This week we review the topic of mitral annular disjunction ("MAD") and the possible association with ventricular arrhythmia or sudden death in the connective tissue disease patient. Is there a 'cut off' distance above which patients deserve more significant arrhythmia surveillance? What is the best way to measure the MAD distance? Can patients with low MAD distances have lower degrees or even no arrhythmic surveillance? How often should this distance be measured on CMR and can an echo measurement provide similar data? Dr. Daniel Castellanos, the first author of this work and Assistant Professor of Pediatrics at Harvard Medical School shares his deep insights this week.
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Episode Transcript
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Speaker 1 (00:16):
Welcome to Pheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm host to this podcast. I am
professor of Pediatrics at the Icon School of Medicine at
Mount Sinai here in New York City. Thank you for
joining me for this three hundred and sixty third episode
of Pdheart. I hope all enjoyed last week's episode on
the topic of caronary artery fistula. As I say most weeks.
(00:36):
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 into the world of connective tissue
disorders as well as cardiac MRI or imaging. The title
of the work we'll be reviewing is mitra Annular disjunction
distance is associated with adverse outcomes in children and young
adults with connective tissue disorders. The first author of this
(00:59):
work is Daniel Castellanos and the senior author Ronald Lacrow.
And this work comes to us from Boston Children's Hospital,
Harvard University. When we're done reviewing this paper, doctor Daniel Castellanos,
the first author, has kindly agreed to speak with us
about it. Therefore, let's move straight onto this article and
then a conversation with the work's first author. This week's
(01:20):
work is on the topic of mitral annular disjunction. Most
listening likely know what this is, but just so e'ar
all on the same page. This sort of so called
disjunction is a structural abnormality where the hinge point of
the posterior mitral valve leaflet is abnormally displaced towards the left,
a trim separating it from the adjacent left ventricular myacardium
(01:41):
during ventricular sistely and this gap between the ventricular muscle
and the annulus can be from a few millimeters to
over a centimeter. This abnormal hypermobile motion of the micro
valve that's associated with this abnormality can create mechanical stress
on the micro valve leaflets, cordae, and adjacent muscle, which
can cause mycardial scarring or fibrosis in the basal infralateral
(02:04):
wall or pepillary muscles. And it's frequently seen in mitrovol
prolapse patients and is also commonly seen in adults with
connective tissue disease like Lowe's DEETS or Morphan syndrome. This
is a rare but important finding because the fibrosis can
cause ventricular arrhythmias or more rarely, can be associated with
sudden cardiac death. This can also cause chest pain, exercise intolerance,
(02:28):
or palpitations. In adults, A disjunction distance exceeding five millimeters
or a combination of late gatolinium enhancement and arrhythmias in
this setting would be considered a high risk indicator. With
this as a background, let's move on to the paper
from the team in Boston. The authors start by reviewing
mitralannular disjunction or MAD as I will refer to it
(02:49):
in this paper, but also mention that though there are
a lot of data in adults, there's relatively little in children,
with some work on Morphan syndrome, where larger microlanular disjunction
distances being associated with increased risk of prophylactic gaortic surgery
or higher incidents of intricular ectopy. However, they explained that
there's essentially no data on its presence in other connected
(03:11):
tissue diseases, and there's also fairly little on CMR and
MAD in children, and so the authors explained that the
purpose of this work was to describe the range of
MAD distance by CMR in children and young adults with
connected tissue disease and in healthy control subjects, and then
to assess ways in which the MAD distance can be
(03:31):
represented in children and young adults to possibly discriminate those
who have or do not have adverse clinical outcomes. This
was a single center retrospective cohort of patients with connected
tissue disorders and controls with cardiac MRIs between twenty twenty twenty.
At this center, measurements were made on two chamber, four
chamber and lv auflo tract views in both systily and diastole,
(03:54):
and values were reported as absolute and index to body
surface area and height. There were two hundred and fifty
four connective tissue disease patients with a mean age of
seventeen plus or minus six years, and thirty healthy controls
aged fourteen plus or minus three years with a mean
connective tissue disease follow up of five years. For this work,
the primary outcome was a composite of significant ventricular arrhythmias
(04:18):
to find as symptomatic VT, sustained VT, or placement of
an implantable cardiac defibrillator, cardiac arrest and or death and
dawns of the results. Again, there were thirty healthy controls
in two hundred and fifty four patients with connective tissue disease,
of which fifty three percent had morphan syndrome. The mean
height was greater in the connective tissue patients, who were
(04:39):
of course older and had syndromes associated with greater height,
but there were no differences in weight or body surface area.
And what were some of the more important findings. First,
perhaps not unexpectedly, the maximum MAD distance in the control
group was three point six millimeters, but was larger in
patients with connective tissue disease in all standard CMR views
when compared to the control The authors did perform late
(05:02):
gatilinium enhancing testing in about forty nine of the connected
tissue disease patients. In three cases did have LV late
gatilinium enhancement, but the prevalence was so low that its
presence could not be meaningfully studied or used in their models.
In the median follow up period of five years, twenty
one patients, or eight point three percent of the patients
in the connected tissue disease group, met the composite outcome
(05:24):
with a mean age of thirteen point three at the
CMR versus seventeen point four for those with connected tissue
disease without the composite outcome. Amongst these, twenty one patients,
two had significant ventricular arrhythmias, two had a cardiac arrest,
and eighteen patients died. And what about the MAD distance
Did it help identify those with the composite outcome? Yes,
(05:45):
it did. The MAD distance was generally larger in patients
with the composite outcome, whether assessed in the absolute distance,
the body surface area index distance, or the height indexed value.
