Circulation January 10, 2017 Issue

Dr.
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 episode marks the six
month milestone of our run together, a run that has taken us
around the world from the United States to Europe, South Africa,
and Asia, and one that is shared by listeners all over the world.


                                               
On behalf of the editors, and from the bottom of my heart, I want
to thank you for your support and request that you please
subscribe to our podcast and share it with your friends and
colleagues. We commit to bringing you the best of cardiovascular
science in the most accurate and digestible way possible, thus
suiting the busy cardiologist on the run.


Dr.
Lam:                              
All right, here are your highlights of this week's issue.


                                               
The first paper looks at tissue plasminogen activator, or TPA
treatment in ischemic stroke, addressing two aspects that are
still unclear. Number one, the degree of additional benefit
accrued with treatment in the first 60 minutes after onset of
ischemic stroke; and number two, the shape of the time-benefit
curve through 4.5 hours. First author, Dr. Kim, corresponding
author Dr. Saver and colleagues from UCLA stroke center analyzed
more than sixty-five thousand acute ischemic stroke patients
treated with intravenous TPA within 4.5 hours of onset from the
"Get With the Guidelines" Stroke U.S. National Program.


                                               
They found that 878 of these over sixty-five thousand patients
were treated within the first 60 minutes after onset, a ten-fold
increase over previously available data. Thrombolytic treatment
within the first 60 minutes was associated with the highest rates
of favorable discharge outcomes. The shape of the time-benefit
curve throughout the first 4.5 hours was non-linear for some
outcomes. Discharge to home and discharge free of disability
decayed more rapidly in the first hundred to a hundred and
seventy minutes after onset than later. While independent
ambulation at discharge and in-hospital mortality declined in a
steady fashion through the time window.


                                               
These findings reinforce the importance of quality improvement
programs to accelerate door to needle time for thrombolytic
therapy in acute ischemic stroke.


Dr.
Lam:                              
The next study sheds light on mechanisms underlying red blood
cell mediated hypoxic vasodilation. A highly conserved response
coupling oxygen delivery to metabolic demands of the tissues, and
very clinically relevant in states of systemic hypoxemia and
impairment in oxygen delivery, such as in patients suffering from
cardiovascular, pulmonary, or hemolytic diseases.


                                               
In this paper, Dr. Bailey and colleagues from University of
British Columbia Okanagan in Canada studied ten healthy
participants who were randomly assigned to a normoxic, or 21%
oxygen, and hypoxic, or 10% oxygen trial with measurements
performed at rest and following 30 minutes of cycling at 70% of
maximal power output. Blood was sampled simultaneously from the
brachial artery, internal jugular, and femoral veins with plasma
and red blood cell nitric oxide metabolites measured. Cerebral
and femoral venous blood flow were determined by transcranial
doppler ultrasound and constant infusion thermodilution
respectively.


                                               
The authors found that hypoxia was associated with a mild
increase in both cerebral and femoral blood flow, with further
more pronounced increases observed in femoral blood flow during
exercise. Plasma nitrite gradients reflecting consumption were
accompanied by red blood cell iron nitrosyl hemoglobin formation
at rest in normoxia, during hypoxia and especially during
exercise, with the most pronounced gradients observed across the
femoral circulation. In contrast, there were no gradients
consistent with S-nitrosohemoglobin consumption.


                                               
Collectively, these findings suggest hypoxia, and to a far
greater extent exercise, independently promote arteriovenous
delivery gradients of intravascular nitric oxide with
deoxyhemoglobin mediated nitrite reduction, identified as the
dominant mechanism underlying hypoxic vasodilation. This is as
opposed to the competing hypothesis of S-nitrosohemoglobin
formation.


                                               
In summary, by distinguishing between the two competing
mechanisms that underpinned endocrine nitric oxide
vasoregulation, that is, the S-nitrosohemoglobin hypothesis
versus the nitrite reductase hypothesis, these data help us to
understand the dynamic interplay that takes place between nitric
oxide metabolites as a function of oxygen demand in vivo, and
will help to establish the most specific and sensitive prognostic
markers of vascular health and therapeutic interventions that
optimize tissue oxygenation.


Dr.
Lam:                              
The next study addresses the controversial issues of thrombus
aspiration during percutaneous coronary intervention, or PCI, for
the treatment of ST elevation myocardial infarction, or STEMI.


