Unwrapping phase contrast MRI by iterative graph cuts.

PURPOSE: To develop and evaluate a phase unwrapping method for cine phase contrast MRI based on graph cuts. METHODS: A proposed Iterative Graph Cuts method was evaluated in 10 cardiac patients with two-dimensional flow quantification which was repeated at low venc settings to provoke wrapping. The images were also unwrapped by a path-following method (ROMEO), and a Laplacian-based method (LP). Net flow was quantified using semi-automatic vessel segmentation. High venc images were also wrapped retrospectively to asses the residual amount of wrapped voxels. RESULTS: The absolute net flow error after unwrapping at venc = 100 cm/s was 1.8 mL, which was 0.83 mL smaller than for LP. The repeatability error at high venc without unwrapping was 2.5 mL. The error at venc = 50 cm/s was 7.5 mL, which was 8.2 mL smaller than for ROMEO and 5.7 mL smaller than for LP. For retrospectively wrapped images with synthetic venc of 100/50/25 cm/s, the residual amount of wrapped voxels was 0.00/0.12/0.79%, which was 0.09/0.26/8.0 percentage points smaller than for LP. With synthetic venc of 25 cm/s, omitting magnitude information resulted in 3.2 percentage points more wrapped voxels, and only spatial/temporal unwrapping resulted in 4.6/21 percentage points more wrapped voxels compared to spatiotemporal unwrapping. CONCLUSION: Iterative Graph Cuts enables unwrapping of cine phase contrast MRI with very small errors, except for at extreme blood velocities, with equal or better performance compared to ROMEO and LP. The use of magnitude information and spatiotemporal unwrapping is recommended.

Medical treatment of heart failure with renin-angiotensin-aldosterone system inhibitors and beta-blockers in aortic stenosis: association with long-term outcome after aortic valve replacement.

Aims: There is a lack of robust data on the optimal medical treatment of heart failure in patients with severe aortic stenosis, with no randomized controlled trials guiding treatment. The study aimed to study the association between exposure to renin-angiotensin-aldosterone system (RAS) inhibitors or beta-blockers and outcome after aortic valve replacement in patients with aortic stenosis and heart failure. Methods and results: The study included all patients with heart failure undergoing aortic valve replacement for aortic stenosis in Sweden between 2008 and 2016 (n = 4668 patients). Exposure to treatment was assessed by a continuous tracking of drug dispensations, and outcome events were all-cause mortality and hospitalization for heart failure collected from national patient registries. After adjustment for age, sex, atrial fibrillation, hypertension, diabetes mellitus, and prior myocardial infarction, Cox regression analysis showed that RAS inhibition was associated with a lower risk of all-cause mortality in patients with reduced left ventricular ejection fraction (LV-EF) [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51-0.65] and preserved LV-EF (HR 0.69, 95% CI 0.56-0.85). Beta-blockade was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.81, 95% CI 0.71-0.92), but not in preserved LV-EF (HR 0.87, 95% CI 0.69-1.10). There was no association between RAS inhibition or beta-blockade and the risk of hospitalization for heart failure. Conclusion: The RAS inhibition was associated with a lower all-cause mortality after valve replacement in patients with both reduced and preserved LV-EF. Beta-blockade was associated with lower all-cause mortality only in patients with reduced LV-EF.

Global longitudinal strain in long-term risk prediction after acute coronary syndrome: an investigation of added prognostic value to ejection fraction.

