Circulation March 19, 2019 Issue

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


Dr Greg
Hundley:            
And I'm Greg Hundley, also Associate Editor from the Pauley Heart
Center in Richmond, Virginia, VCU Health Sciences.


Dr Carolyn
Lam:               
How well are we doing with guideline-directed stroke prevention
therapy in atrial fibrillation? Well, there are going to be very
important results that you need to hear about from Get With the
Guidelines Atrial Fibrillation. That's our feature paper coming
right up in a future discussion. But first, you've got Greg and I
discussing really important papers that we've spotted in The
Journal. Greg.


Dr Greg
Hundley:            
Absolutely, Carolyn. And my favorite kind of follows from that
'cause it's really about left atrial electromechanical remodeling
following two years of high intensity exercise training in
sedentary middle-aged adults, kind of like me. The studies from
Ben Levine at University of Texas Southwestern Medical Center in
Dallas. So, what he's driving at here are moderate-intensity
exercises associated with a decrease in incidents of atrial
fibrillation. However, extensive training in competitive athletes
is associated with an increased atrial fibrillation risk.


                                               
So, in this study, they're looking at the effects of 24 months of
high-intensity exercise training on left atrial mechanical as
well as electrical remodeling in sedentary, healthy, middle-aged
adults. So, he had 61 individuals, their average age was 53.5
years, quite young, who were randomized to 10 months of exercise
training followed by 14 months of maintenance exercise and some
stretching or stretching and balance control. He also had another
group of 14 master's athletes that were added for a comparison
and he looked at three of the echocardiograms to assess left
atrial and left ventricular volumes and also had signal average
EKG's for filtered P-wave durations and atrial light potentials.
He made assessments at baseline, so before everyone started, and
10 and 24 months.


Dr Carolyn
Lam:               
Hold on, hold on. Let's really understand here how much exercise
were these sedentary middle-aged adults subjected to.


Dr Greg
Hundley:            
So, let's talk about that because that was very interesting
because a lot of us are out there exercising. So briefly the way
he started this, there was an initial phase that was comprised of
six months of regressive training during which an increase in the
frequency, the duration, and the intensity of exercise, including
two high-intensity aerobic interval sessions per week that were
prescribed to peak training load. The peak training load included
five to six hours of exercise per week that included two interval
sessions, at least one being an hour-long session, and then two
30-minute sessions.


                                               
Once you got that peak training load, that was sustained for four
months and then he made these 10-month measurements as part of
his study design. Now following that phase, a 14-month sort of a
continuation, all of the 24 months, a 14-month period of
maintenance exercise was completed where the frequency of
high-intensity intervals was reduced to once per week plus
continuous training all the way to that 24-month time point. And
during the maintenance phase, participants performed a total of
about three hours a week of aerobic exercise.


Dr Carolyn
Lam:               
Well, don't keep us in suspense now. What did the study show?


Dr Greg
Hundley:            
So at the 24 month time point of high-intensity exercise, it led
to a disproportionate dilation of the left atrium compared to the
left ventricle. So, mechanical changes, but no electrical
remodeling was seen. And interesting, and remember he had that
comparison cohort with master's athletes. Those participants
randomized exercise training demonstrated lower absolute left
atrial and left ventricular volumes, but a similar left atrial to
left ventricular ratio after 24 months of exercise training.


                                               
So, what's going on here, if you're middle-aged or young, some of
us like to think, and you start one of these aggressive training
sessions, you do have some changes mechanically in the shaping of
your left atrium and left ventricle, but they're concordant, but
no electrical remodeling that was observed in this situation. So,
how do those elite athletes develop atrial fibrillation in the
electrical remodeling? Don't know. It may be they need a longer
duration of exercise. Maybe they start at a different time point
because these are relatively sedentary individuals, and maybe
their training regimen is very different.


                                               
So, more research is needed, but it was interesting that these
middle-aged folks that start with this little bit more aggressive
regimen really didn't develop the electrical remodeling. So,
Carolyn, you've got a couple of papers that are sort of tied
together.


Dr Carolyn
Lam:               
Indeed. A couple of papers centered on lipoprotein little A. Now,
we know that lipoprotein little A levels predict the risk of
myocardial infarction and this has been shown in populations of
European ancestry, however there's very little data available in
other ethnic groups. And so, this was addressed by Dr Paré from
McMaster University and the Interheart Investigators who looked
at more than 6000 cases of first myocardial infarction and more
than 6800 controls, all from the Interheart study, and were
stratified by ethnicity and included African, American, Chinese,
European, Latin American, South Asian, and Southeast Asian
ancestries.


