Feb 27, 2023
This week, please join author Jennifer Conway as she discusses the article "The Prevalence and Association of Exercise Test Abnormalities With Sudden Cardiac Death and Transplant-Free Survival in Childhood Hypertrophic Cardiomyopathy."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass of the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Dr. Greg Hundley:
And I'm Dr. Greg Hundley, associate editor and director of the Pauley Heart Center at VSU Health in Richmond, Virginia. Carolyn, wow. We're closing out the month of February, this is February 28th. And the feature discussion today, very interesting. So in patients with hypertrophic cardiomyopathy, we often see them as adults, and guidelines are very clear on how to manage them. What about patients' children that present with hypertrophic cardiomyopathy? How do we manage them? Should we do exercise testing? Well, to get the answers to some of those questions, you'll have to wait listeners to our feature discussion today. But first we're going to grab a cup of coffee and jump into some of the other articles in the issue. Carolyn, would you like to start?
Dr. Carolyn Lam:
I would love to. With this first paper, which is a preclinical study revealing a novel signaling axis in cardiorenal interaction.
Dr. Greg Hundley:
Wow. Pray tell.
Dr. Carolyn Lam:
I will. So this paper is from Dr. Molkentin and colleagues from University of Cincinnati. And using mouse models of ischemia reperfusion acute kidney injury and unilateral ureteral obstruction, these authors found that interleukin 33 release from the kidney endothelium during acute kidney injury communicates with the heart through the suppression of tumorigenicity 2 or ST2L receptor on cardiomyocytes. And that's where it causes hypertrophy, fibrosis, and loss of cardiac function. Mice lacking interleukin 33 or mice lacking the gene encoding this ST2L receptor on cardiomyocytes, but not endothelial cells or fibroblasts, were protected from acute kidney injury induced hypertrophy and cardiomyopathy. Indeed, inhibition of acute interleukin 33 release from the kidney after acute kidney injury with a monoclonal antibody prevented cardiomyopathy. So the interleukin 33 ST2L signaling axis is a novel potential therapeutic target to protect the heart during kidney injury.
Dr. Greg Hundley:
Wow, Carolyn, really interesting preclinical science relating acute kidney industry and cardiomyopathy. Well, I have another paper from the World of Preclinical Science. And, Carolyn, this pertains to the metalloprotease ADAMTS7, and it is a novel locus associated with human coronary atherosclerosis. ADAMTS7 deletion protects against atherosclerosis and vascular restenosis in rodents. Carolyn, these authors led by Professor Wei Kong from Peking University designed three potential vaccines consisting of distinct B-cell epitopic peptides derived from ADAMTS7 and conjugated with the carrier protein KLH as well as aluminum hydroxide as an adjuvant. And they tested the efficacy of the vaccines to evaluate coronary intimal hyperplasia in mirroring wire models and after stent implantation in porcine models.
Dr. Carolyn Lam:
Oh, wow. So a vaccine against atherosclerosis? Cool.
Dr. Greg Hundley:
Yeah, it is really a vaccine concept against restenosis. Carolyn, this peptide vaccine against metalloproteinase ADAMTS7 efficiently mitigated atherosclerosis in vaccinated hyperlipidemic mice without lowering lipid levels and impeded intimal hyperplasia in both the murine wired injured arteries and the swine stented coronary arteries without any significant immune related organ injuries. Carolyn, the clinical implications are that the vaccine against the metalloproteinase ADAMTS7 is a novel atherosclerosis vaccine, mainly targeting vascular remodeling, thereby also alleviating instent restenosis. And perhaps in the future the application of this vaccine would be a complimentary therapeutic avenue to current lipid loading strategies for atherosclerotic disease. And this is nicely followed by an editorial from Professors Heribert Schunkert and Thorsten Kessler.
Dr. Carolyn Lam:
Cool, thanks, Greg. Well, this next paper asks the question that if coronary artery calcium can be identified on non-gated chest CTs, can this finding be effectively incorporated into care with the help of AI? So the Notify One was a randomized quality improvement project in the Stanford healthcare system. Patients without known atherosclerotic cardiovascular disease or a prior statin prescription were screened for coronary arterial calcium on a prior nongated chest CT from 2014 to 2019 using a validated deep learning algorithm with radiologist confirmation. Patients with incidental coronary artery calcium were randomized to notification of the primary care clinician and patient versus usual care. Notification included a patient specific image of coronary artery calcium and guideline recommendations regarding statin use. And the primary outcome was statin prescription within six months.
Dr. Greg Hundley:
Really interesting, Carolyn. So coronary artery calcium observed when a patient might happen to come in for another chest CT scan or actually randomizing a patient population to being notified and maybe doctors act on it versus not. So what did they find?
