Dr Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our featured discussion today centers on the challenges of cardiovascular disease risk evaluation in people living with HIV infection, an important discussion coming right up after these summaries.
The first original paper this week provides experimental evidence that nicotinamide riboside could be a useful metabolic therapy for heart failure. First author Dr. Diguet, corresponding author Dr. Mericskay, from University Paris-Sud investigated the nicotinamide adenine dinucleotide or NAD homeostasis pathways in the failing heart. They found that an expression shift occurs in both murine and human failing hearts in which the nicotinamide riboside kinase two enzyme, which uses the nucleoside nicotinamide riboside was strongly up-regulated for NAD synthesis.
Nicotinamide riboside supplemented diet administered to murine models of dilated cardiomyopathy or pressure overloaded induced heart failure restored the myocardial NAD levels and preserved cardiac function. Nicotinamide riboside increased glycolysis as well as citrate and Acetyl-CoA's metabolism in these cardiomyocytes. Thus, nicotinamide riboside supplemented diet may be helpful in patients suffering from heart failure and may help them to cope with the limited myocardial ATP supply by restoring NAD coenzyme levels and its associated signaling.
In the single ventricle reconstruction trial, one year transplant-free survival was better for the Norwood procedure with the right ventricle to pulmonary artery shunt compared with the modified Blalock‒Taussig shunt in patients with hypoplastic left heart and related syndromes. In the paper in this week's journal, authors compare transplant-free survival and other outcomes between these groups at six years. First and corresponding author Dr. Newburger from Children's Hospital Boston and her group showed that the right ventricular pulmonary artery shunt group had similar transplant-free survival at six years, but required more catheter interventions before the Fontan procedure.
Right ventricular ejection fraction, New York Heart Association class and complications did not differ by shunt time. Cumulative incidences of morbidities by six years included 20% with a thrombotic event, 15% with a seizure, and 7.5% with a stroke. These data therefore emphasize the importance of continued follow-up of the cohort, and the need to find new strategies to improve the long-term outlook for those with single ventricle anomalies.
The next paper presents results of the CREATIVE trial, which stands for Clopidogrel Response Evaluation and Anti-Platelet Intervention in High Thrombotic Risk PCI Patients). First and corresponding author Dr. Tang from Fuwai Hospital National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College conducted a head-to-head comparison of the safety and effectiveness of intensified anti-platelet therapies either a double dose clopidogrel or adjunctive cilostazol and conventional strategy in 1078 post-PCI patients at high thrombotic risk as identified thromboelastography, which is a platelet function test.
The primary outcome was the incidence of major adverse cardiac and cerebral vascular events at 18 months post-PCI they find as a composite of all cause death, myocardial infarction, target vessel revascularization, or stroke. The authors found that the primary end point occurred in 14.4% of those in the conventional strategy. 10.6% in those given double dose clopidogrel alone. And 8.5% in those also given adjunctive cilostazol. Now, although both intensified anti-platelet strategies achieved increased platelet inhibition, only the triple strategy with adjunctive use of cilostazol significantly reduced adverse events in the long-term follow-up.
No increased rates of major bleeding was found with the intensified anti-platelet therapy regimes. Thus, in patients with low responsiveness to clopidogrel as measured by thromboelastography, the intensified anti-platelet strategies with adjunctive use of cilostazol significantly improved the clinical outcomes without increasing the risk of major bleeding.
The final original paper sheds light on the prevalence and predictors of cholesterol screening awareness and statin treatment among American adults with familial hypercholesterolemia or other forms of severe dyslipidemia. First and corresponding author Dr. Bucholz from Boston's Children's Hospital and their colleagues used data from the National Health and Nutritional Examination Survey, and showed a high prevalence of screening and awareness above 80%. However, there were relatively low rates of statin use among individuals with familial hypercholesterolemia at 52.3%.
And even lower rates among those with severe dyslipidemia at 37.6%. The discrepancy between the prevalence of cholesterol screening and treatment was most pronounced in younger patients, uninsured patients, and patients without a usual source of healthcare. This study highlights an imperative to improve the frequency of cholesterol screening and statin prescription rates to better identify and treat this high risk population. Additional studies are needed to better understand how to close these gaps in screening and treatment.
And that brings us to the end of our summaries. Now for our feature discussion. The natural history of infection with HIV has completely changed with the use of potent antiretroviral therapies. We now know that people living with HIV actually have morbidity and mortality patterns that really resemble the general population, especially with regards to cardiovascular disease, which is very prominent in this population. And I suppose it's this that has led to the assumption perhaps that risk prediction tools and intervention strategies that we apply in the general population may be used in patients living with HIV.
Is this the case however? Well, this week's feature discussion is going to be so enlightening. And it's so important we are talking across the world here, from South Africa to the United States, and of course with me here in Singapore. I am so pleased to have the authors of this week's feature paper and they are none other than Dr. Virginia Triant from Massachusetts General Hospital, Dr. Ralph D’Agostino from Boston University. And our associate editor, Dr. Bongani Mayosi from University of Cape Town. Thank you so much for joining me for today's exciting discussion. Virginia, could I ask you to first describe your study?
Dr Virginia Triant: As you mentioned in the introduction, we have found that patients infected with HIV have an increased risk of cardiovascular disease. That includes both myocardial infarction and stroke compared to age-matched controls in the general population. And extensive data has suggested that the etiology of this increased risk is related both to traditional cardiovascular risk factors, as well as novel risk factors that are specific to HIV infection. And these include chronic inflammation in the immune activation. So consequently, it remains relatively unknown whether established cardiovascular risk prediction functions are accurate for patients with HIV because they include only risk factors that are traditional factors and they don't reflect the complete mechanism that we know is at play in cardiovascular disease associated with HIV.
So in our study, we assess the performance of three established cardiovascular risk prediction functions, two Framingham functions, and then the ACC/AHA pooled cohort's equations and we applied this to a longitudinal HIV infected cohort that was comprised of men. And we investigated the performance of the risk scores in terms of comparing regression coefficients, discrimination and calibration, which are standard metrics in cardiovascular risk prediction. So I'll briefly summarize our overall results as a start. We found that overall, the risk prediction functions underestimated risk in our group of HIV-infected men.
We found that discrimination was modest to poor, and this was indicated by low c-statistics for all of the equations. And we also found that the calibration or the agreement between observed or predicted risk was also poor across the board for all three risk prediction functions. So our results suggests that simply taking the risk prediction functions and transporting them to an HIV infected group may actually result in mis-classification in terms of patient risk. And in underestimation of cardiovascular risk.
Dr Carolyn Lam: Well, Virginia, beautifully summarized of a beautiful paper. But perhaps at this point, we should take a step back and ask ourselves how exactly were these risk prediction scores originally developed. And I can't imagine asking a better person than Ralph. Ralph, could you take us on a jaunt along history and tell us how were those Framingham risk scores developed in the first place? Who are they supposed to be applied to? And did these results surprise you?
Dr Ralph D’Agostino: After the second World War, what was becoming quite clear is things like cardiovascular disease were becoming very prominent. Things like infections and what have you, we were developing all sorts of ways of handling them with medicines and so forth. But with cardiovascular disease, it's a thing that progresses slowly over the years and it starts wiping out people. And back in those days, one out of three men between the ages of 30 and 60 had some kind of cardiovascular event. Women weren't that bad off, but they were pretty bad off also. And so what happened is the American government and the American Heart Institute set up this study in Framingham, where they took a third of the individuals between the ages of 30 and 60 and actually followed them. They took values of variables like blood pressure, cholesterol, things they thought might be useful.
And took values on them. And they had to come back every two years and after as time went on, they took the data after six years, after 10 years they took the data, and started to look at how each individual's blood pressure related to cardiovascular disease. Does cholesterol, and the answer was yes. And then I started getting involved and we were developing these cardiovascular functions where you could actually take an individual, take their measurements now, and make a prediction that had a lot of validity, good discrimination, high predictability over what was going to happen in ten incidents and then the government, the US Government, started having guidelines and what we did is we ran a study where we took a number of different studies in the US, different cardiac studies, the ARIC studies, number of 'em, and we thought applying our functions how well would they do. And it turned out that for whites in the country, the Framingham functions did very well.
But Japanese-Americans in the country, it over-predicted. Then we found out that you could make a calibration adjustment and what we've gone to, like in China, we have a big study where we had a function and Framingham function it over-predicted but calibration adjustment would make enough corrections and so now with Jeanne and the HIV, our hope was that you could take these functions and see how they work on the HIV population. When we did it we were quite well aware, because people have been looking at different things, there's something beyond the original cardiovascular risk. And what the paper shows, quite nicely, these cardiovascular risks do have some relationship but they don't explain enough. The HIV population have a much bigger burden and a simple calibration adjustment just isn't going to work. We need new variables, we need new insights on what to add to these functions.
Dr Carolyn Lam: Thank you so much for that. That's just such important part of history because I have to thank you for those equations. We apply those definitely in our Asian cohorts with that calibration factor. But I was just reflecting as you were telling that story of how we've come full circle now to actually talk about an infection again. It's the midst of an infection, like HIV infection, that we're now testing these equations once again. What better than to ask than Bongani, you're in the epicenter, if I may, of HIV infection. What do you think of the applicability of these findings to the patients you see?
Dr Bongani Mayosi: Yes. These findings are clearly of great interest to us here in the Sub-Saharan African region because it is really the epicenter HIV pandemic. We found population, in terms of risk factors for arteriosclerosis disease still remains low although there clearly derives, for example, in the incidence of myocardial infarction that's being detected in a number of the leading centers now. And with HIV we have observed cases of myocardial infarction while they tend to be younger men who almost always smoke and who get a lot more of a thrombotic episodes.
When you catch them on a thrombotic load, you do not find arteriosclerosis disease. It's going to be important, I think, as we move forward to make sure that as we develop risk functions that will predict cardiovascular disease in patient HIV that the African epidemiological context is completed teaching that HIV affects younger people, affects large numbers of women, but that, quite clearly, is associated with decreased cardiovascular event and stroke and stroke is well demonstrated. But in terms of actually looking at the risk factor this population was still in the early day and certainly in future studies would have to have a major contribution of the African cohort.
Dr Carolyn Lam: That's true, Bongani, but may I ask how would you, perhaps, advise your African colleagues now to look at these data? Then I'd also like to turn that same question over to you, Virginia. What do we do? What's the clinical take home message of these findings?
Dr Bongani Mayosi: I think the message is true that HIV infection is associated with the increased risk of cardiovascular event, there's no doubt about that. That there are some risk factors that can carry through, such as the smoking population but it's important for all clinicians to be aware of that. The ordinary risk you find in using Framingham and other established risk functions is not going to give us all the information that we need. So that recommendation should come through we need to know that risk factors are unknown, that they're important and we need to learn more about these patients in order to give us a perfect prediction of what will happen in the future.
Dr Virginia Triant: I think the findings have a lot of clinical relevance. This suggests, I think, that there are a lot of clinical implications for any patient who has novel cardiovascular risk factors that may not be accounted for in heart functions. And what our findings suggest is that if functions don't reflect the actual composition of risk factors in the population, that can result in misclassification and thus we underestimate risk, we might miss high-risk individuals, high-risk patients who would benefit from aggressive risk reduction but are not currently receiving it. This is a real clinical challenge as sit in clinic and we pull up the scores and calculate them for our patients, whether that is a trustworthy number or whether we should, perhaps, thinking that it's higher, thinking that it's different than what we're seeing for predicted 10-year risk. I think what this suggests is that the functions may need to be further tailored to different populations and sub-populations to reflect the actual composition of risk factors in that population. Even within HIV patients and populations, the risk factors in South Africa might be different than those in Boston, with different relative contributions.
One of the next stepped planned for our team is to actually look at developing, new risk functions which are tailored to HIV and incorporating both HIV itself as a risk factor, as well as HIV specific variables and to attempt to see if we can improve the performance of these functions for HIV populations. Perhaps HIV or HIV related factors might become sort of a new cardiovascular risk equivalent and we can serve patients in this population as higher cardiovascular risk baseline. I also just wanted to mention, briefly, that I think that there are important clinical implications beyond HIV that extend to other chronic inflammatory conditions. Inflammation is increasingly recognized as important in cardiovascular risk and this way HIV can serve as a prototype population. But these results are likely to extend to a lot of different populations who have chronic inflammation for different reasons.
Dr Carolyn Lam: That's a great point, Virginia. As I'm listening, I'm wondering is there no end to this because now we say HIV and then we put other inflammatory diseases, then we say, "Well, women may be different from men," and then different ethnicities may be different. I think gonna be going closer and closer to precision risk prediction, if I might say. Could I just pick your brain here? What do you think the future is? Where's the room for machine learning approaches for risk prediction, individual almost down to that level? What do you think?
Dr Ralph D’Agostino: I think you're right on target. In some sense, the functions we have there's a sort of massiveness about it, when you come to view this population, back in the 50s and 60s and so forth, cardiovascular disease was such a major ... it still is a major problem ... such a major problem you identify some of the real items like the blood pressure and cholesterol, and you attack and develop functions on that and you'd find that you're affecting positively a huge number of individuals, but now as, like Jeanne was saying, and others have been saying, you start focusing, you've got this massive group of individuals who should have their blood pressure controlled and what have you, but if you go into HIV, you go into a number of other populations and so forth, there are other things that are driving these disease and driving the manifestations of the disease. It isn't that blood pressure isn't important, it's that there's other things that are important. And so it's machine learning and so forth and deep learning that you're gonna have to be dealing with manifestations on very high levels and maybe even get into genetics.
Look in the cancer field ... I do a lot of work with the FDA ... look at the cancer field now; how it's so genetically driven in terms of a lot of the drugs the so-called biomarkers, which are basically driven by uniqueness in populations. I think that's definitely going to be, or is the future of these cardiovascular functions.
Dr Carolyn Lam: Okay audience. You heard it, right here. These are exciting times. In the meantime, thank you so much for this precious, valuable piece of work. Virginia, Bongani, Ralph, it was great having you on the show.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore.
Our featured discussion today is really a very important message, that hospitals have the capacity to influence a patient's adherence to secondary prevention and thereby potentially impacting long-term patient outcomes. Much more on this important paper coming right up.
Higher physical activity is known to be associated with lower heart failure risk. However, what is the impact of changes in physical activity on heart failure risk? The first paper in this week's journal, by first author Dr. Roberta Florido, corresponding author Dr. Ndumele from Johns Hopkins Hospital, provides us some answers. These authors evaluated more than 11,350 participants of the Atherosclerosis Risk in Communities, or ARIC, study who were followed for a median of 19 years during which there were 1,750 heart failure events.
They found that, while maintaining recommended activity levels was associated with the lowest heart failure risk, initiating and increasing physical activity even in late middle age were also linked to lower heart failure risk. Augmenting physical activity may, therefore, be an important component of strategies to prevent heart failure.
The next paper highlights the importance of bystander automated external defibrillator use. First author Dr. Pollack, corresponding author Dr. Weisfeldt from Johns Hopkins University School of Medicine sought to determine the association of bystander automated external defibrillator use with survival and functional outcomes in shockable observed public out-of-hospital cardiac arrests.
From 2011 to 2015, the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at 9 regional centers. The exposures were shock administration by a bystander applied automated external defibrillator in comparison with initial defibrillation by emergency medical services. The primary outcome measure was discharged with near or normal functional status as defined by a modified ranking score of two or less.
The authors found that among 49,555 out-of-hospital cardiac arrests, 8% were observed public out-of-hospital cardiac arrests, of which 61% were shockable. Overall bystanders shocked a remarkable 19% of shockable observed public out-of-hospital cardiac arrests. Bystander automated external defibrillation in shockable observed public out-of-hospital arrest was associated with an increased odds of survival with full or nearly full functional recovery compared to emergency medical services defibrillation.
The benefit of bystander automated external defibrillation use increased as the arrival of emergency medical service was delayed. Thus, efforts to increase the availability and use of automated external defibrillators in public locations are likely the most promising immediate ways to improve survival from out-of-hospital cardiac arrests.
The next paper suggests that the complement pathway may contain the secret to a successful cardiac regeneration. First author Dr. Natarajan, corresponding author Dr. Lee from Harvard University, and their colleagues performed a cross-species transcriptomic screen in 3 model organisms for cardiac regeneration, the axolotl, neonatal mice, and zebrafish, all of which underwent apical resection.
RNA-seq analysis showed that genes associated with inflammatory processes were found to be upregulated in a conserved manner. Complement receptors were found to be highly upregulated in all 3 species, particularly the induction of gene expression for complement 5a receptor 1. Inhibition of this particular complement receptor attenuated the cardiomyocyte proliferative response to heart injury in all 3 species.
Furthermore, following left ventricular apical resection, the cardiomyocyte proliferative response was abolished in mice with genetic deletion of complement 5a receptor 1. These data, therefore, identified the complement pathway activation as a common pathway for a successful cardiac regeneration.
The final study sheds light on the association between hyperoxia exposure after resuscitation from cardiac arrest and clinical outcomes. First author Dr. Roberts, corresponding author Dr. Trzeciak from Cooper University Hospital performed a prospective multicenter protocol directed cohort study that included 280 adult postcardiac arrest patients.
They found that early hyperoxia exposure, defined as a partial pressure of oxygen of above 300 millimeters mercury during the first 6 hours after return of spontaneous circulation, was an independent predictor of poor neurologic function at hospital discharge even after adjusting for a potential baseline and postcardiac arrest confounders.
That brings us to the end of our summaries. Now, for our featured discussion.
Medication nonadherence is a common problem worldwide and, indeed, the very topic of our featured discussion today. Our featured paper is so interesting because it tells us that hospitals may have the capacity to influence a patient's adherence to secondary preventive cardiac medications, thereby, potentially impacting long-term patient outcomes, and there are a lot of implications of that.
I'm so pleased to have with us the first and corresponding author, Dr. Robin Mathews, from Duke Clinical Research Institute, as well as the editorialist for this paper, Dr. Jeptha Curtis from Yale University School of Medicine, and our associate editor, Dr. Sandeep Das from UT Southwestern. Lots to talk about.
Robin, could you perhaps start by telling us what made you look at this issue of nonadherence and what did you find?
Dr Robin Mathews: The issue of medication adherence has been something that I think we've been dealing with in healthcare for some time now and, traditionally, we looked at factors that, on a patient level, you sort of also have an idea that maybe they might provider level factors that contribute to nonadherence, so we started thinking about this, what's the health system's role in adherence and is there a role? Do hospital and do providers have more of a role in promoting adherence than we acknowledged in the past?
We are fortunate to have a lot of great clinical data sources available, and the one that we used for this study is the ACTION-Get With The Guidelines Registry, and this is a quality improvement registry that's been around for some time. It's a great source of research and observational studies that has produced a lot of data over the years.
ACTION is a voluntary registry; there are several hundred hospitals that participate, and it gives us very good data, detailed data on the patient experience in the hospital for patients who come in with acute coronary syndrome, so we looked at patients who were enrolled in ACTION over the course of 3 years, from 2007 to about 2010, and looked at the typical patient level factors, medications that were given on admission, how they were treated and what medications they went home on.
What ACTION doesn't give us is longitudinal data, which is really what we were trying to get at here, so we were able to link this clinical data set using CMS data, which is administrative data, claims data, in order to ascertain longitudinal adherence, so we ended up, after exclusions of about 19,500 patients or so, and this spanned about 347 hospitals, of patients that we followed up to 2 years out, and our objectives of the study were 2-fold, one to assess adherence at 90 days for cardio vascular medication, secondary prevention medications that are typically used, so, in this case, we looked at beta blockers, ACE inhibitors, ARB, phenoperidine, and statins.
We looked at 90-day adherence, and then the question we had specifically was does adherence vary among hospitals? The second thing we wanted to knowledge was, if adherence does vary among hospitals, is there a relationship between hospital adherence and cardiovascular outcomes at 2 years, so we looked at MACE, which is MI, revascularization, readmission, stroke. We also looked at death and all-cause readmission, and also mortality.
What we found is that the adherence actually did markedly vary within the medication classes, but also among hospitals, and once we divided these groups into essentially high adherence hospitals, low adherence hospitals, and moderate adherence hospitals, there were these typical differences in terms of patient characteristics that one would expect in terms of comorbidity, socioeconomic status. Patients who were in the high adherence hospitals were more likely to be from ... to have a less comorbidity burden. They had higher income based on ZIP code, and they were more often represented from non-southern hospitals in the United States.
When we then correlated these two outcomes, what we found is pretty interesting. Patients who were in the low adherence hospitals were more likely to have the outcomes that I mentioned earlier. That's not too surprising, yeah, because I had mentioned that the patient mix in terms of the ... their case mix varied among these hospitals, so the logical question as well, maybe the hospitals that are ... have low adherence have low adherence because the patients are generally just sicker.
We know that there are certain high-risk groups and we know that the patients who are treated at some hospitals might be sicker than others, so we did our best to adjust to these, so we did a multivariable model. We adjusted for various patient differences, and we also looked at hospital-level differences, the best that we can ascertain based on the ACTION Registry. That was sort of where the interesting finding was the rates of major adverse cardiac events and death at readmission were mitigated somewhat closer to the null, but they remained significant.
Dr Carolyn Lam: What a detailed summary. Thanks so much.
Jeptha, I love your editorial that accompanied it. Could you put the study into context a bit for all of us? Why are these finding so impactful?
Dr Jeptha Curtis: It's rare that you get to review and editorialize a paper that has so many implications both from a clinical practice and policy standpoint, so I think they really hit on a understudied area, and really this paper should cause people to reflect on what's going on in their practice and at the institutions that they practice in.
I would say that adherence is just such a challenging problem that, as Robin articulated, has been refractory to change over 15 years. We've been studying this for a long time, and we know that the numbers had not improved over time.
What's different about this paper is that it really suggests a completely different approach to addressing nonadherence among patients, and if this is ... if their findings are true, if nonadherence is really actionable at the hospital level or attributable to the hospital level, it really opens up new avenues both for research as well as for quality measurements.
As I read this paper for the first time, I was really struck by thinking about how invisible adherence is to frontline clinicians. We just don't have the information to tell us are our patients taking their medications on a day-to-day basis, and we know that most of them are not because the research has consistently shown that a large proportion failed to take their medication, and Robin's paper showed that yet again, but I can't say that there's any steps that our hospitals are really doing to address that in a systematic fashion.
All of our efforts for quality improvement have really been towards making sure that patients are prescribed the medication on discharge, and in the setting of readmission and trying to prevent readmission to our hospitals, we are now having follow-up phone calls with patients to assess failures to taking medications and follow-up, but it's really ... That's it. There's really no systematic way that we're trying to ... if an individual patient or a group of patients are adherent to their medications, so this is really a whole new avenue.
What we don't know is how to improve it, right? I think that the first implication of this paper is that there are differences at the hospital level. Some hospitals seem to be doing this better than others. That could be driven by differences in case mix, but it could also be driven by differences in hospital practices, and I think this is a wonderful opportunity for future direction of research perhaps using positive deviance methodologies to go to those hospitals that have high adherence rates in really trying to understand what differentiates their practices from those of other hospitals.
Dr Carolyn Lam: Indeed, Sandeep, I remember some of the conversations we had as editors about this paper. We, too, were struck by the novelty, and you've mentioned before, Sandeep, that the novelty of perhaps nonadherence or adherence as a new performance measurement. Would you like to comment on that?
Dr Sandeep Das: Yeah, first thing, what was kind of interesting about the discussion surrounding this paper, there were some people who read it and just sort of read it as the message being nonadherence associated with worst outcomes, and I thought like that was pretty established, known, but then there were some people like Jeptha and Erica who really got it, who really understood what was novel and interesting about this, and I also congratulate Robin on a fantastic paper.
One thing I think that's really interesting, in my day job, I wear a couple of quality hats. I am the cardiology division quality officer, and health system quality officer for UT Southwestern, so I spend a lot of time thinking about quality, and I'll tell you there's quite a bit of metrics that he ... there's just a lot of things that now you feel they're not particularly substantive and they're very difficult to change, you have, you know, if aspirin on discharge, as Robin mentioned discharge adherence, aspirin on discharge is 99% and getting people to document the last 1% rather than fail to document it, there's not really a fulfilling challenge where you think, "I'm really impacting patient endpoints."
I was really struck by the opportunity here. We know that from studies like MI FREEE that adherence to medications even at a year is probably about a third of patients are not adherence, so it's really kind of interesting to take that as an opportunity. We should fixate on what are these therapeutic option or not therapeutic option can move the needle by a fraction of a percent, but these are medications that are proven to prevent MI and change lives, and there's a massive delta here that we can address. The concept that this is addressable on the hospital level is fascinating, and I'm a big fan of coming up with sort of systems level approaches to addressing problems.
Dr Carolyn Lam: Congratulations once again on this great paper. Just tell us what do you think of the next steps and what would your message be to those of us who practice outside of the US?
Dr Robin Mathews: Jeptha talked about where our focus should be in terms of what we can do on a hospital level. I think the ultimate answer is there's a lot of heterogeneity in terms of what is done, and I think that, expanding on his point about better investigating practices that currently exist, and whether that's surveying things, and we have a lot of great professional societies and registries that we can sort of reach out to these hospitals, find out what they're doing, what makes them different from the hospitals that are not doing those things and then really doing some rigorous testing to figure out if in fact these specific interventions that these hospitals have put in place are with the high likelihood leading to the effects that we've seen, so I think that surveying sort of what's out there, understanding what works in a rigorous way and then being able to systematically apply this or distribute this to other hospitals to share the knowledge and say, "Hey, this is what we think. We've actually done it."
Like Sandeep said, with the inpatient management of patients who come in with acute coronary syndrome, we've done it well. I think it sort of contributed. Our guidelines and adherence to these guidelines and the metrics that we've used have really demonstrated that we've sort of achieved high levels, but we sort of reached I think the ceiling for a lot of that, and you always have to be open to novel metrics and then the idea of focusing in on the transition from hospital to home and what we can do once they leave their door, once they leave the door of the hospital, I think would be useful.
In terms of the rest of the world, I mean, the US has very unique problems based on our payment models and access to care and whatnot, but I think a lot of the themes that we sort of have seen with medication nonadherence when it comes to patient-level factors and provider-level factors are sort of universal.
At the end of the day, patients need to be empowered, and they also need to have the tools to allow them to be successful in my opinion. I think we've for a long time in this space often said, "Well, this is sort of a patient that there's only so much that we can do as providers," but I think that papers like this highlight the possibility that there's probably more that we can do to make these impacts.
Dr Sandeep Das: One of the comments or a question that I had was the controversial thing is to what extent hospitals should be accountable for things that happen well after discharge? I think readmission is one that always comes up. There's factors that are outside our control, so one question is kind of to what extent should we be responsible for stuff that happens forward of 6, 9 months down the road?
The second question that I had or a comment that I had was I do think that there's going to be a generalizability to non-US settings because there's elements of this ... For example, this now would incentivize hospitals and discharging physicians to make sure that patient education is substantive, right? If the metric is, "Did you provide discharge instructions, yes or no?" then that's sort of trivially accomplished by handing them a piece of paper and checking a box, but, now, if we follow a metric like this, we're really going to be accountable for making sure people understand what they're supposed to be taking and have a path to get it and things like that, so it makes some of the transitions of care stuff, and that's a great point, some of the transitions of care stuff much more substantive.
Dr Robin Mathews: Sandeep's point is a very good point, and it's very difficult to come up with a clear answer for that and, like you said, the issue with readmissions and all sort of the factors that are involved from a social level and research level cloud that, so ... and, hence, I think something like readmission is controversial, and I think this sort of question will generate a lot of further questions about whether using medication adherence and holding hospitals responsible.
I will say that when we looked at adherence sort of in the short term at 90 days and we looked at it in the long term at a year, we saw there was sort of a drop off, but it wasn't as substantial it was earlier, so I think a lot of adherence in the short term after hospital discharge continues to decline over time, but it doesn't drop down as precipitously downstream as it does early on, and I think that, just like with readmission, there's been some data to suggest that near term readmission are more likely things that "could be preventable" as opposed to maybe a readmission toward the end of the month.
At the end of the day, it's a very difficult thing and there's a lot more discussion that needs to be had about this topic, but I think that with this, it gives me some hopefulness and I think everybody else on this call that at least we wouldn't then be able to prevent every adverse outcome that happens 2 years down the road, but we might be able to at least affect a substantial portion of them.
Dr Carolyn Lam: Listeners, you heard it. There's lots that we can do. This paper says a lot. Please do pick it up. Read the editorial as well.
Thank you so much for listening today, and don't forget to tune in again next week.
Dr Joseph Hill: My name is Joe Hill. I'm the Editor-in-Chief of Circulation and I'm very pleased today to be here today with Professor Daida from Juntendo University in Tokyo, Japan, as well as one of our associate editors, Professor Shinya Goto from Tokai University in Kanagawa, Japan. Dr. Daida is one of the senior authors on a very exciting clinical trial that we're publishing in Circulation. The first and largest trial comparing high-dose versus low-dose statins in Asia. Dr. Daida, would you please tell us more about the study?
Dr Hiroyuki Daida: Yes. Thank you. The trial, called REAL-CAD, is a randomized trial. We compare high-dose statins with low-dose statins in Japanese patients with stable coronary artery disease. The number of the patients is 13,000. It's the largest trial ever comparing high-dose and low-dose statins. We found that with that reduction of the primary end point, which is a composite end point, including cardiovascular death, non-fatal MI, non-fatal stroke, and unstable angina requiring hospitalization.
That is very exciting result because it is the largest trial ever and also the very first trial in Asia.
Professor Shinya Goto: Congratulations, Professor Daida, for that great achievement, in the REAL-CAD trial. Could you explain a little bit about the background and that the dose of statins in Japan is generally low, and what was the reason why we kept using low-dose statins, and is care to try change the standard of care in Japan and also East Asia? Could you give a comment on those two topics?
Dr Hiroyuki Daida: Our trial is quite similar to that of PNP trial of comparing Western extensive statin treatment and the Asia statin treatment. However, that extensive statin treatment, intensive statin treatment, is not popular in Asia, so we did that maximum clinical dose of statin, we use this dose in Japan. It is the maximum dose of statin approved in Japan.
Dr Joseph Hill: So as I understand it, the rationale was the thinking that Asians, East Asians, are unable to tolerate high-dose statin therapy. In this case you used pitavastatin. And, in fact, what you found was there were no increase in serious adversive events in high dose patients. And, just like Caucasians, they derived considerable benefit at multiple points in atherosclerotic cardiovascular disease metrics.
Dr Hiroyuki Daida: Actually, they didn't experience a really high-dose of statin in Japan so government approval is up to 4 mg of pitavastatin, a dose of that about 20.
Dr Joseph Hill: So, this is not what we would call high-intensity statin therapy but nonetheless, there was a dramatic benefit including an all-cause mortality, irrespective of the starting LDL level at the beginning of the trial?
Dr Hiroyuki Daida: That is right. We found that the effect is similar that the patient, the LDL is greater than 95 or less than 95. So, the effect is independent of the basal based on LDL level.
Professor Shinya Goto: The one thing, very exciting just like Joe mentioned, all cause of mortality, especially known cardiovascular caused mortality reduced with the use of high-intensive care of the statin. If any kind of speculation, what is the cause, reduce the inflammation or maybe reduce cancer, something like that. They have any kind of advance to an analysis?
Dr Hiroyuki Daida: We didn’t have further analysis but we are not so keen to emphasis the total mortality because maybe that is a chance of the effect but this is the largest trial, so the result is really exciting in this kind of aspect.
Dr Joseph Hill: So, I would reiterate Shinya’s congratulations. This is a monumental piece of work. The largest clinical trial comparing high dose versus low dose statin. The largest ever. The first in Asia. You found a benefit that makes total sense across what we know from other trials and this will change practice. Your work, I believe, will change the way patients with atherosclerotic cardiovascular disease is handled in Japan.
