June 27, 2025 • 29 mins
This week we speak with congenital heart surgeon T. Konrad Rajab of Arkansas Children's Hospital about a recent report he co-authored on piglet experiments on partial heart transplantation. How did transplanted heart valves grow in comparison to standard homografts and how did the valvular function differ with time? Is there a minimum dose of immunosuppresion that can protect these valves and can this dose be lower than full heart transplantation immunosuppresion therapy? Is partial heart transplantation considered a potential life-long approach to valve replacement or mostly something used to allow for growth of valves during childhood? What do we know about the world's limited experience in humans of this approach? Dr. Rajab shares the answers this week in an exciting 'sci-fi' episode. The future is now.
https://doi.org/10.1016/j.jacbts.2024.10.015
https://doi.org/10.1016/j.jacbts.2024.10.015
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:16):
Welcome to Pdheart Pediatric Cardiology today. My name is doctor
Robert Pass and I'm the host of this podcast. I
am Professor of Pediatrics at the Icon School of Medicine
at Mount Sinai, where I'm also the chief of Pediatric
Cardiology and the co director of the Children's Heart Center.
Thank you very much for joining me for this three
hundred and forty sixth episode of Pdheart. I hope all
enjoyed last week's episode on the topic of the outcomes
(00:38):
of neonatal heart surgery in Europe. For those of you
interested in congenital heart surgery, I'd certainly recommend you to
take a listen to last week's episode three hundred and
forty five. As I say most weeks, if you'd like
to get in touch with me, my email is easy
to remember. It's Pdheart at gmail dot com. This week
we move onto the world of congenital heart disease and
cardiac transplantation. This week's article is a letter and it's
(01:02):
entitled partial heart transplant growth and Hemodynamic Function in Piglets.
The first author is Lilian Kang and the senior author
is Taufik k Rajab, and the authors come to us
from Arkansas Children's Hospital in Little Rock, Arkansas. When we're
done reviewing this brief letter to the editor, we'll be
speaking with the work's senior author, doctor T. Conrad Rajab. Therefore,
(01:25):
let's move straight on to this brief discussion of the article,
then a conversation with its senior author. This week's work
is a brief research letter on the topic of partial
heart transplantation, which is when we've discussed previously back in
episode two hundred and thirty six in early twenty twenty three.
The authors of this work, one of whom is the
same author, doctor Rajab, start by explaining that the pulmonary
(01:46):
valve of an infant is smaller than any bioprosthesis that
presently exists, and for this reason, when the pulmonary valve
needs to be replaced, a homograph is used, but that
these cataveric prostheses have no viable cells and so are
unable to grow, and so when a surgeon chooses to
place a homograph, they know that this will effectively commit
the patient to serial valve replacements until in adult sized
(02:09):
processes can be used. They then review the main rationale
for a partial heart transplant, which is that these valves
in transplanted hearts grow, and they review how just transplanting
a valve rather than the valve and the heart muscle itself,
may eliminate graph dysfunction from rejection. Though there are a
few case reports of these valves growing, The authors endeavor
(02:30):
to study this hypothesis of valvular growth by comparing pulmonary
valve replacements with homographs and partial heart transplants in infant piglets.
The authors explain and for the partial heart transplant piglets,
there were three donors and three recipients that were ABO
matched and two piglets that were wild type. Donor piglets
donated the pulmonary valve root and blood to prime the
(02:52):
cardiopulmonary bypass circuit. The recipient piglets had induction immunotherapy with
oral tacri limits at zero point zero five milligrants kilogram
and micofhenylate A twenty milligrams perkilo, and they underwent surgical PVR.
Methyl prednisilone a ten miligrams perkilo was given before the
graft was reprofused. Following surgery, the partial heart transplant recipients
(03:13):
were aminosuppressed with tacrolimus t traded to a trough level
of five to ten nanograms per millileter and micofhenylate ten
milligrams pekilo two times a day, and prednisolone was tapered
ultimately to zero point five milligrams per kilogram bid for
homograph recipient donors. There were three donors and three recipients
and they were not ABO matched. The donor pulmonary valve
(03:36):
root was cryo preserved for at least one month, and
then the pulmonary valve replacement was performed on bypass as usual,
and the cardiopulmonary bypass circuits were primed with blood from
the ABO matched blood donor piglets. No imminosuppression was given
to the piglets that received homographs following surgery. The recipients
had serial ecocrdigrams and for this study, the primary outcome
(03:57):
was pulmonary valve gradient and secondary outcomes were pulmonary valve regrigetation,
pulmonary valve annular dimension, and aortic valve anulist dimension. The
experiment was considered to end when the weight of the
subjects had doubled from the time of surgery. The investigators
also used green fluorescent protein visualization since the donors expressed
this protein, and the valves were examined both macroscopically and microscopically.
(04:22):
And so what did the investigators see? First, the homograph
recipients were demonstrated to show increase ingradients that developed rapidly
in contrast to the partial heart transplant recipients who did
not have such a change, and the difference was highly significant.
In regards to pulmonary valve regrigetation, no partial heart piglet
had more than physiological regurgitation, and in the homographs, two
(04:45):
had no more than physiological regurgetation and one mild regurgitation.
And what about pulmonary valve annular growth, Well, it turns
out both increased in diameter, but the increase was significantly
faster in the partial heart transplant piglets than a those
receiving homographs. But there was no difference in growth rates
of the aortic valves. Finally, when the authors looked under
(05:07):
fluorescence testing, the grown partial heart transplant piglets remained positive
for the donor green fluorescent proteins and had normal macro
and microscopic morphology in their concluding comments, the authors state,
and I quote, this study contributes preclinical evidence to support
the use of partial heart transplants over homographs for valve
(05:28):
replacement in infants, as recipients more than double their weight,
partial heart transplants demonstrated stable valve gradients and adaptive valve growth.
