Pulmonary Hypertension Assessment - Bench to Bedside by Dr. Jeffrey Fineman for OPENPediatrics
Pulmonary Hypertension Assessment - Bench to Bedside by Dr. Jeffrey Fineman for OPENPediatrics
In this World Shared Practice Forum video, Dr. Jeffrey Fineman speaks about the classification and epidemiology of pediatric pulmonary disease. He details the natural history of pulmonary hypertension associated with congenital heart disease, reviews evidence proving that it is an endothelial-based disease (at least initially), and outlines current and future research involving the hemodynamic forces associated with different congenital heart disease. Upon viewing this presentation, participants will be able to:
-Characterize pediatric pulmonary hypertension
-Identify the epidemiology of the disease
-Understand the role of the endothelial cell in the disease
-Speak about current and future research into influencing hemodynamic forces associated with different congenital heart diseases.
Initial publication: August 23, 2019.
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Content
11.84 -> Welcome to World Shared Practice Forum.
13.5 -> I’m Dr. Jeff Burns, Chief of Critical Care
at Boston Children’s Hospital and Harvard
16.88 -> Medical School.
17.88 -> We’re very pleased to have with us today
Dr. Jeffrey Fineman.
21.04 -> Dr. Fineman is Professor of Pediatrics at
the University of California, San Francisco,
25.81 -> and Benioff Children’s Hospital.
28.34 -> He is also the Vice Chair of Pediatrics, the
Director of the Critical Care Program, and
33.67 -> the Director of the Pulmonary Hypertension
Service at Benioff Children’s Hospital in
38.16 -> San Francisco.
39.16 -> He is also a faculty member at the Cardiovascular
Research Institute at the University of California,
44.13 -> San Francisco, where he has had a lab that’s
been continuously funded over the last several
49.42 -> decades by the NIH (National Institutes of
Health)—where he has studied pulmonary vascular
53.35 -> resistance in the infant and pediatric population.
56.8 -> Jeff, welcome.
58.8 -> Pleasure to be here. Thank you.
60.52 -> You are an expert in pulmonary hypertension.
63.37 -> Could you update us on the current working
definition of pulmonary hypertension—and,
68.64 -> of course, in particular, in the pediatric
population—, and what we know about the
72.5 -> epidemiology of pediatric pulmonary hypertension?
75.46 -> I’d be happy to.
77.06 -> First, just with the nomenclature: Pulmonary
hypertension, as a disease, is really defined
84.75 -> with a hemodynamic parameter.
86.52 -> So, it’s defined as having a mean pulmonary
arterial blood pressure of greater than 25
91.99 -> millimeters of mercury at rest, and greater
than 30 millimeters of mercury at exercise.
97.59 -> And there is a lot of discussion now, actually,
about redefining that to as low as 20 millimeters
103.149 -> of mercury.
104.68 -> And the calculated pulmonary vascular resistance
is greater than 3 Wood units.
111.81 -> Having said that: to call the
disease “pulmonary hypertension,” particularly
119.1 -> in the pediatric population, I think is problematic, because there are clinically relevant pulmonary
126.68 -> vascular disorders within pediatrics—and
single ventricle physiology, for example,
132.19 -> is one example—where you may not reach that
pulmonary hypertension criteria yet.
140.47 -> You have clinically relevant pulmonary vascular
disease.
142.92 -> So many of us are starting to think of using
the nomenclature-- instead of “pulmonary
148.09 -> hypertension,” more either “pediatric
pulmonary hypertensive vascular disease”
154.26 -> or just “pulmonary vascular disease in general.”
159.09 -> The other part of the problem with talking
about pulmonary hypertension is: it’s a
164.409 -> broad spectrum of different diseases that--
ultimately you end up with elevated pressure
171.68 -> and resistance, but there’s a variety of
different etiologies and probably a variety
177.19 -> of different underlying pathobiologies.
180.5 -> If you look at the last updated classification
of pulmonary hypertension—it was in 2014
186.81 -> at the World Congress—, there are five groups.
190.659 -> Group 1 is “Pulmonary arterial hypertension,”
which is the most common form in adult pulmonary
195 -> vascular disease.
196.17 -> So, within primary arterial hypertension,
you have the idiopathic pulmonary hypertension.
200.87 -> You have the familial forms of pulmonary hypertension.
204.109 -> You also have congenital heart disease, which,
as you know, is a major part of pediatric
209.819 -> pulmonary vascular disease.
211.709 -> And you also have drug-induced or toxin-induced,
et cetera.
215.09 -> Group 2 is “Pulmonary hypertension due to
left heart disease,” which is very much
220.129 -> more common in the adult world.
224.549 -> Group 3 is “Pulmonary hypertension due to
lung diseases and/or hypoxia.”
229.129 -> Altitude comes into play there-- sleep-disordered
breathing, for example.
234.269 -> And within pediatrics, you have a lot of your
lung hypoplasias, chronic lung disease, interstitial
240.219 -> lung disease, developmental lung disorders.
243.59 -> And Group 4 is more of a hematologic problem,
“Chronic thromboembolic pulmonary hypertension”--
250.04 -> not nearly as common in pediatrics.
252.999 -> And then Group 5 is what we call “Unclear
multifactorial mechanisms:” variety of hematologic
258.709 -> disorders, systemic disorders, metabolic disorders.
261.269 -> So, clearly there are significant differences
in not only the epidemiology but the pathobiology
267.46 -> of pediatric versus adult pulmonary vascular
disorders.
271.07 -> Obviously, as you can see on this slide, there
are a lot more chromosomal and genetic aberrations
276.8 -> associated with pediatric pulmonary vascular
disease.
