Stem cell therapy for cardiac dysfunction

SpringerPlus, Aug 2014

Following significant injury, the heart undergoes induced compensation and gradually deteriorates towards impending heart failure. Current therapy slows but does not halt the resultant adverse remodeling. Stem cell therapy, however, has the potential to regenerate or repair infarcted heart tissue and therefore is a promising therapeutic strategy undergoing intensive investigation. Due to the wide range of stem cells investigated, it is difficult to navigate this field. This review aims to summarize the main types of stem cells (both of cardiac and extra-cardiac origin) that possess promising therapeutic potential. Particular focus is placed on clinical trials supporting this therapeutic strategy.

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Stem cell therapy for cardiac dysfunction

Amer A Matar 1 James JH Chong 0 1 0 Department of Cardiology, Westmead Hospital , Sydney, NSW, Australia 1 Sydney Medical School, University of Sydney , Sydney, NSW, Australia Following significant injury, the heart undergoes induced compensation and gradually deteriorates towards impending heart failure. Current therapy slows but does not halt the resultant adverse remodeling. Stem cell therapy, however, has the potential to regenerate or repair infarcted heart tissue and therefore is a promising therapeutic strategy undergoing intensive investigation. Due to the wide range of stem cells investigated, it is difficult to navigate this field. This review aims to summarize the main types of stem cells (both of cardiac and extra-cardiac origin) that possess promising therapeutic potential. Particular focus is placed on clinical trials supporting this therapeutic strategy. - Introduction Myocardial infarction (MI) remains a leading cause of death and disability worldwide. In the United States alone, approximately 1 million cases of MI occur annually (Roger et al. 2011). The implementation of cardiovascular prevention strategies continues to reduce the incidence of MI. Concurrently, however, evolution of pharmacological approaches and coronary reperfusion interventions has led to an increased post-MI survival rate, which in turn has raised MI disease morbidity. Previous estimates indicate that approximately 9095% of patients survive their first MI (Rosamond et al. 2012), contributing to a current epidemic of heart failure and imposing an enormous health burden on individuals and the community. After MI, local cardiac compensatory mechanisms are activated giving rise to a vicious cycle of cardiac metabolic insufficiency, leading to heart failure and potentially sudden death (Orn et al. 2007). Timely reperfusion together with optimal drug and device-based interventions has improved MI management by reducing the initial burden of injury and slowing progression of resultant adverse remodeling (White et al. 2005). Nevertheless, no current therapy is able to reverse the inexorable decline in cardiac function. Therefore, new strategies investigating cardiac regeneration have demanded considerable interest. These involve either 1) the implantation of stem cells or their derivatives directly into the heart or 2) the activation of endogenous cardiac repair mechanisms in order to replace damaged cardiomyocytes and promote vascular reconstruction (Laflamme and Murry 2011). This review provides physicians with a concise overview of the major types of stem cells, both from cardiac or extra-cardiac origins, being investigated for post-MI treatment. For further detail and information on endogenous cardiac regeneration, the interested reader is directed to the following detailed reviews (Laflamme and Murry 2011; Choi and Poss 2012; Rasmussen et al. 2011). Extra-cardiac stem cells Skeletal myoblasts Skeletal myoblasts (SKM) are the progenitor cells of skeletal muscle. Initial observations that SKMs could be harvested from an autologous origin, easily expanded ex vivo and undergo spontaneous differentiation into contractile muscle sparked interest in SKMs for cardiac myoplasty (Taylor et al. 1998). Early uncontrolled clinical studies reported that SKMs could engraft in the injured heart with remarkable efficiency and enable significant improvement in cardiac function (Menasche et al. 2003). These findings were not reproduced in a subsequent prospective randomized placebo-controlled trial (Menasche et al. 2008), where 97 participants with severe left ventricular (LV) dysfunction underwent transepicardial autologous SKM injection at the time of coronary artery bypass grafting. Six months following the procedure, no improvement in LV function was found when compared to placebo. Importantly, a high prevalence of ventricular tachyarrhythmias was observed leading to premature discontinuation of the trial. Similar results were observed in the SEISMIC trial which used transendocardial injection of autologous SKMs (Veltman et al. 2008). A follow-up study conducted four years later reported no significant change in LV function compared to the placebo group. The general consensus amongst clinicians now is that SKMs do not electrically couple to host cardiomyocytes (Leobon et al. 2003). Notably, it is now understood that the gap-junction protein, connexin 43, can augment intracellular coupling of cardiomyocytes and confers a protective effect against ventricular tachyarrhythmias following cell transplantation (Roell et al. 2007). Bone marrow mononuclear cells The major stem cell type in the bone marrow (BM) is the hematopoietic stem cell (HSC). HSCs comprise less than 0.1% of unfractionated bone marrow mononuclear cell (BMMNC) samples (Challen et al. 2010). Although the vast majority of BMMNCs are not stem cells, they are still considered a significant source of hematopoietic progenitors which may be useful for cardiac repair. In 200 (...truncated)


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Amer A Matar, James JH Chong. Stem cell therapy for cardiac dysfunction, SpringerPlus, 2014, pp. 440, Volume 3, Issue 1, DOI: 10.1186/2193-1801-3-440