Pig heart transplant failed as its heart muscle cells died(arstechnica.com)
arstechnica.com
Pig heart transplant failed as its heart muscle cells died
https://arstechnica.com/science/2022/06/pig-heart-transplant-failed-as-its-heart-muscle-cells-died/
98 comments
I'd be very curious to see what the glucose/lactic acid curve looked like during and after the transplant! Usually it's a good leading indicator of broader issues. We've done a few studies in swine (they're the gold standard of blood sugar modelling) and if an animal was not doing well, we'd always see a spike in lactic acid right before death.
Given that pig heart transplants are only a candidate for people that are a really bad shape, how does your friend see this field advance after this current result?
The idea is that right now, this is only for people in really bad shape, but with advances and experience, this may become a more standard thing for people in less bad shape.
You first try the new, experimental drug on people who may die soon anyways, before you hand it out like smarties at the local drugstore.
You first try the new, experimental drug on people who may die soon anyways, before you hand it out like smarties at the local drugstore.
Still have to get through that stage though with some good results to show for it, even if we suspect healthy bodies would handle it much better (although I wouldn't personally lose faith based on one instance)
Seven weeks with no sign of immune rejection is a good result here, for the very first attempt. It's largely what they would have been hoping for.
The number of people working on xenotransplantation in the world is very small. My mom (https://tts.org/74-ixa/889-ixa-in-memoriam-agnes-marie-azimz...) was part of the group who conducted basic research in xeno at the University of Maryland and established the collaboration to start testing Revivicor's genetically modified pigs, before her lab (https://www.massgeneral.org/transplant/cts/research/pierson-...) moved to Boston a few years ago.
The international xenotransplantation community found out about David Bennett's heart transplant through the news, and some people feel as though competition between groups may have contributed to a lack of sharing of clinically relevant information that could have benefited Mr. Bennett.
The international xenotransplantation community found out about David Bennett's heart transplant through the news, and some people feel as though competition between groups may have contributed to a lack of sharing of clinically relevant information that could have benefited Mr. Bennett.
Do you maybe know if they just wanted to check if it will work for some time or hoped that failing organs may benefit from new heart?
The point is that his heart failed, not some other organ, and while it was functional for a time, the surgeons had stated that it would be functional for longer.
While you can soften the failure by highlighting the patient's broad systemic issues, this is still a notable failure that will likely put a damper on future similar pig transplants.
While you can soften the failure by highlighting the patient's broad systemic issues, this is still a notable failure that will likely put a damper on future similar pig transplants.
The first human to human heart transplant failed even sooner and was considered wildly successful. Edit: Even though the immunosuppressants ended up killing him.
7 weeks doesn’t sound like long, but a great many things needed to work for the patient to survive even 1 week.
7 weeks doesn’t sound like long, but a great many things needed to work for the patient to survive even 1 week.
I just looked to fact check this, and all the sources I can find says the patient died of pneumonia, not heart failure and that the heart didn't fail and continued to work up until death.
So no, the first transplant didn't "fail even sooner" because it wasn't the heart that failed.
So no, the first transplant didn't "fail even sooner" because it wasn't the heart that failed.
Very different contexts.
Before human heart transplantation was available, you could pick someone with severe heart disease but otherwise in good condition as a test candidate. It was entirely ethical; they'd die without the transplant anyways.
Now that we have viable human heart transplantation, you have to pick sicker patients as candidates - people who wouldn't survive even if they got a human heart transplant. Giving someone who'd survive with a human heart an experimental pig heart isn't ethical.
It makes sense that the failure model would be different.
Before human heart transplantation was available, you could pick someone with severe heart disease but otherwise in good condition as a test candidate. It was entirely ethical; they'd die without the transplant anyways.
Now that we have viable human heart transplantation, you have to pick sicker patients as candidates - people who wouldn't survive even if they got a human heart transplant. Giving someone who'd survive with a human heart an experimental pig heart isn't ethical.
