The selection criteria for bone marrow stem cell (BMSC) therapy are not well established for ST segment elevation myocardial infarction (STEMI) patients. This investigation seeks to utilize total ischemic time (TIT), time of symptom onset to percutaneous coronary intervention (PCI), as a criterion for giving BMSC to STEMI patients. A meta-analysis and metaregression were conducted to evaluate improvement of LVEF with BMSC and its association with TIT (<6 and ≥6 hours) and baseline LVEF (<45% and ≥45%) at short (3–6 months) and long term (>6 months) followup. At short term, BMSC allowed improvement of LVEF with prolonged TIT (6.62%, 95% CI, 2.26 to 10.98 for <45%; 6.13%, 95% CI, 2.59 to 9.67 for ≥45%). Similarly, for long term, receiving BMSC allowed significant improvement of LVEF for prolonged TIT (9.19%, 95% CI, 2.34 to 16.05 for <45%; 7.64%, 95% CI, 3.72 to 11.56 for ≥45%). Additionally, TIT was a significant predictor of LVEF improvement independent of baseline LVEF in both short (4.96%, 95% CI, 0.72 to 9.19, ) and long term (6.24%, 95% CI, 0.46 to 12.02, ) followup. Consequently, BMSC therapy allows LVEF improvement in prolonged TIT and future studies for BMSC should include TIT ≥ 6 hours as an inclusion criterion. 1. Introduction Autologous bone marrow stem cell (BMSC) injection in patients with ST segment elevation myocardial infarction (STEMI) has been investigated as a new treatment strategy for the past decade. After the first encouraging pilot study [1] in 2002, many trials have since been published. Although several studies failed to show any favorable outcomes from BMSC [2–5], there have been many trials which demonstrated the beneficial effects of BMSC [6–12]. Several meta-analyses have confirmed that BMSC injections improved left ventricular systolic function, on average, by 3% [13–15]. Despite the promising results in these studies, there were many inconsistencies in the selection criteria; incongruent cell types, varying administration time, and variable injection routes are a few examples. Selected patients were also heterogeneous in terms of baseline left ventricular ejection fraction (LVEF) and time from symptom onset to reperfusion. Unfortunately, it is still difficult to identify the best model to demonstrate the effectiveness of stem cell therapy. In this study, we attempted to define an independent parameter which can increase the efficacy of BMSC: we focused on whether the total ischemic time (TIT), defined by the time of symptom onset to the time of percutaneous coronary intervention (PCI), was associated with LVEF improvement
References
[1]
B. E. Strauer, M. Brehm, T. Zeus et al., “Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans,” Circulation, vol. 106, no. 15, pp. 1913–1918, 2002.
[2]
S. Janssens, C. Dubois, J. Bogaert et al., “Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial,” The Lancet, vol. 367, no. 9505, pp. 113–121, 2006.
[3]
K. Lunde, S. Solheim, S. Aakhus et al., “Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction,” The New England Journal of Medicine, vol. 355, no. 12, pp. 1199–1209, 2006.
[4]
M. Tendera, W. Wojakowski, W. Ruy？？o et al., “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,” European Heart Journal, vol. 30, no. 11, pp. 1313–1321, 2009.
[5]
S. Grajek, M. Popiel, L. Gil et al., “Influence of bone marrow stem cells on left ventricle perfusion and ejection fraction in patients with acute myocardial infarction of anterior wall: randomized clinical trial,” European Heart Journal, vol. 31, no. 6, pp. 691–702, 2010.
[6]
K. C. Wollert, G. P. Meyer, J. Lotz et al., “Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial,” The Lancet, vol. 364, no. 9429, pp. 141–148, 2004.
[7]
J. M. Hare, J. H. Traverse, T. D. Henry et al., “A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction,” Journal of the American College of Cardiology, vol. 54, no. 24, pp. 2277–2286, 2009.
[8]
V. Sch？chinger, S. Erbs, A. Els？sser 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,” European Heart Journal, vol. 27, no. 23, pp. 2775–2783, 2006.
[9]
S.-L. Chen, W.-W. Fang, F. Ye et al., “Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction,” American Journal of Cardiology, vol. 94, no. 1, pp. 92–95, 2004.
[10]
J. Ge, Y. Li, J. Qian et al., “Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI),” Heart, vol. 92, no. 12, pp. 1764–1767, 2006.
[11]
J. Meluzín, J. Mayer, L. Groch et al., “Autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction: the effect of the dose of transplanted cells on myocardial function,” American Heart Journal, vol. 152, no. 5, pp. 975.e9–975.e15, 2006.