Dr Hiroyuki Daida: Yes, actually the current guideline in Japan for the secondary condition. The condition is LDL less than 100 and for the really high-risk secondary condition listed seventh. We didn't recommend high-dose statin initially, so, this trial result is kind of like this, changing.
Dr Joseph Hill: I can't resist asking, what comes next? What's your next project?
Dr Hiroyuki Daida: Maybe we need to have a further reduction of LDL. We have another drug, other potent drug recently. We need to investigate all of the new drug such as PCSK9 inhibitor in secondary prevention.
Professor Shinya Goto: That's wonderful. Do you have any time to extend observation of the trial? I think the trial is relatively still superior as compared to the global long-standing trial. Really, that's fine, that effect of statin on the cholesterol and even it's different from Japan and other regions of the world. There ought to be intriguing thing, I would like to know, what are you waiting to extend that observation now?
Dr Hiroyuki Daida: Fortunately, we do not intend to extend the follow-up. The whole thing is about four years but we do not plan to extend. We will further analyze the data for some group and our kind of CRP and effect of the baseline.
Dr Joseph Hill: Lots of secondary analysis underway, undoubtedly. Let me thank both of you for being here, Professor Daida and Professor Goto, I congratulate you again. It's not often that you make a practice-changing intervention in modern-day medicine. I salute you and we are honored and thrilled to publish your outstanding work in Circulation. Thank you both.
Dr Hiroyuki Daida: Thank you very much.
Professor Shinya Goto: Thank you very much.
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 of Singapore and Duke National University of Singapore. Our featured discussion today is a wake-up call because despite substantial efforts to promote cardiac rehabilitation in guidelines and performance measures only a small percentage of patients are receiving this and there is a remarkable regional variation. Lots of lessons to be learned here coming right up after these summaries.
More children with congenital heart disease are surviving into adulthood, and congenital heart disease is associated with risk factors for dementia. But what is the actual risk of dementia in congenital heart disease adults? Well, in this first paper from first and corresponding author Dr. Bagge from Aarhus University Hospital in Denmark, the authors used medical registries and a medical record review of all Danish hospitals to identify more than 10,600 adults with congenital heart disease diagnosed between 1963 and 2012 and followed up until the hospital diagnosis of dementia or death, emigration, or the end of the study in the end of December 2012.
For each individual with congenital heart disease the authors identified 10 members of the Danish general population matched on sex and birth year. They found that the risk of all-cause dementia was increased by about 60% in congenital heart disease adults compared with the matched general population. The risk was higher for early onset dementia, that is dementia at less than 65 years of age, in which the risk was more than double. The risk was also elevated for all levels of congenital heart disease complexity, including those with cyanotic potential. The relative risk remained increased for those without extra cardiac defect or acquired cardiovascular diseases.
These results really underscore the importance of understanding the risk of adverse long-term neurologic outcomes in the growing and aging population with congenital heart diseases.
The next paper suggests that patient outcomes after lower limb revascularization have improved in England over recent times. This paper from first and corresponding author Dr. Heikkila from London School of Hygiene and Tropical Medicine used individual patient records from hospital episode statistics to identify almost 104,000 patients who underwent endovascular or surgical lower limb revascularization for infrainguinal peripheral artery disease in England between 2006 and 2015. During this 10-year period the estimated one-year risks of major amputation and death reduced after both endovascular and surgical lower limb revascularization in England. These trends were observed for all categories of peripheral artery disease severity, with the largest reductions seen among patients with the most severe underlying disease.
These encouraging trends coincided with a period of centralization and specialization of vascular services in England, although the current findings cannot be interpreted as resulting directly from this reconfiguration of services.
The next paper presents experimental data showing that targeting the Janus kinase and signal transducer and activator of transcription or JAK-STAT pathway may represent a disease-modifying strategy in inflammatory vasculopathy. First author Dr. Zhang, corresponding author Dr. Weyand from Stanford University School of Medicine examined whether persistent vessel wall inflammation in giant-cell arthritis is maintained by lesional T cells and whether such T cells are sensitive to the cytokine signaling inhibitor tofacitinib, which is a JAK inhibitor that targets JAK3 and JAK1.
To do this, vascular inflammation was induced in human arteries and grafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant-cell arthritis. Mice carrying inflamed human arteries were then treated with tofacitinib or vehicle. They found that tofacitinib suppressed T cell invasion into the artery, inhibited proliferation and cytokine production of vasculitogenic T cells and curbed survival of artery resident T cells. Tofacitinib treatment prevented neoangiogenesis and intimal hyperplasia in these inflamed arteries. Thus, inhibition of JAK-STAT signaling with tofacitinib effectively targeted multiple disease-relevant processes in inflammatory vasculopathy and thus represents a potential disease-modifying agent.
The next paper provides important insights into how coronary artery calcification burden and cardiorespiratory fitness, which are actually two independent predictors of cardiovascular disease but may interact with each other to impact cardiovascular risk. First author Dr. Radford, corresponding author Dr. Levine from the Institute of Exercise and Environmental Medicine Texas Health Presbyterian Hospital and UT Southwestern Medical Center studied 8,425 men without clinical cardiovascular disease who underwent preventive medical examinations that included an objective measurement of coronary artery calcification and cardiorespiratory fitness between 1998 and 2007.
They found that cardiovascular disease events increased with increasing coronary artery calcification and decreased with increasing cardiorespiratory fitness. Adjusting for coronary artery calcification levels for each additional MET of fitness there was an 11% lower risk of cardiovascular disease events. When both coronary artery calcification and cardiorespiratory fitness were considered together there was a strong association between continuous cardiorespiratory fitness and cardiovascular disease incident rates in all coronary artery calcium groups. Thus, the take-home message is for any baseline age and level of coronary artery calcification greater fitness is associated in a continuous fashion with lower risks of cardiovascular disease events.
And that wraps up our summaries. Now for our feature discussion.
We all know how cardiac rehabilitation is. It's strongly advocated in guidelines, it's very well highlighted in performance measures. But how well are we actually doing? Well, today's feature paper really gives us some very valuable information and really kind of holds a mirror in our face, doesn't it? I'm so pleased to have with us the first and corresponding author of the paper Dr. Alexis Beatty from VA Puget Sound Health Care System and University of Washington as well as Jarett Berry, our associate editor from UT Southwestern. Alexis, could you tell us what did you see when you looked at cardiac rehabilitation among the Medicare and VA populations?
Dr Alexis Beatty: Overall participation in cardiac rehab after an MI or a PCI or a bypass surgery is pretty low, only about 16% of people in Medicare and about 10% of people on the VA actually participate in cardiac rehab. But the interesting thing is that we saw pretty wide variations from state to state in participation. So some states had pretty high participation, upwards of 40% of patients, and some states had only 1, 2, 3% of people participating.
Dr Carolyn Lam: Were there any patterns to this, any factors that you teased apart?
Dr Alexis Beatty: We did observe that some regions of the country appeared to be doing better than others. So for instance, the West North Central region of the United States, Nebraska, South Dakota area has high participation in both populations and other regions like the Pacific, California, Oregon, Washington, Hawaii, Alaska, have lower participation in both populations.
Dr Carolyn Lam: And any postulations on why this may be the case?
Dr Alexis Beatty: Yeah, I have some theories. We did try to look at whether it was due to patient characteristics, hospital characteristics, socioeconomic status, and it doesn't really seem to be any of those things that are driving the differences, which leads me to believe that it's actual practice variations. So I think that literally the systems are set up better in some areas of the country than others to get patients into cardiac rehab.
Dr Carolyn Lam: And as you beautifully wrote in your paper, that means that there may be an opportunity here to identify best practices here, isn't it? Jarett, you've been thinking about this a lot. What do you think?
Dr Jarett Berry: Yeah, I was curious, Alexis, it is interesting that the hospital variation that you saw, the on-site cardiac rehab was fairly consistent across cardiac rehab participation rates in Medicare but there was quite a bit of variability in the access to an on-site cardiac rehab site in the VA patients. I thought that was an interesting observation because it does suggest perhaps that what's driving regional variability looks to be fairly complex as you point out in your paper. But I just wanted to have you speculate a little bit or think a little bit about strategies for how we might think about improving cardiac rehab participation given the fact that there doesn't seem to be one particular answer to this problem. And so as you think about this longstanding challenge, how would you think about the future, about how we could actually really move the needle in increasing cardiac rehab participation?
Dr Alexis Beatty: There's a lot of different ways that I think that we can work to start moving the needle. And as you point out, not every VA location has a cardiac rehab center on-site and sites that do have cardiac rehab on-site do tend to do better at getting their patients into cardiac rehab. And I think it may just be that there are people there who are interested in cardiac rehab and are promoting it to patients. And then there probably are some access issues as well. But I think it's not just kind of an "if you build it they will come" sort of proposition. Having cardiac rehab centers is important but then having systems in place to get people into cardiac rehab and get people going to cardiac rehab are just as important.
And so I've talked to a lot of the VAs that have centers, don't have centers, do a good job of getting people in, don't do a good job of getting people in. And even in these places that don't have cardiac rehab on-site, if they have a system in place that helps get patients into cardiac rehab they're still able to achieve pretty high rates. And so a lot of that is just doing kind of setting it up as an automatic order and having a nurse or exercise physiologist or somebody be a navigator for the patients through the process.
And then the other thing I really want to stress is the importance of providers recommending it to patients. I think that's the strength with which the providers sell cardiac rehab can really make a big difference.
Dr Jarett Berry: It's interesting, I just took over cardiac rehab as a medical director here at Southwestern about a year and a half ago and I've been struggling with this. And one of the interesting things that I just would love to get your thoughts on that I noted, which doesn't seem to get a lot of attention in the literature to me, is the role of co-payments. I don't know if most physicians who aren't involved in this space appreciate that for most insurance and for Medicare, it may not be the case for VA, I can't speak to that, but the co-payment amount for each time you come, for each visit is between $30 and $50 per visit. That seems to me in some ways ... I know you didn't address it at all in your paper, but just keeping this conversational ... What do you think the role of some of these other less discussed factors are such as just co-payment amounts that might actually be having a bigger effect on participation? Because I know if I had to pay a 1,000 bucks to go to cardiac rehab I might think twice about it.
Dr Alexis Beatty: Yeah, and I think the co-payment issue is a very real issue too and there's a lot of policy level things that makes cardiac rehab difficult. So one is this co-pay issue, there also then other changes to the way it's administered like where the location of the cardiac rehab can be and how hospitals get reimbursed for that. It has to be prescribed by a physician, it can't be prescribed by a nurse practitioner or a PA, it has to be supervised by a physician. There's a lot of restrictions on cardiac rehab that can just, practically speaking, make it difficult to deliver both from the patient and the provider and health system level.
And what I tell my patients when I am trying to get them to go to cardiac rehab, and we do have co-payers in the VA too that are kind of on a sliding scale depending on patients’ means. And so I tell them that it's an investment. You are making this upfront investment of your time and money and effort to get yourself healthy and learn how to be healthy in the long term. So we know that people who attend cardiac rehab are less likely to be hospitalized and are less likely to die from their heart disease, and so it's an important investment to make and that's sometimes the hard message to sell and I wish it were easier to sell.
Dr Jarett Berry: I totally agree with you. My own patients and also the patients that I helped manage through cardiac rehab have received such benefit in many different areas from the participation. But yeah, it is an investment.
I wanted to ask another question, if I may Carolyn, about the future. And you alluded to this in your paper, I know your work with Mary Whooley, you guys have done great work thinking about rolling out home-based cardiac rehab. And I think personally that the future of cardiac rehab for most patients, that we're really going to move the needle—I mean some of the policy issues are really important—but can you comment on just telling us what home-based cardiac rehab is and to what extent you think that is a potential solution to deal with these persistently low participation rates?
Dr Carolyn Lam: Actually Jarett, if I may just butt in before Alexis answers, I was about to ask that because I was just placing myself in the patient's point of view. And I mean even me, I hate going to gyms now and much rather work with a home app instructing me what to do and I can just do it here, you know what I mean? So I think that's a great question. Alexis?
Dr Alexis Beatty: I agree, the future is home cardiac rehab and using all the tools that we have at our disposal to make it easy to deliver home cardiac rehab. The evidence isn't quite as strong for home cardiac rehab but the existing evidence does suggest that it's equally effective to center-based cardiac rehab, it's just not reimbursed in the United States. So functionally it only exists in sort of integrated health systems like the VA.
The VA, for instance, has started delivering home-based cardiac rehab programs. I think it's now at over 30 centers in the US. And this has basically started in the last five years. And the programs are pretty similar to a center-based cardiac rehab program in that patients come in and they get an in-depth assessment from cardiac rehab professionals. But then the difference is that they go and exercise on their own at home and they check in with the cardiac rehab professionals usually on a weekly basis over the telephone. And so it ends up being more of like a coaching relationship between the cardiac rehab professionals and the patients who are exercising on their own at home. And a lot of patients really like it because, as you pointed out, it's much more convenient for them, they don't like going to a gym, they'd rather be walking around in their neighborhood or going to their local community pool to swim. So it just sort of addressed a lot of these patient issues and they don't have to pay a co-payment. So it can take some of these other barriers that are there.
Dr Jarett Berry: Like a Peloton bike for cardiac rehab, right?
Dr Alexis Beatty: Yeah. I mean you could even do that. For instance, in HF-ACTION they actually gave people exercise equipment for a HF-ACTION study for the home segment of the HF-ACTION study. So there certainly are models whereby we could just be giving exercise equipment. And in the VA I can mail people these little exercise paddlers that they can put on their floor or their table and you can use them with your legs or your arms. So certainly being able to send some of this exercise equipment to your patients may help them get them into doing things. But I think home cardiac rehab is the future.
And then also I do work on using technology to help deliver home cardiac rehab and I view technology for this space not as the solution but as a tool to help you deliver home cardiac rehab. And now that technology is so ubiquitous, I think that we need to now learn how to use the technology to help us better deliver cardiac rehab in a way that meets the patients' needs.
Dr Carolyn Lam: Wow. Jarett, I've actually got a question for you. You were just saying that you run the rehab unit there, so what messages did you take home from this paper?
Dr Jarett Berry: What I took home from this was exactly what we've been discussing, this issue of low uptake of cardiac rehab even in the scenario where you have a model where you're delivering this through Medicare or the VA we still see very low participation, albeit there is some variability. And so my interpretation after doing cardiac rehab here at Southwestern for the last year and half is exactly what Alexis is saying, is that we need to be really thinking more creatively about how we can deliver cardiac rehab where the patients are and not requiring them to participate in centers of cardiac rehab that are maybe 30, 40 miles from their home and in the middle of the workday, all of which just really makes such a model inefficient.
So I just think what this paper does really solidify is that we really need to be thinking broadly and creatively about how to bring cardiac rehab to more patients because the way we're doing this now I think unfortunately is just ineffective.
Dr Carolyn Lam: Anything to add, Alexis? This is great.
Dr Alexis Beatty: So one other point that I would like to mention. I think about 10 years ago there was another paper that used a very similar method, and we based a lot of our methods off of that paper by Suaya about 10 years ago. And they found that the rate of participation in cardiac rehab was somewhere very close to ours, I think it was 18% and we observed 16%. And since that paper was published cardiac rehab got included in guidelines, included as a performance measure, and there has been a big push and a lot of attention to try to get people into cardiac rehab and we have moved the needle zero since that time. So I think clearly something new is needed to move the needle for cardiac rehab just as Jarett was pointing out. So we got to do something because what we're doing isn't working.
Dr Carolyn Lam: That's a great call and thank you for showing that to us so clearly in your paper.
Dr Jarett Berry: Yeah, thanks Alexis and thanks for being so responsive in the revision process, it was a real pleasure to work with you all on this really important paper.
Dr Alexis Beatty: Thank you so much for publishing this paper. I feel I've been working on this for like five years.
Dr Carolyn Lam: Well you heard it here, listeners. Thank you for joining us today. Don't forget to tune in again next week.
Dr Carolyn Lam: Welcome to "Circulation On The Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center, and Duke National University of Singapore. Our featured paper today is so important for cardiac surgeons and their patients. It answers a question of whether targeting a higher versus a lower blood pressure during cardiopulmonary bypass helps to prevent cerebral injury. Curious? Well, more soon right after these summaries.
In the first original paper this week, MicroRNA-22 is shown to be a novel mediator of vascular smooth muscle cell, phenotypic modulation, and neointima formation. Co-first authors, Drs. Yang and Chen, co-corresponding authors, Dr. Zhang from Zhejiang University and Dr. Xiao from Queen Mary University of London and their colleagues used wire injury mouse models to show that MicroRNA-22 controls vascular smooth muscle cell phenotype and injury-induced arterial remodeling by modulating multiple target genes, including methyl-CpG-binding protein 2, histone deacetylase 4, and ecotropic virus integration site 1 protein homolog.
The authors observed that MicroRNA-22 expression was suppressed in human femoral arteries with atherosclerotic plaques, and that there was an inverse relationship between MicroRNA-22 and its target genes in healthy and diseased arteries. Furthermore, local delivery of MicroRNA-2 in the injured arteries prevented adverse arterial remodeling, thus suggesting that site-specific delivery of MicroRNA-22 mimics may be a potential therapy for in-stent restenosis.
The next paper adds to our understanding of the pathobiology of pulmonary hypertension related to left-sided heart failure and importantly adds histomorphometric evidence from human lung specimens at autopsy or surgery.
First author Dr. Fayyaz, corresponding author Dr. Redfield, and colleagues from the Mayo Clinic studied patients with heart failure with preserved or reduced ejection fraction and pulmonary hypertension and compared these to normal controls, as well as patients with primary pulmonary veno-occlusive disease.
They found that patients with heart failure and pulmonary hypertension had global pulmonary vascular remodeling with thickening of the media and intima in arteries and thickening of the intima in veins and small pulmonary vessels compared to normal control subjects.
This venous and small-vessel intimal thickening was more severe than the arterial intimal thickening in heart failure with a pattern that was similar to patients with pulmonary veno-occlusive disease. In fact, the severity of pulmonary hypertension correlated most strongly with venous and small vessel remodeling rather than arterial remodeling.
These findings expand our understanding of the pathobiology of pulmonary hypertension in heart failure. It also suggests that pulmonary venous remodeling in heart failure may predispose to worsening alveolar edema with pulmonary vasodilators as in primary pulmonary veno-occlusive diseases.
Are there sex and race differences in the lifetime risk of HFpEF versus HFrEF? First author Dr. Pandey, corresponding author Dr. Berry from UT Southwestern Medical Center, and their colleagues used participant level data from two large respective cohort studies, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis to determine remaining lifetime risk estimates for heart failure with preserved and reduced ejection fraction at different index ages.
They found that compared to women, men have a higher lifetime risk of HFrEF, heart failure reduced ejection fraction with a similar lifetime risk of HFpEF, or heart failure preserved ejection fraction. Compared with blacks, non-blacks have a similar lifetime risk of developing HFrEF but a higher risk of HFpEF.
Lifetime risks of HFpEF and HFrEF were similar and substantially higher in those with versus without antecedent myocardial infarction.
In summary, these findings provide novel insights on sex and race differences in the lifetime risks of HFpEF and HFrEF, and may help health policymakers in appropriate resource allocation for targeting HFpEF and HFrEF specific preventive therapies at the at-risk population.
What are evidence-based blood pressure targets during pediatric cardiopulmonary resuscitation? Well, first and corresponding author Dr. Berg from Children's Hospital of Philadelphia and his colleagues studied a multi-center population of children with invasive arterial blood pressure monitoring during in-hospital ICU cardiac arrest, and the Collaborative Pediatric Critical Care Research Network Intensive Care Units, between 2013 and 2016.
They found that a mean diastolic blood pressure greater or equal to 25 millimeters of mercury during cardiopulmonary resuscitation in infants, and greater or equal to 30 millimeters of mercury in children 1 year old or greater, was associated with a 70% greater likelihood of survival to hospital discharge, and a 60% higher likelihood of survival with a favorable neurologic outcome.
On the other hand, survival rates were markedly lower with mean diastolic pressures less than 20 in infants and less than 25 in children 1 year or older. Thus, clinicians should consider targeting diastolic blood pressure of 25 or greater in infants, and 30 or greater in children 1 year old or older during cardiopulmonary resuscitation when invasive arterial blood pressure is monitored.
That wraps up our summaries for this week. Now for our featured discussion.
Does a higher versus a lower blood pressure target during cardiopulmonary bypass surgery reduce the risk of cerebral injury? Well, the feature paper today provides some answers, and we have the first and corresponding author, Dr. Anne Vedel from University of Copenhagen with us today, as well as our associate editor, Dr. Timothy Gardner, who's a cardiac surgeon from University of Pennsylvania.
Thank you so much for being with us today and this was a terrific trial, a very difficult trial to carry out. Could you please tell us a bit more about it?
Dr Anne Vedel: Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. Up to half of our patients suffer these perioperative silent strokes. Therefore, in Copenhagen we conducted a trial investigating the importance of two distinct blood pressure levels during cardiopulmonary bypass. Now, on this subject of optimal perfusion strategy during bypass, there are many opinions, but also a stunning lack of convincing evidence, for instance, when it comes to blood pressure management.
Now, the question is whether normal physiological principles, such as cerebral autoregulation therapy, whether they apply during bypass, or if perfusion pressure indeed does play a less important role when blood flow is mechanically provided in an uncomplicated and sufficient way by the heart and lung machine.
So, in a patient on the assessor-blinded randomized trial, we allocated patients to a higher or a lower MAP target, 70 to 80, or 40 to 50 millimeters of mercury, respectively, by titrating intravenous norepinephrine during bypass.
Pump flow levels were set at 2.4 liters per minute per square meter of body surface, and our primary outcome was the total volume of new ischemic cerebral lesions, expressed as a baseline MRI, and opposed to the difference between the baseline MRI and the postop MRI on day three to six. Secondary outcomes were a number of new ischemic lesions and newer psychological test evaluations.
Now among the 197 patients enrolled who were scheduled for coronary artery bypass, or heart valve repair surgery, or a combination of both, we found that 53% of patients in the low target group as opposed to 56 in the high target group had new cerebral lesions on their postop cerebral MRI.
The primary outcome of volume of new cerebral lesions was comparable between groups, and so was the total number of newer lesions. No significant difference was observed in stroke rates in frequencies of postoperative cognitive dysfunction, or in severe adverse event rate.
Therefore, we concluded that among patients undergoing on-pump cardiac surgery, targeting higher versus a lower mean arterial pressure did not seem to affect the volume or number of new infarcts.
Dr Carolyn Lam: Wow, thank you so much, Anne. Tim, you think about these issues a lot more than I do as a non-surgeon. Could you tell me what your insights were?
Dr Tim Gardner: You know, it's a very difficult study to do a randomized control trial in this environment, and they're really to be congratulated for doing it. As Anne acknowledges, this is not an area where randomized trials are very frequent.
The first thing about the trial, I think, is a growing awareness among all of us that there seems to be a lot of imaging evidence of what we call injury or changes based on diffusion-weighted imaging in patients after cardiopulmonary bypass. This is not the first study that shows that.
But the question is are these incidental, trivial lesions? I'd have to, again, ask Anne to clarify how many of the patients in either group, what percentage had what we would consider evidence of overt strokes?
Dr Anne Vedel: Well, overt strokes, as opposed to silent strokes, 1 patient in the lower target group had stroke and 6 patients in the high target group, which corresponds to 1 as opposed to 7%.
Dr Tim Gardner: That was not quite statistically significant difference but headed in that direction with the assumption that if you have a larger sample size there might be, in fact, some association with overt stroke using the high target vasopressor approach, is that right?
Dr Anne Vedel: We can only speculate. But as you do, yes, I agree.
Dr Tim Gardner: To go back to the original question, the significance of these, well, you were referring to as silent strokes. Can you comment on the clinical significance there? We hear of silent heart attack. What is a silent stroke and what are the implications of that long term for patients?
Dr Anne Vedel: In other fields of research on the silent strokes, it's been shown that they correlate to both frequency of postoperative cognitive dysfunction and also later development of mild cognitive impairment and dementia. But these kinds of results, there isn't enough research in the field of cardiac study for us to say the same. But those are the implications from other research fields.
Dr Tim Gardner: But you can understand from the perspective of a cardiac surgeon, and this concern has been expressed and talked about in the literature for 20 years or more, the possibility that even what seems to be, with no injury apparent and no overt stroke, there may be some neurological consequence to cardiopulmonary bypass.
So just to move on from that because I agree that we just don't have any reliable information that these silent strokes result in late or permanent injury, I think again the finding that manipulating the blood pressure, which seems to be intuitively beneficial in patients, especially elder patients, did not, in fact, show any benefit and, in fact, may have been associated with a slight increase in overt stroke. Is that a fair conclusion from your study? A summary of your study?
Dr Anne Vedel: I would say it is a fair conclusion, and surprisingly so. The question is whether it is the blood pressure or the means that we apply to have this increase in blood pressure that is the point of interest here.
Dr Tim Gardner: You mean whether, in fact, using the norepinephrine, the vasoconstrictor, to increase the blood pressure whether that itself, it certainly didn't benefit, it may have been a problem.
Dr Anne Vedel: Exactly. That's what I speculate might be the case. But I also think it's fair to say at this point that this is somewhat artificial physiological scenario, the cardiopulmonary bypass.
Dr Tim Gardner: I agree with that, that you're controlling blood flow and the patient is exposed to a lower hemoglobin and oxygen-carrying capacity and so on. But I think what struck me about your findings, or strikes me about your findings, is what appears to be in many of the patients, the low target patients, pretty effective autoregulation of the cerebral circulation, despite the artificiality of cardiopulmonary bypass.
I think that's, again, something that has been not well known or well accepted by many people, thinking that if you lower body temperature, you lower hemoglobin, autoregulation may not be enough to maintain good cerebral perfusion. It looks like this study shows that in these patients, autoregulation worked fine. Is that fair?
Dr Anne Vedel: Yes. Or sufficient blood flow was delivered. All in all, what's new in our study, I think, is that hypertension per se shouldn't necessarily be considered a proxy for hyperperfusion during bypass.
Dr Tim Gardner: Yeah, that's a very good qualification. So none of your patients, despite being in their mid to late 60s had evidence of carotid artery disease or whatever? Those patients were excluded from the trial, is that right?
Dr Anne Vedel: No, that's not correct. We didn't screen for carotid artery disease because we don't routinely do that in our institution. As we describe in our discussion, we included quite a heterogeneous study sample by enrolling the patients that came to us. We didn't screen and we didn't exclude these patients that you mention.
Dr Tim Gardner: Do you know how does your group handle a patient that is known to have carotid artery disease, comes in with a known either prior endarterectomy or established disease? Do those patients, are they treated any differently either as a result of the study or just in general?
Because that is a targeted group of patients, at least in my own experience, that we would be more concerned about allowing autoregulation to be the determinant, feeling that if there is a fixed stenosis in the carotid artery that we might need to increase the mean arterial pressure.
Dr Anne Vedel: I can certainly understand your point and, of course, it is a concern in our center, as well. But having said that, there were no patients in the PPCI trial that came to us with a history of carotid artery disease, so it wasn't a concern for us in this study.
Dr Tim Gardner: That would be one point that I would make that we probably should pay attention to patients who do come for surgery and have known significant obstructive extracranial disease, but I understand that you didn't specifically have those patients or were aware of those patients.
I think that this is a very useful study for us concerned about the possibility of inducing cerebral injury with cardiopulmonary bypass. To some people it's sort of counterintuitive that increasing perfusion pressure didn't improve the tolerance of patients to cardiopulmonary bypass but that's why you did the study. I think it's a very notable and important report that's going to be in circulation.
The significance of these "silent infarcts" is merely something that we have to sort of sort out. I know you said that silent infarcts, as I agree, are associated with or presumed to be predictive of later cognitive dysfunction, dementia and so on. It really is a concerning message if that's the main message that comes out of these imaging studies. Because these are patients that, obviously, didn't have heart surgery for no reason, there was obviously a compelling indication for patients to have it.
You would hate to re-ignite this concern as we had in and around year 2000 when the group at Duke was talking about writing about patients who had cognitive decline after cardiac surgery, were going to end up being demented five or 10 years down the line, so, that's from the perspective of a cardiac surgeon. Let's stick with the evidence but let's follow-up and see how predictive these silent infarcts are and what the consequences are long term. Do you think that's fair, Anne? Am I making a fair statement?
Dr Anne Vedel: I absolutely do think it's fair. And for a cardiac surgeon as yourself, I would find it very interesting to see that these kind of studies are also conducted in TAVR patients where you have sometimes a 200% incidence of these silent strokes.
I mean you have a good taste as a cardiac surgeon if you only see them in 50% of your patients, understand me correctly, but I don't necessarily think that this high incidence, it's high, yes, but compared to other patient groups, such as TAVR patients, it's not necessarily that bad.
Dr Tim Gardner: Right. Anne, I don't know whether you've seen the editorial that's going to accompany your paper, but it's very good. It's very supportive of your study and has some good comments. You'll be pleased with the editorial, I believe, if you haven't seen it.
Dr Anne Vedel: Thank you very much. I'm happy to hear that. I know we do things a bit controversially over here in Copenhagen, compared to many centers in the U.S.
Dr Tim Gardner: That is not what the editorialists think. An anesthesiologist from Stanford and a neurologist from Penn, they have a very good commentary on your study and the whole field, so you'll be pleased.
Anne Vedel: I'm very happy to hear that. Thank you.
Carolyn Lam: Well, listeners, I'm sure you learned a lot. Thank you for joining us today, and don't forget to tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Does NT-proBNP-guided therapy improve outcomes in acute decompensated heart failure? Well the Prima II trial results are coming right up after these summaries.
Is hospital volume a good structural metric assessing the quality of care in heart failure? Well, in the first original paper this week from Dr. Kumbhani and colleagues at UT Southwestern Medical Center, authors determined the relationship between admission volume, process of care metrics, and short and long-term outcomes admitted with acute heart failure in the Get With the Guidelines-Heart Failure registry, which has linked Medicare in patient data at 342 hospitals.
They found that lower volume hospitals had worse adherence to important heart failure process measures, than higher volume hospitals. There was no association between risk adjusted in-hospital mortality and hospital heart failure admission volume among older adults.
After adjusting for adherence with process measures at discharge, annual heart failure admission volume had a minimal association with mortality, and readmissions up to six months post-discharge. Thus, rather than focusing solely on hospital volume, hospital profiling efforts should perhaps focus more on participation in quality improvement initiatives, adherence to process metrics, and risk standardized outcomes.
The next study describes the association between air pollution and heart disease mortality in the United States, with a focus on whether the association differs by race and ethnicity. First and corresponding author Dr. Jennifer Parker from the National Center of Health Statistics Centers of Disease Control and Prevention and her colleagues use data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and the Annual Estimates of Fine Particulate Matter or PM2.5 as an index of air pollution.
They found that the association between air pollution and heart disease mortality in this national sample was elevated and similar to estimates found in prior studies. After controlling for social demographic and geographic factors, the associations between air pollution and heart disease mortality for non-Hispanic black and Hispanic adults were not statistically significantly different from that of non-Hispanic white adults.
Thus, this study supports the application of findings from prior studies of air pollution and mortality, albeit largely from non-Hispanic white adults, but to other races and ethnicities in the United States.
The next study suggests that large cardiac muscle patches engineered from human induced pluripotent stem cells may be a reality. First author Dr. Gao, corresponding author Dr. Zhang from University of Alabama at Birmingham generated human cardiac muscle patches of clinically relevant dimensions of 4 x 2 centimeters and they did that by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells in a fibrin matrix and culturing this construct on a dynamic platform.
