Circulation August 22, 2017 Issue

Dr Carolyn Lam:     Welcome to Circulation on
the Run, your weekly podcast summary and backstage pass to the
journal and its editors. And Dr. Carolyn Lam, Associate Editor
from the National Heart Center, and Duke National University at
Singapore.


                               
What is the effect of obesity and underweight status on
perioperative outcomes of congenital heart operations?


                               
Our feature paper this week sheds light from the Society of
Thoracic Surgeons Database. More soon, right after these
summaries.


                               
The first original paper highlights the role of micro RNAs in
metabolic remodeling and heart failure. As a reminder, micro RNAs
are small, noncoding RNAs important in post transcriptional
modification and influencing many cellular processes
simultaneously.


                               
First author, Dr. Heggermont, corresponding author, Dr. Heymans,
and colleagues from Maastricht University in the Netherlands use
mice subjected to pressure overload by means of endotension to
infusion or transverse aortic constriction. They show that micro
RNA 146A was up regulated in whole-heart tissues in these murine
pressure overload models, as well in left ventricular biopsies of
aortic stenosis patients. Over expression of micro RNA 146A in
cardio cardiomyocytes provoked cardiac hypertrophy and left
ventricular dysfunction in vivo, whereas genetic knockdown or
pharmacological blockade of micro RNA 146A blunted the
hypertrophic response and attenuated cardiac dysfunction in Vivo.


                               
Mechanistically, micro RNA 146A reduced its target dihydrolipoyl
succinyltransferase or DLST, a mitochondrial protein that
functions as a TCA cycle transferase. DLST protein levels were
reduced in pressure overload mice, while they were partially
maintained in micro RNA 146A knockout mice. Furthermore,
overexpression of DLST in wild type mice, protected against
cardiac hypertrophy and dysfunction in Vivo. Thus, micro RNA 146A
and its target DLST are important metabolic players in LV
dysfunction. These results also opened the door to novel
therapies to treat metabolic disturbances and improve energy
efficiency of a failing heart.


                               
Program cell death is critically involved in ischemic cardiac
injury, pathologic cardiac remodeling, and heart failure
progression. Our next paper sheds light on the regulatory
mechanisms of necroptosis and its significance in the
pathogenesis of heart failure. Using genetic mouse models, first
authors Dr. Guo and Yin, corresponding author Dr. Liu, and
colleagues from University of Washington in Seattle, identified a
critical role for a tumor necrosis factor receptor associated
factor 2 or TRAF2 in myocardial survival and homeostasis by
suppressing necroptosis.


                               
The authors delineated an important TRAF2 mediated NF-KB
independent pro-survival pathway in the heart by suppressing
necroptotic signaling. They identified novel molecular mechanisms
whereby TRAF2 suppressed TNF receptor 1 mediated, receptor
interacting protein 3 dependent necroptosis, which is critical
for myocardial survival and homeostasis. Thus, this finding
suggests that the necroptosis suppressing TRAF2 signaling pathway
and its effectors may serve as novel therapeutic targets for
pathologic cardiac remodeling and heart failure.


                               
Our next paper tells us that cerebral hyperperfusion may be
associated with accelerated cognitive decline and an increased
risk of dementia in the general population. First author Dr.
Walters, corresponding authors Dr. Ikram, and colleagues from
Erasmus University Medical Center in Rotterdam, The Netherlands,
measured cerebral blood flow by 2D phase contrast MRI in
non-demented participants of the population based Rotterdam
study. A 4,759 participants with a median age of 61 years, and a
median follow up of 6.9 years, 123 participants developed
dementia.


                               
Lower cerebral perfusion was associated with higher risk of
dementia and this risk was even higher with increasing severity
of white matter hyperintensities on MRI. At cognitive
reexamination after an average of 5.7 years, lower baseline
perfusion was associated with accelerated decline in cognition,
which was similar after excluding those with incident dementia,
and again, most pronounced in individuals with higher volumes of
white matter hyperintensities.


                               
Thus, lower cerebral perfusion was associated with accelerated
cognitive decline and increased risk of dementia in the general
population. This association was modified by hypertension and
cerebral small vessel disease, possibly reflecting impaired
arteriola and capillary function. This paper calls for further
long term study and evaluation of optimizing cerebral perfusion
as a means to prevent cognitive deterioration, for example, in
patients with heart failure or carotid artery stenosis.


                               
Well, that wraps it up for our summaries. Now for our feature
discussion. For today's feature discussion, we will be looking at
data from the Society of Thoracic Surgeons Database. This time
looking at the effect of body mass index on perioperative
outcomes of congenital heart operations in children, adolescents,
and young adults. To discuss this, we have none other than the
first and corresponding author, Dr. Michael O’Byrne from
Children's National Medical Center in Washington D.C., as well as
Dr. Naveed Sattar, Associate Editor from University of Oxford.
Welcome gentlemen.


Dr Michael O’Byrne:       Good
morning.


Dr Naveed
Sattar:           
Good morning.


