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Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy

Abstract

Background

Limited data is available for investigating the long-term safety and effects of intracoronary progenitor cell therapy in patients with acute myocardial infarction (AMI).

Objective

To assess the clinical course, NT-proBNP and MRI data as objective markers of cardiac function of the TOPCARE-AMI patients at 5-year follow-up.

Design

The TOPCARE-AMI trial was the first randomized study investigating the effects of intracoronary infusion of circulating (CPC) or bone marrow-derived progenitor cells (BMC) in 59 patients with successfully reperfused AMI.

Results

Five-year follow-up data were completed in 55 patients, 3 patients were lost to follow-up. None of the patients showed any signs of intramyocardial calcification or tumors at 5 years. One patient died during the initial hospitalization, no patient was rehospitalized for heart failure and 16 patients underwent target vessel revascularization (TVR). Only two TVRs occurred later than 1 year after cell administration making it very unlikely that the infused cells accelerate atherosclerotic disease progression.

Serum levels of NT-proBNP remained significantly reduced at the 5-year follow-up indicating the absence of heart failure. MRI subgroup analysis in 31 patients documented a persistent improvement of LV ejection fraction (from 46 ± 10% at baseline to 57 ± 10% at 5 years, p < 0.001)). Simultaneously, there was a reduction (p < 0.001) in functional infarct size measured as late enhancement volume normalized to LV mass. However, whereas LV end-systolic volume remained stable, LV end-diastolic volume increased significantly.

Conclusions

The 5-year follow-up of the TOPCARE-AMI trial provides reassurance with respect to the long-term safety of intracoronary cell therapy and suggests favorable effects on LV function.

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Abbreviations

AMI:

Acute myocardial infarction

BMC:

Bone marrow-derived mononuclear cells

BSA:

Body surface area

CPC:

Circulating progenitor cells

LVEF:

Left-ventricular ejection fraction

LAD:

Left anterior descending coronary artery

LV:

Left ventricular

LVEDV:

Left-ventricular end-diastolic volume

LVESV:

Left-ventricular end-systolic volume

MRI:

Magnetic resonance imaging

STEMI:

ST-segment elevation myocardial infarction

TOPCARE-AMI:

Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction trial

References

  1. Abdulla J, Barlera S, Latini R, Kjoller-Hansen L, Sogaard P, Christensen E, Kober L, Torp-Pedersen C (2007) A systematic review: effect of angiotensin converting enzyme inhibition on left ventricular volumes and ejection fraction in patients with a myocardial infarction and in patients with left ventricular dysfunction. Eur J Heart Fail 9:129–135

    PubMed  Article  CAS  Google Scholar 

  2. Assmus B, Honold J, Schachinger V, Britten MB, Fischer-Rasokat U, Lehmann R, Teupe C, Pistorius K, Martin H, Abolmaali ND, Tonn T, Dimmeler S, Zeiher AM (2006) Transcoronary transplantation of progenitor cells after myocardial infarction. N Engl J Med 355:1222–1232

    PubMed  Article  CAS  Google Scholar 

  3. Assmus B, Rolf A, Erbs S, Elsasser A, Haberbosch W, Hambrecht R, Tillmanns H, Yu J, Corti R, Mathey DG, Hamm CW, Suselbeck T, Tonn T, Dimmeler S, Dill T, Zeiher AM, Schachinger V (2010) Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circ Heart Fail 3:89–96

    PubMed  Article  Google Scholar 

  4. Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N, Grunwald F, Aicher A, Urbich C, Martin H, Hoelzer D, Dimmeler S, Zeiher AM (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI). Circulation 106:3009–3017

    PubMed  Article  Google Scholar 

  5. Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D (2002) Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 106:2351–2357

    PubMed  Article  Google Scholar 

  6. Chavakis E, Koyanagi M, Dimmeler S (2010) Enhancing the outcome of cell therapy for cardiac repair: progress from bench to bedside and back. Circulation 121:325–335

    PubMed  Article  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  8. Dirksen MT, Vink MA, Suttorp MJ, Tijssen JG, Patterson MS, Slagboom T, Kiemeneij F, Laarman GJ (2008) Two year follow-up after primary PCI with a paclitaxel-eluting stent versus a bare-metal stent for acute ST-elevation myocardial infarction (the PASSION trial): a follow-up study. EuroIntervention 4:64–70