For a height indexed maximum systolic MAD threshold of zero
point three to three millimeters per centimeter, the sensitivity was
seventy nine percent, specificity seventy percent, accuracy was seventy one percent,
(06:09):
and positive predictive value nineteen percent, with a negative predictive
value of ninety seven percent. The authors explained that while
the cases with an outcome were more likely to have
a longer MAD distance than those without an outcome event,
they were cases with an event that did not have
a MAD distance enlargement. The authors then evaluated the height
indexed maximal systolic MAD with the threshold of zero point
(06:32):
three to three millimeters per centimeter in a covariate adjusted
logistic regression model including other predictors of the composite outcome,
and the model once again demonstrated that height indexed maximum
systolic MAD was an independent predictor of the composite clinical outcome,
with an ODDS ratio of eleven point eight and a
P value of zero point zero zero four. The authors
(06:54):
compared the connective tissue disease patients and saw a significant
difference in height indexed MAD distance among the six different
connected tissue diseases in this work, with similar height indexed
MAD in Marfan and Lowe's date syndromes that were longer
than the other genetic groups, and perhaps not shockingly, the
early onset severe marphan subset, of which there were seven patients,
(07:15):
had a longer height indexed MAD distance. The composite event
rate was similar between all the different connected tissue disease
patient groups, but the seven patients with early onsets severe
marphans did have higher vent rates than all the other groups.
In their discussion, the author's state and I quote this
study found that a small separation up to three point
six millimeters between the mitrovalve hinge point and vetricular myacardium
(07:38):
can be observed in healthy children and young adults and
is likely not indicative of adverse outcomes. By comparison, children
and young adults with connected tissue disease have a longer
MAD distance compared to healthy control subjects. This longer MAD
distance is not limited to morphan syndrome, but also is
present in other connected tissue diseases, including various forms of
(07:59):
Lowe's deep scs indrome, atypical connected tissue diseases, and connected
tissue disease without a specifically identified genetic mutation. In patients
with connected tissue disease, longer absolute BSA index than height
indexed systolic MAD distances were associated with the composite outcome
of significant ventricholarrhythmia, cardiac arrest, or death in these patients.
(08:20):
A height indexed value of zero point three to three
millimeters per centimeter for the maximum systolic MAD distance best
discriminated between those with and without the composite outcome. Furthermore,
in a covaried adjusted model, the cutoff value of zero
point three to three millimeters per centimeter for the maximum
systolic height indexed MAD distance was an independent predictor of
(08:42):
the composite outcome. The authors suggest that when doing a
CMR and a patient with connected tissue disease to assess
the aortic dimensions, which is often the reason for these studies,
it would be useful to obtain the maximal systolic MAD
distance among the two chamber, four chamber and lvflow views,
and they recommend doing at least lest one CMR with
these measurements in a connected tissue patient, even if that's
(09:04):
not the actual purpose of the study. They suggest that
the four chamber view by itself is suboptimal to measure
the MAD distance. They make arguments regarding why all three
different measurements are of benefit in each patient. They re
emphasize that the height indexed MAD distance was constant over
time and how this was seen previously in other works,
but also how it best discriminated between those with and
(09:26):
without the composite outcome. They suggest an I quote. In
agreement with prior studies, we recommend using height indexed MAD
distances as the optimal method to describe MAD in children
and young adults with connected tissue disease. More studies on
the prognostic value of MAD distance in children without connected
tissue disease are needed. The author's review how MAD was
(09:48):
seen in the connected tissue patients and how the composite
endpoint was seen in those without marphan syndrome, meaning it
can happen in any of these diseases, though they do
point out again that the early onset severe marfin patient
had the highest proportion of patients meeting the composite outcome
of all of the connected tissue disease patients in this work.
Given the high negative predictive value of the height indexed
(10:09):
MAD distance in identifying patients at risk for the composite outcome,
they suggest that it may be useful as a factor
to aid in stratifying patients with connected tissue disease in
regards to risks for VT or sutten cardiac death. Limitations
of this work included the retrospective single center design with
a possible selection or referral bias CMR spanning over a
(10:30):
very long time period from twenty to twenty twenty, in
which imaging protocols and resolution have varied, and the composite
outcome was relatively uncommon, so external validation and prospective study
would be important before adopting a firm clinical cutoff, and
so they conclude quote A small fibrous separation between the
microvalve hinge point and ventricular micardium can be visualized by
(10:52):
CMR and normal children and young adults. Children and young
adults with connected tissue disease have a longer MAD distance
than healthy can subjects. MAD and associated adverse cardiovascer outcomes
were observed in patients with Marphin syndrome, as well as
in patients with Lowey's ded syndrome, atypical connected tissue diseases,
and with connected tissue diseases without a specific genetic diagnosis.
(11:15):
A height indexed value of zero point zero three to
three millimeters per centimeter for the maximum systolic MAD distance
was the best binary discriminator for patients with the composite
outcome of significant ventrichlarrythmia, cardiac arrest, or death from patients
without these outcomes. Height indexed MAD distance remains an independent
predictor of the composite outcome in a covariate adjusted model.
(11:37):
The proportion of patients in this young cohort who met
the composite outcome was low careful longitonal followup is needed
to assess the cumulative risk of adverse events over long term,
and further studies needed to better understand the prognostic value
of the mad distance in children without connected tissue disease,
as well as on the management of children with mad Well.
This is an important report because it provides us with
(11:59):
a clue as to the prediction of sudden cardiac arrest
or sudden cardiac death amongst patients with connected tissue disorders. Clearly,
this is a retrospective study, and I am in agreement
that prospective work is needed to confirm these findings, but
it is certainly interesting to see how this distance can
be used, as it is in adults, as a possible
line in the sands to increase concerns about ventricular arrhythmias
(12:21):
or sudden cardiac arrest. Given that patients with these disorders
often have a ortopathy and require cmrs, it seems that
adding this measurement to at least one CMR is valuable
and likely not too difficult. It's interesting how there was
very little scarring seen in the hearts of these patients,
but I suspect that maybe this is because of the
(12:41):
ages of the patients in comparison to older cohorts, studies
and adults. I wonder also what doctor Castellanos and colleagues
believe should be done with these data in regards to
enhance surveillance in the interests of time. Therefore, I think
we should move forward to our conversation with the work's
first author, doctor Daniel Castellanos, joining us now to discussed
this week's work is the works first author, Doctor Daniel Castellanos.
(13:04):
Doctor Castellanos is a graduate undergraduate from the University of
Notre Dame, followed by medical school at the Florida International
University Herbert Wertheim College of Medicine in Miami, Florida. Following this,
Doctor Castellanos performed his residency at the Children's Hospital of
Los Angeles. Following his residency, he completed his fellowship at
Baylor College of Medicine, Texas Children's Hospital and the University
(13:26):
of Texas Southwestern in Dallas, Texas. Doctor Castellanos is an
Associate cardiologist in the Department of Cardiology at Boston Children's
Hospital and is Assistant Professor of Pediatrics at Harvard Medical School.
