Circulation March 12, 2019 Isuue

Dr Carolyn
Lam:               
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr Greg
Hundley:            
And I'm Greg Hundley, associate editor and director of the Pauley
Heart Center at VCU Health, in Richmond, Virginia.


Dr Carolyn
Lam:               
So Greg, are ARNI's now going to be used for functional, mitral
regurgitation and heart failure? Well, we're going to be chatting
all about that with our feature paper, coming right up after
these summaries.


                                               
Greg, you've got a biggie to start with, haven't you?


Dr Greg
Hundley:            
Oh yes, Carolyn, I'm really excited about this paper. The senior
author Wanpen Vongpatanasin from University of Texas Southwestern
Medical Center in Dallas and looking at high phosphate diets and
their relationship to exercise intolerance. I really felt this
was an exceptional study and combining that key that we have, for
basic science papers and translation, where we're looking at data
from both human and basic science, in both in a single
manuscript.


                                               
So, this study focuses on inorganic phosphates and they are
present in 40-70 percent of the foods, really as a preservative
enhancer, in western diets. We see it in colas, meats, dry food
mixes, bakery products.


                                               
For the human subject component of this study, the investigators
examine the relationship between physical inactivity, assessed
with ActiGraphs that were worn, and serum phosphate levels. They
also obtained MRI measures of cardiac function and participants
were recruited from the Dallas Heart Study too.


                                               
In animals, they looked at the direct effects of dietary,
inorganic phosphate on exercise capacity, oxygen uptake, serum
non-esterified fatty acids, and glucose was measured during
exercise treadmill tests in mice fed either high inorganic
phosphate diets or normal in-organic phosphate diets. And they
were on that for 12 weeks.


                                               
To determine the direct effect of phosphate on muscle metabolism
and expression of genes involved in fatty acid metabolism,
additional studies in the differentiated myotubes were conducted
after subjecting those cells to media with high or low phosphate
conditions.


Dr Carolyn
Lam:               
So, what did the study show?


Dr Greg
Hundley:            
In the human part, among 1603 participants, higher serum
in-organic phosphate was independently associated with reduced
time spent in moderate to vigorous physical activity and
increased sedentary time. And interestingly, there was no
association between serum phosphate levels and left ventricular
ejection fraction or volumes.


                                               
In the animal studies, mechanistic insight was obtained. Compared
to controlled diets, consumption of high phosphate diet for 12
weeks did not alter body weight or left ventricular function,
thereby confirming what we saw in the human subjects, but reduced
maximal oxygen uptake, treadmill duration, spontaneous locomotor
activity, fat oxidation, fatty acid levels, and led to
down-regulations of genes involved in fatty acid synthesis.


                                               
So, the take-home on this is that the results of this study
demonstrate a detrimental effect of dietary, phosphate excess on
skeletal muscle, fatty acid metabolism, and exercise capacity,
which is independent of obesity and cardiac contractile function.


                                               
And as such, dietary in-organic phosphate may represent a novel
and modifiable target to reduce physical inactivity associated
with the western diet. I think, Carolyn, we're going to see a
large number of epidemiologic studies that are going to really
look at this as something we might be able to modify in our diet
to help impact some of these sedentary lifestyles and the harmful
cardiovascular effects that we find associated with that
lifestyle.


Dr Carolyn
Lam:               
Yikes. Remind me again, so phosphates in colas, meats, dried food
mixes, and bakery products and so on, the preservative. Wow,
you're right; big paper.


Dr Greg
Hundley:            
It's amazing. It's in 40-70 percent of the food products here in
the United States. So, wow. Something really striking. So
Carolyn, how about one of the papers that you liked?


Dr Carolyn
Lam:               
Moving to related cardio metabolic disease, we know that patients
with type 2 diabetes and prevalent atherosclerotic cardiovascular
disease, there is a tenfold variation in future cardiovascular
risk in these patients. The current paper actually analyzes data
from EMPA-REG OUTCOME where the authors, led by David Fitchett
from St. Michael's Hospital in Toronto, sought to investigate
whether the beneficial effects of Empagliflozin, observed in the
EMPA-REG OUTCOME trial, varied across the spectrum of baseline,
cardiovascular risk.


                                               
What they found was that in patients with type 2 diabetes and
atherosclerotic cardiovascular disease, the relative reductions
in risk of cardiovascular death, all-cause mortality, 3-point
MACE, and heart failure hospitalizations with Empagliflozin
versus placebo, were consistent in patients with and without a
prior, myocardial infarction, with and without a prior stroke,
and across sub-groups by the 10-point TIMI Risk Score for
secondary prevention at baseline.


Dr Greg
Hundley:            
Does this suggest, Carolyn, that we use these inhibitors in all
patients with type 2 diabetes?


