Skip main navigation

Circulation on the Run: September 19, 2023

  • Carolyn S.P. Lam, MBBS, PhD orcid
  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20230918.938511

Dr. Greg Hundley:

Welcome listeners to this September 19th issue of Circulation on the Run. And I am one of your co-host, Dr. Greg Hundley, associate editor at Circulation, and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

And I am the other co-host, Dr. Peder Myhre, social media editor at Circulation from Akershus University Hospital and University of Oslo in Norway. And today, Greg, we have such an interesting feature paper, discussing the clinical problem of bleeding in patients with atrial fibrillation treated with direct acting oral anticoagulants (DOACs). And this study really digs into the development and validation of the DOACs score to predict this bleeding risk. But first, Greg, there are some other interesting papers in the issue, and do you mind if I go first?

Dr. Greg Hundley:

Absolutely. Take off.

Dr. Peder Myhre:

So the first study describes the three-year results of the FAME three trial. And Greg, to remind you, the FAME three trial was the first randomized controlled trial comparing FFR, so that's fractional flow reserve-guided PCI, using current generation drug-eluting stents, and that was compared with cabbage, coronary artery bypass grafting for patients with three vessel coronary artery disease. And the primary results from the FAME three trial was published in New England Journal of Medicine in 2022 and showed that PCI did not meet the criteria set for non-inferiority versus cabbage with respect to major adverse cardiac and cerebrovascular events at one year. However, in this study which comes to us from corresponding author William Fearon from Stanford University School of Medicine, we get the results of the three-year incidences of the composite of death, MI, or stroke, which was a pre-specified key secondary endpoint in the FAME three trial.

Dr. Greg Hundley:

Oh, wow, Peder. So a really important study given that earlier publications found a benefit of cabbage over PCI and how that increased with longer follow-up. So what did they find in this study?

Dr. Peder Myhre:

Exactly, Greg, very interesting study. And in total 1500 patients were randomized to FFR-guided PCI or cabbage, and follow-up after three years was achieved in over 96% of patients in both groups. And the primary results, the composite of death, MI, or stroke in the FFR-guided PCI group was 12.0% and in the cabbage group it was 9.2%. So this was actually not statistically significant different with an acid ratio of 1.3 and a 95% confidence interval ranging from 0.98 to 1.83, and a p-value of 0.07. Also, the rates of death and stroke were no different. However, myocardial infarctions occurred more frequently after PCI, so that was 7.0% versus 4.2%, and a hazard ratio of 1.7 with a p-value of oh 0.02. So Greg, the authors conclude that in patients with three vessel coronary artery disease, there was no significant difference in the instant of the composite of death, MI or stroke between FFR-guided PCI with current generation drug-eluting stents in cabbage, a three-year follow-up.

Gladly, the event rates were lower compared with historical data, which is also interesting. And these contemporary data should be incorporated in shared decision-making with patients requiring revascularization for three vessel coronary artery disease.

Dr. Greg Hundley:

Very nice Peder. So again, of those severe outcomes, death, MI and stroke, no difference between FFR-guided PCI with current drug-eluting stents and cabbage three years after follow-up, beautifully described. Well, Peder, next we're going to turn to the world of preclinical science, and we're going to focus on smooth muscle cell phenotypic switching. Now, Peder, that phenomenon has been increasingly detected in aortic aneurysm and dissection tissues. However, the diverse smooth muscle cell phenotypes in aortic aneurysm and dissection tissues and the mechanism driving smooth muscle cell phenotypic alterations really remain to be identified. So this team with senior corresponding author Dr. Ying Shen from the Baylor College of Medicine examined the transcriptomic and epigenomic dynamics of aortic smooth muscle cell phenotypic changes in mice with angiotensin two induced aortic aneurysm and dissection by using single cell RNA sequencing and single cell sequencing assay for transposase accessible chromatin. And Peder, another aspect of many of our preclinical science articles that we publish in circulation is that we involve a clinical or a human subjects component.

And so also in this study the authors evaluated smooth muscle cell phenotypic alteration in aortas from patients with ascending thoracic aortic aneurysm and dissection and that was examined using the single cell RNA sequencing methods.

