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Circulation on the Run

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.