European Heart Journal Advance Access published May 28, 2015
EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehv219
Changing of the guard? James T. Willerson 1*, Maria G. Cabreira-Hansen 1, Doris A. Taylor 2, and Emerson C. Perin 1 1
Stem Cell Center, Texas Heart Institute, Houston, TX; and 2Department of Regenerative Medicine Research, Texas Heart Institute, Houston, TX
This editorial refers to ‘Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial)’, by A.B. Mathiasen et al., on page doi:10.1093/eurheartj/ehv136.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Texas Heart Institute, 6770 Bertner (MC 3-116), Houston, TX 77030. Tel: 832-355-6839; Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on June 1, 2015
Cell therapy continues to hold promise as a future therapeutic modality for patients with heart failure. The first cells to be utilised in clinical trials in cardiovascular disease were autologous bone marrow-derived mononuclear cells (ABMMNCs).1 – 3 This was likely due to the fact that these cells are readily accessible and can be easily processed and given back to patients as an autologous fresh product in a short amount of time. In the absence of clinical experience, this was a good starting point. Over the next decade, important additional data were obtained with the use of ABMMNCs,4 – 6 and the initial positive results were tempered by negative results. Nonetheless, after much scrutiny, there seems to be a therapeutic signal,7 albeit a weak one. Overall, treated patients have shown relatively small but statistically significant improvements in LV function and reductions in future major adverse cardiac events (MACE).8 Because of the limitations of ABMMNCs and a general drive towards finding more effective treatments based on preclinical work, there has been a parallel and progressive development of single-cell therapies from both bone marrow and other tissues. The therapeutic properties of mesenchymal stromal cells have been extensively investigated in a wide range of disease conditions (Figure 1).9 In this issue of the European Heart Journal, Dr Mathiasen and colleagues10 showed that transendocardial injections of autologous bone marrow-derived mesenchymal cells (MCS) resulted in positive effects on left ventricular (LV) contractility in patients with ischemic cardiomyopathy and no other treatment options. Treated patients received a mean of 77.5 + 67.9 × 106 cells. The primary endpoint of their trial was a change in LV end-systolic volume (LVESV), as measured by magnetic resonance imaging or computed tomography at the 6-month follow-up. In this placebocontrolled, randomised trial comprising 55 patients (37 treated with MSCs and 18 treated with placebo), they found that LVESV decreased by 7.6 mL in the MSC-treated group and increased by 5.4 mL in the placebo-treated group. The difference between the
2 groups was 13.0 mL (P ¼0.001). Compared to the placebo group, the treated group also showed a 6% increase in LV ejection fraction (P , 0.001), an 18 mL increase in stroke volume (P , 0.0001), and a 5.7 g increase in myocardial mass (P ¼0.001). No significant differences were found in New York Heart Association classification, 6-minute walk time, or the Kansas City cardiomyopathy questionnaire. No side-effects attributable to the treatment were identified. These findings are in agreement with those from several previous clinical studies that also assessed the use of mesenchymal cells in similar patients.11 – 14 In these previous studies, allogeneic and autologous bone marrow-derived and adipose tissue-derived mesenchymal stem cells showed beneficial effects on various aspects of LV function and the occurrence of MACE in patients with ischemic cardiomyopathies and no other option for revascularization. Taken together, these newer studies represent a shift away from ABMMNC therapy. The mesenchymal cell has taken centre stage. Based on more robust results,13 a large phase 3 trial is currently underway to investigate the therapeutic role of these cells in heart failure patients (DREAM HF, NCT02032004). However, one must always be cautious as this is a very dynamic field, and another cell type, such as cardiac-derived stem cells or iPS cells, may take over as the best candidate after further development. In addition to the progress in pursuing more potent single-cell therapies, it also seems possible that combinations of stem cells may be more effective than a single cell type alone. In a pre-clinical study, Williams and colleagues15 showed that the combination of cardiac resident c-kit cells and mesenchymal cells administered transendocardially reduced infarct size and improved LV function more than either stem cell type alone in a porcine model of myocardial infarction. The Cardiovascular Cell Therapy Research Network will soon begin a clinical trial in the United States in which patients with ischemic cardiomyopathies will receive similar treatments (ie, mesenchymal cells, c-kit+ cells, or the 2 cell types in combination) (CONCERT-HF). This trial will help determine the potential benefits of combining mesenchymal and c-kit+ stem cells for treating patients with heart failure due to coronary heart disease and no other treatment options. In summary, important progress has been made in the search for the ideal cell type, or combinations thereof, to obtain the best therapeutic effect for patients with heart failure. Mathiasen et al’s positive
Page 2 of 3
Editorial
Figure 1 Proposed therapeutic mechanisms of mesenchymal progenitor cells.
