Circulation October 5, 2021 Issue

This week's episode features highlights from Circulation's 2021 Cardiovascular Surgery Themed Issue. Join Executive Editor James de Lemos along with Associate Editors Marc Ruel and Michael Fischbein as they discuss all of the articles found in this special issue.

Dr. James de Lemos:

Hi, my name is James de Lemos. I'm a cardiologist at University of Texas Southwestern Medical Center in Dallas, and the executive editor for Circulation. And I'm standing in for Carolyn and Greg today to host our annual cardiovascular surgery-themed issue podcast. And I'm delighted to be joined by Marc Ruel, professor and chairman of the Division of Cardiothoracic Surgery at the Ottawa Heart Institute, and the director of cardiac surgery content for Circulation, as well as Michael Fischbein, associate professor of cardiothoracic surgery at Stanford and the director of the thoracic and aortic programs there. Marc, thanks for all that you do for Circulation with cardiovascular surgery content and let me turn it over to you to introduce the issue.

Dr. Marc Ruel:

Well, James, thank you very much. We're very delighted to introduce this 2021 cardiovascular surgery-themed issue. We already feel that this is going to put together some of the very best science at the interface between cardiac surgery or cardiovascular surgery, I should say, because there's some peripheral vascular topics as well, cardiology, and as well, mechanistic research. I think you're going to find that this is really a very jam-packed issue that has a lot of important messaging that will change the field going forward.

Dr. Marc Ruel:

Also, this year, I want to highlight a couple of changes in the preparation of the issue. I want to first thank the tremendous contributions over the years to Circulation and to the entire field of cardiac surgery of Tim Gardner. Really, Tim, is an absolute giant. I think he's the only person known to me who was both president of the American Heart Association and of the ATS in the field of cardiac surgery.

Dr. Marc Ruel:

Tim has really paved the way for us to develop and enhance this issue over the years, and I think 2021 is a testament to his legacy, because I would argue it's our strongest issue ever. And I also want to introduce Mike Fischbein, James and everybody, who's associate professor at Stanford. Mike is a thoracic-aortic surgery expert, also runs a translational lab, so has a very dedicated, basic science and translational surgical science expertise. So we're very, very happy to welcome Mike to the themed issue of Circulation.

Dr. James de Lemos:

Well, thanks Marc. We'll do is follow the order of the issue so that our readers and listeners can really get a sense of the content and its various types that we're publishing this year. And the issue starts with a provocative frame of reference piece from Verma and colleagues discussing the surgical left atrial appendage occlusion. Marc, what were your thoughts on that piece?

Dr. Marc Ruel:

It's obviously a game changer in cardiac surgery. I was privileged to serve as a part of the BSMB for this trial, and we can now say we toyed with the decision as to stop the trial at the appropriate time. And that's always a very difficult BSMB decision, which, frankly, you want to get it right, and you don't want to err on either side. Anyways, LAAOS III was recently published and we have a fantastic editorial in Circulation from Subodh Verma, Deepak Bhatt, and Elaine Tseng saying, which essentially highlights the importance of the trial for practice of cardiac surgery.

Dr. Marc Ruel:

It probably is that no patient who comes to cardiac surgery with a history of atrial fibrillation should, based on those findings, not have their atrial appendage ablated. There's already very little caveat, the trial has not shown what was feared prior with regards to an increased incidence of heart failure or symptoms. And really, the surgery has been effective. The ablation of the left atrial appendage is very effective in diminishing the primary outcome or of stroke, ischemic stroke or cerebral hemorrhage.

Dr. Marc Ruel:

And essentially, this was, in most cases, a surgical ablation, so cut and sew. So we don't have all the information about either endovascular devices or even ablative devices at the time of surgery. But it was a very large trial, it was a publicly funded trial. It is really the authoritative information in the field that's available so far.

Dr. Marc Ruel:

Mike, what are your thoughts around this? Do you now come to any one of your patients needing a cardiac surgical cooperation with a history of atrial fibrillation and thinking that I now need to address the left atrial appendage? Is that what you get out of this paper as well?

