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Circulation on the Run

Jan 3, 2022

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