The grown partial heart transplants remained GFP positive, which confirmed
the presence of donor cells and had normal morphology, and
the authors contrasted this to the homograph patients who had
(05:49):
rapid increases in homograph conduit gradients. And they also spoke
of the growth seen in annuli in the homographs and
wondered if this might be due to dilation rather than growth.
The authors conclude by stating, and I quote, these findings
are clinically relevant because partial heart transplants can eliminate the
need for serial valve replacements during childhood. Though once again
(06:11):
we're reviewing another of these studies on partial heart transplantation,
and again by one of its pioneers, doctor Rajab, it's
certainly of interest to see that these transplanted valves are
growing with time, much as we have seen in full
cardiac transplantation. I wonder if the degree or the requirement
of rejection prophylaxis is as high, or if that has
(06:31):
even been studied in patients undergoing a partial heart transplant. Clearly,
if the doses of anti rejection therapies could be lower
than are common for full heart transplants, one would think
that this would be a major plus for avoidance of
possible opportunistic infections or cancers that are rarely seen in
transplant patients associated with this type of therapy. I also
(06:53):
wonder if doctor Raja believes that this is a potential
lifelong approach or if he sees us more as a
bridge to more conventional surgical or trans Catholic solutions later
in life. Thus, at this point, I think we should
move forward to our conversation with the works senior author
doctor Rajab joining us now to discuss this week's work
is the work's senior author, Doctor T. Conrad Rajab. Doctor
(07:15):
Roschab works at Arkansas Children's Hospital, where he is a
congenital heart surgeon. He is well known for his research
in cardiac transplantation and particularly this topic of partial heart transplantation.
He received his medical degree from the University of Cambridge,
followed by residents at Royal Papworth Hospital and then Brigham
and Women's Hospital in Boston. Following this, he trained at
(07:36):
Children's Hospital of Colorado. As already mentioned, doctor Rajab is
a former guest on the podcast, speaking on this very
topic a few years ago. It is a delight and
honor to have him join us once again to learn
a bit more about this potentially game changing approach of
using transplantation techniques to treat congenital heart disease.
Speaker 2 (07:55):
Welcome doctor Rajab to Pdheart.
Speaker 3 (07:57):
I'm here now with doctor T. Conrad Raschab. Doctor Rajab,
thank you very much for joining us this week on
podcast on the podcast, and thank you also for coming
back a second time. You have great bravery.
Speaker 4 (08:07):
Thank you, Robert.
Speaker 5 (08:08):
It is a great pleasure to be here and I'm
a huge fan of your podcast.
Speaker 4 (08:12):
Thank you.
Speaker 3 (08:12):
It's very very kind of you to say thank you. Conrad,
really as usual, very interesting and innovative approach. You know,
one of the things that jumped out at me was
that the pulmonary valve annualist growth rate was higher in
the partial heart transplant piglets than homograph piglets, presumably because
there was growing tissue there. But what do you think
(08:35):
the implications are of this, and I was interested to
see that the homograph annual I also were getting bigger.
Why is that happening if there aren't any viable cells
in the actual homographs.
Speaker 5 (08:48):
So the original hypothesis was based on the fact that
heart transplants grow in neonates and that the valves contained
in heart transplants also grow in units. And that led
me to conclude that if we were to transplant just
a part of the heart that contains the valve, that
these valves would also grow. And our thought is that
(09:11):
it hinges on the presence of viable valve cells, specifically
the valve intestitial cells. If you have if you maintain
these viable cells, the valve is going to grow just
like a native valve, just like a valve in a
heart transplant, and just like the valve in a ross autotransplant.
(09:34):
Whereas in a homograph the valve is decalarized or the
cells do not survive. Homographs maintain the extra cellular matrix
of the valve, so those valves are able to fulfill
their hemodynamic function by mechanically stopping blood flow from regarditating
and preventing stenosis. But they lack the biological functions that
(09:59):
are endowed by the valve cells.
Speaker 4 (10:01):
Yes, yes, So the question that you raised is very important.
Speaker 5 (10:06):
Why is there any increase at all in the homografts?
And our hypothesis is that this is not growth but dilation.
We know that homografts tend to dilate, and we think
that this is what happened in our piglets too.
Speaker 3 (10:21):
I see, I see, yeah, I think you did reference
that in the article, So thank you.
Speaker 4 (10:27):
Very interesting.
Speaker 3 (10:28):
You know, as I was reading this, I am not
a heart transplant doctor, although my colleagues doctor Lamour and
doctor Bosel sometimes think I fancy myself one. But it
seemed that you used fairly usual anti rejection doses of
medication for prevention of rejection in the piglets in your experiments,
and I wondered if you had any thoughts on what
(10:50):
rejection prevention medication amount is actually needed and whether you
thought it was possible that you would need less than
a typical full heart travel plant patient, because it would
seem to me that if you could use less of
this type of medication, you could get potentially all the
benefits without some of the negatives associated with aminos suppression.
(11:11):
So how are you studying this and do you think
there's any evidence that these doses could be different between
a full heart transplant and partial as you're describing in
this experiment.
Speaker 4 (11:21):
That is a very good point.
Speaker 5 (11:22):
So the reason we used the same immune suppression as
for full heart transplants in this experiment was that we
each wanted to prove the principle that these valves grow. Also,
the experiments are very expensive, so to put these pickets
on bypass, to survive them, to analyze them, to immune
(11:43):
suppress them, We're talking about tens of thousands of dollars
for each experiment, so I had to have success. I
knew that if you fully immune suppress a heart transplant
with triple immunotherapy, that those valves grow. So for this
experiment and I just replicated the exact same immune suppression
that we use for heart transplants in order to maximize
(12:07):
the chances of success. And just like you point out,
the next question is how much immune suppression do you.
Speaker 4 (12:13):
Actually need for a partial heart transplant.
Speaker 5 (12:17):
And we looked at the outcomes of heart transplant rejections
and the effect of those on the valve function.
Speaker 4 (12:30):
When heart transplants get rejected.
