Circulation on the Run: Special COVID-19 Edition

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:


I'm Dr. Greg Hundley, the director of the Pauley Heart Center at
VCU health in Richmond, Virginia.


Dr. Carolyn Lam:


Oh, Greg. Today we have a special episode focused on COVID‐19
pandemic, something that has just


affected us so severely worldwide, it really needs no
introduction. Why are we doing a special issue?


Well, I think it very quickly got recognized that patients with
cardiovascular disease do seem


predisposed to severe COVID‐19 syndrome, and that these patients
can have an acute COVID‐19


cardiovascular syndrome, in fact. We're going to be talking all
about this in a series of interviews about


the syndrome, the clinical presentations, what this implies for
management. Is the pulmonary embolism


involved in the pathophysiology of all of it? And what are ways
that we should use to monitor or even


screen these patient?, For example, what's the role of troponins?


Dr. Greg Hundley:


Yes, Carolyn. I am excited, just as well as you, and our first
paper today is from Dr. Leslie Cooper, from


the Mayo Clinic. He's really done a nice review describing the
disease process and the management of


acute COVID‐19 and the cardiovascular syndromes.


Dr. Greg Hundley:


Leslie, we'd like to welcome you to Circulation on the Run and
just to get started, I'm wondering, could


you tell us a little bit about the genesis of your paper and then
also perhaps some of the mechanism,


how does this virus affect our systems and promote cardiovascular
disease?


Dr. Leslie Cooper:


In mid‐March as the COVID, crisis was taking off in this country,
I was on a telephone call with Dr.


[Biykem] Bozkurt and [Dr. Mark] Drazner, from Texas. We realized
that there was a terrific need for


clinicians to have an overview of how to manage the COVID‐19
impact on the heart. There was also, at


that point, very little clinical data about the mechanisms and
what the real pathogenesis was. We set


about and the rapidly put together the available world's
literature. That is what was ultimately


published here in Circulation about two weeks ago.


Dr. Greg Hundley:


Tell us a little bit about that mechanism.


Dr. Leslie Cooper:


It became apparent that there is not one specific mechanism. We
initially thought that like the Coxsackie


viruses, this could be a direct cardiac damage, but clinically as
we reviewed the literature, it became


clear that it's more systemic. The older patients who have
preexisting cardiac disease, hypertension,


coronary disease, other risk factors, such as diabetes or obesity
have a much greater risk of cardiac


involvement and the consequences of that cardiac involvement are
very substantial.


Dr. Leslie Cooper:


In addition, when you get a profound cytokine storm from the
systemic infection, that can depress


cardiac function. A combination, in individuals, of cytokine
mediated damage from systemic


inflammation, stress induced cardiomyopathy, as you would see in
takotsubo, as well as hypoxia and


perhaps increased pressures in the lung from, as Carolyn
mentioned, pulmonary emboli, and finally


direct viral damage. Viruses can infect macrophages in the heart.
There is a growing body of literature


that there can be a direct effect independent of the systemic
infection. The answer is there are multiple


factors each of which may have its own therapeutic target.


Dr. Carolyn Lam:


Oh, I love the way you explained that so clearly Leslie, and in
fact, this is really bringing back sweet


memories of when I was training under you at Mayo Clinic. I won't
say how many years ago, but there


comes the question, you know so much about myocarditis, in
general, and a different viral myocarditis.


Could you maybe tell us a little bit about how this one may or
may not differ and also how this impacts


management?


Dr. Leslie Cooper:


The coronaviruses have a very different mechanism of cell entry
and propagation. It does not appear


that this particular infection in the heart is causing the kind
of antigen specific immune reaction that you


see classically with a Coxsackie virus. We're not seeing
necessarily a lot of auto‐antibody, molecular


mimicry. We're not seeing a lot of T‐cell infiltrate. We are
seeing some infection of macrophages, and


it's not yet clear how many of those were infected peripherally
and then migrated to the heart. The


histology is quite different and the acute damage is therefore,
more subtle. You're not seeing sheets of


lymphocytes and the targeted therapies would not be necessarily
directed at those cells.


