Circulation April 9, 2019 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.


Dr Greg
Hundley:            
And I'm Greg Hundley, also associate editor from VCU Health
Systems, the Poly Heart Center in Richmond, Virginia.


Dr Carolyn
Lam:               
So arrhythmogenic cardiomyopathy that will make most of us think
of right ventricular disease and fatty infiltration of the
muscle, but could arrhythmogenic cardiomyopathy really be a
bi-ventricular disease? Well you've got to stay tuned to find out
more in a fantastic interview coming right up after our little
coffee chat. So Greg, what are your picks this week?


Dr Greg
Hundley:            
My first paper is from Chris Lim at NYU in New York. And it's
looking at the relationship between Mediterranean diet, air
pollution and cardiovascular events.


                                               
So, it's unknown whether usual individual dietary patterns can
modify the association between long-term air pollution exposure
and health outcomes. And so, in this large cohort with detailed
diet information at the individual level, they had 548000
individuals across six states and two cities within the U.S. and
a follow up period of 17 years. And that occurred between 1995
and 2011. And they evaluated whether a Mediterranean Diet
modified the association between long-term exposure to ambient
air pollution and then cardiovascular disease and mortality risk.
And so, the average exposures to parts per billion and nitric
oxide air pollution that the residential census track level were
measured, and the investigators found that for the particulate
matter there were elevated significant associations with
cardiovascular disease. So, a hazard ratio of 1.13, ischemic
heart disease similar hazard ratio and cerebrovascular disease
with also a similar hazard ratio.


                                               
For the nitric oxide, there were also significant associations
with cardiovascular disease, as well as ischemic heart disease.
And then the analysis indicated that Mediterranean diet modified
the relationships. Those with a higher Mediterranean diet score
had significantly lower rates of air pollution related mortality.
These results therefore indicate Carolyn, that Mediterranean diet
reduce cardiovascular disease mortality related to long-term
exposure to air pollutants in a large perspective, U.S. cohort.
Can you believe increased consumption of foods rich in
antioxidant compounds actually may aid in reducing the
considerable disease burden associated with ambient air
pollution?


Dr Carolyn
Lam:               
Oh wow. That is hugely interesting. Gosh, what do we do about
this clinically now?


 Dr Greg
Hundley:           
Remember, first of all, this is an associate study, so we can't
infer cause effect. And what we need next are some more
independent studies from other cities around the world,
prospective cohorts, examinations of clinical outcomes and
randomize interventions. And so, I think the results add to a
growing body of literature suggesting that dietary patterns may
help reduce cardiovascular events in these high air pollution
exposure areas. And how does this work? Well, potentially through
augmenting antioxidants and reducing oxidative stress.


Dr Carolyn
Lam:               
That's really cool. So from one region, talking about air
pollution to another region that often reports about air
pollution and that's China. But this study from China is actually
the largest registry study to evaluate sex related differences
and hospital management and outcomes of patients with acute
coronary syndrome in China.


                                               
This is from corresponding author Dr Zhao from Beijing Anzhen
Hospital, Capital Medical University, Beijing Institute of Heart,
Lung and Blood Vessel Disease. With colleagues of the improving
care for cardiovascular disease in China, Acute Coronary Syndrome
project, which is an ongoing nationwide registry of the American
Heart Association and the Chinese Society of Cardiology. So, the
authors use data from this project and evaluate at sex
differences in the acute management, medical therapies for
secondary prevention and in hospital mortality in more than 82000
patients admitted for acute coronary syndrome in 192 hospitals
across China from 2014 to 2018.


Dr Greg
Hundley:            
What did they show in this study?


Dr Carolyn
Lam:               
They showed that women hospitalized for acute coronary syndrome
in China less frequently received acute treatments and strategies
for secondary prevention and had a higher in hospital mortality
rate than men. Now the observed sex differences in this in
hospital mortality were likely due to older age, worse clinical
profiles and fewer evidence base acute treatments provided to
women. And that's because the sex differences were no longer
observed after adjustment for these clinical characteristics and
acute treatments.


                                               
What this all means though is specifically targeted quality
improvement programs may be warranted to narrow these sex related
disparities in patients with acute coronary syndrome in China.


 Dr Greg
Hundley:           
Very interesting. I'm going to take sort of the next paper and
it's looking at a different aspect of acute myocardial
infarction. And these papers from Yong Wang from the Division of
Molecular and Translational Cardiology at Hannover Medical School
in Hanover, Germany.