It makes sense that the failure model would be different.
Is there no shortage of human hearts to transplant? Don't you have people who would live with a human heart transplant, but where the risk of waiting a short period of time for a pig heart transplant is about the same as the risk of waiting a long period of time for a human heart transplant?
I mean if we do have enough human hearts to transplant into anyone who needs it I suppose that's a good thing, but all I hear about transplants is how long the wait times usually are for human organs.
I mean if we do have enough human hearts to transplant into anyone who needs it I suppose that's a good thing, but all I hear about transplants is how long the wait times usually are for human organs.
The shortage means the people likely to survive longest after transplant get preferential treatment.
Which means if someone has stage 4 cancer etc they aren’t on the list.
Which means if someone has stage 4 cancer etc they aren’t on the list.
The heart didn’t directly fail, however the procedure failed due to the immunosuppressants used.
“After Washkansky’s surgery, he was given drugs to suppress his immune system and keep his body from rejecting the heart. These drugs also left him susceptible to sickness, however, and 18 days later he died from double pneumonia.”
“After Washkansky’s surgery, he was given drugs to suppress his immune system and keep his body from rejecting the heart. These drugs also left him susceptible to sickness, however, and 18 days later he died from double pneumonia.”
Why would the failure of one extremely experimental transplant put a damper on subsequent extremely experimental transplants?
Is the idea that they should have it all worked out before they even try it?
Is the idea that they should have it all worked out before they even try it?
It’s because they don’t know why the heart muscles died.
And if they come up with a theory that they can test with another procedure?
Ideally, yes? I mean it would be strictly better. I’m not saying they shouldn’t try even though they don’t.
That's why it's called an experimental treatment, and is why you only try it out on people who will certainly die if only treated in more conventional ways. You can't possibly have everything worked out before you try an experimental treatment by it's very definition. It's inherently risky, but it's also a very important way in which medical science is advanced.
Did they try it on other primates first?
> that will likely put a damper on future similar pig transplants
I should hope not. Not everything works first time. Hopefully it gives data such that the next one works for 16 weeks, and the one after that for 3 months, until this is a standard source of transplant organs.
I should hope not. Not everything works first time. Hopefully it gives data such that the next one works for 16 weeks, and the one after that for 3 months, until this is a standard source of transplant organs.
Ah well, if you’ll likely die tomorrow then even 7 weeks is pretty good.
Not sure that’s a good trade for the pig though.
Not sure that’s a good trade for the pig though.
Good question. Maybe not, maybe actually yes. Using animals for transplants gives place for all kind of discussions. But this pig only existed as it was raised for that purpose. Like basically all pigs, which are raised for meat production. In contrast to those, the pig in question was probably well raised in good conditions and fed quality food and no bad pharmaceuticals.
And indeed, humans use many animals, a lot of that use involves their deaths. But here it at least isn't for some random food, and a lot of meat just goes waste, but to keep a human alive. That is at least a very good reason.
It’s very easy to sympathize with the pig. But, if a doctor came into the room and said “a pig or your daughter” what would anyone say?
For the humans. I very much doubt the pig sees it that way (or would see it that way, if they were human).
Don’t misunderstand me, I love meat, and while I think that killing pigs (at least someone else killing pigs) is acceptable for that purpose, I would have a harder time justifying killing a whole pig to keep someone alive a little longer. For the same reasons we don’t just raise humans as cattle to use as organ transplant sources. We tell ourselves that it is acceptable with pigs, and while this certainly makes it easier on the humans (and they grow faster), I’m not sure it’s fundamentally different.
Don’t misunderstand me, I love meat, and while I think that killing pigs (at least someone else killing pigs) is acceptable for that purpose, I would have a harder time justifying killing a whole pig to keep someone alive a little longer. For the same reasons we don’t just raise humans as cattle to use as organ transplant sources. We tell ourselves that it is acceptable with pigs, and while this certainly makes it easier on the humans (and they grow faster), I’m not sure it’s fundamentally different.