Dr Carolyn
Lam:               
Michael, we know that extreme body mass indices, very high or
very low, has been associated with increased risk of at first,
perioperative outcomes in mainly older adults undergoing cardiac
surgery. We also know about the obesity paradox in conditions
like heart failure, so why was it important to look at this
specific group of patients? Congenital heart patients and
children, adolescents, and young adults?


Dr Michael O’Byrne:       Yeah, I
think that as a pediatric cardiologist, a lot of the data that we
use to guide our management is extrapolated from adult studies.
However, in this particular case, it wasn't clear necessarily
that adult data would necessarily be applicable to children and
adolescents and young adults. We are aware that there are
epidemiologic trends that congenital heart disease population
ages and there are also in increasing problems of obesity among
children in the United States.


                               
The convention wisdom among surgeons in the United States is that
obesity would increase perioperative risk and the thought is that
some combination of exposure to hypertension and diabetes and
peripheral vascular disease might impede wound healing and that
body habit as itself might be a risk for the technical approach
in wound healing. Acknowledging that there's a lot of evidence
both for extreme BMI being a risk in surgical patients and
adults, but also the idea that obesity paradox might be important
in children because the biological mechanisms might be different.


                               
Children themselves are exposed, their sort of dose response or
dose exposure is less, they're younger, and so haven't been obese
for a prolonged period of time, so that the integrated effect of
having diabetes, hypertension, and obesity might be less. At the
same time, we also acknowledge that in children with heart
disease, we have congenital cardiac disease, the same issues with
cachexia and frailty are present. i.e. that children with very
low body mass index might be assigned to their own medical
frailty, or a part of a heart failure cachexia syndrome.


                               
One of the challenges in dealing with children with congenital
heart disease, however, as you know is that its rarer than
cardiac disease of the aging and additionally, that the
population is very heterogenous in terms of the actual defects
that are present and the surgeries that are performed. It was
relevant to look and see over a wide range of sort of technical
complexity surgeries with a wide range of sort of intrinsic
preoperative risk of perioperative outcome, whether or not BMI
would be associated with an adverse outcome. Either operative
mortality in this case, or a composite outcome of mortality,
major adverse events, and wound infection.


Dr Carolyn
Lam:               
Wow, that makes a lot of sense and congratulations. This is not
just the first, it's huge and really comprehensive. Could you
just tell us a little bit more about what you did and what you
found?


Dr Michael O’Byrne:       I think
as this point, I'd have to acknowledge that the challenges that
we described in terms of both a sample size and in terms of
getting a representative sample, is a constant challenge in our
field and we have to give credit to my co-authors Marshall and
Jeff Jacobs for their work in developing the collaboration that
allowed for the STS Congenital Heart Surgery Database to exist.
Also, on top of shepherding the database, their research, along
with the people at Duke Clinical Research Institute, they've
developed a robust risk stratification model for mortality that
we utilize as part of this study. Without that, this would be
really be very challenging.


                               
What we did is performed an observational cohort study using the
STS Congenital Heart Surgery Database to look at the risk of
perioperative mortality and composite outcome in patients
undergoing surgery in the United States between 2010 and 2015. We
looked at both the actual events, the sort of observed events, in
terms of mortality and adverse events, and then created
multivariate models to adjust for the known covariance.


                               
We hypothesized that extreme BMI, either very high or very low,
would be associated with increased risk of mortality and
increased risk of that composite outcome. What we found that
operative mortality and that perioperative adverse events
occurred more frequently in obese and severely underweight
subjects. However, because they have an unequal distribution of
potentially important covariance, we used multivariate modeling
to adjust for those covariance.


                               
Our multivariate models for death, however, the severely
underweight subjects had an odds ratio of 1.4 and obese subjects
had an odds ratio of 1.3, but neither was specifically
significant in that context. We sort of anticipated that with a
possibility given the very low event rate. That's the reason
we've used a composite outcome, a higher event rate.


                               
For that composite outcome, in both different versions of the
multivariate model that we used, the severely underweight
subjects had an odds ratio of 1.5, underweight subjects had an
odds ratio of 1.3, and obese subjects had an odds ratio of 1.2.
An increased risk in all three of those populations of interest
relative to normal weight or just overweight subjects.


Dr Carolyn
Lam:               
We're always saying that at circulation we do want to publish
papers that have direct and important clinical implications, so
Naveed, could you share some thoughts on what this means
clinically?


Dr Naveed
Sattar:           
Yeah, I think they went through the review process and I think
the paper was very well written. I think Michael and his
colleagues clearly understood the strength and the limitations of
the data so that you can only ever itself prove associations here
and therefore, clinically when we push them on trying to make
clinical inferences, I think clearly they recognize that once
they find associations between obesity and adverse outcomes and
underweight.


                               
What they need to do next, now this is a paper that then leads
you to think, "Well actually, I need to do some clinical trials
to prove that module ..." You're preventing these outcomes or in
very under knowledge where they're actually increasing the BMI
but improving their nutrition, cannot also improve outcomes
following surgery. Now those are tough things to do. Michael,
what do you think from some of the clinical inference? My
inferences were the associations were there, particularly for the
normal [inaudible 00:12:35] outcomes, but actually to prove that,
to make a difference, you probably might need to do some
intervention trials or is that how you take it as well?


