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 issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries.
The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP.
In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure.
We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis.
The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening.
Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention.
The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy.
The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival.
The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion.
Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper.
I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared.
Dr Mandeep Mehra: The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics.
The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics.
Dr Carolyn Lam: Nice! And now drumroll, please tell us what you found in your brilliant study this week.
Dr Mandeep Mehra: First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis.
The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices.
We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3.
Dr Carolyn Lam: Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this?
Dr Biykem Bozkurt: First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant.
Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost.
Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot?
Dr Mandeep Mehra: Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility.
For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there.
The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt.
Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices.
Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms.
At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well.
Dr Carolyn Lam: How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem?
Dr Biykem Bozkurt: It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable.
Dr Carolyn Lam: Wow, that's amazing. How about you, Mandeep, what do you think?
Dr Mandeep Mehra: Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult.
There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted.
Dr Carolyn Lam: I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation.
Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.
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. The ORBITA Trial of percutaneous coronary intervention and stable single vessel coronary artery disease has to be one of the most hotly discussed in the cardiology world. The featured paper of this week adds important knowledge that will help us understand the physiology stratified results of ORBITA.
Coming right up after these summaries.
The first original paper this week provides novel mechanistic insights that may lead to a new treatment approach for obesity and hypertriglyceridemia. Co-corresponding authors, Drs Xiang and Xia from Central South University of Xiangya in China, looked at Reticulin 3, which is an endoplasmic reticular protein that has previously shown to play a role in neurodegenerative diseases.
In the current paper, the authors show that over-expression of Reticulin 3 in mice induced obesity and a greater accumulation of triglycerides. Remarkably, increased Reticulin 3 expression was also found in patients with obesity and hypertriglyceridemia. They further showed that Reticulin 3 played critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Thus, these results suggest that inhibiting the expression of Reticulin 3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia in the future.
The next study provides insights into the genetic determinates of residual cardiovascular risk in patients already receiving statins. First author Dr Wei, corresponding Dr Denny from Vanderbilt University Medical Center and their colleagues performed a genome-wide association study and identified that a variation at the LPA Locus was associated with coronary heart disease events during statin therapy and independent of the extent of LDL cholesterol lowering. The association of the LPA Locus with coronary heart disease events persisted in individuals with an LDL cholesterol less than 70 milligrams per deciliter. These findings, therefore, provide support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce coronary heart disease events in patients already receiving statins.
The next paper provides important mechanistic results that help us understand pathways in atherosclerotic plague regression. Co first authors, Drs Mueller and Zhu, corresponding author Dr Fazio from Oregon Health and Science University and their colleagues have previously shown that mice lacking an LDL receptor with beta protein 1 in macrophages undergo accelerated atherosclerotic plague formation. However, in the current study they sought to explore the role of macrophage LDL receptor protein 1 during plague regression. They did this by placing EPO E deficient mice on a high fat diet for 12 weeks, then reconstituting their bone marrow using wall type or macrophage LDL receptor protein 1 deficient mice as donors, and finally switching them back to a chow diet for 10 weeks. The authors found that the lack of LDL receptor protein 1 expression in macrophages unexpectedly caused more atherosclerosis regression. Mice with macrophages lacking LDL receptor protein 1 showed less M1 macrophages in the plague and increased CCR7 dependent egress of macrophages from the plague. Thus, loss of macrophage LDL receptor protein 1 has a dual and opposite effect on plague biogenesis, depending on whether the plague is growing or shrinking.
The next paper highlights the intercalated disc, which is a specialized intercellular junction, coupling cardiomyocyte electrical activity in forced transmission as a mechanosensitive signaling hub for causative mutations in cardiomyopathy. First author Dr Trembley, corresponding author Dr Small from University of Rochester School of Medicine and Dentistry and their colleagues showed that myocardin related transcription factors associated with desmosome proteins of their intercalated disc in both murine and human hearts. Genetic deletion of myocardin related transcription factors in cardiomyocytes led to rapid onset of dilated cardiomyopathy in response to pressure overload hypertrophy. Furthermore, myocardin related transcription factors were required for the maintenance of sacromere and intercalated disc integrity under pathological stress. These findings, therefore, provide a unique link between the intercalated disc and mechanosensitive transcriptional regulations. Since myocardin related transcription factors redistribute from intercalated disc in human heart failure, this may represent a novel signaling complex present in cardiomyopathic characterized by desmosome dysfunction.
The next paper investigated the association of blood pressure with peripheral arterial disease events, using data from the ALLHAT Trial. Co first authors Drs Itoga and Tawfik, corresponding author Dr Chang from Stanford University School of Medicine and their colleagues found that both lower systolic blood pressure of less than 120 and higher systolic blood pressure of above 160 millimeters of mercury were both associated with higher rates of peripheral arterial disease events. Diastolic blood pressure less than 70 and a pulse pressure above 65 millimeters mercury were also associated with increased rates of lower extremity peripheral arterial disease events. Given that the recent revised blood pressure guidelines advocate lower systolic blood pressure targets for overall cardiovascular risk reduction, the authors called for future, further refinement of optimal blood pressure targets, specific for peripheral artery disease.
The final original paper this week provides the first integrated atherosclerotic disease risk calculator to incorporate risk factors including high sensitivity C reactive protein, family history, and coronary artery calcium data. First and corresponding author Dr Khera from UT Southwestern Medical Center and colleagues used 3 population-based cohorts to develop Cox Proportional Hazards Models for the outcome of atherosclerotic cardiovascular disease. The derived Astro-CHARM model incorporated factors like age, sex, systolic blood pressure, total and HDL cholesterol, smoking, diabetes, hypertension treatment, family history of myocardial infarction, high sensitivity c reactive protein, and coronary artery calcium scores. The model performance was validated externally in a 4th cohort, and shown to improve risk prediction compared with traditional risk factor equations, and showed good discrimination in calibration in the validation cohort. A mobile application and web based tool was developed to facilitate the clinical application of this tool, and is available at www.astrocharm.org.
And that brings us to the end of this week's summaries. Now for our featured discussion.
Gosh, I am learning for the first time today that it's terribly inconvenient to lose my voice when I am a podcaster. This is Carolyn Lam and our featured discussion that I am so excited about, but the cool thing is the thing we are talking about is so hot that you don't even need me to say anything. And what we are talking about is the ORBITA Trial. That was greeted with as much hype and hoopla and sensationalism since its publication in 2017. I am so proud to have the first and corresponding author Dr Rasha Al-Lamee from National Heart and Lung Institute Hammersmith Hospital in London. I also have Dr Ajay Kirtane from Columbia University Medical Center in New York Presbyterian Hospital and the Cardiovascular Foundation in New York as the editorialist for the paper. And finally, our associate editor Dr Manos Brilakis from UT Southwestern. Rasha, why don't you just take it away and just tell us, what is your paper focusing on in this week's issue?
Dr Rasha Al-Lamee: The paper that was published in this issue in circulation is basically our second analysis of the ORBITA Trial, a substudy analysis. Essentially, looking at the primary endpoint and the secondary endpoints of ORBITA, and having a look at those patients from ORBITA and seeing whether there was any association between their invasive physiological assessment using FFR and ISR at the pre-randomization stage and seeing whether the level of ischemia on ISR or FSR was associated or predicted in the way in which they performed in terms of their endpoints. To see whether there was any difference in the placebo control efficacy of angioplasty in those patients who have more or less severe ischemia on their invasive physiological assessment.
