Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
RSS Feed Subscribe in Apple Podcasts
Circulation on the Run



All Episodes
Now displaying: 2018
Mar 12, 2018

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 Centre and Duke National University of Singapore.

                                                Have you ever wondered, which is better for heart health, low calorie vegetarian or a Mediterranean diet? Well, this week's feature paper provides some answers with a very intriguing discussion coming right up after these summaries.

                                                The first original paper this week suggests that human fat pools are not the same and in fact are highly diverse in their response to lifestyle interventions during weight reduction first author Dr. Gepner, co-corresponding authors Dr. Shai from Israel and Dr. Stampfer from Boston aim to assess whether distinct lifestyle strategies could differentially affect specific body adipose depos. They performed at 18-month randomized control trial among 278 sedentary adults with abdominal obesity or dyslipidemia in an isolated work place with a monitored, provided lunch.

                                                Participants were randomized to an isocaloric low fat or a Mediterranean low carbohydrate diet with or without added moderate physical activity. The overall primary outcome was body fat redistribution and the main specific endpoint was visceral adipose tissue. The authors further followed the dynamics of different fat depos by magnetic resonance imaging. They found that Mediterranean diet was superior to the low fat diet in mobilizing specific ectopic fat depos such as visceral, hepatic, cardiac and pancreatic fats. Exercise had an additional independent contribution to visceral fat loss. Long term persistent moderate weight loss inadequately reflected the significant beneficial effects of diet and exercise on the fat depos. Independent of weight loss, visceral and hepatic fat reduction was mainly associated with improved lipids profile whereas deep subcutaneous fat loss was associated with improved insulin resistance and superficial fat loss was neutral.

                                                In other words, two distinct patterns were identified, a differentially responsive depo that was sensitive to the type of intervention, and those recites mostly directly related cardiometabolic health and a uniformly responsive depo, which corresponded only to weight loss per se irrespective of the intervention. Overall, these results suggest that more specific strategies for weight loss may be considered to treat distinct organ specific fat depos in the management of cardiometabolic risk.

                                                Current guidelines recommend nonvitamin K antagonist oral anticoagulants or NOACs in patients with nonvalvular atrial fibrillation as these drugs have several benefits over the vitamin K antagonists but do these benefits remain when NOACs have to be combined with aspirin therapy? Well co-first authors Dr. Bennaghmouch and de Veer, corresponding author Dr. ten Berg and colleagues from the Netherlands provided a meta analysis comparing NOACs and Vitamin K antagonists in more than 21700 patients with atrial fibrillation who are treated with concomitant aspirin therapy. NOACs were found to be more effective in terms of stroke or systemic embolism reduction as well as vascular death reduction and as safe as vitamin K antagonist with respect to major bleeding. NOACs were in fact safer with respect to the reduction of intracranial hemorrhage. Thus, these authors found that NOACs were an effective and safe alternative as compared to vitamin K antagonists in atrial fibrillation patients treated with concomitant aspirin therapy.

                                                The next study shows that an integrative approach using genomics and proteomics has the potential to identifying new biological pathways for biomarker discovery and pharmacologic targeting in early cardiovascular disease. Co-first authors Dr. Benson and Yang, co-corresponding authors Dr. Wang and Gerszten from Beth Israel Deaconess Medical Center in Boston had recently identified 156 proteins in the human plasma that were each associated with a net Framingham cardiovascular disease risk score using an aptamer-based proteomic platform in the Framingham Heart Study Offspring participants.

                                                Now, in the current student these authors hypothesized that performing a genome-wide association study and exome array analyses on the levels of each these 156 proteins may identify genetic determinants of risk associated circulating factors and provide insights into early cardiovascular pathophysiology. Indeed, they discovered dozens of novel genetic variants that were each strongly associated with circulating levels of the Framingham Risk Score associated proteins. They highlighted numerous examples of how these novel gene locus protein associations provided new insights into cardiovascular disease risk pathophysiology including a novel pathway by which the gene phosphatase 1G modulated circulating levels of apolipoprotein E, a key regulator of cholesterol handling.

                                                The final study suggests that bariatric surgery represents an effective strategy for reducing antihypertensive drugs in patients with obesity and hypertension. First and corresponding author Dr. Schiavon from Heart Hospital in Sao Paulo, studied 100 patients with obesity and hypertension who were randomized to gastric bypass or medical therapy alone. The patients randomized the gastric bypass were six times more likely to reduce by 30% or more the total number of antihypertensive medications while maintaining controlled blood pressure levels. In addition, 51% of the patients undergoing gastric bypass showed remission of hypertension. Now, the authors are quick to alert that given the morbidity of surgery these results do not imply that all patients with obesity and hypertension should be submitted for bariatric surgery. Rather, these results suggest that gastric bypass surgery represents one extra option to consider in achieving blood pressure control in these patients.

                                                That wraps it up for our summaries now for our feature discussion.

                                                So, which is better for heart health the vegetarian or the Mediterranean diet? Oh, what an awesome topic and to be able to discuss it from Asia to the United States to Italy, I'm so please to have the first and corresponding author of our feature paper this week Dr. Francesco Sofi from University of Florence in Italy and our dear associate editor Dr. Wendy Post from Johns Hopkins. Francesco, could you please start by telling us what inspired you to do this trial?

Dr Francesco Sofi:            The aim of the study was to compare two of the most beneficial diets we know from the literature in relation to the occurrence of many chronic degenerative diseases so the Mediterranean diet we have a lot of studies showing that Mediterranean diet is beneficial for many different diseases as well as we have some studies for the beneficial effect of a lacto-ovo vegetarian diet but no studies are available comparing these two diets' dietary profiles. Our hypothesis was to compare in the same population different times the two diets, which were the similar calories, the same isocaloric but just different in terms of composition especially for meat and fish.

Dr Carolyn Lam:                Tell us the bottom line. I'm holding my breath because I think I've said it before, I'm vegetarian. Half my household is Mediterranean diet so what did you find?

Dr Francesco Sofi:            We found that in the same group of patients, which were a low risk population because a low risk population here in Italy they were already following a Mediterranean diet but if you control their calories and their composition in terms of the Mediterranean, which included all the different food groups and the lacto-ovo vegetarian diet so all the different groups except for meat and meat-based and fish we noticed that after three months, the lacto-ovo vegetarian diet already determined a reduction of total cholesterol and LDL cholesterol and Mediterranean diet already determined reduction of triglycerides and both were effective for reduction of body weight and fat mass.

                                                We noticed with great interest that after three months, all the study population were quite good in [inaudible 00:09:45] with this diet. I mean they didn't have any kind of problems. This is the one of the most important thing and most of the population or many of the patients after the end of the study they started or continued to follow a vegetarian diet. It means that they accepted very well. There was no problem at all. Also, in feasibility and acceptability of this diet and in relation to this also they have a beneficial effect in some parameters such as also oxidative stress parameters and the inflammatory parameters.

Dr Carolyn Lam:                Right, so if I could summarize maybe crudely so the vegetarian diet, very effective for LDL, the Mediterranean very effective for triglycerides. I know that's a simplification but Wendy, I'd like to know do you think this is the dawn of maybe a more, "Oh, here we go again individualized diet planning"?

Dr Wendy Post:                I think that this study is really important because there really have been few randomized trials about the vegetarian diet and we've learned a lot of the potential beneficial effects of a Mediterranean diet. I think what was really interesting about this study is seeing that they were both equally effective as a low calorie Mediterranean diet or vegetarian diet at reducing body weight, which is most often the biggest challenge for our patients who are either at risk for cardiovascular disease like these patients potentially were or who have cardiovascular disease.

                                                I think the vegetarian diet is potentially an excellent option for some of our patients but it really is an individual choice and I have trouble getting some patients to just give up the red meat let alone any kind of animal meat. I think it really is potentially an individual choice and those who are interested in becoming vegetarian for either health reasons or other reasons these are additional data to suggest potential beneficial effects more to the Mediterranean diet.

Dr Francesco Sofi:            I think one of the most important things to know from this study is that we have now two options. We need to individualize the diets to patients but if a person wants to follow a vegetarian diet for different reasons including also healthy reasons, we can say that it's beneficial. He or she can follow this diet without no problems so without having any health problems as well as if a person wants to follow also a Mediterranean diet, which included meat and fish with a regular and moderate consumption during the week.

Dr Wendy Post:                Right but this is just a three month trial with intermediate outcomes so I'm not sure we can necessarily make definitive statements that this is potentially not leading to any adverse effects or some of the other statements that you made. I think we could just make the statements better relative to the outcomes that were seen here related to weight loss and traditional cardiovascular risk factors. Whereas, we have had long term clinical trials of the Mediterranean diet suggesting reduction in risk for events so I think this is definitely supportive of the vegetarian diet but I think we can't say that more studies aren't needed to potentially look at longer term outcomes and more definitive events as opposed to intermediate outcomes that this is a great first start and is really helpful in trying to understand some of the potential differences between the vegetarian diet and the Mediterranean diet.

Dr Francesco Sofi:            Of course, I completely agree on that. We need more studies and larger studies and longer duration to establish some things but it was just a pilot study but the good thing is the first comparing two beneficial diets. In the literatures now, most of the studies were investigated either already a vegetarian person or vegetarian diet versus a westernized diet so probably there were some biases.

Dr Carolyn Lam:                Indeed, I want to just echo in these words. Congratulations, Francesco. Beautifully done, very elegant, controlled in terms of caloric intact and I like that message that it's not saying that one is bad and the other is good. It's saying, "They're different but they both resulted in weight loss". I love that comment about getting a bigger study. I want to do it right here in Asia because the diets are just so different here and I'm just wondering how about in the US? Wendy, your perspective? How adoptable are these results?

Dr Wendy Post:                Well, again I think it's a personal choice and if somebody is willing to become vegetarian then that's potentially wonderful especially if they have high LDL cholesterol and are trying to lose weight but we have to be careful about with the vegetarian diet is the carbohydrate intake, which might affect triglycerides. It might be an individualized approach based on the patient's individual risk factor profile and they're preferences but this is really impressive data suggesting that the vegetarian diet is very similar to the Mediterranean diet in many aspects especially as it relates to weight loss, which is really important.

Dr Carolyn Lam:                You've hit the nail on the head. Let's remember that this is a low calorie vegetarian diet. I think that's the issue. Sometimes when I say vegetarian diet to some communities here in Asia that is actually a lot of calories and a lot of starch, which is not what we're talking about here.

Dr Wendy Post:                Right, a low calorie diet so that's the key. That's the hard part isn't it?

Dr Carolyn Lam:                Yeah, sadly.


Dr Francesco Sofi:            We should say that most diets are similar background I mean in the backbone is similar so a dietary profile full of fruit and vegetables, complex carbohydrates, fiber, so the different things are meat and fish but with you can see in a regular consumption also Mediterranean diet of course, especially Mediterranean diet is beneficial for cardiovascular profile.

Dr. Wendy Post:               Yeah, if we could get our patients in the United States to follow either the vegetarian or the Mediterranean diet that would be fabulous because they are obviously eating too much in the way of sugar sweetened beverages and deserts and fast food so just trying to follow either of these diets would be especially beneficial if it was a low fat vegetarian or Mediterranean diet. I think we need to get all our patients to be eating more fruits and vegetables, which is a key component of both of these diets and what they share in common, which often can lead to beneficial effects with weight loss due to the increased fiber and satiety and the healthful benefits of high fruit and vegetable diet.

Dr Carolyn Lam:                Thank you so much.

                                                Audience, thanks also for joining us. You've been listening to Circulation on the Run. Don't forget to tune in again next week.


Mar 5, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's journal features an international external validation study of the 2014 ESE Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy. A very exciting discussion coming right up after these summaries.

                                                The first original paper this week suggests that proteomics, a tool of precision medicine may prove useful in improving the safety and efficiency of drug development. First author, Doctor Williams, Corresponding Author, Doctor Ganz, from the Zuckerberg San Francisco General Hospital retrospectively applied large scale proteomics to blood samples from Illuminate, the trial of Torcetrapib, a cholesterol estrotransfer protein inhibitor, which raised HDL and lowered LDL cholesterol. Recall that this trial was terminated due to increases in cardiovascular events and mortality.

                                                In the current study, the authors found that plasma concentrations of 200 proteins changed significantly with Torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in aldosterone function and glycemic control. A previously validated nine protein risk score was similar in the two treatment arms at baseline, but higher in participants with subsequent events. At three months, the absolute nine protein derived risk increased in the Torcetrapib plus Atorvastatin arm compared to the Atorvastatin only arm. Thus, this protein-based risk score predicted harm from Torcetrapib within just three months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. This is discussed in an accompanying editorial entitled "Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials" by Doctor Maggie Lam and Ying Ge.

                                                The next study suggests that personalized monitoring of heart transplant outcomes may be achieved by profiling the genetic and phenotypic markers of the CD16-dependent natural killer cell activation pathway. First and corresponding author Dr. Paul from Vascular Research center in Marseilles in France and his colleagues collected blood samples from 103 patients undergoing routine coronary angiography for cardiac allograph vasculopathy diagnosis, a median of five years since their heart transplantation. They used a non-invasive natural killer cellular-humoral activation test to evaluate the association between genetic and phenotypic markers of the CD16 dependent natural killer cell activation pathway. They showed that the Fc-gamma receptor IIIAVV polymorphic variant, which encodes the highly responsive CD16-Fc receptor, was an independent baseline predictor of cardiac allograph vasculopathy, and may be useful for stratifying patients at higher risk of rejection. The implications of these findings also include the fact that individualized natural killer cell targeted therapies may limit vascular damage in responsive patients.

                                                The next study suggests that estimation of polygenic atrial fibrillation risk is feasible, and together with clinical risk factor burden, can explain lifetime risk of atrial fibrillation. Co-first authors Dr. Weng and Preis, corresponding author Dr. Lubitz from Massachusetts General Hospital, and colleagues estimated the lifetime risk of atrial fibrillation in individuals from the community-based Framingham Heart Study. Polygenic risk for atrial fibrillation was derived using a score of approximately 1000 atrial fibrillation-associated SNPs. Clinical risk factor burden was calculated for each individual using a validated risk score for incident atrial fibrillation comprised of height, weight, systolic and diastolic blood pressure, current smoking, anti-hypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure.

                                                They found that the lifetime risk of atrial fibrillation after age 55 years was 37 percent was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of atrial fibrillation at the age of 55 years, those in the low polygenic and clinical risk tertiles, had a lifetime risk of 22 percent, whereas those in the high risk tertiles had a risk of 48 percent. Atrial fibrillation developed at an older age among individuals with a favorable clinical risk profile regardless of genetic predisposition. Nevertheless, the lifetime risk of atrial fibrillation in individuals with high genetic predisposition was substantial, even when the clinical risk factor burden was low. Thus, individualized projections of lifetime risk of atrial fibrillation may be refined by accounting for both genetic predisposition and clinical risk factor burden.

                                                The final study tells us that in contrast to previous perceptions, Takotsubo cardiomyopathy has long-lasting clinical consequences. First and corresponding author Dr. Skally from University of Aberdeen in the UK and their colleagues did an observational case controlled study of 37 patients with prior Takotsubo cardiomyopathy and 37 age, sex, and co-morbidity matched controls. Although Takotsubo cardiomyopathy occurred 20 months before the study, the majority of patients had persisting symptoms compatible with heart failure and cardiac limitation on exercise testing. Despite a normal left ventricular ejection fraction in serum biomarkers, patients with prior Takotsubo cardiomyopathy had impaired cardiac deformation indices on echo cardiography, increased native T1 mapping values on cardio magnetic residence imaging and impaired cardiac energetic status on p31 spectroscopy. Taken together, these findings demonstrate that after Takotsubo cardiomyopathy, patients appear to develop a persistent long-term heart failure phenotype.

