Circulation on the Run

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Jun 29, 2016

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.

I am excited to be joined today by 2 guests and we will be discussing the feature paper on phenotype specific treatment of heart failure with preserve ejection fraction but first here are the highlights from 5 original papers in this week's issue.

(0:42) The first paper by first author doctor Haas, corresponding author Dr. Bidinger and colleagues from Boston Children's Hospital aim to investigate the role of PCSK9 in nephrotic syndrome associated hypercholesterolemia. The authors did this by first looking at 50 patients with nephrotic syndrome and showing that resolution of nephrotic syndrome was associated with a decrease in their plasma cholesterol, as well as a decrease in their plasma PCSK9 levels. They then looked at two mouse models of nephrotic syndrome. One using nephrotoxic serum to induce immune mediated damage of the kidney podocytes. The second, a model of genetic ablation of the kidney podocyte.

In both these models nephrotic syndrome produced hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9 levels. The authors then went on to look at the effect of knocking out PCSK9 both in the whole body as well as specifically in the liver in these mice. They showed that mice lacking PCSK9 no longer showed the increase in LDL cholesterol with nephrotic syndrome induced by nephrotoxic serum. Thus in summary, podocyte damage triggered mocked inductions in plasma PCSK9 and conversely knocking out PCSK9 in ameliorated this lepodimia in a mouse model of nephrotic syndrome. The cool thing about this data is that they now opened the door to the consideration of PCSK9 inhibitors in patients with nephrotic syndromes associated hypercholesterolemia.

(2:45) The second paper by Dr. Fortis and colleagues from Duke Clinical Research Institute aimed to address an important knowledge gap that has not yet been addressed in the pivotal noac trials or large registries. Which is whether outcomes differ among atrial fibrillation papers with worsening renal function compared with those with stable renal function while taking a noac versus warfarin. The authors looked a this by studying more than 12,600 patients who were treated with rivaroxaban compared to warfarin in the ROCKET AF trial. On treatment worsening renal function was defined as a decrease of more than 20% from screening creatinine clearance measurement any time point during the study.

The main finding was that among patients with on treatment worsening renal function, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin without an increase in the composite leading end point. This is really encouraging to all of us who treat these patients, knowing that it is possible to safely anti-coagulate patients with worsening renal function without excessive bleeding and to know that rivaroxaban may be an alternative to warfarin in these patients. This paper is accompanied by a beautiful editorial on the multifaceted dilemma of renal function and atrial fibrillation by doctors Hijazi and Wellington.

(4:30) The third paper by doctor [inaudible 00:04:32] and colleagues from Massachusetts Journal Hospital describes a randomized controlled trial of an advanced care planing video decision support tool in 246 patients with advanced heart failure. Patients were randomized to an intervention arm which consisted of a six minute video as well as an advanced care planning checklist or to a control arm where patients received only a verbal description of the goals of care. This video began by first introducing to the patient the concept of advanced care planning and then using images to depict the three part goals of care namely, life prolonging care, limited medical care and comfort care. Patients in the intervention arm who were showed the video, were more likely to be informed, to select a focus on comfort and less likely to desire CPR and intubation compared to patients receiving the verbal information only. The clinical application of this finding is that advanced care planning video decision needs can stimulate and supplement patient decision communication. Indeed we need such tools to enhance patients understanding of their goals of care options and to ensure that our patients get care that reflects their well-informed wishes.

(6:10) The fourth paper is by first author Dr. [inaudible 00:06:12] and corresponding author Dr. Lloyd Jones and colleagues from the Northwestern University Feinburg school of medicine in Chicago. These authors provided the first prospective evaluation of atherosclerotic cardiovascular disease outcomes in adults with heterozygous familial hypercholesterolemia in the US population. They did this by using individual pool data from 6 epidemiologic cohorts including more than 68,500 baseline person exams and 1.2 million person years of follow up. They confirmed substantially elevated long term, meaning up to 30 year risks of coronary heart disease and total atherosclerotic cardiovascular disease including stroke in US adults with a familial hypercholesterolemia phenotype defined as LDL cholesterol above 190 milligrams per deciliter. This was associated with an acceleration of coronary heart disease risk by up to 20 to 30 years. These findings were independent of other risk factors and were consistent using various definitions of the familial hypercholesterolemia phenotype.

What are the clinical implications of these findings? This was discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an editorial, the take home message is that there is likely an important long term burden of atherosclerotic cardiovascular disease in phenotypic but unrecognized familial hypercholesterolemia patients in the United States. Current efforts to identify patterns and gaps in the diagnosis and management are well justified. The findings also have implications for risk communication to patients.