Isn't killing a pig for meat technically "killing a whole pig to keep someone alive a little longer" too?
I'm a little baffled by your ethical calculus here. Raising pigs for muscle to eat seems substantially less ethical than raising pigs for organs to transplant; you can eat plant-based alternatives, but good luck pumping blood with a soybean.
I'm a little baffled by your ethical calculus here. Raising pigs for muscle to eat seems substantially less ethical than raising pigs for organs to transplant; you can eat plant-based alternatives, but good luck pumping blood with a soybean.
I don't understand how killing pigs for meat to eat to survive is different than killing pigs for a heart to implant to survive.
What if there were humans who only existed because they were bred and raised for organ transplant? It wouldn't surprise me if this already exists.
The human body is a system, I'm not a physiologist so I don't fully understand everything. That being said, if organs which normally supply some sort of supportive function to the heart no longer work, it's definitely possible for the heart to fail first. The heart is a mechanical pump remember, easy for it to fail
You're being wildly pessimistic.
The first human heart transplant was successful for a little less than three weeks, until the patient died of systemic organ failure. That procedure is historically regarded as wildly successful.
A team of medical scientists did something even more amazing. This procedure was a success. The next one will be better.
The first human heart transplant was successful for a little less than three weeks, until the patient died of systemic organ failure. That procedure is historically regarded as wildly successful.
A team of medical scientists did something even more amazing. This procedure was a success. The next one will be better.
I think so too. I wonder if they are considering editing more genes to make the heart more human. I bet 100 years from now, there will genetically modified pigs running around with human hearts, and other modifications to support that heart.
His heart was failing for some reason(s). I don't see how transplant would ever make those go away, at best it would only buy him some time allowing those reasons to be removed. In some lucky cases, those do get removed automatically but I would expect in most of the cases, they would be left intact and will eventually cause heart to fail again soon. This does not even consider the immune system reactions, taking those into consideration, the chance would be very little.
If the reason is a faulty heart, replacing the heart makes the reason go away.
At this point in order to be a candidate for such a risky/previously untested procedure, doesn't the person need to be in an absolute worst case scenario, where they've been rejected for all forms of human heart or artificial transplant and highly likely to die soon?
That's exactly the situation he was in.
Huh? He was.
So then, if it does not work in those conditions, what’s the point?
It may have extended life even in this first time. And now we have a bunch of data to try and identify what exactly went wrong.
We can try a couple a year, steadily improving until we ultimately get lucky and someone's life is significantly extended.
We can try a couple a year, steadily improving until we ultimately get lucky and someone's life is significantly extended.
He was going to die without this. It would have been immoral to give him a human donor heart that could have gone to someone who could have lived ten or more years with it. Every pig heart transplant they’ll get better at it until eventually if you need a heart transplant you’ll just get one.
That’s the point.
That’s the point.
It allows you to test the heart in a human patient without worsening their prognosis.
Validating that it's possible allows for carefully expanding to the patients not undergoing massive multi-system organ failure at the time.
Validating that it's possible allows for carefully expanding to the patients not undergoing massive multi-system organ failure at the time.
What I take from your question is, were the other health issues the thing that actually killed the heart? Following from that, how can we declare something not successful when the odds are significantly stacked against it from the start?
What made the patient so unwell? I can't access the original paper.
[edit]
A 57-year-old man with chronic mild thrombocytopenia, hypertension, nonischemic cardiomyopathy, and previous mitral valve repair was hospitalized for severe heart failure with a left ventricular ejection fraction (LVEF) of 10%. His care was escalated to include multiple intravenous inotropic agents, and the placement of an intraaortic balloon pump was added on hospital day 11. Despite these measures, he had multiple ventricular arrythmias with arrests leading to resuscitation and began to receive peripheral venoarterial extracorporeal membrane oxygenation (ECMO) on hospital day 23.
