Preview Mode Links will not work in preview mode

Circulation on the Run

Aug 10, 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 Dr Greg Hundley, associate editor, director of the Pauley Heart Center, VCU Health in Richmond, Virginia.

Dr Carolyn Lam: Greg, guess what we're discussing for the feature discussion? We're talking about sugar sweetened beverage tax. Isn't that interesting? We talk about sugar sweetened beverages and their health impacts, but don't actually look at how tax policies may impact cardiovascular outcomes. So this paper is super interesting, can't wait to get to it, but I really want to get my cup of coffee and discuss a couple of other really cool stuff in today's issue. I'm going to start. Do you think about factor V Leiden much?

Dr Greg Hundley: Carolyn, we are early in August and we have all new house officers rotating, and actually we do discuss factor V Leiden, and we think about Protein C and Protein S deficiencies, et cetera. But how about if you tell us about your paper and educate us a little bit more on the topic?

Dr Carolyn Lam: Okay. So first of all, it's Leiden or Leiden, I'm not sure. So I'm going to go with your pronunciation. Factor V Leiden is a genetic variant leading to alteration of the inactivation site of factor V, which in turn leads to activate a Protein C resistance and a prothrombotic state, just like you said, Greg. Affecting almost 5% of the Caucasian population, carriers of a factor V Leiden mutation have a fourfold higher risk of venous thromboembolism. However, the risk of arterial atherothrombotic events, such as myocardial infarction or stroke, conferred by the presence of this variant is less certain. So Dr Patel from University College London, and Dr Asselbergs from University Medical Center Utrecht and colleagues assess the association of the factor V Leiden polymorphism with subsequent atherothrombotic events, including mortality in individuals with established coronary heart disease using an individual level data meta-analysis of 25 prospective studies from the genetics of subsequent or GENIUS coronary heart disease consortium.

Dr Greg Hundley: Well Carolyn, what did they find?

Dr Carolyn Lam: In nearly 70,000 patients with established coronary heart disease, factor V Leiden was not associated with an increased risk of further atherothrombotic events or death compared to non-carriers. A post hoc analysis, however, suggested that factor V Leiden carriers with established coronary heart disease may gain greater protection from subsequent coronary heart disease, death, or myocardial infarction from dual antiplatelet therapy compared to non-carriers. The routine assessment of factor V Leiden genotype to improve risk stratification in secondary prevention settings is therefore unlikely to be of value and is not recommended. However, further work is required to understand if there may instead be a pharmacogenomic role for factor V Leiden status to help personalize treatment with intensive antiplatelet therapy.

Dr Greg Hundley: Very nice, Carolyn. Well, my next paper is from Dr Michelle O'Donoghue from Brigham and Women's Hospital, and creates an interesting question for you, Carolyn. Would you be comfortable discontinuing aspirin three months after PCI in lieu of continuing a P2Y12 inhibitor?

Dr Carolyn Lam: Ah, big, big question. Not until guidelines change, but tell me, tell me, tell me, Greg, what this paper said.

Dr Greg Hundley: Well, before we get some of these more randomized trial, this study included a meta-analysis of 32,145 patients, 14,095, or 43%, with stable coronary artery disease and 18,000, nearly 56%, with ACS from randomized trials during the time period of 2001 to 2020. And they had to study discontinuing aspirin one to three months after PCI with continued P2Y12 inhibitor monotherapy compared to traditional dual antiplatelet therapy. Five trials were included, and the follow-up duration range from 12 to 15 months after PCI. The primary bleeding and MACE outcomes were the pre-specified definitions in each trial.

Dr Carolyn Lam: An important study. So what did they find, Greg?

Dr Greg Hundley: Well in the experimental arm, background use of a P2Y12 inhibitor with Clopidogrel in 16.5% of cases, and prasugrel or ticagrelor in 84% of patients. In total, 820 patients experienced a primary bleeding outcome and 937 experienced MACE. So the results, discontinuation of aspirin therapy one to three months post PCI significantly reduced the risk of major bleeding by 40% compared to dual antiplatelet therapy with no observed increase in the risk of MACE, myocardial infarction, or death. The findings were consistent among patients who underwent PCI for an ACS in whom discontinuation of aspirin after one to three months reduced bleeding by 50%, to 1.78% versus 3.58%, and did not appear to increase the risk of MACE where both were 2.5% and 2.98%.