Dr. Peder Myhre:

What a beautiful design, Greg, I'm so excited to learn more about smooth muscle cell in aortic aneurysms and dissections now. So what did they find?

Dr. Greg Hundley:

Right, so several things, Peder. So first, aortic stress induces the transition of aortic smooth muscle cells from a primary contractile phenotype to diverse phenotypes including proliferative, extracellular matrix producing, inflammatory, and then also dying phenotypes. And second, these phenotypic alterations are controlled by chromatin remodeling in smooth muscle cells that reduces the chromatin accessibility of contractile genes and induces the chromatin accessibility of proliferation, extracellular matrix formation, inflammation, and also those cell death genes. Third pro-inflammatory transcription factor was found to be a key driver of the transition of smooth muscle cells from the contractile phenotype to one of the inflammatory phenotypes. And then finally, petter cytosolic DNA signals through its sensor sting to activate IRF three, which drove smooth muscle cell phenotypic alteration by epigenetically repressing smooth muscle cell contractile genes and then inducing inflammatory genes.

Dr. Peder Myhre:

Very, very nice, Greg. So do you even have some clinical implications for us?

Dr. Greg Hundley:

Absolutely, Peder. So the conclusions here are that cytosolic DNA, which commonly accumulates as a consequence of nuclear or mitochondrial DNA damage and leakage, is an important trigger for smooth muscle cell phenotypic alteration and dysfunction in aortic aneurysms and dissection. And then additionally targeting cytosolic DNA sensing sting signaling may block smooth muscle cell phenotypic alteration, preserve smooth muscle cell functions and prevent aortic aneurysm and dissection formation and progression. And thus this could really serve as a target in future studies.

Dr. Peder Myhre:

Excellent, Greg, thank you for that summary. And now, let's go through what else is in the mailbag. And first we have an exchange of letters between Doctors Figliozzi and Enriquez-Serano regarding the article,
“How Can You Assess the Risk Incurred by Patients with Mitral Valve Prolapse Diagnosed in Routine Practice?”

Dr. Greg Hundley:

Great, Peder. Finally, a really nice perspective piece by Dr. Parkash entitled, “The Role of Ablation Based Rhythm Control in the Tangled Web of Atrial Fibrillation and Heart Failure.” Well, Peder, I can't wait to learn more about DOACs and also this new score system. And so how about we transition now to that feature discussion.

Dr. Peder Myhre:

Let's go.

Dr. Carolyn Lam:

Today's feature discussion describes a very novel DOAC score. Now, this is a totally new bleeding risk prediction tool for patients with atrial fibrillation on DOACs or direct acting oral anticoagulants. When I read the title, I was like, oh my goodness, what a smart idea. Why didn't I think of that? That is such a smart idea. Well, why? Because we use a lot of risk scores in atrial fibrillation. We're so familiar with the stroke risk score, CHADS-VASc. We're, so familiar with the bleeding risk score, HAS-BLED, but all of that was on Orfarin. And now that we're all on DOAC, what is the score that we should use? Well, we're about to find out, because we have the first author, Dr. Rahul Aggarwal from Brigham and Women's Hospital, the corresponding author, Dr. Robert Yeh, from Beth Israel Deaconess Medical Center, and our associate editor, Dr. Mark Link from UT Southwestern, all here to discuss this very important paper. Bobby, if I may, Dr. Yeh, you want to say a few words on what gave you this smart idea?

Dr. Robert Yeh:

Sure, happy to. And really a pleasure for Rahul and I to be here. I think for many years now, our group has been thinking about how to best stratify individuals on the basis of their ischemic and their bleeding risk. Whether it's patients who are taking dual antiplatelet therapy after coronary stenting in this case for atrial fibrillation, who might be candidates or poor candidates for anticoagulation. And one of the things that we've noticed of course for many years, and I think it is known in the community, is that bleeding is something that is very hard to predict. I think it's been proven time and time again, bleeding is a difficult thing to predict over the long-term. In addition, when we've chosen anticoagulation for our patients with atrial fibrillation, we've often principally focused on the ischemic risk, everybody's familiar with CHADS-VASc scores, et cetera. And the HAS-BLED score while commonly used, I think still less commonly used than CHADS-VASc scores and in part because the performance hasn't been quite as good.