                                                Well that wraps it up for our summaries. Now for our featured discussion.

                                                Sudden cardiac death prevention and hypertrophic cardiomyopathy. Always such an important topic. I'm so pleased to have with us the author from our featured paper this week, Dr. Perry Elliot from University College London, nd our associate editor, Dr. Mark Link from UT Southwestern who also wrote a beautiful accompanying editorial with Tera Lynn Ho. So welcome both of you. Perry, I think to set us up, I'd really love if you could tell us a little bit more about the 2014 ESE guidelines for sudden cardiac death prevention and hypertrophic cardiomyopathy. And particularly pointing out how they may differ from the 2011 ACC AHA guidelines please.

Dr Perry Elliot:                   So, the 2014 guideline on sudden death prevention HCM, the aim of that guideline was to try to quantify the risk of sudden cardiac death. As you pointed out, sudden death is a significant complication of hypertrophic cardiomyopathy and one which we all as clinicians spend a lot of time trying to determine. If we look back over at, I don't know, a period of twenty, thirty years the approach we've developed is based upon the recognition of a number of clinical features of the disease that we know associate with a higher risk of sudden death. So things such as, you know, unexplained syncope or severity of hypertrophy. And it was that model of sort of taking those so called major risk factors which form the basis of the 2011 US guidelines and the essential model was the more of those things you have, the greater is your risk, and I suppose the  higher indication for an ICD.

                                                One of the problems with that approach was that it's not quantitative so you know, you could say, "Okay. Well I think you're at higher risk, but I can't say how much that risk is." And another problem with that way of doing things is when you start to think about some of the individual risk factors, it doesn't make a great deal of sense clinically.

                                                And I suppose a good example of that is wall thickness. You know we have this magical number of 30 millimeters, above which we say you're at risk, but of course are we really saying that if your wall thickness is 29 millimeters you're at low risk? We know it doesn't really work that way in biology. So when we drew up the 2014 guideline we wanted to say, "Okay let's develop a model in exactly the same way that we do with atrial fibrillation or primary prevention in coronary disease so that we can say to the patient sitting in front of us, 'Based on your clinical assessment we think you've got a one, five, ten percent risk of something bad happening to you in the next five years.'" And then we can use that information to inform our decision about ICD implantation.

                                                The model itself is not so revolutionary. I mean, it uses a lot of the conventional risk factors such as wall thickness, such as non-sustained VT on Holter monitoring, but what it did introduce was the factor of age, because we know that the age of the patient certainly determines their risk. We brought in [inaudible 00:10:12] obstruction because we've now got reasonable evidence showing that if you've got a big gradient, that certainly modulates your risk. And also probably for the first time, I suppose, left atrial size, which was one of those missing things I think in previous assessments. You know, it's a fantastic surrogate for restrictive physiology and certainly when we added it to the model it improved the predictive power of that model.

                                                So I suppose in summary what we've done is to produce a tool which allows you to estimate risk and then use that to help you decide on whether an individual needs a defibrillator in the clinic.

Dr Carolyn Lam:                You know Perry I believe you led those guidelines and I just want to congratulate you as well as that was such a beautiful explanation of what was going on behind those. Yup, but the proof is in the pudding isn't it? But you're providing that proof in today's paper. Tell us about it. So it's an external validation, a large international multi-centers study to actually validate these 2014 guidelines.

Dr Perry Elliot:                   That's right. I mean, I think when we generate these kind of models it's really important to test those models in different settings. The original model was based upon a relatively small number of European centers and I think what this paper does is it brings insights into different geographies and different health care systems. So we have participating centers from North America from the Middle East from the Far East and the idea here is to get as diverse a population as we can and just see if the model performs in the same way. And you know in a study just short of 4000 people, I think that we've shown that the model does indeed seem to behave in the same way. In fact, the numbers were remarkably similar. You know the ability of this model to discriminate between high and low risk patients was almost exactly the same as in the original paper, which I think gives us a level of reassurance that this model, this tool that we've developed, can be used in different health care settings.

Dr Carolyn Lam:                Mark. I really enjoyed your editorial. I love the way that you started out with a case that really shows why this is so important. And I also love that you discuss some other studies that tried to validate the 2014 ESE guidelines as well. Could you just give us some of your thoughts there.

Dr Mark Link:                     Yeah. I first want to congratulate Perry and his fellow authors for this paper. I think it was a very nice paper. I was a champion of this paper from the time it got sent into circulation. And, you know, the big change in the 2014 European guidelines compared to the American guidelines is really the linear risk of age, wall thickness, and I'll put tract gradient. And as Perry says, I agree, it's not a simple you have it or you don't, it's a linear risk and I applaud them for including that in their risk factor stratifier. And if you look at the current paper, I mean it was very good at picking out high risk patients. So if you have greater than a four percent, six percent risk over five years, you did. And so for picking out the high risk patients it was very good. And for picking out the medium risk patients, it didn't function as well. It was best for separating out the high risk and the low risk population.

                                                And I will say, based on this paper, I've started using the European risk stratifier in my clinical practice. So I do want to applaud them, you know, for the risk stratifier tool and this paper. But I do want to say, and I'm sure Perry will agree, that we're not there yet. We need better tools, because not only in this data set but in other data sets, because more of these individuals reside in the low risk population, more of the sudden deaths are in that population. And we need better tools. And over time they will come. You know, they may be MRI tools. They may be scar tools. They may be other tools that we aren't even aware of that are coming on the horizon, but we do need better tools as we move forward to identify those at risk for sudden death in hypertrophic cardiomyopathy.

Dr Perry Elliot:                   Yeah. No. I agree. I mean I think what I would say is if you sort of take a step back and look at the overall perspective in this paper, despite the fact that, you know, we've got nearly 4000 people and they're followed in different health care settings, the overall sudden death rate in hypertrophic cardiomyopathy pretty low. You know, so that's good for patients 'cause I think it shows that at least in managed populations, the risk of sudden death which is real and we've got to assess it, but I think it's really important to get that message over to patients that for most people with HCM they're at low risk. It is of course the challenge because when you're dealing with rare events, it's really hard to predict them. And this model is far from perfect. I would argue it's probably the best we've got for the moment, but you know, it's not that bad. It's not that bad.

                                                I mean agree with you absolutely Mark, 'cause you know, either end it performs pretty well. In the middle there it's not as predictive, although what it tends to do is overpredict, rather than underpredict. So you know, I think if you use this model in your every day practice just the greatest risk is that you'd end up putting in probably more ICDs then you really need to rather than missing a lot of patients. You know, we really want to prevent every sudden death if we possibly can, but that's always going to be really hard I think and I think the fight goes on. We got to look for new risk predictors. It may be that we can interchange some of these predictors. They might be easier to assess in some practices, but I'm not a born optimist, but I really think it's amazing just how well in such a complex heterogeneous disease that this relatively simple assessment works. You know?

Dr Mark Link:                     Going forward, what do you think the future of HCM [inaudible 00:15:47] stratification will include? We've got the risk stratifiers in your calculator ready. And more specifically where do you think gadolinium enhancement will play a role in the future? So MRI findings of scar or gadolinium enhancement.

Dr Perry Elliot:                   The base we have at the moment show that the more scar you have, the greater risk of sudden death. It sort of makes sense, doesn't it? It's part of that substrate for ventricular arrhythmia. My own reading of it just so far is that I'm not sure what it adds to the existing way of doing things. I mean I think this is true of any biomarker, you know. I've got a new biomarker, what does it tell me that I don't already know? And with scar, we know the greater amount of scar, it often tracks with wall thickness. You're likely to have a thicker heart, you're more likely to have non-sustained VT. But I'm openminded on that front. The beauty about this model, for me, is that it's a tool to into which you can plug other things and you know, if we can get big enough data sets and we can use gads and the amount of scar and put that into the model and if it improves the performance of the model that's great. Those studies are underway at the moment and I think we eagerly wait the results of those studies.

                                                For me, one of the missing things is the genetics. This is a heterogeneous disease with quite a complex genetic architecture, and despite the fact that you know it's 20, 30 years now since we identified the first gene, we haven't really factored that in to our risk models and I think that for me is one of the big challenges and opportunities over the coming years is to put together really large international data sets so that we can answer once and for all whether your mutation determines your prognosis.

Dr Mark Link:                     Yeah. I agree with the genetics also I think getting more information on that. And it’s been 30 years it still is not helping us prognosticate the risk of sudden death, but it should. I mean it really should. And I do think hopefully we will find other tools also as time goes on because it really is imprecise and it's very difficult when you're sitting there in front of ... You know, I just had a 20 year old yesterday come in with his family and he's got a three centimeter septum and he's got 12 percent scar and he's saying, "Gee what would you do and what would you do if I were your son?" And it's easy when you're looking at it in the aggregate. It's much more difficult when you're sitting there one on one with a patient in front of you.

Dr Perry Elliot:                   Of course. Of course. And I think another factor I think which is changing the dynamic of that kind of discussion is the evolution of ICD technology. You know, I think when you're dealing with young people the fear is long-term complications with leads isn't it? And I think with the advent of the SICD I sense it's already tipping the balance into perhaps a slightly more liberal approach to ICD implantation exactly in the kind of scenario you've just described Mark, you know you've got guy who's 20. He's got a really severe hypertrophy. Well you know, if you and mess ICD you know your threshold for implantation might be a bit lower.

Dr Mark Link:                     Yeah and in fact, after a two hour discussion that's what we decided on is that subcu ICD was the right thing for him. And everyone's very happy with that choice.

Dr Perry Elliot:                   Yep. I think it also raises another thing which I often think about is that as medics we're also probably not good at considering what acceptable risk actually is. You know? We develop models in different settings and hyeprtrophic cardiomyopathy, coronary disease, heart failure, and actually if you go back and critically look at the thresholds that are used to put in defibrillators, the absolute risks vary enormously. So you know, here in [inaudible 00:19:02] we're talking about an approximate annual risk of sudden death of about one percent per annum is sufficient to put in an ICD, but in long-QT world it's quite a different threshold that's used and of course that's because there is no defined number. You know the number's we used in the ESE model of greater than six percent you should have an ICD, well yeah that's the consensus number, there's nothing magical about it. There's nothing biological about it. And I think we've probably had greater debates at what acceptable risks really are.

Dr Mark Link:                     And that's become a big shared decision now in the States and actually everywhere. It's become a big word because it sued to be that the physicians would decide on who gets an ICD and who doesn't. And it's no longer that way it's a discussion with the patient, with the family. How much risk are they willing to take, both with an ICD and without an ICD, because there are issues with ICD, even though I'm a big fan. There are issues and especially with transvenous ICDs, but also with subcutaneous ICDs.

Dr Perry Elliot:                   Absolutely. Absolutely.

Dr Mark Link:                     You know, it's a different world now than it was 15 20 years ago.

Dr Carolyn Lam:                Perry and Mark, this has been one of the most wonderful conversations I've had on these podcasts. I just can't thank you enough. I'm sure all our listeners are thanking you too. You've been listening to Circulation on the Run. You must tune in again next week for more beautiful conversations.


Feb 27, 2018

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. The new ACC/AHA hypertension guidelines are hotly discussed. So much so that we have invited perspectives of these new guidelines from around the world and authors will be discussing this right here on Circulation on the Run. Stay tuned, as it's coming right up after these summaries.

                                                The first original paper this week is a translation study suggesting that the parasympathetic system may be a novel therapeutic target in pulmonary arterial hypertension. Co-corresponding authors Dr. Handoko and de Man from University Medical Center Amsterdam used heart rate recovery after maximal cardiopulmonary exercise testing as a surrogate for parasympathetic activity, and assessed white ventricular ejection fraction in 112 patients with pulmonary arterial hypertension. They found that patients with a lower right ventricular ejection fraction had a significantly reduced heart rate recovery compared to patients with a higher right ventricular ejection fraction.

                                                Furthermore, they looked at tissues from the right ventricle of 11 patients undergoing heart-lung transplantation, and found that there was increased expression of nicotinic receptors with no difference in muscarinic receptor expression compared to controls.

                                                Finally, in a rat model of pulmonary hypertension, they showed that chronic pharmacologic sympathetic stimulation by pyridostigmine, which is an acetylcholinesterase inhibitor, improved surviving right ventricular function and reduced pulmonary vascular remodeling.

                                                In summary, the study shows that right ventricular dysfunction is associated with reduced systemic parasympathetic activity in patients with pulmonary arterial hypertension, with an inadequate adaptive response of the cholinergic system in the right ventricle. Furthermore, enhancing the parasympathetic activity in these patients may be a novel therapeutic strategy.

Dr. Carolyn Lam:               The next study unveils a new mechanism by which pericardial adipose tissue coordinates immune cell activation and outcomes following a myocardial infarction. First author Dr. Horckmans, corresponding author Dr. Steffens, and colleagues from Institute of Cardiovascular Prevention in Munich identified larger B-cell clusters in epicardial adipose tissue of human patients with coronary artery disease compared to controls without coronary artery disease. Furthermore, they showed that infarcted mice had larger pericardial clusters, and a 3-fold up regulator numbers of GM-CSF producing B-cells within the pericardial adipose tissue, but not in the spleen or lymph nodes. This was associated with higher dendritic cell and T-cell counts in the pericardial adipose tissue.

                                                Further experiments show that activated dendritic cells migrated from infarcts into the pericardial adipose tissue. Cytokines and growth factors released locally within the pericardial adipose tissue as well as systemically promoted immune cell proliferation and emergency granulopoiesis after myocardial infarction.

                                                Finally, the enhanced fibrosis and worsened ejection fraction in mice was limited by removal of the pericardial adipose tissue.

                                                In summary, these pre-clinical data suggest that pericardial adipose tissue may be a central compartment for innate and adaptive immune responses, which regulate post-myocardial infarction healing.

Dr. Carolyn Lam:               The next study reports for the first time in a large, comprehensive national cohort study, the incidence of atrial fibrillation in children and young adults with congenital heart disease. First and corresponding author Dr. Mandalenakis and colleagues from University of Gothenburg in Sweden used data from the Swedish Patient and Cause of Death registers to identify all patients with a diagnosis of congenital heart disease who were born between 1970 and 1993. Each patient with congenital heart disease was matched by birth year, sex, and county with ten controls from Sweden. Follow-up data were collected until 2011.

                                                The authors found that the risk of atrial fibrillation in children and young adults with congenital heart disease was 22 times higher than that in matched controls. Up to the age of 42 years, one in 12 patients with congenital heart disease had developed atrial fibrillation and one in 10 patients with congenital heart disease with atrial fibrillation had developed heart failure. In particular, patients with the most complex congenital malformations, conotruncal defects, had the highest risk to develop atrial fibrillation. These patients should be considered for targeted monitoring.

Dr. Carolyn Lam:               The next study provides a novel and simple risk score for right-sided heart failure in adults undergoing Left Ventricular Assist Device implantation with the current mainstream devices. First and corresponding author Dr. Solomon and colleagues from University Medical Center Rotterdam studied almost 3000 adults who underwent continuous flow Left Ventricular Assist Device implantation in the largest EU registry of mechanical circulatory support devices. They derived and validated a right-sided heart failure prediction model that out-performed several published scores and well-known hemodynamic and echocardiographic individual markers of right-sided heart failure.