Dr. Michael Fischbein:

Yeah. Thanks, Marc. I think that's an excellent question. Yeah, now, every patient after this trial, I talk to them ahead of time and offer them to have their appendage ligated in this setting if they have a history of atrial fibrillation. I don't think this adds much to our operation, it doesn't increase much the clamp time. And especially, although the trial was more surgically excising with some of the newer clips out there, it really doesn't add much time to the operation. So I think this is really an important paper that will change what we do as surgeons.

Dr. James de Lemos:

Can I just comment that I think the trial has indirect implications well beyond surgery, because the demonstration of combined benefit for oral anticoagulation with left atrial appendage occlusion really suggests that, even for patients not going for cardiac surgery, at some point in the future, we may be thinking about not and either/or between the devices and anticoagulation, but maybe both.

Dr. James de Lemos:

Mike, let me come back to you. There's a really fascinating paper by DeCarlo evaluating penetrating aortic ulcers that really change my thinking on this. Can you talk a little bit about this paper and your thoughts?

Dr. Michael Fischbein:

Thanks very much, James. I think this is really an important paper that's going to change what we do as surgeons. As you know, symptomatic penetrating aortic ulcers are grouped with dissections in tremula hematoma where we treat those patients immediately. None of us know what to do though with the asymptomatic aortic ulcer, which is actually more common. A lot of us are basing our reports on some observational studies. Many of these studies are mixed, symptomatic and asymptomatic. And so the treatment really varies, from watching them conservatively to treating them with open or endovascular approaches.

Dr. Michael Fischbein:

However, this paper by DeCarlo's really excellent. They followed 273 asymptomatic penetrating ulcer patients over time following their CT scans. And they really had two key important findings. One that these ulcers really didn't change much over time, and two, the risk of some complication occurring, whether that's rupture, symptoms or progression of disease was very low at 6.5% over 10 years. And so I think this is really going to be important, because we know that these asymptomatic penetrating ulcers, we can watch them conservatively. They do have to be still followed, but we don't have to go immediately to perform some surgical procedure.

Dr. James de Lemos:

Marc, any thoughts from you on this paper? Does this change what you guys will be doing in Ottawa?

Dr. Marc Ruel:

Absolutely. Yeah, I think this is, as Mike was saying, a very germane finding that's very helpful. I think the key word here, as Mike was alluding to, is really the word asymptomatic and how do you define that? Right? I mean, many of these findings are incidental findings. Someone comes in with a bit of shortness of breath or this or that, gets a PE protocol CT scan and then a penetrating aortic ulcer is found.

Dr. Marc Ruel:

So where do you draw the line between symptoms that may be a small left lateral effusion or a bit of shortness of breath. And it's also, I think that nuance will have to be determined going forward, what is truly asymptomatic versus a few symptoms that may be less specific and perhaps not relate to the penetrating aortic ulcer. But I think it's tremendously helpful in guiding practice going forward.

Dr. James de Lemos:

Fantastic. Thank you both. Mike, I want to come back to you on another really important paper from the vascular surgery standpoint, which is the paper from the Voyager investigators on the combination of rivaroxaban and aspirin for patients with surgical treatment of peripheral arterial disease.

Dr. Michael Fischbein:

Yeah, no, I think this is another or provocative paper. And as you know, peripheral arterial disease is a really highly-significant clinical problem. We say that affects 200 million people globally. And this includes patients with claudication, arrest pain, limb threat ischemia. And currently, the treatment for this is to either a open surgical or endovascular revascularization of the lower extremity. And the problem is while these patients, they have immediate symptomatic relief where you can save their limb, we say that one out of five will develop some sort of symptom or limb ischemia by three years.

Dr. Michael Fischbein:

And so the field is really looking for some sort of adjuvant therapy to help prevent these occurrences later on. And so the Voyager trial randomized over 6,000 patients who underwent surgery, whether it was open or endovascular, and then they randomized to either receiving rivaroxaban plus aspirin, versus aspirin and a placebo. And they showed that if you received riva, that those patients had a significant reduction in the instance of their primary endpoint, which included ischemia, limb loss or symptoms. And importantly, there was not an increase in major bleeding risk in these individuals.

Dr. James de Lemos:

So fascinating. I mean, this does this change practice and is this now the standard for surgically-treated peripheral arterial disease?

