This week we go back in time to 2022 to re-enter the world of cardiogenetics and electrophysiology when we review the topic of catecholaminergic polymorphic ventricular tachycardia (CPVT). Is there a 'best' beta blocker for the treatment of this condition? Why is one better than others? How should one manage the patient who is intolerant of beta blockade but needs it for prevention of arrhythmia? What is the role of flecainide, sympathectomy or even ICD's for these patients? PhD candidate and physician Dr. Puck Peltenburg and CPVT world authority, Dr. Christian van der Werf (both of University of Amsterdam) share their deep insights this week. doi: 10.1161/CIRCULATIONAHA.121.056018. Epub 2021 Dec 7
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Episode Transcript
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Speaker 1 (00:00):
Hello everybody, This is Rob Pass, the host of the podcast.
This week, we're going back in time to twenty twenty
two to review the optimal treatment of catacholaminertic polymorphic ventricular
attack at cardia. You'll recall that we spoke with doctor
Puck Peltenberg and doctor Christian van der Verf, both from
the University of Amsterdam. I hope you enjoyed this replay episode.
I'll see you next week with a brand new episode.
(00:38):
Welcome to Pediheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm the host of this podcast. I'm
Professor of Pediatrics at the Icon School of Medicine at
Mount SINAI thank you for joining me for this two
hundred and thirty fourth and second to last episode of
twenty twenty two. I hope everybody enjoyed last week's episode
on the topic of bioprosthetic valves and the pregnant patient.
We spoke with doctor er We shurch Schmidt of Austria,
(01:02):
and for those of you with an interest in pregnancy
and adult congenital heart disease, I'd strongly recommend you to
take to listen to last week's informative episode two hundred
and thirty two. 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 on to the world of electrophysiology. The
title of the work we'll be reviewing is an international
(01:24):
multi center cohort study on beta blockers for the treatment
of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. The first
author of this work is Puck Jay Peltenberg and the
senior author is Arthur Wilda. And this work comes to
us from multiple centers. The main authors come to us
from the University of Amsterdam Heart Center in the Netherlands.
(01:46):
When we're done reviewing the paper, doctor Puck Peltenberg and
doctor Christian van der Werf have both kindly agreed to
speak with us about it. Therefore, let's move on to
the article and then a conversation with its authors. This
week's work is on the topic of catacholminergic polymorphic ventricular tachycardia,
or so called CPVT, and we all know that this
(02:06):
condition is characterized by bidirectional or polymorphic ventricular tachycardia. That's
usually seen at times of elevated adrenergic tone, such as
times of stress or physical exertion, and these arrhythmias are dangerous,
potentially resulting in syncope, cardiac arrest, or even death, and
patients with this condition usually have structurally and functionally normal
(02:27):
hearts with a normal resting surface electric cardiogram. For many
years now, we've known that beta blockers, in concert with
appropriate recommendations regarding activity, are the main stays of therapy
for this condition, and use of these agents, much as
in long QT syndrome, has been shown to reduce serious
arrhythmia or cardiac events. However, despite their use, the literature
(02:49):
is full of reports of patients with CPVT who continue
to have events, and most of us who've cared for
this patient group would certainly concur with this point. The
authors explain that on adherence to beta blocker recommendations may
account for some of the arrhythmeas that are seen, but
not all, and in some the breakthrough arrhythmias or cardiac
events seen may be due to the particular type of
(03:11):
beta blocker that the patient was taking, and certainly there
is evidence in other conditions of the superiority of some
beta blockers over others for conditions of this nature, with
long QT syndrome being one such condition. The authors remind
us that when patients with CPVT have these breakthroughs, typically
fleckanide may be added or left carniac sympathetic denervation may
(03:32):
be performed. The authors then explained that a few small
studies have suggested that non selective beta blockers like nata
law or propanolol have been shown to be superior to
beta one selective beta blockers in patients with CPVT, but
there are no large scale studies assessing the efficacy of
different beta blockers for this condition until, of course, this
(03:53):
work which we're reviewing this week, and so the authors
state here data from two large international multi center CPVT
patient registries were used to evaluate the association of non
selective versus beta one selective beta blockers and of specific
beta blockers with a rhythmic event rates in a high
risk CPVT population of symptomatic children. The authors conducted an
(04:17):
observational cohort study using two CPVT registries, specifically the PACES
Registry and the International CPVT Registry. These are both very
large registries. Of these patients who have CPVT and combine.
There are nearly sixty participating centers for this work. Only
symptomatic children to find a syncope without or with seizures
(04:41):
and sudden cardiac arrest before initiation of beta blockers and
those whose age and initiation was less than eighteen were included. Additionally,
only patients who had a variant of unknown significance or
a likely pathogenic variant in the RyR two gene that
encodes the cardiac ryanodine receptor were included, and those who
(05:01):
had a VUS also had to have had a definitive
CPVT phenotype. The study excluded those with other cardiac disease
or those who had an RyR two loss of function
variant or a gene encoding a cardiac calciquestrin gene, in
which case again these patients were excluded. For this work.
(05:22):
The primary outcome was a composite of first occurrence of
an arrhythmic event after beta blockers were started, and these
included sudden cardiac death, sudden cardiac arrest, appropriate ICD shock,
or syncope thought to be due to cardiac origin. The
secondary outcome studied was a more strict composite outcome of
the first occurrence of a near fatal event such as
(05:43):
sudden cardiac death, sudden cardiac arrest, or an appropriate ICD
shock and syncope was removed from the secondary outcome group.
The authors reviewed the complex statistical analysis for this work
and for the granular detail. I would certainly recommend you
review this paper, specifically page three hundred and thirty five
and altso the results. In total, there were three hundred
(06:05):
and ninety symptomatic children with CPVT who met criteria to
be included in this study. Forty three percent or one
hundred and forty of these three hundred and ninety total
kids were initially treated with natalol, with twenty one percent
or seventy patients on propranolol, sixteen percent or fifty one
on a tenolol, ten percent or thirty three at metoprolol,
(06:25):
and nineteen patients or six percent on bisoprolol. Five percent
or sixteen patients were on other fairly rarely prescribed beta
blockers such as as sebutolol and carveatalol. Thus, to summarize, basically,
two thirds of patients were initially treated with a non
selected beta blocker like natalol or perpenolol. Importantly, there were
no significant differences in the baseline characteristics of the patients
(06:48):
started on different beta blockers. Two thirds of patients were
treated with a single beta blocker, whereas twenty nine percent
switched to another beta blocker and five percent even switched
two times. One of patients or six percent, were on
phlecanide at the baseline, and only seven percent or twenty
three patients had an ICD. And on to the important data.
(07:09):
Thirty percent of patients or ninety nine patients experienced the
primary outcome of sudden cardiac death, sudden cardiac arrest, appropriate
ICD shock, or syncope presumed to be cardiac in origin,
and twenty three percent or seventy four patients experienced the
secondary outcome of sudden cardiac death, sudden cardiac arrest, or
an appropriate ICD shock. And here is perhaps the most
(07:30):
important finding of this entire work. The risk for both
the primary or secondary outcome was higher for those on
beta one selected beta blockers in comparison to non selected
beta blockers, with a hazard ratio of two point four
for the primary and one point nine nine for the
secondary outcomes. When looking at the individual beta blockers and
comparing them to natolol. The hazard ratio for the primary
(07:53):
outcome was two point seven for a tenolol, three point
two for bisoprolol, and two point two for metopolol, but
the hazard ratio did not differ when comparing these agents
to propenolol. When looking at the secondary outcome of sudden
cardiac death or sudden cardiac arrest or an appropriate ICD shock,
only a tenolol had a higher hazard ratio than natoalol
at two point seven, suggesting pretty clearly that at the
(08:16):
very least, a tenolol was not anywhere near as good
as natalol for patients with CPVED. The authors tried to
assess the doses of medication that the patients were taking,
and they had data on about two thirds of the
patients in the cohort. They discovered that twenty four percent
of patients had a suboptimal dose at the time of
a arythmic event, with a range of nine to forty
four percent depending on the particular beta blocker used. In
(08:39):
regard to non adherents to the beta blockers and a
possible relationship of this to events, they discovered the thirty
nine percent of patients in which they had the data
had not adherence to meds at the time of an event.
