Circulation July 4, 2017 Issue

Dr. Carolyn
Lam:              
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. I'm Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore. What is the association
between fetal congenital heart defects and maternal risk of
hypertensive disorders of pregnancy? We will be discussing new
data in this area in just a moment, following these summaries.


                                               
The first paper describes the effect of long-term metformin and
lifestyle measures on coronary artery calcium. This is a paper
from Dr. Goldberg of George Washington University Biostatistics
Center and colleagues of the Diabetes Prevention Program Research
Group. The Diabetes Prevention Program and its outcome study is a
long-term intervention study in subjects with prediabetes, which
showed reduced diabetes risk with lifestyle and metformin
compared to placebo.


                                               
In the current study, the authors looked at subclinical
atherosclerosis, which was assessed in 2,029 participants using
coronary artery calcium measurements after 14 years of average
follow-up. They found that men but not women with prediabetes
treated with metformin for an average duration of 14 years had
lower coronary calcium scores than their placebo counterparts. No
difference in coronary calcium scores was observed in the group
receiving a lifestyle intervention as compared to the placebo
group.


                                               
These findings provide the first evidence that metformin may
protect against coronary atherosclerosis in men with prediabetes,
although demonstration that metformin reduces cardiovascular
disease events in these subjects is still needed before firm
therapeutic implications of these findings can be made. The
reason for an absence of an effect in women is unclear and
deserves further study.


                                               
The next study provides insights on the physiology of angina from
invasive catheter laboratory measurements during exercise. Dr.
Asrress of Royal North Shore Hospital in Sydney, Australia, and
colleagues, studied 40 patients with exertional angina and
coronary artery disease who underwent cardiac catheterization via
radial axis and performed incremental exercise using a supine
cycle ergometer. As they developed limiting angina, sublingual
GTN was administered to half the patients and all patients
continued to exercise for two minutes at the same workload.
Throughout exercise, distal coronary pressure and flow velocity,
and central aortic pressure were recorded using sensor wires.


                                               
Using this novel invasive approach, the authors showed that
administration of GTN ameliorated angina by reducing myocardial
oxygen demand as well as increasing supply with a key component
being the reversal of exercise-induced coronary lesion
vasoconstriction. This was evidenced by the fact that there was a
relationship between the diastolic velocity pressure gradient
with significant increase in relative stenosis severity. In
keeping with exercise-induced vasoconstriction of stenosed
epicardial segments and dilation of normal segments, with trends
towards reversal with GTN.


                                               
Thus, this study describes the development of a paradigm where
patients with coronary artery disease can exercise while
simultaneously having coronary and central aortic hemodynamics
measured invasively, and has shown that this provides a unique
opportunity to study mechanisms underlying the physiology of
angina. In treating patients with exercise-induced angina, the
results highlight the importance of after-load reduction and the
use of agents that reduce arterial wave reflection and promote
coronary artery vasodilation.


                                               
The next study provides mechanistic insights into reverse
cholesterol transport, where excess cholesterol is removed from
macrophage-derived foam cells in atherosclerotic plaques. It
suggests that melanocortin receptor-1, or MC1-R, may play a role.
As background, the melanocortin system, consisting of
melanocyte-stimulating hormones and their receptors, regulate a
variety of physiological functions, ranging from skin
pigmentation to centrally-mediated energy balance control. At the
cellular level, the biological actions are mediated by G
protein-coupled melanocortin receptors, such as MC1-R. MC1-R not
only affects melanogenesis in the skin but also has
immunomodulatory effects through its wide expression in the cells
of the immune system.


