Circulation February 7, 2023 Issue

Please join author Petr Ostadal and Associate Editor
Dharam Kumbhani as they discuss the article "Extracorporeal
Membrane Oxygenation in the Therapy of Cardiogenic Shock: Results
of the ECMO-CS Randomized Clinical Trial."


Dr. Carolyn Lam:


Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, associate editor from the National
Heart Center and Duke National University of Singapore.


Dr. Peder Myhre:


And I'm Dr. Peder Myhre, social media editor from Akershus
University Hospital and University of Oslo in Norway. And today
Carolyn will have such an interesting feature discussion. We are
going to look into the use of ECMO to treat patients with
cardiogenic shock, the results of the ECMO-CS randomized clinical
trial. Isn't that interesting?


Dr. Carolyn Lam:


Awesome. Can't wait. But I suppose you're going to tell us about
some papers in the issue first. I'm getting my coffee.


Dr. Peder Myhre:


Yeah, go ahead. Because first we're going to talk about a very
interesting paper that relates to diabetes and the progression of
coronary artery disease. So as you know, Carolyn, diabetes
remains associated with an increased risk of cardiovascular
morbidity and mortality. And although the absolute risk
difference between patients with and without diabetes have
declined over the past 20 years, we still don't know what is the
diabetes associated differences in coronary plaque morphology and
lipid content.


Dr. Carolyn Lam:


It's true. That's a very interesting question. And will you tell
us more?


Dr. Peder Myhre:


Yeah. So the investigators in the prospect two study who enrolled
patients exclusively from Denmark, Norway in Sweden who presented
with biomarker positive MI and assessed both culprit lesions and
untreated non-culprit lesions in these patients. And then they
stratified the patients by diabetes status and examined with
three vessel quantitative coronary angiography and near infrared
spectroscopy and intravascular ultrasound imaging after
successful percutaneous coronary intervention.


Dr. Carolyn Lam:


Okay, that's deep investigation. And what did they find?


Dr. Peder Myhre:


So diabetes was present in about 12% of patients and during a
median or 3.7 year follow up, MACE occurred almost twice as free
frequently in patients with versus without diabetes. And that was
primarily due to an increased risk of MI related to culprit
lesion stenosis and non-culprit relation related spontaneous MI.
However, baseline prevalence of high-risk plaque characteristics
was similar for patients with versus without diabetes, concerning
culprit and the non-culprit lesions and in multi-variable models,
diabetes was associated with MACE in lesions but not with
prevalence of high-risk plaque characteristics. So Carolyn, the
authors conclude that diabetes related plaque characteristics
that might underlie the increased risk were not identified by
multimodal imaging.


Dr. Carolyn Lam:


Oh, I just love studies like that so elegant with just a really,
really intriguing results that make us ask more important
questions. Love it. Thank you. Well, the next paper is also about
myocardial infarction, but this time looking at the fibrotic
remodeling after myocardial infarction because we know that MI
induces a repair response that ultimately generates a stable
fibrotic scar. And although the scar is important to prevent
cardiac rupture, excessive pro-fibrotic response impairs optimal
recovery because it promotes a development of non-contractual
fibrotic areas. So would it be possible to regulate the expansion
of cardiac fibroblast after MI through a paracrine action on the
cardiac stromal cells? So the authors led by corresponding author
Dr. Hulot from University of Paris performed a bioinformatic
secretome analysis of cardiac stromal PW1 positive cells isolated
from normal and post MI mouse hearts to identify novel secreted
proteins.


And they found that first cardiac PW1 positive stromal cells
responded to myocardial infarction by secreting factors that
promoted the proliferation and activation of resident fibroblasts
and one such factor growth differentiation factor three or GDF3
was highly upregulated in the ischemic hearts and promoted a high
induction of fibroblast proliferation via interaction with TGF
beta receptors and activation of SMAD1/5 and SMAD2/3 signaling
cascades. The upregulation of GDF3 was detected in the plasma of
mice and humans following MI and high levels of plasma GDF3 in
the days following MI predicted adverse outcomes measured six
months later including cardiac dilation and limited recovery of
contractile function in humans.


