Jul 6, 2021
This week's show features a panel discussion between authors Adrian Wells and Hyeon Chang Kim as they discuss their articles "Improving the Effectiveness of Psychological Interventions for Depression and Anxiety in Cardiac Rehabilitation PATHWAY—A Single-Blind, Parallel, Randomized, Controlled Trial of Group Metacognitive Therapy" and "Associations of Ideal Cardiovascular Health and Its Change During Young Adulthood With Premature Cardiovascular Events: A Nationwide Cohort Study."
Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to 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, also your co-host. And Associate Editor, Director of the Pauley Heart Center, VCU Health in Richmond, Virginia.
Dr. Carolyn Lam:
Greg, we're starting off the month with double features, and these are just so interesting. The first paper talks about psychological interventions for depression and anxiety in cardiac rehabilitation. And the next talks about ideal cardiovascular health and its change during young adulthood and how that relates to premature cardiovascular events. Cool, huh?
Dr. Greg Hundley:
Absolutely. Well, Carolyn. How about we grab a cup of coffee and start discussing some of the other articles in the issue? And I could go first. Carolyn, the first article that I've got is from Mrs. Elizabeth Jordan from Ohio State University Wexner Medical Center. And it really pertains to cardiomyopathies. And remember, Carolyn, classically, we categorize hypertrophic, dilated, and arrhythmogenic right ventricular cardiomyopathy. And each has a signature genetic theme. Hypertrophic cardiomyopathy and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins. But in contrast, there are over 250 genes spanning more than 10 gene ontologies that have been implicated in dilated cardiomyopathy. And therefore, it really represents a very complex and diverse genetic architecture. So to clarify this, a systematic curation of evidence to establish the relationship of genes with dilated cardiomyopathy was conducted by an international panel with clinical and scientific expertise in dilated cardiomyopathy genetics. And they evaluated evidence supporting monogenic relationships of genes with idiopathic dilated cardiomyopathy.
Dr. Carolyn Lam:
Oh, wow. That sounds like a lot of work. And what did they find, Greg?
Dr. Greg Hundley:
Right, Carolyn. So in the curation of 51 genes, 19 had high evidence. 12 are definitive strong, and seven moderate. And notably, these 19 genes only explain the minority of cases, leaving the remainder of dilated cardiomyopathy genetic architecture really incompletely addressed. And clinical genetic testing panels include most high evidence genes. However also, the panel noted that genes lacking robust evidence are very commonly observed clinically.
Dr. Greg Hundley:
So Carolyn, the take home message from this international panel is that while dilated cardiomyopathy genetic testing panels include an average of about 60 genes, when curating published evidence for dilated cardiomyopathy, only 19 have really emerged as high levels of evidence. And then in this study, 51 genes were evaluated. And the 19 genes appraised as high evidence were recommended to be routinely used in the genetic evaluation of dilated cardiomyopathy. And one more point. Rare variants from genes without moderate, strong, or definitive evidence should not be used in clinical practice to predict dilated cardiomyopathy risk most importantly when also you're screening at risk family members.
Dr. Carolyn Lam:
Wow. Very nice. Stunning numbers. Well, my paper is identifying a novel therapeutic target in pulmonary arterial hypertension. Do you want to know what that is?
Dr. Greg Hundley:
Ah, yes, Carolyn. Very interesting. So what is it?
Dr. Carolyn Lam:
It's switch-independent 3A. Which is an epigenetic modifier, which is drastically down-regulated in pulmonary arterial hypertension patients and rodent models of pulmonary arterial hypertension. And strongly associated with decreased bone morphogenic protein receptor type two, or BMPR2 expression. So this switch-independent 3A overexpression up-regulated BMPR2 expression by modulating critical epigenetic pathways and decreasing a specific transcription factor binding to the BMPR2 promoter in pulmonary vascular smooth muscle cells. Furthermore, aerosolized lung-targeted gene transfer of adeno-associated virus zero type one and containing switch-independent 3A reversed and prevented pulmonary arterial hypertension phenotype in preclinical animal models. So this beautiful study, from Dr. Hadri from Icahn School of Medicine at Mount Sinai in New York and colleagues, really suggests that switch-independent 3A can be a clinically relevant molecule for the treatment of pulmonary arterial hypertension.
Dr. Greg Hundley:
Wow, Carolyn. Really nice. Very intricate science for the study of pulmonary hypertension. Well, my next paper actually comes to us from Dr. Joe Hill and colleagues at UT Southwestern Medical Center. And Carolyn, as we know, cardiac hypertrophy is an independent risk factor for heart failure. Of course, the leading cause of morbidity and mortality globally. And the calcineurin NFAT, or nuclear factor of activated T-cells pathway, and the MAP kinase ERK, or extra cellular signal regulated kinase pathway, contributes to the pathogenesis of cardiac hypertrophy as an interdependent network of signaling cascades. However, Carolyn, how these pathways interact really remains unclear. And so Dr. Hill and colleagues engineered a cardiomyocyte-specific ETS2, a member of the E26 transformation specific sequence or ETS domain family knockout mouse, and investigated the role of ETS2 in cardiac hypertrophy. Primary cardiomyocytes were also used to evaluate ETS2 function in cell growth.
Dr. Carolyn Lam:
Wow. Okay. So what were the results, Greg?
Dr. Greg Hundley:
Right, Carolyn. Three main findings. First, ETS2 is activated by ERK1/2, or extracellular signal-regulated kinase 1/2, in both hypertrophied murine hearts and in human dilated cardiomyopathy. Second, ETS2 is required for both pressure overload, and calcineurin induced cardiac hypertrophy responses involving signaling cascades distinct from, but interdependent with ERK1/2 signaling. And third, this group discovered that ETS2 synergizes with NFAT to transactivate RCAN1-4, an established downstream target of NFAT, or nuclear factor of activated T-cells. And they identified an MIR-223 as a novel transcriptional target of NFAT ETS2 in cardiomyocytes.
Dr. Carolyn Lam:
Wow. Wow. That sounds like a lot of detailed work. Could you tell us what the clinical implications are, Greg?
Dr. Greg Hundley:
You bet, Carolyn. So in aggregate, these findings unveil a previously unrecognized molecular interaction between two conical hypertrophic signaling pathways, MAP kinase-driven hypertrophy, and calcineurin driven hypertrophy. And therefore, as pathological cardiac hypertrophy is an established risk factor for heart failure development, this unveiling of novel signaling mechanisms really is of potential clinical relevance.
Dr. Carolyn Lam:
Thanks, Greg. Well, let's round up with what else there is in this week's issue. There's a Frontiers paper by Dr. Chris Granger. And it's a big call to action to the cardiology community, to incorporate SGLT2 inhibitors and GLP-1 receptor agonists for cardiovascular and kidney disease risk reduction. There's a Joint Opinion piece from the American Heart Association, World Heart Federation, American College of Cardiology, and European Society of Cardiology on, “The Tobacco Endgame: Eradicating a Worsening Epidemic,” by Dr. Elkind.
Dr. Greg Hundley:
Oh great, Carolyn. Well, I've got an On My Mind piece from Professor Bhatt. And it's entitled, “Does SGLT1 inhibition Add Benefit to SGLT2 Inhibition in Type 2 Diabetes Mellitus?” And next, Dr. Viskin has an ECG Challenge entitled, “Long QT Syndrome and Torsade de Pointes Ultimately Treated With Quinidine, The Concept of Pseudo Torsade de Pointes.” And then finally, there's a Letter to the Editor by Dr. Lu regarding the article, “Association of Body Mass Index and Age with Morbidity and Mortality in Patients Hospitalized with COVID-19, Results from the American Heart Association COVID-19 Cardiovascular Disease Registry.” Well, Carolyn, I can't wait to get on to this double feature.
Dr. Carolyn Lam:
Me too. Let's go.
Dr. Greg Hundley:
Welcome, listeners, to our feature discussion today. And again, we're going to create today a forum, because we have two very interesting papers to present during this timeframe. Our first is going to come to us from Dr. Adrian Wells from University of Manchester. And our second paper will come to us from Dr. Hyeon Chang Kim from Yonsei University. I want to welcome you both, gentlemen. And Adrian, I would like to start with you. Tell us a little bit about the background related to your study. And then what was the hypothesis that you wanted to address?
