Circulation December 5, 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. This week's journal
features important information, that will aide identification of
children with latent rheumatic heart disease, who are at highest
risk of unfavorable outcomes. This important discussion is coming
right up after these summaries.


                                               
The first original paper this week describes the largest study to
date to examine payer approvals and rejections of PCSK9 inhibitor
therapy, and describe the patient characteristics associated with
successful prescribing. First author, Dr. Hess, corresponding
author Dr. Yeh and colleagues from Beth Israel Deaconess Medical
Center in Boston, Massachusetts, performed a retrospective
descriptive cohort study utilizing nationwide pharmacy claims
linked to electronic medical records from a nationwide data
warehouse. The data set included over 220 million patients from
all 50 states, and all pair types with more than 5,000 distinct
health plans. PCSK9 inhibitor prescriptions were submitted for
51,422 patients in the pharmacy data set.


                                               
The authors found that among patients who were prescribed a PCSK9
inhibitor, 47% were approved for coverage by the payer. Variables
that were associated with approval included age above 65 years,
history of atherosclerotic cardiovascular disease, prescription
by a cardiologist or a non-primary care provider, statin
intolerance, longer statin duration, and non-commercial payers.
Interestingly, higher LDL cholesterol levels were not associated
with higher approval rates. Commercial third-party payers had the
lowest approval rates of 24 from 4% and Medicare had the highest
at 60.9%. Thus, rates of approval for PCSK9 inhibitor therapy are
low, even for patients who appear to meet labeled indications.
While a combination of clinical characteristics increase the
likelihood of approval, payer type is the most significant
factor.


                                               
The next study identifies a novel mitochondrial localized protein
that plays a role in cardiac dysfunction, remodeling, and heart
failure. This protein is FUN14 domain-containing 1, or FUNDC1, a
highly conserved outer mitochondrial membrane protein. In today's
study, first author, Dr. Wu, co-corresponding authors, Dr. Xie
and Zou from Georgia State University, and their colleagues,
showed that in cardio myocytes, FUNDC1 bound to inositol 1, 4,
5-triphosphate type 2 receptor, to form mitochondria-associated
endoplastic reticular membranes.


                                               
These, in turn, modulate a calcium release from endoplasmic
reticulum into mitochondria and the cytosol. FUNDC1 deletion
lowered the levels of calcium in both mitochondria and the
cytosol. A reduction at intracellular calcium resulted in
mitochondrial fusion, mitochondrial dysfunction, cardiac
dysfunction, and heart failure. In summary, this study identifies
FUNDC1 as a novel mitochondrial localized protein that plays a
role in maintaining mitochondrial dynamics, and cardiac function,
and may therefore be a therapeutic target in heart failure.


                                               
The next study takes a deep dive into the J-Curve phenomenon of
systolic blood pressure by providing an experimental approach to
an observational paradigm. First and corresponding author, Dr.
Kalkman, from University of Amsterdam and colleagues assess the
association between on-treatment systolic blood pressure levels,
cardiovascular events, and all cause mortality in patients
randomized to different systolic blood pressure targets in the
pool database of the SPRINT-6 and ACCORD trials. For both the
intensive blood pressure target of less than 120 millimeters
mercury, and the conventional target of less than 140 millimeters
of mercury, the authors found an identical shape of the J-curve
was present with a [inaudible 00:04:44] for cardiovascular events
and all cause mortality just below the systolic blood pressure
target.


                                               
The advantage of the intensive treatment group persisted at any
level of the difference between the intended target and the
achieved blood pressure targets. As discussed in an accompanying
editorial by Dr. Verdecchia from Hospital of Assisi in Italy,
these data suggest that if two patients achieve identical low
values of blood pressure during treatment, prognosis is expected
to be better in the patient actually targeted to achieve low
values. Conversely, the outcome might be worse in the patient
randomized to a higher blood pressure target, because low values
in this case possibly reflect masked or unmasked confounders
linked to a poorer outcome.


                                               
Thus, physicians should not be reluctant in lowering blood
pressure in their patients because of an expected detrimental
effect of BP reduction on death or major cardiovascular events.
Rather, they should carefully monitor the possible occurrence of
other adverse effects linked to blood pressure lowering, such as
syncope, renal impairment, or electrolyte disturbances. This
study further suggests that the benefit or risk associated with
intensive blood pressure lowering treatment can only be
established via randomized clinical trials and should not be
extrapolated from observational data.