                                               
Lipoprotein little A concentration was measured in each
participant, first using an SA that was insensitive to iso-form
size and then iso-form size itself was also assessed by Western
Blot in a subset of more than 4200 participants. So, what they
found was that lipoprotein little A concentration and iso-form
size varied markedly among the ethnic groups. Africans had the
highest concentrations with the smallest iso-form size whereas
Chinese had the lowest concentrations with the largest iso-form
size.


                                               
Furthermore, higher lipoprotein little A concentrations were
associated with an increased risk of myocardial infarction and
carried an especially high population burden in South Asians and
Latin Americans. And a high concentration above 15 milligrams per
deciliter was associated with significantly increased risk of
myocardial infarction in all populations except Arabs and
Africans. The iso-form size, on the other hand, was inversely
associated with lipoprotein little A concentrations and did not
significantly contribute to the risk.


Dr Greg
Hundley:            
So, Carolyn, how do we use this clinically? I mean, do we measure
this in folks?


Dr Carolyn
Lam:               
Yeah. So, there are two take-home messages. I think one is about
the monitoring or measuring and it supports a clinical use of the
actual lipoprotein A concentration rather than iso-form size as a
marker of myocardial infarction in this ethnically diverse
population. But this is, other than Africans and Arabs where,
remember that cut off did not seem to associate with a risk of
MI's in these two ethnicities. The second take-home is that the
effects of clinical interventions that reduce lipoprotein A
should be investigated especially in South Asians and Latin
Americans where the population attributable risk is really high.
And that actually brings me to the second study.


                                               
So, we've always been looking for intervention that can reduce
lipoprotein A and this current paper is really interesting 'cause
it talks about insights from the Fourier trial. So, we may
finally have a therapy that can reduce it. Dr O'Donoghue from the
TIMI study group and Brigham and Women's Hospital in Boston,
Massachusetts and colleagues looked at the relationship between
lipoprotein A levels, PCSK9 inhibition, and cardiovascular risk
in the Fourier trial, which you remember is a randomized trial of
Evolocumab versus placebo in patients with established
atherosclerotic cardiovascular disease.


                                               
So, they found that patients with a higher concentration of
lipoprotein little A were at increased risk of coronary events
independent of the LDL concentration. And individuals with a
higher baseline LP little A concentration tended to have a
greater relative and absolute coronary risk reduction with
Evolocumab and therefore a lower number needed to treat. It was
as low as four T for individuals with a lipoprotein A above the
median versus 105 number needed to treat for those at or below a
lipoprotein A level below the median.


Dr Greg
Hundley:            
So should we start checking this in all our patients now, these
lipoprotein little A levels?


Dr Carolyn
Lam:               
Yeah. So, this issue was discussed beautifully in a company
editorial by Dr Thanassoulis from McGill University Health
Center. And here he mentions that there remains tremendous
clinical inertia honestly for the measurement of lipoprotein A in
North America and in fact, worldwide. For this to be successful,
we really need to be proactively screening our patients with
myocardial infarction and stroke and especially those with
premature events or a family history. And particular attention
will need to be made on screening individuals with recurrent
events despite adequate lipid or LDL lowering who frequently may
still have high lipoprotein little A. It's encouraging to know
that the most recent version of the US Lipid Guidelines has newly
recommended LP little A measurements in select individuals as a
risk enhancer and so this should further raise awareness of
lipoprotein little A as a risk marker.


                                               
Finally, the editorialist mentioned that common misconception
that we have a lack of therapeutic options to lower high LP
little A. Still, we need to remember that these individuals may
obtain significant benefit from more aggressive lifestyle
modifications. And now we have these results of this trial that
suggest that PCSK9 may be one of the few drugs that can lower
lipoprotein little A. And so, the editorialist actually ended
with targeting therapy for lipoprotein A is around the corner and
a test of this hypothesis is really imminent, so we should watch
this space.


Dr Greg
Hundley:            
Yeah, so it sounds like another wonderment of PCSK9 inhibitors.


Dr Carolyn
Lam:               
Yeah.


Dr Greg
Hundley:            
Well Carolyn, let me jump in and finish our chat here talking
about iron. This particular paper is from Dr Jean-Sébastien
Silvestre from Paris, France, and he's looking at the iron
regulator Hepcidin. So, we know that iron deficiency is frequent
in patients with coronary artery disease and increases morbidity
in those with high risk profiles such as those with diabetes and
anemia and then conversely, excess iron is also detrimental to
cardiac function. We see this with iron overload cardiomyopathies
and as a major co-morbidity in patients with genetic
hemochromatosis.


