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Circulation on the Run

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Now displaying: May, 2018
May 29, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

                                                What do salty, Chinese meals, neurotransmitters, cancer, and pulmonary arterial hypertension have in common? Well, you are not going to want to miss this week's feature discussion. It's going to reveal a new therapeutic approach to pulmonary arterial hypertension that may just surprise you, coming up right after these summaries.

                                                Do congenital heart defects signal a familial predisposition to cardiovascular disease? Well, this question was addressed in this week's first original paper from first and corresponding author, Dr. Auger, from University of Montreal Hospital Research Center in Quebec, Canada. Dr. Auger and colleagues aimed to determine whether the risk of cardiovascular disorders later in life was higher in women who had newborns with congenital heart defects. To answer the question, they studied a cohort of more than one million women who had delivered infants between 1989 and 2013 in Quebec. They showed for the first time that congenital heart defects in offspring were associated with increased risk of maternal cardiovascular morbidity later in life, including atherosclerotic disease, cardiac hospitalization, and cardiac transplantation. The association with subsequent cardiovascular morbidity risk was present for both critical and noncritical congenital heart defects. Thus, women who have given birth to offspring with congenital heart defects may benefit from early attention to traditional cardiovascular risk factors and more aggressive primary prevention strategies.

                                                Acute myocardial infarction, or AMI, is a major cardiovascular complication of non-cardiac surgery, but what are the outcomes following perioperative AMI? This question was answered in the next paper from co-corresponding authors, Dr. Smilowitz and Berger, from New York University School of Medicine. The authors identified more than 8,000 patients who were diagnosed with AMI during hospitalization for major non-cardiac surgery using the 2014 US Nationwide Readmission Database. They found that perioperative AMI after non-cardiac surgery was associated with a high in-hospital mortality and a 19% risk of 30-day hospital readmission among survivors. The majority of hospitalizations after perioperative AMI were because of infectious, cardiovascular, or bleeding complications. Recurrent AMI occurred in 11% of patients re-hospitalized after perioperative AMI. At six months after perioperative AMI, more than 36% of patients were re-hospitalized, and the overall risk of in-hospital deaths was almost 18%. Thus, hospital readmissions and mortality among patients with perioperative AMI pose a significant burden to the healthcare system. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.

                                                What is the recent status of hypertension in China? Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital, Peking Union Medical College, and Chinese Academy of Medical Sciences in China used a stratified, multistage, random sampling method to obtain a nationally representative sample of more than 450,000 residents from 31 provinces in mainland China from 2012 to 2015. The authors found that more than 23% of Chinese aged 18 years or old had hypertension, and that's equivalent to an estimated 284.5 million individuals. The prevalence of hypertension was similar in rural and urban settings, whereas three municipalities, mainly Beijing, Tianjin, and Shanghai had the highest prevalence of hypertension. Almost half the hypertensive population was aware of their hypertension. About 41% were treated, and only 15% achieved a blood pressure control. Among treated patients, barely 32% were prescribed two or more antihypertensive medications. Thus, this study revealed a considerable prevalence of hypertension in Chinese adults, as well as low awareness and control rates, representing an urgent public health message in China.

                                                Patients with systemic sclerosis-associated pulmonary arterial hypertension have a far worse prognosis than those with idiopathic pulmonary arterial hypertension. But why is this the case? In the next paper, from co-corresponding authors, Dr. Hsu and Dr. Kass, from Johns Hopkins University School of Medicine, these authors tested whether the disparity involved underlying differences in myofilament function. They studied cardiac myocytes isolated from the right ventricular septal endomyocardial biopsies from patients with systemic sclerosis-associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, or systemic sclerosis with exertional dyspnea but without pulmonary arterial hypertension. They also looked at control right ventricular septal tissue obtained from non-diseased donor hearts.

                                                They found that right ventricular myofilaments isolated from humans with systemic sclerosis-associated pulmonary arterial hypertension exhibited diminished contractile force and abnormal calcium sensitivity versus control myofilaments. This is in sharp contrast to the hypercontractile compensation in idiopathic pulmonary arterial hypertension. Systemic sclerosis patients with dyspnea and only exercise-induced pulmonary hypertension exhibited an intermediate right ventricular myocardial filament phenotype. These myofilament contractile abnormalities correlated strongly with in vivo right ventricular function at rest and right ventricular contractile reserve during exercise, suggesting a central role of right ventricular myofilament dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.

