Circulation January 4, 2022 Issue

Please join author George Dangas and Associate Editor
Brendan Everett as they discuss the article “Colchicine in
Cardiovascular Disease.”


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. Greg Hundley: Welcome, everyone, to 2022. I'm Dr. Greg
Hundley, Associate Editor, Director of the Pauley Heart Center at
VCU Health in Richmond, Virginia.


Carolyn, oh, we're starting off the year with a twist on the
feature article. It's a review article on colchicine and
cardiovascular disease.


But before we get to that, how about we grab a cup of coffee and
jump into some of the other articles in the issue?


Dr. Carolyn Lam: Absolutely. The new year is starting off with a
bonanza issue. This first topic is so important. We know that
various non-invasive, intermittent rhythm monitoring strategies
have been used to assess arrhythmia recurrences in atrial
fibrillation ablation trials. But the question is, what is the
frequency and duration of non-invasive rhythm monitoring that
accurately detects arrhythmia recurrences and approximates the
atrial fibrillation burden derived from continuous monitoring
using the gold standard, implantable cardiac monitor?


Now to answer this question, investigators Jason Andrade and
colleagues from the Montreal Heart Institute, who looked at the
rhythm history in 346 patients enrolled in the CIRCA-DOSE trial.
They reconstructed the rhythm history using computer simulations
and evaluated event-free survivals, sensitivity, negative
predictive value, and AF burden in a range of non-invasive
monitoring strategies including those used in contemporary AF
ablation trials.


Dr. Greg Hundley: Ah, very interesting, Carolyn. So what did they
find?


Dr. Carolyn Lam: Detection of arrhythmia recurrence following
ablation was highly sensitive to the monitoring strategy employed
between trial discrepancies and outcomes, in fact, may reflect
these different monitoring protocols. Binary efficacy outcomes,
such as time to AF recurrence, appeared to underestimate the true
impact of catheter ablation on the burden of atrial arrhythmia.


The most commonly performed intermittent rhythm monitoring
techniques, like short duration 24- or 48-hour ambulatory Holter,
they do miss a substantial proportion of arrhythmia recurrences
and significantly overestimate the true AF burden in patients
with recurrences. So based on measures of agreement, serial
long-term, that is four seven-day or two 14-day intermittent
monitors accumulating at least 28 days of annual monitoring
provide estimates of AF burden that are comparable with the
implantable cardiac monitor.


However, implantable cardiac monitors outperform intermittent
monitoring for arrhythmias and should be considered the gold
standard for clinical trials.


Dr. Greg Hundley: Very nice, Carolyn. It sounds like a lot of
clarification on monitoring of AF burden. Well, my first paper
comes to us from Dr. Prabhakara Nagareddy from The Ohio State
University, The Wexner Medical Center.


Carolyn, acute myocardial infarction results in an overzealous
production and infiltration of neutrophils in the ischemic heart,
and this is mediated in part by granulopoiesis induced by the
S100A8/A9 NLRP3, IL-1 beta signaling axis in injury-exposed
neutrophils.


In this study, Carolyn, the investigators evaluated a hypothesis
as to whether IL-1 beta is released locally within the bone
marrow by inflammasome prime and reverse migrating neutrophils.


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


Dr. Greg Hundley: Okay, Carolyn. In response to myocardial
infarction, the NLRP3 inflammasome prime neutrophils upregulated
CXCR4 and reverse migrated to the bone marrow, where they adhered
to adhesion molecules like P-selectin on the bone marrow
endothelial cells.


Second, Carolyn, in the bone marrow, the inflammasome prime
neutrophils released IL-1 beta through gasdermin-dependent
conduit pores without undergoing the mandatory pyroptosis.


Third, genetic and/or pharmacological strategies aimed at
limiting reverse migration of inflammasome prime neutrophils to
the bone marrow or release of IL-1 beta, both suppressed
granulopoiesis and improved cardiac function in mouse models of
myocardial infarction.


So Carolyn, therefore, strategies aimed at targeting specific
signaling pathways within the neutrophils or reducing retention
of the inflammasome prime neutrophils in the bone marrow may
provide novel avenues to regulate inflammation and improve
cardiac outcomes.


