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Soluble markers of apoptosis in myocardial infarction patients during acute phase and 6-month follow up
Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.ORCID iD: 0000-0002-9375-5087
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Chemistry.
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2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Objectives

The aim of the study was to investigate circulating markers of apoptosis in the acute phase and at follow8up in patients with ST8elevation myocardial infarction (STEMI) or non8ST8elevation myocardial infarction (NSTEMI).

Background

Myocardial cell death during acute MI results from necrosis, apoptosis and autophagy. An elevated rate of apoptosis can continue for several days after the acute event, contributing to an increased final infarct size. Moreover, a lower but still increased apoptosis can continue for months resulting in left ventricular (LV) dysfunction and heart failure. Few studies have analysed markers of apoptosis longitudinally in MI patients.  Also, it is not known whether STEMI and NSTEMI patients differ in regard to these markers. 

Methods

This study is a prespecified substudy of the APACHE trial. We included 61 STEMI and 40 NSTEMI patients. Blood samples for analysis of soluble tumor necrosis factor receptor (sTNFR) 1, sTNFR2, sFas, sFas ligand (sFasL) and IL86 were collected at baseline prior to PCI, at 3 days and at 6 months. High sensitivity troponin T (hsTnT) was measured at 688 hours and echocardiography was performed at 283 days after admission to hospital.

Results

STEMI compared to NSTEMI patients showed very similar temporal patterns for each of the markers of apoptosis analyzed. Levels of sTNFRs increased from baseline to day 3 and the absolute increase as well as day 3 levels correlated significantly with TnT. At 6 months, sTNFR1 had returned to baseline whereas levels of sTNFR2 were still elevated. Soluble Fas and sFasL did not change from baseline to day 3, and both markers were significantly lower in the acute phase compared to 6 months. Indeed, sFas at day 3 correlated negatively with TnT. At all time points, plasma sTNFRs were significantly higher in patients with reduced LV function, whereas no such associations with sFas or sFasL was observed. 

Conclusions

The TNF and Fas/FasL pathways of apoptosis, as reflected by soluble markers, show markedly different temporal changes after an acute MI, indicating diverse roles of these two systems. STEMI compared to NSTEMI patients showed very similar temporal patterns for all the analyzed markers, suggesting apoptosis to be equally involved in myocardial damage of either infarct type.

Place, publisher, year, edition, pages
2015.
Keyword [en]
Apoptosis, ST-elevation myocardial infarction, non- ST-elevation myocardial infarction
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
URN: urn:nbn:se:liu:diva-121116OAI: oai:DiVA.org:liu-121116DiVA: diva2:851835
Available from: 2015-09-07 Created: 2015-09-07 Last updated: 2016-04-14Bibliographically approved
In thesis
1. Detection of apoptosis in patients with coronary artery disease: Assessment of temporal patterns and potential sources
Open this publication in new window or tab >>Detection of apoptosis in patients with coronary artery disease: Assessment of temporal patterns and potential sources
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The atherosclerotic process and its consequences are considered driven by an imbalance between pro- and ant-inflammatory actions. One contributing factor in this scenario is an altered regulation of apoptosis, which affects both immune, vascular and myocardial cells. The general aim of this thesis was to measure soluble markers of apoptosis in peripheral venous blood, in various clinical stages of coronary artery disease (CAD) and to further identify possible sources with specific focus on natural killer (NK) cell apoptosis and myocardial ischemia-reperfusion (IR)-injury.

There was evidence of an increased apoptosis of NK cells, but not T cells, in the circulation of CAD patients. Spontaneous NK cell apoptosis and the cells´ sensitivity to oxidative stress in the form of oxidized lipids ex vivo, were increased. Findings were thus suggestive of an enhanced apoptosis contributing to the reduced NK cell activity seen in CAD. However, we could not verify that oxidative stress in the circulation was a driving force behind this loss.

Soluble forms of the cell surface bound receptors of apoptosis include soluble (s) Fas and sFas ligand (L). They are detected in plasma and used as surrogate markers of apoptosis. Here we investigated the relationship between these markers and NK cell apoptosis and NK cell levels, in a 12 month longitudinal study on CAD patients. Plasma levels of sFasL correlated with increased susceptibility to NK cell apoptosis ex vivo but also with the levels of NK cells in the circulation after a coronary event. NK cells undergoing apoptosis ex vivo were also found to be a major source of sFasL themselves, indicating potential usefulness of sFasL in monitoring changes in NK cell levels.

Apoptosis is suggested to be a key event in IR-injury, resulting in increased infarct size, left ventricular (LV) dysfunction, remodeling and heart failure. We investigated soluble markers of apoptosis in relation to these parameters in a ST-elevation myocardial infarction (STEMI) population. In addition to sFas and sFasL, we also measured tumor necrosis factor (TNF) receptor (R) I and II in this study. Acute phase levels of sTNFRI and sTNFRII, but not sFas or sFasL, correlated to cardiac MR (CMR) measures of infarct size and LV-dysfunction at 4 months after the ischemic event. Also, the soluble markers of apoptosis were correlated with matrix metalloproteinase (MMP)-2, a mechanistic trigger for cardiomyocyte apoptosis, further strengthening the role of apoptosis in IR-injury.

Finally we explored the temporal patterns of soluble markers of apoptosis after an MI and, furthermore, investigated possible differences between patients presenting with a non(N)-STEMI versus STEMI. The sTNFRI/II and the sFas/sFasL pathways of apoptosis showed different temporal changes indicating diverse roles of these two systems. NSTEMI and STEMI patients however, shared these temporal patterns pointing to apoptosis as equally involved in either infarct type. Furthermore sTNFRs, but not sFas/sFasL correlated to levels of cytokine interleukin (IL)-6 illustrating the overlapping role TNF signaling in inflammation and apoptosis, while again suggesting differences between the TNF and the Fas/FasL systems during myocardial IR--‐injury.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 89 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1467
National Category
Cardiac and Cardiovascular Systems Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:liu:diva-121122 (URN)10.3384/diss.diva-121122 (DOI)978-91-7519-029-7 (print) (ISBN)
Public defence
2015-10-09, Berzeliussalen, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-09-08 Created: 2015-09-08 Last updated: 2016-06-14Bibliographically approved

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Szymanowski, AleksanderJanzon, MagnusLindahl, Tomas L.Swahn, EvaJonasson, LenaNilsson, Lennart
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Department of Cardiology in LinköpingDivision of Cardiovascular MedicineFaculty of Medicine and Health SciencesDepartment of Medical and Health SciencesDepartment of Cardiology in LinköpingDivision of Microbiology and Molecular MedicineDepartment of Clinical Chemistry
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