Circulation July 14, 2020 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 in Duke National University of Singapore.


Dr Greg Hundley: I'm Greg Hundley, associated editor from the VCU
Pauley Heart Center in Richmond, Virginia.


Dr Carolyn Lam: Greg, today's speaker paper is really special on
a number of levels. First, it's a research letter and secondly,
it's actually basic science. Now, this tells you it's got to be
really special. Well, I'll just give you a hint. It talks about a
new therapy for stroke. I'm going to leave it at that, leave you
guessing because you've got to hang on as we tell you about the
rest of the issue and then listen to the feature discussion. Now,
the first original paper here, I want to describe as a basic
paper focusing on PDE4B in heart failure.


Dr Greg Hundley: All right, Carolyn, I'm not even going to let
you start to quiz me on this. Can you tell me what in the world
is PDE4B?


Dr Carolyn Lam: All right. Phosphodiesterases, or PDEs, really
represent a highly diverse super family of enzymes among which
PDE3 and PDE4 are the main phosphodiesterases that degrading
cyclic AMP with a high affinity in the heart. The cyclic AMP
hydrolyzing phosphodiesterase 4B, which is PDE4B, is the key
negative regulator of cardiac beta-adrenergic receptor
stimulation. PDE4B deficiency leads to abnormal calcium handling
and PDE4B is decreased in pressure overload hypertrophy
suggesting that increasing PDE4B in the heart may be beneficial
in heart failure. These authors led by Dr Vandecasteele from
Inserm tested this hypothesis in elegant experiments involving
both human cardiac tissues and transgenic mouse lines.


Dr Greg Hundley: Carolyn, that was just a wonderful explanation
and I really learned about these phosphodiesterases. Now, tell me
what did they find in their study?


Dr Carolyn Lam: The cyclic AMP hydrolyzing enzyme, PDE4B, was
decreased in human failing hearts. Cardiac over expression of
PDE4B in mice, resulting in a 15-fold increase in cyclic AMP
hydrolysis decreased cardiac contraction and protected against
the cardiotoxic effects of chronic beta-adrenergic stimulation.
Whereas transgenic mice with a 50-fold increase in cardiac cyclic
AMP hydrolysis underwent maladaptive remodeling. Furthermore,
cardiac PDE4B gene transfer with serotype nine adeno associated
viruses resulted in a significantly lower increase in cardiac
PDE4B and protected against chronic catecholamine stimulation and
transaortic constriction without depressing basal cardiac
function. These results overall suggest that a moderate increase
in cardiac PDE4B is beneficial to counteract the detrimental
effects of excessive sympathetic system activation in heart
failure and increase in PDE4B in the human heart could be
achieved by gene therapy with adeno associated viruses or by
using recently developed small molecules with PDE4 activating
properties.


Dr Greg Hundley: Wow, Carolyn. Very interesting. I mean, perhaps
this'll work its way into heart failure management. Well, my
study, our first study to describe involves the comparative
efficacy and safety of oral P2Y12 inhibitors and acute coronary
syndromes. It's a meta-analysis of 52,816 patients from 12
randomized trials. It comes to us from Professor Eliano Navarese
from Nicholas Copernicus University. All right, Carolyn, here's
your quiz. Have you wondered which PGY inhibitor is optimal for
reducing risk of adverse cardiovascular events?


Dr Carolyn Lam: Oh, that's an easy one. Of course I've wondered,
but you're going to tell us the results.


Dr Greg Hundley: It's getting harder and harder to trip you up
Carolyn. Very clever, okay. This study aims to evaluate current
evidence comparing the efficacy and safety profile of prasugrel,
ticagrelor and clopidogrel in acute coronary syndrome by
meta-analysis of 12 randomized clinical trials. Again, involving
those 52,816 patients with ACS.


 Dr Carolyn Lam: Wow. What did they find Greg?


Dr Greg Hundley: Compared clopidogrel, ticagrelor significantly
reduced cardiovascular mortality and all-cause mortality. Whereas
there was no statistically significant mortality reduction with
prasugrel.


Dr Greg Hundley: Next, compared with each other there were no
significant differences in mortality with prasugrel versus
ticagrelor. In addition, compared with clopidogrel, prasugrel
reduced myocardial infarction, whereas ticagrelor showed no risk
reduction.


Dr Greg Hundley: Now stint thrombosis risk was significantly
reduced by both ticagrelor and prasugrel versus clopidogrel.
Compared with clopidogrel, both prasugrel and ticagrelor
significantly increased major bleeding. There was no significant
difference between prasugrel and ticagrelor for all outcomes
explored.


