This Article Full Text Full Text (PDF) All Versions of this Article: 115/25/3165    most recent CIRCULATIONAHA.106.687376v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Losordo, D. W. Articles by Henry, T. D. Search for Related Content PubMed PubMed Citation Articles by Losordo, D. W. Articles by Henry, T. D. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Angina Related Collections Chronic ischemic heart disease Coronary circulation Catheter-based coronary and valvular interventions: other Other Treatment Other Vascular biology Angiogenesis

(Circulation. 2007;115:3165-3172.)
© 2007 American Heart Association, Inc.

Coronary Heart Disease

Intramyocardial Transplantation of Autologous CD34⁺ Stem Cells for Intractable Angina

A Phase I/IIa Double-Blind, Randomized Controlled Trial

Douglas W. Losordo, MD; Richard A. Schatz, MD; Christopher J. White, MD; James E. Udelson, MD; Vimal Veereshwarayya, PhD; Michelle Durgin, MHA; Kian Keong Poh, MD; Robert Weinstein, MD; Marianne Kearney, BS; Muqtada Chaudhry, MD; Aaron Burg, BS; Liz Eaton, BS; Lindsay Heyd, BS; Tina Thorne, BS; Leon Shturman, MD; Peter Hoffmeister, MD; Ken Story, PhD; Victor Zak, PhD; Douglas Dowling, BS; Jay H. Traverse, MD; Rachel E. Olson, MS; Janice Flanagan, RN; Donata Sodano, RN; Toshinori Murayama, MD; Atsuhiko Kawamoto, MD; Kengo Fukushima Kusano, MD; Jill Wollins, MD; Frederick Welt, MD; Pinak Shah, MD; Peter Soukas, MD; Takayuki Asahara, MD; Timothy D. Henry, MD

From Feinberg Cardiovascular Research Institute and Program in Cardiovascular Regenerative Medicine (D.W.L., V.V., M.D., T.T.), Division of Cardiovascular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine and Northwestern Memorial Hospital, Chicago, Ill; Division of Cardiovascular Medicine (D.W.L., V.V., M.D., K.K., R.W., M.K., M.C., A.B., L.E., L.H., T.T., L.S., P.H., V.Z., J.F., D.S., T.M., A.K., K.F.K., J.W., F.W., P. Shah, P. Soukas, T.A.), Department of Medicine, Caritas St. Elizabeth’s Medical Center, Boston, Mass; Division of Cardiovascular Research (R.A.S.), Scripps Green Hospital, La Jolla, Calif; Department of Medicine (C.J.W.), Ochsner Clinic, New Orleans, La; Division of Cardiology (J.E.U.), Tufts-New England Medical Center, Boston, Mass; Baxter Healthcare (K.S.), Deerfield, Ill; Division of Cardiology (J.H.T., R.E.O., T.D.H.), Minneapolis Heart Institute, Minneapolis, Minn; and Cardiovascular Core Laboratories Inc (D.D.), Boston, Mass.

Correspondence to Douglas W. Losordo, MD, Feinberg Cardiovascular Research Institute and Northwestern Memorial Hospital, Tarry 12-703, 303 E Chicago Ave, Chicago, IL 60611. E-mail d-losordo{at}northwestern.edu

Received December 29, 2006; accepted April 11, 2007.

Background— A growing population of patients with coronary artery disease experiences angina that is not amenable to revascularization and is refractory to medical therapy. Preclinical studies have indicated that human CD34⁺ stem cells induce neovascularization in ischemic myocardium, which enhances perfusion and function.

Methods and Results— Twenty-four patients (19 men and 5 women aged 48 to 84 years) with Canadian Cardiovascular Society class 3 or 4 angina who were undergoing optimal medical treatment and who were not candidates for mechanical revascularization were enrolled in a double-blind, randomized (3:1), placebo-controlled dose-escalating study. Patients received granulocyte colony-stimulating factor 5 µg · kg^–1 · d^–1 for 5 days with leukapheresis on the fifth day. Selection of CD34⁺ cells was performed with a Food and Drug Administration–approved device. Electromechanical mapping was performed to identify ischemic but viable regions of myocardium for injection of cells (versus saline). The total dose of cells was distributed in 10 intramyocardial, transendocardial injections. Patients were required to have an implantable cardioverter-defibrillator or to temporarily wear a LifeVest wearable defibrillator. No incidence was observed of myocardial infarction induced by mobilization or intramyocardial injection. The intramyocardial injection of cells or saline did not result in cardiac enzyme elevation, perforation, or pericardial effusion. No incidence of ventricular tachycardia or ventricular fibrillation occurred during the administration of granulocyte colony-stimulating factor or intramyocardial injections. One patient with a history of sudden cardiac death/ventricular tachycardia/ventricular fibrillation had catheter-induced ventricular tachycardia during mapping that required cardioversion. Serious adverse events were evenly distributed. Efficacy parameters including angina frequency, nitroglycerine usage, exercise time, and Canadian Cardiovascular Society class showed trends that favored CD34⁺ cell–treated patients versus control subjects given placebo.

Conclusions— A randomized trial of intramyocardial injection of autologous CD34⁺ cells in patients with intractable angina was completed that provides evidence for feasibility, safety, and bioactivity. A larger phase IIb study is currently under way to further evaluate this therapy.

---

 

CLINICAL PERSPECTIVE

This article has been cited by other articles:

				F. Baldazzi, E. Jorgensen, R. S. Ripa, and J. Kastrup Release of biomarkers of myocardial damage after direct intramyocardial injection of genes and stem cells via the percutaneous transluminal route Eur. Heart J., June 4, 2008; (2008) ehn233v1. [Abstract] [Full Text] [PDF]

				T. J. Povsic and P. J. Goldschmidt-Clermont Review: Endothelial progenitor cells: markers of vascular reparative capacity Therapeutic Advances in Cardiovascular Disease, June 1, 2008; 2(3): 199 - 213. [Abstract] [PDF]

				I. S. Jovin and F. J. Giordano Differentiation by association: is a cell's fate determined by the company it keeps? Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1503 - H1504. [Full Text] [PDF]

				R. K. Burt, Y. Loh, W. Pearce, N. Beohar, W. G. Barr, R. Craig, Y. Wen, J. A. Rapp, and J. Kessler Clinical Applications of Blood-Derived and Marrow-Derived Stem Cells for Nonmalignant Diseases JAMA, February 27, 2008; 299(8): 925 - 936. [Abstract] [Full Text] [PDF]

				S. Dimmeler, J. Burchfield, and A. M. Zeiher Cell-Based Therapy of Myocardial Infarction Arterioscler. Thromb. Vasc. Biol., February 1, 2008; 28(2): 208 - 216. [Abstract] [Full Text] [PDF]