(8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25] and colleagues of the TIMI study group from Brigham and Women's Hospital. These authors looked at the impact of renal function on outcomes with edoxaban and oral factor 10 A inhibitor with 50% renal clearance compared to warfarin in the ENGAGE AF-TIMI 48 trial. In the pre-specified subgroups of granting clearance 30 to 50 and more than 50 ml per minute. The higher dose edoxaban regiment was comparable to warfarin for preventing stroke or systemic embolism and resulted in significantly less major bleeding. In further exploratory analysis, there was a suggestion of lower relative efficacy for prevention of stroke or systemic embolism with the high dose edoxaban regiment, compared to warfarin in the upper range of creatinine clearance beyond 95 ml per minute. Due to lower rates of major bleeding, the net clinical benefit was more favorable with the higher dose edoxaban regiment across the range of creatinine clearance.

In summary, edoxaban demonstrated superior safety and comparable efficacy to warfarin for the prevention of thromboembolic events in many patients with atrial fibrillation. However the authors were careful to note that there was insufficient evidence to allow definitive conclusions to be drawn in patients with normal renal clearance above 95 ml per minute. The authors called for further investigation of optimal dosing of edoxaban in the higher range of creatinine clearance.

(10:14) Those were our highlights now for our feature paper of the week. Phenotype specific treatment of heart failure with preserved ejection fraction, a multi-organ road map. The first author is Dr. [inaudible 00:10:31] from Northwestern University Feinberg School of Medicine in Chicago and colleagues. To discuss this very special paper today I have two guests, one is a corresponding author, Dr. Walter Paulus from the VU, University medical center in Amsterdam as well as Dr. Jarett Berry, associate editor from UT Southwestern. Welcome Walter and Jarett.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn.

Carolyn Lam: To start us off this is an in depth review paper and it is a really very special type of paper that it's new to Circulation. Jarett could you tell us a little bit about these reviews and how this paper came to be?

Jarett Berry: As we think about the new Circulation and our goals to really make the content of Circulation as clinically relevant as possible, as we think of the different circumstances and clinically challenges faced by practicing physicians, many different topics come to mind and one in particular, therapeutic area heart failure with preserved ejection fraction is one particular type of cardiovascular disorder that has been very difficult to find novel treatments for. As we all know there has been a number of large scale clinical trials that have failed to improve clinical outcomes in these patients, in situations like this what we really need is wisdom and a guide from those with expertise in this area so we can take that wisdom and that perspective and incorporate it into our approach to caring for these patients in a way that can provide a road map moving forward.

This particular review addressing heart failure with preserved ejection fraction was timely in that sense and the choice of author, of course, Walter and his colleagues are leaders in the field in terms of the research and our understanding of HFpEF. With that goal, we're really trying to reach out to these types of investigators for these types of reviews to provide us with a framework to help us think about charging our way forward and we couldn't think of a more appropriate choice to lead that effort other than Walter Paulus.

Carolyn Lam: Thank you so much Jarett, that's so well put and I couldn't agree more. I mean HFpEF is one of those disease syndromes were guidelines haven't changed in years and basically the first sentence is that we don't have outcome improving treatments available. Walter this must have been particularly challenging and I really congratulate you because one of the central figures that I'm so impressed with in this review is actually a clinical application figure and I'm referring to figure 2. Do you think you could tell the readers a little bit more about this?

Walter Paulus: I would like to thank first the editors of Circulation for having given us the opportunity to write this in-depth review. I must admit before answering Carolyn's question that I really enjoy this [inaudible 00:13:37]. We have a very challenging team of co-authors and the most difficult part of the enterprise was to have all the noses directed in the same direction. You have to align very many ideas and it has been a very challenging in-depth but I think it will be teamed out with a, not a compromise but something, a paper where everybody is still happy with its content. This is somehow also reflected in the figure 2 to which Carolyn is alluding.

