The Pig Heart Transplant Surgeon on What He Learned
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The Pig Heart Transplant Surgeon on What He Learned

An Interview with Bartley P. Griffith

Ileana L. Piña, MD, MPH; Bartley P. Griffith, MD

Disclosures

August 15, 2022

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This transcript has been edited for clarity.

Ileana L. Piña, MD, MPH: Hello. I'm Ileana Piña, professor of medicine at Thomas Jefferson University in Philadelphia. I am part of the heart failure transplant team and the chief quality officer. This is a more recent position for me.

I am absolutely thrilled to have with me Dr Bart Griffith, whom I've known for a long time, and his reputation precedes him as a superb cardiac surgeon transplant surgeon. He made the news this year with a xenotransplantation. Since I was in medical school, I've heard about xenotransplantation, but it's never been a reality. We've asked him to come here today. He is chair of cardiac surgery at the University of Maryland, where he has been for how many years now, Bart?

Bartley P. Griffith, MD: Some would say too many. More than 20 years.

Piña: That is where I first met him long ago. Welcome, Bart. Tell me, how long have you been thinking about a xenotransplant into a human?

Xenotransplant Hype and Hurdles

Griffith: I'm probably a good person to ask that question to because like many folks my age or just a little bit younger, I'm someone who looked at xenotransplant as one of those things that very few people have gotten into for many reasons. It seemed that over the decades, somebody would get very interested, go to the meetings wearing a necktie with a pig on it, give a couple of talks, and then they would be lost to follow-up. They'd lose funding or interest or there would be a hurdle.

I never really took it that seriously until about 7 years ago, when my now-partner Muhammad Mohiuddin, MBBS, moved from the National Institutes of Health (NIH) to join us at the University of Maryland in the research laboratory. He did so after having contributed significantly to the xeno field using a gene-edited animal and obtaining in the heterotopic, intra-abdominal, non–life sustaining model of the baboon greater than 3 years of survival without rejection.

He showed that the antirejection medication, which he helped to pioneer, in fact, was critical for that survival because when he stopped it after 3 years, those hearts stopped beating in the abdomen. It appeared that he had — I don't know whether it was luck or just a combination — got the right combination of immune suppression such that the hearts seemed to be regularly surviving well past a year. Again, these were nonstressed hearts; these were in the abdomen.

He was recruited to work with someone like me who knew how to work in a laboratory in a large animal model, and we converted his lessons to the intrathoracic, orthotopic heart transplant model. We struggled a little bit because the hearts kept going into this postimplant dysfunction. Chris McGregor, MB, MD, had termed this xenograft heart dysfunction postimplant, and he thought it was maybe related to calcium metabolism.

Well, it wasn't until our good friends in Munich were able to demonstrate, by way of a wonderful paper, 3-month survival in the nonhuman primate orthotopic position of the gene-edited pig heart that we cracked the secret. The secret was that if we put those pig hearts immediately on a nonischemic perfusion system... And in our case, we used that which the Germans had used, which was ex vivo, and has a lot of Steen solution and some blood and all kinds of stuff in there.

Basically, I don't think there's any magic, but it kept the heart nice and cool. It was a cool preservation and it had a perfusion pressure at the root of the aorta of about 20 mL, so not high pressure, just a nice gentle kind of flow through, and we were able to suddenly get excellent survival. Animals were extubated in a cage within 2 hours of coming off bypass. Then we took off. All of those frustrations in the past and very expensive modeling seemed like a distant past to us. We got routine survivals at 3 months, then 6 months, and now we're beginning to look at each other and say, "Wow, this is going to work."

