective single-centre analysis studied 1478 patients undergoing TAVI from 2014 to 2019 for severe AS. All patients received echocardiographic, multislice computed tomography (MSCT) and invasive hemodynamic evaluation with simultaneous pressure measurements in left ventricle and aorta prior to TAVI. Anatomic AS severity was assessed according to MSCT-derived aortic valve calcification density (AVCd) defined as calcium volume per annulus area. All hemodynamic parameters were calculated offline using a dedicated software. Results Median patients' age was 81.2 (76.8–84.7) years and 807 (54.6%) were women. Predicted operative risk for mortality was 3.8 (2.6–5.7)% according to STS Score. Medians of invasively derived parameters were 70.0 ms (46.0–98.0) for T-LVAo, 308.0 ms (276.0–336.0) for ET, 180.0 ms (146.0–206.0) for AT. In spline analysis correlation of T-LVAo (Spearman: r=0.35; p Conclusion T-LVAo provides the highest diagnostic value among the investigational hemodynamic parameters, however correlation with AVCd was weak. ET and AT are strong independent outcome predictors beyond clinical risk factors and standard echocardiographic parameters in AS patients following TAVI. Accordingly, use of ET and AT might improve risk assessment in patients scheduled for TAVI. Funding Acknowledgement Type of funding sources: None.

Background The 2019 ESC dyslipidaemia guidelines recommend a more intense LDL-cholesterol (LDL-C) reduction for patients with coronary artery disease (CAD). As a result the need for PCSK9 inhibitors (PCSK9i) is projected to increase significantly, with a concomitant substantial impact on treatment cost. Adding the novel lipid lowering agent bempedoic acid (BA) to established oral lipid lowering therapy could provide an affordable alternative to PCSK9i to attain the LDL-C treatment target, particularly in patients with statin intolerance. Aims To quantify the target populations for BA and PCSK9i as well as the related treatment costs to achieve the LDL-C target of the 2019 ESC dyslipidaemia guidelines assuming addition of BA to lipid lowering medication. Methods We included 1922 patients (mean age 69.3 years) with angiographically documented CAD from an observational cohort study ongoing since 2015. A Monte Carlo simulation incorporating an algorithm for intensification of lipid lowering medication was applied in order to achieve the LDL-C treatment goal of Results Figure 1 displays the baseline LDL-C distribution (median LDL-C 86.0 mg/dL) and lipid lowering medications. The need for PCSK9i in scenario 1 would be 41.4% for a moderate and 46.1% for a high rate of statin intolerance. Addition of BA in scenario 2 would reduce the need for PCSK9i to 25.3% and 29.4%. Figure 2 displays the LDL-C distributions and lipid lowering medications for scenarios 1 and 2 assuming a moderate rate of statin intolerance. Use of BA would lower the annual overall treatment cost incurred through use of PCSK9i ± BA per 1,000,000 CAD patients by 13.3% and 10.5%. The cost per prevented event in the entire cohort would be lower (−5.0 and −6.3%), however at the price of less prevented cardiovascular events (−8.7% and −4.5%). Amongst patients with full statin intolerance, the cost per prevented event would be reduced (−6.8% for both rates of statin intolerance) whilst more cardiovascular events would be prevented (+7.5% and +6.9%). Conclusion Use of BA in patients with CAD would reduce the need for PCSK9i as well as the overall treatment cost for add-on lipid lowering therapy. The subpopulation of patients with full statin intolerance might profit particularly. Funding Acknowledgement Type of funding sources: None. Figure 1. Baseline LDL-C distribution and LLMFigure 2. LDL-C and LLM after LLM intensification

Background Heart failure with preserved ejection fraction (HFpEF) is common in patients presenting with dyspnoea. Nevertheless, diagnosing HFpEF remains challenging. Recently, different algorithms were developed to predict the likelihood of HFpEF. Purpose Our objective was to provide an in-depth comparison of the ESC 2016 algorithm, the H2FPEF- and the HFA-PEFF algorithm for diagnosing and characterising HFpEF in the general population. Methods The study included 5,613 participants of the population-based H. City Health Study (HCHS), aged 62±8.7 years (51.1% women), that were enrolled between 2016 and 2019. Exclusion criteria were other common causes of dyspnea. We calculated the prevalence and compared characteristics of HFpEF according to the different diagnostic algorithms applying the ESC 2016 heart failure guidelines and the cut-off values suggested by the authors of the HFA-PEFF and H2FPEF score for defining HFpEF. Results Unexplained dyspnea was present in 407 (7.3%) subjects. In those, the estimated prevalence of HFpEF was 20.4% (ESC 2016), 12.3% (H2FPEF), and 7.6% (HFA-PEFF). The majority of subjects was classified as HFpEF not excludable according to the HFA-PEFF (57.7%) and the H2FPEF (59.2%) score. For all algorithms, subjects diagnosed with HFpEF showed elevated age and body mass index as well as a higher prevalence of atrial fibrillation, diabetes, and arterial hypertension compared to those without HFpEF or HFpEF not excludable. The distribution of those comorbidities and risk factors varied between the differently diagnosed HFpEF groups with the highest burden in the HFpEF group defined by the H2FPEF score. The overlap of subjects diagnosed with HFpEF according to the different algorithms was very limited. Conclusion Unexplained dyspnoea is common in the middle-aged general population. The ESC 2016 algorithm, the H2FPEF-, and the HFA-PEFF score detect different, discordant sub-populations of probands with breathlessness. Further classification of the HFpEF syndrome is desirable. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Innovative medicine initiative Figure 1. Prevalence and concordance of the three HFpEF algorithms in subjects with unexplained dyspnea. Of the 407 subjects with unexplained dyspnea, the prevalence ranged from 20.4% (n=83, ESC 2016 guideline) to 12.3% (n=50, H2FPEF score) and 7.6% (n=31, HFA-PEFF score). The concordance was highest between the ESC 2016 guidelines and the HFA-PEFF score reflected by a kappa coefficient of 0.38 and a reclassification rate of 16%. RecR = reclassification rate.

Aims Atrial fibrillation (AF) is becoming increasingly common and is associated with serious complications. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood-based biomarkers reflecting cardiac injury may help close this gap. High-sensitivity troponin I (hsTnI) has emerged as a potential predictor. Methods We investigated the predictive ability of hsTnI for incident AF in 29,227 participants (median age 52.6 years, 51.2% men) across four different European community cohorts of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) consortium in comparison to CVRF and established biomarkers (high-sensitive C-reactive protein (hsCRP), N-terminal pro B-type natriuretic peptide (NT-proBNP)). Results During a median follow-up of 13.8 (lower and upper quartiles 4.5, 21.3) years, 1,509 (5.2%) participants developed AF. Those in the highest fourth of hsTnI values at baseline (≥5.1 ng/L) had a 2.71-fold (95% confidence interval (CI) 2.31, 3.17; P Conclusion hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRFs. However, it is associated with AF complications and mortality after AF onset probably reflecting underlying subclinical cardiovascular impairment. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Seventh Framework Programme (FP7/2007-2013

Background Glycated haemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment; however, its role in predicting cardiovascular outcomes in the general population remains uncertain. Purpose The additional use of glycated haemoglobin A1c (HbA1c) as a biomarker might highlight subjects of the general population with an increased risk for cardiovascular outcomes with cardiovascular disease, cardiovascular mortality or overall-mortality. Methods Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analysed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular diseases (CVD), and overall mortality in the study population, in non-diabetic (N=32,477), and diabetic participants (N=3,703). Results Kaplan-Meier curves showed higher event rates with increasing continuous log-transformed HbA1c levels. Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) log-transformed divided by interquartile range and the examined outcomes, with a hazard ratio (HR) of 1.12 (95% confidence interval (CI): 1.04–1.20, p=0.0019) for cardiovascular mortality, 1.10 (95% CI: 1.04–1.16, p An increased risk of CVD was observed in subjects without diabetes with increased HbA1c levels (HR 1.09; 95% CI: 1.01–1.16, p=0.021). An HbA1c cut-off value of 39.89 mmol/mol (5.8%), 36.62 mmol/mol (5.5%), and 38.80 mmol/mol (5.7%) for cardiovascular mortality, CVD, and overall mortality, respectively, was determined for selecting individuals at an increased risk. Conclusion HbA1c was demonstrated to be an independent prognostic biomarker for all investigated outcomes in the general European population. An approximately linear relationship was observed between an increase of HbA1c levels and the outcomes. Elevated HbA1c levels were also associated with the outcomes in participants without diabetes (i.e. HbA1c levels Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union Seventh Framework ProgrammeEuropean Union FP 7 project CHANCES Kaplan-Meier curves for the outcomesPenalised cubic splines HbA1c/time event

Background High-sensitivity Troponin T and I (hsTnT/I) concentration is independently associated with coronary artery disease (CAD) severity and cardiovascular outcome. Here we explored whether hsTnT/I blood levels add predictive information irrespective of CAD severity and further confounders in unselected stable patients with angiographically characterized CAD. Methods Between 2015 and 2020, 3,012 patients undergoing coronary angiography were included in the observational Hamburg INTERCATH study. In 2,209 consecutive patients Troponin levels were quantified for hsTnT (Roche Diagnostics Elecsys) and hsTnI (Abbott Diagnostics ARCHITECT STAT). Patients presenting with acute coronary syndromes and heart transplant recipients were excluded, leaving 1,841 patients for analyses. CAD severity was graded according to the Gensini score. Major adverse cardiac events (MACE) as a composite of cardiovascular death, stroke, myocardial infarction, and coronary revascularization were defined as endpoint. Kaplan-Meier analyses stratified by hsTnT/I quartiles were performed. Multivariable Cox models were computed for the association of hsTnT/I with MACE adjusting for age, gender, arterial hypertension, hyperlipoproteinemia, smoking, diabetes mellitus, body-mass index, eGFR and Gensini Score. Results Mean age was 68.5±10.9 years (27.9% female). 81.1% were diagnosed with CAD by coronary angiography. Gensini score was 21.0±30.2. Median follow-up time was 4.42 years. hsTnT quartiles differentiated MACE across all categories (Figure 1A). For hsTnI, cardiovascular risk was differentiated between the lowest and highest quartiles as well as the 1st and 2nd quartile particularly beyond 24 months of follow-up (Figure 1B). However, MACE after 3 years was not associated with hsTnT after adjustment for classical cardiovascular risk factors and CAD severity (Figure 1C), whereas the hazard of MACE was increased in the 3rd and 4th hsTnI quartiles compared to the 1st quartile (HR 1.3, IQR 1.1–1.6 for both categories; Figure 1D). Conclusion Increasing hsTn concentration was related to intermediate term cardiovascular outcome in unselected stable patients. Only hsTnI concentration remained as independent predictor after testing for most possible confounders, including CAD severity. This data underpins the role of hsTnI in outcome prediction. Funding Acknowledgement Type of funding sources: None.

