Relationship between plasma Neuregulin-1 and cardiac function in patients with ST-elevation myocardial infarction.

BACKGROUND: Neuregulin-1 (NRG-1) is a stress-mediated transmembrane growth factor. Reduced myocardial damage and higher NRG-1 levels upon treatment with remote ischemic conditioning (RIC) has been described in rats. However, the role of NRG-1 in patients with acute myocardial infarction (MI) is unknown. Thus, we conducted a post hoc analysis of a randomized controlled trial that tested RIC in patients with MI scheduled for primary percutaneous coronary intervention (PCI). METHODS: Blood was drawn from 30 patients before RIC/PCI, within 1 hour, 4 days and 1 month later. Median left ventricular ejection fraction (LVEF) in the overall study population following MI was 48.5%. RESULTS: NRG-1 plasma levels decreased significantly following PCI/RIC and remained decreased up to 1 month following MI (p < 0.0001). We observed no association of NRG-1 with other variables, including total ischemic time, LVEF or RIC. CONCLUSIONS: Thus, we identified NRG-1 may be independently affected by MI. However, further large clinical trials are warranted to clarify this hypothesis.

Role of Cardiac Biomarkers in Epidemiology and Risk Outcomes.

BACKGROUND: The use of biomarkers associated with cardiovascular disease (CVD) is established for diagnostic purposes. Cardiac troponins, as specific markers of myocardial injury, and natriuretic peptides, reflecting myocardial dilation, are routinely used for diagnosis in clinical practice. In addition, a substantial body of research has shed light on the ability of biomarkers to reflect the risk of future major cardiovascular events. Among biomarkers, troponin and members of the natriuretic peptide family have been investigated extensively in the general population, in those at higher risk, and in patients with known CVD. Both biomarkers have been shown to contribute substantially to statistical models describing cardiovascular risk, in addition to and independently of important clinical characteristics. The more precise identification of individuals at risk by appropriate use of biomarkers might lead to an earlier initiation of preventive therapies and potentially avoid significant events. CONTENT: We summarize the current evidence concerning risk prediction using cardiac biomarkers at different stages in the development of CVD and provide examples of observational studies and large-scale clinical trials testing such application. Beyond the focus on troponin and natriuretic peptides, we also discuss other important and emerging biomarkers in the field with potential for such application, including growth differentiation factor-15, soluble ST2 (alias for IL1RL1 [interleukin 1 receptor like 1), and galectin-3. SUMMARY: Incorporating biomarkers in risk prediction models might allow more precise identification of individuals at risk. Among the various biomarkers, cardiac troponin appears to be the most promising for prediction of future cardiovascular events in a wide variety of patient populations.

Diagnostic Validation of a High-Sensitivity Cardiac Troponin I Assay.

BACKGROUND: Emergency departments worldwide are increasingly adopting rapid diagnosis of patients with suspected myocardial infarction (MI) based on high-sensitivity troponin. We set out to assess the diagnostic accuracy of a high-sensitivity cardiac troponin I (hs-cTnI) assay in a prospective study. METHODS: In a cohort study including 1800 patients presenting with suspected acute MI, we developed and temporally validated a 0/1 h diagnostic algorithm using the Siemens Atellica IM hs-cTnI assay. The algorithm was established in the first 928 patients and validated in the following 872 patients. RESULTS: The derived algorithm consisted of a baseline rule-out of non-ST-segment elevation MI using a cutoff <3 ng/L in patients with symptom onset ≥3 h or an admission troponin I level <6 ng/L with a Δ change of <3 ng/L from 0 h to 1 h. For rule-in, an admission troponin I level ≥120 ng/L or an increase within the first hour ≥12 ng/L was required. Application of the algorithm to the validation cohort showed a negative predictive value of 99.8% (95% CI, 98.7%-100.0%), sensitivity of 99.1% (95% CI, 95.1%-100.0%), and 48.3% of patients ruled out, whereas 15.1% were ruled in with a positive predictive value of 68.0% (95% CI, 59.1%-75.9%) and specificity of 94.4% (95% CI, 92.5%-96.0%). The diagnostic performance was comparable to guideline-recommended application of an established hs-cTnI assay in a rapid 0/1 h strategy. CONCLUSIONS: The Siemens hs-cTnI assay is well suited for application in rapid diagnostic stratification of patients with suspected MI. STUDY REGISTRATION: www.clinicaltrials.gov (NCT02355457).