                                               
Now as we know, the heart can undergo deleterious changes and
left ventricular geometry and function during that vulnerable
period before scar formation has stabilized the infarct area. And
so inflammatory cell trafficking from hematopoietic organs like
the spleen to sites of tissue injury is coordinated by chemokine
chemokine receptor networks. Therapeutically modulating these
chemokine chemokine receptor interactions may promote infarct
healing by limiting excessive inflammation induced tissue damage
or by enhancing the recruitment of angiogenic cell populations to
the infarct or the wound. Inflammatory cell trafficking after a
myocardial infarction is controlled by a CXC motif chemokine
ligand 12 or CXCL12 and its receptor CXC motif chemokine receptor
4. CXC receptor 4 antagonists, mobilize inflammatory cells and
promote infarct repair. But the cellular mechanisms are unclear.


                                               
So, what do these investigators do? In mouse models, the
investigators found that inflammatory cell trafficking between a
hematopoietic organs and sites of tissue injury is controlled by
CXCL12 and its receptor CXC receptor 4. And bolus injectives of a
highly selected peptidic macrocycles CXC receptor 4 antagonist,
enhanced tissue repair and functional recovery after re-perfused
acute myocardial infarction in mice. And interestingly, the
therapeutic effects require a dendritic cell priming and we're
specifically mediated by t-regulator cells. Intermittent CXC R4
blockade mobilized the t-regulator cells from their splenic
reservoir. Leading to their enhanced recruitment to the infarct
region.


Dr Carolyn
Lam:               
So bring it home for us, Greg. What does this mean clinically for
MI management in humans?


Dr Greg
Hundley:            
Right. Highlighting the translational potential. What we might
infer is that CXC receptor 4 blockade reduces infarct volume and
improved systolic function in a porcine close chest model of
re-perfuse acute myocardial infarction.


                                               
And so, the results of both the mouse experiments and this sort
of translational model in pigs should stimulate further research
into therapeutic potential of CXC R4 blockade after MI and in
other acute conditions were excessive, innate or adaptive immune
responses cause immunopathology.


Dr Carolyn
Lam:               
Fascinating. So from one preclinical paper to another, but this
time focused on heart failure. And focus specifically on titin.
Titin is this giant elastic protein that spans the half-sarcomere
from the Z-disk to the M band, and it acts like a molecular
spring and a mechanosensor that has been linked to striated
muscle disease. Now the pathways that govern tight independent
cardiac growth and contribute to disease are diverse and have
been really difficult to dissect. And so corresponding author Dr
Gotthardt, from Max Delbruck Center for Molecular Medicine and
the German Center for Cardiovascular Research and his colleagues
aimed to study titin deficiency versus titin dysfunction.


                                               
And how they did that is they generated and compared striatum
muscles specific knockouts with progressive postnatal loss of the
complete titin protein. And that's by removing Exxon 2. Or an
M-band truncation that eliminates the proper structure and
integration, but retains all the other functional domains. So
they then evaluated cardiac function, cardiomyocytes mechanics,
and the molecular basis of the phenotype. Now, what they found
was that progressive depletion of titin led to sarcomere
disassembly an atrophy in striated muscle. And in the complete
knockout, remaining titin molecules had increased strain
resulting in mechanically induce trophic signaling and eventual
dilated cardiomyopathy.


                                               
On the other hand, the truncated titin helped maintain passive
properties and thus reduced mechanically and do signaling. In
other words, truncations versus loss of titin, differentially
affected cardiac pathology with atrophy versus dilated
cardiomyopathy respectively. And together, these findings really
contribute to the molecular understanding of why titin mutations
differentially affect cardiac growth and have implications
importantly for genotype, phenotype relations that support a
personalized approach to the diverse titinopathy.


Dr Greg
Hundley:            
Interesting, Carolyn. All this information on titin. So why is it
clinically important?


Dr Carolyn
Lam:               
Well, first of all, tightened mutations are the most common
genetic basis of heart disease and the findings are clinically
relevant, as I said, for understanding the genotype phenotype
relations at the Titin mutation. But understanding the
integration of Titin based signaling and sarcomere biology could
indeed help personalize diagnostics by improved clinical
decisions and maybe identify suitable therapeutic targets for
these titinopathy. But that of course requires much further work.
Well that brings us to the end of our summaries. Let's go to our
feature discussion.


