Acute Coronary Syndrome Subphenotypes Based on Repeated Biomarker Measurements in Relation to Long-Term Mortality Risk.

BACKGROUND: We aimed to identify patients with subphenotypes of postacute coronary syndrome (ACS) using repeated measurements of high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 in the year after the index admission, and to investigate their association with long-term mortality risk. METHODS AND RESULTS: BIOMArCS (BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome) was an observational study of patients with ACS, who underwent high-frequency blood sampling for 1 year. Biomarkers were measured in a median of 16 repeated samples per individual. Cluster analysis was performed to identify biomarker-based subphenotypes in 723 patients without a repeat ACS in the first year. Patients with a repeat ACS (N=36) were considered a separate cluster. Differences in all-cause death were evaluated using accelerated failure time models (median follow-up, 9.1 years; 141 deaths). Three biomarker-based clusters were identified: cluster 1 showed low and stable biomarker concentrations, cluster 2 had elevated concentrations that subsequently decreased, and cluster 3 showed persistently elevated concentrations. The temporal biomarker patterns of patients in cluster 3 were similar to those with a repeat ACS during the first year. Clusters 1 and 2 had a similar and favorable long-term mortality risk. Cluster 3 had the highest mortality risk. The adjusted survival time ratio was 0.64 (95% CI, 0.44-0.93; P=0.018) compared with cluster 1, and 0.71 (95% CI, 0.39-1.32; P=0.281) compared with patients with a repeat ACS. CONCLUSIONS: Patients with subphenotypes of post-ACS with different all-cause mortality risks during long-term follow-up can be identified on the basis of repeatedly measured cardiovascular biomarkers. Patients with persistently elevated biomarkers have the worst outcomes, regardless of whether they experienced a repeat ACS in the first year.

Serially measured high-sensitivity cardiac troponin T, N-terminal-pro-B-type natriuretic peptide, high-sensitivity C-reactive protein, and growth differentiation factor 15 for risk assessment after acute coronary syndrome: the BIOMArCS cohort.

AIMS: Evidence regarding the role of serial measurements of biomarkers for risk assessment in post-acute coronary syndrome (ACS) patients is limited. The aim was to explore the prognostic value of four, serially measured biomarkers in a large, real-world cohort of post-ACS patients. METHODS AND RESULTS: BIOMArCS is a prospective, multi-centre, observational study in 844 post-ACS patients in whom 12 218 blood samples (median 17 per patient) were obtained during 1-year follow-up. The longitudinal patterns of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal-pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and growth differentiation factor 15 (GDF-15) were analysed in relation to the primary endpoint (PE) of cardiovascular mortality and recurrent ACS using multivariable joint models. Median age was 63 years, 78% were men and the PE was reached by 45 patients. The average biomarker levels were systematically higher in PE compared with PE-free patients. After adjustment for 6-month post-discharge Global Registry of Acute Coronary Events score, 1 standard deviation increase in log[hs-cTnT] was associated with a 61% increased risk of the PE [hazard ratio (HR) 1.61, 95% confidence interval (CI) 1.02-2.44, P = 0.045], while for log[GDF-15] this was 81% (HR 1.81, 95% CI 1.28-2.70, P = 0.001). These associations remained significant after multivariable adjustment, while NT-proBNP and hs-CRP were not. Furthermore, GDF-15 level showed an increasing trend prior to the PE (Structured Graphical Abstract). CONCLUSION: Longitudinally measured hs-cTnT and GDF-15 concentrations provide prognostic value in the risk assessment of clinically stabilized patients post-ACS. CLINICAL TRIAL REGISTRATION: The Netherlands Trial Register. Currently available at URL https://trialsearch.who.int/; Unique Identifiers: NTR1698 and NTR1106.

Evolution of renal function and predictive value of serial renal assessments among patients with acute coronary syndrome: BIOMArCS study.

BACKGROUND: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. METHODS: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). RESULTS: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2-3. During hospitalization for index ACS (median [IQR] duration: 5 (3-7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03-2.74]). CONCLUSION: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score.

Temporal Pattern of Growth Differentiation Factor-15 Protein After Acute Coronary Syndrome (From the BIOMArCS Study).