279.74 -> You really have to think about developmental
biology and developmental disorders associated
285.27 -> with the lung parenchyma and lung vasculature
and then pathological insults on a growing
291.99 -> premature lung and vasculature.
294.49 -> And then maturational issues related to the
right and left side of the heart are very
298.78 -> important.
299.72 -> Obviously, this becomes not just a disease
of the pulmonary vasculature, but it becomes
304.55 -> a disease of right heart strain and failure.
307.919 -> So there are some fundamental pathobiologic
differences between adult and pediatric pulmonary
313.03 -> vascular disease.
314.03 -> And this next slide gets to the differences
in epidemiology.
317.87 -> This is taken from the Pediatric Pulmonary
Hypertension Network registry, where we’ve
322.4 -> put a database with 1,500 pediatric pulmonary
hypertension patients in North America.
327.3 -> Here, you can see that, actually, the
most common etiology right now of pediatric
333.38 -> pulmonary vascular diseases is Group 3: that
associated with lung and hypoxia.
338.68 -> And then Group 1—pulmonary arterial hypertension—is
the second most, and then
343.389 -> Groups 2, 4, and 5 are very uncommon.
345.81 -> That’s compared to the adult epidemiology,
where Group 1 is clearly the most common,
351.69 -> followed by Group 2 and then Group 3-- so,
clear differences in the epidemiology and
358.37 -> the pathobiology.
359.889 -> Unfortunately, we are stuck with the current
adult classification, but I think we need
365.88 -> to make modifications as it relates to the
pediatric pathobiology.
371.36 -> Jeff, thank you for that overview.
374.86 -> The definition, as you noted, encompasses
so many different etiologies, and yet you’ve
379.33 -> been studying this in the lab, at the bench,
for several decades now.
383.83 -> How did you go about thinking about: How are
you going to isolate this down to a model
389.72 -> that you can study?
391.319 -> Well, I made a decision long ago to focus
on congenital heart disease.
396.139 -> I think, even though we call it all pulmonary
hypertension, I think it’s very clear that
401.21 -> these are all different diseases.
403.199 -> So, I focus on congenital heart disease for
several reasons.
407.6 -> I’m a clinician-scientist, and I work in
the cardiac ICU.
414.069 -> And as you know, perioperative pulmonary hypertension
is a major source of morbidity and mortality.
421.53 -> And so, clinically, I was very interested
in trying to understand this disease and help
428.389 -> come up with therapies.
430.96 -> Also, there are some aspects of the congenital
heart disease subpopulation that are rather
435.949 -> unique to pulmonary hypertension.
438.51 -> The overwhelming majority of patients that
present with pulmonary hypertension are presenting
443.23 -> with symptoms of right heart failure.
445.08 -> So, they already have very advanced disease.
449.069 -> With congenital heart disease-- and we don’t
really understand when it started, how it
455.889 -> started, why it started-- With the subpopulation
of congenital heart disease, we understand
462.04 -> that it’s the holes in the heart that create
these aberrant mechanical forces on the pulmonary
469.5 -> vasculature that lead to the development of
pulmonary hypertension.
473.88 -> And there are some very, very nice, natural
history studies showing over time, these
480.44 -> changes become irreversible.
483.84 -> But we also know that if we fix these congenital heart defects at a young age, that the vascular
494.24 -> phenotype actually reverses.
496.14 -> So, there are several rather unique aspects
of congenital heart disease.
500.88 -> One, we have some sense of what the underlying
initial insult is.
505.87 -> Two, we have a good sense of the natural history.
509.84 -> Three, we know that it’s one of the few
diseases that, if you take away these abnormal
515.01 -> mechanical forces, it can completely reverse, where other forms are never completely
521.36 -> reversible.
522.599 -> And four, there seems to be a time where it
is no longer reversible.
528.07 -> So, even if you fix the defect, it continues
to progress.
531.87 -> And so, if we can understand those mechanisms,
we can really learn a lot about this particular
541.02 -> pathobiology and, hopefully lead to better therapies.
545.59 -> Here’s a slide showing what we know about
the natural history of pulmonary vascular
551.85 -> disease with congenital heart defects.
553.41 -> So, these are if the repair is not corrected.
558.47 -> We know that those lesions that result in
increased pulmonary blood flow, like a ventricular
562.23 -> septal defect-- that the lesions that give
you not only a lot of flow to the pulmonary
567.88 -> vasculature but a direct pressure head to
the pulmonary vasculature, like a truncus
572.42 -> arteriosus-- if you don’t fix them,
100% of them go on to have irreversible
576.74 -> pulmonary vascular disease.
578.88 -> And it occurs very early in life—clearly
within the first two years of life, if not
583.65 -> the first year of life.
585.21 -> On the other end of the spectrum, the ASD,
or atrial septal defect: that is a pre-tricuspid
591.58 -> defect where there’s no direct pressure
head to the pulmonary vasculature, but just
596.54 -> increased flow-- so, flow-alone.
599.85 -> And that-- The incidence of developing irreversible
pulmonary vascular disease without surgery
604.75 -> is only about 10% to 20%.
607.46 -> And for that defect-- it takes, actually,
decades for you to develop irreversible pulmonary
613.44 -> vascular disease.
614.44 -> So, there’s some interesting natural history
and lessons here that I think we can start
619.13 -> to focus on and figure out potential mechanisms
of disease.
623.37 -> So, it seems like the high-pressure, high-flow
lesions are much more susceptible to pulmonary
628.7 -> vascular disease versus the flow-alone lesions.
632.51 -> The other big subcategory of congenital heart
disease that can lead to pulmonary vascular
639 -> disease is those that result in increased
pulmonary venous pressure, like left heart
643.46 -> failure-- very common in the adults in Group
2.