Speaker 5 (12:32):
It is always the ventricles that develop dysfunction, it's never
the valves.
Speaker 4 (12:37):
So for this reason I agree with.
Speaker 5 (12:38):
You that it's very likely that partial heart transplants will
need less immune suppression than a full heart transplant. Clinically,
we use the taco lamas only protocol from the tik
Tak trial Tetrolamus combined tacolamus monotherapy trial, and that is postoperatively,
(13:02):
staris are started ato point six milligrams per kilogram daily
and then weaned off eight weeks after the transplant. Microfedilate
is stopped fourteen days after the transplant, and tacolamus trough
levels are initially targeted at nine to twelve nanograms per
descilator during the first three months, and then seven to
(13:24):
nine nanograms pedcilator through the first year, and then six
to eight nanograms per desolator. And the reason we use
this protocol is that this was shown to be non
inferior in pediatric whole heart transplants. If the valves in
those grow, we can assume that the valves in the
(13:44):
partial heart transplants will also grow with that tacolamus monotherapy protocol.
The question you asked, is goes beyond that? It is
can you use even less than the lowest possible immune
suppression for a whole heart transplant? And that question is
so far unanswered, and we're trying to study this in the.
Speaker 3 (14:07):
Pigments I see and you know, as I'm sitting and
listening to you, Conrad, I'm wondering, is there like you
can't like soak a heart intacraliveness? But I was thinking
maybe you could do something like that though with a valve.
You know, is there any local preparation that you could
(14:27):
do to a partial heart transplant valve that might hold
the promise of being more resistant to rejection. I'm just
thinking out of my just wondering if there's something that
can be done.
Speaker 5 (14:42):
It's absolutely fascinating, and we're thinking along the exact same
lines because partial heart transplants are relatively simple grafts compared
to whole organs, and people have tried to use gene
therapy XVVO to knock out SEE molecules, for example, and
modify those grafts in that fashion. People have tried to
(15:06):
use nanoparticles.
Speaker 4 (15:09):
I think that you.
Speaker 5 (15:10):
Would need to permanently alter and change the genetics of
the cells in the graph to have long term effect.
Speaker 4 (15:19):
It sounds like science fiction.
Speaker 5 (15:20):
But if you can do it in any transplant, I
would try the partial heart transplant first.
Speaker 3 (15:27):
I see very interesting, really exciting. You know, well, I
was wondering when you think about this potentially therapeutic, this
potential therapeutically for children who need a PVR. The potential
benefits could be obviously be massive in prevention of the
need for multiple reoperations. However, how do you think about
(15:48):
this therapy like in older kids? In other words, it
seems to me like in small kids the potential is
very substantial for benefit. But when a child is adult sized,
do you anticipate that if this valve continued to grow
and you're now an adult size patient, that you would
discontinue anti rejection therapy with subsequent trans catheter procedures for PVR,
(16:10):
or do you think it might be possible that one
could even consider continued amminus suppression without the need for
a PVR, and maybe this would be maybe superior overall.
I was just wondering what your thoughts were on that.
Speaker 5 (16:25):
So I think it depends on the indications and the
indications hinge on the benefits of avoiding reoperations versus the
risks of immune suppression. Our hypothesis is that the valve cells,
the biological functions of the valve cells are on the
one hand to allow the valve to grow, but on
the other hand to also remodel and self repair and
(16:46):
the extracellular matrix. It's actually just like native heart valves do,
which last until old age. So I think that if
you were to immune suppress or keep the valve phanologically quiescent,
it would continue to function until old age, just like
a native valve. And I think this is most valuable.
(17:11):
The biological functions of develop are most valuable in younger
children and in the aortic position. I think that as
you go to the pulmonary position, maybe the importance of
avoiding reoperations are less than in the lytic position.
Speaker 3 (17:29):
Yeah, yeah, that makes good sense.
Speaker 4 (17:31):
Well, and yes, just one more thing I wanted to
say about this.
Speaker 5 (17:34):
It depends on what you asked me in the question before,
how much immune suppression you actually end up needing. The
less immune suppression you end up needing, that would expand
the indications and the age range for partial heart transplants.
Let's say enough if you just need non life altering
immune suppression, like an asthmatic or someone who has the EXIMA.
(18:00):
If that were sufficient, then I would say that all
means continue themmon suppression beyond.
Speaker 4 (18:10):
Teenage years into adulthood.
Speaker 3 (18:12):
I guess this just highlights how credit call to research
you and your colleagues are doing on this topic, because
if you can demonstrate that exima levels of aminosuppression are
adequate to protect the valves, I think most of us
will take that bed over open heart surgery.
Speaker 4 (18:31):
That's what.
Speaker 5 (18:31):
Yeah, And I want to just give credit to you
mentioned colleagues. I want to credit Joe Torrek at Duke University,
who has been an incredible proponent of this. He was
the first person to believe in this whole concept. Everyone
else dismissed, dismissed this before he yeah, before he started
(18:53):
to believe in it. And then David Kalfa at Columbia University,
who has also done incredible work of course, both in
the basic science area clinically.
Speaker 3 (19:03):
Yes, I appreciate your mentioning both, gentlemen. For those in
the audience, I think you're aware, doctor Kalfa is starting
soon at Nicholas Children's Hospital in Florida. So it'll be
very exciting bringing some of those techniques there as well
well for those in the audience. As is usually the
case when we're interviewing prominent people, we're doing this late
at night, and so I don't want to keep doctor
(19:23):
Rajab too late here. So I'm going to finish up
with one final question, and I just wanted to ask,
you know, what do we know about the few human
cases that have been done in regards to the longevity
and the function of valves that have been transplanted in
this manner? And I wondered if you could, in any
fashion without breaking any hippo laws, let us know how
(19:45):
that patient is doing. That we talked about a year
and a half ago on the podcast when this was
really front and center, brand new.