Dr. Carolyn Lam: Wow, neat, Greg. Thanks for explaining that so
nicely. Well, the next paper deals with my favorite topic, heart
failure with preserved ejection fraction of HFpEF, and this time
looks at mechanisms of sinoatrial node dysfunction.


The investigators, led by Dr. Cingolani from Smidt Heart
Institute at Cedars-Sinai Medical Center, sought to investigate
the role of the intrinsic pacemaker on chronotropic incompetence
in HFpEF. They performed extensive sinoatrial node phenotyping,
both at baseline and after stress in the well-characterized Dahl
salt-sensitive rat model of HFpEF.


These rats exhibited limited chronotropic response associated
with intrinsic sinoatrial node dysfunction, including impaired
beta-adrenergic responsiveness and an alternating leading
pacemaker within the sinoatrial node. Prolonged sinoatrial node
recovery time and reduced sinoatrial node sensitivity to
isoproterenol were confirmed in the two hit mouse model.
Adenosine challenge unmasked conduction blocks within the
sinoatrial node, which were associated with structural
remodeling.


Finally, single-cell studies and transcriptomic profiling
revealed HFpEF-related alterations in both the membrane clock or
iron channels and the calcium clock of the spontaneous calcium
release events.


Dr. Greg Hundley: Wow, Carolyn, lot of really interesting data
here. So what were the clinical implications?


Dr. Carolyn Lam: Yeah, it's a really great study. Two models of
HFpEF-consistent result in an important topic. Basically, here at
the take-home messages. Provocative testing can be valuable to
elicit functional abnormalities to facilitate HFpEF diagnosis and
considering the exceptionally high clinical and epidemiologic
convergence between AFib and HFpEF, sinoatrial node dysfunction
may underlie the development of abnormal atrial rhythms in HFpEF.


Dr. Greg Hundley: Very nice, Carolyn. More information on HFpEF,
again, one of your favorite subjects. Next, we're going to turn
to a paper from Dr. Jian Li from the Peking Union Medical College
Hospital. Carolyn, doxycycline has previously been demonstrated
in a retrospective study to be associated with greater survival
in patients with light chain AL amyloidosis.


Therefore, Carolyn, this group prospectively compared the
efficacy of bortezomib, cyclophosphamide, dexamethasone, or
cyclophosphamide B or D, and cyclophosphamide B or D combined
with doxycycline for cardiac amyloidosis.


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


Dr. Greg Hundley: Carolyn, this was a multi-center, open-label,
randomized controlled trial, and 140 patients underwent
randomization. The primary outcome was two-year progression-free
survival. Progression-free survival was defined as the time from
randomization to death, hematologic progression or organ
progression, and that's the heart, the kidney, or the liver.


And so Carolyn, these investigators in this trial demonstrated
that doxycycline combined with cyclophosphamide B or D failed to
prolong progression-free survival or cardiac progression-free
survival compared with cyclophosphamide B or D alone in patients
with cardiac AL amyloidosis.


So Carolyn, a negative study that's quite informative and a very
nice editorial that accompanies this article pertaining to future
directions for management of AL cardiac amyloid.


Dr. Carolyn Lam: Indeed important. Thank you. And there are other
important papers in today's issue. There's a Research Letter by
Dr. Pfeffer on the impact of sacubitril/valsartan versus ramipril
on total heart failure events in the PARADISE-MI trial.


Dr. Greg Hundley: Great, Carolyn. In the nail bag, boy, I've got
a big list today. First, Dr. Churchwell has an AHA update on the
need for policy change to improve maternal cardiovascular health.
Next, Dr. Piazza has a Perspective piece on expanding the role of
coronary CT angiography in interventional cardiology. There's an
ECG challenge from Dr. Yarmohammadi entitled “Dancing Bundles
with Stable Sinus Rhythm.” And next, we have our own Darren
McGuire who, in this issue for all of 2021, is really recognizing
our outstanding reviewers.


And we want to thank all the listeners and everyone that reviews
for us in this journal. Such an important feature and aspect to
the publication of the wonderful articles that we receive. And
then finally, there are some highlights from the circulation
family of journals. Well, Carolyn, how about we get on to that
feature discussion and learn more about colchicine and its use in
cardiovascular disease.


