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Circulation on the Run

May 11, 2020

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.

Dr Greg Hundley: And I'm Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia.

Well, our feature article this week, Carolyn, is really interesting and evaluates management of patients that are suspected to have atrial fibrillation and how we should screen them, what kind of monitoring and the like, very interesting discussion that will be coming up.

But before we get to that, how about we start into the papers and would you like to go first?

Dr Carolyn Lam: I would love to. And the first one is a basic paper on regenerative therapy, very important topic. Now remember that mammalian adult hearts have limited regenerative capacity. However, a transient regenerative capacity is maintained in the neonatal heart.

So co-corresponding authors, Dr Wang and Dr Guo from Nanjing Medical University hypothesize that by analyzing systemic phosphorylation signaling in ischemic neonatal myocardium, they may unlock key pathways involved in heart regeneration.

They therefore used quantitative phosphorylation proteomics to analyze the kinase substrate network of regenerative myocardium post MI in neonatal mice. And they found that activated Chk1 kinase was responsible for neonatal regeneration and could enhance cardiac regeneration in adult hearts post MI via activating the mTORC1 P70-S6K axis.

Dr Greg Hundley: Wow, Carolyn. Sounds like this could have a lot of clinical application several years down the road. So what are your thoughts on that?

Dr Carolyn Lam: I thought you may ask. Well, potentiation of Chk1 kinase, therefore, may be a promising regenerative therapy and authors gave this example that Chk1 injection could for example, in the form of a hydrogel, be injected into the myocardial infarction region and surrounding areas and may even be a novel therapeutic option to promote cardiac regeneration post MI.

Dr Greg Hundley: Very good, Carolyn. Well, my paper comes from the PARTNER 3 trial and remember PARTNER 3 is a comparison of transcatheter versus surgical aortic-valve replacement in low risk patients.

The corresponding author is Dr Philippe Pibarot from Quebec. The placement of aortic transcatheter valve three or PARTNER 3 trial randomized a thousand patients with severe aortic stenosis and low surgical risk at 71 centers to undergo either transfemoral TAVR with the balloon expandable SAPIEN 3 valve versus undergoing SAVR or surgical aortic valve replacement.

Transthoracic echocardiograms were obtained at baseline and at 30 days and one-year post procedure and they were analyzed by a consortium of two echocardiography core labs.

The objective of this study is to compare echocardiographic findings in low risk patients with severe aortic stenosis following surgical or transcatheter aortic valve replacement.

Dr Carolyn Lam: Important topic, very hot. So what did they find?

Dr Greg Hundley: In patients with severe aortic stenosis and low surgical risk, TAVR with the SAPIEN 3 valve was associated with a similar percentage of moderate to severe AR compared with SAVR, but a higher percentage of mild AR with no association between any grade of AR and outcomes.

Trans-prosthetic gradients, valve areas and LV mass regression were similar in TAVR versus SAVR. And SAVR was associated with a significant deterioration of RV systolic function and greater tricuspid regurgitation, which persisted at one year.

So Carolyn, very interesting results. Another study from PARTNER 3 comparing TAVR versus SAVR for patients with severe aortic stenosis.

Dr Carolyn Lam: Nice. So going from PARTNER 3, I want to talk about MESA and this time focusing on coronary artery calcium. Now we know that the recent ACC/AHA primary prevention guidelines recommend considering low dose aspirin therapy only among adults who are at high atherosclerotic cardiovascular risk but not at high risk of bleeding. However, it remains unclear how these patients are best identified.

So the current study aimed to assess the value of coronary artery calcium for guiding aspirin allocation in primary prevention using the 2019 aspirin meta-analysis data on cardiovascular disease relative risk reduction and bleeding risk.

So corresponding author Dr Cainzos-Achirica from Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and colleagues studied 6,470 participants from MESA all of whom underwent coronary artery calcium scoring at baseline to assess benefit versus harm.

A 12% relative risk reduction in cardiovascular disease events was used for five-year number needed to treat calculations, while a 42% relative risk increase in major bleeding events was used for the five-year number needed to harm estimations.