                                               
In the current study from Dr. Rinne of University of Turku in
Finland, and colleagues, human and mouse atherosclerotic samples
and primary mouse macrophages were used to study the regulatory
functions of MC1-R. The impact of pharmacological MC1-R
activation on atherosclerosis was further assessed in
apolipoprotein E deficient mice. Their findings identified a
novel role for MC1-R in macrophage cholesterol transport.
Activation of MC1-R conferred protection against macrophage foam
cell formation through a dual mechanism. It prevented cholesterol
uptake while it concomitantly promoted reverse cholesterol
transport by increasing the expression of ATP-binding cassette
transporters, ABCA1 and ABCG1.


                                               
Thus, the identification of MC1-R in lesional macrophages,
demonstration of its role in regulating reverse cholesterol
transport, combined with its established anti-inflammatory
effects, suggests that MC1-R could be a novel new therapeutic
target for preventing atherosclerosis.


                                               
The next study suggests that obesity-related heart failure with
preserved ejection fraction, or HFpEF, is a genuine form of
cardiac failure and a clinically relevant phenotype that may
require specific treatments. First author, Dr. Obokata,
corresponding author, Dr. Borlaug, and colleagues from Mayo
Clinic Rochester and Minnesota studied 99 patients with obese
HFpEF with a BMI above 35, with 96 non-obese HFpEF with a BMI
less than 30, and 71 non-obese controls without heart failure.
All subjects underwent detailed clinical assessment,
echocardiography, and invasive hemodynamic exercise testing.


                                               
The authors found that, compared to non-obese HFpEF, obese HFpEF
patients displayed greater volume overload, more biventricular
remodeling, greater right ventricular dysfunction, worse exercise
capacity, more impaired pulmonary vasodilation, and more profound
hemodynamic arrangements, despite a lower NT-proBNP level. Obese
HFpEF patients displayed other important contributors to high
left ventricular filling pressures, including greater dependence
on plasma volume expansion, increased pericardial restraint, and
enhanced ventricular interaction, which was exaggerated as
pulmonary pressure load increased.


                                               
These data provide compelling evidence that patients with the
obese HFpEF phenotype have real heart failure and display several
pathophysiological mechanisms that differ from non-obese patients
with HFpEF. These and other issues are discussed in an
accompanying editorial by Dr. Dalane Kitzman and myself. We hope
you enjoy it.


                                               
The final study identifies a novel long noncoding RNA that
regulates angiogenesis. As background, although we know that the
mammalian genome is pervasively transcribed, a large proportion
of the transcripts do not encode a protein, and are thus regarded
as noncoding RNAs. Based on their length, they can be divided
into small or long noncoding RNAs, long being described as more
than 200 nucleotides. Although their function is not fully
understood, long noncoding RNAs have been increasingly reported
to mediate the expression of other genes, affect the organization
of the nucleus, and modify other RNAs.


                                               
In the current study by first author, Dr. Leisegang,
corresponding author, Dr. Brandes, and colleagues of Goethe
University in Frankfurt, Germany, epigenetically controlled long
noncoding RNAs in human umbilical vein endothelial cells were
searched by axon array analysis following knockdown of the
histone demethylase JARID1B. The authors discovered a novel
noncoding RNA named MANTIS to be strongly upregulated. MANTIS is
located in the antisense strand of an intronic region of the gene
for annexin A4, calcium- and phospholipid-binding protein. MANTIS
is a nuclear long noncoding RNA that is enriched in endothelial
cells but also expressed in other cell types. Reducing MANTIS
levels led to impaired endothelial sprouting, tube formation,
attenuated endothelial migration, and inhibition of the alignment
of endothelial cells in response to shear stress.


                                               
Brahma-like gene 1, or BRG-1, was identified as a direct
interaction partner of MANTIS, implying a role of MANTIS in the
formation of the switch/sucrose non-fermentable chromatin
remodeling complex. MANTIS binding to BRG-1 was shown to
stabilize the BRG-1 interaction, hence by inducing an open
chromatin conformation, MANTIS was proposed to maintain the
endothelial angiogenic potential. The implications of these
findings are discussed in an accompanying editorial by Dr.
Zampetaki and Mayr from Kings College London.


