Circulation May 25, 2021 Issue

Please join editorialist Padma Kaul and Associate Editor Karol
Watson as they discuss the original research article "Preterm
Delivery and Long-Term Risk of Stroke in Women: A National Cohort
and Cosibling Study" and the editorial "Pregnancy as Oracle: What
it Augurs for Women's Health."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast, summary
and backstage pass to the journal and its editors. We're your
co-hosts, I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, associate editor, director of the
Pauley Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Oh Greg, today's feature paper is really important. It's about
preterm delivery and the long-term risk of stroke in women. A
very, very important cardiovascular risk factor that we don't
talk about. This is important data from the national cohort and
co-sibling study. So hang on, look out for it. But first, how
would you take us through some of your spotted original papers?


Dr. Greg Hundley:


So Carolyn, my first paper comes to us from Dr. Guido Claessen
from University Hospitals in Leuven. Exertional intolerance,
Carolyn, is a limiting and often crippling symptom in patients
with chronic thromboembolic pulmonary hypertension, and
traditionally, the etiology has been attributed to central
factors, including ventilation, perfusion mismatch, increased
pulmonary vascular resistance and right heart dysfunction and
uncoupling. So pulmonary endarterectomy and balloon pulmonary
angioplasty provides substantial improvement of functional status
and hemodynamics. However, despite normalization of these
pulmonary hemodynamics, exercise capacity often does not return
to age-predicted values. So by systemically evaluating the oxygen
pathway, these authors aim to elucidate the causes of functional
limitations of chronic thromboembolic pulmonary hypertension
patients before and after these pulmonary vascular interventional
procedures.


Dr. Carolyn Lam:


So very interesting. Tell us more, what did they find, Greg?


Dr. Greg Hundley:


Yeah, well Carolyn, they utilize cardiovascular magnetic
resonance, as you know, one of my big interests, but guess what?
They also did it with exercise and simultaneous invasive
hemodynamic monitoring. The authors in doing so, sought to
quantify the steps of the oxygen transport cascade from the mouth
to the mitochondria in patients with this pulmonary hypertension.
So they had 20 subjects with pulmonary hypertension and they
compared those to 10 healthy individuals. Furthermore Carolyn,
the authors evaluated the effect of pulmonary vascular
intervention procedures, both endarterectomy or balloon
angioplasty, on the individual components of the cascade in 10 of
those 20 individuals.


Dr. Greg Hundley:


So what did they find? They found that in this chronic
thromboembolic pulmonary hypertension condition, these patients,
they have significant impairments of all steps in the oxygen
utilization cascade, resulting in markedly impaired exercise
capacity, the thick equation uncoupled. And pulmonary vascular
interventions increased, peak VO2, by partly correcting the
oxygen delivery, but having no impact on abnormalities in
peripheral oxygen extraction.


Dr. Greg Hundley:


So Carolyn, this suggests that the current interventions only
partially address patient's limitations and that additional
therapies may improve functional capacity, such as improvement in
skeletal muscle function and metabolism. So maybe one of your
faves, cardiac rehab, perhaps could work on some of those
peripheral factors in these patients. So, really interesting,
very well accomplished study.


Dr. Carolyn Lam:


Nice, elegant and clinically impactful. Very nice. Well, the next
paper is the same. We know that prenatal detection has benefits
for infants with hypoplastic left heart syndrome and
transposition of the great arteries. Well, this next paper
describes the largest multicenter study to evaluate whether
social economic quartile, public insurance, race or ethnicity,
rural residence and distance from the residence are associated
with the prenatal detection of critical congenital heart diseases
in North America. This study is from Dr. Krishnan from Children's
National Medical Center in Washington, DC and colleagues.
Basically, what they found was that lower socioeconomic position,
Hispanic ethnicity, and rural residence were all associated with
decrease prenatal detection rates of hypoplastic left heart
syndrome and transposition of the great arteries.


Dr. Greg Hundley:


Wow Carolyn, so social determinants of health, interesting. So
how do we, as clinicians, apply these results?


Dr. Carolyn Lam:


Well, clinicians can use the findings of the study to focus
efforts on improving overall prenatal detection rates for
congenital heart disease. They can specifically improve health
equity in prenatal detection and timing of prenatal detection by
improving linkages between tertiary care centers and these
populations and regions that were identified in this study.


Dr. Greg Hundley:


Very nice Carolyn. Well, I'm going to turn to the world of aortic
aneurysms and this next paper comes to us from Dr. Maria
Mittelbrun from Centro de Biología Molecular Severo Ochoa.
Carolyn, it involves Marfan syndrome, which you know, is an
autosomal dominant disorder of the connective tissue caused by
mutations in the FBN1 gene, encoding a large glycoprotein in the
extracellular called fibrillin one. The major complication, again
as you know, of this connective disorder is the risk to develop
thoracic aortic aneurysms. To date, no effective pharmacological
therapies have been identified for the management of thoracic
aortic disease and the only options capable of preventing
aneurysm rupture are surgery. So here, the authors studied the
role of mitochondrial dysfunction in the progression of thoracic
aortic aneurysm dilation, and mitochondrial boosting strategies
as a potential treatment to manage these aneurysms.