And now here are the results. Only 5% of MESA participants would qualify for aspirin consideration for primary prevention according to the ACC/AHA guidelines and using more than 20% estimated atherosclerotic cardiovascular disease risk to define higher risk.

Among the 3,540 aspirin naive participants less than 70 years old and not at high risk of bleeding, the overall number needed to treat in five years with aspirin to prevent one cardiovascular disease event was 476, while the number needed to harm in five years was 355.

The numbers needed to treat in five years was also greater than or similar to the numbers needed to harm among estimated ASCVD risk strata by pool cohort equations.

Conversely, with a coronary artery calcium score of more than a hundred or more than 400, both these cutoffs identified subgroups in which the number needed to treat in five years was lower than the number needed to harm in five years.

Also, coronary calcium score of zero identified subgroups in which the number needed to treat was much higher than the number needed to harm.

Dr Greg Hundley: Lots of data. So we're mixing aspirin and MESA coronary calcium scores. What do we take home from this?

Dr Carolyn Lam: So here's the take home message. Coronary artery calcium may be superior to the pool cohort equations to inform the allocation of aspirin in primary prevention.

Individuals with a coronary artery calcium score above hundred and particularly above 400 may be good candidates for aspirin therapy for primary prevention. Although the net expected benefit will likely be modest.

In the presence of zero coronary artery calcium, the risk of bleeding is greater than the potential benefit and aspirin therapy for primary prevention should probably be avoided.

Overall, implementation of the current 2019 ACC/AHA guideline recommendations together with the use of coronary artery calcium scoring for further risk assessment may result in a more personalized, safer allocation of aspirin for primary prevention. Although ,of course, confirmation and external settings are required.

Dr Greg Hundley: That was really interesting. Combining coronary calcium scores, if you happen to have it, if someone's considering primary prevention with aspirin, it looks like those calcium scores could really be helpful there.

Well, I've got a couple other papers to talk about in this week's issue. There's an ECG challenge from Abdulhamied Alfaddagh from Johns Hopkins reviewing the quote unquote de Winter EKG pattern in a truck driver presenting with chest pain.

Second, there's an in-depth article from Alexander Fletcher from Edinburgh in the United Kingdom who discusses the metabolic pathways involved in inherited aortopathies trying to move beyond just diameter assessments to predict risk above future dilation and rupture.

And then lastly, there's a research letter from Petra Frings-Meuthen from the German Aerospace Center, the reports on how weightlessness shifts intravascular volumes and concentration of natriuretic peptides in astronauts.

Dr Carolyn Lam: Huh. And I would like one on my mind by Dr Kowey and it talks about the relentless pursuit of new drugs to treat cardiac arrhythmias.

Wow. What a nice issue. Let's move on now to our feature discussion.

Dr Greg Hundley: Welcome everyone to our feature discussion. In this particular paper will focus on atrial fibrillation and we're delighted to have Dr Søren Diederichsen from Copenhagen presenting this work and Dr Changsheng Ma, one of our associate editors from Beijing, China to have nice discussion.

Søren, I was wondering if we could get started with you. Could you tell us a little bit about what was the background related to this study and perhaps even a little bit about the hypothesis that you wanted to test?

Dr Søren Diederichsen:  The background for this study is that, as we all know, atrial fibrillation is actually big and it's a growing health problem throughout the world and we also know that AF is often asymptomatic. So many cases of atrial fibrillation go undetected until complications occur.

And, of course, one of the most feared complications from AFib is a disabling stroke. And there's more and more evidence growing that a large proportion of people with risk factors for stroke do have some subclinical atrial fibrillation when they investigated or when they are followed, for instance, with a pacemaker.

So there has been a recent meta-analysis that found that the at risk of stroke in patients with subclinical AFib was fairly large compared to the risk of stroke in patients without subclinical AFib.

So, in this study, we want to look at the subclinical AFib in patients from the general population using loop recorders to follow these patients. And we want to sort of look at how could we screen the patients to find those with subclinical AFib using different screening scenarios which are less intensive than using a loop recorder for everyone.

Dr Greg Hundley: Søren, could you tell us a little bit about your study population and your study design?