Background Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. Purpose The aim of the study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. Methods This study was conducted as part of the BiomarCaRE project using harmonised data from 12 population-based cohorts (n=40,212) from Europe. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and with competing mortality risk after adjusting for covariates. Results Mean age at baseline was 51.1 (standard deviation 11.9) years, and 49.3% were men. Overall, 3.5% had CKD at baseline. The rate for incident AF was 3.9 per 1000 person-years during follow-up. The HR for AF for those with CKD compared with those without was 1.23 (95% CI 1.00–1.52, p=0.0465) after adjustment for covariates. The rate for incident HF was 3.9 per 1000 person-years and the associated risk in the presence of CKD was HR 1.67 (95% CI 1.39–2.01). In subjects with CKD, N-terminal pro-B-type natriuretic peptide (NT-proBNP) showed an association with AF, while NT-proBNP and C-reactive protein (CRP) showed an association with HF. Conclusion CKD is an independent risk factor for subsequent AF and even more so for HF. In patients with CKD, NT-proBNP was clearly associated with subsequent risk of AF. In addition to this marker, hs-CRP was also associated with risk of subsequent HF. Funding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): 7th framework programme collaborative project, grant agreement no. HEALTH-F2-2011_278913. Atrial Fibrillation and HF in CKD

Background A growing number of patients are currently treated for severe mitral regurgitation (MR) using a transcatheter mitral valve repair (TMVr). In clinical routine, the potential risk of elevated post-procedural mitral valve pressure gradient (MPG) may prohibit optimal MR reduction driven by the avoidance of additional clip implantations. Thus, the unfavorable impact on survival and functional outcome of increased MPG in patients undergoing TMVr is currently debatable. Methods In this single-center, prospective study, survival and functional outcome of 780 consecutive patients with severe MR undergoing TMVr between September 2008 and January 2020 were investigated. After exclusion of patients with unsuccessful procedure and those lost to follow-up, data of 676 patients with a median follow-up time of 5.26 (5.11, 5.51) years were analyzed. MPG was determined by transthoracic echocardiography at discharge and considered elevated in excess of 4.5 mmHg. Kaplan-Meier analysis as well as multivariable Cox regression models were performed for the impact on elevated MPG on 5-year outcomes for the subgroups of functional MR (FMR) and degenerative MR (DMR). The primary outcome measure was a combined endpoint of death or rehospitalization for congestive heart failure. Results Among 676 patients undergoing TMVr (mean age 74.6±8.5 years, 59.0% male, median STS Score 3.9 [interquartile range 2.5; 6.0]), 179 (26.4%) patients had elevated MPG >4.5 mmHg. FMR was present in 426 (63.0%) patients. In the overall patient cohort, Kaplan-Meier and Cox Regression analyses could not demonstrate significant differences for the combined endpoint (p=0.99). In contrast, subgroup analysis according to MR etiology indicated a significant adverse influence of elevated MPG on the combined endpoint as well as functional outcome in patients with DMR, but not with FMR (Figure 1). After adjustment, multivariate Cox Regression analysis showed an inferior prognosis in patients with DMR and elevated MVPG >4.5 mmHg (hazard ratio 1.79 [1.17, 2.72], p=0.0069, Figure 2). Conclusions TMVr-patients with DMR and measurable elevated post-procedural MVPG face an inferior prognosis and reduced functional outcomes compared to patients with FMR. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

This commentary refers to ‘Multi-organ assessment in mainly non-hospitalized individuals after SARS-CoV-2 infection: The Hamburg City Health Study COVID programme’ by E.L. Petersen et al., https://doi.org/10.1093/eurheartj/ehab914 and the discussion piece ‘Alarmist reporting on the pandemic: time to say no!’, by A. Roy https://doi.org/10.1093/eurheartj/ehac163.

Background The H2FPEF score enables identification of patients with high probability of prevalent heart failure with preserved ejection fraction (HFpEF). High H2FPEF scores have proven to be associated with adverse outcome in patients with known HFpEF. Objective The aim of this study was to assess the prognostic impact of the H2FPEF score in patients undergoing Transcatheter Aortic Valve Implantation (TAVI) for severe aortic stenosis (AS) and preserved left ventricular ejection fraction (EF). Methods In this multi-centre study a total of 832 patients from two German high-volume centres, who received TAVI for severe AS and preserved EF (≥50%), were identified for calculation of the H2FPEF score. Score variables included BMI >30 kg/m2, arterial hypertension, atrial fibrillation, systolic pulmonary artery pressure >31 mmHg, age >60 years, and invasively assessed elevated LV filling pressure. Patients were dichotomized according to low (1–5 points; n=570) and high H2FPEF scores (6–9 points; n=262). Kaplan-Meier and Cox regression analyses were applied to assess the prognostic impact of the H2FPEF score. Median follow-up time was 1.08 years. Results Patients presenting with high H2FPEF scores had higher prevalence of moderate to severe mitral and tricuspid regurgitation compared to those with low H2FPEF scores. Stroke volume index (SVI) (Figure 1A) and mean transvalvular gradient (Pmean) consistently decreased with increasing H2FPEF score. All-cause mortality 30 days after TAVI was significantly higher in patients with high H2FPEF scores (p Conclusion An elevated H2FPEF score of ≥6 is independently predictive for mortality in patients with preserved EF undergoing TAVI for severe AS, which might be due to a higher proportion of paradoxical low flow low gradient AS in these patients. Our findings provide evidence that the H2FPEF score may help identify AS patients with preserved ejection fraction that are at higher risk for adverse outcome after TAVI. Spline/SVI (A) and 3y-mortality KM (B) Funding Acknowledgement Type of funding source: None

Aim Evidence on non-ischaemic cardiogenic shock (CS) is scarce. The aim of this study was to investigate differences in presentation characteristics, use of treatments and outcomes in patients with ischaemic vs. non-ischaemic CS. Methods Patients with CS admitted to a tertiary care hospital between October 2009 and October 2017 were identified and stratified as ischaemic CS/non-ischaemic CS based on the presence/absence of acute myocardial infarction. Missing data was handled by chained equation multiple imputation. Logistic and Cox regression models were fitted to investigate the association of non-ischaemic CS with presentation characteristics (adjusted for all baseline variables), and use of treatments as well as30-day in-hospital mortality (adjusted for relevant confounders including age, sex, prior cardiac arrest, haemodynamics, pH and lactate). Results A total of 978 patients were enrolled in this study; median age was 70 (interquartile range 58, 79) years and 70% were male. 505 patients (43%) had non-ischaemic CS. Patients with non-ischaemic CS were more likely younger and female; were less likely to be active smokers or to have diabetes, but more likely to have chronic renal disease and history of myocardial infarction; and were more likely to present with unfavourable haemodynamics and with mechanical ventilation. Regarding use of treatments, patients with non-ischaemic CS were more likely to be treated with catecholamines [odds ratio (OR) 1.58, 95% confidence interval (CI) 1.11–2.27, p0.01], but less likely to be treated with extracorporeal membrane oxygenation (OR 0.66, 95% CI 0.48–0.92, p=0.02) or percutaneous left ventricular assist devices (OR 0.51, 0.35–0.74, p Conclusion In this large study, non-ischaemic CS accounted for almost 50% of all CS cases. Non-ischaemic CS was not only associated with relevant differences in presentation characteristics and use of treatments, but also with a worse prognosis. These findings highlight the need for effective treatment strategies for patients with non-ischaemic CS. Figure 1 Funding Acknowledgement Type of funding source: None

Background Renal impairment is a common complication after CABG (coronary artery bypass graft) surgery associated with an adverse outcome. Purpose To further characterize the molecular framework of the disease through omics analyses. Methods In N=165 CABG patients we performed multi-omics-analyses in preoperatively collected blood and tissue samples as well as 991 creatinine measurements. We used multivariable mixed-model regression analyses to analyse post-operative creatinine increase and to find common genetic polymorphisms, transcripts, metabolites and/or proteins associated with changes in postoperative creatinine increase. Multiple testing was accounted for by setting a 5%-limit on the false discovery rate (FDR) using the Benjamini-Hochberg procedure. Results Post-operative increase of log transformed creatinine was 0.035 (8%); 95% confidence interval (CI) 0.025, 0.045; P Conclusions In an integrated approach we identified omics-biomarkers for the prediction of renal impairment after CABG surgery. The underlying pathophysiological associations of these genes and proteins are not fully understood. MELK might be an interesting target for further investigations, as it plays a prominent role in cell cycle control, cell proliferation, apoptosis, cell migration and cell renewal. Our results may help to better identify individuals at risk and lay the methodological groundwork for further omics analyses. Funding Acknowledgement Type of funding source: None