Dr. Leslie Cooper:


Having said that, inflammation more broadly, for example,
anti‐IL‐6, anti‐IL‐1 type, anti‐cytokine


mechanisms are currently under evaluation in clinical trials, and
they may be quite meaningful. Quite


meaningful in the setting of the systemic inflammation. When you
compare this to a SARS and other


coronavirus infections, I'd like to say, we have known that
occasionally a coronavirus can cause


myocarditis, for 40 years. It's simply not very common. It
predisposes the individual or makes the


particular virus more cardiovirulent at this point.


Dr. Carolyn Lam:


All listeners, you have to get ahold of this beautiful paper. As
Greg was actually suggesting a little bit


earlier, they're this beautiful figure that you have to refer to
that shows a management pathway and


considerations. Also, very lovely illustrations of potential
mechanisms. Leslie, could you also let us know


then, in the overall management, not just treatment, where is the
place then, for things like myocardial


biopsy?


Dr. Leslie Cooper:


I think you have to start with the clinical presentation.
COVID‐19 as a syndrome, and SARS‐CoV‐2 as a


virus, can present with multiple cardiac syndromes. The first
would be ST segment elevation, like


myocardial infarction with normal coronary arteries. In that
setting, it may be microvascular obstruction,


or it could be myocarditis or stress cardiomyopathy, perhaps in a
younger person who doesn't have risk


factors.


Dr. Leslie Cooper:


Can also present with a primary cardiomyopathy, a heart failure
presentation, shortness of breath,


systolic dysfunction. And finally it can present as a pericardial
effusion, not the most common


presentation, but it's important to realize that just like other
viruses, this can cause an epicardial or


pericardial inflammation.


Dr. Leslie Cooper:


Management really depends on the clinical syndrome and I'd
emphasize guideline‐directed medical


management. If it's an arrhythmia, a ventricular tachycardia or
heart block, manage that per the current


guidelines. The same is true for systolic heart failure.


Dr. Leslie Cooper:


In addition, I would say that since most patients with COVID
infection do not have cardiac involvement,


you should first treat the whole patient. First, see the clinical
syndrome. What is the dominant problem?


Is it a lung problem? Is it kidneys? Then, if there is a cardiac
manifestation, we recommend starting with


a troponin. If the troponin is elevated, proceed to a point of
care echo.


Dr. Leslie Cooper:


We do want to minimize exposure of allied health staff and
physicians to the virus. We do not


recommend multimodality imaging or heart biopsy upfront. Having
said that, if the patient has


substantial left ventricular systolic dysfunction, and they're
already in the cath lab, because you're


excluding coronary disease, our paper does recommend that you
consider an endomyocardial biopsy to


find the mechanism of left ventricular dysfunction.


Dr. Greg Hundley:


Very good, Leslie.


Dr. Greg Hundley:


Could you close this out, a little bit about therapy when we have
patients with this severe hypertension,


respiratory abnormalities requiring ventilation, and then also
these devastating cardiovascular effects.


Are we looking at anti‐inflammation is primarily the target as
opposed to antiviral therapy?


Dr. Leslie Cooper:


Right now, there are a couple of clinical pearls. Number one, as
in all cardiogenic shock, you don't


have... Sinus tachycardia is not a therapeutic target. You may
need that because of low stroke volume.


You want to allow when it's compensatory for the tachycardia.
Once you've treated with guideline


directed therapy, the arrhythmias and the cardiomyopathy
appropriately, specific mechanistic


interventions, such as antiviral therapy or anticytokine therapy
should be given within the context of a


clinical trial, wherever possible.


Dr. Leslie Cooper:


Our article recommends that if you have access to a clinical
trial and in this country, the convalescent


plasma trial, is up and running. Mayo is leading that for the
country. It's available at approximately 600


sites. We would recommend, first of all, enrollment in a trial
because we then will understand the


mechanisms and the best treatment. If you don't have access, it
really depends on the clinical syndrome


and how sick the patient is. Patients who are less sick have been
treated with things like


hydroxychloroquine. People who are more sick, we move on to a
convalescent plasma and anticytokine


therapy such as tocilizumab.


