Put on a happy face? Perspectives on Mayo Clinic stem cells for heart disease Ph3 pub

One of the first regenerative medicine talks I ever saw was on stem cells for heart disease. I was still a trainee at the time. The professor, whom I won’t name, presented data from an early phase trial reporting that direct injections of some kind of cells right into the heart improved outcomes.

Stem cells for heart disease arena

It sounded exciting but maybe too good to be true, and, in the end, it wasn’t replicated in the years that followed.

stem cell therapy for hearts
How much promise is there for stem cell therapy for heart disease?

Since then, there have been dozens of different cell therapy clinical studies in this cardiovascular area. Mostly these studies report small possible benefits just from post-hoc analysis. However, often the studies are initially hyped in the media anyway.

For broader background on stem cells for heart disease, see this post I did last year: stem cell therapy for heart disease.

There is such a need for novel approaches to various forms of cardiovascular disease. I keep hoping a cellular approach might be rigorously proven to work and be safe. I also keep an eye open for new trials and papers.

A new trial paper from The Mayo Clinic caught my eye in this space. The new paper reports on a Phase III trial with a heavy emphasis on patient perceptions of quality of life. There are some unusual things about this publication.stem cells for heart disease

Graphical abstract from Yamada et al. SCTM paper on stem cells for heart disease. What do you think of using smiley and sad faces in an academic publication?

Phase 3 trial

Here it is: Cell Therapy Improves Quality-of-Life in Heart Failure: Outcomes From a Phase III Clinical Trial, Stem Cells Translational Medicine. 

The team delivered autologous marrow-derived mesenchymal cells right into the heart. Why would such cells help the failing heart? To me, it’s not clear there is a strong rationale here. I might have missed it, but I also didn’t find the team’s rationale articulated clearly in the paper.

Admittedly, the fact that the stem cells for heart disease arena has had so many ups and downs was on my mind as I started reading this pub. So I went into it with a somewhat skeptical mindset. The fact that I saw a graphical abstract with smiley/sad-type faces on it likely influenced my perspective too.

The group led by Andre Terzic focused not just on measuring readouts related to the heart itself but also on patient perceptions of their quality of life. Hence the emoji-like overall figure.

This was a randomized, double-blinded study. Controls underwent a sham procedure, which is a big challenge to those running the trial and participants, so kudos to all of them on that.

Yamada, stem cells hearts
Yamada et al Fig. 1B on stem cells for hearts and perceptions of quality of life. Lower scores are better. SCTM 2023.

Overall, unfortunately, there was only a small, non-significant improvement in quality of life with cell therapy as measured by the The Minnesota Living with Heart Failure Questionnaire (MLHFQ).

Note that the cell therapy intervention is called C3BS-CQR-1. This kind of intervention is sometimes referred to as cardiopoiesis.

Glimmer of hope: LV enlargement subgroup may have benefitted

When the team then just looked at a subgroup with severe enlargement of the left ventricle of the heart, the quality of life improvement was reported as significant.

This improvement also went along with reduction in death and hospitalization, which are more traditional measures of trials of heart failure. This is the area of hope from the paper, but is it a real, meaningful signal that others will find too in independent studies?

Is that kind of subgroup analysis reasonable? I’m also not clear on whether this heart enlargement grouping was an original primary or secondary endpoint. So is this also posthoc analysis?

Even in the chamber enlargement group given cells, the improvements were not huge, but they could be meaningful to patient’s quality of life if reproducible.

Adverse events

I was also concerned to see that the group getting stem cells had some modest but potentially meaningful increases in adverse events. See red arrows I added onto the table below. Overall, patients receiving cells had more deaths and hospitalizations than the sham group.

This wasn’t discussed in the article either, which is an issue in my view. The potential increases in adverse events were moderate but then so was the possible improvement in quality of life. Again, the LV enlargement subgroup seemed to do better.

stem cells for heart disease adverse events
Those receiving mesenchymal cells for heart disease had more adverse events overall. Yamada, et al. Note the increases in percentages in those receiving the cells.

The take-home on this stem cells for heart disease paper

Overall, I’m left with a bit of deja vu from this paper. Another stem cells for heart disease trial paper that doesn’t have strongly positive, clear data. These trials are very difficult and expensive. Looking ahead is it worth focusing on a new trial using these cells just on those with LV enlargement? Or do these data suggest stopping is the most rational decision?

There are more than 350 trial listings on Clincialtrials.gov for stem cells for heart disease. Do all of these trials make sense?

It’s also notable in the big picture that this paper put major emphasis on patient perceptions of quality of life. Should that be a more common measurement in the cell therapy field? How rigorous is it?

6 thoughts on “Put on a happy face? Perspectives on Mayo Clinic stem cells for heart disease Ph3 pub”

  1. the University of Miami is currently conducting a double blind, placebo-controlled clinical trial to see if umbilical cord mesenchymal stem cells really can cure congestive heart failure. I hope this one succeeds. I think this is the first time umbilical cord derived mesenchymal stem cells have ever gone through a legitimate clinical trial for the treatment of congestive heart failure, all the other ones used bone marrow MSCs.

    Well, the thing is, umbilical cord MSCs are superior to bone marrow MSCs. So I’ve got my fingers crossed. I think this one should have good results.

  2. I have asked this question previously without a reply from you. Are there stem cells (MSCs, pericytes) in cardiac muscle? I cannot find any evidence that the myocardium contains stem cells. The endocardium apparently has MSCs and may have some effect and benefit on the myocardium. If that is true, injecting an MSC from bone marrow into the myocardium will have little or no effect on the heart muscle’s ability to contract.

    1. @John, I don’t know if there are true MSCs in adult heart tissue. It in part depends on how one defines MSCs. There are fibroblasts in the connective tissue in the heart. There should be pericytes along the vasculature but they have limited potential. For example, it’s not clear that pericytes could differentiate into cardiomyocytes. I doubt it.

  3. Dan S Kaufman, MD, PhD

    I agree with your assessment. First, it is great they did a randomized trial. I do have a question if this was really double blinded. That would mean those who got the sham treatment still had a bone marrow harvest to collect the MSCs. If they did not have the harvest, they would know they are in the sham group (not blinded). If they did have the harvest but cells not used, this is great scientifically, but ethically a bit circumspect. BM harvests are invasive and not trivial procedures, especially in patients with bad heart failure. The consent process here would be interesting.

    Second, my main interpretation is the treatment had no significant benefit compared to sham treatment, based on the quality of life measurements. There may be a small subgroup (LV enlargement) that benefited, but that would probably be hard to sort out if this procedure widely offered. The main issue is there is no other assessment. I have no problem with using a well validated quality of life assessment as a metric, but I would think some physiologic assessments (EF, etc), would also be there. Of course, overall survival is also important, and this seemed to show no benefit, if not worse outcome, in the treated vs sham group.

    In summary (to me), this study shows in a sham controlled study that there is no benefit to the cell therapy for treatment of heart failure. Good to know.

    1. @Dan, Thanks for your take on this. The question of whether this was truly sham-controlled is an excellent one.

      I wonder if some folks will use this trial paper’s emphasis on what they argue are signals of potential benefit as the basis for more similar trials. Does this study justify a new trial that is just for patients with LV enlargement?

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