Dr. Carolyn Lam:
Yep, beautifully summarized. And this is from Dr. Sandhu and colleagues from Stanford University. And what they found was among more than 2000 patients who met initial and clinical inclusion criteria, coronary artery calcium was identified by the algorithm in 424 patients and confirmed by a radiologist in 89% who were randomized to notification or usual care. At six months, the statin prescription rate was 51% in the notification arm versus 7% with usual care. Thus, opportunistic coronary artery calcium screening of prior nongated chest CTs followed by clinician and patient notification led to a significant increase in statin prescriptions. Further research is of course needed to determine whether this approach can actually reduce atherosclerotic cardiovascular disease events. This is discussed in an editorial by Doctors Joshi, Nasser, and Navar.
Dr. Greg Hundley:
Wow, Carolyn, you know, this all fits with behavioral science. When we see something, then often we change our behavior much more readily. And so, gosh, boy, just a perfect example of that in this last paper. Well, there's some other articles in the issue, and I see again, just as it was last week, you've got a whole list here to describe.
Dr. Carolyn Lam:
Oh, you bet Greg. First, there's an exchange of letters between Doctors Du and Lee on physical activity has no significant association with stroke. There's a primer by Dr. Leyva on “Declining Risk of Sudden Cardiac Death in Heart Failures, Is that a Fact or a Myth?” There's a Research Letter by Dr. Soehnlein on “Time Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice.” There's also Highlights from the Circulation Family of Journals by Molly Robbins. The characteristics of patients with recurrent sudden cardiac death are described in circulation arrhythmia and electrophysiology. A proof of principle gene therapy for correction of long QT two and short QT one syndromes is presented in circulation, genomic and precision medicine.
The impact of food insecurity on heart failure mortality is reported in circulation heart failure. The associations of hypertension and hypertension treatment with differences in sexual identities are presented in circulation, cardiovascular quality and outcomes. A multi-modality imaging and biomarker strategy to detect early decompensation with chronic aortic regurgitation is reported in circulation cardiovascular imaging, and an analysis of revascularization at the time of TAVR on cardiovascular outcomes is reported in circulation cardiovascular interventions. Finally, that's a Perspective piece by Dr. Turer on cardiac myosin inhibitors unlocking potential to improve treatment in hypertrophic cardiomyopathy.
Dr. Greg Hundley:
Wow, Carolyn, just another issue that's so rich with both preclinical and clinical science. Well, how about we get off to that feature discussion and learn more about management of children and young adults with hypertrophic cardiomyopathy?
Dr. Carolyn Lam:
So important. Let's go.
Dr. Greg Hundley:
Welcome listeners to this February 28th feature discussion where we're going to work into the world of hypertrophic cardiomyopathy in children. And we have with us today Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta. Welcome Jennifer. And maybe Jennifer, let's start off, could you describe for us some of the background information that went into the preparation of your study, and what was the hypothesis that you wanted to address?
Dr. Jennifer Conway:
Sure. And I would just like to start by thank you for inviting us to really present the information from our paper. We think it's a very exciting paper and are excited to share our results. When you think about hypertrophic cardiomyopathy in children, a lot of the information in the past has really been extrapolated from adults. And we know from the recent 2020 guidelines that exercise testing is really no longer part of risk stratification for adults. It's mostly used to look at functional outcomes and really when assessing patients more for heart failure related symptoms. So we wanted to see whether or not exercise testing in children had a different role because we know the recent risk stratifying calculators such as the primacy calculator that's come from this cohort of patients or HCM risk kids, has different risk factors that have been identified for sudden events, for instance, than in the adult population. And that's really kind of sparked us to see, well, maybe exercise has a different role in children than it does in adults.
Dr. Greg Hundley:
And so we wanted to investigate the role of exercise testing in children with hypertrophic cardiomyopathy. So how did you arrange your study design, and what was your study population?
Dr. Jennifer Conway:
This is an international cohort of 20 centers from the US, Canada, and Australia. And it's an observational cohort, and there is over 724 patients' information that has been collected within this cohort of patients. And for this particular study, 630 of them had an exercise test and therefore were included in the study to look at.
Dr. Greg Hundley:
And in the study population, I know it's a pediatric population, what was the age range?
Dr. Jennifer Conway:
The average range was about 13 years old with probably the youngest being around eight because that's really where you can do an exercise test with and that's up to 18 years of age. So that's kind of the general age range of patients.
Dr. Greg Hundley:
And of these pediatric populations, what percentage were, I guess, boys versus girls?
Dr. Jennifer Conway:
Yeah, so just over 75% were males within this study population.
Dr. Greg Hundley:
Okay. And then now Jennifer, can you describe for us your study results?
Dr. Jennifer Conway:
Sure. I think the first main result is that we can really think about what we defined as an abnormal exercise test so maybe we'll start with that and kind of explain our findings there. So abnormal exercise test in this study was really a threefold one if you had an abnormal blood pressure response. The other one is if you had ventricular ectopy or if you had ST-T wave changes, which we described as ischemia. And so taking those three together, about 28% of our pediatric patients had an abnormal finding on their exercise test. So that's kind of the first main finding. So then we took those abnormal exercise patients and compared those with a normal exercise test to try to look for outcomes. And the two outcomes that we mainly focused on all cause mortality and transplantation is one outcome and the other one was sudden cardiac death events.