Our sponsor, which was Revivicor, a subsidiary of United Therapeutics, was in the process of beginning to think about a US Food and Drug Administration (FDA)–sponsored new drug evaluation, a New Drug Application (NDA). We're not used to following the Investigational New Drugs (INDs) process for devices, but the gene-edited pig heart is considered a drug so it goes through that regulatory quagmire, if you wish. We were beginning to meet with the FDA for premeetings, so they had a portfolio of our outcomes. We knew it was going to be maybe 2 years before that multicenter trial might get launched — and more likely 3 years — based upon what we're hearing back about additional studies that needed to be done.

Dr Mohiuddin and I looked at each other and said, "What are we going to learn? We've learned a ton to this point. Once we get into that IND, we can't change anything." I think we're maxed out. Are we going to wait 3 years before we expose a patient to what we already think we know? Is there a group of patients that might be critically ill without option that we just might help? That's how we got to it. Sorry if that was long-winded.

Immunosuppression Protocols

Piña: I think that's perfect. My first question was about the immunosuppression protocols that he used at the NIH on the baboon. How different are they from what we use today with the mycophenolate and the steroids?

Griffith: It was surprisingly very similar. From my previous understandings of this work, it required radiation therapy and all kinds of intense immune suppression. Well, other than some early induction therapy with antithymocyte globulin (ATG) and rituximab to knock B cells down and T cells early, which is unusual for us in clinical work unless there's a high panel reactive antibody (PRA) or some kind of antibody-mediated issue or renal failure, and you want to be tacrolimus-avoiding.

Piña: We don't usually do that.

Griffith: Basically, other than that introduction, it looked like a pretty standard three-drug regimen. The odd part was that we avoided the use of tac, and the backbone of our therapy was an anti-CD40 antibody. Anti-CD40 attacks the receptor site of the B cell and it doesn't enable the B cell to activate when trying to be engaged by the T-cell population. It is very true that xenograft rejection likely is B-cell oriented, much more so than allo–T-cell business.

Piña: I would think so.

Griffith: The T cells are involved but much less so than they would be. The regimen was anti-CD40, a standard dose of mycophenolate mofetil (MMF), and then really quick-wean steroids.

Piña: You even weaned them quickly. That's interesting. The patient expired eventually. I know that you guys have looked at that graft very carefully. What did it look like?

Griffith: Well, it's remarkable, actually. I don't think you would believe it if you looked at it. I guess at 32 days, we did our first endomyocardial biopsy. He was bone marrow deficient and had a very low platelet count. We were very concerned to do biopsies.

Piña: Obviously.

Good Biopsy Then A Decline

Griffith: We were nervous that we might get into trouble because of the very low platelet count. We did an elective biopsy at 32 weeks because we couldn't stand waiting much longer. The scientific need to know...

Piña: Curiosity.

Griffith: We looked at it; it was perfectly normal. I ran around the hospital showing it. I took the slide, and I just showed it to everybody, not that there were microscopes around. I was so excited because it looked like an absolutely normal biopsy. There wasn't one inflammatory cell that we could find in the interstitium.

At that time, the heart was squeezing like a rock star. We had beautiful strain echoes, beautiful diastolic relaxation, good systolic function. Really, almost unbelievable, right? If I were to show you this, you would just shake your head in disbelief. That's a pig heart that's been in there a month. Are you kidding?

It was very unnerving, but exciting, too. We did get into more bone-marrow white-cell trouble. We had to drop the MMF out. We reduced the steroids very low. We were basically on monotherapy with anti-CD40 for a long period of time and we gave that regularly in order to keep the level at a point that we thought might be adequate — that drug had never been in a human. We were guessing from what our laboratory had told us. It was all guesstimating.

What happened, we believe, is one of three things. He got sick at about 45 days. He looked septic. His circulating immunoglobulin G (IgG) was very low, at around 170 mg/dL. I think it's supposed to be 1000 mg/dL, so it was supposed to be much higher than it was. I remember we were all sitting around on the weekend and saying, "Well, my goodness, that's not good. He's getting septic and he may not be here tomorrow." We gave him antibiotics, antifungals, antivirals, and then intravenous immunoglobulin (IVIG).

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