Dr Manos Brilakis: First off, that's a phenomenal paper, and I think she puts things into perspective. I know Ajay put an excellent tutorial. I think all of us were surprised about the findings. You would expect that the more ischemia, that you might see a little more response. Any thoughts as to why there wasn't such an association?
Dr Rasha Al-Lamee: I think it's so difficult because, of course, as we all know from the primary paper that was published in The Lancet, in terms of the primary endpoint, which would be change in exercise time and the difference between the two groups, the difference is actually much smaller than we expected. And when we have such a small difference in exercise time, the ability to be powered enough to be able to split that endpoint based on stratification of invasive physiology becomes very difficult, and we're perhaps underpowered to be able to do that.
Where we did see a very great effect in terms of the primary assessment in The Lancet paper was in stress echo ischemia. What we saw is those patients who had angioplasty were far more likely to have an improvement, or indeed, a normalization of their ischemia on their stress echo. Where we saw a big difference the two groups we were then clearly powered to be able to stratify those patients based on their invasive physiology, and for that secondary endpoint we saw that, in fact, tied to your stenosis or the lower your ISR or FRR, the more likely you are to have an improvement in stress echo, having had placebo controlled angioplasty.
Dr Manos Brilakis: Ajay, I know you had a lot of things insight into the vision of the tutorial for the ORBITA Trial. What are your thoughts about the findings?
Dr Ajay Kirtane: I would, first of all, congratulate Rasha and the ORBITA team, there are others, for not only doing the main trial, but for conducting these detailed analyses, which were clearly set up ahead of time, and that's been one of the critiques of the trial is why were patients with normal-ish range FFRs included. Well, part of it was to test this hypothesis, and perhaps to show that there would be a correlation between the change in the FFR, if you will, and the endpoints that were measured.
So, I think that that's the first part, that this is actually a scientific experiment, and a thoughtful one in doing so. I think exactly as Rasha said though, if there is a limited signal, with respect to the overall trial, then further subsetting is less likely to show a significant signal. I think that's exactly what the investigators found. The only other comment I would make though is, I would commend Rasha and the team for producing other analyses that are novel in this manuscript including the freedom from angina analysis, as well as responding to some of the earlier critiques of the trial and not using specific methodologies to adjust the baseline differences improves. Those are also included in this analysis.
Dr Manos Brilakis: Yeah, absolutely, I think that was very enlightening to see, the freedom of angina. And I know there was some questions whether that might change the overall findings from the studies, so there is some quality of life benefit. Rasha, what is your thoughts about this? I mean, you must understand this study better than anyone else. People who have stable angina, should they undergo PCI or not?
Dr Rasha Al-Lamee: I think the freedom from angina signal was very important, and obviously not something that we had pre-specified, so it wasn't reported in the primary analysis. We're obviously much more able now, since we've published that primary analysis to do secondary analyses and look at things that perhaps we haven't pre specified. And it's interesting to see that 20% more patients are free from angina having had angioplasty vs. placebo. Having said that, to me, it's a fantastic finding, but still a little unexpected. Much less than we might expect looking at unblinded data, or our unblinded clinical experience. I would have expected much higher levels from freedom of angina.
Dr Rasha Al-Lamee: I think what we know, and what we've seen both from this paper, very importantly, and also the primary manuscript, is that the efficacy of angioplasty is very tightly linked to the improvement in ischemia. We've actually, in fact, got more papers that are coming out from our group recently. And that you can predictably tell your patients that if I sense a lesion that's causing a reduction in ISR or FFR, and potentially symptoms, then I will improve your ischemic burden.
What I think is more tricky is how much I will relieve your symptoms, or make you feel better. That may be because symptom assessment itself is very tricky, and perhaps that actually just diagnosing cardiac angina is actually a very difficult thing. The easiest way to piece out improvement in symptoms is to find those patients who become free of angina because, of course, that's the binary end point. When we look at grades of symptoms, and whether their angina frequency improves, or whether the level of angina improves in terms of PCI, then I think it becomes much harder, especially in a blinded trial where, of course, when people come back, even with atypical chest pain, it will still be recorded as potentially angina because, of course, both the investigators and the patients have no idea what they've had done, which is quite different from real life where, of course, you are able to think more about whether this chest pain might indeed be from the heart or from other causes.
Dr Manos Brilakis: Perfect, thank you very much. And I would completely agree with you that, the study was perfect. And, as Ajay said, it is something that we needed, and more of them should be done. And I think you are right that this is the best way to piece out the symptom improvement.
Ajay, any final comments?
Dr Ajay Kirtane: I think that the toughest challenge with trials like this is to really enroll the patients that many of us as interventionists feel would really improve in terms of their symptom class. Even despite these efforts, if one looks at the baseline of anginal frequency in the trial, the means are relatively high, which suggest that the anginal burden, at least in terms of measurements through the anginal questionnaire is not that severe. One could argue that somebody has severe angina that is occurring all the time, that those are types of patients that are hard to randomize in a clinical trial.
I think, at least my overview stepping back perspective of the context of ORBITA within clinical practice, is exactly that. The trial is an important scientific advance, but this does not encompass the answer for every single patient that comes to see us in the office that have a range of symptoms, very severe to less severe. That was something Rasha has been saying all along as well. It's not something that we could over extrapolate this to every patient that we see. So, I think that when the hype dies down, these types of scientific analyses will stand out. They emphasize the need for regular clinical research, and in that way, I think has generated a lot of attention not only to the clinical field here, but also the scientific pursuit of evidence. That's a really magical thing.
Dr Rasha Al-Lamee: I think, if I can add to that Ajay, I think it's probably also sort of the assessment of symptoms is incredibly important. I think many of us, and I'll include myself in this, when we see a very tight stenosis, are happy to essentially correlate any level of symptoms to that tight stenosis. One thing I've learned from all this, I want to see reproducible angina that very much is textbook, cardiac caused chest pain, and the atypical anginas we see, perhaps some of that pain is not from that stenosis, but from somewhere else. Therefore, by fixing that stenosis, we don't necessarily make that pain go away.
Dr Manos Brilakis: Absolutely, and I think you are absolutely, if it is something simple vessel disease, if it's something a little more straightforward, then I think you are right Ajay, that this is much harder, multiple vessel disease especially in people with reduced ejection fraction.
Dr Carolyn Lam: You've been listening to Circulation on the Run! Don't forget to tune in again next week!
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. Will artificial intelligence replace the human echocardiographer? Aha, well to find out the answer, you have to wait for the incredibly exciting discussion of today's feature paper coming right up after these summaries.
The clinical benefits of the cholesterol ester transfer protein, or CETP inhibitor dalcetrapib depends on adenylate cyclase type 9, or ADCY9 genotype. However, what are the underlying mechanism responsible for the interactions between ADCY9 and CETP activity? In the first paper from today's journal first author Dr Rautureau, corresponding author Dr Tardif from Montreal Heart Institute, and colleagues used a mouse atherosclerosis model inactivated for ADCY9 and demonstrated that loss of ADCY9 protected from atherosclerosis and was associated with improved endothelial function, but only in the absence of CETP. ADCY9 in activation increased weight gain, adipose tissue volume, and feed efficiency, but only in the absence of CETP.
