Circulation February 28, 2017

Dr. Carolyn
L.:                   
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. On our podcast today we
are discussing the role of diastolic stress testing and the
evaluation of heart failure with preserved dejection fraction, a
really hot topic indeed, but first here's your summary of this
week's issue.


                                               
The first study tackles the obesity paradox in cardiac surgery,
where morbidity and mortality are lower in obese patients. This
study sought to ask the question, "Is this due to reverse
epidemiology, bias, or confounding?" To answer this question, Dr.
Maris Kelko and colleagues from University Leicester in United
Kingdom used two separate analysis. One, registry data from the
National Adult Cardiac Surgery Registry and two, a systematic
review in meta-analysis of studies. Of more than 400,000 patients
in the cohort study and more than 550,000 patients in the
systematic review, the authors found a U shape association
between mortality and body mass index classes, where lower
mortality was observed in overweight and obese class one and two
patients, relative to normal weight patients, and mortality was
increased in underweight individuals.


                                               
Now, the obesity paradox has been attributed to reverse
epidemiology where the survival benefit associated with obesity
is thought to actually reflect worse outcomes in the underweight
patients who also had frailty, cachexia, or severe chronic
disease. However, in the current study, counter to the reverse
epidemiology hypothesis, the protective effects of obesity were
less in patients with chronic renal, lung, or cardiac disease and
greater in older patients as well as in those with complications
of obesity, such as metabolic syndrome and atherosclerosis.
Furthermore, adjustments for important confounders did not alter
the results. The authors therefore concluded that obesity is
associated with lower risks after cardiac surgery with consistent
effects noted in multiple analysis even after attempting to
address residual confounding and reverse causation.


                                               
The authors even went as far as to suggest that their findings do
not support common practice where weight loss is recommended
prior to surgery or where very obese patients are refused surgery
in the morbidly obese. These provocative findings are discussed
in an accompanying editorial by Doctor's Carnethon and Kahn from
Northwestern University. While the editorialists agree that this
well-designed study highlights an important knowledge gap, they
pointed out that the obese class two patients had nearly five
times greater risk for deep sternal wound infection and 25%
higher likelihood of needing renal replacement therapy.


                                               
In such patients additional intervention in the perioperative
period may still be indicated and include weight loss
recommendations and postoperative surveillance for complications.
Thus, a more cautious final recommendation may be for future
studies to prospectively assess weight loss interventions prior
to elective surgery in the context of overall surgical risk as
assessed by the EuroSCORE or STS models.


                                               
The next paper describes mechanistic studies showing for the
first time that nucleoside diphosphate kinase suppresses
cyclic-AMP formation in human heart failure. In this paper by
First Authors, Dr. Abu Taha and Hagemann, corresponding authors
Dr.'s Tobref and Weilend from the Heidelberg University in
Germany, the authors performed biochemical studies of nucleoside
diphosphate kinase and G Protein signaling in human and rat
tissue samples, assessed the functional impact of nucleoside
diphosphate kinase C on cyclic-AMP levels and contractility and
isolated red cardiomyocytes and determined that in vitro effects
of these nucleoside diphosphate kinases on contractility in
zebra, fish and mice.


                                               
They identified nucleoside diphosphate kinase as the critical
isoform for the regulation of G Protein function and cyclic-AMP
levels in the heart with important consequences for cardiac
contractility. The increased nucleoside diphosphate kinase
membrane content in human heart failure could potentially
counteract a fading beta adrenoceptor response in the early
stages of heart failure by increasing the amount of G Alpha
stimulatory proteins in the plasma membrane. However, by
switching from stimulatory to G Alpha inhibitory to activation,
nucleoside diphosphate kinase may play a role in heart failure
progression by reducing cyclic-AMP levels, typical for end-stage
human heart failure.


                                               
The study, therefore contributes to a better understanding of the
molecular processes, underlying alter G Protein signaling in
heart failure, and may help to develop new heart failure
therapies.


                                               
The next study tested the hypothesis, that high intensity
interval training is superior to moderate continuous training in
reversing cardiac remodeling and increasing aerobic capacity in
patients with heart failure and reduced ejection fraction.