Speaker 5 (19:52):
Well, David Kalf, I've just presented the Worldwide Experience with
partial heart transplant at the ag TEST Presidential Canary Session,
and he very kindly made available to me his manuscript
that he's preparing together with Elie Cordovez. So the worldwide
(20:13):
experience is thirty patients who received thirty six heart valves
with a median age of nine zero point ninety six years.
Speaker 4 (20:24):
So eleven months.
Speaker 5 (20:25):
The median follow up in this study was seven months,
and he found that the median diameter of the erotic
valves grew from eleven millimeters to fourteen millimeters, and the
median diameter of the palmary valves that were transplanted increased
from ten millimeters to seventeen millimeters, and the median.
Speaker 4 (20:48):
Erotic gradients through that time.
Speaker 5 (20:50):
Sorry, at the last follow up was just four point
six millimeters of mercury, which I think is remarkable in
the growth in the face of the growth of these children,
and the peak palmary ingredients was twenty so that's.
Speaker 4 (21:06):
A little higher.
Speaker 5 (21:07):
Yes, I have to say that the immune suppression in
this series was heterogeneous. There was no single protocol, and
so some of these kids had more immune suppression, some
of them had less immune suppression, and it's not entirely
clear how that affects growth and function of those valves.
Speaker 3 (21:26):
I see, Well, I guess, so we're going to guess
maybe there's a signal there that there is maybe some
minimal dose below which we can't be confident that the
Bible they protected.
Speaker 5 (21:37):
Maybe I'm pretty sure that there is a minimum. Because
Yakoub in England he had introduced these homovitographs. At the
very early experience with homographs, these were non immune.
Speaker 4 (21:50):
Suppressed fresh valves and they did not grow.
Speaker 5 (21:54):
So for that reason, I think you need to keep
you need to keep the the valve a question with
at least a small amount of immune suppressence.
Speaker 4 (22:05):
But I don't know the true I don't know.
Speaker 3 (22:07):
The answer, Conrad. As I'm talking to I'm wondering, I'm
gonna take advantage of the fact that we have you here.
You know, when we're doing a heart transplant, of course,
is scheming time is critical and I've got to get
that heart from the donor to the recipient. Is there
a similar time crunch when you're doing a partial heart transplant?
(22:27):
In other words, does that have to similarly have a
short schemic time or is there something that you can
do to these valves that will sort of protect them longer. Right,
we know that the longer there's the ischemic time, the
higher the risks are for a regular full heart transplant.
Is there is that Do we believe that that's similar
(22:48):
for partial as well?
Speaker 4 (22:50):
That's another very interesting question.
Speaker 5 (22:54):
So the risk of long schemia times in full heart
transfer kinds our primary graph dysfunction, and the problem is
that if the heart does not beat, the patient comes
out on EKMO.
Speaker 4 (23:04):
It's not a survivable state.
Speaker 5 (23:07):
We can preserve kidneys for forty hours, much longer than
hearts because they don't need to function right away. The
biological function of the valve is also.
Speaker 4 (23:18):
Not needed right away.
Speaker 5 (23:19):
They have a humandynamic function, but that doesn't depend on
the metabolism and the functioning of the metabolically active cells.
So Geoe Tuk just published a paper in JTCBS.
Speaker 4 (23:35):
In piglets together with.
Speaker 5 (23:38):
Bert Ikuld who is his research fellow, and they looked
at up to seven days of the schemea time, and
they were able to show that those valves still grow.
They didn't have a control group, so we don't know
if they grow at the same rate as fresh valves,
but it seems to be clear that you can preserve
(24:00):
There are partial heart transplants much longer than full heart transplants.
And again, if you think back at the situation with
full heart transplants, primographics function never affects the velops. It
always affects particular function. So that is another indication that
there is more scope, more room for longer scheme your
(24:21):
times with partial heart transplants.
Speaker 3 (24:24):
Wow, well this is just mind blowing, very exciting work,
and kudos to you doctor Turrek, doctor Kalfa, and so
many of your many different collaborators. I want to congratulate
all of you, and I want to thank you so
much for coming back on the podcast to discuss this
exciting new work, which I know sounds like there's a
(24:46):
lot to learn and a lot coming down the pike
in the next few years. So congratulations and thank you.
Speaker 4 (24:52):
Thank you so much for having me Robert. It is
a great pleasure.
Speaker 3 (24:55):
Thank you very much.
Speaker 2 (24:56):
Well, as I'm fond of saying, when the guest is good,
there's really not much to say. Doctor Rajab shared a
lot of the exciting work that he and his collaborators
are studying in this burgeoning field of partial heart transplantation.
There are many unanswered questions about this, including which valves
would most benefit from this form of therapy, but it
seems clear that if this could be performed safely with
(25:18):
much lower levels of aminosuppression than what is typically used
in a whole heart transplant, the role for this approach
is likely to grow. Given the generally larger supply of
donors for partial heart transplant. There's so much to think of,
and I'm sure that doctor Rajab's comments gave you a
lot to contemplate as we sit and wait for the
works of pioneers in this field like himself, doctor Kalfa,
(25:41):
and doctor Turk. I can't wait to speak with doctor
Kalfa on the podcast in a few months to discuss
the larger report that doctor Rajab referenced in the interim.
I'd like to end by thanking doctor Rajab once more
for joining us this week to discuss this exciting work
on PD heart.
Speaker 1 (25:56):
To conclude this three hundred and forty six episode of
PD heartp Theatric Cardiology, Today we end with the wonderful
American soprano Angel Blue, who was born in Los Angeles
and she is the daughter of Sylvester Blue, who was
a leading Black church minister and musician. MS Blue started
a career as a beauty queen, winning many different pageants,
but opera was always her talent and she has become
(26:19):
one of the great soprano superstars of the present era,
singing all over the world. Just this week, she's singing Violetta.
Speaker 2 (26:26):
In Verona, Italy. Today we hear her in a live
recital performance of vs DCTE from Puccini's Tosca. Thank you
for joining me for this week's episode, and thanks once
again to doctor rajab I. Hope I'll have a good
week ahead.
