Skip to main content
Log in

Extracorporeal Shock Wave Therapy for Ischemic Cardiovascular Disorders

  • Review Article
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Ischemic heart disease is the leading cause of death and a major cause of hospital admissions, with the number of affected patients increasing worldwide. The current management of ischemic heart disease has three major therapeutic options: medication, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG). However, the prognosis for patients with severe ischemic heart disease without indications for PCI or CABG still remains poor due to the lack of effective treatments. It is therefore crucial to develop alternative therapeutic strategies for severe ischemic heart disease. Extracorporeal shock wave (SW) therapy was introduced clinically more than 20 years ago to fragment kidney stones, which has markedly improved the treatment of urolithiasis. We found that a low-energy SW (about 10% of the energy density used for urolithiasis) effectively increases the expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. Based on this in vitro study, we initiated in vivo studies and have demonstrated that extracorporeal cardiac SW therapy with a low-energy SW up-regulates the expression of VEGF, induces neovascularization, and improves myocardial ischemia in a porcine model of chronic myocardial ischemia, without any adverse effects in vivo. On the basis of promising results in animal studies, we performed a series of clinical studies in patients with severe coronary artery disease without indication for PCI or CABG, including, firstly, an open trial followed by a placebo-controlled, double-blind study. In both studies, our extracorporeal cardiac SW therapy improved symptoms, exercise capacity, and myocardial perfusion in patients with severe coronary artery disease. Importantly, no procedural complications or adverse effects were noted. The SW therapy was also effective in ameliorating left ventricular remodeling after acute myocardial infarction (MI) in pigs and in enhancing angiogenesis in hind-limb ischemia in rabbits. Based on these animal studies, we are also conducting clinical studies in patients with acute MI and in those with peripheral artery disease. Thus, our extracorporeal cardiac SW therapy appears to be an effective, safe, and non-invasive angiogenic approach in cardiovascular medicine and its indication could be extended to a variety of ischemic diseases in the near future. In this article, we briefly summarize our work in animals and humans, and discuss the advantages and perspectives of our extracorporeal SW therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Jessup M, Brozena S. Heart failure. N Engl J Med 2003; 348: 2007–18.

    Article  PubMed  Google Scholar 

  2. Kawamoto A, Tkebuchava T, Yamaguchi J, et al. Intramyocardial transplantation of autologous endothelial progenitor cells for therapeutic neovascularization of myocardial ischemia. Circulation 2003; 107: 461–8.

    Article  PubMed  Google Scholar 

  3. Khan TA, Sellke FW, Laham RJ. Gene therapy progress and prospects: therapeutic angiogenesis for limb and myocardial ischemia. Gene Ther 2003; 10: 285–91.

    Article  PubMed  CAS  Google Scholar 

  4. Rutanen J, Rissanen TT, Markkanen JE, et al. Adenoviral catheter-mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural angiogenesis in porcine heart. Circulation 2004; 109: 1029–35.

    Article  PubMed  CAS  Google Scholar 

  5. Schächinger V, Assmus B, Britten MB, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 2004; 44:1690–9.

    Article  PubMed  Google Scholar 

  6. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004; 364: 141–8.

    Article  PubMed  Google Scholar 

  7. Kastrup J, Jørgensen E, Rück A, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: a randomized double-blind placebo-controlled study. The Euroinject One trial. J Am Coll Cardiol 2005; 45: 982–8.

    Article  PubMed  CAS  Google Scholar 

  8. Choi JS, Kim KB, Han W, et al. Efficacy of therapeutic angiogenesis by intramyocardial injection of pCK-VEGF165 in pigs. Ann Thorac Surg 2006; 82: 679–86.

    Article  PubMed  Google Scholar 

  9. Schächinger V, Erbs S, Elsässer A, et al. Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: final 1-year results of the REPAIR-AMI trial. Eur Heart J 2006; 27: 2775–83.

    Article  PubMed  Google Scholar 

  10. Qian HS, Liu P, Huw LY, et al. Effective treatment of vascular endothelial growth factor refractory hindlimb ischemia by a mutant endothelial nitric oxide synthase gene. Gene Ther 2006; 13: 1342–50.

