Effect of Shock Wave–Facilitated Intracoronary Cell Therapy on LVEF in Patients With Chronic Heart Failure: The CELLWAVE Randomized Clinical Trial | Stem Cell Transplantation | JAMA | JAMA Network
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1.
Steinhauser ML, Lee RT. Regeneration of the heart.  EMBO Mol Med. 2011;3(12):701-71222095736PubMedGoogle ScholarCrossref
2.
Bolli R, Chugh AR, D’Amario D,  et al.  Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial.  Lancet. 2011;378(9806):1847-185722088800PubMedGoogle ScholarCrossref
3.
Makkar RR, Smith RR, Cheng K,  et al.  Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS).  Lancet. 2012;379(9819):895-90422336189PubMedGoogle ScholarCrossref
4.
Schächinger V, Erbs S, Elsässer A,  et al; REPAIR-AMI Investigators.  Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction.  N Engl J Med. 2006;355(12):1210-122116990384PubMedGoogle ScholarCrossref
5.
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(5):551-56822730444PubMedGoogle ScholarCrossref
6.
Kang HJ, Lee HY, Na SH,  et al.  Differential effect of intracoronary infusion of mobilized peripheral blood stem cells by granulocyte colony-stimulating factor on left ventricular function and remodeling in patients with acute myocardial infarction versus old myocardial infarction: the MAGIC Cell-3-DES randomized, controlled trial.  Circulation. 2006;114(1):(suppl)  I145-I15116820564PubMedGoogle Scholar
7.
Assmus B, Honold J, Schächinger V,  et al.  Transcoronary transplantation of progenitor cells after myocardial infarction.  N Engl J Med. 2006;355(12):1222-123216990385PubMedGoogle ScholarCrossref
8.
Perin EC, Willerson JT, Pepine CJ,  et al.  Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.  JAMA. 2012;307(16):1717-172622447880PubMedGoogle ScholarCrossref
9.
Schächinger V, Aicher A, Döbert N,  et al.  Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium.  Circulation. 2008;118(14):1425-143218794392PubMedGoogle ScholarCrossref
10.
Ceradini DJ, Kulkarni AR, Callaghan MJ,  et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1.  Nat Med. 2004;10(8):858-86415235597PubMedGoogle ScholarCrossref
11.
Askari AT, Unzek S, Popovic ZB,  et al.  Effect of stromal-cell–derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.  Lancet. 2003;362(9385):697-70312957092PubMedGoogle ScholarCrossref
12.
Penn MS. Importance of the SDF-1:CXCR4 axis in myocardial repair.  Circ Res. 2009;104(10):1133-113519461103PubMedGoogle ScholarCrossref
13.
Aicher A, Heeschen C, Sasaki K,  et al.  Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia.  Circulation. 2006;114(25):2823-283017145991PubMedGoogle ScholarCrossref
14.
Assmus B, Schächinger V, Teupe C,  et al.  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).  Circulation. 2002;106(24):3009-301712473544PubMedGoogle ScholarCrossref
15.
Leistner DM, Fischer-Rasokat U, Honold J,  et al.  Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI): final 5-year results suggest long-term safety and efficacy.  Clin Res Cardiol. 2011;100(10):925-93421633921PubMedGoogle ScholarCrossref
16.
Li K-H. Imputation using Markov chains.  J Stat Comput Simul. 1988;30:57-79Google ScholarCrossref
17.
Rubin DB. Multiple Imputation for Nonresponse in Surveys. New York, NY: Wiley; 1987
18.
Andersen PK, Gill RD. Cox's regression model for counting processes.  Ann Stat. 1982;10(4):1100-1120Google ScholarCrossref
19.
Laird NM, Ware JH. Random-effects models for longitudinal data.  Biometrics. 1982;38(4):963-9747168798PubMedGoogle ScholarCrossref
20.
Liu J, Narsinh KH, Lan F,  et al.  Early stem cell engraftment predicts late cardiac functional recovery: preclinical insights from molecular imaging.  Circ Cardiovasc Imaging. 2012;5(4):481-49022565608PubMedGoogle ScholarCrossref
21.
Seeger FH, Rasper T, Koyanagi M,  et al.  CXCR4 expression determines functional activity of bone marrow–derived mononuclear cells for therapeutic neovascularization in acute ischemia.  Arterioscler Thromb Vasc Biol. 2009;29(11):1802-180919696399PubMedGoogle ScholarCrossref
22.
Sovalat H, Scrofani M, Eidenschenk A,  et al.  Identification and isolation from either adult human bone marrow or G-CSF-mobilized peripheral blood of CD34(+)/CD133(+)/CXCR4(+)/Lin(−)CD45(−) cells, featuring morphological, molecular, and phenotypic characteristics of very small embryonic-like (VSEL) stem cells.  Exp Hematol. 2011;39(4):495-50521238532PubMedGoogle Scholar
23.
Tang YL, Zhu W, Cheng M,  et al.  Hypoxic preconditioning enhances the benefit of cardiac progenitor cell therapy for treatment of myocardial infarction by inducing CXCR4 expression.  Circ Res. 2009;104(10):1209-121619407239PubMedGoogle ScholarCrossref
24.
Baek SJ, Kang SK, Ra JC. In vitro migration capacity of human adipose tissue–derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors.  Exp Mol Med. 2011;43(10):596-60321847008PubMedGoogle ScholarCrossref
25.
Kramer DG, Trikalinos TA, Kent DM,  et al.  Quantitative evaluation of drug or device effects on ventricular remodeling as predictors of therapeutic effects on mortality in patients with heart failure and reduced ejection fraction.  J Am Coll Cardiol. 2010;56(5):392-40620650361PubMedGoogle ScholarCrossref
26.
Wong M, Staszewsky L, Latini R,  et al.  Severity of left ventricular remodeling defines outcomes and response to therapy in heart failure: Valsartan Heart Failure Trial (Val-HeFT) echocardiographic data.  J Am Coll Cardiol. 2004;43(11):2022-202715172407PubMedGoogle ScholarCrossref
27.
Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials.  Eur Heart J. 2009;30(4):469-47719066207PubMedGoogle ScholarCrossref
28.
Cleland JG, Pennell DJ, Ray SG,  et al; Carvedilol Hibernating Reversible Ischaemia Trial: Marker of Success Investigators.  Myocardial viability as a determinant of the ejection fraction response to carvedilol in patients with heart failure (CHRISTMAS trial).  Lancet. 2003;362(9377):14-2112853194PubMedGoogle ScholarCrossref
29.
Kissel CK, Lehmann R, Assmus B,  et al.  Selective functional exhaustion of hematopoietic progenitor cells in the bone marrow of patients with postinfarction heart failure.  J Am Coll Cardiol. 2007;49(24):2341-234917572250PubMedGoogle ScholarCrossref
30.
Assmus B, Fischer-Rasokat U, Honold J,  et al; TOPCARE-CHD Registry.  Transcoronary transplantation of functionally competent BMCs is associated with a decrease in natriuretic peptide serum levels and improved survival of patients with chronic postinfarction heart failure.  Circ Res. 2007;100(8):1234-124117379833PubMedGoogle ScholarCrossref
Preliminary Communication
April 17, 2013

