Transplantation of mesenchymal stem cells for prevention of acute myocardial infarction induced heart failure: study protocol of a phase III randomized clinical trial (Prevent-TAHA8)

Armin Attar, Ahmad Monabati, Mohammad Montaseri, Massoud Vosough, Seyed Ali Hosseini, Javad Kojouri, Alireza Abdi-Ardekani, Peyman Izadpanah, Negar Azarpira, Gholamreza Pouladfar, Mani Ramzi, Armin Attar, Ahmad Monabati, Mohammad Montaseri, Massoud Vosough, Seyed Ali Hosseini, Javad Kojouri, Alireza Abdi-Ardekani, Peyman Izadpanah, Negar Azarpira, Gholamreza Pouladfar, Mani Ramzi

Abstract

Background: Results from recent clinical trials on bone marrow mononuclear cell (BM-MNC) transplantation show that this intervention can help reduce the incidence of heart failure (HF) after acute myocardial infarction (AMI). However, no study has evaluated the effect of the transplantation of mesenchymal stem cells (MSCs) on a clinical endpoint such as HF.

Methods: This single-blinded, randomized, multicenter trial aims to establish whether the intracoronary infusion of umbilical cord-derived Wharton's jelly MSCs (WJ-MSCs) helps prevent HF development after AMI. The study will enroll 390 patients 3 to 7 days following AMI. Only patients aged below 65 years with impaired LV function (LVEF < 40%) will be included. They will be randomized (2:1 ratio) to either receive standard care or a single intracoronary infusion of 107 WJ-MSCs. The primary outcome of this study is the assessment of HF development during long-term follow-up (3 years).

Discussion: Data will be collected until Nov 2024. Thereafter, the analysis will be conducted. Results are expected to be ready by Dec 2024. We will prepare and submit the related manuscript following the CONSORT guidelines. This study will help determine whether or not the infusion of intracoronary WJ-MSCs in patients with AMI will reduce the incidence of AMI-induced HF.

Trial registration: ClinicalTrials.gov NCT05043610 , Registered on 14 September 2021 - retrospectively registered.

Keywords: Acute myocardial infarction; Cell therapy; Intracoronary injection; Mesenchymal stem cells; Myocardial infarction; Regenerative medicine.

Conflict of interest statement

M. V. is the regulatory affairs manager in Cell Tech Pharmed. Cell Tech Pharmed Co. will provide us with cGMP grade WJ-MSCs but is not involved in the design or interpretation of the research.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
SPIRIT flow diagram of the study