When we start speaking about the phenotypic diversity, it's very difficult to [inaudible 00:14:13] with a conceptual theme on how we're going to organize therapy when there are many different phenotypes around. I think this is what this figure is all about, it tries to organize the phenotypic diversity and come up with a type of personalized medicine for each phenotype in a very comprehensive way. This figure, in fact, orders the phenotypes, presentation phenotypes and pre-disposition phenotypes with presentation phenotypes on the abscissa and the pre-disposition phenotypes on the ordinate. Then you get a matrix configuration, you start out in the matrix in the left hand corner for the most common phenotype which is metabolic risk combined with [inaudible 00:14:59] congestion. Then you go on and you see that you can have [inaudible 00:15:04] hypertension, then you have additional measures that need to be taken. You can go downwards in the graph and then you'll find out that it might be renal dysfunction and then you find specific measures that have to be taken when renal dysfunction is present.

By combining the ordinate and the abscissa in the matrix, you find a very personalized type of therapy for the individual phenotype. I think this to me what makes the figure that feeling is that it's structured, it's organized, it's something very complex in something which is easily comprehensible.

Carolyn Lam: Walter, I have not seen a figure like this that it's so novel and I know that clinicians will really welcome this because as Jarett so nicely put, it's wisdom and some sort of simplification and yet with in-depth understanding that we so need in the management of this syndrome. Another thing that I thought was very special about your paper is that you tackled head on the divergent results of several recent trials. You described the low nitric oxide, low cyclic guanosine monophosphate cycle that's present in HFpEF but also try to put into context the need trial, the relax trial, top cat and even mention Socrates preserved in all of this. Do you have any quick top line comments, not to give the whole story away because I'm sure readers are now encouraged to look at the paper but on how all of this actually falls into place in your schema.

Walter Paulus: I think how everything falls into place is illustrated in the figure 1. Figure 1 shows a very broad perspective on the problems of HFpEF as it shows HFpEF to be the result of systemic inflammatory state but so far we have focused only on the project manifestations of the systemic inflammatory state [inaudible 00:17:08] cardiac manifestations, which is the stiffness of the myocardium, and the [inaudible 00:17:12] of the myocardium. There are also things going in the pulmonary [inaudible 00:17:16], there are things going on in the skeletal muscle and there are things going on in the kidney. I think that if you do not take these other organs into perspective, then the image you will have from the results of your trials is getting blurred. For instance, we have so many trials about look at the exercise [inaudible 00:17:35] in terms of elevation of [inaudible 00:17:37].

It's my feeling that many patients with HFpEF just get treated diabetic. You see them afterwards again in your [inaudible 00:17:46] patient clinic and they have symptoms of nasal fatigue. They no longer being hindered by the elevation of [inaudible 00:17:52] probably because of the administration of the diabetic but they're still highly symptomatic and they have moved over to another board and that limits the [inaudible 00:18:01] mainly the skeletal muscle. It's of course nicely illustrated already for years by the work of Dalane Kitzman which is one of the co-authors, but still these issues, the same goes for the hypertension, a field in which Carolyn has been very active. There are some patients who are persistent [inaudible 00:18:18] hypertension, I'm intrigued by our classification.

It's clear that these patients have moved to a [three catalyst 00:18:24] type of hypertension and we should pay attention to this and we should try to treat it in a very specific way. Again [inaudible 00:18:33] the failure of our trials is also comprehensible. He have two, [inaudible 00:18:38] focus on the myocardium and we should try to keep a very broad perspective and look at [inaudible 00:18:43] in major broader way. Just to support this point is the result of the Socrates reserve trial which I was very intrigued by it, just listen to the results couple of days ago at the European Heart Failure Society meeting in Florence. Turns out if you give this very [inaudible 00:19:01] patients that there is no change in nature at [inaudible 00:19:05], no change in left atrial dimension, there's no single argument that something is changing in the myocardium. Nevertheless the effort tolerance of the patients was greatly increased and the question is in quality of life, how that has drastically improved? What I think is going on, is that maybe on the dose of the [inaudible 00:19:23] you are using this very [inaudible 00:19:24].

The main effect might be going on the [inaudible 00:19:27] and you just took the wrong end point, you are again focusing very narrowly on the myocardium. I think most of the patients have entered such a trial are relatively stable. You're not going to put in a trial a patient who is unstable, they must be all be treated with diabetics and you shift symptoms from the myocardium to the other organs. I think that the index review which we provide, I think has 2 main issues, that you should have a broad perspective on HFpEF with inclusion of the other organs and secondly, that we provide a matrix configuration for phenotypes specific treatment.

Carolyn Lam: Walter that is beautifully put and Jarett I think I'm speaking on behalf of you too that this paper has really accomplished what our in-depth reviews were aiming to do, which is to provide a clinical perspective and really insightful comments regarding the syndrome. Is there anything else you'd like to add Jarett?