This mouse model reproduced the interactions between ADCY9 and CETP activity observed in patients, and offers new mechanistic insights for the importance of ADCY9 in determining the responses to CETP inhibition. For example, the dal-GenE clinical trial is currently testing prospectively whether patients with coronary disease and the favorable ADCY9 genotype will benefit from dalcetrapib.
The next study addresses the controversy around the cardioprotective effects of Omega-3 polyunsaturated fatty acids, and uncovers signaling pathways associated with eicosapentaenoic acid, or EPA supplementation that may mediate protective effects in atherosclerosis. First author Dr Laguna-Fernandez, corresponding author Dr Bäck from Karolinska Institute, and their colleagues showed that EPA supplementation significantly attenuated atherosclerotic lesion growth. They performed a systematic plasma lipidomic analysis and identified that 18 monohydroxy eicosapentaenoic acid was a central molecule formed during EPA supplementation. 18 monohydroxy eicosapentaenoic acid was a precursor for the plural resolving lipid mediator called resolvent E1.
In the present study, a resolve in E1 was shown to regulate critical atherosclerosis related functions in macrophages through its downstream signaling receptor to transfuse protective effects in atherosclerosis.
Are there racial differences and long-term outcomes among survivors of in-hospital cardiac arrest? In the next paper first and corresponding officer Dr Chen from University of Michigan and her colleagues performed a longitudinal study of patients more than 65 years of age who had an in-hospital cardiac arrest and survived until hospital discharge between 2000 and 2011 from the National Get With The Guidelines Resuscitation Registry whose data could be linked to Medicare claims data. They found that compared with white survivors of in-hospital cardiac arrest, black survivors had a more than 10% lower absolute rate of long-term survival after hospital discharge. This translated to a 28% lower relative likelihood of living to one year, and a 33% lower relative likelihood of living to five years after hospital discharge for black versus white survivors.
Nearly one-third of the racial difference in one-year survival was dependent on measured patient factors. Only a small proportion was explained by racial differences in hospital care, and approximately one-half was the result of differences in care after discharge, or unmeasured confounding. Thus, further investigation is warranted to understand to what degree unmeasured, but modifiable factors, such as post-discharge care may account for the unexplained disparities.
The next study provides insights into a novel mechanism of atherogenesis that involves protease-activated receptor 2, a major receptor of activated factor 10, which is expressed in both vascular cells and leukocytes. Co-first authors Dr Hara and Phuong, corresponding author Dr Fukuda from Tokushima University Graduate School of Biomedical Sciences, and their colleagues showed that in ApoE-Deficient deficient mice, protease-activated receptor 2 signaling activated macrophages and promoted vascular inflammation, increasing atherosclerosis.
Furthermore, they showed that in humans, plasma-activated factor 10 levels positively correlated with the severity of coronary artery disease, suggesting that the signaling pathway may also participate in atherogenesis in humans. Thus, the protease-activated receptor 2 signaling pathway may provide a novel mechanism of atherogenesis and serve as a potential therapeutic target in atherosclerosis.
The next paper tells us that biomarkers may help to predict specific causes of death in patients with atrial fibrillation. First and corresponding author Dr Sharma and colleagues from Duke Clinical Research Institute evaluated the role of biomarkers in prognosticating specific causes of death among patients with atrial fibrillation and cardiovascular risk factors in the ARISTOTLE trial.
They looked at the following biomarkers: high sensitivity troponin T, growth differentiating factor 15, N-terminal pro-B-type natriuretic peptide, and interleukin 6. They found that sudden cardiac death was the most commonly adjudicated cause of cardiovascular death, followed by heart failure and stroke or systemic embolism deaths. Biomarkers were some of the strongest predictors of cause-specific death, and may improve the ability to discriminate among patients' risks for different causes of death.
How do the complement and coagulation systems interact in cardiovascular disease? Well in the final original paper this week, first author Dr Sauter, corresponding author Dr Langer from Eberhard Karls University Tübingen, and their colleagues used several in vitro, ex vivo, and in vivo approaches as well as different genetic mouse models to identify the anaphylatoxin receptor C3AR and its corresponding ligand C3A as platelet activators that acted via intra -platelet signaling, and resulted in activated platelet fibrinogen receptor GP2B3A. This in turn mediated intravascular thrombosis, stroke, and myocardial infarction. This paper, therefore, identifies a novel point of intersection between the innate immunity and thrombosis with relevance for the thrombolic disease of stroke and myocardial infarction.
That wraps up with week's summary. Now for our featured discussion.
Can we teach a machine to read echocardiograms? Well today's feature paper is going to be all about that. I am so excited to have with us the corresponding author of an amazing, and I think, landmark paper, Dr Rahul Deo from the One Brave Idea Science Innovation Center and Brigham and Women's Hospital in Boston, as well as our associate editor Dr Victoria Delgado from Leiden University Medical Center in The Netherlands. Now let me set the scene here. We know that echocardiography is one of the most common investigations that we do in cardiology, and in fact even outside of cardiology, and it is hands down the most accessible, convenient tool to image the heart.
Now let's set this up by remembering that echocardiograms are performed with machines, but led by echocardiologists like me. Now this is really scary Rahul because I think your paper is trying to say ... Are you trying to put people like me out of business?
Dr Rahul Deo: Definitely not. I think what I'm hoping to do is actually two things. One of them is, despite the fact that it's an accessible and safe tool, because it needs people like us, it's probably not used as often as ideally it could be. So part of our hope was to democratize echocardiography by being able to take out some of the expenses from the process so that we can hopefully get more simpler studies done at an earlier stage in the disease process. Because in many ways, at least from my experiences being an attending, it feels like if we could just have gotten to these patients earlier we may have been able to start therapy that could've changed the disease course, but our system can't really afford to do huge numbers of echoes on asymptomatic patients. Really we were trying to find some way of facilitating this by at least helping out on trying to quantify some of the simple things that we do with echocardiography.
Dr Carolyn Lam: I love that phrase, democratizing echo. And you're absolutely right, if we could put it in the hands of non-experts and help them interpret them, we could really lead to detecting disease earlier, and so on and so forth. Wow. But everyone's wondering, how in the world do you go about doing that?
Dr Rahul Deo: One of the things that's really been amazing in these last five years or so is that the field of computer vision, so the field by which computers are trained to mimic humans in terms of visualizing, recognizing, identifying images, has really advanced, and incredibly rapidly. And one of the reasons for that is that the video game type of computing system, the same things that go into Playstations and such, have resulted in much, much more rapid computing. And that's allowed us to train more complex models.
So that's one of the things that's changed, and also, it's just much easier to get our hands-on training data. So machines can be trained to do things, but they need lots of examples. And the harder the task, the more examples they need. So the widespread availability of digital data has made that easier, though I would say that it wasn't that easy to get our hands on enough echocardiography data to be able to train. But in general, almost any task where there's enough data has been solved on the computer vision side. So this has really been an exciting advance in these last few years. So we thought we could very well just used these same technologies on a clinical problem.
Dr Carolyn Lam: Okay, but Rahul what are you talking about here? Like the machine's actually going to recognize different views, or make automated measurements? That's the cool thing, frankly, that you've written about because we know that the machines can already kind of do EF, ejection fraction, but you're talking about something way bigger. So tell us about that.
