Circulation October 3, 2017 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 and Duke National University of Singapore.

                                                Today's issue features striking results from the ASSERT 2 trial of the prevalence of subclinical atrial fibrillation detected with implantable monitors in a group of high-risk older individuals. Much more soon, right after these summaries.

                                                The first original paper in this weeks' journal shows for the first time that myocardial edema, in the week after STEMI in humans, is a bimodal phenomenon. First off, there is Dr. Fernandez Jimenez and Barreiro-Perez, corresponding author Dr. Ibañez, and colleagues from CNIC in Madrid, Spain, evaluate that the time course of edema reaction in 16 patients with anterior STEMIs successfully treated by primary angioplasty compared to 16 matched controls using cardiac magnetic resonance and assessing its implications for myocardium at risk quantification. The STEMI patients were scanned serially within the first three hours after reperfusion and at, one, four, seven and 40 days, while controls were scanned once. Furthermore, they performed an experimental study of 20 pigs undergoing 40 minute ischemia reperfusion, followed by serial cardiac magnetic residence exams at 120 minutes, one, four and seven days after reperfusion.

                                                The authors found that am initial wave of edema appeared abruptly at reperfusion, but it was significantly attenuated by 24 hours. The initial wave of edema was followed by a second or differed healing related wave of edema several days after reperfusion, reaching a plateau around four to seven days after myocardial infarction. Of note, cardiac magnetic resonance myocardium at risk quantification at 24 hours post-reperfusion severely underestimated the infarct size.

                                                In summary, post-MI edema in patients follows a bimodal pattern, which affects cardiac magnetic resonance in estimates of myocardium at risk. The dynamic changes in post-STEMI edema, highlight the need for standardization of cardiac magnetic resonance timing to retrospectively delineate myocardium at risk and quantify myocardial salvage. According to the present clinical and experimental data, a time window between day four and seven, post-MI, seems a good compromise for standardization. However, further studies are needed to study the effect of other factors on these variables.

                                                The next paper sheds light on molecular mechanisms underline the progression of atherosclerosis, involving multiple inflammatory events, as well as the counteraction by inflammatory responses in cells such as the endothelium, circulating monocytes and resident macrophages in the arterial wall.

                                                Co-first authors, Dr. Li and Martin, corresponding author Dr. Shyy from Xi’an Jiaotong University Health Science Center and University Health Science Center and University of California, San Diego and colleagues, analyzed RNA seek data to identify cholesterol oxidation and e-flux genes regulated by Kruppel-like factor 4, which is a key anti-inflammatory transcription factor. They found that Kruppel-like factor 4 upregulates cholesterol 25 hydroxylase and liver X receptor in vascular endothelial cells and macrophages. In further in vitro and in vivo experiments, they show that access enhanced reverse cholesterol transport from the vascular wall, mitigated inflammation through suppression of sterile regulatory binding protein two and NOD-like receptor family hiring pyrin domain containing protein three inflammasome in endothelial cells and also promoted cholesterol e-flux in M1 to M2 transition in macrophages.

                                                In summary, Kruppel-like factor 4 trans-activates cholesterol 25 hydroxylase and liver X receptor, promoting the synergistic effects between individual cells and macrophages to protect against atherosclerosis susceptibility, and this may therefore be a therapeutic target for cardiovascular disease.

                                                The next study provides data on the safety and efficacy of a novel cobalt alloy-based coronary stent eluting the antiproliferative agent, ridaforolimus, for treatment of patients with coronary artery disease.

                                                Dr. Kandzari from Piedmont Heart Institute in Atlanta, Georgia and colleagues, reported the primary results of the bionics trial, which was a prospective international, one-to-one randomized trial conducted to evaluate in a noninferiority design, the relative safety and efficacy of ridaforolimus-eluting stents compared to slow release zotarolimus-eluting stents among 1,919 patients at 76 centers undergoing PCI. At 12 months, the primary endpoint of target lesion failure was 5.4% for both devices, thus meeting the prespecified criteria of noninferiority of ridaforolimus stent compared to the zotarolimus stent.

                                                Angiographic and intravascular ultrasound measures of restenosis, late lumen loss and nepintimal hyperplasia measured at 13 months, were similar in both devices. Treatment with the ridaforolimus-eluting stent resulted in low rates of myocardial infarction, repeat revascularization and stent thrombosis, and results were consistent in predefined patients and lesion groups. The authors therefore concluded that these results support the safety and efficacy of ridaforolimus-eluting stents in patients representative of every day clinical practice.

                                                Well, that wraps it up for your summaries. Now, for our future discussion.

                                                Today for our future discussion, we are going to talk about a true global public health problem. It's a condition that affects 33 million people worldwide, a number that is expected to double by 2050, and what we're talking about is atrial fibrillation. Those are the numbers of just what we know of detected atrial fibrillation, but today's paper deals with silent subclinical atrial fibrillation and the results of the ASSERT 2 trial. I'm so pleased I have the first and corresponding author with us today, Dr. Jeff Healey from Population Health Research Institute at McMaster University in Hamilton, Ontario. Welcome, Jeff.

