Advertisement

Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties

Published:October 24, 2005DOI:https://doi.org/10.1016/j.ijcard.2005.07.036

      Abstract

      Direct intramyocardial injection of mesenchymal stem cells (MSCs) improves left ventricular ejection fraction (LVEF) and may increase ventricular arrhythmia in hearts with myocardial infarction (MI). We hypothesized that intravenous MSCs given early after acute MI would engraft in injured myocardium, improve LV function, and result in pro-arrhythmic electrical remodeling. We created an apical infarction in swine by balloon occlusion/reperfusion, administered diI-labeled allogeneic bone marrow derived MSCs intravenously 30 min post-reperfusion and measured LVEF and wall thickness at baseline, 1 month, and 3 months. Epicardial effective refractory periods (ERPs) were determined before sacrifice. At 3 months, treated pigs [n=7] had significantly higher LVEF than controls [n=8] (49±2% vs. 44±3%, P=0.015)and significantly less wall thickening of non-infarcted myocardium. ERPs were significantly shorter than controls at all pacing cycle lengths (P0.002), suggesting a pro-arrhythmic potential. DiI was found in the lungs, in infarct, and peri-infarct myocardium. Conclusion: IV infusion of MSCs soon after acute MI in swine improves LVEF and limits wall thickening in the remote non-infarcted myocardium, consistent with a beneficial effect on post-MI ventricular remodeling. Since there is no need for immune suppression or clinical expertise, IV infusion of MSCs may expand the potential clinical application of stem cell therapy.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Pittenger M.F.
        • Mackay A.M.
        • Beck S.C.
        • et al.
        Multilineage potential of adult human mesenchymal stem cells.
        Science. 1999; 284: 143-147
      1. Shake JG, Gruber PJ, Baumgartner WA, et al. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 2002;73:1919–25; discussion 1926.

        • Devine S.M.
        • Bartholomew A.M.
        • Mahmud N.
        • et al.
        Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion.
        Exp Hematol. 2001; 29: 244-255
      2. Yau TM, Tomita S, Weisel RD, et al. Beneficial effect of autologous cell transplantation on infarcted heart function: comparison between bone marrow stromal cells and heart cells. Ann Thorac Surg 2003;75:169–76; discussion 176–7.

