An emerging need for developing new models for myocardial infarction as a chronic complex disease: lessons learnt from animal vs. human studies on cardioprotective effects of Erythropoietin in reperfused myocardium

BackgroundErythropoietin (EPO) has been suggested to promote cardiac repair after MI. However, the randomized, double-blind, placebo controlled REVIVAL-3 trial showed that short term high dose EPO in timely reperfused myocardium does not improve left ventricular ejection fraction after 6 months. Moreover, the study raised safety concerns due to a trend towards a higher incidence of adverse clinical events as well as a increase in neointima formation after treatment with EPO. The present study therefore aimed to assess the 5-year clinical outcomes.MethodsAfter successful reperfusion 138 patients with STEMI were randomly assigned to receive epoetin beta (3.33×104 U, n = 68) or placebo (n = 70) immediately, 24 and 48 h after percutaneous coronary intervention. The primary outcome of the present study- the combined incidence of MACE 5 years after randomization - occurred in 25% of the patients assigned to epoetin beta and 17% of the patients assigned to placebo (RR 1.5; 95% CI 0.8-3.5; p = 0.26). Target lesion revascularization was required in 15 patients (22.1%) treated with epoetin-ß and 9 patients (12.9%) treated with placebo (p = 0.15). Analysis of patients in the upper and lower quartile of baseline hemoglobin as an indirect estimate of endogenous erythropoietin levels revealed no significant impact of endogenous erythropoietin on efficiency of exogen administered epoetin-ß in terms of death and MACE.ConclusionThese long-term follow-up data show that epoetin beta does not improve clinical outcomes of patients with acute myocardial infarction.Trial registrationURL www.clinicaltrials.gov; Unique identifier NCT00390832; trial registration date October 19th 2006

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“…A central issue of the erythropoietin paradox however might lay in the difference between animal models and the real human world [27]. …”

Section: Discussionmentioning

confidence: 99%

Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial

Steppich

Groha

Ibrahim

et al. 2017

BMC Cardiovasc Disord

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“…It also explains why erythropoietin (EPO) is a protector in acute-induced MI in healthy myocytes but not in the adapted myocytes. Increased EPO secreted during chronic hypoxia previously saturated EPO receptors and implemented its cell protective effects; in fact, extra EPO, in this case, will not augment extra cell protection [3].…”

Section: Chronicity Is Not Reflected In Most Of the Current Modelsmentioning

confidence: 95%

“…Actually, acute myocardial infarction is the final sequence of the atherosclerosis drama as a chronic process. In the case of MI modeling, the erythropoietin paradox certified inappropriate modeling of MI as a complex phenomenon [3]. Almost 500 drugs underwent trial for stroke; among them, only aspirin and early recombinant tissue plasminogen activator did not fail [17,18].…”

Section: Gene Therapy: Another Illusion Of Scientific Revolutionmentioning

confidence: 99%

“…g. In experimental studies, the efficacy of treatment in models is evaluated by infarct volume, while the clinical relevance of infarct volume with the patients' outcome is in doubt. Infarct size has been shown to have a moderate correlation with the patients' clinical status and outcome [3]. h. Preconditioning is of great importance specially in terms of applying recombinant cell protectors such as EPO; nevertheless, preconditioning has not been modeled in animal models of stroke and MI.…”

Section: Myocardial Infarctionmentioning

confidence: 99%

“…In order to efficiently indorse the translational medicine as the "catalyzer" for the practical implementation of the accumulated scientific achievements, an appropriate dialogue is essential between three clusters of "clinician, clinical investigator, and PPPM relevant professional groups," "the bench scientists," and "industry and policy-makers" [1,2]. Animal models made a revolution in biomedical research [3]. Plenty of treatment modalities were developed on the basis of animal experimentations.…”

Section: Introductionmentioning

confidence: 99%

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Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

Seifirad

Haghpanah

2019

EPMA Journal

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Preclinical investigations such as animal modeling make the basis of clinical investigations and subsequently patient care. Predictive, preventive, and personalized medicine (PPPM) not only highlights a patient-tailored approach by choosing the right medication, the right dose at the right time point but it as well essentially requires early identification, by the means of complex and state-of-the-art technologies of unmanifested pathological processes in an individual, in order to deliver targeted prevention early enough to reverse manifestation of a pathology. Such an approach can be achieved by taking into account clinical, pathological, environmental, and psychosocial characteristics of the patients or an individual who has a suboptimal health condition. Inappropriate modeling of chronic and complex disorders, in this context, may diminish the predictive potential and slow down the development of PPPM and consequently modern healthcare. Therefore, it is the common goal of PPPM and translational medicine to find the solution for the problem we present in our review. Both, translational medicine and PPPM in parallel, essentially need accurate surrogates for misleading animal models. This study was therefore undertaken to provide shreds of evidence against the validity of animal models. Limitations of current animal models and drug development strategies based on animal modeling have been systematically discussed. Finally, a variety of potential surrogates have been suggested to change the unfavorable situation in medical research and consequently in healthcare.

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The antioxidants dilemma: are they potentially immunosuppressants and carcinogens?

2014

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An emerging need for developing new models for myocardial infarction as a chronic complex disease: lessons learnt from animal vs. human studies on cardioprotective effects of Erythropoietin in reperfused myocardium

Cited by 5 publications

References 46 publications

Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial

Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

The antioxidants dilemma: are they potentially immunosuppressants and carcinogens?

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