In their discussion, the author stayed and I quote in
this large cohort of symptomatic children with CPVT, treatment with
beta wine, unselected beta blockers was independently associated with a
(09:03):
higher risk for rhythmic events and near fatal arrhythmic events
compared with non selected beta blockers. The association was most
evident for natilol. The author's common on possible explanations for
why the different beta blockers assessed had varying levels of efficacy,
and they start by reminding us that this large, multi
institutional study has confirmed what has been previously demonstrated on
(09:24):
smaller studies on this topic regarding the superiority of non
selected beta blockade for the management of CPVT. They suggest
that the differences seen might be related to non adherents
with the correct dose for non selected beta blockers, and
they re emphasize how thirty nine percent of patients were
non adherent at the time of their first arrhythmic event
and twenty four percent were taking a suboptimal dose at
(09:46):
the time of their event. They mentioned how most of
the beta blockers other than natolol have shorter half lives,
meaning that missing a dose for those agents may leave
a patient more exposed for events than someone who's taking
an agent like natolol that had longer half life. They
also mention the impact of puberty on events and wonder
if the non adherence seen in this is due to
(10:07):
issues of non adherance that are known to occur for
all medications that are required in the teenager. The authors
also speak of genetic variability in the metabolism of beta
blockers of different types, and how natilol is known to
have fairly low pharmacokinetic variation in comparison to other agents
like a tenolol or meritoprolol or per penolol, where differences
in cytochrome P four fifty metabolism, where the presence of
(10:30):
a full or an empty stomach at the time of
administration can affect effective levels of the agent. The authors
then explain how different beta blockers have different effects on
cardiac ion channels, and they review how affecting the peak
sodium current, which is something that natalol can do but
most other beta blockers cannot, may provide at least a
partial explanation for why it may reduce the chances of
(10:51):
delayed after depolarizations which have been associated with arrhythmias in
this condition. In regard to limitations, the authors review the
retrospective design in its news natural bias, the absence of
granular data regarding the arrhythmias that were seen in these
patients prior to starting the medication and how this may
have impacted outcomes, the lack of data regarding adherents in
(11:11):
beta blocker dosage on the majority of patients at the
time of event, and in general information regarding compliance with
medication was poor in this work. Additionally, some of the
beta blockers were used so infrequently that meaningful conclusions couldn't
be drawn, and so they conclude. We conclude that beta
one selective beta blockers are associated with the higher risk
(11:31):
for a rhythmic events and near fatal arhythmic events and
symptomatic children with CPVT. When beta blockers were assessed separately,
the association of a higher risk for a rhythmic events
was evident with a tenolol, bisoprolul and the toprolol compared
with natilol. In the absence of perspective randomized trials in
this topic, and the perspective. Thereof, we believe that natalol
(11:52):
should be the preferred initial beta blocker for treatment of
this population. Therefore, we deem it necessary that natalol is
made available and continue to be available in all countries.
Even though perpenolol did not reach statistical significance over beta
one selected beta blockers in terms of lower risk for
rhythmic events, we would recommend remaining with a non selected
beta blocker such as per penolol in situations where natalol
(12:15):
is either unavailable or not tolerated. Furthermore, the rate of
non adherents in suboptimal doses at the time of an
event in the population is high. Clinicians should be aware
of this to treat and counsel their patients appropriately well.
I would say that this is a very important work,
pretty much showing that in the absence of a larger,
more detailed perspective study on this topic, it seems clear
(12:36):
that natalol is the best treatment for most patients with
CPVT and should be the treatment of choice for this
patient group. I found it interesting to learn that it's
not actually readily available in all countries despite its relatively
low cost and generic status. I wonder if some of
the listeners have had the same experience I have had
of having to haggle with insurance companies that would rather
(12:57):
that we prescribe something else other than natalol for patients
who have arrhythmic conditions like CPVT or long QT syndrome.
Seems that a lot of plans did not include this
agent on their regular formulary. I do wonder about the
impact of compliance on these data. So many patients in
this work were not compliant, and the data in this
was very incomplete, and so I'm marginally worried that we
(13:19):
don't really know how important that issue is in affecting
these data. And certainly I think we all know that
natalol in general is less well tolerated by most patients
due decide effects like feeling tired, and so I think
this factor does need to go into the calculus in
thinking about what to prescribe for these patients. At this point,
I think it would be best for us to move
(13:39):
forward to our discussion with two of the works authors,
doctors Peltenberg and Vanderwerf. Doctor Christian Vanderwerf is a graduate
of Utrech Medical School in the Netherlands and he completed
a PhD on sudden death and the Young and clinical
aspects of inherited cardiac diseases at the University of Amsterdam.
Doctor Puck Peltenberg is a PhD student at the University
(13:59):
of Amsterdam and has already won awards for her work
on inherited cardiac arrhythmic conditions. She is a graduate of
mass Streek University for Medical school and it is certainly
one of the up and coming superstars in this fascinating field.
It is a great pleasure to welcome them both to
the podcast. Welcome doctor Peltenberg and doctor van Deverf. I'm
here now with Christian van der Werf and Puck Peltenberg.
(14:20):
Doctor van Derverv, Doctor Peltenberg, what a great pleasure to
have you all the way from Amsterdam to speak with
us today on the podcast.
Speaker 2 (14:27):
Yeah, thank you very much for having us.
Speaker 1 (14:29):
It's a pleasure, real pleasures. Pleasure is all ours, guys,
very much enjoyed. This work really confirmed something that I
think most of us thought was the case, but you
certainly sealed the deal with this report. You know, your
work assessed a number of aspects of the treatment of CPVT,
and one of the things you mentioned was that improper
(14:49):
dosage of beta blockers might have been a possible cause
of some of some bad outcomes. And I was wondering,
even though I've been practicing as a p meatric electrophysiologists
for over twenty years, what is your view on what
is the actual proper dose of natal al for the
treatment of CPVT.
Speaker 3 (15:09):
Yeah, thank you for this question, and I think it's
a very important question.
Speaker 2 (15:13):
In our study, we also defined.
Speaker 3 (15:16):
Suboptimal dosage, but I think that dosage doesn't really reflect
what the optimal dosage is for patients with CPVT, So
we define the dosage of one milligram particligram of anolol
in CPVT patients as the minimum for optimal treatment. But
I think in general all pediatric cardiologists or cardiologists will
(15:39):
up increase the dosage of beta blocker if that is
tolerated by the patients to reduce the number of premature
fortricure complexes on the exercise stress test and also the
risk for rhythmia.
Speaker 1 (15:55):
And does that just I mean in an adult sized patient,
you just keep increasing the dose. In words, if you
have a ninety kilo seventeen year old, are you recommending
that the patient get essentially ninety milligrams a day minimum
of natolol or is there some sort of usual maximal
adult dose.
Speaker 4 (16:16):
Well, the thing is, I think we will speak about
it later as well. We don't have natolol in the Netherlands,
so for example, my own clinical experience with not a
lool is zero never perspective because we simply don't have it.
So all my own clinical experiences with perpenalol, yeah, and
they're usually yeah, you indeed try to keep up with this.
