Circulation March 21, 2023 Issue

This week, please join author Mikael Dellborg and
Associate Editor Gerald Greil as they discuss the article "Adults
With Congenital Heart Disease: Trends in Event-Free Survival Past
Middle Age."


Dr. Greg Hundley:


Welcome listeners to this March 21st issue. And I am one of your
co-hosts, Dr. Greg Hundley, Associate Editor Director of the
Pauley Heart Center at VSU Health in Richmond, Virginia.


Dr. Peder Myhre:


And I am the other co-host, Dr. Peder Myhre, from Akershus
University Hospital and University of Oslo in Norway.


Dr. Greg Hundley:


Well, Peder, we have a very interesting feature discussion this
week. It focuses on adults with congenital heart disease. And as
you are aware, over the last 25 to 30 years the survival rate of
individuals with congenital heart disease has really improved.
And this group, led by Professor Dellborg, will discuss with us
more on results from a Swedish registry examining patients after
the age of 18 with adult congenital heart disease. But before we
get to that, how about we grab a cup of coffee and jump into some
of the other articles in the issue? Would you like to go first?


Dr. Peder Myhre:


I would love it to, Greg, thank you. So Greg, the first paper is
about aortic stenosis and the genome-wide association study
looking at aortic stenosis in patients from the Million Veteran
Program. And as you know, Greg, calcific aortic stenosis is the
most common valve of heart disease in older adults and has no
effective preventive therapies. Genome-wide Association studies,
GWAS, can identify genes influencing disease and may help
prioritize therapeutic targets for aortic stenosis. And in this
study, which comes to us from co-corresponding authors, O'Donnell
from VA Boston Health System and Dr. Natarajan from Massachusetts
General Hospital, both in Boston Massachusetts, performed genetic
analysis in 14,451 cases with aortic stenosis and almost 400,000
controls in the Multiancestry Million Veteran Program. And
replication for these results was performed in five other
cohorts.


Dr. Greg Hundley:


Wow, Peder, so a very large gene-wide association study. So what
did they find?


Dr. Peder Myhre:


So Greg, the authors found 23 lead variants representing 17
unique genomic regions. And of the 23 lead variants, 14 were
significant in replication, representing 11 unique genomic
regions. And five replicated genomic regions were previously
known risk loci for aortic stenosis, while six were novel. And of
the 14 replicated lead variants, only two of these were also
significant in atherosclerotic cardiovascular disease GWAS. And
in Mendelian randomization, lipoprotein a and LDL cholesterol
were both associated with aortic stenosis, but the association
between LDL cholesterol and aortic stenosis was attenuated when
adjusting for LP a. So Greg, in conclusion this study identified
six novel genomic regions for aortic stenosis, and secondary
analysis highlighted roles of lipid metabolism, inflammation,
cellular senescence and adiposity in the pathobiology of or
stenosis, and also clarified the shared and differential genetic
architectures of aortic stenosis with atherosclerotic
cardiovascular disease.


Dr. Greg Hundley:


Wow, Peder, what a beautiful description. Very comprehensive
study. Well, my study comes to us from the world of preclinical
science and, Peder, it involves embryonic heart development. So
Peder, placental and embryonic heart development occur in
parallel, and these organs have been proposed to exert reciprocal
regulation during gestation. Poor presentation has been
associated with congenital heart disease, an important cause of
infant mortality. However, the mechanisms by which altered
placental development can lead to congenital heart disease remain
really unresolved. So in this study, led by Dr. Suchita Nadkarni
from Queen Mary University of London and colleagues, the team
used an in vivo neutrophil-driven placental inflammation model
via antibody depletion of maternal circulating neutrophils at key
stages during time-mated murine pregnancy, embryonic day 4.5,
7.5, and then the animals were culled at embryonic day 14.5 to
assess placental and embryonic heart development.


Dr. Peder Myhre:


Oh, wow. Very interesting design. And, Greg, I'm curious to know
what did they find?