AIMS: This study aimed to investigate the additional value of global longitudinal strain (GLS) on top of left ventricular ejection fraction (LVEF) in long-term risk prediction of combined death and heart failure (HF) re-hospitalization after acute coronary syndrome (ACS). METHOD AND RESULTS: This retrospective study included patients admitted with ACS between 2008 and 2014 from the three participating university hospitals. LVEF and GLS were assessed at a core lab from images acquired during the index hospital stay. Their prognostic value was studied with the Cox proportional hazards model (median follow-up 6.2 years). A nested model comparison was performed with C-statistics. A total of 941 patients qualified for multivariable analysis after multiple imputation of missing baseline covariables. The combined outcome was reached in 17.7% of the cases. Both GLS and LVEF were independent predictors of the combined outcome, hazard ratio (HR) 1.068 (95% CI 1.017-1.121) and HR 0.980 (95% CI 0.962-0.998), respectively. The C-statistic increased from 0.742 (95% CI 0.702-0.783) to 0.749 (95% CI 0.709-0.789) (P = 0.693) when GLS entered the model with clinical data and LVEF. CONCLUSION: GLS emerged as an independent long-term risk predictor of all-cause death and HF re-hospitalization. However, there was no significant incremental predictive value of GLS when LVEF was already known.

Associations between inflammatory and angiogenic proteomic biomarkers, and cardiovascular events and mortality in relation to kidney function.

Background: The links between chronic kidney disease (CKD) and the high burden of cardiovascular disease remain unclear. We aimed to explore the association between selected inflammatory and angiogenic biomarkers, kidney function and long-term outcome in patients with an acute coronary syndrome (ACS) and to test the hypothesis that CKD status modifies this association. Methods: A total of 1293 ACS patients hospitalized between 2008 and 2015 were followed until 31 December 2017. Plasma was collected on days 1-3 after admission. A total of 13 biomarkers were a priori identified and analysed with two proteomic methods, proximity extension assay or multiple reaction monitoring mass spectrometry. Boxplots and multiple linear regression models were used to study associations between biomarkers and kidney function and adjusted standardized Cox regression with an interaction term for CKD was used to assess whether CKD modified the association between biomarkers and major adverse cardiovascular events and death (MACE+). Results: The concentrations of nine biomarkers-endothelial cell-specific molecule-1 (ESM-1), fibroblast growth factor 23 (FGF-23), fractalkine (CX3CL1), interleukin-1 receptor antagonist (IL-1RA), interleukin-18 (IL-18), monocyte chemotactic protein-1 (MCP-1), placenta growth factor (PlGF), transmembrane immunoglobulin 1 (TIM-1) and vascular endothelial growth factor A (VEGFA)-were inversely associated with kidney function. ESM-1, FGF-23 and TIM-1 showed associations with MACE+. Only FGF23 remained independently associated after adjustment for the other biomarkers (hazard ratio per standard deviation increase 1.34; 95% Bonferroni corrected confidence interval 1.19-1.50). None of the biomarkers showed an interaction with CKD. Conclusions: The concentrations of 9 of the 13 prespecified inflammatory and angiogenic proteomic biomarkers increased when kidney function declined. Only FGF-23 demonstrated an independent association with MACE+, and this association was not modified by CKD status. These findings further support FGF-23 as an independent prognostic marker in ACS patients with and without CKD.

The role of imaging in the selection of patients for HFpEF therapy.

Heart failure with preserved ejection fraction (HFpEF) traditionally has been characterized as a form of heart failure without therapeutic options, in particular with a lack of response to the established therapies of heart failure with reduced ejection fraction (HFrEF). However, this is no longer true. Besides physical exercise, risk factor modification, aldosterone blocking agents, and sodium-glucose cotransporter 2 inhibitors, specific therapies are emerging for specific HFpEF etiologies, such as hypertrophic cardiomyopathy or cardiac amyloidosis. This development justifies increased efforts to arrive at specific diagnoses within the umbrella of HFpEF. Cardiac imaging plays by far the largest role in this effort and is discussed in the following review.

Impact of clinical diagnosis of myocardial infarction in patients with elevated cardiac troponin.