Effect of Shock Wave–Facilitated Intracoronary Cell Therapy on LVEF in Patients With Chronic Heart Failure: The CELLWAVE Randomized Clinical Trial

Author Affiliations

Author Affiliations: Division of Cardiology, Department of Medicine III (Drs Assmus, Walter, Seeger, Leistner, and Zeiher and Mss Steiner and Ziegler) and Center for Molecular Medicine, Institute for Cardiovascular Regeneration (Drs Seeger and Dimmeler), Goethe University Frankfurt, Germany; Clinical Research and Development, Dornier Med Tech Systems GmbH, Wessling, Germany (Drs Lutz and Khaled); German Rheumatism Research Centre, Leibnitz Institute, Berlin, Germany (Dr Klotsche); German Red Cross Blood Service, Baden-Wuerttemberg-Hessen (Dr Tonn); and Institute for Transfusion Medicine and Immunohematology, Goethe University, Frankfurt, Germany (Dr Tonn). Dr Tonn is currently with the German Red Cross Blood Service East, Dresden, Germany.

JAMA. 2013;309(15):1622-1631. doi:10.1001/jama.2013.3527
Abstract

Importance The modest effects of clinical studies using intracoronary administration of autologous bone marrow–derived mononuclear cells (BMCs) in patients with chronic postinfarction heart failure may be attributed to impaired homing of BMCs to the target area. Extracorporeal shock wave treatment has been experimentally shown to increase homing factors in the target tissue, resulting in enhanced retention of applied BMCs.

Objective To test the hypothesis that targeted cardiac shock wave pretreatment with subsequent application of BMCs improves recovery of left ventricular ejection fraction (LVEF) in patients with chronic heart failure.

Design, Setting, and Participants The CELLWAVE double-blind, randomized, placebo-controlled trial conducted among patients with chronic heart failure treated at Goethe University Frankfurt, Germany, between 2006 and 2011.

Interventions Single-blind low-dose (n = 42), high-dose (n = 40), or placebo (n = 21) shock wave pretreatment targeted to the left ventricular anterior wall. Twenty-four hours later, patients receiving shock wave pretreatment were randomized to receive double-blind intracoronary infusion of BMCs or placebo, and patients receiving placebo shock wave received intracoronary infusion of BMCs.

Main Outcomes and Measures Primary end point was change in LVEF from baseline to 4 months in the pooled groups shock wave + placebo infusion vs shock wave + BMCs; secondary end points included regional left ventricular function assessed by magnetic resonance imaging and clinical events.

Results The primary end point was significantly improved in the shock wave + BMCs group (absolute change in LVEF, 3.2% [95% CI, 2.0% to 4.4%]), compared with the shock wave + placebo infusion group (1.0% [95% CI, −0.3% to 2.2%]) (P = .02). Regional wall thickening improved significantly in the shock wave + BMCs group (3.6% [95% CI, 2.0% to 5.2%]) but not in the shock wave + placebo infusion group (0.5% [95% CI, −1.2% to 2.1%]) (P = .01). Overall occurrence of major adverse cardiac events was significantly less frequent in the shock wave + BMCs group (n = 32 events) compared with the placebo shock wave + BMCs (n = 18) and shock wave + placebo infusion (n = 61) groups (hazard ratio, 0.58 [95% CI, 0.40-0.85]; P = .02).

Conclusions and Relevance Among patients with postinfarction chronic heart failure, shock wave–facilitated intracoronary administration of BMCs vs shock wave treatment alone resulted in a significant, albeit modest, improvement in LVEF at 4 months. Determining whether the increase in contractile function will translate into improved clinical outcomes requires confirmation in larger clinical end point trials.

Trial Registration clinicaltrials.gov Identifier: NCT00326989

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