Speaker 6 (27:00):
Why what forre.
Speaker 3 (27:39):
Cones? This is.
Speaker 6 (27:44):
Not me, make off my sold it harder and horror
he saw siday Honifa the Concris signal cry, recalled calls
(28:26):
sweet stand Still, sing You the goat
Speaker 3 (29:36):
Co
Welcome to Pdheart Pediatric Cardiology today. My name is doctor
Robert Pass and I'm the host of this podcast. I
am Professor of Pediatrics at the Icon School of Medicine
at Mount Sinai, where I'm also the chief of Pediatric
Cardiology and the co director of the Children's Heart Center.
Thank you very much for joining me for this three
hundred and forty sixth episode of Pdheart. I hope all
enjoyed last week's episode on the topic of the outcomes
(00:38):
of neonatal heart surgery in Europe. For those of you
interested in congenital heart surgery, I'd certainly recommend you to
take a listen to last week's episode three hundred and
forty five. As I say most weeks, if you'd like
to get in touch with me, my email is easy
to remember. It's Pdheart at gmail dot com. This week
we move onto the world of congenital heart disease and
cardiac transplantation. This week's article is a letter and it's
(01:02):
entitled partial heart transplant growth and Hemodynamic Function in Piglets.
The first author is Lilian Kang and the senior author
is Taufik k Rajab, and the authors come to us
from Arkansas Children's Hospital in Little Rock, Arkansas. When we're
done reviewing this brief letter to the editor, we'll be
speaking with the work's senior author, doctor T. Conrad Rajab. Therefore,
(01:25):
let's move straight on to this brief discussion of the article,
then a conversation with its senior author. This week's work
is a brief research letter on the topic of partial
heart transplantation, which is when we've discussed previously back in
episode two hundred and thirty six in early twenty twenty three.
The authors of this work, one of whom is the
same author, doctor Rajab, start by explaining that the pulmonary
(01:46):
valve of an infant is smaller than any bioprosthesis that
presently exists, and for this reason, when the pulmonary valve
needs to be replaced, a homograph is used, but that
these cataveric prostheses have no viable cells and so are
unable to grow, and so when a surgeon chooses to
place a homograph, they know that this will effectively commit
the patient to serial valve replacements until in adult sized
(02:09):
processes can be used. They then review the main rationale
for a partial heart transplant, which is that these valves
in transplanted hearts grow, and they review how just transplanting
a valve rather than the valve and the heart muscle itself,
may eliminate graph dysfunction from rejection. Though there are a
few case reports of these valves growing, The authors endeavor
(02:30):
to study this hypothesis of valvular growth by comparing pulmonary
valve replacements with homographs and partial heart transplants in infant piglets.
The authors explain and for the partial heart transplant piglets,
there were three donors and three recipients that were ABO
matched and two piglets that were wild type. Donor piglets
donated the pulmonary valve root and blood to prime the
(02:52):
cardiopulmonary bypass circuit. The recipient piglets had induction immunotherapy with
oral tacri limits at zero point zero five milligrants kilogram
and micofhenylate A twenty milligrams perkilo, and they underwent surgical PVR.
Methyl prednisilone a ten miligrams perkilo was given before the
graft was reprofused. Following surgery, the partial heart transplant recipients
(03:13):
were aminosuppressed with tacrolimus t traded to a trough level
of five to ten nanograms per millileter and micofhenylate ten
milligrams pekilo two times a day, and prednisolone was tapered
ultimately to zero point five milligrams per kilogram bid for
homograph recipient donors. There were three donors and three recipients
and they were not ABO matched. The donor pulmonary valve
(03:36):
root was cryo preserved for at least one month, and
then the pulmonary valve replacement was performed on bypass as usual,
and the cardiopulmonary bypass circuits were primed with blood from
the ABO matched blood donor piglets. No imminosuppression was given
to the piglets that received homographs following surgery. The recipients
had serial ecocrdigrams and for this study, the primary outcome
(03:57):
was pulmonary valve gradient and secondary outcomes were pulmonary valve regrigetation,
pulmonary valve annular dimension, and aortic valve anulist dimension. The
experiment was considered to end when the weight of the
subjects had doubled from the time of surgery. The investigators
also used green fluorescent protein visualization since the donors expressed
this protein, and the valves were examined both macroscopically and microscopically.
(04:22):
And so what did the investigators see? First, the homograph
recipients were demonstrated to show increase ingradients that developed rapidly
in contrast to the partial heart transplant recipients who did
not have such a change, and the difference was highly significant.
In regards to pulmonary valve regrigetation, no partial heart piglet
had more than physiological regurgitation, and in the homographs, two
(04:45):
had no more than physiological regurgetation and one mild regurgitation.
And what about pulmonary valve annular growth, Well, it turns
out both increased in diameter, but the increase was significantly
faster in the partial heart transplant piglets than a those
receiving homographs. But there was no difference in growth rates
of the aortic valves. Finally, when the authors looked under
(05:07):
fluorescence testing, the grown partial heart transplant piglets remained positive
for the donor green fluorescent proteins and had normal macro
and microscopic morphology in their concluding comments, the authors state,
and I quote, this study contributes preclinical evidence to support
the use of partial heart transplants over homographs for valve
(05:28):
replacement in infants, as recipients more than double their weight,
partial heart transplants demonstrated stable valve gradients and adaptive valve growth.
The grown partial heart transplants remained GFP positive, which confirmed
the presence of donor cells and had normal morphology, and
the authors contrasted this to the homograph patients who had
(05:49):
rapid increases in homograph conduit gradients. And they also spoke
of the growth seen in annuli in the homographs and
wondered if this might be due to dilation rather than growth.