It is a delight to welcome him to our podcast
this week, Welcome doctor Castellanos to PDHART. I'm here now
with doctor Daniel Castellanos at Boston Children's Hospital. Doctor Castellanos,
(13:47):
thank you very much for joining us this week on PDHART.
Speaker 2 (13:50):
Oh, thank you.
Speaker 3 (13:50):
I'm a longtime listener of the podcast and it's a
real privilege to be able to contribute.
Speaker 1 (13:55):
That's very nice of you. Thank you very much. You know.
I often will start these interviews by starting by asking
the interviewee if they might be able to summarize for
the audience what they view as the three or four,
shall we say, take away points of your work This week.
Speaker 2 (14:11):
Of course, I'll go over four points.
Speaker 3 (14:13):
The first one is that although my triangular disjunction is
a fiber separation between the mitroblve hitch point and the
ventricular milcardium, a small fiber separation can be visualed by
CMR in normal children young adults and is not itself
an indication of a verse Olcome two is that children
young adults with connective disorders have a longer miitraniator disjunction
(14:36):
distance than healthy control subjects. Three would be that in
those children young adults with connective tissue disorders, a height
index cut off value for the maximum systolic my tri
annular disjunction distance is in our study was the best
primary discriminator for patients with a composite outcome of significant ventric.
Speaker 2 (14:58):
L arrhythmia cardiger a debt.
Speaker 3 (15:01):
And note that we did look into how to best
look at that value of that my tranitor's junction distance
and the value is systolic was not diestolic and our
cohort and mac and it's the maximum value of three
among three commonly obtained cmrviews, So the two chamber review,
the four Chamber review, and the LBOT view. And finally
the fourth point I'll say is we did look at
(15:21):
a variety of connected tissue disorders. My trailers junction is present,
can be seen in multiple of them, and it may
play a role in the valgular pathology for children with
early on set Marfan syndrome.
Speaker 1 (15:33):
I see, wow, that's great, very interesting, and a number
of points you made that I did not make, and
you're just inscribing your paper. So I'm really happy we
had you to speak about that. Thank you very much.
You know, Danny, your work had thirty four patients who
met the composite end point and yet interestingly, very few
patients had lake gatolinium enhancement, which would be sometimes consistent
(15:55):
with fibrosis, which you might be expected if that were
a man mechanism for the presumed a rhythmias that these
patients can have. And I wondered if you had any
thoughts on why there were so many patients in the
work who had VT or some cardiac arrest but so
few who had lake gattolinium enhancement on the CMR.
Speaker 3 (16:15):
Yeah, I think this retrospective work not every patient had
the same imaging protocol. In other words, not every patient
had lake gettolium enhancement imaging, so it wasn't looked for
in every patient. So the two hundred and fifty four
patients with connected tissue disorders, the imaging four late gtalinium
enhancement was performed only in forty nine, or roughly nineteen percent,
(16:36):
So this is a smaller sample size to begin with,
and therefore this variable wasn't even included in our clinical outcome.
Speaker 2 (16:42):
Analysis for the manuscript.
Speaker 3 (16:44):
You know, of the forty nine patients with lg ASSESSM performed,
only five patients there met the composite outcome. One with
a pentricl arrhythmia and forward deaths, but none were positive
for LG at the time of CMR. In terms of
my person and old thoughts about this, you know, I
can start by reviewing that my Trier leader disjunction or
(17:05):
m MAYD results in a systelic curling motion of the
basal left ventricular milcardium, and it's hypothesized that this results
in abnormal stretch of the popular muscles and their attachment
and the poplar muscle attachments to like the inferior basal
segment of the left ventricle, and that results in fibrosis
of these areas. And so perhaps the development of clinically
(17:25):
visible late gettalinium enhancement due to stretch from NAD occurs
over time, and so if the fibrosis, fibrosis build up
is gradual and LG assessment in childhood.
Speaker 2 (17:36):
May be a bit too early to show up.
Speaker 3 (17:38):
On our imaging, although determining this is beyond the scope
of our study.
Speaker 2 (17:42):
But this is maybe one hypothesis.
Speaker 1 (17:44):
I see, you know, Danny. For the non MRI oriented
folks who are listening, including myself, I wonder how difficult
is it to get the micro annular disjunction distance as
you describe in three different views on the CMR. Does
this add substantially to the length of these studies? Is
this a challenging thing to do?
Speaker 2 (18:05):
Yeah?
Speaker 3 (18:05):
So. A version of the imaging protocol for patients with
connective connective tissue disorders at our center focuses on obtaining
vascular measurements and thus does not include the two chamber
SINA and the four chamber CINNA, mainly because you're not
making measurements.
Speaker 2 (18:20):
Off of those for the vessels.
Speaker 3 (18:23):
However, obtaining a two chamber SINA a four chamber SINA
any left and trickly alphloa tract views are commonly performed
in CMR centers around the world, so adding a two
chamber and four chamber SINNING to the protocol would increase
the scan time by only a few minutes, and this
minimal increasing scan time should be achievable in many scenarios.
I was thinking about this and another related question is
(18:46):
if and when to perform late GTELINA enhancement imaging. Doing
so is more involved compared to SINA imaging, as it
involves obtaining IB access and administering gata lineum, which is
different from the SINNA imaging which does.
Speaker 2 (18:59):
Not require contract.
Speaker 3 (19:00):
Yes, while gata linium is sometimes administering our center for
patient connective tititius or it's not done for every scan
as these patients didn't have multiple scans, and so doing
so potentially extends the patient encounter by tens of minutes
and introduces the risk associated contrast administration.
Speaker 2 (19:16):
Albeit we think that it's low.
Speaker 3 (19:19):
So I do think LGA imaging LGE or like gatilinium
enhancement imaging should be considered at some point if the
patient has mitrila intersjunction, and ideally it would be performed
if and.
Speaker 2 (19:28):
When gata linium is being administered for an angelgram.
Speaker 1 (19:31):
I say, yeah, it's a very good point you raised.
