Circulation April 18, 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. Our feature paper this
week discusses the very important patient group with myocardial
infarction and non-obstructive coronary artery disease, a paper
that we will be digging deep into right after these summaries.


                                               
The first paper identifies a novel therapeutic target in
pulmonary arterial hypertension, and that is nicotinamide
phosphoribosyltransferase, a cytozyme which regulates
intracellular NAD levels and cellular redox state, regulates
histone deacetylases, promotes cell proliferation, and inhibits
apoptosis.


                                               
This is a paper from first author Dr. Chen and co-corresponding
authors Dr. Machado from University of Illinois Chicago and Dr.
Garcia from the University of Arizona. The authors found that
plasma and mRNA and protein levels of  nicotinamide
phosphoribosyltransferase  were all increased in the lungs
and the isolated pulmonary arterial endothelial cells from
patients with pulmonary arterial hypertension.


                                               
They were also increased in the lungs of rodent models of
pulmonary hypertension. Nicotinamide
phosphoribosyltransferase deficient mice were protected from
hypoxia mediated pulmonary hypertension; whereas, enhanced
activity promoted human arterial smooth muscle cell proliferation
via paracrine effect and inhibition of activity attenuated
pulmonary hypertension in rats.


                                               
This paper, therefore, provides evidence that nicotinamide
phosphoribosyltransferase plays a role in pulmonary vascular
remodeling and its inhibition could be a potential therapeutic
target for pulmonary arterial hypertension.


                                               
The next study suggests that high sensitivity cardiac troponin T
may be an early biochemical signature for clinical and
subclinical heart failure. In this study from first author Dr.
Seliger, corresponding author Dr. deFilippi, and colleagues from
Inova Heart and Vascular Institute, the authors measured high
sensitivity cardiac troponin T at baseline among almost five
thousand participants in the multi-ethnic study of
atherosclerosis MESA cohort, who were initially free of overt
cardiovascular disease.


                                               
Cardiac magnetic resonance imaging was performed at baseline and
repeated 10 years later among 2,831 participants who remain free
of interim cardiovascular disease events, among whom 1,723 also
received gadolinium enhanced cardiac magnetic resonance for
characterization of replacement fibrosis by late gadolinium
enhancement. Results showed that a mild elevation of high
sensitivity cardiac troponin T identified subjects at highest
risk for an increase in left ventricular mass and end diastolic
volume over the next 10 years.


                                               
Higher levels also associated with an increased incidence of
replacement fibrosis, but with no differentiation between
ischemic or non-ischemic fibrosis patterns. For the more high
levels remained an independent predictor for incident heart
failure, coronary heart disease events and cardiovascular events,
independent of underlying left ventricular hypertrophy or
ejection faction.


                                               
The implications are that myocyte injury, measured with a highly
sensitive cardiac specific troponin assay may ultimately be an
important early signal used to target therapy to prevent or delay
left ventricular remodeling and progression to heart failure.


                                               
Does maintenance of cardiovascular risk factors at target
eliminate the excess risk of mortality in cardiovascular diseases
associated with type 1 diabetes? Well, this question was
addressed in the next paper by Dr. Rawshani and colleagues of the
Swedish National Diabetes Register in Gothenburg Sweden. The
authors compared more than 33,300 patients with type 1 diabetes
to more than 166,500 match controls without diabetes from the
Swedish National Diabetes Register. They found that patients with
type 1 diabetes, with five selected cardiovascular risk factors
at target, demonstrated a non-significant access risk of death
compared to controls.


                                               
These five risk factors included glycated hemoglobin, blood
pressure, albuminuria, smoking, and LDL cholesterol. Nonetheless,
despite having all risk factors at target, persons with type 1
diabetes still had 82% to 97% elevated risk of myocardial
infarction and heart failure respectively. For every incremental
risk factor not at target, the excess risk of death in
cardiovascular outcomes increased in a graded fashion.


                                               
In conclusion, there was a steep graded association between
decreasing number of cardiovascular risk factors at target and
major adverse cardiovascular outcomes with patients with type 1
diabetes. While achievement of current evidence based target
levels of five cardiovascular risk factors markedly reduced or
even potentially eliminated the excess mortality risk, these
patients remained at higher risk of myocardial infarction and
heart failure compared with controls.


                                               
The final paper suggests that hemodynamic guided heart failure
management may be beneficial in general clinical practice and not
just in the context of controlled trials. In this study by Dr.
Heywood and colleagues from Scripps Clinic Torrey Pines in La
Jolla, California, the authors examined the first 2,000 patients
implanted with the novel Pulmonary Artery Pressure Sensor,
CardioMEMS, in the general cardiology practice setting.


