Regular ArticleEndothelin-1 levels predict endothelial progenitor cell mobilization after acute myocardial infarction
Graphical abstract
Highlights
► Relationship between ET-1, CEC and EPCs after myocardial infarction. ► Samples withdrawn acutely and 1 week after myocardial infarction onset. ► High ET-1 levels on admission predicted a lower EPC mobilization. ► ET-1 provides better prognostic information than do CEC and EPCs.
Introduction
Endothelial impairment is an independent predictor of acute cardiovascular events in patients with and without coronary artery disease (CAD) (Halcox et al., 2002). Endothelial dysfunction is also considered a predictor of left ventricular ejection fraction (LVEF) (Bae et al., 2004) associated with worse left ventricle remodeling after myocardial infarction (Matsuo et al., 2006).
Endothelin-1 (ET-1) is a well-known marker of endothelial dysfunction in patients with CAD (Iglarz and Clozel, 2007). In acute myocardial infarction (AMI), high ET-1 values on admission have been linked to poor angiographic outcomes after primary angioplasty (Eitel et al., 2010, Niccoli et al., 2006) and poor prognosis, including higher 30-day mortality (Khan et al., 2007, Yip et al., 2005).
The measurement of circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) also represents an important and novel technique for the assessment of endothelial injury and repair, respectively. Circulating endothelial cells are biomarkers of damage that correlate with several well-established markers of endothelial dysfunction and predict poor outcomes when elevated (Blann et al., 2005, Lee et al., 2005). In contrast, EPC are biomarkers of endothelial repair with potential cardioprotective effects. Low EPC levels after an AMI have been linked to poor outcomes, including worse LVEF and higher NT-proBNP concentrations (Wojakowski et al., 2006). The main mechanism of EPC mobilization from the bone marrow seems to depend on the activation of endothelial nitric oxide synthase (eNOS) in the presence of several mobilizing factors, such as vascular endothelial growth factor and placental growth factor (Li et al., 2006). Endothelin-1 decreases eNOS expression and could therefore play an important role in CEC and EPC mobilization (Sud and Black, 2009). However, no studies to date have assessed this potential interaction. The aim of the present study was to establish the relationship between ET-1 levels and CEC/EPC mobilization patterns in the early hours after an AMI.
Section snippets
Study population
Between June 2007 and January 2009, the study enrolled 61 nonconsecutive patients who underwent primary angioplasty for a first AMI with elevation of the segment ST in the electrocardiogram (STEMI). Inclusion criteria were prolonged chest pain (> 30 min) and ST-segment elevation > 1 mm in 2 or more adjacent leads within the first 12 h after onset of symptoms. Exclusion criteria were acute or chronic inflammatory disease, malignancy, or recent surgery, trauma, or infection. The study protocol was
Patient characteristics
The clinical characteristics of the study population are shown in Table 1. Mean symptoms-to-angioplasty time was 317 ± 255 min. The clinical and angiographic characteristics of the cohort are listed in Table 2. Suboptimal reperfusion was observed in 43.5% of patients. Three patients died within the first 30 days (2 of heart failure and 1 of cardiogenic shock). Mean peak CK-MB and troponin I after AMI were 182.8 ± 122.2 ng/ml and 178.65 ± 285.7 ng/ml, respectively. Left ventricular ejection fraction after
Discussion
The results of the present study suggest an association between high ET-1 levels on admission and low EPC mobilization after AMI. To our knowledge, this is the first study to assess the potential relationship between ET-1 and both CEC and EPC counts.
High ET-1 levels have been associated with poor angiographic (Niccoli et al., 2006) and clinical outcomes (Freixa et al., 2011, Yip et al., 2005). In agreement with previous studies (Niccoli et al., 2006, Yip et al., 2005), we found a significant
Limitations
There are several limitations to this study. First, although sample size is similar to previous studies, the number of patients is still relatively small and insufficient to establish the prognostic value of CEC/EPC mobilization for risk prediction in STEMI patients. Additionally, the small size of the sample led to a very low number of events that did not allow for a valid and stable multivariable analysis. Second, without serial ET-1, CEC and EPC measurements, we could not determine actual
Conclusions
In STEMI patients, high ET-1 levels on admission predict a lower EPC mobilization after 1 week. Endothelin-1 provides better clinical, angiographic and echocardiographic information for prognosis than do CEC and EPC concentrations.
Acknowledgments
Project funded by the Spanish Society of Cardiology, the Hospital Clinic of Barcelona and RD06/0009/1003 (Red HERACLES, Instituto de Salud Carlos III).
References (31)
- et al.
Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging
Am. Heart J.
(2010) - et al.
Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus
J. Am. Coll. Cardiol.
(2005) - et al.
Usefulness of endothelin-1 assessment in acute myocardial infarction
Rev. Esp. Cardiol.
(2011) - et al.
C-terminal pro-endothelin-1 offers additional prognostic information in patients after acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study
Am. Heart J.
(2007) - et al.
Circulating endothelial cells, von Willebrand factor, interleukin-6, and prognosis in patients with acute coronary syndromes
Blood
(2005) - et al.
Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: statins for regeneration after acute myocardial infarction and PCI (STRAP) trial
Int. J. Cardiol.
(2008) - et al.
Dimensional accuracy of magnetic resonance in studies of the heart
Lancet
(1985) - et al.
Direct evidence of endothelial injury in acute myocardial infarction and unstable angina by demonstration of circulating endothelial cells
Blood
(1999) - et al.
Prognostic value of circulating levels of endothelin-1 in patients after acute myocardial infarction undergoing primary coronary angioplasty
Chest
(2005) - et al.
Stem cell mobilization by granulocyte colony-stimulating factor for myocardial recovery after acute myocardial infarction: a meta-analysis
J. Am. Coll. Cardiol.
(2008)
The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group
N. Engl. J. Med.
Impact of left ventricular ejection fraction on endothelial function in patients with coronary artery disease
Clin. Cardiol.
Circulating endothelial cells. Biomarker of vascular disease
Thromb. Haemost.
Improvement in left ventricular remodeling by the endothelial nitric oxide synthase enhancer AVE9488 after experimental myocardial infarction
Circulation
Ischemia–reperfusion injury at the microvascular level: treatment by endothelin A-selective antagonist and evaluation by myocardial contrast echocardiography
Circulation
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