Thank you. Uh. Sort of following up on this, you know,
it seemed that the height index MAD distance didn't change
with time in your work. I think that was one
of the secondary findings. And I'm wondering if you all
feel confident in suggesting that this measurement, if obtained properly
(19:52):
in one study, doesn't need to be obtained serially in
the connective tissue disease patient if it seems to be relatively.
Speaker 3 (20:00):
Yeah, if level of confidence on the fact that the
height index MD distance does not change over time is
on a spectrum my level of confidence. I probably characterize
my confidence as moderate. Okay, you know, the number of
patients within our cohort for which the systemic my training
insjunction distance could be measured in all three CINI views
on serial cardiac m RII examinations was thirty four, which
(20:23):
is not a high number. However, my confidence is bolstered
by a separate study from Texas Cholm's Hospital in which
sixty three patients is my training insjunction had cereal echo cardiograms,
and the height index my training instruction value in this
independent cohort was also constant over time. So the fact
that two separate cohorts from two separate centers using two
(20:44):
different imaging modalities reach the same conclusion and increases my
confidence from what otherwise have been lowered.
Speaker 2 (20:51):
This was only seen in our cohort.
Speaker 1 (20:53):
Yeah, Danny, it's just strikes me from your answer. I'm
sure people are going to wonder. Obviously, doing an m
is a bit more invasive, a little bit of a
bigger deal, Scheduling takes more time, cooperation, et cetera. Can
these measurements be accurately performed on echo or is it
your belief that the MRI is tremendously more accurate and
(21:17):
that that really should be how we make this measurement.
Speaker 2 (21:20):
So we personally haven't looked into that.
Speaker 3 (21:24):
I don't the team on texasholn'sossible has at some point,
and they would say.
Speaker 2 (21:28):
That they can.
Speaker 3 (21:30):
You know, my caveat here would be the same caveats
that you have when you think about imaging in general,
ego cardiography. You may have issues with windows right and
and not being maybe in a plane that is a
true two chamber, true four chamber or true like personal
long access or lefend true.
Speaker 2 (21:47):
Batpho chunk view.
Speaker 3 (21:48):
And so if you are having any difficulty with your
eco cardiogram, for sure I would consider a CARDIOGAMMERI these
patients obtain cardiogameriz regularly, and so I I do think
that if you're doing a partigamurai, it should still be
measured from that view.
Speaker 2 (22:05):
As you know, the data on comparing and.
Speaker 3 (22:08):
MRI is just from a single center so far, and
I do I do wonder how generalizable would be to
make sure that those measurements would be similar.
Speaker 2 (22:18):
So I do think it's.
Speaker 3 (22:19):
Value to do it both, but if you have a
good echo podiogram, you should be getting an assessment for
med up from that as well too.
Speaker 1 (22:25):
I see, thank you well for those in the audience.
Danny offline informed me that he was just back from
vacation and I'm sure this is just about the worst
time ever to have to do something not related to
work when you have to catch up with everything. So
I'm going to finish up this interview with the last question,
which is like the hardest question of all, which is
you know, if a clinician identifies a higher risk MAD
(22:47):
height index distance in their connected tissue disease patient who
is at that time asymptomatic, I'm wondering, as the expert
in this area, now, what would you suggest should be
the optimal follow up given the negative for predictive value
of a smaller distance or alternatively, the possibility that a
(23:07):
longer distance is associated with the problem. Is there any
VT or VF surveillance warranted in as, for example, in
a connective tissue disorder passion who had a normal MAD distance,
and similarly, when they're abnormal, what do you recommend.
Speaker 3 (23:24):
So you know, I don't consider myself a content expert
for FALLO up in the clinic. So I'm venturing into
this based off of prior discussions with some of my
electric physiology colleagues, including some Lizzie de Witt, who has
dedicated time and thought to this. Patients with connective tissue
disorders in a higher my shiner insjunction distance it should
have some regular rhythm monitoring it, and one should consider
(23:46):
doing that up to an annual basis the MRI. Let's
say the MRI also had Lakenly enhancement, then that may
be even higher risk, and there have been discussions about
considering an EP consultation if they're not being followed by electrophysiologists,
where discussions can even consider an.
Speaker 2 (24:03):
Implentable loop recorder at that point.
Speaker 3 (24:06):
Otherwise, if a pision with connective tissue disorder has no
rhythmic symptoms and my trying to instruction distance is low,
then there's.
Speaker 2 (24:13):
No real need to do anything beyond what may be
your usual standard of care for that passion.
Speaker 1 (24:20):
I see, well, I think that's very important, and I
certainly think that the very high negative predictive value of
a small, smaller or a normal distance was a very
reassuring finding in your study. Well, Danny, I can't thank
you enough for joining us this week on PD HEART.
I want to congratulate you and all of your many
co investigators, especially your senior co investigator Ron Lacrow, who
(24:43):
tried hard to teach me how to echo a long
time ago. Didn't succeed, but that was more me than him.
Congratulations and thank you so much.
Speaker 2 (24:50):
Yeah again, it was a pleasure. Thanks for the invitation.
Speaker 1 (24:53):
Thank you again.
Speaker 2 (24:54):
Well.
Speaker 1 (24:54):
As I map to say when the guest is good,
there's really not much to add. Doctor Castellanos shared with
us as take on the important points of this paper,
and I found it really helpful to hear the author
crystallized for us or focus us on the important take homes.
I think also his points on the generally more benign
arrhythmic course of the normal mad distance patients to be reassuring,
(25:15):
and I think that some of his recommendations regarding follow
up for this possibility and who might merit follow up
were very important. Once again, I'd like to thank him
from taking time from his very busy schedule to speak
with us this week on PD heart to conclude this
three hundred and sixty third episode of Pedheart Pediatric Cardiology.
Today we hear the wonderful up and coming Romanian soprano
(25:36):
Paula Yanchek, who studied singing in Romania and who received
a master's degree in singing from the National Academy of
Music of Romania. She has sung in much of Europe,
with most of her career so far centered in Germany
as well as Romania, but with a voice as lovely
as hers, I'm sure she is just at the start
of what will hopefully be a very big international career.
(25:57):
Today we hear her sing the aarya iosun lu melee
ancella from Chilea's Adriana Lecouvreur. Sorry for the quick ending
of this live recording, but it was abbreviated in this
live pirated recording. But I'm sure you will see exactly
why it is so likely that this young singer has
a big career ahead of her. Thank you very much
for joining me for this episode, and thanks once again
(26:18):
to our guest doctor Castellanos.