Dr Carolyn Lam: Nice, Greg. Could you summarize the take home message for us?

Dr Greg Hundley: Sure, Carolyn. So in summary, discontinuation of aspirin with continued P2Y12 inhibitor monotherapy reduced the risk of bleeding when stopped one to three months after PCI. An increased risk of MACE was not observed following discontinuation of aspirin, including patients that had previously sustained ACS.

Dr Carolyn Lam: Thanks Greg. Well, my next paper is a preclinical one showing that circular RNAs delivered via extracellular vesicles may be a new treatment for ischemic stroke.

Dr Greg Hundley: Oh my goodness. Carolyn, can you orient us to circular RNAs and these extracellular vesicles?

Dr Carolyn Lam: Sure, Greg. I decided not to quiz you on them. Circular RNAs are a type of endogenous non-coding RNA molecule characterized by back splicing and covalently closed continuous loops, hence circular. Previous studies have demonstrated that multiple circular RNAs have functional roles relating to ischemic brain injury. Although administering circulating RNAs using lentiviruses is efficient for experimental examination, this route is limited for clinical translation due, of course, to disadvantages in onset time and safety issues. So this is where the extracellular vesicles come in as a potential cargo delivering system, if you may, for brain remodeling after stroke. These extracellular vesicles are lipid membrane vesicles of 30 to 150 nanometers in diameter that are released by cells and can cross the blood brain barrier and have been shown capable of carrying proteins, lipids, and nucleotides as their cargo.

So today's co-corresponding authors, Dr Yao from Medical School of Southeast University in Nanjing, and Dr Wang from Chinese Academy of Sciences Kunming, Yunnan in China envisioned the potential of delivering candidate circular RNAs to the brain in vivo by constructing engineered extracellular vesicles bearing circular RNAs. They initially explored this circular RNA delivery strategy idea in the context of their ongoing work regarding the functional roles of circulating RNAs in ischemic brain injury. Their microarray based profiling of acute ischemic stroke patients reveal that a circular RNA generated from the SCM-polycomb group protein homolog 1, or SCMH1 gene, is decreased in plasma of acute ischemic stroke patients and confirmed that a similar decrease occurs in stroke model mice. So they successfully engineered extracellular vesicles with circular SCMH1 over-expression and were thus able to experimentally characterize the ischemia related functional benefits of this circular RNA administration in stroke models in both mice and macaque monkeys. Cool, huh?

Dr Greg Hundley: Yeah. Very nice, Carolyn. That was a great explanation. My study comes from Dr Juyong Kim from Stanford University School of Medicine, and Carolyn, this study combined RNA sequencing, chip sequencing, ATEC sequencing, and in vitro assays in human coronary artery smooth muscle cells with single cell RNA sequencing, histology, and RNA scope in a smooth muscle cell specific lineage tracing aryl hydrocarbon receptor knockout mouse model of atherosclerosis to better understand the role of the aryl hydrocarbon receptor in vascular disease. This aryl hydrocarbon receptor, heretofore AHR, is an environment sensing transcription factor that contributes to vascular development.

Dr Carolyn Lam: Wow, what a comprehensive study. So what do they find?

Dr Greg Hundley: The authors identified a novel population of cells derived from smooth muscle cells, termed condramyocytes, which have gene expression features of cartilage and bone formation within an atherosclerotic lesion. In addition, the environment sensing transcription factor aryl hydrocarbon receptor plays an important role in smooth muscle cell differentiation, ossification, and maintains the smooth muscle cell derived fibrous cap structure.

Dr Carolyn Lam: Interesting. Okay, you know what I'm going to ask. What are the clinical implications?

Dr Greg Hundley: Yeah, I knew you'd ask me that, Carolyn. So human genetics suggests a protective role of the aryl hydrocarbon receptor in the smooth muscle cell during atherosclerosis, and therapies targeted to increase the aryl hydrocarbon receptor activity in smooth muscle cells may confer protection against adverse calcific remodeling of the atherosclerotic plaque. This study also highlights a methodological advance, and further characterization of the pathways that direct the modulation of smooth muscle cells during atherosclerosis at the single cell level may be able to identify potential therapeutic targets to mitigate the risk of atherosclerosis.