Dr. Greg Hundley:


Very good. Well, Leslie, we want to thank you for sharing this
wonderful review with us at Circulation.


We feel very privileged to have the opportunity to publish this
and also to share it with our readership.


Again, thank you for all of your frontline work at the Mayo
clinic and helping participate in trials and


things of this nature to combat this terrible disease.


Dr. Leslie Cooper:


Thank you so much.


Dr. Carolyn Lam:


Greg, from acute COVID‐19 cardiovascular syndrome to now, all
about troponins. I am so, so thrilled that


Dr. Nicholas Mills is here with us, not only our associate
editor, but also corresponding author of the


next paper. He's from University of Edinburgh in UK. Nick, I love
the question that you asked in your


title, "Are troponins an ally or a foe in the fight against
COVID?" Explain, please.


Dr. Nicholas Mills:


I strongly believe that they can be an ally, but I recognize
amongst cardiologists and clinicians around


the world that are grappling with this new condition, that the
use of biomarkers can be contentious.


We're still learning very much about this condition and how it
affects the heart. Therefore, it's difficult


to provide very clear guidelines. It's how you interpret the
cardiac biomarkers in this condition. The


reason I feel strongly that they can be an ally is, they're easy
to measure, they're cheap, and you don't


require a direct patient contact to obtain the result of the
test. It gives us some fundamental


information about whether the heart is involved or not.


Dr. Greg Hundley:


Nick, can you tell us which biomarkers do you favor and is it
high sensitivity troponin? Is it regular


troponin? For our listeners in many different hospitals across
the world, what would you suggest?


Dr. Nicholas Mills:


The evidence that has that merged very rapidly over the last few
weeks and months suggests that our


range of cardiac markers have very, very high prediction for poor
outcome. Whether that's predicting a


patient that might deteriorate and require admission to an
intensive care unit for ventilation, or


develop complications such as acute kidney injury or death.


Dr. Nicholas Mills:


There are a number of biomarkers that look very useful for
predicting the course of a patient. The


strongest, in most studies, is cardiac troponin. I think it's
because we do have such sensitive assays now.


High sensitive assays are such a fabulous way of getting a
barometer of your heart health. The heart of


course, is a fairly fundamental organ. If this condition is going
to affect to any other organ out with the


lungs. If it's the heart, you're going to be in trouble. I think
high sensitive troponins, in particular, give us


such exquisite information about the systemic complications of
this virus that they are perhaps above all


other markers, the most useful for predicting outcomes. Now, that
clinical question goes beyond that.


We need to understand how this virus is affecting the heart and
whether we can intervene in any shape


or form in response to these results in order to try and improve
the course for these patients. That is a


more challenging question.


Dr. Greg Hundley:


Nick, you've got a wonderful figure and we just heard from Leslie
Cooper about the different


cardiovascular disorders. Once we have elevation or experience,
we see elevation in a patient with a


biomarker, whether that be high sensitivity, proponent, BNP, et
cetera. How does that point us in a


direction of where our next move is, clinically, to combat this
disease process in patients?


Dr. Nicholas Mills:


I think the first thing to say is that biomarkers do need to be
interpreted in the clinical context and to


understand that the pre‐test probability of having underlying
structural chronic disease in your patient


who presents with COVID‐19. That will very much influence your
interpretation. If you think about the


spectrum of conditions that you might see, and in fact, that we
are seeing, there are a number that I


would highlight. In particular, we know from many years of
looking after patients with bacterial or viral


pneumonia, that the pro inflammatory state of those conditions in
patients who are vulnerable, older,


and have underlying coronary heart disease is a really powerful
risk factor for acute coronary syndrome


and type one myocardial infarction.


Dr. Nicholas Mills:


Often in ventilated patients or patients who have clearly an
alternative diagnosis, these important


conditions, which are treatable, are overlooked. I think in
considering the potential causes of myocardial


injury of these patients, we should not overlook the probability
that vulnerable patients have triggered


acute cornea events in the context of their illness.