5.
Acknowledgments The authors would like to thank Heather Leibrecht, MS, and Marianne Mallia, ELS, of the Section of Scientific Publications at the Texas Heart Institute for their assistance in the editing of this manuscript. 6.
Funding Support was provided by the NHLBI’s Cardiovascular Cell Therapy Research Network. Conflict of interest: Dr Perin is a consultant for Mesoblast Ltd. Drs Willerson, Taylor, and Cabreira-Hansen have no conflicts to disclose.
References 1. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107:2294 –2302. 2. Strauer BE, Brehm M, Zeus T, Bartsch T, Schannwell C, Antke C, Sorg RV, Kogler G, Wernet P, Muller HW, Kostering M. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol 2005;46:1651 –1658. 3. Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003;361:47–49. 4. Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research
7.
8. 9.
10.
11.
N. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 2012;307:1717 –1726. Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, Taylor DA, Cogle CR, Thomas JD, Silva GV, Jorgenson BC, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Smith DX, Baraniuk S, Piller LB, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research N. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 2011;306:2110 –2119. Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, Forder JR, Anderson RD, Hatzopoulos AK, Penn MS, Perin EC, Chambers J, Baran KW, Raveendran G, Lambert C, Lerman A, Simon DI, Vaughan DE, Lai D, Gee AP, Taylor DA, Cogle CR, Thomas JD, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Kappenman C, Westbrook L, Piller LB, Simpson LM, Baraniuk S, Loghin C, Aguilar D, Richman S, Zierold C, Spoon DB, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research N. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA 2012;308:2380 – 2389. Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2014;4:CD007888. Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res 2015;116:1361 –1377. Sharma RR, Pollock K, Hubel A, McKenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 2014;54: 1418 –1437. Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Fischer-Nielsen A, Kofoed KF, Haack-Sørensen M, Ekblond A, Kastrup J. Bone-marrow derived mesenchymal stromal cell treatment in patients with severe ischemic heart failure; a randomized placebo-controlled trial (MSC-HF trial). Eur Heart J 2015; doi:10.1093/eurheartj/ ehv136. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial
Downloaded from by guest on June 1, 2015
results are an important addition to the current knowledge. We believe that mesenchymal cells represent a step in the right direction towards improving the therapeutic benefits of cell therapy in heart failure patients.
Editorial
injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012;308:2369 –2379. 12. Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, Mushtaq M, Williams AR, Suncion VY, McNiece IK, Ghersin E, Soto V, Lopera G, Miki R, Willens H, Hendel R, Mitrani R, Pattany P, Feigenbaum G, Oskouei B, Byrnes J, Lowery MH, Sierra J, Pujol MV, Delgado C, Gonzalez PJ, Rodriguez JE, Bagno LL, Rouy D, Altman P, Foo CW, da Silva J, Anderson E, Schwarz R, Mendizabal A, Hare JM. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014;311:62 –73. 13. Perin EC, Dib N, DeMaria A, Marroquin OC, Huang PP, Traverse JH, Silva GS, Krum H. A phase II dose-escalation study of allogeneic mesenchymal precursor
Page 3 of 3 cells in patients with ischemic and nonischemic heart failure (abstract). Circulation 2011;240:2372. 14. Perin EC, Sanz-Ruiz R, Sanchez PL, Lasso J, Perez-Cano R, Alonso-Farto JC, Perez-David E, Fernandez-Santos ME, Serruys PW, Duckers HJ, Kastrup J, Chamuleau S, Zheng Y, Silva GV, Willerson JT, Fernandez-Aviles F. Adiposederived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 2014;168:88 –95 e82. 15. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW, Hare JM. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 2013;127:213 –223.
