Mar 21, 2022
This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening."
Dr. Carolyn Lam:
Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center in Duke National University of Singapore.
Dr. Greg Hundley:
And I'm, Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center, at VCU Health in Richmond, Virginia.
Dr. Greg Hundley:
Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic.
Dr. Greg Hundley:
But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first?
Dr. Carolyn Lam:
Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more.
Dr. Carolyn Lam:
But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance?
Dr. Carolyn Lam:
So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic.
Dr. Greg Hundley:
Really interesting results from this eMERGE III study, Carolyn. So what's the take home message?
Dr. Carolyn Lam:
As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation.
Dr. Carolyn Lam:
Huh. Nice. So what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation.
Dr. Carolyn Lam:
Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy.
Dr. Greg Hundley:
Ah, Carolyn. And so what did they find here?
Dr. Carolyn Lam:
So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home.
Dr. Carolyn Lam:
There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion.
Dr. Greg Hundley:
Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature.
Dr. Carolyn Lam:
Ah, a very interesting and important topic. So what, or how, did they do this, Greg?
Dr. Greg Hundley:
Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points
Dr. Carolyn Lam:
Okay, so what were the results?
Dr. Greg Hundley:
Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension.
Dr. Greg Hundley:
Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function.
Dr. Carolyn Lam:
Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making.” There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?”
Dr. Greg Hundley:
And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study.
Dr. Greg Hundley:
Well, now onto that perspective and discussion from two viewpoints on xenotransplantation.
Dr. Carolyn Lam:
Xenotransplantation. Cool. Let's go.
Dr. Greg Hundley:
Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both.
Dr. Greg Hundley:
And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient?
Dr. Josef Stehlik:
Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi.
Dr. Josef Stehlik:
The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again.
Dr. Greg Hundley:
Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual?
Dr. Maryjane Farr:
Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation.
Dr. Maryjane Farr:
Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility.
Dr. Maryjane Farr:
One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option.
Dr. Greg Hundley:
And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes?
Dr. Maryjane Farr:
This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery.
Dr. Maryjane Farr:
And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy.
Dr. Greg Hundley:
Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy?
Dr. Josef Stehlik:
Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned.
Dr. Josef Stehlik:
There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR.
Dr. Josef Stehlik:
Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant.
Dr. Josef Stehlik:
And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And pigs do have endogenous retroviruses that are parts of their genome, and those have been edited out as well. And so in this way, some of the previous obstacles have been removed.
Dr. Josef Stehlik:
So to your question, who might be a candidate? And I absolutely agree with Jane, that in the first step, it should really be patients who are not candidates for other clinically approved approaches, like allotransplantation from human donors, or mechanical assist, that can be durable, and those are the characteristics that the patient met. And I think, the next patients that will come now, hopefully, will probably be in the same category.
Dr. Josef Stehlik:
Now, I believe, and again, this is a little bit of a speculation, that the next step will be patients who are not eligible for transplant, but who may be eligible for durable ventricular assist devices. And our goal will be to show, that survival and quality of life after xenotransplantation can approach survival and quality of life, on LVADs. And of course, LVADs are evolving, as well.
Dr. Josef Stehlik:
And then, to some degree, it might be the choice of the recommendation of the team, of the multidisciplinary team. What is the best match for the patient? And to some degree, I think patient preference, to really share decision making in patient preference.
Dr. Josef Stehlik:
And in the next step, I believe, that's what we are hoping for, that at some point, we will achieve is that, xenotransplant will rival the outcomes of human allotransplantation. And so, that will be probably, the next group of patients. How long this will take is to be seen. But I think, that it addresses your question, who could be the candidates for xenotransplant in the future?
Dr. Greg Hundley:
Very good. And Jane, Josef was touching on a topic here. How do the anti-rejection treatments differ in xenotransplantation, as compared to allograft transplantation?
Dr. Maryjane Farr:
And so, that's been the thing for all these decades. And so, the first thing is, genetically engineered xenotransplant organs, that can mitigate some of the anticipated xenoantigenic responses.
Dr. Maryjane Farr:
So first, these carbohydrates that we do not see, so they are foreign to us, so there can be acute fulminant rejection. So that's, one step, and the gene knockout can take care of that mostly, but not completely. And then there's humeral rejection, and then, cellular rejection.
Dr. Maryjane Farr:
The cocktail that gets put together for a xenotransplant includes, some of the things that we standardly use, like steroids, ATGAM, or antithymocyte globulin, which is a generalized T and B-cell depleting therapy. What's nuanced, and there's also some role for anti-CD20 B-cell therapy, but what it is nuanced in xenotransplant is anti-CD40 monoclonal antibody therapy. And that was specifically developed, and then studied in heterotopics, or non-human primate pig transplant. Because what turns out is that, the robust T-cell responses, by what's called the indirect pathway, really requires significant costimulatory blockade, where anti-CD40 therapy has been critically important, and well studied by these scientists and others at the University of Maryland, and elsewhere.