 Dr Greg
Hundley:           
Welcome everyone to our second segment of our program. We're
discussing an interesting paper today entitled Sudden Death and
Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.
And we want to welcome our coauthors Elijah Behr and Mary
Sheppard from St George's University in London. And also, our own
associate editor, Sami Viskin to discuss this paper. Mary, can
you tell us a little bit about your study design here, the
population and the hypothesis and some of your results?


Dr Mary
Sheppard:          I
am a cardiac pathologist of 20 years and I have a special
interest in sudden death. Over this time, I've established a
national pathology database, where pathologists throughout the
country when they have a sudden death, which is likely cardiac
and non-ischemic, they will send the heart or tissue blocks
insides to me for my opinion concerning the death. We have as a
result developed a large number, over 5200 cases which has now
built up to 6000. It's the largest pathological series in the
world.


                                               
And I was also discovering the pathologists were either under or
over diagnosing all types of cardiomyopathy but particularly
ergogenic cardiomyopathy. And that is why with Chris Miles, our
research fellow, we looked in detail at what I had diagnosed, or
the pathologist as ergogenic cardiomyopathy and we actually honed
are pathological diagnostic criteria for this very important
entity. Establishing that left ventricular is five and
ventricular and left and ventricular is the norm almost. That
right or left ventricular is unusual by themselves and even in
20%, one in five, the heart can look macroscopically normal. So
that histology is essential when you're making this diagnosis.
You cannot make the diagnosis pathologically without
histologically examining the heart.


Dr Greg
Hundley:            
Very good, Mary. And did you also examine some genetic markers in
some of the subsets of the patients? And how did you decide who
those individuals would be that received the genetic analysis?


Dr Mary
Sheppard:          A
small subset and I will hand over to Elijah Behr, my colleague
concerning that.


Dr Elijah
Behr:                  
The genetic tissue is only available in a minority of cases.
We've developed a pipeline now with the referring pathologists
who are increasingly they're sending samples of spleen suitable
for DNA extraction that allow us then to do a retrospective
postmortem genetic testing or molecular autopsy. But
unfortunately, in this particular series we only had a small
proportion. I think there were roughly about 24 out of the 202
cases, so just over ten percent. And interestingly, while we
didn't necessarily mirror the expected yield of genetic testing
that is seen in clinical cases, where you may see about 40%
carrying pathogenic variance. We certainly picked up some
important pathogenic variance, particularly those that are often
associated with highly penetrant and more severe disease. In
particular TMEM43 and desmoplakin. These findings may reflect the
small size of the sample, but it also may reflect where the
greatest risk for sudden death from ergogenic cardiomyopathy
lies.


Dr Greg
Hundley:            
Elijah, getting back to some of the patients that experienced the
sudden death in the study population Mary was referring to, were
there characteristics that were associated with the sudden death?
For example, those that might be related to gender or activity?


Dr Elijah
Behr:                  
So the majority of the cases were male. The majority has never
had prior symptoms. These were unheralded deaths. The majority
did not have a family history and I think the majority were
addressed, but those that were athletes, we're much more likely
to have died during exertion. So as we found with ergogenic
cardiomyopathy in general and exertion is a trigger to sudden
death. The risk was higher and compared to the athletes in death
during exertion was associated with being younger as well. I
think exertion and sports clearly play a role in ergogenic
cardiomyopathy. It didn't appear to play a role in whether there
was left ventricular involvement or not, but certainly a role at
more severe presentation.


 Dr Greg
Hundley:           
Maybe both Mary and Elijah answering this. You found
histopathological evidence of fibrosis and fatty infiltration.
How extensive was that? And do you think that could be identified
with a test like maybe magnetic resonance imaging?


Dr Mary
Sheppard:         
Yes. Our diagnostic criteria which is illustrated in the addendum
is that it was at least two blocks of tissue. We always look at
10 to 12 to 15 blocks of tissue from both right and left
ventricle. And at least two of the blocks had to have fibrosis
with fat in 20% of the area examined. We did not include
inflammation because inflammation is, an important histological
criterion in our experience. We were very precise about that
because you need that much at least to make the diagnosis. A
little bit of fibrosis or a little bit of fat is not sufficient
by itself.


Dr Greg
Hundley:            
When you mention a block, for us clinically, how much myocardium
would that be? For example, on an imaging test like an echo or an
MRI scan.


Dr Mary
Sheppard:         
One to two centimeters squared.


Dr Greg
Hundley:            
So quite a bit.


