There has naturally been more preclinical than clinical research into different aspects of the use of MSCs, including their collection, treatment and application.

In vitro differentiation of MSCs into cardiomyocytes was first demonstrated by Makino et al. in 1999,4 while in 2004 Wang et al.5 demonstrated the potential of MSCs for regeneration of myocardium in a rabbit model of MI, with considerable impact on mortality (16.7% in the treatment group vs. 35% in controls, p<0.05). These and other animal studies also showed the advantages of treating stem cells in different ways before application. In a 2005 study, Hattan et al.6 transplanted purified cardiomyocytes differentiated from bone marrow MSCs in vitro into adult mouse hearts; three months later the transplanted cells had survived and were oriented in parallel to the cardiomyocytes of the recipient heart.

There is growing evidence that MSCs have multiple paracrine effects that even without cell replacement can affect cardiac remodeling, angiogenesis and cytoprotection, with significant clinical benefits. In 2007, Dai et al.7 showed that injecting a medium containing cell factors secreted by MSCs improved post-infarction myocardial regeneration in rats, although this was more marked when the cells themselves were also injected. In the same year Ohnishi et al.8 demonstrated the role of MSCs in inhibiting cardiac fibrosis through regulation of collagen synthesis by cardiac fibroblasts, as well as their effects on fibroblast proliferation.

The hostile environment of the ischemic zone resulting from MI rapidly leads to the death of many transplanted MSCs, but ischemic preconditioning of the cells can improve their survival. In a 2005 study in an in vivo mouse model, Tang et al.9 showed that preconditioning increased the survival and viability of MSCs in the ischemic heart. Research into this treatment is ongoing, including a study by Chacko et al.10 in 2010 which found improved expression of MSCs cultivated initially in normoxia followed by 24hours of hypoxia prior to administration.

In 2006, Amado et al.11 used magnetic resonance imaging to monitor myocardial repair following mesenchymal stem cell therapy in a swine model, and found regeneration of viable tissue with contractile function in a previously fibrotic area.

With regard to the delivery of the cells, safety and effectiveness are a major concern. Llano et al.12 showed that infusion of MSCs improves distal coronary blood flow in a swine model when administered in a single 20-ml/min bolus, an advance on previous studies in which multiple administrations had led to reduced flow. Different delivery routes also vary in effectiveness, particularly in terms of immediate homing, as shown in a 2008 study by Hale et al.13 in which intracoronary delivery resulted in 15% of the cells being retained in an infarcted rat heart model, while none were retained following intravenous administration. In 2009 the same group14 used a collagen matrix as a means of delivery of MSCs, which increased retention of cells in damaged tissue, although with no significant improvement in myocardial function. The search for better delivery routes continues, and in 2011 Hamdi et al.15 showed excellent results with epicardial delivery of MSCs in a mouse infarction model.

Several studies have shown the benefits of transplanting MSCs in animal models of heart disease, particularly following MI, but also in non-ischemic cardiomyopathy and other cardiovascular disorders. In 2009 Umar et al.16 showed that administering MSCs in a rat model of pulmonary hypertension influenced the pathophysiology of the disease by reducing the hypertension and thus right ventricular overload.

Although few clinical trials on coronary disease have been concluded, this is the area in which there has been most research into stem cell therapy.

In 2004, Chen et al.17 showed significant improvement in left ventricular ejection fraction (LVEF) following intracoronary injection of MSCs in 69 patients 18 days after MI; the patients thus treated had a favorable clinical course, with no complications related to the therapy.

In 2005, Katritsis et al.18 presented the results of transplanting autologous MSCs and endothelial progenitor cells in eleven MI patients. There were no adverse effects related to the therapy and left ventricular function improved, while myocardial scarring assessed by scintigraphy was reduced.

In a 2009 randomized, double-blind clinical trial by Hare et al.19 of allogenic MSCs (Prochymal®, Osiris Therapeutics) administered intravenously to 60 patients after MI, treated patients had fewer arrhythmic events. Two trials are under way by the same group (at the Miller School of Medicine at the University of Miami) of MSCs in ischemic cardiomyopathy: PROMETHEUS, in which patients with indication for coronary artery bypass grafting (CABG) and LVEF of 15–50% will receive either 20 × 106 (low dose group) or 200 × 106 (high dose group) of autologous MSCs by direct intramyocardial injection, and TAC-HFT, in which patients with similar characteristics but candidates for cardiac catheterization will receive MSCs by transendocardial injection.

A 2010 trial by Yang et al.20 of intracoronary transplantation of autologous MSCs in 16 patients with anterior MI showed no adverse effects and improved LVEF at six months. In the same year, in a study by Viswanathan et al.21 in 31 patients in whom MSCs were injected transepicardially in the border zone of the infarcted area during CABG, no adverse effects were observed and myocardial perfusion improved in treated patients.