Background Risk stratification among patients with coronary artery disease (CAD) and acute coronary syndrome (ACS) is of considerable interest due to the potential to guide secondary preventive therapies. Cardiac troponins as well as the inflammatory biomarker C-reactive protein (CRP) and natriuretic peptides have now emerged as useful blood-based biomarkers for risk stratification concerning incident cardiac events. Nevertheless, it has not been tested, whether one of these biomarkers yields predictive value beyond the others. Thus, we evaluated the head-to-head potential of high-sensitivity troponin I (hsTnI), high-sensitivity (hs) CRP and NT-proBNP as prognostic biomarkers for adverse outcome in patients with manifest CAD. Methods Plasma levels of hsTnI, hsCRP and NT-proBNP were measured in a cohort of 2,193 patients with documented CAD –including 837 patients with ACS and 1,356 patients with stable angina pectoris (SAP). Cardiovascular death and/or non-fatal acute myocardial infarction (MI) were defined as the main outcome measures. The association of circulating biomarker levels, used after log-transformation, with cardiovascular mortality and non-fatal MI during follow-up was assessed by Cox proportional hazards analyses adjusted according to three different models including cardiovascular risk factors and either the biomarkers hsCRP, NT-proBNP or hsTnI. Additionally, the net reclassification index (NRI) was calculated using the category five-year event probabilities for two models. Results During a median follow-up of 3.8 years, a total of 231 events were registered (10.5%). All three biomarkers reliably predicted cardiovascular death and/or MI, as evidenced by survival curves stratified for tertiles of circulating levels. In Cox regression analyses with adjustments for sex, age, and conventional cardiovascular risk factors, the hazard ratio (HR) per standard deviation (SD) for the prediction of cardiovascular (CV) death and/or non-fatal MI during follow-up was 1.39 [95% CI: 1.24–1.57, p Conclusions NT-proBNP reliably predicted cardiovascular death and myocardial infarction in patients with manifest CAD and provides incremental value beyond hsCRP and hsTnI. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): “Stiftung Rheinland-Pfalz für Innovation”, Ministry for Science and Education

Introduction According to the 4th Universal Definition of Myocardial Infarction (UDMI), anemia may cause acute and chronic myocardial injury indicated by elevated high-sensitive troponin (hs-cTn) concentrations, with unknown influence on triaging patients with suspected acute myocardial infarction (AMI). Purpose To investigate the influence of anemia on hs-cTnI and the diagnostic performance of the ESC 0/1 and 0/3 hour (h) algorithms. Methods Patients with suspected AMI were prospectively enrolled and stratified based on the hemoglobin (Hb) concentration at admission (females Results We included 2,223 patients (64.1% males, age 65 [52; 75]) of whom 415 (18.7%) had anemia. The prevalence of AMI was numerically different for patients with and without anemia (16.4% and 12.9%, p=0.072). Hs-cTnI concentrations were significantly higher in patients with anemia and no AMI (p Conclusion Despite the revealed association of Hb and hs-cTnI in the stable setting, the application of the ESC 0/1h and 0/3h algorithms in patients with suspected AMI and concomitant anemia is safe and provides similar efficacy. Patients with anemia experience considerable worse outcome and might therefore benefit from additional diagnostic measures and, potentially, treatment targeting anemia and its cause. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): German Center of Cardiovascular Research (DZHK) and an unrestricted grant by Abbott Diagnostics, Prevencio and Singulex.

Introduction Current guidelines and Universal Definition of Myocardial Infarction (UDMI) recommend using rising and falling patterns (RP and FP, respectively) of high-sensitive cardiac troponins (hs-cTn) equally to distinguish acute from chronic myocardial injury. Purpose To compare patients with RP and FP and assess the diagnostic performance of the ESC 0/1 and 0/3 hour (h) algorithms using a RP or FP. Methods Prospectively enrolled patients with suspected MI (excluding those with ST-elevation) were stratified according to their troponin deltas. A RP was defined by an elevation and a FP as a decline in hs-cTnI of ≥2 or >6 ng/L between baseline and 1 or 3h later, respectively. All other patients were classified stable. Three independent cardiologists adjudicated the final diagnoses according to the 3rd UDMI. Our primary endpoints were efficacy measures (positive predictive value [PPV] and specificity in % [95% confidence intervals]) of both algorithms. Patients were followed for up to 4 years for a combined endpoint of all-cause death, incident MI, revascularization or cardiac rehospitalization. Results In total, 3,528 patients (age 64.0 (52.0, 74.0), males 64.0%) were included, of those 418 (11.8%) had a FP and 829 (23.5%) a RP. Compared to patients with a RP, those with a FP had similar age (67.0 [55.0, 76.0] vs. 67.0 [56.0, 75.0]), had generally less cardiovascular risk factors and the number of angiographies was lower (39.5% vs. 58.0%), while the number of late-presenters (>6h after symptom onset) was higher (66.4% vs. 48.8%). The prevalence of MI was higher in the RP (22.6% vs 29.1%). The risk of experiencing the combined endpoint was significantly higher for both, FP and RP, with a greater risk for a RP (age-/sex adjusted (adj) HR 1.6 [9%%CI 1.4, 1.9]) than a FP (adjHR 1.3 [95% CI1.2, 1.5]) compared to stable patients (p Conclusion Despite the known elevated risk of dynamic hs-cTnI changes (defining myocardial injury), patients with FP are at even greater risk for future events despite having fewer cardiovascular risk factors. The rule-in of MI using established and recommended stratification algorithms is worse in these patients, wherefore the equal treatment of a FP and RP should be questioned. Funding Acknowledgement Type of funding source: Other. Main funding source(s): German Center of Cardiovascular Research (DZHK), Abbott Diagnostics, Prevencio, Singulex, University Medical Center of the Johannes Gutenberg University of Mainz, BRAHMS Aktiengesellschaft

Background In the Universal Definition of Myocardial Infarction (MI) myocardial injury was introduced as a specific diagnosis in patients with elevated troponin concentrations, but without evidence of acute myocardial ischemia. However, their differentiation within the acute setting might be challenging. Therefore, we sought to investigate a multibiomarker panel in these patients and determine the discriminative capacity to differentiation MI from myocardial injury. Methods We use a cohorts of acute patients presenting to the emergency department. All final diagnoses were adjudicated by two physicians in a blinded fashion and based on the fourth universal definition of MI. In case of disagreement a third physician referred. For the present analyses only patients diagnosed with MI or myocardial injury were used. A panel of 28 biomarkers was measured in blood samples collected directly at admission. Spearman correlations were calculated. A multivariable logistic regression model using MI as the dependent variable was used and the predictors were chosen via backward step-back selection. Odds ratios (OR) were calculated for each predictor. Results We included 359 patients; 138 were diagnosed as having MI and 221 has having myocardial injury. The median age of the study population was 73 years and 59.1% were males. Hypertension was diagnosed in 80.4%, dyslipidemia in 45.4% and diabetes in 19.0%.The biomarker panel showed a wide range of correlations (Figure 1). In the multivariable model five logarithmized biomarkers (N-terminal prohormone of brain natriuretic peptide [OR 0.62], pulmonary and activation-regulated chemokine [OR 0.51], tumor-necrosis-factor-receptor 2 [OR 2.22], copeptin [OR 1.59] and high-sensitivity troponin I [OR 1.80]) were significant discriminators between MI and myocardial injury. Internal validation of the model via bootstrap shows a for overoptimism corrected area under the curve of 0.84. Conclusion In the multivariable model five biomarkers were discriminators between MI and myocardial injury. Spearman correlations Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Research fellowship by the Deutsche Forschungsgemeinschaft

Background Prevalence of functional tricuspid valve regurgitation (TR) in the adult population is high and mostly considered as a consequence of left-sided heart failure. In patients with moderate-to-severe and severe mitral regurgitation (MR), relevant concomitant TR is found in about 30–50%. For many years the concept of a reduction of secondary TR after mitral valve surgery has been widely accepted. However, more recently, compelling data have shown that surgically untreated functional TR can persist or even worsen despite the correction of the associated left-sided lesion. In line with previous research, studies have indicated that preexisting concomitant TR is an independent predictor for adverse outcome in patients undergoing percutaneous mitral valve Edge-to-Edge Repair (pMVR). Purpose This study intends to determine the extent to which the severity of tricuspid regurgitation, measured six months after pMVR, impacts the outcome. Methods Between September 2008 and July 2018, 805 consecutive patients with moderate-to-severe or severe MR underwent pVMR therapy with the MitraClip device at our center. We exclude patients with missing date of follow-up (n=54) and patients with missing values for baseline tricuspid regurgitation (n=93). We analyze, therefore, data of 658 patients with a median follow-up time of 4.93 (4.2, 4.99) years. Severity of TR was evaluated at baseline and six months after pMVR. Results Among 658 high-risk patients (mean age 75.4±8.7 years, 59.7% male, median STS Score 3.9 [2.4, 6.1]), 248 patients were suffering from no/mild (37.6%), 213 from moderate (32.6%) and 197 patients from severe (29.9%) TR. Functional MR was present in 429 (65.5%) patients. Procedural success was achieved in the majority of patients (no/mild TR 90.3%, moderate TR 91.1%, severe TR 90.4%). Overall, mortality rates up to two-year follow-up were highest for patients with severe TR (no/mild TR 30.2%, moderate TR 37.6%, severe TR 42.6%, p=0.023). The risk for overall mortality (Kaplan-Meier analysis, p=0.0027, Figure 1) was related to increasing TR severity. However, Kaplan-Meier analysis showed no relevant differences for the combined endpoint of death and rehospitalization (p=0.058). Interestingly, in a pairwise comparison, the risk for patients with pre-existing severe TR and postprocedural reduction to mild or moderate TR (n=17) was reduced for the combined endpoint (p=0.021) compared to patients with persistent severe TR (n=28). Conclusion Moderate and severe TR in high-risk patients undergoing pMVR is associated with an increased risk for overall mortality. While preliminary, the presented data suggest a favorable outcome in patients with a postprocedural reduction in the severity of TR. The results of this study indicate the importance of developing new therapeutic strategies in high-risk patients with combined MR and TR, probably leading to concomitant tricuspid valve interventions. Figure 1 Funding Acknowledgement Type of funding source: None

