Circulation February 13, 2018 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.


                                               
Today's feature paper is going to cause us to rethink the way we
prognosticate patients with pulmonary arterial hypertension
following their initial management. Think you know the
hemodynamic variables? Well, stay tuned for this discussion
coming right up after these summaries:


                                               
Our first original paper this week shows for the first time the
predictive value of coronary artery calcification progression for
coronary and cardiovascular events in a population base study.
Authors Dr. Erbel and Lehmann from University Hospital Essen in
Germany and their colleagues evaluated several progression
algorithms between CTs performed at baseline and after a mean of
five years for the risk prediction of coronary and cardiovascular
events in a population base cohort of more than 3,200
participants initially free from cardiovascular disease.


                                               
The authors found that coronary artery calcification progression
added some predictive value to the baseline CT and risk
assessment, and even when the five-year risk factors were taken
into account. However, the progression yielded no additional
benefit when the five-year coronary artery calcification results
were taken into account instead of the baseline coronary artery
calcification results.


                                               
Double zero coronary artery calcification scans in a five-year
interval meant an excellent prognosis, which was better than the
prognosis for incident coronary artery calcification after five
years. Thus, the authors concluded that sophisticated coronary
artery calcification progression algorithms may be unnecessary
and clinicians can instead rely on the most recent risk and
coronary artery calcification assessment.


                                               
The next paper demonstrates for the first time cell-specific
effects of Smad3 signaling in the infarcted myocardium. Now, in
the infarcted heart, Smad3 signaling is known to be activated in
both cardiomyocytes and the interstitial cells. In the current
paper, co-first authors, Doctors Kong and Shinde, corresponding
author Dr. Frangogiannis from Albert Einstein College of Medicine
in New York, and their colleagues hypothesized that cell-specific
actions of Smad3 may regulate, repair, and remodeling in the
infarcted myocardium.


                                               
In order to dissect the cell-specific Smad3 actions in myocardial
infarction, these authors generated mice with Smad3 loss
specifically in activated fibroblasts or in cardiomyocytes. They
found that fibroblast-specific Smad3 activation played a critical
role in repair following myocardial infarction by restraining
fibroblast proliferation and contributing to scar organization by
stimulating integrin synthesis.


                                               
On the other hand, cardiomyocyte-specific Smad3 signaling did not
affect acute ischemic injury, but triggered nitrosative stress
and induced matrix metalloproteinase expression in the remodeling
myocardium, thereby promoting cardiomyocyte death and
contributing to systolic dysfunction.


                                               
In summary therefore, these authors demonstrated the cellular
specificity of Smad3-dependent actions that stimulate distinct
cellular responses in fibroblasts versus cardiomyocytes in the
healing myocardial infarction. The implications are that
nonspecific therapeutic targeting of Smad3 signaling in
pathologic conditions may interfere with both detrimental and
beneficial actions. On the other hand, design of interventions
with specific cellular targets may be needed for the development
of safe and effective therapies.


                                               
Good news from the next paper! Genetically predetermined high
blood pressure and its complications may be offset by healthy
lifestyle. Well, at least, to some extent. First author, Dr.
Pazoki, co-corresponding authors Dr. Elliott from Imperial
College London and Dr. Tzoulaki from University of Ioannina in
Greece aimed to investigate the extent to which lifestyle factors
could offset the effect of an adverse blood pressure genetic
profile as well as its effects on cardiovascular disease risk.


                                               
To do this, they constructed a genetic risk score for high blood
pressure using 314 published blood pressure loci in more than
277,000 individuals without previous cardiovascular disease from
the UK Biobank study. They scored participants according to their
lifestyle factors including body mass index, healthy diet,
sedentary lifestyle, alcohol consumption, smoking, and urinary
sodium excretion levels measured at recruitment. They examined
the association between tertiles of genetic risk and tertiles of
lifestyle score with blood pressure levels and incident
cardiovascular disease.


                                               
They found that adherence to a healthy lifestyle was associated
with lower blood pressure regardless of the underlying blood
pressure genetic risk. Furthermore, adherence to a healthy
lifestyle was also associated with lower risk of myocardial
infarction, stroke, and the composite cardiovascular disease at
all levels of underlying blood pressure genetic risk. Healthy
compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower
risk of cardiovascular disease respectively among participants at
low, middle, and high genetic risk groups. Thus, these results
strongly support population-wide efforts to lower blood pressure
and subsequent cardiovascular disease risk through lifestyle
modification.


                                               
The final paper is an aggregate report from two large randomized
trials, which demonstrate for the first time that more potent
antiplatelet therapy further lowers venous thromboembolism risk
relative to aspirin alone. First author Dr. Cavallari,
corresponding author Dr. Bonaca, and colleagues from the TIMI
Study Group in the Brigham and Women's Hospital ascertained and
characterized symptomatic venous thromboembolism events in more
than 47,600 patients randomized in the TRA 2°P-TIMI 50 and
PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous
thromboembolism over time, independent risk factors for venous
thromboembolism, and the efficacy of more intensive antiplatelet
strategies at reducing venous thromboembolism risk.


