Circulation June 11, 2019 Issue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summery
and backstage pass to the journal and it's editors. We're your
co-hosts, I'm Doctor Carolyn Lam, Associate Editor from the
National Heart Center and Duke National University of Singapore.


Dr Gregory Hundley:       And I'm
Doctor Greg Hundley, Associate editor for Circulation and
Director of the Pauley Heart Center at VCU of Health in Richmond,
Virginia. Well Carolyn, in the second half of our feature we're
going to discuss a randomized clinical trial in lower risked
surgical patients related to, the five year clinical
echocardiographic outcomes from aortic valve intervention. So
Carolyn, do you want to go first this time and discuss on of your
favorite papers?


Dr Carolyn
Lam:               
Absolutely! So, are Cardiac Troponin T and I equivalent measures
of cardiovascular risk in the general population? Well that's the
question Doctor Paul Welsh and colleagues from University of
Glasgow aimed to look at. They wanted to compare and contrast the
associations of Cardiac Troponin T and Cardiac Troponin I with
cardiovascular disease and non-cardiovascular disease outcomes,
and also determine their genetic determinants in a genome wide
association study involving more than nineteen-thousand, five
hundred individuals in generation Scotland, Scottish family
health study.


Dr Gregory Hundley:       How about
that. So this is kind of interesting. So most of us kind of use
these two chests interchangeably Carolyn, and I think, I guess
we'd consider them to be almost equivalent. So are you going to
tell us that they are the same?


Dr Carolyn
Lam:               
Ah-hah! So this is what the authors found. Both Cardiac Troponins
T and I were strongly associated with cardiovascular risk,
however, Cardiac Troponin I but not T was associated with both
myocardial infarction and coronary heart disease. Both Cardiac
Troponins I and T had strong associations with cardiovascular
death and heart failure, however, Cardiac Troponin T, but not I
was associated with non-cardiovascular disease death. They also
identified five genetic loci in fifty-three individuals snips
that had GWAS significant associations with Cardiac Troponin I
and a different set of four loci of four snips for Cardiac
Troponin T.


                                               
So, the upstream genetic causes of low-grade elevations of
Cardiac Troponins I and Cardiac Troponin T appear to be distinct
and their associations with outcomes also differ. Elevations of
Cardiac Troponin I are more strongly associated with some
cardiovascular disease outcomes whereas Cardiac Troponin T, is
more strongly associated with the risk of non-cardiovascular
disease death. These findings can help inform selection of an
optimal Troponin essay for future clinical care and research in
these settings.


Dr Gregory Hundley:       Very
good! So, does sound like there could be a little bit of a
difference, depending upon what outcome you're looking for. So,
Carolyn I'm going to discuss a paper from Doctor Alison Wright
and colleagues at the University of Manchester, and it involves
cardiovascular risk and risk factor management in type two
diabetes.


                                               
So in this retrospective cohort study, using the clinical
practice research data link, linked to hospital and death records
for people in England, investigators identified 79,985 patients
with incident type two diabetes, between the years 2006 and 2013,
matched to three 386,547 patients without diabetes, and
sex-stratified Cox models were used to assess cardiovascular
risk.


Dr Carolyn
Lam:               
Oh I'm dying to know, what did they find?


Dr Gregory Hundley:       Well
compared to women without type two diabetes mellitus, women with
type two diabetes mellitus had a higher cardiovascular event risk
than the adjusted hazard ratios 1.2, with similar corresponding
data in men, so their hazard ratio is 1.1. And that lead to a
nonsignificant relative risk in women with a risk ration of 1.07,
however, some important sex differences in the management of risk
factors were observed. Compared to men with type two diabetes,
women with type two diabetes were more likely to be obese,
hypertensive, and have hypercholesterolemia but were less likely
to be described lipid lowering medication, ace inhibitors,
especially if they had cardiovascular disease. So Carolyn,
compared to men developing type two diabetes mellitus, women with
type two diabetes mellitus do not have a significantly higher
relative increase in cardiovascular risk, but, ongoing sex
disparities in prescribing should prompt heightened efforts to
improve the standard and equity of diabetes care in women as
compared to men.