                                               
Doctor Ellingson and colleagues from the Norwegian University of
Science and Technology, performed a multicenter trial, comparing
twelve weeks of supervised interventions of high-intensity
interval training at 90 to 95% maximal heart rate, moderate
continuous training at 60 to 70% maximal heart rate, or a
recommendation of regular exercise in 261 patients with heart
failure and ejection fraction less than 35%, in New York Heart
Association class II or III status.


                                               
The primary end point of change in left ventricular end-diastolic
diameter from baseline to twelve weeks was not different between
the high-intensity and moderate continuous groups. There was also
no difference between the high-intensity and moderate groups in
peak oxygen uptake, although both were superior to the
recommendation for regular exercise. None of these changes were
maintained at follow up after 52 weeks. Serious adverse events
were not statistically different. However, training records
showed that 51% of patients exercised below the prescribed
target, during supervised high-intensity interval training, and
80% above the recommended target in those with moderate
continuous training. Given that high-intensity interval training
was not superior to moderate continuous training, in reversing
remodeling or improving secondary end points, and considering
that adherence to the prescribed exercise intensity based on
heart rate was difficult to achieve even in the supervised
setting.


                                               
The authors concluded that moderate continuous training remains
the standard exercise modality for patients with chronic heart
failure.


                                               
The final paper tells us, that brain emboli after left
ventricular endocardial ablation may be more common than we knew.
First author Doctor Whitman, corresponding author Doctor Marcus
and colleagues from University of California studied eighteen
consecutive patients, scheduled for ventricular tachycardia or
premature ventricular contraction ablation, over a nine month
period. Twelve patients undergoing left ventricular ablation were
compared to a control group of six patients, undergoing right
ventricular ablation only. Heparin was administrated with a goal
activated clotting time of 300 to 400 seconds for all left
ventricular procedures. Pre impulse procedural brain magnetic
resonance imaging was performed on each patient within a week of
the ablation procedure. The authors found that seven of the
twelve patients, or 58% undergoing left ventricular ablation,
experienced a total of sixteen cerebral emboli, compared with
none among patients undergoing right ventricular ablation. Seven
of the eleven patients undergoing a retrograde approach to the
left ventricle, developed at least one new brain lesion. Thus,
more than half of patients undergoing routine left ventricular
ablation procedures, experienced new brain emboli after the
procedure, even in the absence of clinically apparent stroke.


                                               
Future research is critical to understanding the long-term
consequences of these lesions and to determine optimal strategies
to avoid them. This is further discussed in an editorial entitled
"The Sound of Silence". How much noise should we make about post
ablation silence strokes? By Doctor Z and Vora from Stanford
University. Well, those were your summaries, now for our featured
discussion.


                                               
I am so thrilled to have with me two special guests to discuss
the topic of the diagnosis of heart failure preserved ejection
fraction or HFpEF. As you all know, that's my favorite topic and
I have favorite people with me today. First, the corresponding
author of our feature paper, Doctor Barry Borlaug from Mayo
Clinic, Rochester, Minnesota. And, for the first time on the
podcast, Doctor Mark Drazner, Senior Associate Editor from UT
Southwestern. So, welcome Barry and Mark.


Barry
Borlaug:                   
Thank you Carolyn.


Mark
Drazner:                  
Thank you, great to be here.


Dr. Carolyn
L.:                   
So, Barry, you talked about the role of stress diastolic testing,
shall I call it, in the  diagnosis of HFpEF in your paper.
Could you tell us why you looked at it and what you found?


Barry
Borlaug:                   
Sure, Carolyn. When you have dyspnea and fatigue and you got a
low EF, it's pretty easy to make the diagnosis of heart failure
reduced EF, but we've been struggling for years with making the
diagnosis of dyspnea, whether it's HFpEF or not in people with
normal ejection fraction. And that's because physical and
laboratory and clinical signs of high filling pressures and
congestion, are either difficult to see or only present during
stress, like physical exercise, in patients. So that's really
what motivated us to pursue this study.