Jarett Berry: Yeah, I just wanted to echo your congratulations and just to really highlight the importance of this figure 2. I think it is an important step for us to begin to take the concept of the heterogeneity the phenotype, whether it's something happening centrally or peripherally and take that heterogeneity and try to incorporate that into our practice pattern. I think that's obviously been discussed in length in literature before but has not been put together in a practical way for practicing clinicians. I just want to echo your comments that Walter and his coauthors have done an important service for all of us as we think about how to take care of our patients with HFpEF.

Carolyn Lam: That's awesome, I think anyone listening is really going to want to take hold of that journal and have a look at both figures, 1 and 2 and read this beautiful paper. Thank you very much Jarett and Walter for your time, today.

Jarett Berry: Thanks Carolyn.

Walter Paulus: Thank you very much Carolyn, [good night 00:21:20].

Carolyn Lam: You've been listening to Circulation on the Run, thank you for listening and don't forget to join us next week for more highlights.



Apr 27, 2016

Carolyn: Welcome to Circulation on the Run. You're weekly podcast summary and backstage pass to the journal. I'm Dr. Carolyn Lam from the National Heart Center in Duke National University of Singapore. I am thrilled to be your host every week. Joining me today to introduce our podcast are two very very special guests. Dr. Joseph Hill from UT Southwestern is editor and chief of Circulation. Hi Joe.

Joe: Pleasure to be here, Carolyn. Carolyn: Thanks, and your second guest, Dr Amit Kara is also from UT Southwestern and the associate editor for digital strategies of Circulation. Hi Amit.