Dr. Greg Hundley:


Right, Peder. So they found that neutrophil-driven placental
inflammation leads to inadequate placental development and loss
of barrier function. And consequently, placental inflammatory
monocytes of maternal origin become capable of then migrating to
the embryonic heart and alter the normal composition of resonant
cardiac macrophages and cardiac tissue structure. This cardiac
impairment continues into postnatal life, hindering normal tissue
architecture and function. Also, they found that tempering
placental inflammation can prevent this fetal cardiac defect and
is sufficient to promote normal cardiac function in postnatal
life.


So in conclusion, Peder, these observations provide a mechanistic
paradigm whereby neutrophil-driven inflammation in pregnancy can
preclude normal embryonic heart development as a direct
consequence of poor placental development. And this in turn
certainly has major implications on cardiac function into the
adult life of these animals. And this really warrants further
study in larger animal models and perhaps human subjects.


Dr. Peder Myhre:


Very interesting, Greg. Thank you for summarizing that. And we
also have some other articles in the mail bag today. Do you mind
going first?


Dr. Greg Hundley:


Sure, Peder. So what I've got is a very nice exchange of letters
from Doctors Deng, Schmidt, and Tabák regarding a prior paper
entitled, "Risk of Macrovascular and Microvascular Disease in
Diabetes Diagnosed Using Oral Glucose Tolerance Test With and
Without Confirmation by Hemoglobin A1c: The Whitehall II Cohort
Study."


Dr. Peder Myhre:


And Greg, we also have a Research Letter from Dr. Niklas Bergh
entitled, "Risk of Heart Failure in Congenital Heart Disease: A
Nationwide Register-based Cohort Study." And then there is an
article summarizing Highlights from the Circulation Family
written by Molly Robbins [and Dr. Parag Joshi] where she
summarizes, first the characteristics of pleomorphic ventricular
tachycardia described in Circulation: A and E, then racial
inequities in assessing advanced heart failure therapies reported
in Circulation: Heart Failure. Outpatient clinic-based vascular
procedure outcomes are compared with those done in a hospital
setting in Circulation: Cardiovascular Quality and Outcomes. Then
there's a paper about immune cell imaging using nuclear methods
from Circulation: Cardiovascular Imaging. And finally, temporal
trends in left main PCI from the UK described in Circulation:
Cardiovascular Interventions.


And then Greg, we have one final very interesting paper, which is
a joint opinion from the European Society of Cardiology, American
Heart Association, and American College of Cardiology, in
addition to the World Heart Federation and it's entitled,
"Randomized Trials Fit for the 21st Century."


And I'm going to read you a quote from the beginning of this
article, Greg. It is, "Randomized controlled trials are the
cornerstones for reliably validating therapeutic strategies.
However, during the past 25 years, the rules and regulations
governing randomized trials and their interpretation have become
increasingly burdensome, and the cost and complexity of trials
has become prohibitive. The present model is unsustainable, and
the development of potentially effective treatments is often
stopped prematurely on financial grounds, while existing drug
treatments or non-drug interventions, such as screening
strategies or management tools, may not be assessed reliably."
What do you think about that?


Dr. Greg Hundley:


Oh, wow, Peder. Very provocative. So it'd be interesting for our
listeners to take a gander at that particular paper. Well, what a
great issue and how about we get on to that feature discussion?


Dr. Peder Myhre:


Let's go.


Dr. Mercedes Carnethon:


Thank you for joining us on this episode of Circulation on the
Run Podcast. My name is Mercedes Carnethon. I'm an Associate
Editor at the journal Circulation and Professor and Vice Chair of
Preventive Medicine at the Northwestern University, Feinberg
School of Medicine. I'm thrilled today to be able to host this
podcast alongside my colleague at Circulation, Gerald Greil, and
with our special guest today, Dr. Mikael Dellborg from the
Sahlgrenska Academy at the University of Gothenburg and
Sahlgrenska University Hospital. Welcome this morning, Mikael, to
our podcast. We're really excited that you shared this important
work to us about adults with congenital heart disease,
particularly given the burden of the condition and how many more
individuals are living to adulthood with congenital heart
disease. So I'd love to really just open with asking you to tell
us a little bit about your study and what you found.


