Circulation April 25, 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. Our feature paper this
week really adds to our understanding of the cause/effect
relationship between obesity and heart failure, this time by
comparing the effects of gastric bypass surgery versus intensive
lifetime treatment on heart failure risk. Before we talk about
that, though, let me give you your summary of this week's
journal.


                                               
The first paper brings us one step closer to understanding
cardiac recovery in response to mechanical unloading by left
ventricular assist devices and it does this by showing that this
process may involve the transverse tubular system, which is a
micro structural feature of ventricular cardiomyocytes important
for contractility and consisting of tubular invaginations of the
sarcolemma predominantly located at the Z-lines of sarcomeres.
This transverse tubular system is crucial for efficient
excitation contraction coupling by bringing L-type calcium
channels in the sarcolemma in proximity to clusters of ryanodine
receptors in the sarcoplasmic reticulum.


                                               
In the current study by co-corresponding authors, Dr. Seidel and
Drakos and Sachse from University of Utah, the authors studied
left ventricular biopsies obtained from five donors and 26
patients with chronic heart failure undergoing implantation of
left ventricular assist devices or LVAD's. They used three
dimensional confocal microscopy and computational image analysis
to assess the transverse tubular system's structure, density, and
distance of ryanodine receptor clusters to the sarcolemma.


                                               
They found that the majority of heart failure myocytes showed
remarkable transverse tubular system remodeling, particular
sheet-like invaginations of the sarcolemma, which is previously
unknown phenotype. This sheet-like transverse tubular system
remodeling led to increased distances of ryanodine receptors to
the sarcolemma causing heterogeneous intracellular calcium
release and consequently inefficient excitation contraction
coupling. High degrees of transverse tubular remodeling at the
time of LVAD implantation was associated with absence of
functional cardiac recovery during mechanical unloading, whereas
preserved transverse tubular systems structure was associated
with recovery.


                                               
In summary, cardiac recovery during unloading may require an
intact transverse tubular system at the time of LVAD
implantation. And characterizing this system may help to identify
patients with a high probability of functional cardiac recovery
in response to mechanical unloading.


                                               
There have been a proliferation of algorithms based in high
sensitivity assays for cardiac troponins for the diagnosis or
exclusion of myocardial infarction. All these algorithms have the
potential to overwhelm clinicians with options. Well, there is
help in this week's issue with two observational studies directly
comparing the diagnostic performances of multiple
high-sensitivity troponin testing strategies.


                                               
Now, before I describe these two studies in detail, here are some
important reminders. Remember that as of early 2017, although
high-sensitivity troponin assays are routinely used in many
regions of the world, they are not available in the United
States. Thus, the specific algorithms discussed here are not
applicable with the contemporary sensitive assays that are
presently used in the United States. Next, let's remind ourselves
that both the United States and European professional guidelines
recommend serial measurement of cardiac troponins at presentation
or zero hours and three to six hours later with additional
testing beyond six hours in patients who have
electrocardiographic changes, or intermediate or high clinical
risk features.


                                               
The 2015 European Society of Cardiology Guidelines also included
an alternative strategy reducing the sampling interval to one
hour when using a high sensitivity troponin assay with a
validated zero and one hour algorithm based on the 99 percentile
cutoff of these high sensitivity troponin assays. Now to the two
studies in the current issue, which tie together the expanding
evidence with direct comparisons of several of the strategies
using the same high sensitivity cardiac troponin assay by Abbott.


                                               
Dr. Chapman and colleagues from the royal infirmary of Edinburgh,
United Kingdom, compared the standard ECS zero and three hour
strategy based on the 99th percentile upper reference limit at
both time points with the high sensitivity troponin in the
evaluation of patients with acute coronary syndrome, or high
stakes algorithm, and that would be a zero, three, and six hour
algorithm that incorporates a zero hour criteria and at a very
low cutoff of five nanogram per liter and a three hour criterion
that directs patients with either a rising concentration or with
an absolute concentration above the upper reference limit to
additional testing.


                                               
Among 1,218 patients with suspected myocardial infarction, the
high stakes algorithm delivered both a higher proportion ruled
out for myocardial infarction at zero hours and a higher negative
predictive value of 99.5% versus 97.9%. The ESC pathway missed 18
index and two recurrent myocardial infarction events, whereas the
high stakes pathway missed two index and two recurrent myocardial
infarction events. These findings demonstrate the value of adding
a very low zero hour cutoff to facilitate earlier rule out as
well as the value of a delta criterion to exclude increasing
values among patients that progress to three hour sampling.


                                               
In the next study, first author, Dr. Boeddinghaus, corresponding
author Dr. Mueller and colleagues from University Hospital of
Basel, Switzerland compared the ESC alternative zero and one hour
strategy with three other approaches using either a single cutoff
at zero hours, or the one hour strategy. Among 2,828 patients
with symptoms suspicious for myocardial infarction and no ST
elevation, each of these four approaches delivered a negative
predicted value above 99% comparing favorably to the ESC zero and
three hour algorithm that had a negative predictive value of
98.4%.