Sad.
[edit]
A 57-year-old man with chronic mild thrombocytopenia, hypertension, nonischemic cardiomyopathy, and previous mitral valve repair was hospitalized for severe heart failure with a left ventricular ejection fraction (LVEF) of 10%. His care was escalated to include multiple intravenous inotropic agents, and the placement of an intraaortic balloon pump was added on hospital day 11. Despite these measures, he had multiple ventricular arrythmias with arrests leading to resuscitation and began to receive peripheral venoarterial extracorporeal membrane oxygenation (ECMO) on hospital day 23.
Sad.
That was before the transplant. Things were arguably a bit better for 7 weeks afterwards.
Isn't there a risk of introducing new zoonotic diseases?
Very much - hence why the pig is "raised in conditions that should limit pathogen exposure" and the multiple virus tests on both the heart and the patient before and after the transplant. And even then they missed one pig virus.
Maybe
> The presence of an apparent pig cytomegalovirus was worrying, but the researchers indicate there's some question about whether the tests that picked it up might have been recognizing a closely related human virus—one that's often associated with organ transplant problems.
> The presence of an apparent pig cytomegalovirus was worrying, but the researchers indicate there's some question about whether the tests that picked it up might have been recognizing a closely related human virus—one that's often associated with organ transplant problems.
>raised in conditions that should limit pathogen exposure
Except the pig still got porcine CMV from somewhere.
Except the pig still got porcine CMV from somewhere.
Maybe.
> the researchers indicate there's some question about whether the tests that picked it up might have been recognizing a closely related human virus
> the researchers indicate there's some question about whether the tests that picked it up might have been recognizing a closely related human virus
Yes - the risk is substantially higher because blood flow will allow a virus to move from one tissue type to the other very efficiently repeatedly, and immune response is reduced but not eliminated allowing rapid adaption.
As a society we need to think about the ethics implications of using this technique to save some lives while dramatically increasing the risk of zoonotic viruses which will impact many others.
As a society we need to think about the ethics implications of using this technique to save some lives while dramatically increasing the risk of zoonotic viruses which will impact many others.
labtheory(1)
But the reason for that death isn't clear, and the typical signs of rejection by the immune system weren't present.
Perhaps because it involved a pig heart, not a human heart? If this is new territory, I see no reason to expect failure to follow "typical" patterns.
Perhaps because it involved a pig heart, not a human heart? If this is new territory, I see no reason to expect failure to follow "typical" patterns.
Transplantation of organs from animals into humans has been tried in the past. Because of that, we know what full on rejection of non-human organs looks like.
It sounds like this was actually quite successful in that the immune system didn’t immediately start attacking it, as would be the case with a normal pig heart.
It sounds like this was actually quite successful in that the immune system didn’t immediately start attacking it, as would be the case with a normal pig heart.
That’s a great thought, however, when you look at tissue under a microscope you should see evidence that the immune system was at play. This means the presence of complement activation (an ancient arm of the immune system), antibodies, white blood cells, nuclear debris, and so on. Presumably when they saw no evidence of immune mediated rejection, they saw none of this.
My lay person understanding as someone with a condition where people get a lot of transplants is that we don't actually know what causes rejection.
Perhaps in some cases the organ contains unidentified infective agents, thus the typical pattern with white blood cells etc.
Perhaps in this case the body decided it was straight up foreign matter and the process of failure was fundamentally different.
Perhaps in some cases the organ contains unidentified infective agents, thus the typical pattern with white blood cells etc.
Perhaps in this case the body decided it was straight up foreign matter and the process of failure was fundamentally different.
Your point that this is uncharted territory is well-taken, we can't say for sure, but the above poster has it right. I do not know of any circumstance in medicine in which evidence of immune reaction against foreign material would be non-obvious. I'm a pathologist and this is my area of expertise.