 Dr Carolyn Lam: Summarize that for us.


Dr Greg Hundley: Okay Carolyn. Prasugrel and ticagrelor reduced
ischemic events, but increased bleeding in comparison to
clopidogrel. A significant mortality reduction was observed with
ticagrelor only. There was no efficacy and safety difference
between prasugrel and ticagrelor. So a really nice summary
evaluating these P2Y12 inhibitors,


Dr Carolyn Lam: Indeed. Question for you, Greg, what is the
prevalence of deep venous thrombosis, a DVT and its risk factors,
prognosis and potential prophylaxis strategies for hospitalized
patients with COVID-19? That's what the next paper is about. It
is a single center observational study of 143 hospitalized
patients confirmed of COVID-19. And this is from co-corresponding
authors, Doctors Xi and Hu from Union Hospital in Wuhan China, Dr
Zhang from Beijing Chaoyang, and Dr Ge from St. Christopher
Hospital for Children in Philadelphia, United States, they found
that DVT was found in a high percentage of these patients.
Forty-six percent of the 143 patients and was associated with
adverse outcomes with CURB-65 score three to five. Padua
prediction score four a more and D-dimer greater than one
microgram per mil, which in combination predicted DVT with a
sensitivity of more than 88.5%. Thrombo prophylaxis was
associated with lower DVT in a subgroup of patients with high
Padua prediction score.


Dr Greg Hundley: Now, what does this mean for all of us in this
era of COVID-19?


Dr Carolyn Lam: So this suggests that DVT is more common in
hospitalized patients with COVID-19. So ultrasound screening of
high-risk patients, as I mentioned before, may be indicated for
the more prevention of DVT with low molecular weight heparins in
high risk patients, such as those with a high Padua prediction
scores may reduce DVT in hospitalized patients with COVID-19. Of
course more work needs to be done, but a very interesting paper.


Dr Greg Hundley: What a fantastic description. Well, my next
paper is more from the world of basic science and involves
phosphodiesterase 3A in arterial hypertension and comes to us
from Dr Enno Klussmann from the Max Delbruck Center for Molecular
Medicine. So Carolyn, autosomal dominant hypertension with
brachydactyly clinically resembles salt resistant, essential
hypertension and causes death by stroke before the age of 50
years. So in this study, the authors use genetic mapping,
sequencing, transgenic technology, CRISPR-CAS based nine gene
editing, immunoblotting, and fluorescence resonance energy
transfer to identify new patients perform extensive animal
phenotyping and explore new signaling pathways related to
hypertension with brachydactyly.


 Dr Carolyn Lam: Wow. So what did they find, Greg?


Dr Greg Hundley: Well, Carolyn, the authors described a novel
mutation within a 15 BP region of the PDE3A gene, and define this
segment as a mutational hotspot in hypertension with
brachydactyly, the mutations cause an increase in enzyme
activity, a CRISPR-Cas9 generated rat model with a nine BP
deletion within the hotspot analogous to human deletion
recapitulated the hypertension with brachydactyly in mice,
mutant, transgenic PDE3A over expression and smooth muscle cells
confirmed that mutant PDE3A caused hypertension. The afferent
signaling found in these models was associated with an increase
in vascular smooth muscle cell proliferation and changes in
vessel morphology and function.


 Dr Carolyn Lam: Gosh, so what are the clinical
implications? Greg?


Dr Greg Hundley: The mutated PDE3A gene drives mechanisms that
increase peripheral vascular resistance and cause hypertension.
These authors presented two new animal models that serve to
elucidate these underlying mechanisms further, and their findings
could facilitate the search for new anti-hypertensive treatments.


Dr Carolyn Lam: Very nice Greg. Well, the next paper is actually
one we've already discussed in our special COVID-19 edition and
that was aired on 22nd, May, 2020. That's the paper from Dr
Poissy and Susen from University Lille in Inserm, and they
reported a case-series of COVID-19 patients with pulmonary
embolism in their institution of Lille University Hospital. So,
please everybody remembers to tune in to that as a refresher.
Also in today's journal, the issue of COVID-19 coagulopathy in
venous thromboembolism is further discussed in an editorial by Dr
Alex Spyropoulos and Dr Jeffrey Weitz. Let me tell you a bit more
about other papers in this week's issue. There are letters to the
editor from Dr Mueller and from Dr Gulati all about the paper
incidents, trends and outcomes of type two myocardial infarction
in the community cohort. There's a letter from Dr Siontis on the
blood pressure myocardial infarction paradox.