                                               
Dr. Jolly and colleagues from Hamilton General Hospital in
Ontario, Canada performed an individual patient meta-analysis of
three eligible large randomized trials that is the TAPAS, TASTE
and TOTAL trials including more than eighteen thousand patients
who underwent PCI for STEMI. They found that as a routine
strategy thrombus aspiration did not reduce cardiovascular
mortality for STEMI patients undergoing primary PCI, and that
exploratory analysis of patients with high thrombus burden
suggested that thrombus aspiration may improve cardiovascular
mortality but at the price of an increased risk of stroke or
transient ischemic attack.


                                               
In summary, these data suggest that thrombus aspiration should
not be used as a routine strategy in patients with STEMI, however
in patients with high thrombus burden, further large randomized
trials are needed to determine if improved forms of thrombus
aspiration can reduce cardiovascular mortality and to determine
its safety with regards to stroke.


Dr.
Lam:                              
The next paper is the first study to look at coronary artery
calcium imaging as a tool to personalize systolic blood pressure
treatment goals.


                                               
Dr. McEvoy and colleagues from Johns Hopkins University School of
Medicine in Baltimore, Maryland studied 3,733 participants from
the multi-ethnic study of atherosclerosis with systolic blood
pressure between 120 to 179 millimeters of mercury. Within
subgroups categorized by both systolic blood pressure and
estimated ten year atherosclerotic cardiovascular disease risk,
they compared multi-variable adjusted hazards ratios for the
composite outcome of incident atherosclerotic cardiovascular
disease or heart failure after further stratifying by coronary
artery calcium.


                                               
The authors found that combining coronary artery calcium imaging
and assessment of global atherosclerotic cardiovascular disease
risk had potential to guide personalized systolic blood pressure
goals, particularly among adults with an estimated risk between
five to fifteen percent, and pre-hypertension, or mild
hypertension.


                                               
For example, among those with an atherosclerotic cardiovascular
disease risk of less than fifteen percent and who had systolic
blood pressure between 140 and 159, those with a coronary artery
calcium score up to 100 were at two times the risk, while those
with a coronary artery calcium score more than 100 were at 5.7
times the risk of events, all compared to a coronary artery
calcium score of zero. Thus, information on coronary artery
calcium burden may be considered when making personalized
treatment decisions about blood pressure targets, particularly
among patients with an estimated cardiovascular risk between five
and fifteen percent, and who have either pre-hypertension or mild
hypertension.


                                               
In summary, information on coronary calcium burden may be
considered when making personalized treatment decisions about
blood pressure targets, for example, choosing a traditional goal
of 140 or a more intensive goal of 120 millimeters of mercury.
The authors ended by calling for a precision medicine clinical
trial evaluating risk-based blood pressure treatment goals,
preferably incorporating coronary artery calcium.


                                               
Well, those were your highlights, now for your feature
discussion.


Dr.
Lam:                              
On today's episode we are going to be discussing the very
important issue of type-two myocardial infarction, very important
yet usually neglected compared to type-one myocardial infarction.
As a reminder to our listeners, type-two MIs are the ones where
there is myocardial demand-supply mismatch whereas type one is
the usual acute coronary artery plaque rupture and thrombosis. To
discuss this I am really honored to have two James' on the
podcast. The first is Dr. James Januzzi from Massachusetts
General Hospital, the second is Dr. James de Lemos, executive
editor of Circulation from UT Southwestern.


                                               
Welcome to you both.


Dr.
Januzzi:                        
Thank you very much Carolyn, really great to be speaking with
you.


Dr. de
Lemos:                   
Thanks Carolyn, it's great to be on.


Dr.
Lam:                              
Dr. Januzzi, could you please let us know what you found in this
paper, it's really extraordinary. Just give us a top line of the
results.


Dr.
Januzzi:                        
Basically we set out to examine the question of how frequent
type-two myocardial infarction is in a population of patients
followed longitudinally after they have taken a trip to the cath
lab for one reason or another. Really with the goal to better
understand the type-two MI syndrome. It was our hypothesis that
type-two MI was perhaps more common than people may have
recognized, and that type-two MI would be higher risk in terms of
the likelihood for ischemic complications than what people had
previously recognized. As you point out, type-two MI is often
neglected from a management perspective.