The authors conclude by stating, and I quote, these findings
are clinically relevant because partial heart transplants can eliminate the
need for serial valve replacements during childhood. Though once again
(06:11):
we're reviewing another of these studies on partial heart transplantation,
and again by one of its pioneers, doctor Rajab, it's
certainly of interest to see that these transplanted valves are
growing with time, much as we have seen in full
cardiac transplantation. I wonder if the degree or the requirement
of rejection prophylaxis is as high, or if that has
(06:31):
even been studied in patients undergoing a partial heart transplant. Clearly,
if the doses of anti rejection therapies could be lower
than are common for full heart transplants, one would think
that this would be a major plus for avoidance of
possible opportunistic infections or cancers that are rarely seen in
transplant patients associated with this type of therapy. I also
(06:53):
wonder if doctor Raja believes that this is a potential
lifelong approach or if he sees us more as a
bridge to more conventional surgical or trans Catholic solutions later
in life. Thus, at this point, I think we should
move forward to our conversation with the works senior author
doctor Rajab joining us now to discuss this week's work
is the work's senior author, Doctor T. Conrad Rajab. Doctor
(07:15):
Roschab works at Arkansas Children's Hospital, where he is a
congenital heart surgeon. He is well known for his research
in cardiac transplantation and particularly this topic of partial heart transplantation.
He received his medical degree from the University of Cambridge,
followed by residents at Royal Papworth Hospital and then Brigham
and Women's Hospital in Boston. Following this, he trained at
(07:36):
Children's Hospital of Colorado. As already mentioned, doctor Rajab is
a former guest on the podcast, speaking on this very
topic a few years ago. It is a delight and
honor to have him join us once again to learn
a bit more about this potentially game changing approach of
using transplantation techniques to treat congenital heart disease.
Speaker 2 (07:55):
Welcome doctor Rajab to Pdheart.
Speaker 3 (07:57):
I'm here now with doctor T. Conrad Raschab. Doctor Rajab,
thank you very much for joining us this week on
podcast on the podcast, and thank you also for coming
back a second time. You have great bravery.
Speaker 4 (08:07):
Thank you, Robert.
Speaker 5 (08:08):
It is a great pleasure to be here and I'm
a huge fan of your podcast.
Speaker 4 (08:12):
Thank you.
Speaker 3 (08:12):
It's very very kind of you to say thank you. Conrad,
really as usual, very interesting and innovative approach. You know,
one of the things that jumped out at me was
that the pulmonary valve annualist growth rate was higher in
the partial heart transplant piglets than homograph piglets, presumably because
there was growing tissue there. But what do you think
(08:35):
the implications are of this, and I was interested to
see that the homograph annual I also were getting bigger.
Why is that happening if there aren't any viable cells
in the actual homographs.
Speaker 5 (08:48):
So the original hypothesis was based on the fact that
heart transplants grow in neonates and that the valves contained
in heart transplants also grow in units. And that led
me to conclude that if we were to transplant just
a part of the heart that contains the valve, that
these valves would also grow. And our thought is that
(09:11):
it hinges on the presence of viable valve cells, specifically
the valve intestitial cells. If you have if you maintain
these viable cells, the valve is going to grow just
like a native valve, just like a valve in a
heart transplant, and just like the valve in a ross autotransplant.
(09:34):
Whereas in a homograph the valve is decalarized or the
cells do not survive. Homographs maintain the extra cellular matrix
of the valve, so those valves are able to fulfill
their hemodynamic function by mechanically stopping blood flow from regarditating
and preventing stenosis. But they lack the biological functions that
(09:59):
are endowed by the valve cells.
Speaker 4 (10:01):
Yes, yes, So the question that you raised is very important.
Speaker 5 (10:06):
Why is there any increase at all in the homografts?
And our hypothesis is that this is not growth but dilation.
We know that homografts tend to dilate, and we think
that this is what happened in our piglets too.
Speaker 3 (10:21):
I see, I see, yeah, I think you did reference
that in the article, So thank you.
Speaker 4 (10:27):
Very interesting.
Speaker 3 (10:28):
You know, as I was reading this, I am not
a heart transplant doctor, although my colleagues doctor Lamour and
doctor Bosel sometimes think I fancy myself one. But it
seemed that you used fairly usual anti rejection doses of
medication for prevention of rejection in the piglets in your experiments,
and I wondered if you had any thoughts on what
(10:50):
rejection prevention medication amount is actually needed and whether you
thought it was possible that you would need less than
a typical full heart travel plant patient, because it would
seem to me that if you could use less of
this type of medication, you could get potentially all the
benefits without some of the negatives associated with aminos suppression.
(11:11):
So how are you studying this and do you think
there's any evidence that these doses could be different between
a full heart transplant and partial as you're describing in
this experiment.
Speaker 4 (11:21):
That is a very good point.
Speaker 5 (11:22):
So the reason we used the same immune suppression as
for full heart transplants in this experiment was that we
each wanted to prove the principle that these valves grow. Also,
the experiments are very expensive, so to put these pickets
on bypass, to survive them, to analyze them, to immune
(11:43):
suppress them, We're talking about tens of thousands of dollars
for each experiment, so I had to have success. I
knew that if you fully immune suppress a heart transplant
with triple immunotherapy, that those valves grow. So for this
experiment and I just replicated the exact same immune suppression
that we use for heart transplants in order to maximize
(12:07):
the chances of success. And just like you point out,
the next question is how much immune suppression do you.
Speaker 4 (12:13):
Actually need for a partial heart transplant.
Speaker 5 (12:17):
And we looked at the outcomes of heart transplant rejections
and the effect of those on the valve function.
Speaker 4 (12:30):
When heart transplants get rejected.
Speaker 5 (12:32):
It is always the ventricles that develop dysfunction, it's never
the valves.
Speaker 4 (12:37):
So for this reason I agree with.
