Erythropoietin to Augment Myocardial Salvage Induced by Coronary Thrombolysis in Patients With ST Segment Elevation Acute Myocardial Infarction

doi:10.1016/j.amjcard.2009.05.050

The American Journal of Cardiology

Volume 104, Issue 8, 15 October 2009, Pages 1035-1040

https://doi.org/10.1016/j.amjcard.2009.05.050 Get rights and content

To determine whether the administration of erythropoietin (EPO) early after the onset of ischemia could enhance the preservation of jeopardized myocardium by reperfusion, 236 patients admitted <6 hours after the onset of chest pain indicative of acute coronary syndromes confirmed to be ST-segment elevation acute myocardial infarctions who were treated with tenecteplase to induce coronary thrombolysis were studied. Patients were randomized to standard care or standard care plus the administration of a single dose of EPO 30,000 IU intravenously immediately before the onset of treatment with tenecteplase. The primary end point was enzymatically estimated infarct size. The results indicated that infarct size index was virtually identical in the 2 groups, with a mean ± SE of 13.2 ± 0.1 creatine kinase-MB gram equivalents in controls and 12.4 ± 0.9 creatine kinase-MB gram equivalents in patients treated with EPO. In conclusion, although the early administration of EPO was apparently safe, it did not enhance the preservation of jeopardized ischemic myocardium.

Section snippets

Methods

We enrolled and randomized 254 primarily male patients admitted to Rashid Hospital in Dubai, United Arab Emirates, very early after the onset of myocardial infarction and are reporting the results from the 236 for whom we were able to acquire complete blood sample sets (i.e., sets of samples that arrived at our laboratory in Vermont without thawing, without clots, and intact). Patients were studied after the acquisition of written informed consent and in accordance with a protocol approved by

Results

The patients treated with EPO were similar to those who were not (Table 1). The concentrations in plasma of EPO assayed by a 2-site enzyme-linked immunosorbent assay procedure with kits from MD Biosciences (St. Paul, Minnesota) 30 minutes after administration of the thrombolytic drug were profoundly elevated in the patients treated with EPO, averaging 8,554 ± 812 mU/ml compared to the normal concentrations in those who were not treated with the drug (10 ± 1 mU/ml). Furthermore, in samples

Discussion

The results of this study demonstrate that the administration of EPO in quantities comparable to those that have been reported to provide tissue protection in the hearts of experimental animals did not change the extent of infarction in patients with STEMIs treated with the early administration of a thrombolytic drug. The echocardiographic results indicated that no functional differences were present between the 2 groups and were concordant with the lack of differences in enzymatic estimates of

Acknowledgment

We thank Rania Medhat Seliem and Faiza Ahmed Al Najjar of the Rashid Hospital laboratory; Wafig Hassan Shafiq, head of the Health Informatics Unit at Rashid Hospital; Rahila Sarwar Bhatti and the staff of the Coronary Care Unit at Rashid Hospital; Patricia Baumann and Dagnija Neimane for technical and biostatistical support; and Lori Dales for preparation of the report.