Dr Søren Diederichsen:  First of all, this study is part of an ongoing randomized control trial called the loop study. And in the loop study we recruited study participants from the general population.

The participants had to be at least 70 years old. And besides age as a stroke risk factor, they also had to have at least one additional stroke risk factor, hypertension, diabetes, heart failure or previous stroke. And importantly, they could not have AFib.

And the included participants were then randomized to control or screening for AFib using implantable loop recorder with remote monitoring and adjudication of new onset AF episodes.

In this particular study, we looked at the first participants in the loop recorder group who had been monitored for the entirety of the device's battery life, which is approximately three and a half years. So for these persons, we know whether or not they actually have AFib and we know exactly when they were in AFib and when they were in sinus rhythm.

So we use this data from the loop recorders to reconstruct full heart rhythm histories for each person, including exact time of onset and termination of each episode after exclusion of any clinically detected AF in the patients.

And it's a bit complicated study design because we have these heart rhythm histories. Now you can imagine where we have a string of data which is approximately three and a half years long and we know exactly when is AFib present and when a sinus rhythm present in this patient.

So we could use that data to simulate that the persons had been invited to an AFib screening by the health care service and had undergone a different type of screening at a random time. And these screenings that we investigated were time-point screening using standard ten second ECG during office hours and intermittent screening using single list devices, for instance, and short term continuous screening using external devices such as Holter or event recorder.

So we simulated that the patients had undergone such screenings and we could also assimilate that the patients were screened several times on a monthly or annual basis such as, for instance, taking an ECG every year.

And this simulation was then used to evaluate the sensitivity and negative predictive value of various screening regiments using the loop recorders' gold standard.

Dr Greg Hundley: What were your study results?

Dr Søren Diederichsen:  All of this data comprised, as I told you, the first participant in our trial that had been monitored for the full battery life of the device.

So that was 590 participants entering nearly 700,000 days of continuous monitoring. So that was our data. And one third of those participants actually had previously unknown AFib and the number of AF episodes in our data was more than 20,000 AF episodes.

The main results were that if we simulate the pseudo-random daytime ECG in those patients, we would have identified only 1.5% of those who had AFib while performing by daily 32nd ECGs during 14 days, we would have identified 8% of those with AFib.

And if we took a 72-hour Holter, we would have identified 15% or a longer, for instance, a 30-day event recorder, we would have identified about a third of all those with AFib.

So that was actually our main results. We were able to see how many would we have identified of those with AFib if we'd done anything from taking a daytime ECG to performing a rather long event recorder.

Dr Greg Hundley: Were you able to put together maybe a combination of other variables along with the more lengthy recordings that could forecast future atrial fibrillation?

Dr Søren Diederichsen: One of the things we wanted to do with this study was not only did we want to see what is actually the diagnostic performance of doing an ECG or screening patients at risk with different kinds of screening, we also want to look at specific subgroups of the population who were more likely to maybe benefit from the screening in terms of having their AFib diagnosed.

So we looked at some population characteristics, age, sex and NT-proBNP. And we saw that the sensitivity of the screening was consistently higher among those who were older with a cutoff at 75 years, and also among males and among those with a high NT-proBNP.

So we could see that if we had screened one of those risk factor groups, age, male sex or high NT-proBNP, we would have been more or less likely to identify if AF was actually present.

Dr Greg Hundley: Changsheng, I'd like to turn to you. Can you help us put this results into perspective? How should we use this information in managing patients with atrial fibrillation?

Dr Changsheng: The AI for screening is a very important clinical problem and a hot topic issue. The heart rate monitoring is a cornerstone for detecting suspected AF patients. And then emerging new technology make monitoring more convenient than before.

But however the best screening strategy for those at higher risk of future AF stroke. And probably the strategy for the general population screening remain undetermined.

On the contrary, they evaluated the performance of a large panel of AF screening strategy among the 600 persons with a stroke risk factor that was not known yet.

The study used as an implantable loop recorder as a gold standard to assess the detection or difference in simulating a screening model.

I've got to say, the method employed in this study is quite exquisite and there's a key finding our clients tried to forward.