Dr Carolyn
Lam:               
Nice Greg. Important message. My next one has an important
message too. Now it goes to the pediatric population now. We know
that brain injury, impaired brain growth, and long term neuro
development problems are common in children with transposition of
the great arteries. Now does the age at arterial switch operation
predict these neuro developmental outcomes in infants with
transposition of the great arteries or TGA?


                                               
Well Doctor Mike Seed from Hospital for Sick Children in Toronto,
Canada and colleges addressed this question by imaging the brains
of 45 infants with TGA, undergoing surgical repair, pre and post
operatively using MRI. Their main finding was that surgery beyond
two weeks of age is associated with impaired brain growth and
slower language development in infants with TGA.


Dr Gregory Hundley:       Wow
Carolyn, this seems like, this could have really important
clinical implications for the management of these patients.


Dr Carolyn
Lam:               
Yeah, indeed. Expediting surgical repair could be neuro
protective in newborns with Transposition. While the mechanisms
underline this association are still unclear, extended periods of
cyanosis and pulmonary over circulation maybe factors that
inversely impact brain growth and subsequent neurodevelopment if
the surgery's not done early. The timing of surgery may have an
impact on neurodevelopment in other forms of congenital heart
disease, too, therefore. So all of this is discussed in an
editorial entitled Correction of TGA, "Sooner Rather than
Later?", and this is by Doctors Rollins and Newburger, from
Boston's Children's Hospital.


Dr Gregory Hundley:       Fantastic
Carolyn, well I'm going to discuss a paper from the World of
Basic Science from the Ohio State University, Wexner Medical
Center from Doctor Douglas Lewandowski. And it involves the
preservation of Acyl-CoA and how that attenuates pathological and
metabolic cardiac remodeling through selective lipid trafficking.
So Carolyn, it has been shown that metabolic remodeling in heart
failure contributes to dysfunctional lipid trafficking, and
lipotoxicity. Acyl-Coenzyme A Synthase One, or ACLACSL1
facilitates long chain fatty acid uptake an activation with
coenzyme A, mediating the fate of the long chain fatty acids. The
authors tested wither cardiac Acyl coenzymes A synthase One
over-expression aided long chain fatty acid oxidation and reduced
lipotoxicity under the pathologic stress of transverse aortic
constriction or TAC.


Dr Carolyn
Lam:               
Interesting, I like that concept of metabolic remodeling. So what
did they find?


Dr Gregory Hundley:       So
Carolyn, the studies were performed in both mice and in human
subjects, and in mice at 14 weeks, TAC induced cardiac
hypertrophy and disfunction was mitigated in MHCACSL1 hearts
compared to nontransgenic hearts. This was manifest by retain
greater rejection fraction, 65.8 percent versus the nontransgenic
hearts of 45.9 percent. An improvement in diastolic E over E
prime. Also, functional improvements were mediated by ACSL1
changes to cardiac long chain fatty acid trafficking. In humans,
long chain Acyl-CoA was reduced in human failing myocardium and
restored to control levels by mechanical unloading.


                                               
So, Carolyn, this is the first demonstration on reduced Acyl-Co-A
in failing hearts of humans and mice, and suggest possible
mechanisms for maintaining mitochondrial oxidative energy
metabolism by restoring long chain Acyl-CoA through ASCL1
activation and mechanical unloading.


Dr Carolyn
Lam:               
Awesome Greg! Thanks so much for sharing that paper. Let's go on
to our feature discussion.


Dr Gregory Hundley:       You bet.