    Article  PubMed  CAS  Google Scholar 

  11. Kajiguchi M, Kondo T, Izawa H, et al. Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J 2007; 71: 196–201.

    Article  PubMed  Google Scholar 

  12. Tatsumi T, Ashihara E, Yasui T, et al. Intracoronary transplantation of non-expanded peripheral blood-derived mononuclear cells promotes improvement of cardiac function in patients with acute myocardial infarction. Circ J 2007; 71: 1199–207.

    Article  PubMed  Google Scholar 

  13. Epstein SE, Fuchs S, Zhou YF, et al. Therapeutic interventions for enhancing collateral development by administration of growth factors: basic principles, early results and potential hazards. Cardiovasc Res 2001; 49: 532–42.

    Article  PubMed  CAS  Google Scholar 

  14. Forrester JS, Price MJ, Makkar RR. Stem cell repair of infarcted myocardium: an overview for clinicians. Circulation 2003; 108: 1139–45.

    Article  PubMed  Google Scholar 

  15. Mathur A, Martin JF. Stem cells and repair of the heart. Lancet 2004; 364: 183–92.

    Article  PubMed  CAS  Google Scholar 

  16. Davani S, Deschaseaux F, Chalmers D, et al. Can stem cells mend a broken heart? Cardiovasc Res 2005; 65: 305–16.

    Article  PubMed  CAS  Google Scholar 

  17. Dimmeler S, Zeiher AM, Schneider MD. Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 2005; 115: 572–83.

    PubMed  CAS  Google Scholar 

  18. Choi JH, Choi J, Lee WS, et al. Lack of additional benefit of intracoronary transplantation of autologous peripheral blood stem cell in patients with acute myocardial infarction. Circ J 2007; 71: 486–94.

    Article  PubMed  Google Scholar 

  19. Kang S, Yang YJ, Li CJ, et al. Effects of intracoronary autologous bone marrow cells on left ventricular function in acute myocardial infarction: a systematic review and meta-analysis for randomized controlled trials. Coron Artery Dis 2008; 19: 327–35.

    Article  PubMed  Google Scholar 

  20. Martin-Rendon E, Brunskill SJ, Hyde CJ, et al. Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review. Eur Heart J 2008; 29: 1807–18.

    Article  PubMed  CAS  Google Scholar 

  21. Nishida T, Shimokawa H, Oi K, et al. Extracorporeal cardiac shock wave therapy markedly ameliorates ischemia-induced myocardial dysfunction in pigs in vivo. Circulation 2004; 110: 3055–61.

    Article  PubMed  Google Scholar 

  22. Ito K, Fukumoto Y, Shimokawa H. Extracorporeal shock wave therapy as a new and non-invasive angiogenic strategy. Tohoku J Exp Med 2009; 219: 1–9.

    Article  PubMed  Google Scholar 

  23. Fukumoto Y, Ito A, Uwatoku T, et al. Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease. Coron Artery Dis 2006; 17: 63–70.

    Article  PubMed  Google Scholar 

  24. Mariotto S, Cavalieri E, Amelio E, et al. Extracorporeal shock waves: from lithotripsy to anti-inflammatory action by NO production. Nitric Oxide 2005; 12:89–96.

    Article  PubMed  CAS  Google Scholar 

  25. Yip HK, Chang LT, Sun CK, et al. Shock wave therapy applied to rat bone marrow-derived mononuclear cells enhances formation of cells stained positive for CD31 and vascular endothelial growth factor. Circ J 2008; 72: 150–6.

    Article  PubMed  CAS  Google Scholar 

  26. Nurzynska D, Di Meglio F, Castaldo C, et al. Shock waves activate in vitro cultured progenitors and precursors of cardiac cell lineages from the human heart. Ultrasound Med Biol 2008; 34: 334–42.

    Article  PubMed  Google Scholar 

  27. Tamma R, dell’Endice S, Notarnicola A, et al. Extracorporeal shock waves stimulate osteoblast activities. Ultrasound Med Biol 2009; 35: 093–2100.

    Article  Google Scholar 

  28. Apfel RE. Acoustic cavitation: a possible consequence of biomedical uses of ultrasound. Br J Cancer 1982; 45 Suppl.: 140–6.

