title: Intravenous Allogeneic Mesenchymal Stem Cells for Nonischemic Cardiomyopathy: Safety and Efficacy Results of a Phase II-A Randomized Trial.
abstract: BACKGROUND
  Potential benefits of mesenchymal stem cell (MSC) therapy in heart failure may be related to paracrine properties and systemic effects, including anti-inflammatory activities. If this hypothesis is valid, intravenous administration of MSCs should improve outcomes in heart failure, an entity in which excessive chronic inflammation may play a pivotal role.
  
  
  OBJECTIVE
  To assess the safety and preliminary efficacy of intravenously administered ischemia-tolerant MSCs (itMSCs) in patients with nonischemic cardiomyopathy.
  
  
  RESULTS
  This was a single-blind, placebo-controlled, crossover, randomized phase II-a trial of nonischemic cardiomyopathy patients with left ventricular ejection fraction ≤40% and absent hyperenhancement on cardiac magnetic resonance imaging. Patients were randomized to intravenously administered itMSCs (1.5×106cells/kg) or placebo; at 90 days, each group received the alternative treatment. Overall, 22 patients were randomized to itMSC (n=10) and placebo (n=12) at baseline. After crossover, data were available for 22 itMSC patients. No major differences in death, hospitalization, or serious adverse events were noted between the 2 treatments. Change from baseline in left ventricular ejection fraction and ventricular volumes was not significantly different between therapies. Compared with placebo, itMSC therapy increased 6-minute walk distance (+36.47 m, 95% confidence interval 5.98-66.97; P=0.02) and improved Kansas City Cardiomyopathy clinical summary (+5.22, 95% confidence interval 0.70-9.74; P=0.02) and functional status scores (+5.65, 95% confidence interval -0.11 to 11.41; P=0.06). The data demonstrated MSC-induced immunomodulatory effects, the magnitude of which correlated with improvement in left ventricular ejection fraction.
  
  
  CONCLUSIONS
  In this pilot study of patients with nonischemic cardiomyopathy, itMSC therapy was safe, caused immunomodulatory effects, and was associated with improvements in health status and functional capacity.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT02467387.
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.). javed.butler@stonybrookmedicine.edu.
authors.forename: Javed
authors.initials: J
authors.lastname: Butler
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Greene
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Arshed A
authors.initials: AA
authors.lastname: Quyyumi
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Sikora
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Kim
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Allen S
authors.initials: AS
authors.lastname: Anderson
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Jane E
authors.initials: JE
authors.lastname: Wilcox
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Nikolai I
authors.initials: NI
authors.lastname: Tankovich
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lipinski
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Yi-An
authors.initials: YA
authors.lastname: Ko
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Robert T
authors.initials: RT
authors.lastname: Cole
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Hal A
authors.initials: HA
authors.lastname: Skopicki
authors.affiliation: From the Division of Cardiology, Department of Medicine, Stony Brook University, NY (J.B., H.A.S.); MedStar Heart and Vascular Institute, MedStar Washington Hospital Center, Washington, DC (S.E.E., M.J.L.); Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC (S.J.G., R.J.K.); Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA (A.A.Q., R.T.C.); CardioCell LLC, San Diego, CA (S.S.); Division of Cardiology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (A.S.A., J.E.W.); Stemedica Cell Technologies Inc, San Diego, CA (N.I.T.); Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA (Y.-A.K.); Division of Cardiology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (K.B.M.); and Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).
authors.forename: Mihai
authors.initials: M
authors.lastname: Gheorghiade
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000097:blood / Q000175:diagnosis* / Q000628:therapy*; D018592:Cross-Over Studies; D005260:Female; D006304:Health Status; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008875:Middle Aged; D010865:Pilot Projects; D020127:Recovery of Function / Q000502:physiology; D016037:Single-Blind Method; D014184:Transplantation, Homologous / Q000379:methods; D016896:Treatment Outcome
keywords: cardiomyopathy; clinical trial; heart failure; noni; schemic; stem cells; viable myocardium