Dr Rahul Deo: Yeah, so there are many cute examples in the popular press about machines being able to recognize the differences between cats and dogs, or some breeds of dogs. And so if you think about things that way, it really shouldn't be that much more difficult to imagine recognizing between different views, which probably are much more dramatically different than different breeds of dogs. So you could really just take the same models, or the same approaches, give enough examples, label them, and then say figure out what the differences are.
And I think one of the challenges with these systems is they're often black boxes. They can't tell us exactly what it is that they're using, but when it comes to something like recognizing whether something is an apical four chamber view or a parasternal long axis view, we actually don't care that much as to how it is that the computer gets there. We just wanted them to do it accurately, and that's one of the places for some of these computer vision models. It's a field broadly called deep learning, and it's just great at achieving complex tasks.
So, once you recognize views, then the other thing that computers have been shown to be able to do is recognize specific objects within an image. For example, you could give an entire football field and you could find a single player within it. You could recognize where the players are, where the ball is, where the grass is. So computers can distinguish all those things too. And then once you know where something is, you can trace it and you can measure it. So in that sense it's very similar to what a human reader would do, it's just broken down into individual steps, and each one of those needs to be trained.
Dr Carolyn Lam: You put that so simply so that everyone could understand that. That's so cool. You mentioned, though, accuracy. I could imagine that a machine would likely interpret one image the same way again and again, and that addresses something that we really struggle with in echo doesn't it? Because, frankly, one reader against another, we always know. Ejection fraction has got a plus minus seven or something, and then even within the same reader you could read the same thing and say something one day, and say something the other. So this is more than just automating it, is it?
Dr Rahul Deo: Yeah, so it's certainly making it more consistent, and the other thing that we were able to do, I mean once you can teach it to identify and traces the contours of the heart in one image you can have it do it in every single image within the video, and every single video within the study. So now, I mean it's quite painful. I know this from my own experience in terms of tracing these things, so a typical reader can't trace 150, 200, 300, 500 different hearts, that's not going to happen. So instead, they'll sort of sift through manually, pick one or two, and if there's variability from one part of the study to the other, that really won't be captured.
And in this case, the computer will very happily do exactly what you ask it to do, which is to repeat the same thing again and again and again, and then be able to average over that, capture variability. So that's one of the tasks that is much more easy to imagine, setting a computer who won't talk back to you and won't resist and won't refuse to actually taking on the mundane aspect of just getting many, many, many more measurements. And that could happen not only in a single study, but also could happen more frequently. So you could imagine that, again, there's just not that resistance that's coming from having to have an individual do these things.
Dr Carolyn Lam: Oh, my goodness, and not only does he not ... well he, machine, not say no, I mean they don't need to take time off or weekends off. We could get immediate reports directly. Oh my goodness. Victoria I have to bring you in on this. We knew as editors when we found this paper that this is something we just have to publish in Circulation that's going to be groundbreaking. Could you tell us a little bit more about what you think the implications of this is?
Victoria Delgado: I think that this is a very important paper because it's a very large study and it's sets, I would say, three important questions that we deal every day in clinical practice. One is how to reduce burden in very busy echo labs by facilitating the reporting of the echoes and the interpretation of the echoes. Second: to have an accurate measurement and quantification of the images that we are acquiring, and third: this is recognition of the pattern.
And I think that this very important, particularly in primary care because, for example in Europe here, echocardiography is not really in the primary care and the patients are being referred to secondary level hospitals or third level hospitals. That means that the waiting days sometimes is too long. If we train the general practitioners, for example, to do simple echocardiograms with the handheld systems which are also the technologies that are coming and are really available in your iPhone, for example, on your phone, you can get an echocardiographic evaluation of a patient that comes to a general practitioner.
And if you don't have too much knowledge on interpretation, these tools that can have recognition of the pattern of the disease can trace a red flag and say, okay this patient may have this disease or may have this problem, you should consider sending or referring this patient to us at Leiden Hospital where he's going to have a regular check-up and a complete echocardiogram. That could lead to less burden in very busy labs and only refer the patients in a timely manner to the centers when they have to be referred, when the others can wait of can be referred much later.
I think that that's important, and next two technologies that are coming now and it will be very important, some groundbreaking technologies. One is the handheld systems, the ones that you can have in your phone, the ones that you can have in your tablet for example. And the other one is going to be the artificial intelligence to, if not diagnose completely, at least to recognize the pattern that there is a pathology where we need to focus, and we need to act earlier.
Dr Rahul Deo: I think that one place we would like to see this used is in a primary care setting where you have individuals who have risk factors that we know would be risk factors, for example, for let's say heart failure with preserved ejection fraction. But really, my experience in that phase of clinical practice is there's a lot of resistance from patients to get on the medications. So hypertension is, at that point, often, I just got worked up because I had a hard time finding parking, and so on, and so on, where there's just a natural resistance.
So if you could imagine having objective measures describing, let's say how their left atrium is doing at that point, how it looks the next year, what the change in therapy is doing, all these things, you actually can bring in that quantification at a low enough cost that makes it actually practical, then that would be one place we could imagine motivating or intensifying therapies on the basis of something like this.
And I think one area we have to admit we didn't solve is we haven't solved the ability to facilitate getting the data in the first place. We do know that there are these focused workshops around trying to get some simple views, and more and more of our internal medicine residents are able to get some of these, but we can't dismiss that this is still an important challenge in terms of being able to get the images. What we want to do is say, well you can get some images and we can help you interpret them and quantify in an effort to try to motivate therapies being initiated or intensified in a way that's sometimes difficult to do in the current system.
Dr Carolyn Lam: So, Rahul and Victoria, you both mentioned that one of the key aspects is the acquisition of the echo. Not just the machine that does it, but also who takes the images that will then be automatically analyzed. So, Rahul, do you think that sometimes you're going to invent something that will replace even the acquisition, or maybe even simplify it so that we may not need Doppler anymore?
Dr Rahul Deo: One of the things that we thought about was, we wanted to limit ourselves to views that might be easier to acquire, in part because we wanted to reduce the complexity of the study and yet still try to capture as much information as possible. And getting back to the first part of your question, you could imagine that recognizing a view is not that different from recognizing that a view is 10 degrees off from where it should be. You could imagine training a computer to do just that very same thing too. It could recognize a slightly off axis apical four chamber view and guide you into correctly positioning the probe, and you could even imagine a robotic system that does this and just takes the person out of it all together. In part because a very skilled sonographer can quickly look at something and say, oh I just need to tilt my wrist this way and move it this way. I was always humbled by that because I never could quite do that myself.
But in the same way, and in the way, that's happening is that an image is recognized, and then the reference image is held in one's brain, and then they just know from experience what needs to be done to turn one into the other. But that very well-oiled machine could very well be taught to do that exact same thing too.
Dr Carolyn Lam: Oh wow. That is just totally amazing. I know the listeners are being blown away by this just as I am. Let me just end by asking for any last words, Victoria and Rahul, of the clinical application of this. When are we going to have this primetime? What do you think?
Victoria Delgado: I think that this is coming. This is one, for example, of the first studies showing the feasibility of this technology. In terms of accuracy, probably we need improvement, but that depends very much on the quality of the echocardiographic data that we obtain. And in the future, I think that we are going to rely more and more on this technology, and we will have the expert view for those cases that are ambiguous or where the technology has limitations. But in terms of accuracy, for example, I can imagine one of the clinical scenarios that we face in everyday clinical practice is the evaluation of the effect of the treatment in heart failure patients for ejection fraction, and in patients, for example, treated with chemotherapy to see changes in ejection fraction.