Immature cell fractions after cessation of chronic P2Y12-inhibition in patients with coronary artery diseases.

Changes in circulating cell populations may promote ischemic events that occur soon after discontinuation of P2Y12-inhibition. The aim of the study was to track the course of thrombopoietic and erythropoietic cells in patients with coronary artery diseases (CAD) after planned and physician-driven cessation of chronic P2Y12-inhibition (clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID). Cell fractions were determined in 62 patients at baseline (the last day of P2Y12-inhibitor intake), on day-10, day-30, and day-180 thereafter. Immature platelet fraction (IPF), immature reticulocyte fraction (IRF), reticulocyte hemoglobin content (Ret-Hb) and red blood cell count (RBC) significantly increased from baseline to day-180 (IPF: p = .003; IRF: p = .013; Ret-Hb: p < .001; RBC: p = .044). Platelet count, leucocyte count and immature granulocyte fraction did not change over time (p = .561, p = .869, and p = .161, respectively). Fibrinogen levels significantly declined over time (p = .011), thrombopoietin levels increased in a non-significant manner (p = .379). We did not observe any significant interaction with choice of P2Y12-inhibitor, therefore suggesting a drug class-effect. Our data shows, that discontinuation of dual antiplatelet therapy is associated with raised thrombopoietic and erythropoietic activity in the bone marrow, without significant upregulation of thrombopoietin. This provides further evidence for a direct stimulation of precursor cells by P2Y12-inhibitors.

Effect of marathon and ultra-marathon on inflammation and iron homeostasis.

The physiological response to high-level endurance exercise, such as running a marathon, poses several beneficial but also potentially harmful metabolic changes. The objective of this study was to determine the impact of marathon (M) and ultra-marathon (UM) on inflammation and iron homeostasis in paired samples. Fifteen well-trained, non-professional endurance athletes (14 males, 1 female) performed both a 130 km ultra-marathon and a traditional 42.195 km marathon. We determined markers of inflammation and iron homeostasis before, immediately after, and within 5 days after finishing each run, respectively. Biomarkers of inflammation (leucocytes, neutrophil granulocytes, monocytes, and c-reactive protein [CRP]) increased significantly after both marathon and ultra-marathon with higher levels of CRP after ultra-marathon compared with marathon both immediately after the race (18.15 ± 12.41 vs 5.58 ± 9.65 mg/L, P < .001) and at follow-up (15.67 ± 16.97 vs 7.19 ± 7.75 mg/L, P = .045) Concentrations of ferritin also increased significantly after both races and remained high at follow-up. Higher levels of ferritin immediately after the race (111.5 ± 103.2 vs 84.8 ± 86.3, P = .001) and at follow-up (102.7 ± 79.5 vs 74.6 ± 65.6, P = .001) were found in ultra-marathon finishers. The observed increase of serum iron and transferrin saturation (TSAT) after marathon and the decrease of serum iron and TSAT after ultra-marathon resulted in a significant absolute difference between the two races. The present data suggest a higher degree of inflammation after ultra-marathon compared with marathon. Markers of iron homeostasis also showed different response patterns with regard to running distance.

Meta-Analysis of Cell Therapy Studies in Heart Failure and Acute Myocardial Infarction.

Heart failure (HF) is one of the leading causes of death worldwide and has reached epidemic proportions in most industrialized nations. Despite major improvements in the treatment and management of the disease, the prognosis for patients with HF remains poor with approximately only half of patients surviving for 5 years or longer after diagnosis. The poor prognosis of HF patients is in part because of irreparable damage to cardiac tissue and concomitant maladaptive changes associated with the disease. Cell-based therapies may have the potential to transform the treatment and prognosis of HF through regeneration or repair of damaged cardiac tissue. Accordingly, numerous phase I and II randomized clinical trials have tested the clinical benefits of cell transplant, mostly autologous bone marrow-derived mononuclear cells, in patients with HF, ischemic heart disease, and acute myocardial infarction. Although many of these trials were relatively small, meta-analyses of cell-based therapies have attempted to apply rigorous statistical methodology to assess the potential clinical benefits of the intervention. As a prelude to larger phase III trials, meta-analyses, therefore, remain the obvious means of evaluating the available clinical evidence. Here, we review the different meta-analyses of randomized clinical trials that evaluate the safety and potential beneficial effect of cell therapies in HF and acute myocardial infarction spanning nearly 2 decades since the first pioneering trials were conducted.