OBJECTIVE: Type 2 myocardial infarction (MI) and myocardial injury are common conditions associated with an adverse prognosis. Physicians experience uncertainty how to distinguish these conditions, as well as how to manage and treat them. Therefore, the objective of this study was to compare treatment and prognosis in patients with an adjudicated diagnosis of type 2 MI and myocardial injury, who were discharged with and without a clinical diagnosis of MI. DESIGN: The study consisted of two cohorts, 964 and 281 consecutive patients with elevated cardiac troponin, discharged with and without a clinical diagnosis of MI, respectively. All cases were adjudicated into MI type 1-5 or myocardial injury and followed regarding all-cause death. RESULTS: The adjudication identified 138 and 37 cases of type 2 MI, and 86 and 185 of myocardial injury, with and without a clinical MI diagnosis, respectively. In patients with type 2 MI, a clinical MI diagnosis was associated with more coronary angiography investigations (39.1% vs 5.4%, p<0.001) and an increased use of secondary prevention medications (all p<0.001). However, no difference was observed in adjusted 5-year mortality between patients with and without a clinical MI diagnosis (HR: 0.77 with 95% CI 0.43 to 1.38). The results were similar for adjudicated myocardial injury. CONCLUSION: In both type 2 MI and myocardial injury, a clinical diagnosis of MI at discharge was associated with more investigations and treatments. However, no prognostic effect of receiving a clinical MI diagnosis was observed.

Myocardial External Efficiency in Asymptomatic Severe Primary Mitral Regurgitation Using 11C-Acetate PET.

Subjects with asymptomatic moderate-to-severe or severe primary mitral regurgitation are closely observed for signs of progression or symptoms requiring surgical intervention. The role of myocardial metabolic function in progression of mitral regurgitation is poorly understood. We used 11C-acetate PET to noninvasively measure myocardial mechanical external efficiency (MEE), which is the energetic ratio of external cardiac work and left ventricular (LV) oxygen consumption. Methods: Forty-seven patients in surveillance with mitral regurgitation and no or minimal symptoms prospectively underwent PET, echocardiography, and cardiac MRI on the same day. PET was used to simultaneously measure cardiac output, LV mass, and oxygen consumption to establish MEE. PET findings were compared between patients and healthy volunteers (n = 9). MEE and standard imaging indicators of regurgitation severity, LV volumes, and function were studied as predictors of time to surgical intervention. Patients were followed a median of 3.0 y (interquartile range, 2.0-3.8 y), and the endpoint was reached in 22 subjects (47%). Results: MEE in patients reaching the endpoint (23.8% ± 5.0%) was lower than in censored patients (28.5% ± 4.5%, P = 0.002) or healthy volunteers (30.1% ± 4.9%, P = 0.001). MEE with a cutoff lower than 25.7% was significantly associated with the outcome (hazard ratio, 7.5; 95% CI, 2.7-20.6; P < 0.0001) and retained independent significance when compared with standard imaging parameters. Conclusion: MEE independently predicted time to progression requiring valve surgery in patients with asymptomatic moderate-to-severe or severe primary mitral regurgitation. The study suggests that inefficient myocardial oxidative metabolism precedes clinically observed progression in mitral regurgitation.

Reliability of estimating left ventricular ejection fraction in clinical routine: a validation study of the SWEDEHEART registry.

OBJECTIVE: Patients hospitalized with acute coronary syndrome (ACS) in Sweden routinely undergo an echocardiographic examination with assessment of left ventricular ejection fraction (LVEF). LVEF is a measurement widely used for outcome prediction and treatment guidance. The obtained LVEF is categorized as normal (> 50%) or mildly, moderately, or severely impaired (40-49, 30-39, and < 30%, respectively) and reported to the nationwide registry for ACS (SWEDEHEART). The purpose of this study was to determine the reliability of the reported LVEF values by validating them against an independent re-evaluation of LVEF. METHODS: A random sample of 130 patients from three hospitals were included. LVEF re-evaluation was performed by two independent reviewers using the modified biplane Simpson method and their mean LVEF was compared to the LVEF reported to SWEDEHEART. Agreement between reported and re-evaluated LVEF was assessed using Gwet's AC2 statistics. RESULTS: Analysis showed good agreement between reported and re-evaluated LVEF (AC2: 0.76 [95% CI 0.69-0.84]). The LVEF re-evaluations were in agreement with the registry reported LVEF categorization in 86 (66.0%) of the cases. In 33 (25.4%) of the cases the SWEDEHEART-reported LVEF was lower than re-evaluated LVEF. The opposite relation was found in 11 (8.5%) of the cases (p < 0.005). CONCLUSION: Independent validation of SWEDEHEART-reported LVEF shows an overall good agreement with the re-evaluated LVEF. However, a tendency towards underestimation of LVEF was observed, with the largest discrepancy between re-evaluated LVEF and registry LVEF in subjects with subnormal LV-function in whom the reported assessment of LVEF should be interpreted more cautiously.