Speaker 5 (12:38):
You that it's very likely that partial heart transplants will
need less immune suppression than a full heart transplant. Clinically,
we use the taco lamas only protocol from the tik
Tak trial Tetrolamus combined tacolamus monotherapy trial, and that is postoperatively,
(13:02):
staris are started ato point six milligrams per kilogram daily
and then weaned off eight weeks after the transplant. Microfedilate
is stopped fourteen days after the transplant, and tacolamus trough
levels are initially targeted at nine to twelve nanograms per
descilator during the first three months, and then seven to
(13:24):
nine nanograms pedcilator through the first year, and then six
to eight nanograms per desolator. And the reason we use
this protocol is that this was shown to be non
inferior in pediatric whole heart transplants. If the valves in
those grow, we can assume that the valves in the
(13:44):
partial heart transplants will also grow with that tacolamus monotherapy protocol.
The question you asked, is goes beyond that? It is
can you use even less than the lowest possible immune
suppression for a whole heart transplant? And that question is
so far unanswered, and we're trying to study this in the.
Speaker 3 (14:07):
Pigments I see and you know, as I'm sitting and
listening to you, Conrad, I'm wondering, is there like you
can't like soak a heart intacraliveness? But I was thinking
maybe you could do something like that though with a valve.
You know, is there any local preparation that you could
(14:27):
do to a partial heart transplant valve that might hold
the promise of being more resistant to rejection. I'm just
thinking out of my just wondering if there's something that
can be done.
Speaker 5 (14:42):
It's absolutely fascinating, and we're thinking along the exact same
lines because partial heart transplants are relatively simple grafts compared
to whole organs, and people have tried to use gene
therapy XVVO to knock out SEE molecules, for example, and
modify those grafts in that fashion. People have tried to
(15:06):
use nanoparticles.
Speaker 4 (15:09):
I think that you.
Speaker 5 (15:10):
Would need to permanently alter and change the genetics of
the cells in the graph to have long term effect.
Speaker 4 (15:19):
It sounds like science fiction.
Speaker 5 (15:20):
But if you can do it in any transplant, I
would try the partial heart transplant first.
Speaker 3 (15:27):
I see very interesting, really exciting. You know, well, I
was wondering when you think about this potentially therapeutic, this
potential therapeutically for children who need a PVR. The potential
benefits could be obviously be massive in prevention of the
need for multiple reoperations. However, how do you think about
(15:48):
this therapy like in older kids? In other words, it
seems to me like in small kids the potential is
very substantial for benefit. But when a child is adult sized,
do you anticipate that if this valve continued to grow
and you're now an adult size patient, that you would
discontinue anti rejection therapy with subsequent trans catheter procedures for PVR,
(16:10):
or do you think it might be possible that one
could even consider continued amminus suppression without the need for
a PVR, and maybe this would be maybe superior overall.
I was just wondering what your thoughts were on that.
Speaker 5 (16:25):
So I think it depends on the indications and the
indications hinge on the benefits of avoiding reoperations versus the
risks of immune suppression. Our hypothesis is that the valve cells,
the biological functions of the valve cells are on the
one hand to allow the valve to grow, but on
the other hand to also remodel and self repair and
(16:46):
the extracellular matrix. It's actually just like native heart valves do,
which last until old age. So I think that if
you were to immune suppress or keep the valve phanologically quiescent,
it would continue to function until old age, just like
a native valve. And I think this is most valuable.
(17:11):
The biological functions of develop are most valuable in younger
children and in the aortic position. I think that as
you go to the pulmonary position, maybe the importance of
avoiding reoperations are less than in the lytic position.
Speaker 3 (17:29):
Yeah, yeah, that makes good sense.
Speaker 4 (17:31):
Well, and yes, just one more thing I wanted to
say about this.
Speaker 5 (17:34):
It depends on what you asked me in the question before,
how much immune suppression you actually end up needing. The
less immune suppression you end up needing, that would expand
the indications and the age range for partial heart transplants.
Let's say enough if you just need non life altering
immune suppression, like an asthmatic or someone who has the EXIMA.
(18:00):
If that were sufficient, then I would say that all
means continue themmon suppression beyond.
Speaker 4 (18:10):
Teenage years into adulthood.
Speaker 3 (18:12):
I guess this just highlights how credit call to research
you and your colleagues are doing on this topic, because
if you can demonstrate that exima levels of aminosuppression are
adequate to protect the valves, I think most of us
will take that bed over open heart surgery.
Speaker 4 (18:31):
That's what.
Speaker 5 (18:31):
Yeah, And I want to just give credit to you
mentioned colleagues. I want to credit Joe Torrek at Duke University,
who has been an incredible proponent of this. He was
the first person to believe in this whole concept. Everyone
else dismissed, dismissed this before he yeah, before he started
(18:53):
to believe in it. And then David Kalfa at Columbia University,
who has also done incredible work of course, both in
the basic science area clinically.
Speaker 3 (19:03):
Yes, I appreciate your mentioning both, gentlemen. For those in
the audience, I think you're aware, doctor Kalfa is starting
soon at Nicholas Children's Hospital in Florida. So it'll be
very exciting bringing some of those techniques there as well
well for those in the audience. As is usually the
case when we're interviewing prominent people, we're doing this late
at night, and so I don't want to keep doctor
(19:23):
Rajab too late here. So I'm going to finish up
with one final question, and I just wanted to ask,
you know, what do we know about the few human
cases that have been done in regards to the longevity
and the function of valves that have been transplanted in
this manner? And I wondered if you could, in any
fashion without breaking any hippo laws, let us know how
(19:45):
that patient is doing. That we talked about a year
and a half ago on the podcast when this was
really front and center, brand new.
Speaker 5 (19:52):
Well, David Kalf, I've just presented the Worldwide Experience with
partial heart transplant at the ag TEST Presidential Canary Session,
and he very kindly made available to me his manuscript
that he's preparing together with Elie Cordovez. So the worldwide
(20:13):
experience is thirty patients who received thirty six heart valves
with a median age of nine zero point ninety six years.
Speaker 4 (20:24):
So eleven months.