Dr. Michael Fischbein:

Yeah, I think there's still some questions that we have to answer. Yeah, I think definitely this, I think will be used after the bypass surgery, but some of the things in the trial that we would have to figure out is how applicable is this to everyone. In the trial, the open surgical arm had patients with less risks. Also, some patients received vein conduit versus a prosthetic conduit. And so, I think we'll have to look at some of the sub-analysis to see who we can apply this to.

Dr. James de Lemos:

Fantastic. Marc, any thoughts from your perspective on this one?

Dr. Marc Ruel:

Yeah. Mike provided a great summary. I think one other take-home message to me is that, really, these patients should be viewed as having panvascular disease, a little bit like our CABG patients. And essentially rivaroxaban or DOACs in general have a role, like in the COMPASS trial, in preventing other complications. So here, part of the composite endpoint was myocardial infarction, right? And we know that these peripheral vascular disease patients are very much at risk of it. So it may have an effect locally, but it really, probably, has most of its effect with regards to the panvascular disease that these patients present.

Dr. James de Lemos:

Excellent. And I'll just point out that just today, the FDA released news that they've granted an indication for this combination therapy for patients with peripheral arterial disease. Let me come back to Marc for a really interesting randomized controlled trial, from China, evaluating no-touch vein graft interventions for cardiac surgery. Marc, can you talk to us about this trial and your impressions on this?

Dr. Marc Ruel:

Absolutely. Thank you, James. So this is a trial from seven hospitals in China that randomized 2,600 patients between April, 2017 and June, 2019. And patients were randomized with the use of saphenous vein grafts between a no-touch technique and a conventional saphenous vein graft harvest technique. And I'll explain a little bit what this no-touch technique is. It actually consists of two things. You take the vein by a complete incision. Often, in fact, it's more invasive, and you take the actual saphenous vein with a surrounding layer of fat and connective tissue around it. And because of that, it's not easily amenable to endoscopic vein harvest or even using small incisions.

Dr. Marc Ruel:

The other component of no touch of vein harvesting is to really preserve the anterior layer by not using any syringe inflation and letting the conduit be rinsed, but flow naturally and not be distended at all. So the trial was positive, and the trial already showed a lesser incidence of saphenous vein graft closure at both three months and 12 months on CT scan. So to give you an example, the three months saphenous vein closure was 4.8% in the conventional harvest group, versus 2.8% in the no-touch group.

Dr. Marc Ruel:

Now what's interesting to here is twofold. There may be a couple of aspects in the benefits of the therapy, and one may relate, in fact, to the lack of pressure syringe dilatation. So it's hard to tease out, is it really the surrounding layer of fat or is it the fact that the syringe dilatation procedure is not being performed in the no-touch group? The second issue is the technique is definitely more invasive. The authors found in the trial more local complications, about 50 to a hundred percent increase in terms of a local numbness, exudation, et cetera, delayed wound healing. Because you have to make bigger incisions and you have to take more tissue around where the vein that you're harvesting.

Dr. Marc Ruel:

So it is a very intriguing trial. Obviously, graph patency is something that's tremendously important around the CABG operation. But unfortunately, it steers us towards a more invasive approach. In a nutshell, it is a positive trial, but it does require the surgery to be slightly more invasive, albeit, in most cases, with addressable issues with regards to delayed wound healing and exudation. But it would be ideal if we could combine the benefits of a no-touch technique with a less invasive approach to harvesting.

Dr. James de Lemos:

Mike, this is fascinating to me because you've got a procedure that probably improves the long-term outcomes of the operation, but is associated with a longer surgical time and more local complications. Mike, I'm wondering, what are your surgeon's going to do at Stanford? Are they going to adopt this or is this too difficult and associated with too much inconvenience for the patient to become something that's done routinely?

Dr. Michael Fischbein:

Brilliant, great question, James. Because I think, often, our patients, previous to endoscopic vein harvesting, they often complained more issues with their leg incisions than their actual sternotomy. And I always tell my patients now, though, one of the incredible things is that we can take their vein endoscopically. And now, we're talking about, while we do have improvement in graft patency for the vein, we're going to go backwards and maybe have some of these wound issues again. And I'd be curious what Marc thinks, though. We are trying to do more and more arterial grafts. And so, if we're just using one vein, is it worth accepting these higher wound complications?

