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Circulation on the Run

Apr 20, 2020

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.

Dr Greg Hundley: And I'm Greg Hundley, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. But I am running to hide today, because I am going to get quizzed by the master in the feature discussion. And listeners, it's really interesting. It involves quantitative myocardial perfusion using magnetic resonance imaging, but also adding the twist that artificial intelligence computer algorithms are being used to read the stress test images without any physician interference. Oh, my goodness. I don't know what she's going to quiz me about.

Dr Carolyn Lam: Absolutely about all the AI algorithms and exactly how you derive them. But why don't you tell us what you want to describe first and the rest of the issue.

Dr Greg Hundley: Carolyn, I'm going to start with a paper on peroxynitrite and as you know, that's a very short-lived free radical produced in cells, part of the both oxidative and nitrosative stress pathways. And this article comes from Dr Swapnil Sonkusare from the University of Virginia School of Medicine. Well, Carolyn, this study is involving mouse models, and the investigators evaluated the relationship between peroxynitrite, that powerful oxidative nitrosative stress molecule, and obesity and hypertension.

Dr Carolyn Lam: Nice. And before you ask me anything more about peroxynitrite, because I think you just summarize everything I know. What did the authors find, Greg?

Dr Greg Hundley: What that found is that obesity induced impairment of endothelial AKAP150-TRPV4 channel signaling contributes to the loss of endothelial function and elevated blood pressure. And lowering the levels of this oxidant molecule of peroxynitrite reduces endothelial AKAP150-TRPV4 channel signaling, vasodilation and blood pressure and obesity.

Dr Carolyn Lam: And what are the implications?

Dr Greg Hundley: Well, endothelial TRPV4 channels are essential regulators of resting blood pressure and impairment of endothelial TRPV4 channel activity contributes to obesity induced hypertension. And therefore, therapeutic strategies, perhaps in the future, that lower peroxynitrite levels can be used to rescue endothelial TRPV4 channel activity, endothelial function and blood pressure in obese individuals.

Dr Carolyn Lam: Nice, Greg. Well, I want to tell you a little bit more about plain old hypertension. Now, we know that blood pressure is regulated by the function of the kidney vasculature and sympathetic nervous system, but do immune cells play a role?

Well, Dr Guzik from University Medical College, Krakow, Poland, and University of Glasgow and his colleagues, studied the relationship between major white blood cell types and blood pressure in the UK Biobank population and employed a Mendelian randomization analysis to examine which leukocyte populations maybe causally linked to blood pressure.

Dr Greg Hundley: So we've got another blood pressure article. What did they find?

Dr Carolyn Lam: They found potentially causal positive effects of total blood lymphocyte count with blood pressure. Among the mechanisms that might mediate this relationship, they found evidence that blood lymphocyte count might influence albuminuria. The study may additionally support a reverse, potentially causal positive effect of blood pressure indices on blood neutrophil monocyte and you sit a full count. So fairly interesting.

Dr Greg Hundley: Very nice. So I'm going to switch over and talk a little bit about lifestyle interventions. I know you're a big fitness buff. So this paper is about fitness, body mass index and the risk of heart failure in overweight, obese individuals with type two diabetes mellitus. It's an analysis from The Look AHEAD Trial. The corresponding author is Dr Ambarish Pandey from the University of Texas Southwestern Medical Center. And a little bit of background Carolyn. Type two diabetes is associated with a higher risk of heart failure and the impact of a lifestyle intervention and changes in cardiorespiratory fitness and body mass index on the risk of heart failure in this population is not well established.

So what are the authors do? They had 5,109 participants from The Look AHEAD or The Action for Health in Diabetes Trial, without prevalent heart failure at the time of their inclusion. They implemented time to event analysis to compare the risk of incident heart failure between an intensive lifestyle intervention versus a diabetes support and education group. The association of baseline measures of cardiorespiratory fitness estimated from a maximal treadmill test. The participants, BMI and longitudinal changes in these parameters with the risk of heart failure were evaluated using multi variable models.

Dr Carolyn Lam: Wow. What did they find?

Dr Greg Hundley: Carolyn, very surprising. Among participants with type two diabetes mellitus. In The Look AHEAD Trial, the intensive lifestyle intervention did not, did not appear to modify the risk of heart failure. What they also found is that higher baseline cardiorespiratory fitness and sustained improvements in cardiorespiratory fitness and weight loss were associated with a lower risk of heart failure.

So even that education group where patients started doing things more, had more cardiorespiratory fitness and baseline and sustain that with weight loss, those were the ones that had lower risk of heart failure.

Dr Carolyn Lam: Nice summary. Well let's go through what else is in today's issue. There's a research letter by Dr Eitel on the impact of morphine treatment within without metoclopramide co-administration on ticagrelor-inducted platelet inhibition in AMI and that's the randomized MonAMI trial. There's also an in-depth paper by Dr Eijsvogels on exercise and coronary atherosclerosis. So, this interesting review describes the effects of physical activity and exercise training on coronary atherosclerosis in middle aged and older athletes and really aims to contribute to the understanding of the potential adverse effects of the highest doses of exercise training on the coronary arteries. Very interesting.