So when we looked at the five-year freedom for all cause mortality and transplant, we found that those who had an abnormal exercise test had a lower five-year freedom from all cause mortality and transplantation. And when we sub-analyzed the different abnormalities in the exercise test, we found that ischemia and an abnormal blood pressure response were both associated with kind of a higher risk of mortality and transplantation. And then when we went on to look at sudden cardiac death events, there was really no difference seen between those with an abnormal or normal exercise test in terms of sudden cardiac death events. But when we looked at the individual factors once again exercise induced ischemia was associated with a lower freedom from a sudden cardiac death event.
Dr. Greg Hundley:
Jennifer, frequently in adults we're often examining with exercise how the intracavitary or left ventricular outflow tract gradient may change with exercise. What did you find in children in regards to that parameter?
Dr. Jennifer Conway:
Yeah, so we couldn't actually study that because this was a compilation of different types of exercise tests. So not everybody at each institution did the same form of exercise tests. So some patients had an exercise echo, some had a CPET test, and some had an exercise stress test. And so we took the common parameters from all of those to study, so we weren't specifically able to look at LV outflow tract gradients for instance.
Dr. Greg Hundley:
Jennifer, as a pediatrician managing a patient with hypertrophic cardiomyopathy, how do we use the results of your study to influence how we might manage patients moving forward?
Dr. Jennifer Conway:
I think this is an excellent question, and there's probably really two things that we can think about. The first is, what is the role of exercise testing in pediatrics? And just as we're starting to discover what our risk factors are for sudden cardiac death events, I think we have to do a little bit more to discover what our role is truly going to be with exercise test. So one of the things that we're doing as part of the primacy group is trying to decide is if we add exercise testing abnormalities to the already developed primacy calculator, does it change its power at all? That's one of the things kind of for the future to see with the current kind of sudden death risk factor calculators, can exercise, add to them? The second thing is I think that there is probably a role in exercise testing in general with patients that you see in your clinic to look at these predictive outcomes, and that is not standard across centers.
We know that because not everybody in this cohort had an exercise test. I think there are some higher risk patients that likely are not suitable for exercise tests, but I think a majority of the patients that we see likely can undergo exercise testing. And although it's not published in this paper, of the 630 patients, there's only one patient who had a kind of aborted arrest during the exercise test. And that patient was a higher risk patient who had a previous reported aborted arrest. And this actually corresponds with two other papers in the literature, one from CHOP in Boston where it's a very low event rate when exercise testing is done in a controlled environment with professionals around and have a lab set up to specifically do that. The other aspect of this I think is that as we're starting to understand hypertrophic cardiomyopathy in general better, I think using exercise tests to try to help design exercise interventions is going to be important.
Another study that I'm doing that's not part of this is looking at the cardiovascular health of children with hypertrophic cardiomyopathy across Canada. And we are finding that there's a high level of obesity, sedentary lifestyle, high lipid profiles for instance, all of which put people at risk for cardiovascular disease as adults. And so I think as we're getting more comfortable potentially with looking at exercise prescriptions for hypertrophic cardiomyopathy patients and understanding risks a bit better, then exercise testings going to be a key in trying to design maybe some of that programming for patients.
Dr. Greg Hundley:
Wow, Jennifer, just a beautiful explanation of where we need to move with your research results in the future. One thing that kind of caught my attention as you were speaking, really safety. So for all our listeners, in terms of exercising children with this condition or young adults, would you recommend a specialized center or what would you describe in that, at least in terms of safety precautions?
Dr. Jennifer Conway:
Well, if you look at all the... There's not a lot of studies that have been published, but the ones that have, they're in a lab that commonly exercises children. They have protocols of who they will exercise and who they won't and when you would stop an exercise test. For instance, the paper from CHOP nicely describes how they approach the exercise in hypertrophic cardiomyopathy, and they have clear guidelines of when they stop testing. So in their 140 patients, for instance, they stop testing in two patients, one who had, I think ST segment changes and the other one who developed some ventricular ectopy. I think it needs to be in a controlled environment where you have safety measures in place and you have guidelines to direct you in terms of if this happens, this is the response to that. I think that's all very important when you're kind of thinking about exercising what has been deemed as higher risk patients.
Dr. Greg Hundley:
Very nice. Well, listeners, we want to thank Dr. Jennifer Conway from Stollery Children's Hospital in Edmonton, Alberta for sharing with us these really interesting results, highlighting that exercise abnormalities are common in childhood hypertrophic cardiomyopathy, and an abnormal exercise test was independently associated with lower transplant free survival especially in those with ischemic or abnormal blood pressure responses during that exercise testing.
Well, on behalf of Peter, 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 2023. 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, please visit ahajournals.org.