Dr Carolyn
Lam:               
Our feature discussion today is about transcatheter aortic-valve
replacement. Could this be the new gold standard for the
treatment of aortic stenosis? And yes, I am borrowing from the
title of the editorial that accompanies our feature paper. With
the editorialists right here with us, Dr Bernard Prendergast,
from Saint Thomas' Hospital in London, and we are talking about
the wonderful paper for the notion trial and that's a Nordic
aortic valve intervention randomized clinical trial, and we're
here with the first and corresponding author of that paper Dr
Hans Gustav Thyregod from Copenhagen University Hospital, and we
also have our associate editor Dr Dharam Kumbhani from UT
Southwestern. So welcome gentlemen! And for a start could I ask
Hans to please describe the results of the notion trial.


Dr Hans
Thyregod:          
The notion trial as you said is the Nordic aortic valve
intervention trial. Designed to compare transcatheter therapy and
surgical therapy and patients with severe aortic valve stenosis,
patients have to be thirteen years old or older and we didn't
really specify any risk profile, as in previous trials. So all
patients eligible for both procedures would be enrolled in the
trial. And the main result of the trial was that we couldn't find
a difference when looking at the composite outcome, which was
all-cause mortality, stroke American infraction.


                                               
The primary outcome was after one year, in this paper it's up to
five years and we could not see any difference. So the range was,
in my estimate was 38 percent for transcatheter therapy versus
36.3 percent for surgery. And when looking at the different
components of this composite outcome, all-cause mortality, stroke
American infraction. We couldn't find any surgically significant
difference for any of those outcomes either.


Dr Carolyn
Lam:               
Wow, Bernard, could I ask you to place these results into context
for us, I mean the notion trial is after all the first to compare
TAVR and SAVR in patients with severe isolated valve stenosis at
lower surgical risk, and really has the longest follow-up doesn't
it? So please tell us, what are your thoughts?


Dr Bernard
Prendergast:              
So this is yet another notch the remarkable success story of TAVI
or TAVR, as you call it in the U.S. We pass our congratulations
from the community to Dr Thyregod and the team in Copenhagen for
such a ground-breaking study. The wider context is he say is the
TAVR have demonstrated remarkable efficacy and safety, initially
in operable and high-risk patients, but, more recently randomized
control trials in intermediates and lower risk patients. And the
important perspective of this study provides is the longer term
follow up, because for a number of years we've perhaps considered
TAVI or TAVR as a, let’s say a shorter-term treatment for
patients in their eighty's and older, who perhaps have a shorter
life expectancy. But what the five-year data demonstrates to us
is that TAVI or TAVR is as good as surgery, at five years of
follow up. With very reassuring outcomes, they maintain
durability of the transcatheter heart valve, that's highlighted
in the companion paper, which, is published very recently in
JACC.


                                                               
So really takes TAVI into a new territory, which is patients who
have at least five years or longer to live and allows us to
extend the indication for the procedure into younger patients.
Alongside lower risk patients, who have supported by the recent
landmark studies published in the New England Journal from
Partner Three, and the Core Valve Low Risk trial. So, the
information is very reassuring and it's another very positive
notch in the journey of TAVI across the spectrum of surgical
risk.


Dr Carolyn
Lam:               
Thank you! Beautifully put and Dharam could I just ask you I mean
what more do we need? Do you think this is guideline defining
stuff now? Or do you have questions?


Dr Dharam Kumbhani:   I really want to congratulate the
investigators of the NOTION trial, as far as providing us with
this longer term follow up in a lower risk population, and so,
you know the field is moving incredibly, incredibly quickly and
you know as we just mentioned TAVR has now gone from being
something that's done in patients that are too high risk to level
convention surgery, to now perhaps becoming either one of the
main stream options, or the main stream option. And you know time
will tell, so I think what this study really helps us is, provide
us with a five-year time horizon on follow up, but, to be fair,
you know this trial is very helpful in certain ways because it
was designed a few years ago. You know it was done with the
generation of a valve that is not used much right now for the
most part, and you know so it's some of the things like pacemaker
et cetera, may not translate to current practice.


