Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: December, 2017
Dec 26, 2017

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 feature paper today focuses on LDL cholesterol results from non-fasting samples and a personalized novel method of LDL cholesterol estimation that you will surely want to know about. So stay tuned, coming up right after these summaries.

                                                The first paper provides new evidence that RUNX1, a gene intensively studied in the cancer and blood research fields, has a critical role in cardiomyocytes following myocardial infarction. Co-first authors, Dr. McCarroll and He, corresponding author Doctor Loughrey and colleagues from University of Glasgow generated a novel tamoxifen-inducible cardiomyocyte-specific RUNX1-deficient mouse and showed that RUNX1-deficient mice were protected against adverse cardiac remodeling post-MI, maintaining ventricular wall thickness and contractile function. Furthermore, these mice lacked eccentric hypertrophy and their cardiomyocytes exhibited markedly improved calcium handling.

                                                At the mechanistic level, these effects were achieved through increased phosphorylation of phospholamban by PKA and relief of sarcoplasmic reticulum calcium pump inhibition. Thus, these data identified RUNX1 as a novel therapeutic target with translational potential to counteract the effects adverse cardiac remodeling post-MI.

                                                The next paper invites us to consider that some our resource-intensive quality improvement initiatives may not be fulfilling their intended goals or even justify their costs. In this paper by first author, Dr. Kutty, corresponding author, Dr. Chan and colleagues from St. Luke's Mid America Heart Institute, the authors evaluated the association between the implementation of pediatric medical emergency teams and the risk-adjusted mortality at the hospital level.

                                                To do this, they looked within the pediatric health information system for freestanding pediatric hospitals and calculated the annual risk-adjusted mortality rates for sites between 2000 and 2015. A random slopes interrupted time series analysis was then used to examine whether implementation of a medical emergency team was associated with lower than expected mortality rates based on the pre-implementation trends. The authors found that before medical emergency team implementation, hospital mortality rates were decreasing by 6% annually across all hospitals. After medical emergency team implementation, the hospital mortality continued to decrease by 6% annually with no deepening of the mortality slope as compared with the pre-implementation trend for the overall cohort or when analyzed separately within each of the study hospitals. Five years after implementation across study sites, there was no difference between predicted and actually mortality rates.

                                                Thus, in summary, the implementation of medical emergency teams in a large sample of pediatric hospitals in the US was not associated with a reduction in hospital mortality beyond the existing pre-implementation trends. This study's null findings on hospital mortality suggests that either medical emergency teams have no effect on mortality or are being poorly implemented in the real world. These issues are discussed in an accompanying editorial by Joshua Koch and Sandeep Das from UT Southwestern.

                                                The next study tells us that carotid stent fractures are not associated with adverse events. First and corresponding author, Dr. Weinberg from Massachusetts General Hospital and his colleagues reported the stent fracture rate and its association with instant re-stenosis and adverse outcomes in the Asymptomatic Carotid Trial 1, which was a prospective multi-center trial of standard surgical risk patients with severe asymptomatic carotid artery stenosis randomized to carotid artery stenting or carotid endarterectomy. Stent fracture occurred in only 5.4% of patients and there was no association between stent fracture and in-stent re-stenosis or with the primary endpoint, which was a composite of death, stroke or myocardial infarction during the 30 days after the procedure or ipsilateral stroke during the 365 days after the procedure.

                                                These findings suggest that routine surveillance for carotid stent fracture may be unnecessary and, if a fracture is identified in an asymptomatic patient, intervention may rarely be required.

                                                Heart rhythm disorder management procedures are increasingly being performed and the next paper tells us important information on mortality and cerebrovascular events following such procedures.

                                                Co-first authors Lee and Ling, corresponding authors Dr. Mulpuru and colleagues from Mayo Clinic in Phoenix, Arizona, performed a retrospective cohort study of all patients undergoing heart rhythm disorder management procedures between 2000 and 2016 at the Mayo Clinic from all three campuses in Rochester, Phoenix and Jacksonville. Among almost 49,000 patients undergoing a total of above 62,000 procedures, the overall mortality and cerebrovascular event rate was 0.36% and 0.12%, respectively. Lead extraction procedures had the highest overall mortality of 0.21% and the highest cerebrovascular event rates at 0.62%. However, most of the deaths and cerebrovascular events occurred after device implantation procedures due to the sheer volume of device implantation procedures, which represented 48% of all the procedures performed.

                                                The most common cause of death directly related to these procedures was cardiac tamponade, being responsible for 40% of all directly related deaths. This highlights the importance of development of protocols for quick identification and management of cardiac tamponade, even in procedures typically believed to be of lower risk such as device implantation.

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

                                                Lipid testing plays a major role in our day-to-day management of our cardiovascular patients and fasting samples have long been the standard for assessing LDL cholesterol and triglycerides since fasting is believed to reduce the triglyceride variability and allow for a more accurate derivation of the commonly used Friedewald calculated LDL cholesterol. Well, I think that's an assumption we have taken for granted, I mean, since 1972 when the Friedewald calculation was first proposed, but in this day and age, several clinical guidelines from Europe, Canada and the US have now recommended non-fasting lipid testing for routine clinical evaluations and it's time to re-evaluate perhaps the Friedewald LDL or other methods for determining LDL.

                                                Today's feature paper addresses this issue spot-on and we're thrilled to have with us the corresponding author of a very important paper and he is Dr. Seth Martin from the Johns Hopkins Ciccarone Center for Prevention of Cardiovascular Disease and we also have with us Dr. Anand Rohatgi, associate editor from UT Southwestern. Welcome, gentlemen.

Dr. Anand Rohatgi:          Thank you, Carolyn.

Dr. Seth Martin:                Thank you.

Dr. Carolyn Lam:               Seth, that was a super-long lead up from me, but I just find your paper so intriguing. Could you please paint the background of the idea behind your paper today and the rationale for questioning the Friedewald equation?

Dr. Seth Martin:                Yeah, my pleasure. This was the first paper to look at directly fasting versus non-fasting using our new algorithm. To give a little background on the algorithm, we had recognized that the Friedewald equation, which had been the standard for decades as you mentioned, would really become problematic in the setting of low LDL concentrations. In fact, Dr. Friedewald himself and his co-authors said that in their original publication in 1972 because what's subtracted out is the LDL cholesterol and it's not a particularly accurate estimate by their equation, but at the time, it was viewed as acceptable because the concentrations of LDL weren't all that low.

                                                Now, in the modern era, things are different. We treat the lower LDL. We're lucky to have new drugs that allow us to achieve low LDL levels and meanwhile we have many more patients with obesity and diabetes, leading to higher triglyceride levels, so this all means that that estimated component of the equation becomes a bigger part of the equation and that's what spurred us on to say, "Well, cane we estimate that better?" And we were very lucky to have access to a huge data set that had over a million patients and had directly measured VLDL cholesterol as well as triglycerides, so that allowed us to really more specifically address this estimated component of the equation.

