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Zellersatztherapie am Herzen: Fiktion oder reale Möglichkeit

Eine tierexperimentelle Annäherung

Cell replacement therapy in the heart: fiction or a real possibility

An animal experiment approach

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Zeitschrift für Herz-,Thorax- und Gefäßchirurgie Aims and scope

Zusammenfassung

Aufbauend auf ein murines Kryoinfarktmodell mit reproduzierbarer Infarktgröße, verlässlicher Einschränkung der linksventrikulären Myokardfunktion und niedriger primärer Sterblichkeit konnte der Einfluss der Transplantation verschiedenster Progenitor- und Stammzellen auf linksventrikuläre Kontraktilität, elektrische Vulnerabilität und postoperatives Überleben getestet werden. In die myokardiale Läsion implantierte, embryonale Kardiomyozyten intergrieren in den Gewebsverband, differenzieren in einen adulten Phänotyp und verbessern die Myokardfunktion. Diese Connexin 43 exprimierenden, kontraktilen Zellen koppeln elektrisch an das Wirtsmyokard, verbessern die elektrische Leitfähigkeit und schützen vor Post-Infarkt-Arrhythmien.

Abstract

Transmural cryolesions of a defined size were generated on the free left ventricular wall in mice. Using this approach, reproducible myocardial infarctions with a predictable decrease in myocardial function were generated. The potency of cellular cardiomyoplasty, employing different stem and progenitor cells, to improve contractility and impair electrical vulnerability was investigated. Intramyocardially injected fetal cardiomyocytes engrafted, showed further differentiation, increased left ventricular function and improved mid-term survival of the animals. Connexin 43 expressing cells coupled electrically to the host myocardium and reduced inducibility of ventricular arrhythmias.

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Literatur

  1. Statistisches Bundesamt (2009) Todesursachen in Deutschland 2007. http://www.destatis.de

  2. Hlatky MA, Boothroyd DB, Bravata DM et al (2009) Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: a collaborative analysis of individual patient data from ten randomised trials. Lancet 373:1190–1197

    Article  PubMed  Google Scholar 

  3. Reinecke H, Minami E, Zhu WZ, Laflamme MA (2008) Cardiogenic differentiation and transdifferentiation of progenitor cells. Circ Res 103:1058–1071

    Article  CAS  PubMed  Google Scholar 

  4. Meadows TA, Bhatt DL (2007) Clinical aspects of platelet inhibitors and thrombus formation. Circ Res 100:1261–1275

    Article  CAS  PubMed  Google Scholar 

  5. Faxon DP, Freedman JE (2009) Facts and controversies of aspirin and clopidogrel therapy. Am Heart J 157:412–422

    Article  CAS  PubMed  Google Scholar 

  6. Saini HK, Xu YJ, Arneja AS et al (2005) Pharmacological basis of different targets for the treatment of atherosclerosis. J Cell Mol Med 9:818–839

    Article  CAS  PubMed  Google Scholar 

  7. Insull W Jr (2009) The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med 122:S3–S14

    Article  CAS  PubMed  Google Scholar 

  8. Hunt SA, Abraham WT, Chin MH et al (2009) 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults. A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation Epub ahead of print

  9. Dickstein K, Cohen-Solal A, Filippatos G et al (2008) ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J 29:2388–2442

    Article  CAS  PubMed  Google Scholar 

  10. Anand IS, Carson P, Galle E et al (2009) Cardiac resynchronization therapy reduces the risk of hospitalizations in patients with advanced heart failure: results from the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial. Circulation 119:969–977

    Article  PubMed  Google Scholar 

  11. Hansky B, Vogt J, Zittermann A et al (2009) Cardiac resynchronization therapy: long-term alternative to cardiac transplantation? Ann Thorac Surg 87:432–438

    Article  PubMed  Google Scholar 

  12. Moss AJ, Zareba W, Hall WJ et al (2002) Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 346:877–883

    Article  PubMed  Google Scholar 

  13. Moss AJ, Hall WJ, Cannom DS et al (1996) Improved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. Multicenter Automatic Defibrillator Implantation Trial Investigators N Engl J Med 335:1933–1940

    CAS  Google Scholar 

  14. Christiansen S, Klocke A, Autschbach R (2008) Past, present, and future of long-term mechanical cardiac support in adults. J Card Surg 23:664–676

    Article  PubMed  Google Scholar 

  15. Kolossov E, Bostani T, Roell W et al (2006) Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium. J Exp Med 203:2315–2327

    Article  CAS  PubMed  Google Scholar 

  16. Roell W, Lu ZJ, Bloch W et al (2002) Cellular cardiomyoplasty improves survival after myocardial injury. Circulation 105:2435–2441

    Article  PubMed  Google Scholar 

  17. Pittenger MF, Martin BJ (2004) Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95:9–20

    Article  CAS  PubMed  Google Scholar 

  18. Dimmeler S, Zeiher AM, Schneider MD (2005) Unchain my heart: the scientific foundations of cardiac repair. J Clin Invest 115:572–583