Dr. Carolyn Lam: Let's go and a Happy New Year, again, everyone.


Dr. Greg Hundley: Welcome listeners to this January 4th feature
discussion. This week, we're deviating a little bit because we
are going to have an author discuss one of our in-depth reviews.
As you know, we select those occasionally where they're is a
topic that's very relevant in cardiovascular medicine and an
investigator or team of investigators or authors will put
together a very nice review of a topic.


This week, we're going to talk about colchicine, and we have with
us Dr. George Dangas from the Icahn School of Medicine at Mount
Sinai and our associate editor, Dr. Brendan Everett, who manages
this paper and he is from Brigham and Women's Hospital. Welcome,
gentlemen. George, we'll start with you. George, why colchicine?
Can you tell us a little bit about mechanism of action?
Tolerability? Why would we want to use this particular agent in
patients with cardiovascular disease?


Dr. George Dangas: Thank you very much for the opportunity to
join this interesting podcast. Colchicine is indeed an
interesting drug. It's been around for centuries, in all honesty.
In general, I would say it's a mild anti-inflammatory and in
general, it's rather well tolerated. We'll go into those perhaps
a little bit later.


The precise mechanism is actually interestingly not quite
defined. It may have a few ways to act by blocking perhaps the
chemotaxis of the leukocytes or the adhesion of the leukocytes or
the ability to release their granules, et cetera, but there isn't
a specific major one that is targeting. Perhaps, it's targeting
more than one mechanism in a mild way, and I think that goes into
each utility, as well as the absence of the major side effect
that might limit it.


Dr. Greg Hundley: Very nice. So you started to mention the word
utility, so maybe let's go through some clinical indications, or
clinical uses perhaps rather than indications, can you tell us a
little bit about its use in individuals with pericarditis?


Dr. George Dangas: I think this is where it started to enter the
cardiovascular field because we all recognize that pericarditis
is an inflammatory disease and inflammation of the pericardium of
different reasons perhaps. And anti-inflammatory drug is rather
fitted to treat an inflammatory disease and besides, it's not
like we had any other drug, in all honesty. Clearly, recurrent
pericarditis might be treated with steroids for example, but
steroids is not something any cardiologist would jump as a first
line and give high doses and all that.


Colchicine made its way to pericarditis like acute or recurrent
pericarditis, post-cardiac cardiology syndrome, restless syndrome
or the specific post-cardiac surgery, major inflammation. And
indeed has a daily dosage perhaps with some loading dose or
double the daily dosage or something initially and then we give
it for a prolonged period of time in order to suppress.


I would say this is a reasonable choice rather than jumping to
the steroid. And of course, you reserve the steroid for the, I
would say, more severe or more recurrent cases. I think everybody
understands this type of activity. There've been quite a few
clinical studies in this aspect. Again, in the absence of a
competitor, I think it's a winner in this area.


Dr. Greg Hundley: Very nice. And then, how about atrial
fibrillation? Are there uses of this colchicine in patients with
atrial fibrillation?


Dr. George Dangas: Well, again, it's very interesting that a lot
of atrial fibrillation, it may be in some ways inflammatory in
origin. And quite frankly, we had an interesting [inaudible
00:14:50] clinical trial in American Heart Association in 2021.
I'd like to point out here, the study that postoperative atrial
fibrillation was mitigated when, during cardiac surgery, there
was a slicing of the posterior pericardial. This allowing the
inflammation in some ways that's related there.


To me, that was a very interesting observation, though I related
to colchicine because it validates the fact that there is
something inflammatory in pericardial that related with the
postoperative atrial fibrillation. So along these lines, let's go
back to colchicine, Afib, and postop Afib, and post-ablation I
would say patients. Again, there are risks of some inflammation
and that's where the theory of a mild, rather well-tolerated,
anti-inflammatory might come in. And there's been few studies,
not a large definitive study, but several studies that are the, I
would say, component with interesting results with colchicine in
these patients.


Dr. Greg Hundley: Very good. Another area of cardiovascular
disease that's emerging literally with some demonstrable results
using colchicine is the realm of ischemic heart disease. Can you
walk us through some of the utility myocardial infarction or
maybe even post-percutaneous coronary artery intervention?