                                                This prediction model included the following risk factors: need for three or more inotropic agents, inter-agency registry from mechanically-assisted circulatory support class one through three, severe right ventricular dysfunction on semi-quantitative echo cardiography, ratio of right atrial to pulmonary capillary wedge pressure of more than 0.54, and a hemoglobin level of less than 10 grams per deciliter.

                                                These findings offer a step towards improving prediction of the risk of right-sided heart failure to target future optimal strategies aiming at early and intension right-sided heart failure management for the highest risk subgroups of patients undergoing Left Ventricular Assist Device implantation.

Dr. Carolyn Lam:               Now, sharing a patient-level clinical trial data has been widely endorsed, but just how extensively have these data been used for cardio metabolic diseases? The final study this week attempts to answer this question. First and corresponding author Dr. Vaduganathan and colleagues from Brigima Women's Hospital extracted data from, a large, multi-sponsored data sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.

                                                They found that the median time from study completion to data availability was more than six years. Most data requesters of cardio metabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Only 15% of these trials had been accessed by investigators thus far, and few findings have reached publication. Most requests for shared data access focused on new hypothesis generating questions rather than validation of the original study findings. These data may allow anticipation of barriers to effective system implementation and shared data consumption in cardiology.

                                                Well, that wraps it up for our summaries this week. Now for our feature discussion.

Dr. Carolyn Lam:               We are having a truly global conversation today on a really global problem. That is hypertension. From Canada, we've got Dr. Ernesto Schiffrin from McGill University, from Europe we've got Dr. Giuseppe Mancia from university of Milano, from the United States we have Dr. Wonpen Vongpatanasin from UT Southwestern, our dear associate editor and regular voice on this podcast, and then of course from Asia, that's me. You know what we're talking about? It is the global impact of the 2017 ACC/AHA hypertension guidelines. So many novel aspects about these guidelines, including new definitions of hypertension and it's stages, new thresholds and goals of treatment, consideration of the global risks and treatment decisions, addition of classes of recommendations and levels of evidence. So much to talk about, and let's start right now.

                                                Wanpen, you were the brainchild of suggesting these global perspectives. Perhaps say a few words about the ACC/AHA new guidelines first.

Dr. Wonpen Vongpatanasin:       Yeah, so I think that this is the guidelines that actually incorporating the more recent evidence and trials, particularly SPRINT, and applying this into the threshold and the blood pressure goal across the board. There's three comprehensive guidelines, and obviously ... The first time, the threshold was lower across the board, and that leads to a lot of discussion and concern and trying to see how we're implementing this or is it appropriate to all the population? Particularly not just in the US and around the world. I guess that leads to us reaching out to many hypertension leaders across the globe and really get very interesting and very insightful feedback from the global experts, two of which is on podcast today. I'm really thankful and excited to have some more in depth insight from them.

Dr. Carolyn Lam:               Yeah, exactly. The buzz has really been worldwide, I can see that even from where I'm sitting here in Asia. But maybe Ernesto, I'm just gonna jump straight to the core questions. How are these guidelines different from the hypertension Canada guidelines, and frankly do you think that the ACC American guidelines are going to impact hypertension care in Canada?

Dr. Ernesto Schiffrin:      Well, there are quite a few differences. The definition of hypertension remains the classical one in Canada. We have different thresholds and goals, and interestingly, the hypertension Canada guidelines have adopted a SPRINT-based recommendation for high cardiovascular risk patients in contrast to the AHA/ACC hypertension guideline. Although it has intensified the goals for treatment, it has lowered ... Has introduced as you mentioned a category of elevated blood pressure, a new definition of hypertension equal to or above 130 over 80 in contrast to ours equal to or above 140 over 90. It has not really introduced a SPRINT-based recommendation. As well, I think that one of the major questions remains the measurement of blood pressure. In Canada, we have adopted the AOBP, the Automated Office Blood Pressure measurement, at least for high risk, SPRINT like individuals. In the AHA/ACC hypertension guidelines, there is emphasis on standardized blood pressure measurement, but the SPRINT-like measurement of blood pressure has not been adopted.

Dr. Carolyn Lam:               Very interesting. In Canada, with the AOBP, how do you translate that? I suppose you estimate it as lower than what would otherwise be labeled?

Dr. Ernesto Schiffrin:      That is indeed a problem, because the evidence for the relationship between the AOBP carried out in the absence of a health care professional and the standardized oscillometric measurement, or the osculatory manual measurement, is unclear. The evidence is weak. So we have not really provided a guideline or recommendation with respect to these differences.

                                                In contrast, AHA/ACC provides at least a pragmatic expert-based recommendation on what the differences are between office blood pressure and out-of-office blood pressure measurement. But, as I mentioned, there is no recommendation regarding the SPRINT-like measurement of blood pressure, and that's important because there may be major differences in the order of ten or even 15 millimeters of [inaudible 00:13:32] systolic blood pressure. However, as I see it, the committee for the ACC/AHA hypertension guideline has adopted a prudent and pragmatic approach, and actually simplified thresholds and goals to 130 over 80, and in my view this is a prudent approach.

                                                Will it impact Canada? I think in Canada, most physicians follow the hypertension Canada guidelines, and they are recommended as best practice by governments across the country, provincial and federal. I think that physicians will be aware, but will still carry out their practice following the hypertension Canada guidelines.

Dr. Carolyn Lam:               I like that. Aware but perhaps not so practice-changing in Canada. Let's shift to Europe though. Giuseppe, do you agree with that? How do you think these American guidelines may impact physicians in Europe?

Dr. Giuseppe Mancia:    The American guidelines have been received with interest, lots of interest. But also there has been some criticism. For example, the question of the SPRINT [inaudible 00:14:55], you read the question of how blood pressure was measured as professor Schiffrin mentioned. It was measured at least in large number professions, why they were [inaudible 00:15:10], I'm not sure. This means that values have lower worth than those obtained by conventional office blood pressure measurement. How much room is still debated, but it could be 10, 15 millimeter mercury, which means that you could compare these SPRINT-like values to conventional office blood pressure values. Probably the SPRINT values are not much lower than 140 millimeters to the mercury systolic.

                                                Then there is the question that can SPRINT mutually [inaudible 00:15:50] at the start. Most of them with two hypertensive charts. So if it's difficult to decide the bounds of threshold to treatment, lower these pressures to the high-low of blood pressure range, less than 140 millimeters mercury systolic when you have patients already treated, because their original blood pressure was probably higher than 140 millimeters of mercury. This [inaudible 00:16:15], however there are other data suggesting that, at least in high-risk individuals, one might indeed start treatment when blood pressure is in the 140 millimeter of mercury. You'll see what the European guidelines will recommend ... They are going to be published in June ... But perhaps this fraction of the population will be a candidate for treatment.

                                                One last point, however, collecting the data from SPRINT is what you wish for in this regard, is that there should be a definite reduction in the threshold blood pressure for treatment in the elderly. In Europe, this was about 160 millimeters mercury based on randomized trials but probably in the future it will be about 140 millimeters mercury. So a large fraction of the elderly population will be involved in [inaudible 00:17:14].

Dr. Carolyn Lam:               You know a question I always get though, is what about the side effects? We talk about the benefits of lowering it further, but what about the side effects. I don't know, does anyone have any thoughts on that?

Dr. Ernesto Schiffrin:      I would say that, when you look at SPRINT, although there were increased side effects in the intensive treatment group, actually side effects were relatively rare. Some of them were important, such as acute renal failure and hyperkinemia, and so on, and other electrolyte abnormalities and syncope. But they were rare, and when we are recommending intensified treatment for the elderly, for example, which is SPRINT based in the hypertension Canada guidelines, we do say that this approach should be a gentle and progressive one, very aware that particularly in the elderly orthostatic hypertension may occur. One has to be very careful about this intensification of treatment, but yet we believe that if using automated office blood pressure measurement unobserved, you are able to reach lower blood pressures and they are well tolerated around or below 120 systolic, this will benefit these patients as shown in the SPRINT trial.

Dr. Carolyn Lam:               Yeah, indeed. That's very nicely put, and just brings up the gaps that we still need to answer, like the way blood pressure is measured, standardization. We may be accounting more about risk versus benefits, patient subgroups. Wanpen, have I missed out anything else? What is the other buzz that you've heard?

Dr. Wonpen Vongpatanasin:       I think that we really need to do a better job in measuring blood pressure in basic clinical practice, particularly in the US where we allow only 20 minutes to see your follow-up patient. I don't think that it will be possible to do an AOBP in the US, but I think one thing that makes the issue a little bit murkier is the SPRINT group. I actually just had an abstract presentation at the last HA meeting, that said only half of that site measure in the intended way on AOBP.

                                                Actually, at UT Southwestern we also SPRINT site and we actually did not use AOBP, and when that stratified the treatment side by using AOBP versus non-AOBP, the outcomes was still the benefit of intensive blood pressure reduction for what it's worth. I think that the AOBP story is still controversial, but I think that I agree that we hardly have patient, sit down quietly, for five minutes before we do the measurement. I think that's first and foremost, we need to be able to do that, and do at least two measurements. We'd be lucky if we'd get one measurement after sitting down immediately, that's what we usually get in clinical practice. I definitely agree with Dr. Schifferin that when we ... Particularly the elderly, we have to be careful about orthostatic hypertension. Particular in the SPRINT trial, they actually exclude anyone who had standing systolic blood pressure less than 110. These people who are high risk of having [inaudible 00:20:35] never get into those trials to begin with.

Dr. Carolyn Lam:               I can't thank you enough, everyone, for joining me in this chat around the world. It has been a learning conversation for me, as I'm sure it has been for our listeners as well.

                                                Listeners out there, you've been listening to Circulation on the Run. Thank you for joining us today.



Feb 19, 2018

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. This week’s issue is the Go Red for Women issue, my favorite discussions of the year happened during this podcast.

                                                Today, I am so delighted to have with me, our Editor-in-Chief himself, Dr. Joe Hill, from UT Southwestern, as well as, of course, the editor that made this issue possible, Dr. Sharon Reimold, also from UT Southwestern. Joe, would you like to tell us a little bit about this year’s Go Red issue? From the birds eye view.

Dr. Joseph Hill:                  Well Carolyn, I share your enthusiasm. This is our second annual Go Red for Women issue and it is fantastic. It has generated great interest in the community. We had a number of papers coming in, unsolicited. Our frame of reference-type content. Original research articles. State of the art.

                                                We clearly touched a nerve with this issue. As we will discuss further, we shine a bright light here on some of the very best science, focusing on sex-based differences in the biology of heart disease, the presentation of heart disease, how women function, and are treated in the academic environment. The ways in which they are impacted by psychological stress. It's an absolute bonanza of science, in this issue.

Dr. Carolyn Lam:               You took the words out of my mouth. It is a bonanza issue. I mean, we had seven original articles. Lots of new stuff, but lots of good, important papers on plain old ischemic heart disease. What I really liked was that, three of these original papers focused on myocardial infractions, in the young, and their risk factors, prevention, and so on. Sharon, shall we go through those? I mean, there was the one on genetics, lifestyle, and LDL in young women.

Dr. Sharon Reimold:        That would be great. That manuscript looked at, sort of, a distribution of lipids, in women, that would have otherwise expect to be healthy. They sorted them out by individuals that had extremely low LDL levels and those that had high LDL levels. They pointed out that the individuals with high LDL levels. Ended up having hypercholesterolemia heritable, but they also found genetic variance of related to those with low LDL levels. I think this manuscript points out the importance of screening younger women for lipid disorders and incorporating those data into their clinical management.

Dr. Carolyn Lam:               Absolutely. Then, there was that paper that, again, talked about young women experiencing myocardial infarction, and the sex differences in their presentation, and perception. That was super cool. From the Virgo trial.

Dr. Sharon Reimold:        There are several other papers, that are published, demonstrating that women tend to have multiple symptoms when they present with symptoms of ischemia. That's true for both myocardial infarction, as well as for other unstable syndromes. They certainly have more symptoms than men.

                                                But what was very interesting about this particular paper, is that when women presented with multiple symptoms, providers were less likely to think that the symptoms were due to a cardiac etiology. So even when women are trying to tell their providers what is going on, sometimes, they're not taken seriously, because they have multiple symptoms. So I'm hoping that this resonates with our providers, clinical providers, and we think about this. Whether we're cardiologist, or emergency room providers, or even EMTs.

Dr. Carolyn Lam:               Exactly. Then, the third original paper in these young women, kind of scary, mental stress induced myocardial ischemia.

Dr. Sharon Reimold:        Right. So there's been a lot of interest in the myocardial infarction without obstructive coronary disease, in the last year or two. Because a lot of those individuals, even thought, they don't have typical atherosclerotic pathologies, they don't have good outcomes. So this article looks at the role that mental stress plays in inducing ischemia, by EKG, in these individuals.

                                                I think we still need to understand more about how this contributes to the biology, and outcomes, in these individuals. Also, get a better understanding if this is also true in older women, who have ischemic heart disease.

Dr. Carolyn Lam:               Exactly. You know, but speaking of the older women, it's not like the issue left out the older women this time either. I did think that the study on the metabolic predictors of incident ischemic events, in postmenopausal women, was really interesting, as well. Basically, the authors identified a cluster of novel metabolites, that were related to oxidative stress, that added to. you know?

                                                They weren't correlated with the traditional biomarkers. Really suggesting that there may be a whole area of metabolites, and other biomarkers, that we may be needing to check, and to understand better, for risk prediction. At least, in older women. But, of course, in men as well. Then, finally, there was the data on sex differences from the STICH trial, on surgical revascularization. What did you think of that one?

Dr. Sharon Reimold:        Well, I thought that this was a very important addition to the cardiology literature. Because we are accustomed to thinking of women as having poor outcomes, after they have cabbage revascularization surgery. Certainly, the STICH trial enrolled patients who were more sick than the average patient, with their underline LV dysfunction. They found that sex did not influence the outcomes in this trial.

                                                So the importance of that, for the medical community, is obviously we should not consider sex as a barrier to sending women to surgery, even if they're at high risk, because they can have equally good outcomes.

Dr. Carolyn Lam:               Exactly. Important message. Important paper. Then, moving from ischemic heart disease. We also had a paper focusing on stroke, which I thought was a really intriguing one, talking about atrial fibrillation, and questioning if being a woman is a risk modifier, or a risk factor. Do you want to elaborate on that one?

Dr. Sharon Reimold:        So instead of the using the CHA2DS2–VASc algorithm they use the CHADS2-VA program and then looked to see how well that predicted risk, and how much the S and C, the gender actually influenced outcome. I think this is an important issue. I'll say it's for women, perhaps. because as a woman, you know, without doing anything, you start out with a risk factor of one. Then, once you get to a certain age you have a risk factor of two. That's even for somebody who has no other disease processes.

Dr. Carolyn Lam:               Yeah.

Dr. Sharon Reimold:        So I think it's a little different way to look at how the risk is modified. They propose that if your CHADS2-VA score is two, or greater, certainly, your risk goes up if you're also female. They propose, then, that you would treat those patients more intensively. It's just a little twist on the CHA2DS2–VASc and maybe will provide us different ways to refine our knowledge about outcomes in atrial fibrillation.

Dr. Carolyn Lam:               Yeah. I love that paper, too, because it's quite different from the papers that we had in the first Go Red issue. Isn't it? But in the first Go Red issue, we had lots of papers on pregnancy. The current issue certainly has those papers as well.

Dr. Sharon Reimold:        Yes. There are increasing number of pregnancy related complications. Both maternal, and offspring, complications that predict increased cardiac risk, down the line. This issue has a series of women who had, had preeclampsia during pregnancy, and found that 17% of their women had a coronary artery calcium score of greater than 95th percentile. While that doesn't entirely get you from the biology, in between those two, it at least gives you an idea of where to start going back, and taking a look at what's going on.