That, if we do it manually as we do now, we know that we have limitations in terms of the own viability of the observer. If you leave it for artificial intelligence, maybe that viability may be reduced, and you may be better in terms of adjusting the medication if needed. Because you removed completely what would be the individual viability. So these are the fields that probably I see more and more application of this technology in order to improve the reproducibility of the measurements and accuracy. But yeah, for that we need probably very good image quality, and I see in echocardiography we always tend to say, yeah the image quality is not that good. I'm sure that echocardiography can give you much more than just using through the echocardiography. You can use contrast, you can use many other techniques in order to improve the image quality. And artificial intelligence, the better the image quality is, probably the better it's going to be as well, the accuracy of the measurements and the recognition of disease.
Dr Carolyn Lam: Wow, and Rahul?
Dr Rahul Deo: I completely agree with Victoria. I think that we're going to have to be clever about where we incorporate something like this into the current clinical workflow. You have to choose your problem carefully, you have to understand it. Any system like this is going to make some mistakes. To figure out how to minimize the impact of those mistakes, and at the same time add benefit and potentially enable things that wouldn't even be done. So I think that the fun stuff is yet to come here in terms of really incorporating this in a way that can really change clinical practice.
I want to add one thing that I really haven't mentioned. And we, at this point, really just focused on trying to mimic the stuff that we're already doing. Part of the motivation of this work is to try to potentially see things that we can't even see right now and try to potentially predict onset of disease or early latent forms of something that would really be difficult to detect by the human eye. And we've seen examples of that in some of the other fields around radiology, and I think that's going to be a place that would be augmenting beyond what we're even doing currently.
But of course, the challenge is that the system has to be interpretable enough that we understand what it is that it's seeing, because otherwise I'm sure we'll be reluctant to embrace something clinically that we don't understand.
Dr Carolyn Lam: You've been listening to Circulation on the Run. Don't forget to tune in again next week.
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. Sacubitril-valsartan reduces the risk of cardiovascular mortality among patients with heart failure with reduced ejection fraction. However, what are its effects on kidney function and cardiac biomarkers in people with moderate-to-severe chronic kidney disease? Well, stay tuned to find out, as we will be discussing the results of the UK Harp III Trial, right after these summaries.
The first original paper this week reveals that inhibition of a long non-coding RNA may serve as a novel molecular therapy for aortic aneurysms. First author, Dr Li, corresponding author, Dr Maegdefessel from Technical University Munich, and colleagues, identified the long non-coding RNA H-19 with functional relevance in experimental aortic aneurysm progression in two mirroring models, a novel genetically mutated mini-pig model, as well as end-stage human disease. They found that H-19 mediated expression levels of the transcription factor hypoxia inducible factor 1-Alpha. Which, in the chronic hypoxic environment of an aneurysm, triggers apoptosis in aortic smooth muscle cells. This study, therefore, introduces inhibition of H-19 as a novel molecular therapy to limit smooth muscle cell death in progressing aortic aneurysms.
The next study provides insights into molecular mechanisms underlying heart failure progression in chronic pressure overload. Co-first author, Dr Chiang and Alsina, co-corresponding authors, Dr Heck, from Utrecht University, and Dr Wehrens, from Baylor College of Medicine, and their colleagues developed a novel and unbiased way to comprehensively study protein phosphatase 1 or PP1 interactors in a mouse model of progressive heart failure induced by elevated afterload. This so-called PP1 interaction enabled simultaneous interrogation of multiple pathways relevant to heart failure pathogenesis. They found nine specific PP1 interactors that were strongly associated with heart failure progression. Among these, the PP1 regulatory subunit 7 was shown to play a central role by regulating the PP1 interaction, and by acting as a competitive molecular sponge of PP1.
In clinical trials of direct oral anticoagulants for atrial fibrillation, patients with end stage kidney disease on dialysis were excluded. Today's study answers the question, "What are the outcomes with Apixaban in dialysis dependent end stage kidney disease patients with atrial fibrillation?"
Co-corresponding authors Dr Siontis and Dr Saran from University of Michigan and their colleagues performed a retrospective cohort study of Medicare beneficiaries included in the United States Renal Data System from 2010-2015. All eligible patients were those with end stage kidney disease and atrial fibrillation undergoing dialysis who had initiated treatment with an oral anticoagulant.
In prognostic score-matched analysis, Apixaban was associated with lower rates of major bleeding compared with Warfarin, whereas there was no difference in stroke or systemic embolism. Patients on standard dose of Apixaban of 5 mg had a lower rate of stroke and death compared to those on reduced dose Apixaban of 2.5mg. Thus, Apixaban may be associated with superior safety and comparable effectiveness outcomes as Warfarin in dialysis patients with atrial fibrillation. However, these findings require confirmation in a randomized trial setting.
Does Canagliflozin have benefits in people with chronic kidney disease, including those with an Estimated Glomerular Filtration Rate, or EGFR, between 30 and 45, in whom the drug is currently not approved? First author Dr Neuen, corresponding author Dr Perkovic from the George Institute of Global Health, and their colleagues performed a secondary analysis of the CANVAS Program to describe outcomes in participants with and without chronic kidney disease, as well as according to baseline kidney function as measure by EGFR.
They found that the effect of Canagliflozin on HbA1c was progressively attenuated at lower EGFR levels, but blood pressure and body weight reductions were comparable. The reduction in risk of major adverse cardiovascular events, hospitalization for heart failure and progression of kidney disease appeared similar across different levels of kidney function, down to an EGFR of 30. Safety outcomes were also mostly consistent, but the risk of hypoglycemia may increase as EGFR declines.
That wraps it up for our summaries, now for our feature discussion.
Cubitalis-valsartan improves outcomes in patients with heart failure with reduced ejection fraction, and we know that from the Paradigm trial, but what about its effects on kidney function and cardiac biomarkers in people with chronic kidney disease?
Well, this week's feature paper provides important randomized trial data addressing this question. To discuss it, we have none other than the first and corresponding author, Dr Richard Haynes from University of Oxford, as well as our editorialist for the paper, Braden Manns and Matthew James, both from University of Calgary and in addition, we have Dr Justin Ezekowitz, associate editor who manages paper, and Justin is from University of Alberta.
Welcome gentlemen, we have a full house. Richard, could you start by sharing about your trial and your findings?
Dr Richard Haynes: So, the trial was called UK Harp-III, and it was really a pilot trial, just to work to investigate the effects of Cubitalis-valsartan on patients with chronic kidney disease, and in particular to see what it did for their kidney function in the short term, and also what it did to other measures of interest like their blood pressure and cardiac biomarkers.
It was a randomized control trial double blind, among just over 400 people with chronic kidney disease, and we compared Cubitalis-valsartan with Irbesartan, which is standard of care for most of these patients. Our primary outcome was really to look at the effects of these drugs on kidney function when it was being precisely measured in hospitals. We found, actually, that Cubitalis-valsartan had very similar effects to Irbesartan on kidney function. So, there was no real difference in kidney function at any point in the trial between patients who were allocated the Cubitalis-valsartan or those allocated Irbesartan.
Dr Carolyn Lam: Richard, the way you described it I'm sure you're prepared for this question so why Irbesartan as the control versus Valsartan?