                                               
So, among the multiple regulators of iron homeostasis is
Hepcidin. It plays an instrumental role in fine-tuning systemic
iron trafficking by modulating the transfer of dietary, recycled,
and stored iron from intracellular compartments to extracellular
fluids. Hepcidin is a catatonic peptide hormone. It's produced
primarily by hepatocytes, but also, it's produced in macrophages.
So, given the role of Hepcidin to locally regulate cardiac
function and that inflammation guides cardiac remodeling after
acute MI, the investigators hypothesized that inflammatory
macrophages may control cardiac repair through a
Hepcidin-dependent mechanism. And until now, the role of Hepcidin
in some other cardiac diseases challenged by inflammation hasn't
really been explored.


Dr Carolyn
Lam:               
Huh, interesting. So, what did they find?


Dr Greg
Hundley:            
Great question and let's lead to the main results of this study.
The hormone Hepcidin, they found, was produced by a distinct
sub-population of inflammatory cardiac macrophages residing in
infarcted heart tissue and the deletion of Hepcidin in
macrophages improved tissue remodeling and stimulated
cardiomyocyte renewal in both, just as our wonderful basic
science studies have, in both adult mice with myocardial
infarction, neonatal animals with apical resection and also in
human subjects. And so, this study provided novel insights into
the complex roles of the immune response during cardiac repair
following MI and suggests and deleterious role for the
macrophage-derived Hepcidin in cardiac repair.


                                               
Interesting, Carolyn. Another role for iron in acute MI and more
research to come.


Dr Carolyn
Lam:               
Indeed. Well, thanks Greg. Let's move on to our feature
discussion, shall we?


                                               
For our feature discussion today, we are talking about the first
results from the Get With the Guidelines atrial fibrillation.
That is huge, and I have none other than the first author, Dr
Jonathan Piccini from Duke Clinical Research Institute, as well
as Dr William Lewis from Case Western Reserve University here to
discuss these really important results, so listen up. I think to
start with it is such an honor to have you with us, Bill. I mean,
as Chair of the Get With the Guidelines atrial fibrillation work
group, could you give us a background on how did this start? How
far has it come?


Dr William
Lewis:            
The Get With the Guidelines program started in 2000. Greg Fonarow
figured out that if we put in place mechanisms to improve
adherence, that we could get people on appropriate therapies. In
2012, there was some focus on atrial fibrillation and I had been
participating in the program since 2004 and I kept telling them
that A-fib was a big, big problem. And in 2012, they said, "Let's
do this," so we built this program to try to improve adherence in
atrial fibrillation. Get With the Guidelines is a national,
hospital-based, quality improvement program that improves
adherence to guidelines over time and it has been very successful
at doing that.


                                               
So, by 2013 we were ready to start enrolling patients and we
started getting patients in the database and we're now up to
about 162 hospitals nationwide, in the United States, and we've
enrolled about 75000 patients in the program. So, it's been very
successful from that standpoint.


Dr Carolyn
Lam:               
Congratulation. And today we're actually going to be talking
about that very question you asked. Adherence. How well are we
adhering to guideline-directed stroke prevention therapy for
atrial fibrillation? Jonathan, wanna share the key results?


Dr Jonathan
Piccini:         I think
you're getting exactly to the point of what was the rationale for
this study and I think most individuals that are familiar with
the field and atrial fibrillation and also clinicians across the
world who are treating patients with atrial fibrillation know
that most large reports, most nationwide studies have shown that
adherence for oral anticoagulation to prevent stroke in patients
with atrial fibrillation usually ranges in the 50, 60, 70 percent
range at best. And there's been some notable publications in the
past several years from nationwide registries that have shown
rates as low as 50 percent or lower in high-risk patients. So,
one of the main goals of the program, as Bill articulated, was to
try and improve the use of oral anticoagulation in patients who
had a guideline recommendation. So, patients who had a
CHA2DS2-VASc score of two and higher with atrial fibrillation.


                                               
And so, looking at over 30000 admissions between 2013 and 2017
and the guidelines A-fib program, we saw that just under 60
percent of patients who had known AF at the time of admission
were on oral anticoagulation. And not surprisingly, the patients
who were on oral anticoagulation had lower rates of stroke during
their hospitalization. But the major finding from the program was
that in this quality improvement program, the program was able to
improve adherence to oral anticoagulation at discharge from 60
percent to admission all the way up to 93.5 percent in the
overall cohort. And if you looked at results over time, adherence
improved from 80 percent at discharge all the way to 96 percent
and those improvements were sustained in follow up as well.