Dr. Carolyn Lam:               What about the one in rheumatic mitral valve disease? Pregnancy outcomes in women with those?

Dr. Sharon Reimold:        So rheumatic heart disease and pregnancy outcomes, you know, we don't see much written about it anymore. because most of the active disease is in certain areas, in the world. But obviously, these women can have symptoms related to their mitral stenosis and/or their regurgitation during their pregnancy, with heart failure being the most common presenting cardiovascular complication. While some of that is much more quantitative, than perhaps, it was in the past, which is useful.

                                                I think that the take-home message from this particular trial is that you need to talk to these patients, and screen them, prior to pregnancy, if possible, to help achieve the best possible outcome. I think that the risk of heart failure was a little bit less than 2% during the trial, which is obviously much higher than the average woman's cardiovascular risk during pregnancy.

Dr. Carolyn Lam:               this is still definitely an important issue, in many other parts of the world. I really appreciate that you invited this editorial, that gave that global perspective. The editorial, by Athena Poppas and Katharine French, really beautiful work there. You know, I have to say that one of my favorite papers, in this issue, was that in depth paper, regarding gender versus sex, as a social determinant of cardiovascular risk. I found that so intriguing, the first time I read it, and just love it.

Dr. Sharon Reimold:        Social determinants of health is a hot topic, in a lot of different areas of medicine these days. But they point out some really interesting things, that I don't think I had thought about. One is the fact that, when you are a child, you know maybe 10 or 12, that boys are encouraged more to be physically active. Athletics and other sorts of activities. Whereas many girls, don't have the opportunity or are not as interested. Perhaps we set up an abnormal social situation very early in most people's lives.

Dr. Carolyn Lam:               Yeah, that represents cardiovascular risk. I know. That stuck out to me too.

Dr. Sharon Reimold:        Obviously, how and where people live, as children, can influence outcome. That can be influential for both boys and girls. But I think bringing the idea back to cardiovascular diseases, and risk, are really long term, lifelong processes, that we can make changes in, from a preventative standpoint, even in young people.

Dr. Carolyn Lam:               Something we don't usually think about and I just love the way it was presented, so clearly, and I just love it. Now, to an area that really cuts close to the heart. Pun intended. That is the bias in research grants, bias in manuscript authorship. Joe you mentioned that, right from the introduction, I would love your comments on those papers.

Dr. Joseph Hill:                  The reality, that we all are aware of, is, in many countries, including the United States, 50% of medical students now are female. But as we move through the ranks, into the different subspecialties, and up the career ladder of academic cardiology, we see a thinning of female representation. Arguably, it's been improving, over the last number of years.

                                                But the reality is, that there remains a bias against representation of women, in terms of extra mural grant funding, authorship on high-profile papers. This article digs into that, and analyzes those numbers, takes a snapshot of what it looks like at the present time. In some ways, I believe it's a call to arms on how we must do a better job of recognizing this and rectifying it, going forward.

Dr. Carolyn Lam:               Sharon, did you have comments to add?

Dr. Sharon Reimold:        Yeah. I mean, I think, I wholeheartedly agree with Joe about those sorts of things. I mean, we see the same types of issues in clinical cardiology as well as in the research components of what we do. we need to figure out how to do this better, so that we all can be productive, going forward.

Dr. Carolyn Lam:               You know it's just such a beautiful issue. So rich, in so many ways. Was there anything else you might want to highlight to our listeners?

Dr. Joseph Hill:                  I might add that Sharon and I kicked off the issue with a brief introduction. Pointing out that the reality is, that one and four women will die of heart disease. Most women don't know that. Most healthcare providers don't know that. Many Cardiologist don't know that.

                                                When you compare that to the realities of breast cancer, it's 1 in 40. It's 10 times different. Now, that community has done a fantastic job. The Susan G. Komen program, in the United States. The pink ribbons, that we see all around the world. That community has done a fabulous job of getting the message out about that grievous disorder.

                                                We have to do better. We have to do better educating ourselves, educating the lay public, about the realities of heart disease in women. 1 in 4, around the world. We also have to do a better job of digging into the science. That's where this issue does an especially good job.

                                                That the reality is that heart disease is different in men and women. It presents differently. It presents at a different age. The way in which women respond to therapies, can differ from men. So there's work to be done, in terms of awareness. There's work to be done, in terms of the underline biology. This is an especially exciting time in this arena.

Dr. Carolyn Lam:               I couldn't agree more. I'd add to it, even sex differences and the perceptions about own symptoms, and that of women versus men with chest pain. Then, the whole gender, social element to it. Oh, just so much to discuss, so much to learn from.

                                                Well, listeners you heard it right here. I want you to please send this episode, share it with as many other women as you can think of. Do help us to spread this message, it's such an important one.

                                                Thank you so much, Joe and Sharon, for joining me today. Thank you, listeners, as well. Tune in again next week.


Feb 12, 2018

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.

                                                Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:

                                                Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.

                                                The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.

                                                Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.

                                                The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.

                                                In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.

                                                On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.

                                                In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.

                                                Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.

                                                To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.

                                                They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.

                                                The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.

                                                They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.

                                                These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.

                                                Well, that wraps it up for our summaries. Now for our feature discussion.

                                                For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.

                                                Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.

                                                Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found?

Dr. Jason Weatherald:   This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.

                                                We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective.

Dr. Carolyn Lam:               Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them?

Dr. Kelly Chin:                    I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.

                                                The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.

                                                Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.

                                                I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing.

Dr. Carolyn Lam:               Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.

                                                The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason?

Dr. Jason Weatherald:   Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.

                                What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.

                                                  I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration.

Dr. Carolyn Lam:               Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.

                                                Kelly, what do you think are the real take home messages from this?

Dr. Kelly Chin:                    I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment.

Dr. Carolyn Lam:               Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason?

Dr. Jason Weatherald:   I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.

                                                At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.

                                                I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic.

Dr. Kelly Chin:                    I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.

                                                But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization.

Dr. Carolyn Lam:               Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment?

Dr. Jason Weatherald:   Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening.

Dr. Carolyn Lam:               And Kelly, what do you think should be next steps?

Dr. Kelly Chin:                    I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.

                                                But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies.

Dr. Carolyn Lam:               You've been listening to Circulation on the Run. Tune in again next week.


Feb 5, 2018

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. In today's feature discussion, we are talking about external validation of the DAPT score, a discussion that's going to take us all the way to east Asia, but for now, here are your weekly summaries.

                                                In this week's journal, two studies are presented which compare ductal stenting to surgical shunts in the current era of ductal dependent pulmonary blood flow. As background, infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt between the subclavian artery and either pulmonary arteries. This modified Blalock–Taussig shunt allows progress through early life to an age and weight at which repair or furthermore stable palliation can be safely achieved. However, these modified Blalock–Taussig shunts continue to present concern for post-procedure instability and early mortality.

                                                Duct stenting has emerged as an alternative with potential for greater early stability and improved survival. In the first study, first and corresponding author Dr. Bentham from Yorkshire Heart Centre reviewed data from the National Congenital Heart Audit, comparing the outcomes of 171 neonates who underwent a modified Blalock–Taussig shunt and 83 who underwent attempted ductal stenting, all in the setting of duct dependent pulmonary blood flow between 2012 and 2015. They found that stenting the arterial duct was preferable over the modified Blalock–Taussig shunt in terms of survival to next stage surgery, early post-procedure hemodynamic stability and shorter intensive care and hospital stay. There was a high failure rate both early, with the inability to stent the duct and late, with a greater need for re-intervention on the stented duct compared to the surgical shunt.

                                                The second study originated from four North American pediatric cardiology centers representing the Congenital Catheterization Research Collaborative. First and corresponding author, Dr. Glatz from Children's Hospital of Philadelphia performed a retrospective cohort study reviewing all infants with ductal dependent pulmonary blood flow under a year of age, having either a ductal stent or a modified Blalock–Taussig shunt between 2008 and 2015. Although the observed risks of the primary outcome of death or unplanned re-intervention to treat cyanosis was higher in the surgical shunt group, there was no significant difference between groups after adjusting for patient level factors. Furthermore, after adjusting for patient factors, other outcomes favored the stent group, including fewer procedural complications, shorter intensive care unit length of stay, less frequent need for diuretics and larger and more symmetric pulmonary arteries at last follow up.

                                                These companion papers are discussed in an elegant editorial by Drs. Benson and Van Arsdell from Hospital for Sick Children in Toronto.

                                                The next study tells us that there may be a higher risk of vascular dementia in patient who survive a myocardial infarction. First and corresponding author, Dr. Sundbøll from Aarhus University Hospital in Denmark performed a nationwide, population based study including almost 315,000 patients with myocardial infarction and found that the risk of vascular dementia was higher compared to a matched general population comparison cohort. The risk of vascular dementia was incrementally higher in patients who suffered stroke or developed severe heart failure during the first year after myocardial infarction and in patients who underwent coronary artery bypass grafting. There was no association with all caused dementia, Alzheimer's disease or other dementia sub-types. Take home message is that among one year survivors of myocardial infarction, attention should be placed to persistently higher risk of vascular dementia.

                                                The next study identifies a novel mechanism whereby the RNA binding protein, fragile X mental retardation autosomal homologue one or FXR1, directly regulates gap junction remodeling, leading to dilated cardiomyopathy. Co-first authors Drs. Chu and Novak, corresponding author Dr. Gregorio and colleagues from University of Arizona studied human left ventricle dilated cardiomyopathy biopsy samples as well as mouse models of dilated cardiomyopathy. They found that FXR1 expression was significantly increased in human and mouse dilated cardiomyopathy. Up regulation of FXR1 in the heart altered the location and distribution of gap junctions, subsequently leading to ventricular tachycardia in mice.

                                                Mechanistically, FXR1 associated with intercollated discs and directly interacted with integral gap junction proteins to regulate their expression in cardiomyocytes. Finally, loss of FXR1 in the heart led to dilated cardiomyopathy. Together, these results provide a novel function of FXR1, namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. Thus, the authors concluded that FXR1 may be a promising target for therapeutic strategies to improve gap junction function in dilated cardiomyopathy.

                                                Well everyone, that wraps it up for our summaries. Now for our feature discussion.

                                                The dual anti-platelet therapy or DAPT score is widely used everywhere to estimate bleeding versus ischemic risk in patients undergoing percutaneous pulmonary intervention. However, very few studies have provided external validation of its utility. Well we have a very important paper in this week's journal that addresses just that in a Japanese population. So pleased to have with us the corresponding author, Dr. Takeshi Kimura from Kyoto University Graduate School of Medicine. Not just him, but also the editorialist for this paper, Dr. Shinya Goto, also an associate editor of Circulation from Tokai University of Japan and last but not least of course, our dear Senior Associate Editor of Circulation, Dr. Laura Mauri from Brigham and Women's Hospital. What an important topic. Takeshi, would you mind to please tell us about your study to start?

Dr Takeshi Kimura:          Actually we thought about the utility of the DAPT score provided from the DAPT study in Japanese patient population. In a full cohort of three studies that are conducted in Japan, we compare the risks for ischemic and bleeding risks from 13 to 36 months after a PCI between patients with DAPT score (high-DS) and DAPT score <2 (low-DS) in patients in the Japanese population. We evaluated 12,223 patients. There were 1,344 patients with high DAPT score, 8,279 patients with low DAPT score. The cumulative incidence of primary ischemic end point myocardial infarction or stents from both is significantly higher in the high DAPT score group than in the low DAPT score group. 

                                                One of the cumulative incidence of the primary bleeding end point tended to be lower in high DAPT score than in the low DAPT score group, therefore the DAP score has successfully stratified ischemic and bleeding risks in Japanese patients. We've externally validated DAPT score successfully.

Dr Carolyn Lam:                Thank you so much Takeshi. Shinya, you wrote an excellent editorial to this paper. Could you let us know why it was so important to validate this in the Japanese population?

Dr Shinya Goto:                It's quite homogenous in one way and the other way in the world is heterogeneous. Some may say the risk of thrombotic and the bleeding event in Japanese or East Asia might be different from other regions of world. Dr. Kimura’s paper is the first validation of the DAPT score in the East Asian patient. Original attempts to study didn't include patients from East Asia. This is the real first validation of the DAPT score in that East Asian population. The world is quite homogeneous. It is very important message.

Dr Carolyn Lam:                Yes, yes, I agree. Could I just ask maybe a cheeky question. What would you have thought may be any differences?

Dr Shinya Goto:                Indeed, previous global trial and also global registry showed relatively low risk of ischemic event. Maybe not many of the US reader doesn't know we are using relatively low dose over anti-coagulant agent for preventing stent thrombosis. Dr. Kimura's paper provides very important insight. DAPT score is predictable for that event but even in the population with lower use of anti-coagulant agent like standard dose of prasugrel in Japan is just 3.75 milligram. Maybe that thrombogenicity in Japanese populations is lower as compared to the global population. Still that’s quite predictable for the ischemic event. That's very important message.

Dr Carolyn Lam:                I agree and I have to tell you, practicing in Asia too, I have a tendency to think the bleeding risk may be underestimated by existing scores. We also tend to use lower doses, so it's so important to show objective data such as these. Laura, what are your thoughts coming from the US?

Dr Laura Mauri:                 Well I think it's very important. I want to congratulate Takeshi, it's a wonderful study, very large randomized data set and very important. I think in the grand scheme of things we do randomized trials, we can't represent every single population in every study. The DAPT study was done in the US, Europe, as well as in Australia and New Zealand, but it's true. We weren't able to also include sites in Asia just from practical reasons. I think it's very exciting to see, looking at this question of the DAPT score in patients in Japan.

                                                I think in general, it matters a lot to understand the generalizability of our randomized trial results across different populations. I think Shinya's mentioned some of the important sources of variability. It may be this great interest in understanding genetics and how they relate in different populations, but there are also clear differences in medical practice across the world. Doing this type of study where one looks at different populations is quite important and I think it's also one of the reasons that circulation in terms of the editors are really seeking to expand the international scope of the randomized trials and secondary studies from randomized studies such as this that really impact patient care across the world.

Dr Takeshi Kimura:          I think one of the difference from the DAPT studies in this Japanese closed study is the proportion of the high DAPT score versus low DAPT score is a little bit different. In the Japanese study population, the low DAPT score patients are dominant and also ischemic event risk are lower. However, the DAPT score clearly differentiates that, stratifies the bleeding and the ischemic risks so we should see both the bleeding and ischemic risk and also the difference of absolute event rates in each geographic ischemic population. I think it's important message from this paper.

Dr Carolyn Lam:                That is such a great point, Takeshi. In other words, there may be some heterogeneity around the world in baseline risks, as Laura said, baseline practice patterns and I'm talking about baseline both ischemic and bleeding risks. What your paper definitely shows is that the DAPT score however, performs similarly and as we've said so many times, that's such an important message. Shinya, what do you think? What's your message to all the audience out there in Japan and abroad?

Dr Shinya Goto:                As Takeshi told me and also how Laura pointed out, if we try to find the difference in the world, there is a difference and if we try to find the similarity, there is a similarity. Dr. Kimura paper shows similarity in the risk factor determining the ischemic and bleeding event. Matched, absolute event risk is low. Background medication is not the same. Majority of the patient taking [inaudible], 200 milligrams a day. [Inaudible] is a bad drug already in the world, but still in Japan, the doctor is still using. Clopidogrel, 75 milligram is also very widely used. The prasugrel dose is just 3.75 milligrams. That is different from the world. Ticagrelor with the dose similar to the world was not successful in the clinical trial in East Asia.