Amit: Hi, Carolyn. Happy to be here. Carolyn: No Joe and Amit, if you don't mind I'm going to start the ball rolling by sharing my little story of how these podcasts came to be. Now do you guys remember when we first talked about this? All right well I do. Joe: Absolutely. Carolyn: Ha ha because frankly, and I don't know if you know this Joe, it wasn't a very good day for me. I had just landed very early in the morning from a long trip and I was battling jet lag while trying to get a million things done such as unpack, clear my mail, get ready for work. You know, the usual. Of course the thing I needed most was to learn that I also needed to do weekly podcasts for Circulation right. So after our chat I did I suppose what a lot of us do when things seem a little bit overwhelming. I dropped everything and I headed for a run in the gym. But in the gym as always I was trying to multitask as well, so I brought my mobile device for my jog so that I could read my mail at the same time, you know. I can already see the smiles of everyone listening because I know you've done this before. Anyone who's done it will know what a pain it is trying to read while you're bouncing up and down on the treadmill. It was just at this point when I was about to go cross-eyed that the radio in the gym started to play the morning news and the news headlines. I remember thinking to myself, oh wow, how I wish I could have someone read my mail or at least the headlines of the mail to me so that I could get the gist of everything even while I was literally on the run. That's how the Circulation podcast idea came to me and hence it's name, Circulation on the Run. To me it's an audio summary of the headlines of the journal so that you the listener can in 15 minutes get caught up literally on the run or drive or whatever it is you're doing when you'd rather listen than read. Just so you know you haven't missed the big things. But in addition to getting an overview of the issues contents every week, you get main take home messages as a clinician. Because it will be dull to talk to myself every week I will be inviting an author, an editor, of a featured article of particular clinical significance so that we can give you a behind the scenes look of the paper. That is the idea of the Circulation podcast. Joe, how does this fit with your vision of the journal? Joe: Carolyn, I love your story behind the scenes on how this all got started and I really, truly appreciate your energy and leadership here. This is such an important endeavor for where we want to take the journal. In fact, your leadership here illustrates one of the major initiatives that we have started and that is a global footprint of editorial oversight for Circulation. We are afforded an extraordinary privilege here to see the best science as it emerges from all around the world and we want to do everything we can to make sure that the journal meets the needs of the clinicians, the practitioners, and the investigators everywhere in the world. Here you are leading this important initiative from your home base in Singapore. That's exactly what we're looking to foster and develop going forward. Carolyn: Oh Joe thanks so much for that. I really so appreciate this privilege of doing this and it's true that I'm a living example of the journal going global so to speak. I also really like the way you say that with this overwhelming knowledge that we're facing, we do need help to synthesize and synergize that information. Especially in the clinically oriented way. I think you made that very clear to us in your leadership of our editorial board. Thanks for that. Maybe speaking of trying to reach the world, social media and digital strategies play a big roll. Amit maybe you could tell us a little bit more about how the podcasts fit in your larger scheme for the journal. Amit: Absolutely and I just want to echo Joe's comments and thank you, Carolyn, for taking the lead of this important endeavor. We couldn't think of a better person to do so. When we look digital strategies we have to remember that the journal is producing so much valuable content. The authors are working very hard and creating such an immense amount of new knowledge. We have to appreciate that people consume knowledge in different ways. In the current era there's so many different ways to do that. One hand we still have the traditional print journal which is incredibly valuable and important. Has depth of information that certainly many and most people would want to investigate. But the other end of the spectrum we have our bite sized information which is Twitter and Facebook and so forth which certainly helps people sort of prioritize or are able to glean what's exciting that week and then they can go back and do a deeper dive. The podcast fits somewhere in between. I love what you said, Circulation on the Run, you're example was a great one for people who are wanting to consume this information but perhaps in a different way. The audio component and also a time component where they have 10 to 15 minutes to take in this information. Your vision for this is a great one. We'll have a brief component where you will review the weekly articles and people can then learn what's in the journal and what's the most important findings and content that week. Similarly they have the opportunity to really get to know an author and get to know some editors and to really get behind the scenes. This backstage pass if you will. We finally have to remember that we're appealing to a broad audience. People of different ages and around the world. People like to consume information in different ways. We really like to have this as an important part of our offering towards helping people consume this information. Carolyn: Oh Amit. I couldn't have said it better. Thank you so much. Just to be true to ethos. Let me remind everyone that it's going to be a 15 minute podcast and we're going to do our very best to compress all that you need to know into those 15 minutes. I just want to echo what you said that this is only part of the broader strategy and it doesn't mean that the print journal is dead in any way. In fact I am so excited to see the new journal. I don't know about you. It's got a whole new look. It is really really quite good looking, if I might say so. Everyone out there, you're going to expect this new journal on June 29th, 2016. Look out for it. Trust me. You won't be disappointed because there's also a very special little part of the cover that I'd like to discuss before we sign off. That is the doodle. Joe could you tell us a little bit more about the doodle? Joe: As you say the journal look I think is fantastic. It has a clean and modern look to it. The judicious use of color to highlight the different types of content, which as before spans a spectrum of basic science, the definition going forward is vertebrate models, pre clinical models, and disease oriented questions. Starting there, traversing through clinical science, population sciences, health services research, the entire spectrum. Again we are afforded an extraordinary privilege here to help frankly shape the future of cardiovascular medicine. We take that responsibility very seriously. That's why we've recruited an extraordinary team of editors from literally around the world. At the same time, we want to have a little fun. We want to make it fun and engaging as well as very very serious. As part of that, we've launched something that we're calling the Circulation Doodle. That is an idea that leverages the website where I think everyone is familiar with. They, based on an event that occurred that day or week or month, they play around with the visual depiction of the word Google. We're going to do the same thing with Circulation. Every month we will reach out and solicit doodles from artists all around the world. Everyone who's listening to this podcast, I encourage you to think about this. Every month there will be a doodle theme. The first one for July will be Texas. Commemorating the fact that the journal headquarters is moving back to Texas after having been in Boston for 12 years. Previous to that it was under the leadership of Jim Willerson. It's coming back to Texas and the first Circulation doodle depicts a Texas theme. In fact, if you're interested you can find this in the April 25th issue of the journal where in the third of four notes from the incoming editor in that third one on April 25th, we show the first doodle. We're asking people to submit doodles according to monthly themes. The month of August will be vacation. I can tell you start thinking about ways in which you might incorporate a vacation theme in the depiction of the world Circulation for August and the one that comes in that's the best, that the editors like the most, it will be placed on the cover of the print journal and on the website for a full month. We've also conceived themes for the rest of the year all the way through to June of 2017, and in the first issue that comes out from our team, we will list those themes and you'll have plenty of time to start thinking about what you would like to submit. Then in subsequent years, those monthly themes will also evolve. We'd like to get people's ideas about issues that come up related to holidays or national heritage months. Things that we might not know about from our base in the US. We want to do that around the world. It's an opportunity to be creative at the level of themes, and again artistic depiction of the word circulation. Carolyn: I love that. Thank you so much Joe and that just exemplifies that we are all about science and all about having fun at the same time. That was a brilliant introduction to what our podcasts are going to be like as well. Thank you so much Joe and Amit for joining me today. Again, everyone, this was Circulation on the Run. Don't forget, first issue coming out 29th June, 2016.

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