Abstract

Cardiovascular disease (CVD) continues to be one of the main causes of death in the western world. A high burden of disease and the high costs for the healthcare systems claim for novel therapeutic strategies besides current conventional medical care. One decade ago first clinical trials addressed stem cell based therapies as a potential alternative therapeutic strategy for myocardial regeneration and repair. Besides bone marrow derived stem cells (BMCs), adult stem cells from adipose or cardiac tissue have been used in current clinical studies with inconsistent results. Although outcomes in terms of safety and feasibility are generally encouraging, functional improvements were mostly disappointingly low and have failed to reach expectations. In the future, new concepts for myocardial regeneration, especially concerning recovery of cardiomyocyte loss, have to be developed. Transplantation of novel stem or progenitor cell populations with true regenerative potential, direct reprogramming of scar tissue into functional myocardium, tissue engineering or stimulation of endogenous cardiac repair by pharmacological agents are conceivable. This review summarizes current evidence of stem cell based regenerative therapies and discusses future strategies to improve functional outcomes.

KEYWORDS : Myocardial infarction, regenerative medicine, stem cells, tissue engineering, reprogramming

In 2009 cardiovascular disease (CVD) still accounted for 32.3% of all deaths in the United States and therefore continues to be one of the main causes of death (1). From 1999 to 2009, the rate of death due to CVD has declined, but nevertheless the burden of disease remains high. Although improved medical care and acute management of myocardial infarction have led to a considerable reduction of early mortality rate survivors are susceptible to an increased prevalence of chronic heart failure as they develop scarring followed by ventricular remodeling despite optimum medical care (2,3).

Interestingly, cardiovascular operations and interventional procedures increased by 28% from 2000 to 2010 implicating an enormous cost factor for the healthcare system (1). For 2009, it was estimated that the direct and indirect costs of CVD and stroke add up to about $312.6 billion in the United States, which was more than for any other diagnostic group (1).

The main issue of current pharmacological, interventional or operative therapies is their disability to compensate the irreversible loss of functional cardiomyocytes (4). Hence, the future challenge of cardiovascular therapies will be the functional regeneration of myocardial contractility by novel concepts, like cell based therapy, tissue engineering or reprogramming of scar fibroblasts (5,6).

After promising preclinical results using adult stem and precursor cells for cardiac regeneration a rapid clinical translation using autologous bone marrow cells (BMCs) in patients was initiated (7,8). In the last few years numerous clinical trials addressing the transplantation of various adult stem cell populations for cardiac regeneration have been performed. Essential characteristics for the selected adult stem cell populations are the potential to proliferate, migrate and the ability to transdifferentiate into various mature cell types (9). Today, different adult stem cell sources like BMCs, myocardium or adipose tissue derived cells were already used in clinical trials. Beside direct intracoronary or intramyocardial transplantation of adult stem cells into the heart mobilization of autologous progenitor cells by administration of different cytokines [i.e., erythropoietin (EPO) or granulocyte colony stimulating factor (G-CSF)] were also evaluated in first clinical trials (summarized in and ,).

Regenerative therapies and cell sources currently administered in clinical trials. Current clinical trials use BMCs, ADRCs or CPCs to regenerate impaired myocardium after ischemic events. Alternatively cytokines like EPO or G-CSF are employed to mobilize ...

Transplantation of adult stem cells-clinical trials mentioned in the text.

Mobilization of adult stem cells-clinical trials mentioned in the text.

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Cardiac regeneration: current therapies—future concepts

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