                                                There is a similarity and heterogeneity. Dr. Kimara beautifully demonstrated both in his registry.

Dr Carolyn Lam:                Indeed. Laura, looking at this now with these new data, do you think clinical trials should be done any different? Should we be doing multiple small trials maybe in different parts of the world now? Should we power trials to look at regional differences? This trial business is really hard, isn't it?

Dr Laura Mauri:                 That's a great question. It does come up practicality, whether we should do the same clinical trial in multiple different countries. I don't think it's the six answer, I think that as Shinya, I think, was alluding to, I think that patients responses worldwide are more similar than they are different. That doesn't mean when we plan our trials we shouldn't think about what the differences are and how they might impact the results and whether we might need to make confirmations across the world. I think this study is quite important because it finds the commonality across different populations even though there may be underlying differences that Takeshi mentioned in the baseline rate. I think a similar approach worldwide where we go in with a hypothesis about where things may be consistent or different to determine whether trials need to be replicated elsewhere is useful to have.

Dr Carolyn Lam:                Thanks so much, Laura. I don't think any of us could have said it better.

                                                Thank you all for joining me on the show today and thank you ladies and gentlemen throughout the world for listening in today. You've been listening to Circulation on the Run, don't forget to tune in again next week.


Jan 29, 2018

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.

                                                In just a moment, we are going to be discussing the diagnostic conundrum of elevated high sensitivity cardiac troponin levels in a patient with renal disease, but also suspected of acute coronary syndrome. Aha! I bet I caught your attention. A very, very familiar diagnostic dilemma. So stay tuned right after these summaries.

                                                Cardiac allograft vasculopathy is the leading cause of death in patients more than five years post cardiac transplantation. It has been hypothesized that cardiac allograft vasculopathy results from interrupted lymphatic drainage post surgery. Since the donor lymphatic vessels are not inesthimozed to that of the recipient during transplantation, thus the lymphatic system may play a crucial role in the alloimmune response.

                                                Well, these hypothesis are addressed in the first paper in today's journal from first author Dr. Edwards, corresponding author Dr. Wong and colleagues from Kings College, London. These authors use spect CT lymphoscintigraphy in a pre-clinical model. And therefore provided objective quantification of lymphatic flow following transplantation and showed that this correlated to cardiac allograft vasculopathy. They demonstrated that cardiac lymphatic remodeling and lymphatic transport dysfunction post transplant was associated with cardiac allograft vasculopathy and transplant rejection.

                                                They further showed that lymphatic flow was increased during chronic rejection. This in turn may have resulted in enhanced trafficking of antigen presenting cells to the local draining lymph nodes in an augmented alloimmune response. Now although the cause and effect of this phenomenon could not be fully established, these data provided the impetus for the investigation of lymphangiogenesis inhibition as a means to dampen chronic rejection.

                                                The absorb bioresorbable vascular scaffold is known to completely resolve within three years after coronary artery implantation. However, what is the safety and effectiveness of these bioresorbable scaffolds during this critical three year period. First author Dr. Ali, corresponding author Dr. Stone and colleagues from Columbia University Medical Center performed an individual patient level meta analysis of the four randomized absorb trial and demonstrated that compared with metallic everolimus eluting stents, the bioresorbable vascular scaffold had higher rates of target lesion failure and device thrombosis cumulatively to three years and between one and three years. Multi-variable analysis identified the number of treated lesions, current tobacco use and previous cardiac interventions as independent predictors of three year target lesion failure. Whereas diabetes was predictive of three year device thrombosis in bioresorbable vascular scaffold treated patients.

                                                The next paper reported the three year follow up of the FAME 2 trial, which compared PCI guided bi-fractional flow reserve with best medical therapy in patients with stable coronary artery disease to assess clinical outcomes and cost effectiveness. First and corresponding author Dr. Fearon and colleagues from Stanford cardiovascular institute showed that major adverse cardiac events at three years were significantly lower in the PCI group, compared with the medical treatment group. This difference was primarily as a result of a lower rate of urgent revascularization. Mean initial costs were higher in the PCI group, but by three years, were similar between the two groups. The incremental cost effectiveness ratio for PCI compared to medical therapy was more than $17,000 per quality adjusted life year at two years and $1,600 per quality adjusted life year at three years. Thus the authors concluded that percutaneous coronary intervention in patients with stable coronary artery disease and at normal fractional flow reserve may be advantages compared to with medical therapy alone, because it results in improved clinical outcomes and quality of life at no increased cost by the end of three years follow up.

                                                The next study shows for the first time, that pioglitazone may prevent stroke as a single stand-alone outcome. Today's paper by first author Dr. Yaghi, corresponding author Dr. Kernan from Yale School of Medicine and colleagues was a secondary analysis of the iris trial, which showed that pioglitazone reduced the risk for a composite outcome of stroke on myocardial infarction among non-diabetic patients with insulin resistant and a recent stroke or transient ischemic attack. Now, the current planned secondary analysis used updated American Heart Association 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. The study found that pioglitazone reduced the risk by 25% by five years, with absolute rates of 8% with pioglitazone versus 10.7% with placebo. Pioglitazone reduced the risk for ischemic strokes, but had no effect on the risk of hemorrhagic events. These findings add to the evidence that pioglitazone may be a potent therapy for vascular disease risk reduction and may help inform shared decision making by providers and patients for the use of pioglitazone after ischemic stroke or transient ischemic attack.

                                                Well, that ends it for our summaries. Now for a feature discussion.

                                                The cardiac troponins have really revolutionized cardiology. We use them in of course the diagnosis of myocardial infarction and in fact the recent European Society of Cardiology recommendations say that the rapid zero and one hour triage algorithm for rule in or rule out of non STEMI should use high sensitivity troponins and interestingly irrespective of renal function. Now this latter point has caused some confusion, some questions, since we all know that patients with chronic kidney disease frequently have higher or increased levels of cardiac troponins, especially since we now can detect them with the high sensitivity essays. And this is even in the absence of an acute coronary syndrome.

                                                Well, this week's journal contains two papers that address this topic so well. And I am delighted to have with us the corresponding author of the first paper, Dr. Christian Mueller from University Hospital Basel in Switzerland and the author of the second paper, Dr. Nicholas Mills from University of Edinburgh in Scotland. For the more, we have Dr. Torbjorn Omland, associate editor from University of Oslo in Norway.

                                                Lot's to talk about. Christian, could I start with you? Could you say in your own words the rationale for looking at this vulnerable population and then perhaps describe what you did in your study?

Dr. Christian Mueller:     I'm very thankful that Circulation shed a lot of light on the population of patients with renal dysfunction, because both as a clinician and as a researcher, I'm definitely convinced that they merit a lot of our attention for several reasons.

                                                So first, it's important to be aware that the incidents of acute myocardial infarction among patients presenting with acute chest pain is much higher in patients with renal dysfunction, as compared to patients with normal renal function. And second, atypical clinical presentations also are more frequent in patients with renal dysfunction. Then possibly third, the ECG of course also a mandatory tool in our assessment is more often showing unspecific signs that may mimic or obscure the presence of myocardial infarctions and most of them are related to left ventricular hypertrophy. And in addition, patients with renal dysfunction are more prone to adverse events, both related to cardiovascular medication. For example, anticoagulation as well as our cardiovascular procedures, including PCI. Now again, as both papers have a strong focus on troponin, also cardiac troponin is a bit more difficult to interpret in patients with renal dysfunction related to exactly as you mentioned chronic elevations of cardiac troponin, TNI related to chronic cardiovascular disease.

                                                And I think that's so important to stress, any troponin signal in a patient with renal dysfunction is real and should not be incorrectly attributed to just a problem of impaired secretion by the kidneys.

Dr. Carolyn Lam:               So definitely an even greater need to diagnose myocardial infarction accurately in this very high risk population. So tell us what you did.

Dr. Christian Mueller:     We assessed this challenging sub group within the APACE study. So APACE is a large international prospective diagnostic study that is run in five countries with 12 centers. And we actually enroll consecutive patients presenting with suspected myocardial infarction. And then all patients get a very detailed workup and then adjudicated final diagnosis. And the adjudicated file diagnosis is done by two independent cardiologists and is based on two enormous extensive sets of data. The clinical data set that has been obtained at the local site and of course includes cardiac imaging and standard troponin testing, ECG data.

                                                In the second set of data that includes the study specific data sets, including serial measurements with high sensitivity carry troponin essay and a lot of details characterization of patients and patient follow up. So this is the reference standard against which the one hour algorithm the European Society of Cardiology evaluated. And the one hour algorithm has been derived and previously validated in overall population. Mainly patients with normal renal function. And so we tried to evaluate the performance of this predefined algorithm specifically in patients with renal dysfunctions.

                                                So among a bit more than 3,000 patients, the prevalence of patients with renal dysfunction was 15%. So we had about 500 patients with renal dysfunction. And the interesting finding from our work is that first the prevalence of N-STEMI was nearly threefold in patients with renal dysfunction as compared to patients with normal renal function. And, fortunately the rule out part of the algorithm regarding sensitivity still works very well. It is, however, the efficacy of rule out that is lower in patients with renal dysfunction, simply because fewer patients really have very low troponin concentration and are therefore ineligible for rule out.

                                                However, as a clinician, the main concern with troponin and renal dysfunction is the rule in part, and specificity. And as you would think, specificity of the one hour algorithm was in fact significantly lower in patients with renal dysfunction. It was still appropriate for therapeutic consequences, but it was lower as compared to patients with normal renal function, so the specificity was 89% in patients with renal dysfunction, as compared to 96.5% in normal renal function.

                                                So the overall efficacy of the algorithm was lower in patients with renal dysfunction, however then when trying to create and derive optimized cut off levels, so all cut off levels optimized for use in renal dysfunction, we didn't really find alternative cut offs that would do a much better job than the official cut off levels recommended in the guidelines. So our conclusion is that in patients with renal dysfunction, the safety of the one hour algorithm still is very high, however the specificity of rule in and overall efficacy are decreased.

Dr. Carolyn Lam:               Right. That's beautifully summarized. And also that different cut offs didn't really help to increase the efficacy of this algorithm. And just to clarify to our listeners, I believe you defined renal dysfunction as an estimated GFR of less than 60, which is so beautiful because it's perfectly consistent with the second paper.

                                                Nick, could you please tell us about your study and your take home messages as well.

Dr. Nicholas Mills:            So high stakes is our clinical trial that we're conducting across hospitals in Scotland to evaluate the best way to use high levels of cardiac troponin in clinical practice. One of the areas of uncertainty is whether these assets really add any additional value for patients with chronic kidney disease, where troponin concentrations tend to be higher. And the premise of a high sensitive test is that we can measure lower concentrations and improve the sensitivity. But is this just going to create uncertainty for clinicians?

                                                So we evaluated 5,000 consecutive patients for performance of high sensitivity cardiac to put in testing. And those with and without renal impairment. And based upon what Christian, we identified that patients with renal impairment are less likely to have very low concentrations, but that you can rule out myocardial infarction safely in patients with renal impairment. And similarly that those with renal impairment are more likely to have an abnormal troponin concentration at presentation. Around about 40% of all patients have troponins above the upper reference limit. And whilst the specificity for myocardial infarction is lower, type one myocardial infarction or myocardial infarction due to plaque rupture or cardiac thrombosis remains the most common diagnosis in this group.

                                                Finally we looked at one year outcomes. And this is really critical. Because we found that patients with renal impairment were two to threefold more likely to die from cardiovascular disease one year following their presentation than those without renal impairment. And I think that my general experience during these tests in clinical practice is that troponin elevations in patients with kidney disease are often ignored and there's a concern about what they mean, and therefore these patients don't get access to the fantastic treatments we have for coronary heart disease. So our take home message is that high sets of troponin testing in patients with renal disease does have value, it's useful for identifying low risk patients although there are fewer of them, and it performs well as a diagnostic test, highlighting in particular a group of patients that really have poor clinical outcomes.

                                                As a cardiological community, we need to do better.

Dr. Carolyn Lam:               What I really love about both or your papers is the consistency in the messages. Torbjorn, I want to bring you in on this. You managed both papers. Such a lovely pair of papers that we're so proud to be publishing and you had also invited an editorial by Dr. deFilippi and Seliger. Would you like to comment on your perspective and perhaps the clinical take home message to our audience?

Dr. Torbjørn Omland:     Yes, I think this has been pointed very well out by both Christian and Nick. And I think it's worth recapitulating that renal dysfunction is a major problem that clinicians often try to explain by just lack of renal filtration. But that the closest probably are increased production and underlying cardiac disease. So in the editorial Dr. deFilippi Filippi and Dr. Seliger points also out in these things. Moreover they try to look forward and have made comments to recent studies that showed that in patients with renal dysfunction have different troponin fragments than patients with acute myocardial infarctions.

Dr. Carolyn Lam:               I find that so fascinating. And it really, really relates to the field of heart failure and what we are also talking and thinking about with natriuretic peptides and their different fragments and the possible different meanings. And how different essays maybe non specific for different fragments.

                                                Christian, you think a lot about these things. I'm curious, what are your thoughts on this and areas of future work that are very urgent?

Dr. Christian Mueller:     I think Torbjorn very nicely addressed this. So the current high sensitivity essays for T and I that we use in clinical practice, they are designed kind of to detect everything in blood that looks like troponin, either T or I, including various fragments. And I think it's a fantastic new avenue of research, trying to find out that the biochemical signatures can be further differentiated and exactly that perhaps different troponin fragments or tricordinate products more prominent in patients having ischemic injuries like treat myocardial infarction, as compared to for example other modes of injuries. So I think that's very nice hypothesis and some early data. But at least from my perspectives and to the best of my knowledge until now, the diagnostic algorithms that we have other ways to approach this in clinical practice. And so it's the higher the blood concentration in patients with acute chest pain, the more likely it's acute myocardial infarction. It's not any chronic disease and again the higher the change from presentation to one hour or two hours, the more likely it's acute as a dynamic disorder resulting in an acute increase in cardiac troponin, as compared to the chronic release patterns typically seen in patients with renal dysfunction.

Dr. Carolyn Lam:               Yeah. That's just so fascinating. Nick, we sadly are running out of time, but I do want to give you the last word. The clinical take home message, once again. What do you think listeners should take home that may change their practice, after listening to this podcast?

Dr. Nicholas Mills:            I think the key message for clinicians, is that in a patient with suspected acute coronary syndrome and has renal impairment and elevated troponin concentration, serial testing is mandatory to differentiate between those that have chronic myocardial injury due to subclinical heart disease and those that are having acute myocardial injury as a consequence of a presumed acute coronary syndrome. Field testing is critical to inform which treatment path and what investigations we recommend for our patients.

Dr. Carolyn Lam:               Wonderful. And to take any elevations seriously, because this is a high risk population.

                                                Well, audience you heard it right here on Circulation On The Run. I'm sure you've enjoyed this. I certainly have. Don't forget to tune in again next week.


Jan 22, 2018

Dr. Carolyn Lam:               Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA.

Dr. Joseph Hill:                  I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.

                                                I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim.

Dr. Carolyn Lam:               Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial.

Dr. Dharam Kumbhani:  Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.

                                                At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.

                                                Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.

                                                One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field.

Dr. Carolyn Lam:               Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.

                                                Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think?

Dr. Dharam Kumbhani:  Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well.

Dr. Carolyn Lam:               Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it?

Dr. Dharam Kumbhani:  Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome’s investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.