Speaker 4 (26:20):
I hope we'll have a good week Aheadless
Speaker 1 (28:08):
Ass
Welcome to Pheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm host to this podcast. I am
professor of Pediatrics at the Icon School of Medicine at
Mount Sinai here in New York City. Thank you for
joining me for this three hundred and sixty third episode
of Pdheart. I hope all enjoyed last week's episode on
the topic of caronary artery fistula. As I say most weeks.
(00:36):
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 into the world of connective tissue
disorders as well as cardiac MRI or imaging. The title
of the work we'll be reviewing is mitra Annular disjunction
distance is associated with adverse outcomes in children and young
adults with connective tissue disorders. The first author of this
(00:59):
work is Daniel Castellanos and the senior author Ronald Lacrow.
And this work comes to us from Boston Children's Hospital,
Harvard University. When we're done reviewing this paper, doctor Daniel Castellanos,
the first author, has kindly agreed to speak with us
about it. Therefore, let's move straight onto this article and
then a conversation with the work's first author. This week's
(01:20):
work is on the topic of mitral annular disjunction. Most
listening likely know what this is, but just so e'ar
all on the same page. This sort of so called
disjunction is a structural abnormality where the hinge point of
the posterior mitral valve leaflet is abnormally displaced towards the left,
a trim separating it from the adjacent left ventricular myacardium
(01:41):
during ventricular sistely and this gap between the ventricular muscle
and the annulus can be from a few millimeters to
over a centimeter. This abnormal hypermobile motion of the micro
valve that's associated with this abnormality can create mechanical stress
on the micro valve leaflets, cordae, and adjacent muscle, which
can cause mycardial scarring or fibrosis in the basal infralateral
(02:04):
wall or pepillary muscles. And it's frequently seen in mitrovol
prolapse patients and is also commonly seen in adults with
connective tissue disease like Lowe's DEETS or Morphan syndrome. This
is a rare but important finding because the fibrosis can
cause ventricular arrhythmias or more rarely, can be associated with
sudden cardiac death. This can also cause chest pain, exercise intolerance,
(02:28):
or palpitations. In adults, A disjunction distance exceeding five millimeters
or a combination of late gatolinium enhancement and arrhythmias in
this setting would be considered a high risk indicator. With
this as a background, let's move on to the paper
from the team in Boston. The authors start by reviewing
mitralannular disjunction or MAD as I will refer to it
(02:49):
in this paper, but also mention that though there are
a lot of data in adults, there's relatively little in children,
with some work on Morphan syndrome, where larger microlanular disjunction
distances being associated with increased risk of prophylactic gaortic surgery
or higher incidents of intricular ectopy. However, they explained that
there's essentially no data on its presence in other connected
(03:11):
tissue diseases, and there's also fairly little on CMR and
MAD in children, and so the authors explained that the
purpose of this work was to describe the range of
MAD distance by CMR in children and young adults with
connected tissue disease and in healthy control subjects, and then
to assess ways in which the MAD distance can be
(03:31):
represented in children and young adults to possibly discriminate those
who have or do not have adverse clinical outcomes. This
was a single center retrospective cohort of patients with connected
tissue disorders and controls with cardiac MRIs between twenty twenty twenty.
At this center, measurements were made on two chamber, four
chamber and lv auflo tract views in both systily and diastole,
(03:54):
and values were reported as absolute and index to body
surface area and height. There were two hundred and fifty
four connective tissue disease patients with a mean age of
seventeen plus or minus six years, and thirty healthy controls
aged fourteen plus or minus three years with a mean
connective tissue disease follow up of five years. For this work,
the primary outcome was a composite of significant ventricular arrhythmias
(04:18):
to find as symptomatic VT, sustained VT, or placement of
an implantable cardiac defibrillator, cardiac arrest and or death and
dawns of the results. Again, there were thirty healthy controls
in two hundred and fifty four patients with connective tissue disease,
of which fifty three percent had morphan syndrome. The mean
height was greater in the connective tissue patients, who were
(04:39):
of course older and had syndromes associated with greater height,
but there were no differences in weight or body surface area.
And what were some of the more important findings. First,
perhaps not unexpectedly, the maximum MAD distance in the control
group was three point six millimeters, but was larger in
patients with connective tissue disease in all standard CMR views
when compared to the control The authors did perform late
(05:02):
gatilinium enhancing testing in about forty nine of the connected
tissue disease patients. In three cases did have LV late
gatilinium enhancement, but the prevalence was so low that its
presence could not be meaningfully studied or used in their models.
In the median follow up period of five years, twenty
one patients, or eight point three percent of the patients
in the connected tissue disease group, met the composite outcome
(05:24):
with a mean age of thirteen point three at the
CMR versus seventeen point four for those with connected tissue
disease without the composite outcome. Amongst these, twenty one patients,
two had significant ventricular arrhythmias, two had a cardiac arrest,
and eighteen patients died. And what about the MAD distance
Did it help identify those with the composite outcome? Yes,
(05:45):
it did. The MAD distance was generally larger in patients
with the composite outcome, whether assessed in the absolute distance,
the body surface area index distance, or the height indexed value.
For a height indexed maximum systolic MAD threshold of zero
point three to three millimeters per centimeter, the sensitivity was
seventy nine percent, specificity seventy percent, accuracy was seventy one percent,
(06:09):
and positive predictive value nineteen percent, with a negative predictive
value of ninety seven percent. The authors explained that while
the cases with an outcome were more likely to have
a longer MAD distance than those without an outcome event,
they were cases with an event that did not have
a MAD distance enlargement. The authors then evaluated the height
indexed maximal systolic MAD with the threshold of zero point
(06:32):
three to three millimeters per centimeter in a covariate adjusted
logistic regression model including other predictors of the composite outcome,
and the model once again demonstrated that height indexed maximum
systolic MAD was an independent predictor of the composite clinical outcome,
with an ODDS ratio of eleven point eight and a
P value of zero point zero zero four. The authors
(06:54):
compared the connective tissue disease patients and saw a significant
difference in height indexed MAD distance among the six different
connected tissue diseases in this work, with similar height indexed
MAD in Marfan and Lowe's date syndromes that were longer
than the other genetic groups, and perhaps not shockingly, the
early onset severe marphan subset, of which there were seven patients,
(07:15):
had a longer height indexed MAD distance. The composite event
rate was similar between all the different connected tissue disease
patient groups, but the seven patients with early onsets severe
marphans did have higher vent rates than all the other groups.