To be clear, I have two points:
1. This is uncharted territory.
2. My understanding is we don't actually understand "normal" rejection all that well to begin with.
If we don't know how and why rejection occurs to begin with, we have no reasonable means to distinguish it from some other type of failure.
But I shall stop annoying professionals with my amateur opinions here.
Have a good day.
1. This is uncharted territory.
2. My understanding is we don't actually understand "normal" rejection all that well to begin with.
If we don't know how and why rejection occurs to begin with, we have no reasonable means to distinguish it from some other type of failure.
But I shall stop annoying professionals with my amateur opinions here.
Have a good day.
We may not know what causes rejection, but are pretty good at seeing the signs of it. Extreme example: if a house collapses, you may not know immediately why it collapsed, but all the debris on the ground is a pretty good sign it's not in one piece anymore.
Rejection leads to death.
The guy died.
Anyway, trying to walk away from this particular thread.
The guy died.
Anyway, trying to walk away from this particular thread.
What kind of logic is that? Ok here:
"We don't see signs that this person was shot in the head"
DoreenMichele: Getting shot in the head leads to death. The guy died.
"We don't see signs that this person was shot in the head"
DoreenMichele: Getting shot in the head leads to death. The guy died.
[deleted]
What if it's something like the human blood cells stop delivering oxygen and nutrients to those tissues for one reason or another?
The heart is fundamentally a pump. Are we not able to build a replacement? I understand it’s not simple at all, and that people have tried and failed in the past, but is an artificial heart something that we should be able to build?
It might be a significantly hard problem: for instance, artificial heart valves tend to get infected by bacteria, and if it were the case for a whole artificial heart to get infected, perhaps it could spread and cause damage to the mediastinum (or), maybe, sepsis.
Significantly, the body does a poor job of fighting infection that occurs in artificial heart valves.
Why?
From what I have read, artificial heart valves, being artificial, are simply not really covered by the immune system. In other words, you get white blood cells to the point of infection because you have blood supply and mechanical parts don't have blood vessels running through them.
It's foreign matter, not really part of a living body.
Very likely, they probably also attract infections that like eating plastics and such. These are inherently hard for the human body to combat if they get traction, from what I gather. They aren't a normal infection in humans and tend to be deadly when they do take root.
It's foreign matter, not really part of a living body.
Very likely, they probably also attract infections that like eating plastics and such. These are inherently hard for the human body to combat if they get traction, from what I gather. They aren't a normal infection in humans and tend to be deadly when they do take root.
IIRC, the problem with conventional mechanical pumps is that they're continuous-flow. Various other systems in the human body rely in the ebb-and-flow of a pumping heart to function correctly, and different activities require different flow speeds. Yes, we can probably engineer a variflow pump as well, and maybe also one that increases and decreases its flow based on hormonal signaling, but it's not as simple as taking your average aquarium pump and connecting it in-place. AFAIK, we have no idea how the heart determines its flow rate.
I was under the impression there were implantable impeller style pumps that people used to replace the heart while waiting for a transplant.
They don't replace, they assist. Longest one has lasted is seven years. https://en.wikipedia.org/wiki/Ventricular_assist_device
Artificial hearts already exist. But they usually are only used while waiting for transplants, because they're not as good as the real deal.
Hearts are critical infrastructure in the body, with 100% uptime requirements and not-insignificant energy consumption.
Hearts are critical infrastructure in the body, with 100% uptime requirements and not-insignificant energy consumption.
Carmat has been working on it for a few decades. I believe they have not been approved yet by the FDA but are in the clinical trials phase.
https://www.carmatsa.com/en/
https://www.carmatsa.com/en/
Artificial hearts have existed for years but require an external power source to operate the pump. They can generally only be used for a limited time while waiting for a transplant.
https://syncardia.com/clinicians/our-products/freedom-portab...
https://syncardia.com/clinicians/our-products/freedom-portab...