Downloaded from by guest on June 1, 2015
EDITORIAL
European Heart Journal doi:10.1093/eurheartj/ehv219
Changing of the guard? James T. Willerson 1*, Maria G. Cabreira-Hansen 1, Doris A. Taylor 2, and Emerson C. Perin 1 1
Stem Cell Center, Texas Heart Institute, Houston, TX; and 2Department of Regenerative Medicine Research, Texas Heart Institute, Houston, TX
This editorial refers to ‘Bone marrow-derived mesenchymal stromal cell treatment in patients with severe ischaemic heart failure: a randomized placebo-controlled trial (MSC-HF trial)’, by A.B. Mathiasen et al., on page doi:10.1093/eurheartj/ehv136.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Texas Heart Institute, 6770 Bertner (MC 3-116), Houston, TX 77030. Tel: 832-355-6839; Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected].
Downloaded from by guest on June 1, 2015
Cell therapy continues to hold promise as a future therapeutic modality for patients with heart failure. The first cells to be utilised in clinical trials in cardiovascular disease were autologous bone marrow-derived mononuclear cells (ABMMNCs).1 – 3 This was likely due to the fact that these cells are readily accessible and can be easily processed and given back to patients as an autologous fresh product in a short amount of time. In the absence of clinical experience, this was a good starting point. Over the next decade, important additional data were obtained with the use of ABMMNCs,4 – 6 and the initial positive results were tempered by negative results. Nonetheless, after much scrutiny, there seems to be a therapeutic signal,7 albeit a weak one. Overall, treated patients have shown relatively small but statistically significant improvements in LV function and reductions in future major adverse cardiac events (MACE).8 Because of the limitations of ABMMNCs and a general drive towards finding more effective treatments based on preclinical work, there has been a parallel and progressive development of single-cell therapies from both bone marrow and other tissues. The therapeutic properties of mesenchymal stromal cells have been extensively investigated in a wide range of disease conditions (Figure 1).9 In this issue of the European Heart Journal, Dr Mathiasen and colleagues10 showed that transendocardial injections of autologous bone marrow-derived mesenchymal cells (MCS) resulted in positive effects on left ventricular (LV) contractility in patients with ischemic cardiomyopathy and no other treatment options. Treated patients received a mean of 77.5 + 67.9 × 106 cells. The primary endpoint of their trial was a change in LV end-systolic volume (LVESV), as measured by magnetic resonance imaging or computed tomography at the 6-month follow-up. In this placebocontrolled, randomised trial comprising 55 patients (37 treated with MSCs and 18 treated with placebo), they found that LVESV decreased by 7.6 mL in the MSC-treated group and increased by 5.4 mL in the placebo-treated group. The difference between the