                                                To just give the brief details on what the equation does, is we take the original Friedewald equation from what I view is a one-size-fits-all approach where we divide triglycerides by 5 in milligrams per deciliter and now we just match the patient based on their lipid profile using the same data as the Friedewald equation with the more personalized factors, so taking it from one size fits all to a more precision or personalized fit and it's one of 180 different factors that the patient may get matched with and what we've found is that this type of approach is more flexible, so it's going ... as patients triglyceride levels go up in the setting of low LDL and as they go into non-fasting states, this type of approach can adapt to that better and provide a more reliable, accurate estimate of LDL cholesterol.

Dr. Carolyn Lam:               That is so cool. It really is. It just makes so much sense in this day and age of proceeding towards personalized medicine, to make sure we apply equations that are personalized, so your paper essentially shows that applying this new equation works better than the traditional equation, particularly in the non-fasting states, right? And for states of low LDL cholesterol or perhaps high triglycerides. Would that be a good summary?

Dr. Seth Martin:                Yeah, that's a great summary and this paper ... I'm really lucky. It was led by one of the fantastic Osler medical residents, Vasanth Sathiyakumar, who is going to be a future star in cardiology, I believe, and he did a great job leading our paper, which shows that in the non-fasting state, what happens is triglyceride levels are higher and this means that the Friedewald equation becomes less accurate and I think this has been a little bit overlooked in recent trends where there's been a big push to do more non-fasting lipid profiles, which really is great for patients, more convenient and it makes a lot of sense, but we have to be also, in an era of precision medicine, getting precise data and if we're going to be making clinical decisions based on LDL concentration, we want to make sure we have good information there and what our paper shows is that there should be some level of caution when using non-fasting Friedewald LDL at low levels, but our new algorithm does provide a more robust estimate in that setting.

Dr. Carolyn Lam:               Anand, this is begging for the question, "What do you think are going to be the practical implications of this very important paper?"

Dr. Anand Rohatgi:          I think the clinical implications are huge and I think that's why we were so excited when we received this, that sort of the potential impact was there. I can tell you personally my clinic is in the afternoon and so it's a struggle to try to get patients to get fasting lipid levels and often they can't do it when they're coming to see me and so the importance of non-fasting lipid levels is clear and what Seth's group has done is showed that we can actually accurately estimate the LDL levels. A lot of people struggle with trying to still calculate the non-HDL levels and, as Seth pointed out, oftentimes when you're non-fasting, the triglyceride levels are higher and the calculated LDL from Friedewald is artificially low, so it's very hard to combine the convenience of just looking at the lipid levels and having sort of a confidence in the actual calculated LDL, so in this case clinicians can have their patients get their lipid levels at any time and with this algorithm that's already being used by major laboratory services will have relatively high confidence that the LDL that they see is very accurate and then they can make a decision based off of that and they can counsel in real time based off of that, so it really changes the ability to engage with patients at any time and is not restrictive.

                                                I can tell you many patients sometimes won't even get their lipid levels for weeks just because they can't arrange for it to be done on a fasting state and so this really liberates patients and it really enhances the doctor-patient relationship, I think.

Dr. Carolyn Lam:               I agree, Anand. I like that word that you used, "liberate" the patient. Honestly, I think some of my patients cheat a little too and they don't really fast as they should before their fasting lipids and this is going to be incredibly helpful.

                                                I have a couple of questions for you, though, Seth. In terms of understanding the limitations of what you may have tested in the current study, we all know that with triglycerides in the super-high level of more than 400, for example, the Friedewald equation breaks down. Did you test this with the new equation because I think you excluded this group as well in the current study, did you not?

Dr. Seth Martin:                That's correct, yes. Traditionally, the Friedewald equation has excluded folks from calculation who have triglyceride levels, as you said, of 400 milligrams per deciliter or more and the reason for that is that's the setting where chylomicrons are more likely to be present and therefore we're trying to estimate VLDL cholesterol and it wouldn't make sense to do that if there's a lot of triglycerides and chylomicrons.

                                                That being said, we did look at this previously and found that in that setting our equation works quite a bit better than Friedewald, but it's still inaccurate I would say about a third of the time due to the presence of chylomicrons, so it's an area where we should certainly be more cautious in estimating LDL cholesterol if the triglycerides are that high, but honestly in that setting, often the clinical priority is going to revolve around triglyceride lowering and the LDL may not be the most immediate priority for clinical treatment.

Dr. Carolyn Lam:               And then just another question, recognizing that our podcast is heard throughout the world, in this day and age of precision medicine, how about accounting for potential ethnic differences, possibly? Did you account for differences in race, gender perhaps in these equations?

Dr. Seth Martin:                What we found is that this really is a lipid-dependent phenomenon in terms of the ratio of triglycerides to VLDL in estimating LDL. We previously looked at age and sex and found that they contributed very, very little information to actually explaining this ratio and so I think that it is something that's likely going to be preserved across different demographic groups. I can say to our listeners in places ... in Asia that the equation has been validated over there and so there's some reassurance that even around the world and other places like Brazil, that it is holding up, so I think that largely this is going to be dependent on someone's lipid profile and it is quite simple in that regard, that we don't have to likely worry about too much differences between men, women, older, younger or different ethnicities.

Dr. Anand Rohatgi:          I have a question for Seth. As we mentioned, this is an international audience and guidelines do differ on their emphasis on lipid targets now as everyone is aware, some still emphasizing them and others, like the American guidelines, de-emphasizing targets, so Seth, the question i had for you is based off of your work. Where do you see that fitting in with how the different guidelines and societies are trying to emphasize or de-emphasize lipid targets.

Dr. Seth Martin:                The amazing thing is we're all ... really have access to the same data. We've worked together throughout the globe to generate clinical trial evidence that guides us as well as all sorts of other type of evidence to guide us in clinical practice, so just on a very broad conceptual level, my hope is that over time with the great exchange of information around the world that we're going to converge more on consensus recommendations and then, of course, there may be needs to adapt those recommendations to different cultures and that can be taken into account, so I'm hoping there'll be a push towards more consensus and as we get our updated American guidelines, it's looking like this upcoming year, I hope that we come into even more harmony with the rest of the world.

                                                I think for a long time we've had this LDL goal in many different guidelines as less than 70, so that's part of the reason our work has focused on that level. The European guidelines have a target level for high-risk patients of less than 70 for LDL and I think what we saw in the recent consensus document on non-statins from the American College of Cardiology was a push to be thinking at that level when the LDL is 70 or above as a time to have a clinician and patient discussion about whether we should be intensifying therapy, so I guess would say the guidelines in my view, and Anand I would be curious of your view, are more alike than different, but I hope they become even more in harmony because really we're all basing our decisions on the same evidence base and I think it can be a bit confusing when we have disparate recommendations.

                                                The same can be said for the issue of recommendations for fasting versus non-fasting guidelines, which have not been harmonized either, but Anand I'd be curious to your thoughts as well on this topic.

Dr. Anand Rohatgi:          I would agree with you. I think they're more alike than different. It's just what may be the high level sort of things have come out to the lay public and others, but I agree with you. If you really read them, they're emphasizing risk reduction by the therapies and by controlling the risk factors, in particular the lipid levels, so I think that's where your work is really important and insightful and I think will be incorporated in all of the respective guideline revisions.

