| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2001;103:1920.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Cell Therapy Attenuates Deleterious Ventricular Remodeling and Improves Cardiac Performance After Myocardial Infarction
From the Cardiac Muscle Research Laboratory (M.J., D.A.B., S.N., P.T., C.S.A., R.L.) and the Myocardial Biology Unit (D.B.S., W.S.C.), Boston University School of Medicine, Boston, Mass; and Diacrin, Inc (H.D., A.S.B.E., A.Z., K.W.), Charlestown, Mass.
Correspondence to Dr Ronglih Liao, Boston University School of Medicine, 650 Albany St, X-726, Boston, MA 02118. E-mail rliao{at}bu.edu
Background—Myocardial infarction (MI) promotes deleterious remodeling of the myocardium, resulting in ventricular dilation and pump dysfunction. We examined whether supplementing infarcted myocardium with skeletal myoblasts would (1) result in viable myoblast implants, (2) attenuate deleterious remodeling, and (3) enhance in vivo and ex vivo contractile performance.
Methods and
Results—Experimental MI was induced by 1-hour
coronary ligation followed by reperfusion in adult male Lewis
rats. One week after MI, 106 myoblasts were
injected directly into the infarct region. Three groups of animals were
studied at 3 and 6 weeks after cell therapy: noninfarcted control
(control), MI plus sham injection (MI), and MI plus cell injection
(MI+cell). In vivo cardiac function was assessed by maximum exercise
capacity testing and ex vivo function was determined by pressure-volume
curves obtained from isolated, red cell–perfused, balloon–in–left
ventricle (LV) hearts. MI and MI+cell hearts had indistinguishable
infarct sizes of 
30% of the LV. At 3 and 6 weeks after cell
therapy, 92% (13 of 14) of MI+cell hearts showed evidence of myoblast
graft survival. MI+cell hearts exhibited attenuation of global
ventricular dilation and reduced septum–to–free wall
diameter compared with MI hearts not receiving cell therapy.
Furthermore, cell therapy improved both post-MI in vivo exercise
capacity and ex vivo LV systolic
pressures.
Conclusions—Implanted skeletal myoblasts form viable grafts in infarcted myocardium, resulting in enhanced post-MI exercise capacity and contractile function and attenuated ventricular dilation. These data illustrate that syngeneic myoblast implantation after MI improves both in vivo and ex vivo indexes of global ventricular dysfunction and deleterious remodeling and suggests that cellular implantation may be beneficial after MI.
Key Words: myocardial infarction • remodeling • exercise • myocardial contraction
This article has been cited by other articles:
 |
|
 |
|
  D. Zimpfer, S. Aharinejad, J. Holfeld, A. Thomas, J. Dumfarth, R. Rosenhek, M. Czerny, W. Schaden, M. Gmeiner, E. Wolner, et al. Direct epicardial shock wave therapy improves ventricular function and induces angiogenesis in ischemic heart failure J. Thorac. Cardiovasc. Surg., April 1, 2009; 137(4): 963 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Brinks, H. Tevaearai, C. Muhlfeld, D. Bertschi, B. Gahl, T. Carrel, and M.-N. Giraud Contractile function is preserved in unloaded hearts despite atrophic remodeling. J. Thorac. Cardiovasc. Surg., March 1, 2009; 137(3): 742 - 746. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dib, J. Dinsmore, Z. Lababidi, B. White, S. Moravec, A. Campbell, A. Rosenbaum, K. Seyedmadani, W. A. Jaber, C. S. Rizenhour, et al. One-Year Follow-Up of Feasibility and Safety of the First U.S., Randomized, Controlled Study Using 3-Dimensional Guided Catheter-Based Delivery of Autologous Skeletal Myoblasts for Ischemic Cardiomyopathy (CAuSMIC Study) J. Am. Coll. Cardiol. Intv., January 1, 2009; 2(1): 9 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Hendry II, K. E.A. van der Bogt, A. Y. Sheikh, T. Arai, S. J. Dylla, M. Drukker, M. V. McConnell, I. Kutschka, G. Hoyt, F. Cao, et al. Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells. J. Thorac. Cardiovasc. Surg., October 1, 2008; 136(4): 1028 - 1037.e1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Aharinejad, D. Abraham, P. Paulus, K. Zins, M. Hofmann, W. Michlits, M. Gyongyosi, K. Macfelda, T. Lucas, K. Trescher, et al. Colony-stimulating factor-1 transfection of myoblasts improves the repair of failing myocardium following autologous myoblast transplantation Cardiovasc Res, August 1, 2008; 79(3): 395 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Molina, J. Palma, D. Gupta, D. Torres, J. P. Gaughan, S. Houser, and M. Macha Improvement in hemodynamic performance, exercise capacity, inflammatory profile, and left ventricular reverse remodeling after intracoronary delivery of mesenchymal stem cells in an experimental model of pressure overload hypertrophy. J. Thorac. Cardiovasc. Surg., February 1, 2008; 135(2): 292 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Khan, V. K. Kutala, D. S. Vikram, S. Wisel, S. M. Chacko, M. L. Kuppusamy, I. K. Mohan, J. L. Zweier, P. Kwiatkowski, and P. Kuppusamy Skeletal myoblasts transplanted in the ischemic myocardium enhance in situ oxygenation and recovery of contractile function Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2129 - H2139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Retuerto, J. T. Beckmann, J. Carbray, G. Patejunas, S. Sarateanu, B. J. Kane, B. Smulevitz, D. D. McPherson, and T. K. Rosengart Angiogenic pretreatment to enhance myocardial function after cellular cardiomyoplasty with skeletal myoblasts J. Thorac. Cardiovasc. Surg., February 1, 2007; 133(2): 478 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Murry, H. Reinecke, and L. M. Pabon Regeneration Gaps: Observations on Stem Cells and Cardiac Repair J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. He, D. M. Opland, K. J. Way, K. Ueki, N. Bodyak, P. M. Kang, S. Izumo, R. N. Kulkarni, B. Wang, R. Liao, et al. Regulation of Vascular Endothelial Growth Factor Expression and Vascularization in the Myocardium by Insulin Receptor and PI3K/Akt Pathways in Insulin Resistance and Ischemia Arterioscler Thromb Vasc Biol, April 1, 2006; 26(4): 787 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. R. Mills, N. Mal, F. Forudi, Z. B. Popovic, M. S. Penn, and K. R. Laurita Optical mapping of late myocardial infarction in rats Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1298 - H1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Mouquet, O. Pfister, M. Jain, A. Oikonomopoulos, S. Ngoy, R. Summer, A. Fine, and R. Liao Restoration of Cardiac Progenitor Cells After Myocardial Infarction by Self-Proliferation and Selective Homing of Bone Marrow-Derived Stem Cells Circ. Res., November 25, 2005; 97(11): 1090 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Murry, L. J. Field, and P. Menasche Cell-Based Cardiac Repair: Reflections at the 10-Year Point Circulation, November 15, 2005; 112(20): 3174 - 3183. [Full Text] [PDF]
|
|
|
|
|
|