Screening for Biomarkers Associated with Left Ventricular Function During Follow-up After Acute Coronary Syndrome.

A proportion of patients with the acute coronary syndrome (ACS) will suffer progressive remodeling of the left ventricular (LV). The aim was to screen for important biomarkers from a large-scale protein profiling in 420 ACS patients and define biomarkers associated with reduced LV function early and 1 year after the ACS. Transferrin receptor protein 1 and NT-proBNP were associated with LV function early and after 1 year, whereas osteopontin and soluble ST2 were associated with LV function in the early phase and, tissue-type plasminogen activator after 1 year. Fatty-acid-binding protein and galectin 3 were related to worse GLS but not to LVEF 1 year after the ACS. Proteins involved in remodeling and iron transport in cardiomyocytes were related to worse LV function after ACS. Biomarkers for energy metabolism and fibrosis were exclusively related to worse LV function by GLS. Studies on the functions of these proteins might add knowledge to the biological processes involved in heart failure in long term after ACS.

Prognostic importance of biomarkers associated with haemostatic, vascular and endothelial disturbances in acute coronary syndrome patients in relation to kidney function.

BACKGROUND: Patients with kidney failure have a high risk for cardiovascular events. We aimed to evaluate the prognostic importance of selected biomarkers related to haemostasis, endothelial function, and vascular regulation in patients with acute coronary syndrome (ACS), and to study whether this association differed in patients with renal dysfunction. METHODS: Plasma was collected in 1370 ACS patients included between 2008 and 2015. Biomarkers were analysed using a Proximity Extension Assay and a Multiple Reaction Monitoring mass spectrometry assay. To reduce multiplicity, biomarkers correlating with eGFR were selected a priori among 36 plasma biomarkers reflecting endothelial and vascular function, and haemostasis. Adjusted Cox regression were used to study their association with the composite outcome of myocardial infarction, ischemic stroke, heart failure or death. Interaction with eGFR strata above or below 60 ml/min/1.73 m2 was tested. RESULTS: Tissue factor, proteinase-activated receptor, soluble urokinase plasminogen activator surface receptor (suPAR), thrombomodulin, adrenomedullin, renin, and angiotensinogen correlated inversely with eGFR and were selected for the Cox regression. Mean follow-up was 5.2 years during which 428 events occurred. Adrenomedullin, suPAR, and renin were independently associated with the composite outcome. Adrenomedullin showed interaction with eGFR strata (p = 0.010) and was associated with increased risk (HR 1.88; CI 1.44-2.45) only in patients with eGFR ≥60 ml/min/ 1.73 m2. CONCLUSIONS: Adrenomedullin, suPAR, and renin were associated with the composite outcome in all. Adrenomedullin, involved in endothelial protection, showed a significant interaction with renal function and outcome, and was associated with the composite outcome only in patients with preserved kidney function.

The Role of Novel Cardiac Imaging for Contemporary Management of Heart Failure.