                                               
The final study establishes a causal link between dysregulated
Tryptophan metabolism and abdominal aortic aneurysm. In a series
of elegant mouse experiments from first author, Dr. Wang, two
corresponding authors, Dr. Liu] and Ding from Georgia State
University in Atlanta, Georgia, the authors establish that
3-Hydroxyanthranilic acid or 3-HAA, a key Tryptophan catabolite
of the Angiotensin II induced abdominal aortic aneurysm in
vascular smooth muscle cells was indeed responsible for
Angiotensin II induced abdominal aortic aneurysm in Vivo. 3-HAA
activated nuclear factor kappa-B transcription factor, promoted
matrix metallopeptidase 2 expression in vascular smooth muscle
cells. Human abdominal aortic aneurysm samples had stronger
staining with the antibody against 3-HAA, than those in the
adjacent non-aneurysmal aortic sections of these samples.


                                               
The identification of 3-HAA in Angiotensin II triggered abdominal
aortic aneurysm and in human patients with abdominal aortic
aneurysms, suggests that Tryptophan derived metabolites may be a
biomarker for abdominal aortic aneurysm diagnosis. Furthermore,
agents that alter Tryptophan metabolism may have a therapeutic
potential in preventing or treating abdominal aortic aneurysms.
Well on that intriguing note, we're at the end of this week's
summaries. Now, for our featured discussion.


                                               
Today's feature paper really reminds us that rheumatic heart
disease remains the most common cardiovascular disease among the
world's youth. These days, echocardiographic screening provides a
promising tool for early detection. However, the utility of this
tool really depends on knowing the natural history of screen
detected rheumatic heart disease, so-called latent rheumatic
heart disease. Now, that has remained clear until today's paper.
I'm so pleased to have with us the first and corresponding
author, Dr. Andrea Beaton, from Children's National Medical
Center in Washington D.C., as well as Dr. Bongani Mayosi,
Associate Editor from University of Cape Town, South Africa.
Andrea, could you start by letting us know about your study and
what you found?


Dr. Andrea
Beaton:         As you
mentioned, over the last decade or so it's become clear that in
addition to the substantial burden of clinical rheumatic heart
disease that we see around the world in low and middle income
countries, there's also an even larger burden of latent rheumatic
heart disease or early rheumatic heart disease that we can see on
echo. This brings up the question if echo screening might
represent a very powerful tool for rheumatic heart disease
control, but we can't move forward with that discussion until we
understand the rate of progression of children who are found to
have echo detected rheumatic heart disease, and if we can do
something to intervene to prevent progression in that population.


                                               
That something is likely penicillin, which is known to prevent
progression in clinical rheumatic heart disease. To start to
address that question, we followed a large cohort of children who
had been diagnosed with echo detected rheumatic heart disease
through school-based screening in different areas of Uganda and
had collected about 227 cases of children with latent rheumatic
heart disease who had been in clinical followup between two and a
half and almost six years.


Dr. Carolyn
Lam:              
Great. Could you tell us what you found about the progression and
risk factors perhaps of progression, which I think are most
significant?


Dr. Andrea
Beaton:         Right, so
this is the largest natural history cohort of children with
latent rheumatic heart disease to date and four major findings
emerged from our study. The first is that we find a lot of echo
detected rheumatic heart disease in low income settings that is
more advanced. What we found is that children, even if this is
their first time of diagnosis at echo screening, if they had
moderate to severe rheumatic heart disease on screening, if they
had poor outcomes even if over a very short time period. In our
study, children with moderate to severe disease, only 10% of
those children improved over the study period and 10% had died
after only two to five years of followup.


                                               
We also saw that kids with mild, but definite rheumatic heart
disease, which is more criteria for rheumatic heart disease than
borderline, showed worse outcomes. Although, both children with
mild definite and borderline disease had substantial risk of
progression. 25% progressed in the mild definite group and 10% in
the borderline rheumatic heart disease group. That tells us that
even with very minor changes on echo screening, there is
substantial risk of progression to more severe rheumatic heart
disease, because we had a larger cohort using a multi-variant
model.


                                               
We also found that there were features of rheumatic heart disease
that put children at higher risk of progression. In our cohort,
if children had aortic insufficiency at the time of screening, or
some specific morphological changes, or changes in the mitral
valve at time of screening, then they had higher risk of
progression. While older age at time of screening showed a
protective effect against progression.


Dr. Carolyn
Lam:              
Wow. Andrea, congratulations on this remarkable study and you've
highlighted so many important public health messages just in this
one study. Bongani, what do you think was the most important or
significant finding?


Dr. Bongani Mayosi:        The
most important finding is the reflection of the progression even
in the mild and borderline cases. I think there has been an
understanding that the definite cases do have a higher rate of
progression and on top of that, I think showing the fact that
there are some predictors that can be detected on echo is also
very useful. Those with more advanced disease categories, those
with younger age, as well as those with morphological valve
abnormalities, I think those are very, very valuable points. Of
course, the other point that is not all here is the fact that the
majority of the initial progression appears to occur early and
this is brought out in this study because of the serial echos
that were done, which is again, another very valuable and a
unique aspect of the study.