                                               
They found that the rate of venous thromboembolism in patients
with atherosclerosis was 0.3% per year while on treatment with at
least one antiplatelet agent. This risk increased independently
with the number of symptomatic vascular territories. Furthermore,
more intensive antiplatelet therapy with Vorapaxar and Ticagrelor
in this case reduced the risk of venous thromboembolism.


                                               
These data suggested a relationship between atherosclerosis
burden and venous thromboembolism risk. The data also support the
inclusion of venous thromboembolism as a prospective endpoint in
long-term secondary prevention trials evaluating the risks versus
benefits of antiplatelet therapies in patients with
atherosclerosis.


                                               
Well, that wraps it up for our summaries. Now for our feature
discussion.


                                               
For our feature discussion today, we are talking about pulmonary
arterial hypertension. We've learned so much from registries
about prognostication of pulmonary arterial hypertension at the
time of diagnosis. But these registries have only provided
limited insight into the impact of therapies on long-term
outcomes and how we're supposed to use variables after initiation
of therapy to determine prognosis.


                                               
Well, that gap is being filled by today's paper in circulation.
I'm so pleased to have the first and corresponding author with
us, Dr. Jason Weatherald from University of Calgary, as well as
Dr. Kelly Chin, associate editor from UT Southwestern, to discuss
this very important paper.


                                               
Jason, congratulations on this paper. Could you tell us a bit
more about what you did and why you did it, and what's exciting
about what you found?


Dr. Jason Weatherald:   This is a study that started
during my research fellowship last year when I was spending time
in Paris with the group of Professor Olivier Sitbon and Marc
Humbert. We started this study based on some other recent papers
showing the importance of pulmonary arterial compliance, and some
smaller studies that emphasized the importance of hemodynamic
variables after treatment initiation and the prognostic
importance of that. We wanted to look at the relative importance
of pulmonary arterial compliance as well as the stroke volume in
the cardiac index in newly diagnosed patients.


                                               
We looked at a 10-year cohort from the French registry of
patients who had right heart catheterizations at baseline and
then after treatment initiation. We looked at prognostic
variables, both at baseline and at the first follow-up after
initial treatment. The interesting result is that we found that
actually pulmonary arterial compliance is not the most important
prognostic variable, but it seemed that the stroke volume index,
which was calculated from the cardiac index and the heart rate,
was the most significant independent predictor of long-term
survival from the hemodynamic perspective.


Dr. Carolyn
Lam:              
Kelly, could you help point out why this is so important in
clinical practice? You see a lot of these patients. In what way
did this paper make you think differently about them?


Dr. Kelly
Chin:                   
I think there's a couple different areas that really struck me.
The first one was, as you mentioned in the introduction, the
importance of post treatment values versus baseline values. This
is not to say that the baseline values aren't important because
it does still associate with survival and it's very important
when choosing therapy, but as PAH therapies have become more
effective, we would hope to see that the baseline severity
matters less and that, indeed, seems to be what we're seeing
here. That also reinforces the importance of serial reassessment
to see how your patient is doing and make further decisions for
therapy.


                                               
The second key finding, I think, is what Jason was just talking
about with which hemodynamic measures do we really want to be
keeping a close eye on? Here's where, in the stepwise analysis,
they found that the right atrial pressure and then, the
surprising one, the stroke volume index were the key measures
that were associated.


                                               
Interestingly, cardiac index fell out of that model. That isn't
to say that cardiac index wasn't associated with outcome. It was
a predictor in the univariate analysis. But I think when you step
back and you think about the comparison between those two, if you
have a patient who's maintaining their cardiac index only by
becoming tachycardic, they're probably not doing nearly as well
as a patient who has a normal heart rate and a normal stroke
volume index.


                                               
I think this really struck me as something, "Hey, when I'm in the
cath lab, I probably need to be thinking about this and reporting
it out, so everybody's seeing it right there on the report",
which is not something we've been doing.


Dr. Carolyn
Lam:              
Thanks Kelly. That makes so much sense. What I really appreciated
about the paper as well is that they gave us practical thresholds
through their receiver operating characteristic analyses. Just
for everyone to know, the threshold value for stroke volume index
was 38 mils per minute per meter square, right? And the right
atrial pressure threshold was 9 mils of mercury. These are sort
of very important, 38 and 9, and practical to keep in mind.
Really appreciate that Jason.


                                               
The other thing that struck me is these are just very much saying
that right ventricular function is important. Is it not, Jason?


Dr. Jason Weatherald:   Yeah, I agree. I think that's
one of the interesting insights from the study is that we focused
mostly on the cardiac index, but it can be misleading in certain
patients like Kelly said who perhaps do respond to therapy by
increasing the cardiac index but predominantly through increased
heart rate. That can be somewhat misleading if you don't really
step back and look at it.


