erythropoietin in myocardial infarction: … for beneficial effects of erythropoietin in...

Evidence for beneficial effects of erythropoietin in experimental myocardial infarction

Erythropoietin (EPO) is a member of the cytokine type I family and is mainly synthesised in the peri-tubular cells in the cortex-medullary border of the kidney1 Under hypoxic conditions erythropoietin is released and increases the amount of circulating red blood cells by enhancing the development of precursor red cells and by protecting red blood cells from apoptosis. As a therapeutic agent eythropoi-etin became widely used in treating anaemia result-ing from chronic kidney disease and myelodyspla-sia after chemotherapy or radiation.

The effects of EPO are mediated by a specific trans-membrane EPO receptor which is expressed mainly on haematopoietic progenitor cells2. EPO induces homodimerisation of the EPO receptor with sub-sequent activation of the Janus kinase 2, thyrosine phosphorylation of the EPO receptor and signal transducer and activator of transcription factor 5 (STAT5) 3, 4. This activates PIP3 kinase, Akt and MAP kinases with subsequent suppression of apoptosis5. Moreover, phosphorylation of PLC-γ with subse-quent PIP2 hydrolysis and generation of IP3 induces Ca2+ release from intracellular stores6.

EPO receptors (EPOR) are not only expressed on erythroid precursors, but also on megakaryo-cytes, vascular smooth muscle cells 7, endo-thelial cells 8, skeletal myoblasts 9, neurons 10, nephrons 11 and cardiac myocytes 12, 13.

CORRESPONDENCE

Ilka Ott, Deutsches Herzzentrum der Technischen Universität München, Lazarettstr. 36, 80636 München, Germany.

Tel: +49 89 1218 4073, FAX: +49 89 1218 4006, e-mail: [email protected]

ISSN 2042-4884

ABSTRACT

Erythropoietin produced mainly in the kidney is the main regulator of erythropoiesis. Experimental studies identified additional, non-haematopoietic, protective effects during myocardial ischemia and reperfusion due to inhibition of apoptosis, stimulation of vasculogenesis and progenitor cell mobilisation. Based on these findings, five prospective, randomised, clinical trials have been performed. A short term regimen of erythropoietin was applied during PCI in patients with STEMI up to a cumulative dose of 100.000 IU. No changes in myocardial function or infarct size were observed after erythropoietin. Yet in two studies an increase in adverse events after erythropoietin was observed, whereas one study found an increase in major adverse clinical events in the control group. This review discusses experimental evidence of erythropoietin in acute myocardial infarction and its failure in clinical trials.

Erythropoietin in Myocardial Infarction:Experimental Evidence and Clinical Studies

MYOCARDIAL INFARCTION | REVIEW

Andreas Stein & Ilka Ott,Deutsches Herzzentrum der Technischen Universität München, München, Germany

Received 4/1/2011, Reviewed 15/1/2011, Accepted 19/1/2011 DOI: 10.5083/ejcm.20424884.26

Anti-apoptotic pathways downstream of EPOR are activated by EPO to inhibit apoptosis asso-ciated with ischemia and reperfusion injury in vitro and in vivo. It has also been hypothesised that alternative EPO binding complexes such as a heteroreceptor comprised of the EPOR and the GM-CSF/IL-3/IL-5 receptor ß-common chain may mediate the cytoprotective effects of EPO14.

These non-haematopoietic effects of EPO have been described in different tissues under isch-emic conditions. In a rat model of focal brain ischemia, EPO administration reduced infarct size 15. Similarly, EPO reduced renal 16 and myo-cardial injury 17-19 after ischemia and reperfu-sion. Experimental models of acute reperfused myocardial infarction showed a decrease in in-farct size, an improved cardiac contractility and better haemodynamics 18, 20 ,21, 22 EPO was not only favourable in the setting of ischemia and reperfusion but also in a model of permanent coronary occlusion.