    Article  Google Scholar 

  29. Maisonhaute E, Prado C, White PC, et al. Surface acoustic cavitation understood via nanosecond electrochemistry. Part III: shear stress in ultrasonic cleaning. Ultrason Sonochem 2002; 9: 297–303.

    Article  PubMed  CAS  Google Scholar 

  30. Fisher AB, Chien S, Barakat AI, et al. Endothelial cellular response to altered shear stress. Am J Physiol 2001; 281: L529–33.

    CAS  Google Scholar 

  31. Seidl M, Steinbach P, Wörle K, et al. Induction of stress fibres and intercellular gaps in human vascular endothelium by shock-waves. Ultrasonics 1994; 32: 397–400.

    Article  PubMed  CAS  Google Scholar 

  32. Wang FS, Wang CJ, Huang HJ, et al. Physical shock wave mediates membrane hyperpolarization and Ras activation for osteogenesis in human bone marrow stromal cells. Biochem Biophys Res Commun 2001; 287: 648–55.

    Article  PubMed  CAS  Google Scholar 

  33. Gotte G, Amelio E, Russo S, et al. Short-time non-enzymatic nitric oxide synthesis from L-arginine and hydrogen peroxide induced by shock wave treatment. FEBS Lett 2002; 520: 153–5.

    Article  PubMed  CAS  Google Scholar 

  34. Khattab AA, Brodersen B, Schuermann-Kuchenbrandt D, et al. Extracorporeal cardiac shock wave therapy: first experience in the everyday practice for treatment of chronic refractory angina pectoris. Int J Cardiol 2007; 121: 84–5.

    Article  PubMed  Google Scholar 

  35. Prinz C, Lindner O, Bitter T, et al. Extracorporeal cardiac shock wave therapy ameliorates clinical symptoms and improves regional myocardial blood flow in a patient with severe coronary artery disease and refractory angina. Case Report Med 2009; 2009: 639594.

    PubMed  Google Scholar 

  36. Vasyuk YA, Hadzegova AB, Shkolnik EL, et al. Initial clinical experience with extracorporeal shock wave therapy in treatment of ischemic heart failure. Congest Heart Fail 2010; 16: 226–30.

    Article  PubMed  Google Scholar 

  37. Wang Y, Guo T, Cai HY, et al. Cardiac shock wave therapy reduces angina and improves myocardial function in patients with refractory coronary artery disease. Clin Cardiol 2010; 33: 693–9.

    Article  PubMed  Google Scholar 

  38. Kikuchi Y, Ito K, Ito Y, et al. Double-blind and placebo-controlled study of the effectiveness and safety of extracorporeal cardiac shock wave therapy for severe angina pectoris. Circ J 2010; 74: 589–91.

    Article  PubMed  Google Scholar 

  39. Volpi A, De Vita C, Franzosi MG, et al. Determinants of 6-month mortality in survivors of myocardial infarction after thrombolysis: results of the GISSI-2 data base. The Ad hoc Working Group of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-2 Data Base. Circulation 1993; 88: 416–29.

    Article  PubMed  CAS  Google Scholar 

  40. Olivett G, Ricci R, Beghi C, et al. Response of the border zone to myocardial infarction in rats. Am J Pathol 1986; 125: 476–83.

    Google Scholar 

  41. Uwatoku T, Ito K, Abe K, et al. Extracorporeal cardiac shock wave therapy improves left ventricular remodeling after acute myocardial infarction in pigs. Coron Artery Dis 2007; 18: 397–404.

    Article  PubMed  Google Scholar 

  42. Ito Y, Ito K, Shiroto T, et al. Cardiac shock wave therapy ameliorates left ventricular remodeling after myocardial ischemia-reperfusion injury in pigs in vivo. Coron Artery Dis 2010; 21: 304–11.

    Article  PubMed  Google Scholar 

  43. Sumpio BE. Foot ulcers. N Engl J Med 2000; 343: 787–93.

    Article  PubMed  CAS  Google Scholar 

  44. Regensteiner JG, Stewart KJ. Established and evolving medical therapies for claudication in patients with peripheral arterial disease. Nat Clin Pract Cardiovasc Med 2006; 3: 604–10.

