Circulation August 29, 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 feature paper this week tells us more about aortic wall inflammation, and how this predicts abdominal aortic aneurysm expansion, as well as need for surgical repair. Much more, right after these summaries.

Our first original paper sheds light on a novel mechanism for adult cardiac regeneration. This is a paper from first authors Drs. Wang, and Lee, and corresponding authors Dr. Chen, Houser, and Dr. Jeng from Third Military Medical University from Chongqing, China.

In an elegant series of experiments using mouse models, the authors showed that mature adult cardiomyocytes could re-enter the cell cycle and form new cardiomyocytes though a three-step process: of dedifferentiation, proliferation, and redifferentiation. Intercellular calcium signals from neighboring functioning cardiomyocytes through gap junction induce the redifferentiation process. Furthermore, they showed that this mechanism contributed to new cardiomyocyte formation in post MI hearts in mammals. In summary, this study contributes to our understanding of adult cardiac regeneration and could lead to novel strategies to repair the injured heart.

The next paper provides mechanistic data that may explain why thrombotic complications are more prevalent in patients with diabetes, and why some anti-platelet drugs may have limited efficacy in patients with diabetes. In this paper by first author, Dr. Hu, corresponding author Dr. Ding, and colleagues from Fudan University in Shanghai, China, the authors show that platelets of patients with Type 2 diabetes express high levels of activated P2Y12 receptor.

The P2Y12 inverse agonist inhibited P2Y12 activity of platelets from diabetic patients and rats, more than Cangrelore, leading to a stronger in-vivo antithrombotic effect in thrombosis rat models with diabetes. Increased platelets P2Y12 receptor expression in diabetes was mediated by a high-glucose reactive oxygen species, NF-kappaB pathway. In summary, platelet P2Y12 receptor expression was shown to be significantly increased, and the receptor was constitutively activated in Type 2 diabetic patients, which contributed to platelet hyperactivity, and limited anti-platelet drug efficacy in Type 2 diabetes.

The next paper tells us that the majority of cardiovascular disease events are now occurring amongst adults with a systolic and diastolic blood pressure of less than 140 over 90 millimeters mercury. Prior data have shown us that the majority of incident cardiovascular disease events occurred among U.S. adults with higher systolic and diastolic blood pressures of above 140 over 90. However, over the past several decades, blood pressure has declined and hypertension control has improved. Thus, in the current study, Dr. Tajeu and colleagues from Temple University College of Public Health in Philadelphia estimated the percentage of incident cardiovascular disease events that occur at blood pressures below 140-90 in a pooled analysis of three contemporary U.S. cohorts: the Reasons for Geographic and Racial Differences in Stroke, or, REGARDS study, the Multi-Ethnic Study of Atherosclerosis, or MESA study, and the Jackson Heart study.

In these three U.S. cohorts that enrolled after 2000, more than 60% of incident cardiovascular disease events occurred among participants with blood pressures below 140 over 90 millimeters mercury. In the 2001 to 2008 National Health and Nutritional Examination survey mortality follow-up study, 58% of cardiovascular disease stats occurred in U.S. adults with blood pressures below 140 over 90. Among participants taking anti-hypertensive medication, with blood pressures below 140 over 90, only one-third of those who are eligible for starting treatment were taking one, and approximately 20% met the SPRINT eligibility criteria.

In conclusion, while higher blood pressure levels are associated with increased cardiovascular disease risk, in the modern era the majority of incident cardiovascular disease events occur in U.S. adults with blood pressure below 140 over 90. Although absolute risk and cost effectiveness should still be considered, additional cardiovascular disease risk reduction measures for adults with blood pressure less than 140 over 90, and at high risk for cardiovascular disease, may be warranted.

Well, that brings us to the end of our summaries. Now, for our feature discussion.

Dr. Carolyn Lam: On today's podcast discussion, we will be talking about aortic wall inflammation as a possible functional, or biological, imaging bio-marker that may add to the usual structural measurements of size that we use to predict abdominal aortic aneurysm expansion and rupture. Now, to discuss this very important paper, we have the corresponding author, representing the MA3RS study investigators, Professor David Newby from the Center for Cardiovascular Science in Edinburgh, as well as a familiar voice now, Dr. Joshua Beckman, associate editor from Vanderbilt University. Welcome, gentlemen.

Professor David Newby: Hi, there.

Dr. Joshua Beckman: So great to be here again, thanks for having me.

Dr. Carolyn Lam: So great that you're back again, Josh! But David, let's start with you. Could you just summarize what this trial was about and your main findings?