Dr. Carolyn Lam:               I completely agree and we're so proud to be publishing your excellent work in circulation. Thank you, Seth. Thank you, Anand.

                                                Thank you, listeners, for joining us today. Don't forget to tune again next week.


Dec 18, 2017

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 journal features two papers. One a research letter and the second an original article, both focusing on the effect of ionizing radiation on interventional cardiologists. I'm sure that cuts close to the heart, so please stay tuned. Coming up right after these summaries.

                                                The first two original articles in this week's journal describe a metabolic adaptation that is good for the abnormal cell but bad for the patient. This is a shift in glucose metabolism called the Warburg phenomenon where there is failure of two fundamental pathways. Number one glucose metabolism and number two mitochondrial oxygen sensing. This Warburg phenomenon enables a reliance on glycolysis despite an abundance of available oxygen. These two circulation articles uncover new players in the Warburg phenomenon, both in the setting of pulmonary arterial hypertension. One in the pulmonary arterial endothelial cells, and the second in fibroblasts.

                                                In the first paper, first and corresponding author Dr. Caruso and co-corresponding author Dr. Morrell from the University of Cambridge examined the microRNA and proteomic profiles of blood outgrowth endothelial cells from patients with heritable pulmonary arterial hypertension due to mutations in the bone morphogenetic protein receptor type two, or BMPR2 gene, and in patients with idiopathic pulmonary arterial hypertension. They demonstrated that reduced expression of microRNA-124 in pulmonary arterial hypertension endothelial cells was responsible for the dysregulation of the splicing factor polypyrimidine tract binding protein 1, and its target pyruvate kinase M2 or PKM2, which is a major regulator of glycolysis and which contributes to abnormal cell proliferation. Reduced BMPR2 levels were associated with reduced microRNA-124 expression.

                                                In the second paper first author Dr. Zhang, corresponding author Dr Stenmark and colleagues from the University of Colorado studied pulmonary adventitial fibroblasts isolated from cows and humans with severe pulmonary hypertension. PKM2 inhibition reversed the glycolytic status of pulmonary hypertension fibroblasts, decreased their cell proliferation and attenuated macrophage interleukin beta expression.

                                                Normalizing the PKM2 to M1 ratio in pulmonary hypertension fibroblasts by using microRNA-124 over expression, or by PTBP1 knockdown, reversed the glycolytic phenotype, rescued mitochondrial reprogramming and decreased cell proliferation. Finally, pharmacological manipulation of PKM2 activity or treatment with histone deacetylase inhibitors produced similar results. These findings provide new avenues for the treatment of pulmonary arterial hypertension and are discussed in an accompanying editorial by Stephen Archer from Queen's University in Ontario Canada.

                                                The next paper tells us that the addition of ezetimibe to simvastatin in patients stabilized after acute coronary syndrome reduces the frequency of ischemic stroke, with a particularly large effect seen in patients with a prior stroke. First and corresponding author Dr. Bohula and colleagues from the TIMI study group investigated the efficacy of the addition of ezetimibe to simvastatin for prevention of stroke in the IMPROVE-IT trial where post ACS patients were randomized to placebo and simvastatin or ezetimibe and simvastatin and followed for a median of six years.

                                                The current study focused on patients with a history of stroke prior to randomization. The authors found that the addition of ezetimibe to simvastatin reduced the frequency of ischemic stroke with a hazards ratio of 0.79, with a particularly large effect seen in patients with a prior stroke, where the hazards ratio was 0.52, compared to patients without a prior stroke where the hazards ratio was 0.84. Hemorrhagic strokes were rare and a non significant increase in hemorrhagic stroke was observed with the addition of ezetimibe. Thus, the authors concluded that it is reasonable to consider the addition of ezetimibe, a generic lipid lowering therapy with an acceptable safety profile, to a moderate to high intensity statin regimen for the prevention of ischemic stroke in patients with established ischemic heart disease, with or without a prior stroke.

                                                Atrial fibrillation is the most common sustained arrhythmia in hypertrophic cardiomyopathy, but the influence of atrial fibrillation on clinical course and outcomes in hypertrophic cardiomyopathy had remained incompletely resolved. That is until today's paper in circulation. First and corresponding author Dr. Rowin and colleagues from Tufts Medical Center accessed the records of 1,558 consecutive patients followed at the Tufts Medical Center hypertrophic cardiomyopathy institute for an average of 4.8 years from 2004 to 2014.

                                                20% of patients had episodes of atrial fibrillation, of which 74% were confined to symptomatic paroxysmal atrial fibrillation, while 26% developed permanent atrial fibrillation. They found that the timing and frequency of paroxysmal atrial fibrillation events were unpredictable with an average two year interval between the first and second symptomatic episodes but progressing to permanent atrial fibrillation uncommonly. They further found that atrial fibrillation was not a major contributor to heart failure morbidity, nor a cause of arrhythmic sudden death, and when atrial fibrillation was treated it was associated with low disease related mortality, no different than for patients without atrial fibrillation. Finally, atrial fibrillation was an uncommon primary cause of death in hypertrophic cardiomyopathy, but this was virtually limited to embolic stroke, thus supporting a low threshold for initiating anticoagulation therapy.

                                                That warps it up for our summaries. Now for our feature discussion. This week's journal carries two papers that refer to the health risks of ionizing radiation to interventional cardiologists. Yes, you heard me right. You're going to want to listen up. These are going to send chills up our spine, or rather maybe chills into our brains and into our blood according to the papers.

                                                To discuss these two papers I have with us associate editor from UT Southwestern, Dr. Manos Brilakis, as well as the corresponding author of the first paper Dr. Maria Andreassi from CNR Institute of Clinical Physiology from Pisa Italy. Maria, could you start us off by telling us what you found in your research letter?

Dr Maria Andreassi:        In our study we evaluated the circulating microRNA profile in interventional cardiologists in order to provide insights into the molecular and the biological situation and the underlying association between occupational low dose radiation exposure in cath lab and the potential long term disease risk. The hypothesis of our study was based on the evidence that the microRNAs are crucial regulators of gene expression. And they have been shown to be dysregulated in many human disease. Moreover, the stability and the tissue selectivity of circulating microRNAs make them ideal biomarkers to explore disease potential clinical disease risk.

                                                In summary, our findings exhibited the dysregulation and the down regulation of acute specific circulating microRNA, the brain specific microRNA-154 and the microRNA-2392. This tells us significantly involved in the deregulation of the three brain pathways and the brain cancer pathway as demonstrated by systematic analysis. In particular, the dysregulated labels so the brain specific microRNA-154 in interventional cardiologists support the notion that the brain damage is one of the main potential long term risk on unprotected head radiation in interventional cardiologists with possible long lasting consequences on the cognitive function.

