Healing a broken heart

The adult human heart can’t regenerate on its own, but with some help, it might be able to in the not-too-distant future. Using strategies such as manipulating the cell cycle of cardiac muscle cells, injecting the heart with stem cells, and even putting patients into a huge hypoxic chamber, researchers are closer than ever before. However, the recent successes follow many years of challenging setbacks and even a scientific scandal.

Hosts: Allison Whitten, PhD, Assistant Editor and Stephanie DeMarco, PhD, Managing Editor

Guests:

Charles Murry, University of Washington and University of Southern California

Hesham Sadek, University of Arizona

Jens Tank, German Aerospace Center

James Martin, Baylor College of Medicine and Texas Heart Institute  

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Transcript

Stephanie DeMarco: Hi everyone. Welcome back to a new episode of DDN Dialogues. I'm your host, Stephanie DeMarco. 

Cardiovascular doctors and scientists are familiar with the phrase time is muscle. It means that during a heart attack, the more time that goes by the more heart muscle dies permanently. In today's episode, we're talking about whether it will be possible for scientists to regenerate the human heart and how they might do it. To learn more, we're joined by Allison Whitten, Assistant Editor at Drug Discovery News. She spoke with experts on the cutting edge of heart regeneration research. They're using strategies that include reactivating the cell cycle in heart muscle cells, injecting the heart muscle with stem cells, and even more.

Allison Whitten: That's right, Stephanie, it's finally looking promising that patients with heart diseases and heart failure could one day be treated with a strong dose of regeneration. But it's only become possible after many decades of research, and a long debate about whether the human heart has any natural capacity for regeneration in the first place. And to complicate things further, there's even been a case of scientific fraud. 

But first, let's back up. Why would it be such a groundbreaking advance to get the heart to grow new muscle cells after an injury? To find out, I spoke with Charles Murry, a stem cell researcher at the University of Washington who will join the University of Southern California in August.

Charles Murry: Heart disease is the biggest cause of death in the world, and the fundamental reason for this is because the heart is the least regenerative organ in the human body. There's essentially no regeneration or replacement of cardiac muscle cells after a major cardiac injury, like a heart attack or a myocardial infarction. So instead, it heals by this process of inflammation and scar formation. And that leaves patients with a contractile deficit. If it's a significant enough deficit in contraction, you don't get stable dysfunction, you get unstable dysfunction where a progressive reduction in heart function happens, and the heart starts to spiral downward, essentially, into this dysfunctional loop that we call heart failure, when the body's demand for blood flow cannot be met by the pump function of the organ.

Whitten: Once someone has heart failure, all the currently available therapies aim to prevent the progression to end-stage cardiomyopathy, but they can't reverse the damage that's already there. Heart transplants are the best option right now, but even getting a new heart can't solve the problem. In addition to the risks associated with receiving an organ transplant, patients have decreased survival rates every year after getting their transplant. 

But it turns out that heart failure is actually a relatively new problem. 

Murry: In the '60s when I was a kid, people used to just drop dead. You would have a heart attack, and you would die at age 50. And you never went on to develop heart failure afterwards. And so, we didn't see this epidemic like we see now. We've gotten really good at keeping people alive in the acute phases of their heart attack. But we don't have anything to treat the root cause of muscle deficiency.

Whitten: If scientists could find a way for the heart to fix itself through regeneration to grow new healthy muscle tissue, it would mean not just treating patients to stave off death, but actually finding a cure for heart failure.

For much of its history, the field of heart generation has been plagued by one question: Is it even possible for mammalian hearts to regenerate naturally at any level on their own? Unfortunately, this question became a source of controversy. In the early 2000s, Piero Anversa's lab at Harvard University and Brigham and Women's Hospital claimed to have found stem cells within the heart itself that could regenerate cardiac muscle cells called cardiomyocytes. But after many independent researchers were not able to replicate those results, Harvard opened an investigation. In 2018, they concluded that Anversa falsified data in 31 papers. 

Murry: It took about 18 years but finally, this group's work was realized to be falsified and it was one of the largest perpetrations of scientific misconduct in the history of cardiovascular disease, but I think we've officially put that to rest.

Whitten: The real answer came from the lab of Hesham Sadek, now at the University of Arizona. In 2011, his group published a paper in Science showing that cardiomyocytes in mammalian hearts can indeed regenerate — but only for a very short period of time.

Hesham Sadek: There is a brief window of time after birth in mammals, few days probably, depending on the types of mammals, whereby if you injure the heart, the heart is able to completely regenerate itself. And that happens through proliferative competency of preexisting cardiomyocytes. So the preexisting myocytes can still divide, and as long as they can still divide, they will regenerate the missing part of the heart. And what's fascinating about this is it's not just some haphazard proliferation of myocytes, but there's a regeneration program. Those findings really were amazing to us, because the question then becomes, why would you throw away such an ability. If you have such a program, why would you shut it off, but also shut it off permanently and not be able to activate it again, if you need it?

