Timing and energy of the extracorporeal cardiac shock wave treatment have profound influence on the outcome of therapy in ischemic heart disease.

The notion of the presence of stem and progenitor cells in the adult human heart imposes that all currently used treatments, as well as those in the experimental phase of the study, should be revisited with regards to effects on these cardiac cell population. In fact, novel therapies offer the possibility of inhibition or even reversal of heart failure progression by the mobilization and activation of cardiac stem and progenitor cells, as can be the case with extracorporeal cardiac shock wave (SW) therapy, suggested for patients with myocardial ischemia. The scope of the present study was to evaluate the effects of low and high energy SW treatment on cardiac primitive cells in vitro. CD117(+) cells have been isolated from age-matched adult human normal (n=4, males, mean age 51±5.6 years) and pathological hearts with end-stage ischemic cardiomyopathy (n=4, males, mean age 55±3.2 years). Cells have been treated with 800 shots of SW at the energy flux density of 0.05mJ/mm2 and 0.1mJ/mm2. After one week of culture, cardiac cell lineages were characterized by immunofluorescence and immunoblotting, and their total mRNA was examined by stem cell-specific PCRbased microarray. Above all, the effects of high energy treatment differed profoundly from those observed at low energy, with none the same gene up- or downregulated in any of the groups studied. Moreover, cells isolated from pathological hearts were positively influenced in the more evident manner. In fact, low energy treatment of pathological cells induced the activation of a pool of transient amplifying progenitors of cardiomyocytes (expressing α-sarcomeric actin), endothelial (von Willebrand factor) and smooth muscle cells (smooth muscle actin). In these cell population, we observed the upregulation of mRNA of 14 genes involved in the cytoskeleton biogenesis/organization, mitotic spindle formation and cell motility. In contrast, high energy SW application resulted in upregulation of 5 genes, mostly involved in the extracellular matrix- and cell-cell adhesion, and downregulation of 15 genes regulating protein kinase activity, signal transduction and cell-cell signalling. As regards cells from normal heart, remarkably only high energy treatment induced activation of endothelial cell precursors. On the basis of the above data it is possible to predict that timing (between onset and end-stage of disease) and energy of the SW treatment can have profound influence on the therapy outcome in ischemic heart disease. Further pre-clinical studies of these variables are warranted before broad introduction of the method into clinical practice.