Dr. Nicholas Mills:


The other group that I think are really important are type two
myocardial infarcts. They are an


increasingly well‐recognized group of patients with the use of
high sensitive tests in critical care units


around the world. In the context of profound hypoxia or
hypotension in sepsis, it gives the clinician


managing the patient an idea about the vulnerability of the
patient and their susceptibility and risk. I


think that is also important.


Dr. Nicholas Mills:


Then, I think there's a separate group of conditions that are a
direct consequence of the exposure to


coronavirus and the clinical syndrome of COVID‐19. We are seeing
case reports and have our own


experience locally, of patients who develop myocarditis in this
condition. I think it is rare, but it is real.


When it occurs, it can be particularly severe and associated with
prothrombotic complications. The


other conditions that we are seeing are stress cardiomyopathies
in relation to profound breathlessness,


and that is not uncommon.


Dr. Nicholas Mills:


We are trying to systematically scan our more critically unwell
patients in the intensive care unit to look


for evidence of cardiomyopathy.


Dr. Nicholas Mills:


The final group that I would highlight is in those that are more
severely unwell. Right ventricular


dysfunction as a cost of either prothrombotic changes or of ARDS
itself, is a really important observation


that an elevated cardiac biomarker may be the first clue that
that patient is developing cardiac


decompensation. Although there's a range of different, important
underlying conditions and the


biomarker in itself cannot differentiate between these, I think
recognizing that the patient is at risk of


these underlying cardiac artery disease is an important first
step.


Dr. Carolyn Lam:


Nick, really nicely explained. I'm going to read one of the lines
from, I think, one of the concluding


paragraphs from your paper, because it's really interesting.
"Clinicians must recognize that troponin is


not a test for myocardial infarction and it never was." Now,
that's very interesting. I know in many ways


you've explained it in what you said earlier, but could you maybe
just end by hammering home what you


meant there?


Dr. Nicholas Mills:


Myocardial infarction is a clinical diagnosis. It is not a test,
one test. It's a combination of clinical


features, a variety of different tests that help you arrive at
that final diagnosis. Unfortunately, when


troponin was introduced into clinical practice a number of years
ago, as a replacement for CKMB, it


became a sort of de facto. This is the test we use to
differentiate people with myocardial infarction,


without it, and that has become perpetuated in our clinical
practice.


Dr. Nicholas Mills:


As the technologies move forward and we've developed really high
sensitive tests that allow us to


measure proponent accurately in almost all patients, it's become
abundantly clear that it is a marker of


heart injury in a very wide range of clinical conditions. We need
to almost unlearn that original teaching,


but this was a marker used exclusively to rule in and rule out
myocardial infarction and embrace it as a


test that tells us about your heart health and how it is affected
in a wide range of conditions.


Dr. Nicholas Mills:


For me, it's never really been high sensitivity troponin in any
way, a test exclusively of myocardial


infarction. I use it very widely. I always find it informative in
the clinical setting in order to guide


decisions that I make for my patients. In a patient with ischemic
chest pain and an elevated troponin,


the default is, this is a type one myocardial infarction until
proven otherwise. In all other settings, this is


evidence of acute myocardial injury. Some careful consideration
is required to determine what the


mechanism is that underpins that.


Dr. Carolyn Lam:


There, you heard it, ladies and gentlemen. That kind of wisdom is
going to last beyond COVID‐19. Thank


you so much, Nick, for joining us today. That was awesome.


Dr. Nicholas Mills:


Pleasure.


Dr. Greg Hundley:


Well, listeners, now we're going to switch and talk a little bit
about pulmonary emboli and to introduce


that topic. We have Dr. Sophie Susan from Lille, France, who has
performed a study in France, looking


for this disorder.


Dr. Greg Hundley:


Welcome Sophie. I was wondering, could you start us off, tell us
a little bit about the background for


your study, the hypothesis and the question you were going to
address, and then what was the study


population and some of your results?


Dr. Sophie Susan:


I work in Lille University Hospital, which is in the North of
France. During the early days of March, we


had the first patients with COVID‐19 and we were very surprised.
High number of patients with sudden


aggravation of the respiratory symptoms. We were suspecting high
numbers of, I would rather say


pulmonary thrombi or pulmonary embolisms. We looked back to
medical records of patients admitted


in our institution last year, in the same period of time, to look
at the frequency of these pulmonary


embolism or pulmonary thrombi. We also looked at all the patients
admitted for influenza, ARDS in our


institution last year.


