Cardiac Stem-Cells Increase Viable Myocardium Post-MI: CADUCEUS

Shelley Wood

February 14, 2012

February 13, 2012 (London, United Kingdom) — Authors of a small study using cardiac-derived stem cells in "convalescent" MI patients say they've uncovered some of the first true evidence that the heart can regenerate, describing a new method that, they say, led to "unprecedented" improvements in viable heart muscle [1].

Results of the CADUCEUS study, published online February 13, 2012 in the Lancet, showed not only that scar size was reduced on MRI at six months--something also seen in previous research--but also that the amount of viable heart mass and regional contractility were also improved.

Dr Raj R Makkar (Cedars-Sinai Heart Institute, Los Angeles, CA) and colleagues used a proprietary technique to harvest autologous heart cells from endomyocardial biopsy specimens, then grow these cells--dubbed cardiosphere-derived-cells--to the therapeutic dose. The test population was made up of post-MI patients with left ventricular ejection fractions (LVEFs) ranging from 25% to 45%, with subjects randomized 2:1 to receive cardiosphere-derived cells (17 patients) or to standard care (eight patients).

Previous studies have typically used autologous bone-marrow–derived cells or skeletal myoblasts and even cells derived from liposuction procedures, and the target population has typically been patients with very recent acute MI or patients with chronic ischemic cardiomyopathy. Recently, the SCIPIO trial [2] made headlines after demonstrating that intracoronary infusion of c-kit–positive cells in patients with ischemic cardiomyopathy led to reduction in infarct size by 24% at six months and 30% at one year. In the current study, cells derived from the endomyocardial biopsies were infused between one and a half to three months postinfarct, a period senior author Dr Eduardo Marbán (Cedars-Sinai Heart Institute) called the "convalescent" period.

From the Heart

In this study, Marbán explained, the timing was based on the fact that endomyocardial biopsies were typically taken at two to four weeks, then the cells themselves took roughly five weeks to grow to the target cell volume. But as Marbán explained, infusing the cells at this point meant that the baseline MRI images were "stable"--when MRI is performed immediately post-MI, the myocardium is still healing, meaning that serial imaging will suggest that the scar is shrinking.

It's been our medical fantasy for decades.

By six months postinfarction, scar size was unchanged from baseline in the control group but decreased by 7.7% in the stem-cell group (p<0.001 within group; p=0.001 between groups). By 12 months, that improvement was 12% in the active group, with no statistically significant improvement in the control group ((p=0.001 within group; p=0.007 between groups.) Researchers saw a similar pattern with scar mass, which decreased in patients who received the stem-cell infusion but was unchanged in those who didn't (at both time points). By contrast, viable myocardial mass increased by 13 g from baseline by six months in patients who received the cardiac-derived cells (p=0.001) with a nonsignificant 0.9-g increase seen in the control group (p=0.01 between groups). A similar effect was seen at 12 months. Of note, the amount of viable myocardial mass increased by about 60% more than the scar shrinkage--suggesting that reversal of injury was indeed taking place and explaining the partial restoration of lost LV mass in the cell-treated patients.

A Medical Fantasy

Speaking with heartwire , Marbán pointed out that "spontaneous regeneration" is not uncommon in nature--salamanders regrow their tails, the human liver can regenerate after injury, etc. "The big finding for us with this study is very simple: this is the first study that has demonstrated therapeutic regeneration of the heart. . . . That's never been done before, and certainly it's been our medical fantasy for decades."

No significant differences in safety outcomes were seen, although one patient in the active-treatment group had recurrent MI and four others had additional cardiac interventions. Improvements in six-minute-walk test and peak oxygen consumption were also greater in the intervention group, although differences between groups were not statistically significant. Changes in LVEF did not track with reductions in scar or increases in viable myocardium, something Marbán said was unsurprising given the relatively high LVEFs at study onset.

But commenting on the study for heartwire , Dr Andreas Zeiher (Johann Wolfgang Goethe University, Frankfurt, Germany) called the lack of an effect on LVEF one of the "puzzling" findings in an otherwise "innovative" study. "Despite a significant reduction in scar size and an increase in 'black' tissue by MRI suggestive of viable myocardium, there is no effect at all on global LV function. This is somewhat counterintuitive. Newly formed myocardium should in essence contribute to improved pump function of the heart," he observed.

"Nevertheless, despite the small number of patients studied and the uncertainty about the clinical relevance of the end point measured, the study clearly is a step forward. On the other hand, the results are difficult to compare with those obtained using bone-marrow–derived cells in AMI, since the Marbán study treated patients approximately two to three months post-AMI, but not in the acute phase. Moreover, the improvements in pump function seen with bone-marrow–derived cells seem to translate into clinical benefit as evidenced by reduced [major adverse cardiovascular events] MACE during follow-up. It is much too early to speculate about such effects using cardiac-derived cells, because the number of patients is way too small and duration of follow-up too short; in addition, there was no sham-treated placebo control group in Eduardo's study."

Zeiher, as well as an accompanying editorial [3] by Drs Chung-Wah Siu and Hung-Fat Tse (University of Hong Kong, China) also stressed that further investigations, "involving more patients, longer follow-up, and a true placebo arm, will be needed to confirm the safety and efficacy of cardiosphere-derived cell therapy," the editorialists write.

What's Next

Marbán 's group has since moved from using autologous cardiac-derived stem cells to using an allogenic cell line, using cells harvested from unused transplant-quality hearts ((intended but ultimately not used for transplant), so far tested only in animals. One advantage of an allogenic cell line, which can be cultivated then frozen until needed, is that no weeks would be lost trying to "grow" a large enough cell population (doses of 25 million cells were used in CADUCEUS).

Marbán will also be an advisor, but not an investigator, for a phase 2 trial known as ALLSTAR, a multicenter trial using allogenic cells. His group is moving ahead with a phase 1 study looking at the use of cardiac-derived cells in sicker patients, with more advanced ischemic cardiomyopathy and chronic infarcts. "We see this as a very promising technology. The foot in the door has been with the recent-MI patients who aren't that sick, but we'd like expand that" to patients with longstanding infarcts, which represent a huge group in need.

To heartwire , Marbán noted that patents have been filed on "every aspect" of the technology--and those patents have been licensed by Capricor; however, other groups have also published other papers describing use of cardiac-derived cells.

Marbán is a founder and equity holder in Capricor, the company that has licensed the technology used in this study. Other study authors are Capricor employees, founders/equity holders, and/or have received consulting fees from the company.


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