N. Dib, R. E. Michler, F. D. Pagani, S. Wright, D. J. Kereiakes, R. Lengerich, P. Binkley, D. Buchele, I. Anand, C. Swingen, et al. Safety and Feasibility of Autologous Myoblast Transplantation in Patients With Ischemic Cardiomyopathy: Four-Year Follow-Up Circulation, September 20, 2005; 112(12): 1748 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Laflamme, J. Gold, C. Xu, M. Hassanipour, E. Rosler, S. Police, V. Muskheli, and C. E. Murry Formation of Human Myocardium in the Rat Heart from Human Embryonic Stem Cells Am. J. Pathol., September 1, 2005; 167(3): 663 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Gutstein, S. B. Danik, S. Lewitton, D. France, F. Liu, F. L. Chen, J. Zhang, N. Ghodsi, G. E. Morley, and G. I. Fishman Focal gap junction uncoupling and spontaneous ventricular ectopy Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1091 - H1098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. A. Krombach, C. B. Higgins, M. Chujo, and M. Saeed Gadomer-enhanced MR Imaging in the Detection of Microvascular Obstruction: Alleviation with Nicorandil Therapy Radiology, August 1, 2005; 236(2): 510 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Siminiak, D. Fiszer, O. Jerzykowska, B. Grygielska, N. Rozwadowska, P. Kalmucki, and M. Kurpisz Percutaneous trans-coronary-venous transplantation of autologous skeletal myoblasts in the treatment of post-infarction myocardial contractility impairment: the POZNAN trial Eur. Heart J., June 2, 2005; 26(12): 1188 - 1195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Wollert and H. Drexler Clinical Applications of Stem Cells for the Heart Circ. Res., February 4, 2005; 96(2): 151 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Rastan, T. Walther, M. Kostelka, J. Garbade, A. Schubert, A. Stein, S. Dhein, and F. W. Mohr Morphological, electrophysiological and coupling characteristics of bone marrow-derived mononuclear cells--an in vitro-model Eur. J. Cardiothorac. Surg., January 1, 2005; 27(1): 104 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pouly, A. A. Hagege, J.-T. Vilquin, A. Bissery, A. Rouche, P. Bruneval, D. Duboc, M. Desnos, M. Fiszman, Y. Fromes, et al. Does the Functional Efficacy of Skeletal Myoblast Transplantation Extend to Nonischemic Cardiomyopathy? Circulation, September 21, 2004; 110(12): 1626 - 1631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Christman, A. J. Vardanian, Q. Fang, R. E. Sievers, H. H. Fok, and R. J. Lee Injectable fibrin scaffold improves cell transplant survival, reduces infarct expansion, and induces neovasculature formation in ischemic myocardium J. Am. Coll. Cardiol., August 4, 2004; 44(3): 654 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Ott, S. Berjukow, R. Marksteiner, E. Margreiter, G. Bock, G. Laufer, and S. Hering On the fate of skeletal myoblasts in a cardiac environment: down-regulation of voltage-gated ion channels J. Physiol., August 1, 2004; 558(3): 793 - 805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Toh, S. Kawashima, M. Kawai, T. Sakoda, T. Ueyama, S. Satomi-Kobayashi, S. Hirayama, and M. Yokoyama Transplantation of cardiotrophin-1-expressing myoblasts to the left ventricular wall alleviates the transition from compensatory hypertrophy to congestive heart failure in Dahl salt-sensitive hypertensive rats J. Am. Coll. Cardiol., June 16, 2004; 43(12): 2337 - 2347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Lee and R. R. Makkar Stem-Cell Transplantation in Myocardial Infarction: A Status Report Ann Intern Med, May 4, 2004; 140(9): 729 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Retuerto, P. Schalch, G. Patejunas, J. Carbray, N. Liu, K. Esser, R. G. Crystal, and T. K. Rosengart Angiogenic pretreatment improves the efficacy of cellular cardiomyoplasty performed with fetal cardiomyocyte implantation J. Thorac. Cardiovasc. Surg., April 1, 2004; 127(4): 1041 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Murtuza, K. Suzuki, G. Bou-Gharios, J. R. Beauchamp, R. T. Smolenski, T. A. Partridge, and M. H. Yacoub Transplantation of skeletal myoblasts secreting an IL-1 inhibitor modulates adverse remodeling in infarcted murine myocardium PNAS, March 23, 2004; 101(12): 4216 - 4221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. C. Smits, R.