                                               
They found that patients uploaded information an average of every
1.2 days, and that pressures were significantly reduced by remote
monitoring using the Pulmonary Artery Sensor where patients with
the highest mean pulmonary artery pressures had the highest
reduction in pressures. Furthermore, they found that these
general use patients experienced a greater reduction in pulmonary
artery pressure over time compared to those in the pivotal
CHAMPION clinical trial.


                                               
The results from this large observational study, therefore,
demonstrates hemodynamic heart failure management may be
effective in U.S. clinical practice with high rates of patient
adherence and effective pressure management.


                                               
This paper is accompanied by an excellent editorial by Drs.
Gorter, Rienstra, and van Veldhuisen from University Medical
Center, Groningen, Netherlands, which really places this paper in
the clinical context of heart failure and particularly patients
with heart failure and preserved ejection faction


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


                                               
We're discussing a hugely important emerging issue today. And
it's MINOCA, a myocardial infarction with non-obstructive
coronary arteries, and a very important paper in today's issue,
which really provides the first insight into potential long-term
medical therapy in the management of MINOCA.


                                               
However, now this issue of MINOCA is quite new and I'm sure new
to many of those listening on the line. So, I am with the first
and corresponding author of the paper, Dr. Bertil Lindahl from
Uppsala Clinical Research Center in Sweden. Welcome.


Dr Bertil
Lindahl:              
Thank You.


Dr Carolyn
Lam:               
And also the associate editor who managed this paper, Dr. Gabriel
Steg from Hospital Bichat in Paris, France. Welcome back.


Dr Gabriel
Steg:               
Hello.


Dr Carolyn
Lam:               
Now, we need to start by first understanding what we're talking
about. MINOCA ... give us a good definition of what you mean by
MINOCA. And does it include the non-coronary causes of AMI, or
non-obstructive disease? Does it include myocarditis? Does it
include the non-cardiac causes, like pulmonary embolism?


Dr Bertil
Lindahl:              
Our definition of MINOCA used in this paper is that you received
the ICD code for acute myocardial infarction. If you have a
clinically clear case of myocarditis or Takotsubo and were not
included in this analysis. But we know if we look into patients
that have got the diagnosis of myocardial infarction ... if you
performed, for instance, MRI afterward, you can see that a
portion of the patients experience ... between 10 and 30 percent
of the MINOCA patients, have evidence of myocarditis, although it
was not clinically expected.


                                               
So this is a heterogeneous population ... initial diagnosis was
myocardial infarction.


Dr Carolyn
Lam:               
Thank you for clarifying what you used in your study. Gabriel,
could I just, you know, bring you in on this because you invited
an excellent editorial that accompanies this paper. And,
basically, it helps to get us past all this terminology you know,
MINOCA now. Could you maybe just clarify the overall perspective
of what it means?


Dr Gabriel
Steg:               
Yeah. This area is fairly new and we still have a major
nomenclature problem. Clearly it's been recognized for many years
that patients who have a clinical syndrome of myocardial
infarction do not necessarily have obstructive coronary artery
disease. At least severe obstructive coronary artery disease.
Many patients have mild lesions and some patients apparently have
no lesion at all.


                                               
Now, over the last few years we've understood that this is really
a syndrome. And that under that big umbrella, there are patients
who have non-cardiac causes of troponin elevation and chest pain.
These should be excluded from MINOCA. If you have pulmonary
embolism, this is not MINOCA. This is pulmonary embolism.


                                               
The second aspect is there are more subtle distinctions to be
made with fairly new entities such as Takotsubo. When this study
was started, Takotsubo was an emerging disease concept. And so
the authors were not able to properly rule out the Takotsubos and
probably a few myocarditis from their data set. We now have
learned over the past few years that MRI is an excellent tool to
screen MINOCA patients and flush out patients who have
myocarditis or Takotsubo, which are not rare. Actually it's a
substantial portion of that entity.


                                               
And then we're left with what I call the true MINOCA. Now what's
fascinating in the study here is really that ... first of all I
want to say this is another great study from our Swedish
colleagues leveraging their data collection tools, which are
remarkable. Really an example to the world.


                                               
The second thing is they have collected ten years of data on
MINOCA. And they're able to tease out which are the agents that
should be using secondary prevention in that population.
Elegantly demonstrating with sensitivity analysis and positive
and negative controls what are the agents associated with
improved outcomes and what are the agents that apparently do not
impact outcomes.


