Circulation November 28, 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 journal this week features novel data informing the choice
between conscious sedation and general anesthesia for
transcatheter aortic valve replacement. A very relevant
discussion for those of us who see these patients. Stay tuned,
that's coming right up after these summaries.


                                               
Subclinical hyperthyroidism is known to be associated with an
increased risk of atrial fibrillation, but the association with
thyroid function in the normal range or subclinical
hypothyroidism is unclear. That is, until today's study, which
shows us that variation in thyroid function within the normal
range is associated with atrial fibrillation.


                                               
First author, Dr. Baumgartner, corresponding author, Dr. Rodondi
and colleagues from University of Bern in Switzerland, conducted
a systematic review and obtained individual participant data in
more than 30,000 participants from 11 prospective cohort studies
that measured thyroid function at baseline and assessed incident
atrial fibrillation, which occurred in 8.6% of individuals.


                                               
They found that in youth thyroid individuals, there was a
significant increase in the risk of atrial fibrillation with
increasing free T4 levels within the reference range. Risks did
not differ significantly by age and sex.


                                               
Conversely, there was no association between TSH levels within
the reference range, or subclinical hypothyroidism and the risk
of atrial fibrillation. Thus, free thyroxin levels might add to
further assessment of atrial fibrillation risks. Further studies
are needed to investigate whether these findings apply to
thyroxine treated patients.


                                               
The next study provides insight into how exercise promotes
metabolic remodeling in the heart. First author, Dr. Gibb,
corresponding author, Dr. Hill and colleagues from University of
Louisville, use radiometric, immunologic, metabolomic and
biochemical assays to measure changes in myocardial glucose
metabolism in mice subjected to acute and chronic treadmill
exercise.


                                               
They found that in the heart, glucose utilization via glycolysis
was reduced during exercise and in the early recovery period
after exercise. Low rates of myocardial glycolysis were
sufficient to activate gene programs that instigate physiologic
cardiac growth. Metabolic inflexibility of the heart, such as
occurs in heart failure and diabetes, was sufficient to diminish
mitochondrial function.


                                               
Phosphofructokinase mediated changes in metabolism appeared to
regulate genes involved in processes critical for metabolic
remodeling, transcription, cell division, differentiation, cell
proliferation and contraction. Thus, this study provides
important preclinical evidence, showing how exercise-induced
changes in glucose metabolism may promote physiologic cardiac
growth.


                                               
The next study addresses the question of whether antiarrhythmic
drugs are safe and effective when non-shockable rhythms evolved
to shockable rhythms during resuscitation for out of hospital
cardiac arrests. In this study from first and corresponding
author, Dr. Kudenchuk of University of Washington and his
colleagues, patients who initially presented with non-shockable
out of hospital cardiac arrests were randomized upon subsequently
developing shock refractory VF or VT to receive amiodarone,
lidocaine or placebo by paramedics.


                                               
The primary outcome was survival to hospital discharge, with
secondary outcomes, including discharge functional status and
adverse drug-related effects. The authors found that outcome from
non-shockable turned shockable out of hospital cardiac arrest was
poor, but not invariably fatal. Though not statistically
significant, point estimates for survival showed a trend to
greater survival after amiodarone or lidocaine than placebo
without increased risk of adverse effects or disability.
Together, these findings may signal a clinical benefit that
invites further investigation.


                                               
The final study provides experimental data supporting the
importance of a novel Cardiokine governing the local environment
in infarcted hearts and determining the fate of implanted cells.
This novel Cardiokine is C1q/tumor necrosis factor-related
protein-9, or CTRP9, which is a novel pro survival Cardiokine
that is significantly down regulated after myocardial infarction.


                                               
In today's study by co-first authors, Drs. Yan and Guo and
co-corresponding authors Drs. Ma and Wang from Thomas Jefferson
University in Philadelphia, mice were subjected to myocardial
infarction and treated with adipose-derived mesenchymal stem
cells, CTRP9 or their combination. The authors found that
administration of adipose-derived mesenchymal stem cells alone
failed to exert significant cardio protection.


                                               
However, administration of these cells in addition to CTRP9
further enhanced the cardioprotective effect of CTRP9, suggesting
a synergistic effect. CTRP9 promoted adipose-derived mesenchymal
stem cell proliferation, survival, migration and attenuated
cardio myocyte cell death by signaling mechanisms that included
binding with N-cadherin, activation of ERK, MMP9, and ERK-Nrf2
signaling and upregulation or secretion of antioxidative
proteins.