Dr. Carolyn Lam:


Wow, that's really fascinating. So what did they find?


Dr. Greg Hundley:


So Carolyn, just like in circulation, these wonderful
translational basic science studies, the research here by these
authors was performed in both mice and in patient samples from
Marfans patients. So mitochondrial function of vascular smooth
muscle cells was found to be controlled by the extracellular
matrix and drive the development of aortic aneurysm in the Marfan
syndrome. Interestingly, restoring mitochondrial metabolism with
the NAD precursors nicotinamide riboside rapidly reversed aortic
aneurysm in the fibrillin positive mice. Thus Carolyn, the
clinical implications are that by potentially targeting vascular
metabolism, a new available therapeutic strategy for managing
aortic aneurysms associated with these genetic disorders, such as
Marfan syndrome, may become available. Really interesting new
development in the world of managing aortic aneurysm dilation in
patients with Marfan syndrome.


Dr. Carolyn Lam:


Oh my goodness, that would be paradigm shifting. Wow, hope that's
going to be pursued further. Well, this next one is from the
preclinical world and this study really uncovered a metabolic
transcriptional axis that explains how dividing cells coordinate
metabolism with gene regulation in pulmonary arterial
hypertension. So this is from Dr. Rabinovitch and colleagues from
Stanford University School of Medicine who applied RNA sequencing
to pulmonary artery smooth muscle cells from patients with
pulmonary arterial hypertension with and without a BMPR2 mutation
compared to control pulmonary artery smooth muscle cells,
basically to uncover genes required for their heightened
proliferation and glycolytic metabolism. The assessment of
differentially expressed genes establish metabolism as a major
pathway. The most highly up-regulated metabolic gene was aldehyde
dehydrogenase family 1 member 3, an enzyme previously linked to
glycolysis and proliferation in cancer cells and systemic
vascular smooth muscle cells, but now demonstrated in pulmonary
arterial hypertension. Isn't that cool?


Dr. Carolyn Lam:


The findings were basically like this, an increase in this
particular aldehyde dehydrogenase family 1 member 3, underlined
the heightened proliferation and glycolysis of pulmonary artery
smooth muscle cells in patients with both idiopathic and
hereditary pulmonary artery hypertension, while promoting
survival of their endothelial cells under stress. The authors
further uncovered the way this molecule interacted with genetic
factors in doing so and then finally demonstrated that transgenic
mice with the deletion in smooth muscle cells did not develop
chronic hypoxia-induced pulmonary hypertension.


Dr. Greg Hundley:


Wow Carolyn, really new, inventive material from the world of
basic science. So what's the take-home message?


Dr. Carolyn Lam:


So these findings really suggest that selectively disrupting the
pivotal role of aldehyde dehydrogenase family 1 member 3 in
pulmonary artery hypertension smooth muscle cells, note that was
smooth muscle cells, not the endothelial cells, may be a
important therapeutic consideration in patients.


Dr. Greg Hundley:


Very nice.


Dr. Carolyn Lam:


So Greg, let me tell you about some other articles in today's
issue. There's an exchange of letters between Drs. Pengo and
Kario 00:10:36 regarding the article Nighttime Blood Pressure
Phenotype And Cardiovascular Prognosis, A Practitioner-based
Nationwide JAMP Study.


Dr. Greg Hundley:


Great Carolyn, well also in the mail bag, we have a perspective
piece from Professor Chang entitled Trial By Wildfire, The Need
To Expand The Framework Of Environmental Determinants Of
Cardiovascular Health From Climate Change To Planetary Health.
Also, there's a primer from Professor Miano entitled The Fate And
State Of Smooth Muscle Cells And Atherosclerosis. Then lastly, we
have another article from the world of basic science, a research
letter from Dr. Ieda entitled Overexpression Of GATA4, MEF2C and
TBX5 Generates Induced Cardiomyocytes Via Direct Reprogramming
And Rare Fusion In The Heart. Well, Carolyn, how about we get to
the world of preterm delivery and onto that feature article?


Dr. Carolyn Lam:


I'm there already, let's go.


Dr. Greg Hundley:


Well, listeners. Now we are turning to our feature discussion and
we're so excited today to have with us our editorialist for this
article, Dr. Padma Kaul and our own associate editor, Dr. Karol
Watson and we'll be discussing today, a paper related to preterm
delivery and long-term risk of stroke in women. Padma, I'd like
to start with you. Describe for us a little bit, the context for
this study, and then what were the authors' study population and
study design?


