Circulation July 25, 2017 Issue

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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. Our journal this week features an in-depth review on transcatheter therapy for mitral regurgitation, a very, very hot and interesting topic. You have to listen on, coming up right after these summaries.

Our first original paper this week sheds light on the influence of aging on aldosterone secretion and physiology. First author Dr. Nanba, corresponding author Dr. Rainey and colleagues from the University of Michigan in United States, examine the relationship between age and adrenal aldosterone synthase in 127 normal adrenals from deceased kidney donors. The donors' ages ranged from nine months to 68 years. The authors found that adrenals from older individuals displayed less normal aldosterone synthase expression and zona glomerulosa, and greater content of abnormal foci of aldosterone synthase expressing cells.

Furthermore, older age was independently associated with dysregulated and autonomous aldosterone physiology, in an ancillary clinical study of subjects without primary aldosteronism. This study therefore suggests that aging may be associated with a sub-clinical form of aldosterone excess and provides at least one potential explanation for age related cardiovascular risk.

The next study shows, for the first time, that the chemokine receptor, CXCR4, in vascular cells, limits atherosclerosis. The CXCL12 and CXCR4 chemokine ligand receptor axis is known to control cell homeostasis and trafficking. However, its specific in atheroprotection has thus far been unclear. This is addressed in today's study by first author Dr. During, corresponding author Dr. Weber, and colleagues of The Institute for Cardiovascular Prevention in Munich, Germany. In hyperlipidemic mice, the authors showed that cell-specific deletion of CXCR4 in arterial endothelial cells, or smooth muscle cells, marked the increase atherosclerotic lesion formation. Mechanistically, CXCR4 axis promoted endothelial barrier function through VE-cadherin expression and a stabilization of junctional VE-cadherin complexes. In arterial smooth muscle cells, CXCR4 sustained vascular reactivity responses, and a contractile smooth muscle cell phenotype. Whereas, CXCR4 deficiency favored the occurrence of macrophage-like smooth muscle cells in atherosclerotic plaques and impaired cholesterol efflux.

Finally, in humans, the authors identified a common allele variant within the CXCR4 locus that was associated with reduced CXCR4 expression in carotid RG plaques, and increased risk for coronary heart disease. Thus, the study suggests that enhancing the atheroprotective effect of arterial CXCR4 by selective modulators may open normal therapeutic options in atherosclerosis.

The next paper is the first to study the effects of rosuvastatin on carotid intima-media thickness in children, with heterozygous familial hypercholesterolemia. First author Dr. Braamskamp, corresponding author Dr. Hutten, and colleagues from Academic Medical Center Amsterdam in the Netherlands, study children with heterozygous familial hypercholesterolemia aged 6 to less than 18 years, with LDL cholesterol more than 4.9, or more than 4.1 millimoles per liter in combination with other risk factors, who received rosuvastatin for 2 years, starting at 5 milligrams once daily, with uptitration to 10 milligrams for children aged 6 to 10 years old, or 20 milligrams daily for those aged 10 to 18 years old.

Carotid intima-media thickness was assessed by ultrasonography at baseline, 12 months and 24 months in all patients and in age-matched, unaffected siblings. Carotid intima-media thickness was measured at 3 locations, the common carotid artery, the carotid ball, and the internal carotid artery in both the left and right carotid arteries. At baseline, the mean carotid intima-media thickness was significantly greater for the 197 children with heterozygous familial hypercholesterolemia compared with the 65 unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid intima-media thickness in children with heterozygous familial hypercholesterolemia than in the untreated, or unaffected siblings. As a result, there was no difference in carotid intima-media thickness between the two groups after two years of rosuvastatin. These findings, therefore, support the value of early initiation of statin treatment for LDL cholesterol reduction in children with heterozygous familial hypercholesterolemia.

The final study highlights the therapeutic potential of a novel alpha calcitonin gene-related peptide for the treatment of heart failure. First author Dr. Aubdool, corresponding author Dr. Brain, and colleagues from King's College London in United Kingdom, tested the stable alpha analog of calcitonin gene-related peptide in 2 models ... First, an angiotensin 2 infused mouse, and secondly, pressure overload cardiac hypertrophy mouse model using suprarenal aortic ligation. They showed that systemic colon injection of the alpha analog blunted the angiotensin 2 induced rise in blood pressure, as well as the vascular and cardiac remodeling, changes in water consumption, and renal injury, that are normally associated with angiotensin 2 infusion. Furthermore, protective effects were also seen when starting the alpha analog treatment, only during the last week of the 2-week angiotensin 2 infusion, in other words, when hypertension was already established. Finally, the alpha analog preserved heart function, and diminished the degree of hypertrophy and fibrosis in the aortic ligation model.