Dr. Marc Ruel:

It's a great point, Mike, and perhaps exactly, as you say, perhaps an increased use of arterial grafts can be combined with lack of a pressure syringe dilatation of the vein after harvest, right? And there's already some data suggesting, as provided in the excellent editorial by Vidal, that this may be mechanistically important to enhance patency. So the study is very intriguing and still remains to completely unfold.

Dr. James de Lemos:

Excellent. Really important contribution to the surgical science. Marc, I want to come back to you with another important randomized control trial, this with a really novel therapeutic compound designed to address kidney injury after cardiac surgery. Marc, can you talk about the trial with the small interfering mRNA for renal protection?

Dr. Marc Ruel:

Absolutely. Thank you, James. This is an important trial, in my opinion. It's a Phase II study of a compound named, teprasiran, which is a interfering RNA, which modifies the p53 mediated cell death response in the renal tubal cells. So what does that do, essentially, is that the thought is that it may prevent acute renal injury after cardiac surgery. We know that's a tremendous problem. Most busy cardiosurgical ICUs would have at least between 15 to 25% of the patients requiring dialysis postop, depending on the level of risk acuity that your unit is presenting.

Dr. Marc Ruel:

And it's no different whether you're in Stanford or Ottawa or Germany, in my opinion. So we need solutions here. And this is a relatively simple compound, which is administered within four hours of completion of surgery. So for instance, if the surgery was performed on pump, it was given within four hours of completion of surgery. So, for instance, if the surgery was on-pump, it was given within four of hours completion of CPB, cardiopulmonary bypass. If it had been performed off-pump, it was within four hours of the last anastomosis.

Dr. Marc Ruel:

It's a two-minute infusion, 10 milligrams per kilo, and essentially in the trial, it was not associated with any safety concerns. And quite conversely, it was actually associated with the benefit, with regards to the development of early acute kidney injury, which was 50% prevalence in the patients who were treated with placebo, versus 37% in patients who received the compound, again, named teprasiran. So I think this is quite important. It has led to a Phase III which is currently ongoing, and I think this is a very instrumental finding in the field.

Dr. James de Lemos:

Fantastic. I mean really a testament to the progress in clinical science for cardiac surgery, that we've got these randomized controlled trials moving through a development phase that may be actionable in years to come. Let's finish the discussion of the original research articles, Mike, with a review of the Yang paper, really, which also, I think, is in Circulation's real sweet spot, where we're highlighting the very best of basic and translational science coming from Surgeon Laboratories. Can you talk about that paper for us?

Dr. Michael Fischbein:

Thanks very much, James. I think this is really an exciting paper. Qiong Yang's lab at University of Michigan, they're studying Loeys-Dietz syndrome. As you know, Loeys-Dietz syndrome is one of the connective tissue disorders. There's five subtypes, and these individuals form aortic root aneurysms. Importantly, it's specific to the aortic root that these aneurysms primarily develop. Although later on, you can see them in other locations, including intracranial and some of the branch vessels.

Dr. Michael Fischbein:

But these root aneurysms can dissect and this is life threatening. Currently, the only treatment strategy for these individuals is surgical, where you perform a prophylactic replacement of the aortic root. Unfortunately, there are no real medical therapies, primarily because we don't understand the mechanisms why these aneurysms form. So Dr. Yang's lab, they model this disease using a induced pluripotent stem cell model, where cells are differentiated into the different embryologic origins of the aorta.

Dr. Michael Fischbein:

The aortic group comes primarily from the second heart field. And so, when they studied these smooth muscle cells, they were able to show that there is lineage-specific smooth muscle cell defects, and they discovered some interesting pathways that might explain why aneurysms form specifically in the root in these in individuals. They also came up with some potential pharmacologic strategies to block some of these mechanisms.

Dr. Michael Fischbein:

And so, I think this is really exciting because this is using pluripotent stem cells more as a model to study disease states. And I could see the potential, also, for precision medicine, where you take an individual cells, make their iPSCs and study that individual's mechanisms, and perhaps come up with unique medical strategies for that individual.