Dr Richard Haynes: That's a very good question and a question asked quite often. There were six of one and half a dozen of the other. We could have chosen Valsartan. The difficulty with that is that Valsartan doesn't have a license indication for the treatment of chronic kidney disease so if we found a difference people might have said we just chosen an inferior comparator, so we chose Irbesartan because that does have an indication for the treatment of proteinuria kidney disease and obviously that leaves us open for the question about how different Valsartan and Irbesartan are. My opinion is they might be subtly different, but I don't think the difference is big enough to really impact these results in any meaningful way.
Dr Carolyn Lam: Indeed, and I know Braden and Matthew you have thought about it a lot. Congratulations on the beautiful editorial. I love the way you set the context in the heart failure world where perhaps we have noted something different with regards to kidney function. Would either of you like to start the ball rolling with discussing that?
Matthew James: Sure, this is Matthew James. So really the Paradigm Heart Failure Trial is a very important place to start in thinking about the effect of these medications on kidney function. That was a very large trial that did report changes in estimated Glomerular Filtration Rate and did show a small but statistically significant change in kidney function between the Sacubitril-valsartan arm and the control arm. There are many potential mechanisms for that, but it is important to realize that there were limitations in the population specifically around chronic kidney disease due to the level of kidney function that the patients were enrolled in to the study. So, some of the patients with more advanced chronic kidney disease wouldn't have been included in the Paradigm Heart Failure Trial so this trial is actually giving us more information about patients with kidney disease who we would expect to be at higher risk of seeing progressive loss of kidney function or progression of their kidney disease.
Dr Carolyn Lam: Thanks for setting that up and just to clarify for the audience here so in Paradigm EGFR went down to 30 right, and here in UK Harp we are talking about measured GFR down to 20. Am I right?
Dr Richard Haynes: Eligibility was actually determined by the EGFR, the estimated GFR.
Yeah it went down to 20, up to 60. We also had a much more proteinuria in the patients in Paradigm.
Dr Carolyn Lam: Right, and do you have a take Richard on why the results seem different from at least the secondary analysis that Milton Packer wrote about on its effects on kidney function in Paradigm?
Dr Richard Haynes: I do have a take. I'm really interested to hear what Braden and Matthew thought. My take was that probably when you've got heart failure one of the major determinants of how well your kidneys work is actually how well your heart is working. That is probably one of the major determinants in that setting and because we know Sacubitril-valsartan has such beneficial effects on cardiac function in people with heart failure perhaps it's not surprising that it then is protected by kidney function a little bit better than people given Enalapril in Paradigm. However, in UK Harp III, we had a group of patients whose kidney had very definite kidney disease and probably the determinants of kidney progression quite different and having any impact on their heart function probably wouldn't really be noticed because the effect of their kidney disease would outweigh that. Perhaps, Sacubitril-valsartan doesn't have any beneficial effects on the kidney itself. As far as we can tell, from what is a relatively small and a relatively short trial.
Dr Carolyn Lam: Justin, I mean you come from the heart failure world too just like me. What was your take?
Dr Justin Ezekowitz: I think there are a number of features here we should take a step back and think about. Number one is as Richard outlined there is a lot more proteinuria here than would typically be seen in a heart failure related population. So, the comparator between the two groups, while similar in overlap while co-manage these patients is somewhat different in terms of what the result we are looking for. So, you know, it brings to mind that what we look at in the secondary analysis in for example Paradigm, is simple EGFR creatinine changes versus here we are looking at a much more sophisticated measure of GFR plus also looking at a comparator that is known to reduce proteinuria and I would say stabilize or not change or prevent their progression of renal disease in the larger trials in the renal population. So, it's a slightly different population, a slightly different comparator as well. The importance in the choice of comparators becomes really important when we are looking for this specific effect.
Now, to Richard's point, which he opened with, which is talking about this as a pilot project to a larger outcome trial, it is hard to know whether or not the effects that Richard and his team on the NT-proBNP, troponin, and other effects would play out in the larger cardiovascular outcomes trial that would be potentially different results than simply a GFR change or proteinuria change. I would be interested in Richard's thoughts on that and Matt and Braden's as well.
Matthew James: Maybe we can also get add another question to Richard which this was a really well-done study and you talked about it being relatively small and certainly by heart standards this was a relatively small pilot study with a limited duration of follow up. By kidney standards, this is a fairly this would be a usual sized clinical trial and so getting all these patients in the trial was a wonderful result to start with and while the study wasn't directly looking at safety of these medications, there is some I think assurance we have some tolerability data at least with this medication and the challenge as Richard would well know in managing patients with chronic kidney disease once they developed more advanced chronic kidney disease GFR is less than 30 is often difficult to use medications because of side effects, high potassium, and things. The most challenging types of patients we see are patients with lower levels of kidney function and with low ejection fractions. So at least this paper provides some hope that we've got a medication that is reasonably well tolerated in that population.
I think that when Richard talks about this being a pilot study where a lot of patients, in fact patients with chronic kidney disease are much more likely to die from heart disease than they are to develop end stage renal disease. For many types of patients that is true at least. So, we are often thinking about what medications could be used to improve cardiovascular outcomes. So, in that sense, again given that the majority of the structural heart disease is not necessarily reduced heart function but is left ventricular hypertrophy I'm sure, and perhaps Richard has some comments as to the next study that might be considered given this medication seemed tolerable. It didn't have the effects that were perhaps hoped on progression although in the Paradigm sub study there was only a difference of 0.5 ml per minute and they were powered to detect 3 ml per minute in this study but actually the immediate hemodynamic drop was about 3 ml per minute and then kidney function was relatively stable thereafter. So hard to imagine this study would have showed a difference in kidney function now in retrospect but potentially this opens up some additional studies to look at cardiovascular outcomes in patients with chronic kidney disease who don't have reduced ejection fraction.
Dr Richard Haynes: I think that's a really good point. I think it would be fascinating to see the results of the Paradigm Trial with Sacubitril-valsartan in patients with heart failure and preserved ejection fraction. Nevertheless, I think this trial does raise the hypothesis that this might be a drug that could improve regardless of whether it has any effect on the kidney or not. It could be possibly be used for improving cardiac outcomes but I just don't think the trial that we've done is enough to justify that at the moment. I think it's a good indicator that it may well work, but I think before anybody could recommend that with much enthusiasm I think it would require a large outcomes trial but focusing quite rightly on cardiovascular outcomes in people with chronic kidney disease which as Matthew said is actually the major burden of disease in those patients.
Dr Justin Ezekowitz I think the question remains though is if as a pilot trial at that time as a longer-term trial would there be any difference because the mechanism of action of Sacubitril is different from that of Irbesartan and that was also shown in the nice table you have in the supplemental file which talks about the Sacubrital lapse concentration going up with the lower GFR's. So, there is the potential for those small subgroups where the GFR is lower they may have a substantial benefit over a longer period of time, not measured necessarily by GFR but measured by clinical outcomes. I think that is where the balance of getting the pilot trial versus a longer follow-up clinical outcomes trial is really important to get.
I may actually just state one other thing or two. First, it's really important to investigate or initiate a trial and this is one of critical parts of why we do clinical trials. Medicine tests the effects initially a pilot and then hopefully a larger trial.