Growth differentiation factor-15 (GDF-15) has appeared as a promising biomarker with strong predictive abilities in acute coronary syndrome (ACS). However, studies are solely based on single measurements in the acute phase of an ACS event. The way GDF-15 patterns in post-ACS patients behave on the long term is largely unknown. We conducted a nested case-control study within our multicenter, prospective, observational biomarker study (BIOMArCS) of 844 ACS patients. Following an index ACS event, high-frequency blood sampling was performed during 1-year of follow-up. GDF-15 was determined batchwise by electrochemiluminescence immunoassays in 37 cases with a recurrent event during 1-year follow-up, and in 74 event-free controls. Cases and controls had a mean ± standard deviation age of 66.9 ± 11.3 years and 81% were men. From 30 days onwards, patients showed stable levels, which were on average 333 (95% confidence interval 68 to 647) pg/mL higher in cases than controls (1704 vs 1371 pg/mL; p value 0.013). Additionally, in the post 30-day period, GDF-15 showed low within-individual variability in both cases and controls. In conclusion, post-ACS patients experiencing a recurrent event had stable and systematically higher GDF-15 levels during 30-day to 1-year follow-up than their event-free counterparts with otherwise similar clinical characteristics. Thus, postdischarge blood sampling might be used throughout the course of 1 year to improve prognostication, whereas, in view of the low within-individual variation, the number of repeated sampling moments might be limited.

The temporal pattern of immune and inflammatory proteins prior to a recurrent coronary event in post-acute coronary syndrome patients.

PURPOSE: We assessed the temporal pattern of 29 immune and inflammatory proteins in post-acute coronary syndrome (ACS) patients, prior to the development of recurrent ACS. METHODS: High-frequency blood sampling was performed in 844 patients admitted for ACS during one-year follow-up. We conducted a case-control study on the 45 patients who experienced reACS (cases) and two matched event-free patients (controls) per case. Olink Proteomics' immunoassay was used to obtain serum levels of the 29 proteins, expressed in an arbitrary unit on the log2-scale (Normalized Protein eXpression, NPX). Linear mixed-effects models were applied to examine the temporal pattern of the proteins, and to illustrate differences between cases and controls. RESULTS: Mean age was 66 ± 12 years and 80% were men. Cases and controls had similar baseline clinical characteristics. During the first 30 days, and after multiple testing correction, cases had significantly higher serum levels of CXCL1 (difference of 1.00 NPX, p = 0.002), CD84 (difference of 0.64 NPX, p = 0.002) and TNFRSF10A (difference of 0.41 NPX, p < 0.001) than controls. After 30 days, serum levels of all 29 proteins were similar in cases and controls. In particular, no increase was observed prior to reACS. CONCLUSIONS: Among 29 immune and inflammatory proteins, CXCL1, CD84 and TNFRSF10A were associated with early reACS after initial ACS-admission.

Cohort profile of BIOMArCS: the BIOMarker study to identify the Acute risk of a Coronary Syndrome-a prospective multicentre biomarker study conducted in the Netherlands.

PURPOSE: Progression of stable coronary artery disease (CAD) towards acute coronary syndrome (ACS) is a dynamic and heterogeneous process with many intertwined constituents, in which a plaque destabilising sequence could lead to ACS within short time frames. Current CAD risk assessment models, however, are not designed to identify increased vulnerability for the occurrence of coronary events within a precise, short time frame at the individual patient level. The BIOMarker study to identify the Acute risk of a Coronary Syndrome (BIOMArCS) was designed to evaluate whether repeated measurements of multiple biomarkers can predict such 'vulnerable periods'. PARTICIPANTS: BIOMArCS is a multicentre, prospective, observational study of 844 patients presenting with ACS, either with or without ST-elevation and at least one additional cardiovascular risk factor. METHODS AND ANALYSIS: We hypothesised that patterns of circulating biomarkers that reflect the various pathophysiological components of CAD, such as distorted lipid metabolism, vascular inflammation, endothelial dysfunction, increased thrombogenicity and ischaemia, diverge in the days to weeks before a coronary event. Divergent biomarker patterns, identified by serial biomarker measurements during 1-year follow-up might then indicate 'vulnerable periods' during which patients with CAD are at high short-term risk of developing an ACS. Venepuncture was performed every fortnight during the first half-year and monthly thereafter. As prespecified, patient enrolment was terminated after the primary end point of cardiovascular death or hospital admission for non-fatal ACS had occurred in 50 patients. A case-cohort design will explore differences in temporal patterns of circulating biomarkers prior to the repeat ACS. FUTURE PLANS AND DISSEMINATION: Follow-up and event adjudication have been completed. Prespecified biomarker analyses are currently being performed and dissemination through peer-reviewed publications and conference presentations is expected from the third quarter of 2016. Should identification of a 'vulnerable period' prove to be feasible, then future research could focus on event reduction through pharmacological or mechanical intervention during such periods of high risk for ACS. TRIAL REGISTRATION NUMBER: NTR1698 and NTR1106.

Prognostic significance of residual cumulative ST-segment deviation after mechanical reperfusion in patients with ST-segment elevation myocardial infarction.