Administration of EPO was not only beneficial directly after induced myocardial infarction but even led to an improved remodelling and cap-illary density if given three weeks thereafter.23 In most of these experimental studies, EPO was given systemically and a high-dose regimen was used. Treatment duration differed from single dose administration to daily injections over a week (Table 1). Long-term application of EPO increased the haematocrit as expected, where-as short-term EPO application only increased reticulocytes without changing haemoglobin levels.24

57EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III

HEALTHCARE BULLETIN | MYOCARDIAL INFARCTION

Studies using low-dose EPO therapy also led to an improved cardiac function and neovascularisation in rats after myocardial infarction without altering haematocrit.17, 23 This is particularly important as large clinical trials showed that an increase of haematocrit due to long term EPO treatment was accompanied by increased rates of thromboembolic events.25-27

Potential mechanisms that may contribute to the cytoprotective effect of EPO include inhibition of apoptosis and improved cardio-myocyte survival since infarct size and reperfusion injuries are relat-ed to the extent of myocardial apoptosis. Functional recovery after ischemia and reperfusion was associated with a decrease in apop-totic cells and was abolished in the presence of specific inhibitors of the PI3K/Akt pathway 28, 29. Other signalling pathways involved are MAPK p38 and p42/44 30. Additional mechanisms for protection of ischemia/reperfusion injury may include attenuation of inflamma-tory responses31 and oxidative stress.12, 32-35, modulation the car-diac Na+/K+ pump36 and stimulation of atrial natriuretic peptide release37 (Figure 1).

Figure 1:

Anti-Apoptosis Oxidative Stress Vasculogenesis

Erythropoiesis Progenitor Mobilization

Immunomodulation

EPO

Table 1: Effects of EPO in experimental myocardial infarction

Animal Model Species EPO dosage EPO application time Ref. Outcome

Ischemia/Reperfusion Rat 5.000 IU/kg daily for 7 days 18Reduction in cardiomyocyte loss, normalization of hemodynamic

functions within 1 week

Ischemia/Reperfusion Rat 5.000 IU/kg 30 min. after ischemia 50 Reduction in infarct size

Ischemia/Reperfusion Rat 5.000 IU/kg Before, at the beginning or at the end of ischemia 17 Reduction in infarct size and myocte

apoptosis

Ischemia/Reperfusion Rabbit 5.000 IU/kg After ischemia 20 Improvement in myocardial function, reduction in myocyte apoptosis

Ischemia/Reperfusion Dog 100-1000IU/kg After ischemia 29 Reduction in infarct size

Ischemia/Reperfusion Rat 30µg/kg darbopoietin Before ischemia 51 Reduction in infarct size, improved LV EF,

decrease in apoptosis

Permanent Occlusion Rat 40µg/kg darbepoietin 3 weeks after occlusion 23

Improved cardiac function, progenitor cell mobilisation,

increased vascularisation

Permanent Occlusion Rat 5.000 IU/kg After occlusion 21

Improved survival, haemodynamic parameters, progenitor cell

mobilisation, decreased apoptosis, increased vascularisation

Permanent Occlusion Rat 5.000 IU/kg After occlusion 52 Reduction in apoptosis

Permanent Occlusion Rat 3.000 IU/kg After occlusion 34 Reduction in infarct size, improvement LV function

Permanent Occlusion Rat 40µg/kg darbe-poietin After occlusion 53 Reduction in infarct size, improvement

LV function, increase in capillaries

58 EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III

However, recent studies question the concept of EPOR signalling in endothelial cells and cardiomyocytes since no functional EPOR was detected on these cells38. Accordingly in some non-haemato-poietic tissue protection models EPO was unable to preserve re-nal function after ischemia reperfusion injury 39 and did not alter lipopolysaccaride-induced myocardial depression and myocyte apoptosis 40.

Recent studies investigating the local EPO application in myocar-dial ischemia revealed contradictory results. A single high-dose intramyocardial administration of EPO led to an enhanced intracar-diac proliferation and improved cardiac function after permanent coronary occlusion in rats.41-43 After ischemia and reperfusion, however, a single intramyocardial dose of EPO was not sufficient to improve cardiac left ventricular ejection fraction measured in MRI.44 Yet, additional application with endothelial progenitor cells improved regional wall movement by MR as compared to EPC in-jection alone. Underlying mechanisms may include anti-apoptotic and immunomodulatory effects.

Clinical studies using erythropoietin in acute myocardial infarctionBased on the promising results of the experimental studies numer-ous prospective, randomised, clinical trials have been initiated to assess potential clinical benefits of EPO administration in patients presenting with myocardial infarction.45-49 So far five studies have been completed; three further trials are still recruiting patients. (Table 2).

