Circulation March 27, 2018 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 Centre and
Duke National University of Singapore. Our featured paper this
week is an in-depth paper on the cardiovascular and metabolic
heterogeneity of obesity, and we will have a discussion with the
authors on the clinical challenges, implications for management,
and much more coming right up after these summaries.


                                               
How does MRI quantification compare with standard Doppler echo
approach to identify organic mitral regurgitation and predict
adverse outcomes? Well, our first paper this week addresses this
question, led by first and corresponding author, Dr. Penicka from
the Cardiovascular Center OLV Clinic in Belgium. These authors
studied 258 asymptomatic patients with preserved left ventricular
ejection fraction and chronic moderate and severe organic mitral
regurgitation by echo. All patients underwent MRI to quantify
regurgitant volume of this organic mitral regurgitation by
subtracting aortic flow volume from the total left ventricular
stroke volume. Severe organic mitral regurgitation was defined as
a regurgitant volume of greater or equal to 60 milliliters.


                                               
The authors found that mean echo-derived regurgitant volume was
an average 17 milliliters larger than the MRI-derived regurgitant
volume. Concordant grading of organic mitral regurgitation
severity with both techniques was observed in 76% of individuals.
In the remaining 24% of individuals with discordant findings
between the two techniques, this was mainly observed in patients
with late systolic, eccentric, or multiple jets.


                                               
The MRI-derived regurgitant volume showed the highest
discriminative power among all the imaging parameters to predict
all cause mortality or its combination with development of
indication for mitral valve surgery. Thus, this study
demonstrates that MRI-derived assessments of organic mitral
regurgitation are clinically accurate to identify asymptomatic
patients with severe organic mitral regurgitation and at first
outcomes. This may be particularly so when the mitral
regurgitation is late systolic, eccentric, or multiple in jets
where misclassification may occur with echo-derived approach.


                                               
The next study is the first large population-based study to
analyze the association between low-dose ionizing radiation from
cardiac procedures and incident cancer in adults with congenital
heart disease. First author Dr. Cohen, corresponding author Dr.
Marelli from McGill University, studied the population from the
Quebec Congenital Heart Disease Database and performed a nested
case control study comparing cancer cases with controls matched
on sex, congenital heart disease severity, birth year, and age.
They found that the cumulative incidence of cancer in adults with
congenital heart disease between the ages of 18 and 64 years was
15%. The cumulative low-dose ionizing radiation exposure from
cardiac procedures was independently associated with incident
cancer after adjusting for age, sex, year of birth, congenital
heart disease severity and comorbidities.


                                               
Results were similar using either the number of procedures or
estimates of the effective doses with a possible dose-related
response relationship between the low-dose ionizing radiation
exposure level and cancer risk. Thus, increasing exposure to
low-dose ionizing radiation from cardiac imaging in adults with
congenital heart disease raises concerns about life-long risk of
malignancy.  Confirmation of these findings by prospective
studies is needed to reinforce policy recommendations for
radiation surveillance in patients with congenital heart disease.


                                               
The next study characterizes the long-term dynamics of potassium
in heart failure and its associated risk of mortality. First and
corresponding author, Dr. Nunez from Hospital Clinic University
of Valencia in Spain, evaluated the prognostic implications of
long-term longitudinal monitoring and dynamics of serum potassium
in a prospective and consecutive cohort of patients following a
hospitalization for acute heart failure. In these patients, serum
potassium was measured at every physician-patient encounter,
including hospital admissions and ambulatory settings.


                                               
The authors found that on a continuous scale, the followup
trajectory of serum potassium levels independently predicted
mortality through a U-shaped association with higher risk at both
ends of the distribution, and the same was true using potassium
categories. Furthermore, dynamic changes in potassium were
independently associated with substantial differences in
mortality risk. Persistence of normal potassium levels was linked
to a higher risk of death compared to patients who maintained or
returned to normal values. Conversely, potassium normalization
was independently associated with a lower mortality risk.