Dr. Jeff Healey:                 Good morning.

Dr. Carolyn Lam:               Also on the show today is Dr. Sami Viskin, associate editor from Tel Aviv Medical Center. Hi, Sami.

Dr. Sami Viskin:                 Hi. Hello, everybody.

Dr. Carolyn Lam:               Jeff, from ASSERT to ASSERT 2, could you give us a bit of the picture of what made you do ASSERT 2 and what have we learned?

Dr. Jeff Healey:                 The ASSERT trial was a large 2,500 patient trial in patients in with pacemakers and also implantable defibrillators and it was really an easy first place to study this entity of sub-clinical atrial fibrillation because, of course all of these patient had implanted devices with electrodes in their atrial where they could report all of the internal activity continuously for many years at a time. This was done with really no incremental costs or inconvenience to the patient, the data were already being collected, so in ASSERT we asked the question, how common is atrial fibrillation as it is not detected clinically and is it associated with stroke? What we found was that over time, somewhere between 30% and 40% of patients with an implemented device developed atrial fibrillation, which we termed subclinical atrial fibrillation, because this was not detected by the usual clinical mean. Great results, very interesting, but begged the question, is this a unique entity that we see only in pacemaker patients or if you just took older individuals in the more general population, would you see subclinical atrial fibrillation as well? That was really the impetus for doing that ASSERT 2 trial in patients who are over the age of 65, had cardiovascular condition, placed them at increased risk or stroke in atrial fibrillation, but did not have implanted devices.

Dr. Carolyn Lam:               Indeed, Jeff. That's a beautiful set up. The ASSERT was really quite a landmark study suggesting that what we know as clinical may be just the tip of the iceberg, isn't it? Now you've extended it, and I think it'd be really important for the audience to understand that ASSERT 2 was really a high risk cohort. Could you maybe tell us a little bit more of what you did and what more we learned?

Dr. Jeff Healey:                 Sure. These were typical patients who might be attending a cardiology clinic, an outpatient general medicine clinic who did not have pacemakers and did not have any history of atrial arrhythmias, but you're right, they were high-risk. These were patients over 65 who have had clinical risk factors, things like hypertension, or diabetes, but also some other marker of increased risk such as a BNP that was elevated or left atrial enlargement.

Dr. Carolyn Lam:               Yeah and your findings were so striking. Tell us.

Dr. Jeff Healey:                 What was quite was surprising was, indeed, we found that in the non-pacemaker, non-defibrillator population from ASSERT 2, we also found high prevalence of subclinical atrial fibrillation. This was really quite surprising. In fact, it was many times higher than we had predicted. We found that over time, the annual risk of developing atrial fibrillation in this cohort was 34.4% per year, which is truly astounding number of patients who developed atrial fibrillation.

Dr. Carolyn Lam:               That's like one in three of such patients experiencing at least one of these episodes lasting at least five minutes? That's really impressive.

Dr. Jeff Healey:                 It was high.  You could look into that study and find groups where the risk was even higher, so we chose to cut off left atrial volume of 58 millimeters and not correspondent with the median volume of the population series of Olmstead County for people over the age of 65 who came in for an echocardiogram, and that was the minimum left atrial size to get into the trial. If you then looked at within the ASSERT 2 trial and looked at the volumes within the trial, somewhere around 72 1/2 milliliters, if you looked at the patients who had the top of atrial size, that risk was as high 50% per year, so one in two.

Dr. Carolyn Lam:               Another thing I noticed though about your results is that the frequency of these episodes, it's not that frequent, and so what we would do typically in a 24-hour monitoring or even a seven-day monitoring would have captured only a small proportion of these. Isn't that the case, Jeff? Could you give us some numbers there?

Dr. Jeff Healey:                 Yes, of course. The episodes that qualified were at last five minutes in duration, we then do longer episodes in course, but these were much less frequent in the single digit percent risk, and what we found was there were, as you say, quite infrequent. So with the standard 24-hour halter monitor, for example, you would have had a very low pickup. It really goes to show that the longer you monitor, the more you will find. I think that's the key message out of this study and other studies like it.

                                                I think conversely, you also have to realize that the more you look, or the harder you look, you may be uncovering atrial fibrillation that behaves differently than atrial fibrillation you find, for example, in the single 12 lead ECG. We have found, and others have found, that the risk of stroke we find when we would have short episode picked up only with long term continuous monitoring is real but it's much lower than we see with atrial fibrillation that was picked up by ECB where patients are presenting in emergency rooms stroke with symptoms.

Dr. Carolyn Lam:               That's such relevant points, and it really brings up the unanswered questions perhaps, exactly what is the correlation with stroke risk? What should we do about it? Sami, I'm sure you have other questions when you handle this paper and we had so many discussions among the editor, would you like to just start the ball rolling in some of these considerations?