The association of P2Y12 inhibitors with pro-coagulatory extracellular vesicles and microRNAs in stable coronary artery disease.

Extracellular vesicles (EV) act as a cellular communication tool by carrying lipids, proteins and micro RNA (miR) between cells, thereby playing a pivotal role in thromboembolic processes. The effect of P2Y12 inhibitors on pro-coagulatory, phosphatidylserine (PS)-expressing EV has been investigated previously, but only in vitro or during confounding clinical conditions, such as acute coronary syndrome. Hence, we enrolled 62 consecutive patients 12 month after percutaneous coronary intervention and stent implantation and consequent treatment with dual-antiplatelet therapy consisting of low-dose aspirin and P2Y12 inhibitors. Blood for platelet function testing and EV and miR measurements was taken on the last day of P2Y12 inhibitor intake (baseline, on-treatment) and 10, 30 and 180 days thereafter (off-treatment). We did not observe any influence of P2Y12 inhibitors on the levels of PS-EV or EV sub-population from platelets, erythrocytes, monocytes or endothelial cells, respectively. There was no relationship between platelet function and EV levels in plasma. However, the association of miR-21 and miR-150 with platelet EVs was significantly different between on- and off-treatment measurements. Hence, our study suggests no influence of P2Y12 inhibition on the count of EVs in plasma, but on the potential cargo of platelet-derived EV.

Course of platelet miRNAs after cessation of P2Y12 antagonists.

BACKGROUND: Circulating platelet micro-RNAs (miRNAs) may be used to monitor platelet function during dual antiplatelet therapy (DAPT). Aim of the study was to measure plasma levels of specific miRNAs (miRNA-223, -150, -21 and -126) after physician-driven cessation of chronic P2Y12 inhibition and to study differences in the expression levels of these miRNAs between the different oral P2Y12 inhibitors clopidogrel, prasugrel and ticagrelor, respectively. DESIGN: Patients with coronary artery disease (CAD) on DAPT maintenance dose (including aspirin 100 mg OD, plus clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID) were prospectively enrolled before cessation of the P2Y12-inhibitor therapy. MiRNA-223, -150, -21 and -126 were determined at baseline (=last day of P2Y12-inhibitor intake) and 10, 30 and 180 days thereafter. RESULTS: Cessation of P2Y12-inhibitor therapy did not significantly change miRNA levels. However, in ticagrelor-treated patients, miRNA levels were significantly increased at baseline (miRNA-223 and -21), day 10 (miRNA-223, -150, -21, -126) and day 30 (miRNA-223, -150, -21, -126) as compared to prasugrel, and at day 10 (miRNA-150 and -21) and day 30 (miRNA-150) as compared to clopidogrel (all P < 0.05). At day 180, only miRNA-126 levels differed significantly with respect to the P2Y12 inhibitor used (P < 0.05). After adjustment for confounders, choice of P2Y12-inhibitor was the strongest predictor of miRNA levels (P < 0.001), while cessation of P2Y12-inhibitor therapy did not significantly impact miRNA levels. CONCLUSION: In patients with CAD, ticagrelor intake is associated with increased levels of platelet miRNAs as compared to clopidogrel and prasugrel. Platelet miRNAs are not useful to monitor platelet function after cessation of P2Y12 inhibitors.

Impact of Quantitative ST-T Analysis in Patients with Suspected Myocardial Infarction Presenting with Right Bundle Branch Block.