Dr. George Dangas: Again, the hallmark in this type of diseases,
cardiovascular disease or coronary heart disease, is the hallmark
of role of inflammation in this disease. And we know very well
from the studies of the C-reactive protein, importance is a
marker of inflammation. Very, very important in the CAD as well
as in even the treatment with the antibody canakinumab a little
bit earlier in the CANTOS trial a few years earlier at the very
high level inhibited inflammation had a benefit and colchicine
comes in maybe a milder anti-inflammatory about this agent, but
at the same time with significantly less cause and significantly
better recognition among the clinicians and a lot less, I would
say, tolerability problems or issues are less unknowns. And I
think that's where it comes in.


The difficulty has been that whenever you go to cardiovascular,
the cardiovascular, I would say coronary artery disease
specifically, ACS and all that, the level evidence required for
the doctors to believe in a therapy is very different than the
areas we discussed before where there's little bit of a
pericardial disease, for example, not that many drugs, all of a
sudden, coronary artery disease, the bar is so high, and that's
where the difficulty has been.


There've been several studies. They've been interesting results
with some benefits, particularly due to the decrease in
inflammation and the secondary prevention, one can say. That is
really the hallmark of where it aims to benefit in the secondary
prevention, but there hasn't been one massive study with clearly
superb results. I would say adequately powered single study that
is missing in some ways.


But several studies have been, again, very, very encouraging, but
we learned that there's no much point if loading a lot of doses
of high doses of colchicine, and it's a little bit better, again,
when you aim with a daily dose towards reduced recurrences,
particularly if you started early after an acute event.


Dr. Greg Hundley: Very nice. Well, listeners, we're going to now
turn to our associate editor, Dr. Brendan Everett, from Brigham
and Women's Hospital. Brendan, you have a lot of papers come
across your desk. First and foremost, what attracted you to this
particular article?


Dr. Brendan Everett: Well, thanks, Greg. And kudos to George and
his team for putting together a really nice paper. It's great to
have this kind of paper come into my inbox. That's specifically
because colchicine, I think, has exploded as a really important
novel therapy even though the therapy itself is perhaps hundreds
of years old, as you heard George say a moment ago, but its role
in treating cardiovascular diseases has really begun to emerge
rapidly.


I think there's a tremendous amount of enthusiasm for other ways
to treat our patients who have really a recalcitrant
cardiovascular disease, whether that's pericarditis, atrial
fibrillation or I think, importantly, ischemic heart disease,
because that's such a common disease and something where we're
always looking for new ways to help patients live longer with
fewer recurrent events. And so this paper I thought did a really
good job of capturing the existing evidence for these conditions
and some others and giving us a sense of where the strengths of
that evidence lay and where the weaknesses were.


I thought particular strength was in the tables where the authors
laid out each of the trials and the results of the trial, their
endpoints, where the benefit was potentially. And also
importantly, where risks were seen because I think that's one of
the really important questions that remains open with respect to
colchicine therapy when we begin to talk about using it in a vast
population of people with stable ischemic heart disease or
post-myocardial infarction ischemic heart disease.


Dr. Greg Hundley: Brendan, tell us a little bit about those
risks.


Dr. Brendan Everett: I'd be happy to do that. I want to emphasize
before I dive in that I think the benefits that George has laid
out are important, and I don't want to overshadow what the major
trials have seen. But I think the thing that it is at least a
little bit of the fly in the ointment, if you will, for
colchicine in ischemic heart disease is that a couple of the
large trials have shown an increased risk of non cardiovascular
mortality or bad non-cardiovascular outcomes.


And that's of concern, I think, as we saw in the CANTOS trial,
which was the monoclonal antibody trial for canakinumab that
George mentioned earlier, there was an increase in
infection-related mortality. And so whenever you use an
anti-inflammatory drug, you're worried about whether or not
you're blunting other compensatory mechanisms that the body has
to protect against infection and other diseases.


I think it's likely that these findings are the play of chance,
but we don't know for sure. For example, in the COLCOT trial,
which I think is probably the largest and most interesting trial,
which was designed and run in Canada, there was a slightly higher
level of pneumonia in patients who got active therapy as compared
to placebo.


