Thank you very much, Pedro.
And good evening and welcome to all of you.
It's a pleasure to have you.
As Pedro said, so many old friends.
This is truly terrific.
My topic this evening is to try to answer the question,
when to intervene in asymptomatic aortic
regurgitation in children and young adults?
And what is my plan is to discuss a little bit
the natural history of chronic aortic regurgitation;
the pathophysiology of left ventricular
failure in aortic regurgitation, which is what we are trying
to avoid; how to predict that outcome;
and then to end up with some recommendations on when
to intervene in these patients.
So as a way of background, severe chronic aortic
regurgitation can be tolerated for many years.
But ultimately, it catches up with our patients.
And patients then become symptomatic,
mostly developing symptoms of heart failure,
and the disease leads to premature death.
But timely aortic valve replacement or repair,
as we'll discuss later in this symposium,
results in symptomatic improvement
and reduced mortality.
So in order to try to answer the question, when it is best
to do surgical intervention on a severe chronic aortic
regurgitation in an asymptomatic child,
we need to understand the natural history
and pathophysiology of the disease.
So let me get one thing out of the way.
And that is, symptomatic patients
with severe chronic aortic regurgitation,
they usually exhibit symptoms of angina, dyspnea, and heart
failure.
And without surgery, these patients
have an annual mortality rate that exceeds 10%.
Medical therapy is not the solution.
They do not respond to medical therapy.
And when patients with severe chronic AR do have symptoms,
this is a Class I indication for valve replacement or repair.
So we are going to focus most of the talk
on patients who are asymptomatic and have
severe chronic aortic regurgitation.
Let's begin with what we know from adults,
because the vast majority of information in this area
comes from adult patients.
Even in adults, there are no truly large-scale studies,
surprisingly enough.
And what I was able to identify are 13 published series
involving a total of 1,250 patients,
with a mean follow-up of about 6.6 years.
Turns out that sudden death is very
unusual in this patient population.
However, if you leave these patients without intervening
on their aortic regurgitation, with or without
medical treatment, they will develop heart failure symptoms
and they will have premature death.
And the annual rate of developing these complications
is about four to six per year.
And you can see this in these Kaplan-Meier graphs
You can see here mortality in one of the largest
series of adults with severe chronic aortic regurgitation,
here stratified by New York Heart
Association at presentation.
So this just confirms that patients who are symptomatic
have very poor outcome.
And here is patients stratified by left ventricular ejection
fraction.
And of course, those who have depressed LV systolic function
measured as ejection fraction have a very poor outcome,
as the study showed.
What is important to recognize is
that severe chronic aortic regurgitation, even
in asymptomatic patients, leads to irreversible myocardial
injury, even prior to onset of symptoms.
So what we actually do in practice--
or what adult cardiologists do in practice,
and we do the same in pediatric cardiology--
is to follow these patients serially in order
to try to identify, if you will, the sweet spot
when they are starting to exhibit
some kind of deterioration in either left ventricular
size or function, but before they develop
irreversible damage to the myocardium.
So let's spend about two minutes or three minutes just on that.
Let's define what stress means, because it's
a key concept in understanding how
patients go from compensated to decompensated disease process.
Stress is defined as the force per unit
of cross-sectional area.
And we make a distinction between fiber stress--
which is a stress on individual myofibers,
which we cannot really measure in vivo--
and ventricular wall stress, which
is the total stress on the myocardial wall, which
is something that--
there are some ways of getting an approximate assessment
of that.
And the key here is the law of Laplace,
which states that wall stress is proportional to the pressure
times the radius divided by wall thickness.
So what we'll see is that if the wall thickness becomes thin
relative to the diameter, wall stress would increase.
Similarly, if pressure goes up, or the radius or volume
goes up, then wall stress will go up as well.
So what we are trying to do here is distinguish not
between normal, which you can see right here,
but between compensated and decompensated
severe chronic aortic regurgitation.
And the key here is that with volume load,
and there's some degree of pressure load
from severe chronic AR, that the chamber dilates.
There's compensatory mechanisms that
attempt to normalize wall stress,
but eventually these mechanisms fail.
So let's follow that, which is what
I tried to do in this slide.
We start out with chronic aortic regurgitation,
which leads to mostly volume load, but some pressure load.
And that leads to eccentric hypertrophy,
characterized by increased myofiber length as well
as width.
That high eccentric hypertrophy would then
lead to normalization of wall stress,
both in end-diastolic and end-systolic.
But with continued volume lot from the AR,
you'll get this chronic stage of compensated state
until that compensatory mechanism will fail,
and it will fail over time.