                                               
That brings us to the end of our summaries. Now for our feature
discussion.


                                               
Today, we are going to be discussing the association between
fetal congenital heart defects and maternal risk of hypertensive
disorders of pregnancy. To discuss this, I have the first and
corresponding author of our feature paper, Dr. Heather Boyd, from
Statens Serum Institut in Copenhagen, and our familiar Dr. Sharon
Reimold, content editor for special populations from UT
Southwestern. Welcome, Heather and Sharon.


Dr. Heather
Boyd:           
Thank you.


Dr. Sharon Reimold:       
Thank you.


Dr. Carolyn
Lam:              
Heather, it's a topic that I can't say I'm very familiar with,
association between fetal congenital heart defects and maternal
risk of hypertensive disorders of pregnancy. Could you start by
sharing why would we think there would be a link? What was the
hypothesis you were testing?


Dr. Heather
Boyd:           
A couple years ago, there was a paper published in the European
Heart Journal that reported evidence of angiogenic imbalance in
women with fetuses with major congenital heart defects, so women
who were pregnant with babies that had heart defects, and then in
fetuses that were terminated because of this kind of defect. My
research group focuses a lot of attention on preeclampsia. In the
last decade or so, angiogenic imbalance in preeclampsia has been
a really hot topic. Women with preeclampsia, particularly women
with early-onset preeclampsia, have big angiogenic imbalances.
When we saw the European Heart Journal paper, we immediately
thought, "What's the connection between preeclampsia and heart
defects in the offspring?"


Dr. Carolyn
Lam:              
Oh!


Dr. Heather
Boyd:           
Exactly. That was our entry point to it, was the term "angiogenic
imbalance" in that paper sort of was a flag for us. It wasn't a
completely new idea, but we in Denmark have one big advantage
when considering research questions that involve either rare
exposures and/or rare outcomes, and that's our National Health
Registry. We have the ability to assemble these huge cohorts and
study conditions like heart defects with good power, so we
decided just to go for it.


Dr. Carolyn
Lam:              
That makes a lot of sense now. Please, tell us what you did and
what you found.


Dr. Heather
Boyd:           
The first thing we did was look at the association between
carrying a baby with a heart defect and then whether the mom had
preeclampsia later in the same pregnancy. We had information on
almost 2 million pregnancies for this part of the study. We found
that women carrying a baby with a heart defect were seven times
as likely as women with structurally normal babies to develop
early preterm preeclampsia. We defined that as preeclampsia where
the baby has to be delivered before 34 weeks, so the really
severe form of preeclampsia. Then, women carrying a baby with a
heart defect were almost three times as likely to develop late
preterm preeclampsia as well. That's where they managed to carry
it until 34 weeks but it has to be delivered some time before 37
weeks.


                                               
These findings were similar to those of other studies, but we
were able to go a step further and look at individual heart
defect subtypes. What we found there waws that these strong
associations were similar across defect categories. Then we
decided to see if we could shed any light on the origin of the
problem, whether it was coming from the mom's side or the baby's
side. To do this, we looked at women with at least two
pregnancies in our study period to see whether preeclampsia in
one pregnancy had any bearing on the chance of having a baby with
a heart defect in another pregnancy or vice versa.


                                               
This part of the study included 700,000 women. We found very
similar findings. We found that women with early preterm
preeclampsia in one pregnancy had eight times the risk of having
a baby with a heart defect in a subsequent pregnancy. Late-term
preeclampsia in one pregnancy was associated with almost three
times the risk of offspring heart defects in later pregnancies.
Then, we found that it worked the other way around too. Women who
had a baby with a heart defect were twice as likely to have
preterm preeclampsia in subsequent pregnancies.


                                               
Those results were really, really exciting, because whatever
mechanisms underlie the associations between preterm preeclampsia
in moms and heart defects in the babies, they operate across
pregnancies. Therefore, that pointed towards something maternal
in origin.