Professor Mikael Dellborg:


Well, first thank you for inviting me to talk about these issues.
I very much appreciate the opportunity and I appreciate having
the paper published by Circulation, which of course is a great
honor.


Our study included 37,278 patients with congenital heart disease
born between 1950 and 1999, and alive at 18 years of age.
Follow-up was started in 1968 and at 18 years of age, and went on
until the end of 2017 or death. So the mean follow-up was 19.2
years. And for every patient with CHD, we had 10 randomly chosen
controls from the general population registry, matched for year
of birth and sex and, of course, without CHD, so 37,000 patients
and 412,000 controls. During the follow-up, 1,937 patients with
CHD died or 5.2%, as compared to 1.6% of controls, a mortality
three to four times higher among patients with CHD.


Still, at 50 years of follow-up, i.e. at age 68, more than 75% of
all patients with CHD were still alive, and I think that is the
positive news of this paper. Mortality wise, this could be
expected highest among those with the most severe defects, the
conotruncal defects, i.e., the transposition of the great
arteries, the tetrology patients, double out ventricles and so
on. And there the hazard ratio for death was 10.1 times that of
controls. But also, for non-com complex conditions such as that
we consider very malignant such as atrial septal defect, the ASD,
there was a slight but significant increase in risk with the
hazard ratio 1.4 times that of controls. We also looked at how
the increased risk of mortality changed over time. And when
comparing birth year by birth year, we could see that things
started to really change in the mid 1970s, where the hazard ratio
began to decline.


So if you were born around 1950, '60 or '70, once you reached 18
years of age, your risk of dying had not really changed over the
years. But once you were born '75, '80, '85 and on, your risk
past 18 years of age declined and was lower as compared to those
born before that, although still higher than the risk for
controls. This decline was dramatic and significant for all
patients with complex CHD. For patients with less complex
conditions, it was smaller and not statistically significant.
Although it trended in the same direction. The excess risk also
declined with age. Typically, it declined from 20 to 100 times
the risk of controls in the first years after turning 18, to
seven to eight times after 30 years of follow-up. In other words,
when you were in your fifties the difference between CHD and
controls was much smaller, although still existed.


Dr. Mercedes Carnethon:


Oh, wow. So that really seems to shift over time and that gap got
a little smaller with aging. What about these findings surprised
you?


Professor Mikael Dellborg:


What surprised us was to see that there is a... For the CHD
population as a group, we can see that the changes in operative
techniques, the possibility to operate on much earlier time that
became used in the '70s, mid-late '70s, early '80s, that has
really changed life for so many patients. When we started the
Adult Congenital Heart Unit at our hospital in 1996, there was a
belief that either you were cured or you are a sad person to
follow. You will only have trouble and you will die in your
thirties or you'll get a transplant. That was the three
conditions that we could see coming, but that's not true. I mean,
again, once you turn 18, once you come to the adult cardiologist,
you will most likely be 68, 70 years, 75 years of age.


Dr. Mercedes Carnethon:


Now, that is fantastic. I want to turn to you, Gerald, because
you were obviously the handling editor of this piece and saw a
lot of strengths. Can you tell us a little bit about why you
wanted this piece for Circulation?


Dr. Gerald Greil:


Mikael, thank you so much for submitting to Circulation. The
numbers of the patients you had for this study, including the
controls, is impressive and we all think that it's one of the
largest patients areas we looked at. Mikael, obviously this is
all exceptional, but can you line out to us what are the
strengths and limitations of your study? And how you think the
results of your investigations are going to impact patient care
in the future?


Professor Mikael Dellborg:


Thank you, Gerald. I think that the strengths are obviously, like
you pointed out, there's 37,000 patients. There is 50 years of
patients, there's 20 years of follow-up on average and that's
clearly a strength. Also, that we have virtually no patients lost
to follow-up. We have many controls and the registers we used are
public, mandatory and have been fully operational for CHD care
and CHD hospitals and including the death registry since 1968,
which is when we really started the follow-up. So it's a broad
and complete spectrum of patients with congenital heart disease,
excluding none, and I think it's fair to say that our data
reflect what you can expect from a population of eight to 10
million people, which is the Swedish population during these
years.