References

    1. Organization WH . The global burden of disease: 2004 update. Geneva: World Health Organization; 2008.
    1. Velagaleti RS, Pencina MJ, Murabito JM, Wang TJ, Parikh NI, D’Agostino RB, et al. Long-term trends in the incidence of heart failure after myocardial infarction. Circulation. 2008;118(20):2057–2062. doi: 10.1161/CIRCULATIONAHA.108.784215.
    1. Hellermann JP, Jacobsen SJ, Gersh BJ, Rodeheffer RJ, Reeder GS. Heart failure after myocardial infarction: a review. Am J Med. 2002;113(4):324–330. doi: 10.1016/S0002-9343(02)01185-3.
    1. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease and stroke statistics--2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2–e220. doi: 10.1161/CIR.0b013e318245fac5.
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr, Colvin MM, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134(13):e282–e293.
    1. Juillière Y, Cambou JP, Bataille V, Mulak G, Galinier M, Gibelin P, et al. Heart failure in acute myocardial infarction: a comparison between patients with or without heart failure criteria from the FAST-MI registry. Rev Esp Cardiol (Engl Ed) 2012;65(4):326–333. doi: 10.1016/j.recesp.2011.10.027.
    1. Lewis EF, Moye LA, Rouleau JL, Sacks FM, Arnold JM, Warnica JW, et al. Predictors of late development of heart failure in stable survivors of myocardial infarction: the CARE study. J Am Coll Cardiol. 2003;42(8):1446–1453. doi: 10.1016/S0735-1097(03)01057-X.
    1. Braunwald E. Cell-based therapy in cardiac regeneration: an overview. Circ Res. 2018;123(2):132–137. doi: 10.1161/CIRCRESAHA.118.313484.
    1. Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med. 1998;4(8):929–933. doi: 10.1038/nm0898-929.
    1. Leor J, Patterson M, Quinones MJ, Kedes LH, Kloner RA. Transplantation of fetal myocardial tissue into the infarcted myocardium of rat. A potential method for repair of infarcted myocardium? Circulation. 1996;94(9 Suppl):Ii332–Ii336.
    1. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001;410(6829):701–705. doi: 10.1038/35070587.
    1. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001;7(4):430–436. doi: 10.1038/86498.
    1. Menasché P, Hagège AA, Scorsin M, Pouzet B, Desnos M, Duboc D, et al. Myoblast transplantation for heart failure. Lancet (London, England) 2001;357(9252):279–280. doi: 10.1016/S0140-6736(00)03617-5.
    1. Assmus B, Schächinger V, Teupe C, Britten M, Lehmann R, Döbert N, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI) Circulation. 2002;106(24):3009–3017. doi: 10.1161/.
    1. Williams A, Hare J. Mesenchymal stem cells: biology, pathophysiology, translational findings, and therapeutic implications for cardiac disease. Circ Res. 2011;109:923–940. doi: 10.1161/CIRCRESAHA.111.243147.
    1. Houtgraaf JH, den Dekker WK, van Dalen BM, Springeling T, de Jong R, van Geuns RJ, et al. First experience in humans using adipose tissue–derived regenerative cells in the treatment of patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2012;59(5):539–540. doi: 10.1016/j.jacc.2011.09.065.
    1. Karantalis V, Schulman I, Balkan W, Hare J. Allogeneic cell therapy a new paradigm in therapeutics. Circ Res. 2015;116:12–15. doi: 10.1161/CIRCRESAHA.114.305495.
    1. Hare JM, Fishman JE, Gerstenblith G, DiFede Velazquez DL, Zambrano JP, Suncion VY, et al. Comparison of allogeneic vs autologous bone marrow-derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial. JAMA. 2012;308(22):2369–2379. doi: 10.1001/jama.2012.25321.
    1. Heldman AW, DiFede DL, Fishman JE, Zambrano JP, Trachtenberg BH, Karantalis V, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014;311(1):62–73. doi: 10.1001/jama.2013.282909.
    1. Raposo L, Lourenço AP, Nascimento DS, Cerqueira R, Cardim N, Leite-Moreira A. Human umbilical cord tissue-derived mesenchymal stromal cells as adjuvant therapy for myocardial infarction: a review of current evidence focusing on pre-clinical large animal models and early human trials. Cytotherapy. 2021;23(11):974–979. doi: 10.1016/j.jcyt.2021.05.002.
    1. Traverse JH, Henry TD, Ellis SG, Pepine CJ, Willerson JT, Zhao DX, et al. 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(19):2110–2119. doi: 10.1001/jama.2011.1670.
    1. Traverse JH, Henry TD, Pepine CJ, Willerson JT, Zhao DX, Ellis SG, et al. 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(22):2380–2389. doi: 10.1001/jama.2012.28726.
    1. Fisher SA, Zhang H, Doree C, Mathur A, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2015;30(9):Cd006536.
    1. Gao LR, Chen Y, Zhang NK, Yang XL, Liu HL, Wang ZG, et al. Intracoronary infusion of Wharton’s jelly-derived mesenchymal stem cells in acute myocardial infarction: double-blind, randomized controlled trial. BMC Med. 2015;13:162. doi: 10.1186/s12916-015-0399-z.
    1. Attar A, Bahmanzadegan Jahromi F, Kavousi S, Monabati A, Kazemi A. Mesenchymal stem cell transplantation after acute myocardial infarction: a meta-analysis of clinical trials. Stem Cell Res Ther. 2021;12(1):600. doi: 10.1186/s13287-021-02667-1.
    1. Hosseinpour A, Kheshti F, Kazemi A, Attar A. Comparing the effect of bone marrow mono-nuclear cells with mesenchymal stem cells after acute myocardial infarction on improvement of left ventricular function: a meta-analysis of clinical trials. Stem Cell Res Ther. 2022;13(1):203. doi: 10.1186/s13287-022-02883-3.
    1. Attar A, Hosseinpour A, Hosseinpour H, Kazemi A. Major cardiovascular events after bone marrow mononuclear cell transplantation following acute myocardial infarction: an updated post-BAMI meta-analysis of randomized controlled trials. BMC Cardiovasc Disord. 2022;22(1):259. doi: 10.1186/s12872-022-02701-x.
    1. Sanganalmath S, Bolli R. Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res. 2013;113:810–834. doi: 10.1161/CIRCRESAHA.113.300219.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する