Introduction Left ventricular outflow tract (LVOT) calcification is known to be associated with adverse outcomes after TAVI in patients receiving first-generation transcatheter heart valves (THV). Second-generation THV have been shown to improve outcomes of TAVI patients. Thus, aim of this study is to assess the prevalence of LVOT calcification as well as its impact on procedural and clinical outcomes in patients with severe aortic stenosis undergoing transfemoral TAVI with second-generation THV in a real-world patient cohort. Methods In this retrospective single-center analysis patients receiving transfemoral TAVI with second-generation THV for the treatment of aortic stenosis (AS) between 05/2012 and 06/2018 and with adequate CT data were included (n=836). Amount of LVOT calcification was measured quantitatively from contrast-enhanced multislice CT using a dedicated software. Baseline characteristics and outcomes were compared according to presence of significant LVOT calcification (none/≤10 mm3 vs. >10 mm3). Procedural and clinical outcome were assessed in accordance with VARC-2 criteria. All-cause mortality was assessed by Kaplan-Meier method, median follow-up was 1.4 years. Results Significant LVOT calcification was present in 37.0% of patients. Patients with LVOT calcification were older (all results as follows without (w/o) vs. with (w) LVOT calcification: 81.4 (77.1, 84.8) vs. 82.3 (78.0, 86.3) years, p=0.006), but presented similar STS scores compared to those without LVOT calcification (5.4±4.7 vs. 5.4±3.5%, p=0.94). Moreover, patients with LVOT calcification had higher mean transvalvular gradients at baseline (30.0 (21.0, 41.0) vs. 37.0 (25.7, 47.0) mmHg, p Conclusions Significant LVOT calcification is present in a substantial proportion of patients receiving TAVI. In such patients, higher rates of cerebrovascular events and more than mild PVL occurred compared to those without significant LVOT calcification even with currently available second-generation THV. Although these findings did not translate into higher mortality rates in the present study, they underline the need for further optimization of THV technology in order to improve outcomes among all TAVI patients. Figure 1. 1-year mortality Funding Acknowledgement Type of funding source: None

Introduction Cardiac inflammation with subsequent remodeling of the extracellular matrix (ECM) with fibrosis formation is an important precursor of heart failure. In myocardial inflammation release of cytokines, such as TNF-α was previously linked to the development of fibrosis. However, their exact role in fibroblasts activation, leading to their transformation into myofibroblasts and ultimately fibrosis is unknown. Therefore, the purpose of this work was to study the secretome of isolated cardiac fibroblasts of heart failure patients in vitro. Methods and results Human cardiac fibroblasts were obtained from endomyocardial biopsies of patients with reduced ejection fraction. Secretome- and gene expression analysis was performed on TNF-α (10 ng/ml) and TGF-β (5 ng/ml) treated and untreated fibroblasts. The analysis of the secretome in cell culture supernatant of these fibroblasts was performed by nano-LC-ESI tandem mass spectrometry. Subsequently, RNA was isolated from fibroblasts and expression analysis was performed using affymetrix gene chips and verified for the stimulation experiments using TaqMan. The secretome and gene expression studies are constistent regarding the most frequent ECM components. The proteins involved in the construction of the ECM accounted for 56% of the total protein intensity. The fibronectin represented the largest proportion of ECM proteins (50%), with collagens accounting for 29% and MMPs and TIMPs for approximately 5% and a small proportion of cytokines. In the secretome as well as in the gene expression, Il-6 and Il-8 showed the highest proportion of cytokines and type I as well as type IV (each approx. 40%) of collagens. MMP2, MMP1 and TIMP1 accounted for the largest proportion of MMPs and TIMPs. Stimulation with TGF-β and TNF-α led to changes in the composition of the cytokines and ECM proteins. After the stimulation with TNF-α, the proportion of cytokines increased from 3.1% to 6.6%, while the proportion of ECM proteins decreased slightly. Accordingly, after stimulation with TGF-β a well-known inductor of fibrosis, the proportion of collagens and other matrix proteins increased, while the proportion of cytokines decreased slightly. Conclusion In this study, we identified the most abundant proteins of the ECM and demonstrated their expansion caused by TGF-β stimulation of fibroblasts. Surprisingly, TNF-α led to an increase of cytokines secreted by the fibroblasts with a minimal reduction of ECM proteins. Here, the differentiated regulation of the fibroblast in the transformation of the ECM could be seen. TNF-α stimulation demonstrated to increase gene expression of the cytokines in fibroblasts, which in turn maintain inflammation with chemotactic effect. Hence, cardiac fibroblasts seem to be supporting cells for cardiac inflammation. There seemed to be no pro-fibrotic effect. In this work we could show the pro-inflammatory role of the cardiac fibroblast upon inflammatory stimulation. Funding Acknowledgement Type of funding source: None

Background The discrimination of patients with type 1 myocardial infarction (T1MI) from patients with type 2 MI (T2MI) is often challenging in the emergency department. Earlier we presented a discrimination model, which based on clinical variables, as well as on troponin concentrations. In the present analyses we sought to investigate the discriminative power of 28 biomarkers in patients with T1MI and T2MI. Methods Patients presenting to the emergency department with symptoms suggestive of MI were recruited. The final diagnosis of all patients was adjudicated by two physicians in a blinded fashion and based on the fourth universal definition of MI. For the present analyses only patients with T1MI and T2MI were used. In total 28 biomarkers were measured in blood samples collected directly at admission. A multivariable logistic regression model for T1MI vs T2MI as the dependent variable was used and the predictors were chosen via backward step-down selection. Results In total 138 patients (107 T1MI and 31 T2MI) were available for the analyses. The median age of the study population was 65 years and 66.7% were males. Hypertension was present in 77.4% and dyslipidemia in 41.3%. In the multivariable model four biomarkers (apolipoprotein A-II, n-terminal prohormone of brain natriuretic peptide, copeptin and high-sensitivity troponin I) were significant discriminators between T1MI and T2MI (Table 1). Internal validation of the model via bootstrap shows a for overoptimism corrected area under the curve of 0.82. Conclusion Using a multibiomarker approach discrimination between T1MI and T2MI could be improved. External validation of our findings is warranted. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Research fellowship by the Deutsche Forschungsgemeinschaft

Background Natriuretic peptides are extensively studied biomarkers for atrial fibrillation (AF) and heart failure (HF). Their role in the pathogenesis of both diseases is not entirely understood and in previous studies several single nucleotide polymorphisms (SNPs) at the NPPA-NPPB locus associated with natriuretic peptides have been identified. Purpose We investigated whether a causal relationship exists between natriuretic peptides and AF as well as HF using a Mendelian randomization approach. Methods N-terminal pro B-type natriuretic peptide (NT-proBNP) (N=6669), B-type natriuretic peptide (BNP) (N=6674) and mid-regional pro atrial natriuretic peptide (MR-proANP) (N=6813) were measured in the FINRISK 1997 cohort. Thirty common SNPs related to NT-proBNP, BNP and MR-proANP were selected from prior studies. We performed six Mendelian randomizations for all three natriuretic peptide biomarkers and for both outcomes, AF and HF separately. Polygenic risk scores (PRS) based on multiple SNPs were used as the genetic instrumental variable in Mendelian randomizations. Results PRS were significantly associated with the three natriuretic peptides. PRS were not significantly associated with incident AF nor HF. Most cardiovascular risk factors showed significant confounding percentages, but no association with PRS. A causal relation, other than a weak one, is unlikely. Conclusion In our Mendelian randomization approach, based on common genetic variation at the NPPA-NPPB locus, associations of the common polymorphisms with natriuretic peptides and the protein biomarkers themselves with incident disease could be confirmed. A strong causal relationship between natriuretic peptides and incidence of AF as well as HF was ruled out. Therapeutic approaches targeting natriuretic peptides will therefore very likely work through indirect mechanisms. Comparison of hazard ratios Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme, German Ministry of Research and Education

Background The aim of the present study was to compare clinical characteristics and cardiac structure and function in competitive triathletes with and without myocardial fibrosis. Methods Cardiac fibrosis in 61 healthy male competitive triathletes (>10 hrs of training per week, age 45±10 yrs) was quantified using LGE-sequences in CMR (1.5 tesla scanner). Transthoracic echocardiography, physical examination, past medical history and routine lab diagnosis for exclusion of other conditions were performed. Baseline characteristics like blood pressure at rest (BP), bodymass-index (BMI), and systolic and diastolic echocardiographic parameters (left atrial volume index (LAVI), e', E, A, right ventricular pressure gradient) as well as global longitudinal strain, were analysed by two independent observers blinded to the CMR measurements. Triathletes were sub-divided into LGE-positives (LGE+) vs. LGE-negatives (LGE-). Results All individuals appeared healthy with no drug history. Focal non-ischaemic LGE was detected in 19 triathletes. Compared to LGE-negative triathletes, LGE-positives showed significantly higher systolic BP (142 vs. 128 mmHg, p=0.004). Logistic regression showed, that per 10 mmHg enhanced blood pressure the chance for LGE rises by 89%. Triathletes with and without LGE demonstrated no difference in conventional echocardiographic measurements such as left ventricular ejection fraction and volumes and no difference in diastolic parameters. But the presence of MF did mediate global longitudinal strain (GLS). Global longitudinal strain was significantly reduced in LGE positive athletes (LGE+: −19.8±3.4; LGE-: −21.7±2.4, p=0.04) Conclusions Reduced global longitudinal strain mediated as an early echocardiographic marker for subclinical changes in asymptomatic competitive triathletes with myocardial fibrosis compared to triathletes without LGE. Novel echocardiographic parameter such as longitudinal strain might serve as an easy tool to identify high endurance athletes at higher risk for cardiovascular events and that individuals with enhanced blood pressure should undergo cardiac consultation before starting endurance-training in competitive disciplines. Funding Acknowledgement Type of funding source: None