Dr Carolyn Lam: Does hypertension exert a protective effect in
type two MI? In the ECG challenge Dr Di Cosola talks about the
high, the low end, the narrow QRS in a peripartum cardiomyopathy.
There's an online mind piece by Dr Kohli entitled surfing the
waves of the COVID-19 pandemic as a cardiovascular clinician, a
perspective piece by Dr Albert titled "The Heart of the Matter
Unmasking and Addressing COVID-19's Toll on Diverse Populations".
In Paths the Discovery series, Dr Rutherford talks about serial
innovation to bring transformative precision medicines to people
with serious diseases. And this is a conversation with Dr Jeffrey
Leiden.


Dr Greg Hundley: Very nice. Carolyn, I've got a couple other
papers to discuss similar to your paper on DVT, Professor Lin Cai
has a research letter involving the extremely high incidents of
lower extremity, deep venous thrombosis in 48 patients with
severe COVID-19 from Wuhan China. In an on my mind piece, Dr Anum
Saeed from University of Pittsburgh discusses reinforcing
cardiology training during a pandemic. It's an open letter to our
leaders. Our own Bridget Kuhn has a piece entitled COVID-19 leads
to major changes for cardiologists in training. And then finally,
Dr Stephen Archer from Queens University provides a nice
perspective on differentiating COVID-19 pneumonia from ARDS and
high-altitude pulmonary edema, and what are the therapeutic
implications. And now Carolyn, how about we get onto that feature
discussion, one of the unusual times where we emphasize an
important point in a research letter?


Dr Carolyn Lam: You bet, Greg. Today's feature discussion is I
think one of the most impactful, basic science papers we have,
and that is why we're discussing it. I am so pleased to have the
first author Dr Luca Liberale from University of Zurich, as well
as Dr Peipei Ping associate editor from UCLA. So welcome both.
Luca, I really need your help here. Can you please explain what
your experiment was and your main findings?


Dr Luca Liberale: We really happy that we could set up an
experiment design, which has some kind of translation of value.
So, differently from any other set up involving the tandem middle
cerebral artery occlusion, which is among the most used model for
ischemic stroke in basic science. In this case, the treatment is
done post-ishchemically. So the mice received the neutralizing
antibody against IL-1α only after they scan making salts. And we
specifically thought to duties to keep the translational relevant
side. As I said before, and trying to mirror the case of a
patient, we think come have a stroke that goes to the emergency
department, and he is eligible for revascularization therapy. And
together with this revascularization therapy being at EPA or
whatever for it, it received is also the kind of anti-IL-1α
treatment. And another good translation of relevancy we thought
this may have is that identifying of IL-1α antibody is already
available in the market and being in many phase three trial. So
we thought this is a ready to go, ready for the translation from
the bench to the bedside, as we used to say.


Dr Carolyn Lam: It's just so interesting because when we think
about ischemic stroke, you know, we think about thrombolysis as
practically the only thing we can do, and forgive me I'm not in
neurologist here, but this is so unique to go with an
anti-inflammatory mechanism. Now, when you see that this
neutralizing antibody is currently in use, do you mean in cancer
in other diseases?


Dr Luca Liberale: Mainly it's cancer, but it's also other
dermatological diseases. It's not only cancer, but oh yes,
definitely. Cancer is one of the major fields of its application.


Dr Carolyn Lam: Wow. So with that very interesting background,
could you tell us about the experiment and what you found?


Dr Luca Liberale: What we found is that after inducing ischemia
in the animal for 45 minutes, we let them reperfuse for 48 hours
during which the animal are under the treatment. So they received
a bolus of anti-IL-1α immediately at the time of reperfusion. So
when we take out from the carotid artery, the filament, and they
received these volumes and they are let survive for 48 hours. So
they are free to go in the cage, to seek drinks. After 48 hours,
we assessed the neurological deficit and we sacrifice the animal
to assess the stroke size by using the quite common PTC staining.
And what we could find is that indeed the treatment with the
higher dose, because we use two doses, and we could see a dose
response, could that reduce the stroke size by 36% as compared to
the treatment with the isotype control. And this went together
with a significant reduction in that neurological impairment. So
it's not only an experimental reduction, but it's also
physiologically relevant for the animals.


Dr Carolyn Lam: That really is incredible, and the way you manage
to convey such a lot of data in a research letters is also
remarkable. So, to the audience, you have to pick this up. It's a
succinct read, just this one central figure that tells the whole
story, and you're about to hear from Dr Ping. Dear Peipei, if you
could tell us what the significance of this paper is, maybe some
of the discussions that occurred behind the doors, so to speak
among the editors.