                                               
In summary, these results suggest that CTRP9 is a Cardiokine
critical in maintaining a healthy microenvironment facilitating
stem cell engraftment in infarcted myocardial tissue. Well, that
wraps it up for your summaries, now for our feature discussion.


                                               
Conscious sedation is very frequently used during transcatheter
aortic valve replacement, or TAVR, but with limited evidence as
to the safety and efficacy of this practice. Well, that is until
this week's journal and this feature paper. We're so lucky to
have with us the corresponding author, Dr. Jay Giri from Hospital
of University of Pennsylvania, to discuss his novel findings, as
well as Dr. Dharam Kumbhani, Associate Editor from UT
Southwestern.


                                               
Jay, tell us your study findings and how this really helps us to
characterize anesthesia choice and clinical outcomes of at least
U.S. patients undergoing TAVR.


Dr. Jay Giri
:                       
We looked at 11,000 patients treated over a 15-month period in
2014 and 2015 with percutaneous transfemoral TAVR. Notably, this
was a time period that was identified as the start of the era of
conscious sedation for TAVR in the United States.


                                               
Also, this five quarter period that we looked at represented a
time of relative technological stability where only two valve
types, the Sapien XT and original Medtronic CoreValve were being
used in America.


                                               
Looking at that 15-month period when conscious sedation was first
being used in TAVR, we elected to compare those patients to a
propensity matched group of patients who underwent TAVR by, what
at that time was, the more traditional approach of general
anesthesia.


                                               
Our primary outcome within hospital mortality, because we had
complete followup for this outcome. We also looked at 30-day
outcomes for which we had about 90% followup. What we discovered
was actually an associated reduction in mortality, an absolute
reduction of about 1% in the patients who were treated with
conscious sedation.


                                               
We also noted that they had modest decreases in the hospital
length of stay, as well as significant decreases in the rates of
ICU length of stay and the rates of pressor or inotrope use
during the procedure. Obviously, the most provocative of the
findings was the fact that we seemed to discover, after
propensity matching a slight improvement in in-hospital mortality
that held true at 30 days, as well.


Dr. Carolyn
Lam:              
Thank you, Jay. What important findings ... I mean, mainly
because, we really didn't have much data, did we? About conscious
sedation and TAVR before this. Now, it's observational data, and
I suppose the question always becomes what about bias by
indication? More well patients get selected for conscious
sedation versus general anesthesia, perhaps? Or even the other
way around. Could you elaborate a little bit on how you think
that may have impacted results and the measures you took to look
at that?


Dr. Jay Giri
:                       
I think it was something that we were highly aware of and I also
have to give credit to Dr. Kumbhani and the editorial staff at
circulation for pushing us on that issue of selection bias for
the two procedures. The obvious concern here, when you saw that
there was a potential mortality reduction with conscious sedation
patients, was that perhaps the conscious sedation patients
actually represented a healthier cohort to start with, or they
were perhaps treated at centers that were more highly experienced
and by operators that were more highly experienced with TAVR in
general.


                                               
We tried to account for this in a number of different fashions.
The first, as we mentioned, was with an inverse probability
treatment weighted analysis that accounted for 51 co-variants
that were balanced between the groups. Additionally, we did
adjust for site characteristics and utilized a hierarchical
method technique to take into account both the experience of
sites and operators.


                                               
Finally and most importantly, we performed what's called a
falsification end point analysis in a postdoc fashion to verify
that it looked like other outcomes outside of things, like
mortality, length of stay, things we would expect to be
influenced by sedation type, ended up being equal between the two
groups. Falsification end point analysis represents, essentially,
a negative control. You're supposed to theorize for potential
outcomes that you would think would not be influenced by your
intervention. In this case, those outcomes we theorized were
vascular complications, major bleeding and pacemaker
implantation, which we theorized would not be influenced by
sedation type. In fact, we discovered that those outcomes were
similar after adjustment, even though they had some differences
before adjustment.


Dr. Dharam Kumbhani:  Jay, I want to congratulate you and
your team on this paper. You guys really picked a very important
topic to look at and then you jump ... as you outlined, you
jumped through a lot of statistical hoops and try to really
provide evidence for a field in which a randomized controlled
trial is probably going to be just logistically probably hard to
conduct, just given the sample size requirements, which also
you've provided in your discussion.


                                               
I think all the metrics that you looked at as far as utilization
of therapies and length of stay, things like that, I think many
people believe that and you were the first one to systematically
evaluate and show that.