In their discussion, the author's state and I quote this
study found that a small separation up to three point
six millimeters between the mitrovalve hinge point and vetricular myacardium
(07:38):
can be observed in healthy children and young adults and
is likely not indicative of adverse outcomes. By comparison, children
and young adults with connected tissue disease have a longer
MAD distance compared to healthy control subjects. This longer MAD
distance is not limited to morphan syndrome, but also is
present in other connected tissue diseases, including various forms of
(07:59):
Lowe's deep scs indrome, atypical connected tissue diseases, and connected
tissue disease without a specifically identified genetic mutation. In patients
with connected tissue disease, longer absolute BSA index than height
indexed systolic MAD distances were associated with the composite outcome
of significant ventricholarrhythmia, cardiac arrest, or death in these patients.
(08:20):
A height indexed value of zero point three to three
millimeters per centimeter for the maximum systolic MAD distance best
discriminated between those with and without the composite outcome. Furthermore,
in a covaried adjusted model, the cutoff value of zero
point three to three millimeters per centimeter for the maximum
systolic height indexed MAD distance was an independent predictor of
(08:42):
the composite outcome. The authors suggest that when doing a
CMR and a patient with connected tissue disease to assess
the aortic dimensions, which is often the reason for these studies,
it would be useful to obtain the maximal systolic MAD
distance among the two chamber, four chamber and lvflow views,
and they recommend doing at least lest one CMR with
these measurements in a connected tissue patient, even if that's
(09:04):
not the actual purpose of the study. They suggest that
the four chamber view by itself is suboptimal to measure
the MAD distance. They make arguments regarding why all three
different measurements are of benefit in each patient. They re
emphasize that the height indexed MAD distance was constant over
time and how this was seen previously in other works,
but also how it best discriminated between those with and
(09:26):
without the composite outcome. They suggest an I quote. In
agreement with prior studies, we recommend using height indexed MAD
distances as the optimal method to describe MAD in children
and young adults with connected tissue disease. More studies on
the prognostic value of MAD distance in children without connected
tissue disease are needed. The author's review how MAD was
(09:48):
seen in the connected tissue patients and how the composite
endpoint was seen in those without marphan syndrome, meaning it
can happen in any of these diseases, though they do
point out again that the early onset severe marfin patient
had the highest proportion of patients meeting the composite outcome
of all of the connected tissue disease patients in this work.
Given the high negative predictive value of the height indexed
(10:09):
MAD distance in identifying patients at risk for the composite outcome,
they suggest that it may be useful as a factor
to aid in stratifying patients with connected tissue disease in
regards to risks for VT or sutten cardiac death. Limitations
of this work included the retrospective single center design with
a possible selection or referral bias CMR spanning over a
(10:30):
very long time period from twenty to twenty twenty, in
which imaging protocols and resolution have varied, and the composite
outcome was relatively uncommon, so external validation and prospective study
would be important before adopting a firm clinical cutoff, and
so they conclude quote A small fibrous separation between the
microvalve hinge point and ventricular micardium can be visualized by
(10:52):
CMR and normal children and young adults. Children and young
adults with connected tissue disease have a longer MAD distance
than healthy can subjects. MAD and associated adverse cardiovascer outcomes
were observed in patients with Marphin syndrome, as well as
in patients with Lowey's ded syndrome, atypical connected tissue diseases,
and with connected tissue diseases without a specific genetic diagnosis.
(11:15):
A height indexed value of zero point zero three to
three millimeters per centimeter for the maximum systolic MAD distance
was the best binary discriminator for patients with the composite
outcome of significant ventrichlarrythmia, cardiac arrest, or death from patients
without these outcomes. Height indexed MAD distance remains an independent
predictor of the composite outcome in a covariate adjusted model.
(11:37):
The proportion of patients in this young cohort who met
the composite outcome was low careful longitonal followup is needed
to assess the cumulative risk of adverse events over long term,
and further studies needed to better understand the prognostic value
of the mad distance in children without connected tissue disease,
as well as on the management of children with mad Well.
This is an important report because it provides us with
(11:59):
a clue as to the prediction of sudden cardiac arrest
or sudden cardiac death amongst patients with connected tissue disorders. Clearly,
this is a retrospective study, and I am in agreement
that prospective work is needed to confirm these findings, but
it is certainly interesting to see how this distance can
be used, as it is in adults, as a possible
line in the sands to increase concerns about ventricular arrhythmias
(12:21):
or sudden cardiac arrest. Given that patients with these disorders
often have a ortopathy and require cmrs, it seems that
adding this measurement to at least one CMR is valuable
and likely not too difficult. It's interesting how there was
very little scarring seen in the hearts of these patients,
but I suspect that maybe this is because of the
(12:41):
ages of the patients in comparison to older cohorts, studies
and adults. I wonder also what doctor Castellanos and colleagues
believe should be done with these data in regards to
enhance surveillance in the interests of time. Therefore, I think
we should move forward to our conversation with the work's
first author, doctor Daniel Castellanos, joining us now to discussed
this week's work is the works first author, Doctor Daniel Castellanos.
(13:04):
Doctor Castellanos is a graduate undergraduate from the University of
Notre Dame, followed by medical school at the Florida International
University Herbert Wertheim College of Medicine in Miami, Florida. Following this,
Doctor Castellanos performed his residency at the Children's Hospital of
Los Angeles. Following his residency, he completed his fellowship at
Baylor College of Medicine, Texas Children's Hospital and the University
(13:26):
of Texas Southwestern in Dallas, Texas. Doctor Castellanos is an
Associate cardiologist in the Department of Cardiology at Boston Children's
Hospital and is Assistant Professor of Pediatrics at Harvard Medical School.
It is a delight to welcome him to our podcast
this week, Welcome doctor Castellanos to PDHART. I'm here now
with doctor Daniel Castellanos at Boston Children's Hospital. Doctor Castellanos,
(13:47):
thank you very much for joining us this week on PDHART.