                                                However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo.

Dr. Carolyn Lam:               That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic?

Dr. Joseph Hill:                  Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content.

Dr. Carolyn Lam:               Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are.

Dr. Joseph Hill:                  Absolutely.

Dr. Carolyn Lam:               That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but-

Dr. Joseph Hill:                  Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit.

Dr. Carolyn Lam:               Exactly. That was striking to me too.

Dr. Joseph Hill:                  From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital.

Dr. Carolyn Lam:               Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers?

Dr. Laura Mauri:                No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation.

Dr. Carolyn Lam:               Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction.

Dr. Joseph Hill:                  Your favorite topic.

Dr. Carolyn Lam:               Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that?

Dr. Laura Mauri:                Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.

                                                The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control.

Dr. Carolyn Lam:               Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial?

Dr. Laura Mauri:                Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients.

Dr. Carolyn Lam:               What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it?

Dr. Laura Mauri:                Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step.

Dr. Carolyn Lam:               That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six.

Dr. Joseph Hill:                  Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that.

Dr. Carolyn Lam:               Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting?

Dr. Laura Mauri:                I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print.

Dr. Carolyn Lam:               That’s great, and to discuss it as well.

Dr. Dharam Kumbhani:  Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year.

Dr. Carolyn Lam:               Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.


Jan 15, 2018

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. This week's feature paper takes a deep dive into nitric oxide signaling, that extremely important pathway in cardiovascular health and disease. This time, taking a novel look at genetic predisposition, phenotypic consequences, and therapeutic implications. All that coming right up after these summaries.

                                                The first original paper describes the derivation and validation of a novel model to stratify the risk of death due to circulatory etiology in patients resuscitated from cardiac arrest without an ST elevation MI.

                                                First author, Dr. Bascom, corresponding author Dr. Setter from Maine Medical Center in Portland and their colleagues use the International Cardiac Arrest Registry to derive a novel model termed the CREST Model, which describes an incrementally high risk of circulatory etiology death with an increasing score.

                                                Now, CREST is a simple score with components of C for prior coronary artery disease. R for non-shockable rhythm. E for ejection fraction less than 30% on admission. S for shock at the time of admission. T for ischemic time more than 25 minutes. The authors showed that this CREST tool may allow for estimation of circulatory risk and improve triage of cardiac arrest survivors without STEMI at the point of care.

                                                The next study reports associations between usual sodium, potassium and blood pressure using gold standard 24-hour urinary data collected for the first time among a nationally representative sample of adults in the United States.

                                                First and corresponding author Dr. Jackson from Centers for Disease Control and Prevention used cross-sectional data from 766 participants aged 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 national health and nutrition examination survey.

                                                They found that there was a strong direct relationship between higher sodium excretion and higher blood pressure and hypertension. In addition, there was an inverse relationship between potassium excretion and blood pressure and hypertension. When added to the evidence based from longitudinal and interventional studies, these results support clinicians dietary advise to lower sodium intake and increase consumption of potassium containing foods.

                                                The next two studies in this week's journal examine the utility of circulating biomarkers to aid in the diagnosis of acute aortic dissection. As a reminder, the AHA/ACC guidelines published in 2010, proposed using the aortic dissection detection risk score or ADD risk score as a primary screening tool based on scoring the presence of three categorical risks.

                                                Number one, high risk conditions such as Marfan Syndrome, a family history of aortic disease, known aortic valve disease, known thoracic aortic aneurysm or previous aortic manipulation. Number two, The pain features such as chest, back or abdominal pain described as being of abrupt onset severe intensity or ripping, tearing. Number three, the examination features such as evidence of profusion deficit, systolic blood pressure difference, spoken neurological deficit or aortic diastolic murmur and hypertension or shock.

                                                The presence of one or more markers within each of these categorical features is given an ADD score of one with a maximum cumulative score of three if all three categorical features are present. In the first of these two papers in this week's journal, first author Dr. Nazareen, corresponding author Dr. Morello and colleagues from Molinette Hospital in Italy performed the advised International Multi Centers Study, which prospectively assessed the diagnostic performance of standardized strategies integrating pre-test probability assessment and D-dimer in 1,850 patients from the emergency department.

                                                They found that in patients with an ADD risk score above one and D-dimer less than 500 nanograms per milliliter, the rate of acute aortic syndromes was significant at one in 22 cases. Rule out strategies for acute aortic syndromes integrating an ADD risk score of zero or one with D-dimer less than 500 were found to miss only around 1 in 300 cases of acute aortic syndrome.

                                                Integrating the ADD risk score with D-dimer could help to standardize diagnostic decisions on advanced imaging for suspected acute aortic syndrome balancing the risks of misdiagnosis and over testing. The authors concluded that patients at high probability of acute aortic syndrome such as with an ADD risk score above one should proceed to computer tomography and geography or other conclusive imaging irrespective of D-dimer levels.  However, in those with an ADD risk score of zero or one, with a D-dimer of less than 500 were possible rule out diagnostic strategies for acute aortic syndrome.

                                                The second manuscript in the present issue suggests that soluble ST2 might be an even better biomarker than D-dimer to rule out aortic dissection. In this paper by first author, Dr. Wang, co-corresponding authors, Dr. Du and Guo from Beijing Anzhen Hospital and Peking University respectively, the authors measured plasma concentrations of soluble ST2 using the R&D Systems assay in 1,360 patients including 1,027 participants in the retrospective discovery set and 330 patients with an initial suspicion of acute aortic dissection and ruled in a prospective validation cohort.

                                                The proportion of acute aortic dissection, this acute chest pain cohort was high at more than 40%. The authors found that soluble ST2 measured using this research grade assay showed higher levels in acute aortic dissection than in acute myocardial infarction or in acute pulmonary embolism. The result suggested that soluble ST2 levels could be useful as a rule out marker possibly even to an extent moderately superior to D-dimer.

                                                A cut-off level of around 35 nanograms per milliliters using the research grade soluble ST2 assay appeared to reliably rule out acute aortic dissection if used within 24 hours after symptom onset with a negative likelihood ratio of 0.01 and a negative predictive value of more than 99%. These intriguing findings are discussed in an accompanying editorial by Dr. Toru Suzuki from University of Leicester and Dr. Kim Eagle from University of Michigan. Well, that wraps it up for our summaries. Now, for our future discussion.

                                                Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. In fact, the pharmacologic stimulation of nitric oxide pathway is emerging as a therapeutic strategy in cardiovascular medicine in many areas including in heart failure preserved dejection fraction.

                                                Today's paper is therefore all the more intriguing because it seeks to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on the risk for cardiovascular disease as a way of informing of the potential utility of pharmacologic stimulation of the nitric oxide pathway.

                                                Intrigued? Well, I certainly and I'm so glad to have with us the corresponding author, Dr. Sekar Kathiresan from Massachusetts General Hospital as well as a familiar voice, Dr. Peipei Ping, associate editor from UCLA here to discuss this paper.

                                                Sekar, could I ask you as an introduction to tell us a little bit more of the general approach of looking at genetic predisposition as a way of perhaps forecasting potential utility of pharmacologic stimulation? Could you tell us a little bit more about that?

Dr. Sekar Kathiresan:      Yes. I'm delighted to speak a little bit more about this idea of using naturally occurring genetic variation to understand if a medicine developed against a target is going to work in terms of efficacy and also potentially lead to on target side effect.

                                                As you know, there are lots of variants for mutations in genes that eventually become targets for medicines. Over the last 10, 15 years, there's been an explosion in our understanding of human genetic variation, specifically in genes targeted by medicines.

                                                The idea here is that if there's a naturally occurring mutation in that target gene, you can simply ask what are the phenotypic consequences of carrying that mutation. Also use that information to predict, as I said, the efficacy of pharmacologic manipulation and potentially on-target side effects. This approach has become a very powerful approach.

                                                A famous recent example of gene, PCSK9, where mutation in this gene occur naturally. A lower function of PCSK9 and individuals who carry this mutations have lower LDL levels and lower risk of heart attack. This information has led to the development of medicine that mimic those mutations and those medicines have been proven now to lower LDL as well as lower risk of heart attack, a phenomenon anticipated by the genetics.

Dr. Carolyn Lam:               If I understand it right then, with regards to today's paper, the idea is that if a genetic predisposition to enhanced nitric oxide signaling associates with reduced risk of cardiovascular disease, then that would support the hypothesis that pharmacologic stimulation of the nitric oxide pathway would prevent or treat the cardiovascular disease, right? Could you further expand? Because you also did a meditation analysis. How would we understand that?

Dr. Sekar Kathiresan:      Let me walk you through the basics of this paper. Our hypothesis initially was a genetic predisposition to enhance nitric oxide signaling would actually affect a range of cardiovascular diseases. Nitric oxide is a well-known molecule, a regulator of a number of important processes; vascular tone, blood pressure, platelet aggregation.

                                                A couple of important genes in the nitric oxide pathway are, one, nitric oxide synthase, the key enzyme that generates NO. Second is a soluble guanylyl cyclase that is a regulatory molecule involved in NO biology. One of the genes that is part of that pathway is called GUCY183, which is basically a subunit of the soluble guanylyl cyclase.

                                                What we did was we looked at those two genes and asked, "Are there naturally occurring variations in those two genes that actually give us a sense that they gain function that they actually activate nitric oxide signaling. It turned out there are two polymorphisms. One in nitric oxide synthase and the other is in the soluble guanylyl cyclase subunit that are essentially gain of function. They're common polymorphisms.

                                                We know their gain of function because the carriers of these DNA variants have lower blood pressure. An indicator that there's enhanced NO signaling. We use these two polymorphisms as an instrument to understand the phenotypic consequences of having lifelong enhanced nitric oxide signaling.

                                                What we looked at was the relationship of individuals who carried both of the gene variants or gained a function and asked whether these individuals what the relationship of carrying the variant was to a range of cardiovascular diseases as well as a range of quantitative traits like blood pressure or kidney function.

                                                We looked at this in extremely large human population samples where genotype and phenotype had been collated. Most important of these samples is a recent study of a population-based cohort study called the UK Biobank, which has involved about a half million people where genotype and have phenotype have been assembled.

                                                What we found was that genetic predisposition to enhance nitric oxide signaling was associated with reduced risk of several important cardiovascular diseases. First, coronary heart disease. Second, peripheral arterial disease, and third, ischemic stroke.

                                                That provide a very compelling evidence that atherosclerotic cardiovascular disease would be lower based on enhanced nitric oxide signaling. What was surprising to us is we also found a couple of other diseases where it seemed to benefit from enhanced nitric oxide signaling namely kidney function and pulmonary function. These were a little surprising to us, but I think it really suggest that NO plays an important role in a range of diseases.

                                                In terms of your question about what aspect of NO biology is leading to be relationship to these diseases, is it simply the blood pressure effect for example or could you actually infer a mechanisms beyond the blood pressure? We looked at that specifically in the context of cardiovascular disease and we're able to show that the protection afforded by the enhanced nitric oxide signaling gene variants, that protection exceeded the amount predicted by the blood pressure change. In fact, by quite a bit suggesting that there are probably non-blood pressure mechanisms that are at play in terms of the protection afforded by enhanced nitric oxide signaling gene variants.

Dr. Carolyn Lam:               Peipei, I have to invite your thoughts now. This is such an amazing paper. We had great discussions as an editor team. Tell us your thoughts.

Dr. Peipei Ping:                 The editorial team as well as the reviewers have been very impressed with the quality of the datasets and the value and detail, the metadata analysis together with the appropriate analytical approach. The study is done in our view in a very careful manner and the analysis was performed through the highest standards.

                                                What we also recognized is the potential impact that this particular study may have on multiple areas of studies, in particularly with their findings, the spectrum of individuals, how they carry nitric oxide signaling trends. You could appreciate that the individual score or genetic score paired with the analysis of the genetic variance that they have done, they see from the mental idea that examine both genetic as well as phenotype of each individual is critically important for medicine to be prescribed in the next step of therapies.

Dr. Carolyn Lam:               Building on that thought, Sekar, could I ask you? You found some rare inactivating variance. Are these the patients then you think should be targeted for NO enhancing therapies? What's the clinical implications of your findings?

Dr. Sekar Kathiresan:      I think there are two ways to think about the implications of these findings. One is there's just a simple biologic insight, the pharmacologic activation of NO signaling maybe protective beyond pulmonary hypertension. As you know, there are actually compounds in the clinic right now that are pharmacologic activators of soluble guanylate cyclase. Those medicines work in the rare condition of pulmonary hypertension.

                                                our work suggest that those medicines are likely to work in a broader range of indications including atherosclerotic cardiovascular disease, kidney disease and pulmonary function. At a simple level, those experiments, I think, should be looked at. Those indications should be looked at.

                                                Whether we've identified a subset of a population that particularly will respond versus it will be a general phenomenon across a range of different individuals that have impaired nitric oxide signaling, I think time will tell. Certainly, one group to think about would be those who are indigenously deficient in nitric oxide signaling and we did find that there are small subset of patients who have inactivating mutations in these two genes and they have higher blood pressure and increased risk for cardiovascular disease.

                                                It was a pretty rare phenomenon, so very small number of individuals would be relevant there. I'm not sure actually that you necessarily want to limit the potential benefit of NO signaling, enhanced NO signaling to just that subgroup. In fact, my prediction would be that the medicine would be relevant for a very large percentage of the population. That you do not need to limit the potential application of this therapy to just those who carry the inactivating mutations.

Dr. Peipei Ping:                 I agree largely of what Sekar has discussed. I would add that in situations where genetic information are available with the patients, what the study has offered is fairly clear in the patients where rare variance that inactivate the NOS3 or the guanylyl cyclase off the genes. Maybe a failure it is with a higher systolic blood pressure risk. I'm entirely supportive with the general conclusion that we have come to a time point where NOS outside signaling activation is a critical new element of therapy in cardiovascular health and disease.

Dr. Sekar Kathiresan:      Thank you Peipei. Thank you Sekar for taking the time to share your thoughts with us. We are so proud to be publishing paper in circulation. So proud and happy to be chatting about this on this podcast. You've been listening to Circulation on the Run. Thank you for joining us and please tune in again next week.

Jan 8, 2018

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 featured discussion this week focuses on the new 2017 ACC/AHA high blood pressure guidelines, and the potential impact of these guidelines on the U.S. population. A must listen, coming right up after these summaries.

The first original paper this week provides insights into how extracellular matrix remodeling contributes to in‐stent restenosis and thrombosis. First author, Dr. Suna, corresponding author, Dr. Mayr, and colleagues from King's College London, implanted bare metal and drug‐eluting stents in pig coronary arteries with an overstretch and then harvested the stented segments up to 28 days poststenting for proteomics analysis of the media and neointima.

The authors found significant differences by proteomics in the extracellular matrix of coronary arteries after stent implantation. Most notably, an upregulation of aggrecan, a major extracellular matrix component of cartilaginous tissues that confers resistance to compression. In fact, this study provided the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting. This opens a door to consideration of aggrecanase activity as new drug targets that may alter extracellular matrix remodeling in the vasculature.

The next paper tells us that empagliflozin could address a significant unmet need in patients with chronic kidney disease. First and corresponding author, Dr. Wanner, from Wurzburg University Clinic in Germany investigated the effects of empagliflozin on clinical outcomes in patients with chronic kidney disease in the EMPA‐REG OUTCOME trial, where patients with type 2 diabetes, established cardiovascular disease, and an eGFR above 30 at screening were randomized to receive empagliflozin or placebo, in addition to standard of care.