Dr Carolyn Lam: Oh, I like that summary, Greg. Thanks. Now, let's move on to other things in today's issue. There's a perspective by Dr Al-Lamee on the ISCHEMIA trial asking was it worth the wait? There's also a perspective by Dr Levine on the ISCHEMIA-CKD trial, providing contemporary randomized clinical data at last in this important population. There's a white paper by Dr Emmaullee on Fontan-Associated Liver Disease, screening, management, and transplant consideration. And finally, there are letters to the editor from Dr Helgestad, Chieffo, and Waksman, with replies from Dr Amin on the article The Evolving Landscape of Impella Use in the United States Among Patients Undergoing PCI With Mechanical Circulatory Support.

Dr Greg Hundley: Very good, Carolyn. Well, I have a few other items in the mail bag. Xiang Cheng has a research letter entitled Cardiac Troponin I is an Independent Predictor for Mortality in Hospitalized Patients with Coronavirus Disease 2019. Also, Corinne Frere has a research letter regarding the Systemic Inflammatory Response Syndrome is a Major Contributor to COVID-19-Associated Coagulopathy, and they provide insights from a perspective single center cohort study. And finally, Dr Jeffrey Wagner has an ECG challenge regarding the infamous is it VT or not VT? Well, Carolyn, how about we get on to that feature discussion.

Dr Carolyn Lam: Let's go, Greg. Beverage Texas are a promising policy approach to reduce consumption of sugar sweetened beverages. And as we know, these are linked to adverse health outcomes, such as Type 2 diabetes and obesity. Now these taxes have been adopted by seven localities in the United States, and in more than 40 countries around the world using different tax designs, but until now a critical answered question where we lack empirical data is the health impact of these beverage taxes. That is until today's feature paper, and I'm so pleased to have with us, Dr Yujin Lee from Friedman School of Nutrition Science and Policy, Tufts University, as well as our associate editor, Dr Naveed Sattar from University of Glasgow. Welcome both, and Yujin, could I start with you please? What an interesting and important idea to look at this. Could you start by perhaps first explaining to us what are the different types of tax designs?

Dr Yujin Lee: There are three types of tax design. First, the volume tax is taxing sugar sweetened beverages based on the volume. For example, a penny per owns for volume tax. So the tax rate is same whether a beverage contains 5 or 20 grams of added sugar for 8 ounces. The second design is the absolute sugar content tax, which is taxing beverages based on the sugar content regardless of the volume. So for example, one cent per one teaspoon of sugar, or one cent per one gram of sugar. Lastly, tier tax is hybrid of volume and absolute sugar content tax. For example, creating different tiers products based on the sugar content and taxing based on the volume at different rates. So for example, the American Heart Association suggested three tiers. First, no tax on beverages with less than five grams of added sugar per eight ounces. And second, 1 cent per ounce on beverages with 5 to 20 grams of added sugar per 8 ounces. And lastly, 2 cents per ounce on beverages with more than 20 grams of added sugar per 8 ounces.

Dr Carolyn Lam: Great. So thank you for explaining that. I mean, to be honest, I didn't even realize there were so many different tax designs. Now, could I understand a bit better? So in the US, are they mostly volume-based? And then perhaps you could tell us how did you go about your study of comparing these things, and looking on their impact on outcomes.

Dr Yujin Lee: Sure. So as you mentioned, all seven US locality have been implementing the volume tax, and in this study, this is the modeling study, so we're using the nationally representative data and using a microsimulation model, and we wanted to compare and estimate the health and economic impact of the volume, absolute sugar content. And the tier tax designs in the United States.

Dr Carolyn Lam: Great. And tell us what you found.

Dr Yujin Lee: What we found is we found that implementing a volume-based sugar sweetened beverage tax could prevent 850,000 cardiovascular events and 270,000 diabetes over a lifetime of current US adults aged 35 years or older. And this tax design could save tens of billions of dollars in healthcare costs. In addition, taxing sugar sweetened beverage based on their sugar content, for example, the tier or absolute sugar content based tax design, could generate about double the health and economic benefits compared to the volume tax.

Dr Carolyn Lam: Wow, that is so intriguing. Naveed, I have to bring you in here. So in the UK they use a tier tax. Do you? And what are your thoughts?