[12]
M. Plewka, M. Krzemińska-Paku？a, P. Lipiec et al., “Effect of intracoronary injection of mononuclear bone marrow stem cells on left ventricular function in patients with acute myocardial infarction,” American Journal of Cardiology, vol. 104, no. 10, pp. 1336–1342, 2009.
[13]
S. Zhang, A. Sun, D. Xu et al., “Impact of timing on efficacy and safety of intracoronary autologous bone marrow stem cells transplantation in acute myocardial infarction: a pooled subgroup analysis of randomized controlled trials,” Clinical Cardiology, vol. 32, no. 8, pp. 458–466, 2009.
[14]
E. Martin-Rendon, S. J. Brunskill, C. J. Hyde, S. J. Stanworth, A. Mathur, and S. M. Watt, “Autologous bone marrow stem cells to treat acute myocardial infarction: a systematic review,” European Heart Journal, vol. 29, no. 15, pp. 1807–1818, 2008.
[15]
S. Singh, R. Arora, K. Handa et al., “Stem cells improve left ventricular function in acute myocardial infarction,” Clinical Cardiology, vol. 32, no. 4, pp. 176–180, 2009.
[16]
J. Meluzín, S. Janou？ek, J. Mayer et al., “Three-, 6-, and 12-month results of autologous transplantation of mononuclear bone marrow cells in patients with acute myocardial infarction,” International Journal of Cardiology, vol. 128, no. 2, pp. 185–192, 2008.
[17]
M. Penicka, J. Horak, P. Kobylka et al., “Intracoronary injection of autologous bone marrow-derived mononuclear cells in patients with large anterior acute myocardial infarction: a prematurely terminated randomized study,” Journal of the American College of Cardiology, vol. 49, no. 24, pp. 2373–2374, 2007.
[18]
M. F. Piepoli, D. Vallisa, M. Arbasi et al., “Bone marrow cell transplantation improves cardiac, autonomic, and functional indexes in acute anterior myocardial infarction patients (cardiac study),” European Journal of Heart Failure, vol. 12, no. 2, pp. 172–180, 2010.
[19]
J. H. Traverse, D. H. McKenna, K. Harvey et al., “Results of a phase 1, randomized, double-blind, placebo-controlled trial of bone marrow mononuclear stem cell administration in patients following ST-elevation myocardial infarction,” American Heart Journal, vol. 160, no. 3, pp. 428–434, 2010.
[20]
G. P. Meyer, K. C. Wollert, J. Lotz et al., “Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial,” Circulation, vol. 113, no. 10, pp. 1287–1294, 2006.
[21]
J. O. Beitnes, E. Hopp, K. Lunde et al., “Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study,” Heart, vol. 95, no. 24, pp. 1983–1989, 2009.
[22]
M. Yousef, C. M. Schannwell, M. K？stering, T. Zeus, M. Brehm, and B. E. Strauer, “The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction,” Journal of the American College of Cardiology, vol. 53, no. 24, pp. 2262–2269, 2009.
[23]
B. Assmus, A. Rolf, S. Erbs et al., “Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction,” Circulation: Heart Failure, vol. 3, no. 1, pp. 89–96, 2010.
[24]
M. Egger, G. D. Smith, and D. G. Altman, Systematic Reviews in Health Care: Meta-Analysis in Context, BMJ Publishing Group, London, UK, 2001.
[25]
S. T. Normand, “Meta-analysis: formulating, evaluating, combining and reporting,” Statistics in Medicine, vol. 18, pp. 321–359, 1999.
[26]
H. Chu, L. Nie, Y. Chen, Y. Huang, and W. Sun, “Bivariate random effects models for meta-analysis of comparative studies with binary outcomes: methods for the absolute risk difference and relative risk,” Statistical Methods in Medical Research, vol. 21, no. 6, pp. 621–633, 2010.
[27]
D. Follmann, P. Elliott, I. Suh, and J. Cutler, “Variance imputation for overviews of clinical trials with continuous response,” Journal of Clinical Epidemiology, vol. 45, no. 7, pp. 769–773, 1992.
[28]
J. W？hrle, N. Merkle, V. Mail？nder, et al., “Results of intracoronary stem cell therapy after acute myocardial infarction,” American Journal of Cardiology, vol. 105, no. 6, pp. 804–812, 2010.
[29]
A. E. Denktas, H. V. Anderson, J. McCarthy, and R. W. Smalling, “Total ischemic time: the correct focus of attention for optimal ST-segment elevation myocardial infarction care,” JACC: Cardiovascular Interventions, vol. 4, no. 6, pp. 599–604, 2011.