646.98 -> But mitral stenosis, obstructed veins, cor
triatriatum-- there we know much less about
653.58 -> the natural history of the disease, and that’s
why, on this table, it’s very variable.
659.1 -> So, the next slide is representative of the
vascular changes associated with a very common
666.22 -> congenital heart defect: a ventricular septal
defect.
668.67 -> So, first, you see the blood going from the
left side of the heart to the right side of
672.28 -> the heart, resulting in increased pulmonary
blood flow.
675.35 -> So, initially, the normal vascular phenotype—noted
by the red there—is that there’s a thin
681.32 -> muscle layer, and it’s very proximal.
684.42 -> It doesn’t extend down to the periphery.
686.64 -> The initial change that you see over time
with increased flow—and, in this case, pressure—is
692.84 -> that the muscle layer gets thick.
694.43 -> So, it’s called medial hypertrophy.
696.57 -> The proximal layer becomes more muscular.
700.63 -> With time, the muscle layer then extends abnormally
down to the periphery where it, in the normal
707.43 -> form, is not present.
709.19 -> And then ultimately, with irreversible disease,
you actually lose your distal arterials, so-called
715.17 -> “pruning of the vessels.”
716.64 -> The anatomic morphology was classically described
by Heath and Edwards in 1958, and these were
723.48 -> mostly autopsy specimens.
725.77 -> And a big subset, actually, of these patients
had unrepaired congenital heart disease.
731.45 -> And it’s very nice to categorize the spectrum
of advancing pathological lesions.
737.78 -> But Marlene Rabinovitch actually took lung
biopsy samples of patients undergoing repair
744.29 -> of their congenital heart defects right here
in Boston Children’s Hospital and looked
748.66 -> at the morphologic abnormalities and related
them to the perioperative physiology.
753.73 -> And she characterized them as three grades.
758.45 -> Grade A is where you have some abnormal extension
of the muscle down to the periphery with mild
763.65 -> medial hypertrophy.
765.5 -> Those patients tend to have altered reactivity
of the pulmonary vascular bed postoperatively,
770.54 -> but easy to manage, usually normal resistance,
and clearly very reversible phenotype once
776.81 -> you close the repair.
779.2 -> Grade B had some abnormal extension of the
muscle, but moderate to severe medial hypertrophy.
784.92 -> And then grade C is where you actually started
to see the decreased arterial size and number.
790.3 -> And those patients tended to be irreversible
patients.
793.18 -> And even if you fix them, they’d
go on to have advanced pulmonary vascular
797.38 -> disease.
798.48 -> But there’s a big gray area in the middle
where it’s not clear whether they’re reversible
803.31 -> or irreversible.
805 -> And then just to touch on the right heart
because, as we talked about, there’s a lot
809.19 -> of focus on the pulmonary vasculature, appropriately,
but many of the signs and symptoms that you
814.74 -> show are related to the right heart failing.
817.94 -> So, here’s just a cartoon.
819.97 -> As we can see, different grades of pulmonary
vascular change are on top.
824.28 -> The pulmonary artery pressure continues to
rise.
827.79 -> And then at some point, when you get right
heart dysfunction, your cardiac output falls.
832.5 -> So, the PA pressure actually can go down a
little bit, but your calculated resistance
836.58 -> continues to go up.
838.16 -> But the point here is that this becomes a
disease of right heart failure.
843.76 -> And what’s interesting is: there are different
right heart phenotypes.
847.83 -> We all know that the adult thin right ventricle
really does not tolerate an acute afterload
855.79 -> very well.
856.79 -> That’s where an acute pulmonary embolus
has such high morbidity and mortality.
861.38 -> But there are some patients with pulmonary
hypertension that, actually, the right ventricle
865.57 -> becomes quite adaptive, and it actually hypertrophies
and can maintain a good cardiac output despite
872.38 -> a very high resistance.
874.22 -> And then there are other patients where, instead
of hypertrophy, the right heart actually
879.61 -> dilates and fails rather quickly.
882.81 -> And when we see those things, that dictates
how aggressive we are with therapy.
888.26 -> But I also think there are a lot of lessons
to be learned there-- and: Why are some right
893.99 -> hearts adaptive and others are not?
897.27 -> And are there potential therapeutic targets
to be learned from those lessons?
902.14 -> And that’s a whole area that really needs
to be investigated.
908.56 -> As the pulmonary vascular disease progresses
in an unrepaired congenital heart defect,
915.42 -> ultimately, instead of the blood going from
the left side of the heart to the right side
918.8 -> of the heart, a portion or all of it begins
to go from the right side of the heart to
922.14 -> the left side of the heart where you get,
now, desaturated blood going to the systemic
926.54 -> circulation.
927.54 -> And as you know, that’s referred to as the
Eisenmenger’s syndrome, and this is the
931.29 -> report in 1958 by Paul Wood, which is a tremendous,
insightful report of these patients.
939.18 -> Interestingly, if you look at the survival
of patients with congenital heart disease,
944.8 -> they tend to do much better than other forms
of Group 1 pulmonary arterial hypertension,
950.98 -> most notably idiopathic.
952.57 -> This is a lovely, long study by Manes in his
clinic where he followed them-- in this case,
960.32 -> I think it was 14 years-- 278 patients.
964.96 -> And he showed that survival of those with
congenital heart disease was overall 85% at
971.35 -> 10 years, 77% at 20 years, compared to their
group-- same clinic, same treatments, the
978.37 -> idiopaths-- 46% survival at 10 years and a
38% survival at 15 years-- much improved with
987.07 -> congenital heart disease.
988.32 -> Why that is is very interesting.
990.19 -> And again, I think further evaluation of that
will lead to new therapeutic targets.