The results from in vitro assessments of calcium transience, action potential propagation, and forced generation, as well as the presence of intercalated disc-like structures, suggested that cardiomyocytes matured in these human cardiac muscle patches. During the 7-day dynamic culture period. When transplanted onto infarcted swine heart, measurements of cardiac function, infarct size, wall stress all improved with no increase in arrhythmias.
Changes in the expression profile of myocardial proteins indicated that the human cardiac muscle patch transplantation partially reversed abnormalities in sarcomeric protein phosphorylation. Collectively, these observations indicate that human cardiac muscle patches can be successfully generated and may improve recovery from ischemic myocardial injury.
Does a second arterial conduit improve outcomes after multivessel coronary artery bypass grafting? Well, in the next study from first author Dr. Goldstone, corresponding author Dr. Woo, from Stanford University and their colleagues used a clinical registry including all 126 non-federal hospitals in California to compare all-cause mortality, and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score matched cohorts, who underwent primary isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit or a venous conduit between 2006 and 2011.
The authors found that receipt of a second arterial conduit was associated with lower mortality, and at first cardiovascular events, compared with receipt of a venous conduit. The survival benefit associated with the use of a second arterial conduit extended to patients up to 78 years old. As a second arterial conduit, the right internal thoracic artery offered no benefit, compared with the radial artery, but it was associated with an increased risk of sternal wound infection.
These findings therefore suggest that surgeons should perhaps consider lowering their threshold for using arterial grafts and that the radial artery may be the preferred second conduit.
That wraps it up for our summaries. Now for our future discussion.
NT-proBNP and natriuretic peptides in general, have really become mainstay in management of heart failure, in the diagnosis, in the prognostication, but questions still remain regarding NT-proBNP-guided therapy. We heard about the guided trial in chronic heart failure just reported last year, and this year, in fact this week, in this week's journal, we're about to hear about PRIMA II trial in acute heart failure.
And how NT-proBNP was tested as a potentially guiding strategy for the management of acute heart failure. I'm so pleased to have the corresponding author with us, Dr. Wouter Kok, from University of Amsterdam, as well as our Senior Editor Dr. Biykem Bozkurt from Baylor College of Medicine. So welcome both of you, and Wouter may I just jump straight in it?
PRIMA II means that there was a PRIMA I trial, so could you just briefly tell us a bit about PRIMA I and the rationale for PRIMA II?
Dr Wouter Kok: Well the PRIMA II was an in-hospital guiding therapy that was preceded by the PRIMA II, it was a chronic heart failure patient population and one of things that we noticed in PRIMA I was the lack of effect of trying to reach a percentage drop in chronic heart failure patients. Why is that? Is that because there is a long time before you can achieve a therapy adjustment? Or is it something else? And shouldn't we start before patients are discharged from hospitals?
So the idea was born to do an in-hospital guiding study instead of chronic heart failure patients study.
Dr Carolyn Lam: Interesting. And could you tell us briefly, the design of PRIMA II and your findings?
Dr Wouter Kok: So the PRIMA II was designed based on the previous publication of several authors indicating that a 30% reduction in NT-proBNP would be a good target for heart failure therapy. Now, we first asked ourselves the questions, whether we should put this target in front of the hospital admission, so in the first 2 days or perhaps at the end of the hospital admission? And the 30% reduction was validated only for discharge purposes, so but we also tried to establish whether we could precede this date a little bit before discharge, but it appears that you cannot precede it too much.
So you cannot do it at day 3 or day 4, when patients are not stable. Because then you may expect a rise in proBNP again before discharge, and then you already ran the rise patients to discharge. So we decided to do it at discharge. At least 1 or 2 days before discharge, when patients would be clinically stable. And this definition of clinical stability was important because there should be one guideline for doctors to say, OK this patient has been treated well, or not.
Dr Carolyn Lam: Interesting. And so patients were randomized only after clinical stabilization, though in hospital after an acute decompensation, right? And then maybe the randomization arms, and the results please?
Dr Wouter Kok: Yeah, so the patients were randomized about day 7 or 8 after clinical stabilization, and day 3, but also patients at day 9, but when they were stable, they were randomized. And then the proBNP was measured, and when it was not reduced more than 30% they were guided. And when they were reduced more than 30% they were not guided but they were made ready for discharge.
So this was the randomization group. And the conventional group, the NT-proBNPs were measured at the randomization, and also at discharge, but nothing was revealed to the doctors. So it was only as a comparison for example, in the number of days necessary to wait before discharge, if this would influence the results.
The main finding is that the end point was negative for total mortality after 6 months, in combination with heart failure readmissions. So there were about 36% end point in both groups.
Dr Carolyn Lam: Yeah Wouter, you know, we've just come from the guided trial that was so soon neutral and infect, ended early and that was in the chronic heart failure setting so very different from what you tested in PRIMA II. Congratulations first of all for a beautifully done study.
But may I just ask, because in guided it was mentioned repeatedly that perhaps even the control arm was treated so well because these were such specialized centers. So what kind of centers took part in PRIMA II?
Dr Wouter Kok: We started at centers in Amsterdam, they were all very well educated in heart failure treatments, and all were using proBNP before the study started, so they were experienced in interpreting proBNPs. Because we had too little centers, and the inclusion rate was not so fast, then we asked other centers to participate, and we asked 2 for instance in Barcelona and Porto in Portugal, which helped us to complete the trial.
Dr Carolyn Lam: Oh that's really nice. And the design is really quite special, and I'm so appreciative that you took the time to explain that they were randomized only when stabilized.
Biykem, what do you think of that?
Dr Biykem Bozkurt: It's a fascinating trial, I have to congratulate Wouter and his colleagues. The number one very important finding I think is, about two-thirds of the patients before randomization are able to achieve reduction of NT-proBNP more than 30%. So subsequent to that in the guided therapy we're able to achieve maybe an incremental additional 15% adding to about, I think 80% of the patients initially randomized to the NT-proBNP arm. Achieving a reduction more than 30%. So overall, if the patient's naturally before randomization, achieve a reduction NT-proBNP, two-thirds of the time, pushing it further, trying to achieve a further dry state, by randomization does not appear to make any changes in readmission rates, or mortality at six months.
So this very important finding is the majority of the patients on conventional strategies are able to be decongested and achieve clinical stability. Now the other important finding is, I think about 17-20% of the patients regardless of what we do, do not demonstrate this significant drop in their NT-proBNP levels. Which I call as a non-responder team, which is a fascinating group of individuals. So we have the yin-yang, individuals may actually demonstrate that they're responsive. And when they're responsive, then the majority of the patients do demonstrate a reduction by more than 30%, and even if we push it further by targeted therapies, don't make a difference in outcomes.
About 17-20% regardless of what we do, do not respond, and from former studies we know that those patients are associated with worse outcomes. The other important finding I think, is what changed in the study? What medications, what therapies were changed? It was fascinating from Wouter's group to recognize that there was a little, significant, but a little increase in the ACE admission prescription. But there was also an interesting finding in the guided therapy, that the beta blocker used was slightly lower.
That raises a question of if we were to just chase the numbers, meaning try to just target therapies according to the NT-proBNP levels, whether we would see some unintended consequences such as reduction in medications, just because the numbers may be going in one way or the other. This is acknowledged in Lynne Warner Stevenson's editorial that will be accompanying the paper. And the editorial is very nicely titled "Getting to Dry". So I found that fascinating to recognize that the therapies, when especially the conventional arm is treated well, did not differ.
As was the case in the guided trials. When you treat the patients very well, as was seen in this trial, there was not much of a difference. But again trying to treat a number by targeted therapies may not result in all the optimization that as we envisioned to see. And the third concept is the length of stay, of course in the U.S. is a major issue, and I do realize when we're trying to treat a number, sometimes the length of stay may end up being longer. And I do realize that perhaps in the targeted therapy group, the length of stay was a little bit longer, maybe Wouter can comment on that.
But overall it didn't result in any change in outcomes, or was not associated with any of the outcomes. So that was also an interesting finding. Because we tend to focus a lot on length of stay, but interestingly I guess by secondary analysis, there was no association with the clinical outcome.
Dr Carolyn Lam: Wouter, would you want to comment the length of stay concept?
Dr Wouter Kok: Well it's indeed in the guided group, and the randomized group who were trying to attain the 30% NT-proBNP reduction, the length of stay was longer. Something about 11 days, compared to those who did not need guiding was about 8 days. Still long compared to U.S. standards, but it was the same in the conventional group, so about 9 days is respective of whether they reached a 30% reduction or not.
So here is the clinical experience. So the patient cannot tell whether he is reduced more than 30%, and the doctor isn't able to tell either. Because then the admission would have been longer probably. But trying to lower the 30% more, has some effect. There's little effect, but it has some effect. And then they have to do a sort of economic analysis, is 3 days longer in hospital, is it worthwhile to do that compared to for example reduction in admissions that you receive? This is a small population, only one-third of the patients who need guiding, and more than half of them you will reach somewhat more reduction than if you don't try at all.
So for us, that is the main result of the trial, if there is a signal, then it is still possible to do something, and the other remark about whether you increase or decrease medication, that's something that was discussed in the guided study too. So what is the best for the patient, is that the maximum medication or not, and we see for example, that if we reduce beta blockers, in some patients then some will improve in their functioning and also in the BNP.
So it's not always necessary to increase and increase medication. So that was also some signal that we tried to do some more research in. What is the target? Is the target a guideline, saying that more medication is better? Or is the target itself for proBNP a possibly better target than that?
Dr Biykem Bozkurt: And the other interesting finding for that, there were no differences in chemo concentration levels in the guided versus non-guided groups. And last point that I wanted to make is the larger BNP reduction was amongst the individuals who did not require any guidance in successfully guided versus unsuccessfully guided, compared to those who did not need the guidance.
Those who were able to achieve the more than 30%, when you look at the magnitude, meaning amongst the individuals who are going to naturally respond to therapy, the natural responders, the decrement, or the decrease in the BNP levels are larger, than those ones we're trying to push. So that was another interesting, fascinating ... I was almost thinking whether that in the future we should look at responsiveness of patients, if we see they're responders then try to target their therapy or not.
So in a sense the non-responders, they now respond regardless of what we do. Responders may be gaugeable or titratable, or maybe with the precision respond to targeted therapies that almost have a dichotomous approach. What do you think about that Wouter?
Dr Wouter Kok: I say yeah we made a big mistake in thinking that more than 30% for patients who still needed guiding would be the same as rating the more than 30% without guiding. But the difficulty you have in reaching the 30% is already indicative somewhat less increase in prognosis than you will reach it spontaneously.
So we have to adapt our numbers for the trial, so it is recalculation that how many patients we would need to be successful in our trial, and that would be 600 patients in every arm, and then even then, you have to recalculate some of the effects that you will have to reach them. Perhaps the mid-range risk group is a better risk group to target than the highest risk group. That's something that we have to think about too.
Dr Biykem Bozkurt: I think we will probably need to focus on individualization, I almost feel as though we will need to learn from the cancer trials, and see whether we could try to target rather than you know the population based clinical trials, trying to do the targeted therapies. Maybe fine tune the ability to precisely target, and of course that requires a little bit more layering of the markers and or a signal that we're going to be profiling in the individual.
So I don't think it's the end of targeted therapies, perhaps requiring a little bit of a more precision, and maybe individualization. But I am fascinated by first realizing it's a responder, and then maybe trying to accelerate and or optimize therapy, perhaps especially when we are forced or driven by administrative concepts such as length of stay or others. So making sure that maybe these variables, these biomarkers may help us recognize that maybe we haven't achieved that appropriately dry state yet.
But those all need to be determined, of course, by future trials, so far targeted therapies both in the acute and in the chronic does not seem to result in implementing outcomes.
Dr Wouter Kok: Well and the next step for us is to try and think how can reduce proBNP in all patients, we tried it with medication, but didn't do that much of catheterizations for those who were ... there were 50% of patients who were ischemic so why don't we do much of these catheterizations now days. So that's something we're thinking about how can we improve these patients? What are we missing?
Dr Carolyn Lam: Yeah, if I could add my two cents. So Wouter mentioned finding the right therapies that can effectively reduce NT-proBNP safely, and well you mentioned choosing the right patients to use this in. And if I may, you know, just adding perhaps the right settings as well. Because it's well known that not all of us take care of heart failure patients the same way. And maybe there are settings where having a number to guide us may be more useful than others. But what do you do? You know, we wait for more data, but in the meantime, just congratulations. Heartfelt, heartfelt congratulations Wouter for a beautiful study, thank you so much for the privilege of publishing it in Circulation.
Thank you for being on this podcast, and listeners don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I am Dr. Caroline Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Can we reverse the cardiac effects of sedentary aging? Well if you're curious, you have to read the feature paper in this week's journal, as well as listen to the upcoming discussion of a trial that addresses this issue. All coming right up, after these summaries.
Desmond mutations are known to cause skeletal and cardiac muscle disease, and also recently has been described in patients with inherited arrhythmogenic right ventricular cardiomyopathy or dysplasia. In today's first original paper, however, authors identified a novel Desmond mutation in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy or dysplasia, and a high incidence of, at first, cardiac events.
First in corresponding author, Dr. Bermudez Jimenez from Granada, Spain, describe for the first time the largest family to date with a single Desmond mutation with a phenotype of left dominant arrhythmogenic dysplasia in the absence of skeletal myopathy symptoms and atrioventricular conduction disorders and supported by strong clinical and functional data. In a series of elegant experiments using explanted cardiac tissues and mesenchymal stem cell derived cardio myocyte from the family members, the author showed that the pathogenic mechanism probably corresponds to alteration in Desmond dimer and oligomer assembly and its connection with membrane proteins within the intercalated discs, thus Desmond mutations should be suspected in patients presenting with a cardiomyopathy characterized by mild left ventricular systolic dysfunction and/or dilatation, fibrosis, ventricular arrhythmias and a family history of sudden death.
The next study is the first large scale report examining the incremental risk of surgical aortic root enlargement in patients undergoing aortic valve replacement.
First author Dr. Rocha, corresponding author Ouzounian from University of Toronto and their colleagues sought to evaluate the early outcomes of patients undergoing aortic valve replacement with or without surgical aortic root enlargement.
Now aortic root enlargement allows for larger prosthesis implantation and maybe an important adjunct to surgical aortic valve replacement in the transcatheter valve in valve era.
Among more than 7,000 patients undergoing aortic valve replacement at a single institution from 1990 to 2014, the authors observed no incremental risk in post-operative mortality or adverse events following surgical enlargement of the aortic root as compared to aortic valve replacement alone. They therefore concluded that surgical aortic root enlargement appears to be a safe adjunct to surgical aortic valve replacement in the modern era.
The next study suggests that in patients with acute coronary syndrome and an LDL cholesterol above 50 milligrams per deciliters, health care providers should consider adding ezetimibe to statins, particularly in two patient subgroups.
First in corresponding author Dr. Giugliano from the TIMI study group at Harvard Medical School in Boston, Massachusetts and his colleague explored outcomes stratified by diabetes in the "improve it" trial where patients with a recent acute coronary syndrome were randomized to ezetimibe versus placebo on top of backgrounds in the statin.
They found that patients with diabetes derived significantly greater relative and absolute benefit with the addition of ezetimibe relative to patients without diabetes. This enhanced benefit was driven by reductions in acute ischemic events including myocardial infarction and ischemic stroke in diabetics, while non-diabetic patients who were more than 75 years of age or who had a high risk score also significantly benefited from the addition of Ezetimibe to Simvastatin.
These benefits of Ezetimibe were achieved without an increase in safety events compared to placebo. Thus, the two patient subgroups of acute coronary system who are likely to achieve greater benefits with the addition of ezitimibe include: one, patients with diabetes, and two, patients without diabetes who have a high risk score.
The final study provides insight into sudden cardiac arrests in the young and the potential contribution of standard cardiovascular risk factors to this risk, even in the young.
First author, Dr. Reshmy Jayaraman, corresponding author Dr. Chugh from Cedars-Sinai Medical Center in California and their colleagues, prospectively ascertained 3,775 individuals who suffered sudden cardiac arrest between the ages of 5 and 34 years in the Portland, Oregon Metropolitan area and who were also followed up for 13 years. They found that 5% of cases occurred in young residents between the age of 5 and 34 years.
Among the young, there was an unexpectedly high prevalence of classical cardiovascular risk factors, such as obesity, diabetes, hypertension, hyperlipidemia and smoking. In fact, one or more risk factor was observed in 58% of cases, with obesity being the most common.
Less than a third had warning symptoms prior to their lethal event and sports activity was a trigger in only 14% of young cases. Thus, standard cardiovascular risk factors, especially obesity, may play a larger role in sudden cardiac arrests in the young than previously recognized. This suggests the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.
And that wraps it up for our summaries, now for our feature discussion.
Oh boy, today's featured discussion is gonna make everyone listening fall in love with exercise and seriously get off your chair right now as you listen to this discussion.
It's about how exercising may reverse cardiac aging and I am so delighted to have with me none other than the corresponding author, Dr. Ben Levine from the institute of exercise and environmental medicine at Texas Health Presbyterian and UT Southwestern, as well as Dr. Jarett Berry, and he's our dear associate editor from UT Southwestern.
Ben, I have been dying to have you on this show, so welcome and please, tell us what you did.
Dr. Ben Levine: Thank you very much, it's a pleasure to be here Carolyn, thanks for inviting me to talk about it. As you know, our lab has been particularly interested in the components of aging that are related to senescent versus those that are related to senescence activity.
Perhaps the most dramatic reason that we're interested in this, I'm just gonna give you a little bit of background, if you don't mind, comes from one of the most important studies ever done in our field, that was done in Dallas in the mid-1960s. It's called the Dallas Bedrest and Training Study.
At that time, my mentors, G Blomqvist, Jerry Mitchell, Bengt Saltin, took five young men, put them to bed for three weeks and then trained them for two months and virtually everything we know about the adaptive capacity of the circulation to exercise starts without study.
I was only ten years old, so I really had nothing to do with it, but 1996, 30 years later, we found those same five guys and brought them back to Dallas to study them again.
Now, these are the most intensively studied humans probably in the history of the world. 78 pages of circulation in 1968. What we found was quite amazing. We found that not a single one of those five guys was in worse shape 30 years later, than they were after three weeks of bed rest when they were in their 20s.
So, three weeks of bed rest was worse for the body's ability to physically work than 30 years of aging. And so, we sort of launched off that in a series of experiments, trying to figure out when in the aging process does the shrinking and stiffening of the heart develop, that is the sine qua non. if you will, of the cardiac aging. So, when does it start? How much exercise do you have to do to prevent that?
We did one interesting study where we compared a group of very highly selected seniors, all aged around 70, who were healthy, but did no exercise, compared to a group of elite Masters Athletes. Amazingly, the healthy seniors, their hearts got smaller and it shrunk and they got stiffer and the athletes had hearts that were indistinguishable from healthy 30 year olds.
So, a lifelong training at the level of being an elite athlete completely prevented that aging response, which is really interesting scientifically, but not a very good public health measure.
So, we then asked how much exercise do you need to do over a lifetime to preserve the compliance, the youthfulness, if you will, of the circulation, and at times, they act like you need to do about 4 or 5 days a week over a lifetime. 2 to 3 days a week didn't do anything. 4 to 5 days a week did almost as much as being an elite competitive athlete. So, now we've got the dose. 4 to 5 days a week.
We said, "okay, if we do that, can we reverse cardiac aging once it's occurred?" So, we took our healthy sedentary people and we also looked at a group of HFpEF patients and we trained them for a year, at the right dose, using high intensity exercises. We made them fitter, but we couldn't touch their cardiac or vascular stiffness. Quite disappointing actually.
Last thing then, we said "okay, this leads up in to our current study maybe, just maybe, if we pick the right sweet spot in time, when the heart is just beginning to stiffen in that late middle age period and deal the right dose at the right time for a long enough period, we could reverse the effects. And, that's what we did. We took 60 people, healthy, middle aged, 45-64, mean age around 50. We randomly assigned them to two years of exercise training or two years of yoga, balance, flexibility, and we did 2 light heart caths. We measured their cardiac compliance directly invasively and we showed that our 2 year training program, which included high intensity intervals, reversed the effects of decades of sedentary aging.
Dr. Carolyn Lam: Wow, Ben, you know, no one tells the story like you and I have to tell you, I've been a fan of your work, citing it since I was 10. Thank you so much for this amazing contribution to the Journal this week. I just know everybody's asking questions like "So, you've given us when to start, you given us the dose, but we want to understand a bit better, what do you mean high intensity, how many minutes and what exactly." Could you give us an idea?
Dr. Ben Levine: Sure. There are multiple different ways to go about doing HIIT or High Intensity Interval Training. And there's no magic to intervals. Intervals just allow you to do something for a shorter period of time and harder than you could do for a longer period of time. That is the strategy that athletes use to go faster and stronger and higher, because the body adapts to the load that's placed on it.
Interval training, what I like, is based on an old Norwegian ski team workout. It's called the "4x4". What that means is 4 minutes at 95% of your maximum followed by 3 minutes of recovery, active recovery, repeated 4 times. So, basically, you go as hard as you can go for 4 minutes and at the end of those 4 minutes, you should be ready to stop. Typically, your heart rate will drift up towards 95% of maximum or so. Then, at the end of the 3 minutes of recovery, you should be ready to do the next interval.
As it turns out, that's extremely effective training stimulus. Not just for healthy people or athletes, for the patients with hypertension and with heart failure.
Dr. Carolyn Lam: I noticed that you have to screen over 260 individuals to finally get your 60, so how doable is this and what was the compliance?
Dr. Ben Levine: Right. You have to remember that out of those 260 individuals that we screened, the majority of them were excluded up front because they had hypertension or if they were obese or they already had heart disease. So, the first round of screening was making sure we're getting people of the right age and were healthy. And, then another fraction, say 40 of them or so, didn't wanna undergo two light heart catheterizations. And, I get that. We were pretty pleased that somebody volunteered to do it, but you know, it's an intense commitment. People have to be willing to be randomized. So, they couldn't say "Well, I wanna do your study, but only if I get randomized to exercise", that was not acceptable.
So, everybody had to be prepared to be randomized to either yoga or the fitness training and the yoga, it makes people feel better, it's relaxing. I think it provided that clinical equipoise and it ensured that even the controlled patients had close contact with our research team.
Then, what we had was, on average 88% of the prescribed sessions were followed by our exercisers and a fraction of them, 15 or 20%, actually did 100% of their prescribed sessions over two years, didn't miss a single one.
Dr. Carolyn Lam: So, Jarett, have you started doing that yourself now?
Dr. J Berry: I tell you, I pried my kids out of bed last summer, to go do 4x4s and get them ready for cross country. I talked all about Ben Levine and told my kids that we were doing what Dr. Levine recommended. That didn't help too much, they found it rather challenging. It was interesting that the VO2 plateaus a little bit at that 10 month mark, when you guys backed off on that additional interval training. Do you think that the plateau is just a limitation of the training effect or do you think that something that has to do with the lower level of interval training at that time?
Dr. Ben Levine: You know Jarett, I think that's a fascinating question and it's one of the things that really surprised me. So, Jarett pointing to the fact that at that 10 month mark, we measured VO2 max, we didn't cath them, but we did an Echo, and it showed that from 10 months to 2 years VO2 max didn't increase very much.
There was a dramatic increase from baseline to 10 months. It took 3 months at that peak dose. But then, when we dropped one interval and did the same thing every week for 2 years, there wasn't an influence of time. The heart didn't continue to get bigger, the stroke volume didn't continue to enlarge.
I think it highlights a critical part, an essential element, to that exercise training and that is, doing the same thing, over and over again doesn't get you fitter. If you wanna get fitter than you are, you have to change things around, you have to increase the load. So, I think that if we had wanted to make them even fitter than they were at 10 months, we'd have had to either kept that second interval or added another one or increase the duration of some of the base training sessions.
It's really interesting to me, that they didn't continue to improve simply on the basis of time. That surprised me.
Dr. Jarett Berry: Yeah, cause you wonder. You think about, the guidelines suggest moderate intensity exercise, which is obviously much lower intensity than what you're talking about with this interval training, but very little guidance with regard to interval training.
Your data here obviously suggests that it's not just getting off the couch and doing something, and not just doing a decent amount, it seems to suggest that the interval training component may be a secret ingredient that might be most helpful, at least for those patients who can tolerate that level of training.
Dr. Ben Levine: Yeah, I think that maybe it's the secret sauce, Jarett, but I think, you do have to ask yourself, what is the goal of training and what is your objective outcome? What you want is to reduce cardiovascular mortality. I think we would all agree that you get the biggest bang for your buck by going from sedentary to active. And, the mechanism of that is uncertain, but could relate to autonomic function or clotting or improving stabilization of endothelium or other risk factors, inflammation, who knows, there's a lot of different candidates. So, I think that particularly for people who are at the highest risk for heart failure, either from their family history or other risk factors, like hypertension and diabetes, those are the ones who were likely to get in a special benefit on altering cardiac structure.
That's why I think our data is still an important poll. We didn't really know why do you get the biggest bank for your buck with a little training, but if you really wanna prevent heart failure, you gotta do more.
In our data that we did partnered with the Cooper Clinic and looked at people who had done the same number of exercise sessions over 25 years. None, 2-3, 4-5 or 6-7, over 25 years, we saw virtually no effect of 2-3 days a week of what we call casual training on anything we could measure, related to cardiac structure. Their vascular stiffness was the same as people who were sedentary, their cardiac stiffness was the same as people who were sedentary. They were a little fitter and perhaps there were other important differences that are related to just improving immortality, but you have to get past that low to moderate dose to have the structural effects on the circulation.
Dr. Jarett Berry: These are really great points here, Ben. I want for our listeners to hear you comment a little bit more on the primary outcome and how you guys measured stiffness, because I think in addition to the level of training, it's also the approach and the phenotype that you collected to measure this and I think it would be helpful for you to walk us through that a little bit and how you guys measured stiffness.
Dr. Ben Levine: We used an old physiological technique called "Lower Body Negative Pressure". We first let the subject settle down, we measure a variety of cardiovascular variables, cardiac output, and we do an advanced ECHO imaging and some arterial stiffness measures and after about 40-45 minutes or so, we'll measure the pulmonary capillary wedge pressure, that's what we use as an index, and plus ventricular and diastolic pressure. We'll do 3D ECHO volumes and then we unload the heart by doing Lower Body Negative Pressure. We basically seal the subject in a box at the iliac crest and turn on a vacuum cleaner and suck blood into their venous capacitance. It's a very simple way to unload the heart.
In contrast to people who do put in conductants or reflectant catheters and occlude the IVC and do pressure volume rudes, we have taken a little bit of a different approach. I do steady state and diastolic pressure volume curves. So that means, we look at the pressure and volume in the heart at baseline at two different unloading levels. So, let's say the baseline ledge is 10. The first level of LBNT of minus 15 will get it down to 6 or 7. The next level of minus 30 gets it down to 2 or 3. And, so we get a nice unloading of the heart and we're able to establish a steady state, which is probably more afunctional than a release of an IVC occlusion.
Then, we let go of the suction, everything returns to normal. We repeat our baseline measures and then we give the rapid saline infusion. When I say rapid saline, I mean 15 and 30 mls per kilogram, that's at 200 mls a minute. That's a big volume infusion, but we'll give those doses and we'll raise the ceiling pressure from 10 at baseline to 15 and then 19, 18, 19. So, we get a large physiologic range of the diastolic pressure volume curve, and then we'll fit that to an extremely widely accepted exponential equation, which allows us to calculate the overall stiffness of the heart, the diastolic component, and then we'll do a few other things, we'll measure distensibility , which is the volume at any given pressure and DPDV, the change in pressure for a given volume, which is the hansen float to the exponential curve fitting.
Dr. Jarett Berry: Can you comment a little bit about what this means for how this is distinguished perhaps from maybe more conventional non invasive measurements of cardiac stiffness?
Dr. Ben Levine: I think the most important thing to realize is that, cardiac compliance is dynamic. It depends on the volume at which you're making that measurement. So, as you unload the heart, any heart, even the stiff heart, it gets more compliant, and as you load the heart, even a compliant heart, it gets stiffer. Part of that is a function of pericardial constraint, as well as myocardial stiffness.
The whole idea that there is a measure of diastolic function that you can measure by ECHO that is load independent is frankly an oxymoron, because, diastole is load dependent. I think the ECHO measurements are interesting and useful, depending on what you're trying to find out, because there are many different aspects of feeling and diastolic suction and diastolic stiffness. All of which influence how well the heart feels at rest and during exercise.
Dr. Carolyn Lam: I have to ask you one last question. I am so pleased that you included at least 52% women. Were there any differences by sex?
Dr. Ben Levine: Of course, Carolyn, it's critical to include women, since they're 50% of the population. We've been very interested in their training responses in men and women at different age groups in many of our other studies. What's interesting is that in premenopausal women, there's a quite clear distinction in how women respond to training. They don't hypertrophy as much, even for the same stimulus, heart beats a heart beat, over a year, there's a much less hypertrophic response to premenopausal women than young men.
We didn't see anywhere near that difference in our mostly postmenopausal middle aged men and women. We didn't have enough power to clearly be confident that there was no difference, but when we tried to test that hypothesis, whether there was a different response in men or women, we could not detect a difference.
Dr. Carolyn Lam: That is a good thing. So, women out there, you heard it from Dr. Levine. We got to exercise too. High intensity. All the time.
Thank you audience, for listening today. Don't forget to tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
Today's feature paper is about statins, and it's the first population-based study to show a dose-dependent benefit on amputation and survival in peripheral artery disease. Very important data and a very important discussion coming right up after these summaries.
The first original paper this week indicates for the first time that the natural history of coronary stenosis is better predicted by physiologic information by FFR, or fractional flow reserve, than by anatomic information from angiography. First author, Dr. Ciccarelli, corresponding author, Dr. DeBruyne, from OLV Hospital in Belgium compared the values of angiographic diameter stenosis and of fractional flow reserve in predicting the natural history among 607 patients from the FAME 2 trial who had documented stable coronary disease and in whom no revascularization was performed. The primary end point was defined as vessel oriented clinical end point at two years, and this was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and non-urgent revascularization.
The overall results showed that FFR predicted the natural history better than diameter stenosis. In addition, among the stenosis with mismatch between diameter stenosis and FFR, more than half had a low FFR in the presence of an angiographically mild stenosis and the rate of primary outcome was higher in those with reduced FFR regardless of whether diameter stenosis was significant or not. The take-home message is, therefore, that measurements of FFR should be considered not only an angiographically intermediate stenosis but also perhaps a mild or severe stenosis by visual evaluation.
The next study provides population-based data on cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter-2 inhibitor, or SGLT2 inhibitor. First and corresponding author, Dr. Udell, from University of Toronto, and his colleagues, performed population-based cohort study among type 2 diabetes patient with established cardiovascular disease and newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between 2013 and 2016. After propensity matching, more than 25,250 patients were followed for a median of 1.6 years. Initiation of SGLT2 inhibitors was associated with a lower all-cause mortality, lower hospitalization for heart failure events, lower major adverse cardiovascular events, but higher below-knee amputation risk. Findings underscore the potential benefits and risks to be aware of when initiating SGLT2 inhibitors. Importantly, it remains unclear whether the risk of below-knee amputation extends across a class of medications as the study was not powered to make comparisons among individual treatments.
The next paper reports results of the redefined trial, which is the first trial to study the effects of renin-angiotensin-aldosterone system inhibitors in adults with tetrology of Fallot and mild right ventricular dysfunction in the absence of severe valvular lesions. First author, Dr. Bokma, and corresponding author, Dr. Bouma from Academic Medical Center Amsterdam, and their colleagues, studied 95 patients in the redefined trial and found that 150 mg of losartan daily did not significantly improve the primary outcome of right ventricular ejection fraction change compared to placebo. There were no significant treatment effects on secondary outcomes of left ventricular ejection fraction, peak aerobic exercise capacity or NT-proBNP. However, in a post hoc analysis, losartan was associated with improved right ventricular ejection fraction in a subgroup of 30 patients with nonrestrictive right ventricles and incomplete remodeling. The conclusion is, therefore, that losartan had no significant effect on right ventricular dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups.