Introduction The recently updated ESC guidelines on the management of dyslipidaemias recommend a more intense LDL-cholesterol (LDL-C) reduction. For patients with atherosclerotic cardiovascular disease (ASCVD) the LDL-C goal has been revised to ≤55 mg/dl with a concomitant class IA upgrade for cost intensive PCSK9 inhibitors. Purpose We aim to quantify the need for PCSK9 inhibitors to achieve the revised LDL-C target compared to former ESC recommendations in ASCVD patients Methods We included all patients with ASCVD (angiographically documented coronary artery disease, history of peripheral artery disease or stroke) from an observational cohort study ongoing since 2015. A simulation treatment algorithm adding sequentially a high intensity statin, ezetimibe and a PCSK9 inhibitor in case of a missed treatment target was applied with consideration of both partial and total statin intolerance. The need for PCSK9 inhibitors was calculated for 3 recommendations: 1. LDL-C treatment target ≤55 mg/dl (ESC 2019 Guidelines), 2. LDL-C treatment target ≤70 mg/dl (ESC 2016 Guidelines) and 3. risk-based use of PCSK9 inhibitors restricted to patients with a residual LDL-C >140 mg/dl or >100 mg/dl with clinical/angiographic risk factors (ESC consensus update 2017). Results We included 1936 patients (mean age 69 years, 74% male). Median LDL-C at inclusion was 86 mg/dl, with 60% of patients taking lipid lowering medication (55% statin only, 4% statin + ezetimibe, 1% ezetimibe only). Table 1 shows the distribution of medications required to meet recommendations 1–3. After simulated stepwise intensification of lipid lowering therapy 99% of patients achieved the revised LDL-C target of ≤55 mg/dl, with a need of 23.5% for a PCSK9 inhibitor. For the former LDL-C target of ≤70 mg/dl the need for PCSK9 inhibitors was 10.5%. Restricting the use of PCSK9 inhibitors to the highest risk patients according to the ESC 2017 consensus statement reduced the need for PCSK9 inhibition to only 1.4% with slightly fewer patients achieving their LDL-C target (78% for ≤55 mg/dl and 91% for ≤70 mg/dl respectively). Conclusion The revised LDL-C treatment goals substantially increase the projected need for PCSK9 inhibitors with an unclear health economic impact. Identification of ASCVD patients with a reasonable benefit/cost-ratio of PCSK9 inhibition remains to be investigated urgently. Funding Acknowledgement Type of funding source: None

Aims The differentiation of type 1 and type 2 myocardial infarction (T1MI, T2MI) is important, but challenging in the emergency department. We aimed to investigate the clinical characteristics and cardiovascular outcome of T2MI patients and to develop a clinical decision tool to differentiate T1MI and T2MI patients. Methods and results We prospectively enrolled 1548 patients with suspected MI. All patients were followed for up to 2 years to assess mortality. We used logistic regression with backward step-down selection to determine the most important predictors of T2MI. Based on these regression coefficients, we developed a diagnostic prediction model (score) to diagnose T2MI. T2MI was the final diagnosis of 99 patients. Patients with T2MI showed a high 1-year mortality rate (13.8%), which equals that of T1MI patients (9.4%). Female sex (Beta 1.27 [95% confidence interval; CI 0.67-1.90]), not having radiating chest pain (Beta 1.62 [CI 0.96-2.34]) and a baseline high-sensitivity troponin I concentration ≤ 40.8 ng/L (Beta 1.30 [CI 0.74-1.89]) were the strongest predictors for T2MI. Their combination resulted in an area under the curve of 0.71 to discriminate T1MI and T2MI. The binary score based on this model assigns one point to each of the predictors. Patients with the highest score value of 3 had a 72% probability of T2MI. Conclusion T2MI patients are a heterogeneous population with high-cardiovascular risk. A score based on laboratory and clinical parameters might help to differentiate T1MI and T2MI patients. The additional use of this score in clinical routine needs to be investigated prospectively. Trial registration www.clinicaltrials.gov (NCT02355457).

Recent research has demonstrated that the non-coding genome plays a key role in genetic programming and gene regulation during development as well as in health and cardiovascular disease. About 99% of the human genome do not encode proteins, but are transcriptionally active representing a broad spectrum of non-coding RNAs (ncRNAs) with important regulatory and structural functions. Non-coding RNAs have been identified as critical novel regulators of cardiovascular risk factors and cell functions and are thus important candidates to improve diagnostics and prognosis assessment. Beyond this, ncRNAs are rapidly emgerging as fundamentally novel therapeutics. On a first level, ncRNAs provide novel therapeutic targets some of which are entering assessment in clinical trials. On a second level, new therapeutic tools were developed from endogenous ncRNAs serving as blueprints. Particularly advanced is the development of RNA interference (RNAi) drugs which use recently discovered pathways of endogenous short interfering RNAs and are becoming versatile tools for efficient silencing of protein expression. Pioneering clinical studies include RNAi drugs targeting liver synthesis of PCSK9 resulting in highly significant lowering of LDL cholesterol or targeting liver transthyretin (TTR) synthesis for treatment of cardiac TTR amyloidosis. Further novel drugs mimicking actions of endogenous ncRNAs may arise from exploitation of molecular interactions not accessible to conventional pharmacology. We provide an update on recent developments and perspectives for diagnostic and therapeutic use of ncRNAs in cardiovascular diseases, including atherosclerosis/coronary disease, post-myocardial infarction remodelling, and heart failure.

Aims Heart failure (HF) is an increasingly important contributor to the overall burden of cardiovascular disease in the population. We aimed to determine the distribution of the cardiac biomarkers high-sensitivity cardiac troponin I (hs-cTnI) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) concentrations across the European population to characterize the association with incident HF. Methods and results Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 48,455 individuals from four prospective population-based cohort studies (DanMONICA, FINRISK, Moli-Sani, Northern Sweden MONICA study) across Europe with a maximum follow-up of 27 years. The median age of the participants was 50.7 years (25th percentile: 40.0 years, 75th percentile: 61.7 years) and 49.1% (25,146) were men. Considered endpoints were incident HF and all-cause mortality. The median follow-up time for occurrence of HF was 6.61 (6.55; 6.66) years. We found that cardiovascular risk factors (CVRFs), especially diabetes with HR of 2.11 (95% CI 1.8, 2.5) and smoking status with HR of 1.79 (95% CI 1.59, 2.1) (Figure 1) were associated with incident HF. Furthermore, beyond the CVRFs, elevated hs-cTnI and NT-proBNP concentrations contributed to risk of HF in the general population with HR of 1.49 (95% CI 1.21, 1.9) and HR of 2.37 (95% CI 1.97, 3.0) respectively. As a cut-off value to select individuals, who would benefit most from preventive strategies, a hs-cTnI concentration of 2.8 ng/L was calculated using the optimal cut-off methodology by Contal and O'Quigley in CSDA 1999. Hazard ratio for incident HF Conclusion In our large population-based cohort, hs-cTnI and NT-proBNP were independently associated with incident HF. Use of biomarkers for HF screening thus may help to select those individuals in the general population who would benefit most from preventive strategies. Based on the cut-off value future studies are needed to evaluate therapeutic options.

Introduction Modifiable lifestyle risk factors (modRF) of coronary artery disease (CAD) such as smoking, lack of physical activity (PA) and poor diet are associated with high inflammatory burden. An optimisation of modRF might significantly affect the target population for pharmacological anti-inflammatory treatment (AIT) as determined by a hsCRP ≥2 mg/l. Aim To analyse the influence of modRF on hsCRP in a contemporary CAD cohort and model the effect of modRF optimisation on hsCRP in a target population with high inflammatory burden. Methods We included all patients with angiographically documented CAD from an observational cohort study ongoing since 2015 and excluded patients with recent myocardial infarction, malignancy, infectious disease, and immunosuppressive medication. ModRF were assessed by questionnaire at enrolment. Lack of PA was defined as PA Results Of the 1003 patients (mean age 69 years, 72% male) included, 48% (N=479) had a hsCRP ≥2 mg/l. HsCRP increased with the incremental number of modRF (median hsCRP-values for 0–3 modRF: 1.1, 1.6, 2.1, 2.7 mg/l, p12, and smoking (Table 1). Recalculation of hsCRP levels identified 21% (N=102/479) of patients with hsCRP ≥2 mg/l who could achieve a hsCRP Table 1. Linear regression results Univariate Multivariate exp(β) (95% CI) p-value exp(β) (95% CI) p-value PA ≥1.5 h/week 0.63 (0.54, 0.72) 12 0.74 (0.65, 0.86) Conclusion Modifiable lifestyle risk factors are independently associated with hsCRP levels in CAD patients. A relevant portion of patients with high inflammatory burden might achieve a hsCRP

Introduction Stratification for subsequent coronary events among patients with coronary artery disease (CAD) is of considerable interest due to the potential to guide secondary preventive therapies. Soluble urokinase-type plasminogen activator receptor (suPAR) is expressed on various cells involved in atherogenesis and plaque instability, and has been associated with poor clinical outcomes in patients with various conditions. Purpose In this study we investigated the potential role of suPAR as a prognostic biomarker for adverse outcome in patients with CAD, and acute coronary syndrome (ACS) in particular. Methods Plasma levels of suPAR were measured in a cohort of 1,703 patients (AtheroGene Study) with documented coronary artery disease –including 626 patients with ACS and 1077 patients with stable angina pectoris (SAP). The main outcome measures were defined as cardiovascular death and non-fatal myocardial infarction (MI). Survival curves for the endpoints considered were computed according to thirds of the suPAR distribution. The equality of survival curves was tested using the log-rank test. Multivariable models adjusted for common cardiovascular risk factors and the biomarkers CRP, NT-proBNP and high-sensitivity troponin I (hs-TnI) in particular were also computed. Results The prognostic utility of suPAR was evidenced by survival curves stratified for tertiles of circulating suPAR levels –both, in the overall cohort (p=0.00062), and in the ACS cohort (p=0.00099) with a median follow-up of 3,5 years. In multivariable-adjusted Cox regression analyses the hazard ratio (HR) for the prediction of cardiovascular death was 3.60 for log-transformed suPAR levels (p Conclusions Our study demonstrates that suPAR has a strong prognostic value independent of hs-TnI in secondary prevention settings, and thereby might represent a valuable biomarker for risk estimation in CAD. Acknowledgement/Funding Stiftung Rheinland-Pfalz für Innovation, European Union 7th Framework Programme, DZHK e.V., ERA-Net, Abbott Diagnostics