Now, I'll say that Rahul Aggarwal, who's just actually just a phenomenal research fellow with us and just a superstar in the making for outcomes research and clinical research, came to me with this idea. He said, why don't we build an updated model for DOACs, because actually the HAS-BLED score and other bleeding scores have never been used or validated, really we're not created in patients who are taking these new modern anticoagulants. And so maybe Rahul, I'll leave it to you and describe some of your thinking on why you wanted to pursue this study.

Dr. Rahul Aggarwal:

Thanks again for having Bobby and I. Really, the motivation for this study is that I saw clinically a lot of individuals with atrial fibrillation had the choice of whether to be on anticoagulation or not. And a tough factor in deciding this is that we all kind of understood that there was a risk for stroke, but it was hard to quantify the risk for bleeding and specifically major bleeding type events. And so our hope at this risk score is to really provide clinicians with a tool to be able to sit down with their patients and say, this is your likelihood of having a major bleed. And use that to inform the conversation, so that providers and patients can have shared decision-making on the best medical approach for their atrial fibrillation.

Dr. Carolyn Lam:

That's great. So how did you do it, and what did you find?

Dr. Rahul Aggarwal:

So we developed the bleeding risk score in a clinical trial known as RE-LY. This was a clinical trial shared through the Weebly platform. And essentially this clinical trial looked at patients who were on dabigatran, the first DOAC. And what we did is we used those patients on dabigatran, and we identified clinical risk factors to predict bleeding. Once we identified those clinical risk factors, we used some feature selection models to basically decide the best approach for which variables to include in the model. Now, one of the most important things in creating a bleeding risk score is ensuring that it is able to extrapolate to populations outside of what it was developed in. And so we actually use three different cohorts after developing the risk score in RE-LY. We used the GARFIELD-AF cohort, COMBINE AF, and RAMQ. And each of these cohorts has a different characteristic and were selected for a different reason. One was a randomized clinical trial cohort, one was a real world registry, and one was a claims' database.

And we basically saw that the prediction of the DOAC score, which we created, was similar in all three different types of cohorts, suggesting that the generalizability of the risk score.

Dr. Carolyn Lam:

Wow, that's really nice. And before you end, I mean, everyone's dying to know out there what's in that risk score? How does it differ from HAS-BLED?

Dr. Rahul Aggarwal:

I think the biggest difference in this risk score is actually two different things. One is it was designed for DOACs and so it was designed and validated in populations with different DOACs. The second is it includes 10 different variables, but what's different is it weighs these variables differently according to their influence on bleeding risks. So for example, age is a risk factor that is known to be very strongly associated with bleeding and the higher the age the more likelihood for bleeding. So it gives a disproportionate weight to those variables that are more likely to cause bleeding and less weight to those that are less likely to cause bleeding. It has 10 easily accessible variables that you're able to get in the clinical setting very quickly and very rapidly. And it includes variables such as renal dysfunction, BMI, bleeding history, and medications that increase risk for bleeding.

Dr. Carolyn Lam:

Nice. Mark, please share some thoughts of when you first saw this. And I mean I'm so thrilled that you also invited an editorial, and I read it with great interest, it was from Dr. Michael Ezekowitz and Dr. Mohammad Kamareddine. So tell us, what do you think?

Dr. Mark Link:

Yeah, we were very excited at Circulation when we got this paper, because the HAS-BLED has been around for a while and as has been mentioned it was based on Orfarin. And so Orfarin is not used much anymore in the states for AFib bleeding. But I do have some questions for the authors. So let me start with Bobby. Bobby, one of the hurdles this paper had to overcome was how different was it than the HAS-BLED, because it does share quite a number of variables with the HAS-BLED, and how would you answer that?