In the current study, prevalent kidney disease was defined as an eGFR of less than 60 or urine albumin/creatinine ratio of more than 300 at baseline. In these patients, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo, reduced the risk of all‐cause mortality by 24%, and reduced the risk of hospitalization for heart failure by 39%, and the risk of allcause hospitalization by 19%.

The effects of empagliflozin on these outcomes were independent of renal function or albuminuria status at baseline. Furthermore, the adverse event profile of empagliflozin was similar across subgroups by renal function at baseline. Adverse events of particular concern in this population, such as urinary tract infection, acute renal failure, hypokalemia or fractures, lower limb amputations or hypoglycemia were not increased with empagliflozin compared to placebo.

The next study provides mechanistic insights into exercise intolerance in heart failure with preserved ejection fraction or HFpEF. First author, Dr. Houstis, corresponding author, Dr. Lewis and colleagues from Massachusetts General Hospital, investigated the mechanism of exercise intolerance in 79 patients with HFpEF and 55 controls referred for cardiopulmonary exercise testing who were also studied with invasive monitoring to measure hemodynamics, blood gases and gas exchange during exercise.

These measurements were used to quantify six steps of oxygen transport and utilization in each HFpEF patients, identifying the defective steps that impaired each one's exercise capacity. The authors then quantified the functional significance of each pathway defect by calculating the improvement in exercise capacity that a patient could expect from correcting the defect.

The authors found that the vast majority of HFpEF patients harbored defects at multiple steps of the pathway, the identity and magnitude of which varied widely. Two of these steps, namely, cardiac output and skeletal muscle oxygen diffusion were impaired relative to controls by an average of 27% and 36% respectively. Due to interactions between a given patient's defects, the predicted benefit of correcting any single defect was often minor. At the individual level, the impact of any given pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects.

The authors concluded that a personalized pathway analysis could identify patients most likely to benefit from treating a specific defect. However, the system properties of oxygen transport favor treating multiple defects at once, such as, with exercise training.

What are the potential benefits or risks of intensive systolic blood pressure lowering in individuals with a low diastolic blood pressure? Well, the final paper today tells us. In this study by first and corresponding author, Dr. Beddhu, and colleagues from Salt Lake City in Utah, a post hoc analysis of the SPRINT trial was performed. Remember that the SPRINT trial was a randomized control trial that compared the effects of intensive versus standard systolic blood pressure control in older adults with high blood pressure at increased risk of cardiovascular disease. The current post hoc analysis examined whether the effects of the systolic blood pressure intervention differed by baseline diastolic blood pressure.

The authors found that there were U‐shaped relationships of baseline diastolic blood pressure with the primary cardiovascular disease outcome and all‐cause death. However, the beneficial effects of intensive systolic blood pressure lowering on the primary cardiovascular disease outcome in all‐cause death were not modified by baseline level of diastolic blood pressure.

Increased risk of kidney events and serious adverse effects of the intervention were consistent across baseline diastolic blood pressure quintals. Therefore, there was no evidence that the benefit of intensive systolic blood pressure lowering differed by baseline diastolic blood pressure levels.

These findings suggest that the reason for the observed associations of worse outcomes with lower diastolic blood pressure was due to underlying processes, such as increased arterial stiffness that lead to a decline in diastolic blood pressure, rather than the level of diastolic blood pressure per se. Furthermore, lower levels of diastolic blood pressure within the ranges examined in SPRINT, should not be an impediment to intensive treatment of hypertension, at least in those without diabetes or stroke.

Well, that wraps it up for our summaries. Now for our feature discussion. The ACC/AHA guidelines for the management of hypertension in adults has really been a hot topic. Just published this year, and it really updates the seventh JNC report, which was published in 2003. Well, today's feature paper deals directly with a comparison of these two guidelines and how it may impact our practice.

I'm so pleased to have with us today the first and corresponding author of this paper, Dr. Paul Muntner, from University of Alabama at Birmingham and a very familiar wonderful voice, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome!

Dr. Paul Muntner: Hi. Thank you for having me.

Dr. Wanpen Vongpatanasin: Hi, Carolyn.

Dr. Carolyn Lam: Paul, could I ask for you to start by painting the differences between the 2017 ACC/AHA guidelines and the JNC 7? We understand you were part of writing the guidelines, so who better than to draw our attention to the main differences.

Dr. Paul Muntner: I think that the new guideline, the ACC/AHA guideline, it was fairly comprehensive included 15 chapters, so there's a lot of new information in the guideline, everything from a dedicated section on the measurement of blood pressure to aspects of patient care.

The manuscripts featured in "Circulation" in this issue is focused on, in the past, there's different blood pressure thresholds in the guideline for defining hypertension, as well as recommendations for antihypertensive medication treatments, as well as blood pressure goals.

As everyone probably knows form JNC 7, hypertension was defined as a systolic blood pressure greater than or equal to 140 mmHg and/or a diastolic blood pressure greater than or equal to 90 mmHg, versus in the 2017 ACC/AHA guideline, these were lowered to 130/80.

In terms of treatment recommendations, there's really a fundamental shift with the new guideline, where the new guideline focuses not just on blood pressure levels, but also on overall cardiovascular disease risk. So going to the new guideline, people are recommended treatment if their blood pressure is above 140/90 but also there's a group with a blood pressure in the 130 to 139 range for systolic blood pressure, of 80 to 89 mmHg for diastolic blood pressure, who are recommended treatment if they have a high cardiovascular disease risk.

Finally, I'll just finish with this last note is that blood pressure control for people taking antihypertensive medication is now 130/80 so a goal blood pressure for people taking antihypertensive medication is systolic blood pressure less than 130 mmHg, and a diastolic blood pressure less than 80 mmHg.

Dr. Carolyn Lam: That was beautifully explained. Paul, I just really loved table 1 of your paper, and I want to refer our audience to it. It so nicely summarizes the differences between the 2017 guidelines and JNC 7. At risk of oversimplifying, when you compare the two in this approach, it's sort of comparing using a cardiovascular risk in conjunction with blood pressure‐type approach with a blood pressureonly number approach, isn't it?

Dr. Paul Muntner: Right. I think that's a key important piece of the new guideline and really CVD risk is used in conjunction with blood pressure levels to guide the recommendation to initiate antihypertensive medication. This decision was based on a wide variety of data from randomized trials, observational studies, as well as simulation or economic analyses that consistently showed the benefits of considering an individual's overall cardiovascular disease risk and providing effective and efficient treatment for lowering blood pressure.

Dr. Carolyn Lam: Right. And you analyzed the impact of this in the NHANES data in today's paper. Could you tell us a bit more about that?

Dr. Paul Muntner: The U.S. National Health and Nutrition Examination Survey, or NHANES, provides an opportunity to generate national representative point estimates on the prevalence of hypertension and treatment recommendations. So we're able to use data on about 9500 U.S. adults. Each person came in for a clinic examination where they had their blood pressure measured three times, and they were asked about their use of antihypertensive medication. What we found was the prevalence of hypertension, or the percentage of U.S. adults with hypertension according to the new guideline, is about 46%, which compares to 32% according to the JNC 7 guideline, so really a big increase in the prevalence of hypertension of about 14%. However, by using the combination of risk and blood pressure, we're not recommending treatment for everyone with hypertension but rather people with hypertension with very high blood pressure as well as those at high cardiovascular disease risk.

So antihypertensive treatment, pharmacological antihypertensive treatment, is now being recommended for about 36% of U.S. adults compared to 34% of U.S. adults according to JNC 7. The rest of the people with hypertension are recommended nonpharmacological therapies; exercise, diet, alcohol reduction, weight loss for people who are overweight and obese.

Really, it's an opportunity to treat people with pharmacological therapy if they're high risk. Then for people who aren't high risk, there's an opportunity for nonpharmacological therapies, so they can, hopefully, prevent the need for further treatment.

Overall, this equates to about 103 million U.S. adults with hypertension, so it's a very large number. However, only about 82 million of these individuals are recommended pharmacological antihypertensive treatment, so there's a big portion of the U.S. population who have hypertension, have high blood pressure, yet we think would benefit from nonpharmacological therapy.

Dr. Carolyn Lam: Wanpen, could I get you to chime in on what you think of the clinical implications of today's paper?

Dr. Wanpen Vongpatanasin: I think that this paper gives us at least reassurance that although we have 30 million more people with hypertension now, not all of them have to be started on medication right away. But it also put an emphasis on cardiovascular risk assessment, which we as the cardiologist are already doing this on a regular basis. It is a major step forward to incorporate cardiovascular risks as another way to gauge how people should be treated intensively, which we like that aspect of it.

Dr. Carolyn Lam: I agree. I think it's reassuring because most people think, "Oh, my goodness. We have got so much more hypertensives to manage." But then it tells us that a restratified approach really keeps it manageable, I suppose. But Wanpen, did you have some specific concerns or questions?

Dr. Wanpen Vongpatanasin: We look at the people who by JNC 7 calls prehypertension, which it's now some of them turn out to be a stage 1 hypertension. The question I have for Paul is that even though guidelines call for nonpharmacologic treatment first, the guidelines said give a try from three to six months, but what happens after that if they're still not reaching the goal?

Would people on the guidelines propose drug treatment eventually because, as you know, nonpharmacology treatment is easier said than done. Even though you might be able to tackle some aspect of it, but I doubt you can tackle everything; exercise, diet, sodium, weight loss all at the same time in a three to six month period.

Dr. Paul Muntner: It's a great question and it's something that the guidelines really spent a lot of time considering and reviewing the evidence. First, what the recommendation is that we recommend nonpharmacological intervention as you mentioned and the re‐evaluation. If the person's blood pressure remains in the stage 1 hypertension range and they're not a high cardiovascular disease risk, then they are recommended to continue attempts at the nonpharmacological interventions.

I've been asked several times since the guideline has been published, "What, are we supposed to just wait until people become high risk?" And my viewpoint on this is, it's hard enough to get people to adhere to their medications currently, let's be judicious about this, focus on the high‐risk people, and maybe if we can communicate with people that have high‐risk for cardiovascular disease, we can work with patients to improve medication adherence and really focus on the low‐risk people in preventing the need for lifelong therapy.

Dr. Wanpen Vongpatanasin: That's great, I think that's really helpful in clarifying this point. Because even if you say that 30 million doesn't need to be started on the drug right away, that eventually have to be started on drug in six months, I think that doesn't really give us a reassurance but, obviously, we still have to continue to

work on these patients who are on the fence of needing pharmacology intervention.

Dr. Paul Muntner: Right. I think what's interesting here is a lot of people since the guideline has been published have said to me, "Now this is done." I said, "No. Now we're really just starting. Now is the most important part of the guideline, which is implementation." And how are we going to implement the guideline, which, as we were just discussing, isn't just about initiating pharmacological therapy, but it's also about the nonpharmacological therapies as well as medication adherence and all these other issues that are in the guideline, proper measurement of blood pressure, etc.

I think that now is going to be the most important time to really have a big impact on our patients' lives by really using the evidence and now that it's in the guideline, we're using the evidence to direct treatment appropriately.

Dr. Carolyn Lam: Indeed, Paul. Just one thing. Along the lines of implementation, how about the issue of the lower target BP, to treat to? What did your study from NHANES show about that, numbers reaching targets, and do you see that as an issue?

Dr. Paul Muntner: It's an interesting question because the findings from our study found that it's currently over half of U.S. adults according to the new guideline, over half of U.S. adults on antihypertensive medication, have blood pressure above the goal in the new guideline. So in our study, 53% of U.S. adults taking antihypertensive medication had a blood pressure above 130/80. This represents an increase from the JNC 7 guideline of people with blood pressure above 140/90, of course, of about 14.4%. According to our estimates, there are about 8 million U.S. adults who are going to be recommended more intensive antihypertensive medication.

The blood pressure of less than 130/80 is a uniform goal for all people taking antihypertensive medication. This comes from several meta‐analyses that have consistently shown the cardiovascular and mortality risk reduction associated with achieving a blood pressure of less than 130/80. I think there's very firm evidence to stand on.

One interesting thing from the guidelines, it's in one of the tables, and I think it's a very important point to make, is that a lot of people who have above goal blood pressure, according to the new guideline, they're only taking one or two classes of antihypertensive medication. The vast majority of them are not taking multiple classes of antihypertensive medication, so we feel that these therapies can be optimized and we're not going to be pushing people into antihypertensive polypharmacy but rather they can receive substantial risk reductions without really giving them too many additional pills.

Dr. Carolyn Lam: Wow. Really about implementation. Wanpen, did you have any other comments before we close?

Dr. Wanpen Vongpatanasin: Yes, I think that is really interesting to see also with these guidelines how is this going to be embraced to the rest of the world. Actually, prior to this guideline, at least hypertension control rate in the U.S. is better than most countries, European countries, as well as in Asia. But now even lowering the bar, we use the same criteria for the rest of the world, that would be a lot worse control rate than now. I think it will be challenging, not only in this country but throughout the world.

Dr. Paul Muntner: That's a great point. Obviously, these guidelines are U.S. guidelines, however, new European guidelines should be coming out in 2018, is what I've heard. I think that even though these guidelines were developed by the American College of Cardiology and the American Heart Association, the data that we're using really comes from worldwide evidence. The evidence didn't stop at the borders. A lot of the evidence that was used in choosing the blood pressure levels to define hypertension, the blood pressure levels to recommend pharmacological interventions, as well as the blood pressure goals do come from other countries. A lot of data from Asia, Europe, Australia, so I think that the data used in these guidelines should be generalized when it's out of the United States.

I think there may be challenges with implementing these guidelines in different settings, and, obviously, a lot of things will have to be tailored to where they will be implemented. However, the overall goal is to reduce the burden of cardiovascular disease and renal disease related to hypertension and, hopefully, that can be a worldwide goal.

Dr. Carolyn Lam: What a great reminder. It is worldwide data, worldwide evidence for a worldwide problem. Well, listeners, you heard it right here on "Circulation on the Run." Thank you so much for joining us today and don't forget to tune in again next week.

Jan 2, 2018

Dr Carolyn Lam:                (Music playing)...Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and his editors I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Today is one of my favorite podcasts as always because it is the fellows in training podcast.

                                                This is where the center stage and we’re so pleased to have two brilliant fellows with us today. Dr. Tom Ford from University of Glasgow and Dr. Kevin Shah from UCLA and of course joining us today as well is our editor for digital strategies, Dr. Amit Khera. Hi everyone.

Dr Kevin Shah:                   Hi Carolyn.

Dr Carolyn Lam:                Hey Kevin. Since you're there in wonderful bright and sunny California and going to talk about one of my favorite topics HFpEF. Could you please tell yourself and then please tell us also about the paper you chose?

Dr Kevin Shah:                   I am a third-year general cardiology fellow at UCLA. I have a career interest in advanced heart failure and transplant cardiology. I'm going to be doing a one-year fellowship in that next year at Cedars Sinai in Los Angeles.

                                                The article that I picked to discuss was the Reduced LAP Heart Failure I Trial and it was specifically testing a novel device in a small cohort of patients to see if the creation of intraatrial septal connection in patients with HFpEF can improve their filling pressures as well as their symptoms with exercise.

Dr Carolyn Lam:                Yeah so Kevin what about this paper stood out to you?

Dr Kevin Shah:                   The two biggest things that were impressive to me and that really stood out were 1) this concept that keeps coming up more frequently in contemporary research, which is the idea of using a sham trial. Specifically, in this study they did perform a one-to-one randomized trial. With one of the arms, if they did not receive the actual device, they underwent a complete sham undertaking including headphones in music and blind folding the patient who were not sure if they received the device or not.