One of the first trials to be completed was the Efficacy Study of Erythropoietin After Revascularization in Myocardial Infarction (RE-VIVAL 3) trial 46. Patients presenting with ST-elevation myocardial infarction and an onset of symptoms of less than 24 hours were treated with primary percutaneous coronary intervention (PCI). Im-mediately after reperfusion of the infarcted vessel, after 24 hours and after 48 hours, 3.33×104 IU of EPO (n=68) or placebo (n=70) was given intravenously. With a cumulative dose of 100,000 IU this was the highest dose given compared to other trials. There was no significant difference in primary endpoint defined as left ventricular ejection fraction assessed by MRI after six months (EPO 52.0±9.1%, placebo 51.8±9.3%).

Table 2: Effects of EPO in experimental myocardial infarction

Trial PatientsApplication

TimeSingle

EPO DoseCumulative

EPO DoseFollow

upPrimary

EndpointSecondary Endpoints

REVEAL 138 < 4h after PCI 60.000 U 60.000 U 12 weeks No change in infarct size assessed by MRI

No change in cardiac volumes, increase ad-verse clinical events with EPO, increase in

infarct size in pats. >70yrs.

HEBE III 529 < 3h after PCI 60.000 U 60.000 U 6 weeksNo Change in LVEF by Radionuclide Ventricu-

lography

Lower MACE in EPO group

REVIVAL 3 138 during PCI,

24h and 48h 33.300 U 100.000 U 6 months No change in LVEF frac-tion assessed by MRI

MACCE increased by trend in EPO group

EPOC AMI 35 after PCI, 48h

and 96h 6.000 U 18.000 U 6 months No change in infarct size assessed by SPECT

No change in cardiac volumes or MACE

Suh et al. 57 before PCI 50 U/kg 50 U/kg 4 daysNo change in infarct

size by cardiac biomark-ers

No change in infarct size assessed by MRI

EPOMI Study Recruiting directly after

PCI 1000 U/kg 1000 U/kg 3 months Infarct size assessed by MRI

Cardiac Volumes, ejection fraction,

MACE

Intra-CO-EpoMI Recruiting during PCI 150 µg 150 µg (Dar-

bepoetin) 3 months Infarct size assessed by MRI

Cardiac enzymes, Echocardiography

E P A M I -NONDAS Recruiting after PCI, 24h

and 48h100 or 200

IU/kg300 or 600

IU/kg12

months

Infarct size assessed by MRI and cardiac

biomarkersMACE

ERYTHROPOIETIN IN MYOCARDIAL INFARCTION


The cumulative six-month incidence of death, recurrent myocardial infarction, stroke or target vessel revascularisation was 13.2% in the erythropoietin group and 5.7% in the placebo group (P=0.15). The recently published HEBE III trial was the largest trial so far and en-rolled 529 patients with STEMI and successful PCI 47. Patients were randomised to either receive standard medical care alone (n =266), or in combination with a single dose 60,000 IU of epoetin alfa (EPO n= 263) within 3 h after PCI.

Left ventricular ejection fraction after six weeks assessed by planar radionuclide ventriculography was defined as primary endpoint and showed no significant difference between erythropoietin group (53±10%) and control group (52±11%; P = 0.41). However the incidence of cardiovascular events within six weeks after PCI including cardiovascular death, re-infarction, emergency re-PCI or coronary artery bypass grafting, stroke and clear symptoms of heart failure was increased in the control group as compared to the EPO group (19 vs. 8; P = 0.032).

In the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial, 138 patients presenting with STEMI were enrolled and randomised to either receive a single dose of 60,000 IU EPO within four hours after successful PCI or placebo. There was no significant difference concerning the primary endpoint defined as infarct size assessed by MRI after 12 weeks. In a subgroup analysis patients >70 years EPO treatment even increased infarct size although the low patient number needs to be taken into account. EPO treatment was also as-sociated with an increased number of adverse clinical events. After EPO four per cent of the patients underwent death, recurrent myo-cardial infarction, stroke or stent thrombosis, none of these events were observed after placebo 54.