Dr Carolyn Lam:                That is really striking. Brain specific microRNA was shown to be dysregulated in interventional cardiologists compared to controls who were not exposed to radiation. As I understand it, these dysregulated microRNAs can be seen in certain forms of epilepsy and Alzheimer's disease and certain brain cancers and so the concern is very obvious for those of us who are interventional cardiologists. But your study did not actually relate these two specific adverse events. Is that correct?

Dr Maria Andreassi:        You're right. Yes. microRNA-154 was first identified as a brain specific microRNA which is involved with inner synapse development and the directly implicated in [inaudible 00:12:15] and memory. Additionally, decreased expression of this microRNA class, was previously reported in several brain disorders including the thymus disease and bipolar disorder. This microRNA has also been shown to be down regulated in several brain cancers such as neuroblastomas. The reduced expression of the microRNA-154 is a predictor of progression and prognosis of human gliomas. This data strongly support it's important role in brain tumors. Our findings are of particular interest in relation the handle exposure to the pathology of the head, the [inaudible 00:13:13] 20, 50 millisieverts. The equivalent to 1,000, 2,000 chest x-rays and can reach a lifetime cumulative exposure around two sieverts for left hippocampus and one sievert for right hippocampus.

Dr Carolyn Lam:                That really makes me go, yikes. But Manos, as an interventional cardiologist yourself, what are your thoughts? And also your thoughts please on that other paper that's in this week's journal?

Dr Manos Brilakis:            First of all, let me just congratulate Maria Andreassi, she's been one of the leaders in this area and published several papers and this is one of them. It's really important to have these studies because unfortunately we as interventional cardiologists tend to forget about the negative affects of radiation because as you hear, people don't really see them and this can happen many years down the line. And by the time they happen, it's too late. It's really useful to have the studies to bring our attention the importance of keeping the radiation exposure to the patient and to ourselves as low as possible.

                                                The other paper in addition to the one just discussed, is a paper that looks at DNA damage on operators performing endovascular aortic repair. As a preface, these are procedures demonstrated the aortic aneurism repairs which are very intense radiation wise. They are long procedures, fielding can sometimes be challenging for the operator. There is significant exposure of the operator to x-ray. What they did is they measured some markers of DNA damage and repair. Specifically gamma-H1AX and DDR, the DNA damage response marker and the pATM. They measured them in circulating lymphocytes in operators who performed the endovascular aortic aneurism. What they found is that there were significantly higher levels of those markers immediately after those operators performed those procedures. And they did the same thing after x-ray using leg shielding.

                                                That's a very good reminder for us that the x-ray tube actually is not on the top of the table, but the x-ray tube, the generator, of the x-rays is actually on the bottom. Then the x-ray goes through the patient and the detector is at the top of the table and what happens is the x-ray comes from below the patient and gets scattered from the patient and coming towards the operator so actually it's the legs get the higher dose during any sort of x-ray guided procedure. Sometimes we're forgetting importance of shielding the legs 'cause we think the legs, whatever the muscles, the bones, they're fine. But as the study shows, it's not just the muscles and the bones there but the whole circulation blood gets exposed to x-ray in the lower extremity circulation and that can translate to many other potentially adverse events.

Dr Carolyn Lam:                Manos, I love that you manage both these papers. What important messages for increase in risk awareness. This was really very, very well accomplished by both these papers. As well by the editorial that you asked for and that was so well written by Dr. Charles Chambers on both these papers. But beyond risk awareness, what I really love is what you brought up just a while earlier about risk reduction and methods that we can take, for example, in the second paper, by Dr. Modoari and colleagues about shielding the legs. What are the implications for example, wearing a helmet or shielding the head for interventional cardiologists? What do you think?

Dr Manos Brilakis:            These are very, very good points. The reality is for the head there have been a couple studied that looked at shielding with lead caps or there's some lead free caps that can be worn and also there are radiation protective glasses. However, what was interesting, there was a paper earlier last year that showed that because the radiation actually comes from below the operator that wearing those helmets, although it seems appealing, it is simple to do obviously, it actually did not significantly reduce the dose to the brain and it only partially reduced the dose to the eyes. Though shielding is useful but may not be as good as we think it is.

                                                In my mind, the starting point of all this is the basics of radiation safety which again, sound very simple and we learn about them in the beginning of training, unfortunately what happen is people tend to forget them as time goes by. These are things like don't step on the x-ray pedal unless you need to look at the pictures and that's very common done. People just have this heavy foot syndrome. They keep on x-raying when they don't need to. There's also the important things having the patient as high as possible and the detector as close to the patient so there is not as much distance for the x-ray to travel. Things like using low, not very steep angles so there is not as much radiation because they have to go through less amount of tissue. And there's some technologies actually coming along there's some technologies that focus the radiation beam only specific areas. And cut the overall dose. And there are x-ray machines that also can have much less radiation overall for the patient and the operator. As you said, having good shielding habits is very important.

Dr Carolyn Lam:                Yeah, that's exactly it. That risk awareness should lead to action. I'm just curious, who do you think should primarily take hold of these risk reduction and safety procedures and the enforcement and so on? Us as a community, but what do you think of the role of things like professional societies, quality improvement programs, FDA even?

Dr Manos Brilakis:            It's a great point. What we hear here Maria's comments on this as well. But my feeling is absolutely societies are very important for leading these efforts and they do have actually guidelines. There's procedural guidelines for radiation protection. But the end of the day it's the individuals themselves, the operators, each and every one who is in charge of this in their care or his own cath lab and their procedures.

Dr Maria Andreassi:        I agree. We all of our findings can contribute to the increase of cross cultural assessment in cath lab and by promoting the diffusion but not the reduction technologies whereas diligent about your protection habits. Moreover it is important to let the design, the relationship between occupational radiation exposure, clinical risk and there are very important future studies studying larger population. We should focus on the molecular epidemiology studies by using biomarkers and this will be clinical and points as early predictors of a clinical event. Because this information is a model likely to better define the risk of radiation use disease at low doses as a comparative tool, the classical epidemiological approach that require a very large sample sizes spread over [inaudible 00:20:51].

                                                Now it's time where largest studies involving scientific societies at an international level. Possible breaking the additional exposure in already recruited the Roth case. And by combining the conventional epidemiology, and the molecular studies and the expected results to better define the clinical risk as a good lesson to implement a more effective protection program. And better as the surveillance at the individual level.

Dr Carolyn Lam:                That is wonderful. And thank you, this truly is an international call, isn't it? Another thing that we should keep in mind that all measures that we use to protect our patient from receiving excessive radiation is likely to help us as well as cardiologists.

                                                Thank you so much, both of you, for joining me today on this podcast. What an important message and I'm sure that our listeners will agree. Thank you listeners for joining us. Tune in again next week.


Dec 11, 2017

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 feature discussion today centers on patients with acute stroke due to large vessel occlusion, and asks the question, "Does interhospital transfer prior to thrombectomy relate to delayed treatment and worse outcomes?" Well, stay tuned for more right after these summaries.

