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In patients with a recent myocardial infarction, infusion of their own cardiac progenitor cells safely reduces scar tissue while increasing viable myocardium over 1 year, according to a first-in-man study published online September 11, 2013, ahead of print in the Journal of the American College of Cardiology. Although global ventricular function and quality of life were not improved compared with controls, the investigators say the strong signal of tissue regeneration merits further clinical investigation of the therapy. 

For the 2-center CADUCEUS trial, Eduardo Marbán, MD, PhD, of the Cedars-Sinai Heart Institute (Los Angeles, CA), and colleagues enrolled 25 patients with moderate LV dysfunction  no more than 4 weeks after successful stenting. Subjects were randomized in a 2:1 ratio to autologous cardiosphere-derived cells (n = 17) or standard care (n = 8). Patients allocated to cell therapy underwent endomyocardial biopsy; the harvested cells were expanded ex vivo and then infused in the infarct-related artery at the site of the blockage 6 to 12 weeks after the index MI. (One patient was infused at 14 months.) All patients underwent baseline magnetic resonance imaging (MRI). 

Initial results, reported in the Lancet in February 2012, showed that the therapy was feasible and safe, and resulted in a decrease in scar size and increase in viable myocardium at 6 months. 

Protocol Appears Safe 

No complications were associated with coronary biopsy, while 2 patients experienced mild troponin increases and 1 suffered chest pain related to infusion. Over 13.4-month follow-up, only 1 serious adverse event, a non-ST-elevation MI (NSTEMI), was deemed possibly related to the therapy. In Holter monitoring, 47.1% of cell therapy patients vs. 25.0% of controls had at least 1 brief episode of ventricular tachycardia (P = 0.4). In addition, there were 8 hospitalizations in the cell therapy group and 2 in the control group (P = 0.36). Beyond the NSTEMI, there were no instances of death, MACE, or tumor formation in either group.

At 1 year, MRI showed that, compared with baseline, scar mass and scar size (relative to total LV mass) decreased substantially, while viable mass increased in the cell-treated group; these parameters were virtually unchanged in the control group. In addition, a substantial portion of infarcted myocardial segments in the cell therapy group showed a decrease in the percentage of scar tissue, which correlated strongly with improvement in systolic function (P < 0.001). However, there were no differences between the groups in LVEF, end-systolic or end-diastolic volume, or cardiac output (table 1).

Table 1. Changes in MRI Parameters: Baseline to 1 Year

In multilinear regression analysis, higher baseline scar size was associated with regenerative efficacy at 1 year after cell infusion (P < 0.001). Interestingly, scar size treatment effect did not correlate with the length of time from MI to cell therapy.

In addition, New York Heart Association (NYHA) functional class, peak VO2, and total Minnesota Living with Heart Failure Questionnaire score remained basically unchanged from baseline in both groups. However, unlike controls, patients in the cell-therapy group showed a trend toward improvement in the 6-minute walk test compared with baseline.

According to the authors, “the correlation of scar shrinkage with increase in viability and improvement in regional function is consistent with genuine therapeutic regeneration.” However, they add, given the absence of improvements in LVEF and quality of life metrics, appropriately powered studies are needed to assess the true functional efficacy of the cell therapy.

Cardiosphere Cells Work Better

In a telephone interview with TCTMD, Dr. Marbán explained the rationale for using cardiac progenitor cells as therapy. In principle, “we felt they were better suited to heal the heart than cells from the bone marrow or skeletal muscle or bloodstream,” he said. Supporting that concept, research shows that the heart has a small capacity for self-repair, he added, and the idea was to leverage that capacity by amplifying cardiac stem cells and delivering them to the site of the infarct. “We know from preclinical studies and now CADUCEUS that these [cardiosphere-derived cells] work better than any others that have been studied in terms of their ability to regrow healthy heart muscle,” he said.

Another attractive feature of these cells, Dr. Marbán noted, is that they do not simply replace damaged cells. “Instead, they work by engrafting temporarily and during that time they trigger a tremendous cascade of healing and regeneration that has a life of its own after the [infused] cells disappear in 4 or 5 weeks,” he explained.

The relatively wide time window for treatment after the MI was a surprise, Dr. Marbán commented. The practical reason for the delay was that it takes 3 to 5 weeks to grow enough cells for the target dosage. But that may have been fortuitous, he observed, adding that although the assumption has been that the earlier treatment begins, the better the outcome, “it’s possible we need to let the heart begin its healing phase before we go in with cell therapy.”

New Trial Tests Allogeneic Cells

Dr. Marbán said the follow-up ALLSTAR trial will explore the importance of timing by treating patients up to 1 year after their MI. Moreover, the randomized study, which will enroll 270 patients at 20 US sites, will substitute allogeneic for autologous cells. That not only facilitates cell amplification but also ensures that the off-the-shelf therapy will be identical for all patients, Dr. Marbán noted, adding, “It’s more like giving a pill than giving a blood transfusion, which is what we do now.”

In addition, the trial will be limited to patients who have a low ejection fraction and a substantial scar and thus are likely to develop heart failure, Dr. Marbán said. This avoids a confounder of previous acute MI studies that treated many patients who would have done well anyway, he noted

ALLSTAR’s primary endpoint is infarct size. This anatomical metric is more indicative of the regenerative power of cell therapy than ejection fraction and more prognostic of long-term outcome, Dr. Marbán observed. “But of course at some point we’re going to have to move beyond surrogate endpoints and look at clinical events, and that will require larger trials than the ones we’re doing now,” he concluded.

Study Details

There were no differences in baseline characteristics between the groups. In the cell therapy group, 4 patients received a low dose (12.5 million cells), 12 received a high dose (25 million cells), and 1 received an intermediate dose (17.3 million cells).

The LAD was the MI culprit vessel in 92% of patients. The average baseline LVEF was 39 ± 12%, the average scar size equaled 24 ± 10% of the left ventricle, and 74% of patients had NYHA class 1 function.

 

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Source:
Malliaras K, Makkar RR, Smith RR, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence for therapeutic regeneration in the final 1-year results of the CADUCEUS trial. J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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