Heart failure is becoming the central problem in cardiology. Its recognition, differential diagnosis, and the monitoring of therapy are intimately coupled with cardiac imaging. Cardiac imaging has witnessed an explosive growth and differentiation, with echocardiography continuing as the first diagnostic step; the echocardiographic exam itself has become considerably more complex than in the last century, with the assessment of diastolic left ventricular function and strain imaging contributing important information, especially in heart failure. Very often, however, echocardiography can only describe the fact of functional impairment and morphologic remodeling, whereas further clarification of the underlying disease, such as cardiomyopathy, myocarditis, storage diseases, sarcoidosis, and others, remains elusive. Here, cardiovascular magnetic resonance and perfusion imaging should be used judiciously to arrive as often as possible at a clear diagnosis which ideally enables specific therapy.

Updates for the diagnosis and management of cardiac amyloidosis.

A substantial increase in the interest in transthyretin cardiac amyloidosis (ATTR-CA) is a result of the constantly growing number of patients, the use of clear diagnostic protocols and the availability of the first selective drug for these patients. This has also raised the awareness of the disease among physicians of all specialties. The topic is particularly relevant to cardiologists, who use non-invasive multimodal imaging in their daily practice. The differential diagnosis of the causes of myocardial hypertrophy includes arterial hypertension, hypertrophic cardiomyopathy, aortic stenosis (AS), athletic heart syndrome, Fabry disease, and cardiac amyloidosis (CA). It turns out that in patients with myocardial hypertrophy >15 mm, amyloidosis is the most common cause of left ventricular (LV) hypertrophy. In parallel, CA is one of the most common infiltrative diseases leading to a clinical picture that may mimic heart failure with preserved ejection fraction (HFpEF). The accumulation of amyloid in the extracellular space impairs the diastolic function of the myocardium, which is observed as the restrictive cardiomyopathy phenotype. In advanced cases, the LV systolic function is also impaired. Moreover, protein deposits contribute to the disturbances of calcium metabolism and cell metabolism as well as to cardiotoxicity, leading to edema and damage to cardiomyocytes.

Diagnosis of left ventricular hypertrophy using non-ECG-gated 15O-water PET.

AIM: To develop a method for diagnosing left ventricular (LV) hypertrophy from cardiac perfusion 15O-water positron emission tomography (PET). METHODS: We retrospectively pooled data from 139 subjects in four research cohorts. LV remodeling patterns ranged from normal to severe eccentric and concentric hypertrophy. 15O-water PET scans (n = 197) were performed with three different PET devices. A low-end scanner (66 scans) was used for method development, and remaining scans with newer devices for a blinded evaluation. Dynamic data were converted into parametric images of perfusable tissue fraction for semi-automatic delineation of the LV wall and calculation of LV mass (LVM) and septal wall thickness (WT). LVM and WT from PET were compared to cardiac magnetic resonance (CMR, n = 47) and WT to 2D-echocardiography (2DE, n = 36). PET accuracy was tested using linear regression, Bland-Altman plots, and ROC curves. Observer reproducibility were evaluated using intraclass correlation coefficients. RESULTS: High correlations were found in the blinded analyses (r ≥ 0.87, P < 0.0001 for all). AUC for detecting increased LVM and WT (> 12 mm and > 15 mm) was ≥ 0.95 (P < 0.0001 for all). Reproducibility was excellent (ICC ≥ 0.93, P < 0.0001). CONCLUSION: 15O-water PET might detect LV hypertrophy with high accuracy and precision.

Development and validation of an artificial neural network algorithm to predict mortality and admission to hospital for heart failure after myocardial infarction: a nationwide population-based study.