BACKGROUND: While left bundle branch block (LBBB) is a well-known risk feature in patients with acute myocardial infarction, and a rapid invasive management is recommended, data supporting this strategy for patients with right bundle branch block (RBBB) is less robust. METHODS: In total, 2139 patients with suspected ST-elevation myocardial infarction (STEMI) were triaged to acute coronary angiography based on a prehospital 12-lead electrocardiogram (ECG). Sensitivity and specificity for STEMI-ECG criteria were compared in RBBB and non-BBB patients. Adjusted hazard ratios for 1-year overall mortality were computed. RESULTS: STEMI was adjudicated in 1832/2139 (85.6%) of all patients and in 102/117 (87.2%) of RBBB patients. ST-segment deviation followed typical ST-T patterns in most RBBB patients. Of 17 RBBB patients without significant ST changes, STEMI was adjudicated in 14 (82%). Diagnostic accuracy of STEMI criteria was comparable in RBBB and non-RBBB patients for inferior (sensitivity: 51.1% vs 59.1%, P = .14; specificity: 66.7% vs 52.1%, P = .33) and anterior STEMI (sensitivity: 35.2% vs 36.6%, P = .80; specificity: 58.3% vs 49.5%, P = .55). Diagnostic performance was lower for lateral STEMI in RBBB patients (sensitivity: 14.8% vs 4.4%, P = .001; specificity: 75.0% vs 98.4%, P < .001). Patients with RBBB had higher 1-year mortality compared with non-BBB patients (hazard ratio 2.3%; 95% confidence interval, 1.25-4.21. CONCLUSION: ECG criteria used for detection of STEMI showed comparable diagnostic accuracy in RBBB and non-BBB patients. However, STEMI was frequently present in RBBB patients not fulfilling diagnostic ECG criteria. RBBB patients showed poorer outcome after 1 year. Consequently, the presence of RBBB in suspected STEMI cases signifies a high-risk feature, aligning with established guidelines.

Oral anticoagulation in patients with left ventricular thrombus - a systematic review and meta-analysis.

AIMS: Direct oral anticoagulants (DOACs) are increasingly used off-label to treat patients with left ventricular thrombus (LVT). We analyzed available meta-data comparing DOACs and vitamin K antagonists (VKAs) for efficacy and safety. METHODS: We conducted a systematic search and meta-analysis of observational and randomized data comparing DOACs versus VKAs in patients with LVT. Endpoints of interest were stroke or systemic embolism, thrombus resolution, all-cause death, and a composite bleeding endpoint. Estimates were pooled using a random-effect model meta-analysis, and their robustness was investigated using sensitivity and influential analyses. RESULTS: We identified 22 articles (18 observational studies, 4 small randomized clinical trials) reporting on a total of 3,587 patients (2,489 VKA vs. 1,098 DOAC therapy). The pooled estimates for stroke or systemic embolism (OR 0.81; 95% CI [0.57, 1.15]) and thrombus resolution (OR 1.12; 95% CI [0.86; 1.46]) were comparable, and there was low heterogeneity overall across the included studies. DOAC use was associated with lower odds of all-cause death (OR 0.65; 95%CI [0.46; 0.92]) and a composite bleeding endpoint (OR 0.67; 95%CI [0.47; 0.97]). A risk of bias was evident particularly for observational reports, with some publication bias suggested in funnel plots. CONCLUSION: In this comprehensive analysis of mainly observational data, the use of DOACs was not associated with a significant difference in stroke or systemic embolism, or thrombus resolution compared to VKA therapy. The use of DOACs was associated with a lower rate of all-cause death and fewer bleeding events. Adequately sized randomized clinical trials are needed to confirm these findings, which could allow a wider adoption of DOACs in patients with LVT.

The LIPL study: Postprandial lipid profile, inflammation, and platelet activity in patients with chronic coronary syndrome.

Background and aims: It is suggested that the changes in atherosclerosis happen mainly under the influence of non-fasting lipids. To date, the studies in the postprandial state were primarily performed on healthy subjects. This exploratory, cross-sectional study investigates the change in lipid profile, inflammation, and platelet activation in patients with different cardiovascular risk profiles in the postprandial state. Methods: The studied population consists of 66 patients with different cardiovascular risks: patients with a history of the chronic coronary syndrome (CCS) and diabetes mellitus type 2 (DM2) (n = 20), CCS without DM2 (n = 25), and a healthy control group (n = 21). Lipid variables and markers of platelet function and inflammation were assessed during the fasting state and three and 5 h after a standardized fat meal using a standardized oral fat tolerance test (OFTT), a milkshake with 90 g of fat. Results: Patients with CCS and DM2 were significantly older and had the highest BMI. All patients with CCS were on acetylsalicylic acid, and 95% of CCS patients were on high-dose statins. The absolute leukocyte and neutrophile count increased significantly in the control group during the OFTT in comparison to CCS subjects. There was a significant decrease of HDL and increase of triglycerides during the OFTT, however with no difference between groups. There was no difference in the change of platelet activity between all groups. Conclusion: This study showed that OFTT leads to an increased postprandial inflammation response in healthy group compared to CCS ± DM2 while there was no change in lipid profile and platelet activity.