Dr. Peder Myhre:


Oh, that's so interesting. We already know GDF15 were very well,
but now we hear about GDF3 in predicting fibrotic remodeling post
myocardial infarction. So Carolyn, what are the clinical
implications of these findings?


Dr. Carolyn Lam:


Exactly, Peder, in fact you said it. So the detection of high
circulating GDF3 in plasma may serve as a novel biomarker of
adverse fibrotic remodeling in heart tissue. That's one. And next
the measurement of GDF3 plasma levels in the early post MI phase
may allow for the identification of patients within an increased
risk of severe myocardial fibrosis and heart failure and
therefore could guide specific disease management.


Dr. Peder Myhre:


Thank you. That was an excellent summary of the paper, Carolyn.
And now I'm going to look into a paper that relates to the
important issue of arteriosclerosis following heart
transplantation because as you know, transplant arteriosclerosis
characterized by concentric and diffuse narrowing of vastly lumen
is a major complication in long-term survivors of heart
transplant patients. And increased lymph flow from donor heart to
host lymph nodes has been reported to play a role in transplant
arteriosclerosis. But how lymphangiogenesis affects this process
is unknown. The authors of this paper, which comes to us from
corresponding author Sue from Sejong University, transplanted
vascular allografts between various combinations of mice
including mice with severe combined immune deficiency and studied
the lymphatic vessels within the grafted arteries.


Dr. Carolyn Lam:


Wow, that is really cool. Studying lymphatics and
lymphangiogenesis in atherosclerosis. Interesting. What did they
find, and what are the clinical implications?


Dr. Peder Myhre:


So Carolyn, lymphangiogenesis within allograft vessels began at
the anastomotic sites and extended from preexisting lymphatic
vessels in the host. Tertiary lymphatic organs were identified in
transplanted arteries at the anastomotic site and lymphatic
vessels expressing CCL21 were associated with these immune
structures. Fibroblasts in the vascular allografts released
VEGFC, which stimulated lymphangiogenesis into the grafts and
inhibition of VEGFC signaling inhibited lymphangiogenesis,
neointima formation and adventitial fibrosis of vascular
allografts. And these studies identified VEGFC released from
fibroblasts as signal stimulating lymphangiogenesis extending
from the host into the vascular allografts. So, Carolyn, the
authors conclude that the formation of lymphatic vessels play a
key role in the immune response to vascular transplantation and
inhibition of lymphangiogenesis may be a novel approach to
prevent transplant atherosclerosis.


Dr. Carolyn Lam:


Wow, that is super interesting. Thanks, Peder. While also in this
issue, there's an exchange of letters between Drs. Tanaka and
Schulze regarding SGLT2 inhibitor treatment in acute
decompensated heart failure. Why do we initiate it early? There's
also a really nice On My Mind paper by Dr. Schiattarella on
Cardiometabolic HFpEF. Is it the NASH of the heart?


Dr. Peder Myhre:


Oh, that's interesting. We also have some cardiology news by our
own ‪Bridget Kuehn entitled “No Benefit Seen for Nighttime Dosing
Over Morning Dosing for Antihypertensive Medications.” And this
is a summary of the time trial, which was presented at European
Society of Cardiology Congress in 2022. And finally, Carolyn, we
have a Research Letter entitled “Stepwise Generation of
Human-Induced Pluripotent Stem Cell Derived Cardiac Parasites to
Model Coronary Microvascular Dysfunction” by Dr. Joseph Wu from
Stanford University School of Medicine.


Dr. Carolyn Lam:


While cool, Peder. But now I'm so excited to hear about the
ECMO-CS randomized trial. Let's go.


Dr. Greg Hundley:


Welcome listeners to this February 7th feature discussion and we
have with us today Dr. Petr Ostadal from Na Homolce Hospital in
Prague in the Czech Republic and our own associate editor, Dr.
Dharam Kumbhani from UT Southwestern in Dallas, Texas. Welcome,
gentlemen. Well, Petr, we'll start with you. Can you describe for
us some of the background information that really led you to
perform this study, and what was the hypothesis that you wanted
to address?