Dr Elijah
Behr:                  
You're looking at probably around two to four millimeters of
potential depth of fibrosis. And what we've seen clinically in LV
involvement of MRI scans is miss two epicardial late enhancement.
Now the question is whether our scans are sensitive enough to
pick that up? Given the technology available or a sense to the
histopathology and I think that's why maybe some of the clinical
studies have tended to miss the true proportion of left
ventricular involvement. Because of the relative subtlety of the
fibrosis compared to the technological ability to discriminate
it. I mean certainly when you look at our cases that were
diagnosed previously with cardiomyopathy, either they were
arrhythmogenic or dilated, many did have imaging findings if MRI
was performed, that would indicate or suggest some left
ventricular involvement. But as you know, the task force criteria
for arrhythmogenic cardiomyopathy having very much right
ventricular focus. An LV imaging findings and LV ECG findings are
just not part of those at the moment.


Dr Greg
Hundley:            
Was there a particular location within the heart where there was
a predilection toward the findings of fibrosis and fat?


Dr Mary
Sheppard:         
In the posterior basal wall particularly, transmural involves
going from the epicardium to the sub endocardium and also the
interior walls of the left ventricular were the predilection
areas.


Dr Elijah
Behr:                  
I think that's what we see on our MRI scans as well. When you
look at these patients, that posterior basal area, is the one
that tends to light up the most.


Dr Mary
Sheppard:         
It is believed that increased stress in that area gives more
damage because of the stretching away from the septum.


Dr Greg
Hundley:            
Very interesting. So Elijah, you had mentioned task force
criteria. I want to shift to Sami now and ask, Sami, can you help
us put this in perspective relative to the existing task force
criteria and then the findings in this study? And how that could
lead to subsequent changes down the road?


 Dr Sami
Viskin:                
Okay, so it is difficult to place this in the context of the task
force because mentioned by Elijah, the taskforce are focused on a
disease that is believed to be in the right ventricle. And the
study shows that many of the sudden death cases will involve the
left ventricle. One of the most important messages of this paper
is importance of her forensic examination. And importance of
making it for anything examination in the center of expertise. We
know of patients that will travel a thousand miles to undergo
surgery or an ablation procedure, but families do not think that
way when there is casualty or family dies. You may take a
postmortem as a given, but in many countries, including my own,
most cases of sudden death would not be followed by a post mortem
and will not go into center of expertise. And you cannot
overemphasize the importance of doing that because then you have
to know what you are looking for in the remaining relatives is
extremely important.


Dr Greg
Hundley:            
Very good. How about from the perspective as an
electrophysiologist? Does this impact in any way how you might
evaluate a younger person with syncope?


Dr Sami
Viskin:                 
Well, it is difficult to conclude from this paper about how to
evaluate patients with syncope because most of the cases in this
series don't have symptoms at all. But this paper calls to very
interesting investigations by Mario del Mar and others in New
York. Looking about the electrophysiology consequences of a
disease like right ventricle are like a bit mechanical in
[inaudible 00:21:58] The tissues becomes editing the disease, the
electrical properties how the patients in brugada can cause
malfunction of this sodium channel and create a disease that is
more like brugada and dysplasia at the beginning. So, the entire
correlation between a morphologic disease and the metrical
disease and we used to think they are two different things. And
now we see that we can actually put them together and you can go
through stages where one disease is before an electrical disease
and only at later stages it becomes a morphological evident
disease.


 Dr Greg
Hundley:           
A fantastic discussion on pathologic findings. Sami making the
point that certainly in cases for young individuals having a
postmortem examination performed at centers that have expertise
such as what Mary's described, can be very important. And then
Elijah, helping us to understand with arrhythmogenic
cardiomyopathy, number one, findings are not, we shouldn't just
be thinking about the right ventricle in isolation, but also the
left ventricle. Fibro fatty infiltration, particularly in the
posterior basal wall could be an important thing to look for, for
those that are performing the magnetic resonance imaging exams.
And then lastly, many of the patients in the study like this, the
first presentation was of sudden death. And we need to be
cognizant that this condition could be prevalent in the
population and not necessarily appreciated by some of our current
task force guidelines and examinations. So, what an outstanding
discussion. And I think for today, we want to thank our authors
and our associate editor and wish everyone a great week.


                                               
On behalf of Carolyn and myself, we look forward to seeing you
next week. Thank you very much.


Dr Carolyn
Lam:               
This program is copyright American Heart Association 2019.