Dr Carolyn
Lam:               
Remember the EMPA-REG OUTCOME; all patients had established
atherosclerotic cardiovascular disease. This paper really adds to
the understanding of the gradient of risk within these patients
who had atherosclerotic cardiovascular disease and says
Empagliflozin could be beneficial. But remember, there are
patients with type 2 diabetes without established, cardiovascular
disease and I think there's still equipoise in this primary
prevention population.


Dr Greg
Hundley:            
That was great, Carolyn. Now I'm going to grab another sip of
coffee and go onto my next paper.


Dr Carolyn
Lam:               
Sure, as long as it's not cola. No phosphates.


Dr Greg
Hundley:            
Right, thank you very much, Carolyn. I'm going to talk about
screening for small and medium abdominal aortic aneurysms. This
particular study comes from the surveillance of the National
Health Service screening program by Dr Earnshaw. Basically,
population screening for abdominal, aortic aneurysms has been
shown to reduce AAA-related mortality by up to 50%. Most men who
screen positive have a AAA below 5.5 centimeters in diameter, and
that's really our current referral threshold for treatment. When
they have smaller diameter aneurysms they're entered into an
ultrasound surveillance program.


                                               
In this study, the investigators looked and reviewed those that
had small, 3-4.4 centimeter diameter aneurysms or medium ,4.5 up
to 5.4 centimeter aneurysms, and they were followed. They were
looking at the risk of rupture in these under surveillance.


                                               
They had a total of 18,652 men and the risk of rupture overall
per annum was 0.03% for men with small, abdominal aortic
aneurysms and 0.28% for medium size. That was just below the
threshold for the 5-5.4 centimeters, which was 0.4% over time.
The risk of abdominal aortic aneurysm surveillance is below .5%
per year and that is just below our current referral threshold
for surgery, which is 5.5 centimeters.


                                               
This is a study that really confirms, Carolyn, that the target
mark or diameter that we've selected is appropriate.


Dr Carolyn
Lam:               
Nice. These just confirm the current guidelines?


Dr Greg
Hundley:            
Yeah, they do and Gil Upchurch from University of Florida, a
surgeon, had a very nice editorial. The point he wants to make is
yep, diameter of 5.5 is the threshold, but a couple key points.
As patients are coming in for these visits, we need to continue
to emphasize to them other factors related to growth of abdominal
aortic aneurysms and their rupture. So, tobacco cessation,
treatment of your lipids, management of your hypertension.


                                               
The other point that he makes, is we really don't need to be
operating on those individuals with an abdominal aortic aneurysm
diameter of less than 5.5 centimeters. He makes an argument here
that's in some countries with fee-for-service reimbursement, up
to 30% of AAA repairs are for aneurysms less than this diameter
of 5.5 centimeters. This over utilization of resources can add
considerable costs to the healthcare system for managing this
condition and is unlikely to increase the overall survival of
these patients.


                                               
A nice study confirming that what we're doing, really in terms of
size and diameter, is correct, but also emphasizing this patient
population often has a lot of other cardiovascular co-morbidities
that we need to aggressively manage. How about your next paper?


Dr Carolyn
Lam:               
From one very clinically, applicable paper to another. This one
answers the question, what's the optimal duration of emergency
department and post-emergency department rhythm monitoring among
patients with syncope. And the authors, led by Dr
Thiruganasambandamoorthy and his colleagues from the Ottawa
Hospital Research Institute, prospectively studied adults
presenting within 24 hours of syncope at six emergency
departments. They collected baseline characteristics, the time of
syncope, the time of emergency department arrival, and the
Canadian Syncope Risk Score, risk category. They followed
subjects for 30 days and adjudicated the primary outcome, which
was serious arrhythmic conditions and that includes arrhythmias
or interventions for arrhythmias and unexplained death.


                                               
Their results showed that the overall arrhythmia risk, and the
risk after two hours of emergency department arrival from
Canadian Syncope Risk Score, low-risk patients, was indeed very
low. Similarly, the overall risk and after six hours of emergency
department arrival for medium and high-risk patients was moderate
and high, respectively. No low-risk patients suffered ventricular
arrhythmia or unexplained death and most of the arrhythmias among
the non-low-risk patients occurred within 15 days of the index
syncope.


Dr Greg
Hundley:            
Carolyn, what's the take home message here?


Dr Carolyn
Lam:               
The results really support brief monitoring in the emergency
department for two hours for Canadian Syncope Risk Score low-risk
patients, and six hours for medium and high risk patients
followed by selective admissions and the results also support a
15-day outpatient monitoring for medium-risk patients at a
selected threshold and for all high-risk patients. So very
practical advice.


Dr Greg
Hundley:            
Very good. Until next week, I'm going to watch out for
phosphates.


Dr Carolyn
Lam:               
Indeed, and let's go on now to our featured discussion.