Dr. Sami Viskin:                 Well, actually, we understood from the beginning of the study was not powered to show any difference in outcome by intervention, by treating any of these patients that had discovered atrial fibrillation with anticoagulation, so we took this paper as what it is, a paper that shows the unexpectedly high privileges of atrial fibrillation in patients who have neither symptoms nor electrocardiographic documentation of atrial fibrillation when they undergo implantation of our recording device. So we took this paper for what it is, a very interesting finding that opens the door for new studies, testing perhaps the value of intervention with anticoagulation at an earlier stage.

Dr. Carolyn Lam:               Yeah, I agree. I'd love to hear Jeff’s thoughts on what those next steps may be, but just to point out to the audience, I mean, at the moment, our decisions on whether to anti-coagulate, like the CHADSVASC score and so on, doesn’t really take into account the type of atrial fibrillation or the duration of atrial fibrillation? Does it? What do we do now? What do we do in the context of the fact that results, like the COMPASS trial, that maybe just based on the presence of vascular disease, we should anti-coagulate, right? Jeff, how about your thoughts? What are the next steps?

Dr. Jeff Healey:                 You're right. I mean, is there a value for empirically anticoagulating individuals. That's really going to boil down to the individuals with an absolute risk of stroke and how well they do on anticoagulants. Good question.

                                                In the post-stroke world or post-cryptogenic stroke, which we now report to as [inaudible 00:16:48], these individuals are being evaluated with two large clinical trials, looking at this idea of just empiric anticoagulation with low dose, NOAC in comparison to aspirin.  These trials are ongoing, and they expect to report findings by the end of 2018.

                                                In the general population, no such large scale trial is ongoing at the present time. You mentioned COMPASS and the big COMPASS results were clearly a big result at the European Society meeting, but it must be clarified that the dose of NOAC or rivaroxaban used in COMPASS was not the typical dose that we would use in the treatment of patients with atrial fibrillation, so much lower. I think we have to be careful when we're talking about doses that may be different 5 to 10 fold and what is then coagulating a patient and what is not. I think, certainly, I would not consider the COMPASS tests right now to be an effective atrial fibrillation dose, but as we've discussed, subclinical atrial fibrillation is different and we may have further data in the future.

                                                Now, how do we get there? I think many people are aware of two ongoing trials, the ARTESIA trial, which is run by our group, the NOAH-AF Trial run by Kirchof and the group from Birmingham and the AF-NET organization, and these two ongoing trials have taken this question back again, so the pacemaker population that we are enrolling thousands of patients with pacemakers and defibrillators who have these short episodes, and they're being randomized treatment with a full dose new oral anticoagulant vs aspirin. These trials are ongoing, and I think these trials and the pacemaker population will actually give us the answer to what is the risk benefit for treating, so interesting course of event. We started in the pacemaker population to show there was risk for these short episodes, that this was hotly debated 10 - 15 years ago, and now we take ASSERT 2 and other trials into the non-pacemaker population to show that this is actually a problem for older individuals in general, and now the third step, go back into the pacemaker clinic again and to do trials to study the effectiveness in therapy.

Dr. Carolyn Lam:               Great point and great takeaways. How about, Sami? What do you think would be the take-home message for clinicians at this moment based on what we know now and based on this new data?

Dr. Sami Viskin:                 Well, the message is clear, the message is that atrial fibrillation is far more prevalent than what we think it is, the message is that for every event of atrial fibrillation that we feel we probably have many events that we don't feel we should be distrustful about judging the decision to anti-coagulate or not based on symptoms, and I'm referring now to patients who already have one event documented of atrial fibrillation and are waiting until they feel the next one, before they start taking anti-coagulations. This is another warning about how we should be careful about trusting symptoms when deciding to treat and when not to treat. I just said this opens a new door for a new line of studies, looking at how early to intervene with anticoagulation, what dosage should be used for these patients who probably have lower burden of atrial fibrillation. If you can see that the patients who have atrial fibrillation documented on the electric cardiogram, as patients who simply have a higher burden and therefore they are more likely to come up with documentation on a regular ACG, so perhaps those only have subclinical atrial fibrillation have a lower burden, perhaps they can benefit from lower doses of anticoagulation, but these are all fit, that need to be proven by trials.

Dr. Jeff Healey:                 It is not only an issue for implanted devices but with the implantable cardiac monitors, this is now relevant for many other patients who have these devices implanted for things like syncope, but also there's been a lot of progress in the last 5 to 10 years on surface-attached based monitors or other types of monitors that can be with patients for days, weeks and even months, and we're all grappling with this in clinical medicine, what to do with a person with 25 beats of an atrial tachycardia or 37 seconds on a 30-day monitor? It's all an issue of the density, the burden of arrhythmia, and we do believe there is some gradience in the risk of stroke ... You're right, the treatment is not obvious, but we should take our treatment for patients who are in atrial fibrillation a lot or all the time, and simply apply it upstream like, that we may have very different treatment or approaches that are more tailored to individual patient risk.

Dr. Carolyn Lam:               Thanks, Jeff, and thank you so much, Sami. Congratulations, Jeff. We discussed a lot of other questions that need to be answered, but you've really opened the door to look at some of these questions with your paper today and we're really very proud to be publishing your paper in this week's journal.

                                                Thank you very much, listeners for joining us this week. Don't forget to tune in again next week.