Two smaller trials were conducted with results that were in line with these trials: In the Erythropoietin Prevention Trial of Coronary Re-stenosis and Cardiac Remodeling After ST-Elevated Acute Myocar-dial Infarction (EPOC-AMI), 35 patients presenting with STEMI were randomised to either receive 6,000 IU of EPO after PCI, at 48 and 96 hours of standard medical care 48. No improvement in infarct size assessed by single photon emission computed tomography (SPECT) after six months could be observed. Moreover, no signifi-cant differences in cardiac volumes or major adverse cardiac events (MACE) were observed. The study conducted by Suh et al. ran-domised 57 patients with STEMI either to PCI and standard medical care or to an additional single dose of 50 U/kg EPO before PCI 49.After four days the release of cardiac enzyme and the absolute in-farct volume in MRI did not differ between two groups.

DISCUSSION

The clinical trials outlined above used greatly different regimens of EPO treatment, ranging from 50 IU/kg up to a cumulative dose of 100,000 IU. As compared to the experimental studies even the highest dose of EPO is at least fourfold lower of the dosages used in experimental myocardial infarction. Thus, it cannot be excluded that higher dosages or prolonged application may prove beneficial. Yet, considering the experimental data with decreases in infarct size up to 40% after EPO and efficacy of even low dose EPO, sug-gest that the preclinical finding of a beneficial effect of EPO in AMI does not translate into clinical practice.

Efficacy of short-term and high-dose EPO treatment in the REVIV-AL-3 trial is assumed as increased levels of reticulocytes, platelets and progenitor cells were observed. With the lower EPO dose of 18,000 IU in the EPOC-AMI trial, no increase in progenitor cells or platelet count was described. Haematocrit and haemoglobin lev-els remained unchanged in all of the published trials. Accordingly, no higher rates in thromboembolic events during EPO treatment were observed. Nevertheless the number of patients enrolled in the clinical trials is not sufficient to fully exclude an increased thrombo-embolic risk, so further evaluation of EPO´s influence on platelet function and coagulation parameters in these patients may aid in determining this risk.

The performed trials showed that short-term treatment with EPO in AMI is safe, but seems to have no clinical benefit concerning im-provement in myocardial function assessed by either left ventricu-lar ejection fraction or infarct size in SPECT or MRI or reduction in infarct size. The time point for evaluation of the primary endpoint differed from four days to six months. In the HEBE III trial, the larg-est study with 526 patients, left ventricular ejection fraction was evaluated after six weeks using radionuclide ventriculography. The REVIVAL 3 trial had a longer follow up and analysed left ventricu-lar ejection fraction after six months in MRI. Independent from the time point or imaging method no improvement could be observed in any study published so far.

A possible clinical benefit was observed in the HEBE III trial, where the incidence of MACE was lower in the EPO group. This was due to a higher rate of heart failure in the control group (7 vs. 1; p=0.034). In contrast, patients enrolled in the REVIVAL 3 trial had a trend to-wards a higher MACCE, mainly due to a higher incidence of target lesion revascularisation. Similarly the REVEAL trial an increased number of adverse events was found after treatment with EPO. Considering these controversial results it has to be taken into ac-count that these studies are underpowered for clinical endpoints.

The evidence from animal studies that erythropoietin could en-hance re-endothelialisation leading to inhibition of in-stent reste-nosis by directly protecting endothelial apoptosis and mobilising endothelial progenitor cells was addressed in the EPOC-AMI trial. Primary endpoints included in-stent neointimal volume and in-stent late lumen loss but showed no effect of low dose EPO treat-ment on neointima generation. Results of the other trials regarding neointima generation may further clarify the role of high dose EPO on neointima generation.

All trials enrolled patients whose left ventricular ejection fraction (LVEF) was mildly reduced, but kept over 50% on follow-up, sug-gesting that all patients were treated optimally by PCI and stan-dard therapy. Although subgroup analysis in the REVIVAL-3 study showed no benefit of EPO treatment in patients with severely im-paired LV function the number of patients may be too low to allow detecting subtle changes in LVEF. Moreover, in the current clini-cal setting LV function might not be the best surrogate marker to evaluate the possible beneficial effects of EPO during AMI. Since recovery of LV function in many patients with AMI occurs up to six months after the event, it would be interesting to evaluate LVEF af-ter six months in patients in the REVEAL and the HEBE III trials.