The final study reinforces that vesicle trafficking plays an essential role in the signal regulation of pathologic hypertrophy and identifies a novel potential target in this process. This novel target is the transmembrane BAX inhibitor motif containing 1, or TMBIM1. First author, Dr. Deng, corresponding author, Dr. Li, from Wuhan University in China, and their colleagues, found that TMBIM1 expression levels were substantially decreased in both clinical and experimental hypertrophic hearts. Mechanistically, TMBIM1 interacted directly with tumor susceptibility gene 101 and accelerated the formation of multivesicular bodies to degrade activated toll-like receptor 4. Toll-like receptor 4 degradation in turn was essentially for the progression of cardiac hypertrophy. Importantly, expressing TMBIM1 in monkeys via lentivirus protected their hearts from aortic banding induced cardiac hypertrophy. In summary, these findings shed light on the role of vesicle trafficking in signal regulation during cardiac hypertrophy and provide a novel therapeutic target for treating hypertrophy.
That wraps it up for our summaries. Now for our feature discussion.
Peripheral artery disease, a disease that affects more than 200 million individuals worldwide and associated with a high risk of cardiovascular events and death and, of course, the much feared amputations. Yes, statin guidelines for peripheral artery disease are largely based on coronary artery disease or stroke data. Well, today's feature paper really addresses an important knowledge gap between statins, doses, amputation survival in peripheral artery disease. I'm delighted to have the first and corresponding author, Dr. Shipra Arya from Stanford University School of Medicine and, of course, our favorite, Dr. Josh Beckman, Associated Editor from Vanderbilt University.
Now, Josh. I understand there's a bit of a back story of how this paper came to circulation. Want to share?
Dr Josh Beckman: Oh, absolutely. First of all, I have to say that one of the jobs of an associated editor is someone who kind of goes antiquing in every single store. Every place I am where people are presenting really good science, I'm kind of scoping it out. I'm interested. I want to see what's going on. I like to talk to the people who are doing the work to see how they're thinking about it, and I was lucky enough to see Dr. Arya's presentation. I think it was at an ATVB meeting, wasn't it?
Dr Shipra Arya: That's right.
Dr Josh Beckman: I thought that this is an incredibly cool piece of work, and I basically hoped, I prayed, I asked. I said, "You know, maybe you should send this to us because we would really like to see the full manuscript," because inside I hoped that it would be just as impressive when it was written out as a full manuscript as it was when she was discussing it at the meeting. And, lo and behold, we were lucky enough that she submitted it to us and you can see the results online right now.
Dr Carolyn Lam: Indeed! Well put. Shipra, with that kind of lineup, please, tell us about your study and what you found.
Dr Shipra Arya: Thank you for that invitation to submit to Circulation because initially I wasn't sure if Circulation would be interested in my work, so it was really great to hear when Josh said that this is something that it would certainly consider. The basic premise was to try and find out whether high-intensity statins as defined by the 2013 lipid guidelines, they would also have limb protective effects for PAD along with reduction mortality. As you said in the introduction, most of the data comes from either coronary data or comes from small groups of PAD patients, but never from such a large population.
We identified about 150,000 veterans in the National VA database from 2003 to 2014 and excluded people who didn't have a diagnosis of PAD before 2003, and why this was such a labor of love was also to figure out how to identify the certainty that people had PAD and then getting into their pharmacy files and trying to parse out whether they were on high-intensity, low, moderate, or no statin. Initially, I had done the analysis of no statin, but then after review and discussion, it became clear that we needed a control group, which was people who were also on some guideline-directed therapy and not just no statin because they could be patients who were the noncompliant patients and who don't show up to the doctor's visits, and that's why they do poorly.
That's why we chose a control group which were on antiplatelet therapy, at least aspirin or Plavix, any other antiplatelet agent. Even in that comparison, we find that after risk adjustment, patients who are on high-intensity statin had a more than 30% risk reduction of amputation as well as about a 24, 25% risk reduction of mortality compared to people who did not take a statin but at least took an aspirin. Low to moderate intensity statins were also effective, about 20%. Risk reduction in both amputation and mortality, but high-intensity statins when directly compared to the low to moderate intensity statins outperformed them.
Just to be sure of our findings, we did it so many different ways. We did the Cox modeling. Then we did propensity matching that which person is more likely to receive the statin versus the other. Then we did subgroup analyses where we put people in different subgroups that people who had coronary artery disease as an indication, maybe that's why they were on these statins. But, people without coronary artery disease also same association [stack 00:11:12]. We were pretty confident in our findings, and that's why we sent it to Circulation.
Dr Carolyn Lam: Wow. You know, Josh, you are the best at putting papers like this into context and really expounding on the significant. Tell us, why did this catch your attention so much?
Dr Josh Beckman: Every time I think that statins have become just a standard part of therapy for patients with atherosclerosis, the first thing I noticed in this paper was that there were so many people who were still not on any statins or people who were on homeopathic doses of statins, and I can't understand how that happens. I think the mortality data was nice and consistent, but the amputation data is what really made a big difference. I'll ask Dr. Arya, but in my impression, the literature has been sort of back and forth as to whether or not statins really reduced limb outcomes. Your paper, I think, was clearly the largest sample that had taken a look at that question. Can you sort of separate out your papers from some of the previous work in that area?
Dr Shipra Arya: Sure. I would add that a lot of work about amputations has been coming out from vascular surgery data, and a lot of that work just focuses on short term outcome for limb loss. They look at 30 days. Maybe they'll go look up to six months to a year, but actually patency of bypasses, patency of vessels is a long-term phenomenon. Much like mortality that can happen years later, your amputation risk can happen years later, too. I think what separates us is the lifetime followup for these patients, and we are looking in a cohort of patients who are in this veterans' healthcare system so the data is automatically getting captured even if they get their care outside. Records do make it back and diagnoses do make it back. It's the VA [inaudible 00:13:03], and we did some sensitivity analysis to show that, yes, most of the veterans we have in [inaudible 00:13:09] actually get their care and have data being added continuously into the corporate data warehouse.
That was something I think that lent to the power of making the [sure 00:13:20] conclusion and that's where previous studies have not been able to show a significant association with amputation. The studies, if they are single center or they are focused from electronic medical records or perspective followup, either the patients get lost to followup or go see other doctors or other healthcare systems, and that information doesn't get back to the researchers, while mortality data you can get from Social Security Death Index or other sources. I think that's what makes the study different than other studies in this similar field in terms of followup.
Dr Josh Beckman: I don't think you're giving yourself enough credit. There's a whole bunch of things that make the study unique. One of the things that I was most taken with right upfront was the way that you defined peripheral artery disease for this population. There has been, as far as I know, at least seven or eight different definitions that people have used with administrative data to try and ferret out who has PAD, and in contrast to coronary disease and stroke, it's a much more complicated endeavor to do that. So, when I saw the way that you did it ... I'm going to say this in a way that I know is going to sound funny, but you made the complicated look really simple. Your definition is not something that required 3,000 lines of ICD-9 codes within inclusion and exclusion criteria and speaks, in my opinion, to the power of the large sample because, basically, they needed one ICD-9 code and either two ABIs, a visit to a vascular surgeon or procedural code. Now, I know that this definition comes from some of your work, so can you tell us how you derive this and then let's talk about what that means.
Dr Shipra Arya: Absolutely. We looked at practice patterns for patients with vascular disease across the VA, and most patients who undergo procedures for PAD, we can confidently say that they do have PAD. When we look at the specificity of just that occurrence, it's pretty high, like [90% 00:15:23]. Then what we did was we did some random sampling in the VA data, about 300 patients, and used different codes to see if patients came back to the vascular surgeon within ... We used 14 months because it's usually one year followup that most people prescribe, so whether they went two months before or after because the appointment hours. We found that that was again a high specificity of about 80%. Then, when you look at patients who come back with ABI followup. So, we looked at CPT codes for ABI. We found out it's like a 99% specificity. If you have ABI followup within a year, and we relaxed it to 14 months, you could be 99% confident that this patient does have PAD.
We just combined all those three together, and this is ... If Circulation is interested, I can send you this, too. We are working on this manuscript where we are giving researchers different algorithms that they could use to identify PAD because I wanted a more specific sample because I was looking at PAD outcomes. I wanted the PAD definition to be tight. Our specificity is greater than 80% combining all these three together, about 84%. We are fairly confident in this that, yes, these patients truly have PAD, so when we follow them up for outcomes, we can be confident in our results. If researchers wanted a more relaxed definition of PAD, they could use other algorithms that we are putting in that paper where they could say, "We will only use one ABI measurement, or we would use a combination of these."
Dr Josh Beckman: That brings up two points. You talk about this brings up the power of large data and the ability to tone down on people who really, truly, absolutely have PAD without any question. So, number one, are you worried that you're missing people that probably do have PAD and would benefit from therapy, and number two, do you worry that you're basically concentrating on the sickest right end of the curve of the group of PAD patients?
Dr Shipra Arya: Right. That's a great point, and I discussed that with my coauthors and mentors and we wanted to be sure about our outcomes and not want to include people who did not have PAD, and then we are kind of including the effect size of what we may find, but yes, these are truly what we are calling a symptomatic PAD, and I think I mentioned that in the manuscript somewhere, that we probably would be missing people who are asymptomatic and not really being followed up. If we extended this analysis to people who are not regularly being followed or being under surveillance for their PAD, the results could be different. So, yes, it does not generalize the whole of that population. If we had gone that route and relaxed our inclusion, my worry was that we would get ... Because of large data setting up, as you say, if we include a bunch of people who are truly not PAD, we would be a [threading 00:18:17] risk in non-PAD patients.
Dr Carolyn Lam: Josh and Shipra, I loved the paper, but after this discussion I'm even more in love with the paper and impressed, so I think I just have a question for both of you. Is there any excuse not to give statins now? Do we actually think a trial is going to come on this topic? Is this the best data that we have? Is it going to enter guidelines? What do you think?
Dr Josh Beckman: I can give you my opinion first, if you want, because you're the person who actually has control of all the data. I would say this. I think it's been well known that statins should be used in all the patients with PAD for their cardiac outcome. My guess is that there are two things that are going to happen that are going to make people consider statins for limb outcomes.
One, data like this and there's never going to be a trial, a prospective randomized trial at this point, I mean unless you disagree, but there's no way people will randomize to not statin. I think the second reason is the recent data on the PCSK9 inhibitor, evolocumab, which showed that on top of statins in PAD patients, there was a further reduction in limb events. I think we're heading towards getting the LDL to zero. It may take a couple more steps, but that's basically what's going to happen.
Dr Shipra Arya: I agree. I think there has been time and time again data that shows, especially those already data supporting the mortality benefit for larger cohorts of patients with cardiovascular disease including PAD. I think this study really nails down the limb protector effects of statins, and doing a trial of this magnitude would be very difficult to do because to get that would be effect size that you have. You would need a huge cohort of patients, and you probably won't find statin-naïve patients because you have already half the patients with PAD have coronary artery disease, as well. So, not every study needs a trial. Not every question needs a trial, in my opinion. I think that's the power of large data sets. I think the evidence is overwhelming, and I would agree with Josh.
Dr Josh Beckman: I have always had a hard time explaining to people who came to see me for legs problems that they have to take a drug for their heart. It's sort of a weird two-step that people have a hard time accommodating. Do you think by telling them that this drug will also save their leg that they're going to be more likely to take the medicine by the end of the year?
Dr Shipra Arya: Yes, absolutely. That's what I tell my patients who come and see me, that this medication works on arterial plaques, and it stabilizes them. It's not just the same plaque that you have in your heart is the one you have in your leg. Maybe a little different, but to oversimplify, yes. This is not just a heart medication, and this is not just a cholesterol medication. This is a medication for your plaques, for your blockages. That's how I explain it to them, and I think the uptake would be more if we explain to them that, yes, this will help you keep your leg, stay ambulatory and stay at home and not end up in assisted living or nursing home.
Dr Josh Beckman: Carolyn, this is so much fun, especially when we get to talk to the people that do so much hard work to put stuff in circulation, so I just want to say thanks again to Shipra and her coauthors.
Dr Shipra Arya: Thank you so much, and thank you for giving us the opportunity. I think the comments from Circulation really made our paper better, so thank you for doing that.
Dr Carolyn Lam: I wish that we could just keep going on and on because I just know that Josh has even more great questions up his sleeve. See, Shipra, I told you, he's amazing. But, there you go. You're amazing, too. Your paper is amazing. Thank you so much for joining us today.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Our featured paper this week is an in-depth paper on the cardiovascular and metabolic heterogeneity of obesity, and we will have a discussion with the authors on the clinical challenges, implications for management, and much more coming right up after these summaries.
How does MRI quantification compare with standard Doppler echo approach to identify organic mitral regurgitation and predict adverse outcomes? Well, our first paper this week addresses this question, led by first and corresponding author, Dr. Penicka from the Cardiovascular Center OLV Clinic in Belgium. These authors studied 258 asymptomatic patients with preserved left ventricular ejection fraction and chronic moderate and severe organic mitral regurgitation by echo. All patients underwent MRI to quantify regurgitant volume of this organic mitral regurgitation by subtracting aortic flow volume from the total left ventricular stroke volume. Severe organic mitral regurgitation was defined as a regurgitant volume of greater or equal to 60 milliliters.
The authors found that mean echo-derived regurgitant volume was an average 17 milliliters larger than the MRI-derived regurgitant volume. Concordant grading of organic mitral regurgitation severity with both techniques was observed in 76% of individuals. In the remaining 24% of individuals with discordant findings between the two techniques, this was mainly observed in patients with late systolic, eccentric, or multiple jets.
The MRI-derived regurgitant volume showed the highest discriminative power among all the imaging parameters to predict all cause mortality or its combination with development of indication for mitral valve surgery. Thus, this study demonstrates that MRI-derived assessments of organic mitral regurgitation are clinically accurate to identify asymptomatic patients with severe organic mitral regurgitation and at first outcomes. This may be particularly so when the mitral regurgitation is late systolic, eccentric, or multiple in jets where misclassification may occur with echo-derived approach.
The next study is the first large population-based study to analyze the association between low-dose ionizing radiation from cardiac procedures and incident cancer in adults with congenital heart disease. First author Dr. Cohen, corresponding author Dr. Marelli from McGill University, studied the population from the Quebec Congenital Heart Disease Database and performed a nested case control study comparing cancer cases with controls matched on sex, congenital heart disease severity, birth year, and age. They found that the cumulative incidence of cancer in adults with congenital heart disease between the ages of 18 and 64 years was 15%. The cumulative low-dose ionizing radiation exposure from cardiac procedures was independently associated with incident cancer after adjusting for age, sex, year of birth, congenital heart disease severity and comorbidities.
Results were similar using either the number of procedures or estimates of the effective doses with a possible dose-related response relationship between the low-dose ionizing radiation exposure level and cancer risk. Thus, increasing exposure to low-dose ionizing radiation from cardiac imaging in adults with congenital heart disease raises concerns about life-long risk of malignancy. Confirmation of these findings by prospective studies is needed to reinforce policy recommendations for radiation surveillance in patients with congenital heart disease.
The next study characterizes the long-term dynamics of potassium in heart failure and its associated risk of mortality. First and corresponding author, Dr. Nunez from Hospital Clinic University of Valencia in Spain, evaluated the prognostic implications of long-term longitudinal monitoring and dynamics of serum potassium in a prospective and consecutive cohort of patients following a hospitalization for acute heart failure. In these patients, serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings.
The authors found that on a continuous scale, the followup trajectory of serum potassium levels independently predicted mortality through a U-shaped association with higher risk at both ends of the distribution, and the same was true using potassium categories. Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Persistence of normal potassium levels was linked to a higher risk of death compared to patients who maintained or returned to normal values. Conversely, potassium normalization was independently associated with a lower mortality risk.
These findings support the need for close monitoring of serum potassium after an episode of acute decompensated heart failure and suggest that maintaining serum potassium levels within normal range may be considered a therapeutic target.
The next study gives us an example of how functional metabolomics can translate into metabolomics derived biomarkers of disease mechanisms. Co-first authors, Dr. Zhang, Wei, and Li; co-corresponding authors, Dr. Zhu, Li, and Qi from Nanjing, China, studied a cohort of 2324 patients who underwent coronary angiography from four independent centers. They used a combination of ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode for untargeted analysis of metabolites in the plasma.
The authors identified a total of 36 differential metabolites related to coronary artery disease progression. In particular, N-Acetyl-neuraminic acid, a metabolic marker highly elevated during coronary artery disease progression, acted as a signaling molecule to trigger RhoA and Cdc42 dependent myocardial injury via activation of the Rho-RACK signaling pathway.
Silencing neuraminidase-1, which is the enzyme that regulates N-Acetyl-neuraminic acid generation, ameliorated myocardial injury in vitro and in vivo. Pharmacologic inhibition of neuraminidase by anti-influenza drugs protected cardiomyocytes and the heart from myocardial injury.
Thus, in summary, functional metabolomics identified a key role for N-Acetyl-neuraminic acid in acute myocardial injury, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for coronary artery disease.
The final study addresses the controversy of whether high density lipoprotein, or HDL cholesterol, plays a causal role in cardioprotection. First and corresponding author, Dr. Jensen from Harvard T.H. Chan School of Public Health and colleagues, hypothesized that subspecies of HDL defined by apolipoprotein C3, a key regulator of lipoprotein metabolism, may contribute new information to prediction of cardiovascular risk.
They used immunoaffinity chromatography to measure the apo A1 concentrations of HDL that contained or lacked apolipoprotein C3, or apo C3, in two prospective studies of adults free of coronary heart disease, the Multiethnic Study of Atherosclerosis and the Danish Diet, Cancer and Health Study. They then conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins.
The authors identified a subspecies of HDL that contained apo C3. HDL that contained apo C3 comprised 5 to 6% of apo A1 or 10 to 15% of HDL cholesterol. In the four prospective studies, HDL containing apo C3 was associated with a greater risk of coronary heart disease, whereas HDL that lacked apo C3 was inversely associated with risk more strongly than the total HDL.
These findings support the hypothesis that apo C3 may mark a subfraction of HDL cholesterol that is associated with higher risk of coronary heart disease. These findings therefore provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations. And that brings us to a close for the summaries. Now for our feature discussion.
For today's featured discussion, we are talking about obesity, a universal issue, or is it? And when we talk about obesity, are we talking about one thing or many things? Today's in-depth review is just such a great paper. I highly recommend it to everyone. So pleased to be discussing it with Dr. Ian Neeland today from UT Southwestern Medical Center.
Ian, first of all, congratulations. A beautiful paper. I learned so much reading it, and I've got so many questions. You started off pointing out that we talk about obesity. We've always defined it by body mass index, but that may not be the ideal biomarker. I love the way you said that. So, tell us a bit more about the reason for this review.
Dr Ian Neeland: Obesity, like you said, we define it by body mass index, but body mass index is such a crude marker. It's great to use for the clinic. It's easy to implement, but it doesn't really tell us a lot of information about the person. And so you can just look at a third of the population in the US right now is thought to be obese. And if you take a third of the population, clearly not everyone has diabetes and heart disease.
So, obesity in and of itself, defined by the body mass index really is very heterogeneous, and it's not possible to use that alone to tell an individual if they're really at risk for disease. And so this review is really about getting deeper under the skin, no pun intended, to really get a sense of what it means to be obese, how the body fat plays a role in disease, and really getting to the different aspects of obesity and how we can understand it a little bit better.
Dr Carolyn Lam: Yeah. You know, Ian, you had me at hello if I could say when I read your paper because I'm from Asia, and here, the World Health Organization actually even suggests that we use lower body mass index cutoffs to define obesity, simply because there's a different relationship as well with cardiometabolic disease. So, so true, but before we get there, to maybe ethnic differences, I want to ask you something. I heard the term, obesity paradox, thrown around a lot, and sometimes I think we don't really know what we're talking about when we say obesity paradox.
I love the way, in your paper, you broke it down into four types. There are four paradoxes. Do you want to just clarify this for the audience? I think it's important.
Dr Ian Neeland: So, the obesity paradox, what we mean by that is we think that obesity causes disease and gives someone an increased risk for disease and mortality and death, but the obesity paradox means that some people who are obese we see actually have better outcomes than those who are not obese. And how to describe that paradox and why that exists is really the subject of lots and lots of research and discussion.
And so when we talk about the obesity paradox, really it's important to understand that most of the time we're talking about people who already have established disease. Let's say, for example, heart disease. So people with heart disease who are obese tend to have better outcomes than those who are not, and there are a few ways to understand that.
So people who have obesity with established disease who may have better outcomes; that's the classic obesity paradox. Then there's a paradox really about fitness and being fat and fit, and that concept that you can be fat, but if you're fit, if you're able to do exercise and you have good cardiorespiratory fitness, that you actually may be protected from disease as well. And then there's also the obesity paradox of basically the pre-obesity paradox, so that overweight, right, where you haven't yet met the threshold for obesity can also be protective in people who don't have disease. And so being a little bit plump may be protective for different diseases down the road. And then the final one is that the metabolically health obesity. When we say that, it means that the person who is obese by body mass index but doesn't really have any hypertension or diabetes or lipid abnormalities. So, that's the metabolically healthy obese person.
Those are the four types of individuals we see who may be obese but actually have better outcomes long term, and the question is why that exists. So there's a lot of thinking about it. Maybe it has to do with the fact that being normal weight nowadays, often we have older folks that are normal weight. Well, they tend to be more deconditioned. They may be frail. They may have undiagnosed disease like cancer. And that might be why those people are the worst. And there are the naysayers out there who think that it's all just about what we call confounding, so things we can't account for when we look at that. People who smoke tend to be lower weight, and obviously they have worse outcomes, and then also people who are older. So it's kind of a conundrum, this obesity paradox, but there's lots and lots of data out there coming out all the time that we keep seeing it again and again and again.
One of the areas in the paper that I wanted to address was this concept of obesity heterogeneity in the obesity paradox, meaning to say is it potentially where the body fat is that may be playing a role in which obese person gets disease, and which obese person may be protected from disease. So it could be that it's not how much fat you have but where that fat is that is really telling about what someone's risk is, and that might help to describe the obesity paradox and get us a little bit more understanding.
Dr Carolyn Lam: Yeah, now, I thought that bit was just so key and important. Not how much fat, not weight per se, but where that fat is. Do you want to elaborate on that a bit?
Dr Ian Neeland: Sure. For, I don't know, 50, 60 years we've had this concept of the apple and the pear. Right? Fat in the belly being the apple shape and fat in the pear being fat in the hips and buttocks and that being two different body types of body fat. So we have a lot of technology nowadays, and we can actually directly image body fat and where it is in the body. So we can do MRI, we can do CT, and we can actually see where the body fat is distributed and how much body fat in one area may be related to disease compared with another area.
So we've gone away from the apple and pear and really getting down to what we call body fat depots or adipose tissue depots where we deposit fat. And the area that we deposit fat that has the most risk for cardiometabolic diseases is this visceral adipose tissue or VAT. VAT is fat that's around the intra-abdominal organs, also near the kidneys, and you can't actually tell how much visceral fat someone has just by BMI or waist circumference or just looking at them. You really have to do this dedicated imaging to find out. And the reason for that is that in the belly there's two types of fat. There's the visceral fat, and there's the subcutaneous, which is the fat under the skin. Both those fat areas make up the belly fat, but they're very different. And part of the review is really going into depth about why these are different and how they're different.
They have completely different metabolic profiles, so if you would take blood, lipids, inflammatory markers, they would look completely different even in a single individual. And then if you look at the genetics of where the fat is, they're different. If you look at what these fat areas secrete, they're completely different. So it's really important to know where the fat is, and that's why I think this concept of sick fat versus healthy fat comes into play.
So, sick fat is fat that's usually in this visceral fat depot, and that is really the three central tenets we talk about are visceral fat or ectopic fat. Ectopic means fat where it doesn't belong. Then inflammation and cytokines, so secretion of abnormal factors in the blood from this fat, and then insulin resistance. So those are the three kind of tenets of this sick fat. So that's why we think that the sick fat plays a role in disease, and then there's a concept of less sick fat or healthy fat, which is maybe a sink. It actually buffers some of these cytokines and inflammation from causing disease in the body.
Dr Carolyn Lam: Yeah. I found that concept so fascinating, and just to bring it back to the obesity paradox. So, some larger people may enjoy better outcomes because they actually have a predisposition to put the fat subcutaneously perhaps, rather than viscerally. Would that be correct? You worded it so eloquently in your paper. There are some ethnicities or some genetic predispositions that could make one lose that inability to put it peripherally, and therefore it all goes viscerally, is what I got from it. And that's the stuff that puts people at risk.
Dr Ian Neeland: Yeah. We find that fat in the lower body, the hips and the buttocks, is actually in epidemiology, protective against heart disease, protective against cancer. And the problem is we don't know why some people put fat in the belly and some people put it in the hips and buttocks. There's very interesting twin-twin studies that show if someone has a predisposition for obesity, so twins may be both obese, but there is some difference in where they actually put the fat. So I think genetics certainly plays a role, but environment also plays a role. And environments, things like appropriate nutrition and physical activity can really alter genetics and help someone to put fat where it should be and prevent disease.
So this obesity paradox, this concept of putting fat where it should be, is really the next frontier for this type of research. How can we modulate it? How can we fix it?
Dr Carolyn Lam: Exactly, and I love the way you ended your review when you said, "Therefore, maybe in all our complaints and so on, saying that we want weight loss, we should actually be focusing on waist loss. You could redistribute the fat to healthy areas, not change your weight, and still become healthier." That was the concept, right?
Dr Ian Neeland: That's right. Yeah. It really is amazing, and it's been shown again and again that people can stay the same weight, but their body fat really is very plastic. It can change, and it's modifiable. And that really makes a difference with health outcomes. So whether we can do that with lifestyle changes, so there's some data to support that. There's also some data to support pharmacology, so medications may be able to move fat from one area to another. And then certainly surgery, which is now getting a lot of popularity for people who are really high risk for cardiometabolic disease. Bariatric surgery has been shown to decrease visceral fat significantly, and that may be one of the reasons why it works so well.
Dr Carolyn Lam: Exactly, Ian. Fascinating, fascinating. I tell you what. Could I just ask you to give us some take-home messages?
Dr Ian Neeland: Sure. So one take-home message I think is that we can move beyond the BMI, beyond the body mass index. Obesity is no longer just a number. It's really about the entire individual, biologic systems, what's going on, and there's just remarkable heterogeneity in the structure of obesity, where body fat is, the activity of body fat, the physiology of it, and also how it relates to diseases, either causing disease and potentially being protective for harmful outcomes.
I think it's also a key message to understand that there's sick fat and there is healthy fat and they're very different. And we can get to the bottom of those using specialized tools like imaging and special testing, but they're really very different, and not all body fat is created equal.
And then lastly, I think it's important to consider, like you mentioned earlier, that really public health and lifestyle going forward is going to be so important, and focusing on those areas that will have the biggest impact for people such as trying to promote waist loss, like you said, as opposed to weight loss. Really focusing and using our knowledge of body fat and obesity and how it's so different across individuals and populations, that it's really important to use that knowledge for our future goals and to have that mind when we recommend weight-modifying therapies for our patients.
It's really going to be a new frontier in weight. We're really moving beyond this concept of just check your weight and your height, and we can tell you what your risk is. No, it's really much more complex and complicated and much more interesting than that.
Dr Carolyn Lam: Oh, Ian, that's just so wonderful. I cannot help this last question. Who knows whether we'll put it in, but I just have to ask you. So how do you monitor your own status or your patients' status? Do you really get them DEXAs, all of them? Or PETs, FDGs? Or do you take your own weight?
Dr Ian Neeland: Yeah. I do. One thing I have noticed, I actually started an exercise and diet program for myself to improve my health about a year and a half ago. I took the research, and I said, "Okay, I'm really going to use this and apply this to my life." So, what's interesting is what I found and actually what other colleagues of mine in research are finding is that you can actually melt away visceral fat just with exercise alone, even if you don't actually go on a diet. And they've done studies like this where they do DEXA scans, and they give people high-intensity interval training. They don't give them a special diet. They just say maintain your current diet, and the visceral fat goes away.
It's really remarkable how lifestyle can be so important and make such a change. And you can see people who have diabetes who can cure their diabetes with a lifestyle program by really decreasing the visceral fat. Even if their weight doesn't change or only changes by a small amount, but their weight may change by, I don't know, five, 10 pounds, but their visceral fat may go away by 50%. And that really makes the difference.
It's obviously hard to monitor. We don't really have these tools clinically every day. Not everyone can do a DEXA and has the software to measure the visceral fat. Certainly could be coming in the future, but right now we should use the tools we do have and use the biomarkers we have and the clinical use, the waist circumference, triglycerides. These things are all surrogates for visceral fat but can be very useful to monitor for change. And it's not just about the scale. It's really about more than that with a person's metabolic status.
Dr Carolyn Lam: That is so helpful. Thank you so much, and I'm so glad you said that it was exercise, and you don't jump into a ice pool or something to try and convert the fat to brown fat or something. That's really, really encouraging to me. Thank you, Ian. This was so enjoyable. I'm sure all our listeners are thanking you as well.
Listeners, you've been listening to Circulation on the Run. Please tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. How common is perioperative myocardial injury after non-cardiac surgery, and what is its significance? A very important question and a very important feature discussion coming right up after these summaries.
Our first original paper this week tells us that risk assessment using only non-laboratory based risk factors may be a useful alternative in the absence of informational lipids, in predicting adolescents at risk of developing pre-clinical atherosclerosis.
First and corresponding author, Dr. Koskinen from University of Turku Finland and colleagues, studied almost 2,900 participants, age 12-18 years, from four longitudinal cohort studies from the United States, Australia, and Finland, and followed these adolescents into adulthood. When carotid intima media thickness was measured, a mean followup of 23 years later. Non-laboratory based risk factors such as age, blood pressure, body mass index, and lipids measured in adolescence, independently predicted high carotid intima media thickness in young adulthood. The addition of lipid measurements to these traditional clinic based risk factor assessments provided a statistically significant but clinically modest improvement on adolescent prediction of high carotid intima media thickness in adulthood.
The next study demonstrates the feasibility of large scale aptamer multiplexing at a level that has not previously been reported and with sample proof that greatly exceeds other existing proteomic methods.
Now, like antibodies, DNA aptamers can be generated as affinity reagents for proteins. Emerging data suggests that they can be used to measure blood protein levels in clinical cohorts. However, the technology has, to date, remained in its infancy. In today's study, co-first authors, Dr. Jacob and Dr. Ngo, co-corresponding authors, Dr. Jennings and Gerszten, from Beth Israel Deaconess Medical Center in Boston, tested the scalability of a highly multiplexed expended proteomic technique that uses single stranded DNA aptamers to assay human proteins with a markedly expended platform containing approximately 5,000 aptamers targeting a far broader range of analytes than previously examined using this technology. They applied the platform to a cohort of individuals undergoing septal alcohol ablation for hypertrophic cardiomyopathy, using this as a human model of planned myocardial injury.
Now, in addition to confirming findings from prior studies, they identified nearly 150 additional putative markers of myocardial injury. Thus, these findings suggest that the expanded aptamer based proteomic platform may provide a unique opportunity for biomarker and pathway discovery following myocardial injury.
The next study addresses the potential long-term effects of low LDL cholesterol on neurocognitive impairment and decline. This has been a concern with pharmacologic PCSK9 inhibition. The first author, Dr. Mefford, corresponding author, Dr. Levitan from University of Alabama at Birmingham, investigated the association between PCSK9 loss of function variants and neurocognitive impairment and decline in the regards study.
