title: Intracoronary cardiosphere-derived cells after myocardial infarction: evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction).
abstract: OBJECTIVE
  This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial.
  
  
  BACKGROUND
  Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown.
  
  
  METHODS
  Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients.
  
  
  RESULTS
  In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI.
  
  
  CONCLUSIONS
  Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction [CADUCEUS]; NCT00893360).
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Malliaras
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Raj R
authors.initials: RR
authors.lastname: Makkar
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Smith
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois.
authors.forename: Edwin
authors.initials: E
authors.lastname: Wu
authors.affiliation: Division of Cardiology, Department of Medicine, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, Illinois.
authors.forename: Robert O
authors.initials: RO
authors.lastname: Bonow
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Linda
authors.initials: L
authors.lastname: Marbán
authors.affiliation: EMMES Corporation, Rockville, Maryland.
authors.forename: Adam
authors.initials: A
authors.lastname: Mendizabal
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cingolani
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Peter V
authors.initials: PV
authors.lastname: Johnston
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Gary
authors.initials: G
authors.lastname: Gerstenblith
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Schuleri
authors.affiliation: Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, Maryland; Department of Biomedical Engineering, The Johns Hopkins University, Baltimore, Maryland.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Lardo
authors.affiliation: Cedars-Sinai Heart Institute, Los Angeles, California. Electronic address: eduardo.marban@csmc.edu.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000368:Aged; D001706:Biopsy; D003331:Coronary Vessels; D015716:Electrocardiography, Ambulatory; D005260:Female; D005500:Follow-Up Studies; D006352:Heart Ventricles / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007269:Injections, Intra-Arterial; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology / Q000601:surgery*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation*; D020127:Recovery of Function; D033581:Stem Cell Transplantation / Q000379:methods*; D013997:Time Factors; D014182:Transplantation, Autologous; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology / Q000601:surgery*; D016277:Ventricular Function, Left / Q000502:physiology*
keywords: CDC; CK-MB; CT; DSMB; Data and Safety Monitoring Board; EDV; EF; ESV; Ecc; FWHM; ICD; LV; LVEF; MI; MRI; NYHA; New York Heart Association; SAE; TnI; Vo(2); cardiosphere-derived cell; cardiosphere-derived cells; computed tomography; creatine kinase-myocardial band; ejection fraction; end-diastolic volume; end-systolic volume; full width at half maximum; implantable cardioverter-defibrillator; left ventricular; left ventricular ejection fraction; magnetic resonance imaging; myocardial infarction; myocardial regeneration; oxygen consumption; serious adverse event(s); systolic circumferential strain; troponin I
references.citation: N Engl J Med. 2007 Jun 7;356(23):2388-98
references.pmid: 17554120
references.citation: Cell Transplant. 2012;21(6):1121-35
references.pmid: 22405128
references.citation: Circulation. 2005 Nov 29;112(22):3391-9
references.pmid: 16301343
references.citation: Stem Cells. 2010 May;28(5):903-4
references.pmid: 20309960
references.citation: Circulation. 2007 Oct 9;116(15):1683-92
references.pmid: 17875967
references.citation: Lancet. 2012 Mar 10;379(9819):895-904
references.pmid: 22336189
references.citation: Lancet. 2006 Jan 14;367(9505):113-21
references.pmid: 16413875
references.citation: Clin Pharmacol Ther. 2011 Oct;90(4):532-41
references.pmid: 21900888
references.citation: Magn Reson Med. 2002 Dec;48(6):934-41
references.pmid: 12465101
references.citation: Dev Dyn. 2004 Aug;230(4):787-94
references.pmid: 15254913
references.citation: J Am Coll Cardiol. 2009 Dec 8;54(24):2277-86
references.pmid: 19958962
references.citation: Int J Cardiovasc Imaging. 2002 Feb;18(1):539-42
references.pmid: 12135124
references.citation: Dev Cell. 2009 Feb;16(2):233-44
references.pmid: 19217425
references.citation: Circulation. 2006 Mar 14;113(10):1287-94
references.pmid: 16520413
references.citation: Circulation. 2007 Feb 20;115(7):896-908
references.pmid: 17283259
references.citation: Circulation. 1999 Nov 9;100(19):1992-2002
references.pmid: 10556226
references.citation: Circ Res. 2010 Mar 19;106(5):971-80
references.pmid: 20110532
references.citation: Eur Heart J. 2009 Jun;30(11):1313-21
references.pmid: 19208649
references.citation: J Cell Biol. 1991 Sep;114(5):1059-68
references.pmid: 1874786
references.citation: Br Med Bull. 2011;98:161-85
references.pmid: 21652595
references.citation: J Am Coll Cardiol. 2012 May 22;59(21):1897-907
references.pmid: 22595410
references.citation: West J Emerg Med. 2008 Jan;9(1):6-8
references.pmid: 19561695
references.citation: N Engl J Med. 2011 Feb 3;364(5):453-64
references.pmid: 21288097
references.citation: Radiology. 1988 Oct;169(1):59-63
references.pmid: 3420283
references.citation: Circ Res. 2012 Nov 9;111(11):1434-45
references.pmid: 22931954
references.citation: Circulation. 2012 Jul 31;126(5):551-68
references.pmid: 22730444
references.citation: Stem Cell Res. 2012 Jan;8(1):58-73
references.pmid: 22099021
references.citation: Cytotherapy. 2006;8(4):315-7
references.pmid: 16923606
references.citation: JACC Cardiovasc Imaging. 2011 Dec;4(12):1284-93
references.pmid: 22172785
references.citation: J Am Coll Cardiol. 2012 Jan 31;59(5):539-40
references.pmid: 22281257
references.citation: J Am Coll Cardiol. 2004 Dec 21;44(12):2383-9
references.pmid: 15607402
references.citation: Circulation. 2005 May 31;111(21):2760-7
references.pmid: 15911694
references.citation: JAMA. 2012 Dec 12;308(22):2369-79
references.pmid: 23117550
references.citation: Radiology. 2001 Jan;218(1):215-23
references.pmid: 11152805
references.citation: Circ Res. 2013 Mar 1;112(5):816-25
references.pmid: 23429605
references.citation: Heart. 2008 Jun;94(6):730-6
references.pmid: 18070953
references.citation: Circulation. 2009 Sep 22;120(12):1075-83, 7 p following 1083
references.pmid: 19738142
references.citation: J Am Coll Cardiol. 2013 Mar 12;61(10):1108-19
references.pmid: 23352785
references.citation: EMBO Mol Med. 2013 Feb;5(2):191-209
references.pmid: 23255322
references.citation: Circulation. 2000 Mar 7;101(9):981-8
references.pmid: 10704164
references.citation: Circulation. 2012 Jan 3;125(1):100-12
references.pmid: 22086878
references.citation: N Engl J Med. 2006 Sep 21;355(12):1210-21
references.pmid: 16990384
references.citation: Expert Rev Cardiovasc Ther. 2012 Sep;10(9):1185-94
references.pmid: 23098154
references.citation: Circulation. 2012 Sep 11;126(11 Suppl 1):S54-64
references.pmid: 22965994
references.citation: Cardiovasc Res. 2000 May;46(2):250-6
references.pmid: 10773228
references.citation: Am Heart J. 1992 Oct;124(4):1017-25
references.pmid: 1529875
references.citation: Cell. 2003 Sep 19;114(6):763-76
references.pmid: 14505575
references.citation: N Engl J Med. 2006 Sep 21;355(12):1199-209
references.pmid: 16990383