                                                In summary, these findings uncover key deficiencies in the right ventricles of systemic sclerosis-associated pulmonary arterial hypertension, and these findings suggest that therapies targeted at right ventricular myofilament contractile dysfunction may prove particularly useful for this vulnerable subpopulation. That wraps it up for our summaries. Now, for our feature discussion.

                                                Today's feature paper promises a new therapeutic approach in pulmonary arterial hypertension. We know that pulmonary arterial hypertension is a rare disease, but nonetheless it casts a large shadow because it most commonly afflicts young women and remains a disabling disease. Despite treatment advanced in the last 20 years, high-risk patients still succumb at a rate of 15% annually. Moreover, our most effective therapy is a continuous infusion of parenteral prostacyclin, which is both cumbersome and expensive. Thus, there remains an urgent need for better therapies to improve survival and quality of life. Today's feature paper introduces a novel approach to this.

                                                I'm so pleased to have the corresponding author, Dr. Sylvia Cohen-Kaminsky, from Inserm, Paris, France, as well as associate editor Dr. Charlie Lowenstein, from University of Rochester, to discuss today's special paper. You know, I'm gonna start with Charlie, because you have a way of explaining things and just putting the background to mechanistic papers so well. Could you do that for us, please?

Dr Charlie Lowenstein:  Sure. When I started in research, I worked in a neuroscience laboratory. One of the things we studied was glutamate and its class of receptors. Glutamate, as you know, is one of the major neurotransmitters in the brain. The brain releases small amounts of glutamate, which acts as a messenger, neurons talking to other neurons. But when there's a stroke, the brain releases huge amounts of glutamate, and it's actually toxic and can cause damage, and mediate neuronal damage and cell death. Glutamate is a hot topic in the world of neuroscience. But in the cardiovascular field, people don't know much about glutamate. They don't appreciate glutamate as being important at all. So, I have a question for you, Sylvia. How did you start to get interested in glutamate and its family of receptors?

Dr Sylvia Cohen-Kaminsky:          It started around 2000, and since 2000 we are having some clues about peripheral glutamate receptor in different cells in different organ. But basically, for vascular cells and for the topic of PAH, there was two things that make me thought about it. First of all, it was shown that the NMDA receptor contributes to the proliferation of different cancer cell types. Human tumor cells express the NMDA receptor, then an NMDA-receptor antagonist may inhibit cancer cell growth and migration. We know that pulmonary vascular cells from PAH patients have cancer-like properties. They are also proliferative and resistant to apoptosis, and they have several properties of cancer cells, such as metabolic shift and so on.

                                                In addition, not only neurons in the brain express the NMDA receptor, but also brain microvascular endothelial cells that respond to an NMDA receptor activation by gross production, disruption of endothelial cell barrier, and monocyte transmigration. All these three processes are relevant to PAH development. That's why I thought that perhaps an NMDA receptor is expressed on microvascular cells from the lung, and perhaps we could have a process involving an NMDA receptor in this vascular remodeling.

Dr Charlie Lowenstein:  As you know, there are three flavors of glutamate receptors. How did you discover that there was one particular kind, the NMDA receptor, that was really important for smooth muscle cells?

Dr Sylvia Cohen-Kaminsky:          You are right. We did analysis of mRNA expression, and most of the known receptor in the brain, either metabotropic or ... ionotropic, sorry, indeed expressed in vascular cells and they may cooperate to activate this NMDA receptor exactly as it happens in the brain. We didn't work that on these other receptor, but we are pretty sure they are at work in cooperation with the NMDA receptor. Why though an NMDA receptor? Because it's an ion channel permeable to calcium, and the calcium is an event which can be important in cell proliferation. In addition, the first thing we have shown in these remodeled vessels when we did mass spectrometry imaging was increased level of glutamate and glutamine, its precursor. That was also an additional element that makes us think about this NMDA receptor.

Dr Charlie Lowenstein:  I want to go from the receptor to glutamate. There are three or four amazing things about your paper. One of them is that you suggest that cells in the vascular are releasing glutamate, which is a neurotransmitter. Do you think those are the smooth muscle cells that are talking to other smooth muscle cells by releasing these messenger molecules?

Dr Sylvia Cohen-Kaminsky:          Yes. Smooth muscle cells are talking to other smooth muscle cells. But we also did some work on endothelial cells, and they are also able to release this glutamate. So we think that vascular cells in the vascular wall are discussing together through glutamate, although we don't know yet the normal function of this NMDA receptor in the vascular system. However, in the pathology it's very clear that there is this release. What is very interesting is that this release can be triggered by pathways which are already down-regulated in PAH, such as the endothelin-1 pathway.