BACKGROUND: Patients have an estimated mortality of 15-20% within the first year following myocardial infarction and one in four patients who survive myocardial infarction will develop heart failure, severely reducing quality of life and increasing the risk of long-term mortality. We aimed to establish the accuracy of an artificial neural network (ANN) algorithm in predicting 1-year mortality and admission to hospital for heart failure after myocardial infarction. METHODS: In this nationwide population-based study, we used data for all patients admitted to hospital for myocardial infarction and discharged alive from a coronary care unit in Sweden (n=139 288) between Jan 1, 2008, and April 1, 2017, from the Swedish Web system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies (SWEDEHEART) nationwide registry; these patients were randomly divided into training (80%) and testing (20%) datasets. We developed an ANN using 21 variables (including age, sex, medical history, previous medications, in-hospital characteristics, and discharge medications) associated with the outcomes of interest with a back-propagation algorithm in the training dataset and tested it in the testing dataset. The ANN algorithm was then validated in patients with incident myocardial infarction enrolled in the Western Denmark Heart Registry (external validation cohort) between Jan 1, 2008, and Dec 31, 2016. The predictive ability of the model was evaluated using area under the receiver operating characteristic curve (AUROC) and Youden's index was established as a means of identifying an empirical dichotomous cutoff, allowing further evaluation of model performance. FINDINGS: 139 288 patients who were admitted to hospital for myocardial infarction in the SWEDEHEART registry were randomly divided into a training dataset of 111 558 (80%) patients and a testing dataset of 27 730 (20%) patients. 30 971 patients with myocardial infarction who were enrolled in the Western Denmark Heart Registry were included in the external validation cohort. A first event, either all-cause mortality or admission to hospital for heart failure 1 year after myocardial infarction, occurred in 32 308 (23·2%) patients in the testing and training cohorts only. For 1-year all-cause mortality, the ANN had an AUROC of 0·85 (95% CI 0·84-0·85) in the testing dataset and 0·84 (0·83-0·84) in the external validation cohort. The AUROC for admission to hospital for heart failure within 1 year was 0·82 (0·81-0·82) in the testing dataset and 0·78 (0·77-0·79) in the external validation dataset. With an empirical cutoff the ANN algorithm correctly classified 73·6% of patients with regard to all-cause mortality and 61·5% of patients with regard to admission to hospital for heart failure in the external validation cohort, ruling out adverse outcomes with 97·1-98·7% probability in the external validation cohort. INTERPRETATION: Identifying patients at a high risk of developing heart failure or death after myocardial infarction could result in tailored therapies and monitoring by the allocation of resources to those at greatest risk. FUNDING: The Swedish Heart and Lung Foundation, Swedish Scientific Research Council, Swedish Foundation for Strategic Research, Knut and Alice Wallenberg Foundation, ALF Agreement on Medical Education and Research, Skane University Hospital, The Bundy Academy, the Märta Winkler Foundation, the Anna-Lisa and Sven-Eric Lundgren Foundation for Medical Research.

Myocardial infarction with non-obstructive coronary artery disease.

As a result of the increased use of coronary angiography in acute myocardial infarction in the last two decades, myocardial infarction with non-obstructive coronary arteries (MINOCA) has received growing attention in everyday clinical practice. At the same time, research interest in MINOCA has increased significantly. MINOCA is a heterogeneous disease entity seen in 5-10% of all patients with myocardial infarction, especially in women. Clinically, MINOCA may be difficult to distinguish from other non-ischaemic conditions that can cause similar symptoms and myocardial injury. There is still some confusion around the diagnosis, investigation and management of patients with MINOCA. The present review summarises the current knowledge of MINOCA regarding epidemiology, pathophysiology, investigation, and treatment, with a special focus on imaging modalities. In addition, remaining important knowledge gaps are highlighted.

Imaging of the left atrium: pathophysiology insights and clinical utility.

Left atrial imaging and detailed knowledge of its pathophysiology, especially in the context of heart failure, have become an increasingly important clinical and research focus. This development has been accelerated by the growth of non-invasive imaging modalities, advanced image processing techniques, such as strain imaging, and the parallel emergence of catheter-based left atrial interventions like pulmonary vein ablation, left atrial appendage occlusion, and others. In this review, we focus on novel imaging methods for the left atrium, their pathophysiological background, and their clinical relevance for various cardiac conditions and diseases.