Speaker 2 (13:50):
Oh, thank you.
Speaker 3 (13:50):
I'm a longtime listener of the podcast and it's a
real privilege to be able to contribute.
Speaker 1 (13:55):
That's very nice of you. Thank you very much. You know.
I often will start these interviews by starting by asking
the interviewee if they might be able to summarize for
the audience what they view as the three or four,
shall we say, take away points of your work This week.
Speaker 2 (14:11):
Of course, I'll go over four points.
Speaker 3 (14:13):
The first one is that although my triangular disjunction is
a fiber separation between the mitroblve hitch point and the
ventricular milcardium, a small fiber separation can be visualed by
CMR in normal children young adults and is not itself
an indication of a verse Olcome two is that children
young adults with connective disorders have a longer miitraniator disjunction
(14:36):
distance than healthy control subjects. Three would be that in
those children young adults with connective tissue disorders, a height
index cut off value for the maximum systolic my tri
annular disjunction distance is in our study was the best
primary discriminator for patients with a composite outcome of significant ventric.
Speaker 2 (14:58):
L arrhythmia cardiger a debt.
Speaker 3 (15:01):
And note that we did look into how to best
look at that value of that my tranitor's junction distance
and the value is systolic was not diestolic and our
cohort and mac and it's the maximum value of three
among three commonly obtained cmrviews, So the two chamber review,
the four Chamber review, and the LBOT view. And finally
the fourth point I'll say is we did look at
(15:21):
a variety of connected tissue disorders. My trailers junction is present,
can be seen in multiple of them, and it may
play a role in the valgular pathology for children with
early on set Marfan syndrome.
Speaker 1 (15:33):
I see, wow, that's great, very interesting, and a number
of points you made that I did not make, and
you're just inscribing your paper. So I'm really happy we
had you to speak about that. Thank you very much.
You know, Danny, your work had thirty four patients who
met the composite end point and yet interestingly, very few
patients had lake gatolinium enhancement, which would be sometimes consistent
(15:55):
with fibrosis, which you might be expected if that were
a man mechanism for the presumed a rhythmias that these
patients can have. And I wondered if you had any
thoughts on why there were so many patients in the
work who had VT or some cardiac arrest but so
few who had lake gattolinium enhancement on the CMR.
Speaker 3 (16:15):
Yeah, I think this retrospective work not every patient had
the same imaging protocol. In other words, not every patient
had lake gettolium enhancement imaging, so it wasn't looked for
in every patient. So the two hundred and fifty four
patients with connected tissue disorders, the imaging four late gtalinium
enhancement was performed only in forty nine, or roughly nineteen percent,
(16:36):
So this is a smaller sample size to begin with,
and therefore this variable wasn't even included in our clinical outcome.
Speaker 2 (16:42):
Analysis for the manuscript.
Speaker 3 (16:44):
You know, of the forty nine patients with lg ASSESSM performed,
only five patients there met the composite outcome. One with
a pentricl arrhythmia and forward deaths, but none were positive
for LG at the time of CMR. In terms of
my person and old thoughts about this, you know, I
can start by reviewing that my Trier leader disjunction or
(17:05):
m MAYD results in a systelic curling motion of the
basal left ventricular milcardium, and it's hypothesized that this results
in abnormal stretch of the popular muscles and their attachment
and the poplar muscle attachments to like the inferior basal
segment of the left ventricle, and that results in fibrosis
of these areas. And so perhaps the development of clinically
(17:25):
visible late gettalinium enhancement due to stretch from NAD occurs
over time, and so if the fibrosis, fibrosis build up
is gradual and LG assessment in childhood.
Speaker 2 (17:36):
May be a bit too early to show up.
Speaker 3 (17:38):
On our imaging, although determining this is beyond the scope
of our study.
Speaker 2 (17:42):
But this is maybe one hypothesis.
Speaker 1 (17:44):
I see, you know, Danny. For the non MRI oriented
folks who are listening, including myself, I wonder how difficult
is it to get the micro annular disjunction distance as
you describe in three different views on the CMR. Does
this add substantially to the length of these studies? Is
this a challenging thing to do?
Speaker 2 (18:05):
Yeah?
Speaker 3 (18:05):
So. A version of the imaging protocol for patients with
connective connective tissue disorders at our center focuses on obtaining
vascular measurements and thus does not include the two chamber
SINA and the four chamber CINNA, mainly because you're not
making measurements.
Speaker 2 (18:20):
Off of those for the vessels.
Speaker 3 (18:23):
However, obtaining a two chamber SINA a four chamber SINA
any left and trickly alphloa tract views are commonly performed
in CMR centers around the world, so adding a two
chamber and four chamber SINNING to the protocol would increase
the scan time by only a few minutes, and this
minimal increasing scan time should be achievable in many scenarios.
I was thinking about this and another related question is
(18:46):
if and when to perform late GTELINA enhancement imaging. Doing
so is more involved compared to SINA imaging, as it
involves obtaining IB access and administering gata lineum, which is
different from the SINNA imaging which does.
Speaker 2 (18:59):
Not require contract.
Speaker 3 (19:00):
Yes, while gata linium is sometimes administering our center for
patient connective tititius or it's not done for every scan
as these patients didn't have multiple scans, and so doing
so potentially extends the patient encounter by tens of minutes
and introduces the risk associated contrast administration.
Speaker 2 (19:16):
Albeit we think that it's low.
Speaker 3 (19:19):
So I do think LGA imaging LGE or like gatilinium
enhancement imaging should be considered at some point if the
patient has mitrila intersjunction, and ideally it would be performed
if and.
Speaker 2 (19:28):
When gata linium is being administered for an angelgram.
Speaker 1 (19:31):
I say, yeah, it's a very good point you raised.
Thank you. Uh. Sort of following up on this, you know,
it seemed that the height index MAD distance didn't change
with time in your work. I think that was one
of the secondary findings. And I'm wondering if you all
feel confident in suggesting that this measurement, if obtained properly
(19:52):
in one study, doesn't need to be obtained serially in
the connective tissue disease patient if it seems to be relatively.