995.52 -> But if you break up the congenital heart disease
into, kind of, the different subtypes-- Here
1000.91 -> is an updated classification of congenital
heart disease.
1003.98 -> There’s the Eisenmenger’s syndrome.
1005.86 -> There are the ones with the large left-to-right
shunts—what I consider, really, pre-Eisenmenger.
1011.01 -> They just haven’t started going right to
left yet, but the pathobiology is probably
1015.81 -> the same.
1016.81 -> The third group is an interesting group: the
pulmonary arterial hypertension with coincidental
1020.78 -> congenital heart disease.
1022.16 -> This is a subset of the atrial septal defects,
1024.96 -> Where they have very high resistance,
a very small defect, a very small shunt.
1030.34 -> They are probably idiopathic, and they happen
to have a small atrial shunt.
1035.189 -> They probably don’t have real congenital
heart disease-induced pulmonary hypertension.
1040.44 -> And then the patients where you made a decision
that you think they’re reversible with surgical
1044.78 -> repair: you operate, you get them through
the surgery, and then they reemerge—
1050.66 -> a year, five years, 10 years—with advancing
pulmonary hypertension: that’s a group that
1057.36 -> the clinical phenotype is very, very aggressive.
1061.19 -> And that’s why it’s such a vital decision,
before you operate, as to whether you think
1065.149 -> they’re reversible or irreversible, because
if you look at the survival: the top two curves
1069.59 -> are the Eisenmenger’s—the Group 1 and
the Group 2, the Eisenmenger’s and the large
1073.34 -> left-to-right shunts; the pre-Eisenmenger’s:
they have the best survival compared to the
1078.33 -> Group 3, which have the small defects and
which are really similar to idiopath.
1084.75 -> And then the last group where they’re corrected:
their survival at 20 years was 36%-- so much,
1091.36 -> much lower than the Eisenmenger’s or the
pre-Eisenmenger’s.
1094.58 -> So, it’s really vital to make the right
decision in terms of surgical correction.
1099.42 -> Now, why Eisenmenger’s do better
is fascinating to me.
1103.22 -> I think: clearly, they have the ability to
pop off.
1107.549 -> So, when their pulmonary vascular resistance
goes really high, instead of the right heart
1111.32 -> acutely failing, they just shunt more blood
to the left side.
1114.7 -> So, they can get very blue, but they can maintain
their left-sided output.
1119.49 -> There’s no question that that attenuates
the incidence of syncope and sudden death.
1126.32 -> But, also, there are some elegant studies
showing that, anatomically, the right ventricle
1132.929 -> kind of maintains its fetal dominance.
1136.45 -> The right ventricle, as you know, is dominant
in the fetus.
1139.51 -> And there are pictures of 77-year-olds with
Eisenmenger’s where the right ventricle
1144.92 -> looks identical to the fetal right ventricle;
that there’s something intrinsic
1148.82 -> about the right ventricle never getting to
remodel as pulmonary vascular resistance falls
1155.82 -> because it doesn’t fall normally.
1158.38 -> And this right ventricle for, let’s say,
a large unrestricted VSD is always exposed
1163.42 -> to increased flow and pressure.
1166.86 -> So, we think that there’s something related
to maintaining that fetal phenotype and perhaps
1171.89 -> genotype that makes it protective.
1175.54 -> And again, the theme here is: If you could,
with those insights, look at what those mechanisms
1181.83 -> are, there may be some nice therapeutic targets
for the right ventricle that can help these
1186.71 -> patients as well as other patients with right
ventricular dysfunction.
1190.2 -> Jeff, that was a fascinating overview.
1192.71 -> So, you took congenital heart disease not
as a convenient sample, but, as you said,
1197.96 -> it provided you with the kind of perfect model
to study because you had the natural history
1203.429 -> from fetus to outcome of unrepaired infants
and children.
1209.909 -> And from that work, you’ve been able to
distill these distinctions between flow and
1214.8 -> flow with pressure.
1217.96 -> Now, what have we learned about therapies?
1220.26 -> Because we're upstairs
in the ICU using these therapies right now.
1225.14 -> Take us through: How did you and others learn
about how to target the mechanisms that are
1232.639 -> causing these issues?
1236.139 -> Sure.
1237.149 -> So, as you know, all the therapies currently
being utilized in adults and in children are
1243.039 -> really based on endothelial biology.
1245.53 -> And there’s a clear picture that, early
on, with congenital heart disease, that
1254.22 -> there's endothelial cell dysfunction.
1257.54 -> And it’s interesting because, in the old
days, people would look at the blood vessels
1263.21 -> and knew that all the action was at the smooth
muscle cell layer.
1266.62 -> The constriction, the relaxation was mediated
by the smooth muscle cell layer.
1270.92 -> And the endothelial cell was kind of just
seen as a barrier cell layer between the blood
1275.58 -> and where all the action was, the smooth muscle
cell.
1278.64 -> But it wasn’t until the mid-1980s, with
a landmark study by Bob Furchgott in
1284.18 -> Brooklyn, New York, Downstate, where he
did a very elegant, simple study, but he basically
1290.66 -> showed that the endothelial cells were making
something that caused the blood vessel to
1295.98 -> relax.
1297.1 -> The smooth muscle cell then relaxed based
on what the endothelial cell was making, showing
1301.799 -> this interaction between the two layers and
that the endothelial cell was actually functional.
1307.71 -> And he first coined that an “endothelium-derived
relaxing factor,” or EDRF, and there were
1313.539 -> years where we called it EDRF and went to
EDRF meetings.
1318.63 -> And then, as you know, it was subsequently
shown to be nitric oxide.
1323.32 -> And so, all the subsequent therapies have
really been based on this.
1328.08 -> So, I’ve had a real interest in early endothelial
dysfunction as a major player in the pathobiology
1336.039 -> of congenital heart disease.