Dr Naveed Sattar: Oh, well clearly, Carolyn, I mean, I think taxation of sugar sweetened beverages is something that all of us can agree on is beneficial. I think it's really important that many other countries and states consider this. I'm surprised that only seven states in the US are currently doing this. And in some respects, this papers is very timely. It's based on modeling. I mean maybe you can come back to Yujin about how good the modeling is, but if you think about the issue we have now in terms of health inequalities and COVID related deaths, going forward we need mechanisms to help reduce health inequalities. And this particular paper will flag up that places need to think about sugar sweetened beverage taxes and how best to do them.

And I completely agree, they should be based on sugar content. I don't see why they should be more convoluted than that. And although Yujin explained it, it still seems a bit complex to me, the different mechanisms, but I think your paper is very timely and very important. And for me, the key question for Yujin is people looking at this may say well, how robust is that model? How do we know how accurate you've been in terms of the money saved, because that's going to be really important going forward, and in particular, the number of lives or cardiovascular and diabetes cases prevented?

Dr Yujin Lee: Sure. So let me explain how we estimated how many cases of cardiovascular disease and Type 2 diabetes were prevented. So we use a microsimulation model, which is a computer simulation model, which is developed by the research team, led by Dr Thomas Casiano and Harvard School of Public Health. So this model predicts the probability of an individual experiencing cardiovascular disease or diabetes based on each person's risk factor, such as sex, age, total cholesterol, or smoking or diabetes, and also their SSB-consumption also be part of this input. So it estimate the probability of one person, individual, developing the future cardiovascular disease, or Type 2 diabetes, and it estimate how this prevention can save healthcare costs associated with these diseases. So in this study, this model simulates the status quo, so the way things now stand, and also it assimilate the three different tax design. After that, we compute the health outcome and costs associated with this policy options and, by comparing this model, outputs for these three tax design with the status quo.

Dr Naveed Sattar: Has any country got long enough perspective data that have implemented such taxes to validate the model, or is that still to come? I mean it would be nice to get it validated in real life, but I think most people would accept that reducing sugar in beverages is a really good thing, and presumably the part of the mechanisms by reducing weight, and reducing all of the implications of excess calorie intake, particularly refined sugar, on a variety of different diseases. Is that fair?

Dr Yujin Lee: Yeah, and I wanted to make a point that, since this is a modeling study, so our study cannot prove the health and economic impacts of this tax design in the United States, so rather our estimates provide evidence that can be considered and incorporate into the design, and implementation, and evaluation of future SSB taxes.

Dr Carolyn Lam: That's a really good point. And maybe just to round up, Yujin, could I just ask you to were any particular individuals in the population simulated to experience larger gains? We know that it's exactly like Naveed said, it's the minorities, it's perhaps lower income region individuals who might need this more. I mean did your simulation show anything to that effect?

Dr Yujin Lee: We also investigate this tax design and how this influence in sub population. Particularly we found that the SSB taxes have a larger benefit among younger adults, minorities, and adults with the lower income. Given that these population, their SSB consumption is higher than the other group, so this SSB tax implementation gives them a greater health and economic benefit to these subpopulations.

Dr Carolyn Lam: Thank you so much, Yujin, for this really, really, I think, novel and very important data. Naveed, could I give you the last say as the associate editor who is managing this, and you even invited an editorial, which I liked very much, the title, Simple is Better for Local Beverage Tax Policy Diffusion. It's kind of in line with what you've been saying, but maybe some take home messages?

Dr Naveed Sattar: Obviously in Circulation, we get lots of beautiful papers that very molecular depth and various other factors, but actually this paper brings us back to the reality that for many of the diseases that we treat, diet and drink intake is really relevant to our diseases and the likelihood of diseases, and there are simple mechanisms whereby we can help people in the community to actually lead better lifestyles that also are actually economically beneficial. And I think that in this paper, if it was to be implemented and looked at seriously by many states in the US, by many other countries to go along this route would have huge potential benefits on health, And it's really important at this time, given what's happened with the pandemic, and as we move forward over the next 5 to 10 years. So I think it's really timely and I congratulate the authors on it.

Dr Carolyn Lam: Well, listeners, you heard it right here, novel, impactful data. That's what Circulation is about. Thank you for 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.