(16:39):
Those of milligram per kilogram. On the other hand, has
also shown in our paper there's a significant proportion of
patients who get a suboptimal dose. But I think every
clinician who treats this kind of patient recognizes that these
young people frequently suffer from side effects from beta blockers.
I mean, beta blockers are nice drugs. In our study,
(17:04):
one in five patients of whom we had this information
reported side effects. So sometimes I'm sure you will recognize
this as well. It's difficult to actually achieve this optimal
or even higher dosages.
Speaker 1 (17:17):
Yeah, well, I'm glad you brought that up. It's sort
of a nice segue into my second question. Doctor van
der Werth you know a large number of your patients
did need to change the dose, or at least did
change change the beta blocker itself. I assume most of
the time it was because it wasn't well tolerated. And
I'm wondering, as a practicing physician, do you have any
(17:39):
clinical tips on how to deal with this sort of
situation where patients are not tolerating it, short of recommending
a sympathetic innervation surgery or changing to something like fleckanine. Yeah.
Speaker 3 (17:51):
So, first of all, the assumption that it's due to
side effects, that's probably true for a number of patients.
Also know that in some countries not at all became
available during several years ago, so patients who were on
a beta one selective beta blocker were then switched not all,
So these are also included in the patients who switch
(18:14):
between beta blockers. But the second part of your question,
I think also flack and eye should have an important
place in the treatment for patients with CPVT. So if
they don't tolerate their beta blocker well, flack and eye
can be added, and therefore the beta blocker dose you
might be able to reduce I see.
Speaker 1 (18:32):
And so in other words, you would in some cases
consider lowering the natal to a dose or the beta
blocker to a dose that's tolerable and adding to that
flack Andie in certain cases. Is that is that? Is
that what you're trying to suggest that, doctor Peltenberg.
Speaker 4 (18:49):
Yeah, that's correct, Okay, If I might add that's what
I h that's my tinical experience as well. That's exactly
what I do with them with perpenal. So if they
don't tolerate it, well, yeah, we add Flackaye to see
the effects, and then if the effect is there, I
sometimes lower the dose of properalal or a not a
(19:10):
beta blocker, and then do another exercise stress test to say,
to see that that the effect remained similar.
Speaker 1 (19:18):
You know. Earlier this year I was involved in a
debate at pd Rhythm meeting in which I was debating
the question of whether flack and I could be started
as an out patient in children. I'm wondering if you
start this as an outpatient in your patients, or if
you admit everybody and observe for potential pro rhythmic associated
(19:41):
with flacanine.
Speaker 4 (19:42):
No, So, I think we have a very different perspective
on that topic in the US and in the Netherlands
and probably in a lot of other European countries as well.
In adult patients we never admit them. Also elut patients
with atrifibulations for other indications black andites, we always started
(20:03):
on an outpatient basis, so I also do that for
young eighteen year old CPPT patients. But then you know,
usually we let them take it for a few days
and then repeat the exercise stress test in this case,
to check for the efficacy but also for the potential
for a review.
Speaker 1 (20:20):
I see, I see. Well. Actually the person I was
debating was from Scotland and she strongly opposed admissions to
the hospital, so I guess this is a European thing.
I'm wondering you reviewed a little bit in your paper,
but for those of us who haven't read the paper,
I'm wondering if you could review with us some of
(20:42):
the cellular mechanisms by which it's thought that natalol actually
may be superior to other beta blockers for the treatment
of CPVT.
Speaker 2 (20:51):
Yeah, thank you for your question.
Speaker 3 (20:52):
That's indeed very interesting, and the short answer would be
that we don't know exactly why this is different as
we saw in our paper, but there's a few hypotheses,
one of which is a cellular mechanism. So in CPVT,
the diseases or symptoms are caused by delayed after depolarization.
Speaker 2 (21:17):
Patients with CPVT, most of.
Speaker 3 (21:20):
Them have a variant in the reality channel, which is
in the sarcoplasmic reticulum, and calcium leaks through the cercoplasmic
reticulum in the intracardiac cell, and then the sodium calcium
exchanger starts to get calcium out of the cell and
(21:42):
sodium in, which can cause a phase zero of the
action action potential and therefore delayed after depolarizations. Another law
has an effect on the sodium influx, though very small.
Properal also has this effect, and it's a bigger effect.
So I think, yeah, it's a really broad hypothesis. It's speculation.
(22:05):
We can't say that this is really what's happening in
the difference in not a law and other beta blockers.
And I think more importantly there's also a difference in
non selectivity versus selectivity, and also the half life of
not a law which is longer compared to other beta blockers.
And I think in CPBT, as in long uty or
(22:26):
other diseases everywhere. Non adherence is a very important topic.
So if not a law has a longer half life,
a missdows might pose a patient at a lower risk
compared to a better booker with a shorter half life.
Speaker 1 (22:39):
Yes, yes, very interesting. Thank you for that explanation. You
know you've already mentioned doctor Vanderwerth that natal ol is
not even available in the Netherlands. I wasn't aware that
there were multiple countries where this was in fact the case.
It's interesting. You might find it interesting to know that
sometimes in the United States, if a patient is on
(23:01):
natalol and it is not covered by their insurance carrier,
they will often ask us if we can put the
patient on a different beta blocker which is in their formulary.
So I'm glad to have your paper to show them
that the answer to that question would be no. But
I'm wondering what are you recommending. It sounds like in
your country pretty much everybody gets propranolol plus or minus
(23:24):
fleck Andy. But what are you generally recommending? Is that?
Is that the only agent that you're recommending or any others.
Speaker 4 (23:30):
Well, I think it's important to realize that we in
this study, we included symptomatic children, so these are really
the highest risk patients. So I think in symptomatic children
and probably also in adults presenting with a singcoopy or
certain cardigorists, or having one of these events during treatment
(23:53):
with another beta blocker, I think propenalo should be the
beta blocker prescribed and then lack a NITE or sympathectomy
can be edited. Obviously, we also have a lot of
mainly adult patients, but also children who are asymptomatic and
who are identified by cascade screening, so who are tested
(24:14):
for the familial or we are to mutation, and those
are lower risk patients.
Speaker 1 (24:20):
So yeah, I'm not.
Speaker 4 (24:23):
Sure if propanal is really needed in those lower risk patients.
We we usually start them on perpenalal, but if they're
already on a different beta blocker, I don't always change
it to perpenalal, and if they don't tolerate perpenalal. Yeah,
I also, you know, it's less of a problem problem
for me to to change to bizopolo for example. You
(24:43):
know sometimes edit with fleck and eite edit as well.
Speaker 1 (24:47):
I see, thank you for that. I think it'll be
very useful for people who don't have have it as
an agent at present. You know, non adherence is something
we've been talking about was a large problem for patients
in this work, but I know you don't have complete
data on that aspect from your data set. Was the
(25:07):
degree of non adherence similar between the beta blockers, in
other words, that people not tolerate things like natalow to
a greater degree than other beta blockers, or was the
non adherent similar amongst all of the different types of
beta blockade.
Speaker 3 (25:23):
So what we know was at the time of the
arythmic event in some patient, the physician knew whether or
not the patient was adherent, so the patient informed the physition.
But I can also imagine in real world you also
don't know the true adherent because a patient might say
he is adherent but might actually not take their medicine
(25:45):
at all according to prescription. So we didn't know it
for every patient, but from the patient we did know it.