                                               
Now, although each of the strategies performed similarly among
patients presenting more than two hours after symptom onset,
among the early presenters, the negative predictive value and
sensitivity were diminished using the single zero hour cutoff of
five nanograms per liter. The authors concluded that the single
cutoff strategy, the one hour algorithm, and the zero and one
hour algorithm, allow the triage towards rule out of myocardial
infarction in more than half of consecutive patients presenting
with suspected MI to the emergency department. However, the
single cutoff strategy should not be used in patients presenting
early after chest pain onset.


                                               
These papers are discussed in an excellent editorial, which also
puts everything in perspective by Dr. David Morrow from Brigham
and Women’s Hospital in Boston, Massachusetts. I particularity
want to refer all of you to the figure that's found in its
editorial which really helps you to understand the different
strategies involved.


                                               
The final study tells us about potential death averted and
serious adverse events occurred from the adoption of the SPRINT
intensive blood pressure regimen in the United States. As a
reminder, the systolic blood pressure intervention trial, or
SPRINT demonstrated a 27% reduction in all caused mortality with
a systolic blood pressure goal of less than 120 versus less than
140 mm Hg among American adults at high cardiovascular risk, but
without diabetes, stroke, or heart failure.


                                               
In the current study, Dr. Bress and colleagues from the
University of Utah School of Medicine applied the SPRINT
eligibility criteria to the 1999 to 2006 National Health and
Nutrition Examination Survey or NHANES and linked this with the
national death index through December, 2011. They found that if
fully implemented in eligible US adults, intensive blood pressure
treatment was projected to prevent about 107,500 deaths and
46,100 of heart failure per year. But, you also give rise to
about 56,100 episodes of hypertension. 34,400 episodes of
syncope, 43,400 serious electrolyte disorders, and 88,700 of
acute kidney injury per year compared to standard blood pressure
treatment. Thus, they take home message is careful patients
selection and implementation are important because intensive
treatment while preventing deaths is associated with increased
risks of hypertension, syncope, electrolyte abnormalities and
acute kidney injury.


                                               
Well, that brings us to a close for the summaries, now for our
feature discussion.


                                               
We are discussing obesity and heart failure. Now, we've heard of
the obesity paradox, but we also know that obesity may be a risk
factor for heart failure and the study today really puts
perspective on this and is really one of the largest most
convincing studies I've read on this topic. I am so pleased to
have the person corresponding author, Dr. Johan Sundstrom from
Uppsala University Hospital in Sweden. Welcome, Johan.


Dr Johan Sundstrom:      Thank you,
lovely to talk to you.


Dr Carolyn
Lam:               
And especially pleased to have back on the show again, Dr.
Torbjorn Omland from University of Oslo, Norway. Hi, welcome
back, Torbjorn.


Dr Torbjorn Omland:      Thank you very
much. It's a great pleasure being here.


Dr Carolyn
Lam:               
Johan, you know what? Could you just start by telling us about
your study?


Dr Johan Sundstrom:      So, we were
fortunate enough to have two great databases here in Sweden. One
was the obesity surgery registry called SOREG in which all people
have a gastric bypass surgery, for people who are registered. And
we also have a company called Itrim who provide intensive
lifestyle program, which takes people down on average about 11
kilos, and they have a very structured database as well. So, we
were able to pull this data in order to try and understand the
effects of intentional weight loss to two different levels of
weight loss, what that does to the heart failure incidence.


                                               
This is a bit of a comparative effectiveness study, so it's of
course necessary to make the examples as similar as possible to
apply exclusion criteria. We took away everyone who had a body
mass index of less than 30 and above 50 and then we applied
propensity scores to those two data sets and we had to trim the
data sets a little bit further in order to get so called region
of common support, which means that we were left with two samples
who could have either had surgery or a lifestyle intervention.
And then we applied an inverse probability weighting scheme to
that. It's statistically complicated but what that does, is it's
a matching, but it's not as complicated as matching. With
matching, you just give people a weight of 1 or 0, but this gives
people other weights as well.


                                               
So, we end up with characteristics that were very similar at
baseline. So, we tried to mimic as close as possible what a
randomized clinical trial looks like, but of course we did it
posthoc and it’s observational. So, we get our table one, sort
of, in this paper that shows very similar characteristics of the
two groups. So, what we did then is we noted what happened to the
people in these two groups in terms of heart failure incidence
and we followed them in our national inpatient registry. So, all
the Swedish citizens get a personal identification number so we
can use that to follow people in our patient registry.  So,
we know exactly what drugs people will collect from pharmacies,
and we know what they died from, and we know all of their
hospitalizations. And we previously validated their heart failure
diagnosis in the Swedish Inpatient Registry and we noted that you
were in a pretty good position if you were hospitalized with
heart failure as the main cause of hospitalization and we noted
that people who had agreed to do surgery, had about half the
incidence of heart failure than people who were in the intensive
lifestyle program.


