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A New Route for Stem Cell-based Cardiac Disease Therapy

Review of “REVIVE Trial: Retrograde Delivery of Autologous Bone Marrow in Patients with Heart Failure” from Stem Cells Translational Medicine by Stuart P. Atkinson.

Stem cell therapy for the treatment of cardiac disease currently favor treatment with autologous bone marrow [1, 2] using numerous different routes for delivery. Each of these routes has disadvantages and one interesting alternative is the retrograde venous delivery (that is, against the flow) of large amounts of cells via the coronary sinus [3, 4]. 

Based on earlier studies using this method, the REVIVE trial, a prospective randomized, multicenter, open-label study of the safety and feasibility, sought to assess the effectiveness of retrograde bone marrow aspirate concentrate (BMAC) delivery to treat ischemic heart failure (IHF) and non-ischemic heart failure (NIHF). The results of this trial, published in Stem Cells Translational Medicine, suggest that BMAC treatment is a safe for cardiac disease therapy and provides the basis for larger trials to fully assess effectiveness [5].

The trial randomly placed 30 patients in the each group (IHF or NIHF) with 24 receiving BMACs and 6 acting as controls. The cell delivery procedure (cell infusion through the coronary sinus accessed via the right femoral vein) demonstrated no technical problems, and allowed the infusion of around 4 billion cells (mean CD34+ stem cell count of ~40 million). Encouragingly, the delivery of this large cell number did not give rise to any adverse effects or hemodynamic changes related to BMAC delivery.

Non-serious adverse events occurred in 22.7% of ischemic patients and 16.7% of non-ischemic patients while serious adverse effects occurred in 33% of ischemic patients and 16.7% of non-ischemic patients. A total of 9 patients died, with 7 of these having received BMAC treatment. However, site primary investigators classified these as “unrelated” or “unlikely” to be related to the procedure.

Encouragingly, cardiovascular symptoms did not worsen with BMAC treatment, and the trial observed a trend for improved function after BMAC treatment for the ischemic and non-ischemic (less pronounced) groups, although this was not significant. Brain natriuretic peptide (BNP) levels, which rise when heart failure worsens, dropped in the non-ischemic BMAC group only, although this again was not significant. The study found no differences between the BMAC and control groups in mean ejection fraction measurements or in end-diastolic diameter, although they did find a significant decrease in the LV end-systolic diameter (LVESD) in the BMAC group of the non-ischemic stratification, but not the ischemic BMAC group.

This first prospective randomized clinical trial of BMAC infusion using retrograde coronary sinus delivery has demonstrated this therapy route to be safe and, even though the trial only dealt with a small cohort of patients, the trial also demonstrated some signs of clinical improvement after BMAC treatment. This new route allows for the safe delivery of very large amounts of cells under low pressure as compared to other delivery modalities which carry disadvantages such as perforation, poor cell distribution, and cell microclumping leading to infarct. Future larger trials will hopefully define whether this improved cell delivery strategy can lead to the desired improvement in heart function in cardiac disease patients.


  1. Sanganalmath SK and Bolli R Cell therapy for heart failure: a comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ Res 2013;113:810-834.
  2. 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;126:551-568.
  3. Talwalkar NG, Lawrie GM, Earle N, et al. Can retrograde cardioplegia alone provide adequate protection for cardiac valve surgery? Chest 1999;115:135-139.
  4. Tuma J, Fernandez-Vina R, Carrasco A, et al. Safety and feasibility of percutaneous retrograde coronary sinus delivery of autologous bone marrow mononuclear cell transplantation in patients with chronic refractory angina. J Transl Med 2011;9:183.
  5. Patel AN, Mittal S, Turan G, et al. REVIVE Trial: Retrograde Delivery of Autologous Bone Marrow in Patients With Heart Failure. Stem Cells Transl Med 2015;4:1021-1027.