It was two thirds of the patients. The non adherence
rate was similar between all beta booker groups. I don't
think this affected our results, but I do think it's
maybe underlying our results the difference in detta bookers, and
(26:09):
I do think it's a very important problem, and we
also need to dig further into it. What is the
true rate of non adherence, but also what are reasons
of the non adherence. Is it not tolerating the better
blocker well, experience so well, experiencing a lot of side effects,
or also believes about CPID, about the disease itself, or
(26:29):
about the medication. Something we can discuss in the Ugurt
patient clinic and might help us to improve the experience
in patience with CBILD. But this is also a topic
we aim to study in the coming months with the
survey in patience with CBLD to be able to improve
that in the future.
Speaker 1 (26:49):
I see, I see well for those in the audience,
it's in the evening time in Amsterdam, and so I
don't want to take up a whole lot more time
of doctor Peltenberg and doctor Vanderwrel's time. So I'm going
to finish up with the last question. I'm going to
take advantage of the fact that we have two world
authorities on CPVT, both in the same podcast, to just
(27:10):
ask you, you know, I think it's clear from your
work and from what we've discussed tonight that propranolol or
i should say natalol and then alternatively, propranolol would be
your first agents used in the treatment of these patients.
But I was wondering, how do you decide if a
patient needs a sympathetic denervation surgery or and then also
(27:35):
how do you We've talked a little bit about how
you choose to put some patients on fleck, and I
maybe you could just give us your thoughts on like
a treatment algorithm, an unofficial treatment algorithm.
Speaker 4 (27:45):
Yes, thank you for that question. To start with sympathetic denovation.
I think the choice to do that and also in
which phase of the treatment depends very much on the
availability of a capable surgeon to perform that procedure. For example,
you know important collaborators in the International CIPIFT Registry are
(28:09):
our professor Eckermann and colleagues from the Mayo Clinic. They
have a very large sympathetic to me program, so so
they decide to perform a sympathect to me much earlier
than in many other centers. So that's I think an
important factor to consider. Generally, we also have a very
skilled surgeon in our center perform sympathet too me, but
(28:30):
still in our patients we start with a beta blocker
and black aite, and then sympathet toomy comes in the
third place. And yeah, if a patient presents with a syncopy,
especially with a certain cardi carest we will at least
start properal and blackanite. If we are not happy about
(28:55):
the result of the exercise stress test or have some
doubts about adherents, that we will also recommend sympathectomy. You know,
great advantage of sympathectomy is that there's no problem with
medication adherents obviously, and you know, in lower risk patients
who present with ventricular rhythmias but are asymptomatic, we will
(29:18):
start for pro penalt lol than at flackenite if needed,
and only if there's still a significant burden of ventricular
rhythmias or they experience of breakthrough events, then then we
will recommend sympathectomy. And maybe just very important, we think
that there should be a very high threshold to implant
the fibrillators in these patients. You know, we know that
(29:42):
sometimes there's actually a very low threshold. You know, CPFD
is considered a very malignant channel opathy, so so many colleagues, unfortunately,
you know, are very quick with implanting and the fibrillator,
and then maybe have less attention for adequate B blockade
and and adding phleacanite and considering sympathectomy. But you know,
(30:04):
an ICD, there have been some cases of patients and
experiencing inappropriate shocks which then turned into an electrical storm
which was fatal. Sometimes so And on the other hand,
we have also shown that the defibrillator is not clearly
associated with an improved survival in patients presenting with a
(30:24):
sudden cardigorest. So we apply very high threshold for implanting
defibrillators and think that most of the patients, even the
ones that present with a sudden cardiquorest, are well protected
with propeneral or preferably natural placonite and sometimes sympathectomy.
Speaker 1 (30:42):
And doctor Vanderworth, you sometimes you know, in these circumstances,
a patient has a cardiac arrest and you know they
had an arrhythmia, but you're they're not really in a
state to do a stress test day afterwards, and your
genetic testing may take a couple of weeks to get
the result. I don't know, maybe an answer dam it's faster,
But here we're at least two or three weeks and
(31:05):
the patient's ready to go home and just had this
terribly dramatic situation. So even in those circumstances when you
don't yet have the data to confirm that a patient
may have CPVT, you would still, I guess, lean heavily
on a beta blocker until you had a diagnosis. Is
that is that right, and not go straight to a
(31:25):
defibrillator and someone who had a structurally normal heart, a
normal QT interval, but had an event like this.
Speaker 4 (31:34):
Yeah, that's obviously a very difficult question. But we've also
seen these kind of cases. So it depends very much,
I guess on you know, on the events, but also
for example, indeed on the resting EKG, on the telemetry
telemetry during admission. You know, patients with TBVT don't have
a lot of to be addressed, so you don't expect
(31:56):
a lot of to be when they're still admitting it.
Speaker 2 (32:01):
You know.
Speaker 4 (32:01):
Sometimes a penferent challenge can be considered in patients who
are unable to perform exercise, although it seems like the
accuracy of that test is not as good as an
exercise stress test. Yeah, so it depends a little bit.
If the suspicion is very high, we still try to
get the genetic test very quickly. Sometimes we can, so
(32:24):
if the suspicion is very high, then we might say, Okay,
there's such a high suspicion of CPFT, we might, you know,
just treat the patient with a bit of blocker and
fleckenite and no defibrillator if there's too much doubts. You know,
sometimes the defibrillator is implanted, but you know, the defibrillator
can also be taken out. You know, we've seen several
(32:46):
patients who will refer to us with the clinical diagnosis
of long Fite syndrome and we actually actually diagnosed CPVT
and they only had the defibrillator for a few months,
and we were so convinced by the efficacy of the
other therapies that we took to defibrillate on.
Speaker 1 (33:02):
I think those are extremely important points that you raise
and very important for people listening well, Doctor Peltenberg, Doctor Vandervelf,
I can't thank you enough for joining us this week.
It's a great honor and a pleasure to have you
join us this week on the podcast. Thank you and
congratulations to you and the many, many co authors on
your work really wonderful work and very much appreciate the
(33:25):
opportunity to speak with you this week about it. Thank
you well. I think you'll agree that doctors Peltenberg and
Van Derveerf really provided us with a great discussion regarding
the proper way to manage CPVT patients who are sometimes
at very high risk for sudden cardiac def I found
their comments about how they prioritize therapies for these patients
(33:47):
to be very interesting, and how they move from beta
blockers to possibly fleckin eyed and then possibly a sympathectomy.
I also found their very important comments on the inadvisability
of ICD implantation in this patient group except in very
rare circumstances, and the risks that these devices may pose
to these patients to be very important and something we
(34:09):
all likely need to take to heart. I'd like to
thank doctor Peltenberg and doctor Van der Werf for spending
their time with us and sharing their deep knowledge of
this paper and topic this week. It was a great
pleasure to meet and speak with them both to conclude
this repeat episode of Pedhart Pediatric Cardiology. Today we hear
the magnificent and tragic American tenor Mario Lanza Lonzo was
(34:32):
a handsome Italian American man from Philadelphia who was in
many movies and had a true operatic voice. Despite not
really ever having had an opera career, he sang opera
in the movies of the nineteen forties and fifties, most
notably and perhaps his most famous movie, The Great Caruso,
which was a movie that inspired many great operatic tenors
(34:54):
enamored of Lonzo's magnificent voice in stage presence. Tragically, he
died at thirty eight of what was believed to pulmonary embolism.
Today we hear him sing the wonderful aria Lamento di
Ferrico from Chile's Larceliana in a very rare live recital
with pianist in London, just a bit over a year
before his untimely death. Thank you very much for joining
(35:17):
me for this repeat episode. I'll see everyone next week
in an extra special three hundred and fiftieth episode of.
Speaker 5 (35:24):
Padheart Pasora il sol su sun lovely.
Speaker 6 (36:13):
Be coor me you all.
Speaker 7 (36:33):
Unk me?
Speaker 5 (36:40):
Of course, he let a sun more.
Speaker 7 (36:47):
Lovely love is the conga bong is call.