Background Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNA) and long non-coding RNAs (lncRNA), have been implicated as novel cardiac biomarkers, but no comparative analysis has been performed on their release kinetics and detection range in myocardial injury without confounding by heparin. Purpose To assess the release kinetics of different ncRNA species in heparinase-treated plasma and serum samples in comparison with protein biomarkers for myocardial injury, including troponin and cardiac myosin binding protein C (cMyC). Methods and results Screening of 158 circRNAs and 21 lncRNAs in human cardiac tissue identified 12 circRNAs and 11 lncRNAs as potential biomarkers with cardiac origin. Two cardiac-enriched miRNAs (miR-208b and miR-499) and two muscle-enriched miRNAs (miR-1 and miR-133a) as well as 7 further well-known miRNAs with good detectability in plasma/serum were included. To compare the expression levels of ncRNAs with established and novel protein biomarkers (cardiac troponins and cMyC, respectively), human myocardial tissue was spiked into plasma. At low spike-in concentrations, significantly higher regression coefficients were observed for all ncRNA species. Serial plasma and serum samples were obtained of patients undergoing transcoronary ablation of septal hypertrophy (TASH). Heparinase-treatment resolved dense correlation network clusters by removing spurious correlations between miRNAs in non-heparinase-treated samples. After TASH, muscle-enriched miRNAs showed a steeper increase at an earlier time point than cardiac-enriched miRNAs. Putative cardiac lncRNAs, including LIPCAR, did not rise after TASH, refuting a predominant cardiac origin. Cardiac circRNAs remained below detectability. In a validation cohort of patients presenting with acute myocardial infarction, the release kinetics of ncRNAs was compared with cardiac troponins and cMyC. While receiver operating characteristic analyses revealed noninferiority of cardiac-specific miRNAs to high-sensitive cardiac troponin, miRNAs failed to identify cases presenting with low troponin values. Validating previous reports, cMyC showed better baseline detectability and a steeper rise at early time points after MI. Conclusions We assessed ncRNAs as biomarkers for myocardial injury after heparinase-treatment. MiRNAs emerged as the most promising candidates to integrate ncRNAs with protein biomarkers. The release kinetics of miRNAs is different from cardiac proteins, but the sensitivity of current miRNA detection is inferior to high-sensitive protein assays. We validate recent reports of cMyC showing properties of a very sensitive biomarker for the early detection of myocardial injury. Acknowledgement/Funding SCHU 2983/1-1 and SCHU 2983/1-2; FS/16/32/32184; FS/13/18/30207; 81Z0710102; CH/16/3/32406; RG/16/14/32397

Background Troponin is the gold-standard biomarker for diagnosing acute myocardial infarction (AMI). High-sensitivity assayed troponin has furthermore proven to be a promising biomarker for the prediction of future adverse cardiovascular events. Objective Aim of the current study was to assess and compare the prognostic value of a single troponin I measurement in patients with suspected AMI analysed by a novel high-sensitive Troponin I (hs-TnI) assay, promising detection of very low troponin I plasma levels, as well as by a well-established hs-TnI assay. Methods Data was derived from two prospective studies of patients presenting with suspected AMI to the emergency department. Hs-TnI was measured in a total of 2,312 patients using both a novel hs-TnI assay (1; Singulex Clarity cTnI) and a widely applied and approved hs-TnI assay (2; Abbott Diagnostics, ARCHITECT i1000SR). The prognostic impact for overall mortality of both hs-TnI assays was assessed in the total patient cohort as well as in the subgroups of patients with AMI (n=498) and without AMI (n=1,813). Kaplan-Meier analyses stratified by hs-TnI tertiles in each subgroup were performed. Moreover, prognostic impacts of both hs-TnI assays were analysed in a multiple adjusted cox regression model. We compared the performance of both hs-TnI assays in predicting adverse outcome using c-statistics. Median follow up time was 2.4 years. Results Patients with AMI presented with significantly higher hs-TnI values on admission. Unadjusted Kaplan-Meier analysis survival curves in the entire study population (Figure 1) as well as in the non-AMI subgroup indicated a significantly higher event-rate in the third tertiles of both hs-TnI assays for overall mortality. In contrast, irrespective of the used assay we found no association between troponin I plasma levels and overall mortality in the AMI group. Cox regression models revealed significant associations between hs-TnI and overall mortality in the entire study cohort (1: HR 1.17 [1.10–1.25], p Figure 1. Overall mortality Conclusion Hs-TnI assayed on admission is an independent predictor of adverse outcome beyond conventional risk factors in patients presenting to the emergency department with suspected but ruled-out diagnosis of AMI. In patients with the established diagnosis of AMI hs-TnI is not predictive for adverse outcome. Our findings demonstrate the potential role of hs-TnI as a biomarker for risk prediction. Both assessed hs-TnI assays performed equally in predicting adverse events.

Background Recently, the H2FPEF score has been developed in an evidence-based approach relying on simple clinical and echocardiographic variables. It enables the identification of patients with high probability of prevalent heart failure with preserved ejection fraction (HFpEF) which is associated with a dismal prognosis. Left ventricular diastolic dysfunction, a key mechanism in HFpEF, is also a common finding in patients with severe aortic stenosis. Objective To assess the prognostic impact of the H2FPEF score in patients with preserved ejection fraction and severe aortic stenosis undergoing Transcatheter Aortic Valve Replacement (TAVR). Methods Among 1148 patients with preserved ejection fraction who received TAVR at our institution between 2013 and 2018, data for calculation of the H2FPEF score was available in 535 patients. Score variables include BMI >30 kg/m2, arterial hypertension, atrial fibrillation, pulmonary hypertension >35 mmHg, age >60 years, and elevated LV filling pressure. Patients were dichotomized according to “low” (1–5 points; n=377) and “high” H2FPEF scores (6–9; n=158). Kaplan-Meier survival curves and Cox regression analyses were used to assess the prognostic impact of H2FPEF scores. Median follow-up time was 0.3 years. Results TAVR patients presenting with high H2FPEF scores had higher prevalence of moderate to severe mitral regurgitation (19.4% vs. 33.6%, p55 mmHg (HR=2.68, 95% CI: 0.97–7.40, p=0.057) were strong independent predictors of adverse outcome. Figure 1. All-cause mortality of patients undergoing TAVR after one year stratified by low (1–5 points) and high (6–9) H2FPEF score Conclusion An elevated H2FPEF score of >6 is independently predictive for mortality in patients with preserved ejection fraction undergoing TAVR for severe aortic stenosis. Our findings provide evidence that the H2FPEF score, which was meant for diagnostic use originally, is able to serve as a prognostic tool in patients with preserved ejection fraction undergoing TAVR, highlighting the adverse impact of diastolic dysfunction in patients with preserved ejection fraction and aortic stenosis.

Introduction Chronic kidney disease (CKD) represents a global public health problem and affects a large proportion of the adult population worldwide. Early detection, adequate risk stratification and specific treatment can prevent or delay the adverse effects of CKD. Purpose To assess cardiovascular risk and total mortality of subjects with CKD using cystatin C based and Crea-based estimated glomerular filtration rate (eGFR) equations (CKDEpi) in the general population, in diseased cohorts, and in specific subgroups. Methods The present study has been conducted within the BiomarCaRE project, with harmonized data from 21 population-based cohorts from 6 European countries and 3 cardiovascular disease (CVD) cohorts from Germany. Cox proportional hazards models were used to assess hazard ratios (HRs) for the various CKD definitions with adverse outcomes and mortality after adjustment for age, sex, cohort, smoking status, body mass index, history of diabetes, history of hypertension, and total cholesterol. Results 21 population-based cohorts (n=76,954, median age 51 years, 52.2% men, 4.4% diabetic) and 3 diseased cohorts (n=4,982, median age 63 years, 75.6% men, 18.7% diabetic) with an average follow-up between 2.8 and 23.5 years and between 0.5 and 9.4 years, respectively, were included in the analysis. Prevalence of CKD-stage 3–5 by CKD-EPIcrea and CKD-EPIcys eGFR respectively, was 3.4% and 7.3% in the population-based cohorts and 13.9% and 14.4% in the diseased cohorts. In the population-based cohorts the incidence (per 1000 person years) of a non-fatal or fatal CVD event and total mortality respectively, was 10.0 and 11.8, whereas it was 21.2 and 17.8 in the diseased cohorts. In the population-based cohorts the HR for a CVD-event was 1.32 (95% CI 1.21–1.44) for the population with CKD-EPIcrea stage 3–5 and it was 1.47 (95% CI 1.35–1.60) based on CKD-EPIcys after adjustment for covariates. The HR for total mortality for those with CKD-EPIcrea stage 3–5 was 1.31 (1.21–1.41) and for CKD-EPIcys it was 1.86 (95% CI 1.73–2.00). Discrepancies between CKD-EPIcrea and CKD-EPIcys were even more striking across subgroups with and without diabetes or across specific age groups. Conclusion CKD is an important risk factor for subsequent CVD events and total mortality. However, point estimates of CKD-EPIcrea and CKD-EPIcys eGFR differ considerably between specific risk groups. Therefore, the clinical utility of both equations in different risk groups has to be considered and should be evaluated further. Acknowledgement/Funding 7th framework programme collaborative project, grant agreement no. HEALTH-F2-2011-278913

Background Patients with diabetes mellitus (DM) may have elevated levels of high-sensitive cardiac troponin (hs-Tn) despite acute myocardial ischemia being present. However, it is unclear whether this constrains diagnostic strategies in patients with suspected acute myocardial infarction (MI). Purpose We aimed to assess the diagnostic performance of the European Society of Cardiology (ESC) 0/1 hour (h) and 0/3h-algorithms comparing patients with and without DM and to derive optimized cut-offs. Methods We prospectively enrolled patients with symptoms suggestive of MI in two large clinical cohorts and measured hs-TnI at admission (baseline) and 1 (cohort A) and 3h (cohort A+B) thereafter. Patients with ST-elevation MI were excluded. Patients were stratified based on a diagnosis of DM at baseline. Final diagnoses were adjudicated independently by two cardiologists using all clinically available information, including hs-TnT, but blinded to hs-TnI values. Our primary outcomes of interest were safety of rule-out (defined by sensitivity and negative predictive value [NPV]), accuracy of rule-in (defined by specificity and positive predictive value [PPV]) and the overall performance (% of patients adjudicated to either rule-out or -in). For optimized cut-offs, a NPV >99.0% and a PPV >75.0% were targeted. Results DM was prevalent in 563 (15.29%) of 3683 included patients. MI was more prevalent among patients with DM (137 [24.3%] vs. 498 [16.0%], p Conclusion Application of the ESC 0/1h- and 0/3h-algorithms in diabetic patients provided reduced safety and accuracy for rule-out and rule-in of MI, respectively. Use of alternative cut-offs resulted in improved diagnostic safety and accuracy. Acknowledgement/Funding Abbott Diagnostics, German Center of Cardiovascular Research, German Heart Foundation, Else-Kröhner-Stiftung angegeben