Dr Charlie Lowenstein:  Another remarkable part of your observation is that the signaling with glutamate and glutamate receptors is hyperactivated in the setting of a major human disease, pulmonary artery hypertension. How did you figure out that glutamate is so important in this special disease?

Dr Sylvia Cohen-Kaminsky:          Because we showed, as I already told you, this glutamate accumulation in the remodeled vessel. We used this mass spectrometry imaging which allows analysis of metabolites directly in the remodeled vessels from sections performed from extended lengths. We saw this glutamate accumulation together with glutamine accumulation, so the ligand was overexpressed. In addition, when doing western blots from these remodeled tissue dissected from ongoing arteries, we have shown that we have a particular phosphorylation of this receptor which is very well-known in the CNS. This phosphorylation is involved in sending the receptor to the membrane and stabilizing the receptor to the membrane. Having this phosphorylation means that NMDA receptor is engaged, activated in the remodeled vessels in situ.

Dr Charlie Lowenstein:  In an experimental model, you explored the role of glutamate in two very nice, complementary ways. One is with a genetic approach, the NMDA receptor deficiency. The other is using drugs. What were the drugs, what were the pharmacology that you used to block glutamate's transmission, and how did that affect the mice?

Dr Sylvia Cohen-Kaminsky:          We used drugs that are very well known in the CNS. We used two drugs. One is memantine, which is already commercialized for the treatment of Alzheimer's disease. The other one is MK-801, which has been produced initially as a potential pharmacological drug but it was too potent to be used in the CNS. Therefore, this drug is only used in research at the moment. But these two drugs were able to act on this vascular remodeling and a number of PAH parameters. We have explored at least 12 parameters involved in this animal model of PAH, and hemodynamic stable parameters of hemodynamics including intra-arterial pressure, vascular remodeling, right ventricular remodeling with different parameters that shows a certain index. The cardiomyocyte hypertrophy, the fibrosis, the inflammation inside the right heart and around remodeled vessels, all these parameters were modified by the drug.

                                                In addition, in vivo we have shown the destruction of the NMDA receptor glutamate axis with decreased engagement of the NMDA receptor in pulmonary arteries by following this phosphorylation I mentioned, decrease of apoptosis resistance and also proliferation. This was shown also after the treatment with the drugs, and also decrease of endothelial cell dysfunction that could be followed in the blood through selecting those H.

Dr Charlie Lowenstein:  Your results with this drug were really impressive. I love that part of your study. You showed when you block glutamate signaling, first of all, the blood vessels looked much better in a model of pulmonary artery hypertension. In an experimental model, blocking glutamate transmission really improved the way the vessels look. But secondly, what was really amazing was, normally in humans one of the big problems with pulmonary artery hypertension, as you said, is the right ventricle gets inflamed and fibrotic, and a lot of patients die from complications of right ventricular dysfunction. In your model, when you treat with MK-801, blocking glutamate receptor, the right ventricle looks a lot better. It was really an impressive part of your study.

Dr Sylvia Cohen-Kaminsky:          I think that this is view on the effect of the vessels themselves, then the right heart can recover. But we may have a direct effect in the heart. If you remember this Chinese restaurant syndrome, when you eat too much Chinese food, which is full of glutamate, you have some cardiac involvement, arrhythmia, and so on. Initially, toxicologists thought that it passed through the central nervous system. But then they realized that maybe the NMDA receptor is expressed in cardiac cells, and indeed it is expressed and is colocalized with the ryanodine receptor, meaning that it could have a function in the heart as well. But this has, of course, to be explored precisely. We know from the transplantation that, when we transplant on with the lung, the heart can recover very well. We may have these two effects. One due to the relief on vascular remodeling, and the other perhaps a direct effect on the heart.

Dr Carolyn Lam:                You know, I have to chime in now. That cuts too close to home with the Chinese food and glutamate. First and foremost, I just really have to say, Charlie and Sylvia, it's people like you who make basic science come alive and simply extraordinarily exciting. Taking glutamate, something that we've talked about in the context of Chinese food and neurotransmitters, and therefore showing the potential to even repurpose perhaps some drugs for pulmonary arterial hypertension. So let me just round up by asking you, what do you think our next steps, how far are these findings away from clinical application? Perhaps, Charlie, your thoughts?