In this general population sample of African American adults, they found no association between PCSK9 loss of function variants and neurocognitive impairment or longitudinal neurocognitive decline. There was also no association between lower LDL cholesterol levels and neurocognitive impairment or decline during follow-up.
The study, therefore, provides evidence in a contemporary population that PCSK9 loss of function variants and resulting lifelong exposure to low LDL cholesterol levels are not associated neurocognitive impairment or decline.
The final study explores long-term outcomes in patients with Type 2 myocardial infarction and injury. First and corresponding author, Dr. Chapman from University of Edinburgh and his colleagues identified more than 2,000 consecutive patients with elevated cardiac troponin I concentrations at a tertiary cardiac center. All diagnoses were adjudicated as per the universal definition of myocardial infarction. They found that at five years, all cause death rates were higher in those with type 2 myocardial infarction or injury compared with type 1.
Although the majority of excess deaths with type 2 myocardial infarction or injury were due to non-cardiovascular causes, the observed crude major at-risk cardiovascular events are MACE rates were similar between groups. Coronary heart disease wan an independent predictor of MACE in those with type 2 myocardial infarction or injury. Thus, despite an excess in non-cardiovascular death, patients with type 2 myocardial infarction or injury have a similar crude rate of major at-risk cardiovascular events to those with type 1 myocardial infarction. Identifying underlying coronary heart disease in this vulnerable population may help target therapies that could modify future risks.
That wraps it up for our summaries. Now, for our feature discussion.
So, I'm gonna go back to my first question on this podcast. How common is perioperative myocardial injury after non-cardiac surgery and what is its significance? Well, to give us an answer, I am delighted to have the first and corresponding author of today's feature paper, Dr. Christian Mueller from University of Basel in Switzerland, and we also have Dr. Torbjorn Omland, and he is associate editor form University of Oslo in Norway. Now, in case you're having deja vu, you are right. I have had these gentlemen on this podcast before and they were so successful, I had to call them back. So, welcome, welcome Torbjorn and Christian. Thank you for coming back again. Christian, congratulations on another beautiful paper. Could you tell us the highlights of what you did and what you found, but this time in particular tell us the novel aspects in view of the previously published vision study that was just published last year. Maybe you could just point out some of the differences.
Dr Christian Mueller: The topic is about an interdisciplinary topic and something, I think that is so important for us as cardiologists to get involved in with much more detail in the future. So, we are aware of acute myocardial infarction, sustained myocardial infarction event that we have studied extensively for decades and for which I think we have a fuller understanding of its cardiophysiology and we have excellent treatments. Completely novel entity is perioperative myocardial injury, so cardiomyocytes that die in the context of non-cardiac surgery. It's something that we as cardiologists should be really focused on because its likely the most important contributor to death in the perioperative period. So, the death rate among non-cardiac surgery is despite improvements in anesthesia and surgery remains remarkably high, between 1 and 4% within 30 days, depending on patient characteristics and surgical directives. And, it seems from our current understanding that the heart really plays a major role, rather high percentage of these deaths.
So, what is new in our study? Overall, our study took advantage of insight gained in the first phase of the vision study in that its has been documented that this perioperative myocardial injury fairly commonly occur without the patient or we as physicians getting aware of it. Either because the patient is still having anesthesia or because he may have symptoms that are atypical. So, we can only reliably detect this event if we screen an appropriate population, and that's what we have done. So, I think the criteria where a patient that's at higher risk of cardiovascular complication is defined at an age of 65 or higher or having pre-existing cardiovascular disease. So, this is the first major difference in which also much younger patients were enrolled. That's the most important differentiate as we had an open label screening. So, the screening was part of clinical routine and it was fine tuned to patients of whom we thought may have a reasonable high risk of developing this complication.
Dr Carolyn Lam: And, your main findings, because they were striking.
Dr Christian Mueller: As our most important finding, we were able to report the incidence of how many patients actually have a relevant amount of cardiomyocytes dying during the operation, and it was one out of seven patients entering our study. So, an incredible high incidence of this complication and that this complication not only is a very good end point that you shouldn't care too much was highlighted again and in full agreement, the suspicious is that if patients develop this complication of perioperative myocardial injury, their risk factor of whether they have any symptoms or atypical ischemic symptoms, and again, only a small minority had the risk of dying both within 30 days as well as in one year, was substantially increased.
Dr Carolyn Lam: Christian, before you go on, could you just please clarify, how did you define perioperative myocardial injury in this case, and was it the same as the definition used in Vision?
Dr Christian Mueller: The perioperative myocardial injury concept initially in Vision it was defined as detecting an elevated troponin just after a non-cardiac surgery, and why this was a perhaps an appropriate definition at the time when we were still using very poorly sensitive troponin assays inevitably is no longer appropriate nowadays because its obvious that particularly elderly patients may have chronic elevations and high sensitive troponin usually. Mild elevations due to a variety of disorders and [inaudible 00:11:51] important studies for us to understand that it is mild elevations troponin is quite common in patients with heart failure, with coronary artery disease or hypertensive heart disease, whatever. So, if we could detect or start detecting likely elevated troponin only after operation, we would never know whether this is something related to the operation itself or whether it's perhaps had already been around for months and weeks and represents the chronic condition. So, the novel concept is that we have to identify an acute rise in troponin, a dynamic genetics or just like that requested for the universal definition of myocardial infarction also of course [inaudible 00:12:32] So, we requested in this study, an increase from the concentration prior to surgery of at least 14 ng/l of high sensitivity cardiac troponin.
Dr Carolyn Lam: Right. Wow. What a great study. So systematic. So, all patients, basically had readings before and after surgery. You know, I've got so many questions, but I really, since you mentioned Torbjorn, I would really like to ask his perspective on what you think was the most striking parts of it and any questions you may have on Christian.
Dr Torbjorn Omland: First, I would like to say that this is a very impressive study with some very important results in a neglected area of medicine, really. So, there are several very strong points with this study, and I think that if we're able to, in such a large population, both have pre-operative and post-operative and was able to calculate the delta, and the importance of that was a very strong part of the study, because it showed that, as Christian alluded to, the baseline level did carry some information but there was also important additional information from the serial measurements. So, that's maybe one of the most important findings, I think.
Then, we addressed the question, how should we use these data? So, my question to Christian is actually, how will screening for exceptional myocardial injury affect clinical practice? Will it lead to clinical deficiency interventions that will improve outcome or will it just result in unnecessary testing?
Dr Christian Mueller: Very good important point, Torbjorn. I think you are absolutely right in indicating that I think we are just beginning to understand all of the part of physiology behind the event that we can now capture, detect really, rather simple and precisely with troponin screening. So, I think it's important that we highlight that the part of physiology behind this event differs from patient to patient. So, there are some patients who clearly have a type 1 myocardial infarction as the cause of myocardial injury. Very likely, they are the minority in this setting. Likely, the majority to have a kind of a type 2 myocardial infarction have a physiology with imbalance between supply and demand, and again, in these patients, of course, the management needs to be to identify the trigger and to correct the trigger as rapidly as possible. And it can be that detecting myocardial injury by the rise in troponin, is the first indication that there is a problem ongoing. Now the patient can have a physiological rearrangement might have already been aware to the physicians if it's a type 1 myocardial infarction, then obviously very likely the same therapy will be beneficial to this patient as we would apply in spontaneous myocardial infarction.
A very important, and I'm glad you alluded to that the different ways of, a rather wide variety of patient settings that are summarized of the term perioperative myocardial injury. And the consequences, likely will have to be individualized to really ensure that we do something good for the patient.
And if I may, I would like to ask you and Carolyn for your thoughts about the most appropriate wording. So, the current wording that we used, of course, has to be in any scientific precaution, a very conservative one, perioperative myocardial injury. And it's important that, in fact, there are some entities where likely injury is derived from the patients who have the injury related to serious sepsis or related to a stroke, or pulmonary embolism. However, it's very likely that the vast majority of patients, the term perioperative myocardial infarction would be appropriate. And, I think it's so important to be aware of the implication that this, perhaps, on first slight small difference might have. As long as we keep using the term "injury", cardiologists will not really feel the same need to be involved, the same need to really take care of this patient as compared to the use of "myocardial infarction". So, I think it's a balance between scientific accuracy, but also the need to create awareness.
So, I feel that if cautiously applied, we'll do more good if would more liberally use "myocardial infarction" within this context. So, would you agree with this perchance?
Dr Carolyn Lam: I think "injury" is at least better than what we used to say, "a leak'. You know, we used to say, "Oh, it's just a troponin leak". So, at least we're saying injury, recognizing that there is damage done. I just wanna highlight that in your paper, something that really struck me was that these patients with perioperative myocardial injury or infarction, indeed did as badly as those who did or did not fulfill myocardial infarction criteria. So, that kind of supports what you are suggesting. I did get that right, right? In your paper?
Dr Christian Mueller: Absolutely. I think for spontaneous myocardial infarctions, so clearly that the criteria defined in the universal definition are mandatory. There's nothing to discuss about, but we cannot criticize a patient who is undergoing general anesthesia that he doesn't feel chest pain, and therefore, we deny him the appropriate word of the events. I think is just important that we clearly highlight that it really can be the same event in the chest without symptoms. But, not due to anything else but because he is undergoing anesthesia.
Dr Carolyn Lam: Very good point. You know, I would really like, though, to go back to Torbjorn’s point, because I think that skeptics are gonna say we've created a problem that we don't know how to solve, or that we don't know how to treat. Do you know what I mean? So we're detecting all these things, because now we have all these assays. Patients are asymptomatic, and then we really don't know whether it's modifiable. We don't know what to do to improve outcome. So, could I ask both your expert thoughts on what the future should hold? What is next step? Because, I see a gap.
Dr Torbjorn Omland: Yes, that's of course, a key question. So, I think we need to be innovative and patient, because what we really need is clinical trials, perhaps and more clinical trials looking into different strategies. But, of course, that's also challenging because as Christian told us, the path of physiology among this group of patients with perioperative myocardial injury differs. So, what's going to be appropriate for one patient, may not be the appropriate therapy for the next patient. So, I think his suggestion of an individualized approach is the best thing we can say at this moment, while we are awaiting data from future clinical trials.
Dr Christian Mueller: I fully agree with Torbjorn [inaudible 00:19:53] what you said, you will criticize some people will argue to that it's irrelevant. Why do you measure this and you don't want to hear it? You don't want to see it. But, I think it's important to remember the starting point for us as cardiologists is to get involved is death. If death is within 30 days after non-cardiac surgery in a patient who was fit, relatively fit otherwise, who underwent a surgery that was not a very high risk surgery from which he would expect a certain percentage of patients to die. So, that's the starting point. Again, of course perioperative myocardial infarction is not the only contributor to perioperative death. But, it seems, in addition to severe sepsis, to be the second commonest and most important. So, I think it's really, really important to first, as a really as a first important thing to increase the awareness of this problem and to encourage our colleagues to start bringing their research efforts, so that we get smarter in identifying the underlying part of physiology in these infarcts or injuries.
Because, only once we understand, or have a reasonable understanding what is the mechanism, we will be smart enough to select the most important priority for any intervention study.
Dr Carolyn Lam: Wow. What a wonderful note to end this podcast on. Words of wisdom, as always from both of you, Christian and Torjorn.
See, listeners. Didn't I tell you this was gonna be a great podcast? Don't forget to tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore.
Have you ever wondered, which is better for heart health, low calorie vegetarian or a Mediterranean diet? Well, this week's feature paper provides some answers with a very intriguing discussion coming right up after these summaries.
The first original paper this week suggests that human fat pools are not the same and in fact are highly diverse in their response to lifestyle interventions during weight reduction first author Dr. Gepner, co-corresponding authors Dr. Shai from Israel and Dr. Stampfer from Boston aim to assess whether distinct lifestyle strategies could differentially affect specific body adipose depos. They performed at 18-month randomized control trial among 278 sedentary adults with abdominal obesity or dyslipidemia in an isolated work place with a monitored, provided lunch.
Participants were randomized to an isocaloric low fat or a Mediterranean low carbohydrate diet with or without added moderate physical activity. The overall primary outcome was body fat redistribution and the main specific endpoint was visceral adipose tissue. The authors further followed the dynamics of different fat depos by magnetic resonance imaging. They found that Mediterranean diet was superior to the low fat diet in mobilizing specific ectopic fat depos such as visceral, hepatic, cardiac and pancreatic fats. Exercise had an additional independent contribution to visceral fat loss. Long term persistent moderate weight loss inadequately reflected the significant beneficial effects of diet and exercise on the fat depos. Independent of weight loss, visceral and hepatic fat reduction was mainly associated with improved lipids profile whereas deep subcutaneous fat loss was associated with improved insulin resistance and superficial fat loss was neutral.
In other words, two distinct patterns were identified, a differentially responsive depo that was sensitive to the type of intervention, and those recites mostly directly related cardiometabolic health and a uniformly responsive depo, which corresponded only to weight loss per se irrespective of the intervention. Overall, these results suggest that more specific strategies for weight loss may be considered to treat distinct organ specific fat depos in the management of cardiometabolic risk.
Current guidelines recommend nonvitamin K antagonist oral anticoagulants or NOACs in patients with nonvalvular atrial fibrillation as these drugs have several benefits over the vitamin K antagonists but do these benefits remain when NOACs have to be combined with aspirin therapy? Well co-first authors Dr. Bennaghmouch and de Veer, corresponding author Dr. ten Berg and colleagues from the Netherlands provided a meta analysis comparing NOACs and Vitamin K antagonists in more than 21700 patients with atrial fibrillation who are treated with concomitant aspirin therapy. NOACs were found to be more effective in terms of stroke or systemic embolism reduction as well as vascular death reduction and as safe as vitamin K antagonist with respect to major bleeding. NOACs were in fact safer with respect to the reduction of intracranial hemorrhage. Thus, these authors found that NOACs were an effective and safe alternative as compared to vitamin K antagonists in atrial fibrillation patients treated with concomitant aspirin therapy.
The next study shows that an integrative approach using genomics and proteomics has the potential to identifying new biological pathways for biomarker discovery and pharmacologic targeting in early cardiovascular disease. Co-first authors Dr. Benson and Yang, co-corresponding authors Dr. Wang and Gerszten from Beth Israel Deaconess Medical Center in Boston had recently identified 156 proteins in the human plasma that were each associated with a net Framingham cardiovascular disease risk score using an aptamer-based proteomic platform in the Framingham Heart Study Offspring participants.
Now, in the current student these authors hypothesized that performing a genome-wide association study and exome array analyses on the levels of each these 156 proteins may identify genetic determinants of risk associated circulating factors and provide insights into early cardiovascular pathophysiology. Indeed, they discovered dozens of novel genetic variants that were each strongly associated with circulating levels of the Framingham Risk Score associated proteins. They highlighted numerous examples of how these novel gene locus protein associations provided new insights into cardiovascular disease risk pathophysiology including a novel pathway by which the gene phosphatase 1G modulated circulating levels of apolipoprotein E, a key regulator of cholesterol handling.
The final study suggests that bariatric surgery represents an effective strategy for reducing antihypertensive drugs in patients with obesity and hypertension. First and corresponding author Dr. Schiavon from Heart Hospital in Sao Paulo, studied 100 patients with obesity and hypertension who were randomized to gastric bypass or medical therapy alone. The patients randomized the gastric bypass were six times more likely to reduce by 30% or more the total number of antihypertensive medications while maintaining controlled blood pressure levels. In addition, 51% of the patients undergoing gastric bypass showed remission of hypertension. Now, the authors are quick to alert that given the morbidity of surgery these results do not imply that all patients with obesity and hypertension should be submitted for bariatric surgery. Rather, these results suggest that gastric bypass surgery represents one extra option to consider in achieving blood pressure control in these patients.
That wraps it up for our summaries now for our feature discussion.
So, which is better for heart health the vegetarian or the Mediterranean diet? Oh, what an awesome topic and to be able to discuss it from Asia to the United States to Italy, I'm so please to have the first and corresponding author of our feature paper this week Dr. Francesco Sofi from University of Florence in Italy and our dear associate editor Dr. Wendy Post from Johns Hopkins. Francesco, could you please start by telling us what inspired you to do this trial?
Dr Francesco Sofi: The aim of the study was to compare two of the most beneficial diets we know from the literature in relation to the occurrence of many chronic degenerative diseases so the Mediterranean diet we have a lot of studies showing that Mediterranean diet is beneficial for many different diseases as well as we have some studies for the beneficial effect of a lacto-ovo vegetarian diet but no studies are available comparing these two diets' dietary profiles. Our hypothesis was to compare in the same population different times the two diets, which were the similar calories, the same isocaloric but just different in terms of composition especially for meat and fish.
Dr Carolyn Lam: Tell us the bottom line. I'm holding my breath because I think I've said it before, I'm vegetarian. Half my household is Mediterranean diet so what did you find?
Dr Francesco Sofi: We found that in the same group of patients, which were a low risk population because a low risk population here in Italy they were already following a Mediterranean diet but if you control their calories and their composition in terms of the Mediterranean, which included all the different food groups and the lacto-ovo vegetarian diet so all the different groups except for meat and meat-based and fish we noticed that after three months, the lacto-ovo vegetarian diet already determined a reduction of total cholesterol and LDL cholesterol and Mediterranean diet already determined reduction of triglycerides and both were effective for reduction of body weight and fat mass.
We noticed with great interest that after three months, all the study population were quite good in [inaudible 00:09:45] with this diet. I mean they didn't have any kind of problems. This is the one of the most important thing and most of the population or many of the patients after the end of the study they started or continued to follow a vegetarian diet. It means that they accepted very well. There was no problem at all. Also, in feasibility and acceptability of this diet and in relation to this also they have a beneficial effect in some parameters such as also oxidative stress parameters and the inflammatory parameters.
Dr Carolyn Lam: Right, so if I could summarize maybe crudely so the vegetarian diet, very effective for LDL, the Mediterranean very effective for triglycerides. I know that's a simplification but Wendy, I'd like to know do you think this is the dawn of maybe a more, "Oh, here we go again individualized diet planning"?
Dr Wendy Post: I think that this study is really important because there really have been few randomized trials about the vegetarian diet and we've learned a lot of the potential beneficial effects of a Mediterranean diet. I think what was really interesting about this study is seeing that they were both equally effective as a low calorie Mediterranean diet or vegetarian diet at reducing body weight, which is most often the biggest challenge for our patients who are either at risk for cardiovascular disease like these patients potentially were or who have cardiovascular disease.
I think the vegetarian diet is potentially an excellent option for some of our patients but it really is an individual choice and I have trouble getting some patients to just give up the red meat let alone any kind of animal meat. I think it really is potentially an individual choice and those who are interested in becoming vegetarian for either health reasons or other reasons these are additional data to suggest potential beneficial effects more to the Mediterranean diet.
Dr Francesco Sofi: I think one of the most important things to know from this study is that we have now two options. We need to individualize the diets to patients but if a person wants to follow a vegetarian diet for different reasons including also healthy reasons, we can say that it's beneficial. He or she can follow this diet without no problems so without having any health problems as well as if a person wants to follow also a Mediterranean diet, which included meat and fish with a regular and moderate consumption during the week.
Dr Wendy Post: Right but this is just a three month trial with intermediate outcomes so I'm not sure we can necessarily make definitive statements that this is potentially not leading to any adverse effects or some of the other statements that you made. I think we could just make the statements better relative to the outcomes that were seen here related to weight loss and traditional cardiovascular risk factors. Whereas, we have had long term clinical trials of the Mediterranean diet suggesting reduction in risk for events so I think this is definitely supportive of the vegetarian diet but I think we can't say that more studies aren't needed to potentially look at longer term outcomes and more definitive events as opposed to intermediate outcomes that this is a great first start and is really helpful in trying to understand some of the potential differences between the vegetarian diet and the Mediterranean diet.
Dr Francesco Sofi: Of course, I completely agree on that. We need more studies and larger studies and longer duration to establish some things but it was just a pilot study but the good thing is the first comparing two beneficial diets. In the literatures now, most of the studies were investigated either already a vegetarian person or vegetarian diet versus a westernized diet so probably there were some biases.
Dr Carolyn Lam: Indeed, I want to just echo in these words. Congratulations, Francesco. Beautifully done, very elegant, controlled in terms of caloric intact and I like that message that it's not saying that one is bad and the other is good. It's saying, "They're different but they both resulted in weight loss". I love that comment about getting a bigger study. I want to do it right here in Asia because the diets are just so different here and I'm just wondering how about in the US? Wendy, your perspective? How adoptable are these results?
Dr Wendy Post: Well, again I think it's a personal choice and if somebody is willing to become vegetarian then that's potentially wonderful especially if they have high LDL cholesterol and are trying to lose weight but we have to be careful about with the vegetarian diet is the carbohydrate intake, which might affect triglycerides. It might be an individualized approach based on the patient's individual risk factor profile and they're preferences but this is really impressive data suggesting that the vegetarian diet is very similar to the Mediterranean diet in many aspects especially as it relates to weight loss, which is really important.
Dr Carolyn Lam: You've hit the nail on the head. Let's remember that this is a low calorie vegetarian diet. I think that's the issue. Sometimes when I say vegetarian diet to some communities here in Asia that is actually a lot of calories and a lot of starch, which is not what we're talking about here.
Dr Wendy Post: Right, a low calorie diet so that's the key. That's the hard part isn't it?
Dr Carolyn Lam: Yeah, sadly.
Dr Francesco Sofi: We should say that most diets are similar background I mean in the backbone is similar so a dietary profile full of fruit and vegetables, complex carbohydrates, fiber, so the different things are meat and fish but with you can see in a regular consumption also Mediterranean diet of course, especially Mediterranean diet is beneficial for cardiovascular profile.
Dr. Wendy Post: Yeah, if we could get our patients in the United States to follow either the vegetarian or the Mediterranean diet that would be fabulous because they are obviously eating too much in the way of sugar sweetened beverages and deserts and fast food so just trying to follow either of these diets would be especially beneficial if it was a low fat vegetarian or Mediterranean diet. I think we need to get all our patients to be eating more fruits and vegetables, which is a key component of both of these diets and what they share in common, which often can lead to beneficial effects with weight loss due to the increased fiber and satiety and the healthful benefits of high fruit and vegetable diet.
Dr Carolyn Lam: Thank you so much.
Audience, thanks also for joining us. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week's journal features an international external validation study of the 2014 ESE Guidelines on Sudden Cardiac Death Prevention in Hypertrophic Cardiomyopathy. A very exciting discussion coming right up after these summaries.
The first original paper this week suggests that proteomics, a tool of precision medicine may prove useful in improving the safety and efficiency of drug development. First author, Doctor Williams, Corresponding Author, Doctor Ganz, from the Zuckerberg San Francisco General Hospital retrospectively applied large scale proteomics to blood samples from Illuminate, the trial of Torcetrapib, a cholesterol estrotransfer protein inhibitor, which raised HDL and lowered LDL cholesterol. Recall that this trial was terminated due to increases in cardiovascular events and mortality.
In the current study, the authors found that plasma concentrations of 200 proteins changed significantly with Torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in aldosterone function and glycemic control. A previously validated nine protein risk score was similar in the two treatment arms at baseline, but higher in participants with subsequent events. At three months, the absolute nine protein derived risk increased in the Torcetrapib plus Atorvastatin arm compared to the Atorvastatin only arm. Thus, this protein-based risk score predicted harm from Torcetrapib within just three months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients. This is discussed in an accompanying editorial entitled "Harnessing the Power of Proteomics to Assess Drug Safety and Guide Clinical Trials" by Doctor Maggie Lam and Ying Ge.
The next study suggests that personalized monitoring of heart transplant outcomes may be achieved by profiling the genetic and phenotypic markers of the CD16-dependent natural killer cell activation pathway. First and corresponding author Dr. Paul from Vascular Research center in Marseilles in France and his colleagues collected blood samples from 103 patients undergoing routine coronary angiography for cardiac allograph vasculopathy diagnosis, a median of five years since their heart transplantation. They used a non-invasive natural killer cellular-humoral activation test to evaluate the association between genetic and phenotypic markers of the CD16 dependent natural killer cell activation pathway. They showed that the Fc-gamma receptor IIIAVV polymorphic variant, which encodes the highly responsive CD16-Fc receptor, was an independent baseline predictor of cardiac allograph vasculopathy, and may be useful for stratifying patients at higher risk of rejection. The implications of these findings also include the fact that individualized natural killer cell targeted therapies may limit vascular damage in responsive patients.
The next study suggests that estimation of polygenic atrial fibrillation risk is feasible, and together with clinical risk factor burden, can explain lifetime risk of atrial fibrillation. Co-first authors Dr. Weng and Preis, corresponding author Dr. Lubitz from Massachusetts General Hospital, and colleagues estimated the lifetime risk of atrial fibrillation in individuals from the community-based Framingham Heart Study. Polygenic risk for atrial fibrillation was derived using a score of approximately 1000 atrial fibrillation-associated SNPs. Clinical risk factor burden was calculated for each individual using a validated risk score for incident atrial fibrillation comprised of height, weight, systolic and diastolic blood pressure, current smoking, anti-hypertensive medication use, diabetes, history of myocardial infarction, and history of heart failure.
They found that the lifetime risk of atrial fibrillation after age 55 years was 37 percent was substantially influenced by both polygenic and clinical risk factor burden. Among individuals free of atrial fibrillation at the age of 55 years, those in the low polygenic and clinical risk tertiles, had a lifetime risk of 22 percent, whereas those in the high risk tertiles had a risk of 48 percent. Atrial fibrillation developed at an older age among individuals with a favorable clinical risk profile regardless of genetic predisposition. Nevertheless, the lifetime risk of atrial fibrillation in individuals with high genetic predisposition was substantial, even when the clinical risk factor burden was low. Thus, individualized projections of lifetime risk of atrial fibrillation may be refined by accounting for both genetic predisposition and clinical risk factor burden.
The final study tells us that in contrast to previous perceptions, Takotsubo cardiomyopathy has long-lasting clinical consequences. First and corresponding author Dr. Skally from University of Aberdeen in the UK and their colleagues did an observational case controlled study of 37 patients with prior Takotsubo cardiomyopathy and 37 age, sex, and co-morbidity matched controls. Although Takotsubo cardiomyopathy occurred 20 months before the study, the majority of patients had persisting symptoms compatible with heart failure and cardiac limitation on exercise testing. Despite a normal left ventricular ejection fraction in serum biomarkers, patients with prior Takotsubo cardiomyopathy had impaired cardiac deformation indices on echo cardiography, increased native T1 mapping values on cardio magnetic residence imaging and impaired cardiac energetic status on p31 spectroscopy. Taken together, these findings demonstrate that after Takotsubo cardiomyopathy, patients appear to develop a persistent long-term heart failure phenotype.
Well that wraps it up for our summaries. Now for our featured discussion.
Sudden cardiac death prevention and hypertrophic cardiomyopathy. Always such an important topic. I'm so pleased to have with us the author from our featured paper this week, Dr. Perry Elliot from University College London, nd our associate editor, Dr. Mark Link from UT Southwestern who also wrote a beautiful accompanying editorial with Tera Lynn Ho. So welcome both of you. Perry, I think to set us up, I'd really love if you could tell us a little bit more about the 2014 ESE guidelines for sudden cardiac death prevention and hypertrophic cardiomyopathy. And particularly pointing out how they may differ from the 2011 ACC AHA guidelines please.
Dr Perry Elliot: So, the 2014 guideline on sudden death prevention HCM, the aim of that guideline was to try to quantify the risk of sudden cardiac death. As you pointed out, sudden death is a significant complication of hypertrophic cardiomyopathy and one which we all as clinicians spend a lot of time trying to determine. If we look back over at, I don't know, a period of twenty, thirty years the approach we've developed is based upon the recognition of a number of clinical features of the disease that we know associate with a higher risk of sudden death. So things such as, you know, unexplained syncope or severity of hypertrophy. And it was that model of sort of taking those so called major risk factors which form the basis of the 2011 US guidelines and the essential model was the more of those things you have, the greater is your risk, and I suppose the higher indication for an ICD.
One of the problems with that approach was that it's not quantitative so you know, you could say, "Okay. Well I think you're at higher risk, but I can't say how much that risk is." And another problem with that way of doing things is when you start to think about some of the individual risk factors, it doesn't make a great deal of sense clinically.
And I suppose a good example of that is wall thickness. You know we have this magical number of 30 millimeters, above which we say you're at risk, but of course are we really saying that if your wall thickness is 29 millimeters you're at low risk? We know it doesn't really work that way in biology. So when we drew up the 2014 guideline we wanted to say, "Okay let's develop a model in exactly the same way that we do with atrial fibrillation or primary prevention in coronary disease so that we can say to the patient sitting in front of us, 'Based on your clinical assessment we think you've got a one, five, ten percent risk of something bad happening to you in the next five years.'" And then we can use that information to inform our decision about ICD implantation.
The model itself is not so revolutionary. I mean, it uses a lot of the conventional risk factors such as wall thickness, such as non-sustained VT on Holter monitoring, but what it did introduce was the factor of age, because we know that the age of the patient certainly determines their risk. We brought in [inaudible 00:10:12] obstruction because we've now got reasonable evidence showing that if you've got a big gradient, that certainly modulates your risk. And also probably for the first time, I suppose, left atrial size, which was one of those missing things I think in previous assessments. You know, it's a fantastic surrogate for restrictive physiology and certainly when we added it to the model it improved the predictive power of that model.
So I suppose in summary what we've done is to produce a tool which allows you to estimate risk and then use that to help you decide on whether an individual needs a defibrillator in the clinic.
Dr Carolyn Lam: You know Perry I believe you led those guidelines and I just want to congratulate you as well as that was such a beautiful explanation of what was going on behind those. Yup, but the proof is in the pudding isn't it? But you're providing that proof in today's paper. Tell us about it. So it's an external validation, a large international multi-centers study to actually validate these 2014 guidelines.
Dr Perry Elliot: That's right. I mean, I think when we generate these kind of models it's really important to test those models in different settings. The original model was based upon a relatively small number of European centers and I think what this paper does is it brings insights into different geographies and different health care systems. So we have participating centers from North America from the Middle East from the Far East and the idea here is to get as diverse a population as we can and just see if the model performs in the same way. And you know in a study just short of 4000 people, I think that we've shown that the model does indeed seem to behave in the same way. In fact, the numbers were remarkably similar. You know the ability of this model to discriminate between high and low risk patients was almost exactly the same as in the original paper, which I think gives us a level of reassurance that this model, this tool that we've developed, can be used in different health care settings.
Dr Carolyn Lam: Mark. I really enjoyed your editorial. I love the way that you started out with a case that really shows why this is so important. And I also love that you discuss some other studies that tried to validate the 2014 ESE guidelines as well. Could you just give us some of your thoughts there.
Dr Mark Link: Yeah. I first want to congratulate Perry and his fellow authors for this paper. I think it was a very nice paper. I was a champion of this paper from the time it got sent into circulation. And, you know, the big change in the 2014 European guidelines compared to the American guidelines is really the linear risk of age, wall thickness, and I'll put tract gradient. And as Perry says, I agree, it's not a simple you have it or you don't, it's a linear risk and I applaud them for including that in their risk factor stratifier. And if you look at the current paper, I mean it was very good at picking out high risk patients. So if you have greater than a four percent, six percent risk over five years, you did. And so for picking out the high risk patients it was very good. And for picking out the medium risk patients, it didn't function as well. It was best for separating out the high risk and the low risk population.