Dr Greg Hundley: And Carolyn, I've got a perspective piece and it comes from Dr Robert Stravitz, as well as Dr George Vetrovec from VCU, and it evaluates the risk of invasive cardiac procedures in patients that have liver cirrhosis.

Then finally there's a very nice ECG challenge. It's the anterior STEMI without S T elevation in lead one and it comes from Dr Yun-Tao Zhao from the Peking University Aerospace School of Clinical Medicine. Oh no. Oh, I've got to run.

Dr Carolyn Lam: Now, we're going straight into the prolonged Dr Hundley quiz.

Dr Greg Hundley: Very good.

Dr Carolyn Lam: Oh boy. Today's feature paper is really a biggie. It talks about AI and its approach in quantitative myocardial perfusion by cardiac magnetic resonance imaging. Now, I know we've been building up to this discussion already right from the start because I've got my beloved cohost, Greg Hundley talking about this, but wearing the hat as the editor who managed this paper and also so pleased to have with us the corresponding author, Dr James Moon from University College, London and Barts Heart Centre in UK, as well as from across the other side of the world. We have Dr Peter Kellman from the National Heart, Lung and Blood Institute of NIH. So welcome gentlemen, what a great paper. I think in Greg's words he said earlier just really landmark. I'm almost paradigm shifting in this area. So let's dive straight into it. And so maybe James, could you start by telling us how does CMR quantitative myocardial perfusion usually work in today's world without the AI and perhaps you know what the study showed that it can do. What can AI help us do?

Dr James Moon: If we want to understand where chest pain comes from, we can sometimes use cardiac CT, or we can use a functional test and a different function test. But a particular test with bandages is chronic MRI. And what we do is we give a dye into a vein and track that through the heart. And the upslope can tell us about a fusion. And if you do that during vasodilators stress, you can see regional differences visually. Now, the interesting thing is that if you take those signals and using a team such as Peter Kamina, NIH, you can make that constative and, in fact, do that inline on the scanner, so you get color maps where the pixels of valid in mils per gram per minute. So you can see exactly how much facilitation there is. And what we share in here is that if you quantify that, literally, automatically on the scanner using artificial intelligence approaches from the NIH, those values are incrementally prognostic predicting outcomes for patients.

Dr Carolyn Lam: Wow. Okay. So give us a little bit more here, James. What do you mean by incrementally prognostic? Did you compare it with the best human readers and perhaps have a subset and I think you did, of course, who the human readers can see something, and AI did, right? Could you tell us a little bit more about that?

Dr James Moon: We've been doing a lot of the sort of technical development papers after the common initiatives from the NIH. So we've been doing the correlations across a number of sensors with, for example, pets and animal models. And really what we did here was we overlaid our clinical service with the AI and in more than a thousand patients actually at two sites, we were able to follow up patients and a number of those of course, and sadly underwent an event, death, or mace. And what we are able to see is that the stress flow and the ratio stress to rest flow, were independently associated by death and base and mace. So for each mil decrease in stress flow that has a great share went up. And that was as you say, something that you just can't do viscerally because you can't get that global background change.

Dr Carolyn Lam: Oh this is scary. So AI beating out humans, I suppose is what you're saying, not quite maybe. Or is it right?

Dr Greg Hundley: You know, we have to do a number of things in health care and we're often drawing circles, drawing consoles, identifying regions of interest and these are quite mundane tasks and if you can train your AI correctly, then that can do that for you, leaving you and freeing you up to higher executive functions, like discussing the results with patients. And I wouldn't be scared of the AI here because the way PISA implemented this, the contours are all drawn, so it's completely explicable.

Dr Carolyn Lam: I really liked that explanation. And so what most people fear when AI comes about is, they fear this black box approach that they cannot understand. And what you're saying here is it something understandable and it will facilitate efficiency, which is beautifully done, and what you've shown as well. So Peter, it sounds to me that it took a long time to develop this. Could you describe what it takes to get an algorithm and AI algorithms like this?

Dr Peter Kellman: This is quantitative perfusion and perfusion in general using cardiac mechanisms has been in development by a lot of labs around the world over the past 20 years. And the specific objectives we had were to get it out of the laboratory into the hands of the clinicians and do that, we chose to implement everything fully, automatically and integrated onto a clinical scanner so that the clinicians would get the answers on the fly.

That is to say they would perform a scan and it would be transparent. They'd run the scan the way they normally do today, and the results of the myocardial blood flow would appear on the scanner within a minute. So, we probably worked on this, myself and Dr Wie Wzei at NIH, for the past five years. Gradually building this up to the state where it is now at sites like The Barts Heart Centre can use it.

