Refractory angina revisited: stem cells for a growing unmet clinical need?

Refractory angina as per definition is a frequent re-occurring form of stable symptomatic angina, refractory to standard medical treatments. In those patients with refractory angina, surgical or percutaneous coronary revascularization often cannot be considered because of the complexity of coronary artery disease (CAD) and/or pertinent comorbidities. Even if intervention is possible, very often patients do not see significant pain relief and/or improvement of symptoms. Demographically this patient group is very important as it forms a continuously growing population with a percentage of up to 15% of all CAD patients. With respect to the involved vessels, not only the larger coronary vessels are often diseased, but in particular the cardiac microvasculature. Here, surgical and/or percutaneous coronary interventions cannot help directly, and other alternative approaches are obviously needed. In general, success with bone marrow stem cell therapies with the aim of improve the ejection fraction in patients with myocardial infarction and heart failure has been modest to disappointing. However, in selected patient groups, such approaches may be beneficial. Such a group may be patients with refractory angina. Current treatment approaches for refractory angina aim to (i) increase the coronary blood oxygen supply; (ii) decrease cardiac oxygen consumption; (iii) modulate myocyte metabolism; or (iv) redistribute coronary flow. The clinically symptom-orientated multidisciplinary management of refractory angina patients combines established traditional and newer medical agents with novel nonpharmacological interventional and non-interventional techniques (reviewed in Henry et al.). In the following, a few alternative approaches that have been tested to improve pain relief and/or blood supply to the ischaemic heart are highlighted. Recently, a vascular endothelial growth factor (VEGF) gene therapy in a phase I/IIa study with 1-year follow-up was shown to be safe, feasible, and well tolerated. Myocardial perfusion increased at 1 year in the treated areas with impaired myocardial perfusion reserve (MPR) at baseline. Another study showed apheresis to be a novel effective treatment for refractory angina patients with raised lipoprotein(a) levels. Also, the coronary sinus ‘Reducer’ is a novel technology designed to reduce disabling symptoms and improve quality of life of patients suffering from refractory angina. Future perspectives of the optimal utilization of this innovative technology have been recently discussed. A relatively novel approach to modulate tissue vascularization is the use of non-coding RNA-based treatment approaches. Such therapies may also be very effective in refractory angina patients, as angiogenesis can by supported directly. A summary of current clinically used as well as experimental therapies for refractory angina is depicted in Figure 1. In this issue of the journal, a meta-analysis revisited three doubleblind randomized trials (n = 304), where comparisons were made between patients that received intramyocardial (IM) auto-CD34positive cells and those that received placebo injections. As endpoints, total exercise time (TET), angina frequency (AF), and major adverse cardiac events (MACE) were investigated. The authors concluded that treatment with auto-CD34-positive cells resulted in clinically meaningful improvements in TET and AF at 3, 6, and 12 months. Importantly, an impressive reduction in 24-month mortality in this patient-level meta-analysis was also reported. The results of this meta-analysis are exciting especially given the positive results with the 24-month mortality endpoint. However, caution is needed as these analyses were performed retrospectively from three different trials, which used comparable but importantly not similar designs. For instance, ranolazine treatment has only been used in the newest (third) study but not in the other two (as it became available only later). This retrospective meta-analysis shows safety and beneficial effects on refractory angina patients. However, larger studies are needed due to the relatively heterogeneous refractory angina patient population. The meta-analysis is also