And I will say, based on this paper, I've started using the European risk stratifier in my clinical practice. So I do want to applaud them, you know, for the risk stratifier tool and this paper. But I do want to say, and I'm sure Perry will agree, that we're not there yet. We need better tools, because not only in this data set but in other data sets, because more of these individuals reside in the low risk population, more of the sudden deaths are in that population. And we need better tools. And over time they will come. You know, they may be MRI tools. They may be scar tools. They may be other tools that we aren't even aware of that are coming on the horizon, but we do need better tools as we move forward to identify those at risk for sudden death in hypertrophic cardiomyopathy.
Dr Perry Elliot: Yeah. No. I agree. I mean I think what I would say is if you sort of take a step back and look at the overall perspective in this paper, despite the fact that, you know, we've got nearly 4000 people and they're followed in different health care settings, the overall sudden death rate in hypertrophic cardiomyopathy pretty low. You know, so that's good for patients 'cause I think it shows that at least in managed populations, the risk of sudden death which is real and we've got to assess it, but I think it's really important to get that message over to patients that for most people with HCM they're at low risk. It is of course the challenge because when you're dealing with rare events, it's really hard to predict them. And this model is far from perfect. I would argue it's probably the best we've got for the moment, but you know, it's not that bad. It's not that bad.
I mean agree with you absolutely Mark, 'cause you know, either end it performs pretty well. In the middle there it's not as predictive, although what it tends to do is overpredict, rather than underpredict. So you know, I think if you use this model in your every day practice just the greatest risk is that you'd end up putting in probably more ICDs then you really need to rather than missing a lot of patients. You know, we really want to prevent every sudden death if we possibly can, but that's always going to be really hard I think and I think the fight goes on. We got to look for new risk predictors. It may be that we can interchange some of these predictors. They might be easier to assess in some practices, but I'm not a born optimist, but I really think it's amazing just how well in such a complex heterogeneous disease that this relatively simple assessment works. You know?
Dr Mark Link: Going forward, what do you think the future of HCM [inaudible 00:15:47] stratification will include? We've got the risk stratifiers in your calculator ready. And more specifically where do you think gadolinium enhancement will play a role in the future? So MRI findings of scar or gadolinium enhancement.
Dr Perry Elliot: The base we have at the moment show that the more scar you have, the greater risk of sudden death. It sort of makes sense, doesn't it? It's part of that substrate for ventricular arrhythmia. My own reading of it just so far is that I'm not sure what it adds to the existing way of doing things. I mean I think this is true of any biomarker, you know. I've got a new biomarker, what does it tell me that I don't already know? And with scar, we know the greater amount of scar, it often tracks with wall thickness. You're likely to have a thicker heart, you're more likely to have non-sustained VT. But I'm openminded on that front. The beauty about this model, for me, is that it's a tool to into which you can plug other things and you know, if we can get big enough data sets and we can use gads and the amount of scar and put that into the model and if it improves the performance of the model that's great. Those studies are underway at the moment and I think we eagerly wait the results of those studies.
For me, one of the missing things is the genetics. This is a heterogeneous disease with quite a complex genetic architecture, and despite the fact that you know it's 20, 30 years now since we identified the first gene, we haven't really factored that in to our risk models and I think that for me is one of the big challenges and opportunities over the coming years is to put together really large international data sets so that we can answer once and for all whether your mutation determines your prognosis.
Dr Mark Link: Yeah. I agree with the genetics also I think getting more information on that. And it’s been 30 years it still is not helping us prognosticate the risk of sudden death, but it should. I mean it really should. And I do think hopefully we will find other tools also as time goes on because it really is imprecise and it's very difficult when you're sitting there in front of ... You know, I just had a 20 year old yesterday come in with his family and he's got a three centimeter septum and he's got 12 percent scar and he's saying, "Gee what would you do and what would you do if I were your son?" And it's easy when you're looking at it in the aggregate. It's much more difficult when you're sitting there one on one with a patient in front of you.
Dr Perry Elliot: Of course. Of course. And I think another factor I think which is changing the dynamic of that kind of discussion is the evolution of ICD technology. You know, I think when you're dealing with young people the fear is long-term complications with leads isn't it? And I think with the advent of the SICD I sense it's already tipping the balance into perhaps a slightly more liberal approach to ICD implantation exactly in the kind of scenario you've just described Mark, you know you've got guy who's 20. He's got a really severe hypertrophy. Well you know, if you and mess ICD you know your threshold for implantation might be a bit lower.
Dr Mark Link: Yeah and in fact, after a two hour discussion that's what we decided on is that subcu ICD was the right thing for him. And everyone's very happy with that choice.
Dr Perry Elliot: Yep. I think it also raises another thing which I often think about is that as medics we're also probably not good at considering what acceptable risk actually is. You know? We develop models in different settings and hyeprtrophic cardiomyopathy, coronary disease, heart failure, and actually if you go back and critically look at the thresholds that are used to put in defibrillators, the absolute risks vary enormously. So you know, here in [inaudible 00:19:02] we're talking about an approximate annual risk of sudden death of about one percent per annum is sufficient to put in an ICD, but in long-QT world it's quite a different threshold that's used and of course that's because there is no defined number. You know the number's we used in the ESE model of greater than six percent you should have an ICD, well yeah that's the consensus number, there's nothing magical about it. There's nothing biological about it. And I think we've probably had greater debates at what acceptable risks really are.
Dr Mark Link: And that's become a big shared decision now in the States and actually everywhere. It's become a big word because it sued to be that the physicians would decide on who gets an ICD and who doesn't. And it's no longer that way it's a discussion with the patient, with the family. How much risk are they willing to take, both with an ICD and without an ICD, because there are issues with ICD, even though I'm a big fan. There are issues and especially with transvenous ICDs, but also with subcutaneous ICDs.
Dr Perry Elliot: Absolutely. Absolutely.
Dr Mark Link: You know, it's a different world now than it was 15 20 years ago.
Dr Carolyn Lam: Perry and Mark, this has been one of the most wonderful conversations I've had on these podcasts. I just can't thank you enough. I'm sure all our listeners are thanking you too. You've been listening to Circulation on the Run. You must tune in again next week for more beautiful conversations.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal it's editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center, and Duke National University of Singapore. The new ACC/AHA hypertension guidelines are hotly discussed. So much so that we have invited perspectives of these new guidelines from around the world and authors will be discussing this right here on Circulation on the Run. Stay tuned, as it's coming right up after these summaries.
The first original paper this week is a translation study suggesting that the parasympathetic system may be a novel therapeutic target in pulmonary arterial hypertension. Co-corresponding authors Dr. Handoko and de Man from University Medical Center Amsterdam used heart rate recovery after maximal cardiopulmonary exercise testing as a surrogate for parasympathetic activity, and assessed white ventricular ejection fraction in 112 patients with pulmonary arterial hypertension. They found that patients with a lower right ventricular ejection fraction had a significantly reduced heart rate recovery compared to patients with a higher right ventricular ejection fraction.
Furthermore, they looked at tissues from the right ventricle of 11 patients undergoing heart-lung transplantation, and found that there was increased expression of nicotinic receptors with no difference in muscarinic receptor expression compared to controls.
Finally, in a rat model of pulmonary hypertension, they showed that chronic pharmacologic sympathetic stimulation by pyridostigmine, which is an acetylcholinesterase inhibitor, improved surviving right ventricular function and reduced pulmonary vascular remodeling.
In summary, the study shows that right ventricular dysfunction is associated with reduced systemic parasympathetic activity in patients with pulmonary arterial hypertension, with an inadequate adaptive response of the cholinergic system in the right ventricle. Furthermore, enhancing the parasympathetic activity in these patients may be a novel therapeutic strategy.
Dr. Carolyn Lam: The next study unveils a new mechanism by which pericardial adipose tissue coordinates immune cell activation and outcomes following a myocardial infarction. First author Dr. Horckmans, corresponding author Dr. Steffens, and colleagues from Institute of Cardiovascular Prevention in Munich identified larger B-cell clusters in epicardial adipose tissue of human patients with coronary artery disease compared to controls without coronary artery disease. Furthermore, they showed that infarcted mice had larger pericardial clusters, and a 3-fold up regulator numbers of GM-CSF producing B-cells within the pericardial adipose tissue, but not in the spleen or lymph nodes. This was associated with higher dendritic cell and T-cell counts in the pericardial adipose tissue.
Further experiments show that activated dendritic cells migrated from infarcts into the pericardial adipose tissue. Cytokines and growth factors released locally within the pericardial adipose tissue as well as systemically promoted immune cell proliferation and emergency granulopoiesis after myocardial infarction.
Finally, the enhanced fibrosis and worsened ejection fraction in mice was limited by removal of the pericardial adipose tissue.
In summary, these pre-clinical data suggest that pericardial adipose tissue may be a central compartment for innate and adaptive immune responses, which regulate post-myocardial infarction healing.
Dr. Carolyn Lam: The next study reports for the first time in a large, comprehensive national cohort study, the incidence of atrial fibrillation in children and young adults with congenital heart disease. First and corresponding author Dr. Mandalenakis and colleagues from University of Gothenburg in Sweden used data from the Swedish Patient and Cause of Death registers to identify all patients with a diagnosis of congenital heart disease who were born between 1970 and 1993. Each patient with congenital heart disease was matched by birth year, sex, and county with ten controls from Sweden. Follow-up data were collected until 2011.
The authors found that the risk of atrial fibrillation in children and young adults with congenital heart disease was 22 times higher than that in matched controls. Up to the age of 42 years, one in 12 patients with congenital heart disease had developed atrial fibrillation and one in 10 patients with congenital heart disease with atrial fibrillation had developed heart failure. In particular, patients with the most complex congenital malformations, conotruncal defects, had the highest risk to develop atrial fibrillation. These patients should be considered for targeted monitoring.
Dr. Carolyn Lam: The next study provides a novel and simple risk score for right-sided heart failure in adults undergoing Left Ventricular Assist Device implantation with the current mainstream devices. First and corresponding author Dr. Solomon and colleagues from University Medical Center Rotterdam studied almost 3000 adults who underwent continuous flow Left Ventricular Assist Device implantation in the largest EU registry of mechanical circulatory support devices. They derived and validated a right-sided heart failure prediction model that out-performed several published scores and well-known hemodynamic and echocardiographic individual markers of right-sided heart failure.
This prediction model included the following risk factors: need for three or more inotropic agents, inter-agency registry from mechanically-assisted circulatory support class one through three, severe right ventricular dysfunction on semi-quantitative echo cardiography, ratio of right atrial to pulmonary capillary wedge pressure of more than 0.54, and a hemoglobin level of less than 10 grams per deciliter.
These findings offer a step towards improving prediction of the risk of right-sided heart failure to target future optimal strategies aiming at early and intension right-sided heart failure management for the highest risk subgroups of patients undergoing Left Ventricular Assist Device implantation.
Dr. Carolyn Lam: Now, sharing a patient-level clinical trial data has been widely endorsed, but just how extensively have these data been used for cardio metabolic diseases? The final study this week attempts to answer this question. First and corresponding author Dr. Vaduganathan and colleagues from Brigima Women's Hospital extracted data from clinicalstudydatarequest.com, a large, multi-sponsored data sharing platform hosting individual patient-level data from completed studies sponsored by 13 pharmaceutical companies.
They found that the median time from study completion to data availability was more than six years. Most data requesters of cardio metabolic clinical trial data were from academic centers in North America and Western Europe, and half the proposals were unfunded. Only 15% of these trials had been accessed by investigators thus far, and few findings have reached publication. Most requests for shared data access focused on new hypothesis generating questions rather than validation of the original study findings. These data may allow anticipation of barriers to effective system implementation and shared data consumption in cardiology.
Well, that wraps it up for our summaries this week. Now for our feature discussion.
Dr. Carolyn Lam: We are having a truly global conversation today on a really global problem. That is hypertension. From Canada, we've got Dr. Ernesto Schiffrin from McGill University, from Europe we've got Dr. Giuseppe Mancia from university of Milano, from the United States we have Dr. Wonpen Vongpatanasin from UT Southwestern, our dear associate editor and regular voice on this podcast, and then of course from Asia, that's me. You know what we're talking about? It is the global impact of the 2017 ACC/AHA hypertension guidelines. So many novel aspects about these guidelines, including new definitions of hypertension and it's stages, new thresholds and goals of treatment, consideration of the global risks and treatment decisions, addition of classes of recommendations and levels of evidence. So much to talk about, and let's start right now.
Wanpen, you were the brainchild of suggesting these global perspectives. Perhaps say a few words about the ACC/AHA new guidelines first.
Dr. Wonpen Vongpatanasin: Yeah, so I think that this is the guidelines that actually incorporating the more recent evidence and trials, particularly SPRINT, and applying this into the threshold and the blood pressure goal across the board. There's three comprehensive guidelines, and obviously ... The first time, the threshold was lower across the board, and that leads to a lot of discussion and concern and trying to see how we're implementing this or is it appropriate to all the population? Particularly not just in the US and around the world. I guess that leads to us reaching out to many hypertension leaders across the globe and really get very interesting and very insightful feedback from the global experts, two of which is on podcast today. I'm really thankful and excited to have some more in depth insight from them.
Dr. Carolyn Lam: Yeah, exactly. The buzz has really been worldwide, I can see that even from where I'm sitting here in Asia. But maybe Ernesto, I'm just gonna jump straight to the core questions. How are these guidelines different from the hypertension Canada guidelines, and frankly do you think that the ACC American guidelines are going to impact hypertension care in Canada?
Dr. Ernesto Schiffrin: Well, there are quite a few differences. The definition of hypertension remains the classical one in Canada. We have different thresholds and goals, and interestingly, the hypertension Canada guidelines have adopted a SPRINT-based recommendation for high cardiovascular risk patients in contrast to the AHA/ACC hypertension guideline. Although it has intensified the goals for treatment, it has lowered ... Has introduced as you mentioned a category of elevated blood pressure, a new definition of hypertension equal to or above 130 over 80 in contrast to ours equal to or above 140 over 90. It has not really introduced a SPRINT-based recommendation. As well, I think that one of the major questions remains the measurement of blood pressure. In Canada, we have adopted the AOBP, the Automated Office Blood Pressure measurement, at least for high risk, SPRINT like individuals. In the AHA/ACC hypertension guidelines, there is emphasis on standardized blood pressure measurement, but the SPRINT-like measurement of blood pressure has not been adopted.
Dr. Carolyn Lam: Very interesting. In Canada, with the AOBP, how do you translate that? I suppose you estimate it as lower than what would otherwise be labeled?
Dr. Ernesto Schiffrin: That is indeed a problem, because the evidence for the relationship between the AOBP carried out in the absence of a health care professional and the standardized oscillometric measurement, or the osculatory manual measurement, is unclear. The evidence is weak. So we have not really provided a guideline or recommendation with respect to these differences.
In contrast, AHA/ACC provides at least a pragmatic expert-based recommendation on what the differences are between office blood pressure and out-of-office blood pressure measurement. But, as I mentioned, there is no recommendation regarding the SPRINT-like measurement of blood pressure, and that's important because there may be major differences in the order of ten or even 15 millimeters of [inaudible 00:13:32] systolic blood pressure. However, as I see it, the committee for the ACC/AHA hypertension guideline has adopted a prudent and pragmatic approach, and actually simplified thresholds and goals to 130 over 80, and in my view this is a prudent approach.
Will it impact Canada? I think in Canada, most physicians follow the hypertension Canada guidelines, and they are recommended as best practice by governments across the country, provincial and federal. I think that physicians will be aware, but will still carry out their practice following the hypertension Canada guidelines.
Dr. Carolyn Lam: I like that. Aware but perhaps not so practice-changing in Canada. Let's shift to Europe though. Giuseppe, do you agree with that? How do you think these American guidelines may impact physicians in Europe?
Dr. Giuseppe Mancia: The American guidelines have been received with interest, lots of interest. But also there has been some criticism. For example, the question of the SPRINT [inaudible 00:14:55], you read the question of how blood pressure was measured as professor Schiffrin mentioned. It was measured at least in large number professions, why they were [inaudible 00:15:10], I'm not sure. This means that values have lower worth than those obtained by conventional office blood pressure measurement. How much room is still debated, but it could be 10, 15 millimeter mercury, which means that you could compare these SPRINT-like values to conventional office blood pressure values. Probably the SPRINT values are not much lower than 140 millimeters to the mercury systolic.
Then there is the question that can SPRINT mutually [inaudible 00:15:50] at the start. Most of them with two hypertensive charts. So if it's difficult to decide the bounds of threshold to treatment, lower these pressures to the high-low of blood pressure range, less than 140 millimeters mercury systolic when you have patients already treated, because their original blood pressure was probably higher than 140 millimeters of mercury. This [inaudible 00:16:15], however there are other data suggesting that, at least in high-risk individuals, one might indeed start treatment when blood pressure is in the 140 millimeter of mercury. You'll see what the European guidelines will recommend ... They are going to be published in June ... But perhaps this fraction of the population will be a candidate for treatment.
One last point, however, collecting the data from SPRINT is what you wish for in this regard, is that there should be a definite reduction in the threshold blood pressure for treatment in the elderly. In Europe, this was about 160 millimeters mercury based on randomized trials but probably in the future it will be about 140 millimeters mercury. So a large fraction of the elderly population will be involved in [inaudible 00:17:14].
Dr. Carolyn Lam: You know a question I always get though, is what about the side effects? We talk about the benefits of lowering it further, but what about the side effects. I don't know, does anyone have any thoughts on that?
Dr. Ernesto Schiffrin: I would say that, when you look at SPRINT, although there were increased side effects in the intensive treatment group, actually side effects were relatively rare. Some of them were important, such as acute renal failure and hyperkinemia, and so on, and other electrolyte abnormalities and syncope. But they were rare, and when we are recommending intensified treatment for the elderly, for example, which is SPRINT based in the hypertension Canada guidelines, we do say that this approach should be a gentle and progressive one, very aware that particularly in the elderly orthostatic hypertension may occur. One has to be very careful about this intensification of treatment, but yet we believe that if using automated office blood pressure measurement unobserved, you are able to reach lower blood pressures and they are well tolerated around or below 120 systolic, this will benefit these patients as shown in the SPRINT trial.
Dr. Carolyn Lam: Yeah, indeed. That's very nicely put, and just brings up the gaps that we still need to answer, like the way blood pressure is measured, standardization. We may be accounting more about risk versus benefits, patient subgroups. Wanpen, have I missed out anything else? What is the other buzz that you've heard?
Dr. Wonpen Vongpatanasin: I think that we really need to do a better job in measuring blood pressure in basic clinical practice, particularly in the US where we allow only 20 minutes to see your follow-up patient. I don't think that it will be possible to do an AOBP in the US, but I think one thing that makes the issue a little bit murkier is the SPRINT group. I actually just had an abstract presentation at the last HA meeting, that said only half of that site measure in the intended way on AOBP.
Actually, at UT Southwestern we also SPRINT site and we actually did not use AOBP, and when that stratified the treatment side by using AOBP versus non-AOBP, the outcomes was still the benefit of intensive blood pressure reduction for what it's worth. I think that the AOBP story is still controversial, but I think that I agree that we hardly have patient, sit down quietly, for five minutes before we do the measurement. I think that's first and foremost, we need to be able to do that, and do at least two measurements. We'd be lucky if we'd get one measurement after sitting down immediately, that's what we usually get in clinical practice. I definitely agree with Dr. Schifferin that when we ... Particularly the elderly, we have to be careful about orthostatic hypertension. Particular in the SPRINT trial, they actually exclude anyone who had standing systolic blood pressure less than 110. These people who are high risk of having [inaudible 00:20:35] never get into those trials to begin with.
Dr. Carolyn Lam: I can't thank you enough, everyone, for joining me in this chat around the world. It has been a learning conversation for me, as I'm sure it has been for our listeners as well.
Listeners out there, you've been listening to Circulation on the Run. Thank you for joining us today.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Centre and Duke National University of Singapore. This week’s issue is the Go Red for Women issue, my favorite discussions of the year happened during this podcast.
Today, I am so delighted to have with me, our Editor-in-Chief himself, Dr. Joe Hill, from UT Southwestern, as well as, of course, the editor that made this issue possible, Dr. Sharon Reimold, also from UT Southwestern. Joe, would you like to tell us a little bit about this year’s Go Red issue? From the birds eye view.
Dr. Joseph Hill: Well Carolyn, I share your enthusiasm. This is our second annual Go Red for Women issue and it is fantastic. It has generated great interest in the community. We had a number of papers coming in, unsolicited. Our frame of reference-type content. Original research articles. State of the art.
We clearly touched a nerve with this issue. As we will discuss further, we shine a bright light here on some of the very best science, focusing on sex-based differences in the biology of heart disease, the presentation of heart disease, how women function, and are treated in the academic environment. The ways in which they are impacted by psychological stress. It's an absolute bonanza of science, in this issue.
Dr. Carolyn Lam: You took the words out of my mouth. It is a bonanza issue. I mean, we had seven original articles. Lots of new stuff, but lots of good, important papers on plain old ischemic heart disease. What I really liked was that, three of these original papers focused on myocardial infractions, in the young, and their risk factors, prevention, and so on. Sharon, shall we go through those? I mean, there was the one on genetics, lifestyle, and LDL in young women.
Dr. Sharon Reimold: That would be great. That manuscript looked at, sort of, a distribution of lipids, in women, that would have otherwise expect to be healthy. They sorted them out by individuals that had extremely low LDL levels and those that had high LDL levels. They pointed out that the individuals with high LDL levels. Ended up having hypercholesterolemia heritable, but they also found genetic variance of related to those with low LDL levels. I think this manuscript points out the importance of screening younger women for lipid disorders and incorporating those data into their clinical management.
Dr. Carolyn Lam: Absolutely. Then, there was that paper that, again, talked about young women experiencing myocardial infarction, and the sex differences in their presentation, and perception. That was super cool. From the Virgo trial.
Dr. Sharon Reimold: There are several other papers, that are published, demonstrating that women tend to have multiple symptoms when they present with symptoms of ischemia. That's true for both myocardial infarction, as well as for other unstable syndromes. They certainly have more symptoms than men.
But what was very interesting about this particular paper, is that when women presented with multiple symptoms, providers were less likely to think that the symptoms were due to a cardiac etiology. So even when women are trying to tell their providers what is going on, sometimes, they're not taken seriously, because they have multiple symptoms. So I'm hoping that this resonates with our providers, clinical providers, and we think about this. Whether we're cardiologist, or emergency room providers, or even EMTs.
Dr. Carolyn Lam: Exactly. Then, the third original paper in these young women, kind of scary, mental stress induced myocardial ischemia.
Dr. Sharon Reimold: Right. So there's been a lot of interest in the myocardial infarction without obstructive coronary disease, in the last year or two. Because a lot of those individuals, even thought, they don't have typical atherosclerotic pathologies, they don't have good outcomes. So this article looks at the role that mental stress plays in inducing ischemia, by EKG, in these individuals.
I think we still need to understand more about how this contributes to the biology, and outcomes, in these individuals. Also, get a better understanding if this is also true in older women, who have ischemic heart disease.
Dr. Carolyn Lam: Exactly. You know, but speaking of the older women, it's not like the issue left out the older women this time either. I did think that the study on the metabolic predictors of incident ischemic events, in postmenopausal women, was really interesting, as well. Basically, the authors identified a cluster of novel metabolites, that were related to oxidative stress, that added to. you know?
They weren't correlated with the traditional biomarkers. Really suggesting that there may be a whole area of metabolites, and other biomarkers, that we may be needing to check, and to understand better, for risk prediction. At least, in older women. But, of course, in men as well. Then, finally, there was the data on sex differences from the STICH trial, on surgical revascularization. What did you think of that one?
Dr. Sharon Reimold: Well, I thought that this was a very important addition to the cardiology literature. Because we are accustomed to thinking of women as having poor outcomes, after they have cabbage revascularization surgery. Certainly, the STICH trial enrolled patients who were more sick than the average patient, with their underline LV dysfunction. They found that sex did not influence the outcomes in this trial.
So the importance of that, for the medical community, is obviously we should not consider sex as a barrier to sending women to surgery, even if they're at high risk, because they can have equally good outcomes.
Dr. Carolyn Lam: Exactly. Important message. Important paper. Then, moving from ischemic heart disease. We also had a paper focusing on stroke, which I thought was a really intriguing one, talking about atrial fibrillation, and questioning if being a woman is a risk modifier, or a risk factor. Do you want to elaborate on that one?
Dr. Sharon Reimold: So instead of the using the CHA2DS2–VASc algorithm they use the CHADS2-VA program and then looked to see how well that predicted risk, and how much the S and C, the gender actually influenced outcome. I think this is an important issue. I'll say it's for women, perhaps. because as a woman, you know, without doing anything, you start out with a risk factor of one. Then, once you get to a certain age you have a risk factor of two. That's even for somebody who has no other disease processes.
Dr. Carolyn Lam: Yeah.
Dr. Sharon Reimold: So I think it's a little different way to look at how the risk is modified. They propose that if your CHADS2-VA score is two, or greater, certainly, your risk goes up if you're also female. They propose, then, that you would treat those patients more intensively. It's just a little twist on the CHA2DS2–VASc and maybe will provide us different ways to refine our knowledge about outcomes in atrial fibrillation.
Dr. Carolyn Lam: Yeah. I love that paper, too, because it's quite different from the papers that we had in the first Go Red issue. Isn't it? But in the first Go Red issue, we had lots of papers on pregnancy. The current issue certainly has those papers as well.
Dr. Sharon Reimold: Yes. There are increasing number of pregnancy related complications. Both maternal, and offspring, complications that predict increased cardiac risk, down the line. This issue has a series of women who had, had preeclampsia during pregnancy, and found that 17% of their women had a coronary artery calcium score of greater than 95th percentile. While that doesn't entirely get you from the biology, in between those two, it at least gives you an idea of where to start going back, and taking a look at what's going on.
Dr. Carolyn Lam: What about the one in rheumatic mitral valve disease? Pregnancy outcomes in women with those?
Dr. Sharon Reimold: So rheumatic heart disease and pregnancy outcomes, you know, we don't see much written about it anymore. because most of the active disease is in certain areas, in the world. But obviously, these women can have symptoms related to their mitral stenosis and/or their regurgitation during their pregnancy, with heart failure being the most common presenting cardiovascular complication. While some of that is much more quantitative, than perhaps, it was in the past, which is useful.
I think that the take-home message from this particular trial is that you need to talk to these patients, and screen them, prior to pregnancy, if possible, to help achieve the best possible outcome. I think that the risk of heart failure was a little bit less than 2% during the trial, which is obviously much higher than the average woman's cardiovascular risk during pregnancy.
Dr. Carolyn Lam: this is still definitely an important issue, in many other parts of the world. I really appreciate that you invited this editorial, that gave that global perspective. The editorial, by Athena Poppas and Katharine French, really beautiful work there. You know, I have to say that one of my favorite papers, in this issue, was that in depth paper, regarding gender versus sex, as a social determinant of cardiovascular risk. I found that so intriguing, the first time I read it, and just love it.
Dr. Sharon Reimold: Social determinants of health is a hot topic, in a lot of different areas of medicine these days. But they point out some really interesting things, that I don't think I had thought about. One is the fact that, when you are a child, you know maybe 10 or 12, that boys are encouraged more to be physically active. Athletics and other sorts of activities. Whereas many girls, don't have the opportunity or are not as interested. Perhaps we set up an abnormal social situation very early in most people's lives.
Dr. Carolyn Lam: Yeah, that represents cardiovascular risk. I know. That stuck out to me too.
Dr. Sharon Reimold: Obviously, how and where people live, as children, can influence outcome. That can be influential for both boys and girls. But I think bringing the idea back to cardiovascular diseases, and risk, are really long term, lifelong processes, that we can make changes in, from a preventative standpoint, even in young people.
Dr. Carolyn Lam: Something we don't usually think about and I just love the way it was presented, so clearly, and I just love it. Now, to an area that really cuts close to the heart. Pun intended. That is the bias in research grants, bias in manuscript authorship. Joe you mentioned that, right from the introduction, I would love your comments on those papers.
Dr. Joseph Hill: The reality, that we all are aware of, is, in many countries, including the United States, 50% of medical students now are female. But as we move through the ranks, into the different subspecialties, and up the career ladder of academic cardiology, we see a thinning of female representation. Arguably, it's been improving, over the last number of years.
But the reality is, that there remains a bias against representation of women, in terms of extra mural grant funding, authorship on high-profile papers. This article digs into that, and analyzes those numbers, takes a snapshot of what it looks like at the present time. In some ways, I believe it's a call to arms on how we must do a better job of recognizing this and rectifying it, going forward.
Dr. Carolyn Lam: Sharon, did you have comments to add?
Dr. Sharon Reimold: Yeah. I mean, I think, I wholeheartedly agree with Joe about those sorts of things. I mean, we see the same types of issues in clinical cardiology as well as in the research components of what we do. we need to figure out how to do this better, so that we all can be productive, going forward.
Dr. Carolyn Lam: You know it's just such a beautiful issue. So rich, in so many ways. Was there anything else you might want to highlight to our listeners?
Dr. Joseph Hill: I might add that Sharon and I kicked off the issue with a brief introduction. Pointing out that the reality is, that one and four women will die of heart disease. Most women don't know that. Most healthcare providers don't know that. Many Cardiologist don't know that.
When you compare that to the realities of breast cancer, it's 1 in 40. It's 10 times different. Now, that community has done a fantastic job. The Susan G. Komen program, in the United States. The pink ribbons, that we see all around the world. That community has done a fabulous job of getting the message out about that grievous disorder.
We have to do better. We have to do better educating ourselves, educating the lay public, about the realities of heart disease in women. 1 in 4, around the world. We also have to do a better job of digging into the science. That's where this issue does an especially good job.
That the reality is that heart disease is different in men and women. It presents differently. It presents at a different age. The way in which women respond to therapies, can differ from men. So there's work to be done, in terms of awareness. There's work to be done, in terms of the underline biology. This is an especially exciting time in this arena.
Dr. Carolyn Lam: I couldn't agree more. I'd add to it, even sex differences and the perceptions about own symptoms, and that of women versus men with chest pain. Then, the whole gender, social element to it. Oh, just so much to discuss, so much to learn from.
Well, listeners you heard it right here. I want you to please send this episode, share it with as many other women as you can think of. Do help us to spread this message, it's such an important one.
Thank you so much, Joe and Sharon, for joining me today. Thank you, listeners, as well. Tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
Today's feature paper is going to cause us to rethink the way we prognosticate patients with pulmonary arterial hypertension following their initial management. Think you know the hemodynamic variables? Well, stay tuned for this discussion coming right up after these summaries:
Our first original paper this week shows for the first time the predictive value of coronary artery calcification progression for coronary and cardiovascular events in a population base study. Authors Dr. Erbel and Lehmann from University Hospital Essen in Germany and their colleagues evaluated several progression algorithms between CTs performed at baseline and after a mean of five years for the risk prediction of coronary and cardiovascular events in a population base cohort of more than 3,200 participants initially free from cardiovascular disease.
The authors found that coronary artery calcification progression added some predictive value to the baseline CT and risk assessment, and even when the five-year risk factors were taken into account. However, the progression yielded no additional benefit when the five-year coronary artery calcification results were taken into account instead of the baseline coronary artery calcification results.
Double zero coronary artery calcification scans in a five-year interval meant an excellent prognosis, which was better than the prognosis for incident coronary artery calcification after five years. Thus, the authors concluded that sophisticated coronary artery calcification progression algorithms may be unnecessary and clinicians can instead rely on the most recent risk and coronary artery calcification assessment.
The next paper demonstrates for the first time cell-specific effects of Smad3 signaling in the infarcted myocardium. Now, in the infarcted heart, Smad3 signaling is known to be activated in both cardiomyocytes and the interstitial cells. In the current paper, co-first authors, Doctors Kong and Shinde, corresponding author Dr. Frangogiannis from Albert Einstein College of Medicine in New York, and their colleagues hypothesized that cell-specific actions of Smad3 may regulate, repair, and remodeling in the infarcted myocardium.