                                                Our first original paper this week tells us that cardio protection is alive, and mitochondrial cardiomyocyte calcium-activated potassium channels of the BK type may be a promising target. In this study from first author Dr. Frankenreiter, corresponding author Dr. Lukowski, from University of Tuebingen in Germany, the authors used a combination of transgenic, pharmacologic and electrophysiological approaches to show that mice with a cardiomyocyte-specific knockout of BK channels had larger infarct size after 30 minutes of coronary occlusion, and 120 minutes of reperfusion, and were less protected by ischemic pre- and post-conditioning maneuvers, such as guanylate cyclase stimulators or activators and phosphodiesterase-5 inhibitors.

                                                In a chronic infarct model, mice with cardiomyocyte-specific knockout of BK channels had more fibrosis and lower left ventricular function. Mechanistically, the activation of BK channels in the inner mitochondrial membrane by cyclic GMP and protein kinase G was identified by patch clamping, and resulted in reduced formation of reactive oxygen species and activation of cardioprotective signaling. In summary, deficiency of BK channels in cardiomyocyte mitochondria rendered the heart highly vulnerable to ischemic and reperfusion injury, whereas the beneficial effects of cardioprotective agents known to target the nitric oxide cyclic GMP pathway required these cardiomyocyte BK channels. This thus establishes these cardiomyocyte mitochondrial BK channels as a promising target for limiting acute cardiac damage and adverse long-term events following myocardial infarction.

                                                The next study suggests that integration of maximal myocardial blood flow and coronary flow reserve, termed coronary flow capacity, may be helpful in predicting cardiovascular mortality in patients with stable coronary artery disease. First author Dr. Gupta, corresponding author Dr. Di Carli, and colleagues from Brigham and Women's Hospital, quantify myocardial blood flow and coronary flow reserve in more than 4,000 consecutive patients referred for myocardial perfusion PET scans from 2006 to 2013.

                                                Maximal myocardial blood flow of less than 1.8 mLs per gram per minute, and coronary flow reserve of less than two, were considered impaired. Four patient groups were then identified based on the concordant or discordant impairment of maximal myocardial blood flow, or its coronary flow reserve. The authors found that in patients with known or suspected coronary artery disease, impaired coronary flow reserve with preserved maximal myocardial blood flow identifies patients at an increased risk of cardiovascular mortality, despite a lack of myocardial ischemia. Patients who may be targeted for initiation or intensification of lifestyle preventive therapies for cardiovascular risk reduction. Conversely, preserved coronary flow reserve, even in the absence of impaired myocardial blood flow, identifies patients at low risk, in whom the need for revascularization should be reevaluated.

                                                The next study provides insights into cardiac regeneration, particularly with regards to using resident cardiac progenitor cells expressing the tyrosine kinase receptor c-Kit, which is being tested in clinical trials. In this study from first authors Dr. Chen and Zhu, corresponding authors Dr. van Berlo from University of Minnesota and colleagues, the authors used single-cell sequencing and genetic lineage tracing to show that there was innate heterogeneity within these c-Kit positive cardiac cells, where some have either endothelial or mesenchymal identity. Cardiac pressure overload resulted in a modest increase in c-Kit derived cardiomyocytes, with significant increases in the number of endothelial cells and fibroblasts. On the other hand, doxorubicin-induced acute cardio toxicity did not increase c-Kit derived endothelial cell fates, but instead induced cardiomyocyte differentiation.

                                                Although the overall rate of cardiomyocyte formation from c-Kit positive cells was below clinically-relevant levels, the authors further showed an important role for p53 in the differentiation of c-Kit positive cells to cardiomyocytes. Thus, this paper shows that different pathologic stimuli induced different cell fates in c-Kit positive target cells. These are novel findings that could aid in the development of strategies to preferentially regenerate cardiomyocytes.

                                                Since December 2014, a series of pivotal trials have shown that endovascular thrombectomy was highly effective in acute stroke management, prompting calls for reorganization of stroke systems of care. But how have these trials influenced the frequency of endovascular thrombectomy in clinical practice? Well, the last original paper in this week's journal tells us how. First and corresponding author, Dr. Smith from University of Calgary in Alberta, Canada, and colleagues, used data from the Get With The Guidelines stroke program to determine how the frequency of endovascular thrombectomy has changed in U.S. practice. They analyzed prospectively-collected data from a cohort of more than two million ischemic stroke patients, admitted to more than 2,000 participating hospitals between 2003 and the third quarter of 2016.

                                                The authors found that the use of endovascular thrombectomy for acute ischemic stroke accelerated sharply after the publication of pivotal randomized control trials beginning in December 2014. The endovascular thrombectomy case volume doubled at hospitals providing therapy. In the third quarter of 2016, endovascular thrombectomy was provided to 3.3% of all ischemic stroke patients. This represented 15.1% of all patients who were potentially eligible for endovascular thrombectomy based on stroke duration and severity. In summary, endovascular thrombectomy use is increasing rapidly, however there are still opportunities to treat more patients. Reorganizing stroke systems to route patients to adequately resourced endovascular thrombectomy-capable hospitals might increase treatment of eligible patients, improve outcomes, and reduce disparities.

                                                Coming right up, we will be discussing even more about endovascular thrombectomy in acute stroke management. Just hang on, our feature discussion is coming right up.

                                                Endovascular treatment with mechanical thrombectomy is beneficial for acute stroke patients suffering a large vessel occlusion. And that is in the guidelines, however we also know that treatment efficacy is highly time-dependent. And so, will interhospital transfer to an endovascular-capable center help in cases of acute large vessel stroke? Well, today's feature paper really helps to present novel data to answer that question. And it is from the STRATIS study. I'm so delighted to have with us the first and corresponding author, Dr. Michael Froehler from Vanderbilt University Medical Center, who will tell us about his findings, as well as Dr. Graeme Hankey, associate editor from University of Western Australia, joining us today. Welcome, gentlemen.

Dr. Michael Froehler:     Hello Carolyn.

Dr. Graeme Hankey:       Thank you Carolyn.

Dr. Carolyn Lam:               Thanks for making the time. Mike, tell us about the STRATIS study. What inspired it, what you found.

Dr. Michael Froehler:     Well, the STRATIS study was actually a large registry of the use of the Solitaire device for large vessel occlusion. Those results, the primary results, were published separately. But what we did in this study is look at one key aspect of the system of care for stroke delivery, in terms of its effect on time to treatment and patient outcomes.

                                                And so in short, what we found is that patients that are transferred from one hospital to another for mechanical thrombectomy take longer to receive treatment, and do worse in terms of functional outcome, compared to the patients that present directly to that thrombectomy center.

Dr. Carolyn Lam:               Wow. Could you put some numbers to that?

Dr. Michael Froehler:     Well, so we looked at 984 patients, almost a thousand patients. And what we found was that the time from stroke onset to revascularization, until the time the vessel was actually opened, was 202 minutes on average, for patients that presented directly to the thrombectomy center. Compared to over 311 minutes for patients that were transferred from one hospital to another. So that's a difference, on average, of over 100 minutes.

Dr. Carolyn Lam:               And I really was impressed with this other analysis you did. So I was wondering if you could share, where you did a hypothetical bypass modeling. Could you tell us about that? Because I thought that was really practical with a feasible message as well.