                                               
For today's featured paper, we are discussing the results of the
PRIME Study and that is Angiotensin Receptor Neprilysin
Inhibitor, or ARNIs, for functional mitral regurgitation. A
terribly interesting study. So pleased to have with us an author
Dr Sung-Hee Shin from Inha University Medical center in Incheon,
Korea as well as our associate editor Dr Victoria Delgado from
University of Leiden in the Netherlands.


                                               
Sung-Hee, what an interesting study. ARNI or Entresto for
functional mitral regurgitation. Could you tell us what inspired
this study and what did you find?


Dr Sung-Hee
Shin:           
Our study was the designed to tell if ARNI or functional mitral
regurgitation because secondary functional mitral regurgitation
was developed as a result of a reduced function.
Guideline-directed medical therapy for heart failure would be a
mainstay for a therapy.


                                               
But despite use of the traditional drugs such as BETA blocker,
ACE inhibitor or angiotensin receptor blockers, you know that the
functional mitral regurgitation may be common and significant in
the person having this functional mitral regurgitation would be
related to increased morbidity and mortality.


                                               
So, that trial showed that trans-catheter mitral valve repair
effectively reduced the function mitral patient and resulted in
lower rate of heart related mortality among patients with heart
failure and function mitral regurgitation.


                                               
In our blind trial, we also tried to tell whether an ARNI is more
effective in improving function mitral regurgitation and randomly
assigned 118 patients with heart failure and chronic secondary
function mitral regurgitation lasting more than six months
despite medical therapy and ejection fraction between 25% and 50%
to receive either sacubitril/valsartan or valsartan in addition
to standard medical therapy for heart failure.


                                               
What happened with that change of mitral regurgitation after 12
months which was assessed by means of transthoracic area ways
echo. What we observed was that transthoracic area as well as the
volume of mitral regurgitation saw a decrease much more effective
in the sacubitril/valsartan group than valsartan group.


                                               
We also looked at the various other measures of the left
ventricle remodeling and showed that the valsartan group had
smaller left ventricle volume at 12 months and had a greater
reduction of end-diastolic volume index.


                                               
Also, among the completers ARNI, for the reduced left ventricle
volume and the yearly time than the control group. So, what we
think is that these factors might contribute to greater reduction
of function mitral regurgitation in patients in the
sacubitril/valsartan group.


                                               
But our study was a mechanism study, but it was not designed to
see outcomes. So further research and data would be necessary to
check is this transthoracic echo end point can translate into
better outcome in this population.


Dr Carolyn
Lam:               
Sung-Hee, this is just so interesting to have hypothesized this
about functional mitral regurgitation. And not only that, I mean,
to my mind, this is the largest echo-based studies of patients
before and after Entresto that I can think of. It's nice to know,
on top of knowing in paradigm that we can improve outcomes in
heart failure reduced ejection fraction, that we now can look at
the heart and see what happens in so many dimensions.


                                               
So, congratulations.


                                               
Victoria, were you surprised by these results? And do you agree
with the mechanisms that Sung-Hee suggested?


Dr Victoria Delgado:        I
think that this study is very important because in the field of
functional mitral regurgitation, there is still a lack of
consensus on how to treat these patients, which are very
challenging.


                                               
If the patient needs revascularization they will be referred for
certain. But it still should be CBR mitral regurgitation and
moderate and mile mitral regurgitation are not considered.


                                               
I think that we discuss often which is the optimal medical
therapy or the guidelines based medical therapy but it's not
really consensus because the studies before have not been like
this one. That large in order to answer a specifically that
question.


                                               
I think that this article brings an important message and brings
more evidence to our field that there is not that much data. So,
I think it's very important for that research, in particularly
after the research of the co-op and the mitral trial where it
seems that the selection of patients is very important in order
to identify the patients that will really benefit from those
therapies.


Dr Carolyn
Lam:               
That's such a good point. Going to that selection of patients,
Sung-He, you mentioned very carefully the ejection fractions that
you allowed up to 50% in these patients. Could you explain how
you reasoned the selection of this patient cohort?


Dr Sung-Hee
Shin:           
The reason why we chose the patients we did, the range of
ejection fraction condition, was that we thought the
reversibility of the left ventricle mortality and function mitral
regurgitation might be more pronounced in these patients.


                                               
When we considered the fraction condition in mitral regurgitation
with ejection fraction used under [inaudible 00:18:17] LV
dysfunction, our inclusive criteria of ejection fraction between
25 to 50% might correspond to ejection fraction of 20 to 40% in
patients with mitral regurgitation.


                                               
We concluded that if a patient had ejection fraction less than
25% because the reversibility of mortality and function mitral
regurgitation might be smaller when all the LV dilation is too
extreme and advanced heart failure is already established.


                                               
So, I just thing how it can be provided to the patient who have
functional mitral regurgitation associated with too extreme LV
dilation and LV ejection fraction too.