                                               
What we found, basically, was among a cohort of patients, 1,250
patients coming through the cath lab at the Massachusetts General
Hospital Heart Center, in follow up over a several year follow up
period with a maximum of eight years of follow up, with a mean of
about 3.4, a median of 3.4 years follow up. Out of the 1,251
patients that we enrolled and followed, 152 actually had an
incident type-two myocardial infarction during follow up.
Additionally, type-two MI was actually quite recurrent in many
patients, and in each of the cases whether individual or in most
patients with recurrent type-two MI, the mortality risk was
really quite striking. Patients that had a type-two MI, partially
because they were more complicated medically speaking, as one
might have expected, they were older and had lower blood
pressure, more coronary disease, heart failure and other medical
comorbidities. The likelihood for a major adverse cardiovascular
event was more than doubled in patients that suffered an incident
type-two MI, the risk for mortality was actually remarkably
almost ten-fold higher with a cardiovascular death rate that was
around nine-fold higher, heart failure was tripled.


                                               
Really just illustrates the very morbid nature of the type-two
myocardial infarction, and illustrates the fact that studies are
urgently needed to better understand how we should manage these
patients.


Dr.
Lam:                              
Dr. Januzzi when I manage patients I find this diagnosis of type
two-MI to be a very dirty one to make, if you know what I mean.
It's hard to really be sure what's happening, and what to
attribute rises in troponin to, and so on. Could you tell us a
little bit more about how difficult it was to adjudicate the
events, and what's the risk of misclassification in your study?


Dr.
Januzzi:                        
It's a challenge, and that's something that came up during the
peer-review process. We really wanted to make sure that we got
this right, so in fact we went back and did a cross-sectional
re-review of cases to make sure that our adjudication process was
accurate. It's not a very straightforward thing to judge,
obviously. A rise and/or fall in troponin may be from a type-one
myocardial infarction. There's increasing interest in a syndrome
of myocardial injury in the absence of a classical myocardial
infarction. Then lastly, we recognized that troponin may rise and
fall, for example, in patients with heart failure, possibly due
to non-coronary mechanisms. You are correct, it may be a
challenge to classify these patients solely on the basis of the
presence of a rise or fall of troponin.


                                               
What we did was classify them utilizing the Universal Definition
of MI Task Force criteria, which includes symptoms and signs, as
well as a rise and/or fall of troponin, plus evidence for loss of
myocardial function on non-invasive testing. We were pretty
strict, actually, in terms of how we judged them, and when we
went back and re-reviewed ten percent of the cases, we actually
found that all of the fifteen cases that we went back and
re-reviewed met the criteria that we had articulated in the front
end. We feel pretty confident that we got the diagnosis correct,
but obviously it's a challenge in every day practices, as you
rightfully point out.


Dr.
Lam:                              
It does certainly sound very rigorous, indeed. Dr. de Lemos, you
managed this. He mentioned reviewers giving him a hard time, what
was it like managing this paper?


Dr. de
Lemos:                   
It was fascinating because the Universal Definition that
introduced type-two MI into the classification scheme is only a
decade old. It's remarkable how little we know about the problem,
and how much we struggle in clinical practice. We thought this
paper was one of the first and most comprehensive evaluations to
put some construct around the problem. As you pointed out,
Carolyn, it is a messy diagnosis. Even when you do it in an
organized, researched fashion this reflects what we all deal with
in clinical practice where it's not so easy to define myocardial
infarction even when given the criteria of the Universal
Definition. The challenge really is that only a minority of the
troponin elevations that are the classic type-one MIs that we
know what to do with. The rest of them are either these troponin
elevations NOS, type-two MI, or something on a continuum on this
spectrum that's really hard to differentiate.


                                               
This paper's important because it really highlights that these
non-type-one MIs whatever they are, are common and associated
with really high risk, and it's sort of a call to arm that we
better start to understand and sub-classify these if we're going
to be able to reduce risk in this very high risk population.
That's really why we were so interested in the paper, and why we
worked so closely with Jim and his team to address some of the
issues that you just raised.


Dr.
Lam:                              
I completely agree, in fact it's beginning to remind me of the
world of HFpEF when we first started realizing that people with
heart failure, even though ejection fraction's normal are
definitely not doing well. James Januzzi, if you don't mind, what
do you think are the implications for treatment, what are the
things that you think need to be examined going forward?