    PubMed  Article  Google Scholar 

  9. Erbs S, Linke A, Schachinger V, Assmus B, Thiele H, Diederich KW, Hoffmann C, Dimmeler S, Tonn T, Hambrecht R, Zeiher AM, Schuler G (2007) Restoration of microvascular function in the infarct-related artery by intracoronary transplantation of bone marrow progenitor cells in patients with acute myocardial infarction: the Doppler substudy of the reinfusion of enriched progenitor cells and infarct remodeling in acute myocardial infarction (REPAIR-AMI) trial. Circulation 116:366–374

    PubMed  Article  Google Scholar 

  10. Jung C, Fischer N, Fritzenwanger M, Thude H, Ferrari M, Fabris M, Brehm BR, Barz D, Figulla HR (2009) Endothelial progenitor cells in adolescents: impact of overweight, age, smoking, sport and cytokines in younger age. Clin Res Cardiol 98:179–188

    PubMed  Article  CAS  Google Scholar 

  11. Lipinski MJ, Biondi-Zoccai GG, Abbate A, Khianey R, Sheiban I, Bartunek J, Vanderheyden M, Kim HS, Kang HJ, Strauer BE, Vetrovec GW (2007) Impact of intracoronary cell therapy on left ventricular function in the setting of acute myocardial infarction: a collaborative systematic review and meta-analysis of controlled clinical trials. J Am Coll Cardiol 50:1761–1767

    PubMed  Article  Google Scholar 

  12. Meyer GP, Wollert KC, Lotz J, Pirr J, Rager U, Lippolt P, Hahn A, Fichtner S, Schaefer A, Arseniev L, Ganser A, Drexler H (2009) Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. Eur Heart J 30:2978–2984

    PubMed  Article  Google Scholar 

  13. Miettinen JA, Ylitalo K, Hedberg P, Kervinen K, Niemela M, Saily M, Koistinen P, Savolainen ER, Ukkonen H, Pietila M, Airaksinen KE, Knuuti J, Vuolteenaho O, Makikallio TH, Huikuri HV (2011) Effects of intracoronary injection of autologous bone marrow-derived stem cells on natriuretic peptides and inflammatory markers in patients with acute ST-elevation myocardial infarction. Clin Res Cardiol 100(4):317–325. doi:10.1007/s00392-010-0246-3

    Google Scholar 

  14. Montalescot G, Barragan P, Wittenberg O, Ecollan P, Elhadad S, Villain P, Boulenc JM, Morice MC, Maillard L, Pansieri M, Choussat R, Pinton P (2001) Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 344:1895–1903

    PubMed  Article  CAS  Google Scholar 

  15. Neizel M, Katoh M, Schade E, Rassaf T, Krombach GA, Kelm M, Kuhl HP (2009) Rapid and accurate determination of relative infarct size in humans using contrast-enhanced magnetic resonance imaging. Clin Res Cardiol 98:319–324

    PubMed  Article  Google Scholar 

  16. Reffelmann T, Konemann S, Kloner RA (2009) Promise of blood- and bone marrow-derived stem cell transplantation for functional cardiac repair: putting it in perspective with existing therapy. J Am Coll Cardiol 53:305–308

    PubMed  Article  Google Scholar 

  17. Rollag A, Abdelnoor M, Mangschau A, Jonsbu J, Aase O, Erikssen J (1991) First myocardial infarction: 5-year survival predicted from routine clinical, laboratory, and radionuclide findings during the acute stage. Eur Heart J 12:968–973

    PubMed  CAS  Google Scholar 

  18. Schächinger V, Assmus B, Britten MB, Honold J, Lehmann R, Teupe C, Abolmaali ND, Vogl TJ, Hofmann WK, Martin H, Dimmeler S, Zeiher AM (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

    PubMed  Article  Google Scholar 

  19. Schächinger V, Assmus B, Honold J, Lehmann R, Hofmann WK, Martin H, Dimmeler S, Zeiher AM (2006) Normalization of coronary blood flow in the infarct-related artery after intracoronary progenitor cell therapy: intracoronary Doppler substudy of the TOPCARE-AMI trial. Clin Res Cardiol 95:13–22

    PubMed  Article  Google Scholar 

  20. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Holschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221

