ABSTRACT
INTRODUCTION: Sex- and age-specific high-sensitivity Troponin T (hs-cTnT) cutpoints for the diagnosis and prognosis in acute coronary syndromes are not well established. We evaluated the use of such dichotomous thresholds for calculation of the GRACE score. METHODS: We analyzed a retrospective cohort study of 1146 patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). Sex-dependent hs-cTnT cutpoints comprised 15.5â¯ng/L for men and 9.0â¯ng/L for women, while the sex-/age-specific cutpoints comprised 17â¯ng/L for 50-64-year-old men and ≥65-year-old women, 31â¯ng/L for ≥65-year-old men and 14â¯ng/L for the remainder of patients. RESULTS: For the diagnosis of NSTEMI using sex-specific hs-cTnT cutpoints, in women, the positive likelihood ratio (LR+) was 2.04 (1.68-2.47) while in men, the negative likelihood ratio (LR-) was 0.05 (0.04-0.07). Using sex-/age-specific hs-cTnT cutpoints, in ≥65-year-old women the LR- was 0.09 (0.06-0.15), in 50 to 64-year-old men the LR- was 0.08 (0.04-0.13) while in ≥65-year-old men the LR- was 0.32 (0.28-0.37). Sex-specific hs-cTnT cutpoints achieved an NRI of -0.020 (95% CI, -0.101-0.118) for women and 0.030 (95% CI, -0.013-0.079) for men, and the sex-/age-specific hs-cTnT cutpoints achieved an NRI of 0.061 (95% CI, -0.019-0.132) for women and 0.021 (95% CI, -0.062-0.108) for men, while net benefit and clinical utility were highest for women using the sex-/age-specific hs-cTnT cutpoints. CONCLUSIONS: Sex-dependent hs-cTNT cutpoints imply increasing diagnostic sensitivity for women at the cost of specificity. Considering age for hs-cTNT cutoffs slightly improves risk reclassification, although the overall gain in terms of the clinical management appears negligible.
Subject(s)
Acute Coronary Syndrome/diagnosis , Electrocardiography , Troponin T/blood , Acute Coronary Syndrome/blood , Acute Coronary Syndrome/epidemiology , Age Factors , Aged , Biomarkers/blood , Diagnosis, Differential , Female , Follow-Up Studies , Germany/epidemiology , Humans , Incidence , Male , Middle Aged , Non-ST Elevated Myocardial Infarction/blood , Non-ST Elevated Myocardial Infarction/diagnosis , Predictive Value of Tests , Prognosis , Retrospective Studies , Sex FactorsABSTRACT
BACKGROUND: Clinical trials of bone marrow cell-based therapies after acute myocardial infarction (MI) have produced mostly neutral results. Treatment with specific bone marrow cell-derived secreted proteins may provide an alternative biological approach to improving tissue repair and heart function after MI. We recently performed a bioinformatic secretome analysis in bone marrow cells from patients with acute MI and discovered a poorly characterized secreted protein, EMC10 (endoplasmic reticulum membrane protein complex subunit 10), showing activity in an angiogenic screen. METHODS: We investigated the angiogenic potential of EMC10 and its mouse homolog (Emc10) in cultured endothelial cells and infarcted heart explants. We defined the cellular sources and function of Emc10 after MI using wild-type, Emc10-deficient, and Emc10 bone marrow-chimeric mice subjected to transient coronary artery ligation. Furthermore, we explored the therapeutic potential of recombinant Emc10 delivered by osmotic minipumps after MI in heart failure-prone FVB/N mice. RESULTS: Emc10 signaled through small GTPases, p21-activated kinase, and the p38 mitogen-activated protein kinase (MAPK)-MAPK-activated protein kinase 2 (MK2) pathway to promote actin polymerization and endothelial cell migration. Confirming the importance of these signaling events in the context of acute MI, Emc10 stimulated endothelial cell outgrowth from infarcted mouse heart explants via p38 MAPK-MK2. Emc10 protein abundance was increased in the infarcted region of the left ventricle and in the circulation of wild-type mice after MI. Emc10 expression was also increased in left ventricular tissue samples from patients with acute MI. Bone marrow-derived monocytes and macrophages were the predominant sources of Emc10 in the infarcted murine heart. Emc10 KO mice showed no cardiovascular phenotype at baseline. After MI, however, capillarization of the infarct border zone was impaired in KO mice, and the animals developed larger infarct scars and more pronounced left ventricular remodeling compared with wild-type mice. Transplanting KO mice with wild-type bone marrow cells rescued the angiogenic defect and ameliorated left ventricular remodeling. Treating FVB/N mice with recombinant Emc10 enhanced infarct border-zone capillarization and exerted a sustained beneficial effect on left ventricular remodeling. CONCLUSIONS: We have identified Emc10 as a previously unknown angiogenic growth factor that is produced by bone marrow-derived monocytes and macrophages as part of an endogenous adaptive response that can be enhanced therapeutically to repair the heart after MI.
Subject(s)
Angiogenic Proteins/metabolism , Bone Marrow Cells/metabolism , Membrane Proteins/metabolism , Myocardial Infarction/metabolism , Myocardium/metabolism , Neovascularization, Physiologic , Wound Healing , Angiogenic Proteins/administration & dosage , Angiogenic Proteins/deficiency , Angiogenic Proteins/genetics , Animals , Bone Marrow Transplantation , Cells, Cultured , Disease Models, Animal , Endothelial Cells/metabolism , Genotype , Intracellular Signaling Peptides and Proteins/metabolism , Macrophages/metabolism , Membrane Proteins/administration & dosage , Membrane Proteins/deficiency , Membrane Proteins/genetics , Mice, Inbred C57BL , Mice, Knockout , Monocytes/metabolism , Monomeric GTP-Binding Proteins/metabolism , Myocardial Infarction/drug therapy , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocardium/pathology , Neovascularization, Physiologic/drug effects , Phenotype , Protein Serine-Threonine Kinases/metabolism , Signal Transduction , Time Factors , Wound Healing/drug effects , p21-Activated Kinases/metabolism , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Paracrine-acting proteins are emerging as a central mechanism by which bone marrow cell-based therapies improve tissue repair and heart function after myocardial infarction (MI). We carried out a bioinformatic secretome analysis in bone marrow cells from patients with acute MI to identify novel secreted proteins with therapeutic potential. Functional screens revealed a secreted protein encoded by an open reading frame on chromosome 19 (C19orf10) that promotes cardiac myocyte survival and angiogenesis. We show that bone marrow-derived monocytes and macrophages produce this protein endogenously to protect and repair the heart after MI, and we named it myeloid-derived growth factor (MYDGF). Whereas Mydgf-deficient mice develop larger infarct scars and more severe contractile dysfunction compared to wild-type mice, treatment with recombinant Mydgf reduces scar size and contractile dysfunction after MI. This study is the first to assign a biological function to MYDGF, and it may serve as a prototypical example for the development of protein-based therapies for ischemic tissue repair.
Subject(s)
Interleukins/genetics , Interleukins/metabolism , Myocardial Infarction/metabolism , Myocardial Reperfusion Injury/metabolism , Animals , Bone Marrow Cells/metabolism , Cell Proliferation/drug effects , Cell Proliferation/genetics , Endothelial Cells/drug effects , HEK293 Cells , Humans , Interleukins/pharmacology , Macrophages/metabolism , Mice , Mice, Knockout , Monocytes/metabolism , Myocytes, Cardiac , Neovascularization, Physiologic , Ventricular Remodeling/drug effects , Ventricular Remodeling/geneticsABSTRACT
BACKGROUND: Guidelines recommend the use of validated risk scores and a high-sensitivity cardiac troponin assay for risk assessment in non-ST-elevation acute coronary syndrome (NSTE-ACS). The incremental prognostic value of biomarkers in this context is unknown. METHODS: We calculated the Global Registry of Acute Coronary Events (GRACE) score and measured the circulating concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and 8 selected cardiac biomarkers on admission in 1146 patients with NSTE-ACS. We used an hs-cTnT threshold at the 99th percentile of a reference population to define increased cardiac marker in the score. The magnitude of the increase in model performance when individual biomarkers were added to GRACE was assessed by the change (Δ) in the area under the receiver-operating characteristic curve (AUC), integrated discrimination improvement (IDI), and category-free net reclassification improvement [NRI(>0)]. RESULTS: Seventy-eight patients reached the combined end point of 6-month all-cause mortality or nonfatal myocardial infarction. The GRACE score alone had an AUC of 0.749. All biomarkers were associated with the risk of the combined end point and offered statistically significant improvement in model performance when added to GRACE (likelihood ratio test P ≤ 0.015). Growth differentiation factor 15 [ΔAUC 0.039, IDI 0.049, NRI(>0) 0.554] and N-terminal pro-B-type natriuretic peptide [ΔAUC 0.024, IDI 0.027, NRI(>0) 0.438] emerged as the 2 most promising biomarkers. Improvements in model performance upon addition of a second biomarker were small in magnitude. CONCLUSIONS: Biomarkers can add prognostic information to the GRACE score even in the current era of high-sensitivity cardiac troponin assays. The incremental information offered by individual biomarkers varies considerably, however.