Dr Victoria Delgado:        I
think, Carolyn, it's a very good point what she explained because
we are used to select patients based on ejection fraction, in
particularly patients with functional mitral regurgitation,
ejection fraction is rather misleading because actually it's just
a change of volume in the ventricles emptying in a low pressure
chamber which is the left atrium.


                                               
The moment that you correct that in mitral regurgitation
sometimes then you face, or you see, the true ejection fraction
of that ventricle. And if we wait too long, we may end up with
ventricles that they don't have any more resource in order to
improve ejection fraction after repair of the mitral valve.


                                               
So, I think that this study is important to also realize that
concept. That ejection fraction in patients with functional
mitral regurgitation may not be the most accurate parameter to
assess the function of that ventricle.


Dr Carolyn
Lam:               
Yeah. Exactly. And I thought that was a very clever part of the
design. I'm glad you explained it and also so glad, Victoria, you
invited the editorial by Dr Mullens, who also commented on that.
So, just for the audience to understand that ejection fraction up
to 50% was included and ejection fraction less than 25% was
excluded.


                                               
So also, again, very consistent to your prior point, Victoria.


                                               
Could I ask you, I think Dr Mullens also spent quite some time
talking about the potential mechanisms. What's your take of this
Victoria? ARNI for functional regurgitation. How come?


Dr Victoria Delgado:       
For me, I'm much more from the side of the imaging point of view.
When we have patients with functional mitral regurgitation I
always try to see which is the capability that that ventricle has
to recover.


                                               
Actually, first is always medical therapy, but we know that the
[inaudible 00:20:59] only, for example, we just reduced the
mitral regurgitation, but they don't really improve the function
of that ventricle, while if you reduce the loading conditions of
the ventricle in terms of blood pressure as well and favoring
remodeling of the left ventricle, you can improve the condition
of the mitral valve and reduce the mitral regurgitation.


                                               
How valsartan plus sacubitril works differently than valsartan
alone that I don't think that I have enough knowledge to explain
why but it could be that in a way there is more effective with
sacubitril on top of valsartan can improve the loading conditions
of the ventricle and improve the, or facilitate, the reversing of
morbidity of that ventricle, reducing the mitral regurgitation
and that, by itself, could also lead to reversing morbidity.


                                               
Like a little bit cardiac resynchronization we'd do, for example,
in patients with an ejection fraction below 35% and based on the
EEG you have the synchronous fraction of the papillary muscle or
the walls of the ventricle which could lead to the mitral
regurgitation at the moment that you resynchronize that mitral
regurgitation can produce, you reduce part of the volume of the
load of the ventricle and that can favor that reversing
morbidity.


                                               
So, I think that this study raises a lot of questions and I think
that further research is needed in order to confirm or to know
more how these treatments work.


Dr Carolyn
Lam:               
Goodness, that was so beautifully explained and in fact, many
clues from Sung-Hee's study and the reversal of left ventricle
end diastolic volume index greater with those treated with ARNI,
the LA size and so on.


                                               
But maybe I should ask you, Sung-Hee, in line with what Victoria
said, what are the next steps? Do you already know what are the
next studies that you're going to be looking at in PRIME?


Dr Sung-Hee
Shin:           
We're considering mark of monitoring such as NT pro-BNP or using
auto imaging models such as echo and cardiac MRI to look at the
change of mitral valve regurgitation in more detail.


                                               
This kind of study might be very helpful in understanding
[inaudible 00:23:15] ARNI in functional mitral patient.


Dr Carolyn
Lam:               
Yes, that's clever, too. And Victoria, before we end could you
maybe give us some take home messages?


Dr Victoria Delgado:        I
think that the take home message from this study is that when we
have patients with functional mitral regurgitation, we need to
think what we can offer to them. Not consider mitral
regurgitation just as a base standard. That it's going to respond
only to diuretics. No. We need to do something on that left
ventricle to help it to improve the function and to avoid the
progress to more reduced function.


                                               
It's very important to understand the mechanism of the mitral
regurgitation and to use the guidelines based medical therapy
trying to go step by step in order to optimize the medication of
that patient and later on, see all the potential treatments that
are available right now such as cardiac synchronization therapy,
which we should not forget, and then surgery if the patient needs
catheterization and if the patient needs the benefit from mitral
valve plasty or eventually, for example, trans catheter mitral
valve therapies.


                                               
But we should avoid that the patient goes further down into heart
failure with very dilated ventricles and very poor function
because then probably we may face a point of no return.


Dr Carolyn
Lam:               
Thank you so much, Victoria. Both you and Sung-Hee mentioned this
is a mechanistic study. So many insights. But it's not saying
that everybody with functional mitral regurgitation has to be
treated this way now. It's calling for more work and it's
certainly very, very important study.


                                               
Thank you listeners, for listening today as well. 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.