                                               
We also noted, if you looked at the achieved weight loss one year
after baseline, we noted that a ten kilo weight loss after one
year was related to about a 23% lower risk of heart failure. So
we noted a litany of association between the achieved weight loss
and heart failure incidence. It should said, though, that heart
failure in this age group, they are only 41 on average, 41 years
old. Heart failure's still very unusual at this age, even in many
of these people. We only had 73 cases of heart failure. So, the
exact numbers need to be taken with a pinch of salt and have wide
confidence intervals around them.


Dr Carolyn
Lam:               
Johan, this is exactly why I'm so impressed with your data. First
you showed a dose response relationship between the weight loss
and risk of heart failure. You also show that it's not an event
that occurs very often and so, it would be very difficult to
imagine doing a randomized controlled trial for example in this
setting and having to wait very long for these events. So, it
really goes to show your observational data are extremely
important. And I really like the way you took the pains to
describe how you tried to overcome the differences that exist
between the groups and try to make it as much resembling a
randomized trial setting as you could. So, maybe I could turn it
over to you, Torbjorn. Could you tell us what you think the
implications of this paper are?


Dr Torbjorn Omland:      First, I will
say that that this paper has all the characteristics of a very
high quality study. It's a very timely topic that interests a lot
of people. The paper's very well written. It's a large sample
size as you said and it was very clinically meaningful difference
between the groups and that translated into very clear and robust
answers. So, I think that this has every mark of high quality
paper.


                                               
But, of course, the very important question is how will this
translate into actions?  How can we use this information to
prevent problems? We know heart failure is a very prevalent
disease, especially in the elderly and although the incidence was
lower here, I think my question for Johan at least is what would
be the next step? What changes can we implement to reduce heart
failure among the obese?


Dr Johan Sundstrom:      That's a great
question. I think in this study puts a little piece of the puzzle
on the table and that's trying to add a little more evidence
towards a causal association between obesity and heart failure.
I'm not sure about what we can offer these patients and what will
be the translation to lower heart failure incidence in the long
run. Of course, we need to follow this sample for longer to have
more heart failure cases, because I don't think we've seen the
full impact of weight loss in these two samples. We might need to
follow them into older age where they would have a higher heart
failure incidence.


                                               
But, how to tackle obesity, I think we'll need accommodate
population strategies and high risk strategies. I think if the
general consensus in the scientific community after reading this
and other important papers, is that there's causal link between
obesity and heart failure, then we might need to understand that
people who are obese and who have shortness of breath and perhaps
swelling or what not, may not just be having low fitness, they
might actually behaving signs of heart failure.


                                               
So, I think as a sort of increased diligence on heart failure,
these people might be one thing. But, we didn't really study
that. So, I wouldn't draw conclusion. But, otherwise I think it's
more of a causal inference piece of the puzzle that we've laid
rather than a clinical care piece of the puzzle.


Dr Torbjorn Omland:      No, I agree,
and here you won't to make any recommendations in regards to what
interventions you should recommend particularly based on this
particular study.


Dr Johan Sundstrom:      No, because I
think there are so many other things that need to be taken into
account when it comes to treatment of obesity. Heart failure is
actually one of the uncommon outcomes in this age group. We're
looking at other outcomes after they present. Myocardial
infarction, ventral fibrillation and mortality are actually much
more common. So, I think a lot of other data should go into
decisions on how to treat patients, not just for heart failure,
which is still fairly uncommon at this age.


Dr Carolyn
Lam:               
Going back to the other question that Torbjorn asked, do you
think that this question still needs to be answered in any way?
You've got the Mendelian randomization data. Now, you've got your
data. Do you think it's still a question of whether obesity is a
risk factor for heart failure? And just in case there's any
confusion out there, would you put that together with the so
called obesity paradox in heart failure?


Dr Johan Sundstrom:      To answer the
first one, I think we're not going to have any randomized
evidence. Treatment of heart failure with intensive programs and
prevention of heart failure ... It needs for huge samples that I
don't think we're going to have any much better observational
evidence anytime soon either. So, we can probably set that
question aside a little bit. But, when it comes to the obesity
paradox, first of all that's not what we studied here. We didn't
have anyone with heart failure in this sample. We included all
those people. We can only speculate. I'm a clinical
epidemiologist myself, but I'm envious of people who have animal
and other models because I think there's a lot more work to do in
terms of ppars and and lipid metabolism in obesity and in heart
failure. So, I think there'll be more interesting experimental
research to come that can help us answer the obesity paradox.


Dr Carolyn
Lam:               
Please don't forget to tell your friends about this podcast, and
tune in again next week.