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The temporal impact of erythropoietin administration on mitochondrial function and dynamics in cardiac ischemia/reperfusion injury
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Erythropoietin (EPO) has been shown to provide protection against ischemia/reperfusion (I/R) injury in various experimental models. However, clinical trials revealed unsatisfactory results when EPO was given to patients with myocardial infarction following reperfusion. The timing of EPO administration and its relation to mitochondrial function may largely involve in this controversy. We hypothesized that EPO given at different time points exert varying cardioprotective effects in terms of myocardial infarct size, left ventricular (LV) function, arrhythmia, apoptosis, mitochondrial function, and mitochondrial dynamics in rats with cardiac I/R injury. Male Wistar rats were subjected to either sham (n = 6) or cardiac I/R operation (n = 48). Rats undergoing cardiac I/R operation (30-min ischemia, followed by 120-min reperfusion) were allotted into 4 subgroups (n = 12/group): vehicle, EPO pretreatment, EPO given during ischemia, and EPO given at reperfusion. EPO was administered intravenously at 5000 unit/kg. Arrhythmia and LV function were monitored throughout the protocol. Next, the hearts were collected to determine infarct size, mitochondrial function, mitochondrial dynamics, gap junction protein, and apoptosis. Cardiac I/R promoted arrhythmias, LV dysfunction, infarct size expansion, apoptosis, mitochondrial dysfunction and increased mitochondrial fission. EPO given either before or during ischemia, but not at reperfusion, attenuated arrhythmia scores, LV dysfunction, infarct size, and apoptosis. Only EPO given either before or during ischemia alleviated mitochondrial swelling, mitochondrial depolarization, and reduced the levels of p-Drp1^ser616/Drp1. Data from in vitro study also confirmed that EPO directly attenuated mitochondrial dysfunction in H9c2 cells subjected to hypoxia/reoxygenation. In conclusion, the EPO administration, either before or during ischemia, exerted cardioprotection against I/R injury by attenuating mitochondrial dynamic imbalance, mitochondrial dysfunction, and apoptosis, leading to reduced infarct size and improved LV function.
Erythropoietin Therapy in Critically Ill and Acute Kidney Injury Patients
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The Erythropoietin System Protects the Heart Upon Injury by Cardiac Progenitor Cell Activation
2017, Vitamins and Hormones
Erythropoietin (EPO) is a growth hormone, widely known for its role in erythropoiesis. The broad expression of erythropoietin receptor (EPOR) in adult organs suggested that EPO may also affect other cells besides late erythroid progenitors. In the embryonic heart, EPOR is expressed in all cells including the immature proliferating cardiomyocytes. In contrast to the embryonic heart in adulthood, EPOR expression is decreased and mainly detected in immature proliferating cells (i.e., resident cardiac progenitor cells) rather than in terminally differentiated cells (i.e., cardiomyocytes). Since cardiac progenitor cells are considered a regenerative cell source upon cardiac injury, the protective action of the EPO system was tested by creating an erythroid-rescued EPOR knockout mouse model. Although these mice appear to have less immature proliferating myocytes during embryogenesis, they reach adulthood without apparent morphological defects. However, upon ischemia reperfusion, these animals show a greater infarct size, suggesting that the EPO/EPOR protects the heart upon injury. Indeed preclinical studies showed that EPO administration postinfarction improves cardiac function via neoangiogenesis, antiapoptotic mechanisms, and/or CPC activation. Despite the promising preclinical data, large cohort clinical studies in humans failed to show a significant amelioration in cardiac function upon systemic injection of EPO in patients with myocardial infarctions. The discrepancy between preclinical and clinical trials may be due to differences between the doses, the way of delivery, the homogeneity of the cohorts, and last but not least the species differences. These data pinpoint the importance of carrying out preclinical studies in human models of disease as engineered human cardiac tissue that will provide a better understanding of the expression pattern of EPOR and the role of its ligand in human cardiac cells. Such studies may be able to bridge the gap between preclinical rodent data and human clinical trials and thus lead to the design of more successful clinical studies.
Administration of erythropoietin in patients with myocardial infarction: Does it make sense? An updated and comprehensive meta-analysis and systematic review
2015, Cardiovascular Revascularization Medicine
This systematic review with meta-analysis sought to determine protective effects of erythropoietin on clinical outcomes following percutaneous coronary intervention (PCI). Medline, Embase, Elsevier and Sciences online database as well as Google scholar literature were used for selecting appropriate studies with randomized controlled design. The effect sizes measured were odds ratio (OR) for categorical variables and weighted mean difference (WMD) with 95% confidence interval for calculating differences between mean values of duration of hospitalization in intervention and control groups. Values of P < 0.1 for Q test or I² > 50% indicated significant heterogeneity between the studies. The literature searches of all major databases retrieved 973 studies. After screening, a total of 15 trials that reported outcomes were identified. Pooled analysis was performed on left ventricular ejection fraction (WMD of − 0.047; 95% CI: − 0.912 to 0.819; P = 0.9), left ventricular end diastolic volume (WMD of − 0.363; 95% CI: − 3.902 to 3.175; P = 0.8), left ventricular end systolic volume (WMD of 0.346; 95% CI: − 2.533 to 3.226; P = 0.8), infarct size (WMD of − 0.446; 95% CI: − 2.352 to − 1.460; P = 0.6), stroke (OR of 2.1; 95% CI: 0.58 to 7.54; P = 0.2), re-myocardial infarction (OR of 1.06; 95% CI: 0.52 to 2.185; P = 0.8), heart failure (OR of 0.53; 95% CI: 0.259 to 1.105; P = 0.09), mortality (OR of 0.56; 95% CI: 0.27 to 1.19; P = 0.13), thrombosis (OR of 0.774; 95% CI: 0.41 to 1.45; P = 0.4), major adverse cardiovascular events (OR of 0.926; 95% CI: 0.63 to 1.35; P = 0.6). Short-term administration of EPO in patients with myocardial infarction (MI) undergoing PCI does not result in improvement in cardiac function, reduction of infarct size and all-cause mortality. Low dose EPO therapy may not be the choice of treatment for the patients with MI, while higher doses might be more effective.
The mitochondria as a target for cardioprotection in acute myocardial ischemia
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The ischemic heart suffers from nutrient deprivation, lack of oxygen, metabolic acidosis, hyperkalemia and Ca²⁺ overload as well as high level of reactive oxygen species (ROS) generation; these risk factors endanger the cardiomyoctes and may cause their demise. Nevertheless, the treatment of acute myocardial infarction includes reperfusion, although it can exacerbate the effects of ischemia since resumption of blood supply to the ischemic myocardium is associated with increased ROS production. In the past 20 years, preconditioning and postconditioning were revealed, directing research efforts at finding pharmacological agents that can mimic these techniques. Soon thereafter, the involvement of several molecular pathways such as the reperfusion injury salvage kinase, the ATP-sensitive K⁺ channel, the survivor-activating factor enhancement and the adenosine mono phosphate activated protein kinase pathways were discovered. Further, studies have shown that these pathways convey the adverse effects of ischemia, reperfusion and the combination thereof to the mitochondria, suggesting that the death signals during ischemia and reperfusion are controllable, and can therefore be partially inhibited or even reversed. Hence, the aim of this review is to describe these signaling pathways, the established pre-clinical means to manipulate them, and their current application status in the clinic.
Erythropoietin and the heart: Physiological effects and the therapeutic perspective
2014, International Journal of Cardiology
Citation Excerpt :
The outcomes included all-cause mortality, major cardiovascular events, cardiac function by LV ejection fraction and infarct size. Thirteen clinical studies of rhEpo versus control (1564 participants) were included [44,47–50,94–101]. As indicated above, these authors also concluded that rhEpo administration did not improve LVEF (P = 0.68), and that it had no effect on infarct size (assessed by cardiac MRI [P = 0.90] or by serum peak value of CK-MB [P = 0.87]).
Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided.