BACKGROUND: The analysis of ST-segment resolution is a well established and easy method to assess myocardial perfusion after reperfusion therapy for ST-segment elevation myocardial infarction (STEMI). The aim of the current study was to identify an easy and practical instrument for patients' prognostic stratification after angioplasty for STEMI by the use of only postprocedural ST-segment analysis. METHODS: Our population is represented by a total of 1286 patients treated with primary angioplasty for STEMI. Residual ST-segment elevation and deviation were analyzed at 3 hours after revascularization. One-year follow-up data were collected prospectively in all patients. RESULTS: Patients with impaired ST-segment normalization were older, with larger prevalence of diabetes, anterior infarction, hypertension, signs of heart failure at presentation, lower rate of postprocedural thrombolysis in myocardial infarction 3 flow, myocardial blush grades 2 to 3, and successful reperfusion. A linear relationship was found between both residual cumulative ST-segment elevation and deviation with 1-year mortality. At multivariate analysis, postprocedural residual cumulative ST deviation (RR 1.31, 95% CI 1.06-1.63, P = .014), but not residual cumulative ST elevation (RR 0.95, 95% CI 0.55-1.67, P = .87), was an independent predictor of 1-year mortality. Furthermore, we found that residual cumulative ST-segment deviation provides better prognostic information (area receiver operating characteristic [ROC] = 0.733) than ST-segment elevation resolution (area ROC = 0.636) or ST-segment deviation resolution (area ROC = 0.660) in terms of 1-year mortality. These data were confirmed for both anterior and nonanterior infarct location. CONCLUSION: This study showed that postprocedural residual cumulative ST-segment deviation is an independent prognostic parameter in patients treated with primary angioplasty, providing even better prognostic information than ST-segment resolution.

Impact of ST-segment depression resolution on mortality after successful mechanical reperfusion in patients with ST-segment elevation acute myocardial infarction.

The aim of the present study was to evaluate the additional prognostic effect of ST-depression resolution in 610 patients who had ST-elevation myocardial infarction and underwent successful primary angioplasty (postprocedural Thrombolysis In Myocardial Infarction 3 flow and complete resolution of ST-segment elevation). Incomplete resolution of ST-segment depression (<70%) was observed in 50 patients (8.2%). These patients were older, had a higher Killip's class at presentation, had larger infarcts, and had an increased 1-year mortality (10% vs 2%, p = 0.0004). At multivariate analysis, incomplete resolution of ST-segment depression was an independent predictor of 1-year mortality (p = 0.028).

Combining baseline clinical descriptors and real-time response to therapy: the incremental prognostic value of continuous ST-segment monitoring in acute myocardial infarction.

BACKGROUND: Clinical descriptors and ST-segment recovery variables hold prognostic information for clinical outcome after thrombolysis for acute myocardial infarction (MI). We sought to define the incremental prognostic value of continuous 12-lead ST-segment monitoring variables to clinical risk descriptors identified by the Global Utilization of Streptokinase and TPA (alteplase) for Occluded Coronary Arteries (GUSTO-I) trial 30-day mortality analysis. METHODS: Of 1,777 patients enrolled in continuous ST-segment substudies from the Thrombolysis and Angioplasty in Myocardial Infarction (TAMI-9), GUSTO-I, Duke University Clinical Cardiology Study (DUCCS-II), Integrilin to manage Platelet Aggregation to Combat Thrombus in Acute Myocardial Infarction (IMPACT-AMI), Promotion of Reperfusion by Inhibition of Thrombin During Myocardial Infarction Evolution (PRIME), and Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) trials, 825 patients qualified for assessment of time to recovery. ST recovery variables analyzed were time to stable ST-recovery and late ST elevation. Patients who were at low clinical risk (n = 261) had no high-risk descriptors, and patients at high clinical risk (n = 564) had at least 1 of these high-risk descriptors: age >or=70 years, systolic blood pressure or=90 beats/min, anterior MI, or previous MI. High (n = 90), moderate (n = 318), and low (n =417) ST-risk groups were defined by the presence of both slow ST recovery and late ST elevation, one or the other, or neither, respectively. End points analyzed were inhospital death and combined death, reinfarction, or congestive heart failure. RESULTS: There was a trend toward increased mortality rate in the high-clinical/high-ST-risk group. For the composite end point, ST subgrouping resulted in significant event stratification in both patients at low and high clinical risk. In multivariable analysis, age and heart rate were independent predictors of both mortality and the composite end point. Late ST elevation added incremental prognostic information. CONCLUSION: Age, heart rate, and late ST elevation are powerful, independent predictors of adverse clinical outcome. Continuous monitoring allows noninvasive assessment of the response to therapy. Consequently, this technique will enhance the potential to risk-stratify individual patients in a real-time setting.