Dr. Michael Froehler:     I'm excited about that, and I should also share with you that we're working on a more in-depth bypass analysis, to really understand the implications of going to one center directly versus another. But the model that is built in to this publication is really designed to answer one or two questions. And the first is, how much time would we save if we went directly to the thrombectomy-capable center, compared to what actually happened? Meaning the patient was taken to a regional hospital and then subsequently transferred to the thrombectomy-capable center. And this was basically an ideal scenario.

                                                So if they were taken to one hospital and then transferred to another, we simply calculated what the maximum driving time from the starting position to the thrombectomy-capable center would be. And that did rest on the assumption that you actually had to drive past the first hospital. We didn't take any shortcuts in terms of the driving, and probably that small amount of driving time is actually shorter than the number that we found in our calculation.

                                                So the first question was, how much time would we save with that bypass? And the second question was, what kind of impact would that have on IV-tPA? Because, as a lot of us are thinking right now, with strong evidence in support of endovascular therapy for large vessel occlusion, if necessary how should we prioritize getting to endovascular treatment versus the standard therapy that we've known for 20 years, which is IV-tPA? And if you've got a choice, which one is more important?

                                                I don't know the answer to that question, but to try and help lead up to it, we did this hypothetical bypass analysis to look at the impact of bypass, driving directly to the thrombectomy center, the impact of that on the time to delivery of IV-tPA. And so that was really the second question that we asked with this hypothetical bypass analysis.

Dr. Carolyn Lam:               Yeah. I love that analysis, because I agree with you, it's a very, very practical question, and it's the way we clinicians think, right? So, tell us, what's the bottom line?

Dr. Michael Froehler:     So, the bottom line is, you're gonna save about an hour and a half if you bypass the regional hospital and go directly to the thrombectomy-capable center. On average, you're gonna get to the ultimate treatment center 91 minutes sooner, compared to the transferred group. Contrast that 91-minute time savings with a delay of IV-tPA delivery of 12 minutes. So yes, tPA will be delivered a little bit later, but endovascular therapy will be delivered much sooner.

                                                Now, that solution is probably not going to work everywhere, depending on your geography. So one of the other things we did within the hypothetical bypass analysis was limit that analysis only to patients who were transferred within a 20-mile radius. And that doesn't seem like a long distance, but actually there's a lot of patients in that group, that are still taken to the nearest hospital and then need to be transferred to another hospital that may be less than 20 miles away.

                                                So if we looked at that group of patients, then thrombectomy is still performed an hour and a half earlier, in that analysis it was 94 minutes earlier, but IV-tPA was delayed by only seven minutes. So certainly, there is a large group of patients out there that are perhaps being taken to hospitals that are not necessary, it's not a necessary stop.

Dr. Carolyn Lam:               Wow, Mike, this is really amazing results, it's starting to make me think of the old days of acute myocardial infarction treatment, when we were thinking of intravenous thrombolytics, comparison to primary PCI, an analogy and comparison that was also mentioned in the accompanying editorial that you invited. Graeme, would you like to share some of your thoughts on the implication of all this?

Dr. Graeme Hankey:       Just to take a step back, of course this begins with a stroke occurring out in the field. And unlike acute coronary syndromes, where chest pain is the major symptom, there are many symptoms of stroke. And the first problem is trying to identify the patient who has actually had a stroke, and in particular, one of the 15% or so who's had a large vessel occlusion, who's amenable to large vessel mechanical thrombectomy. So in the field we have an issue with clinical triage, and trying to work out who's the one in six who really need endovascular therapy, and who are the five in six who perhaps don't.

                                                And we're trying to develop clinical triage scales like the RACE scale to work out in the ambulance where someone should go. But we still haven't nailed that yet. Then you have scales that are very sensitive but not very specific, and have a high sort of false-positive rate. So then the question at the ambulance is, where does it go, to the hospital, the primary stroke center nearby, and give the patient the earliest opportunity to get tPA?

                                                And that's the potential benefit of early transfer to a primary center, but tPA is not very effective in dissolving these big clots in large arteries. And so, of course the trials have shown a substantial benefit of endovascular therapy to remove the clots via thrombectomy. But those resources, they're only really limited to comprehensive stroke units, and that's what this paper was about. So the trade-off is early transfer to the primary center so you can get some tPA, versus delaying, as Michael has shown, by 1 1/2 to two hours on average, to get to a comprehensive center that can access the expertise of endovascular thrombectomy experts.

                                                And this paper is really taking us forward in emphasizing again that time is brain, and we really don't want to delay. Perhaps there's a small trade-off in driving a little bit further, another 20 miles at the most perhaps, to get to a comprehensive center directly. And there may be some who are not shown to have a large vessel occlusion at that comprehensive stroke center, but the overall benefit is probably offset, the few who might miss out on tPA. And so this is a really important study, the largest registry of large vessel occlusion patients to observe and compare the outcomes after adjusting for all the different factors. And give us some clues, that perhaps we really need to be trying to focus on building our resources in comprehensive stroke centers, and also being able to more accurately identify those who are likely to benefit and go directly there.

Dr. Michael Froehler:     I agree with everything Graeme said, and I would just amplify one thing that he said, that it does depend on distance, and those distances in turn depend on your own geography. We did an analysis of all our transferred patients and then limited it to those that were within a 20-mile radius. For Graeme in Western Australia, you know Graeme's mailbox is probably 20 miles away. And so there are huge distances in Western Australia to account for. And it may not be possible.

Dr. Carolyn Lam:               Contrast that to me in Singapore. I think if I drive any bit more, and I'll be driving out of my country already.

Dr. Michael Froehler:     I think that you make a great point though, Carolyn, that the solution that works for metro Singapore is not what's going to work for rural Western Australia. And we've seen this in New York City, for example. My colleagues at Mount Sinai are looking at different ways to deliver care across metro New York, which obviously is very different compared to myself in Nashville, Tennessee. So the right solution is not gonna be the same solution for everyone.

Dr. Graeme Hankey:       And that's right Carolyn, because in rural places like out in Western Australia, we are learning now that another important message is to try and help upscale and reorganize our primary stroke centers, or just our medical centers out in the rural and remote areas. Because as Mike's paper shows, the delays once someone comes to a primary stroke center or a rural center, is about 30 minutes for diagnosis, about 30 minutes to arrange the transport, and about 30 minutes to actually do the transport.

                                                So we need to once trying to develop comprehensive stroke units, also build up those peripheral hub and spoke centers to be more slick with their diagnosis, arrangement of transport, and transport times. And one of the important things I think is, we need our primary centers, when a stroke does come, to not just do a plain CT to exclude hemorrhage, but to do a CT angiogram at the time. And find out those who really do have an occlusion, rather than putting them all on the plane and sending them down, and quite a few of them don't actually have an occlusion by the time that they've got here. They haven't been fully investigated, it's just an extra five minutes to do the contrast CT angiogram at the time in the primary center if they're gonna go there.