Another trial currently under way is C-CURE, carried out by Bartunek's group, in patients with chronic ischemic heart disease, using cardiac progenitor cells derived from bone marrow stem cells cultured, expanded and differentiated in a cytokine cocktail. Unpublished six-month results reported in April 2011 were favorable, with improved LVEF and reduced left ventricular end-systolic volume; more detailed results are awaited.

Of the various types of mesenchymal stem cells, there has been particular interest in the adipose lineage, in view of their ready availability and the success of several preclinical studies. In the APOLLO trial, adipose-derived stem cells were administered to 14 patients 24hours after MI. Although the aim of the trial was to assess the safety and viability of this cell type and the means of delivery, 18-month data reported in June 2011 showed an 11% reduction in infarct area and a 6% improvement in LVEF.

Deregulation of the renin-angiotensin-aldosterone, neuroendocrine and inflammatory systems is known to be involved in the pathophysiology of heart failure (HF). Available pharmacological therapies can modify these processes at various levels, but fully effective treatment of HF remains out of reach. Stem cell therapy, particularly with MSCs, with their immunomodulatory properties, thus makes sense in the treatment of HF of whatever etiology, by interrupting the chronic inflammation cascade found in the condition.

There have been few clinical trials in humans showing that stem cell therapy is an effective treatment for HF, but they do indicate that the technique is safe.

In 2006, in a randomized trial of 24 patients with non-ischemic dilated cardiomyopathy receiving standard drug therapy in which the treatment group (n=12) received intracoronary injections of MSCs and the control group (n=12) received saline, Wang et al.22 showed that plasma levels of brain natriuretic peptide (BNP) fell at three and six months, while functional capacity as assessed by the 6-minute walk test improved, although there was no effect on left ventricular function or survival. No major complications were observed, including arrhythmias or adverse side-effects of the stem cell therapy, further evidence of the safety of the technique.

In 2010, Zeinaloo et al.23 presented a case report of intracoronary administration of autologous MSCs in a child with dilated cardiomyopathy ineligible for heart transplantation, which led to improvement in functional class, quality of life and echocardiographic parameters of left ventricular function.

Although many studies in animal models and recently in humans have shown the benefits of MSC therapy in cardiac hemodynamics, there has been little investigation of its arrhythmic and electrophysiological effects.

In 2003 Pak et al.24 noted sprouting of sympathetic nerves in pig myocardium following transplantation of MSCs, which could increase the risk of arrhythmias. However, this was not corroborated by other investigators, including Amado et al.,25 who in 2005 reported no increase in sudden death in pigs undergoing intramyocardial injection of MSCs compared to placebo.

The aim is that stem cells implanted into myocardium in order to repair damaged tissue will form clusters with native myocytes to form homogeneous, functional tissue. It is now known that if the implanted cells present abnormal electrophysiological properties or spontaneous electrical activity, they may be a source of electrical excitation, leading to severe arrhythmias. If the implanted cells do not combine electrically with the surviving myocytes, they may also increase the area of conduction block in the damaged myocardial tissue.

The efficacy of MSC therapy and the risk of arrhythmias depend on the number of cells transplanted and the means of delivery. The intramyocardial route tends to result in clusters of cells in areas of non-viable tissue, which will lead to heterogeneous conduction and possible conduction block, while intracoronary administration is more likely to result in homogeneous delivery and aggregation in the desired location.

Phase 1 clinical trials of transplantation of skeletal myoblasts highlighted the importance of thorough assessment of the risk of arrhythmias before trials in humans. In a laboratory study by Chang et al. in 200626 with optical mapping of an in vitro coculture model, reentrant arrhythmias (the equivalent of monomorphic ventricular tachycardia) were easily induced in cocultures with over 10% of MSCs but not in those with less than 1%. This indicates that MSCs can be proarrhythmic if large numbers are injected intramyocardially, and suggests that arrhythmic risk should be carefully evaluated in MSC transplantation models.

Another area of potential application for MSCs is chronic rhythm disturbances. Most investigators have focused on their use as biological pacemakers, but there is also increasing evidence that they could be used to repair the atrioventricular node. Both of these could in theory replace implantation of electronic pacemakers.

Finally, an emerging area of interest is the transplantation of MSCs that express specific ion channels, with a view to suppressing focal arrhythmias, as an alternative to surgical or catheter ablation. As the number of cells required would be relatively low, it may be easier to bring this therapy to clinical application.

The authors declare that no experiments were performed on humans or animals for this study.

The authors declare that no patient data appear in this article.

The authors declare that no patient data appear in this article.