Scientific

Background

Myocardial infarction due to coronary artery disease still represents the leading cause of death in the western world. Thereby, it remains ever growing as of a demographic increase in life expectancy¹. Patients suffering from myocardial infarction often exhibit severely reduced quality of life despite modern pharmacotherapy. (a) Long hospital stays and rehabilitation, (b) need for repeated intervention and (c) inability to work cause a severe socio-economic burden².

Coronary artery bypass graft surgery (CABG) and interventional implantation of coronary artery stents are current state-of-the-art techniques for revascularization and restoration of blood supply of infarcted myocardium. However, these treatment options remain some kind of palliative as already established impairment of heart function due to irreversibly damaged myocardium cannot be reversed³. Regenerative therapies such as stem cell or gene therapy aim to retrieve lost cardiac muscle to restore heart function. Both strategies have shown promising results in pre-clinical and clinical trials. Nevertheless, despite huge research efforts during the last decades stem cell and gene therapy have not yet gained broad clinical routine use. Reasons thereof include complexity in preparation and application, side effects as well as ethical concerns^4,5. Therefore, clinicians and their patients, as well as public healthcare systems, are still in urgent need of alternative treatment options for heart muscle regeneration after myocardial infarction.

Shockwaves represent a specific type of sound pressure wave that occurs whenever there is a sudden release of energy, e.g. in nature as thunder when lightning. Shockwaves have been used in medicine for more than 30 years for the disintegration of kidney stones (=Lithotripsy)⁶. The incidental finding of iliac bone thickening in Lithotripsy patients in the early 1980’s led to first studies that were conducted to evaluate the effect of shockwaves on bone healing (10, 11). Amazing results were found in the healing of long-bone non-unions (fractures that do not heal within 3 months). Research showed that shockwaves at energy levels ten times lower than in Lithotripsy even increased the regenerative effect. Subsequently, indications were expanded to soft tissue injuries, including chronic tendon lesions and wound healing disturbances. Since then a novel field of medicine was established.

Thereby, the target area of all regenerative therapies in ischemic heart disease (after myocardial infarction) is the so-called peri-infarction zone, the border zone of the infarction. Whereas the infarct area with a total loss of blood supply completely loses its function and gets transformed into fibrotic scar tissue, this border zone remains still vital but chronically undersupplied. It is therefore also called the “hibernating myocardium”. During contraction of the heart muscle, the fibrotic scar tissue evades (Dyskinesia) and thereby causes dead space for blood. By regenerating and strengthening the hibernating myocardium it gets capable of pulling the fibrotic scar inside (Akinesia) during contraction, thereby increasing the amount of blood pumped out of the heart (ejection fraction).

As an underlying working mechanism of shockwave therapy, the release of exosomes that are shedded off cell membranes without harming cells could be identified. Exosomes cargo all types of nucleic acids, including miRNA, long-non coding RNAs and others. Some of these are targeting Toll-like receptor 3 (TLR3)^7,8. TLR3 is a pattern recognition receptor of the innate immune system capable of recognizing nucleic acids. Its downstream signaling regulates transcription factor NFkappaB resulting in the described effects including angiogenesis.

In ischemic muscle tissue growth factors such as VEGF and PlGF get released resulting in angiogenesis^9,10. Bone-marrow-derived endothelial progenitors are recruited via the SDF-1/ CXCR4 axis leading to vasculogenesis^11,12. These effects result in functional improvement of ischemic myocardium as well as skeletal muscle tissue.

References:

Scientific

Background

Myocardial infarction due to coronary artery disease still represents the leading cause of death in the western world. Thereby, it remains ever growing as of a demographic increase in life expectancy¹. Patients suffering from myocardial infarction often exhibit severely reduced quality of life despite modern pharmacotherapy. (a) Long hospital stays and rehabilitation, (b) need for repeated intervention and (c) inability to work cause a severe socio-economic burden².

Coronary artery bypass graft surgery (CABG) and interventional implantation of coronary artery stents are current state-of-the-art techniques for revascularization and restoration of blood supply of infarcted myocardium. However, these treatment options remain some kind of palliative as already established impairment of heart function due to irreversibly damaged myocardium cannot be reversed³. Regenerative therapies such as stem cell or gene therapy aim to retrieve lost cardiac muscle to restore heart function. Both strategies have shown promising results in pre-clinical and clinical trials. Nevertheless, despite huge research efforts during the last decades stem cell and gene therapy have not yet gained broad clinical routine use. Reasons thereof include complexity in preparation and application, side effects as well as ethical concerns^4,5. Therefore, clinicians and their patients, as well as public healthcare systems, are still in urgent need of alternative treatment options for heart muscle regeneration after myocardial infarction.

Shockwaves represent a specific type of sound pressure wave that occurs whenever there is a sudden release of energy, e.g. in nature as thunder when lightning. Shockwaves have been used in medicine for more than 30 years for the disintegration of kidney stones (=Lithotripsy)⁶. The incidental finding of iliac bone thickening in Lithotripsy patients in the early 1980’s led to first studies that were conducted to evaluate the effect of shockwaves on bone healing (10, 11). Amazing results were found in the healing of long-bone non-unions (fractures that do not heal within 3 months). Research showed that shockwaves at energy levels ten times lower than in Lithotripsy even increased the regenerative effect. Subsequently, indications were expanded to soft tissue injuries, including chronic tendon lesions and wound healing disturbances. Since then a novel field of medicine was established.

Thereby, the target area of all regenerative therapies in ischemic heart disease (after myocardial infarction) is the so-called peri-infarction zone, the border zone of the infarction. Whereas the infarct area with a total loss of blood supply completely loses its function and gets transformed into fibrotic scar tissue, this border zone remains still vital but chronically undersupplied. It is therefore also called the “hibernating myocardium”. During contraction of the heart muscle, the fibrotic scar tissue evades (Dyskinesia) and thereby causes dead space for blood. By regenerating and strengthening the hibernating myocardium it gets capable of pulling the fibrotic scar inside (Akinesia) during contraction, thereby increasing the amount of blood pumped out of the heart (ejection fraction).

As an underlying working mechanism of shockwave therapy, the release of exosomes that are shedded off cell membranes without harming cells could be identified. Exosomes cargo all types of nucleic acids, including miRNA, long-non coding RNAs and others. Some of these are targeting Toll-like receptor 3 (TLR3)^7,8. TLR3 is a pattern recognition receptor of the innate immune system capable of recognizing nucleic acids. Its downstream signaling regulates transcription factor NFkappaB resulting in the described effects including angiogenesis.

In ischemic muscle tissue growth factors such as VEGF and PlGF get released resulting in angiogenesis^9,10. Bone-marrow-derived endothelial progenitors are recruited via the SDF-1/ CXCR4 axis leading to vasculogenesis^11,12. These effects result in functional improvement of ischemic myocardium as well as skeletal muscle tissue.