Dr. Petr Ostadal:


According to the current guidelines from the management for the
management of cariogenic shock, it should be considered
administration of inotropes and vasopressor for hemodynamic
stabilization, or it may be considered administration of
inotropes and vasopressors and it should be considered the use of
short-term mechanical circulatory support. And the aim of the
ECMO-CS trial was to compare early conservative therapy with
inotropes and vasopressors and immediate implementation of ECMO
in patients with the rapidly deteriorating or severe cardiogenic
shock. The hypothesis of the ECMO-CS trial was that immediate
implantation of ECMO in patients with cardiogenic shock and
critical hemodynamic condition will be associated with improved
outcomes.


Dr. Greg Hundley:


Very nice. Can you describe for us this study population and then
also what study design did you use to address your hypothesis?


Dr. Petr Ostadal:


We try to select patients who can really profit from the early
ECMO implantation, and we define two categories of patients.
First category where the patients with rapidly deteriorating
cardiogenic shock corresponding to current sky stage D or E. This
patient should have evidence of left ventricle pump failure as
left ventricle ejection fraction below 35% or ejection fraction
35 to 55 in case of severe mitral regurgitation or aortic
stenosis. And this patient also should require a repeated both of
vasopressors to maintain mean arterial pressure about 50
millimeters of mercury. The second category where the patients
with severe cardiogenic shock corresponding to current sky stage
D and this patient should have the criterion of a hemodynamic
conditions which was cardiac index less than 2.2 or systemic
blood pressure below 100 millimeters of mercury in both situation
with higher doses of inotropes and vasopressors. And in case of a
low systolic blood pressure, also the evidence of left ventricle
pump failure based on ejection fractional below 35 or ejection
fraction 35 to 55 in case of severe mitral regurgitation of
aortic stenosis.


The second criteria for the metabolic criteria, that was the
evidence of tissue hypoperfusion and this was defined as a higher
lactate above three millimeters per litter or low ScvO2 below
50%. And the third criterion was exclusion of hypovolemia, and
this was based on central venous pressure or pulmonary artery
wedge pressure. So this was the major inclusion criteria in the
ECMO trial. The study population was not defined based on
theology of cardiogenic shock, but just on severity of
cardiogenic shock.


Dr. Greg Hundley:


Very nice. And so your design, did you have a one-to-one
randomization, or how did that work? And then also how many
subjects did you include in this important trial?


Dr. Petr Ostadal:


The patients were randomized in one-to-one ratio to immediate
implementation of ECMO or to early conservative therapy. But it
is important to point out that in the early conservative therapy
downstream use of ECMO was allowed in case of further hemodynamic
worsening defined as increase of what lactate by three
millimeters per litter. We enrolled 122 patients, 61 were
randomized to early ECMO and 61 to early conservative strategy.
Five patients were excluded due to absence of informed consent
and finally 58 patients were analyzed in the early ECMO or
immediate ECMO arm and 59 patients were analyzed in the early
conservative arm.


Dr. Greg Hundley:


Sounds great Petr. And then tell us and describe your study
results.


Dr. Petr Ostadal:


The primary endpoint was composite of death from any cause,
resuscitated circulatory RS and implementation of another
mechanical circulatory support including ECMO in the early
conservative arm at 30 days. And there was no difference in the
primary endpoint with P 0.2221 and has a ratio of 0.72 with a 95%
confidence in interval 0.46 to 1.12. There was also no difference
in the incidence of death from any cause. 50% in the immediate
ECMO arm and 28%, 47.5% in the early conservative arm. There was
no difference in the incidence of resuscitated circulatory
arrest, 10.3 in the immediate ECMO arm and 13.6 in the early
conservative arm. Less patient required another mechanical
circulatory support in the early ECMO arm through 17.2 in
comparison with 42.4% in the early conservative arm and
downstream ECMO was used in 39% of patients in the early
conservative arm.


Dr. Greg Hundley:


Very nice. So similar results both immediately and then 30 days
later for both arms. And I think that last point that you make is
very interesting. 39% of the individuals randomized to the
conservative arm went on to receive VA-ECMO. Well, listeners
next, we're going to turn to one of our associate editors and
Dharam, you have many papers that you see. How do we put the
results that Petr has just described really in the context of
management of shock and results that have been published
previously?


