Novel cardioprotective and regenerative therapies in acute myocardial infarction: a review of recent and ongoing clinical trials

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Abstract

Following the original large-scale randomized trials of aspirin and β-blockade, there have been a number of major advances in pharmacological and mechanical treatments for acute myocardial infarction. Despite this progress, myocardial infarction remains a major global cause of mortality and morbidity, driving a quest for novel treatments in this area. As the understanding of mitochondrial dynamics and the pathophysiology of reperfusion injury has evolved, the last three decades have seen advances in ischemic conditioning, pharmacological and metabolic cardioprotection, as well as biological and stem-cell therapies. The aim of this review is to provide a synopsis of adjunctive cardioprotective and regenerative therapies currently undergoing or entering early clinical trials in the treatment of patients with acute myocardial infarction.

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A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Joshua Hare, Jay Traverse, Timothy D Henry … (2009)

Our aim was to investigate the safety and efficacy of intravenous allogeneic human mesenchymal stem cells (hMSCs) in patients with myocardial infarction (MI). Bone marrow-derived hMSCs may ameliorate consequences of MI, and have the advantages of preparation ease, allogeneic use due to immunoprivilege, capacity to home to injured tissue, and extensive pre-clinical support. We performed a double-blind, placebo-controlled, dose-ranging (0.5, 1.6, and 5 million cells/kg) safety trial of intravenous allogeneic hMSCs (Prochymal, Osiris Therapeutics, Inc., Baltimore, Maryland) in reperfused MI patients (n=53). The primary end point was incidence of treatment-emergent adverse events within 6 months. Ejection fraction and left ventricular volumes determined by echocardiography and magnetic resonance imaging were exploratory efficacy end points. Adverse event rates were similar between the hMSC-treated (5.3 per patient) and placebo-treated (7.0 per patient) groups, and renal, hepatic, and hematologic laboratory indexes were not different. Ambulatory electrocardiogram monitoring demonstrated reduced ventricular tachycardia episodes (p=0.025), and pulmonary function testing demonstrated improved forced expiratory volume in 1 s (p=0.003) in the hMSC-treated patients. Global symptom score in all patients (p=0.027) and ejection fraction in the important subset of anterior MI patients were both significantly better in hMSCs versus placebo subjects. In the cardiac magnetic resonance imaging substudy, hMSC treatment, but not placebo, increased left ventricular ejection fraction and led to reverse remodeling. Intravenous allogeneic hMSCs are safe in patients after acute MI. This trial provides pivotal safety and provisional efficacy data for an allogeneic bone marrow-derived stem cell in post-infarction patients. (Safety Study of Adult Mesenchymal Stem Cells [MSC] to Treat Acute Myocardial Infarction; NCT00114452).

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Pathophysiology of ischaemia-reperfusion injury.

Donna Carden, D. Granger (2000)

Reperfusion of ischaemic tissues is often associated with microvascular dysfunction that is manifested as impaired endothelium-dependent dilation in arterioles, enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules. Activated endothelial cells in all segments of the microcirculation produce more oxygen radicals, but less nitric oxide, in the initial period following reperfusion. The resulting imbalance between superoxide and nitric oxide in endothelial cells leads to the production and release of inflammatory mediators (e.g. platelet-activating factor, tumour necrosis factor) and enhances the biosynthesis of adhesion molecules that mediate leukocyte-endothelial cell adhesion. Some of the known risk factors for cardiovascular disease (hypercholesterolaemia, hypertension, and diabetes) appear to exaggerate many of the microvascular alterations elicited by ischaemia and reperfusion (I/R). The inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not exposed to the initial ischaemic insult. This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome. Adaptational responses to I/R injury have been demonstrated that allow for protection of briefly ischaemic tissues against the harmful effects of subsequent, prolonged ischaemia, a phenomenon called ischaemic preconditioning. There are two temporally and mechanistically distinct types of protection afforded by this adaptational response, i.e. acute and delayed preconditioning. The factors (e.g. protein kinase C activation) that initiate the acute and delayed preconditioning responses appear to be similar; however the protective effects of acute preconditioning are protein synthesis-independent, while the effects of delayed preconditioning require protein synthesis. The published literature in this field of investigation suggests that there are several potential targets for therapeutic intervention against I/R-induced microvascular injury. Copyright 2000 John Wiley & Sons, Ltd.

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Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

Adam Williams, Joshua Hare (2011)

Mesenchymal stem cells (MSCs) are a prototypical adult stem cell with capacity for self-renewal and differentiation with a broad tissue distribution. Initially described in bone marrow, MSCs have the capacity to differentiate into mesoderm- and nonmesoderm-derived tissues. The endogenous role for MSCs is maintenance of stem cell niches (classically the hematopoietic), and as such, MSCs participate in organ homeostasis, wound healing, and successful aging. From a therapeutic perspective, and facilitated by the ease of preparation and immunologic privilege, MSCs are emerging as an extremely promising therapeutic agent for tissue regeneration. Studies in animal models of myocardial infarction have demonstrated the ability of transplanted MSCs to engraft and differentiate into cardiomyocytes and vasculature cells, recruit endogenous cardiac stem cells, and secrete a wide array of paracrine factors. Together, these properties can be harnessed to both prevent and reverse remodeling in the ischemically injured ventricle. In proof-of-concept and phase I clinical trials, MSC therapy improved left ventricular function, induced reverse remodeling, and decreased scar size. This article reviews the current understanding of MSC biology, mechanism of action in cardiac repair, translational findings, and early clinical trial data of MSC therapy for cardiac disease.

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Author and article information

Journal

Journal ID (nlm-ta): Future Cardiol

Journal ID (iso-abbrev): Future Cardiol

Journal ID (publisher-id): FCA

Title: Future Cardiology

Publisher: Future Medicine Ltd (London, UK )

ISSN (Print): 1479-6678

ISSN (Electronic): 1744-8298

Publication date (Print): November 2016

Publication date (Electronic): 28 October 2016

Publication date PMC-release: 28 October 2016

Volume: 12

Issue: 6

Pages: 655-672

Affiliations

[1 ]Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK

[2 ]Edinburgh Heart Centre, Royal Infirmary of Edinburgh, Edinburgh, UK

Author notes

*Author for correspondence: nick.spath@ 123456ed.ac.uk

Article

DOI: 10.2217/fca-2016-0044

PMC ID: 5985502

PubMed ID: 27791385

SO-VID: 10febf9e-8a5f-4f31-b620-38f1f0a6b658

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This work is licensed under a Creative Commons Attribution 4.0 License

History

Date received : 20 May 2016

Date accepted : 24 August 2016

Date: 28 October 2016

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Novel cardioprotective and regenerative therapies in acute myocardial infarction: a review of recent and ongoing clinical trials

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Most cited references 76

A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction.

Pathophysiology of ischaemia-reperfusion injury.

Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease.

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