        • Pak H.N.
        • Qayyum M.
        • Kim D.T.
        • et al.
        Mesenchymal stem cell injection induces cardiac nerve sprouting and increased tenascin expression in a swine model of myocardial infarction.
        J Cardiovasc Electrophysiol. 2003; 14: 841-848
        • Cao J.M.
        • Qu Z.
        • Kim Y.H.
        • et al.
        Spatiotemporal heterogeneity in the induction of ventricular fibrillation by rapid pacing: importance of cardiac restitution properties.
        Circ Res. 1999; 84: 1318-1331
        • Menasche P.
        • Hagege A.A.
        • Vilquin J.T.
        • et al.
        Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction.
        J Am Coll Cardiol. 2003; 41: 1078-1083
        • Perin E.C.
        • Dohmann H.F.
        • Borojevic R.
        • et al.
        Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure.
        Circulation. 2003; 107: 2294-2302
        • Strauer B.E.
        • Brehm M.
        • Zeus T.
        • et al.
        Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.
        Circulation. 2002; 106: 1913-1918
        • Assmus B.
        • Schachinger V.
        • Teupe C.
        • et al.
        Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).
        Circulation. 2002; 106: 3009-3017
        • Glasser S.P.
        The time course of left ventricular remodeling after acute myocardial infarction.
        Am J Cardiol. 1997; 80: 506-507
        • Shintani S.
        • Murohara T.
        • Ikeda H.
        • et al.
        Mobilization of endothelial progenitor cells in patients with acute myocardial infarction.
        Circulation. 2001; 103: 2776-2779
        • Beltrami A.P.
        • Urbanek K.
        • Kajstura J.
        • et al.
        Evidence that human cardiac myocytes divide after myocardial infarction.
        N Engl J Med. 2001; 344: 1750-1757
        • Wu G.D.
        • Nolta J.A.
        • Jin Y.S.
        • et al.
        Migration of mesenchymal stem cells to heart allografts during chronic rejection.
        Transplantation. 2003; 75: 679-685
        • Kawada H.
        • Fujita J.
        • Kinjo K.
        • et al.
        Nonhematopoetic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction.
        Blood. 2004; 104: 3581-3587
        • Noort W.A.
        • Kruisselbrink A.B.
        • in't Anker P.S.
        • et al.
        Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice.
        Exp Hematol. 2002; 30: 870-878
        • Bartholomew A.
        • Sturgeon C.
        • Siatskas M.
        • et al.
        Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.
        Exp Hematol. 2002; 30: 42-48
        • Haynesworth S.E.
        • Baber M.A.
        • Caplan A.I.
        Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha.
        J Cell Physiol. 1996; 166: 585-592
        • Majumdar M.K.
        • Thiede M.A.
        • Mosca J.D.
        • Moorman M.
        • Gerson S.L.
        Phenotypic and functional comparison of cultures of marrow-derived mesenchymal stem cells (MSCs) and stromal cells.
        J Cell Physiol. 1998; 176: 57-66
        • Dormady S.P.
        • Bashayan O.
        • Dougherty R.
        • Zhang X.M.
        • Basch R.S.
        Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment.
        J Hematother Stem Cell Res. 2001; 10: 125-140
        • Grills B.L.
        • Schuijers J.A.
        Immunohistochemical localization of nerve growth factor in fractured and unfractured rat bone.
        Acta Orthop Scand. 1998; 69: 415-419
        • Orlic D.
        • Kajstura J.
        • Chimenti S.
        • et al.
        Mobilized bone marrow cells repair the infarcted heart, improving function and survival.
        Proc Natl Acad Sci U S A. 2001; 98: 10344-10349
        • Kuethe F.
        • Figulla H.R.
        • Voth M.
        • et al.
        Mobilization of stem cells by granulocyte colony-stimulating factor for the regeneration of myocardial tissue after myocardial infarction.
        Dtsch Med Wochenschr. 2004; 129: 424-428
        • Kuo C.S.
        • Munakata K.
        • Reddy C.P.
        • Surawicz B.
        Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations.
        Circulation. 1983; 67: 1356-1367
        • Bode F.
        • Karasik P.
        • Katus H.A.
        • Franz M.R.
        Upstream stimulation versus downstream stimulation: arrhythmogenesis based on repolarization dispersion in the human heart.
        J Am Coll Cardiol. 2002; 40: 731-736
        • Weiss J.N.
        • Chen P.S.
        • Qu Z.
        • Karagueuzian H.S.
        • Garfinkel A.
        Ventricular fibrillation: how do we stop the waves from breaking?.
        Circ Res. 2000; 87: 1103-1107
        • Leobon B.
        • Garcin I.
        • Menasche P.
        • Vilquin J.T.
        • Audinat E.
        • Charpak S.
        Myoblasts transplanted into rat infarcted myocardium are functionally isolated from their host.
        Proc Natl Acad Sci U S A. 2003; 100: 7808-7811
        • Zhang Y.M.
        • Hartzell C.
        • Narlow M.
        • Dudley Jr., S.C.
        Stem cell-derived cardiomyocytes demonstrate arrhythmic potential.
        Circulation. 2002; 106: 1294-1299
        • Assmus B.
        • Schachinger V.
        • Teupe C.
        • et al.
        Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).
        Circulation. 2002; 106: 3009-3017
        • Stamm C.
        • Westphal B.
        • Kleine H.D.
        • et al.
        Autologous bone-marrow stem–cell transplantation for myocardial regeneration.
        Lancet. 2003; 361: 45-46
        • Fuchs S.
        • Satler L.F.
        • Kornowski R.
        • et al.
        Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study.
        J Am Coll Cardiol. 2003; 41: 1721-1724
        • Smits P.C.
        • van Geuns R.J.
        • Poldermans D.
        • et al.
        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. 2003; 42: 2063-2069
        • Forrester J.S.
        • Price M.J.
        • Makkar R.R.
        Stem cell repair of infarcted myocardium: an overview for clinicians.
        Circulation. 2003; 108: 1139-1145
        • Makkar R.R.
        • Lill M.
        • Chen P.S.
        Stem cell therapy for myocardial repair: is it arrhythmogenic?.
        J Am Coll Cardiol. 2003; 42: 2070-2072
        • Barbash I.M.
        • Chouraqui P.
        • Baron J.
        • et al.
        Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution.
        Circulation. 2003; 108: 863-868
        • Price M.J.
        • Kar S.K.
        • McClean D.
        • De Lara-Llarena A.C.
        • Makkar R.R.
        Sixty-minute balloon occlusion of the left anterior descending artery results in a predictable porcine model of left ventricular dysfunction after acute myocardial infarction.
        Am J Cardiology. 2002; 90: 187H
        • Aicher A.
        • Brenner W.
        • Zuhayra M.
        • et al.
        Assessment of the tissue distribution of transplanted human endothelial progenitor cells by radioactive labeling.
        Circulation. 2003; 107: 2134-2139
        • Farkas D.L.
        • Becker D.
        Applications of spectral imaging: detection and analysis of human melanoma and its precursors.
        Pigment Cell Res. 2001; 14: 2-8