Whitten: Since that early discovery, Sadek's work has focused on identifying the mechanisms that allow regeneration of the heart in that very brief time window after birth. The hope is that by finding out what those factors are, they might be able to reawaken the process in adults. So far, they've identified two main changes that happen shortly after birth that they could target to turn regeneration back on. The first change is that after birth, the newborn’s heart must oxygenate its own blood for the first time, leading to a state of hyperoxia. All that extra oxygen is necessary to make energy that the active and growing body needs. To get the most bang for its buck, the heart quickly shifts from glycolysis, which breaks down glucose for energy, to fatty acid oxidation, which takes place in mitochondria and yields the most ATP. Simultaneously, the second change after birth involves a drastic increase in the mechanical load on the heart because the newborn needs to pump more blood throughout its growing body. This means the heart must make stronger muscle cells that can withstand more pressure. But these adjustments have consequences. They end up shutting down the ability for heart muscle cells to divide and regenerate into new muscle cells.

Sadek: The problem is that you start producing radicals from the mitochondria and those radicals can damage proteins, lipids, DNA, they can damage whatever. And so we start detecting evidence of DNA oxidation in myocyte nuclei. And then over time, you actually activate a cascade known as DNA damage response, or DDR.

Whitten: The DNA damage response protects a cell by repairing the damage and preventing the cell from dividing so that these mutations don't proliferate, like they do in cancer. 

Sadek: We found that DNA damage response is activated spontaneously in myocytes after birth. And if you scavenge radicals, you delay the expression of these markers. And mechanical load also initiates a cascade of differentiations. Our work in the past 12 or 13 years shown that if you interrupt one or more of these pathways, either the hyperoxia pathway, or the mechanical load pathway, and signaling molecules downstream of that, you can influence cell cycling of cardiomyocytes. 

Whitten: By changing the phase of the cell cycle, which is the process that regulates cell growth and division, cells can regenerate again, just like they could briefly after birth. Recently, Sadek's team identified two FDA approved drugs that target the mechanical load pathway by inhibiting the transcriptional activity of genes that are vital to early development. These drugs led to proliferation of cardiomyocytes, and thus, regeneration of the heart in rats, mice and pigs. Sadek hopes that these drugs could be effective in inducing heart regeneration in humans, too. 

This research also recently led to collaboration that Sadek never saw coming.

Jens Tank: My name is Jens Tank. I'm since 2017 in charge of the Cardiovascular Research Department at the German Aerospace Center located in Cologne in Germany.

Whitten: Tank's team got in touch with Sadek after reading a 2017 paper from his lab, where they put mice with heart damage in a hypoxic chamber with about the same amount of oxygen that's available on the top of Mount Everest. Surprisingly, Sadek and his colleagues showed that this setting could reduce the oxidative DNA damage and activate regeneration of heart muscle in the mice. Tank and his colleagues were intrigued.

Sadek: They said we read your paper, and we think we can do that in humans. And I said we didn't do that to be done in humans. I just wanted to show proof of concept that this oxygen makes a difference. They said, “Ah, don't worry about this. We do this all the time.” 

Whitten: The German Aerospace Center houses the largest hypoxic chamber in the world at 3,000 cubic meters of air. 

Tank: Maybe there is one bigger, but I don't know where it might be. Maybe some military guys may have one and we don't know about it.

Whitten: Tank's group has done several studies where they put professional mountaineers into the chamber for multiple weeks at a time to assess their heart function. To see whether they could translate Sadek's findings from mice to men, they found volunteers who had suffered a heart attack. These volunteers had low ejection fractions, which is a measure of heart failure. But other than that, they were very physically fit and capable of being at very high altitudes. 

Tank: Our hope was that after spending the time in the chamber, that this function of the heart gets better, which is a paradox because every cardiologist in the clinic would say, “Hey, man you are crazy, don't put my patient into hypoxia because probably it induce a new infarction.” But that was definitely not the case. All the patients did quite good after the two weeks. And we studied the one patient with the lowest ejection fraction even one year after the study, and he was still in a better shape.

Whitten: But unlike in Sadek's mouse study, they couldn't prove that these patients’ hearts had indeed regenerated.

Tank: We are not able to show anything. We had not the methods to do that in humans. We could not take out to heart and check if there are regenerating cardiomyocytes, but we were able to show it's possible to keep subjects close to their personal hypoxia tolerance limit for quite a long time, up to two weeks. And we see pretty much the same things like Hesham saw in his mice, and which is clearly hypoxia related. So everybody who can do that will switch on these so called hypoxia-induced factors, which is, at least according to Hesham's hypothesis, probably one of the keys that an increase of these hypoxia-induced factors turns on a high number of genes, up to several thousand genes. This mechanism is created to make the cell survive strong hypoxia levels, and it's only switched on if you are under these conditions.