-J. M. van Geuns, D. Poldermans, M. Bountioukos, E. E. M. Onderwater, C. H. Lee, A. P. W. M. Maat, and P. W. Serruys Catheter-Based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: Clinical experience with Six-Month Follow-Up J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2063 - 2069. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Blatt, D. Robinson, G. Cotter, S. Efrati, Y. Simantov, I. Bar, E. Kaluski, R. Krakover, S. Sidenko, Z. Evron, et al. Improved regional left ventricular function after successful satellite cell grafting in rabbits with myocardial infarction Eur J Heart Fail, December 1, 2003; 5(6): 751 - 757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ohno, P. W. M. Fedak, R. D. Weisel, D. A. G. Mickle, T. Fujii, and R.-K. Li Transplantation of cryopreserved muscle cells in dilated cardiomyopathy: Effects on left ventricular geometry and function J. Thorac. Cardiovasc. Surg., November 1, 2003; 126(5): 1537 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bel, E. Messas, O. Agbulut, P. Richard, J. L. Samuel, P. Bruneval, A. A. Hagege, and P. Menasche Transplantation of Autologous Fresh Bone Marrow Into Infarcted Myocardium: A Word of Caution Circulation, September 9, 2003; 108(90101): II-247 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tambara, Y. Sakakibara, G. Sakaguchi, F. Lu, G. U. Premaratne, X. Lin, K. Nishimura, and M. Komeda Transplanted Skeletal Myoblasts Can Fully Replace the Infarcted Myocardium When They Survive in the Host in Large Numbers Circulation, September 9, 2003; 108(90101): II-259 - 263. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. B. Thompson, S. M. Emani, B. H. Davis, E. J. van den Bos, Y. Morimoto, D. Craig, D. Glower, and D. A. Taylor Comparison of Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts Versus Bone Marrow Cells Circulation, September 9, 2003; 108(90101): II-264 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Forrester, M. J. Price, and R. R. Makkar Stem Cell Repair of Infarcted Myocardium: An Overview for Clinicians Circulation, September 2, 2003; 108(9): 1139 - 1145. [Full Text] [PDF]
|
|
|
|
|
|
T. Saito, J.-Q. Kuang, C. C. H. Lin, and R. C.-J. Chiu Transcoronary implantation of bone marrow stromal cells ameliorates cardiac function after myocardial infarction J. Thorac. Cardiovasc. Surg., July 1, 2003; 126(1): 114 - 122. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. H.L. Tang, P. W.M. Fedak, T. M. Yau, R. D. Weisel, A. Kulik, D. A.G. Mickle, and R.-K. Li Cell transplantation to improve ventricular function in the failing heart Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 907 - 916. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Menasche Cell transplantation in myocardium Ann. Thorac. Surg., June 1, 2003; 75(90060): S20 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Whittaker, J. Muller-Ehmsen, J. S. Dow, L. H. Kedes, and R. A. Kloner Development of abnormal tissue architecture in transplanted neonatal rat myocytes Ann. Thorac. Surg., May 1, 2003; 75(5): 1450 - 1456. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. D. Dowell, M. Rubart, K. B.S. Pasumarthi, M. H. Soonpaa, and L. J. Field Myocyte and myogenic stem cell transplantation in the heart Cardiovasc Res, May 1, 2003; 58(2): 336 - 350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Menasche Skeletal muscle satellite cell transplantation Cardiovasc Res, May 1, 2003; 58(2): 351 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Reffelmann and R. A. Kloner Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Cardiovasc Res, May 1, 2003; 58(2): 358 - 368. [Full Text] [PDF]
|
|
|
|
|
|