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: This study was partly supported by a Shaikh Hamdan Bin Rashed Al Maktoum Award (Dubai, United Arab Emirates).

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Coronary artery diseaseErythropoietin to Augment Myocardial Salvage Induced by Coronary Thrombolysis in Patients With ST Segment Elevation Acute Myocardial Infarction

Section snippets

Methods

Results

Discussion

Acknowledgment

Am J Cardiol

Life Sci

J Biol Chem

J Am Coll Cardiol

J Mol Cell Cardiol

An improved basis for enzymatic estimation of infarct size

Circulation

Prompt detection of coronary recanalization by analysis of rates of change of concentrations of macromolecular markers in plasma

Coron Artery Dis

Chronic erythropoietin treatment limits infarct-size in the myocardium in vitro

Cardiovasc Drugs Ther

Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats

Proc Natl Acad Sci U S A

Erythropoietin affords additional cardioprotection to preconditioned hearts by enhanced phosphorylation of glycogen synthase kinase-3 beta

Am J Physiol Heart Circ Physiol

A novel protective effect of erythropoietin in the infarcted heart

J Clin Invest

Delayed erythropoietin therapy reduces post-MI cardiac remodeling only at a dose that mobilizes endothelial progenitor cells

Am J Physiol Heart Circ Physiol

Erythropoietin prevents the acute myocardial inflammatory response induced by ischemia/reperfusion via induction of AP-1

Cardiovasc Res

Recombinant human erythropoietin pretreatment attenuates myocardial infarct size: a possible mechanism involves heat shock protein 70 and attenuation of nuclear factor-kappaB

Ann Clin Lab Sci

Coronary artery disease
Erythropoietin to Augment Myocardial Salvage Induced by Coronary Thrombolysis in Patients With ST Segment Elevation Acute Myocardial Infarction