Thus, these results demonstrate the therapeutic potential of the alpha calcitonin gene-related peptide pathway, and the possibility that this injectable alpha analog may be effective in cardiac disease.

Well, that wraps it up for this week's summaries! Now, for our featured discussion.

For our feature discussion this week, we're talking about trans-catheter therapy for mitral regurgitation, a very hot field and a field in which there have been a lot of advances. To help us break it down, and get right into the insights, the challenges, and potential solutions, I am so pleased to have the first author of this in-depth review paper, Dr. Paul Sorajja from Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital, as well as Dr. Manos Brilakis, associate editor from UT Southwestern, here with us today!

Paul, could I start with you, and just ask you first to give us an idea of what we're talking about here when we talk about mitral regurgitation ... There are different kinds, which are we referring to, and what are the challenges involved in a trans-catheter therapy for mitral regurgitation?

Dr. Paul Sorajja: I think there are a number of challenges, I think the first thing is that MR is often thought of as one disease, but it's really an incredibly heterogeneous disease ... Broadly, we talk about primary versus secondary MR, but the mitral valve is so complex, with multiple different components, any one of which can disrupt and cause MR. When we're talking about trans-catheter therapy, it's often very easy, again, to think we could have one therapy that could treat a simply insufficient valve, but it's way more complex than that, and as a result, there have been many different approaches that have been developed, adding to the complexity of how we manage these patients.

Dr. Carolyn Lam: Right, and in your paper, I loved the way you grouped them, very logically, under those from mitral valve repair, and that for mitral valve replacement ... And then, under repair, you grouped it into leaflet versus targeting the LV ... Could you maybe give us some top-line insights on these techniques?

Dr. Paul Sorajja: Yeah, there are a number of different approaches that have mechanistically gone after the different components through the pathophysiology of MR, where there is leaflets, where there's analysts, cords, or ventricular approach ... I think it's somewhat simplistic to think of it that way, but as catheter-based technology, we are technically limited by what we can do from a catheter standpoint. I think it's inevitable to think about these catheter technologies as eventually being combined, rather than singular, in order to approach what surgeons do in the OR.

Dr. Carolyn Lam: Right, but then even going further, you spent quite a bit of the paper talking about trans-catheter mitral valve implantation ... So, replacing the mitral valve, that's really cool, could you tell us a bit about that, and about that important issue brought up about patient selection.

Dr. Paul Sorajja: Yes, it's a very good point, I think in terms of trans-catheter mitral replacement, I think that that's really where the future is going to go ... The simple analogy is that people think that it will follow the route of TAVR, but I think it will follow the route of TAVR more quickly so, because when you look at how the mitral valve is currently treated in the OR, sometimes, a lot of the times, patients can end up worse. Whereas, a trans-catheter solution actually, I think in terms of the safety margin, actually will equate a degree of safety relative to surgery, if it's done and developed correctly, as opposed to how TAVR's done. I think for TAVR, it's been a number of years for our field to be equivalent or superior to surgery, whereas I think with mitral, I think there's a lot of potential for mitral to have equated a degree of safety. As an example, in the Tendine Feasibility Study, it was published this past January ... A high-risk population, there was not a single procedure death, out of 30 patients ... And for these patients who would go to the OR with an eject fraction of 30 to 40 percent, I think that's quite remarkable.

Dr. Carolyn Lam: Wow, that's really exciting indeed! Manos, you handled this paper, and it's just so beautifully laid out ... That flow chart, I just want to refer all our listeners to the flow chart in Figure 7, that talks about maybe an approach that can be considered. Manos, could you share some thoughts on how this developed?

Dr. Manos Brilakis: Yeah, absolutely, and obviously Paul is the expert on this, but I think it's very important about this paper, and through discussions with Paul and through the development of the paper, is that there's more of a collaboration between the surgeons and the interventionists. So instead, if it's additional style of ... Or the interventionists are doing one thing and the surgeon is doing another, I think the key to success in the mitral field is working very closely together ... Many of those valves right now, the percutaneous valves, are done through a cut down and a typical approach, so working very closely to addressing the anatomic components of the mitral valve problem is a big plus.

