Scientific Background2019-03-20T07:21:16+00:00

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 concerns4,5. 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 angiogenesis9,10. Bone-marrow-derived endothelial progenitors are recruited via the SDF-1/ CXCR4 axis leading to vasculogenesis11,12. These effects result in functional improvement of ischemic myocardium as well as skeletal muscle tissue.

References:

  1. Neumann FJ, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87-165. doi: 10.1093/eurheartj/ehy394.
  2. Hamm CW, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999-3054. doi: 10.1093/eurheartj/ehr236.
  3. Colbert RW, et al. The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease.J Cardiovasc Transl Res. 2015 Jun;8(4):244-52.  doi: 10.1007/s12265-015-9625-5.
  4. Nowbar AN, et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ. 2014 Apr 28;348:g2688.  doi: 10.1136/bmj.g2688.
  5. Abbott A. Doubts over heart stem-cell therapy. Nature. 2014 May 1;509(7498):15-6. doi: 10.1038/509015a.
  6. Ercil H, et al. Treatment of Moderate Sized Renal Pelvis Calculi: Stone Clearance Time Comparison of Extracorporeal Shock Wave Lithotripsy and Retrograde Intrarenal Surgery. Urol J. 2016 Mar 5;13(1):2490-5.
  7. Holfeld J, et al. Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle. Cardiovasc Res. 2016 Feb 1;109(2):331-43. doi: 10.1093/cvr/cvv272.
  8. Holfeld J, et al. Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via toll-Like receptor 3. Inflammation. 2014 Feb;37(1):65-70.  doi: 10.1007/s10753-013-9712-1.
  9. Holfeld J, et al. Epicardial shock-wave therapy improves ventricular function in a porcine model of ischaemic heart disease. J Tissue Eng Regen Med. 2014 May 19. doi: 10.1002/term.1890.
  10. Holfeld J, et al. Low energy shock wave therapy induces angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation. PLoS One. 2014 Aug 5;9(8):e103982. doi:10.1371/journal.pone.0103982.
  11. Tepeköylü C, et al. Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34-positive endothelial cells in a hindlimb ischemia model: implications for angiogenesis and vasculogenesis. J Thorac Cardiovasc Surg. 2013 Oct;146(4):971-8. doi:10.1016/j.jtcvs.2013.01.017.
  12. Gollmann-Tepeköylü C, et al. Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix. J Am Heart Assoc. 2018 Oct 16;7(20):e010025. doi: 10.1161/JAHA.118.010025.

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 concerns4,5. 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 angiogenesis9,10. Bone-marrow-derived endothelial progenitors are recruited via the SDF-1/ CXCR4 axis leading to vasculogenesis11,12. These effects result in functional improvement of ischemic myocardium as well as skeletal muscle tissue.

References:

  1. Neumann FJ, et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2019 Jan 7;40(2):87-165. doi: 10.1093/eurheartj/ehy394.
  2. Hamm CW, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011 Dec;32(23):2999-3054. doi: 10.1093/eurheartj/ehr236.
  3. Colbert RW, et al. The Recovery of Hibernating Hearts Lies on a Spectrum: from Bears in Nature to Patients with Coronary Artery Disease.J Cardiovasc Transl Res. 2015 Jun;8(4):244-52.  doi: 10.1007/s12265-015-9625-5.
  4. Nowbar AN, et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ. 2014 Apr 28;348:g2688.  doi: 10.1136/bmj.g2688.
  5. Abbott A. Doubts over heart stem-cell therapy. Nature. 2014 May 1;509(7498):15-6. doi: 10.1038/509015a.
  6. Ercil H, et al. Treatment of Moderate Sized Renal Pelvis Calculi: Stone Clearance Time Comparison of Extracorporeal Shock Wave Lithotripsy and Retrograde Intrarenal Surgery. Urol J. 2016 Mar 5;13(1):2490-5.
  7. Holfeld J, et al. Toll-like receptor 3 signalling mediates angiogenic response upon shock wave treatment of ischaemic muscle. Cardiovasc Res. 2016 Feb 1;109(2):331-43. doi: 10.1093/cvr/cvv272.
  8. Holfeld J, et al. Shockwave therapy differentially stimulates endothelial cells: implications on the control of inflammation via toll-Like receptor 3. Inflammation. 2014 Feb;37(1):65-70.  doi: 10.1007/s10753-013-9712-1.
  9. Holfeld J, et al. Epicardial shock-wave therapy improves ventricular function in a porcine model of ischaemic heart disease. J Tissue Eng Regen Med. 2014 May 19. doi: 10.1002/term.1890.
  10. Holfeld J, et al. Low energy shock wave therapy induces angiogenesis in acute hind-limb ischemia via VEGF receptor 2 phosphorylation. PLoS One. 2014 Aug 5;9(8):e103982. doi:10.1371/journal.pone.0103982.
  11. Tepeköylü C, et al. Shock wave treatment induces angiogenesis and mobilizes endogenous CD31/CD34-positive endothelial cells in a hindlimb ischemia model: implications for angiogenesis and vasculogenesis. J Thorac Cardiovasc Surg. 2013 Oct;146(4):971-8. doi:10.1016/j.jtcvs.2013.01.017.
  12. Gollmann-Tepeköylü C, et al. Shock Wave Therapy Improves Cardiac Function in a Model of Chronic Ischemic Heart Failure: Evidence for a Mechanism Involving VEGF Signaling and the Extracellular Matrix. J Am Heart Assoc. 2018 Oct 16;7(20):e010025. doi: 10.1161/JAHA.118.010025.