                                               
We took patients, that were referred to our cath lab for invasive
hemodynamic exercise testing, so we directly measured filling
pressures, PA pressures and cardiac output reserve, to get a gold
standard assessment, whether people have heart failure or not.
And then we performed simultaneous echocardiography and blood
testing to measure NT-proBNP levels, and then we just looked at
what we could figure out. Can you accurately discern HFpEF
patients from patients without cardiac dyspnea, using these non
invasive estimates.


                                               
We saw that a lot of people, with, for example, NT-proBNP levels
that are low enough to be where most would consider HFpEF
excluded, actually had HFpEF. And we saw that there were modest
correlations between non-invasive echocardiographic estimates of
filling pressures, specifically the E to E Prime ratio, and
directly measured left heart filling pressures. But when we
applied the criteria that had been initially proposed, we saw
poor sensitivity to make the diagnosis with exercise. And this
was largely related to the difficulty with getting all of the
different echocardiographic indices, that are currently examined
as part of the diastolic stress testing non-invasively. Next, we
looked at just adding the exercise E to E Prime, which is an
estimate of filling pressures, and when we used the cut-point,
that's already been proposed, according to contemporary data, we
found that this substantially improved the sensitivity to
identify HFpEF, but there was a bit of a trade-off in that
specificity decrease.


Dr. Carolyn
L.:                   
That's so cool. So let me summarize some of these take-home
messages here. First of all, using just rest echo. I was really
impressed to see that rest echo indices alone only identifies a
third to maybe up to 60% of the patients you found with
invasively proven HFpEF. So, we may be specific, but we're really
missing quite a number of patients. And then if you exercise
them, what your data is really showing is that it's better to
exercise them and use this data for the negative predictive
value, isn't that what you're saying?


Barry
Borlaug:                   
You know, the exercise is really the gold standard, so it gives
you both, the negative and positive. With the echocardiography,
relying on the exercise E to E Prime ratio, that was really
helping us, as you say, Carolyn, with the higher negative
predictive value. So most people, that had HFpEF, in this series,
where we could get adequate, highly controlled environments,
adequate diagnostic echocardiographic data, most people that
ended up having HFpEF fit those criteria, we could see an
elevation in this E to E Prime on exercise, so it did provide
good negative predictive value.


Dr. Carolyn
L.:                   
These are just such important data, because I think we're all
still struggling with how to make this diagnosis of HFpEF. Mark,
could you just share some thoughts on whether you think this is
going to really change practice, even change guidelines?


Mark
Drazner:                  
I think, if you read this paper, you would recognize it, that
it's certainly a critical question that we're all facing, how to
make the diagnosis of HFpEF. And all of their guidelines that
have been advocated, there really wasn't much data, and these
really are the best data out there. So, certainly, it's
[inaudible 00:15:41] me a direction of changing practices. Barry
says, certainly, the approach will need to be validated, I think,
before it reaches high level guidelines, but certainly I think
it's a step in the right direction, and points the way towards
the future in terms of improving our ability to diagnose HFpEF.
And really, that's why both reviewers and [inaudible 00:15:59]
this is such an important paper.


Dr. Carolyn
L.:                   
Right. Barry, I have a quick question for you though. Doing
exercise echo, not easy. E to E Primes are all over the place
usually. How easy was it? How feasible was this test?


Barry
Borlaug:                   
So, first I'd like to say that we have outstanding, very
well-trained, very highly skilled research scenographers, here at
Mayo doing this. In very controlled environment, we're providing
plenty of time for them to obtain images and that's going to be a
question moving forward, because not everybody in clinical
practice has that capability. But with that said, in this very
controlled environments, skilled scenographers, we were able to
measure the exercise data during low level exercise about 85 to
90% of the time and at peak exercise about 75 to 80% of the time.
So, it's fairly feasible, but even in this best case scenario, we
can't get it on everybody.


Mark
Drazner:                  
Even in the [inaudible 00:19:49] echo lab, the recommended
approach by the ASE with the four measures. How many times they
were not able to acquire all those images, are necessary for
those four techniques and so, here you have a [inaudible
00:20:03] of AS echo lab not being able to do that, and being
transparent about that, and [inaudible 00:20:08] to the
community, saying that, although these are ideal measures, even
the [inaudible 00:20:12] perhaps you can't acquire them. I think
that was another important point that came out of this and then
lead to the focus on the E to E Prime.