                                               
Even though the clinical outcomes were similar, it's probably
some issues with power as well, but, again not in a clinical way,
but, just to kind of say that this trial definitely helps us in
moving the field forward and it kind of adds to the growing body
of literature that supports that. Going forward I guess one
question I would have for this group is, you know as we think
about TAVR and surgical aortic replacement, it would seem that we
would need even longer term data, based off of detonators to be
able to confidently tell patients, there are fairly similar
therapies.


                                               
And then the other question is, this construct of surgical risk
is that we applied telegraphically based on how the evolution of
TAVR has occurred, but one wonder, you know with NOTION and other
trials we should be thinking about this perhaps from an age
perspective as a sort of NOTION trial—those would be my two
comments.


Dr Bernard
Prendergast:              
I think that's a very valuable comment, and of course there are
other ongoing trials, which, will help to address many of these
questions. One important deficit of notion is that it didn't
enroll, for example, patients with bicuspid aortic valves. And we
know that bicuspid aortic stenosis is far more common in younger
patients. So, Hans a few comments regarding the protocol for
notion two maybe helpful for our listeners.


Dr Hans
Thyregod:          
Well this was mentioned, the follow up of five years is obviously
not a very long time in younger patients with a lower risk
profile. We are planning to follow these patients for at least 10
years. And the other comment about the risk profile of the risk
certification of patients is also very interesting because the
SDS and your scores have been developed for surgical patients and
not for transcatheter patients. So we need a whole new
transcatheter risk scoring system to help our team determining
what treatment would be the best suited for each patient.


                                               
And as Dr Prendergast mentioned we are in Copenhagen, and
Scandinavia conducting a NOTION II trial, which, will enroll
patients younger than the previous low risk trials and also the
notion trial. Which, at a mean age, at least for the patient of
around 80 years and in notion two patients must be younger than
75 years old. And we are also including patients with bicuspid
valve stenosis, and also patients which were not included in the
NOTION I trial. Patients with a coronary artery disease, so these
patients are obviously also a different patient category and will
maybe require a different approach regarding the timing of the
revascularization and so forth so there is more research to be
done in those areas.


Dr Carolyn
Lam:               
Well exciting. Thank you for sharing that Hans. Dharam could I
ask you to just wrap us up with the take home message, it's for
our audience right now.


Dr Dharam Kumbhani:   For me one of the most
interesting findings was that in five years, the clinical
performance between TAVR and SAVR were similar, but, more
importantly the valve performance, the hemodynamic performance
was the same, and perhaps slightly better with the self-expanding
design. They are so proud of the self-expanding design that was
studied in the study. So that is helpful because as we discussed
earlier, I think a lot of the controversy discussions centers
around the long-term durability of TAVR compared with surgically
aortic valve replacement, so that is a step in the right
direction. The same investigators have published that hemodynamic
performance elsewhere as well, sot that's I think the number one
take home message that, that's very, very reassuring. The second
thing is you know this study shows us it adds to the growing body
of literature, in lower risk patients so all of this was not
strictly a lower risk trial based on contemporary definition.


                                               
It was definitely a lower risk population and so, this is the
largest pool of patients where they aortic stenosis about 50
percent will have low risk aortic stenosis, low surgical risk
aortic stenosis and so this is very helpful in that space and
then third you know that this is very exciting that NOTION
investigators indeed are the low risk trial investigators, will
be extending their follow up with 10 years. So I think in this
next decade, most people expect as Dr Prendergast also mentioned,
we'll see a gradual change perhaps in how patients with aortic
stenosis manage. But, I will add a word of caution, I think in
the current era, the way things stand right now, it's probably
best in favor to appeal to what the guideline indicates. And for
the low risk patients, surgical aorta valve replacement is still
the center of choice.


Dr Carolyn
Lam:               
Thank you so much Dharam and thank you Hans for the beautiful
paper, and Bernard for that excellent editorial!


                                               
Thank you audience for joining us today, you've been listening to
Circulation on the Run. Don't forget to tune in again next week.


                                               
This program is copyright American Heart Association 2019.