Dr. Robert Yeh:

I'd say that the proof is a little bit in how it performed relative to HAS-BLED in the validation cohorts. And we see that in each of those cohorts it significantly outperformed HAS-BLED. And so maybe the question is how is it outperforming HAS-BLED if some of the variables are overlapping? And I think Rahul alluded to it that part of this is just simply incorporating more information than HAS-BLED does by better refining how we weight different clinical characteristics. The second is that the clinical characteristics are weighted in a manner that is really specific to multiple different cohorts, both clinical trial and real world, who receive DOACs. The third is a little bit of addition by subtraction. Part of the most important thing about HAS-BLED is this consideration of labile INR. A totally irrelevant concept in DOACs, something that's not included in the DOAC score of course, and not relevant to patients on DOACs. So I think all of those things probably contribute to its superior performance. And we're very grateful. We're very sort of happy to see that it significantly outperformed HAS-BLED really in multiple large real world cohorts.

Dr. Mark Link:

Let me ask Rahul this. So, how do we use this clinically when we compare this to CHADS-VASc? How do we relate bleeding to stroke risk, and when should a high DOACs score stop us from using anticoagulation?

Dr. Rahul Aggarwal:

It's an excellent question. I would actually say that for many patients with atrial fibrillation, the decision to anticoagulate is very clear. There's a benefit for reducing stroke, and the bleeding risk is not that high. However, clinically we run into this scenario a lot, where patients have previously had major bleeds or are at exceptionally high risk for bleeding. Often we have to use clinical intuition to decide which of those patients are high risk for bleeding. I believe the score is a way to quantify that risk. You can input the characteristics of a patient, and you can see what level of bleeding likelihood they have. So, for example, our risk score tears patients into different categories, very low, low, moderate, high, and very high bleeding risk. And so I think the score is most useful for those who have high or very high bleeding risk or those that have low bleeding risk.

Because I think that informs a lot of the conversations with patients to say your bleeding risk is high, and CHADS-VASc suggests your ischemic risk is low, maybe this anticoagulation isn't for you, or your bleeding risk is very low, but your ischemic risk is high and anticoagulation may benefit you.

Dr. Robert Yeh:

And Mark, if I may follow your question, and say that I think that if we learn anything from our previous publication of the DAPT Score is that these fields are constantly evolving and there's a lot more evidence to be generated on the DOAC score. I think that at this point what Rahul and this group has put together, we've put together a score that can help restratify patients, how it informs treatment decisions is really not actually something that we can speak to in the data here. And it's a very difficult thing short of really understanding how people ultimately use it in the community, and then maybe even testing these scores as a decision aid in randomized clinical trials. After we published the DAPT Score, for example, that score went on to be validated in more than 10 other studies internationally in more than 100,000 patients. We had a much better understanding of how to use that score years after its publication compared to when we first published it.

And I would hope, and I would anticipate that the same would occur here. I think we need much more data information studies to understand really where the precise clinical utility of something like this will be.

Dr. Mark Link:

Major bleeding is not the same. An intracranial bleed is not the same as a GI bleed, where your hemoglobin drops two points. And I would argue intracranial bleeds are by far the worst bleed. Do you have the numbers to have a DOAC intracranial bleed score, or there are not enough intracranial bleeds that you could do that?

Dr. Rahul Aggarwal:

That's a great question. So one of the things that we did with our DOAC score is we actually validated it in fatal or life-threatening bleeds. So these are bleeds that the ISTH has defined to be very critical bleeds in organ areas that could lead to death, have substantial hemodynamic compromise. And what we found was that the DOAC score performed similarly in these outcomes. We looked at it both in RE-LY and COMBINE AF. And I think you bring up a great point. I think bleeding is a spectrum of severity, and some of the bleeds are much more critical and some are less. And so we present some of this data in the paper to really inform that conversation for how it predicts life-threatening or very, very serious bleeds.

Dr. Carolyn Lam:

That's great. Mark, I'm going to save the last question for you. I really, really liked your question of how do we apply this clinically? I mean, it would be so nice to approach this one patient, and go, your stroke risk is X and almost like an NNT and NNH type of thing. And by the DOAC score, your bleeding risk is like this, something like that on the same scale. What do you think will be the next step? What does it take? And the differentiation of types of bleeds, that's a very, very good point.

