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