Strengthening effects of bone marrow mononuclear cells with intensive atorvastatin in acute myocardial infarction

Yue-Jin Yang, Hai-Yan Qian, Lei Song, Yong-Jian Geng, Run-Lin Gao, Na Li, Hong Wang, Xia-Qiu Tian, Ji Huang, Pei-Sen Huang, Jun Xu, Rui Shen, Min-Jie Lu, Shi-Hua Zhao, Wei-Chun Wu, Yuan Wu, Jun Zhang, Jie Qian, Jun-Yan Xu, Yu-Yan Xiong, Yue-Jin Yang, Hai-Yan Qian, Lei Song, Yong-Jian Geng, Run-Lin Gao, Na Li, Hong Wang, Xia-Qiu Tian, Ji Huang, Pei-Sen Huang, Jun Xu, Rui Shen, Min-Jie Lu, Shi-Hua Zhao, Wei-Chun Wu, Yuan Wu, Jun Zhang, Jie Qian, Jun-Yan Xu, Yu-Yan Xiong

Abstract

Objective: To test whether intensive atorvastatin (ATV) increases the efficacy of transplantation with autologous bone marrow mononuclear cells (MNCs) in patients suffering from anterior ST-elevated myocardial infarction (STEMI).

Methods: This clinical trial was under a 2×2 factorial design, enrolling 100 STEMI patients, randomly into four groups of regular (RA) or intensive ATV (IA) with MNCs or placebo. The primary endpoint was the change of left ventricular ejection fraction (LVEF) at 1-year follow-up from baseline, primarily assessed by MRI. The secondary endpoints included other parameters of cardiac function, remodelling and regeneration determined by MRI, echocardiography, positron emission tomography (PET) and biomarkers.

Results: All the STEMI patients with transplantation of MNCs showed significantly increased LVEF change values than those with placebo (p=0.01) with only in the IA+MNCs patients group demonstrating significantly elevation of LVEF than in the IA+placebo group (+12.6% (95%CI 10.4 to 19.3) vs +5.0% (95%CI 4.0 to 10.0), p=0.001), pointing to a better synergy between ATV and MNCs (p=0.019). PET analysis revealed significantly increased viable areas of myocardium (p=0.015), while the scar sizes (p=0.026) and blood aminoterminal pro-B-type natriuretic peptide (p<0.034) reduced. All these above benefits of MNCs were also attributed to IA+MNCs instead of RA+MNCs group of patients with STEMI.

Conclusions: Intensive ATV treatment augments the therapeutic efficacy of MNCs in patients with anterior STEMI at the convalescent stage. The treatment with the protocol of intensive ATV and MNC combination offers a clinically essential approach for myocardial infarction.

Trial registration number: NCT00979758.

Keywords: acute coronary syndrome; myocardial perfusion; statins.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1
Figure 1
Schematic representation of the study design and grouping. 2DE, two-dimensional echocardiography; IA, intensive atorvastatin; LVEF, left ventricular ejection fraction; MNCs, mononuclear cells; PET, positron emission tomography; RA, routine atorvastatin; SPECT, single-photon emission CT; STEMI, ST-segment elevation myocardial infarction.
Figure 2
Figure 2
Representative MRI images of cardiac left ventricle in myocardial infarct (MI) patients treated with intensive (IA) or regular atorvastatin (RA) in combination with or without transplantation of mononuclear cells (MNCs). MRI was conducted at short axis in the end-diastolic (ED) or end-systolic (ES) phase.
Figure 3
Figure 3
The representative images of SPECT and PET denoting myocardial regeneration after combined treatment with intensive atorvastatin (IA) and MNCs in the same patient shown in figure 2. A, intensive atorvastatin; MNCs, mononuclear cells; PET, positron emission tomography; RA, regular atorvastatin; SPECT, single-photon emission CT
Figure 4
Figure 4
Changes in the blood levels of NT-proBNP after MNC transplantation with or without intensive ATV (IA). ATV, atorvastatin; MNCs, mononuclear cells; proBNP, pro-B-type natriuretic peptide; NS, not significant.