And then, two of the trials that were published more recently
including LoDoCo2, which was a trial of about 5,000 patients run
in the Netherlands and Australia. There was actually a marginally
increased risk of non-cardiovascular mortality. That didn't reach
statistical significance, but it was awfully close, and I think
it gave people some concern.


And then, there was also the COPS trial. Again, all these are
really outlined in wonderful detail in the manuscript where there
was a slight increase of total death and non-cardiovascular
death. These events are few, but they're in a direction in two
trials, and so they make people a little bit worried. I think the
other thing that I noticed was the high prevalence of myalgia as
a side effect.


I think, Greg, you're always interested in the clinical
implications and yesterday I was in clinic and saw a young
patient who had had pericarditis. He had been prescribed
colchicine by his primary care physician, and he literally
couldn't stand and walk up straight because of the amount of
abdominal pain he had, which was unusual. To be honest, I've
given colchicine to a hundred patients at least, and none of them
have had that profound of a side effect, but it's at least worth
considering that some patients will not tolerate the therapy
because of adverse effects.


Dr. Greg Hundley: Very good. Well, in just 30 seconds or so, for
each of you, first George and then Brendan. George, balancing
some of the efficacy and then some of the concerns, what do you
see is the next studies to be performed really in this sphere of
research?


Dr. George Dangas: This is a great question. And indeed, the
concerns one can say or the issues, I would say, regarding this
drug, are indeed real because any drug that suppresses
inflammation has this risk. There are two ways one can address
those. One is with term administration. You don't prescribe it as
an annuity forever, but you prescribe it in a three- to six-month
or one-month or try to control the time. I think this is done in
clinical practice, in all honesty.


I don't think that people are prescribing colchicine for life.
Same way when we prescribe statins, for example. On the other
hand or from investigational point of view, I think the two sets
of information we need and, in all honesty, when you investigate
issues regarding mortality or these are rare events, there's only
one. You need a very large trial or a very large register. A very
large trial preferably and colchicine being an often genetic
drug, funding sources are rather limited, but we have NIH
chipping in with some funding periodically and that might really
be needed.


So I want to outline that in the last table of our very large, I
would say large table of our manuscript but were very happily
outlined many ongoing trials. There are, in atrial fibrillation,
three coronary artery disease. One in PCI and two in stroke.
Something we didn't touch up again. But again, there's the
question of inflammation in stroke. I think there's a lot of work
ongoing. Perhaps you can see some meta-analysis, again, in order
to get a handle of those risks, but at a rather low rate. It's
just a difficult thing to come around.


Dr. Greg Hundley: Very good. Brendan, anything to add?


Dr. Brendan Everett: I would just add I agree a hundred percent
with George just said. I think the only missing piece there is
heart failure, which I think is and many have shown that there's
an inflammatory component to heart failure, whether it's heart
failure with reduced ejection fraction or preserved ejection
fraction.


And the timing of when that intervention might be, whether it
might be before the development of symptoms or because there's a
lot of trials out there that have struggled with this question
and have unfortunately failed to show any benefit, I would just
encourage the listeners of the podcast to look at this paper
because it's a really marvelous compilation of the evidence for
what is a really hot topic in cardiovascular medicine, a really
important topic for a lot of the reasons that George mentioned.
It's just very well done and comprehensive.


Again, kudos to the authors for making such a great effort at
putting something together that has a lot of clinical relevance,
I think, and also points the way forward for research as you ask,
Greg.


Dr. Greg Hundley: Very nice. Well, listeners, we want to thank
Dr. George Dangas from Icahn School of Medicine in Mount Sinai
and our own associate editor, Dr. Brendan Everett from Brigham
and Women's Hospital for bringing us this data pertaining to
colchicine benefits, as we know in acute and recurrent
pericarditis, but also emerging indications related to
post-procedural atrial fibrillation or coronary artery disease.
And really, colchicine's targeting of cardiovascular inflammation
is being helpful in those alleviating those processes.


Well, on behalf of Carolyn and myself, we want to wish you a
great week, and we will catch you next week on the run.


Dr. Greg Hundley: This program, this copyright of the American
Heart Association 2022. 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.