Speaker 6 (37:26):
Wys fornascle and f the lundy sa ay helvag beyond
(38:11):
more solemnicain hap la sently.
Speaker 7 (38:47):
B you cay.
Speaker 1 (39:00):
W me my
Speaker 3 (39:15):
Mon
Hello everybody, This is Rob Pass, the host of the podcast.
This week, we're going back in time to twenty twenty
two to review the optimal treatment of catacholaminertic polymorphic ventricular
attack at cardia. You'll recall that we spoke with doctor
Puck Peltenberg and doctor Christian van der Verf, both from
the University of Amsterdam. I hope you enjoyed this replay episode.
I'll see you next week with a brand new episode.
(00:38):
Welcome to Pediheart Pediatric Cardiology Today. My name is doctor
Robert Pass and I'm the host of this podcast. I'm
Professor of Pediatrics at the Icon School of Medicine at
Mount SINAI thank you for joining me for this two
hundred and thirty fourth and second to last episode of
twenty twenty two. I hope everybody enjoyed last week's episode
on the topic of bioprosthetic valves and the pregnant patient.
We spoke with doctor er We shurch Schmidt of Austria,
(01:02):
and for those of you with an interest in pregnancy
and adult congenital heart disease, I'd strongly recommend you to
take to listen to last week's informative episode two hundred
and thirty two. 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 on to the world of electrophysiology. The
title of the work we'll be reviewing is an international
(01:24):
multi center cohort study on beta blockers for the treatment
of symptomatic children with catecholaminergic polymorphic ventricular tachycardia. The first
author of this work is Puck Jay Peltenberg and the
senior author is Arthur Wilda. And this work comes to
us from multiple centers. The main authors come to us
from the University of Amsterdam Heart Center in the Netherlands.
(01:46):
When we're done reviewing the paper, doctor Puck Peltenberg and
doctor Christian van der Werf have both kindly agreed to
speak with us about it. Therefore, let's move on to
the article and then a conversation with its authors. This
week's work is on the topic of catacholminergic polymorphic ventricular tachycardia,
or so called CPVT, and we all know that this
(02:06):
condition is characterized by bidirectional or polymorphic ventricular tachycardia. That's
usually seen at times of elevated adrenergic tone, such as
times of stress or physical exertion, and these arrhythmias are dangerous,
potentially resulting in syncope, cardiac arrest, or even death, and
patients with this condition usually have structurally and functionally normal
(02:27):
hearts with a normal resting surface electric cardiogram. For many
years now, we've known that beta blockers, in concert with
appropriate recommendations regarding activity, are the main stays of therapy
for this condition, and use of these agents, much as
in long QT syndrome, has been shown to reduce serious
arrhythmia or cardiac events. However, despite their use, the literature
(02:49):
is full of reports of patients with CPVT who continue
to have events, and most of us who've cared for
this patient group would certainly concur with this point. The
authors explain that on adherence to beta blocker recommendations may
account for some of the arrhythmeas that are seen, but
not all, and in some the breakthrough arrhythmias or cardiac
events seen may be due to the particular type of
(03:11):
beta blocker that the patient was taking, and certainly there
is evidence in other conditions of the superiority of some
beta blockers over others for conditions of this nature, with
long QT syndrome being one such condition. The authors remind
us that when patients with CPVT have these breakthroughs, typically
fleckanide may be added or left carniac sympathetic denervation may
(03:32):
be performed. The authors then explained that a few small
studies have suggested that non selective beta blockers like nata
law or propanolol have been shown to be superior to
beta one selective beta blockers in patients with CPVT, but
there are no large scale studies assessing the efficacy of
different beta blockers for this condition until, of course, this
(03:53):
work which we're reviewing this week, and so the authors
state here data from two large international multi center CPVT
patient registries were used to evaluate the association of non
selective versus beta one selective beta blockers and of specific
beta blockers with a rhythmic event rates in a high
risk CPVT population of symptomatic children. The authors conducted an
(04:17):
observational cohort study using two CPVT registries, specifically the PACES
Registry and the International CPVT Registry. These are both very
large registries. Of these patients who have CPVT and combine.
There are nearly sixty participating centers for this work. Only
symptomatic children to find a syncope without or with seizures
(04:41):
and sudden cardiac arrest before initiation of beta blockers and
those whose age and initiation was less than eighteen were included. Additionally,
only patients who had a variant of unknown significance or
a likely pathogenic variant in the RyR two gene that
encodes the cardiac ryanodine receptor were included, and those who
(05:01):
had a VUS also had to have had a definitive
CPVT phenotype. The study excluded those with other cardiac disease
or those who had an RyR two loss of function
variant or a gene encoding a cardiac calciquestrin gene, in
which case again these patients were excluded. For this work.
(05:22):
The primary outcome was a composite of first occurrence of
an arrhythmic event after beta blockers were started, and these
included sudden cardiac death, sudden cardiac arrest, appropriate ICD shock,
or syncope thought to be due to cardiac origin. The
secondary outcome studied was a more strict composite outcome of
the first occurrence of a near fatal event such as
(05:43):
sudden cardiac death, sudden cardiac arrest, or an appropriate ICD
shock and syncope was removed from the secondary outcome group.
The authors reviewed the complex statistical analysis for this work
and for the granular detail. I would certainly recommend you
review this paper, specifically page three hundred and thirty five
and altso the results. In total, there were three hundred
(06:05):
and ninety symptomatic children with CPVT who met criteria to
be included in this study. Forty three percent or one
hundred and forty of these three hundred and ninety total
kids were initially treated with natalol, with twenty one percent
or seventy patients on propranolol, sixteen percent or fifty one
on a tenolol, ten percent or thirty three at metoprolol,
(06:25):
and nineteen patients or six percent on bisoprolol. Five percent
or sixteen patients were on other fairly rarely prescribed beta
blockers such as as sebutolol and carveatalol. Thus, to summarize, basically,
two thirds of patients were initially treated with a non
selected beta blocker like natalol or perpenolol. Importantly, there were
no significant differences in the baseline characteristics of the patients
(06:48):
started on different beta blockers. Two thirds of patients were
treated with a single beta blocker, whereas twenty nine percent
switched to another beta blocker and five percent even switched
two times. One of patients or six percent, were on
phlecanide at the baseline, and only seven percent or twenty
three patients had an ICD. And on to the important data.
(07:09):
Thirty percent of patients or ninety nine patients experienced the
primary outcome of sudden cardiac death, sudden cardiac arrest, appropriate
ICD shock, or syncope presumed to be cardiac in origin,
and twenty three percent or seventy four patients experienced the
secondary outcome of sudden cardiac death, sudden cardiac arrest, or
an appropriate ICD shock. And here is perhaps the most
(07:30):
important finding of this entire work. The risk for both
the primary or secondary outcome was higher for those on
beta one selected beta blockers in comparison to non selected
beta blockers, with a hazard ratio of two point four
for the primary and one point nine nine for the
secondary outcomes. When looking at the individual beta blockers and
comparing them to natolol. The hazard ratio for the primary
(07:53):
outcome was two point seven for a tenolol, three point
two for bisoprolol, and two point two for metopolol, but
the hazard ratio did not differ when comparing these agents
to propenolol. When looking at the secondary outcome of sudden
cardiac death or sudden cardiac arrest or an appropriate ICD shock,
only a tenolol had a higher hazard ratio than natoalol
at two point seven, suggesting pretty clearly that at the
(08:16):
very least, a tenolol was not anywhere near as good
as natalol for patients with CPVED. The authors tried to
assess the doses of medication that the patients were taking,
and they had data on about two thirds of the
patients in the cohort. They discovered that twenty four percent
of patients had a suboptimal dose at the time of
a arythmic event, with a range of nine to forty
four percent depending on the particular beta blocker used. In
(08:39):
regard to non adherents to the beta blockers and a
possible relationship of this to events, they discovered the thirty
nine percent of patients in which they had the data
had not adherence to meds at the time of an event.