Speaker 5 (20:25):
The median follow up in this study was seven months,
and he found that the median diameter of the erotic
valves grew from eleven millimeters to fourteen millimeters, and the
median diameter of the palmary valves that were transplanted increased
from ten millimeters to seventeen millimeters, and the median.
Speaker 4 (20:48):
Erotic gradients through that time.
Speaker 5 (20:50):
Sorry, at the last follow up was just four point
six millimeters of mercury, which I think is remarkable in
the growth in the face of the growth of these children,
and the peak palmary ingredients was twenty so that's.
Speaker 4 (21:06):
A little higher.
Speaker 5 (21:07):
Yes, I have to say that the immune suppression in
this series was heterogeneous. There was no single protocol, and
so some of these kids had more immune suppression, some
of them had less immune suppression, and it's not entirely
clear how that affects growth and function of those valves.
Speaker 3 (21:26):
I see, Well, I guess, so we're going to guess
maybe there's a signal there that there is maybe some
minimal dose below which we can't be confident that the
Bible they protected.
Speaker 5 (21:37):
Maybe I'm pretty sure that there is a minimum. Because
Yakoub in England he had introduced these homovitographs. At the
very early experience with homographs, these were non immune.
Speaker 4 (21:50):
Suppressed fresh valves and they did not grow.
Speaker 5 (21:54):
So for that reason, I think you need to keep
you need to keep the the valve a question with
at least a small amount of immune suppressence.
Speaker 4 (22:05):
But I don't know the true I don't know.
Speaker 3 (22:07):
The answer, Conrad. As I'm talking to I'm wondering, I'm
gonna take advantage of the fact that we have you here.
You know, when we're doing a heart transplant, of course,
is scheming time is critical and I've got to get
that heart from the donor to the recipient. Is there
a similar time crunch when you're doing a partial heart transplant?
(22:27):
In other words, does that have to similarly have a
short schemic time or is there something that you can
do to these valves that will sort of protect them longer. Right,
we know that the longer there's the ischemic time, the
higher the risks are for a regular full heart transplant.
Is there is that Do we believe that that's similar
(22:48):
for partial as well?
Speaker 4 (22:50):
That's another very interesting question.
Speaker 5 (22:54):
So the risk of long schemia times in full heart
transfer kinds our primary graph dysfunction, and the problem is
that if the heart does not beat, the patient comes
out on EKMO.
Speaker 4 (23:04):
It's not a survivable state.
Speaker 5 (23:07):
We can preserve kidneys for forty hours, much longer than
hearts because they don't need to function right away. The
biological function of the valve is also.
Speaker 4 (23:18):
Not needed right away.
Speaker 5 (23:19):
They have a humandynamic function, but that doesn't depend on
the metabolism and the functioning of the metabolically active cells.
So Geoe Tuk just published a paper in JTCBS.
Speaker 4 (23:35):
In piglets together with.
Speaker 5 (23:38):
Bert Ikuld who is his research fellow, and they looked
at up to seven days of the schemea time, and
they were able to show that those valves still grow.
They didn't have a control group, so we don't know
if they grow at the same rate as fresh valves,
but it seems to be clear that you can preserve
(24:00):
There are partial heart transplants much longer than full heart transplants.
And again, if you think back at the situation with
full heart transplants, primographics function never affects the velops. It
always affects particular function. So that is another indication that
there is more scope, more room for longer scheme your
(24:21):
times with partial heart transplants.
Speaker 3 (24:24):
Wow, well this is just mind blowing, very exciting work,
and kudos to you doctor Turrek, doctor Kalfa, and so
many of your many different collaborators. I want to congratulate
all of you, and I want to thank you so
much for coming back on the podcast to discuss this
exciting new work, which I know sounds like there's a
(24:46):
lot to learn and a lot coming down the pike
in the next few years. So congratulations and thank you.
Speaker 4 (24:52):
Thank you so much for having me Robert. It is
a great pleasure.
Speaker 3 (24:55):
Thank you very much.
Speaker 2 (24:56):
Well, as I'm fond of saying, when the guest is good,
there's really not much to say. Doctor Rajab shared a
lot of the exciting work that he and his collaborators
are studying in this burgeoning field of partial heart transplantation.
There are many unanswered questions about this, including which valves
would most benefit from this form of therapy, but it
seems clear that if this could be performed safely with
(25:18):
much lower levels of aminosuppression than what is typically used
in a whole heart transplant, the role for this approach
is likely to grow. Given the generally larger supply of
donors for partial heart transplant. There's so much to think of,
and I'm sure that doctor Rajab's comments gave you a
lot to contemplate as we sit and wait for the
works of pioneers in this field like himself, doctor Kalfa,
(25:41):
and doctor Turk. I can't wait to speak with doctor
Kalfa on the podcast in a few months to discuss
the larger report that doctor Rajab referenced in the interim.
I'd like to end by thanking doctor Rajab once more
for joining us this week to discuss this exciting work
on PD heart.
Speaker 1 (25:56):
To conclude this three hundred and forty six episode of
PD heartp Theatric Cardiology, Today we end with the wonderful
American soprano Angel Blue, who was born in Los Angeles
and she is the daughter of Sylvester Blue, who was
a leading Black church minister and musician. MS Blue started
a career as a beauty queen, winning many different pageants,
but opera was always her talent and she has become
(26:19):
one of the great soprano superstars of the present era,
singing all over the world. Just this week, she's singing Violetta.
Speaker 2 (26:26):
In Verona, Italy. Today we hear her in a live
recital performance of vs DCTE from Puccini's Tosca. Thank you
for joining me for this week's episode, and thanks once
again to doctor rajab I. Hope I'll have a good
week ahead.
Speaker 6 (27:00):
Why what forre.
Speaker 3 (27:39):
Cones? This is.
Speaker 6 (27:44):
Not me, make off my sold it harder and horror
he saw siday Honifa the Concris signal cry, recalled calls
(28:26):
sweet stand Still, sing You the goat
Speaker 3 (29:36):
Co
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