                                               
These findings support the need for close monitoring of serum
potassium after an episode of acute decompensated heart failure
and suggest that maintaining serum potassium levels within normal
range may be considered a therapeutic target.


                                               
The next study gives us an example of how functional metabolomics
can translate into metabolomics derived biomarkers of disease
mechanisms. Co-first authors, Dr. Zhang, Wei, and Li;
co-corresponding authors, Dr. Zhu, Li, and Qi from Nanjing,
China, studied a cohort of 2324 patients who underwent coronary
angiography from four independent centers. They used a
combination of ultra-performance liquid chromatography and
quadrupole time-of-flight mass spectrometry in the negative ion
mode for untargeted analysis of metabolites in the plasma.


                                               
The authors identified a total of 36 differential metabolites
related to coronary artery disease progression. In particular,
N-Acetyl-neuraminic acid, a metabolic marker highly elevated
during coronary artery disease progression, acted as a signaling
molecule to trigger RhoA and Cdc42 dependent myocardial injury
via activation of the Rho-RACK signaling pathway.


                                               
Silencing neuraminidase-1, which is the enzyme that regulates
N-Acetyl-neuraminic acid generation, ameliorated myocardial
injury in vitro and in vivo. Pharmacologic inhibition of
neuraminidase by anti-influenza drugs protected cardiomyocytes
and the heart from myocardial injury.


                                               
Thus, in summary, functional metabolomics identified a key role
for N-Acetyl-neuraminic acid in acute myocardial injury, and
targeting neuraminidase-1 may represent an unrecognized
therapeutic intervention for coronary artery disease.


                                               
The final study addresses the controversy of whether high density
lipoprotein, or HDL cholesterol, plays a causal role in
cardioprotection. First and corresponding author, Dr. Jensen from
Harvard T.H. Chan School of Public Health and colleagues,
hypothesized that subspecies of HDL defined by apolipoprotein C3,
a key regulator of lipoprotein metabolism, may contribute new
information to prediction of cardiovascular risk.


                                               
They used immunoaffinity chromatography to measure the apo A1
concentrations of HDL that contained or lacked apolipoprotein C3,
or apo C3, in two prospective studies of adults free of coronary
heart disease, the Multiethnic Study of Atherosclerosis and the
Danish Diet, Cancer and Health Study. They then conducted a
meta-analysis that combined these results with the previously
published findings from two cohort studies that used similar
laboratory methodology to measure lipoproteins.


                                               
The authors identified a subspecies of HDL that contained apo C3.
HDL that contained apo C3 comprised 5 to 6% of apo A1 or 10 to
15% of HDL cholesterol. In the four prospective studies, HDL
containing apo C3 was associated with a greater risk of coronary
heart disease, whereas HDL that lacked apo C3 was inversely
associated with risk more strongly than the total HDL.


                                               
These findings support the hypothesis that apo C3 may mark a
subfraction of HDL cholesterol that is associated with higher
risk of coronary heart disease. These findings therefore provide
novel insights for cardiovascular risk that extend beyond
traditional plasma HDL cholesterol concentrations. And that
brings us to a close for the summaries. Now for our feature
discussion.


                                               
For today's featured discussion, we are talking about obesity, a
universal issue, or is it? And when we talk about obesity, are we
talking about one thing or many things? Today's in-depth review
is just such a great paper. I highly recommend it to everyone. So
pleased to be discussing it with Dr. Ian Neeland today from UT
Southwestern Medical Center.


                                               
Ian, first of all, congratulations. A beautiful paper. I learned
so much reading it, and I've got so many questions. You started
off pointing out that we talk about obesity. We've always defined
it by body mass index, but that may not be the ideal biomarker. I
love the way you said that. So, tell us a bit more about the
reason for this review.


