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Background The gut incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide) are secreted by enteroendocrine cells following food intake leading to insulin secretion and glucose lowering. Beyond its regulatory effects in glucose metabolism activation of the GLP-1 receptor has been found to improve cardiovascular prognosis in patients with diabetes and high cardiovascular risk. The functional relevance of GIP (the other main incretin) in patients with cardiovascular disease is largely unknown. The aim of this study was to assess the predictive capacity of GIP serum levels for cardiovascular outcome in patients with acute myocardial infarction. Methods and results We investigated the predictive value of GIP serum levels at the time of hospital admission for cardiovascular prognosis in a cohort of 852 patients (67±13 years; 73% men) with acute myocardial infarction (34% STEMI, 66% NSTEMI). Kaplan-Meier curves (GIP median; cut-off: 69 pg/mL) and univariable Cox regression analyses showed that lower GIP levels were associated with an increased cardiovascular mortality (HR of logarithmized GIP values: 0.520; 95% CI: 0.30–0.90; p=0.020). After adjustment for age, sex, smoking, hypertension, hypercholesterolemia, diabetes and family history of cardiovascular disease the association between GIP levels and cardiovascular mortality remained significant with similar hazard ratios as in the univariable Cox regression model. Conclusion In summary, we found lower GIP levels to independently predict a poor cardiovascular outcome in high-risk patients with acute myocardial infarction. Future larger studies are needed to foster our understanding of the gut - heart axis as a yet fairly neglected field of system biology and to elucidate whether the GIP system might open novel therapeutic approaches for the treatment of patients with cardiovascular disease. Funding Acknowledgement Type of funding sources: None.

Background GLP-1 and GLP-2 (glucagon-like peptide-1/2) are gut derived hormones that are co-secreted from intestinal L-cells in response to food intake. While GLP-1 is known to induce postprandial insulin secretion, GLP-2 enhances intestinal nutrient absorption and is clinically used for the treatment of patients with short bowel syndrome. The relevance of the GLP-2 system for cardiovascular disease is unknown. Purpose The aim of this study was to assess the predictive capacity of GLP-2 for cardiovascular prognosis in patients with myocardial infarction. Methods Total GLP-2 levels, NT-proBNP concentrations and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of admission in 918 patients with myocardial infarction, among them 597 patients with NSTEMI and 321 with STEMI. The primary composite outcome of the study was the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (3-P-MACE) with a median follow-up of 311 days. Results Kaplan-Meier survival plots (separated by the median of GLP-2 with a cut-off value of 4.4 ng/mL) and univariable cox regression analyses found GLP-2 values to be associated with adverse outcome (logarithmized GLP-2 values HR: 2.87; 95% CI: 1.75–4.68; p Conclusions In patients admitted with acute myocardial infarction, GLP-2 levels are associated with adverse cardiovascular prognosis. This demonstrates a strong yet not appreciated crosstalk between the heart and the gut with relevance for cardiovascular outcome. Future studies are needed to further explore this crosstalk with the possibility of new treatment avenues for cardiovascular disease. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): German Society of Cardiology (DGK), German Research Foundation (DFG)

Background Cathepsin S is an extracellular matrix degradation enzyme that plays an important role in atherosclerotic cardiovascular disease by inducing vasa vasorum development and atherosclerotic plaque rupture. Purpose To determine the prognostic and reclassification value of baseline serum cathepsin S after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is a clinical guideline recommended risk score in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods Serum cathepsin S was measured by ELISA in 1,129 consecutive patients presenting with acute symptoms to the emergency department for whom a final adjudicated diagnosis of NSTE-ACS was made. All-cause mortality or all-cause death/non-fatal myocardial infarction (MI) after a median follow-up of 21 months were evaluated as the primary or secondary study endpoint, respectively. The Net Reclassification Index (NRI) estimated the reclassification predictive value for risk of each end-point of cathepsin S over the GRACE score. Results After a median follow-up of 21 months 101 (8.95%) deaths were reported. The combined endpoint of death or non-fatal MI occurred in 176 (15.6%) patients. Dose-response curve analysis adjusted for the effect of age, gender, diabetes mellitus, high-sensitivity-cardiac troponin T, high-sensitivity C-reactive protein, revascularization and index diagnosis revealed a non-linear association of continuous cathepsin S with all-cause death (P=0.036 for non-linearity; adjusted HR=1.60 for 80th vs. 20th percentiles, P=0.038) or with the combined endpoint (P=0.008 for non-linearity, adjusted HR=1.53 for 80th vs. 20th percentiles, P=0.011). Serum cathepsin S maintained its predictive value for all-cause death (adjusted HR=1.70 highest vs. lowest tertile, 95% CI 1.03–2.82, P=0.039) after adjusting for the GRACE Score. Similarly, cathepsin S predicted the combined endpoint of all-cause death or non-fatal MI (adjusted HR=1.67 highest vs. lowest tertile, 95% CI 1.15–2.42, P=0.007) independently of the GRACE Score. When cathepsin S was added over the GRACE Score it correctly reclassified risk for all-cause death in 20% of the population (P=0.004). Similarly, serum Cathepsin S conferred a significant reclassification value over the GRACE score for all-cause death or non-fatal MI in 15.9% of the population. Conclusions Serum cathepsin S is a predictor of mortality and improves risk stratification over the GRACE score in patients with NSTE-ACS. The clinical application of cathepsin S as a novel biomarker in NSTE-ACS should be further explored and validated. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Heart Foundation