Dr Carolyn
Lam:               
Could you tell us, what do you think are the key elements that
help this improvement? Is it just because there's a program and
people know they're being watched? Is it that there was a change?
I mean, when you say oral anticoagulants I bet you mean both
Warfarin and the newer oral anticoagulants, so how much did that
help? What do you think is the key ingredient here?


Dr Jonathan
Piccini:         It was
several things. Having visited several of these hospitals and
spoken with them about the impact of the program, I think you
can't emphasize enough that if you don't measure something, you
can't really expect to improve it. So, just the fact that
hospitals were having systematic data on their atrial
fibrillation patients at discharge illustrating who was and who
was not getting oral anticoagulation makes a big difference.
Between the program itself and the conferences affiliated with
the program and teaching sessions affiliated with the program,
there's a heavy emphasis on education of the importance of
guideline recommended treatments for atrial fibrillation, so
that's a second component.


                                               
And then there's an iterative relationship between the sites and
the American Heart Association where improvements in the rates of
oral anticoagulation are recognized and celebrated. And I think
it's not any one thing, in my opinion. I think it's all of those
things taken together. And again, Bill, who's been with the
program since its inception probably has additional thoughts on
that as well.


Dr Carolyn
Lam:               
Bill, did you expect such remarkable results?


Dr William
Lewis:            
No. I actually didn't expect 96, but in a previous study where we
were looking at patients who had had a stroke in the stroke
database, we were able to achieve 93 percent adherence. And so,
96 is remarkable and it's the highest number that's ever been
seen in any A-fib program. I was going to mention about the idea
of what makes the special sauce, if you will, and I think John
put forth a number of items. I think, again, celebrating success,
those kinds of things, but I think that docs, by their very
nature, are very competitive and when you get a data report that
says you're doing x percent and somebody else is doing y percent
and their percentage is higher, you tend to get motivated to
actually do better. And so, we provide these reports in the
program to hospitals so that they can measure their success
against other institutions.


Dr Carolyn
Lam:               
That's such a good idea. And, you know, I practice here in Asia
and there aren't these very massive programs that are accepted in
many places. So, what do you think is the generalizability of
something like this?


Dr Jonathan
Piccini:         That's
such a critical question because a limitation is that these are
hospitals that are saying voluntarily, "We want to commit to the
program because we think quality care for atrial fibrillation
patients is important." And so, you could argue that, well, these
results really don't generalize to your run of the mill hospital
in different parts of the world. And I think while that's a
limitation, it's also a call for what the next steps are. So,
having visited many of these hospitals, these are real hospitals
of brick and mortar that face many of the same challenges other
health systems and hospitals across the world do and I think the
key message is that a hospital that implements these types of
interventions is very likely to see the same improvement with
their patients. And so, I think that's a very important message
and a very positive message for patients all over the US and all
over the world.


Dr William
Lewis:            
I agree. I think it's, not turn-key, it's much more generalizable
than we had ever expected. So, community hospitals do this. The
American Heart Association is using other Get With the Guidelines
programs in China. I think that there is a lot that has to do
with the support that's provided by the program and the tools
that are made available to them to be able to make it so that you
can recreate it in a hospital. I agree, it is more difficult in
some hospitals than others.


Dr Carolyn
Lam:               
John, before we end, what are the take-home messages for
clinicians listening out there?


Dr Jonathan
Piccini:         I'd have
two messages. The first message is that this study shows that
with some assistance any healthcare system or hospital can
achieve optimal adherence to these medications for their patients
and thus in so doing achieve a significant benefit for the public
health. And the second message I would have, which isn't
necessarily specifically related to the paper, but I think it's
equally important, that this is just the beginning for the
American Heart Association and the Heart Rhythm Society Get With
the Guidelines A-fib registry. Though stroke prevention is
obviously just one of many different aspects of quality care for
atrial fibrillation and so keep an eye out 'cause you'll be
seeing a lot of studies coming out about how Get With the
Guidelines A-fib is better informing care and treatment for
atrial fibrillation across many different therapy domains,
including catheter ablation and rate control and other
interventions for rhythm control. And again, on behalf of all the
co-authors and the American Heart Association, the Heart Rhythm
Society sponsors, we really appreciate to have the opportunity to
talk about the program.


Dr Carolyn
Lam:               
Thank you so much for sharing that with us.


                                               
Audience, you heard it right here on Circulation on the Run.
Don't forget to tune in again next week.


                                               
This program is copyright American Heart Association 2019.