Dr Ian
Neeland:               
Obesity, like you said, we define it by body mass index, but body
mass index is such a crude marker. It's great to use for the
clinic. It's easy to implement, but it doesn't really tell us a
lot of information about the person. And so you can just look at
a third of the population in the US right now is thought to be
obese. And if you take a third of the population, clearly not
everyone has diabetes and heart disease.


                                               
So, obesity in and of itself, defined by the body mass index
really is very heterogeneous, and it's not possible to use that
alone to tell an individual if they're really at risk for
disease. And so this review is really about getting deeper under
the skin, no pun intended, to really get a sense of what it means
to be obese, how the body fat plays a role in disease, and really
getting to the different aspects of obesity and how we can
understand it a little bit better.


Dr Carolyn
Lam:               
Yeah. You know, Ian, you had me at hello if I could say when I
read your paper because I'm from Asia, and here, the World Health
Organization actually even suggests that we use lower body mass
index cutoffs to define obesity, simply because there's a
different relationship as well with cardiometabolic disease. So,
so true, but before we get there, to maybe ethnic differences, I
want to ask you something. I heard the term, obesity paradox,
thrown around a lot, and sometimes I think we don't really know
what we're talking about when we say obesity paradox.


                                               
I love the way, in your paper, you broke it down into four types.
There are four paradoxes. Do you want to just clarify this for
the audience? I think it's important.


Dr Ian
Neeland:               
So, the obesity paradox, what we mean by that is we think that
obesity causes disease and gives someone an increased risk for
disease and mortality and death, but the obesity paradox means
that some people who are obese we see actually have better
outcomes than those who are not obese. And how to describe that
paradox and why that exists is really the subject of lots and
lots of research and discussion.


                                               
And so when we talk about the obesity paradox, really it's
important to understand that most of the time we're talking about
people who already have established disease. Let's say, for
example, heart disease. So people with heart disease who are
obese tend to have better outcomes than those who are not, and
there are a few ways to understand that.


                                               
So people who have obesity with established disease who may have
better outcomes; that's the classic obesity paradox. Then there's
a paradox really about fitness and being fat and fit, and that
concept that you can be fat, but if you're fit, if you're able to
do exercise and you have good cardiorespiratory fitness, that you
actually may be protected from disease as well. And then there's
also the obesity paradox of basically the pre-obesity paradox, so
that overweight, right, where you haven't yet met the threshold
for obesity can also be protective in people who don't have
disease. And so being a little bit plump may be protective for
different diseases down the road. And then the final one is that
the metabolically health obesity. When we say that, it means that
the person who is obese by body mass index but doesn't really
have any hypertension or diabetes or lipid abnormalities. So,
that's the metabolically healthy obese person.


                                               
Those are the four types of individuals we see who may be obese
but actually have better outcomes long term, and the question is
why that exists. So there's a lot of thinking about it. Maybe it
has to do with the fact that being normal weight nowadays, often
we have older folks that are normal weight. Well, they tend to be
more deconditioned. They may be frail. They may have undiagnosed
disease like cancer. And that might be why those people are the
worst. And there are the naysayers out there who think that it's
all just about what we call confounding, so things we can't
account for when we look at that. People who smoke tend to be
lower weight, and obviously they have worse outcomes, and then
also people who are older.  So it's kind of a conundrum,
this obesity paradox, but there's lots and lots of data out there
coming out all the time that we keep seeing it again and again
and again.


                                               
One of the areas in the paper that I wanted to address was this
concept of obesity heterogeneity in the obesity paradox, meaning
to say is it potentially where the body fat is that may be
playing a role in which obese person gets disease, and which
obese person may be protected from disease. So it could be that
it's not how much fat you have but where that fat is that is
really telling about what someone's risk is, and that might help
to describe the obesity paradox and get us a little bit more
understanding.


Dr Carolyn
Lam:               
Yeah, now, I thought that bit was just so key and important. Not
how much fat, not weight per se, but where that fat is. Do you
want to elaborate on that a bit?


