Stem cells in heart failure

Heart failure (HF) is a leading public health problem resulting in an increased risk of cardiovascular complications and mortality. Despite advances in medical therapy, the prevalence of HF is still increasing. The Framingham study demonstrated that the life time risk for developing HF is one in five for both men and women. Evidence-based treatment of chronic HF is mainly focused on suppressing the chronic neurohormonal activation, which may prevent the deterioration of heart function. However, despite many therapeutic strategies patients diagnosed with HF have a poor prognosis. Conventional medical strategies for the treatment of HF due to myocardial infarction (MI) do not attempt to correct the underlying cause (i.e. loss of viable or functional myocardial tissue), raising a need for strategies aimed at myocardial regeneration and repair. Therefore novel approaches to increase the number of functioning cardiac muscle cells in the failing heart might open new avenues for the treatment of patients with advanced HF. Over the past few years, several thousand patients have been treated with various forms of bone marrow stem cell therapy during acute MI. On the basis of early animals studies, cell-based therapy clinical trials were quickly initiated, with the hope that injected or circulating haematopoietic stem cells would lead to cardiac regeneration. Indeed, several studies have reported a modest but statistically significant improvement in left ventricular (LV) ejection fraction in patients’ post-MI. In a post hoc analysis of the REPAIR-AMI trial, for example, it was suggested that bone marrow stem cell therapy was most effective in patients with markedly depressed LV function, which may indicate that the possible beneficial effects of bone marrow cell therapy may be restricted to a specific group of patients. Similar results were observed in the HEBE trial, which showed overall no benefit of bone marrow stem cells after MI. However, in a sub-population of patients with a dilated LV at baseline, bone marrow stem cell therapy prevented further dilation compared with controls, which is in concert with other observations. A recent meta-analysis which included 811 participants with acute MI from 13 trials showed a 3% improvement in LV ejection fraction in the experimental group. Thus, intracoronary infusion of bone marrow derived stem cells appears to result in a modest but reproducible short-term improvement in LV systolic function in the setting of acute MI. In the current issue of the journal, Strauer et al. extend these findings to the chronic HF population. In an open label, nonrandomized, prospective study, 391 patients with an ischaemic aetiology of HF were included, of which 191 patients received an intracoronary bone marrow cell infusion. Post-treatment the authors reported an improvement in LV performance and a longterm decrease in mortality of patients treated with stem cells. These results suggest that bone marrow cells may have a positive effect on cardiac remodelling and improving function in patients with chronic HF. Although the study is the largest in its kind, it needs to be emphasized that the study was open label and was not randomized. Patients who refused to undergo bone marrow cell infusion were included in the control group. This may well lead to a significant bias and limits the value of the current trial. In addition, at baseline the intervention group had a 7% lower LV ejection fraction compared with the control group. Despite these reported improvements in LV systolic function, uncertainties remain. For example the preferred route of administration is still subject to debate. Furthermore, the mechanism, by which stem cells exert their potentially beneficial effects remain poorly understood. In the light of several experimental studies, there is little evidence to support the onset of cardiac muscle regeneration following bone marrow therapy. As a result, it has been proposed that the bone marrow derived stem cells may exert a paracrine effect to improve angiogenesis. This is supported by a study in a large animal model of acute MI that showed injection of bone marrow derived stem cells increased capillary density and improved collateral perfusion and regional cardiac function. Furthermore, it has been previously shown