Dr. Dharam Kumbhani:


Yeah, Greg, thank you. And Petr, thank you for this important
paper and again, I'm really honored to be here on behalf of
Circulation on the Run. So again, want to congratulate the
authors for really an important study. I think in terms of
context, what is really interesting is the use of ECMO,
particularly VA-ECMO for patients with shock has really
skyrocketed. And it is interesting that this expansion has
occurred in the absence despite, I guess high quality clinical
trials, this trial certainly fills an important void. Although it
is a small patient population, it is randomized, it is a largest
randomized trial to date on this important population. And so I
think most of the studies that have been done so far have been
done using observational data sets which have sort of inherent
limitations. So I certainly want to congratulate you on trying to
study this very challenging population because in sort of that
acute setting, it's frequently very hard to get patients
randomized.


So just broadly in that context, I think at the same time this
study does sort of pose some important questions and sort of
perhaps leads, just given the limitations of the sample size does
sort of leave a few unanswered questions. So one question I have
is, Petr, in addition to the 40% crossover rate is obviously
important as Greg pointed out. The other thing is it appears that
the use of other mechanical support during the conduct of this
trial was also close to 40%, about 42%. So pretty much everybody
in the conservative arm ended up with some kind of mechanical
support. Now, at least in the last few years, a concept that has
gained a lot of traction is a concept of a shock team where a
number of providers with particular expertise from different
disciplines would get together and sort of decide next steps was
a shock team sort of part of the decision-making, especially for
the conservative arm.


Dr. Petr Ostadal:


Thank you for this question. The situation is maybe a little bit
more simple in the Czech Republic here, the cardiologist are
responsible for the acute cardiac care, usually competent and
experience not only for the diagnosis and examinations and
monitoring of patients in cardiogenic shock, but also experience
in insertion and management of the mechanical circulatory
support. So here this attending cardiologist competent to manage
this patient from different sites from the manage not only the
conservative therapy but also the mechanical circulatory support
therapy in these patients. So in this respect, this is more
simple situation in the Czech Republic.


Dr. Dharam Kumbhani:


I just had a very quick question about, and I don't know if you
want to include this, but Petr, I was curious, were patients with
cardiac arrest, I know you mentioned sky shocks in were patients
with cardiac arrest on the field or in the hospital included?


Dr. Petr Ostadal:


Thank you for this excellent question. And in comparison, with
other trials comparing the or focusing on patients with
cardiogenic shock in the ECMO-CS trials, cardiac arrest survivors
were excluded. And the reason was that the brain damage, which is
the major cause of death in these patients cannot be influenced
by ECMO insertion. And second, in majority of patients after
cardiac arrest, if there is a presence of shock, there is
frequently combined shock with important peripheral component.
And again, it cannot be assumed that this peripheral component
can be reversed by ECMO implantation. So in the ECMO-CS trial,
the cardiac arrest survivors were excluded from that enrollment.


Dr. Greg Hundley:


Well, thank you so much Petr. Petr, what do you think is the next
study to be performed really in this area of research?


Dr. Petr Ostadal:


I think that we are happy because several other clinical trials
focusing on the mechanical circulatory support in patients with
cardiogenic shock underway. And there are other trials focused on
ECMO and trials a bit focused on combination of ECMO with balloon
pump and trials focused on Impella. So I think in the very close
time we will be able to see the results of these current running
trials1.


Dr. Greg Hundley:


And Dharam, do you have anything to add?


Dr. Dharam Kumbhani:


No, I agree completely with Petr. I think this is a very exciting
field. I know there's a lot of interest in doing well conducted
clinical trials in this space. And so certainly, I think the
future is bright for investigation in this field.


Dr. Greg Hundley:


Very nice. Well, listeners, we want to thank Dr. Petr Ostadal
from Prague in the Czech Republic and our own associate editor,
Dr. Dharam Kumbhani from Dallas, Texas for bringing us this study
highlighting that immediate implementation of VA-ECMO in patients
with rapidly deteriorating, or severe cardiogenic shock did not
improve clinical outcomes compared to an early conservative
strategy that permitted downstream use of VA-ECMO in the case
when the patient's hemodynamic status worsened.


Well, on behalf of Carolyn, and Peder, and myself, we want to
wish you a great week and we will catch you next week on the run.
This program is copyright of the American Heart Association 2023.
The opinions expressed by speakers in this podcast are their own
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.