P. Menasche, A. A. Hagege, J.-T. Vilquin, M. Desnos, E. Abergel, B. Pouzet, A. Bel, S. Sarateanu, M. Scorsin, K. Schwartz, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1078 - 1083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Minami, H. Reinecke, and C. E. Murry Skeletal muscle meets cardiac muscle: Friends or foes? J. Am. Coll. Cardiol., April 2, 2003; 41(7): 1084 - 1086. [Full Text] [PDF]
|
|
|
|
|
|
F. D. Pagani, H. DerSimonian, A. Zawadzka, K. Wetzel, A. S. B. Edge, D. B. Jacoby, J. H. Dinsmore, S. Wright, T. H. Aretz, H. J. Eisen, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans: Histological analysis of cell survival and differentiation J. Am. Coll. Cardiol., March 5, 2003; 41(5): 879 - 888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. O. Al-Radi, V. Rao, R.-k. Li, T. Yau, and R. D. Weisel Cardiac cell transplantation: closer to bedside Ann. Thorac. Surg., February 1, 2003; 75(2): S674 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Rademakers, F. Van de Werf, L. Mortelmans, G. Marchal, and J. Bogaert Evolution of regional performance after an acute anterior myocardial infarction in humans using magnetic resonance tagging J. Physiol., February 1, 2003; 546(3): 777 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Ruel, R. A. Kelly, and F. W. Sellke Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750. [Full Text]
|
|
|
|
 |
|
 Y. Yang, J.-Y. Min, J. S. Rana, Q. Ke, J. Cai, Y. Chen, J. P. Morgan, and Y.-F. Xiao VEGF enhances functional improvement of postinfarcted hearts by transplantation of ESC-differentiated cells J Appl Physiol, September 1, 2002; 93(3): 1140 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Saeed, N. Watzinger, G. A. Krombach, G. K. Lund, M. F. Wendland, M. Chujo, and C. B. Higgins Left Ventricular Remodeling after Infarction: Sequential MR Imaging with Oral Nicorandil Therapy in Rat Model Radiology, September 1, 2002; 224(3): 830 - 837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Roell, Z. J. Lu, W. Bloch, S. Siedner, K. Tiemann, Y. Xia, E. Stoecker, M. Fleischmann, H. Bohlen, R. Stehle, et al. Cellular Cardiomyoplasty Improves Survival After Myocardial Injury Circulation, May 21, 2002; 105(20): 2435 - 2441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Grounds, J. D. White, N. Rosenthal, and M. A. Bogoyevitch The Role of Stem Cells in Skeletal and Cardiac Muscle Repair J. Histochem. Cytochem., May 1, 2002; 50(5): 589 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Menasche and M Desnos Cardiac reparation: fixing the heart with cells, new vessels and genes Eur. Heart J. Suppl., April 1, 2002; 4(suppl_D): D73 - D81. [Abstract] [PDF]
|
|
|
|
|
|
N. Watzinger, G. K. Lund, C. B. Higgins, M. Chujo, and M. Saeed Noninvasive assessment of the effects of nicorandil on left ventricular volumes and function in reperfused myocardial infarction Cardiovasc Res, April 1, 2002; 54(1): 77 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.E. MURRY, M.L. WHITNEY, M.A. LAFLAMME, H. REINECKE, and L.J. FIELD Cellular Therapies for Myocardial Infarct Repair Cold Spring Harb Symp Quant Biol, January 1, 2002; 67(0): 519 - 526. [Abstract] [PDF]
|
|
|
|
|
|
C. Toma, M. F. Pittenger, K. S. Cahill, B. J. Byrne, and P. D. Kessler Human Mesenchymal Stem Cells Differentiate to a Cardiomyocyte Phenotype in the Adult Murine Heart Circulation, January 1, 2002; 105(1): 93 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Muller-Ehmsen, K. L. Peterson, L. Kedes, P. Whittaker, J. S. Dow, T. I. Long, P. W. Laird, and R. A. Kloner Rebuilding a Damaged Heart: Long-Term Survival of Transplanted Neonatal Rat Cardiomyocytes After Myocardial Infarction and Effect on Cardiac Function Circulation, April 9, 2002; 105(14): 1720 - 1726. [Abstract] [Full Text] [PDF]
|
|