Circulation Research RES Adult Bone Marrow Cell Therapy for Ischemic Heart Disease: Evidence and Insights from Randomized Controlled Trials Systematic Review of Bone Marrow Cell Therapy CIRCRES/2014/304792 CIRCRES/2014/304792 10.1161/CIRCRESAHA.114.304792 117 08/28/15 6 Bridges-Lyman Gemma 410-3275005 410-3279322 Bolli, Roberto University of Louisville School of Medicine Dr. Buddhadeb Dawn bdawn@kumc.edu Dr. University of Kansas Medical Center 3901 Rainbow Boulevard Rm 1001, Eaton Hall, MS 3006 Kansas City Kansas 66160 UNITED STATES 913-588-6015 913-588-6010 34024 Muhammad Rizwan Afzal University of Kansas Medical Center rafzal@kumc.edu 235900 Anweshan Samanta University of Kansas Medical Center asamanta@kumc.edu 255852 Zubair I Shah University of Kansas Medical Center zshah2@kumc.edu 255853 Vinodh Jeevanantham Heart and Vascular Specialists of Oklahoma vjeevanantham@gmail.com 255854 Ahmed Abdel-Latif University of Kentucky abdel-latif@uky.edu 102861 Ewa K Zuba-Surma Jagiellonian University ewa.zuba-surma@uj.edu.pl 255855 Buddhadeb Dawn University of Kansas Medical Center bdawn@kumc.edu 34024 12/23/2014 12/23/2014 07/01/2015 07/09/2015 07/09/2015 Regular Article <p><i><b><u>Rationale:</u></b></i> Notwithstanding the uncertainties regarding the outcomes of BMC therapy for heart repair, further insights are critically needed to improve this promising approach. </p><p><i><b><u>Objective:</u></b></i> To delineate the true impact of BMC therapy for cardiac repair and gain insights for future trials through systematic review and meta-analysis of data from eligible randomized controlled trials (RCTs). </p><p><i><b><u>Methods and Results:</u></b></i> Database searches through August 2014 identified forty-eight eligible RCTs (enrolling 2602 patients). Weighted mean differences for changes in left ventricular (LV) ejection fraction (EF), infarct size, LV end-systolic volume (LVESV), and LV end-diastolic volume (LVEDV) were analyzed with random-effects meta-analysis. Compared with standard therapy, BMC transplantation improved LVEF (2.92%; 95% confidence interval [CI], 1.91 to 3.92; P<0.00001), reduced infarct size (-2.25%; 95% CI, -3.55 to -0.95; P=0.0007) and LVESV (-6.37 ml; 95% CI, -8.95 to -3.80; P<0.00001), and tended to reduce LVEDV (-2.26 ml; 95% CI, -4.59 to 0.07; P=0.06). Similar effects were noted when data were analyzed after excluding studies with discrepancies in outcomes reporting. The benefits also persisted when cardiac catheterization was performed in control patients as well. Although imaging modalities partly influenced the outcomes, LVEF improved in BMC-treated patients when assessed by MRI. Early (<48h) BMC injection after MI was more effective in reducing infarct size, while BMC injection between 3 and 10 days proved superior toward improving systolic function. A minimum of 50 million BMCs seemed to be necessary, with limited additional benefits seen with increasing cell numbers. BMC therapy was safe and improved clinical outcomes, including all-cause mortality, recurrent MI, ventricular arrhythmia, and cerebrovascular accident (CVA) during follow-up, albeit with differences between acute MI and chronic IHD subgroups. </p><p><i><b><u>Conclusions:</u></b></i> Transplantation of adult BMCs improves LVEF, reduces infarct size and ameliorates remodeling in patients with IHD. These effects are upheld in analyses of studies employing MRI, and also after excluding studies with discrepant outcomes reporting. BMC transplantation may also reduce the incidence of death, recurrent MI, ventricular arrhythmia, and CVA during follow-up. </p> 8 1 0 4 5 no yes CircRes_CIRCRES-2014-304792.xml CircRes_CIRCRES-2014-304792_file1.doc

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CircRes_CIRCRES-2014-304792_supp1.pdf CircRes_CIRCRES-2014-304792_merge.pdf CircRes_CIRCRES-2014-304792_Afzal_235900_disclosure.pdf CircRes_CIRCRES-2014-304792_Afzal_235900_copyright.pdf CircRes_CIRCRES-2014-304792_Zuba-Surma_255855_disclosure.pdf CircRes_CIRCRES-2014-304792_Zuba-Surma_255855_copyright.pdf CircRes_CIRCRES-2014-304792_Shah_255853_disclosure.pdf CircRes_CIRCRES-2014-304792_Shah_255853_copyright.pdf CircRes_CIRCRES-2014-304792_Samanta_255852_disclosure.pdf CircRes_CIRCRES-2014-304792_Samanta_255852_copyright.pdf CircRes_CIRCRES-2014-304792_Dawn_34024_disclosure.pdf CircRes_CIRCRES-2014-304792_Dawn_34024_copyright.pdf CircRes_CIRCRES-2014-304792_Jeevanantham_255854_disclosure.pdf CircRes_CIRCRES-2014-304792_Jeevanantham_255854_copyright.pdf CircRes_CIRCRES-2014-304792_Abdel-Latif_102861_disclosure.pdf CircRes_CIRCRES-2014-304792_Abdel-Latif_102861_copyright.pdf PAP: 07/09/15 Please note that the authors have agreed to pay $2125 in excess page charges. Funding: Howard Hughes Medical Institute (HHMI): No National Institutes of Health (NIH): Yes Not applicable for this manuscript: No Other: No Wellcome Trust: No Subject Codes: [4] Acute myocardial infarction [7] Chronic ischemic heart disease gbridgeslyman