                               
What I found interesting, too, is that when we looked at
subgroups of patients who, in the clinic, you generally think are
low risk patients who had good six-minute walk distance, very few
symptoms NYHA functional class I or II, and had a cardiac index
above the current recommended target of 2.5, that there was
almost a third of patients with a low stroke volume index in that
category and that seemed to be the majority of patients who died
over long-term follow-up within five years.


                                                 
I think that's really telling about the importance of right
ventricular function and just looking at the cardiac index itself
can perhaps mislead you if you don't take all of those other
factors into consideration.


Dr. Carolyn
Lam:              
Yeah, that's just such a great point and important. That even
those classified that we would not have picked up as high risk
are the usual measures that we look at. If you look at stroke
volume index, they still distinguish those who do better than
those who do worse. This is something that was also highlighted,
I think, in the accompanying editorial, Kelly, that you invited
by Lewis Rubin from New York.


                                               
Kelly, what do you think are the real take home messages from
this?


Dr. Kelly
Chin:                   
I think he does make a big point that the functional status of
the right ventricle is a primary goal of therapy, and that we
should definitely be paying attention to it and that there's more
than one way to do this. There's the hemodynamic measurements,
there's also exercise capacity and functional class, which really
do associate with how well the right heart is functioning, both
at rest and exercise. I think he also comes back to the serial
measurements and the importance of reassessment.


Dr. Carolyn
Lam:              
Yeah, as you had also so elegantly summarized earlier. But, a
quick question to both of you. What do we do now about other
measures of right heart function? I mean, magnetic resonance
imaging seems to be used increasingly for this. Where does this
fall in? And what does this say about the routine clinical
parameters that we usually look at, like six-minute walk? Jason?


Dr. Jason Weatherald:   I have a couple points on that.
Number one, I fully agree and our results are really in keeping
with the previous smaller studies looking at cardiac magnetic
resonance and showing the importance of the stroke volume on
imaging. From personal experience, although MR is wonderful,
there's a good population of patients who don't really tolerate
MR, especially for serial measurements, and there's other
contraindications, so I think hemodynamics will continue to fill
an important role and are still useful in the patient where you
can't figure out exactly what's going on and why they're getting
worse.


                                               
At this point, I think it's complementary and certainly I think
there's some centers in many countries that don't have cardiac MR
widely accessible, especially for serial follow-ups, so I think
they're really complementary and that our results support imaging
studies.


                                               
I would say the next thing about the study is that, in the multi
variable models that exercise distance, the six-minute walk
distance and functional capacity remained independent predictors,
so I think, it just highlights the importance and the robustness
of these measures, even though NYHA functional class is
subjective, it remains a very powerful predictor at baseline and
during follow-up. To me, it speaks to the importance of looking
at multiple parameters and coming to a multidimensional
assessment of risk and PAH and not focusing on one particular
variable for making decisions in the clinic.


Dr. Kelly
Chin:                   
I definitely agree with the multidimensional look at a patient
function and heart and catheterization. What I was going to say
was I also liked, Jason, the use of "complementary" when talking
about catheterization and MRI. I see MRI filling a similar niche
to echo for many patients. I think if you get an echo and it
looks great, heart size is good, heart function is good, I don't
see a whole lot of reason to add an MRI, too. We're always
routinely doing catheterizations, at least early post treatment,
to reassess.


                                               
But I do see a role for MRI in some of our patients who are doing
not well at all, but we're not quite sure if they're doing poorly
enough that it's time for transplant, and I'm trying to decide if
the RV is growing or not. It's clearly big, but is it getting
bigger each six months that we're looking at it? Sometimes MRI
just seems to provide so much more precision than we can get with
echo and certainly you're not getting any of those types of
measures off of your catheterization.


Dr. Carolyn
Lam:              
Maybe one last question Jason. It's so interesting. What is the
future? What are the gaps that you're looking to fill at the
moment?


Dr. Jason Weatherald:   Ideally, I think it would be a
noninvasive way to look at the right ventricle that is cheap,
reproducible, and gives us the same confidence that invasive
hemodynamics do. Although I find echo is indispensable and MRI is
very useful, I think at the end of the day, we all go back to the
right heart catheterization and we need to find something that
can replace that, but give us the same confidence in what we
think we're measuring and that it reflects treatment changes and
clinical worsening.


Dr. Carolyn
Lam:              
And Kelly, what do you think should be next steps?


Dr. Kelly
Chin:                   
I have to say I really liked this study. I thought it moves us
forward in assessment of prognosis for this population of
patients in a really big way. It was large and included a large
number of measures that were done very carefully. You always want
to see replication.


                                               
But, what I'd also like to see is the other forms of pulmonary
arterial hypertension. You know this focused mainly on the
idiopathic PAH patients, so what happens in connective tissue
disease, and also what happens late after treatment, because I
think we sometimes see a little bit of a different phenotype in
patients that we've treated for many years and sometimes
hemodynamics have improved, but in different ways than what we
see early on with initial therapies.


Dr. Carolyn
Lam:              
You've been listening to Circulation on the Run. Tune in again
next week.