Modulation of cell fate by shock wave therapy: Commentary

What is it about?

The cardiac shock wave therapy (CST) is supposed to promote angiogenesis at the area of ischemia in the myocardium. The therapeutic potential of CST was first demonstrated in a porcine model of chronic myocardial ischemia, where the treatment heightened the ventricular ejection fraction, regional myocardial blood flow and capillary density in the ischemic region. Experimental studies have been relatively short-term, thus being of limited informative value in regard to late consequences in humans. The evidence supporting efficacy of CST in patients comes mostly from observational studies. Shock waves induce alternating positive/negative pressure and shear stress in targeted tissue; if powerful enough, it can damage cells. Physical characteristics of CST partly overlap with those associated with injury. Mechanisms of curative effect of CST in ischemic heart disease (IHD) are not well understood. Vasodilatation has been ascribed to nitric oxide (NO), the half-life of which in living tissues is a few seconds only. Accordingly, the effects of NO in tissues must be transitory. The stimulation of angiogenesis is supposed to result from activation of the vascular endothelial growth factor (VEGF) and possibly of other growth factors. VEGF plays an ambivalent role in IHD as it can induce proliferation of fibroblasts and myofibroblasts, thus contributing to fibrosis. The consequences of CST (hyperemia, up-regulation of growth factors, angiogenesis) may be manifestations of an unspecific injury-and-repair process, being transient and reactive in their nature. Besides, the placebo effect can explain some subjective improvements. Additional impact upon heart muscle cells, pre-damaged or atrophic due to hypoxia, may cause further injury. Given the limited regeneration capacity of myocardium, this can contribute to interstitial fibrosis and, in the long term, to functional decline. According to a recent experimental study, shock waves enhance DNA accessibility via Toll-like receptor 3 (TLR3) activation and facilitate the transdifferentiation of fibroblasts towards endothelial cells in ischemic myocardium. This was supposed to be a molecular mechanism underlying beneficial effects of CST. However, TLR3 activation is not a priori beneficial. It is generally regarded to be a pro-inflammatory event, triggered by pathogen- and damage-associated factors. Inhibition of TLR3 alleviated inflammation and protected from tissue injury in ischemia-reperfusion murine models. The topic is understudied. It can be reasonably assumed that TLR3 activation is just another component of the non-specific reaction to the physical impact by CST. Evaluation of interstitial fibrosis by morphometry in animal experiments with a longer follow-up is technically feasible. Other potential late outcomes such as accelerated arteriosclerosis, angiogenesis within plaques and their instability, would be difficult or impossible to assess in experiments. A net harm or benefit can be evaluated in animal studies with comparison of average life duration in the test and control groups. In the author’s opinion, experiments with a longer follow-up should be performed prior to large-scale clinical trials. Clinical improvements after CST are probably caused, at least in part, by the placebo effect. However, CST cannot be called placebo-therapy because of insufficiently known adverse events, especially those developing after repeated procedures in the long run.

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