 


Dr Peipei Ping: We were super impressed with the fundamental
message of the submitted report. Carolyn, as you are fully aware,
most ischemic studies speed that in the heart or in a brain
model, often select mechanisms that must be activated pre the
event you bent of ischemia to induce a protective effect, a
neurological protective effect in stroke or cardioprotective
effect in the heart. So, as an associate editor who spent her
entire 30 years career in this area of study, we often fascinated
about the sentencing or the naiveness of the basic scientists in
this area. Because you would have to plan an ischemia in the
patient knowing when that to happen. And then before that
happens, activate all these beautiful signaling and mechanisms,
everything you have generated to prevent that ischemia. So the
search for the possible mechanistic understanding of a
post-ischemic event rescue mechanism has been going on for
decades. And it's very, very challenging, Carolyn.


Dr Peipei Ping: The beauty of the study is it utilized already in
clinical trial, existing human antibody inhibitor, interleukin
alpha-one antibody. You said antibody. So the reagent is already
bile approved. Then examine very carefully in a post-ischemic
fashion to see how relevant that agent in a time window
reasonable to rescue ischemic injury. You can already tell from
Lucas introduction; the results are profound, and it has
stimulated many discussions in the field. It's very relevant to
clinical center piece, even though it's still at that
translational stage. So we saw this as a beautiful representation
of how clinicians and scientists capable of not only bring
something from the bench to the clinic or the clinic or to the
bench. This is something comes to a full circle. It went from
clinic where the reagent was used and created for something to
the bench, understanding mechanistic insight, have a beautiful
animal of human disease stroke model to test them and then take
it to the clinic again.


Dr Carolyn Lam: Goodness, Peipei. I love the way you put that. I
actually didn't see that Luc[a], till you put it that way. I do
have a couple of questions for Luca though. I understand you made
it very clear in your paper that the human monoclonal antibody is
in clinical use, but in this experiment, you had to use the
rodent equivalent because the human antibody doesn't block the
rodent IL-1α, which is very reasonable. But then it brings the
question, how closely does this rodent model recapitulate
thrombotic ischemic, or a stroke in humans? I mean, what do you
think?


Dr Luca Liberale: Well, what we see when we use our usual
approach, this is a model that we're using in our center for
molecular cardiology here in Zurich, and this been used in that
specific group of Professor Ameche for many years. And this is
usually quite well accepted as a model. So that, that the
timeframe is 45 minutes of ischemia and 48 hours of reperfusion.
I'll got to quite mirror the acute phase of an acute ischemic
stroke, which is actually where we think that the inflammatory
pathways can play the major roles. Also. I mean, everybody of us
know that the recent anti-inflammatory trials confirmed this,
that reducing the inflammation and the inflammatory pathways is
good but can also be harmful.


Dr Luca Liberale: So in the case, we can use an approach, which
is limited in the time, maybe really close to that acute phase,
really during the acute rates goes to the acute event. Well,
maybe this can be quite useful and quite a translationally
relevant that prolongs inactivation of such pathways as result.
They can ask some for, so the balance in between the benefits and
the harms cannot be that clear, can, I mean, needs to be quite
well addressed.


Dr Carolyn Lam: And that actually brings me to the next question.
You know, the word translational has been mentioned quite a
number of times here. So can you give us a sneak-peak on what the
translational plans that your team may have? What's the next
steps?


Dr Luca Liberale: The next steps now is back to the company. So
our basic findings are here. They will be published soon, and now
it's all about the clinical scientist, and how they want to
implement these basic findings into the clinic.


Dr Carolyn Lam: So target engagement and mechanistic information
as well. Peipei, could I just give you the last word, if you
don't mind, maybe a bit of a cheeky question. What would you have
loved to see in this paper or in a subsequent paper that offers a
step closer to translation?


Dr Peipei Ping: I think this study has shown most necessary
components as a basic science research paper. I think the next
level closer to the translation as Luca has already alluded to,
has to do with both efficacy studies, as well as safety studies,
and those actually would need to be done in the clinic because
the mouse model. I think it's a fantastic model to offer these
lines of information. Ischemic-wise I think it's very strong and
translational value is very high and that was the predominant
reason we voted to accept the paper. As you know, the accept and
raise of circulation is very, very low as our bar is very high.


Dr Carolyn Lam:  Very nice. So target engagement and
mechanistic information as well. Congratulations, Luca. Thank you
so much Peipei for your great comments. Now, listeners, you heard
it first time here on Circulation on the Run. Thank you for
joining us today.


 Dr Greg Hundley: This program is copyright at the American
Heart Association, 2020.