Circulation March 22, 2022 Issue

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.