    Article  PubMed  CAS  Google Scholar 

  45. Al Mheid I, Quyyumi AA. Cell therapy in peripheral arterial disease. Angiology 2009; 59: 705–16.

    Article  Google Scholar 

  46. Oi K, Fukumoto Y, Ito K, et al. Extracorporeal shock wave therapy ameliorates hindlimb ischemia in rabbits. Tohoku J Exp Med 2008; 214: 151–8.

    Article  PubMed  Google Scholar 

  47. Stojadinovic A, Elster EA, Anam K, et al. Angiogenic response to extracorporeal shock wave treatment in murine skin isografts. Angiogenesis 2008; 11: 369–80.

    Article  PubMed  Google Scholar 

  48. Yan X, Zeng B, Chai Y, et al. Improvement of blood flow, expression of nitric oxide, and vascular endothelial growth factor by low-energy shock-wave therapy in random-pattern skin flap model. Ann Plast Surg 2008; 61: 646–53.

    Article  PubMed  CAS  Google Scholar 

  49. Saggini R, Figus A, Troccola A, et al. Extracorporeal shock wave therapy for management of chronic ulcers in the lower extremities. Ultrasound Med Biol 2008; 34: 1261–71.

    Article  PubMed  CAS  Google Scholar 

  50. Moretti B, Notarnicola A, Maggio G, et al. The management of neuropathic ulcers of the foot in diabetes by shock wave therapy. BMC Musculoskelet Disord 2009; 10: 54–61.

    Article  PubMed  Google Scholar 

  51. Birnbaum K, Wirtz DC, Siebert CH, et al. Use of extracorporeal shock-wave therapy (ESWT) in the treatment of non-unions: a review of the literature. Arch Orthop Trauma Surg 2002; 122: 324–30.

    PubMed  CAS  Google Scholar 

  52. Wang CJ, Wang FS, Yang KD, et al. Shock wave therapy induces neovascularization at the tendon-bone junction: a study in rabbits. J Orthop Res 2003;21:84–9.

    Google Scholar 

  53. Ciampa AR, de Prati AC, Amelio E, et al. Nitric oxide mediates anti-inflammatory action of extracorporeal shock waves. FEBS Lett 2005; 579: 6839–45.

    Article  PubMed  CAS  Google Scholar 

  54. Mariotto S, de Prati AC, Cavalieri E, et al. Extracorporeal shock wave therapy in inflammatory diseases: molecular mechanism that triggers antiinflammatory action. Curr Med Chem 2009; 16: 2366–72.

    Article  PubMed  CAS  Google Scholar 

  55. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science 1997; 275: 964–7.

    Article  PubMed  CAS  Google Scholar 

  56. Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362: 697–703.

    Article  PubMed  CAS  Google Scholar 

  57. Rafii S, Lyden D. Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Nat Med 2003; 9: 702–12.

    Article  PubMed  CAS  Google Scholar 

  58. Millauer B, Wizigmann-Voos S, Schnürch H, et al. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993; 72: 835–46.

    Article  PubMed  CAS  Google Scholar 

  59. Grunewald M, Avraham I, Dor Y, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006; 124: 175–89.

    Article  PubMed  CAS  Google Scholar 

  60. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–64.

    Article  PubMed  CAS  Google Scholar 

  61. Satoh K, Fukumoto Y, Nakano M, et al. Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 2009; 81: 226–34.

    Article  PubMed  CAS  Google Scholar 

  62. Aicher A, Heeschen C, Sasaki K, et al. Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia. Circulation 2006; 114: 2823–30.

    Article  PubMed  Google Scholar 

  63. Sheu JJ, Sun CK, Chang LT, et al. Shock wave-pretreated bone marrow cells further improve left ventricular function after myocardial infarction in rabbits. Ann Vasc Surg 2010; 24: 809–21.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kenta Ito.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, K., Fukumoto, Y. & Shimokawa, H. Extracorporeal Shock Wave Therapy for Ischemic Cardiovascular Disorders. Am J Cardiovasc Drugs 11, 295–302 (2011). https://doi.org/10.2165/11592760-000000000-00000

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/11592760-000000000-00000

Keywords

Navigation