I just love that there is an H&E slide on article cover of Ars
So completely reliable virus testing there because we now from the last 2 years that's 100% reliable. Clearly did a full genomic sequencing...
u1tron(1)
Transplanting organs is an amazing feat of science.
However, how does it make any financial sense? This one of those things that makes sense to cut when you start talking universal healthcare, right?
However, how does it make any financial sense? This one of those things that makes sense to cut when you start talking universal healthcare, right?
Transplants exist in all universal healthcare systems around the world. Due to the scarcity of donor organs and the cost, candidates for transplantation are heavily scrutinized to make sure the organ is used in the best way possible.
In relation to this article, part of the genetic engineering of the pig is to try to not just have a human not reject it, but possibly to end up having the pig heart be less likely to reject than a human heart.
If the chance of rejection can be reduced, that means fewer drugs over time, and lower cost to a universal healthcare system.
Also, reliable transplantation would reduce long term traditional healthcare costs. For example, in the US dialysis is basically the one procedure with universal healthcare. If kidney transplantation was readily available with a low risk of rejection it could actually save the US a lot of money at this point.
In relation to this article, part of the genetic engineering of the pig is to try to not just have a human not reject it, but possibly to end up having the pig heart be less likely to reject than a human heart.
If the chance of rejection can be reduced, that means fewer drugs over time, and lower cost to a universal healthcare system.
Also, reliable transplantation would reduce long term traditional healthcare costs. For example, in the US dialysis is basically the one procedure with universal healthcare. If kidney transplantation was readily available with a low risk of rejection it could actually save the US a lot of money at this point.
There are a lot of surgeries and novel treatments that don’t make any financial sense. We don’t make healthcare decisions on a P&L basis, but hopefully on some kind of cost vs expected benefit to the patient basis.
Transplanting a kidney or liver into a 20 year old has more of my support than transplanting a heart into an 85 year old.
Transplanting a kidney or liver into a 20 year old has more of my support than transplanting a heart into an 85 year old.
Modern eye surgery exists because a few adventurous soldiers who had glass shards in their eyes let doctors experiment on them, same for gender affirming surgery. Originally it was done to reconstruct war wounds. We’ve always had science that existed on the bleeding edge and at the time only benefited a few people, but it’s our own ingenuity that brings these advances to a broader market and to benefit more people. There will always be a small amount of people willing to pay or be lab rats to squeeze an ounce of life or happiness out of their existence, socialized health care or not, and there will be those who recognize a way to expand that experiment into something safe and broadly acceptable.
The financial sense comes down to how you are measuring the value provided, there's not a single objective way to do it.
Systems that use QALYs still often end up considering organ transplants a viable treatment.
Systems that use QALYs still often end up considering organ transplants a viable treatment.
People suffer accidents, and in absence of donation, perfectly fine organs would just rot with them in the grave. With transplants, we take these organs that would otherwise be wasted, and give other people maybe years or decades of additional productive life. The overall economic impact must be overwhelmingly positive to society as a whole.
According to the web site Transplant Living, created by the United Network for Organ Sharing, the average total cost for the first year for a double lung transplant costs $657,800.
And then you take immunosuppressive drugs the rest of your life.
https://www.chron.com/neighborhood/katy/news/article/The-cos...
Also, bear in mind the FTA is about an artificially engineered pig heart, not a human heart.
And then you take immunosuppressive drugs the rest of your life.
https://www.chron.com/neighborhood/katy/news/article/The-cos...
Also, bear in mind the FTA is about an artificially engineered pig heart, not a human heart.
It makes for razzle dazzle headlines. That seems to keep it alive.
I wish there was more emphasis on helping people keep their original equipment from the manufacturer, so to speak.
I wish there was more emphasis on helping people keep their original equipment from the manufacturer, so to speak.
I'm not a medical professional. But I have been present and watched multiple people of systemic failures.