Circulation September 27, 2016 Issue


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Dr. 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 in Duke National University of Singapore.

Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.

The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.

These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.

Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.

They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.

The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.

The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.

Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.

The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.

These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.

The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.

These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.

The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.

The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.

These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.

This brings us to the end of our summaries. Now for our feature paper.

Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.

Dr. Calvert: It's a great pleasure to be here, thank you for inviting me.

Dr. Lam: Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.

Dr. Kumbhani: Hi Carolyn, thanks for having me.

Dr. Lam: Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?

Dr. Calvert: You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.

Dr. Lam: Could you tell us what makes your series special?

Dr. Calvert: Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.

I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.

Dr. Lam: Which types of perivalvular leak are you talking about here?

Dr. Calvert: We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.

Dr. Lam: Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?

Dr. Kumbhani: I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.

Dr. Lam: As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.

Dr. Calvert: Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.

Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.

Dr. Lam: Very important clinically. Take home message from your point?

Dr. Kumbhani: I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?

Dr. Calvert: When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.

Dr. Kumbhani: Exactly.

Dr. Calvert: We all have had personal experiences of that happening.

Dr. Kumbhani: Yes.

Dr. Calvert: The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.

Dr. Kumbhani: After the closure?

Dr. Calvert: After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.

Dr. Kumbhani: One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?

Dr. Calvert: That's approximately correct, yes.

Dr. Kumbhani: You had 20 centers that were doing this?

Dr. Calvert: Yes.

Dr. Kumbhani: 1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?

The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?

Dr. Calvert: I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.

One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.

I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.

I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.

Dr. Kumbhani: It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?

Dr. Calvert: We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.

Dr. Kumbhani: I see.

Dr. Calvert: I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.

Dr. Kumbhani: That's good.

Dr. Lam: That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.

Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.

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