Thus, erythropoietin failed to fulfil the expectations of improving ischemia reperfusion injury that were raised in numerous experi-mental studies since no changes in myocardial function or infarct size were observed in five clinical trials. The increase in adverse events in two of these trials should sound a note of caution.

60 EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III


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REFERENCES (Continued)

CARDIOVASCULAR DISEASES AND MENTAL DISORDERS | ORIGINAL ARTICLE

The Problem

Both cardiovascular diseases (CVD) and mental disorders are major public health issues, which lead to increased disability and mortality. CVD are the worldwide leading cause of death and are responsible for around four million deaths each year in Europe. Mental disorders also demonstrate high lifetime prevalence. For ex-ample, the National Comorbidity Survey (NCS), a population-based study in the USA, revealed that as many as 48.7% of the respondents re-port at least one lifetime disorder, with the most frequent being substance abuse/dependence (35.4%), followed by anxiety (19.2%) and mood disorders (14.7%)[1]

reported in European populations[2 3]. A recent WHO projection concluded, that by 2030, uni-polar depressive disorders and ischemic heart disease will be among the three leading causes of disease burden worldwide[4].

In addition, there is evidence indicating that CVD and mental disorders co-occur more fre-quently than would be expected by chance[5].

The association between mental disorders and CVD

It is well documented that the prevalence of de-pression is increased among patients with vari-ous manifestations of coronary artery diseases (CAD)[6].

1. Department of Medicine, Internal Medicine2. Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

CORRESPONDENCE

Peter Vollenweider,Service de Médecine Interne,BH 10-624, CHUV 1011 Lausanne,Switzerland

Phone: +41 21 314 09 63Fax: +41 21 314 08 71E-mail: [email protected]

ACKNOWLEDGEMENTS

The CoLaus/PsyCoLaus study is supported by research grants from the Swiss National Science Foundation (grants no: 33CSCO-122661 and 3200B0–105993), from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne, Switzerland. The authors also express their grati-tude to the participants in the Lausanne CoLaus study.

ISSN 2042-4884

ABSTRACT

Cardiovascular diseases (CVD), their well-established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, potential causal mechanisms underlying their association still need to be elucidated. Several non-mutually exclusive hypotheses have been suggested to explain this association: a) mental disorders could increase vulnerability to CVD through poor health behaviour including smoking, unbalanced diet,

the development of mental disorders; or c) mental disorders and CVD/CVRF could share risk factors such as common metabolic processes or common genes. Disentangling some of these mechanisms will require studying the temporal relationship of the appearance of CVD and mental disorders.

Herein we review the existing epidemiological evidence of an association between these two types

CoLaus/PsyCoLaus study cohort, a population-based in Lausanne, Switzerland designed to address some of these questions.

Cardiovascular Diseases and Mental Disorders: Bidirectional Risk Factors?

Peter Vollenweider MD1, Gérard Waeber MD1, François Bastardot1 & Martin Preisig MD2

Received 17/12/2010, Reviewed 30/12/2010, Accepted 17/01/2011DOI: 10.5083/ejcm.20424884.23

Similarly, depression can occur from 20% up to

stroke, with poststroke depression occurring in up to 30% of the patients[7]. The development of psychiatric symptoms is associated with a poor functional prognosis and a negative impact on the patient’s quality of life. Conversely, in pop-ulation-based prospective studies, individuals with depression or depressive symptoms have increased cardiovascular morbidity and mortal-ity[8]. However, the large majority of these epi-demiological studies rely on depression scales or self-rating questionnaires for depression rather than diagnostic interviews and did not

mental disorders such as anxiety and substance use disorders.

As these studies could not or only partially ad-just for the presence of CVRF other than depres-sion, the question of whether or not depression is an independent risk factor for CVD is still not resolved. In addition, not only depression but

in patients with CAD [9]. Potential mechanisms involved in this association of CVD and mental disorders have only been partially elucidated. Several non-mutually exclusive hypotheses have been suggested to explain this association: a) mental disorders could increase vulnerabilityto CVD; b) CVD or their treatment could favourthe development of mental disorders and c) CVD/CVRF could share common pathogenic processes.

24 EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III 62 EUROPEAN JOURNAL OF CARDIOVASCULAR MEDICINE VOL I ISSUE III


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