Role of Copeptin and hs-cTnT to Discriminate AHF from Uncomplicated NSTE-ACS with Baseline Elevated hs-cTnT-A Derivation and External Validation Study.

BACKGROUND: In light of overlapping symptoms, discrimination between non-ST-elevation (NSTE) acute coronary syndrome (ACS) and acute heart failure (HF) is challenging, particularly in patients with equivocal clinical presentation for suspected ACS. We sought to evaluate the diagnostic and prognostic properties of copeptin in this scenario. METHODS: Data from 1088 patients from a single-center observational registry were used to test the ability of serial high sensitivity cardiac troponin T (hs-cTnT)-compared to copeptin, or a combination of copeptin with hs-cTnT-to discriminate acute HF from uncomplicated non-ST-elevation myocardial infarction (NSTEMI) and to evaluate all-cause mortality after 365 days. Patients with STEMI, those with unstable angina and either normal or undetectable hs-cTnT concentrations were excluded. The findings were validated in an independent external NSTE-ACS cohort. RESULTS: A total of 219 patients were included in the analysis. The final diagnosis was acute HF in 56 and NSTE-ACS in 163, with NSTEMI in 78 and unstable angina having stable elevation of hs-cTnT >ULN in 85. The rate of all-cause death at 1 year was 9.6% and occurred significantly more often in acute HF than in NSTE-ACS (15 vs. 6%, p < 0.001). In the test cohort, the area under the receiver operator curve (AUC) for the discrimination of acute HF vs. NSTE-ACS without HF was 0.725 (95% confidence interval [CI] 0.625-0.798) for copeptin and significantly higher than for hs-cTnT at 0 h (AUC = 0.460, 0.370-0.550) or at 3 h (AUC = 0.441, 0.343-0.538). Copeptin and hs-cTnT used either as continuous values or at cutoffs optimized to yield 90% specificity for acute HF were associated with significantly higher age- and sex-adjusted risk for all-cause mortality at 365 days. The findings from the test cohort were consistently replicated in the independent external NSTE-ACS validation cohort. CONCLUSIONS: High concentrations of copeptin in patients with suspected NSTE-ACS and equivocal clinical presentation suggest the presence of acute HF compared to uncomplicated NSTE-ACS and are associated with higher rates of all-cause death at 365 days.

Rising and Falling High-Sensitivity Cardiac Troponin in Diagnostic Algorithms for Patients With Suspected Myocardial Infarction.

Background High-sensitivity cardiac troponin (hs-cTn)-based diagnostic algorithms are recommended for the management of patients with suspected myocardial infarction (MI) without ST elevation. Although mirroring different phases of myocardial injury, falling and rising troponin patterns (FPs and RPs, respectively) are equally considered by most algorithms. We aimed to compare the performance of diagnostic protocols for RPs and FPs, separately. Methods and Results We pooled 2 prospective cohorts of patients with suspected MI and stratified patients to stable, FP, and RP during serial sampling separately for hs-cTnI and hs-cTnT and applied the European Society of Cardiology 0/1- and 0/3-hour algorithms comparing the positive predictive values to rule in MI. Overall, 3523 patients were included in the hs-cTnI study population. The positive predictive value for patients with an FP was significantly reduced compared with patients with an RP (0/1-hour: FP, 53.3% [95% CI, 45.0-61.4] versus RP, 76.9 [95% CI, 71.6-81.7]; 0/3-hour: FP, 56.9% [95% CI, 42.2-70.7] versus RP, 78.1% [95% CI, 74.0-81.8]). The proportion of patients in the observe zone was larger in the FP using 0/1-hour (31.3% versus 55.8%) and 0/3-hour (14.6% versus 38.6%) algorithms. Alternative cutoffs did not improve algorithm performances. Compared with stable hs-cTn, the risk for death or MI was highest in those with an FP (adjusted hazard ratio [HR], hs-cTnI 2.3 [95% CI, 1.7-3.2]; RP adjusted HR, hs-cTnI 1.8 [95% CI, 1.4-2.4]). Findings were similar for hs-cTnT tested in 3647 patients overall. Conclusions The positive predictive value to rule in MI by the European Society of Cardiology 0/1- and 0/3-hour algorithms is significantly lower in patients with FP than RP. These are at highest risk for incident death or MI. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02355457, NCT03227159.