Dr. Sophie Susan:


What we observed is that there was a higher frequency of
pulmonary embolism during COVID‐19. We


observed 22 patients. At the moment we sent the [Research] Letter
to Circulation. That means 20% of


patients admitted in ICU. And by comparison, there were only 6%
of patients in the same period of time


in ICU last year. To be sure to avoid any bias in the data
collection, we looked also at the CTPA, the


angiograms, of the angiography of those patients. We observed
that in influenza patients, they were


much more investigation with CTPA than in COVID‐19 patients.
Despite this higher number of CTPA


perform, they were less pulmonary embolism or thrombi identified.
Our conclusion was at that moment,


that there was an awareness on the new increase frequency in
thrombotic pulmonary complications in


COVID‐19 patients.


Dr. Greg Hundley:


Thank you so much, Sophie. You've got a beautiful table in your
article. Were there any particular


patient characteristics that you could identify in this patient
population that you think may make


patients predisposed to this?


Dr. Sophie Susan:


Yes, we were very surprised in my region. My area is a metabolic
area and we were very surprised to


observe the high number of obese patients in our ICU. There was a
publication from our group on the


subject. We looked at the BMI of those patients and on our table,
you can see that almost all of them


were above 25, and the large majority about 30 BMI. They were
also all receiving thromboprophylaxis at


baseline at the entrance in ICU. Although all the patients were
at least receiving 40 milligrams of


Heparin, or even more, and some of them were also on their
particular levels of low molecular weight or


unfractionated heparin therapy.


Dr. Carolyn Lam:


That is a very important point that you just made, that some of
these patients, or a lot of them, had


background prophylaxis already. Sophie, could you end by telling
us how have these results perhaps


influence your management? Or what do you think are the
implications?


Dr. Sophie Susan:


It's a difficult question. The first issue is that regarding the
population admitted in ICU, we've got a lot of


weight patients and there are no current guidelines adapting
thromboprophylaxis to weight. The first


question was that 40 milligram of heparin is good for everyone.
Do we need to increase this regimen in


obese patients?


Dr. Sophie Susan:


There was a proposal of ESC two years ago, and we adapted these
proposals for COVID‐19 patients. We


do believe that 40 milligrams of heparin is not enough for
patients in ICU, for overweight patients in ICU.


So for a BMI above 30, we think that we should increase the
regimen of low molecular weight or


unfractionated heparin. That's the first point.


Dr. Sophie Susan:


We've got also, a disease that is random, very difficult
sometimes to perform CTPA, difficult, to move


patients to those exams. Sometimes we've got to give a
probabilistic treatment and in case of acute


worsening of the respiratory status and in particular, in case of
repositioning patients, when they are


under high‐positive and expiratory pressure, sometimes they get
sudden aggravation. We must think


about probabilistic therapeutic approach with heparin on those
patients. That's the two main


conclusions we made for the adaptation of protocols.


Dr. Carolyn Lam:


Well, thank you so much, Sophie. I really am so grateful that you
published this work here at Circulation.


You very, very, fairly pointed out what you found. I thought that
your inclusion of the control groups was


really the best that we could do, and therefore your data
represent the best available evidence for a


very important question that we've all been asking. Are these
patients at higher risk of pulmonary


embolism?


Dr. Carolyn Lam:


Thank you so much for sharing that with us.


Dr. Sophie Susan:


Thank you very much for the invitation.


Dr. Carolyn Lam:


What an amazing series of papers that we have on COVID‐19. Guess
what? These three that we talked


about today are not the only ones. We really strongly encourage
you to look at


ahajournals.org/coronavirus where you can see many more papers
published in Circulation, relevant to


COVID‐19 as well as some commentary from experts on the front
lines.


Dr. Carolyn Lam:


Thank you very much, once again, everyone for joining us today.


Dr. Greg Hundley:


Have a great week.


Dr. Greg Hundley:


This program is copyright, the American Heart Association, 2020