In their discussion, the author stayed and I quote in
this large cohort of symptomatic children with CPVT, treatment with
beta wine, unselected beta blockers was independently associated with a
(09:03):
higher risk for rhythmic events and near fatal arrhythmic events
compared with non selected beta blockers. The association was most
evident for natilol. The author's common on possible explanations for
why the different beta blockers assessed had varying levels of efficacy,
and they start by reminding us that this large, multi
institutional study has confirmed what has been previously demonstrated on
(09:24):
smaller studies on this topic regarding the superiority of non
selected beta blockade for the management of CPVT. They suggest
that the differences seen might be related to non adherents
with the correct dose for non selected beta blockers, and
they re emphasize how thirty nine percent of patients were
non adherent at the time of their first arrhythmic event
and twenty four percent were taking a suboptimal dose at
(09:46):
the time of their event. They mentioned how most of
the beta blockers other than natolol have shorter half lives,
meaning that missing a dose for those agents may leave
a patient more exposed for events than someone who's taking
an agent like natolol that had longer half life. They
also mention the impact of puberty on events and wonder
if the non adherence seen in this is due to
(10:07):
issues of non adherance that are known to occur for
all medications that are required in the teenager. The authors
also speak of genetic variability in the metabolism of beta
blockers of different types, and how natilol is known to
have fairly low pharmacokinetic variation in comparison to other agents
like a tenolol or meritoprolol or per penolol, where differences
in cytochrome P four fifty metabolism, where the presence of
(10:30):
a full or an empty stomach at the time of
administration can affect effective levels of the agent. The authors
then explain how different beta blockers have different effects on
cardiac ion channels, and they review how affecting the peak
sodium current, which is something that natalol can do but
most other beta blockers cannot, may provide at least a
partial explanation for why it may reduce the chances of
(10:51):
delayed after depolarizations which have been associated with arrhythmias in
this condition. In regard to limitations, the authors review the
retrospective design in its news natural bias, the absence of
granular data regarding the arrhythmias that were seen in these
patients prior to starting the medication and how this may
have impacted outcomes, the lack of data regarding adherents in
(11:11):
beta blocker dosage on the majority of patients at the
time of event, and in general information regarding compliance with
medication was poor in this work. Additionally, some of the
beta blockers were used so infrequently that meaningful conclusions couldn't
be drawn, and so they conclude. We conclude that beta
one selective beta blockers are associated with the higher risk
(11:31):
for a rhythmic events and near fatal arhythmic events and
symptomatic children with CPVT. When beta blockers were assessed separately,
the association of a higher risk for a rhythmic events
was evident with a tenolol, bisoprolul and the toprolol compared
with natilol. In the absence of perspective randomized trials in
this topic, and the perspective. Thereof, we believe that natalol
(11:52):
should be the preferred initial beta blocker for treatment of
this population. Therefore, we deem it necessary that natalol is
made available and continue to be available in all countries.
Even though perpenolol did not reach statistical significance over beta
one selected beta blockers in terms of lower risk for
rhythmic events, we would recommend remaining with a non selected
beta blocker such as per penolol in situations where natalol
(12:15):
is either unavailable or not tolerated. Furthermore, the rate of
non adherents in suboptimal doses at the time of an
event in the population is high. Clinicians should be aware
of this to treat and counsel their patients appropriately well.
I would say that this is a very important work,
pretty much showing that in the absence of a larger,
more detailed perspective study on this topic, it seems clear
(12:36):
that natalol is the best treatment for most patients with
CPVT and should be the treatment of choice for this
patient group. I found it interesting to learn that it's
not actually readily available in all countries despite its relatively
low cost and generic status. I wonder if some of
the listeners have had the same experience I have had
of having to haggle with insurance companies that would rather
(12:57):
that we prescribe something else other than natalol for patients
who have arrhythmic conditions like CPVT or long QT syndrome.
Seems that a lot of plans did not include this
agent on their regular formulary. I do wonder about the
impact of compliance on these data. So many patients in
this work were not compliant, and the data in this
was very incomplete, and so I'm marginally worried that we
(13:19):
don't really know how important that issue is in affecting
these data. And certainly I think we all know that
natalol in general is less well tolerated by most patients
due decide effects like feeling tired, and so I think
this factor does need to go into the calculus in
thinking about what to prescribe for these patients. At this point,
I think it would be best for us to move
(13:39):
forward to our discussion with two of the works authors,
doctors Peltenberg and Vanderwerf. Doctor Christian Vanderwerf is a graduate
of Utrech Medical School in the Netherlands and he completed
a PhD on sudden death and the Young and clinical
aspects of inherited cardiac diseases at the University of Amsterdam.
Doctor Puck Peltenberg is a PhD student at the University
(13:59):
of Amsterdam and has already won awards for her work
on inherited cardiac arrhythmic conditions. She is a graduate of
mass Streek University for Medical school and it is certainly
one of the up and coming superstars in this fascinating field.
It is a great pleasure to welcome them both to
the podcast. Welcome doctor Peltenberg and doctor van Deverf. I'm
here now with Christian van der Werf and Puck Peltenberg.
(14:20):
Doctor van Derverv, Doctor Peltenberg, what a great pleasure to
have you all the way from Amsterdam to speak with
us today on the podcast.
Speaker 2 (14:27):
Yeah, thank you very much for having us.
Speaker 1 (14:29):
It's a pleasure, real pleasures. Pleasure is all ours, guys,
very much enjoyed. This work really confirmed something that I
think most of us thought was the case, but you
certainly sealed the deal with this report. You know, your
work assessed a number of aspects of the treatment of CPVT,
and one of the things you mentioned was that improper
(14:49):
dosage of beta blockers might have been a possible cause
of some of some bad outcomes. And I was wondering,
even though I've been practicing as a p meatric electrophysiologists
for over twenty years, what is your view on what
is the actual proper dose of natal al for the
treatment of CPVT.
Speaker 3 (15:09):
Yeah, thank you for this question, and I think it's
a very important question.
Speaker 2 (15:13):
In our study, we also defined.
Speaker 3 (15:16):
Suboptimal dosage, but I think that dosage doesn't really reflect
what the optimal dosage is for patients with CPVT, So
we define the dosage of one milligram particligram of anolol
in CPVT patients as the minimum for optimal treatment. But
I think in general all pediatric cardiologists or cardiologists will
(15:39):
up increase the dosage of beta blocker if that is
tolerated by the patients to reduce the number of premature
fortricure complexes on the exercise stress test and also the
risk for rhythmia.
Speaker 1 (15:55):
And does that just I mean in an adult sized patient,
you just keep increasing the dose. In words, if you
have a ninety kilo seventeen year old, are you recommending
that the patient get essentially ninety milligrams a day minimum
of natolol or is there some sort of usual maximal
adult dose.
Speaker 4 (16:16):
Well, the thing is, I think we will speak about
it later as well. We don't have natolol in the Netherlands,
so for example, my own clinical experience with not a
lool is zero never perspective because we simply don't have it.
So all my own clinical experiences with perpenalol, yeah, and
they're usually yeah, you indeed try to keep up with this.
(16:39):
Those of milligram per kilogram. On the other hand, has
also shown in our paper there's a significant proportion of
patients who get a suboptimal dose. But I think every
clinician who treats this kind of patient recognizes that these
young people frequently suffer from side effects from beta blockers.