Prognostic utility of a multi-biomarker panel in patients with suspected myocardial infarction.

BACKGROUND: The accurate identification of patients with high cardiovascular risk in suspected myocardial infarction (MI) is an unmet clinical need. Therefore, we sought to investigate the prognostic utility of a multi-biomarker panel with 29 different biomarkers in in 748 consecutive patients with symptoms indicative of MI using a machine learning-based approach. METHODS: Incident major cardiovascular events (MACE) were documented within 1 year after the index admission. The selection of the best multi-biomarker model was performed using the least absolute shrinkage and selection operator (LASSO). The independent and additive utility of selected biomarkers was compared to a clinical reference model and the Global Registry of Acute Coronary Events (GRACE) Score, respectively. Findings were validated using internal cross-validation. RESULTS: Median age of the study population was 64 years. At 1 year of follow-up, 160 cases of incident MACE were documented. 16 of the investigated 29 biomarkers were significantly associated with 1-year MACE. Three biomarkers including NT-proBNP (HR per SD 1.24), Apolipoprotein A-I (Apo A-I; HR per SD 0.98) and kidney injury molecule-1 (KIM-1; HR per SD 1.06) were identified as independent predictors of 1-year MACE. Although the discriminative ability of the selected multi-biomarker model was rather moderate, the addition of these biomarkers to the clinical reference model and the GRACE score improved model performances markedly (∆C-index 0.047 and 0.04, respectively). CONCLUSION: NT-proBNP, Apo A-I and KIM-1 emerged as strongest independent predictors of 1-year MACE in patients with suspected MI. Their integration into clinical risk prediction models may improve personalized risk stratification. Prognostic utility of a multi-biomarker approach in suspected myocardial infarction. In a cohort of 748 patients with symptoms indicative of myocardial infarction (MI) to the emergency department, we measured a 29-biomarker panel and performed regressions, machine learning (ML)-based variable selection and discriminative/reclassification analyses. We identified three biomarkers as top predictors for 1-year major adverse cardiovascular events (MACE). Their integration into a clinical risk prediction model and the Global Registry of Acute Coronary Events (GRACE) Score allowed for marked improvement in discrimination and reclassification for 1-year MACE. Apo apolipoprotein; CRP C-reactive protein; CRS clinical risk score; ECG electrocardiogram; EN-RAGE extracellular newly identified receptor for advanced glycation end-products binding protein; FABP fatty acid-binding protein; GS Grace Score; hs-cTnI high-sensitivity cardiac troponin I; KIM-1 kidney injury molecule-1; LASSO least absolute shrinkage and selection operator; MACE major adverse cardiovascular events; MI myocardial infarction; NRI net reclassification improvement; NT-proBNP N-terminal prohormone of brain natriuretic peptide.

Long-term outcome of patients presenting with myocardial injury or myocardial infarction.

AIMS: Patients with acute or chronic myocardial injury are frequently identified in the context of suspected myocardial infarction (MI). We aimed to investigate their long-term follow-up. METHODS AND RESULTS: We prospectively enrolled 2714 patients with suspected MI and followed them for all-cause mortality and a composite cardiovascular endpoint (CVE; cardiovascular death, MI, unplanned revascularization) for a median of 5.1 years. Final diagnoses were adjudicated by two cardiologists according to the Fourth Universal Definition of MI, including 143 (5.3%) ST-elevation MI, 236 (8.7%) non-ST-elevation MI (NSTEMI) Type 1 (T1), 128 (4.7%) NSTEMI T2, 86 (3.2%) acute and 677 (24.9%) with chronic myocardial injury, and 1444 (53.2%) with other reasons for chest pain (reference). Crude event rates per 1000 patient-years for all-cause mortality were highest in patients with myocardial injury (81.6 [71.7, 92.3]), and any type of MI (55.9 [46.3, 66.7]), compared to reference (12.2 [9.8, 15.1]). Upon adjustment, all diagnoses were significantly associated with all-cause mortality. Moreover, patients with acute (adj-HR 1.92 [1.08, 3.43]) or chronic (adj-HR 1.59 [1.16, 2.18]) myocardial injury, and patients with NSTEMI T1 (adj-HR 2.62 [1.85, 3.69]) and ST-elevation MI (adj-HR 3.66 [2.41, 5.57]) were at increased risk for cardiovascular events. CONCLUSION: Patients with myocardial injury are at a similar increased risk for death and cardiovascular events compared to patients with acute MI. Further studies need to determine appropriate management strategies for patients with myocardial injury. REGISTRATION: Clinicaltrials.gov (NCT02355457).