    CAS  PubMed  Google Scholar 

  19. Barile L, Messina E, Giacomello A, Marban E (2007) Endogenous cardiac stem cells. Prog Cardiovasc Dis 50:31–48

    Article  CAS  PubMed  Google Scholar 

  20. Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872

    Article  CAS  PubMed  Google Scholar 

  21. Kim JB, Sebastiano V, Wu G et al (2009) Oct4-induced pluripotency in adult neural stem cells. Cell 136:411–419

    Article  CAS  PubMed  Google Scholar 

  22. Fleischmann M, Bloch W, Kolossov E et al (1998) Cardiac specific expression of the green fluorescent protein during early murine embryonic development. FEBS Lett 440:370–376

    Article  CAS  PubMed  Google Scholar 

  23. Roell W, Fan Y, Xia Y et al (2002) Cellular cardiomyoplasty in a transgenic mouse model. Transplantation 73:462–465

    Article  PubMed  Google Scholar 

  24. Muller-Ehmsen J, Peterson KL, Kedes L et al (2002) Rebuilding a damaged heart: long-term survival of transplanted neonatal rat cardiomyocytes after myocardial infarction and effect on cardiac function. Circulation 105:1720–1726

    Article  PubMed  Google Scholar 

  25. Zimmermann WH, Melnychenko I, Wasmeier G et al (2006) Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts. Nat Med 12:452–458

    Article  CAS  PubMed  Google Scholar 

  26. Orlic D, Kajstura J, Chimenti S et al (2001) Bone marrow cells regenerate infarcted myocardium. Nature 410: 701–705

    Article  CAS  PubMed  Google Scholar 

  27. Orlic D, Kajstura J, Chimenti S et al (2001) Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci U S A 98:10344–10349

    Article  CAS  PubMed  Google Scholar 

  28. Strauer BE, Brehm M, Zeus T et al (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 106:1913–1918

    Article  PubMed  Google Scholar 

  29. Assmus B, Schachinger V, Teupe C et al (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 106:3009–3017

    Article  PubMed  Google Scholar 

  30. Wollert KC, Meyer GP, Lotz J et al (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148

    Article  PubMed  Google Scholar 

  31. Nygren JM, Jovinge S, Breitbach M et al (2004) Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 10:494–501

    Article  CAS  PubMed  Google Scholar 

  32. Breitbach M, Bostani T, Roell W et al (2007) Potential risks of bone marrow cell transplantation into infarcted hearts. Blood 110:1362–1369

    Article  CAS  PubMed  Google Scholar 

  33. Roell W, Lewalter T, Sasse P et al (2007) Engraftment of connexin 43-expressing cells prevents post-infarct arrhythmia. Nature 450:819–824

    Article  CAS  PubMed  Google Scholar 

  34. Rubart M, Pasumarthi KB, Nakajima H et al (2003) Physiological coupling of donor and host cardiomyocytes after cellular transplantation. Circ Res 92:1217–1224

    Article  CAS  PubMed  Google Scholar 

  35. Xue T, Cho HC, Akar FG et al (2005) Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation 111:11–20

    Article  PubMed  Google Scholar 

  36. Klug MG, Soonpaa MH, Koh GY, Field LJ (1996) Genetically selected cardiomyocytes from differentiating embronic stem cells form stable intracardiac grafts. J Clin Invest 98:216–224

    Article  CAS  PubMed  Google Scholar 

  37. Kehat I, Khimovich L, Caspi O et al (2004) Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22:1282–1289

    Article  CAS  PubMed  Google Scholar 

  38. Murry CE, Soonpaa MH, Reinecke H et al (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 428:664–668

    Article  CAS  PubMed  Google Scholar 

  39. Balsam LB, Wagers AJ, Christensen JL et al (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428:668–673

    Article  CAS  PubMed  Google Scholar 

  40. Wollert KC, Drexler H (2005) Mesenchymal stem cells for myocardial infarction: promises and pitfalls. Circulation 112:151—153

    Article  PubMed  Google Scholar 

  41. Zohlnhofer D, Ott I, Mehilli J et al (2006) Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 295:1003–1010

    Article  PubMed  Google Scholar 

  42. Janssens S, Dubois C, Bogaert J et al (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121

    Article  PubMed  Google Scholar 

  43. Schachinger V, Assmus B, Britten MB et al (2004) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial. J Am Coll Cardiol 44:1690–1699

    Article  PubMed  Google Scholar 

  44. Stamm C, Nasseri B, Choi YH, Hetzer R (2008) Cell therapy for heart disease: Great Expectations, As Yet Unmet. Heart Lung Circ

  45. Abraham MR, Henrikson CA, Tung L et al (2005) Antiarrhythmic engineering of skeletal myoblasts for cardiac transplantation. Circ Res 97:159–167

    Article  CAS  PubMed  Google Scholar 

  46. Menasche P, Hagege AA, Vilquin JT et al (2003) Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 41:1078–1083

    Article  PubMed  Google Scholar 

  47. Yoon YS, Park JS, Tkebuchava T et al (2004) Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation 109:3154–3157

    Article  PubMed  Google Scholar 

  48. Zhang J, Wilson GF, Soerens AG et al (2009) Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ Res 104:e30–e41

    Article  CAS  PubMed  Google Scholar 

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Röll, W., Sasse, P., Breitbach, M. et al. Zellersatztherapie am Herzen: Fiktion oder reale Möglichkeit. Z Herz- Thorax- Gefäßchir 23, 170–176 (2009). https://doi.org/10.1007/s00398-009-0719-8

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