Dr. Padma Kaul:


So Greg, this is a study, which is a retrospective cohort study
from Sweden and they looked at women who had given birth over a
pretty long period of time, from 1973 to 2015. In over two
million women, they looked at the association between preterm
birth and the long-term development of stroke in the mothers.
It's a really interesting study. What they did find is that
preterm birth was associated with a higher hazard ratio for
stroke, over 48 million person years of follow-up. The authors
also did an interesting co-sibling analysis to supplement what
the overall primary analysis. This was by looking at a subset of
women who had at least one sibling in the cohort. The point of
that was to assure that the association between preterm birth and
stroke risk remained, even after you account for familial or
genetic environmental factors. They do find that it was
demonstrated even in the subset.


Dr. Greg Hundley:


Very nice, just a couple quick clarifying points. Were these
ischemic strokes, were they hemorrhagic strokes? And then give me
a little bit of definition. How did they define preterm?


Dr. Padma Kaul:


So preterm was in less than 37 weeks of gestation, and they
looked at both hemorrhagic as well as ischemic strokes in the
women. So they did an overall stroke endpoint as well as looked
at whether these two types of strokes, whether the relationship
stayed.


Dr. Greg Hundley:


And was there any particular age at which these strokes occurred?


Dr. Padma Kaul:


That's an excellent point. As I told you, that the time period of
the study is pretty long. So they did stratify the follow-up
period into 10 year segments, and they found that higher risk in
the early part of the 10 and the 10 to 20 time periods. It stayed
in the latter periods as well, but it was more so associated with
a higher hazard in the early time periods, the 10 and the 20.


Dr. Greg Hundley:


Thank you so much, Padma. Well now listeners, we're going to turn
to our associate editor, Dr. Karol Watson from UCLA. Karol, I
know working on the editorial board at Circulation, you see many
papers come across your desk. What attracted you to this
particular manuscript? And how would you put the results from
this study in the context of other studies that have really
evaluated women's health in this situation?


Dr. Karol Watson:


That's a fabulous question. I think really so many great
manuscripts come in and there are important features of many of
them, but this one caught my eye for a couple of reasons. It was
so incredibly well done. This is a huge, huge cohort of over two
million women and it's from Sweden, where they keep really
exquisite records, so we had so much data on this population. So
we really got to know all about these soliton deliveries in
Sweden, over a 40 year period. So the great cohort that was
really well characterized, the really long follow-up. I love the
co-sibling analysis that they talked about, they really did
control for so many things, shared familial factors, shared
genetic factors, covariates. So they just did a fabulous study.


Dr. Karol Watson:


So, in the whole realm of women's health, we are understanding
that pregnancy is a great window into a woman's vascular future.
So we now know so many things, we know that preterm delivery is
amongst those pregnancy outcomes that we have to look for. So we
have to look for pregnancy-induced hypertension, gestational
diabetes, but also preterm delivery and pregnancy loss. So all of
these things are telling us that a woman's vascular system is
under stress and we have to do things to make sure they have good
outcomes, because we know they're at greater risk.


Dr. Greg Hundley:


Very nice. So as leading experts in the era, Padma first to you,
and then I'll come back to Karol. Padma, tell us, what do you
think is the next area of research that needs to be explored in
this topic area?


Dr. Padma Kaul:


I think that this is an observational study. So one of the things
we have to recognize is how do we add to the evidence that this
study has provided us? That I think, is to see if in other
cohorts, similar pregnancy birth cohorts with longitudinal data,
whether we observe the same patterns that we ever observed in
Sweden. Sweden is actually quite unique in terms of the makeup of
the population and these are historical trends. We do know that
the characteristics of the mothers who are giving birth are
changing over time. Women are delaying childbirth, they are
getting heavier, they may have preexisting conditions. So I think
to keep monitoring the health of the mothers and pregnancy
factors is what is needed to move the field forward.


Dr. Greg Hundley:


Very nice, and Karol? Karol, would you like to add anything?


Dr. Karol Watson:


Yeah, I agree completely with what Padma says. The beauty of the
Swedish cohort is how well characterized it is, but one of the
limitations is it's a fairly homogenous cohort. So I would love
to see similar data in other racial or ethnic groups. We'd also
like to see, again, as Padma said, this is observational cohort
study, so we don't know truly the causal validy here, although
this is a really good study to identify this trend. I would love
to think of ways why this might be, we really don't have a good
handle on the pathobiology. We can surmise some things
endothelial dysfunction, et cetera, but we just don't know for
sure. The other thing I'd like to think of is ways we might
address mitigating risk. If this truly is a risk factor, how are
we going to help these women have better vascular outcomes. But
again, a great study to start all these questions.


Dr. Greg Hundley:


Well, thank you Karol and Padma and listeners. We certainly want
to thank both Drs. Kaul and Watson for their time today and also
the author group under the direction of Dr. Casey Crump for
submitting this article to us at Circulation reporting on this
large cohort of women from Sweden, identifying a preterm delivery
and long-term risk of both ischemic and hemorrhagic stroke.


Dr. Greg Hundley:


Well, on behalf of Carolyn and myself, we want to wish you a
great week and we will catch you next week on the run. This
program is copyright of the American Heart Association, 2021. 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, visit ahajournals.org.