Dr. Michael Froehler:     I think the one other thing I should add, and this is just to reflect back on something Graeme said a minute ago, is that one of the differences we found that really came out of that bypass analysis is the impact on tPA was smaller than we expected. Because the door-to-needle times are actually much longer at the regional hospitals that are not thrombectomy-capable, compared to the thrombectomy centers themselves, that are not only obviously delivering mechanical thrombectomy, but are actually delivering IV-tPA much sooner in terms of door-to-needle times.

Dr. Carolyn Lam:               So, room for improvement even for non-endovascular-capable centers, isn't it?

Dr. Michael Froehler:     Right, I think it's another area where there's room for improvement.

Dr. Carolyn Lam:               Please don't forget to tune in again next week.

Dec 4, 2017

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 journal features important information, that will aide identification of children with latent rheumatic heart disease, who are at highest risk of unfavorable outcomes. This important discussion is coming right up after these summaries.

                                                The first original paper this week describes the largest study to date to examine payer approvals and rejections of PCSK9 inhibitor therapy, and describe the patient characteristics associated with successful prescribing. First author, Dr. Hess, corresponding author Dr. Yeh and colleagues from Beth Israel Deaconess Medical Center in Boston, Massachusetts, performed a retrospective descriptive cohort study utilizing nationwide pharmacy claims linked to electronic medical records from a nationwide data warehouse. The data set included over 220 million patients from all 50 states, and all pair types with more than 5,000 distinct health plans. PCSK9 inhibitor prescriptions were submitted for 51,422 patients in the pharmacy data set.

                                                The authors found that among patients who were prescribed a PCSK9 inhibitor, 47% were approved for coverage by the payer. Variables that were associated with approval included age above 65 years, history of atherosclerotic cardiovascular disease, prescription by a cardiologist or a non-primary care provider, statin intolerance, longer statin duration, and non-commercial payers. Interestingly, higher LDL cholesterol levels were not associated with higher approval rates. Commercial third-party payers had the lowest approval rates of 24 from 4% and Medicare had the highest at 60.9%. Thus, rates of approval for PCSK9 inhibitor therapy are low, even for patients who appear to meet labeled indications. While a combination of clinical characteristics increase the likelihood of approval, payer type is the most significant factor.

                                                The next study identifies a novel mitochondrial localized protein that plays a role in cardiac dysfunction, remodeling, and heart failure. This protein is FUN14 domain-containing 1, or FUNDC1, a highly conserved outer mitochondrial membrane protein. In today's study, first author, Dr. Wu, co-corresponding authors, Dr. Xie and Zou from Georgia State University, and their colleagues, showed that in cardio myocytes, FUNDC1 bound to inositol 1, 4, 5-triphosphate type 2 receptor, to form mitochondria-associated endoplastic reticular membranes.

                                                These, in turn, modulate a calcium release from endoplasmic reticulum into mitochondria and the cytosol. FUNDC1 deletion lowered the levels of calcium in both mitochondria and the cytosol. A reduction at intracellular calcium resulted in mitochondrial fusion, mitochondrial dysfunction, cardiac dysfunction, and heart failure. In summary, this study identifies FUNDC1 as a novel mitochondrial localized protein that plays a role in maintaining mitochondrial dynamics, and cardiac function, and may therefore be a therapeutic target in heart failure.

                                                The next study takes a deep dive into the J-Curve phenomenon of systolic blood pressure by providing an experimental approach to an observational paradigm. First and corresponding author, Dr. Kalkman, from University of Amsterdam and colleagues assess the association between on-treatment systolic blood pressure levels, cardiovascular events, and all cause mortality in patients randomized to different systolic blood pressure targets in the pool database of the SPRINT-6 and ACCORD trials. For both the intensive blood pressure target of less than 120 millimeters mercury, and the conventional target of less than 140 millimeters of mercury, the authors found an identical shape of the J-curve was present with a [inaudible 00:04:44] for cardiovascular events and all cause mortality just below the systolic blood pressure target.

                                                The advantage of the intensive treatment group persisted at any level of the difference between the intended target and the achieved blood pressure targets. As discussed in an accompanying editorial by Dr. Verdecchia from Hospital of Assisi in Italy, these data suggest that if two patients achieve identical low values of blood pressure during treatment, prognosis is expected to be better in the patient actually targeted to achieve low values. Conversely, the outcome might be worse in the patient randomized to a higher blood pressure target, because low values in this case possibly reflect masked or unmasked confounders linked to a poorer outcome.

                                                Thus, physicians should not be reluctant in lowering blood pressure in their patients because of an expected detrimental effect of BP reduction on death or major cardiovascular events. Rather, they should carefully monitor the possible occurrence of other adverse effects linked to blood pressure lowering, such as syncope, renal impairment, or electrolyte disturbances. This study further suggests that the benefit or risk associated with intensive blood pressure lowering treatment can only be established via randomized clinical trials and should not be extrapolated from observational data.

                                                The final study establishes a causal link between dysregulated Tryptophan metabolism and abdominal aortic aneurysm. In a series of elegant mouse experiments from first author, Dr. Wang, two corresponding authors, Dr. Liu] and Ding from Georgia State University in Atlanta, Georgia, the authors establish that 3-Hydroxyanthranilic acid or 3-HAA, a key Tryptophan catabolite of the Angiotensin II induced abdominal aortic aneurysm in vascular smooth muscle cells was indeed responsible for Angiotensin II induced abdominal aortic aneurysm in Vivo. 3-HAA activated nuclear factor kappa-B transcription factor, promoted matrix metallopeptidase 2 expression in vascular smooth muscle cells. Human abdominal aortic aneurysm samples had stronger staining with the antibody against 3-HAA, than those in the adjacent non-aneurysmal aortic sections of these samples.

                                                The identification of 3-HAA in Angiotensin II triggered abdominal aortic aneurysm and in human patients with abdominal aortic aneurysms, suggests that Tryptophan derived metabolites may be a biomarker for abdominal aortic aneurysm diagnosis. Furthermore, agents that alter Tryptophan metabolism may have a therapeutic potential in preventing or treating abdominal aortic aneurysms. Well on that intriguing note, we're at the end of this week's summaries. Now, for our featured discussion.

                                                Today's feature paper really reminds us that rheumatic heart disease remains the most common cardiovascular disease among the world's youth. These days, echocardiographic screening provides a promising tool for early detection. However, the utility of this tool really depends on knowing the natural history of screen detected rheumatic heart disease, so-called latent rheumatic heart disease. Now, that has remained clear until today's paper. I'm so pleased to have with us the first and corresponding author, Dr. Andrea Beaton, from Children's National Medical Center in Washington D.C., as well as Dr. Bongani Mayosi, Associate Editor from University of Cape Town, South Africa. Andrea, could you start by letting us know about your study and what you found?

Dr. Andrea Beaton:         As you mentioned, over the last decade or so it's become clear that in addition to the substantial burden of clinical rheumatic heart disease that we see around the world in low and middle income countries, there's also an even larger burden of latent rheumatic heart disease or early rheumatic heart disease that we can see on echo. This brings up the question if echo screening might represent a very powerful tool for rheumatic heart disease control, but we can't move forward with that discussion until we understand the rate of progression of children who are found to have echo detected rheumatic heart disease, and if we can do something to intervene to prevent progression in that population.