Dr. James de Lemos:

So let's, Marc, finish, that's really all of the original research articles we covered. Really, an amazing spectrum of clinical translational and basic science that is a Testament, both to what you all have done to recruit content, but the tremendous growth in science and the surgical specialties. Marc, let's talk a little bit about the two terrific in-depth reviews that you picked for this issue and what their contributions are.

Dr. Marc Ruel:

Thank you again, James. We have two excellent reviews in this themed issue of Circulation. One is a frontiers piece about cardiac surgery in women in the current era, going over what are the gaps in care. And this is spearheaded by Leslie Cho, from the Cleveland Clinic, and it really goes over, very comprehensively, many of the issues around not only clinical trial enrollment of women, but specific issues pertaining to the care, and which goes back even to basic science of the sex and gender of animals being used in research for reasons that I said, that are very comprehensively, again, I want to emphasize highlighted by the authors.

Dr. Marc Ruel:

And I'll give you an example, for instance. In off-pump surgery, there are some discrepancies with regards to the use of off-pump versus on-pump surgery between males and females. And we off-pump surgeons know that there are really two very different ways from the surgery. Women, for instance, have a smaller heart which is easier to expose, for instance, for lateral and inferior territories. But in the same token, the coronary targets can be smaller. So there's really a number of discrepancies here, which can be anatomic, it can be sometimes due to the disease presentations.

Dr. Marc Ruel:

For instance, women have more tricuspid valve disease, and at a certain age start having an increased incidence of aortic problems versus males. And there's also some what I would call logistical issues with regards, for instance, to clinical trial recruitments from VA centers that typically have very, very few women being eligible for enrollment there. So these issues, again, are comprehensively addressed by Dr. Cho and her colleagues. And it's a very interesting read.

Dr. Marc Ruel:

The other piece you were referring to is a state-of-the-art paper around the use of transit time flow measurements during coronary bypass. And I think our cardiology colleagues and everyone in the cardiovascular field will be very interested to learn a bit more about this. Because essentially, when we perform bypass surgery, we don't have a validated easy way to ascertain whether the grafts that we just built are doing their job. And you may say, "Well, the surgeon's great at cutting and doing anastomosis," but as I like to tell my trainees, there's much more than suturing that might be happening.

Dr. Marc Ruel:

An anastomosis may have an unforeseen flap into it. There could be a small clot that's blocking something. There could be a kink or a twist in the graft that's not readily recognized. So I think it's very important to have a thorough assessment in everybody. I'm the last author of this piece, so I'm obviously somewhat partial to it. But I think it is important for the field to have quality checking of all grafts that are performed at something, especially something as invasive as bypass surgery. The patient should come out with functional grafts and that should be validated and objectively verified.

Dr. James de Lemos:

Fantastic. Marc, and we also have two research letters in this issue of Circulation. These are small pieces, but they pack a really powerful punch. Do you want to just briefly tell us about those two?

Dr. Marc Ruel:

Absolutely. Thank you, James. As a surgeon, I love research letters. I think they are a great venue. They're under a thousand words. Certain, sometimes we're busy, we don't want to always read a 5,000-word manuscript. And they're really, they are well-suited to what I would say are surgical follow-up studies. Once a technique has been described and you want to look at what are the late outcomes of this technique, I think they're an excellent format for that. And precisely, this corresponds to the two research letters that we have in the 2021-themed issue.

Dr. Marc Ruel:

One is a long-term, 10 year analysis of the SAVE RITA trial by Kim and Kim in South Korea. The SAVE RITA trial is a fairly famous trial in our specialty, which essentially, randomized patients to have a Y graft on the left internal thoracic artery, using either a saphenous vein conduit or the right internal thoracic itself. And essentially the early results were neutral. So the two groups were comparable, which is naturally neutral. I would say non-inferior for the saphenous vein graft.

Dr. Marc Ruel:

Now we have 10-year data in over 200 patients, equally randomized between receiving a saphenous vein graft versus the right internal thoracic artery. And the results are 10 years are equally excellent between the saphenous vein graft and the right internal thoracic artery. So this is quite non-intuitive to many. Essentially, what we're showing here is that a vein graft at 10 years has amazing patency. We're talking 90%-plus in those patients who received an angiogram. So I think there's a couple of messages to remember here.

