Primed Mesenchymal Stem Cells May Improve Heart Function

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Specially prepared mesenchymal stem cells derived from patients’ own bone marrow appear to be a safe, feasible, and potentially effective treatment for chronic heart failure, according to a small randomized trial scheduled for release online April 9, 2013, ahead of print in the Journal of the American College of Cardiology.

Findings from the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial were previously presented at the Transcatheter Cardiovascular Therapeutic scientific symposium in November 2011 in San Francisco, CA.

Andre Terzic, MD, PhD, of the Mayo Clinic (Rochester, MN), Jozef Bartunek, MD, of Cardiovascular Center Aalst (Aalst, Belgium), and colleagues randomized 48 patients with ischemic heart failure to standard therapy with (n = 32) or without (n = 15) endomyocardial injection of lineage-specified stem cells.

Cells Offer Greater Improvement in LVEF

All attempts at cell injection, which occurred via femoral access at an average of 1,540 days after MI (range, 192-7,515 days), were successful. After excluding patients for reasons such as lack of bone marrow harvested and failure to meet quality control criteria, 21 subjects (65.6%) ultimately received the full cell therapy and completed 2-year follow-up.

Procedural complications were rare; one patient experienced ventricular tachycardia that was resolved by cardioversion and another patient with pre-existing ophthalmic migraines had blurred vision after treatment.

At 6-month follow-up, patients who received stem cells experienced greater improvement in LVEF (table 1).

Table 1. Change in LVEF^a

^a P < 0.001 for cell therapy vs. standard care.

In addition, there was a greater reduction in LV end-systolic volume among cell therapy patients (-24.8 ± 3.0 mL vs. -8.8 ± 3.9 mL; P < 0.001), who showed gains in 6-minute walk distance (62 ± 18 m) while those on standard care showed losses (-15 ± 20 m; P < 0.01).

Over 2-year follow-up, hospitalization rates were 25% and 28.5% in the control and cell therapy groups, respectively. Two control patients died, 1 from heart failure deterioration at 18 months and the other from sudden cardiac death at 20 months. One cell therapy patient underwent elective heart transplantation at 21 months, developed sepsis, and subsequently died. There were no signs of increased cardiac or systemic toxicity with cell therapy, and no patients withdrew from the study due to adverse events.

Positive Signs But Therapy Presents Challenges

In an editorial accompanying the paper, Charles E. Murry, MD, PhD, Nathan J. Palpant, PhD, and W. Robb MacLellan, MD, of the University of Washington School of Medicine (Seattle, WA), agree that the C-CURE results suggest that treatment with cytokine-primed mesenchymal stem cells is safe and feasible and also shows signs of providing enhanced cardiac performance. The gain in LVEF is “dramatic,” they add, “particularly given the duration between the ischemic injury and cell therapy. It compares favorably with our most potent therapies in heart failure.”

However, Dr. Murry and colleagues point out that the path from harvesting to treatment is far from simple.

“Harvesting marrow locally, shipping it to a central lab for processing, and returning the expanded cells for injection is not a trivial undertaking,” they write, noting that the overall success rate among randomized patients was 70%. The remaining 30% were excluded from further analysis, a decision that the editorial authors say may have biased results in favor of cell therapy.

In an e-mail communication, Dr. Terzic explained, “In fact, prospective follow-up of patients who did not meet criteria showed no difference in outcomes versus those randomized to standard of care.”

C-CURE “introduces a next-generation stem cell technology optimized for the treatment of heart failure,” he said. “While to date stem cells have been used in their native state isolated from noncardiac or cardiac sources, this first-in-class trial employed cardiopoietic lineage-specification to ensure benefit.” The 7% absolute improvement in LVEF seen in the cell therapy arm is “the most exciting finding,” Dr. Terzic noted, particularly because it occurred in conjunction with reduced end-systolic volume, “differentiating this biotherapeutic from drug-based modalities that primarily influence end-diastolic volumes to limit remodeling.”

Based on the promise provided by the C-CURE trial, which ended in 2012, the pivotal phase III CHART-1 trial was recently launched, he reported.

Study Details

In the treatment arm, unique cell blends were created for each patient using autologous bone marrow-derived mesenchymal stem cells that were exposed to a cardiogenic cocktail. Cells were then delivered via endomyocardial injection under electromechanical guidance. Bone marrow harvest and subsequent cell isolation was achieved in 100% of patients, with 75% generating doses of at least 600 x 10⁶ cells (mean dose of 733 x 10⁶ cells).

 

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Sources:
1. Bartunek J, Behfar A, Dolatabadi D, et al. Cardiopoietic stem cell therapy in heart failure: The C-CURE multicenter randomized trial with lineage-specified biologics. J Am Coll Cardiol. 2013;Epub ahead of print.

2. Murry CE, Palpant NJ, MacLellan WR. Cardiopoietry in Motion: Primed mesenchymal stem cells for ischemic cardiomyopathy. J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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