Introduction Use of contrast media is necessary for diagnostic imaging and PCI. However, contrast-induced kidney injury has been identified as the most frequent cause of hospital-acquired acute kidney injury and is associated with poor prognosis. Currently, contrast-induced kidney injury cannot be diagnosed on the day of cardiac catheterization or on the following day, when the majority of patients who undergo elective cardiac catheterization are discharged from the hospital in the real-world setting. Recently, proenkephalin (penKid) was introduced as a new glomerular filtration marker, which is capable of identifying normal subjects at high risk of future decline in renal function. The aim of this study was to investigate whether the change in penKid level on the day following cardiac catheterization can predict kidney injury before hospital discharge and thus allows for early detection of affected patients. Methods A total of 214 consecutive patients who underwent routine cardiac catherization were recruited, and blood was drawn at three time-points: immediately before catherization, 12–24 hours after catheterization and 4–8 weeks after discharge. Creatinine was measured for endpoint definition, while the markers urea, CRP (C-reactive protein), NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury marker-1), cystatin C, suPAR (soluble urokinase-type plasminogen activator receptor), and penKid were measured as biomarkers of interest. The main outcome measure was sustained kidney injury (SKI), which was defined as an increase above 20% in serum creatinine between time-points 1 and 3. The main test was whether the change in biomarkers between baseline and immediately before discharge (time-points 1 and 2) can predict the development of sustained kidney injury. Results While only 5.6% of subjects developed acute kidney injury as defined according to KDIGO guidelines (delta serum creatinine between time-points 1 and 2), sustained kidney injury at mid-term follow-up (4–8 weeks) was found in 28.7% of the subjects. None of the baseline biomarkers, including creatinine, reliably predicted SKI (AUC in ROC analyses between 0.50 and 0.60). In rule-out analyses, stable values of penKid (not increasing from before catherization to discharge next day) reliably ruled out SKI at a specificity of 96.0% (90.1–98.9), while specificity was lower for the other candidate biomarkers [CRP: 63.4% (53.2–72.7); NGAL: 55.3% (44.1–66.1); KIM-1: 63.9% (53.5–73.4); cystatin C: 93.0% (86.1–97.1); suPAR: 52.0% (41.8–62.1)]. Using penKid, only 7 patients were categorized as false-positive, while all other patients would have been discharged safely. Study Flow PANCAKE-Study Conclusion Change in penKid levels between cardiac catheterization and discharge reliably rules out sustained kidney injury after contrast administration. PenKid thereby holds promise as an early biomarker for contrast-induced kidney injury and should be evaluated in pilot interventional trials.

Background Although atrial fibrillation (AF) and heart failure (HF) have a similar cardiovascular risk profile, the differential associations of the risk factors with both disease are incompletely understood. Aim The aim of this study was to understand whether common clinical risk factors and cardiovascular biomarkers show different associations with incident AF and HF, and to investigate predictors of sequential disease onset and mortality. Methods In 58693 individuals free of AF and HF from European population-based cohorts, pooled multivariable Cox regression analysis was used to find predictors for AF, HF and all-cause mortality. P-values for differences between Hazard Ratios (HR) of risk factors for AF and HF were estimated using bootstrapping with 5,000 replications. When AF and/or HF were used in Cox regressions as explanatory variables, they were included as time-dependent variables. Results Median age was 50.5 years, 49.3% were men. Median follow-up time was 13.8 years with an all-cause mortality rate of 15.7%. Incident AF and HF was present in 5.0% and 5.4% of the participants, with 1.8% showing a sequential disease onset. In multivariable-adjusted models we observed stronger associations of body mass index (HR of 1.32 (95% CI 1.25–1.39) vs. 1.42 (95% CI 1.36–1.49), p=0.02), smoking (HR of 1.21 (95% CI 1.08–1.33) vs. 2.11 (95% CI 1.90–2.32), p Total serum cholesterol (HR of 1.10 (95% CI 1.06–1.15), prevalent diabetes (HR of 3.46 (95% CI 2.60–4.32), high-sensitive C-reactive protein (HR of 1.12 (95% CI 1.08–1.16)) and glomerular filtration rate (HR of 0.92 (95% CI 0.85–1.00) were significantly related to incident HF but not AF. Age (HR of 1.54 (95% CI 1.47–1.61) vs. 1.54 (95% CI 1.47–1.62), p=0.95), male sex (HR of 2.87 (95% CI 2.42–3.33), p=0.13), prevalent myocardial infarction (HR of 1.65 (95% CI 1.26–2.04) vs. 1.75 (95% CI 1.36–2.11), p=0.73) and NT-proBNP (HR of 1.59 (95% CI 1.50–1.68) vs. 1.60 (95% CI 1.51–1.69), p=0.86) showed comparable associations with both diseases. Age, male sex, body mass index, total serum cholesterol, prevalent diabetes and NT-proBNP were all predictors of sequential disease onset after multivariable adjustment. In models including cardiovascular risk factors and NT-proBNP, the time-varying covariates incident AF and HF showed a strong association with all-cause mortality, with HR of 2.2 (95% CI 1.9–2.5) and 10.7 (95% CI 9.1–12.6), respectively. Sequential disease onset further increased the hazard ratio to 15.1 (95% CI 11.6–19.5). Conclusion In our pooled analysis of population-based cohorts, new-onset AF and HF showed different associations with common cardiovascular risk factors and biomarkers. Although both diseases significantly increased mortality, the highest risk was observed in individuals with sequential disease onset.

Background Serial measurements of high-sensitivity troponin (hs-Tn) is recommended for rule-out or rule-in of myocardial infarction (MI) in patients presenting with acute chest pain. Based on dynamic hs-Tn changes invasive angiography is recommended in order to identify a culprit lesion. However, the association of hs-Tn with the intracoronary flow is unknown. Purpose We aimed to evaluate the association of hs-TnI with intracoronary flow, measured by the TIMI Coronary Grade Flow in coronary angiography, and its association with outcome. Methods 1,940 consecutive patients presenting with suspected MI to the emergency department were included. Among those 543 patients underwent coronary angiography. Patients with prior coronary artery bypass graft surgery and patients with chronic total occlusion were excluded from further analysis, resulting in 420 available individuals. TIMI Coronary Grade Flow was scored in accordance with the definition of the TIMI study group. For further analysis two groups were distinguished. Group 1: Minimum TIMI Grade Flow Results In patients with reduced TIMI Grade Flow the level of hs-TnI was significantly higher at admission (Group 2: 87.3 ng/l vs. Group 1: 15.0 ng/l, p Figure 1 Conclusion Absolute value and delta change of hs-TnI after 1 and 3 hours help to predict the presence of reduced TIMI Grade Flow in coronary arteries. Patients suffering from a lowered TIMI Grade Flow have higher event rates after 12-months.

Background Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used for treatment of patients with critical cardiopulmonary failure. However, utilization of VA-ECMO support must be carefully weighed against possible complications. Therefore, we investigated the incidence and impact of complications on VA-ECMO support in one of the largest datasets of VA-ECMO therapy. Material and methods We analyzed complications and outcomes of all VA-ECMO procedures performed in Germany from 2007 to 2015 by using administrative data from the German Federal Health Monitoring System. For the present analyses all cases treated with VA-ECMO between 2007 and 2015 were identified and selected by the primary procedural code (OPS) for VA-ECMO (OPS code 8852.3). Results Among 8,351 patients undergoing VA-ECMO between 2007 and 2015, there were significant changes in complication rates over time such as increase in acute kidney injury (from 35.9% in 2007–2012 to 44.6% in 2013–2015), major bleeding (from 11.3% in 2007–2012 to 19.5% in 2013–2015 and abdominal ischemia (from 4.5% in 2007–2009 to 7.2% in 2013–2015). The incidence of stroke and limb ischemia did not differ over time. Procedure-related and ischemic complications were more frequently observed in non-survivors as compared to survivors (12.2% versus 15.3%, p Conclusion In one of the largest registries, major bleeding and ischemic events are the most common complications on VA-ECMO support. Ischemic complications seem to influence outcome more than bleeding complications. However, only stroke and acute kidney injury were independently associated with higher mortality rates. These findings should be incorporated in risk-benefit stratification when initiation of VA-ECMO and in prevention of complications to avoid additional morbidity and mortality in these critically ill patients.