                                               
As you alluded to, I think that mortality, and Carolyn mentioned
that, as well. I think the mortality findings are very
interesting. Again, it's always hard when you have observational
data to really put a lot of stock into that and you guys, as you
outline, looked at so many different ways of doing that.


                                               
Again, I guess, observational data are always inherently going to
have that limitation, no matter what statistical rigor we put
them through. They were definitely very thought-provoking and, as
you outlined, it's definitely come at the right time as the field
is exploding and more and more centers are getting facile at it.


                                               
The other thing that you mentioned, but which I want to make sure
that people fully understand is that you also provided a very
elegant analysis looking at site volumes, because traditionally
the sites that are doing conscious sedation have done a number of
TAVR's before and there is a very clear cumulative volume
outcomes association, for TAVR.


                                               
By accounting for the totality of experience, so you adjusted for
the cumulative volume that sites have been doing this, so these
are not just the high volume, high throughput centers, which have
a lot of experience doing 150, 200 TAVR's a year, that thereby
have really good outcomes by virtue of being expert, both as
operators and as sites, but rather potentially something that is
related to conscious sedation aspect itself. You guys really
stepped up and provided a very elegant analysis to try to
dissociate the two issues here.


Dr. Carolyn
Lam:              
Dharam, and you just provided a very elegant explanation of the
thought processes that were going on with our editors about this
paper. I join you in congratulating Jay. Just a question. This is
the best available evidence now, what are we going to do about
it? I mean, Dharam, you're an inventionist, what now?


Dr. Dharam Kumbhani:  The issues were not so much related to
efficacy, initially. The initial concerns were related to safety,
and Jay's paper clearly addresses that. Then, in addition to
that, it says, "Well, it's not just that it's a safe procedure,
but it's also effective with potential patient level and hospital
level benefits from having a robust conscious sedation program."


                                               
I guess the one question that I have about conscious sedation
and, Jay, I would love to hear your thoughts on this, as well, is
it is possible but it is usually not done, TEE's or
transesophageal echos are typically not done when you're doing
conscious sedation. It is possible, as I said. As you move
towards lower risk patients, on the one hand, these would be
ideal patients for conscious sedation because then it's almost
like a day procedure, in some ways for them.


                                               
But on the other hand, the fidelity of being able to look for
even small paravalvular leaks, things like that, may be harder
with a transthoracic echo. I don't know, as we expand towards the
oldest populations, whether we'll see a greater adoption of
conscious sedation, or whether there'll be some scaling back.


Dr. Jay Giri
:                       
Two points on that. The first is, I totally agree that it's
relatively unusual for a transesophageal echo to be performed in
the setting of conscious sedation. There's no question, secondly
that transesophageal echo allows for the most rigorous evaluation
of paravalvular leaks.


                                               
It is striking, though, that the rates of paravalvular leaks, due
to technological improvements to the valves, are significantly
improving. Even since the time of our study two years ago, a new
generation of valves is consistently coming out with leak rates
in pretty well-conducted analyses that are in the low, single
digit percentages for moderate leak or more.


                                               
Part of I think the move towards conscious sedation, even
initially and especially as we go forward, is predicated on the
fact of continuing technological improvements that essentially
almost solve the leak problem.


                                               
I think it's true that there's always going to be a very small
minority of patients that are stuck with concerns about
paravalvular leak at the end of their TAVR procedure. For those
who have moderate or greater leak, I think that the threshold for
escalating care, even to intubation and TEE to evaluate that
leak, I think should be relatively low in a lower risk
population.


                                               
However, I think the point that you bring up about the potential
harm of trace or trivial leaks, or mild leaks, which may not be
perfectly interpreted with transthoracic echo and aortograms and
[inaudible 00:16:41] assessments at the time of the valve
placement. It's something we're going to have to keep a close eye
on.


                                               
From a practical standpoint, I believe this train has left the
station. Totally unscientific, but around the time they released
the paper online. I just shot out a poll on Twitter and got about
a couple of hundred responses from folks, what they're doing now.


                                               
Now, Twitter certainly, probably doesn't represent the average
transcatheter valve operator in the world, but I was surprised to
see that over 70% of the respondents favored a conscious sedation
approach at this point in time, which obviously is much higher
than what we saw in our paper from two years ago.


Dr. Carolyn
Lam:              
Well, audience, I'm sure you enjoyed that. Thank you for joining
us today. Don't forget to tune in again next week.