The weaknesses are clearly, as with any data of this sort, i.e.
Large public registers, you will always lack the granularity. The
clinical data, the blood pressure, weight, ECG, the
echocardiogram, the cath data, et cetera. And also the lifestyle
information, smoking, exercise, diet.


It's also important to realize that Sweden was, particularly at
this time before 2000, it was a fairly homogenous society in
terms of ethnicity. One feature, which I'm not sure if it's a
strength or a limitation, is that we group patients with CHD into
one or sometimes two complex non-complex or at the most six
groups. And since CHD consists of about 400 different diagnosis
and entities, we paint a broader general picture. But if you want
to know more about specific conditions such as say, hypoplastic
left heart syndrome, you need to look for other and more specific
papers.


We're currently working on several more analysis based on this
material for more narrow patient groups where we can take into
consideration also things such as type of surgery or
intervention, timing of intervention, medication and so on. We
have a lot of data on this, but it was simply not possible to put
everything into one paper.


Dr. Gerald Greil:


Yeah, I mean speaking about getting more specific, we were
fortunate enough having one of your colleagues publishing about
patients with congenital heart disease. They looked at the time
period from 1930 to 2017 using the same database. And they
focused specifically on heart failure in this group of patient
describing it in a research letter, actually in the same volume
your paper's published. How does this study relate to your work?
And how do you think are their results impacting the care of
these patients?


Professor Mikael Dellborg:


I think they relate to our paper in a nice way, because one of
the things we also could show was that the morbidities of
patients with adult congenital heart disease are significant. The
risk of heart failure, atrial fibrillation, stroke, nonfatal MI,
diabetes, and so on, is much larger in that group. And the
cumulative risk of having any such adverse event is about 75% at
age 68 after 50 years of follow-up. The letter by Bergh et al.
focuses on, as you say, heart failure. And during a follow-up or
25 years, there was an overall, like you said, 8.7 times higher
risk for patients with CHD to develop heart failure. The most, I
think, important factor from this is not only that the risk is
increased, it has been described before and it's obvious and
quite intuitive, but there was a dramatic difference in the age
of onset of heart failure, which was about 40 years in patients
with CHD compared to 66 years of age for the controls who
developed heart failure.


And again, it was obvious that it was highest among the most
complex CHD. The risk was 20 to 40 times higher. But also among
non-complex CHD, the atrial receptor defects, the ventricular
receptor defects, the risk was significantly higher, five to 10
times. One thing we saw there was that... That could be seen
there was that the risk was particularly high in the youngest age
group, the youngest patients, as compared to controls. And not so
much, although still significant, it increased also in the higher
age groups. We could also see that the risk of heart failure
seemed to increase. It was higher among those born after 1970 as
compared to those before 1930 to '69.


And I have two explanations for that. One is that a lot of
patients born in 1930 and so on were not captured by our
registers, because they have died before that. But it also
reflects that the most complex patients, the most likely to
develop heart failure, they survive these days. They did not
survive in their thirties, forties, fifties, sixties and early
seventies and so on, so that's why. So things haven't been worse,
but we do have a much sicker group of patients with congenital
heart disease that are alive today.


Dr. Mercedes Carnethon:


That's very hopeful. When I hear that and I think about the
impact that treatment and therapy has had on these improvements
in survival, it's really exciting to hear. We were really
enthusiastic because our colleagues, Dr. Rosenthal and Qureshi
from London, submitted an editorial to discuss your piece as well
as Dr. Bergh's piece. And they're discussing in it some of the
complexity in providing this care and what it has taken to get us
to this point where survival is better. Can you tell us a little
bit based on the findings from your study and what you know of
the field, how do you envision the future care of adults with
congenital heart disease?


