The leading cause of death in America and many other countries of the world is cardiovascular disease (CVD) including heart attacks and strokes. In fact, CVD kills and disables more people than most often top killers combined including cancer.
The myth that CVD is a “man’s disease” only makes the situation worse as in reality CVD is a top killer of women as well, killing dramatically more women than breast cancer, for example.
A new paper out yesterday from a Gladstone team led by Deepak Srivastava provides some hope for treating CVD in a truly new way.
This study suggests that stem cell technology may provide the first truly new approach to treating CVD since angioplasty and clot busting enzymes were introduced.
Many labs have pursued the idea of using stem cell-based cell therapies or regenerative medicine treatments for CVD, but there are a number of challenges to these approaches including most prominently how to deliver cells to the injured heart or brain.
It is possible, but extremely difficult. I discussed one such study in which stem cells were directly injected into heart muscle in this podcast.
How else might we be able to treat aspects of CVD such as heart attacks using stem cell technology?
One quite different, but still stem cell-related approach is to use cellular reprogramming technology to treating the heart. In this case rather than transplant new cells into the damaged heart, instead doctors might tell the heart to heal itself via changing scar tissue into functional, beating heart muscle.
Sounds like sci-fi or alchemy, doesn’t it?
But this technology is on track to become reality. This new paper (check it out here) shows this is a potential new reality for treat heart attacks.
Srivastava and his team used transdifferentiation technology to transform cardiac fibroblasts (cells normally providing mostly a structural role in the heart) into cardiomyocytes (the cells that do the trick of making the heart beat). Transdifferentiation is essentially telling one type of cell to become a fundamentally different type of cell, something that only a few years ago scientists thought was impossible.
In the current study the scientists reprogrammed the heart fibroblasts into myocytes using Gata4, Mef2c, and Tbx5 (GMT). This 3-gene cocktail, delivered by viral transduction in vivo in the actual heart, flips a switch telling cells to behave like they are cardiomyocytes rather than scar-forming cardiac fibroblasts. The more beating muscle and less scar tissue that is present after a heart attack, the better the patient outcome. You can see in Fig. 4a (above right) that there is a lot less scar tissue (blue) in the GMT-injected heart versus the dsRed control.
The fact that this could be accomplished in vivo in the damaged heart is an astounding feat, making the technology all the more powerful if it could one day be applied to human patients.
A number of critically important challenges remain however.
First of all, these are pre-clinical rodent studies. Will the same thing work in human cells or even more challengingly in human hearts? There is reason for hope, but we have to see if this work can be translated to the human. Ed points out that this team is now extending their studies to pigs, whose hearts are much more similar to humans than are those of mice. When I was a lab technician at UCSD in the 1990s, I was in a heart disease lab (Colin Bloor) and we used pigs as an animal model. It struck me then how amazingly similar the pig heart was to the human heart.
Second, as with all reprogramming technologies, a major concern is efficiency. If you can’t get enough cells to change from fibroblasts into beating heart cells, then the technology won’t have a meaningful impact. In this case, they reported ~15% efficiency. Is that enough? At this point we do not know, but it is encouraging that the team reported (see Fig. 4) that the reprogramming yielded statistically significant improvements in heart function including 3 measures of heart activity: ejection fraction (EF), stroke volume (SV), and cardiac output (CO). Together EF, SV, and CO were moderately improved by the cell reprogramming. Such improvements may seem small, but in a human patient could be the difference between death and survival following a heart attack or a patient being disabled versus being able to lead a mostly normal life.
Third, generating new cardiomyocytes is not without risk as the authors themselves point out in their discussion. A major concern is that the new heart tissue could cause arrhythmias where the heart beats out of rhythm, sometimes with fatal consequences.
Fourth, reprogramming technology of this kind done in vivo, essential a combination of transdifferentiation and gene therapy, must be rigorously evaluated for safety. Viruses have a way of doing unexpected, undesired things and reprogramming factors are powerful transcription factors.
Fifth, we have to be patient as this heart healing technology is likely a decade away from being used in people because a long clinical trial road remains ahead of it.
Nonetheless, this paper is extremely encouraging in the sense that it provides a new window to treating CVD, which remains the most likely exit route from this world for all of us at this time.