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus.

AIMS: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. METHODS AND RESULTS: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81). CONCLUSION: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.

In this work, the role of cardiac biomarkers measured from blood to predict cardiovascular events and death is tested in individuals of the general population and particularly in those with known diabetes. The work is based on a cooperation of different population studies across Europe and includes more than 90 000 individuals, with more than 6000 having diabetes. We could demonstrate that the determination of three cardiac biomarkers helps to identify individuals at highest risk for cardiovascular events (e.g. myocardial infarction or stroke) and death, despite accounting for known cardiovascular risk factors in these individuals. Therefore, these biomarkers should be considered for routine risk assessment for cardiovascular diseases and could improve the early identification of high-risk individuals, consequently leading to an earlier initiation of preventive therapies.

Association of Plasma Methylglyoxal Increase after Myocardial Infarction and the Left Ventricular Ejection Fraction.

Background: Preclinical studies suggest that methylglyoxal (MG) increases within the myocardium upon acute myocardial infarction (AMI) and thereafter contributes to adverse postinfarct remodeling. The aims of this study were to test whether MG increases in plasma of humans after AMI and whether this increase is related to the left ventricular ejection fraction (LVEF). Methods: The plasma samples of 37 patients with ST elevation AMI undergoing primary percutaneous coronary intervention (pPCI) acquired in a previously conducted randomized controlled trial testing remote ischemic conditioning (RIC) were analyzed by means of high-performance liquid chromatography. Time courses of the variables were analyzed by means of mixed linear models. Multiple regression analyses served to explore the relationship between MG levels and the LVEF. Results: Compared to the MG levels upon admission due to AMI, the levels were increased 2.4-fold (95% CI, 1.6−3.6) 0.5 h after reperfusion facilitated by pPCI, 2.6-fold (1.7−4.0) after 24 h and largely returned to the baseline after 30 d (1.1-fold, 0.8−1.5). The magnitude of the MG increase was largely independent of that of cardiac necrosis markers. Overall, the highest MG values within 24 h after AMI were associated with the lowest LVEF after 4 d. While markers of myocardial necrosis and stretch quantified within the first 24 h explained 52% of the variance of the LVEF, MG explained additional 23% of the variance (p < 0.001). Conclusions: Considering these observational data, it is plausible that the preclinical finding of MG generation after AMI negatively affecting the LVEF also applies to humans. Inhibition of MG generation or MG scavenging might provide a novel therapeutic strategy to target post-AMI myocardial remodeling and dysfunction.

Serial measurements of protein and microRNA biomarkers to specify myocardial infarction subtypes.

Background: While cardiac-specific troponin (cTn) allows for rapid diagnosis of acute type 1 myocardial infarction (T1MI), its performance to differentiate acute myocardial injury (AI) or type 2 myocardial infarction (T2MI) is limited. The objective was to combine biomarkers to improve discrimination of different myocardial infarction (MI) aetiologies. Methods: We determined levels of cardiac troponin T and I (cTnT, cTnI), cardiac myosin-binding protein C (cMyBP-C), NT-proBNP and ten miRNAs, known to be associated with cardiac pathology in a total of n = 495 serial plasma samples at three time points (on admission, after 1 h and 3 h) from 57 NSTEMI (non-ST-elevation myocardial infarction), 18 AI, and 31 STEMI patients, as defined by fourth universal definition of MI (UDMI4) and 59 control individuals. We then applied linear mixed effects model to compare the kinetics of all molecules in these MI sub-types. Results: Established (cTnT, cTnI) and novel (cMyBP-C) cardiac necrosis markers failed in differentiating T1MI vs T2MI at early time points. All cardiac necrosis markers were higher in T1MI than in T2MI at 3 h after admission. Muscle-enriched miRNAs (miR-1 and miR-133a) were correlated with cardiac necrosis protein markers and did not offer better discrimination. Established cardiac strain marker NT-proBNP differentiated AI and T1MI at all time points but failed to discriminate T2MI from T1MI. However, the combination of NT-proBNP and cTnT along with age returned an overall AUC of 0.76 [95 % CI 0.67-0.84] for differentiating T1MI, T2MI and AI. Conclusions: Rather than using single biomarkers of myocardial necrosis, a combination of clinical biomarkers for cardiac necrosis (troponin) and cardiac strain (NT-proBNP) might aid in differentiating T1MI, T2MI and AI.