Dr. Adrian Wells:
Okay, well thank you for inviting me to take part in this podcast. Following cardiac events, around one in three individuals will develop significant anxiety and depression symptoms. And we know that anxiety and depression can have an impact on prognosis, quality of life, future outcomes. Psychological treatment isn't routinely offered in cardiac rehabilitation for anxiety and depression, despite the fact that we identified that many of our patients felt that they would benefit from a psychological intervention to address these issues. And they felt that their needs were not really being met. So our primary question was, can we improve psychological outcomes in patients with cardiovascular disease?
Dr. Greg Hundley:
Very nice. And Adrian, what was your study population? And also, what was your study design?
Dr. Adrian Wells:
So we selected patients who entered cardiac rehabilitation in the UK. So these are patients with acute coronary syndrome, revascularization, stable heart failure, heart transplantation, and so on. And so, a wide group of individuals. We recruited 332 patients, all of whom had had anxiety and depression scores of eight or more. So these were people showing mild to severe levels of psychological distress. We conducted a two arm single blind randomized controlled trial, with 332 patients who were randomly allocated to one of these two conditions. And we assessed anxiety and depression symptoms before treatment at four months and at 12 months.
Dr. Greg Hundley:
Describe a little bit some of the specifics of your intervention. And then what did you find?
Dr. Adrian Wells:
We use relatively recent new treatment called metacognitive therapy. And this was delivered in a group format over six sessions. And we trained cardiac rehabilitation staff, nurse consultants, physiotherapists, in the delivery of this intervention. Metacognitive therapy works on helping patients discover unhelpful patterns of thinking, such as worrying and ruminating ,and excessive threat monitoring. And to reduce those patterns of thinking that contribute to anxiety, depression, and poor adaptation following stressful life experiences.
Dr. Greg Hundley:
And what did you find?
Dr. Adrian Wells:
Well, what we found was that the addition of metacognitive therapy to treatment to usual cardiac rehabilitation, significantly improved outcomes at four months and 12 months. What was striking about this was that our effect sizes were modest and moderate to large. They seem to be larger than those obtained in other studies or psychological treatments. And of note, the treatment seemed to impact well on both anxiety and depression symptoms. Whereas other types of intervention evaluated in the past have tended to treat the depression, but not so much the anxiety.
Dr. Greg Hundley:
Very good. So it sounds like a group-based intervention. And I'm assuming maybe participants interacted not only with your staff, but with one another. How would you put your results really in the context with other research that's going on in this space?
Dr. Adrian Wells:
Well, there have been a number of studies in the past that have looked at individual and group-based treatments, and patient preference for different types of intervention. I think this is the first study to use a clear manualized intervention that's based on the psychological theory of mechanisms that contribute to the maintenance of psychological problems. Obviously, this tended to use more prescriptive interventions like anxiety management, stress management, taking techniques from a range of different sources. So I think there's a difference of conceptual basis to this kind of intervention. And it's something that is highly manualized and structured, and in fact can be delivered by a range of different healthcare professionals.
Dr. Greg Hundley:
Very nice. And also during cardiovascular rehab. Correct?
Dr. Adrian Wells:
Absolutely, yeah. During cardiac rehab. One interesting finding... And we were a little concerned that this might adversely affect attendance at cardiac rehab. But we found that the treatment was well tolerated, and it didn't have any negative impact on attendance at these other sessions.
Dr. Greg Hundley:
Excellent. Well, congratulations on this new finding. Well, listeners, we're next going to turn to Dr. Hyeon Chang Kim from Yonsei University in Korea. And Yong-Chan, could you describe for us also the background related to your study, and the hypothesis that your research wanted to test?
Dr. Hyeon Chang Kim:
Thank you for inviting me to this wonderful discussion. South Korea is among the countries with the lowest cardiovascular mortality in the world. And the rate is even decreasing. However, cardiovascular risk factor is worsening. Especially in younger generation in Korea. So these young people may not have a very high cardiovascular risk, but I wanted to know the potential impact of worsening cardiovascular risk profile in this younger Korean generation. And furthermore, I wanted to know how much we can lead youth cardiovascular risk by improving their cardiovascular health profile.
Dr. Greg Hundley:
Very nice. And so tell us about your study design and what was the study population, related to your study?