I mean, beta blockers are nice drugs. In our study,
(17:04):
one in five patients of whom we had this information
reported side effects. So sometimes I'm sure you will recognize
this as well. It's difficult to actually achieve this optimal
or even higher dosages.
Speaker 1 (17:17):
Yeah, well, I'm glad you brought that up. It's sort
of a nice segue into my second question. Doctor van
der Werth you know a large number of your patients
did need to change the dose, or at least did
change change the beta blocker itself. I assume most of
the time it was because it wasn't well tolerated. And
I'm wondering, as a practicing physician, do you have any
(17:39):
clinical tips on how to deal with this sort of
situation where patients are not tolerating it, short of recommending
a sympathetic innervation surgery or changing to something like fleckanine. Yeah.
Speaker 3 (17:51):
So, first of all, the assumption that it's due to
side effects, that's probably true for a number of patients.
Also know that in some countries not at all became
available during several years ago, so patients who were on
a beta one selective beta blocker were then switched not all,
So these are also included in the patients who switch
(18:14):
between beta blockers. But the second part of your question,
I think also flack and eye should have an important
place in the treatment for patients with CPVT. So if
they don't tolerate their beta blocker well, flack and eye
can be added, and therefore the beta blocker dose you
might be able to reduce I see.
Speaker 1 (18:32):
And so in other words, you would in some cases
consider lowering the natal to a dose or the beta
blocker to a dose that's tolerable and adding to that
flack Andie in certain cases. Is that is that? Is
that what you're trying to suggest that, doctor Peltenberg.
Speaker 4 (18:49):
Yeah, that's correct, Okay, If I might add that's what
I h that's my tinical experience as well. That's exactly
what I do with them with perpenal. So if they
don't tolerate it, well, yeah, we add Flackaye to see
the effects, and then if the effect is there, I
sometimes lower the dose of properalal or a not a
(19:10):
beta blocker, and then do another exercise stress test to say,
to see that that the effect remained similar.
Speaker 1 (19:18):
You know. Earlier this year I was involved in a
debate at pd Rhythm meeting in which I was debating
the question of whether flack and I could be started
as an out patient in children. I'm wondering if you
start this as an outpatient in your patients, or if
you admit everybody and observe for potential pro rhythmic associated
(19:41):
with flacanine.
Speaker 4 (19:42):
No, So, I think we have a very different perspective
on that topic in the US and in the Netherlands
and probably in a lot of other European countries as well.
In adult patients we never admit them. Also elut patients
with atrifibulations for other indications black andites, we always started
(20:03):
on an outpatient basis, so I also do that for
young eighteen year old CPPT patients. But then you know,
usually we let them take it for a few days
and then repeat the exercise stress test in this case,
to check for the efficacy but also for the potential
for a review.
Speaker 1 (20:20):
I see, I see. Well. Actually the person I was
debating was from Scotland and she strongly opposed admissions to
the hospital, so I guess this is a European thing.
I'm wondering you reviewed a little bit in your paper,
but for those of us who haven't read the paper,
I'm wondering if you could review with us some of
(20:42):
the cellular mechanisms by which it's thought that natalol actually
may be superior to other beta blockers for the treatment
of CPVT.
Speaker 2 (20:51):
Yeah, thank you for your question.
Speaker 3 (20:52):
That's indeed very interesting, and the short answer would be
that we don't know exactly why this is different as
we saw in our paper, but there's a few hypotheses,
one of which is a cellular mechanism. So in CPVT,
the diseases or symptoms are caused by delayed after depolarization.
Speaker 2 (21:17):
Patients with CPVT, most of.
Speaker 3 (21:20):
Them have a variant in the reality channel, which is
in the sarcoplasmic reticulum, and calcium leaks through the cercoplasmic
reticulum in the intracardiac cell, and then the sodium calcium
exchanger starts to get calcium out of the cell and
(21:42):
sodium in, which can cause a phase zero of the
action action potential and therefore delayed after depolarizations. Another law
has an effect on the sodium influx, though very small.
Properal also has this effect, and it's a bigger effect.
So I think, yeah, it's a really broad hypothesis. It's speculation.
(22:05):
We can't say that this is really what's happening in
the difference in not a law and other beta blockers.
And I think more importantly there's also a difference in
non selectivity versus selectivity, and also the half life of
not a law which is longer compared to other beta blockers.
And I think in CPBT, as in long uty or
(22:26):
other diseases everywhere. Non adherence is a very important topic.
So if not a law has a longer half life,
a missdows might pose a patient at a lower risk
compared to a better booker with a shorter half life.
Speaker 1 (22:39):
Yes, yes, very interesting. Thank you for that explanation. You
know you've already mentioned doctor Vanderwerth that natal ol is
not even available in the Netherlands. I wasn't aware that
there were multiple countries where this was in fact the case.
It's interesting. You might find it interesting to know that
sometimes in the United States, if a patient is on
(23:01):
natalol and it is not covered by their insurance carrier,
they will often ask us if we can put the
patient on a different beta blocker which is in their formulary.
So I'm glad to have your paper to show them
that the answer to that question would be no. But
I'm wondering what are you recommending. It sounds like in
your country pretty much everybody gets propranolol plus or minus
(23:24):
fleck Andy. But what are you generally recommending? Is that?
Is that the only agent that you're recommending or any others.
Speaker 4 (23:30):
Well, I think it's important to realize that we in
this study, we included symptomatic children, so these are really
the highest risk patients. So I think in symptomatic children
and probably also in adults presenting with a singcoopy or
certain cardigorists, or having one of these events during treatment
(23:53):
with another beta blocker, I think propenalo should be the
beta blocker prescribed and then lack a NITE or sympathectomy
can be edited. Obviously, we also have a lot of
mainly adult patients, but also children who are asymptomatic and
who are identified by cascade screening, so who are tested
(24:14):
for the familial or we are to mutation, and those
are lower risk patients.
Speaker 1 (24:20):
So yeah, I'm not.
Speaker 4 (24:23):
Sure if propanal is really needed in those lower risk patients.
We we usually start them on perpenalal, but if they're
already on a different beta blocker, I don't always change
it to perpenalal, and if they don't tolerate perpenalal. Yeah,
I also, you know, it's less of a problem problem
for me to to change to bizopolo for example. You
(24:43):
know sometimes edit with fleck and eite edit as well.
Speaker 1 (24:47):
I see, thank you for that. I think it'll be
very useful for people who don't have have it as
an agent at present. You know, non adherence is something
we've been talking about was a large problem for patients
in this work, but I know you don't have complete
data on that aspect from your data set. Was the
(25:07):
degree of non adherence similar between the beta blockers, in
other words, that people not tolerate things like natalow to
a greater degree than other beta blockers, or was the
non adherent similar amongst all of the different types of
beta blockade.
Speaker 3 (25:23):
So what we know was at the time of the
arythmic event in some patient, the physician knew whether or
not the patient was adherent, so the patient informed the physition.
But I can also imagine in real world you also
don't know the true adherent because a patient might say
he is adherent but might actually not take their medicine
(25:45):
at all according to prescription. So we didn't know it
for every patient, but from the patient we did know it.
It was two thirds of the patients. The non adherence
rate was similar between all beta booker groups. I don't
think this affected our results, but I do think it's
maybe underlying our results the difference in detta bookers, and
(26:09):
I do think it's a very important problem, and we
also need to dig further into it. What is the
true rate of non adherence, but also what are reasons
of the non adherence. Is it not tolerating the better
blocker well, experience so well, experiencing a lot of side effects,
or also believes about CPID, about the disease itself, or
(26:29):
about the medication. Something we can discuss in the Ugurt
patient clinic and might help us to improve the experience
in patience with CBILD. But this is also a topic
we aim to study in the coming months with the
survey in patience with CBLD to be able to improve
that in the future.