                                                That something is likely penicillin, which is known to prevent progression in clinical rheumatic heart disease. To start to address that question, we followed a large cohort of children who had been diagnosed with echo detected rheumatic heart disease through school-based screening in different areas of Uganda and had collected about 227 cases of children with latent rheumatic heart disease who had been in clinical followup between two and a half and almost six years.

Dr. Carolyn Lam:               Great. Could you tell us what you found about the progression and risk factors perhaps of progression, which I think are most significant?

Dr. Andrea Beaton:         Right, so this is the largest natural history cohort of children with latent rheumatic heart disease to date and four major findings emerged from our study. The first is that we find a lot of echo detected rheumatic heart disease in low income settings that is more advanced. What we found is that children, even if this is their first time of diagnosis at echo screening, if they had moderate to severe rheumatic heart disease on screening, if they had poor outcomes even if over a very short time period. In our study, children with moderate to severe disease, only 10% of those children improved over the study period and 10% had died after only two to five years of followup.

                                                We also saw that kids with mild, but definite rheumatic heart disease, which is more criteria for rheumatic heart disease than borderline, showed worse outcomes. Although, both children with mild definite and borderline disease had substantial risk of progression. 25% progressed in the mild definite group and 10% in the borderline rheumatic heart disease group. That tells us that even with very minor changes on echo screening, there is substantial risk of progression to more severe rheumatic heart disease, because we had a larger cohort using a multi-variant model.

                                                We also found that there were features of rheumatic heart disease that put children at higher risk of progression. In our cohort, if children had aortic insufficiency at the time of screening, or some specific morphological changes, or changes in the mitral valve at time of screening, then they had higher risk of progression. While older age at time of screening showed a protective effect against progression.

Dr. Carolyn Lam:               Wow. Andrea, congratulations on this remarkable study and you've highlighted so many important public health messages just in this one study. Bongani, what do you think was the most important or significant finding?

Dr. Bongani Mayosi:        The most important finding is the reflection of the progression even in the mild and borderline cases. I think there has been an understanding that the definite cases do have a higher rate of progression and on top of that, I think showing the fact that there are some predictors that can be detected on echo is also very useful. Those with more advanced disease categories, those with younger age, as well as those with morphological valve abnormalities, I think those are very, very valuable points. Of course, the other point that is not all here is the fact that the majority of the initial progression appears to occur early and this is brought out in this study because of the serial echos that were done, which is again, another very valuable and a unique aspect of the study.

                                                Previous studies have only done an echo at the time of diagnosis and perhaps an echo at the end of the followup period. I think that these features really make this study a valuable one. There is one question though that I wanted to put to Andrea, the issue of auscultation is one that we realized very early was not very useful for screening patients with latent rheumatic heart disease. We missed too many. I'd like to ask you now, once we've identified patients with latent disease, do you think auscultation of those patients could in fact identify the ones with clinical disease? Presumably, the more severe aortic regurgitation, mitral regurgitation, may be audible using a stethoscope? In other words, now shifting the role of the stethoscope not so much for diagnosis, but for risk stratification. I just want to know if you looked at this issue at all in this particular cohort?

Dr. Andrea Beaton:         That's a really good question, Professor. We did not specifically look at the role of auscultation in this cohort. Although, it stands to reason that children with moderate to severe rheumatic heart disease, which by our definitions meant at least moderate to severe regurgitation at one of the valves, or presence of mitral stenosis would be audible. In that way, I think separating out children with moderate to severe disease, versus children with mild definite and borderline disease, would be quite possible and reasonable by auscultation.

                                                My worry with the use of auscultation is I don't think it would separate out well children with mild definite disease, who by definition could have no more than mild regurgitation at any one valve, from children with borderline disease. Whether that distinction is important, I think still remains to be understood, but it would not be a very sensitive way to follow children until they had progressed to the point of having much more significant disease. I think echo still remains incredibly sensitive compared to auscultation for minor progressions, which to be clear, were included here as counting as progression of disease, even minor changes on echocardiographic evaluation.

Dr. Carolyn Lam:               I have a question along the same lines Andrea, what kind of expertise was required for these echocardiographic screening procedures, both of the acquisition and then the interpretation? I do notice that you had a trained pediatric cardiologist with expertise in rheumatic heart disease who actually re-reported some of the echos. Do you think this is needed? What do you think about that?

Dr. Andrea Beaton:         This is a complicated question, but a good one. A lot of the research that we've done outside of this paper has been looking at the ability to task shift echo screening, so to have non-physicians, not experts conducting echo screening. What we found across the board, as well as other groups around the world have found, is that you can train non-experts in a relatively short period of time to both screen and diagnose, at least on a screening basis, the presence of absence of rheumatic heart disease. For the purposes of this study, we're using very precise and very detailed diagnosis. According to the World Heart Federation criteria, which do really require experts to interpret.

Dr. Bongani Mayosi:        The other issue, Andrea, which you highlight in the paper is the whole issue of the definition of progression, and regression, and the fact that there isn't consensus in the field about how we handle that, which results in papers not being comparable among each other. What do you suggest is the way of taking this forward so that we can build a consensus and a way of actually following up this patients that will be comparable between studies?

Dr. Andrea Beaton:         That's a really important question and something we struggled with while we were writing this paper. You'll note in our paper that we reported it in two different ways because we couldn't come to a consensus and we thought both had some legitimate importance. Most of the papers in this field have reported the groups as progression and as stable lumped together, versus regression or improvement of disease. We felt the most important endpoint and something we had the numbers to power, was progression by itself. How many children were getting worse over the study period? In one sense, we powered it progression, versus stable plus regression, trying to dichotomize it still.

                                                Then on the other hand, we thought that it was important if you had mild definite disease, even if you remained stable and mildly definite, and so we reported differently on the second outcomes based on if you had definite disease where we grouped progression and stable together, versus if you had borderline where we only counted true progression as a change for the worse. I don't have the perfect answer of how this should be reported. Although, I think the more granular we can be as we report these studies going forward, the more we can separate out the data that is reported to make it comparable. A lot of the previous papers, I think, lack the granularity needed to compare in different ways.

Dr. Carolyn Lam:               We're coming to the end of our time, so may I just wrap up by asking Andrea, what do you think are the next steps?

Dr. Andrea Beaton:         That's a good question and something I feel strongly about. Another part of our paper showed that the other incredibly important outstanding question is if we can find these kids, can we change what happens to them over time, and does penicillin do that? Even with our large cohort of patients, we couldn't determine the effect of penicillin on progression or trajectory of these children over this time period. It's something that now that we have large numbers of children and still can't come to a conclusive response, I think warrants a randomized control trial to look at the effect of penicillin on children with echo detected rheumatic heart disease, because that's really what's going to drive the policy on if echo screening makes sense as a public health policy to reduce the global rheumatic heart disease burden.

Dr. Carolyn Lam:               I'm sure listeners out there, you've appreciated this as much as I have. Tune in again next week.