Introduction Heyde syndrome is known as the association of severe aortic stenosis (AS) and recurrent gastrointestinal bleeding (GIB) from angiodysplasia. To date only few data exist regarding the prevalence of Heyde syndrome and results after transcatheter aortic valve implantation (TAVI) for the treatment of AS. Purpose We sought to evaluate the prevalence of Heyde syndrome in a routine clinical cohort of patients undergoing TAVI and analyze the effectiveness of treatment of AS regarding recurrent GIB in these patients. Methods We conducted a retrospective single-center analysis of 2545 consecutive patients who underwent TAVI for the treatment of AS in 2008–2017. Patients with a history of GIB were identified. The diagnosis of Heyde syndrome was defined as a clinical triad of presence of severe AS, a history of recurrent GIB, and an endoscopic diagnosis of angiodysplasia. GIB of unknown origin or related to other causes was defined as bleeding unrelated to angiodysplasia. Clinical outcomes of patients with Heyde syndrome were evaluated with emphasis on bleeding complications and recurrence of GIB. Results A history of GIB prior to TAVI was detected in 190 patients (7.5%) of the TAVI cohort. Among them, 143 patients had a GIB unrelated to angiodysplasia (5.6%) and 47 patients (1.8%) were diagnosed with Heyde syndrome. Median age and STS-PROM were 80.7 (75.3, 84.0) years and 4.7 (2.7, 9.0) respectively in Heyde patients. TAVI was successfully performed in all cases (66% endovascular access, 34% transapical access). The effective orifice areas increased from 0.8±0.1 cm2 to 2.1±0.5 cm2. Periprocedural major/life-threatening bleeding was found in 6 patients (12.8%), mainly access-related and none due to GIB. In 51% of Heyde-patients transfusion of 4.5±5.7 packed red blood cells was required during the index hospitalisation. During a mean follow-up of 12 months, recurrent GIB after TAVI was detected in 32% of patients with Heyde syndrome. In contrast only 18% of patients with GIB unrelated to angiodysplasia (Non-Heyde) had recurrent GIB after TAVI. In patients diagnosed with Heyde syndrome and recurrent GIB after TAVI the rate of residual mild or moderate paravalvular regurgitation was higher compared to those with an unremarkable course (73% vs. 37%, p=0.045). Figure 1. 1-year Follow-Up Conclusions A relevant number of patients presenting for treatment of AS can be diagnosed with Heyde syndrome. In these patients TAVI can be successfully performed with moderate incidence of periprocedural bleeding complications but significant transfusion rates. Regardless of successful treatment of AS, recurrent GIB was detected in a significant number of Heyde patients during follow-up. The possible association with residual paravalvular regurgitation requires further investigation to improve treatment options in patients with Heyde syndrome.

Objective In patients with suspected coronary artery disease (CAD) and intermediate pretest probability non-invasive stress-testing is recommended in current guidelines. However, sensitivity and specificity of these tests are limited. We aimed to investigate the additional diagnostic value of high-sensitivity troponin I concentrations measured before and after stress-testing. Methods We included patients undergoing non-invasive stress-testing in a prospective cohort study. All patients provided written informed consent, were at least 18 years old and underwent either stress-echocardiography, stress-MRI or myocardial perfusion scintigraphy. Baseline parameters were collected by questionnaire and chart review. Blood samples were collected before, and one hour after the stress-test. Troponin was measured using the Abbott Architect high-sensitivity troponin I (hs-TnI) assay. The diagnostic performance to predict a pathological stress-test was evaluated by calculation of the area under the ROC curve (AUC) using baseline hs-TnI concentrations and the absolute change after one hour. An optimal cutoff was determined by maximization of the Youden Index. Univariate odds ratios (OR) were calculated to identify predictors for a pathological stress-test. Additionally ORs for the optimal hs-TnI cutoff were calculated in a multivarite regression with adjustment for baseline variables. Results In total 391 patients with a median age of 70 years were included. 66.8% were males, 83.4% had prevalent hypertension, 55.9% had dyslipidemia and 55.4% had a prior history of CAD. A pathological stress-test was reported in 21.5% and these patients had a higher cardiovascular risk profile, compared to patients with a non-pathological stress-test. The baseline hs-TnI concentrations were 4.7 ng/L in the overall population, 4.2 ng/L in patients with a non-pathological stress-test and 8.4 ng/L (p Conclusion In patients undergoing non-invasive stress-testing, hs-TnI concentrations did not significantly change one hour after exercise. However, an elevated troponin concentration is an independent predictor for a pathological stress-test.

Background The recently released fourth version of the Universal Definition of Myocardial Infarction (UDMI) introduced substantial changes such as the implementation of the categories acute and chronic myocardial injury. It further recommends the use of sex-specific troponin cut-offs and consideration of absolute rather than relative changes of troponin concentrations for diagnosis of myocardial infarction (MI). Our aim was to apply the updated UDMI in patients with suspected MI to investigate its effect on diagnosis and prognosis. Methods We included 2'304 patients presenting to the emergency department with suspected MI. The final diagnosis was first adjudicated according to the 3rd UDMI by two physicians in a blinded fashion using all available medical records, laboratory findings including high-sensitivity troponin T results as well as clinical and imaging findings. Thereafter all patients were re-adjudicated based on the 4th UDMI, again all available information was used. Included patients were followed up to 4 years to assess all-cause mortality, incident nonfatal MI, revascularization and rehospitalization. Hazard ratios (HR) were calculated to investigate the effect of the diagnoses based on the 4th UDMI on prognosis. Results Out of 2'304 included patients, 708 got reclassified by the 4th UDMI. 442 (19.2%) were diagnosed as having MI compared to 504 (21.9%) based on the 3rd UDMI. Out of 1'862 non-MI patients, 74 (3.97%) patients had acute and 583 (31.3%) chronic myocardial injury (Figure 1). Patients with acute or chronic injury were older, more often female and had worse renal function than other non-MI patients. The most common causes for acute myocardial injury were heart failure, pulmonary embolism and takotsubo cardiomyopathy. For chronic myocardial injury hypertension, heart failure and non-obstructive coronary artery disease were the most frequent reasons. In cox regression analyses unadjusted HR for all-cause mortality in patients with acute or chronic myocardial injury was considerably higher when compared to patients with non-cardiac chest pain (HR 13.2 (confidence interval (CI) 6.7–26.3) (p Figure 1. Re-adjudication Conclusion By introducing the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify non-MI patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in this heterogeneous population. Prevention strategies for this specific population are yet to be investigated.

Background The numbers of patients presenting to emergency departments with suspected acute myocardial infarction (AMI) are increasing worldwide. The use of point of care (POC) troponin assays with an increased sensitivity – equal to laboratory-based high-sensitivity immunoassays – might enable faster decision making in this high-risk population. Objective To validate a rapid diagnostic algorithm using a novel point of care (POC) high-sensitivity troponin I (hs-TnI) assay in comparison to a laboratory-based hs-TnI assay. Methods A diagnostic 0/1h algorithm for the POC hs-TnI assay (PATHFAST hs-cTnI, LSI Medience) was derived in a dataset of 669 patients with suspected AMI, aiming for a negative predictive value (NPV) ≥99.5% for rule-out and a positive predictive value (PPV) ≥75% for rule-in of non-ST-elevation myocardial infarction (NSTEMI). The performance of the developed algorithm was tested in a validation cohort of 610 patients. Diagnostic accuracy of the POC hs-TnI assay was compared to an established hs-TnI assay (Abbott ARCHITECT) using an ESC guideline-recommended 0/1h diagnostic algorithm. Results The derived 0/1h algorithm consisted of an admission POC hs-TnI Conclusion The clinical application of a 0/1h diagnostic algorithm based on a novel POC hs-TnI assay showed good diagnostic performance and was comparable to a laboratory-based hs-TnI assay. Acknowledgement/Funding German Center of Cardiovascular Research, Abbott Diagnostics, DIAneering GmbH, German Heart Foundation/ German Foundation of Heart Research

Background Classical cardiovascular risk factors (CVRF), biomarkers and genetic variation have been suggested for risk assessment of atrial fibrillation (AF). Purpose To evaluate their clinical potential, we analysed their individual and combined effectiveness in AF prediction. Methods In N=6945 individuals of the FINRISK 1997 cohort, we assessed the predictive value of CVRF, N-terminal pro B-type natriuretic peptide (NT-proBNP) and 145 recently identified single nucleotide polymorphisms (SNPs) for incident AF. Results Over a median follow-up of 17.8 years, N=551 participants (7.9%) developed AF. In multivariable-adjusted Cox proportional hazard models, NT-proBNP (hazard ratio (HR) per standard deviation (SD) 1.90, 95% confidence interval (CI): 1.71–2.11, P C-Index for AF prediction Conclusions The PRS and the established biomarker NT-proBNP predicted incident AF comparably. Both provided incremental predictive value over standard clinical variables. Further improvements for the PRS are likely with the discovery of additional SNPs. Acknowledgement/Funding European Research Council, German Ministry of Research and Education, DZHK, European Union Seventh Framework Programme, CHANCES, THL

Aims The recently released 4th version of the Universal Definition of Myocardial Infarction (UDMI) introduces an increased emphasis on the entities of acute and chronic myocardial injury. We applied the 4th UDMI retrospectively in patients presenting to the emergency department with symptoms potentially indicating myocardial infarction (MI) to investigate its effect on diagnosis and prognosis. Methods and results We included 2302 patients presenting to the emergency department with symptoms suggestive of MI. The final diagnosis was adjudicated sequentially according to the 3rd and 4th UDMI. Reclassification after readjudication was assessed. Established diagnostic algorithms for patients with suspected MI were applied to compare diagnostic accuracy. All patients were followed to assess mortality, recurrent MI, revascularization, and rehospitalization to investigate the effect of the 4th UDMI on prognosis. After readjudication, 697 patients were reclassified. Most of these patients were reclassified as having acute (n = 78) and chronic myocardial injury (n = 585). Four hundred and thirty-four (18.9%) patients were diagnosed with MI, compared with 501 (21.8%) MIs when adjudication was based on the 3rd UDMI. In the non-MI population, patients with myocardial injury (n = 663) were older, more often female and had worse renal function compared with patients without myocardial injury (n = 1205). Application of diagnostic algorithms for patients with suspected MI revealed a high accuracy after readjudication. Reclassified patients had a substantially higher rate of cardiovascular events compared with not-reclassified patients, particularly patients reclassified to the category of myocardial injury. Conclusion By accentuating the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in patients with suspected MI. Application of established diagnostic algorithms remains safe when using the 4th UDMI.

AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively.METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement (NRI). We further tested the clinical implication of statin therapy based on troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded an NRI of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and NRI increment. In individuals above 6 ng/L of troponin I, a concentration near the upper quintile in BiomarCaRE (5.9 ng/L) and JUPITER (5.8 ng/L), rosuvastatin therapy resulted in higher absolute risk reduction compared with individuals CONCLUSION: In individuals free of cardiovascular disease, the addition of troponin I to variables of established risk score improves prediction of cardiovascular death and cardiovascular disease.