    PubMed  Article  Google Scholar 

  21. Schaefer A, Meyer GP, Fuchs M, Klein G, Kaplan M, Wollert KC, Drexler H (2006) Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial. Eur Heart J 27:929–935

    PubMed  Article  Google Scholar 

  22. Schroeder J, Peterschroeder A, Vaske B, Butz T, Barth P, Oldenburg O, Bitter T, Burchert W, Horstkotte D, Langer C (2009) Cardiac volumetry in patients with heart failure and reduced ejection fraction: a comparative study correlating multi-slice computed tomography and magnetic resonance tomography. Reasons for intermodal disagreement. Clin Res Cardiol 98:739–747

    PubMed  Article  Google Scholar 

  23. Seeger FH, Tonn T, Krzossok N, Zeiher AM, Dimmeler S (2007) Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J 28:766–772

    PubMed  Article  Google Scholar 

  24. Tendera M, Wojakowski W, Ruzyllo W, Chojnowska L, Kepka C, Tracz W, Musialek P, Piwowarska W, Nessler J, Buszman P, Grajek S, Breborowicz P, Majka M, Ratajczak MZ (2009) Intracoronary infusion of bone marrow-derived selected CD34+ CXCR4+ cells and non-selected mononuclear cells in patients with acute STEMI and reduced left ventricular ejection fraction: results of randomized, multicentre myocardial regeneration by intracoronary infusion of selected population of stem cells in acute myocardial infarction (REGENT) trial. Eur Heart J 30:1313–1321

    PubMed  Article  Google Scholar 

  25. Vasa M, Fichtlscherer S, Aicher A, Adler K, Urbich C, Martin H, Zeiher AM, Dimmeler S (2001) Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 89:E1–E7

    PubMed  Article  CAS  Google Scholar 

  26. Volpi A, De Vita C, Franzosi MG, Geraci E, Maggioni AP, Mauri F, Negri E, Santoro E, Tavazzi L, Tognoni G (1993) 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 88:416–429

    PubMed  CAS  Google Scholar 

  27. Werner N, Kosiol S, Schiegl T, Ahlers P, Walenta K, Link A, Bohm M, Nickenig G (2005) Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med 353:999–1007

    PubMed  Article  CAS  Google Scholar 

  28. Wolf D, Reinhard A, Seckinger A, Gross L, Katus HA, Hansen A (2009) Regenerative capacity of intravenous autologous, allogeneic and human mesenchymal stem cells in the infarcted pig myocardium-complicated by myocardial tumor formation. Scand Cardiovasc J 43:39–45

    PubMed  Article  CAS  Google Scholar 

  29. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148

    PubMed  Article  Google Scholar 

  30. Yoon CH, Koyanagi M, Iekushi K, Seeger F, Urbich C, Zeiher AM, Dimmeler S (2010) Mechanism of improved cardiac function after bone marrow mononuclear cell therapy: role of cardiovascular lineage commitment. Circulation 121:2001–2011

    PubMed  Article  Google Scholar 

  31. Yoon YS, Park JS, Tkebuchava T, Luedeman C, Losordo DW (2004) Unexpected severe calcification after transplantation of bone marrow cells in acute myocardial infarction. Circulation 109:3154–3157

    PubMed  Article  Google Scholar 

  32. Yousef M, Schannwell CM, Kostering M, Zeus T, Brehm M, Strauer BE (2009) The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J Am Coll Cardiol 53:2262–2269

    PubMed  Article  Google Scholar 

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Acknowledgments

We greatly appreciate the enthusiastic support of the staff of our catheterization laboratories and of our technicians Isabel Geweyer and Tabea Kretschmer (study nurses), Tina Rasper, and Nadine Sorg (biological technicians).

Conflict of interest

Drs. Dimmeler and Zeiher are cofounders of t2cure, a for-profit company focused on regenerative therapies for cardiovascular disease, and serve as scientific advisors and shareholders. Dr. Schächinger has received grant support from Guidant. Drs. Assmus and Schächinger report being scientific advisors of t2cure.

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Correspondence to Birgit Assmus.

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Leistner, D.M., Fischer-Rasokat, U., Honold, J. et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy. Clin Res Cardiol 100, 925–934 (2011). https://doi.org/10.1007/s00392-011-0327-y

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  • DOI: https://doi.org/10.1007/s00392-011-0327-y

Keywords

  • Cell therapy
  • Acute myocardial infarction
  • Progenitor cells