                                               
So even though at the time they were not able to rule out
myocarditis and Takotsubo properly, still the sheer size of their
study, long term follow up, and the careful statistical analysis
that they've done are remarkable.


Dr Carolyn
Lam:               
I couldn't agree more. And more so in an area that is really
emerging in importance. And for which we don't have any
prospective clinical trials. I'm correct in saying that, right ?
So Bertil, this would be a great point for you to let us know
what are the main findings from your study please.


Dr Bertil
Lindahl:              
The main findings are that statins are associated with a
beneficial effect on the cardiac event. And also, ACE inhibitors
or ARBs , while we were not able to show statistically things you
can affect with beta blockers and similarly not with dual
anti-platelet treatment. So that's basically the main findings of
the study.


Dr Carolyn
Lam:               
May I ask how have these findings personally impacted your
clinical practice or do you think the next steps are gaps that
need to be addressed first?


Dr Bertil
Lindahl:              
I think that's an ongoing discussion in Sweden now and in our
hospital on how this should be applied to clinical practice.
Nothing. It will have an effect that statins and ACE Inhibitors
or ARBs will be used. I'm not sure whether we still can say that
we should not use beta blockers or dual antiplatelet treatment.
But I think also that we are now discussing we should do a
randomized clinical trial to really tease out whether we should
use beta blockers or not or also verifying the findings regarding
ACE Inhibitors and ARBs.


                                               
So, I think there's always a discussion whether we can really use
observation studies for treatment decision. But I think since we
don't have any better trials so far I think that this is the best
that we can get. So I think it will be used and applied in
clinical practice.


Dr Carolyn
Lam:               
Indeed. I really agree with what Gabriel said this is the best
available evidence we have now. And my personal take home message
was to pay more attention to the statins and the ACE Inhibitors.
So congratulations on this great study.


                                               
Gabriel, what do you think? What are next steps? I mean, MINOCA's
not even in the guidelines now. Our guidelines talk about type 1,
type 2, AMI ...how does it all fit in?


Dr Gabriel
Steg:               
Well, we've seen a sea change in the concepts regarding
myocardial infarction over the last fifteen years with the advent
of troponin and the ability to diagnose new patients that
previously we wouldn't even label as an MI.


                                               
The second aspect is we've recognized over the years that there
are some genuine MI's that don't have severe obstructive coronary
artery disease. Now what's interesting is that some of them may
have apparently mild obstructive disease. Which presumably is
related to coronary dissections, embolism, plaque rupture with
thrombosis that disappeared in the interim. And some of them may
have actually "clean" coronary arteries and have myocardial
infarction related to other mechanisms such as micro vascular
mechanisms. What's interesting, and I'd like to ask the opinion
of Dr. Lindahl is, these three types of diseases; mildly
obstructive disease, coronary dissection, and microvascular
angina are all more frequent among women. And I wonder whether
you have any insights regarding gender differences in your
registry.


Dr Bertil
Lindahl:              
In this study, in the sub-group analysis we saw no significant
interaction between gender and the effects. But unfortunately we
don't have the registry information between , let's say
completely "normal coronary arteries" versus "mildly obstructed
coronary arteries". And that's a clear limitation of this study.
It will be very interesting to see whether these effects are
similar in these two sub-groups.


                                               
It seems from other studies that approximately fifty percent of
the MINOCA patients that have normal coronary arteries and fifty
percent that have mild aortic disease. So this is a limitation of
this study and I think that's just something we have to look for
in the future. And I hope that we will have in the registry
onwards, data on whether this normal or mild coronary artery
disease.


Dr Carolyn
Lam:               
Really appreciate that and really appreciate the insights you
gentlemen have shared. Any final words or concluding remarks,
Gabriel?


Dr Gabriel
Steg:               
Well, again congratulations on the great study. I would refer our
readers to the excellent editorial of John Beltrame that
accompanies this paper, which reviews the concepts of MINOCA, the
nomenclature, and some of the remaining and lingering questions
that plague the field. And delineates way forward for studies.


                                               
I think it's a fascinating area. I'm sure we're going to hear a
lot more, both from the Swedish Heart Registry as well as other
data sources. I think we all need to stay tuned to this important
area. The prognosis of these patients is not so good, so we need
to pay attention to that entity.


Dr Carolyn
Lam:               
Wonderfully put. Well, thank you listeners for joining us this
week. Please share this episode with all of your friends. So
thank you and join us next week.