Dr Ian
Neeland:               
Sure. For, I don't know, 50, 60 years we've had this concept of
the apple and the pear. Right? Fat in the belly being the apple
shape and fat in the pear being fat in the hips and buttocks and
that being two different body types of body fat. So we have a lot
of technology nowadays, and we can actually directly image body
fat and where it is in the body. So we can do MRI, we can do CT,
and we can actually see where the body fat is distributed and how
much body fat in one area may be related to disease compared with
another area.


                                               
So we've gone away from the apple and pear and really getting
down to what we call body fat depots or adipose tissue depots
where we deposit fat. And the area that we deposit fat that has
the most risk for cardiometabolic diseases is this visceral
adipose tissue or VAT.  VAT is fat that's around the
intra-abdominal organs, also near the kidneys, and you can't
actually tell how much visceral fat someone has just by BMI or
waist circumference or just looking at them. You really have to
do this dedicated imaging to find out. And the reason for that is
that in the belly there's two types of fat. There's the visceral
fat, and there's the subcutaneous, which is the fat under the
skin. Both those fat areas make up the belly fat, but they're
very different. And part of the review is really going into depth
about why these are different and how they're different.


                                               
They have completely different metabolic profiles, so if you
would take blood, lipids, inflammatory markers, they would look
completely different even in a single individual. And then if you
look at the genetics of where the fat is, they're different. If
you look at what these fat areas secrete, they're completely
different. So it's really important to know where the fat is, and
that's why I think this concept of sick fat versus healthy fat
comes into play.


                                               
So, sick fat is fat that's usually in this visceral fat depot,
and that is really the three central tenets we talk about are
visceral fat or ectopic fat. Ectopic means fat where it doesn't
belong. Then inflammation and cytokines, so secretion of abnormal
factors in the blood from this fat, and then insulin resistance.
So those are the three kind of tenets of this sick fat.  So
that's why we think that the sick fat plays a role in disease,
and then there's a concept of less sick fat or healthy fat, which
is maybe a sink. It actually buffers some of these cytokines and
inflammation from causing disease in the body.


Dr Carolyn
Lam:               
Yeah. I found that concept so fascinating, and just to bring it
back to the obesity paradox. So, some larger people may enjoy
better outcomes because they actually have a predisposition to
put the fat subcutaneously perhaps, rather than viscerally. Would
that be correct? You worded it so eloquently in your paper. There
are some ethnicities or some genetic predispositions that could
make one lose that inability to put it peripherally, and
therefore it all goes viscerally, is what I got from it. And
that's the stuff that puts people at risk.


Dr Ian
Neeland:               
Yeah. We find that fat in the lower body, the hips and the
buttocks, is actually in epidemiology, protective against heart
disease, protective against cancer. And the problem is we don't
know why some people put fat in the belly and some people put it
in the hips and buttocks. There's very interesting twin-twin
studies that show if someone has a predisposition for obesity, so
twins may be both obese, but there is some difference in where
they actually put the fat. So I think genetics certainly plays a
role, but environment also plays a role. And environments, things
like appropriate nutrition and physical activity can really alter
genetics and help someone to put fat where it should be and
prevent disease.


                                               
So this obesity paradox, this concept of putting fat where it
should be, is really the next frontier for this type of research.
How can we modulate it? How can we fix it?


Dr Carolyn
Lam:               
Exactly, and I love the way you ended your review when you said,
"Therefore, maybe in all our complaints and so on, saying that we
want weight loss, we should actually be focusing on waist loss.
You could redistribute the fat to healthy areas, not change your
weight, and still become healthier."  That was the concept,
right?