1337.039 -> It would make sense because these abnormal
mechanical forces are first being seen by
1343.21 -> the endothelial cell layer.
1345.269 -> And so, there are actually some nice, really
eloquent early observations from Boston Children’s/Harvard
1354.639 -> initially that, I think, really laid the groundwork
for this unifying hypothesis of early endothelial
1361.95 -> dysfunction in the pathobiology of pulmonary
hypertension related to congenital heart disease.
1368.269 -> So, this next slide, I think, really, for
me, was fundamental in pointing me into this
1377.309 -> world of endothelial cell biology.
1379.08 -> Marlene Rabinovitch, as you know, when she was at Boston, took
1382.44 -> these biopsy samples of children undergoing
complete repair of their congenital heart
1386.61 -> defects.
1387.61 -> And these children were young, and they all
had very reversible disease.
1391.309 -> And she did scanning electron microscopy looking at the endothelial cell anatomy.
1396.26 -> Then she went on to show that there were alterations
1398.389 -> on von Willebrand factor production, suggesting
not only anatomic aberrations in the endothelial
1404.289 -> cell—again, early on, before they have any
significant disease—, but also functional
1409.399 -> aberrations of the endothelial cell.
1411.94 -> So, this slide represents that landmark study
by Celermajer.
1416.49 -> This was performed in the cardiac catheterization
laboratory.
1419.249 -> They studied three groups of children.
1423.309 -> These squares that are black are called controls.
1426.45 -> Those are actually children that had normal
pulmonary vasculature, no increased flow or
1431.289 -> pressure.
1432.6 -> The open squares were young children that
had increased pulmonary blood flow but a normal
1437.529 -> calculated pulmonary vascular resistance,
and they were generally all infants.
1441.6 -> And the triangles, or pulmonary
vascular disease: those were older children,
1445.44 -> and they had advanced disease with resistances
calculated greater than 6 Wood units.
1451.049 -> So, the y-axis is flow velocity, and that
was determined by a catheter placed in the
1457.37 -> pulmonary artery.
1458.74 -> And then the x-axis is different conditions.
1461.47 -> C1 and C2 are control or baseline conditions.
1464.96 -> There were three increasing doses of acetylcholine
given, and then sodium nitroprusside—or
1471.529 -> NP—was given at the end.
1474.48 -> What you can see is the control patients dilated
nicely in a dose-dependent fashion to acetylcholine--
1481.779 -> no surprise.
1483.42 -> And then they also dilated nicely to sodium
nitroprusside-- again, not surprisingly.
1488.9 -> If you look at the triangles, the patients
with advanced disease-- so, they have a lot
1492.76 -> of structural remodeling of the pulmonary
vasculature.
1495.76 -> They don’t dilate well to acetylcholine
or sodium nitroprusside.
1500.3 -> The fascinating group to us was the open squares,
the ones with increased flow.
1505.68 -> They’re young, clearly reversible disease,
normal calculated resistance.
1511.44 -> They dilate normally to nitroprusside, but
they dilate just as poorly to acetylcholine
1518.419 -> as the group with advanced disease.
1520.529 -> Now, nitroprusside is what we call an NO donor,
or an endothelium-independent vasodilator.
1526.269 -> It does not require the endothelial cell to
make nitric oxide in order to dilate.
1530.139 -> It just donates nitric oxide by itself.
1533.08 -> Acetylcholine, on the other hand, is a clear
endothelium-dependent vasodilator.
1538.059 -> Acetylcholine dilates by binding to a receptor
on the endothelial cell and forcing the endothelial
1543.679 -> cell to make nitric oxide in order to dilate
the smooth muscle cell layer.
1547.669 -> So, what Celermajer and colleagues were showing
were that patients that were young, had increased
1553.12 -> flow, and normal resistance--
functionally had endothelial cells that were
1558.75 -> not capable of making nitric oxide to the
same extent as normal children.
1563.85 -> To me, this study was really classic evidence
that even young patients with early disease
1570.84 -> had significant endothelial dysfunction as
underlying pathobiology.
1576.88 -> Well, Dr. Fineman, thank you for walking us
through that study.
1580.419 -> This is very interesting.
1582.269 -> How does that translate, or does it translate,
to what we know about perioperative morbidity
1587.32 -> in these patients with increased pulmonary
blood flow and, in particular, increased pulmonary
1592.4 -> blood flow with pressure?
1595.02 -> Right. Well, that’s a great question.
1597.2 -> And actually, the very same year of Celermajer’s
study, there was what I think was a landmark
1603.269 -> study from this institution, with Frank Hanley
and Aldo Castañeda looking at the timing
1609.83 -> of repair of truncus arteriosus.
1611.71 -> And it really was the combination of those
studies that really stayed with me in terms
1617.119 -> of endothelial dysfunction.
1619.71 -> So, back in those days, truncus arteriosus
was really a high-risk surgery because of
1630.72 -> significant morbidity and mortality related
to pulmonary hypertension.
1636.299 -> And because of that, the approach that we
all took was to try to hold off until the
1641.23 -> patient was a little bit older and showed
signs of the pulmonary vascular resistance
1645.36 -> falling, which meant that they had signs of
increased pulmonary blood flow.
1648.45 -> So, we’d often try to get them to go out for six weeks
of age before repairing them, thinking that,
1657.02 -> if their pulmonary vascular resistance has
fallen, they’d have fewer pulmonary hypertension
1662.029 -> episodes perioperatively.
1663.69 -> What doctors Hanley and Castañeda showed
was actually the opposite.