Dr. Maryjane Farr:
And as I understand it, anti-CD40 was really, is the basis, the backbone, of this therapy. And then there's one last thing. And that is, temsirolimus, which is a pro drug of proliferation signal inhibitor therapy, that we standardly use in transplant. That's utilized to arrest the further growth of the xenotransplant. So that sounds like it's the cocktail, and there's some published reports, on these scientists using just such cocktail in their non-human primate transplant models.
Dr. Greg Hundley:
Well, listeners, we've heard a really interesting story here. But now, let's ask these experts, first, Josef, and then, Jane. Josef, moving forward, what are the concerns that you really see in this aspect of research?
Dr. Josef Stehlik:
Greg, I think, one of the issues that will have to be addressed, are ethical considerations. And we've seen, that after the news of xenotransplant was made public, there has been a lot of discussion among public about ethics of xenotransplant. I think it will be important to really proactively address that.
Dr. Josef Stehlik:
One aspect from the past is, we knew that primate xenotransplant have not been embraced by the public, just because of the closeness of primates to humans. I think, some of that will be mitigated, now that we are using pigs. But of course, there are many who feel strongly about humane treatment of animals. And so I think, regulation will need to be established that will address that, and that will make both the professionals and the wary public, comfortable with this approach.
Dr. Josef Stehlik:
And another thing that will need to be addressed, and Jane talked about it a little bit is, what parts of care for xenotransplant will be different from human allotransplant. Right? So how do the assessment of the biopsies differ? Right? We'll probably have a new grading scheme looking at xenotransplant. Should the antimicrobial prophylaxis be different? So we do prevent the possibility of trans-species infections we haven't seen before, et cetera. So there would be a lot of work for the transplant teams to do, as well.
Dr. Greg Hundley:
And, Jane.
Dr. Maryjane Farr:
Yes. One thing that's hard, this is amazing science, and this is a huge opportunity to transplant more patients, many of whom die on the wait list every year. But what really needs to be understood also, as we move into this area, and this is where us, as clinicians, get involved in some of these conversations in particular, is that this patient actually wasn't eligible for transplant. And these are very, very difficult decisions that centers are tasked to make.
Dr. Maryjane Farr:
It can get really tricky, and there's lots of patients who say, "Okay, I'm not a transplant candidate.", because of this or that, or the other reason. And there's, some reasons that are more important than others. They'll say, "Transplant me anyway. Give me a heart that you might turn down. Just give me a chance." And we don't do that. And insurance companies don't pay for that. And we have to actually find a way to be rational in our approach.
Dr. Maryjane Farr:
But truly, acknowledging that, if we had more resources, we could probably expand transplant even with the organs that we do have, because we turn down about, probably about 40% of organs, and maybe even more, every year, because we want to match the best organs. So it's really important that xenotransplant, in centers that can do this, demonstrate that this therapy works, and it provides a good quality and quantity of life, for at least, to be reasonable. And once you get there, then you can start to talk about, whether you need to think about allocation, and all that. So you can see how the conversation's going to go on for the next 10 years, about how this fits in.
Dr. Greg Hundley:
You both alluded to the fact, we need more research. And so, incrementally, for maybe each of you in 30 seconds. What do you see as the next research study that needs to be performed in this space? First, Josef, and then again, Jane.
Dr. Josef Stehlik:
That's a tough question, but I'll try to address it. I think, it will be a little bit in parallel to the first human allotransplant. Now that we've figured out the procedure and the organ that we can use, I think, it will be research focused on the care of the transplant recipient. And the task, number one, will be to identify immunosuppression that will be safe and effective, to protect this heart from dysfunction for many years after transplant.
Dr. Greg Hundley:
And Jane?
Dr. Maryjane Farr:
Yeah. You need to do a case series. The handful of centers in this country, and maybe the world, but I only know about this country, that have been studying and working towards this day, should take the lead. University of Maryland has taken the lead, and there are other centers who have been thinking hard about this, and preparing for this time for a long time, and they should lead the way, and try to do this with all the expertise that they've already built. And then as time passes, we can see what their outcomes are, and then we can start to think about, should there be a randomized controlled clinical trial? What should we compare it against? Who should be offered the opportunity? But at first, we need to find that there's safety and efficacy in the patients that are selected, and also, they themselves select, to go through this operation and therapy.
Dr. Greg Hundley:
Well listeners, we want to thank Dr. Jane Farr and Dr. Josef Stehlik, for providing their perspective on a recent procedure, involving the xenotransplantation of a genetically engineered porcine heart, into a human subject with advanced biventricular heart failure, that was not well suited for human heart allograft transplantation.
Dr. Greg Hundley:
Well, on behalf of Carolyn and myself, we want to wish you a great week, and we will catch you next week On the Run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2022. The opinions expressed by speakers in this podcast are their own, and not necessarily, those of the editors, or of the American Heart Association. For more, please visit ahajournals.org.