Dr.
Januzzi:                        
Carolyn I laughed when you mentioned HFpEF because at one of the
recent Universal Definition of MI Task Force meetings, I actually
said that type-two MI is the HFpEF of the myocardial infarction
world. To answer your question, I have approached this question
very much the way we do in the heart failure space relative to
heart failure with preserved EF. In order to develop a strategy
for treatment for type-two MI, we need considerable advances
still in our understanding of just what exactly is a type-two MI,
what types of patients have type-two MI, and on an individual
level, the treatment strategies may follow.


                                               
The problem here is if you look just at all comers who suffered a
type-two MI in our study, the majority were actually taking
statins, they were taking aspirin, they were more likely to be
taking beta-blockers. So the patients themselves were actually on
the very treatments that we might think about prescribing in
those folks that have a type -wo MI, and yet they still suffered
the MI, and they had worse outcomes. One might think about
coronary disease and revascularization, and indeed one of the
nice things about our study is we enrolled patients at the time
of coronary angiography, and then followed them subsequently, so
we actually had detailed coronary angiograms on every one. Those
suffering an incident type-two MI certainly had more coronary
disease, so one might argue revascularization might either be
protective if done prior to the onset of type-two MI, or at the
time of type-two MI a revascularization-driven strategy might be
a logical approach.


                                               
I think more fundamentally, bringing it back to heart failure and
to the HFpEF analogy, I think that in order to better understand
treatment we need to better understand just who these patients
really are. So much like has been done in the heart failure space
we're now doing cluster phenotype analyses where we're looking at
the various phenotypes of patients with type-two MI using network
analyses, which is one way to approach a problem when you've got
a mix of various diseases that fall under the same title. So in
those patients with preserved ejection fraction heart failure,
there are patients that are younger obese patients, there are the
patients with advanced diabetes, et cetera.


                                               
Our hypothesis for our present research is to examine this
question within the type-two MI diagnosis to see if we can
identify specific clusters of phenotypes that might be treated in
specific ways. The coronary patients might deserve
revascularization, the heart failure patients might deserve a
different approach for their care. That, I think, might be the
way forward, exactly taking a page from the playbook that you
just mentioned with respect to preserved ejection fraction heart
failure.


Dr.
Lam:                              
Wow, how terribly exciting. Congratulations again for this paper,
I really think it's a landmark and will open the door to many
more important papers. I would like to switch tracks a little bit
at the moment. We are coming to six months into the new
Circulation editors that have been under the leadership of Joe
Hill and James de Lemos, and I'd actually like to start by asking
you, Dr. Januzzi, what was it like working with our new
Circulation team? Then handing the mic over to Dr. de Lemos to
tell us a little bit more about what the journey has been so far
in the last six months.


Dr.
Januzzi:                        
Thanks for asking, it was an absolute pleasure. I trained with
Dr. Hill and with Dr. de Lemos in one degree or another during
all of our respective residency and/or fellowship training, so
I've known these guys for a long long time. I think that the most
important aspect in the peer review process is a collaborative
and collegial process where the division between author and
editor can allow for communication. In this experience with this
manuscript, it was a very easy-going and collaborative process
where the paper from beginning to end grew in its quality, and
ultimately landed in the journal, and the way that it did was, I
think, a substantial likelihood for heavy citation. That says a
lot about the editors who really help us to bring it to this
final product.


Dr.
Lam:                              
Dr. de Lemos?


Dr. de
Lemos:                   
We're now six months in to the new Circulation editor team's
tenure, and I think all of us are having a blast. I think we've
put together this team of diverse international experts that
build off each other and thrive off each other, so from the team
perspective, we're just having great fun, working hard, learning
a great deal. We hope that those of you out there that are
listening and reading, and submitting papers, and using our
journal for your own research, are noticing the changes that
we've made and think we're headed in the right direction. We'd
love to hear from you about the things you like, and those things
you don't like. We do think we've, in many ways, modestly changed
the focus of the journal. There's so many new content categories
that are designed to speak to the global burden of cardiovascular
disease, the international aspect of cardiovascular research, and
new clinically relevant problems, translating basic science so
that clinicians can understand it. We hope that clinically
active, as well as basic investigators are finding these changes
useful in their own daily lives.


Dr.
Lam:                              
Thank you both so much for spending time with me on Circulation
on the Run. Thank you everyone, don't forget to tune in next
week.