1668.48 -> They showed that the patients that were operated
on sooner did better in terms of outcomes,
1676.01 -> and they came out of the operating room with
lower pulmonary artery pressures than the
1680.16 -> ones that were done later, and they
had far fewer pulmonary hypertension episodes
1685.78 -> if they were done earlier.
1688 -> So, they concluded—and I completely agree,
and the field 30 years later completely agrees—that
1695.039 -> the longer the pulmonary vasculature—and
I would add: the endothelial cell layer—is
1701.259 -> exposed to these abnormal forces of increased
flow, the shear that’s associated with that,
1706.919 -> and the pressure and the cyclic stretch that’s
associated with that, the worse it is for
1712.58 -> the patient.
1713.679 -> So, by repairing them very early on, you minimize
that time, and, in fact, the endothelial aberrations
1721.86 -> are less, and that relates directly, I think,
to improved perioperative outcomes and decreased
1728.95 -> perioperative morbidity related to pulmonary
hypertension.
1733.61 -> Just as a reminder to the audience: As you
can see in the diagram, there are variations
1738.69 -> on the theme, but a truncus arteriosus is
basically where the pulmonary arteries are
1743.11 -> coming off the common aortic trunk.
1745.96 -> So, it exposes the pulmonary vasculature to
very high pressure and flow.
1750.94 -> Those observations and studies really
have led to this kind of unifying hypothesis
1755.8 -> that, particularly with congenital heart disease,
the initial insult is that pressure and flow
1762.279 -> result in an early endothelial injury, and
that results in the alterations in the vasoactive
1768.539 -> factors that the endothelial cell makes, such
as nitric oxide, prostacyclin, endothelin-1,
1775.409 -> alterations in reactive oxygen species generation,
alterations in extracellular matrix, and the
1781.52 -> combination of these things and probably many
other things that we don’t understand yet
1785.82 -> results in the two fundamental processes of
this disease where there’s intense vasoconstriction
1792.11 -> and significant vascular remodeling of the
pulmonary arterials.
1797.92 -> This is a cartoon of those three endothelial-based
cascades and showing the nitric oxide cascade
1807.94 -> on the left, the endothelium cascade on
the right, and the prostacyclin cascade in
1814.02 -> the middle.
1815.029 -> And there’s a lot of data—both in animal
studies and in humans—suggesting that, with
1819.99 -> pulmonary vascular disease, the nitric oxide
cascade is downregulated as well as the prostacyclin
1826.13 -> cascade.
1827.59 -> Both nitric oxide and prostacyclin promote
vasodilation, and they inhibit smooth muscle
1833.03 -> cell proliferation.
1834.03 -> So, they keep the muscle layer nice and thin.
1837.669 -> Endothelin, on the other hand, which has been
shown to be upregulated in pulmonary vascular
1843.179 -> disease, is a potent vasoconstrictor, and
it actually causes reactive oxygen species
1849.47 -> generation and smooth muscle cell proliferation.
1852.789 -> So, all of the therapies to date-- and, as
you know, over the past decade, they’ve
1858.769 -> increased significantly-- they’re all based
on either augmenting the nitric oxide pathway,
1864.139 -> augmenting the prostacyclin pathway, or blocking
the endothelin pathway.
1870.56 -> Now, the survival of these patients has improved
dramatically with the advent of these therapies.
1877.56 -> And we really hope that as new therapies emerge, as our understanding emerges,
1883.46 -> that, in fact, we’ll ultimately be able to cure some of these patients.
1887.12 -> But this endothelial biology and understanding
underlying pathobiology has really led to
1893.58 -> a tremendous emergence of new therapies.
1896.84 -> Jeff, that’s absolutely fascinating work.
1899.519 -> Has that translated to an animal model?
1903.179 -> That is: Is there a model that exists where
you can examine the outcomes for a lesion
1910.759 -> that’s producing high flow versus a lesion
that’s producing high flow and high pressure?
1915.029 -> Yeah, that’s a great question.
1917.6 -> So, that’s exactly what we’ve been investigating
for the last 15, 20 years.
1923.779 -> We have a large animal model, and we initially
created a model that results in both high
1929.73 -> flow and high pressure.
1932.33 -> And we showed that these aberrations, these
endothelial cell aberrations, occur dramatically,
1940.48 -> and they occur very, very early on.
1943.309 -> For example, the endothelium cascade, which,
again, promotes vasoconstriction and smooth
1948.96 -> muscle cell proliferation: that’s upregulated
in our animal model within the first week
1954.2 -> of life.
1955.2 -> So, they’re born.
1956.409 -> Pulmonary vasculature starts getting exposed
to increased flow and pressure, which is abnormal.
1961.899 -> And within four or five days, there’s a
massive upregulation of the endothelium cascade.
1967.279 -> The levels are high.
1968.919 -> The good receptor that mediates nitric oxide
is down, and the bad receptor that mediates
1975.66 -> vasoconstriction, within a couple weeks later,
is markedly elevated.
1981.1 -> Conversely, on the nitric oxide side of the
equation, we show that, within the first month
1986.28 -> of life, that the enzyme that is making nitric
oxide—endothelial nitric oxide synthase,
1995.48 -> that enzyme which classically gets stimulated
by flow or shear, because there’s flow—is
2002.04 -> massively unregulated.
2003.86 -> But instead of making nitric oxide, the enzyme
is what we call “uncoupled” for a variety
2009.98 -> of reasons, and it actually makes reactive
oxygen species.
2014.85 -> So, that results in decreased what we call
“bioavailable” nitric oxide.
2021.1 -> And in addition, it’s causing oxidative
stress, which causes further injury to the
2027.1 -> vasculature.
2028.44 -> So, that is the work that we’ve done with
a model of high pressure and high flow.