Dr. Carolyn
Lam:              
That is so fascinating. Sharon, please, share some of the
thoughts, your own as well as those of the editors when we saw
this paper.


Dr. Sharon Reimold:        I
think that there's a growing data about the links between
hypertensive disorders of pregnancy and preeclampsia with
subsequent abnormal maternal outcome. But this paper, I think,
has implications for how we look at moms who are going to have
offspring with congenital heart defects as well as those with
preeclampsia. For instance, I would look at a patient now that
has preeclampsia, especially in more than one pregnancy, to
identify that they may be at risk to have offspring with
congenital defects in the future if they have additional
children. But the mom is also at risk based on other data for
developing other cardiovascular risk factors and disease as she
gets older. It was really the link going back and forth with the
hypertensive disorders and the congenital defects that we found
the most interesting.


Dr. Carolyn
Lam:              
That struck me too, especially when you can look at multiple
pregnancies and outcomes. That's amazing. You know what, Heather,
could you share a little bit about what it's like working with
these huge Danish databases? I think there must be a lot more
than meets the eye.


Dr. Heather
Boyd:           
It's an interesting question, because I'm a Canadian and I was
trained in the US. I did my PhD in epidemiology at Emery, and
then I moved to Copenhagen. When I first got here, I was
absolutely floored at the possibility of doing studies with
millions of women in them. It opens some amazing possibilities,
like I said earlier, for certain outcomes and certain exposures.
You just need to have a question where the information you want
is registered.


Dr. Carolyn
Lam:              
Yeah. But I think what I also want to put across is, having
worked with big databases, and certainly not as big as that one,
it's actually a lot of work. People might think, "Oh, it's just
all sitting there." But, for example, how long did it take you to
come to these observations and conclusions?


Dr. Heather
Boyd:           
I have a fabulous statistician. I think she's the second author
there, Saima Basit. She spends a lot of her time pulling together
data from different registers. But yes, you're right. The data
don't always just mesh nicely. The statisticians we have working
with us are real pros at this sort of data slinging.


Dr. Carolyn
Lam:              
Could I just pose one last question to both of you. What do you
think are the remaining gaps?


Dr. Sharon Reimold:        I
think that this is a clinical link. Then, going back to figure
more about what's going on biologically to set up this
difference? Because right now there's really no intervention
that's going to make a difference, it's just a risk going
forward. This is sort of like medicine done backwards, that
there's this association and now we need to figure out exactly
why.


Dr. Heather
Boyd:           
I can piggyback on what Sharon said a little bit, because I think
one of the things we need to remember is that not all women with
preeclampsia have babies with heart defects. Not by a long shot.
What we need to do now is to figure out what distinguishes the
women who do get this double whammy from the vast majority who
don't.


                                               
One of the things that Denmark does really nicely is that there
are large bio banks. One of the things we want to do is go back
to bank first trimester maternal blood samples and see if we can
identify biomarkers that are unique to the women with both
preterm preeclampsia and babies with heart defects. That's one of
the things we're thinking about to address this gap. Because, as
Sharon says, we've got to figure out what the mechanism is.


                                               
The other thing we want to do is to see whether the association
between preeclampsia and heart defects extends, for example, to
other things, to cardiac functional deficits, for example,
because it's probably not just severe structural defects. If
there's an association, it's probably on a continuum. Are babies
born to preeclamptic moms, do their cardiac outputs differ? Do
their electrical parameters differ? Do they just have different
hearts?


                                               
We're really lucky because right now the Copenhagen Baby Heart
Study is offering to scan the hearts of all infants born at one
of the three major university hospitals in the Copenhagen area.
We're about to have echocardiography data on 30,000 newborn
hearts to help us look at this. I'm really excited about that
possibility.


Dr. Carolyn
Lam:              
I've learnt so much from this conversation. I'm sure the
listeners will agree with me. Thank you both very, very much.