In order to dissect the cell-specific Smad3 actions in myocardial infarction, these authors generated mice with Smad3 loss specifically in activated fibroblasts or in cardiomyocytes. They found that fibroblast-specific Smad3 activation played a critical role in repair following myocardial infarction by restraining fibroblast proliferation and contributing to scar organization by stimulating integrin synthesis.
On the other hand, cardiomyocyte-specific Smad3 signaling did not affect acute ischemic injury, but triggered nitrosative stress and induced matrix metalloproteinase expression in the remodeling myocardium, thereby promoting cardiomyocyte death and contributing to systolic dysfunction.
In summary therefore, these authors demonstrated the cellular specificity of Smad3-dependent actions that stimulate distinct cellular responses in fibroblasts versus cardiomyocytes in the healing myocardial infarction. The implications are that nonspecific therapeutic targeting of Smad3 signaling in pathologic conditions may interfere with both detrimental and beneficial actions. On the other hand, design of interventions with specific cellular targets may be needed for the development of safe and effective therapies.
Good news from the next paper! Genetically predetermined high blood pressure and its complications may be offset by healthy lifestyle. Well, at least, to some extent. First author, Dr. Pazoki, co-corresponding authors Dr. Elliott from Imperial College London and Dr. Tzoulaki from University of Ioannina in Greece aimed to investigate the extent to which lifestyle factors could offset the effect of an adverse blood pressure genetic profile as well as its effects on cardiovascular disease risk.
To do this, they constructed a genetic risk score for high blood pressure using 314 published blood pressure loci in more than 277,000 individuals without previous cardiovascular disease from the UK Biobank study. They scored participants according to their lifestyle factors including body mass index, healthy diet, sedentary lifestyle, alcohol consumption, smoking, and urinary sodium excretion levels measured at recruitment. They examined the association between tertiles of genetic risk and tertiles of lifestyle score with blood pressure levels and incident cardiovascular disease.
They found that adherence to a healthy lifestyle was associated with lower blood pressure regardless of the underlying blood pressure genetic risk. Furthermore, adherence to a healthy lifestyle was also associated with lower risk of myocardial infarction, stroke, and the composite cardiovascular disease at all levels of underlying blood pressure genetic risk. Healthy compared to unhealthy lifestyle showed a 30%, 31%, and 33% lower risk of cardiovascular disease respectively among participants at low, middle, and high genetic risk groups. Thus, these results strongly support population-wide efforts to lower blood pressure and subsequent cardiovascular disease risk through lifestyle modification.
The final paper is an aggregate report from two large randomized trials, which demonstrate for the first time that more potent antiplatelet therapy further lowers venous thromboembolism risk relative to aspirin alone. First author Dr. Cavallari, corresponding author Dr. Bonaca, and colleagues from the TIMI Study Group in the Brigham and Women's Hospital ascertained and characterized symptomatic venous thromboembolism events in more than 47,600 patients randomized in the TRA 2°P-TIMI 50 and PEGASUS-TIMI 54 trials. They evaluated risk of symptomatic venous thromboembolism over time, independent risk factors for venous thromboembolism, and the efficacy of more intensive antiplatelet strategies at reducing venous thromboembolism risk.
They found that the rate of venous thromboembolism in patients with atherosclerosis was 0.3% per year while on treatment with at least one antiplatelet agent. This risk increased independently with the number of symptomatic vascular territories. Furthermore, more intensive antiplatelet therapy with Vorapaxar and Ticagrelor in this case reduced the risk of venous thromboembolism.
These data suggested a relationship between atherosclerosis burden and venous thromboembolism risk. The data also support the inclusion of venous thromboembolism as a prospective endpoint in long-term secondary prevention trials evaluating the risks versus benefits of antiplatelet therapies in patients with atherosclerosis.
Well, that wraps it up for our summaries. Now for our feature discussion.
For our feature discussion today, we are talking about pulmonary arterial hypertension. We've learned so much from registries about prognostication of pulmonary arterial hypertension at the time of diagnosis. But these registries have only provided limited insight into the impact of therapies on long-term outcomes and how we're supposed to use variables after initiation of therapy to determine prognosis.
Well, that gap is being filled by today's paper in circulation. I'm so pleased to have the first and corresponding author with us, Dr. Jason Weatherald from University of Calgary, as well as Dr. Kelly Chin, associate editor from UT Southwestern, to discuss this very important paper.
Jason, congratulations on this paper. Could you tell us a bit more about what you did and why you did it, and what's exciting about what you found?
Dr. Jason Weatherald: This is a study that started during my research fellowship last year when I was spending time in Paris with the group of Professor Olivier Sitbon and Marc Humbert. We started this study based on some other recent papers showing the importance of pulmonary arterial compliance, and some smaller studies that emphasized the importance of hemodynamic variables after treatment initiation and the prognostic importance of that. We wanted to look at the relative importance of pulmonary arterial compliance as well as the stroke volume in the cardiac index in newly diagnosed patients.
We looked at a 10-year cohort from the French registry of patients who had right heart catheterizations at baseline and then after treatment initiation. We looked at prognostic variables, both at baseline and at the first follow-up after initial treatment. The interesting result is that we found that actually pulmonary arterial compliance is not the most important prognostic variable, but it seemed that the stroke volume index, which was calculated from the cardiac index and the heart rate, was the most significant independent predictor of long-term survival from the hemodynamic perspective.
Dr. Carolyn Lam: Kelly, could you help point out why this is so important in clinical practice? You see a lot of these patients. In what way did this paper make you think differently about them?
Dr. Kelly Chin: I think there's a couple different areas that really struck me. The first one was, as you mentioned in the introduction, the importance of post treatment values versus baseline values. This is not to say that the baseline values aren't important because it does still associate with survival and it's very important when choosing therapy, but as PAH therapies have become more effective, we would hope to see that the baseline severity matters less and that, indeed, seems to be what we're seeing here. That also reinforces the importance of serial reassessment to see how your patient is doing and make further decisions for therapy.
The second key finding, I think, is what Jason was just talking about with which hemodynamic measures do we really want to be keeping a close eye on? Here's where, in the stepwise analysis, they found that the right atrial pressure and then, the surprising one, the stroke volume index were the key measures that were associated.
Interestingly, cardiac index fell out of that model. That isn't to say that cardiac index wasn't associated with outcome. It was a predictor in the univariate analysis. But I think when you step back and you think about the comparison between those two, if you have a patient who's maintaining their cardiac index only by becoming tachycardic, they're probably not doing nearly as well as a patient who has a normal heart rate and a normal stroke volume index.
I think this really struck me as something, "Hey, when I'm in the cath lab, I probably need to be thinking about this and reporting it out, so everybody's seeing it right there on the report", which is not something we've been doing.
Dr. Carolyn Lam: Thanks Kelly. That makes so much sense. What I really appreciated about the paper as well is that they gave us practical thresholds through their receiver operating characteristic analyses. Just for everyone to know, the threshold value for stroke volume index was 38 mils per minute per meter square, right? And the right atrial pressure threshold was 9 mils of mercury. These are sort of very important, 38 and 9, and practical to keep in mind. Really appreciate that Jason.
The other thing that struck me is these are just very much saying that right ventricular function is important. Is it not, Jason?
Dr. Jason Weatherald: Yeah, I agree. I think that's one of the interesting insights from the study is that we focused mostly on the cardiac index, but it can be misleading in certain patients like Kelly said who perhaps do respond to therapy by increasing the cardiac index but predominantly through increased heart rate. That can be somewhat misleading if you don't really step back and look at it.
What I found interesting, too, is that when we looked at subgroups of patients who, in the clinic, you generally think are low risk patients who had good six-minute walk distance, very few symptoms NYHA functional class I or II, and had a cardiac index above the current recommended target of 2.5, that there was almost a third of patients with a low stroke volume index in that category and that seemed to be the majority of patients who died over long-term follow-up within five years.
I think that's really telling about the importance of right ventricular function and just looking at the cardiac index itself can perhaps mislead you if you don't take all of those other factors into consideration.
Dr. Carolyn Lam: Yeah, that's just such a great point and important. That even those classified that we would not have picked up as high risk are the usual measures that we look at. If you look at stroke volume index, they still distinguish those who do better than those who do worse. This is something that was also highlighted, I think, in the accompanying editorial, Kelly, that you invited by Lewis Rubin from New York.
Kelly, what do you think are the real take home messages from this?
Dr. Kelly Chin: I think he does make a big point that the functional status of the right ventricle is a primary goal of therapy, and that we should definitely be paying attention to it and that there's more than one way to do this. There's the hemodynamic measurements, there's also exercise capacity and functional class, which really do associate with how well the right heart is functioning, both at rest and exercise. I think he also comes back to the serial measurements and the importance of reassessment.
Dr. Carolyn Lam: Yeah, as you had also so elegantly summarized earlier. But, a quick question to both of you. What do we do now about other measures of right heart function? I mean, magnetic resonance imaging seems to be used increasingly for this. Where does this fall in? And what does this say about the routine clinical parameters that we usually look at, like six-minute walk? Jason?
Dr. Jason Weatherald: I have a couple points on that. Number one, I fully agree and our results are really in keeping with the previous smaller studies looking at cardiac magnetic resonance and showing the importance of the stroke volume on imaging. From personal experience, although MR is wonderful, there's a good population of patients who don't really tolerate MR, especially for serial measurements, and there's other contraindications, so I think hemodynamics will continue to fill an important role and are still useful in the patient where you can't figure out exactly what's going on and why they're getting worse.
At this point, I think it's complementary and certainly I think there's some centers in many countries that don't have cardiac MR widely accessible, especially for serial follow-ups, so I think they're really complementary and that our results support imaging studies.
I would say the next thing about the study is that, in the multi variable models that exercise distance, the six-minute walk distance and functional capacity remained independent predictors, so I think, it just highlights the importance and the robustness of these measures, even though NYHA functional class is subjective, it remains a very powerful predictor at baseline and during follow-up. To me, it speaks to the importance of looking at multiple parameters and coming to a multidimensional assessment of risk and PAH and not focusing on one particular variable for making decisions in the clinic.
Dr. Kelly Chin: I definitely agree with the multidimensional look at a patient function and heart and catheterization. What I was going to say was I also liked, Jason, the use of "complementary" when talking about catheterization and MRI. I see MRI filling a similar niche to echo for many patients. I think if you get an echo and it looks great, heart size is good, heart function is good, I don't see a whole lot of reason to add an MRI, too. We're always routinely doing catheterizations, at least early post treatment, to reassess.
But I do see a role for MRI in some of our patients who are doing not well at all, but we're not quite sure if they're doing poorly enough that it's time for transplant, and I'm trying to decide if the RV is growing or not. It's clearly big, but is it getting bigger each six months that we're looking at it? Sometimes MRI just seems to provide so much more precision than we can get with echo and certainly you're not getting any of those types of measures off of your catheterization.
Dr. Carolyn Lam: Maybe one last question Jason. It's so interesting. What is the future? What are the gaps that you're looking to fill at the moment?
Dr. Jason Weatherald: Ideally, I think it would be a noninvasive way to look at the right ventricle that is cheap, reproducible, and gives us the same confidence that invasive hemodynamics do. Although I find echo is indispensable and MRI is very useful, I think at the end of the day, we all go back to the right heart catheterization and we need to find something that can replace that, but give us the same confidence in what we think we're measuring and that it reflects treatment changes and clinical worsening.
Dr. Carolyn Lam: And Kelly, what do you think should be next steps?
Dr. Kelly Chin: I have to say I really liked this study. I thought it moves us forward in assessment of prognosis for this population of patients in a really big way. It was large and included a large number of measures that were done very carefully. You always want to see replication.
But, what I'd also like to see is the other forms of pulmonary arterial hypertension. You know this focused mainly on the idiopathic PAH patients, so what happens in connective tissue disease, and also what happens late after treatment, because I think we sometimes see a little bit of a different phenotype in patients that we've treated for many years and sometimes hemodynamics have improved, but in different ways than what we see early on with initial therapies.
Dr. Carolyn Lam: You've been listening to Circulation on the Run. Tune in again next week.
Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In today's feature discussion, we are talking about external validation of the DAPT score, a discussion that's going to take us all the way to east Asia, but for now, here are your weekly summaries.
In this week's journal, two studies are presented which compare ductal stenting to surgical shunts in the current era of ductal dependent pulmonary blood flow. As background, infants born with cardiac abnormalities causing dependence on the arterial duct for pulmonary blood flow are often palliated with a shunt between the subclavian artery and either pulmonary arteries. This modified Blalock–Taussig shunt allows progress through early life to an age and weight at which repair or furthermore stable palliation can be safely achieved. However, these modified Blalock–Taussig shunts continue to present concern for post-procedure instability and early mortality.
Duct stenting has emerged as an alternative with potential for greater early stability and improved survival. In the first study, first and corresponding author Dr. Bentham from Yorkshire Heart Centre reviewed data from the National Congenital Heart Audit, comparing the outcomes of 171 neonates who underwent a modified Blalock–Taussig shunt and 83 who underwent attempted ductal stenting, all in the setting of duct dependent pulmonary blood flow between 2012 and 2015. They found that stenting the arterial duct was preferable over the modified Blalock–Taussig shunt in terms of survival to next stage surgery, early post-procedure hemodynamic stability and shorter intensive care and hospital stay. There was a high failure rate both early, with the inability to stent the duct and late, with a greater need for re-intervention on the stented duct compared to the surgical shunt.
The second study originated from four North American pediatric cardiology centers representing the Congenital Catheterization Research Collaborative. First and corresponding author, Dr. Glatz from Children's Hospital of Philadelphia performed a retrospective cohort study reviewing all infants with ductal dependent pulmonary blood flow under a year of age, having either a ductal stent or a modified Blalock–Taussig shunt between 2008 and 2015. Although the observed risks of the primary outcome of death or unplanned re-intervention to treat cyanosis was higher in the surgical shunt group, there was no significant difference between groups after adjusting for patient level factors. Furthermore, after adjusting for patient factors, other outcomes favored the stent group, including fewer procedural complications, shorter intensive care unit length of stay, less frequent need for diuretics and larger and more symmetric pulmonary arteries at last follow up.
These companion papers are discussed in an elegant editorial by Drs. Benson and Van Arsdell from Hospital for Sick Children in Toronto.
The next study tells us that there may be a higher risk of vascular dementia in patient who survive a myocardial infarction. First and corresponding author, Dr. Sundbøll from Aarhus University Hospital in Denmark performed a nationwide, population based study including almost 315,000 patients with myocardial infarction and found that the risk of vascular dementia was higher compared to a matched general population comparison cohort. The risk of vascular dementia was incrementally higher in patients who suffered stroke or developed severe heart failure during the first year after myocardial infarction and in patients who underwent coronary artery bypass grafting. There was no association with all caused dementia, Alzheimer's disease or other dementia sub-types. Take home message is that among one year survivors of myocardial infarction, attention should be placed to persistently higher risk of vascular dementia.
The next study identifies a novel mechanism whereby the RNA binding protein, fragile X mental retardation autosomal homologue one or FXR1, directly regulates gap junction remodeling, leading to dilated cardiomyopathy. Co-first authors Drs. Chu and Novak, corresponding author Dr. Gregorio and colleagues from University of Arizona studied human left ventricle dilated cardiomyopathy biopsy samples as well as mouse models of dilated cardiomyopathy. They found that FXR1 expression was significantly increased in human and mouse dilated cardiomyopathy. Up regulation of FXR1 in the heart altered the location and distribution of gap junctions, subsequently leading to ventricular tachycardia in mice.
Mechanistically, FXR1 associated with intercollated discs and directly interacted with integral gap junction proteins to regulate their expression in cardiomyocytes. Finally, loss of FXR1 in the heart led to dilated cardiomyopathy. Together, these results provide a novel function of FXR1, namely that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. Thus, the authors concluded that FXR1 may be a promising target for therapeutic strategies to improve gap junction function in dilated cardiomyopathy.
Well everyone, that wraps it up for our summaries. Now for our feature discussion.
The dual anti-platelet therapy or DAPT score is widely used everywhere to estimate bleeding versus ischemic risk in patients undergoing percutaneous pulmonary intervention. However, very few studies have provided external validation of its utility. Well we have a very important paper in this week's journal that addresses just that in a Japanese population. So pleased to have with us the corresponding author, Dr. Takeshi Kimura from Kyoto University Graduate School of Medicine. Not just him, but also the editorialist for this paper, Dr. Shinya Goto, also an associate editor of Circulation from Tokai University of Japan and last but not least of course, our dear Senior Associate Editor of Circulation, Dr. Laura Mauri from Brigham and Women's Hospital. What an important topic. Takeshi, would you mind to please tell us about your study to start?
Dr Takeshi Kimura: Actually we thought about the utility of the DAPT score provided from the DAPT study in Japanese patient population. In a full cohort of three studies that are conducted in Japan, we compare the risks for ischemic and bleeding risks from 13 to 36 months after a PCI between patients with DAPT score (high-DS) and DAPT score <2 (low-DS) in patients in the Japanese population. We evaluated 12,223 patients. There were 1,344 patients with high DAPT score, 8,279 patients with low DAPT score. The cumulative incidence of primary ischemic end point myocardial infarction or stents from both is significantly higher in the high DAPT score group than in the low DAPT score group.
One of the cumulative incidence of the primary bleeding end point tended to be lower in high DAPT score than in the low DAPT score group, therefore the DAP score has successfully stratified ischemic and bleeding risks in Japanese patients. We've externally validated DAPT score successfully.
Dr Carolyn Lam: Thank you so much Takeshi. Shinya, you wrote an excellent editorial to this paper. Could you let us know why it was so important to validate this in the Japanese population?
Dr Shinya Goto: It's quite homogenous in one way and the other way in the world is heterogeneous. Some may say the risk of thrombotic and the bleeding event in Japanese or East Asia might be different from other regions of world. Dr. Kimura’s paper is the first validation of the DAPT score in the East Asian patient. Original attempts to study didn't include patients from East Asia. This is the real first validation of the DAPT score in that East Asian population. The world is quite homogeneous. It is very important message.
Dr Carolyn Lam: Yes, yes, I agree. Could I just ask maybe a cheeky question. What would you have thought may be any differences?
Dr Shinya Goto: Indeed, previous global trial and also global registry showed relatively low risk of ischemic event. Maybe not many of the US reader doesn't know we are using relatively low dose over anti-coagulant agent for preventing stent thrombosis. Dr. Kimura's paper provides very important insight. DAPT score is predictable for that event but even in the population with lower use of anti-coagulant agent like standard dose of prasugrel in Japan is just 3.75 milligram. Maybe that thrombogenicity in Japanese populations is lower as compared to the global population. Still that’s quite predictable for the ischemic event. That's very important message.
Dr Carolyn Lam: I agree and I have to tell you, practicing in Asia too, I have a tendency to think the bleeding risk may be underestimated by existing scores. We also tend to use lower doses, so it's so important to show objective data such as these. Laura, what are your thoughts coming from the US?
Dr Laura Mauri: Well I think it's very important. I want to congratulate Takeshi, it's a wonderful study, very large randomized data set and very important. I think in the grand scheme of things we do randomized trials, we can't represent every single population in every study. The DAPT study was done in the US, Europe, as well as in Australia and New Zealand, but it's true. We weren't able to also include sites in Asia just from practical reasons. I think it's very exciting to see, looking at this question of the DAPT score in patients in Japan.
I think in general, it matters a lot to understand the generalizability of our randomized trial results across different populations. I think Shinya's mentioned some of the important sources of variability. It may be this great interest in understanding genetics and how they relate in different populations, but there are also clear differences in medical practice across the world. Doing this type of study where one looks at different populations is quite important and I think it's also one of the reasons that circulation in terms of the editors are really seeking to expand the international scope of the randomized trials and secondary studies from randomized studies such as this that really impact patient care across the world.
Dr Takeshi Kimura: I think one of the difference from the DAPT studies in this Japanese closed study is the proportion of the high DAPT score versus low DAPT score is a little bit different. In the Japanese study population, the low DAPT score patients are dominant and also ischemic event risk are lower. However, the DAPT score clearly differentiates that, stratifies the bleeding and the ischemic risks so we should see both the bleeding and ischemic risk and also the difference of absolute event rates in each geographic ischemic population. I think it's important message from this paper.
Dr Carolyn Lam: That is such a great point, Takeshi. In other words, there may be some heterogeneity around the world in baseline risks, as Laura said, baseline practice patterns and I'm talking about baseline both ischemic and bleeding risks. What your paper definitely shows is that the DAPT score however, performs similarly and as we've said so many times, that's such an important message. Shinya, what do you think? What's your message to all the audience out there in Japan and abroad?
Dr Shinya Goto: As Takeshi told me and also how Laura pointed out, if we try to find the difference in the world, there is a difference and if we try to find the similarity, there is a similarity. Dr. Kimura paper shows similarity in the risk factor determining the ischemic and bleeding event. Matched, absolute event risk is low. Background medication is not the same. Majority of the patient taking [inaudible], 200 milligrams a day. [Inaudible] is a bad drug already in the world, but still in Japan, the doctor is still using. Clopidogrel, 75 milligram is also very widely used. The prasugrel dose is just 3.75 milligrams. That is different from the world. Ticagrelor with the dose similar to the world was not successful in the clinical trial in East Asia.
There is a similarity and heterogeneity. Dr. Kimara beautifully demonstrated both in his registry.
Dr Carolyn Lam: Indeed. Laura, looking at this now with these new data, do you think clinical trials should be done any different? Should we be doing multiple small trials maybe in different parts of the world now? Should we power trials to look at regional differences? This trial business is really hard, isn't it?
Dr Laura Mauri: That's a great question. It does come up practicality, whether we should do the same clinical trial in multiple different countries. I don't think it's the six answer, I think that as Shinya, I think, was alluding to, I think that patients responses worldwide are more similar than they are different. That doesn't mean when we plan our trials we shouldn't think about what the differences are and how they might impact the results and whether we might need to make confirmations across the world. I think this study is quite important because it finds the commonality across different populations even though there may be underlying differences that Takeshi mentioned in the baseline rate. I think a similar approach worldwide where we go in with a hypothesis about where things may be consistent or different to determine whether trials need to be replicated elsewhere is useful to have.
Dr Carolyn Lam: Thanks so much, Laura. I don't think any of us could have said it better.
Thank you all for joining me on the show today and thank you ladies and gentlemen throughout the world for listening in today. You've been listening to Circulation on the Run, don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation On The Run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.
In just a moment, we are going to be discussing the diagnostic conundrum of elevated high sensitivity cardiac troponin levels in a patient with renal disease, but also suspected of acute coronary syndrome. Aha! I bet I caught your attention. A very, very familiar diagnostic dilemma. So stay tuned right after these summaries.
Cardiac allograft vasculopathy is the leading cause of death in patients more than five years post cardiac transplantation. It has been hypothesized that cardiac allograft vasculopathy results from interrupted lymphatic drainage post surgery. Since the donor lymphatic vessels are not inesthimozed to that of the recipient during transplantation, thus the lymphatic system may play a crucial role in the alloimmune response.
Well, these hypothesis are addressed in the first paper in today's journal from first author Dr. Edwards, corresponding author Dr. Wong and colleagues from Kings College, London. These authors use spect CT lymphoscintigraphy in a pre-clinical model. And therefore provided objective quantification of lymphatic flow following transplantation and showed that this correlated to cardiac allograft vasculopathy. They demonstrated that cardiac lymphatic remodeling and lymphatic transport dysfunction post transplant was associated with cardiac allograft vasculopathy and transplant rejection.
They further showed that lymphatic flow was increased during chronic rejection. This in turn may have resulted in enhanced trafficking of antigen presenting cells to the local draining lymph nodes in an augmented alloimmune response. Now although the cause and effect of this phenomenon could not be fully established, these data provided the impetus for the investigation of lymphangiogenesis inhibition as a means to dampen chronic rejection.
The absorb bioresorbable vascular scaffold is known to completely resolve within three years after coronary artery implantation. However, what is the safety and effectiveness of these bioresorbable scaffolds during this critical three year period. First author Dr. Ali, corresponding author Dr. Stone and colleagues from Columbia University Medical Center performed an individual patient level meta analysis of the four randomized absorb trial and demonstrated that compared with metallic everolimus eluting stents, the bioresorbable vascular scaffold had higher rates of target lesion failure and device thrombosis cumulatively to three years and between one and three years. Multi-variable analysis identified the number of treated lesions, current tobacco use and previous cardiac interventions as independent predictors of three year target lesion failure. Whereas diabetes was predictive of three year device thrombosis in bioresorbable vascular scaffold treated patients.
The next paper reported the three year follow up of the FAME 2 trial, which compared PCI guided bi-fractional flow reserve with best medical therapy in patients with stable coronary artery disease to assess clinical outcomes and cost effectiveness. First and corresponding author Dr. Fearon and colleagues from Stanford cardiovascular institute showed that major adverse cardiac events at three years were significantly lower in the PCI group, compared with the medical treatment group. This difference was primarily as a result of a lower rate of urgent revascularization. Mean initial costs were higher in the PCI group, but by three years, were similar between the two groups. The incremental cost effectiveness ratio for PCI compared to medical therapy was more than $17,000 per quality adjusted life year at two years and $1,600 per quality adjusted life year at three years. Thus the authors concluded that percutaneous coronary intervention in patients with stable coronary artery disease and at normal fractional flow reserve may be advantages compared to with medical therapy alone, because it results in improved clinical outcomes and quality of life at no increased cost by the end of three years follow up.
The next study shows for the first time, that pioglitazone may prevent stroke as a single stand-alone outcome. Today's paper by first author Dr. Yaghi, corresponding author Dr. Kernan from Yale School of Medicine and colleagues was a secondary analysis of the iris trial, which showed that pioglitazone reduced the risk for a composite outcome of stroke on myocardial infarction among non-diabetic patients with insulin resistant and a recent stroke or transient ischemic attack. Now, the current planned secondary analysis used updated American Heart Association 2013 consensus criteria for ischemic stroke to examine the effect of pioglitazone on stroke outcomes. The study found that pioglitazone reduced the risk by 25% by five years, with absolute rates of 8% with pioglitazone versus 10.7% with placebo. Pioglitazone reduced the risk for ischemic strokes, but had no effect on the risk of hemorrhagic events. These findings add to the evidence that pioglitazone may be a potent therapy for vascular disease risk reduction and may help inform shared decision making by providers and patients for the use of pioglitazone after ischemic stroke or transient ischemic attack.
Well, that ends it for our summaries. Now for a feature discussion.
The cardiac troponins have really revolutionized cardiology. We use them in of course the diagnosis of myocardial infarction and in fact the recent European Society of Cardiology recommendations say that the rapid zero and one hour triage algorithm for rule in or rule out of non STEMI should use high sensitivity troponins and interestingly irrespective of renal function. Now this latter point has caused some confusion, some questions, since we all know that patients with chronic kidney disease frequently have higher or increased levels of cardiac troponins, especially since we now can detect them with the high sensitivity essays. And this is even in the absence of an acute coronary syndrome.
Well, this week's journal contains two papers that address this topic so well. And I am delighted to have with us the corresponding author of the first paper, Dr. Christian Mueller from University Hospital Basel in Switzerland and the author of the second paper, Dr. Nicholas Mills from University of Edinburgh in Scotland. For the more, we have Dr. Torbjorn Omland, associate editor from University of Oslo in Norway.
Lot's to talk about. Christian, could I start with you? Could you say in your own words the rationale for looking at this vulnerable population and then perhaps describe what you did in your study?
Dr. Christian Mueller: I'm very thankful that Circulation shed a lot of light on the population of patients with renal dysfunction, because both as a clinician and as a researcher, I'm definitely convinced that they merit a lot of our attention for several reasons.
So first, it's important to be aware that the incidents of acute myocardial infarction among patients presenting with acute chest pain is much higher in patients with renal dysfunction, as compared to patients with normal renal function. And second, atypical clinical presentations also are more frequent in patients with renal dysfunction. Then possibly third, the ECG of course also a mandatory tool in our assessment is more often showing unspecific signs that may mimic or obscure the presence of myocardial infarctions and most of them are related to left ventricular hypertrophy. And in addition, patients with renal dysfunction are more prone to adverse events, both related to cardiovascular medication. For example, anticoagulation as well as our cardiovascular procedures, including PCI. Now again, as both papers have a strong focus on troponin, also cardiac troponin is a bit more difficult to interpret in patients with renal dysfunction related to exactly as you mentioned chronic elevations of cardiac troponin, TNI related to chronic cardiovascular disease.
And I think that's so important to stress, any troponin signal in a patient with renal dysfunction is real and should not be incorrectly attributed to just a problem of impaired secretion by the kidneys.
Dr. Carolyn Lam: So definitely an even greater need to diagnose myocardial infarction accurately in this very high risk population. So tell us what you did.
Dr. Christian Mueller: We assessed this challenging sub group within the APACE study. So APACE is a large international prospective diagnostic study that is run in five countries with 12 centers. And we actually enroll consecutive patients presenting with suspected myocardial infarction. And then all patients get a very detailed workup and then adjudicated final diagnosis. And the adjudicated file diagnosis is done by two independent cardiologists and is based on two enormous extensive sets of data. The clinical data set that has been obtained at the local site and of course includes cardiac imaging and standard troponin testing, ECG data.
In the second set of data that includes the study specific data sets, including serial measurements with high sensitivity carry troponin essay and a lot of details characterization of patients and patient follow up. So this is the reference standard against which the one hour algorithm the European Society of Cardiology evaluated. And the one hour algorithm has been derived and previously validated in overall population. Mainly patients with normal renal function. And so we tried to evaluate the performance of this predefined algorithm specifically in patients with renal dysfunctions.
So among a bit more than 3,000 patients, the prevalence of patients with renal dysfunction was 15%. So we had about 500 patients with renal dysfunction. And the interesting finding from our work is that first the prevalence of N-STEMI was nearly threefold in patients with renal dysfunction as compared to patients with normal renal function. And, fortunately the rule out part of the algorithm regarding sensitivity still works very well. It is, however, the efficacy of rule out that is lower in patients with renal dysfunction, simply because fewer patients really have very low troponin concentration and are therefore ineligible for rule out.
However, as a clinician, the main concern with troponin and renal dysfunction is the rule in part, and specificity. And as you would think, specificity of the one hour algorithm was in fact significantly lower in patients with renal dysfunction. It was still appropriate for therapeutic consequences, but it was lower as compared to patients with normal renal function, so the specificity was 89% in patients with renal dysfunction, as compared to 96.5% in normal renal function.
So the overall efficacy of the algorithm was lower in patients with renal dysfunction, however then when trying to create and derive optimized cut off levels, so all cut off levels optimized for use in renal dysfunction, we didn't really find alternative cut offs that would do a much better job than the official cut off levels recommended in the guidelines. So our conclusion is that in patients with renal dysfunction, the safety of the one hour algorithm still is very high, however the specificity of rule in and overall efficacy are decreased.
Dr. Carolyn Lam: Right. That's beautifully summarized. And also that different cut offs didn't really help to increase the efficacy of this algorithm. And just to clarify to our listeners, I believe you defined renal dysfunction as an estimated GFR of less than 60, which is so beautiful because it's perfectly consistent with the second paper.
Nick, could you please tell us about your study and your take home messages as well.
Dr. Nicholas Mills: So high stakes is our clinical trial that we're conducting across hospitals in Scotland to evaluate the best way to use high levels of cardiac troponin in clinical practice. One of the areas of uncertainty is whether these assets really add any additional value for patients with chronic kidney disease, where troponin concentrations tend to be higher. And the premise of a high sensitive test is that we can measure lower concentrations and improve the sensitivity. But is this just going to create uncertainty for clinicians?