Dr. Marc Ruel:

There may be a biologic role of connecting a saphenous vein graft onto the left internal thoracic artery with regards to nitric oxide dilution. Also, technically, the authors have readily acknowledged that the harvest the vein, again, back to this saphenous vein harvest issue, they harvest it from the lower leg. Therefore, the diameter of the vein is more suited to a Y graft. And, in fact, using a vein over right internal thoracic artery may have technical advantages, because the diameter is a little bit more facile to use with regards to complex composite grafting. So it may actually be something that, if you can maintain it with patency based on say, nitric oxide dilution, is a little bit easier to maneuver and build at the time of surgery.

Dr. James de Lemos:

Marc, can I ask a question here? Does this change your practice with regard to how often you're using Y graphs, in general, and the vein on artery Y? Because, Mike, outsiders experiences that these graphs aren't used and do these data suggest that we should be using why Y graphs, in general, and this particular type of Y more often in surgery?

Dr. Marc Ruel:

Absolutely. I think these data suggest precisely that. Whether the adoption will follow is another story. There's not a lot of groups, much to your point, that are using this configuration, but it's used commonly as a bailout strategy. Let's say, one of the arteries has been injured or is not available, or you have a porcelain aorta, I think based on these important data, you can now know that you can, if well-constructed, use a saphenous vein graft as a Y graft onto the LITA with relative impunity. In fact, excellent results, if done in the way that Kim and Kim are reporting.

Dr. Marc Ruel:

Our second research letter is actually a follow-up of hybrid palliation for hypoplastic left heart syndrome. This comes from the UK, where a number of centers had used several years ago the concept of a hybrid palliation in patients who were mostly high risk for hypoplastic left heart. So here, again, much to the research letter format, we have a follow-up series with regards to following all these children who had received either a initial Norwood approach or a hybrid approach progressing to a Norwood stage two. And essentially, the overall survival, which is about, between two thirds to 75% of children at three, four years, is no different between an initial Norwood stage one approach versus hybrid palliation.

Dr. Marc Ruel:

So I think this is obviously very intriguing data. It's used to be that a hybrid palliation would only be used in very high-risk cases. I think this would provide credence to using it in a more liberal fashion. There's still the possible caveat that the centers that use hybrid palliation have a little bit of a "expertise bias," if you will, because they have both modalities being available. But I think this is a very important and very intriguing data for this extremely challenging condition.

Dr. James de Lemos:

Well, thank you. And I'd like to thank both you, Marc, and Mike for just tremendous insight. I think for somebody that doesn't live in the cardiac surgery world, having the privilege, not just to hear you explain these terrific studies, but also provide your insights in pearls about cardiac surgery and vascular surgery care in 2021 has been invaluable. And I think our listeners will feel the same way. I'd like to turn it over to you, Marc, as our leader in cardiovascular surgery to close us out today from a wonderful podcast.

Dr. Marc Ruel:

Well, thank you very much, James. Again, I want to reiterate, I think this is really a tremendous issue. It's our best ever. And I want to thank you, James and Joe Hill, as well, our Editor-in-Chief, for your support of surgery within Circulation. I also want to thank Sarah, Molly, Nick, and Augie, really, for their in their indefatigable support of our issue. I want to, again, extend our gratitude to Tim Gardner and to Mike for their tremendous help with this issue. I think this is, again, very important. Do send your best work, and I'm speaking to our readership community and all surgeons to Circulation.

Dr. Marc Ruel:

Circulation is our premier journal and surgery's tremendously important. And the interface together is a strong one, because Circulation realizes that surgery provides, and I'm a bit biased when I say this, but I think it is true. It provides the most robust and durable treatment for advanced heart disease, so it is very important to be featured prominently in Circulation. And I think this is what our current leadership and staff at Circulation are supporting, and I'm tremendously thankful on behalf of all surgeons.

Dr. Greg Hundley:

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. This program is copyright of the American Heart Association, 2021. 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, visit ahajournals.org.