Soluble TNF Receptors Are Associated with Infarct Size and Ventricular Dysfunction in ST-Elevation Myocardial Infarction

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Abstract

Objectives

The aim of the study was to investigate circulating markers of apoptosis in relation to infarct size, left ventricular dysfunction and remodeling in an ST-elevation myocardial infarction (STEMI) population undergoing primary percutaneous coronary intervention (PCI).

Background

Immediate re-opening of the acutely occluded infarct-related artery via primary PCI is the treatment of choice in STEMI to limit ischemia injury. However, the sudden re-initiation of blood flow can lead to a local acute inflammatory response with further endothelial and myocardial damage, so-called reperfusion injury. Apoptosis is suggested to be a key event in ischemia-reperfusion injury, resulting in LV-dysfunction, remodeling and heart failure.

Methods

The present study is a prespecified substudy of the F.I.R.E. trial. We included 48 patients with STEMI undergoing primary PCI. Blood samples were collected prior to PCI and after 24 hours. Plasma was separated for later analysis of soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, sFas and sFas ligand (sFasL) by ELISA. Infarct size, left ventricular (LV) dysfunction and remodeling were assessed by cardiac magnetic resonance imaging at five days and four months after STEMI.

Results

The levels of sTNFR1 at 24 h as well as the relative increases in sTNFR1 and sTNFR2 over 24 h showed consistent and significant correlations with infarct size and LV-dysfunction at four months. Moreover, both sTNFRs correlated strongly with Troponin I and matrix metalloproteinase (MMP)-2 measurements. Soluble Fas and sFasL did not overall correlate with measures of infarct size or LV-dysfunction. None of the apoptosis markers correlated significantly with measures of remodeling.

Conclusions

In STEMI patients, circulating levels of sTNFR1 and sTNFR2 are associated with infarct size and LV dysfunction. This provides further evidence for the role of apoptosis in ischemia-reperfusion injury.

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Most cited references 32

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Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials.

Ellen Keeley, Judith Boura, Cindy Grines (2003)

Many trials have been done to compare primary percutaneous transluminal coronary angioplasty (PTCA) with thrombolytic therapy for acute ST-segment elevation myocardial infarction (AMI). Our aim was to look at the combined results of these trials and to ascertain which reperfusion therapy is most effective. We did a search of published work and identified 23 trials, which together randomly assigned 7739 thrombolytic-eligible patients with ST-segment elevation AMI to primary PTCA (n=3872) or thrombolytic therapy (n=3867). Streptokinase was used in eight trials (n=1837), and fibrin-specific agents in 15 (n=5902). Most patients who received thrombolytic therapy (76%, n=2939) received a fibrin-specific agent. Stents were used in 12 trials, and platelet glycoprotein IIb/IIIa inhibitors were used in eight. We identified short-term and long-term clinical outcomes of death, non-fatal reinfarction, and stroke, and did subgroup analyses to assess the effect of type of thrombolytic agent used and the strategy of emergent hospital transfer for primary PTCA. All analyses were done with and without inclusion of the SHOCK trial data. Primary PTCA was better than thrombolytic therapy at reducing overall short-term death (7% [n=270] vs 9% [360]; p=0.0002), death excluding the SHOCK trial data (5% [199] vs 7% [276]; p=0.0003), non-fatal reinfarction (3% [80] vs 7% [222]; p<0.0001), stroke (1% [30] vs 2% [64]; p=0.0004), and the combined endpoint of death, non-fatal reinfarction, and stroke (8% [253] vs 14% [442]; p<0.0001). The results seen with primary PTCA remained better than those seen with thrombolytic therapy during long-term follow-up, and were independent of both the type of thrombolytic agent used, and whether or not the patient was transferred for primary PTCA. Primary PTCA is more effective than thrombolytic therapy for the treatment of ST-segment elevation AMI.

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The inflammatory response in myocardial infarction.

Nikolaos G Frangogiannis, C. Smith, Mark L. Entman (2002)

One of the major therapeutic goals of modern cardiology is to design strategies aimed at minimizing myocardial necrosis and optimizing cardiac repair following myocardial infarction. However, a sound understanding of the biology is necessary before a specific intervention is pursued on a therapeutic basis. This review summarizes our current understanding of the cellular and molecular mechanisms regulating the inflammatory response following myocardial ischemia and reperfusion. Myocardial necrosis induces complement activation and free radical generation, triggering a cytokine cascade initiated by Tumor Necrosis Factor (TNF)-alpha release. If reperfusion of the infarcted area is initiated, it is attended by an intense inflammatory reaction. Interleukin (IL)-8 synthesis and C5a activation have a crucial role in recruiting neutrophils in the ischemic and reperfused myocardium. Neutrophil infiltration is regulated through a complex sequence of molecular steps involving the selectins and the integrins, which mediate leukocyte rolling and adhesion to the endothelium. Marginated neutrophils exert potent cytotoxic effects through the release of proteolytic enzymes and the adhesion with Intercellular Adhesion Molecule (ICAM)-1 expressing cardiomyocytes. Despite this potential injury, substantial evidence suggests that reperfusion enhances cardiac repair improving patient survival; this effect may be in part related to the inflammatory response. Monocyte Chemoattractant Protein (MCP)-1 is also markedly upregulated in the infarcted myocardium inducing recruitment of mononuclear cells in the injured areas. Monocyte-derived macrophages and mast cells may produce cytokines and growth factors necessary for fibroblast proliferation and neovascularization, leading to effective repair and scar formation. At this stage expression of inhibitory cytokines such as IL-10 may have a role in suppressing the acute inflammatory response and in regulating extracellular matrix metabolism. Fibroblasts in the healing scar undergo phenotypic changes expressing smooth muscle cell markers. Our previous review in this journal focused almost exclusively on reduction of the inflammatory injury. The current update is prompted by the potential therapeutic opportunity that the open vessel offers. By promoting more effective tissue repair, it may be possible to reduce the deleterious remodeling, that is the leading cause of heart failure and death. Elucidating the complex interactions and regulatory mechanisms responsible for cardiac repair may allow us to design effective inflammation-related interventions for the treatment of myocardial infarction.

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Apoptosis in the failing human heart.

G Olivetti, R Abbi, F Quaini … (1997)

Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.

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Author and article information

Contributors

Ali J. Marian: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2013

Publication date (Electronic): 6 February 2013

Volume: 8

Issue: 2

Electronic Location Identifier: e55477

Affiliations

[1 ]Division of Cardiology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden

[2 ]Department of Cardiology, University Hospital, Linköping, Sweden

The University of Texas Health Science Center, United States of America

Author notes

* E-mail: lennart.nilsson@ 123456liu.se

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: LN ES LJ. Performed the experiments: LN AS LJ. Analyzed the data: LN AS ES LJ. Contributed reagents/materials/analysis tools: LN ES LJ. Wrote the paper: LN AS ES LJ.

Article

Publisher ID: PONE-D-12-29520

DOI: 10.1371/journal.pone.0055477

PMC ID: 3566185

PubMed ID: 23405158

SO-VID: 7e146878-f15a-4bc3-a004-1c4bec788beb

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 September 2012

Date accepted : 23 December 2012

Page count

Pages: 6

Funding

This project was supported by grants from the Swedish Heart-Lung Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Soluble TNF Receptors Are Associated with Infarct Size and Ventricular Dysfunction in ST-Elevation Myocardial Infarction

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Abstract

Objectives

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Conclusions

Related collections

PLOS Climate

Most cited references 32

Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials.

The inflammatory response in myocardial infarction.

Apoptosis in the failing human heart.

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