Background Blood-based biomarkers may be useful in the identification of residual risk for death or acute myocardial infarction (AMI) in patients with a previous acute coronary syndrome. Cathepsin S (CTSS) is a lysosomal cysteine protease with potent elastolytic and collagenolytic activity, which plays an important role in cardiovascular disease through extracellular matrix degradation, vasa vasorum development and atherosclerotic plaque rupture. The aim of the present study was to determine the prognostic and reclassification value of baseline circulating levels of CTSS after adjustment for the Global Registry of Acute Coronary Events (GRACE) score, which is widely recommended for risk stratification in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Methods CTSS was measured in blood samples collected from 1,129 consecutive patients with adjudicated NSTE-ACS presenting at an acute chest pain unit for evaluation of a possible acute coronary syndrome. Cardiovascular (CV) death and a composite of all-cause mortality and AMI were evaluated as the primary and secondary endpoints of the study, respectively. The additive prognostic value of CTSS over the GRACE score was estimated by the Net Reclassification Index (NRI) that examines the net upward and downward reclassification into correct pre-defined risk categories. Results After a median follow-up of 21 months, 101 (8.95%) deaths were reported, of which 63 (5.6%) were of cardiac origin. The combined endpoint occurred in 176 (15.6%) patients. Patients with CTSS in the highest tertile presented the greatest risk for all-cause mortality (HR=1.84 for highest versus lowest tertile of CTSS distribution, 95% CI 1.1–3.08, P=0.02) and CV death (HR=2.5 for highest versus lowest tertile of CTSS distribution, 95% CI 1.24–5.05, P=0.011) after adjustment for age, gender, diabetes mellitus, hs-cTnT, hsCRP, revascularization and index diagnosis. Similarly, CTSS was associated with increased risk of cardiovascular death after adjusting for the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=2.34, 95% CI 1.18–4.64, P=0.015). Further, CTSS predicted the combined endpoint of all-cause death or non-fatal MI independently of the GRACE Score (adjusted HR for highest versus lowest tertile of CTSS distribution=1.67, 95% CI 1.15–2.42, P=0.007). When CTSS was added over the GRACE Score, it conferred significant reclassification value for CV death (NRI=21.4%, P=0.008). Similarly, CTSS correctly reclassified risk for all-cause death or non-fatal MI (P=0.006) in 15.9% of the population. Conclusions Circulating CTSS predicts mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score recommended by clinical guidelines. The clinical application of CTSS as a novel biomarker in NSTE-ACS should be further explored and validated.

Aims The feasibility, efficacy and safety of ESC 0/1- and 0/3-hour algorithms using high-sensitivity troponin T (hsTnT) were evaluated in an all-comer cohort with suspected acute coronary syndrome, based on a broad spectrum of symptoms. Methods During 12 months, 2,525 eligible patients were enrolled. In a pre-implementation period of 6 months, prevalence of protocols, disposition, lengths of emergency department (ED) stay and treatments were registered. Implementation of ESC 0/1-hour protocol was monitored for another 6 months. Primary endpoints comprised the change of diagnostic protocols, and all-cause mortality at 30 days following direct discharge from the ED. Secondary endpoints included length of ED stay, hospital discharge, and 1-year mortality. Results Use of the ESC 0/1-hour algorithm increased by 270% at the cost of the standard 0/3-hour protocol. Median follow-up times were 400 (316–459) days, with vital status available for 98.7%. After rule-out (1,588 patients), 1,309 patients (76.1%) were discharged directly from the ED, with an all-cause mortality of 0.08% at 30 days (1 death due to lung cancer). Median lengths of stay were 2.9 (1.9–3.8) and 3.2 (2.7–4.4) hours using a single hsTnT below limit of detection (LoD) (5 ng/L) at presentation and the ESC 0/1-hour algorithm, respectively, as compared to 5.3 (4.7–6.5) hours using the ESC 0/3-hour rule-out protocol. Discharge rates increased from 53.9% to 62.8% (p Mortality by diagnostic rule Conclusion Implementation of the ESC 0/1-hour algorithm seems feasible and safe. It is associated with shorter ED stays than the ESC 0/3-hour protocol and a further increase of discharge rates. Acknowledgement/Funding Roche Diagnostics International Ltd.