Professor Mikael Dellborg:


Yes, Mercedes, thank you. I think this is a very nice editorial.
It summarizes very well where we are today, and I think they see
the future very much along the same lines as I do and as we do.
But the large number of patients with CHD living into their
sixties, seventies, and eighties, they will not only live longer,
they will also have more comorbidities. And I think that's what
our data shown and what the editorial is discussing. This will
require some changes to be made to the care of adults with
congenital heart disease. We will clearly, as pointed out, need
large, highly specialized, very competent ACHD centers located
close to, or at least in close corporation with pediatric
centers. There's no doubt about that building such centers need
to continue and you need roughly one large complete such center
with outpatient clinic, surgical interventions, structured
transfer, specialized physicians, physiotherapists, nurses,
education research, et cetera.


You need about one such center per 5 million people. But over
time the need of ACHD patients will also change and this will
have impact also on the large specialized centers. For instance,
if you have an adult patient with say, tetrology of Fallot,
fairly common disease in this setting, well operated on a early
childhood, well-functioning, modest right ventricular
dysfunction, modest pulmonary valve insufficiency, and it's
followed by a large centralized ACHD unit. You will keep track of
the right ventricle size waiting for the proper time to intervene
and replace the right ventricular outflow tract by surgery or
catheter. This waiting is probably 10, 15, maybe 20 years before
anything needs to be done. But during that time the patient
develops hypertension, type 2 diabetes, AFib, and the chances of
this happening at some time are fairly substantial. So either the
ACHD unit needs to take care of also these comorbidities and
that's not always the case today.


And I think it's unrealistic to expect primary care GPs to do
this. I mean, would you as primary... As a GP start the SGLT2
treatment? Is that okay for a patient with Fallot? Or the
indications for anticoagulation the same as... And that's not
easy patients to handle. So on the other hand, if the ACHD unit
will take care also of all these comorbidities, they will, I
think, have too much to do and I think they will find it
difficult to completely cope with this. So as in increasing role
for cardiologists who are knowledgeable on ACHD care, but who
perhaps spend most of the time caring for the usual patients with
heart failure and AFib, post-MI, type 2 diabetes and who are
confident in using novel anti-diabetic medications, but at the
same time they know about Fallot. They know enough to understand
the do's and don'ts, and they can interact on a regular basis
with the local ACHD units. So patients will see their general
cardiologist twice a year perhaps, and the ACHD center every two
years, something like that. I think there's a great need for
that.


Dr. Mercedes Carnethon:


I really appreciate having your insights on that. Do you have
anything, Gerald, that you'd like to follow up with? I think the
feedback that you've shared with us, Mikael, about where you see
the treatment field going for adults has been very comprehensive
and it's fantastic to be able to have these conversations with
you, because obviously these discussions go beyond what you can
share in the original research article, which is why we really
enjoy this opportunity with the podcast. So Gerald, I'd really
like to turn it to you for a final wrap up, given your expertise
in this area.


Dr. Gerald Greil:


Yeah, I mean, Mikael, thank you so much to you and your
colleagues just giving us this great overview, and even more
importantly giving us the perspective how this field is going. I
think we are getting more and more aware that there are more
patients with and adults with congenital heart disease we need to
take care of. We need to find new strategies, as you correctly
pointed out, to cope with the enormous burden of disease and
providing these patients good quality of life and excellent
outcome after sometimes a very difficult start in their lives.
And we need to be aware of the pediatricians and adult
cardiologists and other subspecialties are forming a team and
working together and not working as separate entities. So thank
you so much for giving us this perspective. And I would hand over
to Mercedes to wrap up the whole discussion please.


Dr. Mercedes Carnethon:


Well, yes, I just really want to thank our listeners for tuning
in with us today. It was such a delight to have you here with us,
Dr. Dellborg, and thank you as well for sharing your insights.


Thank you for joining us again for this episode of Circulation on
the Run Podcast. It's meant to whet your appetite and turn you
towards the journal so that you can read more. So thank you very
much.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2023.
The opinions expressed by speakers in this podcast are their own,
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.