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European Heart Journal Advance Access originally published online on November 5, 2007
European Heart Journal 2007 28(24):2998-3005; doi:10.1093/eurheartj/ehm485
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org
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Prospective randomized trial of direct endomyocardial implantation of bone marrow cells for treatment of severe coronary artery diseases (PROTECT-CAD trial)

Hung-Fat Tse1,*,{dagger}, Sukumaran Thambar3,{dagger}, Yok-Lam Kwong1, Philip Rowlings4, Greg Bellamy3, Jane McCrohon4, Paul Thomas5, Bruce Bastian3, John K.F. Chan6, Gladys Lo6, Chi-Lai Ho7, Wing-Sze Chan1, Raymond Y. Kwong8, Anthony Parker9, Thomas H. Hauser10, Jenny Chan1, Daniel Y.T. Fong2 and Chu-Pak Lau1

1 Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
2 Department of Nursing Studies Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
3 Cardiovascular Division, Hunter Heart-Lung Research Guild, John Hunter Hospital, Newcastle, Australia
4 Hunter Area Pathology Service, Newcastle Mater Misericordiae Hospital, Newcastle, Australia
5 Department of Cardiology, St George Hospital, Sydney, Australia
6 Department of Radiology and Radiotherapy, Hong Kong Sanatorium and Hospital, Hong Kong
7 Department of Nuclear Medicine and Positron Emission Tomography, Hong Kong Sanatorium and Hospital, Hong Kong
8 Cardiac Magnetic Resonance Imaging Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
9 Nuclear Medicine Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA
10 Cardiology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA

Received 25 March 2007; revised 24 August 2007; accepted 26 September 2007; online publish-ahead-of-print 5 November 2007.

* Corresponding author. Tel: +852 2855 3598; Fax: +852 2618 6304. E-mail address: hftse{at}hkucc.hku.hk

Aims: Experimental studies have demonstrated that bone marrow (BM) cells can induce angiogenesis in ischaemic myocardium. Recently, several non-randomized pilot studies have also suggested that direct BM cells implantation appears to be feasible and safe in patients with severe coronary artery diseases (CAD).

Methods and results: We performed a randomized, blinded, and placebo-controlled trial in 28 CAD patients. After BM harvesting, we assigned patients to receive low dose (1 x 106 cells/0.1 mL, n = 9), high dose (2 x 106 cells/0.1 mL, n = 10) autologous BM cells or control (0.1 mL autologous plasma/injection, n = 9) catheter-based direct endomyocardial injection as guided by electromechanical mapping. Our primary endpoint was the increase in exercise treadmill time and our secondary endpoints were changes in Canadian Cardiovascular Society (CCS) and New York Heart Association (NYHA) class, and myocardial perfusion and left ventricular ejection fraction (LVEF) assessed by single-photon emission computed tomography and magnetic resonance imaging, respectively. A total 422 injections (mean 14.6 ± 0.7 per patient) were successfully performed at 41 targeted ischaemic regions without any acute complication. Baseline exercise treadmill time was 439 ± 182 s in controls and 393 ± 136 s in BM-treated patients, and changed after 6 months to 383 ± 223s and 464 ± 196 s [BM treatment effect +0.43 log seconds (+53%), 95% CI 0.11–0.74, P = 0.014]. Compared with placebo injection, BM implantation was associated with a significant increase in LVEF (BM treatment effect +5.4%, 95% CI 0.4–10.3, P = 0.044) and a lower NYHA class (odds ratio for treatment effect 0.12, 95% CI 0.02–0.73, P = 0.021) after 6 months, but CCS reduced similarly in both groups. We observed no acute or long-term complications, including ventricular arrhythmia, myocardial damage, or development of intramyocardial tumour or calcification associated with BM implantation.

Conclusion: Direct endomyocardial implantation of autologous BM cells significantly improved exercise time, LVEF, and NYHA functional class in patients with severe CAD who failed conventional therapy.

Key Words: Angiogenesis • Bone marrow • Coronary artery disease

{dagger} The authors contributed equally to the article as first authors.


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