                                               
Previous studies have only done an echo at the time of diagnosis
and perhaps an echo at the end of the followup period. I think
that these features really make this study a valuable one. There
is one question though that I wanted to put to Andrea, the issue
of auscultation is one that we realized very early was not very
useful for screening patients with latent rheumatic heart
disease. We missed too many. I'd like to ask you now, once we've
identified patients with latent disease, do you think
auscultation of those patients could in fact identify the ones
with clinical disease? Presumably, the more severe aortic
regurgitation, mitral regurgitation, may be audible using a
stethoscope? In other words, now shifting the role of the
stethoscope not so much for diagnosis, but for risk
stratification. I just want to know if you looked at this issue
at all in this particular cohort?


Dr. Andrea
Beaton:         That's a
really good question, Professor. We did not specifically look at
the role of auscultation in this cohort. Although, it stands to
reason that children with moderate to severe rheumatic heart
disease, which by our definitions meant at least moderate to
severe regurgitation at one of the valves, or presence of mitral
stenosis would be audible. In that way, I think separating out
children with moderate to severe disease, versus children with
mild definite and borderline disease, would be quite possible and
reasonable by auscultation.


                                               
My worry with the use of auscultation is I don't think it would
separate out well children with mild definite disease, who by
definition could have no more than mild regurgitation at any one
valve, from children with borderline disease. Whether that
distinction is important, I think still remains to be understood,
but it would not be a very sensitive way to follow children until
they had progressed to the point of having much more significant
disease. I think echo still remains incredibly sensitive compared
to auscultation for minor progressions, which to be clear, were
included here as counting as progression of disease, even minor
changes on echocardiographic evaluation.


Dr. Carolyn
Lam:              
I have a question along the same lines Andrea, what kind of
expertise was required for these echocardiographic screening
procedures, both of the acquisition and then the interpretation?
I do notice that you had a trained pediatric cardiologist with
expertise in rheumatic heart disease who actually re-reported
some of the echos. Do you think this is needed? What do you think
about that?


Dr. Andrea
Beaton:         This is a
complicated question, but a good one. A lot of the research that
we've done outside of this paper has been looking at the ability
to task shift echo screening, so to have non-physicians, not
experts conducting echo screening. What we found across the
board, as well as other groups around the world have found, is
that you can train non-experts in a relatively short period of
time to both screen and diagnose, at least on a screening basis,
the presence of absence of rheumatic heart disease. For the
purposes of this study, we're using very precise and very
detailed diagnosis. According to the World Heart Federation
criteria, which do really require experts to interpret.


Dr. Bongani Mayosi:        The
other issue, Andrea, which you highlight in the paper is the
whole issue of the definition of progression, and regression, and
the fact that there isn't consensus in the field about how we
handle that, which results in papers not being comparable among
each other. What do you suggest is the way of taking this forward
so that we can build a consensus and a way of actually following
up this patients that will be comparable between studies?


Dr. Andrea
Beaton:         That's a
really important question and something we struggled with while
we were writing this paper. You'll note in our paper that we
reported it in two different ways because we couldn't come to a
consensus and we thought both had some legitimate importance.
Most of the papers in this field have reported the groups as
progression and as stable lumped together, versus regression or
improvement of disease. We felt the most important endpoint and
something we had the numbers to power, was progression by itself.
How many children were getting worse over the study period? In
one sense, we powered it progression, versus stable plus
regression, trying to dichotomize it still.


                                               
Then on the other hand, we thought that it was important if you
had mild definite disease, even if you remained stable and mildly
definite, and so we reported differently on the second outcomes
based on if you had definite disease where we grouped progression
and stable together, versus if you had borderline where we only
counted true progression as a change for the worse. I don't have
the perfect answer of how this should be reported. Although, I
think the more granular we can be as we report these studies
going forward, the more we can separate out the data that is
reported to make it comparable. A lot of the previous papers, I
think, lack the granularity needed to compare in different ways.


Dr. Carolyn
Lam:              
We're coming to the end of our time, so may I just wrap up by
asking Andrea, what do you think are the next steps?


Dr. Andrea
Beaton:         That's a
good question and something I feel strongly about. Another part
of our paper showed that the other incredibly important
outstanding question is if we can find these kids, can we change
what happens to them over time, and does penicillin do that? Even
with our large cohort of patients, we couldn't determine the
effect of penicillin on progression or trajectory of these
children over this time period. It's something that now that we
have large numbers of children and still can't come to a
conclusive response, I think warrants a randomized control trial
to look at the effect of penicillin on children with echo
detected rheumatic heart disease, because that's really what's
going to drive the policy on if echo screening makes sense as a
public health policy to reduce the global rheumatic heart disease
burden.


Dr. Carolyn
Lam:              
I'm sure listeners out there, you've appreciated this as much as
I have. Tune in again next week.