Meta-Analysis of Percutaneous Endomyocardial Cell Therapy in Patients with Ischemic Heart Failure by Combination of Individual Patient Data (IPD) of ACCRUE and Publication-Based Aggregate Data.

Individual patient data (IPD)-based meta-analysis (ACCRUE, meta-analysis of cell-based cardiac studies, NCT01098591) revealed an insufficient effect of intracoronary cell-based therapy in acute myocardial infarction. Patients with ischemic heart failure (iHF) have been treated with reparative cells using percutaneous endocardial, surgical, transvenous or intracoronary cell delivery methods, with variable effects in small randomized or cohort studies. The objective of this meta-analysis was to investigate the safety and efficacy of percutaneous transendocardial cell therapy in patients with iHF. Two investigators extracted the data. Individual patient data (IPD) (n = 8 studies) and publication-based (n = 10 studies) aggregate data were combined for the meta-analysis, including patients (n = 1715) with chronic iHF. The data are reported in accordance with PRISMA guidelines. The primary safety and efficacy endpoints were all-cause mortality and changes in global ejection fraction. The secondary safety and efficacy endpoints were major adverse events, hospitalization and changes in end-diastolic and end-systolic volumes. Post hoc analyses were performed using the IPD of eight studies to find predictive factors for treatment safety and efficacy. Cell therapy was significantly (p < 0.001) in favor of survival, major adverse events and hospitalization during follow-up. A forest plot analysis showed that cell therapy presents a significant benefit of increasing ejection fraction with a mean change of 2.51% (95% CI: 0.48; 4.54) between groups and of significantly decreasing end-systolic volume. The analysis of IPD data showed an improvement in the NYHA and CCS classes. Cell therapy significantly decreased the end-systolic volume in male patients; in patients with diabetes mellitus, hypertension or hyperlipidemia; and in those with previous myocardial infarction and baseline ejection fraction ≤ 45%. The catheter-based transendocardial delivery of regenerative cells proved to be safe and effective for improving mortality and cardiac performance. The greatest benefit was observed in male patients with significant atherosclerotic co-morbidities.

Sex-Based Differences in Autologous Cell Therapy Trials in Patients With Acute Myocardial Infarction: Subanalysis of the ACCRUE Database.

Background: Sex-based differences are under-studied in cardiovascular trials as women are commonly underrepresented in dual sex studies, even though major sex-based differences in epidemiology, pathophysiology, and outcomes of cardiovascular disease have been reported. We examined sex-based differences in patient characteristics, outcome, and BM-CD34+ frequency of the ACCRUE (Meta-Analysis of Cell-based CaRdiac studies) database involving patients with acute myocardial infarction (AMI) randomized to autologous cell-based or control treatment. Methods: We compared baseline characteristics and 1-year follow-up clinical data: composite major adverse cardiac and cerebrovascular events (primary endpoint), and changes in left ventricular ejection fraction (LVEF), end-diastolic (EDV), and end-systolic volumes (ESV) (secondary efficacy endpoint) in women and men (N = 1,252; 81.4% men). Secondary safety endpoints included freedom from hard clinical endpoints. Results: In cell-treated groups, women but not men had a lower frequency of stroke, AMI, and mortality than controls. The frequency of BM-CD34+ cells was significantly correlated with baseline EDV and ESV and negatively correlated with baseline LVEF in both sexes; a left shift in regression curve in women indicated a smaller EDV and ESV was associated with higher BM-CD34+ cells in women. Conclusions: Sex differences were found in baseline cardiovascular risk factors and cardiac function and in outcome responses to cell therapy.