References

    1. Strauer BE, Brehm M, Zeus T, et al. . Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913–8. 10.1161/01.CIR.0000034046.87607.1C
    1. Meyer GP, Wollert KC, Lotz J, 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 2006;113:1287–94. 10.1161/CIRCULATIONAHA.105.575118
    1. Janssens S, Dubois C, Bogaert J, et al. . Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006;367:113–21. 10.1016/S0140-6736(05)67861-0
    1. Schächinger V, Erbs S, Elsässer A, et al. . Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210–21. 10.1056/NEJMoa060186
    1. Lunde K, Solheim S, Forfang K, et al. . Anterior myocardial infarction with acute percutaneous coronary intervention and intracoronary injection of autologous mononuclear bone marrow cells: safety, clinical outcome, and serial changes in left ventricular function during 12-months' follow-up. J Am Coll Cardiol 2008;51:674–6. 10.1016/j.jacc.2007.10.032
    1. Delewi R, Hirsch A, Tijssen JG, et al. . Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis. Eur Heart J 2014;35:989–98. 10.1093/eurheartj/eht372
    1. Jeevanantham V, Butler M, Saad A, et al. . Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: a systematic review and meta-analysis. Circulation 2012;126:551–68. 10.1161/CIRCULATIONAHA.111.086074
    1. Lunde K, Solheim S, Aakhus S, et al. . Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006;355:1199–209. 10.1056/NEJMoa055706
    1. Traverse JH, Henry TD, Ellis SG, 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;306:2110–9. 10.1001/jama.2011.1670
    1. Ranganath SH, Levy O, Inamdar MS, et al. . Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 2012;10:244–58. 10.1016/j.stem.2012.02.005
    1. Yang YJ, Qian HY, Huang J, et al. . Atorvastatin treatment improved post-infarction microenvironments to facilitate the survivals and activities of implanted mesenchymal stem cells in swine hearts with acute myocardial infarction and reperfusion. Eur Heart J 2008;29:1578–90.
    1. Song L, Yang Y-J, Dong Q-T, et al. . Atorvastatin enhance efficacy of mesenchymal stem cells treatment for swine myocardial infarction via activation of nitric oxide synthase. PLoS One 2013;8:e65702. 10.1371/journal.pone.0065702
    1. Yang C, Madonna R, Li Y, et al. . Simvastatin-enhanced expression of promyogenic nuclear factors and cardiomyogenesis of murine embryonic stem cells. Vascul Pharmacol 2014;60:8–16. 10.1016/j.vph.2013.10.004
    1. Grove JE, Bruscia E, Krause DS. Plasticity of bone marrow-derived stem cells. Stem Cells 2004;22:487–500. 10.1634/stemcells.22-4-487
    1. Cao F, Sun D, Li C, et al. . Long-Term myocardial functional improvement after autologous bone marrow mononuclear cells transplantation in patients with ST-segment elevation myocardial infarction: 4 years follow-up. Eur Heart J 2009;30:1986–94. 10.1093/eurheartj/ehp220
    1. Hu S, Liu S, Zheng Z, et al. . Isolated coronary artery bypass graft combined with bone marrow mononuclear cells delivered through a graft vessel for patients with previous myocardial infarction and chronic heart failure: a single-center, randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 2011;57:2409–15. 10.1016/j.jacc.2011.01.037
    1. Tendera M, Wojakowski W, Ruzyłło W, 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. Eur Heart J 2009;30:1313–21. 10.1093/eurheartj/ehp073
    1. Simari RD, Pepine CJ, Traverse JH, et al. . Bone marrow mononuclear cell therapy for acute myocardial infarction: a perspective from the cardiovascular cell therapy research network. Circ Res 2014;114:1564–8. 10.1161/CIRCRESAHA.114.303720
    1. Yang Y-J, Qian H-Y, Huang J, et al. . Combined therapy with simvastatin and bone marrow-derived mesenchymal stem cells increases benefits in infarcted swine hearts. Arterioscler Thromb Vasc Biol 2009;29:2076–82. 10.1161/ATVBAHA.109.189662
    1. Zhang Q, Yang Y-J, Wang H, et al. . Autophagy activation: a novel mechanism of atorvastatin to protect mesenchymal stem cells from hypoxia and serum deprivation via AMP-activated protein kinase/mammalian target of rapamycin pathway. Stem Cells Dev 2012;21:1321–32. 10.1089/scd.2011.0684
    1. Chiang K-H, Cheng W-L, Shih C-M, et al. . Statins, HMG-CoA reductase inhibitors, improve neovascularization by increasing the expression density of CXCR4 in endothelial progenitor cells. PLoS One 2015;10:e0136405. 10.1371/journal.pone.0136405
    1. Quintavalle C, Fiore D, De Micco F, et al. . Impact of a high loading dose of atorvastatin on contrast-induced acute kidney injury. Circulation 2012;126:3008–16. 10.1161/CIRCULATIONAHA.112.103317
    1. Li N, Yang Y-J, Qian H-Y, et al. . Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR4. Am J Transl Res 2015;7:1058–70.
    1. Tian X-Q, Yang Y-J, Li Q, et al. . Combined therapy with atorvastatin and atorvastatin-pretreated mesenchymal stem cells enhances cardiac performance after acute myocardial infarction by activating SDF-1/CXCR4 axis. Am J Transl Res 2019;11:4214–31.
    1. Li Q, Dong Q-T, Yang Y-J, et al. . Ampk-Mediated cardioprotection of atorvastatin relates to the reduction of apoptosis and activation of autophagy in infarcted rat hearts. Am J Transl Res 2016;8:4160–71.
    1. Xu H, Yang Y-J, Qian H-Y, et al. . Rosuvastatin treatment activates JAK-STAT pathway and increases efficacy of allogeneic mesenchymal stem cell transplantation in infarcted hearts. Circ J 2011;75:1476–85. 10.1253/circj.CJ-10-1275
    1. Tossios P, Müller-Ehmsen J, Schmidt M, et al. . No evidence of myocardial restoration following transplantation of mononuclear bone marrow cells in coronary bypass grafting surgery patients based upon cardiac SPECT and 18F-PET. BMC Med Imaging 2006;6:7. 10.1186/1471-2342-6-7
    1. Hatzistergos KE, Saur D, Seidler B, et al. . Stimulatory effects of mesenchymal stem cells on cKit+ cardiac stem cells are mediated by SDF1/CXCR4 and SCF/cKit signaling pathways. Circ Res 2016;119:921–30. 10.1161/CIRCRESAHA.116.309281
    1. Abbott JD, Huang Y, Liu D, et al. . Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 2004;110:3300–5. 10.1161/
    1. Hu X, Wang J, Chen J, et al. . Optimal temporal delivery of bone marrow mesenchymal stem cells in rats with myocardial infarction. Eur J Cardiothorac Surg 2007;31:438–43. 10.1016/j.ejcts.2006.11.057

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera