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Outcome of patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention during on- versus off-hours (a Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI] trial substudy) Impact of treatment delay on mortality in ST-segment elevation myocardial infarction (STEMI) patients presenting with and without haemodynamic instability: results from the German prospective, multicentre FITT-STEMI trial Trends and Impact of Door-to-Balloon Time on Clinical Outcomes in Patients Aged <75, 75 to 84, and ≥85 Years With ST-Elevation Myocardial Infarction National assessment of early β-blocker therapy in patients with acute myocardial infarction in China, 2001-2011: The China Patient-centered Evaluative Assessment of Cardiac Events (PEACE)-Retrospective AMI Study 2015 ACC/AHA/SCAI Focused Update on Primary Percutaneous Coronary Intervention for Patients With ST-Elevation Myocardial Infarction: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention and the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infa A prospective, randomised trial of transapical transcatheter aortic valve implantation vs. surgical aortic valve replacement in operable elderly patients with aortic stenosis: the STACCATO trial Fate of post-procedural malapposition of everolimus-eluting polymeric bioresorbable scaffold and everolimus-eluting cobalt chromium metallic stent in human coronary arteries: sequential assessment with optical coherence tomography in ABSORB Japan trial Early invasive versus non-invasive treatment in patients with non-ST-elevation acute coronary syndrome (FRISC-II): 15 year follow-up of a prospective, randomised, multicentre study

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Original ResearchVolume 72, Issue 3, July 2018

JOURNAL：J Am Coll Cardiol. Article Link

Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease

J Sjaarda, H Gerstein, M Chong et al. Keywords: biomarker; coronary artery disease; CSF1; CXCL12; genetics; Mendelian randomization;

ABSTRACT

BACKGROUND - Identification of biomarkers that cause coronary artery disease (CAD) has led to important advances in prevention and treatment. Epidemiological analyses have identified many biomarker-CAD relationships; however, these associations may arise from reverse causation and/or confounding and therefore may not represent true causal associations. Mendelian randomization (MR) analyses overcome these limitations.

OBJECTIVES - This study sought to identify causal mediators of CAD through a comprehensive screen of 237 biomarkers using MR.

METHODS - MR was performed by identifying genetic determinants of 227 biomarkers in ORIGIN (Outcome Reduction With Initial Glargine Intervention) trial participants (N = 4,147) and combining these with genetic effects on CAD from the CARDIoGRAM consortium (60,801 cases and 123,504 controls). Blood concentrations of novel biomarkers identified by MR were then tested for association with incident major adverse cardiovascular events in ORIGIN.

RESULTS - Six biomarkers were found to be causally linked to CAD after adjustment for multiple hypothesis testing. The causal role of 4 of these is well documented, whereas macrophage colony-stimulating factor 1 (CSF1) and stromal cell–derived factor 1 (CXCL12) have not previously been reported, to the best of our knowledge. MR analysis predicted an 18% higher risk of CAD per SD increase in CSF1 (odds ratio: 1.18; 95% confidence interval: 1.08 to 1.30; p = 2.1 × 10−4) and epidemiological analysis identified a 16% higher risk of major adverse cardiovascular events per SD (hazard ratio: 1.16; 95% confidence interval: 1.09 to 1.23; p < 0.001). Elevated CXCL12 levels were also identified as a causal risk factor for CAD with consistent epidemiological results. Furthermore, genetically predicted CSF1 and CXCL12 levels were associated with CAD in the UK Biobank (n = 343,735).

CONCLUSIONS - The study identified CSF1 and CXCL12 as causal mediators of CAD in humans. Understanding the mechanism by which these markers mediate CAD will provide novel insights into CAD and could lead to new approaches to prevention. These results support targeting inflammatory processes and macrophages, in particular, to prevent CAD, consistent with the recent CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study). (Outcome Reduction With Initial Glargine Intervention [ORIGIN]; NCT00069784)

Abstract

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Blood CSF1 and CXCL12 as Causal Mediators of Coronary Artery Disease

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