Barry
Borlaug:                   
I couldn't agree more. You got one of the world renowned labs,
very skilled scenographers doing imaging, and we're still not
able to get it all in each patient, and that just points to the
difficulty of getting really high quality diagnostic images, and
a lot of time you need the next level test, when that happens.
And invasive exercise testing is really that test, the gold
standard.


Mark
Drazner:                  
When you get echos from the outside and you look at the E to E
Primes, are you confident that the data, that's generally
acquired, is gonna be acceptable for this [inaudible 00:20:50]?


Barry
Borlaug:                   
Yes and no, I mean I'm always a little bit concerned, but it's
not just being a control freak, you know, wanting to see
everything, but I think that if it's a still frame doppler,
tissue doppler spectrum, you can see that the sample volume is in
the right place, and it's really unequivocally normal or
abnormal, I feel pretty good about that. Not as good as when they
get a full dedicated study here.


Mark
Drazner:                  
Of course, the gold standard is also difficult. The invasive
measurement.


Barry
Borlaug:                   
Yes it is, I didn't [inaudible 00:21:18] that, but we've been
doing a lot of invasive exercise tests for the last ten years
now. And we do like 250 a year here, so we're really quite
[inaudible 00:21:28] but we have all hands on deck in the lab. We
have a couple technicians running gas samples around, all over
the place. Somebody is on the medgraphics card, measuring oxygen
consumption. We've got a nurse in there, that's helping out, so
it's complicated, and of course we're using the micromanometer
catheters for the pressure assessments, because you get so much
more artifacts from width and under damping and over damping with
the pressure tracing, so that's also not easy to do if you say.


Mark
Drazner:                  
So maybe for practicing cardiologists it's gonna be hard to
duplicate that and perhaps spend the energy in terms of doing the
exercise echo techniques off the speed, for example. Perhaps,
it's another message.


Barry
Borlaug:                   
I would agree completely. And I think that again, when you do
that, if you do a really high quality exercise echo and it's
still not quite definitive, then you can refer on to a center
that does have that capability, because obviously it's just
reality, not everybody is going to be able to do this. Not every
place has the size and resources to be able to do these really
advanced tasks.


 


Dr. Carolyn
L.:                   
And do you apply exercise echo now in making your diagnosis? How
do you use this data, for yourself, clinically?


Barry
Borlaug:                   
We started to think about this, and I think that the best case
scenario where the  people, that really have an intermediate
pretest probability, based on their clinical characteristics.
Somebody has jugular distension and a very high NT-proBNP level,
and edema, you really don't need further testing, you know that
that's going to be HFpEF. And if somebody has no risk factors,
and everything is stone cold normal, they don't.


                                               
But in some of these people that have some signals, but they
don't quite meet criteria, we are doing this, again, if they have
adequate echocardiographic images at rest. And then we're looking
really carefully at the exercise echocardiography data, one
concern from this data, I want to make sure people are very
circumspect and really critically looking at the quality of their
data, because we shouldn't over-interpret equivocal findings. And
as you said earlier, E to E Primes can be all over the map,
they're very difficult to obtain during exercise. But I think
that if everything looks very high quality and is definitely
abnormal or definitely normal, that can be helpful. More so, if
it's normal. We     did see more false
positive, so if it is abnormal, we did suggest that you may want
to perform further confirmatory testing, because of the higher
false positive rate with exercise echo.


Mark
Drazner:                  


                                               
I would say for the listeners, they should take a look at his
figure six, which really is a nice diagnostic algorithm, where
Barry shows, or advocates, for taking patients with intermediate
probability and then using this to restratify that, using
[inaudible 00:19:40] approach. I know that, that figure resonated
with the editors and the reviewers dramatically, so I'd encourage
listeners to take a look at that.


Dr. Carolyn
L.:                   
Listeners, you heard it right. [inaudible 00:22:36] Circulation
on the Run. Don't forget to tell all your friends about this
podcast and tune in next week.