Differences in biomarker concentrations and predictions of long-term outcome in patients with ST-elevation and non-ST-elevation myocardial infarction.

BACKGROUND: Differences in biomarkers reflective of pathobiology and prognosis between ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) are incompletely understood and may offer insights for tailoring of treatment. METHODS: This registry-based study included 538 STEMI and 544 NSTEMI patients admitted 2008-2014. Blood samples were collected day 1-3 after admission and 175 biomarkers were analyzed using Proximity Extension Assay and Multiple Reaction Monitoring mass spectrometry. Adjusted Lasso analysis (penalized logistic regression model) was used to select biomarkers that discriminated STEMI from NSTEMI patients. Biomarkers identified by the Lasso analysis were then evaluated in adjusted Cox regressions for associations with death or major adverse cardiovascular events. RESULTS: Biomarkers strongly discriminated STEMI and NSTEMI when considered simultaneously in adjusted Lasso analysis (c-statistic 0.764). Eleven biomarkers independently discriminated STEMI and NSTEMI; seven showing higher concentrations in STEMI: myoglobin, N-terminal pro-B-type natriuretic peptide, serum amyloid A-1 and A-2 protein, ST2 protein, interleukin-6 and chitinase-3-like protein 1; and four showing higher concentrations in NSTEMI: fibroblast growth factor 23, membrane-bound aminopeptidase P, tumor necrosis factor-related activation-induced cytokine and apolipoprotein C-I. During up to 6.6 years of prognostic follow-up, none of these biomarkers exhibited different associations with adverse outcome between STEMI and NSTEMI. CONCLUSIONS: In the acute setting, biomarkers indicated greater myocardial dysfunction and inflammation in STEMI, whereas they displayed a more diverse pathophysiologic pattern in NSTEMI patients. These biomarkers were similarly prognostic in STEMI and NSTEMI patients. The results do not support treating STEMI and NSTEMI patients differently based on the concentrations of these biomarkers.

Predicting outcome in acute myocardial infarction: an analysis investigating 175 circulating biomarkers.

AIMS: There is a paucity of studies comprehensively comparing the prognostic value of larger arrays of biomarkers indicative of different pathobiological axes in acute myocardial infarction (MI). METHODS AND RESULTS: In this explorative investigation, we simultaneously analysed 175 circulating biomarkers reflecting different inflammatory traits, coagulation activity, endothelial dysfunction, atherogenesis, myocardial dysfunction and damage, apoptosis, kidney function, glucose-, and lipid metabolism. Measurements were performed in samples from 1099 MI patients (SWEDEHEART registry) applying two newer multimarker panels [Proximity Extension Assay (Olink Bioscience), Multiple Reaction Monitoring mass spectrometry]. The prognostic value of biomarkers regarding all-cause mortality, recurrent MI, and heart failure hospitalizations (median follow-up ≤6.6 years) was studied using Lasso analysis, a penalized logistic regression model that considers all biomarkers simultaneously while minimizing the risk for spurious findings. Tumour necrosis factor-related apoptosis-inducing ligand receptor 2 (TRAIL-R2), ovarian cancer-related tumour marker CA 125 (CA-125), and fibroblast growth factor 23 (FGF-23) consistently predicted all-cause mortality in crude and age/sex-adjusted analyses. Growth-differentiation factor 15 (GDF-15) was strongly predictive in the crude model. TRAIL-R2 and B-type natriuretic peptide (BNP) consistently predicted heart failure hospitalizations. No biomarker predicted recurrent MI. The prognostic value of all biomarkers was abrogated following additional adjustment for clinical variables owing to our rigorous statistical approach. CONCLUSION: Apart from biomarkers with established prognostic value (i.e. BNP and to some extent GDF-15), several 'novel' biomarkers (i.e. TRAIL-R2, CA-125, FGF-23) emerged as risk predictors in patients with MI. Our data warrant further investigation regarding the utility of these biomarkers for clinical decision-making in acute MI.