Dr. Hyeon Chang Kim:
My study is basically based on the national health checkup program and national health insurance claim database. In Korea, adults over the age of 20 and employed workers of all ages are required to take general health checkup every two years. The participation rate is between 70 and 80%. So we identified three and a half million adults, age 20 to 39 years, who complete the health checkup. And cardiovascular health scores was calculated as the number of ideal cardiovascular health component, which include non-smoking, moderate physical activity three times a week, body mass index below 2030, normal blood pressure, normal cholesterol and normal fasting glucose. So the score can range from zero to six. And higher score meaning better cardiovascular health. Our outcomes were myocardial infarction, stroke, heart failure, and cardiovascular deaths in about 16 years. In addition, we also evaluate the risk of cardiovascular disease. According to two year change in how the vascular health score using repeated health checkup data.
Dr. Greg Hundley:
Very nice. So evaluating a set of behavioral patterns and risk factors in younger individuals, and then predicting what their longer term adverse cardiovascular outcomes would be. So what did you find?
Dr. Hyeon Chang Kim:
So even in this relatively low risk population, better cardiovascular health score was associated with significantly lower cardiovascular risk. About 20% reduction per one point higher score. And more importantly, people with improving cardiovascular score over two years showed leading toward cardiovascular risk. Even if their baseline cardiovascular health score was very low.
Dr. Greg Hundley:
Really unique findings. Tell us about the impact of your results relative to other studies published in this space. And was this also.... This was unique, because it's an Asian population,
Dr. Hyeon Chang Kim:
Asian population. And we are among the very low risk population. And even in this low risk population, cardiovascular health score was... Fear can be a good predictor of cardiovascular risk. And compared to many Western countries, we have very low cardiovascular risk. And our population was younger than most other studies. So we can provide some evidence that even in the higher risk population, they can do much better, based on our study. Another important thing, we can check the impact of a changing cardiovascular score, even in the younger generation.
Dr. Greg Hundley:
Very good. And just as a frame of reference for our listeners. Give us some characteristics, if you wouldn't mind, on what really constitutes practically a low risk score, versus what would constitute a high risk score
Dr. Hyeon Chang Kim:
In this younger Korean population, their cigarette smoking, and their obesity, and physical inactivity are the most common causes of worsening cardiovascular profile. And the behavioral risk factor also can attack the blood glucose and cholesterol blood pressure. So in this younger generation, they're keeping the good behavior. Past behavior is very important and it's beneficial in the very long-term.
Dr. Greg Hundley:
Very nice, well listeners. We're going to turn to our experts here. Two very interesting studies. And ask them both, what do they think is the next study that needs to be performed in their respective areas of research? So Yong-Chan, we'll start with you. Since we just discussed your paper. What do you think is the next study to be performed really in this sphere of research.
Dr. Hyeon Chang Kim:
Korea is a relatively low cardiovascular risk, has a very small size, and no racial diversity. But even in this country, disparity and inequality in cardiovascular health is becoming an important issue. So I want to identify subcultural relatively poor cardiovascular health among younger population. And also I want to find ways to improve their cardiovascular score. The conventional approaches, such as education and mass campaign, are less effective oppose this younger adults have a poor socioeconomic status. So, we may need to develop newer target-specific strategies to improve their cardiovascular health.
Dr. Greg Hundley:
Good. And Dr. Wells, our agent will turn next to you. What do you see is the next area of investigation or research study that needs to be performed in your sphere of interests?
Dr. Adrian Wells:
Well, I think the next step is to look at rollout of this intervention. Is that feasible, and how acceptable is this to cardiac services? In fact, the National Institute of Health Research have just awarded us some funding to examine feasibility and barriers to implementation in the healthcare system. In addition to that, we're beginning to examine the effects of metacognitive therapy with other health conditions, such as cancer in children and adolescents.
Dr. Greg Hundley:
Nice. Well listeners, we have had just a wonderful discussion today from both Dr. Adrian Wells from University of Manchester. Who brought to us combining a group-mediated, psychological stress-reducing, anxiety-reducing, intervention to the cardiac rehab sphere. And how impactful that was in reducing both anxiety, and overall depressive symptoms. And then also exciting research from Dr. Hyeon Chang Kim from South Korea. Identifying for us that in Asian population, as well as what we know in other races, those individuals in their twenties to thirties with favorable lifestyle habits, have reduced cardiovascular risk much later in life.
Dr. Greg Hundley:
Well, on behalf of both Carolyn and myself, we want to wish you a great week. And we'll catch you next week on the run.
Dr. Greg Hundley:
This program is copyright of the American Heart Association, 2021. 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, visit ahajournals.org.