                                                I think it's an important concept because it does speak to the placebo aspect of procedures. It tries to really control for that when a patient doesn't know if they received a novel device, and we can still test them and see how they feel after-the-fact. I think that's an important strategy in modern trials.

Dr Carolyn Lam:                Kevin, that is such a good point and really quite novel too. So we've discussed this paper before but not quite the aspect that you point out and I couldn't agree more. The REDUCED LAP follows its pilot study results, which was open label single arm right published in the Lancet. So this is a very reassuring results since knowledge sham controlled.

                                                I suppose the lesson comes from other device trials that were sham controlled and then gave maybe slightly different results), right when we're talking about the renal innervation trials before. But you said that there were two points that stood out to you so what was the second?

Dr Kevin Shah:                   The other will also be endpoints and what they chose to target. It was a small trial but I think it's important in a disease state such as HFpEF to select specific endpoint that really reflect the physiology and pathophysiology and the authors should be commended. I think for selecting primary and secondary endpoint that will primarily focus on hemodynamics as well as symptomatic relief.

                                                I know that they are working toward their stage 3 trial and I think in the vein selection of these type of endpoint. Probably more so than endpoints such as mortality are going to favor this disease state in terms of trying to carve out some sort of therapy that actually make patients feel better.

Dr Carolyn Lam:                Great great points. For me to just knowing that a hemodynamic endpoint makes sense, because if we look at the Champion Trial and look at the HFpEF  subgroup of the champion trial it also seems to show that if people just treated patients with HFpEF  according to a hemodynamic guide and in the champion trial that was the pulmonary artery pressure reading. That actually appeared to keep patients out of hospital. And I have to agree with you that sometimes we forget that has HFpEF  is about pulmonary congestion and that the end of the day it is a hemodynamic disease. It is heart failure in other words.

                                                Kevin one last thing what do you think about using this sort of strategy in HFREF?

Dr Kevin Shah:                   That's a good question I can't say I know at least this device has been studied in this trial like you mentioned in one prior trial that was not randomized. I'm sure it's been at least investigated. I can't say I've seen any literature on it. I like to think that it would make some sense from a physiological standpoint, but I don't know if anyone is actually gone to the task of seeing how the device performs in HFREF.

Dr Carolyn Lam:                As I said I think at the end of the day I think they're all part of the same heart failure family. And left atrial hyper tension is kind of the final common pathway. So I agree with you that maybe it's worth considering in HFREF too, but then on the other hand of course and have friends HFREF you've got all this great medical therapy. Well Kevin I really, really appreciate your selection. May I now switch over to Tom? Tom would you like to tell us a little bit about yourself ,and which paper you chose.

Dr Tom Ford:                      Sure thing my name is Tom Ford. I'm very interested in interventional cardiology, and my career path has been a bit unusual because I did my basic cardiology training in Sydney. And then from there I got a great opportunity to pursue a research degree, a PhD, which I’m currently halfway through. That's what Prof. Colin Berry and Prof. Keith Oldroyd here in Glasgow and that’s a British Heart Foundation Fellowship so it's a great opportunity. I went out for recent WOSCOPS Trial from posthoc analysis. In this is a really interesting study a lot of the readers and listeners will be familiar with the original publication. It was actually published 22 years ago. Published in the New England Journal of Medicine.

                                                The WOSCOPS was a landmark trial that looked at statins for primary prevention. And this is the present analysis that looked at just over 2500 Mills with LDL-cholesterol above hundred and 190 mg/dL. So for those of you listeners in the UK 4.5 mmol per liter so quite the high LDL. They looked at these gentlemen without pre-existing vascular disease. There's guideline recommendation for this group but not much evidence. And what they showed was over a five-year period of follow-up that there was a reduction in cardiovascular death and all cause mortality with this treatment. That wasn't just for the period of the trial because of the study design we were able to get a legacy effect which was noted over 20 years of follow-up. So in summary a trial will show the benefits of  statins and primary prevention mortality benefit for people without very high LDL to start with.

Dr Carolyn Lam:                Carolyn awesome Tom. I love that she began saying that your into interventional cardiology but you chose an article about medical therapy and the importance of it, the statins. I fully agree with you. Amit did you have some for Tom?

Dr Amit Khera:                  Sure. First I want to commend you both I don't think you did this on purpose but Carolyn's heart failure HFpEF  expert. I'm sure she loved the other trial and I'm a preventative cardiologists. So we certainly love you choices this week. Tom, thanks for the summary. It's an important article and one that we did highlight on the previous podcasts. You know there's so many things to talk about but certainly remind you that we have great data sets around that can answer unique questions that maybe are unanswerable today and I think this is an example of that.

                                                Can you speak to this ideal of pulling an old 22-year-old child as you mentioned and how that provides insights and kind of as a PhD student ways to think about ways to be creative and research?

Dr Tom Ford:                      One of the reasons I chose this child because it's close to my heart looking at a population in the west of Scotland. Sadly over here we've got too high prevalence of cardiovascular morbidity and mortality. So what this trial speaks to is the benefits of a really carefully planned procedure. I mean these were outstanding researchers that thought ahead of their time, and as a result of their analysis. Over two decades later they are still multiple publications and there's kind of open approach where there's different research groups that have used this data set for number of different outputs.

                                                I think a real outstanding example of what can be done with well-planned study.

Dr Amit Khera:                  Sounds like were in agreement about how to use a fruitful database and continue to learn from it as time goes on. The thing about this as you pointed out is the LDL above 190 component and what the authors say this is sort of the first clinical trial evidence for treatment. In your view, does this change practices or guidelines? Was this already what we were doing? Does this support what we were already doing, or how does this impact clinical care and guidelines currently?

Dr Tom Ford:                      I think it's a good point. People will say we were doing this anyways. I think now it's going to be helpful and practical inside the clinic. If you can say to a patient well actually look I know we’re asking you to take this tablet you've not actually had an event but, ultimately we know the natural history of people in your position may well be unfortunately that they’re high-risk, and that there is actually a mortality benefit to be had from these tablets that you don't necessarily want to take but definitely the benefit’s there.

Dr Amit Khera:                  The neat part as you pointed out also was dual components when they're looking at the on treatments during the trial. We see an improvement in events. What the WOSCOPS investigators have done so creatively over the years is this idea of a legacy affect.

                                                The long-term impact in preventive cardiology – certainly a space for where were going was just looking beyond the short-term. There's obviously problems there too because that was not pre specified people were necessarily on assigned therapies. Tell me when you look at this long-term legacy effect what does that mean to you? How does that add be it the way you counsel patients or how you think about this treatment in patients with high LDL?

Dr Tom Ford:                      The effect of the statin assumes that all the patients are actually taking the drug. I think there has to be an analysis of these patients in this trial and obviously not everyone was compliant. So I think we can maybe extraopolate that for the that there might be in even bigger effect for those patients that were actually taking the drug. And I think if you were to take it for five year period. Obviously we don't know what happens after that. What we do know is the solid mortality data.

                                                What it speaks to me is that if you take the drug and you are at high risk to begin with then potentially it's plaque stabilization, the pleiotrophic effects of statins that we know are beneficial and the hard endpoints are definitely reduced. That persists over 20 years of follow-up. So I think that’s really a great victory for preventive cardiology as you said.

Dr Amit Khera:                  That's a great point about biasing towards the know when you have people crossing over and that this may be conservative of what was seeing in the long term. I think that's a really important point. One last question for you. The West of Scotland trial - generations have changed and back then obviously part of it was trial design but LDLs on average were higher. The median or mean in the group was around 192.

                                                If you look when they look above or below that 190. The people below were 178 or so - still pretty high LDL. So it does beg the question you know we have this paradigm of LDL above 190 should be treated regardless. You wonder if that should be 160 or whether the number should be lower. What are your thoughts about that?

Dr Tom Ford:                      I agree with you. I think it's always a challenge to kinda pass off dichotomous endpoints when you’ve got continuous variable like LDL. It's just a continuum of risk and divided using the figure 190 in the study. In fact the patients with LDL less than 190 they couldn't show statistically significant reductions in all cause mortality. But I think it's again personalization of meds and we may have to discuss the risk with individual patient.

                                                Ultimately we do have to have a firm conclusion. I think in this study the data is quite clear that 190 does seem to be quite robust as the predictor who's gonna get the most benefit.

Dr Amit Khera:                  Listen I think protection article that you pointed out was close to home and you certainly discuss it very well and provided lots of important insights. And again I think it was an excellent choice and one that was really highlighted in the media as well. I think there was a broad allure to this article. If we make change gears now little bit we've heard about the science part know we want to talk about what it means to be a fellow in training.

                                                I just want to say on behalf Circulation also speak for myself. It's so important for us to involve fellows in training into our activities and you're one of our major targets in terms of impact and goals for the journal. We're so delighted to do this twice a year and were always thinking about other ways we can get FITs involved. I mentioned just a couple of things the American Heart Association has of fellows in training program where people can sign up for free and get online access to the journal.

                                                So I hope all fellows are taking part in that. We're starting a new initiative called FAVES where just like you both submitted articles of interest of the fellows can do the same. On Fridays we’ll post those on social media so these are a few ways that were getting FITS more involved and we really hope to continue that. Let me start by maybe asking Kevin to have a chat with you as much.

                                                Kevin in terms of journals there's some me now we're getting inundated with information. I think that's a good thing. How do you consume the medical literature? There's old print journals; there's the online journal; there's a table of contents your social media tell us a little bit about how you consume the medical literature.

Dr Kevin Shah:                   I agree. We’re kinda getting to a space where now the amount of information that's coming out is tremendous. I think that finding a strategy to help filter out what appeals to your clinical and research interest is becoming more challenging. For me I'll say print journals are slowly kind of falling off. I don't subscribe to too many of them but they still do come to my doorstep. The main way that I would say I'm getting access to or at least becoming aware of articles that are kinda relevant to where I am in my training and what I'm doing is the social media. Some primarily at least for me is Twitter.

                                                I'll say it's a helpful tool and that I can follow a group of individuals that have a similar professional interest as me and you can almost always rely on the fact that somebody will post an article that becomes relevant to a common interest. So between sharing on social media I think that's the primary way that I'm really catching my eyes to a major journal articles.

                                                Aside from that I still subscribe by email to a couple larger journals and see their weekly or biweekly updates about what's being published. And the last at least in my institution our division chief Dr. Gregg Fonarow; he goes out of his way to send to the fellows and faculty new articles that are kind of pertinent to clinical practice. Which is very helpful for us.

Dr Amit Khera:                  That's so helpful and you know everyone has their own way of consuming the literature but I certainly appreciate your interest in social media. You know there are some luddites out there that think of it literally as just social and it really has a professional bent to it. Well rapidly you can figure out the most cutting-edge important articles in your field so I certainly appreciate your comments. Tom let me ask you now, at your stage of training. You've had an interesting training path as you said you sort of started as an interventional cardiologist and now you are doing a PhD. There so many different articles in Circulation. We have original research, state-of-the-art reviews. We have these opinion pieces and on my minds and different ones. Tell us a little bit about what articles appeal to you and which other novel formats maybe you'd be interested in seeing.

Dr Tom Ford:                      I think that the original research articles are great if it's in your chosen field. Obviously this is where we're going to a great deal of detail on specific topics but outside of that I think that the review articles are great form if it's something that’s a common clinical topic to kinda brush up on. Your On My Mind section I think is great because it gives you an opportunity to hear from key opinion leaders in the field. I think it was Morton Kern discussing invasive coronary physiological assessment.

                                                So I think there’s different types of articles that can be quite helpful.  To start with the original research ones. I’ll skim through the contents. I'll tend not to read the details if it's not in my chosen field.

Dr Amit Khera:                  Yeah great point. Obviously they are topical depending on what your main interest area and we always say reading around your field to get a broader perspective in cardiovascular medicine. I think you hit on the point about on my mind ones. We really want people be able to free associate and original article are sometimes more stiff and linear. So we really like those pieces as well. Carolyn we’ll give you second set ask a question or two to for today.

Dr Carolyn Lam:                Actually Amit I just wanted to comment. Isn't it so encouraging to hear the variety of approaches and you know Circulation has enough that we’re meeting various different needs. I really wanted to take the opportunity to thank you as editor of digital strategies for just doing so many of these initiatives for Circulation. I think it’s just incredibly important for the Journal to keep up with the times in that sense. Amit, may I be cheeky ask you how do you consume the literature?

Dr Amit Khera:                  Carefully. You know the neat part in being on the editorial board of Circulation and one of the associate editors we get to see so many amazing papers that come through and I think obviously I get to see, essentially and also my digital strategies role I essentially see every paper that comes through that we end up publishing.

                                                Obviously I get wide exposure to Circulation but obviously beyond that I get all the e-Table of Contents for almost every major cardiovascular Journal. Certainly looking at social media and I tend to find hotspots interventions and other areas and podcasts – let’s not forget podcasts. So there's some great podcasts out there. I know of one.

Dr Carolyn Lam:                Oh I love it. All right but just one last question for both Tom and Kevin from me. I honestly would love to know what do you think we could do better or what would you like to see more from Circulation?

Dr Kevin Shah:                   I guess the question I have for Circulation is there any role or have fellows ever gotten involved in the review process for articles?

Dr Amit Khera:                  Listen that's really important because you learn a lot from doing that and obviously in institutions similar to ours where if you asked to review a paper you have a fellow contribute. I think you might be asking something sort of more formal and systematic with Circulation. I will say that one of our Circulation journals I believe it's Circ Heart Failure or  Quality and Outcomes I'll check. It has a formal program where fellows essentially can be assistant editors if you will.

                                                We have our cardiology fellows here at UT Southwestern involved in that process. And I think part of that process is just an IT issue of how to maintain confidentiality of our papers for our authors but yet still let fellows contribute meaningfully. And also timing because you know papers have cycles where you decide if he should go out for review but it'll come back and you never know when that happens you have to make the next level decision.

                                                Then it goes potentially to a meeting and so being able to make sure that fellows can participate at every level, cause that's where the value comes in. We are certainly interested in learning from what our other Circulation of family journals is doing in that space and definitely an area that we've thought about some fellows contribute but need to do more.

Dr Carolyn Lam:                And Tom how about you?

Dr Tom Ford:                      Just picking up on your point on what the sister journals are doing you know I see the Outcomes Journal is looking at more visual abstracts and video abstracts. You know I think it's really important that we increase the efficiency of learning. What's your take on that?

Dr Carolyn Lam:                That is the greatest suggestion. I like first of all your phrase of increasing the efficiency of learning. Amit, I'm going to turf it to you again.

Dr Amit Khera:                  I'll tell you what's amazing you know when I started this role a bit ago. Both of you are obviously contributing to research and everyone on this call is and I think we forget that in the social media space we don't have a lot of data. Some things sound good or feel good. At Circulation my predecessor Carolyn Fox did a randomized trial called intention to tweet if you haven't read it. And there's a follow-up to that that was published. And essentially by randomizing articles to social media or not there was no increase in the views if you will of the article.

                                                There's always limitations to every study but the point is, as you think about novel offerings, something we struggle or something we’ve seen as an opportunity, what works we tried a few things we tried certain videos and we look at what's the uptake and interestingly some things we thought that would be widely of interest really weren’t. Then other avenues we’ve tried have been.  

                                                I love what you said, and as Carolyn also felt, the idea of efficiency of learning. I think we need to do frankly in the social media and journal spaces is to continue not just to innovate but to study and figure out what works and what doesn't to help different learners.

Dr Carolyn Lam:                (Music playing)....Thank you very much audience for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.