Speaker 3 (20:00):
Yeah, if level of confidence on the fact that the
height index MD distance does not change over time is
on a spectrum my level of confidence. I probably characterize
my confidence as moderate. Okay, you know, the number of
patients within our cohort for which the systemic my training
insjunction distance could be measured in all three CINI views
on serial cardiac m RII examinations was thirty four, which
(20:23):
is not a high number. However, my confidence is bolstered
by a separate study from Texas Cholm's Hospital in which
sixty three patients is my training insjunction had cereal echo cardiograms,
and the height index my training instruction value in this
independent cohort was also constant over time. So the fact
that two separate cohorts from two separate centers using two
(20:44):
different imaging modalities reach the same conclusion and increases my
confidence from what otherwise have been lowered.
Speaker 2 (20:51):
This was only seen in our cohort.
Speaker 1 (20:53):
Yeah, Danny, it's just strikes me from your answer. I'm
sure people are going to wonder. Obviously, doing an m
is a bit more invasive, a little bit of a
bigger deal, Scheduling takes more time, cooperation, et cetera. Can
these measurements be accurately performed on echo or is it
your belief that the MRI is tremendously more accurate and
(21:17):
that that really should be how we make this measurement.
Speaker 2 (21:20):
So we personally haven't looked into that.
Speaker 3 (21:24):
I don't the team on texasholn'sossible has at some point,
and they would say.
Speaker 2 (21:28):
That they can.
Speaker 3 (21:30):
You know, my caveat here would be the same caveats
that you have when you think about imaging in general,
ego cardiography. You may have issues with windows right and
and not being maybe in a plane that is a
true two chamber, true four chamber or true like personal
long access or lefend true.
Speaker 2 (21:47):
Batpho chunk view.
Speaker 3 (21:48):
And so if you are having any difficulty with your
eco cardiogram, for sure I would consider a CARDIOGAMMERI these
patients obtain cardiogameriz regularly, and so I I do think
that if you're doing a partigamurai, it should still be
measured from that view.
Speaker 2 (22:05):
As you know, the data on comparing and.
Speaker 3 (22:08):
MRI is just from a single center so far, and
I do I do wonder how generalizable would be to
make sure that those measurements would be similar.
Speaker 2 (22:18):
So I do think it's.
Speaker 3 (22:19):
Value to do it both, but if you have a
good echo podiogram, you should be getting an assessment for
med up from that as well too.
Speaker 1 (22:25):
I see, thank you well for those in the audience.
Danny offline informed me that he was just back from
vacation and I'm sure this is just about the worst
time ever to have to do something not related to
work when you have to catch up with everything. So
I'm going to finish up this interview with the last question,
which is like the hardest question of all, which is
you know, if a clinician identifies a higher risk MAD
(22:47):
height index distance in their connected tissue disease patient who
is at that time asymptomatic, I'm wondering, as the expert
in this area, now, what would you suggest should be
the optimal follow up given the negative for predictive value
of a smaller distance or alternatively, the possibility that a
(23:07):
longer distance is associated with the problem. Is there any
VT or VF surveillance warranted in as, for example, in
a connective tissue disorder passion who had a normal MAD distance,
and similarly, when they're abnormal, what do you recommend.
Speaker 3 (23:24):
So you know, I don't consider myself a content expert
for FALLO up in the clinic. So I'm venturing into
this based off of prior discussions with some of my
electric physiology colleagues, including some Lizzie de Witt, who has
dedicated time and thought to this. Patients with connective tissue
disorders in a higher my shiner insjunction distance it should
have some regular rhythm monitoring it, and one should consider
(23:46):
doing that up to an annual basis the MRI. Let's
say the MRI also had Lakenly enhancement, then that may
be even higher risk, and there have been discussions about
considering an EP consultation if they're not being followed by electrophysiologists,
where discussions can even consider an.
Speaker 2 (24:03):
Implentable loop recorder at that point.
Speaker 3 (24:06):
Otherwise, if a pision with connective tissue disorder has no
rhythmic symptoms and my trying to instruction distance is low,
then there's.
Speaker 2 (24:13):
No real need to do anything beyond what may be
your usual standard of care for that passion.
Speaker 1 (24:20):
I see, well, I think that's very important, and I
certainly think that the very high negative predictive value of
a small, smaller or a normal distance was a very
reassuring finding in your study. Well, Danny, I can't thank
you enough for joining us this week on PD HEART.
I want to congratulate you and all of your many
co investigators, especially your senior co investigator Ron Lacrow, who
(24:43):
tried hard to teach me how to echo a long
time ago. Didn't succeed, but that was more me than him.
Congratulations and thank you so much.
Speaker 2 (24:50):
Yeah again, it was a pleasure. Thanks for the invitation.
Speaker 1 (24:53):
Thank you again.
Speaker 2 (24:54):
Well.
Speaker 1 (24:54):
As I map to say when the guest is good,
there's really not much to add. Doctor Castellanos shared with
us as take on the important points of this paper,
and I found it really helpful to hear the author
crystallized for us or focus us on the important take homes.
I think also his points on the generally more benign
arrhythmic course of the normal mad distance patients to be reassuring,
(25:15):
and I think that some of his recommendations regarding follow
up for this possibility and who might merit follow up
were very important. Once again, I'd like to thank him
from taking time from his very busy schedule to speak
with us this week on PD heart to conclude this
three hundred and sixty third episode of Pedheart Pediatric Cardiology.
Today we hear the wonderful up and coming Romanian soprano
(25:36):
Paula Yanchek, who studied singing in Romania and who received
a master's degree in singing from the National Academy of
Music of Romania. She has sung in much of Europe,
with most of her career so far centered in Germany
as well as Romania, but with a voice as lovely
as hers, I'm sure she is just at the start
of what will hopefully be a very big international career.
(25:57):
Today we hear her sing the aarya iosun lu melee
ancella from Chilea's Adriana Lecouvreur. Sorry for the quick ending
of this live recording, but it was abbreviated in this
live pirated recording. But I'm sure you will see exactly
why it is so likely that this young singer has
a big career ahead of her. Thank you very much
for joining me for this episode, and thanks once again
(26:18):
to our guest doctor Castellanos.
Speaker 4 (26:20):
I hope we'll have a good week Aheadless
Speaker 1 (28:08):
Ass
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