Dr Ian
Neeland:               
That's right. Yeah. It really is amazing, and it's been shown
again and again that people can stay the same weight, but their
body fat really is very plastic. It can change, and it's
modifiable. And that really makes a difference with health
outcomes. So whether we can do that with lifestyle changes, so
there's some data to support that. There's also some data to
support pharmacology, so medications may be able to move fat from
one area to another. And then certainly surgery, which is now
getting a lot of popularity for people who are really high risk
for cardiometabolic disease. Bariatric surgery has been shown to
decrease visceral fat significantly, and that may be one of the
reasons why it works so well.


Dr Carolyn
Lam:               
Exactly, Ian. Fascinating, fascinating. I tell you what. Could I
just ask you to give us some take-home messages?


Dr Ian
Neeland:               
Sure. So one take-home message I think is that we can move beyond
the BMI, beyond the body mass index. Obesity is no longer just a
number. It's really about the entire individual, biologic
systems, what's going on, and there's just remarkable
heterogeneity in the structure of obesity, where body fat is, the
activity of body fat, the physiology of it, and also how it
relates to diseases, either causing disease and potentially being
protective for harmful outcomes.


                                               
I think it's also a key message to understand that there's sick
fat and there is healthy fat and they're very different. And we
can get to the bottom of those using specialized tools like
imaging and special testing, but they're really very different,
and not all body fat is created equal.


                                               
And then lastly, I think it's important to consider, like you
mentioned earlier, that really public health and lifestyle going
forward is going to be so important, and focusing on those areas
that will have the biggest impact for people such as trying to
promote waist loss, like you said, as opposed to weight loss.
Really focusing and using our knowledge of body fat and obesity
and how it's so different across individuals and populations,
that it's really important to use that knowledge for our future
goals and to have that mind when we recommend weight-modifying
therapies for our patients.


                                               
It's really going to be a new frontier in weight. We're really
moving beyond this concept of just check your weight and your
height, and we can tell you what your risk is. No, it's really
much more complex and complicated and much more interesting than
that.


Dr Carolyn
Lam:               
Oh, Ian, that's just so wonderful. I cannot help this last
question. Who knows whether we'll put it in, but I just have to
ask you. So how do you monitor your own status or your patients'
status? Do you really get them DEXAs, all of them? Or PETs, FDGs?
Or do you take your own weight?


Dr Ian
Neeland:               
Yeah. I do. One thing I have noticed, I actually started an
exercise and diet program for myself to improve my health about a
year and a half ago. I took the research, and I said, "Okay, I'm
really going to use this and apply this to my life." So, what's
interesting is what I found and actually what other colleagues of
mine in research are finding is that you can actually melt away
visceral fat just with exercise alone, even if you don't actually
go on a diet. And they've done studies like this where they do
DEXA scans, and they give people high-intensity interval
training. They don't give them a special diet. They just say
maintain your current diet, and the visceral fat goes away.


                                               
It's really remarkable how lifestyle can be so important and make
such a change. And you can see people who have diabetes who can
cure their diabetes with a lifestyle program by really decreasing
the visceral fat. Even if their weight doesn't change or only
changes by a small amount, but their weight may change by, I
don't know, five, 10 pounds, but their visceral fat may go away
by 50%. And that really makes the difference.


                                               
It's obviously hard to monitor. We don't really have these tools
clinically every day. Not everyone can do a DEXA and has the
software to measure the visceral fat. Certainly could be coming
in the future, but right now we should use the tools we do have
and use the biomarkers we have and the clinical use, the waist
circumference, triglycerides. These things are all surrogates for
visceral fat but can be very useful to monitor for change. And
it's not just about the scale. It's really about more than that
with a person's metabolic status.


Dr Carolyn
Lam:               
That is so helpful. Thank you so much, and I'm so glad you said
that it was exercise, and you don't jump into a ice pool or
something to try and convert the fat to brown fat or something.
That's really, really encouraging to me. Thank you, Ian. This was
so enjoyable. I'm sure all our listeners are thanking you as
well.


                                               
Listeners, you've been listening to Circulation on the Run.
Please tune in again next week.