2 groups was 13.0 mL (P ¼0.001). Compared to the placebo group, the treated group also showed a 6% increase in LV ejection fraction (P , 0.001), an 18 mL increase in stroke volume (P , 0.0001), and a 5.7 g increase in myocardial mass (P ¼0.001). No significant differences were found in New York Heart Association classification, 6-minute walk time, or the Kansas City cardiomyopathy questionnaire. No side-effects attributable to the treatment were identified. These findings are in agreement with those from several previous clinical studies that also assessed the use of mesenchymal cells in similar patients.11 – 14 In these previous studies, allogeneic and autologous bone marrow-derived and adipose tissue-derived mesenchymal stem cells showed beneficial effects on various aspects of LV function and the occurrence of MACE in patients with ischemic cardiomyopathies and no other option for revascularization. Taken together, these newer studies represent a shift away from ABMMNC therapy. The mesenchymal cell has taken centre stage. Based on more robust results,13 a large phase 3 trial is currently underway to investigate the therapeutic role of these cells in heart failure patients (DREAM HF, NCT02032004). However, one must always be cautious as this is a very dynamic field, and another cell type, such as cardiac-derived stem cells or iPS cells, may take over as the best candidate after further development. In addition to the progress in pursuing more potent single-cell therapies, it also seems possible that combinations of stem cells may be more effective than a single cell type alone. In a pre-clinical study, Williams and colleagues15 showed that the combination of cardiac resident c-kit cells and mesenchymal cells administered transendocardially reduced infarct size and improved LV function more than either stem cell type alone in a porcine model of myocardial infarction. The Cardiovascular Cell Therapy Research Network will soon begin a clinical trial in the United States in which patients with ischemic cardiomyopathies will receive similar treatments (ie, mesenchymal cells, c-kit+ cells, or the 2 cell types in combination) (CONCERT-HF). This trial will help determine the potential benefits of combining mesenchymal and c-kit+ stem cells for treating patients with heart failure due to coronary heart disease and no other treatment options. In summary, important progress has been made in the search for the ideal cell type, or combinations thereof, to obtain the best therapeutic effect for patients with heart failure. Mathiasen et al’s positive
Page 2 of 3
Editorial
Figure 1 Proposed therapeutic mechanisms of mesenchymal progenitor cells.
5.
Acknowledgments The authors would like to thank Heather Leibrecht, MS, and Marianne Mallia, ELS, of the Section of Scientific Publications at the Texas Heart Institute for their assistance in the editing of this manuscript. 6.
Funding Support was provided by the NHLBI’s Cardiovascular Cell Therapy Research Network. Conflict of interest: Dr Perin is a consultant for Mesoblast Ltd. Drs Willerson, Taylor, and Cabreira-Hansen have no conflicts to disclose.
References 1. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107:2294 –2302. 2. Strauer BE, Brehm M, Zeus T, Bartsch T, Schannwell C, Antke C, Sorg RV, Kogler G, Wernet P, Muller HW, Kostering M. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study. J Am Coll Cardiol 2005;46:1651 –1658. 3. Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003;361:47–49. 4. Perin EC, Willerson JT, Pepine CJ, Henry TD, Ellis SG, Zhao DX, Silva GV, Lai D, Thomas JD, Kronenberg MW, Martin AD, Anderson RD, Traverse JH, Penn MS, Anwaruddin S, Hatzopoulos AK, Gee AP, Taylor DA, Cogle CR, Smith D, Westbrook L, Chen J, Handberg E, Olson RE, Geither C, Bowman S, Francescon J, Baraniuk S, Piller LB, Simpson LM, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research
7.
8. 9.
10.
11.
N. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA 2012;307:1717 –1726. Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, Forder JR, Byrne BJ, Hatzopoulos AK, Penn MS, Perin EC, Baran KW, Chambers J, Lambert C, Raveendran G, Simon DI, Vaughan DE, Simpson LM, Gee AP, Taylor DA, Cogle CR, Thomas JD, Silva GV, Jorgenson BC, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Smith DX, Baraniuk S, Piller LB, Loghin C, Aguilar D, Richman S, Zierold C, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research N. Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 to 3 weeks following acute myocardial infarction on left ventricular function: the LateTIME randomized trial. JAMA 2011;306:2110 –2119. Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, Forder JR, Anderson RD, Hatzopoulos AK, Penn MS, Perin EC, Chambers J, Baran KW, Raveendran G, Lambert C, Lerman A, Simon DI, Vaughan DE, Lai D, Gee AP, Taylor DA, Cogle CR, Thomas JD, Olson RE, Bowman S, Francescon J, Geither C, Handberg E, Kappenman C, Westbrook L, Piller LB, Simpson LM, Baraniuk S, Loghin C, Aguilar D, Richman S, Zierold C, Spoon DB, Bettencourt J, Sayre SL, Vojvodic RW, Skarlatos SI, Gordon DJ, Ebert RF, Kwak M, Moye LA, Simari RD. Cardiovascular Cell Therapy Research N. Effect of the use and timing of bone marrow mononuclear cell delivery on left ventricular function after acute myocardial infarction: the TIME randomized trial. JAMA 2012;308:2380 – 2389. Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2014;4:CD007888. Fisher SA, Doree C, Mathur A, Martin-Rendon E. Meta-analysis of cell therapy trials for patients with heart failure. Circ Res 2015;116:1361 –1377. Sharma RR, Pollock K, Hubel A, McKenna D. Mesenchymal stem or stromal cells: a review of clinical applications and manufacturing practices. Transfusion 2014;54: 1418 –1437. Mathiasen AB, Qayyum AA, Jørgensen E, Helqvist S, Fischer-Nielsen A, Kofoed KF, Haack-Sørensen M, Ekblond A, Kastrup J. Bone-marrow derived mesenchymal stromal cell treatment in patients with severe ischemic heart failure; a randomized placebo-controlled trial (MSC-HF trial). Eur Heart J 2015; doi:10.1093/eurheartj/ ehv136. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, Tracy M, Ghersin E, Johnston PV, Brinker JA, Breton E, Davis-Sproul J, Schulman IH, Byrnes J, Mendizabal AM, Lowery MH, Rouy D, Altman P, Wong Po Foo C, Ruiz P, Amador A, Da Silva J, McNiece IK, Heldman AW, George R, Lardo A. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial
Downloaded from by guest on June 1, 2015
results are an important addition to the current knowledge. We believe that mesenchymal cells represent a step in the right direction towards improving the therapeutic benefits of cell therapy in heart failure patients.
Editorial
injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA 2012;308:2369 –2379. 12. Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, Mushtaq M, Williams AR, Suncion VY, McNiece IK, Ghersin E, Soto V, Lopera G, Miki R, Willens H, Hendel R, Mitrani R, Pattany P, Feigenbaum G, Oskouei B, Byrnes J, Lowery MH, Sierra J, Pujol MV, Delgado C, Gonzalez PJ, Rodriguez JE, Bagno LL, Rouy D, Altman P, Foo CW, da Silva J, Anderson E, Schwarz R, Mendizabal A, Hare JM. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA 2014;311:62 –73. 13. Perin EC, Dib N, DeMaria A, Marroquin OC, Huang PP, Traverse JH, Silva GS, Krum H. A phase II dose-escalation study of allogeneic mesenchymal precursor
Page 3 of 3 cells in patients with ischemic and nonischemic heart failure (abstract). Circulation 2011;240:2372. 14. Perin EC, Sanz-Ruiz R, Sanchez PL, Lasso J, Perez-Cano R, Alonso-Farto JC, Perez-David E, Fernandez-Santos ME, Serruys PW, Duckers HJ, Kastrup J, Chamuleau S, Zheng Y, Silva GV, Willerson JT, Fernandez-Aviles F. Adiposederived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial. Am Heart J 2014;168:88 –95 e82. 15. Williams AR, Hatzistergos KE, Addicott B, McCall F, Carvalho D, Suncion V, Morales AR, Da Silva J, Sussman MA, Heldman AW, Hare JM. Enhanced effect of combining human cardiac stem cells and bone marrow mesenchymal stem cells to reduce infarct size and to restore cardiac function after myocardial infarction. Circulation 2013;127:213 –223.
Downloaded from by guest on June 1, 2015