Dr Charlie Lowenstein:  While I think that the use of MK-801 to treat excess monosodium glutamate during a Chinese meal, maybe that's a little bit premature. I'm much more excited about the idea of using glutamate-receptor antagonists to treat or prevent or even reverse pulmonary artery hypertension, both its vascular and cardiac complications. I'd love to ask Sylvia, do you think these medications in this class, do you think NMDA-receptor antagonists are ready for clinical trials?

Dr Sylvia Cohen-Kaminsky:          In fact, they are not ready as they are. We have a program in which we have designed hypothesized new NMDA-receptor antagonist that do not go to the brain, because we want that treating PAH has to be safe, and we don't want to interfere with brain system. So we created this new NMDA-receptor antagonist that do not go to the brain. At the moment, we are in the process of the documentation. We have two patents for two series of molecules, and we expect the drug conjugate by the end of this year. To reconjugate means that we have a number of properties on this drug, the pharmacokinetics, metabolism, selectivity profile, toxicity, and so on. We are doing all this physical chemical properties, and of course validation of these new molecules in the animal models as therapy alone and also as add-on therapy with existing therapies, such as these vasodilators. We hope that we can have an additive effect between an NMDA-receptor antagonist and current PAH drugs.

Dr Charlie Lowenstein:  Sylvia, as you know, drug companies about 10 or 20 years ago invented all these amazing glutamate-receptor antagonists to treat central nervous disease like stroke. One of the amazing things about your discovery is you're suggesting that glutamate receptors in the periphery are great targets as well. The exciting thing about your observation is you're really opening up new therapeutic approaches for targeting neurotransmitters in the periphery. I think your discoveries are tremendously exciting and could open up new avenues in treatment of a disease, pulmonary artery hypertension, for which there really aren't effective therapies right now.

Dr Carolyn Lam:                I couldn't have said it better. Thank you so much, Charlie. Thank you so much, Sylvia.

                                                See, listeners? Aren't you glad you heard it here right on Circulation on the Run? Don't forget to tune in again next week.

 

May 22, 2018

Dr Carolyn Lam:                Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.

                                                The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.

                                                Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.

                                                In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.

                                                Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.

                                                The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.

                                                The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.

                                                No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.

                                                The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.

                                                And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.

                                                And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.

                                                Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D’Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study?

Dr Virginia Triant:             As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.

                                                So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.

                                                We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk.

Dr Carolyn Lam:                Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you?

Dr Ralph D’Agostino:      After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.

                                                And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.

                                                But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions.

Dr Carolyn Lam:                Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see?

Dr Bongani Mayosi:         Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.

                                                When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort.

Dr Carolyn Lam:                That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings?

Dr Bongani Mayosi:         I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future.

Dr Virginia Triant:             I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.

                                                One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons.

Dr Carolyn Lam:                That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think?

Dr Ralph D’Agostino:      I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.

                                                Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions.

Dr Carolyn Lam:                Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.

                               

May 14, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.

                                                Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.

                                                Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.

                                                They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.

                                                The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.

                                                From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.

                                                The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.

                                                The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.

                                                The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.

                                                RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.

                                                Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.

                                                The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.

                                                They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.

                                                That brings us to the end of our summaries. Now, for our featured discussion.

                                                Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.

                                                I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.

                                                Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find?

Dr Robin Mathews:         The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?

                                                We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.

                                                ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.

                                                What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.

                                                We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.

                                               

                                                What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.

                                                When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.

                                                We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant.

Dr Carolyn Lam:                What a detailed summary. Thanks so much.

                                                Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful?

Dr Jeptha Curtis:               It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.

                                                I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.

                                                What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.

                                                As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.

                                                All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.

                                                What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals.

Dr Carolyn Lam:                Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that?

Dr Sandeep Das:               Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.

                                                One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."

                                                I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems.

Dr Carolyn Lam:                Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US?

Dr Robin Mathews:         Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."

                                                Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.

                                                In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.

                                                At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts.

Dr Sandeep Das:               One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?

                                                The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive.

Dr Robin Mathews:         Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.

                                                I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.

                                                At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them.

Dr Carolyn Lam:                Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.

                                                Thank you so much for listening today, and don't forget to tune in again next week.

May 7, 2018

Dr Joseph Hill:                    My name is Joe Hill. I'm the Editor-in-Chief of Circulation and I'm very pleased today to be here today with Professor Daida from Juntendo University in Tokyo, Japan, as well as one of our associate editors, Professor Shinya Goto from Tokai University in Kanagawa, Japan. Dr. Daida is one of the senior authors on a very exciting clinical trial that we're publishing in Circulation. The first and largest trial comparing high-dose versus low-dose statins in Asia. Dr. Daida, would you please tell us more about the study?