2034.429 -> So, to get to your question of kind of translating
the natural history of a flow-alone lesion,
2039.96 -> like an atrial septal defect, versus a flow
and pressure lesion, like a truncus arteriosus:
2045.25 -> We just recently created a flow-alone model
and compared it to what we’re calling the
2049.74 -> “shunt model”, that I just described.
2052.7 -> So, the flow-alone model, what we do is we just
ligate the left pulmonary artery.
2058.72 -> So, the right lung now gets twice as much
pulmonary blood flow, but without the direct
2064.88 -> pressure head that’s seen with a truncus
arteriosus or an aortopulmonary window.
2072.08 -> This is a CT angiogram comparing-- they’re
all about a month of age, and the controls
2078.8 -> are twin age-matched controls. And this is just the anatomy of the three models.
2086.32 -> The shunt on the right side has very large,
engorged pulmonary vasculature compared to the control.
2093.84 -> And the LPA ligation shows a relatively normal
right side and no left pulmonary artery.
2100.08 -> What we’ve been able to do is culture the
cells, and they maintain a phenotype, which is very, very helpful.
2107.6 -> And this is something called RNA sequencing.
2111.12 -> And so, the control cells, the endothelial
control cells, are in the dark blue, the shunted
2118.8 -> cells are in the light blue, and the flow-alone, or the LPA cells, are in the red.
2123.28 -> And what I hope you can appreciate is kind
of this clustering in terms of their genome
2127.92 -> is that they’re very, very different, these
three groups of animals.
2132.72 -> And then, this heat map: the things in red
are showing an upregulation of genes.
2140.24 -> The things in green are a downregulation in
genes.
2143.68 -> And I hope you can appreciate the marked differences
in the pattern of gene expression between
2149.2 -> the three models.
2150.96 -> So, next, we try to look at kind of the functional
differences between the three groups.
2158.72 -> And so, as you know, classically, patients
with pulmonary hypertension have what we call
2164.82 -> “increased vascular reactivity.”
2166.44 -> It could be a stimulus like hypoxia or alpha-adrenergic
activation that causes pulmonary vasoconstriction
2175.9 -> in all of us, but if you have an abnormal
pulmonary vasculature, it can be very, very intense.
2180.48 -> So, we challenged these three animal models
with either acute alveolar hypoxia or this
2188.32 -> drug called U46619, which is a thromboxane
mimic.
2192.78 -> And, as I think you can appreciate: In the
dark blue, this is a change in pulmonary artery
2196.72 -> pressure in response to those insults-- that
these shunted animals, flow plus pressure,
2203.18 -> have a marked increase in pulmonary artery
pressure in response to them.
2207.02 -> The control, or the normal lambs in light
blue have a much attenuated response, and
2214.66 -> the flow-alone have somewhat of an intermediate
response.
2218.84 -> So, that was in the intact animal.
2220.68 -> If we take the pulmonary arteries out and
hang them in a muscle bath, we can do similar
2225 -> studies with different increasing doses of
drugs.
2228.64 -> And in this case, we study norepinephrine,
the same color-coding.
2233.16 -> I think you can appreciate that the shunted
animals—pressure and flow—have a marked
2237.46 -> increase in reactivity to norepinephrine where
the flow-alone are very similar to normal
2242.46 -> animals, much more attenuated response.
2245.48 -> If you look at the morphology, we talked about
smooth muscle cell layer being thick in this
2250.46 -> classic disease.
2252.5 -> Well, again, these animals are only four weeks
old.
2255.6 -> They’re very, very young, yet they have
some medial hypertrophy in the pressure-and-flow-mediated
2260.78 -> group, the shunted group, where the LPA ligation,
or the flow-alone, their blood vessels looked
2266.46 -> normal.
2267.22 -> Then, lastly, a couple of things we’ve been
looking at-- the ability of the endothelial
2270.44 -> cells to actually make new blood vessels or
angiogenesis that are budding.
2275.46 -> And in fact, the pressure and flow stimulus
seems to increase their ability to do that
2282.2 -> as opposed to the flow-alone, which seems
to be intermediate compared to the normal ones
2287.72 -> Now, whether that’s adaptive or maladaptive
early on is not clear to us.
2293.86 -> But the other thing that’s interesting is
their resistance to apoptosis, or natural
2301.14 -> cell death, the feeling being that an anti-apoptotic
or proliferative state is pathologic.
2309.42 -> I hope you can appreciate in this slide
that the shunted animals-- this is TNF-induced apoptosis.
2315.86 -> It’s kind of a classic assay.
2318.08 -> The cells from the shunted animals don’t
apoptose nearly as much as controls.
2324.86 -> But, again, the flow-alone, the LPA ligation,
they’re somewhat intermediate.
2329.04 -> So, it seems like the stimulus of pressure
and flow is very different than flow-alone.
2336.74 -> And then we’ve just started to look at
some of the basic endothelial functional targets
2343.64 -> that have classically been targeted, endothelin-1
and nitric oxide.
2348.2 -> And where we’re going with this is: Let’s
start with the drugs that we have, and can
2354.54 -> we learn about different physiologic insults
within our patient population?
2359.36 -> What endothelial biology is perturbed with
different insults?
2364.16 -> And maybe we can start by taking the drugs
that we have and targeting the use of them
2369.26 -> based on the underlying physiology.
2372.44 -> It’s a lot of work to go on to try to get
new therapies, but let’s just start with
2376.78 -> the targets we have.
2378.54 -> So, here you can see lung endothelin levels.
2382.88 -> Again, we’ve shown previously and I’ve
spoken about that the shunted animals have
2386.64 -> marked elevation in endothelin levels.
2390.3 -> But the flow-alone animals, really it’s
somewhat maybe intermediate, but not very
2395.36 -> different than control.