The second is the importance of randomization here. We all think that the shiny new medications are important but getting randomization in trials like this done are really advanced knowledge, so we know what to do with the medication if we are faced with it or if we want to make an important choice for a patient that we can really make a point for the patient that we will base it on the best scientific knowledge.
The third point that I would just come back to something else that we have not talked about yet is this overall is a neutral trial. There are no major effects that were seen but the importance of getting a neutral trial done and published is really critical as this advances the field potentially, so others can now decide what to do and perhaps launch larger trials with cardiovascular outcomes or decide to do a different comparator or different other tasks forward. So, this one we emphasize it is critically important to get these types of trials done and then published.
Dr Carolyn Lam: You know Justin, I couldn't have said it better and completely echo your words. We are so proud to be publishing your paper Richard and that beautiful editorial in circulation. So, I'm just going to wrap up then because in the absence of better data at the moment what is the main take home message of this trial for patients with CKD right now and their care providers. I would love to start with Braden because you wrote about it in the editorial as well. What do you think of the take home messages?
Braden Manns: Well again I think that we often struggle when peoples GFRs are in the 20 to 30 range with identifying a medication that's tolerable particularly in the context of people with reduced ejection fraction. I must say personally I would now be comfortable using this medication in patients with reduced ejection fraction who remain symptomatic who have GFRs in the 20 to 30 range. Those patients aren't that common but feel comfortable now using that type of medication there despite the fact that most patients weren't necessarily enrolled in the Paradigm study. A much larger population though of patients with structural heart disease but not reduced ejection fraction who have chronic kidney disease. It is not clear to me where this medication fits in the armamentarium. As Justin says it certainly wouldn't use this in preference to an ace inhibitor or an angiotensin receptor blocker at this point. So, it's hard to know where it fits without some larger studies looking at cardiac outcomes.
Matthew James: I agree with Braden. I think we are already seeing this medication now enter practice here in Canada. There is this overlap in population between the patients with kidney disease and impaired left ventricular ejection fraction, so this is actually very helpful for us when we see these patients in practice around the appropriateness of continuing these medications in this patient population.
Dr Justin Ezekowitz: So, I think it's critically important to remember the take home message here is to do proper clinical trials and then do again the large trial because without that would not really advance in knowledge. There could be a huge value to a newer medication or potentially the old ones are still just as good as we if we continue them safely.
Dr Richard Haynes: I'd like to echo what everybody said already really. I mean I think what Justin just said trial is the key. We can't get away from the need for randomized control trials. I'm pleased that we've managed to deliver this one. In terms of a clinical take home message I think if I was a patient with kidney disease and heart failure, especially with reduced ejection fraction, I hope that I would feel a bit more comfortable to take this drug now knowing is it going to benefit me from a cardiovascular point of view it doesn't seem it is going to do my kidneys any harm either. So, hopefully it will reassure more patients that they can yield the benefits of a trial this drug has.
Dr Carolyn Lam: Great stuff! Thank you so much gentlemen. This has been such an enlightening conversation.
Thank you very much to audience for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
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.
FDG-PET CT was recently introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, can we improve on its diagnostic performance? Well, to learn more you have to listen to the upcoming featured discussion, right after these summaries.
Our first original paper this week describes a potential novel therapy for hypertension. In this study from first author Dr Hu, corresponding author Dr Soong, from Yong Loo Lin School of Medicine National University of Singapore, authors showed that galectin-1 is a key regulator for proteasomal degradation of CaV 1.2 channels. L-type CaV 1.2 channels are known to play crucial roles in the regulation of blood pressure. In a series of elegant in vitro and in vivo experiments, the authors showed that galectin-1 promotes CaV 1.2 degradation by replacing CaV-beta and thereby, exposing specific glycines for polyubiquitination. This mechanistic understanding provided the basis for targeting CaV 1.2 galectin-1 interaction and demonstrated the modulatory role that galectin plays in regulating blood pressure. The study, therefore, offers a potential novel approach for the therapeutic management of hypertension.
Direct oral anticoagulants or DOACs, are surpassing warfarin as the anticoagulant of choice for stroke prevention in non-valvular atrial fibrillation. However, DOACs outcomes in elective peri-procedural settings have not been well elucidated and remain a source of concern for clinicians.
The next paper in today's issue was a meta-analysis designed to evaluate the peri-procedural safety and ethicacy of DOACs versus warfarin. For author Dr Nazha, corresponding author Dr Spyropoulos, from the Feinstein Institute for Medical Research in Northwell Health at Lenox Hill Hospital in New York, reviewed the literature for data from phase three randomized controlled trials comparing DOACs with warfarin in the peri-procedural period among patients with non-valvular atrial fibrillation. Sub study from four trials were included namely RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF. The short-term safety and ethicacy of DOACs and warfarin were not different in patients with non-valvular atrial fibrillation peri-procedurally. Under an uninterrupted anticoagulation strategy, DOACs were associated with a 38% lower risk of major bleeds compared to warfarin.
The next paper presents results from the Sarcomeric Human Cardiomyopathy Registry or SHARE, which combined longitudinal data sets curated by eight international hypertrophic cardiomyopathy specialty centers to provide a better understanding of the factors that contribute to heterogeneous outcomes in lifetime disease burden in patients with hypertrophic cardiomyopathy. First and corresponding author Dr Ho from Brigham and Women's Hospital and colleagues analyzed longitudinal clinical information on 4,591 patients with hypertrophic cardiomyopathy. By examining the data set spanning more than 24,000 patient-years, the mortality of patients with hypertrophic cardiomyopathy was shown to be 3-fold higher than the general population at similar ages. The lifetime cumulative morbidity of hypertrophic cardiomyopathy was considerable, particularly for patients diagnosed before age 40 years and patients with sarcomere mutations. Atrial fibrillation and heart failure were the dominant components of disease burden. Thus, young age of diagnosis and the presence of sarcomere mutations are powerful predictors of adverse outcomes in hypertrophic cardiomyopathy. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.
The final original paper this week provides molecular insights into atherosclerosis and it shows that defective base excision repair of oxidative DNA damage in vascular smooth muscle cells promotes atherosclerosis. Now, we know that atherosclerotic blocks demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine lesions. In today's paper, first author Dr Shah, corresponding author Dr Bennett from University of Cambridge and colleagues studied levels of 8-oxoguanine and its regulatory enzymes in human atherosclerosis. They found that human plaque vascular smooth muscle cells showed defective nuclear 8-oxoguanine repair, associated with reduced acetylation of the base excision repair enzyme 8-oxoguanine-DNA-glycosylase-1. Furthermore, correcting the base excision repair defect in vascular smooth muscle cells alone markedly reduced plaque formation, thus indicating that endogenous levels of oxidative DNA damage in vascular smooth muscle cells promoted plaque development.
And that brings us to the end of this week's summaries. Now for our feature discussion.
Prosthetic valve endocarditis is a life-threatening complication. However, making a timely diagnosis of prosthetic valve endocarditis before the occurrence of severe complications is really difficult. Now, FDG-PET CT has recently been introduced as a new tool for the diagnosis of prosthetic valve endocarditis. However, previous studies reported only modest diagnostic accuracy and may have been hampered by confounders. But today's study, our feature study in Circulation, addresses this issue. We have none other than the corresponding author, Dr Ricardo Budde from Erasmus Medical Center in Rotterdam, the Netherlands, and our dear associate editor, Dr Victoria Delgado, who is in Leiden University Medical Center, also in the Netherlands.