Professor David Newby: Sure, so this was a major clinical trial that we undertook in the U.K. and Scotland. We approached patients who were in a surveillance program who had an abdominal aortic aneurysm, and we asked the question, "Is there anything we can do better than just serial ultrasound measurements that currently are stunned to this care?" So, in Edinburgh, we developed a technique using ultrasmall, superparamagnetic particles of iron oxide, which is a bit of a powerful ... so we shortened that to USPIOs; these are really small iron particles that are so small they can cross vascular spaces and they get gobbled up by tissue resident macrophages, and then causes a signal that we can detect on magnetic residents' scanning MRI.

So we were really asking the question, "Can we do better than ultrasound by using what we call USPIO-enhanced MRI?"

Dr. Carolyn Lam: So a biological or functional imaging parameter versus just structural. And so, what were your main findings?

Professor David Newby: We recruited around 361 patients and ultimately 341 went into the trial because of various exclusions, et cetera. And we followed these patients up for, on average, around three years. And so we were following it up every six months with ultrasound, with other various assessments, and ultimately what we found was that the USPIO-enhanced magnetic residents' scan was positive in around half of patients, and in those patients that took up the USPIOs in their abdominal aortic aneurysm wall, those patients, their aneurysms expanded quicker. So rate of expansion was higher, and they went on the have the primary event of either elective repair, or rupture. And, don't forget, that the clinicians who were looking after these patients, they didn't know the results of the MRI so it didn't influence their clinical minds, when this was completely independent of the clinical team.

So, for the first time, we demonstrated that imaging or tracking macrophages in the abdominal aortic wall could, indeed, predict both disease progression and clinical outcome.

Dr. Carolyn Lam: And Josh, you know, no one can say it better than you: could you just describe what we discussed as the editors about the significance of such a finding?

Dr. Joshua Beckman: I think there's a few things to take home from these three that are really incredible. First, David, were you surprised at the concordance between the USPIO-enhanced imaging and smoking, or was that something that you expected?

Professor David Newby: That was a big surprise. That was, actually, as we discussed in the manuscript, quite an interesting finding, and as always with an interesting find, we dig around in the background, and it actually gets more and more exciting and plausible because of the mechanistic work that we'd seen in the pre-clinical science that preceded our trial. So yes, it was a surprise, but actually the more we got into it, the more it made sense.

Dr. Joshua Beckman: One of the other things that I think is really important to talk about is how you get this study done, and one of the things I found incredibly impressive ... I am unaware of any other multi-sensor MRI study like this. How did you organize this amongst the different institutions?

Professor David Newby: It can be a bit of a challenge. So I've done quite a few multi-sensor trials in Scotland, and imaging trials, and the community in Scotland actually is very, very supportive and we got a good network of folks. So the three centers are actually two imaging centers: one in Edinburgh one in Glasgow, a further recruitment center in a city just in the center of Scotland, Sterling. And the patients ... we were able to obviously make sure the scanners did the same protocols; fortunately, they were the same scanner, make and model. So that all obviously helped, but we had a lot of inundation, phantom work, to make sure both centers got things right.

But there was a huge motivation to get this done, and I'm indebted to Charles Riditi and Colin Barrie in Glasgow for doing the, and supporting the, imaging work, and also a medical physicist here in Edinburgh, Scott Semple, who'd done a lot of the work to get this to happen. So there's a teamwork in Scotland and the NHS, where the access to patients are in the screening program as well, which made recruitment really well and very efficient. And we started exactly to target, which is pretty unusual in clinical trials, often takes longer to recruit patients, but it was a great team effort. The imaging quality, we checked, verified, centrally read, and it was really good to see it delivered in that way.

Dr. Joshua Beckman: Do you think that agent, the iron oxide particles, is going to be the contrast agent, I guess, of the future, or do you think because it is now so consistent with smoking, it's gonna be more of an investigational tool?

Professor David Newby: So there's a couple of things to say here on ferumoxital, which is the USPIO we used. It's currently licensed in the U.S. for the treatment of anemia and chronic renal failure, but it can also be used as an imaging agent and actually this, I think increasingly, might have a role; not just in aneurysms, but elsewhere. So the first thing you can do is actually do angiography with this agent. [Obviously gadolinium is getting a lot of press at the moment, with problems with warnings coming out, of residual brain deposition, and so on. With the USPIOs, you can use this in renal failure patients, so again, another contraindication for us to concern about: NSF in renal failure patients. So actually, for angiography, I think it's going to have an increasing role.

