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Skeletal myoblasts for myocardial regeneration in patients with congestive heart failure: where have all the answers gone?

1. Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN, USA; 2. University of Minnesota Center for Cardiovascular Repair, Minneapolis, MN, USA

As the population ages and cardiovascular mortality declines, there is a large and growing population of patients with CHF, a heterogeneous disease resulting from both ischaemic (60%) and non-ischaemic (40%) aetiologies. Remarkable progress has been made in both medical and device therapy for patients with CHF over the last 20 years. In general, pharmacologic therapies with beta blockers and ACE inhibitors or device therapy with biventricular pacing or ICDs are successful, regardless of the aetiology of CHF. In contrast, successful stem cell therapy for CHF may well require an aetiology-specific approach. For example, the NIH-sponsored FOCUS trial targets CHF patients with Canadian class II-IV angina or NYHA class II-III heart failure and LVEF ≤45%. Patients are required to have areas of myocardium not amenable to revascularisation with reversible myocardial ischaemia. The targeted myocardial ischaemic area must show electrical viability by NOGA electromechanical mapping based on unipolar voltage of >6.9 mv. Eligible patients receive intramyocardial injection of 100 million autologous bone marrow mononuclear cells into the ischaemic zone9. In contrast, similar to the SEISMIC trial, the MARVEL trial enrolled NYHA class II-IV CHF patients with LVEF <35% who received cultured autologous skeletal myoblasts injected into the area of scar based on unipolar voltage <7.0 mv by NOGA10. The FOCUS trial is seeking to stimulate angiogenesis, to increase myocardial perfusion and subsequently improve LV function. In contrast, patients enrolled in MARVEL had normal blood flow, and the goal was to stimulate myogenesis in an attempt to improve LV function. Therefore, despite similar symptoms, LV function and required baseline therapy, CHF patients enrolled in FOCUS would be excluded from MARVEL, and vice versa. This is an important paradigm shift in the design of CHF clinical trials. Myocardial regeneration is a complex process and likely requires more than simple angiogenesis or myogenesis to rebuild living, viable muscle. Understanding the process and the solution in the CHF patient with previous MI and scar remains the major challenge in cardiovascular stem cell therapy. This was the problem addressed in SEISMIC and the cell of choice was autologous skeletal myoblasts.

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