The other thing I think that is very important is the new emergence of imaging, trying to understand whether the new mitral valve is going to create issues with LVOT obstruction or not. I think that's leading to a whole new understanding of when and how patients are even candidates for this approach, and I think Paul can elaborate more on this, but as things evolve, fewer and fewer patients are going to be excluded from these new technologies.

Dr. Carolyn Lam: Paul, would you like to take that? What do you think is happening and will happen with patient selection?

Dr. Paul Sorajja: There has been a challenge in current feasibility studies, in terms of getting patients in, the anatomical restraints are exactly what Dr. Brilakis has outlined. There's a certain bulkiness and size to the valve, which essentially poses risk for LVOT obstruction if the valve is too big ... As a feasibility study that's still early, or a field that's still early in its development, there's been a really conservative approach in terms of patient selection to ensure that LVOT obstruction doesn't happen. I think we're pushing the boundaries for that, and I think we've learned a lot from CT imaging, in terms of predicting LVOT obstruction, and I think the valves are also getting to be shorter in profile, which makes it less likely ... But that is definitely one of the limitations, and it's a limitation that exists, not just for trans-cat therapy but also for surgical therapy.

Dr. Carolyn Lam: Right, and then maybe a question for both of you ... What do you think the future is going to hold? What do we need to make this more mainstream, and where do you think this will leave surgical approaches? I know you said a combined approach, but maybe you could elaborate a little bit more?

Dr. Paul Sorajja: I do think, and I agree, I think Manos' point is spot on about that ... This will have to be multidisciplinary, the surgeons and cardiologists absolutely need to continue to work together, that's what's led to the successful development of TAVR, and I think that will be even more so for mitral, because the mitral valve is just infinitely more complex, and we have a lot to learn from the surgeons. But I think going forward, the collaboration is going to be a requirement, and then the training is also going to be a significant portion ... Putting in a mitral valve is much more complex than putting in an aortic valve ... I think if there's a safety margin that's demonstrated, I still think that it will be more appealing and more rapidly adopted than aortic disease.

Dr. Carolyn Lam: Well, Manos?

Dr. Manos Brilakis: No, I completely agree with Paul on that respect. I think, in my mind, at least, an again, this is from an early standpoint, the next big step would be to make it completely percutaneous, right now, you still have to do the cut down, and it's a little more invasive, although still safer than the completely open surgery, but maybe having a complete percutaneous system would be the next big step ... There's no question in my mind, as well ... And watching very closely how Paul and the surgical team are handling this, I think this is definitely the way for the future. Sometimes, in TAVR, it's not as technically demanding, and you don't really need to have too many people in the room, but for this procedure, it's definitely more important to have everyone in the room, and benefit from everyone's expertise.

Dr. Carolyn Lam: Manos, could I switch tracks for a moment now, and ask you to comment on the question that I get a lot ... You're an Interventionist, you handle a lot of the interventional papers for Circulation, and a lot of people are wondering, what makes papers like Paul's ... What makes interventional papers something that we would want to publish in Circulation? Could you share some thoughts?

Dr. Manos Brilakis: Absolutely, thanks Carolyn ... That's a big part, I think, of the appeal of Circulation right now. We're really trying to communicate to people that cutting-edge, clinical science is actually at the heart and the core of Circulation, and clinical content is what drives a lot of editorial ... Especially in intervention, where particularly interesting and new, cutting-edge technologies, new trials, observational studies ... But essentially, things that are cutting-edge, and are going to have a specific implication and impact in the way the field is going ... And this is part of Dr. Sorajja's paper, showing where the future lies in terms of trans-catheter mitral technologies, but along the same lines, we love to have cutting-edge papers on various aspects ... Coronary, peripheral, all aspects of interventional cardiologies, as well as interventional imaging ... The goal, again is to make the submission easy, there are not many honors requirements for submitting the papers, it's very simple to submit, and there's an answer going out very quick, so we're looking forward to receiving more and more interventional papers on cutting-edge science.

Dr. Carolyn Lam: Thank you so much for joining us today, and don't forget to tune in again next week.

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