Speaker 1 (26:49):
I see, I see well for those in the audience,
it's in the evening time in Amsterdam, and so I
don't want to take up a whole lot more time
of doctor Peltenberg and doctor Vanderwrel's time. So I'm going
to finish up with the last question. I'm going to
take advantage of the fact that we have two world
authorities on CPVT, both in the same podcast, to just
(27:10):
ask you, you know, I think it's clear from your
work and from what we've discussed tonight that propranolol or
i should say natalol and then alternatively, propranolol would be
your first agents used in the treatment of these patients.
But I was wondering, how do you decide if a
patient needs a sympathetic denervation surgery or and then also
(27:35):
how do you We've talked a little bit about how
you choose to put some patients on fleck, and I
maybe you could just give us your thoughts on like
a treatment algorithm, an unofficial treatment algorithm.
Speaker 4 (27:45):
Yes, thank you for that question. To start with sympathetic denovation.
I think the choice to do that and also in
which phase of the treatment depends very much on the
availability of a capable surgeon to perform that procedure. For example,
you know important collaborators in the International CIPIFT Registry are
(28:09):
our professor Eckermann and colleagues from the Mayo Clinic. They
have a very large sympathetic to me program, so so
they decide to perform a sympathect to me much earlier
than in many other centers. So that's I think an
important factor to consider. Generally, we also have a very
skilled surgeon in our center perform sympathet too me, but
(28:30):
still in our patients we start with a beta blocker
and black aite, and then sympathet toomy comes in the
third place. And yeah, if a patient presents with a syncopy,
especially with a certain cardi carest we will at least
start properal and blackanite. If we are not happy about
(28:55):
the result of the exercise stress test or have some
doubts about adherents, that we will also recommend sympathectomy. You know,
great advantage of sympathectomy is that there's no problem with
medication adherents obviously, and you know, in lower risk patients
who present with ventricular rhythmias but are asymptomatic, we will
(29:18):
start for pro penalt lol than at flackenite if needed,
and only if there's still a significant burden of ventricular
rhythmias or they experience of breakthrough events, then then we
will recommend sympathectomy. And maybe just very important, we think
that there should be a very high threshold to implant
the fibrillators in these patients. You know, we know that
(29:42):
sometimes there's actually a very low threshold. You know, CPFD
is considered a very malignant channel opathy, so so many colleagues, unfortunately,
you know, are very quick with implanting and the fibrillator,
and then maybe have less attention for adequate B blockade
and and adding phleacanite and considering sympathectomy. But you know,
(30:04):
an ICD, there have been some cases of patients and
experiencing inappropriate shocks which then turned into an electrical storm
which was fatal. Sometimes so And on the other hand,
we have also shown that the defibrillator is not clearly
associated with an improved survival in patients presenting with a
(30:24):
sudden cardigorest. So we apply very high threshold for implanting
defibrillators and think that most of the patients, even the
ones that present with a sudden cardiquorest, are well protected
with propeneral or preferably natural placonite and sometimes sympathectomy.
Speaker 1 (30:42):
And doctor Vanderworth, you sometimes you know, in these circumstances,
a patient has a cardiac arrest and you know they
had an arrhythmia, but you're they're not really in a
state to do a stress test day afterwards, and your
genetic testing may take a couple of weeks to get
the result. I don't know, maybe an answer dam it's faster,
But here we're at least two or three weeks and
(31:05):
the patient's ready to go home and just had this
terribly dramatic situation. So even in those circumstances when you
don't yet have the data to confirm that a patient
may have CPVT, you would still, I guess, lean heavily
on a beta blocker until you had a diagnosis. Is
that is that right, and not go straight to a
(31:25):
defibrillator and someone who had a structurally normal heart, a
normal QT interval, but had an event like this.
Speaker 4 (31:34):
Yeah, that's obviously a very difficult question. But we've also
seen these kind of cases. So it depends very much,
I guess on you know, on the events, but also
for example, indeed on the resting EKG, on the telemetry
telemetry during admission. You know, patients with TBVT don't have
a lot of to be addressed, so you don't expect
(31:56):
a lot of to be when they're still admitting it.
Speaker 2 (32:01):
You know.
Speaker 4 (32:01):
Sometimes a penferent challenge can be considered in patients who
are unable to perform exercise, although it seems like the
accuracy of that test is not as good as an
exercise stress test. Yeah, so it depends a little bit.
If the suspicion is very high, we still try to
get the genetic test very quickly. Sometimes we can, so
(32:24):
if the suspicion is very high, then we might say, Okay,
there's such a high suspicion of CPFT, we might, you know,
just treat the patient with a bit of blocker and
fleckenite and no defibrillator if there's too much doubts. You know,
sometimes the defibrillator is implanted, but you know, the defibrillator
can also be taken out. You know, we've seen several
(32:46):
patients who will refer to us with the clinical diagnosis
of long Fite syndrome and we actually actually diagnosed CPVT
and they only had the defibrillator for a few months,
and we were so convinced by the efficacy of the
other therapies that we took to defibrillate on.
Speaker 1 (33:02):
I think those are extremely important points that you raise
and very important for people listening well, Doctor Peltenberg, Doctor Vandervelf,
I can't thank you enough for joining us this week.
It's a great honor and a pleasure to have you
join us this week on the podcast. Thank you and
congratulations to you and the many, many co authors on
your work really wonderful work and very much appreciate the
(33:25):
opportunity to speak with you this week about it. Thank
you well. I think you'll agree that doctors Peltenberg and
Van Derveerf really provided us with a great discussion regarding
the proper way to manage CPVT patients who are sometimes
at very high risk for sudden cardiac def I found
their comments about how they prioritize therapies for these patients
(33:47):
to be very interesting, and how they move from beta
blockers to possibly fleckin eyed and then possibly a sympathectomy.
I also found their very important comments on the inadvisability
of ICD implantation in this patient group except in very
rare circumstances, and the risks that these devices may pose
to these patients to be very important and something we
(34:09):
all likely need to take to heart. I'd like to
thank doctor Peltenberg and doctor Van der Werf for spending
their time with us and sharing their deep knowledge of
this paper and topic this week. It was a great
pleasure to meet and speak with them both to conclude
this repeat episode of Pedhart Pediatric Cardiology. Today we hear
the magnificent and tragic American tenor Mario Lanza Lonzo was
(34:32):
a handsome Italian American man from Philadelphia who was in
many movies and had a true operatic voice. Despite not
really ever having had an opera career, he sang opera
in the movies of the nineteen forties and fifties, most
notably and perhaps his most famous movie, The Great Caruso,
which was a movie that inspired many great operatic tenors
(34:54):
enamored of Lonzo's magnificent voice in stage presence. Tragically, he
died at thirty eight of what was believed to pulmonary embolism.
Today we hear him sing the wonderful aria Lamento di
Ferrico from Chile's Larceliana in a very rare live recital
with pianist in London, just a bit over a year
before his untimely death. Thank you very much for joining
(35:17):
me for this repeat episode. I'll see everyone next week
in an extra special three hundred and fiftieth episode of.
Speaker 5 (35:24):
Padheart Pasora il sol su sun lovely.
Speaker 6 (36:13):
Be coor me you all.
Speaker 7 (36:33):
Unk me?
Speaker 5 (36:40):
Of course, he let a sun more.
Speaker 7 (36:47):
Lovely love is the conga bong is call.
Speaker 6 (37:26):
Wys fornascle and f the lundy sa ay helvag beyond
(38:11):
more solemnicain hap la sently.
Speaker 7 (38:47):
B you cay.
Speaker 1 (39:00):
W me my
Speaker 3 (39:15):
Mon
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