Dr Hiroyuki Daida:            Yes. Thank you. The trial, called REAL-CAD, is a randomized trial. We compare high-dose statins with low-dose statins in Japanese patients with stable coronary artery disease. The number of the patients is 13,000. It's the largest trial ever comparing high-dose and low-dose statins. We found that with that reduction of the primary end point, which is a composite end point, including cardiovascular death, non-fatal MI, non-fatal stroke, and unstable angina requiring hospitalization.

                                                That is very exciting result because it is the largest trial ever and also the very first trial in Asia.

Professor Shinya Goto: Congratulations, Professor Daida, for that great achievement, in the REAL-CAD trial. Could you explain a little bit about the background and that the dose of statins in Japan is generally low, and what was the reason why we kept using low-dose statins, and is care to try change the standard of care in Japan and also East Asia? Could you give a comment on those two topics?

Dr Hiroyuki Daida:            Our trial is quite similar to that of PNP trial of comparing Western extensive statin treatment and the Asia statin treatment. However, that extensive statin treatment, intensive statin treatment, is not popular in Asia, so we did that maximum clinical dose of statin, we use this dose in Japan. It is the maximum dose of statin approved in Japan.

Dr Joseph Hill:                    So as I understand it, the rationale was the thinking that Asians, East Asians, are unable to tolerate high-dose statin therapy. In this case you used pitavastatin. And, in fact, what you found was there were no increase in serious adversive events in high dose patients. And, just like Caucasians, they derived considerable benefit at multiple points in atherosclerotic cardiovascular disease metrics.

Dr Hiroyuki Daida:            Actually, they didn't experience a really high-dose of statin in Japan so government approval is up to 4 mg of pitavastatin, a dose of that about 20.

Dr Joseph Hill:                    So, this is not what we would call high-intensity statin therapy but nonetheless, there was a dramatic benefit including an all-cause mortality, irrespective of the starting LDL level at the beginning of the trial?

Dr Hiroyuki Daida:            That is right. We found that the effect is similar that the patient, the LDL is greater than 95 or less than 95. So, the effect is independent of the basal based on LDL level.

Professor Shinya Goto: The one thing, very exciting just like Joe mentioned, all cause of mortality, especially known cardiovascular caused mortality reduced with the use of high-intensive care of the statin. If any kind of speculation, what is the cause, reduce the inflammation or maybe reduce cancer, something like that. They have any kind of advance to an analysis?

Dr Hiroyuki Daida:            We didn’t have further analysis but we are not so keen to emphasis the total mortality because maybe that is a chance of the effect but this is the largest trial, so the result is really exciting in this kind of aspect.

Dr Joseph Hill:                    So, I would reiterate Shinya’s congratulations. This is a monumental piece of work. The largest clinical trial comparing high dose versus low dose statin. The largest ever. The first in Asia. You found a benefit that makes total sense across what we know from other trials and this will change practice. Your work, I believe, will change the way patients with atherosclerotic cardiovascular disease is handled in Japan.

Dr Hiroyuki Daida:            Yes, actually the current guideline in Japan for the secondary condition. The condition is LDL less than 100 and for the really high-risk secondary condition listed seventh. We didn't recommend high-dose statin initially, so, this trial result is kind of like this, changing.

Dr Joseph Hill:                    I can't resist asking, what comes next? What's your next project?

Dr Hiroyuki Daida:            Maybe we need to have a further reduction of LDL. We have another drug, other potent drug recently. We need to investigate all of the new drug such as PCSK9 inhibitor in secondary prevention.

Professor Shinya Goto: That's wonderful. Do you have any time to extend observation of the trial? I think the trial is relatively still superior as compared to the global long-standing trial. Really, that's fine, that effect of statin on the cholesterol and even it's different from Japan and other regions of the world. There ought to be intriguing thing, I would like to know, what are you waiting to extend that observation now?

Dr Hiroyuki Daida:            Fortunately, we do not intend to extend the follow-up. The whole thing is about four years but we do not plan to extend. We will further analyze the data for some group and our kind of CRP and effect of the baseline.

Dr Joseph Hill:                    Lots of secondary analysis underway, undoubtedly. Let me thank both of you for being here, Professor Daida and Professor Goto, I congratulate you again. It's not often that you make a practice-changing intervention in modern-day medicine. I salute you and we are honored and thrilled to publish your outstanding work in Circulation. Thank you both.

Dr Hiroyuki Daida:            Thank you very much.

Professor Shinya Goto: Thank you very much.

 

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