For imaging of inflammation, we've previously demonstrated that you can track inflammation post-myocardial infarction, so you can see air is lighting up following myocardial infarction. We have some papers out on that, and I think, if you are in the business of looking at cellular inflammation, macrophage trafficking, then this technique really can be helpful.

When we come to aneurysm studies, I think it is less clear because ultimately, doing a quick ultrasound, in fact can give you the information together with all of the clinical risk factors, like smoking, and you get to the same end point without doing the MRI. Then, clearly, it's not going to be that impactful. Having said that, I think sometimes we will have patients who've got all this information and we're not sure which way to go. So I think it could be used as an almost umpire test, if you're not sure whether to proceed with surgery or not. And I think, also, if we discover new agents that are anti-inflammatory that may impact on disease progression, with a normal therapy, then clearly this might be a good buyer market to use in future therapeutic trials.

Dr. Joshua Beckman: Yeah, I actually see a huge potential for the testing of new agents, to see whether or not it reduces the inflammation that's associated. I'm gonna ask you a theoretical question, if that's okay with you. Part of the inflammatory process in the aneurysm is based on oxidative stress, but I've always wondered if you provide more oxygen, which may enhance the oxidative stress reaction, are you actually worsening the reaction at the time you're doing the study? Is that possible, or am I just concerned about nothing and making it up?

Professor David Newby: Well, obviously your [inaudible 00:13:19] stressors is important in all of cardiovascular disease, and if you increase oxygen supply, maybe you indeed induce more oxidative stress. In the context of an aneurysm, often there's quite an hypoxic state in the aneurysm wall, because obviously the intraluminal thrombus can buffer the wall itself from it, obviously the vasovasorum come in, but they may not be as efficient in doing that. Some of the areas that we're seeing light up probably are quite hypoxic, so they'll be in an oxygen-deprived state. So I think that needs to be put in the balance, too, and there has been some suggestion that iron particles can increase oxidative stress, and it has been suggested maybe harmful; we've not seen that, we've had absolutely no adverse reactions at all in all of our patients. We had one patient whose blood pressure fell a little bit, but we didn't have to medically intervene at all, so it was just observed and it passed; of course it might be due to many things.

We've also studied this in patients with myocardial infarctions, I've said, also bypass surgery, people who've had bypass surgery. We've also published on using these agents there, and again, we've seen absolutely no adverse reactions. And you would've thought, in the context of those situations, if you were going to see an adverse effect you would've seen it behind.

Dr. Carolyn Lam: David, I've got a question for you. I think you mentioned, a little bit earlier, that end of the day this enhanced MRI did not improve the risk stratification beyond the current predictors of clinical outcome in abdominal aortic aneurysms, but what are the next steps for you?

Professor David Newby: There's a couple of things, which we've been thinking through. Firstly, I think the primary end point of the trial was mostly driven by repair, and when we looked at the emergent events, so dying, and rupturing, the signal got stronger and very close to statistical significance. And obviously when you've got a population of patients whose elective surgeries mostly dominated by the ultrasound scan decision, therefore makes it difficult to prove, on top of that, the MRI will have value. So it's quite high, and on a difficult bar to cross, so some of the thoughts we've had are thinking about predicting rupture, rather than repair. And there will also be potential for actually doing a trial, where we actually base decisions on the aneurysm, and if you've got an intermediate category of patient, where you're not sure which way to go, those patients you then do use as an arbiter, and that might have, therefore, proof or value for it.

And the final area that we're probably thinking about exploring is, "Okay, paths for macrophages." Is there other pathophysiological processes that we might want to explore with other agents, that might predict aneurysm growth and rupture even stronger, and macrophage inflammation? So those are some of the thoughts that we've had about where the next steps will be.

Dr. Joshua Beckman: This is an incredible amount of work and I always think it's important to make clear to everybody who's listening to this podcast that, even though we may not all do the same kinds of research, it needs to be made clear that having a multi-sensor study in this topic, with this technique, is incredibly impressive. And the physiology that was brought forth, in addition to the clinical stuff that we just heard about, I think is what makes this worthy of a podcast.

Dr. Newby, thanks so much for participating.

Professor David Newby: Thank you so much, that's very kind. And just to reiterate, it has been a long journey and a huge effort, but we're reaping the rewards now, and it's nice to see the data being published in circulation.

Dr. Carolyn Lam: Gentlemen, it has been so wonderful having you here to discuss this. Thank you so much for your time.

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