So please tell us, how does your study help us address this issue of the accuracy of FDG-PET CT
Dr Ricardo Budde: What we actually did is that of course endocarditis is a relatively rare disease, so we had six hospitals in the Netherlands that collaborated on this study and in each of the hospitals we searched for PET CT scans that were performed in patients with a prosthetic heart valve, either because they were suspected of having endocarditis, or if they were meant for other purposes, for example oncological follow-up. Then we grouped all those CT scans together, interpreted the PET CTs anew by dedicated interpreters, and then compared the findings with the actual diagnosis in the patient, which of course is always difficult in endocarditis because to make the diagnosis is difficult. So, also, one year follow-up period was included in that to be absolutely certain whether the patient had endocarditis or not. By taking this whole cohort of patients, we were able to determine the diagnostic accuracy of PET CT, as well as by using a logistics model, identify confounders which influence the diagnostic accuracy of PET CT.
I think the study that we did addresses several important aspects and the way it helps physicians in actually interpreting and implementing PET CT to diagnose endocarditis is two-fold. First of all, we identified confounders that have to be taken into account when interpreting and using the PET CT. For instance, low inflammatory activity at the time of imaging and the use of surgical adhesive during a prosthetic heart valve implantation are confounders which should be taken into account when interpreting the PET CT. Furthermore, the guidelines have always insisted on not to use or use it very cautiously PET CT within the first three months after prosthetic heart valve implantation. However, we showed that actually this period after implantation does not necessarily have to be taken into account as also a good diagnostic accuracy can be obtained within the first three months after implantation.
Dr Carolyn Lam: Ricardo, that's wonderfully put. I don't do a CT, PET CT, routinely. In fact, I am echocardiologist and it used to be that infective endocarditis was diagnosed with echo. So Victoria, tell us, how does echo stand now with this information?
Dr Victoria Delgado: That's a very good question but I think the guidelines set a very clear figure of how the diagnostic workup of patients with prosthetic valve endocarditis should be performed. An echocardiography is the first imaging technique. The point is that transthoracic echocardiography in patients with suspicion of prosthetic valve endocarditis is very challenging. In terms of ideal, echocardiography is probably the best imaging technique to do first to evaluate whether it is endocarditis or not. It's difficult, we have to take into account that for a specific prosthetic valve, particularly mechanical, the shadowing can make that we don't see the [inaudible 00:10:22] and sometimes it's difficult, particularly in the early phase immediately after implantation, all the inflammation can be confounder for presence of endocarditis. In those cases, I think that this study provides additional and important data highlighting which are the confounders when you use PET CT to evaluate depressions of endocarditis. I think that, when you take into account those confounders, the accuracy of this technique is very good in order to make or help in the diagnosis of these patients. So, echocardiography, I think that will remain as our first imaging technique to rule out [inaudible 00:11:10] we can see but in those cases where the diagnosis is not confirm or rule out with transthoracic and transesophageal echocardiography this study provides additional data and important data showing that PET CT is a valuable complementary imaging diagnostic test for these patients.
Dr Carolyn Lam: Ricardo, would you agree with that because I think your study also emphasized that perhaps FDG-PET CT should be implemented early in the diagnostic workup to prevent the negative confounding effect of the low inflammatory activity? So how do we put this all together?
Dr Ricardo Budde: Well actually, I agree with Dr Delgado that echocardiography is and should be the first-line test that you do if you have a patient that has a suspicion of endocarditis. I mean, the advantages of echocardiography are many and it's non-invasive, it's bedside-available if needed, it's patient-friendly, and it provides a huge amount of information so you should always start with echocardiography. However, sometimes it can be difficult by echocardiography, for the reasons just explained by Dr Delgado, and I think then PET CT should be considered. And when you want to do a PET CT, then you should do it early within the diagnostic workup.
Actually, in the article, one of the figures is a flow chart which we provide, and it provides information on how we think PET CT can best be implemented in the workup of endocarditis. In this flow chart we also start with doing an echocardiography and also, importantly, consult the endocarditis time to make initial classification of whether it's a rejected, possible, or definite prosthetic heart valve endocarditis. After that, you can follow the flow chart and see when you can best implement PET CT, in our opinion.
Dr Carolyn Lam: Indeed Ricardo, I am so glad you brought up this figure and listeners, you have to take a look at it. I can imagine that everybody will be using this and discussing it and how to incorporate this in the workflow. And indeed you do start with either transthoracic or transesophageal echo and blood cultures, so thank you for clarifying that.
Now, for our clinicians out there, are there any situations you may be telling us to be a little more careful? Could you put it simply for us when it comes to the FDG-PET?
Dr Ricardo Budde: You mean when not to perform a PET CT?
Dr Carolyn Lam: Yeah, or when we have to be really careful about inaccuracies.
Dr Ricardo Budde: I think, of course, the confounders that we indicate in the article, especially if bioglue has been used by the surgeon during the initial surgery. We know that bioglue can be seen on a PET CT as a false positive uptake of FDG and it's also important to note that this is a phenomenon that can persist for a very long time after a valve implantation. It could be for years, so especially that I think is a very important confounder to take into account and be careful when you interpret PET CT or use the PET CT and always read the original surgical report if it is available to obtain this information.
Dr Carolyn Lam: That's wonderful advice. Victoria, do you have anything to add?
Dr Victoria Delgado: No, I think that Dr Budde explained perfectly this figure that is key in the article and also how to evaluate patients with suspected endocarditis of prosthetic valve. One thing that sometimes we forget is starting from the first step that is a good clinical history which includes also a good evaluation of previous history and, if possible, what has been done in the patient. I think that this key information to understand the findings on the echocardiography, transthoracic or transesophageal, and the subsequent investigations that you are going to perform. Either CT which is considered, for example, when you have a definitive prosthetic valve endocarditis and you want to rule out potential complications such as abscess, for example, and if you perform a PET CT or other imaging modalities that then also indicate the presence of infection like, for example, [inaudible 00:15:26] leukocytes with PET, for example.
Dr Carolyn Lam: And I just want to end up with one little point. Ricardo, how about the fact that part of your results don't corroborate the ESC guideline recommendations that they say you have to avoid FDG-PET in the recently implanted prosthetic valve. How do you feel it's going to play out for clinicians?
Dr Ricardo Budde: Well, I think the 2015 ESC guidelines on endocarditis are a very important document. One must take into account that the inclusion of PET CT in the ESC guidelines was a major step, and some might say that it was a little premature to include the use of PET CT because the number of data that was out there were still relatively limited. I think it's something that we are learning along the way. Now that we are using PET CT more often we are more aware of what we do to findings that we get and also the findings that we have within specific timeframes after the implantation of a prosthetic heart valve. One of the things that I think is desperately needed also at the moment is to have a prospective study where we would do PET CT in patients after implantation of a prosthetic heart valve that do not show any signs of endocarditis where we do PET CT just to determine these normal uptake values. I think that would be a major contribution to the whole learning experience that we're currently having with implementing PET CT within prosthetic heart valve endocarditis.
Dr Carolyn Lam: Indeed, and Ricardo your paper has added significantly to our understanding. Readers, remember, it's Figure 6 of our feature paper this week. It is a beautiful figure. Pick it up, take a look. In the meantime just thank you so much Ricardo and Victoria for joining me today.
Listeners, don't forget to tune in again next week.