Background Accelerated diagnostic algorithms using high-sensitivity troponin (hsTn) assays in suspected acute coronary syndrome (ACS) are regarded as particularly beneficial to expedite diagnosis and safe discharge of low risk patients in crowded emergency departments (ED). However, little is known about potential negative effects of crowding on implementation and efficacy of fast diagnostic protocols. We studied the effects of crowding on outcomes and process times in patients admitted with suspected ACS using fast diagnostic protocols. Methods A total of 2,525 consecutive patients were evaluated during 12 months using 2015 ESC guideline recommended fast protocols. Crowding was defined as mismatch between patient visits and monitoring capacities as well as effective physician time per case. Electronic time-stamps were available for length of ED stay, timing of hsTnT measurements, time intervals between measurements, and laboratory turn-around-times (TAT). Patients were followed up for all-cause mortality at 30 days and 1 year. Results Crowding was associated with increasing intervals between blood samples from 98 to 107 minutes (p=0.008), increasing median TAT from 53 to 57 minutes (p Conclusion Time-dependent processes are prolonged in a crowded ED diminishing some positive effects of fast diagnostic protocols for evaluation of suspected ACS. Acknowledgement/Funding Roche Diagnostics International Ltd.

Background Patients with unstable angina (UA) are regarded to be at low risk for future coronary events. Guidelines discourage routine coronary angiography and recommend early discharge after individualized risk stratification. The relative value of clinical risk indicators as compared to cardiac troponin (cTn) alone is unsettled in the era of high-sensitivity cardiac troponin (hsTn) assays. Purpose We aimed to investigate the clinical characteristics, therapies and outcomes of UA patients with different hsTnT concentrations. Methods During 12 months, 2,525 patients were enrolled. UA was defined as unstable symptoms and either undetectable ( Results A total of 280 patients (11.1%) received a diagnosis of UA. Mortality rates at 12 months were 0%, 1.9% and 6.9% in presence of undetectable, normal and stable elevated hsTnT. Elevated hsTnT >99th percentile but not unstable symptoms carried an independent 3.25-fold (1.78–5.93) higher risk for all-cause death after adjustment for other clinical risk indicators or the GRACE score. Utilization of guideline recommended therapies was high albeit lower than for non-ST-elevation myocardial infarction (NSTEMI). Significantly fewer patients with UA received dual antiplatelet therapy (DAPT, odds ratio (OR): 0.51 [95% CI: 0.44–0.59], p Conclusions The current dichotomization of patients into UA and NSTEMI is no longer appropriate. Additional risk stratification seems warranted including the presence and magnitude of hsTn concentration and additional risk indicators. Acknowledgement/Funding Research Grant by Roche Diagnostics

Aims Glucagon-like peptide 1 (GLP-1) is a gut incretin hormone inducing post-prandial insulin secretion. Glucagon-like peptide 1 levels were recently found to be increased in patients with acute myocardial infarction. Glucagon-like peptide 1 receptor agonists improve cardiovascular outcomes in patients with diabetes. The aim of this study was to assess the predictive capacity of GLP-1 serum levels for cardiovascular outcome in patients with myocardial infarction. Methods and results In 918 patients presenting with myocardial infarction [321 ST-segment elevation myocardial infarction and 597 non-ST-segment elevation myocardial infarction (NSTEMI)] total GLP-1, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and the Global Registry of Acute Coronary Events (GRACE) score were assessed at time of hospital admission. The primary composite outcome of the study was the first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Kaplan–Meier survival plots and univariable Cox regression analyses found GLP-1 to be associated with adverse outcome [hazard ratio (HR) of logarithmized GLP-1 values: 6.29, 95% confidence interval (CI): 2.67–14.81; P < 0.0001]. After further adjustment for age, sex, family history of cardiovascular disease, smoking, diabetes, hypertension, hypercholesterinaemia, glomerular filtration rate (GFR) CKD-EPI, hs-CRP, hs-Troponin T, and NT-proBNP levels the HR remained significant at 10.98 (95% CI: 2.63–45.90; P = 0.0010). Time-dependent receiver operating characteristic curve analyses illustrated that GLP-1 levels are a strong indicator for early events. For events up to 30 days after admission, GLP-1 proved to be superior to other biomarkers including hs-Troponin T, GFR CKD-EPI, hs-CRP, and NT-proBNP. Adjustment of the GRACE risk estimate by addition of GLP-1 increased the area under the receiver operating characteristic curve over time in NSTEMI patients. Conclusion In patients hospitalized for myocardial infarction, GLP-1 levels are associated with cardiovascular events.