Whitten: Based on the research in mice, the research team believes that putting the cell in this survival mode switches the heart back into metabolizing glucose, just like it does in that brief window of time after birth. But the work is still in its early stages, and putting patients into hypoxia to induce regeneration may only be feasible for a select few patients.

Sadek: The most important and exciting thing is that we think that the cell cycle arrest of myocytes is not really that brick wall that you can't break through. It is possible to manipulate the factors that cause myocytes to stop dividing to induce proliferation. We really haven't scratched the surface yet. But I will say from a conceptual standpoint, we are not at a stage that we were ten to fifteen years ago, where we say the adult heart cannot reactivate cell cycle. It can, if you push the right buttons. We are not there yet therapeutically, but I think we will be at some point.

Whitten: Another method that researchers are trying out to regenerate the heart centers around the pathway that controls how big organs grow. Jim Martin, a physician scientist at the Baylor College of Medicine and Texas Heart Institute has shown that the Hippo signaling pathway regulates the size of the heart in mice, and essentially acts as a signal to stop it from growing more.

Jim Martin: We showed in 2017 that you could experimentally give mice a heart attack, let them go into heart failure by waiting a number of weeks, and then take away the Hippo pathway after the heart was already sick. And then if you did that, the mice over a period of six weeks got better. The key point there was that by taking away the Hippo pathway, removing the stop signal, if you will, that the heart still has the capacity to recover and reverse its loss of function.

Whitten: Since then, Martin's team developed a reversible RNAi gene therapy that targets the Hippo pathway. So far, they've shown successful heart regeneration after heart attacks in pigs. A company called YAP Therapeutics is now licensing the technology from Baylor University and gearing up to start clinical trials within the next few years.

Finally, one last approach to heart regeneration that may be the closest of all to moving into the clinic is the use of stem cells. Murry has been working on this approach since biologists first converted human cells into pluripotent stem cells back in 2007. But in 2014, when his lab first used stem cells to regenerate the hearts of non-human primates, they ran into some trouble.

Murry: All hell broke loose electrically. We had a toxicity that we've come to call engraftment arrhythmia that we had never seen before. It made the hearts race, fast rates, 200-250 beats a minute and that's an unhealthy heart rate for a large animal and it certainly would be an unhealthy heart rate for a human being. And so, then we had to make a decision, are we going to push on to the clinic, or are we going to try to solve this toxicity before we go?

Whitten: It took years. But eventually, Murry's group found a way to fix the electrical activity going haywire in the heart.

Murry: We screened every drug known to humans, and we found two that seem to help quite a bit, not perfect, but help. One breaks the rhythm and the other slows the rhythm.

Whitten: Those two drugs are already FDA-approved. Taken together, amiodarone breaks the abnormal rhythm and ivabradine slows it down. Now, a company called HELP Therapeutics in China is using these two drugs in one of the first clinical trials testing stem cells to regenerate the heart. Murry's team also recently found another solution for the arrhythmia problem. In 2023, they published a paper in pigs that used gene modified cardiac muscle cells derived from stem cells that only fire when the cell next to them fires. This strategy also effectively got rid of the engraftment arrhythmia. Within the next two years, Murry plans to move their stem cell therapy to clinical trials and to use amiodarone and ivabradine to treat the arrhythmia. Then, if needed, they could use the gene modified cardiac cells as a backup.

Murry: It's an exciting time to be doing this science. I don't know whether I'll be the one. But I think we as a field, I think we're going to make this happen. And this is an area that's been stagnant in terms of drug development innovation. For decades, we haven't had to offer patients. I think we're on to some fundamental biological approaches that are going to change how cardiovascular medicine is practiced.

Whitten: That's it for this episode of DDN Dialogues. I'd like to thank Charles Murry, Hesham Sadek, Jens Tank, and Jim Martin for talking with me. And, thanks to all of you for listening.

DeMarco: Thank you, Allison, for that fantastic episode. Until next time, I'm your host, Stephanie DeMarco. This episode of DDN Dialogues was reported, written, and produced by Allison Whitten with additional audio editing by Jessica Smart and production support by me. To never miss an episode, subscribe to DDN Dialogues wherever you get your podcasts. And, if you like the show, please rate us five stars and leave a review on your favorite podcasting platform. If you'd like to get in touch, you can send me an email at sdemarco@drugdiscoverynews.com. 

And, maybe one day soon, a quick pop into a hypoxia chamber or a dose of stem cells will turn back the clock on heart failure, giving people many more years of a healthy life.