The time-point screening or the short-term monitoring could only identify a very small fraction of AFIB as compared for long-term loop recording screening. And diagnostic yield increased with duration, number and the dispersion of screenings.

So this is done to provide important clinical implications that every relatively intense screening such as even now I knew 30-day monitoring would need more than four in ten with AF.

And about one in six which are underlying more than 24 hours episode of AF. So the authors also gave the practical dispersion concept that when screening for AF, three times 24 hour monitoring are superior to one time 72 hour monitoring.

So I think this is a very important study to understand the condition, to understand the screening of AF patient for the general population.

Dr Greg Hundley: So really, helping us put these results in perspective. Maybe I'll ask each of you Søren first and then Changsheng. What do you think is the next research that needs to be performed after taking your results into account?

Dr Søren Diederichsen:  In terms of what we should do next, I agree with Changsheng that there's a lot of attention towards AF screening at the moment, but we still really don't know if widespread screening in the population is actually something that could prevent heart endpoints.

So the next thing we need to know is, first of all, if we screen, will we have fewer of those events or will we have more side effects from the screening such as anticoagulant-mediated bleedings? It's very important to keep in mind that we don't yet know if screening is something that would prevent heart endpoints.

Second of all, we want to know more about what is actually the relationship between AF burden or amount of AF and risk of stroke. There's some evidences coming up that it's growing.

Is it, for instance, from the CERT study that the amount of AF and the pattern of AF that you have might tell us a little bit about what is your risk of stroke? For instance, if you have long AF episodes, your risk of stroke is higher than if you have all the short AF episodes.

And so that would be two of the next things I would think we should look at.

Dr Greg Hundley: Very good. Changsheng, do you have something to add to that?

Dr Changsheng: Yes, I agree with Søren. Now, on the detection, it's important but as a burden, even more important. So in practice in future, wouldn't we need more advanced technology and the patients or the participants frontally the monitoring device, which has the same ability to loop record them.

But this is more easy to use because when we use frontal monitoring for the patients, the longer duration of your monitoring period. So worse complains to the patients, not as our study because we have a simulation methodology, that 100% of patient accomplishments.

So I think in future, the watch with a diagnostic function of AF differentiation based on not ECG, but only based on the pulse.

So, the watch diagnostic function, not by ECG that are by pulse, like a detection of pulse. And then depend on the artificial intelligence, the AI function, to make a diagnosis of atrial fibrillation, not by ECG. That would be the future.

Dr Søren Diederichsen:  And if you don't mind, I would like to add to that because I think that Changsheng raises an excellent point here with the smartwatch and how could they contribute to our prevention of stroke and in society.

So the current smartwatches work by looking at the pulse by photoplethysmography. And they cannot look at the pulse continuously as we do with the loop recorder looking at the ECG continuously.

This like with the photoplethysmography turns on when the patient is at risk and builds up an algorithm to look at what is actually the likelihood that the patient is an AF at this moment or today.

So at this point it'll only detect fairly long AF episodes, but in this study, we also looked at the longer AF episodes and the AAF burden. How does that impact the likelihood of detecting AF and of course it's more easy to detect it in patients with long AF episodes.

And if we find out in the future that a larger AF burden or longer AF episodes are actually required to increase the risk of stroke, then I believe that technology such as smartwatches could be a very feasible way to screen or to detect that kind of AF in patients at risk.

Dr Greg Hundley: Well listeners we've had a wonderful discussion here with Dr Søren Diederichsen from Copenhagen and our associate editor, Changsheng Ma from Beijing, China.

And really reviewing some important results related to screening for atrial fibrillation and the three 24-hour monitoring sessions combined with risk factors really help us identify who may be experiencing atrial fibrillation in our patients.

And then also, very interesting projections for the future, both using technology to try to identify atrial fibrillation perhaps through watches.

And then also how we could incorporate the duration, the time, et cetera of atrial fibrillation occurrences and how they may relate to adverse events.

Thank you so much Søren. Thank you Changsheng. And to all our listeners, we wish you a very safe week and look forward to meeting with you next week. Take care.

This program is copyright the American Heart Association 2020.