2397.72 -> And then, if you look at the protein levels
of the precursor lung prepro-ET-1, you can
2404.38 -> see marked elevation of the shunt with pressure
and flow, but the flow stimulus does not nearly
2410.78 -> generate the upregulation in endothelin-1.
2415.06 -> If you take these cells and then apply them
in vitro to mechanical forces, if you stretch
2421.06 -> them, which is, we think, one of the stimuli
associated with pressure, distending and stretching
2427.08 -> the pulmonary artery, you can see a marked
elevation with cyclic stretch endothelin-1 levels.
2435.04 -> But if you just expose them to shear, which
is associated with flow, or physiologic shear,
2441.8 -> not abnormally high shear, endothelin levels
actually come down—again, suggesting that
2448.04 -> perhaps those lesions with pressure head are
more prone to have an upregulation of endothelin-1.
2456.06 -> Those may be the patients we want to make
sure we’re blocking that cascade, where
2460.56 -> the flow-alone patients, maybe we don’t
need to block that cascade.
2466.4 -> Lastly, with the nitric oxide: We’ve talked
about the enzyme that makes nitric oxide,
2471.52 -> nitric oxide synthase, classically stimulated
by flow or shear.
2477.2 -> Makes sense that blood flowing across the
endothelial cell will stimulate nitric oxide
2482.22 -> production, keeps it nice and relaxed in the
normal state.
2485.86 -> You can see in the bar on the left—looking
at these enzyme protein levels—that both
2491.26 -> in the shunt and in the flow-alone, the protein
levels of this enzyme are markedly elevated.
2497.88 -> They both have flow as a component to their
defect.
2501.6 -> However, if you look at the end product, are
they making nitric oxide?
2506.04 -> In fact, as we showed previously, the shunted
animals have this uncoupled enzyme where they
2511 -> don’t make nitric oxide, and, in fact, they
make reactive oxygen species.
2515.04 -> You can see, in the shunted animal, that the
amount of nitric oxide in the lung is actually
2519.16 -> significantly lower.
2520.88 -> But the flow-alone actually is making nitric
oxide, and they have similar bioavailable
2526.94 -> nitric oxide levels to control.
2529.22 -> So, even though they’re both upregulated
by the flow, it seems like the pressure associated
2533.94 -> with it causes further perturbation of the
enzyme and actually uncoupled it where just
2539.68 -> flow-alone seems to result in nitric oxide
production.
2543.76 -> So, kind of to summarize where we’re going
with all of this work is we believe that combined
2548.9 -> mechanical forces of pressure and flow result
in abnormal vascular remodeling, abnormal
2555.26 -> functional vascular reactivity, endothelial
cell proliferation, angiogenesis, and anti-apoptosis,
2564.58 -> and marked endothelial dysfunction.
2566.5 -> Particularly, what we’re starting with is
a marked elevation endothelin-1.
2570.88 -> Flow-alone, however, seems to be an intermediate
phenotype.
2574.94 -> And where we want to get with this work--
and as you saw in the heat map, there are
2578.8 -> a lot of genes to explore here-- that we want our
therapy to be informed by the physiologic
2585.6 -> etiology of the particular pulmonary vascular
disease or the congenital heart disease causing
2590.38 -> the pulmonary vascular disease.
2592.26 -> And I think, in general, our pulmonary vascular
disease therapy goal is: To optimize the endothelial-based
2599.12 -> therapies. We’ve got some great ones.
2601.18 -> There may be more targets here within the
endothelial cell pathobiology that can be optimized.
2607.1 -> Right now, we have no targets focused on the
smooth muscle cell.
2610.84 -> There are clearly a lot of aberrations there.
2613.08 -> There’s a lot of nice work showing abnormal
metabolic pathways in the smooth muscle cells
2618.62 -> that are going to be targets.
2621.82 -> As we talked about with Eisenmenger’s, there
are lessons to be learned there in the adaptive
2625.36 -> and maladaptive right ventricle.
2627.62 -> By looking at those mechanisms, perhaps there
are targets to improve RV function in these
2632.18 -> patients.
2633.96 -> And then we’re learning more and more about
genetic predispositions to this disease.
2638.8 -> And as we learn more about these genes and
then their associated signaling abnormalities,
2644.72 -> perhaps there are targets there that we can
get to.
2648.44 -> And as you know, Dr. Burns, currently our
therapy is rather crude.
2654.8 -> We have three types of drugs-- again: augmenting
nitric oxide, augmenting prostacyclin, and
2662.24 -> blocking endothelin.
2664.66 -> If we have mild disease, we give one of these
drugs.
2668.82 -> If we have moderate disease, we give two of
these drugs.
2671.54 -> And if they have really bad disease, we give
all three types of these drugs.
2674.86 -> It’s not based on any underlying mechanism
or pathobiology.
2680.44 -> We must get to a place within congenital heart
disease, but within the field overall, where
2687.02 -> the therapies must be informed by understanding
the underlying pathobiology as opposed to
2693.9 -> how bad the disease is.
2696.84 -> Well, Jeff, that’s a wonderful overview
of several decades of work by you and others
2703.82 -> that has helped advance our thinking.
2706.24 -> And as you just summarized, right now we’re
still in the era of one size fits all.
2712.16 -> It’s all “pulmonary hypertension,” and
“Here’s three medications.”
2715.4 -> But the work that you and others around the
world are doing-- I think we can see that
2719.68 -> we’re entering a more precise era where
we’ll be able to target our therapies.
2725.66 -> So, on behalf of colleagues around the world,
thank you very much for being with us today
2730.02 -> and thank you for all the work you've been doing.
2731.48 -> Thank you for having me and thank you for all the work that you do. Really appreciate it.
Source: https://www.youtube.com/watch?v=Ndms0iwgGng