When it fails, you get into a cascade
of events that starts with inadequate hypertrophy,
afterload mismatch.
At this stage, left ventricular ejection fraction,
if you measure, it's still normal,
as is myocardial Emax, which is a surrogate of contractility.
However, eventually pre-load recruitment,
which is one of the mechanism to compensate for this condition,
will eventually also be exhausted,
leading to decreased mass to volume ratio, increased wall
stress, decreasing contractility, leading
to decreasing ejection fraction.
That's when you will start seeing ejection fraction going
down.
At this stage, still the disease process is reversible.
However, the window of opportunity for reversibility
is now closing.
And if nothing is done and the aortic valve is not prepared,
then the patient will develop irreversible myocardial damage,
symptoms, and death.
And what we are trying to do here
is to identify that time period where the patient still
will not suffer irreversible myocardial damage.
So the literature in adults has identified
preoperative LV ejection fraction--
a very gross or crude marker of global systolic function--
as well as end systolic volume, either diameter or volume,
as the most important predictors and determinants
of survival after aortic valve replacement or repair.
Mostly what adults have been doing,
and the data is based on replacement.
But one would assume that it can be extrapolated to repair.
So if aortic valve replacement or repair
is done within about 14 to 18 months
after the onset of LV dysfunction,
one would anticipate complete recovery.
This is quite old data, but nonetheless it's
the best that we have.
And it turns out, just worth keeping
in mind, that indices so far, aortic regurgitation
the various measurements of aortic regurgitation
are not predictive of outcomes.
So these are the indications.
This is the guidelines, the heart valve guidelines,
published by the American Heart Association,
American College of Cardiology.
Last version is from 2014.
And the distinction here is between
symptomatic and asymptomatic patients.
And the third category are patients
who are getting other types of cardiac surgery.
So these are all patients with aortic regurgitation.
And just to make it a little bit easier to read,
you can see that patients who are symptomatic,
that's Class I. Also, patients who are asymptomatic but have
LV dysfunction, in the adults, that's
categorized as ejection fraction less than 50.
They are also Class I indication for aortic valve replacement.
However, asymptomatic patients with normal LV ejection
fraction but with LV end systolic size
greater than 5 centimeters, or 25 millimeters
per meter squared, are considered Class II indication
for aortic valve replacement.
So what do we know about this topic in children?
Well, it turns out that-- one thing to keep in mind,
that children are not small adults,
and adult they cannot be easily extrapolated to children.
There's paucity of data to support a recommendation.
One thing that characterizes our patients
is that they have many decades of life ahead of them,
so the same considerations that apply to a 70-year-old person
is not the same as you would apply
to a seven-year-old person.
Many of our patients with severe aortic regurgitation
also have other associated congenital heart disease,
oftentimes multiple left heart lesions.
And then the threshold for values for LV size and function
must be adjusted to body size.
We cannot use adult criteria when we are talking about young
children with varied body size.
And body size grows in a non-linear fashion.
It's heteroscedastic.
And the best adjustment is by using Z-scores.
What's heteroscedastic?
Well, it's that variance in the data
that you see in the normal population.
And again, the best way to adjust for that
is by using Z-scores.
So these are the four studies that I
was able to identify that tried to answer the question, what
preoperative parameters predict, post-aortic valve
repair or replacement, that patients then
are left with left ventricular dysfunction after surgery?
And they all identified some combination
of decreased systolic function preoperatively,
and increase in end systolic size before surgery.
And you can see some variability of that threshold,
but there is a consistent story here.
So what are recommendations based on the available data
is that, of course, if a patient has
severe chronic aortic regurgitation and symptoms,
then this is an indication for surgery.
In patients who are asymptomatic,
end systolic dimension Z-score greater than 4.5
standard deviation above the population means.
Or LV ejection fraction Z-score less than minus two, or 55%.
Or a declining left ventricular ejection fractions and Z-scores
that gets the patient to below minus one,
might be considered an indication.
Even in the adult population nowadays,
they're starting to use size end diastolic, either diameter
or volume.
And what oftentimes we do in clinical practice is,
we look at progressive left ventricular dilatation.
What is the exact threshold that trips
the wire for surgical intervention is unclear.
And if you look at the adult guidelines,
you're talking about a Z-score greater than four,
but we typically would use a somewhat higher Z-score,
and I'm listing greater than 5 and 1/2.
Important before aortic valve replacement
or repair to confirm the measurements,
with either a second echo or MRI,
within one to three months.
We would rarely go by a single measurement.
And to consider exercise testing, because--
self-reporting of lack of symptoms
does not always go hand-in-hand with objective data.
So I will stop here, and we'll have some--
we'll answer some questions later on.
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