Dr. Mark Link:

Well, I do think the DOACs score will supplant the HAS-BLED score. I think it has to be further validated, but I do think using three cohorts to validate it already is a big step forward. So in my practice, the DOAC score will supplant HAS-BLED. And it will inform decision making, especially in those at moderate-risk of ischemic stroke. So with a moderate CHADS-VASc, maybe the one to twos. In those that have a higher CHADS-VASc, the threes, fours, and fives, I might accept more bleeding risk than I would certainly in a CHADS-VASc of one or two. So yes, I do think it will be the dominant score now for bleeding.

Dr. Carolyn Lam:

That is so cool. Well, everyone, you heard it right here. Get your hands on this paper. You have to be familiar with the DOACs score. I'm going to be listening to this interview again for sure. I learned so much from all of you. Thank you so much, and thank you audience for joining us today. Well, on behalf of Greg Hundley and Peder Myhre, thank you for listening to Circulation on The Run today. And please tune in again next week.

Dr. Greg Hundley:

This program is copyright of the American Heart Association, 2023. 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.

{ "id": "main-menu", "list": [ { "text": "AHA Journals", "list": [ { "text": "AHA Journals Home", "link": "/" }, { "text": "Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)", "list": [ { "text": "Journal Home", "link": "/journal/atvb" }, { "text": "Current Issue", "link": "/toc/atvb/current" }, { "text": "See All Issues", "link": "/loi/atvb" } ] }, { "text": "Circulation", "list": [ { "text": "Journal Home", "link": "/journal/circ" }, { "text": "Current Issue", "link": "/toc/circ/current" }, { "text": "See All Issues", "link": "/loi/circ" } ] }, { "text": "Circ: Arrhythmia and Electrophysiology", "list": [ { "text": "Journal Home", "link": "/journal/circep" }, { "text": "Current Issue", "link": "/toc/circep/current" }, { "text": "See All Issues", "link": "/loi/circep" } ] }, { "text": "Circ: Genomic and Precision Medicine", "list": [ { "text": "Journal Home", "link": "/journal/circgen" }, { "text": "Current Issue", "link": "/toc/circgen/current" }, { "text": "See All Issues", "link": "/loi/circgen" } ] }, { "text": "Circ: Cardiovascular Imaging", "list": [ { "text": "Journal Home", "link": "/journal/circimaging" }, { "text": "Current Issue", "link": "/toc/circimaging/current" }, { "text": "See All Issues", "link": "/loi/circimaging" } ] }, { "text": "Circ: Cardiovascular Interventions", "list": [ { "text": "Journal Home", "link": "/journal/circinterventions" }, { "text": "Current Issue", "link": "/toc/circinterventions/current" }, { "text": "See All Issues", "link": "/loi/circinterventions" } ] }, { "text": "Circ: Cardiovascular Quality & Outcomes", "list": [ { "text": "Journal Home", "link": "/journal/circoutcomes" }, { "text": "Current Issue", "link": "/toc/circoutcomes/current" }, { "text": "See All Issues", "link": "/loi/circoutcomes" } ] }, { "text": "Circ: Heart Failure", "list": [ { "text": "Journal Home", "link": "/journal/circheartfailure" }, { "text": "Current Issue", "link": "/toc/circheartfailure/current" }, { "text": "See All Issues", "link": "/loi/circheartfailure" } ] }, { "text": "Circulation Research", "list": [ { "text": "Journal Home", "link": "/journal/res" }, { "text": "Current Issue", "link": "/toc/res/current" }, { "text": "See All Issues", "link": "/loi/res" } ] }, { "text": "Hypertension", "list": [ { "text": "Journal Home", "link": "/journal/hyp" }, { "text": "Current Issue", "link": "/toc/hyp/current" }, { "text": "See All Issues", "link": "/loi/hyp" } ] }, { "text": "Journal of the American Heart Association (JAHA)", "list": [ { "text": "Journal Home", "link": "/journal/jaha" }, { "text": "Current Issue", "link": "/toc/jaha/current" }, { "text": "See All Issues", "link": "/loi/jaha" } ] }, { "text": "Stroke", "list": [ { "text": "Journal Home", "link": "/journal/str" }, { "text": "Current Issue", "link": "/toc/str/current" }, { "text": "See All Issues", "link": "/loi/str" } ] }, { "text": "Stroke: Vascular and Interventional Neurology", "list": [ { "text": "Journal Home", "link": "/journal/svin" }, { "text": "Current Issue", "link": "/toc/svin/current" }, { "text": "See All Issues", "link": "/loi/svin" } ] }, { "text": "AIM: Clinical Cases", "link": "/aimcc" } ] }, { "text": "Journal Information", "list": [ { "text": "About ", "link": "/podcasts/about" }, { "text": "Editorial Board", "link": "/podcasts/editorial-board" }, { "text": "Reprints", "link": "/commercial-reprints" }, { "text": "Customer Service and Ordering Information", "link": "/custserv" }, { "text": "AHA Journals RSS Feeds", "link": "/feeds.jsp" }, { "text": "For International Users", "link": "/international-users" }, { "text": "Institutions/Librarians FAQ", "link": "/custserv/institutionalFAQ" }, { "text": "Subscriber Help", "link": "/custserv/help" } ] }, { "text": "All Issues", "link": "/loi/podcasts", "className": "wide_dropdown_list", "list": [ { "content" : true } ] }, { "text": "Subjects", "list": [ { "text": "Arrhythmia and Electrophysiology ", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=arel" }, { "text": "Basic, Translational, and Clinical Research", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=btcr" }, { "text": "Critical Care and Resuscitation", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=ccr" }, { "text": "Epidemiology, Lifestyle, and Prevention", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=elp" }, { "text": "Genetics", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=gen" }, { "text": "Heart Failure and Cardiac Disease", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=hfcd" }, { "text": "Hypertension", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=hyp" }, { "text": "Imaging and Diagnostic Testing", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=idt" }, { "text": "Intervention, Surgery, Transplantation", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=ist" }, { "text": "Quality and Outcomes", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=qo" }, { "text": "Stroke", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=str" }, { "text": "Vascular Disease", "link": "/browse/podcasts?taxonomyUri=hwp-journal-coll&tagUri=vasc" } ] }, { "text": "Features", "list": [ { "text": "Bridging Disciplines", "link": "/browse/circ?taxonomyUri=featured&tagUri=bridging-disciplines" }, { "text": "Circulation at Major Meetings", "link": "/circ/circ-major-meetings" }, { "text": "Special Themed Issues", "link": "/circ/special-themed-issues" }, { "text": "Guidelines Put Into Perspective", "link": "https://www.ahajournals.org/circ/guidelines-perspective" }, { "text": "Circulation Supplements", "link": "/circ/supplements" }, { "text": "Cardiovascular Case Series", "link": "/browse/podcasts?taxonomyUri=features-menus&tagUri=circ-cv-case-series" }, { "text": "ECG Challenge", "link": "/browse/podcasts?taxonomyUri=features-menus&tagUri=circ-ecg-challenge" }, { "text": "Hospitals of History", "link": "/circ/hospitals-history" }, { "text": "On My Mind", "link": "/browse/podcasts?taxonomyUri=features-menus&tagUri=circ-on-my-mind" }, { "text": "Podcast Archive", "list": [ { "text": "Circulation on the Run", "link": "/circ/podcasts" }, { "text": "Subscribe to Circulation on the Run", "link": "/circ/subscribe-circulation-run" }, { "text": "#FITFAVES", "link": "/circ/fitfaves" } ] }, { "text": "Circulation Doodle", "link": "/circ/circulation-doodle" } ] }, { "text": "Resources & Education", "list": [ { "text": "AHA Guidelines and Statements", "link": "https://professional.heart.org/en/guidelines-and-statements", "target": "_blank" }, { "text": "Circulation CME", "link": "/circ/cme" }, { "text": "Information for Advertisers", "link": "https://www.wolterskluwer.com/en/solutions/lippincott-hcp-access/media-kits/circulation", "target": "_blank" } ] }, { "text": "For Authors & Reviewers", "list": [ { "text": "Instructions for Authors", "link": "/circ/author-instructions" }, { "text": "Submission Site", "link": "https://circ-submit.aha-journals.org/cgi-bin/main.plex", "target": "_blank" }, { "text": "AHA Journals EDI Editorial Board", "link": "/edi-editorial-board" }, { "text": "Author Reprints", "link": "/author-reprints" } ] } ] }