Dr Carolyn Lam: Just really hats off. This is amazing because you've summarized it in a few sentences, but you know I kind of personally know what it takes. Just getting an algorithm is one thing but making it clinically usable and then James demonstrating it clinically are all huge achievements. So congratulations. I don't think anyone can say it better than Greg. Greg, tell us why is this paper so important? And see that was an easy question.

Dr Greg Hundley: This is really dramatic in the field of cardiovascular magnetic resonance, but also for stress testing related to patients with cardiovascular disease. As many of our listeners know today, the majority of studies are interpreted visually and while the spatial and temporal resolution is just beautiful like high definition television of the inside of our bodies, the artifacts that sometimes occur and then some of the interobserver variability remains problematic. What I love about this, is this is now a quantitative. It's not a visual interpretation of signal intensity. What both Dr's. Kellman and Moon have developed is something that measures the blood flow in mls per minute, per gram of tissue regionally throughout the heart and then color codes that so that all of us can interpret it readily. I think another big piece of this is that they have created the artificial intelligence that helps interpret that for us and just think now we'll be able standardize readings across medical centers.

That's an enormous advance for this field and combining this information and putting it into, both national as well as international registries, could be very important for identifying abnormalities that would forecast prognosis. And these gentlemen have laid the framework for that because they have a large number of subjects, two centers, and they had comprehensive follow up that looked at heart events and this technology was able to forecast that on the backdrop of all the other parameters, demographic variables, risk factors, etc., that we find in patients that present to us with cardiovascular disease and are symptomatic with chest pain syndromes. So boy, what an outstanding imaging paper and feel so fortunate to actually have this in circulation.

Dr Carolyn Lam: Greg, no one can say it better than you. I would like to emphasize that this just doesn't hold the implications for MR imaging. I think it holds implications for many forms of cardiac imaging if we have AI to assist us. So James, how do you see this helping the patients? These are prospectively performed cardiac MR scans, but you know, what about surveillance of MR databases? What are the implications for perhaps detecting microvascular abnormalities? Another pet topic on my own. If you don't mind, you know, tell us, what do you think are the clinical implications?

Dr James Moon: Quite a lot of clinical implications. We're really starting a journey here. So, one of the things I'm interested in is that we have been in an era of thinking about the epicardial cone use only. We were seeing significance between patient differences in peak hyperemia related to, for example, age and presence of diabetes, but must be reflecting the microvasculature and of course, that may be a key biomarker for the future and understanding what happens to patients. So naturally, of course, when we're assessing the epicardial arteries, we're going to have to understand that those assessments, especially if it's measuring wall flow, will be influenced by the microvasculature because it's a circulation. So, this may just bring that microvasculature into the mainstream as potentially therapeutic target.

If you think about this AI and observe a variation. So what we do is measure things clinically and that sounds like boring old science, but metrology and accuracy and precision translate into something that cascades down. So that key dots the patient relationship where we're making the decisions on what therapies together might influence outcome. And if you can rely on those results and if the results that scanner one in one place and another scan at another place always read the same, then your healthcare system just gets a boost because everything is more reliable.

Dr Carolyn Lam: That's beautifully put. And Peter, thank you to you and your group for developing such AI and James for demonstrating this. Now if I may, this is an amazing collaboration. I understand the British Heart Foundation had a role in supporting this. How did you get together to decide to work across regions and so on, on this? Could you just give us a little bit about that?

Dr Peter Kellman: Our working together was an outgrowth of prior collaborations in areas such as T one map and for tissue characterization and Barts Heart Centre represents the largest cardiac MR site in the world, in terms of volume. And when you have a quantitative method, it was the perfect place to evaluate this kind of ischemic heart disease. And furthermore, when you talk about AI, you need to train the algorithms and develop the models. You need a large volume of data. So, right now we're probably doing on the order of 150 stress tests a week. And so, after a year we had a large volume of data to train the algorithms for segmenting the myocardium. So the collaboration has been ongoing for about five years.

Dr Carolyn Lam: That's great. Greg, you know what, because I adore you, I'm going to ask you to give us the final words. Tell us your thoughts on where this is all heading.

Dr Greg Hundley: I think Peter astutely identified that Barts Heart Centre and you're seeing really in the United Kingdom the primary use of magnetic resonance imaging for cardiovascular stress testing with its accuracy. And now, adding to this these quantitative assessments that can reflect, not only epicardial disease, but as we've heard, have the potential to identify micro circulatory disease. I see this growing and extending worldwide. And I think the next studies will involve the use of this type of technology and multiple different manufacturers of scanners and across different field strengths, 1.5 and three T, and multi-center initiatives using this technology to try to forecast cardiovascular prognosis in patients that present with chest pain syndromes as well as other disease processes that involve both epicardial coronary arteries and micro circulation.

Dr Carolyn Lam: Wow. And we're so pleased and proud to be publishing then this paper here in circulation this week. Thank you so much, gentleman. It's been awesome discussing this with you.

 And thank you, audience for joining us this week. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

Dr Greg Hundley: This program is copyright, The American Heart Association 2020.