Dr Michael O’Byrne:       I agree
with you 100%. I think that as an epidemiologist, I think that
what we see in an observational study like this is an
association. The two next levels of research that are necessary
at this point are to see whether or not in this population BMI is
a modifiable factor in the short run before surgery, or even in
the long run. And the second question to answer is whether those
adjustments in BMI, if they are achievable, affect outcome with
surgery. Absolutely.


                               
It's a tremendous challenge, both logistically in organizing a
study, and honestly, in terms of capturing a cohort that would be
large enough, given that this is almost 100% of the surgeries
that occurred over a six year period in the United States.


Dr Naveed
Sattar:           
I looked at it and thought, "Well, the mortality association once
you adjusted were not quite significant but are there any
individuals you would not do surgery on based on their BMI based
on these results?


Dr Michael O’Byrne:       The
motivation for the study is exactly to try to begin to shed light
on that kind of question. I think that it might be what I would
call a tiebreaker potentially, if you have a situation where a
patient is near meeting criteria but isn't quite at a place where
you need to do surgery at that point. It might dissuade you from
proceeding immediately potentially pursuing a course that might
adjust their BMI in the correct direction.


                               
At the same time also, in a patient who's underweight
particularly to evaluate whether their medical regimen has been
optimized and if there are other residual lesions that can be
addressed in a non-surgical or medical fashion.


Dr Naveed
Sattar:           
I suppose the other trick with this type of research research is
always trying to make sure that people understand these are the
associations and not trying to attribute causality because it's
always physical, isn't it? But I think you and your team did that
very well and I'm sure we had a back and forth with review but I
think your discussion section, your limitation section, is
beautifully written and covers those kinds of caveats, which I
think is important as well.


Dr Michael O’Byrne:       I thank
you for that. That's very complimentary and we certainly strived
for that, but I think that you as an editor, and also in terms of
the reviewers also, were very helpful in that sort of
collaborative process to try to make sure that we're
communicating it. It's not always clear in a project that takes
months and years to finish when you're writing it necessarily,
you may be constantly aware of trying to be clear in your
communication but it's also helpful to have a reviewer from the
outside carefully read the study.


Dr Carolyn
Lam:               
That's wonderful and Michael, may I just join Naveed in
congratulating you on beautiful paper? And maybe just one other
little question, did you have any insights into the mechanisms of
increased risk for composite events in the extremes of BMI?


Dr Michael O’Byrne:       I think
it's an important question. There's been a tremendous amount of
research in adult cardiac disease about whether it is the BMI as
a steady state or BMI changes immediately before and after
surgery that are relevant in this case. From this kind of
observational study, it's very hard and very challenging to try
to make any sort of inferences about the causes. It would be an
important part of any study moving forward to include ways to
investigate that, and honestly, as an interventional cardiologist
and epidemiologist, I probably would defer to Naveed, he might
have more cogent and logical ideas about that than I do.


Dr Naveed
Sattar:           
We've had lots of research from a whole variety of researchers.
We all understand it's finally serious but recognize it's
difficult, so one of the ways moving forward and I think Michael
and his colleagues have this is if you have serial BMI data prior
to surgery, that could try and inform on reverse causality
because of the low BMI, but in terms of the mechanisms, remember
these are associations, but I think mechanisms are well covered
if you are obese and clearly you have risk factors for death,
across the vasculature, across the cardiac functions, across the
whole variety of things.


                               
We know those mechanisms, question is, to what extent are they
actually operating and causing increased risk in the surgical
arena and that's a really tough ask. I think people can come up
with a multitude of mechanisms. I think the key things, like this
particular paper, is that there are potential mechanisms but
these are associations ... Look, this is what we found, and
clinically now we need to try and address this within the
following types of interventions or at least provide some
guidance to colleagues and clinicians.


                               
Exactly as Michael says, if there is somebody who is approaching
surgery whose quite obese, perhaps they should try and intervene
to try and lessen their weight for a short period of time prior
to [inaudible 00:17:07], you know what happens. It would be nice
to do some big trials but I think doing trials in this area is
going to be really tough, but with imagination, with good
collaboration across centers, trials are not impossible. I think
they can be done.


Dr Michael O’Byrne:       Naveed, I
think, actually articulated what I think is both the difficulty
of doing that trial but also the importance of it. I think that
looking at ... In these databases, we don't have a serial BMI and
I think that's an important missing piece of information that we
tried to address in our discussion and I think it's something
that would be really valuable moving forward. And certainly
testing interventions, whether they're medical, interventional,
or surgical, to help these patients who are obese either lose or
maintain an appropriate weight is the next step.


                               
On the converse side, this research highlighted to me the
prevalence of chachectic or underweight patients in our
population and it's something that outside of the infant period,
we don't necessarily think about tremendously and we don't think
about it as a modifiable factor. I think that's another group of
patients who also deserve some attention.


Dr Carolyn
Lam:               
Listeners, you've been listening to Circulation on the Run. I'm
sure you learned a lot as I did. Don't forget to tune in again
next week.