So we evaluated 5,000 consecutive patients for performance of high sensitivity cardiac to put in testing. And those with and without renal impairment. And based upon what Christian, we identified that patients with renal impairment are less likely to have very low concentrations, but that you can rule out myocardial infarction safely in patients with renal impairment. And similarly that those with renal impairment are more likely to have an abnormal troponin concentration at presentation. Around about 40% of all patients have troponins above the upper reference limit. And whilst the specificity for myocardial infarction is lower, type one myocardial infarction or myocardial infarction due to plaque rupture or cardiac thrombosis remains the most common diagnosis in this group.
Finally we looked at one year outcomes. And this is really critical. Because we found that patients with renal impairment were two to threefold more likely to die from cardiovascular disease one year following their presentation than those without renal impairment. And I think that my general experience during these tests in clinical practice is that troponin elevations in patients with kidney disease are often ignored and there's a concern about what they mean, and therefore these patients don't get access to the fantastic treatments we have for coronary heart disease. So our take home message is that high sets of troponin testing in patients with renal disease does have value, it's useful for identifying low risk patients although there are fewer of them, and it performs well as a diagnostic test, highlighting in particular a group of patients that really have poor clinical outcomes.
As a cardiological community, we need to do better.
Dr. Carolyn Lam: What I really love about both or your papers is the consistency in the messages. Torbjorn, I want to bring you in on this. You managed both papers. Such a lovely pair of papers that we're so proud to be publishing and you had also invited an editorial by Dr. deFilippi and Seliger. Would you like to comment on your perspective and perhaps the clinical take home message to our audience?
Dr. Torbjørn Omland: Yes, I think this has been pointed very well out by both Christian and Nick. And I think it's worth recapitulating that renal dysfunction is a major problem that clinicians often try to explain by just lack of renal filtration. But that the closest probably are increased production and underlying cardiac disease. So in the editorial Dr. deFilippi Filippi and Dr. Seliger points also out in these things. Moreover they try to look forward and have made comments to recent studies that showed that in patients with renal dysfunction have different troponin fragments than patients with acute myocardial infarctions.
Dr. Carolyn Lam: I find that so fascinating. And it really, really relates to the field of heart failure and what we are also talking and thinking about with natriuretic peptides and their different fragments and the possible different meanings. And how different essays maybe non specific for different fragments.
Christian, you think a lot about these things. I'm curious, what are your thoughts on this and areas of future work that are very urgent?
Dr. Christian Mueller: I think Torbjorn very nicely addressed this. So the current high sensitivity essays for T and I that we use in clinical practice, they are designed kind of to detect everything in blood that looks like troponin, either T or I, including various fragments. And I think it's a fantastic new avenue of research, trying to find out that the biochemical signatures can be further differentiated and exactly that perhaps different troponin fragments or tricordinate products more prominent in patients having ischemic injuries like treat myocardial infarction, as compared to for example other modes of injuries. So I think that's very nice hypothesis and some early data. But at least from my perspectives and to the best of my knowledge until now, the diagnostic algorithms that we have other ways to approach this in clinical practice. And so it's the higher the blood concentration in patients with acute chest pain, the more likely it's acute myocardial infarction. It's not any chronic disease and again the higher the change from presentation to one hour or two hours, the more likely it's acute as a dynamic disorder resulting in an acute increase in cardiac troponin, as compared to the chronic release patterns typically seen in patients with renal dysfunction.
Dr. Carolyn Lam: Yeah. That's just so fascinating. Nick, we sadly are running out of time, but I do want to give you the last word. The clinical take home message, once again. What do you think listeners should take home that may change their practice, after listening to this podcast?
Dr. Nicholas Mills: I think the key message for clinicians, is that in a patient with suspected acute coronary syndrome and has renal impairment and elevated troponin concentration, serial testing is mandatory to differentiate between those that have chronic myocardial injury due to subclinical heart disease and those that are having acute myocardial injury as a consequence of a presumed acute coronary syndrome. Field testing is critical to inform which treatment path and what investigations we recommend for our patients.
Dr. Carolyn Lam: Wonderful. And to take any elevations seriously, because this is a high risk population.
Well, audience you heard it right here on Circulation On The Run. I'm sure you've enjoyed this. I certainly have. Don't forget to tune in again next week.
Dr. Carolyn Lam: Hello from the American Heart Association meeting in Anaheim. I'm Dr. Carolyn Lam, associate editor from Circulation at National Heart Centre in Duke National University of Singapore and I'm so pleased to be here with the Circulation team led by editor in chief Dr. Joe Hill, as well as with Dr. Laura Mauri, senior editor from Brigham and Women's Hospital, and Dr. Dharam Kumbhani, associate editor from UT Southwestern. Boy, we've got lots to discuss. I mean, I want to just first start with congratulating you, Joe. We have got quite a number of simultaneous publications here at the AHA.
Dr. Joseph Hill: I appreciate that, Carolyn. Don't congratulate me. We have a team that is a privilege to work with. One of the initiatives that we launched right from the start was a desire to foster and shine a bright light on emerging science at the major meetings around the world. Often, that involves simultaneous publication.
I'm proud to say that we have 11 simultaneous publications, a record for us here at AHA. Most of them are clinical trials. A few are clinical science, and two of them are young investigators who are competing in the various different competitions. We reached out to them a few weeks ago and offered them the opportunity to submit to us, of course with no guarantees, and our standard remains the same, but we promised that we would provide them with an external peer review. Two of them made it through the process and they will be simultaneously published with their presentations here in Anaheim.
Dr. Carolyn Lam: Wow, well you heard it. A record 11 simultaneous publications. We've got a lot to talk about. Let me just maybe group the topics a little bit. Let's start with talking about peripheral artery disease. I think there are at least three papers around that area, and then we'll talk about coronary artery disease, and almost focusing more on implementation science, papers, there are two there, and then of course we have to talk about heart failure. Dharam, could you start? Tell us about the FOURIER PAD trial.
Dr. Dharam Kumbhani: Yeah. It's very exciting to have clinical trials in the PAD realm. FOURIER PAD is certainly really well done sub-study of the FOURIER trial. As you remember, this was a landmark trial, which compared a PCSK9 inhibitor Evolocumab in two doses, two placebo. The overall trial was done in about 27,000 patients who were followed for a median of 2.2 years. In this trial, Marc Bonaca and investigators, they looked at the PAD subset, which were about 13% of the total cohort. Now, they specifically set out to look at how patients with PAD, during this trial and very gratifyingly, they also specifically assessed how patients with PAD did as far as limb events, not just cardiovascular events.
At the outset, not surprisingly, patients with PAD had a higher risk of cardiovascular events by, I think it was about 60% higher for the primary end point compared with patients who did not have PAD. There was really no, in fact, modification by PAD in that the benefit of Evolocumab that we saw in the overall trial was preserved among the patients with PAD as well as those without PAD. However, because patients with PAD had higher event rates, the absolute risk reductions were higher in patients with PAD.
Then, these investigators looked specifically at the incidents of major adverse limb events, which is a composite of acute limb ischemia, urgent revasc, and major amputations. What they show is that in the overall cohort, there is a 42% reduction in the risk of these major adverse limb events with Evolocumab compared with placebo. Obviously, the effect is significantly higher in patients with PAD. Although the benefit wasn't noted in the PAD subset specifically, the overall p-value for interaction was negative.
One of the really exciting things about this paper is that just like investigators have shown a monotonic reduction in cardiovascular event rates with LDL reduction, similarly, the investigators show a reduction in limb events, which is dose related and the same way in a monotonic fashion with Evolocumab. I think this is really exciting and I think this will be a very important paper for the field.
Dr. Carolyn Lam: Yeah. Dharam, that was beautifully summarized but once you start talking about the peripheral artery disease and this lack of interaction on effects and so on, I think of the CANVAS trial results that were reported at this meeting too. If I could maybe briefly summarize what the authors did in this circumstance, they looked at the more than 10,000 patients in the CANVAS trial who were randomized into Canagliflozin versus placebo in diabetic patients but this time they looked at whether or not there was a difference in effect with the primary prevention cohort versus the secondary prevention.
Primary prevention meaning those adults who had diabetes and risk factors but no established cardiovascular disease and the secondary prevention were those with peripheral artery disease, for example, and other established cardiovascular disease. The same thing, a lack of interaction, which I think is really important because it was the same sort of idea that the overall risk of cardiovascular events was lower in the primary prevention group. Looking at them as a subgroup alone, you didn't get the p-value that crossed the limit because the power was less in a lower risk group, but the lack of statistical interaction really gives us additional information, I think, that Canagliflozin and maybe the SGLT2s in general may be effective for primary prevention in diabetic patients. What do you think?
Dr. Dharam Kumbhani: Yeah. I mean, I think certainly, very interesting findings along those lines. As you pointed out, the event rates are much lower in the primary prevention cohort. All the confidence intervals overlap one, but because all the p-values for interaction for the three-point maze, the four-point maze, et cetera, one would say that there really isn't a difference between the primary and the secondary prevention subgroups. You would potentially have the same benefit in that subgroup as well.
Dr. Carolyn Lam: Fortunately or unfortunately, in that same study, they looked at the risk of amputations and there was a lack of interaction too for that meaning there was a higher risk of amputations with Canagliflozin versus placebo. That of course is a really hot topic now, isn't it? I just wanted to point out though, when you look at it in the primary prevention group, there are only 33 events. What do you think? It spells caution but further look needs to be done? Yeah. Contrast that with the EMPA-REG outcome PAD analysis. You want to tell us about it?
Dr. Dharam Kumbhani: Yeah. Once the Canagliflozin CANVAS findings came out showing a high rate of amputations with Canagliflozin, the Empagliflozin, the EMPA-REG outcome’s investigators went back and looked at the PAD subset in EMPA-REG outcomes. This was about 20% of the total cohort. I will say that unlike FOURIER, which we just discussed, the ascertainment of amputations was not prospectively defined for this trial and it was really obtained from the CRF forms.
However, having said that, it did not appear that amputation rates were higher with Empagliflozin. They did not break it down by the different doses but one assumes that the benefit is consistent between the two doses that they study. One would imagine the PAD patients would have a higher rate overall, which it was, but even in that group, it was about 6% over three years and there was really no difference between the patients who received Empagliflozin versus those who got placebo.
Dr. Carolyn Lam: That EMPA-REG outcome paper, I mean, interestingly, it was a research letter. Joe, you've been watching this whole field unfold right now and our journal has published so many good papers, including CVD REAL, all in this space. Could you comment on that a little bit and the research letter concept and the fact that we're publishing so many of these interesting papers in this topic?
Dr. Joseph Hill: Well, Carolyn, as you inferred, this field is evolving very rapidly. Now, the interface between metabolic disease and diabetes and heart disease is blurring. Some of these diabetic drugs are really emerging as heart failure drugs, it looks like and so there's a great deal of interest in exploring that and trying to find underlying mechanisms. It's an incredibly exciting time. In parallel with that, we are publishing research letters now for papers where, again, our bar starts with validity. Our bar doesn't change but if it's a story that can be communicated with really one multi-paneled figure and an 800word text, then that is a nice bite-size piece of information that we can get out to our readership. We're publishing one or two a week now. Overall, it appears to be well received and I think it's an effective vehicle for conveying certain types of our content.
Dr. Carolyn Lam: Frankly, it's such a delight to read, isn't it? It's hard to write. I think the shorter, the harder to write but this just goes to show how equally important they are.
Dr. Joseph Hill: Absolutely.
Dr. Carolyn Lam: That we're discussing it here. Well, let's go on to the next topic then, coronary artery disease. Regionalization of the care. I'll say that again, regionalization of the care. Would you like to comment on the two papers that are simultaneously being published? One would be the ACCELERATOR-2 trial. That's in the U.S. Then, a second from New Zealand, the ICare-ACS trial. Slightly different but-
Dr. Joseph Hill: Well, that's exactly right. Often, we know what to do but we don't do what we know we need to do in medicine. The implementation of what we already know is an area of hot research and is an area that's evolving rapidly. These two studies, ACCELERATOR-2 here in the United States, focused on regionalization of the interface between EMS systems and EDs, how to get patients identified in the hospital to their device, whether it's a stent or a balloon pump or whatever it is. The first medical contact to device was the metric and by implementing what we already know, the AHA mission lifeline principles, these investigators were able to optimize this regionalization, so there wasn't so much variability across these 12 metropolitan regions. As a consequence, the time to first medical contact to device was shortened, and there was in fact a striking, maybe even surprising, mortality benefit.
Dr. Carolyn Lam: Exactly. That was striking to me too.
Dr. Joseph Hill: From the street to the lab, another paper from New Zealand that you referred to called ICare-ACS focused on doing a better job in the emergency department with serial ECGs and serial high sensitivity troponins, risk stratification algorithms and they found that, again, by developing these clinical pathways within the ED, they were able to shorten the length of stay in the ED and the length of stay in the hospital.
Dr. Carolyn Lam: Yeah. I thought those were amazing and then also from different parts of the world, really strong public health messages as well. Laura, you take care of these ACS patients right on there. What did you think of these papers?
Dr. Laura Mauri: No, I agree. I think that we've, in the past, focused on science and focused on clinical trials but ultimately, none of that matters if we don't deliver the healthcare to the patient. I think this is just a growing field and I'm glad that we're emphasizing it in circulation.
Dr. Carolyn Lam: Absolutely. If we would now go to another area that is really increasing in prevalence throughout the world. Heart failure, and of course, heart failure with preserved ejection fraction.
Dr. Joseph Hill: Your favorite topic.
Dr. Carolyn Lam: Congratulations, Laura on the paper that you're presenting, that is being presented at this meeting, the REDUCE LAP trial. Could you tell us a little bit more about that?
Dr. Laura Mauri: Sure. Yes, as you know, it's a really challenging field, heart failure with preserved ejection fraction. There aren't a lot of therapies that we have. We really don't have great medical therapy. This study actually looks at a medical device to treat patients. It really is a feasibility study, so it's a relatively small trial, just over 90 patients but it's randomized. We know in the device arena, as in all trials, how important randomization is but also blinding. This was actually a sham-controlled blinded trial really designed to look at this interatrial shunt device in patients who have an elevated wedge pressure.
The REDUCE LAP stands for reduce left atrial pressure. That was the primary endpoint, was pulmonary capillary wedge pressure. This was not only looked at the safety, which showed that the device placement was very safe, but at the same time also looked at the proof of concept that by placing the shunt device, there was actually a reduction in wedge pressure over a period of exercise. It needs to be followed on. It's certainly just the first phase of trials but a pretty good standard with the sham control.
Dr. Carolyn Lam: Yeah, well, congratulations again. I mean, this follows … There was a previous publication of the single arm trial and now, this is the first randomized sham-controlled, and the results are consistent. It's a very difficult trial to carry out. HFpEF patients are notoriously difficult to recruit. Could you tell us a little bit about what it was like successfully completing this trial?
Dr. Laura Mauri: Yeah. Well, we had very enthusiastic centers and principal investigators, Ted Feldman and Sanjiv Shah. I think what it really required in this early phase was sites that were committed to characterizing the exercise physiology. The next stage of rolling this out to a broader number of sites and a larger number of patients to see if there's a clinical effect will really be more focused on the clinical endpoints and quality of life because ultimately that's the goal, is to improve symptoms in these patients.
Dr. Carolyn Lam: What I love about the design and the whole concept, it's so simple and elegant. We almost sometimes forget that HFpEF is heart failure, which means that by definition, there's raised filling pressures. It's hemodynamic at the end and this is just a simple concept of offloading the left atrium. That's so beautiful but it does come with some questions. Every time you mention this to someone, they go, “What about, I don't know, Eisenmenger's syndrome developing later?” The right side, volume overload, pulmonary hypertension, what about atrial fibrillation down the line? How about the safety parts of it?
Dr. Laura Mauri: Right, so the procedural safety was excellent but then I think you raise really important questions and these patients are still in follow-up but looking at the report here at this meeting, there was no pulmonary hypertension in excess in the shunt treated arm. The patient selection was towards patients who had higher wedge compared with right atrial pressure and among those patients, there was no evidence of RV overload. At least at this stage things look good to go on to the next step.
Dr. Carolyn Lam: That's wonderful and exciting. We definitely need a therapy for HFpEF. Joe, would you like to highlight any other trial? We have 11. We've discussed six.
Dr. Joseph Hill: Tonight at the editorial board meeting, we will be saluting these two young investigators who are presenting their work in this competition and simultaneously publishing their work. We've invited these young investigators and their mentor and they will present a short talk to the editorial board dinner. It's an effort to salute and recognize these early career investigators, to congratulate them on outstanding work. We're pleased and privileged to publish it, so I'm particularly excited about that.
Dr. Carolyn Lam: Wow, Joe. That is great. Thank you. I didn't know that was happening either. That's fabulous. Dharam or Laura, any other highlights that you may want to mention in this meeting?
Dr. Laura Mauri: I think that it's just been a wonderful kickoff to the meeting. We've covered, I think, many of the really important trials so it's really exciting to be able to see the work in print.
Dr. Carolyn Lam: That’s great, and to discuss it as well.
Dr. Dharam Kumbhani: Yeah, I agree. This is really exciting and hopefully, we can keep growing from strength to strength every year.
Dr. Carolyn Lam: Yep. You heard it right here everyone. We are going to grow from strength to strength under your leadership and with this great team, so thank you very much for joining us today.
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 feature paper takes a deep dive into nitric oxide signaling, that extremely important pathway in cardiovascular health and disease. This time, taking a novel look at genetic predisposition, phenotypic consequences, and therapeutic implications. All that coming right up after these summaries.
The first original paper describes the derivation and validation of a novel model to stratify the risk of death due to circulatory etiology in patients resuscitated from cardiac arrest without an ST elevation MI.
First author, Dr. Bascom, corresponding author Dr. Setter from Maine Medical Center in Portland and their colleagues use the International Cardiac Arrest Registry to derive a novel model termed the CREST Model, which describes an incrementally high risk of circulatory etiology death with an increasing score.
Now, CREST is a simple score with components of C for prior coronary artery disease. R for non-shockable rhythm. E for ejection fraction less than 30% on admission. S for shock at the time of admission. T for ischemic time more than 25 minutes. The authors showed that this CREST tool may allow for estimation of circulatory risk and improve triage of cardiac arrest survivors without STEMI at the point of care.
The next study reports associations between usual sodium, potassium and blood pressure using gold standard 24-hour urinary data collected for the first time among a nationally representative sample of adults in the United States.
First and corresponding author Dr. Jackson from Centers for Disease Control and Prevention used cross-sectional data from 766 participants aged 20 to 69 years with complete blood pressure and 24-hour urine collections in the 2014 national health and nutrition examination survey.
They found that there was a strong direct relationship between higher sodium excretion and higher blood pressure and hypertension. In addition, there was an inverse relationship between potassium excretion and blood pressure and hypertension. When added to the evidence based from longitudinal and interventional studies, these results support clinicians dietary advise to lower sodium intake and increase consumption of potassium containing foods.
The next two studies in this week's journal examine the utility of circulating biomarkers to aid in the diagnosis of acute aortic dissection. As a reminder, the AHA/ACC guidelines published in 2010, proposed using the aortic dissection detection risk score or ADD risk score as a primary screening tool based on scoring the presence of three categorical risks.
Number one, high risk conditions such as Marfan Syndrome, a family history of aortic disease, known aortic valve disease, known thoracic aortic aneurysm or previous aortic manipulation. Number two, The pain features such as chest, back or abdominal pain described as being of abrupt onset severe intensity or ripping, tearing. Number three, the examination features such as evidence of profusion deficit, systolic blood pressure difference, spoken neurological deficit or aortic diastolic murmur and hypertension or shock.
The presence of one or more markers within each of these categorical features is given an ADD score of one with a maximum cumulative score of three if all three categorical features are present. In the first of these two papers in this week's journal, first author Dr. Nazareen, corresponding author Dr. Morello and colleagues from Molinette Hospital in Italy performed the advised International Multi Centers Study, which prospectively assessed the diagnostic performance of standardized strategies integrating pre-test probability assessment and D-dimer in 1,850 patients from the emergency department.
They found that in patients with an ADD risk score above one and D-dimer less than 500 nanograms per milliliter, the rate of acute aortic syndromes was significant at one in 22 cases. Rule out strategies for acute aortic syndromes integrating an ADD risk score of zero or one with D-dimer less than 500 were found to miss only around 1 in 300 cases of acute aortic syndrome.
Integrating the ADD risk score with D-dimer could help to standardize diagnostic decisions on advanced imaging for suspected acute aortic syndrome balancing the risks of misdiagnosis and over testing. The authors concluded that patients at high probability of acute aortic syndrome such as with an ADD risk score above one should proceed to computer tomography and geography or other conclusive imaging irrespective of D-dimer levels. However, in those with an ADD risk score of zero or one, with a D-dimer of less than 500 were possible rule out diagnostic strategies for acute aortic syndrome.
The second manuscript in the present issue suggests that soluble ST2 might be an even better biomarker than D-dimer to rule out aortic dissection. In this paper by first author, Dr. Wang, co-corresponding authors, Dr. Du and Guo from Beijing Anzhen Hospital and Peking University respectively, the authors measured plasma concentrations of soluble ST2 using the R&D Systems assay in 1,360 patients including 1,027 participants in the retrospective discovery set and 330 patients with an initial suspicion of acute aortic dissection and ruled in a prospective validation cohort.
The proportion of acute aortic dissection, this acute chest pain cohort was high at more than 40%. The authors found that soluble ST2 measured using this research grade assay showed higher levels in acute aortic dissection than in acute myocardial infarction or in acute pulmonary embolism. The result suggested that soluble ST2 levels could be useful as a rule out marker possibly even to an extent moderately superior to D-dimer.
A cut-off level of around 35 nanograms per milliliters using the research grade soluble ST2 assay appeared to reliably rule out acute aortic dissection if used within 24 hours after symptom onset with a negative likelihood ratio of 0.01 and a negative predictive value of more than 99%. These intriguing findings are discussed in an accompanying editorial by Dr. Toru Suzuki from University of Leicester and Dr. Kim Eagle from University of Michigan. Well, that wraps it up for our summaries. Now, for our future discussion.
Nitric oxide signaling plays a key role in the regulation of vascular tone and platelet activation. In fact, the pharmacologic stimulation of nitric oxide pathway is emerging as a therapeutic strategy in cardiovascular medicine in many areas including in heart failure preserved dejection fraction.
Today's paper is therefore all the more intriguing because it seeks to understand the impact of a genetic predisposition to enhanced nitric oxide signaling on the risk for cardiovascular disease as a way of informing of the potential utility of pharmacologic stimulation of the nitric oxide pathway.
Intrigued? Well, I certainly and I'm so glad to have with us the corresponding author, Dr. Sekar Kathiresan from Massachusetts General Hospital as well as a familiar voice, Dr. Peipei Ping, associate editor from UCLA here to discuss this paper.
Sekar, could I ask you as an introduction to tell us a little bit more of the general approach of looking at genetic predisposition as a way of perhaps forecasting potential utility of pharmacologic stimulation? Could you tell us a little bit more about that?
Dr. Sekar Kathiresan: Yes. I'm delighted to speak a little bit more about this idea of using naturally occurring genetic variation to understand if a medicine developed against a target is going to work in terms of efficacy and also potentially lead to on target side effect.
As you know, there are lots of variants for mutations in genes that eventually become targets for medicines. Over the last 10, 15 years, there's been an explosion in our understanding of human genetic variation, specifically in genes targeted by medicines.
The idea here is that if there's a naturally occurring mutation in that target gene, you can simply ask what are the phenotypic consequences of carrying that mutation. Also use that information to predict, as I said, the efficacy of pharmacologic manipulation and potentially on-target side effects. This approach has become a very powerful approach.
A famous recent example of gene, PCSK9, where mutation in this gene occur naturally. A lower function of PCSK9 and individuals who carry this mutations have lower LDL levels and lower risk of heart attack. This information has led to the development of medicine that mimic those mutations and those medicines have been proven now to lower LDL as well as lower risk of heart attack, a phenomenon anticipated by the genetics.
Dr. Carolyn Lam: If I understand it right then, with regards to today's paper, the idea is that if a genetic predisposition to enhanced nitric oxide signaling associates with reduced risk of cardiovascular disease, then that would support the hypothesis that pharmacologic stimulation of the nitric oxide pathway would prevent or treat the cardiovascular disease, right? Could you further expand? Because you also did a meditation analysis. How would we understand that?
Dr. Sekar Kathiresan: Let me walk you through the basics of this paper. Our hypothesis initially was a genetic predisposition to enhance nitric oxide signaling would actually affect a range of cardiovascular diseases. Nitric oxide is a well-known molecule, a regulator of a number of important processes; vascular tone, blood pressure, platelet aggregation.
A couple of important genes in the nitric oxide pathway are, one, nitric oxide synthase, the key enzyme that generates NO. Second is a soluble guanylyl cyclase that is a regulatory molecule involved in NO biology. One of the genes that is part of that pathway is called GUCY183, which is basically a subunit of the soluble guanylyl cyclase.
What we did was we looked at those two genes and asked, "Are there naturally occurring variations in those two genes that actually give us a sense that they gain function that they actually activate nitric oxide signaling. It turned out there are two polymorphisms. One in nitric oxide synthase and the other is in the soluble guanylyl cyclase subunit that are essentially gain of function. They're common polymorphisms.
We know their gain of function because the carriers of these DNA variants have lower blood pressure. An indicator that there's enhanced NO signaling. We use these two polymorphisms as an instrument to understand the phenotypic consequences of having lifelong enhanced nitric oxide signaling.
What we looked at was the relationship of individuals who carried both of the gene variants or gained a function and asked whether these individuals what the relationship of carrying the variant was to a range of cardiovascular diseases as well as a range of quantitative traits like blood pressure or kidney function.
We looked at this in extremely large human population samples where genotype and phenotype had been collated. Most important of these samples is a recent study of a population-based cohort study called the UK Biobank, which has involved about a half million people where genotype and have phenotype have been assembled.
What we found was that genetic predisposition to enhance nitric oxide signaling was associated with reduced risk of several important cardiovascular diseases. First, coronary heart disease. Second, peripheral arterial disease, and third, ischemic stroke.
That provide a very compelling evidence that atherosclerotic cardiovascular disease would be lower based on enhanced nitric oxide signaling. What was surprising to us is we also found a couple of other diseases where it seemed to benefit from enhanced nitric oxide signaling namely kidney function and pulmonary function. These were a little surprising to us, but I think it really suggest that NO plays an important role in a range of diseases.
In terms of your question about what aspect of NO biology is leading to be relationship to these diseases, is it simply the blood pressure effect for example or could you actually infer a mechanisms beyond the blood pressure? We looked at that specifically in the context of cardiovascular disease and we're able to show that the protection afforded by the enhanced nitric oxide signaling gene variants, that protection exceeded the amount predicted by the blood pressure change. In fact, by quite a bit suggesting that there are probably non-blood pressure mechanisms that are at play in terms of the protection afforded by enhanced nitric oxide signaling gene variants.
Dr. Carolyn Lam: Peipei, I have to invite your thoughts now. This is such an amazing paper. We had great discussions as an editor team. Tell us your thoughts.
Dr. Peipei Ping: The editorial team as well as the reviewers have been very impressed with the quality of the datasets and the value and detail, the metadata analysis together with the appropriate analytical approach. The study is done in our view in a very careful manner and the analysis was performed through the highest standards.
What we also recognized is the potential impact that this particular study may have on multiple areas of studies, in particularly with their findings, the spectrum of individuals, how they carry nitric oxide signaling trends. You could appreciate that the individual score or genetic score paired with the analysis of the genetic variance that they have done, they see from the mental idea that examine both genetic as well as phenotype of each individual is critically important for medicine to be prescribed in the next step of therapies.
Dr. Carolyn Lam: Building on that thought, Sekar, could I ask you? You found some rare inactivating variance. Are these the patients then you think should be targeted for NO enhancing therapies? What's the clinical implications of your findings?
Dr. Sekar Kathiresan: I think there are two ways to think about the implications of these findings. One is there's just a simple biologic insight, the pharmacologic activation of NO signaling maybe protective beyond pulmonary hypertension. As you know, there are actually compounds in the clinic right now that are pharmacologic activators of soluble guanylate cyclase. Those medicines work in the rare condition of pulmonary hypertension.
our work suggest that those medicines are likely to work in a broader range of indications including atherosclerotic cardiovascular disease, kidney disease and pulmonary function. At a simple level, those experiments, I think, should be looked at. Those indications should be looked at.
Whether we've identified a subset of a population that particularly will respond versus it will be a general phenomenon across a range of different individuals that have impaired nitric oxide signaling, I think time will tell. Certainly, one group to think about would be those who are indigenously deficient in nitric oxide signaling and we did find that there are small subset of patients who have inactivating mutations in these two genes and they have higher blood pressure and increased risk for cardiovascular disease.
It was a pretty rare phenomenon, so very small number of individuals would be relevant there. I'm not sure actually that you necessarily want to limit the potential benefit of NO signaling, enhanced NO signaling to just that subgroup. In fact, my prediction would be that the medicine would be relevant for a very large percentage of the population. That you do not need to limit the potential application of this therapy to just those who carry the inactivating mutations.
Dr. Peipei Ping: I agree largely of what Sekar has discussed. I would add that in situations where genetic information are available with the patients, what the study has offered is fairly clear in the patients where rare variance that inactivate the NOS3 or the guanylyl cyclase off the genes. Maybe a failure it is with a higher systolic blood pressure risk. I'm entirely supportive with the general conclusion that we have come to a time point where NOS outside signaling activation is a critical new element of therapy in cardiovascular health and disease.
Dr. Sekar Kathiresan: Thank you Peipei. Thank you Sekar for taking the time to share your thoughts with us. We are so proud to be publishing paper in circulation. So proud and happy to be chatting about this on this podcast. You've been listening to Circulation on the Run. Thank you for joining us and please tune in again next week.
Dr. Carolyn Lam: Welcome to "Circulation on the Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke‐National University of Singapore. Our featured discussion this week focuses on the new 2017 ACC/AHA high blood pressure guidelines, and the potential impact of these guidelines on the U.S. population. A must listen, coming right up after these summaries.
The first original paper this week provides insights into how extracellular matrix remodeling contributes to in‐stent restenosis and thrombosis. First author, Dr. Suna, corresponding author, Dr. Mayr, and colleagues from King's College London, implanted bare metal and drug‐eluting stents in pig coronary arteries with an overstretch and then harvested the stented segments up to 28 days poststenting for proteomics analysis of the media and neointima.
The authors found significant differences by proteomics in the extracellular matrix of coronary arteries after stent implantation. Most notably, an upregulation of aggrecan, a major extracellular matrix component of cartilaginous tissues that confers resistance to compression. In fact, this study provided the first evidence implicating aggrecan and aggrecanases in the vascular injury response after stenting. This opens a door to consideration of aggrecanase activity as new drug targets that may alter extracellular matrix remodeling in the vasculature.
The next paper tells us that empagliflozin could address a significant unmet need in patients with chronic kidney disease. First and corresponding author, Dr. Wanner, from Wurzburg University Clinic in Germany investigated the effects of empagliflozin on clinical outcomes in patients with chronic kidney disease in the EMPA‐REG OUTCOME trial, where patients with type 2 diabetes, established cardiovascular disease, and an eGFR above 30 at screening were randomized to receive empagliflozin or placebo, in addition to standard of care.
In the current study, prevalent kidney disease was defined as an eGFR of less than 60 or urine albumin/creatinine ratio of more than 300 at baseline. In these patients, empagliflozin reduced the risk of cardiovascular death by 29% compared with placebo, reduced the risk of all‐cause mortality by 24%, and reduced the risk of hospitalization for heart failure by 39%, and the risk of allcause hospitalization by 19%.
The effects of empagliflozin on these outcomes were independent of renal function or albuminuria status at baseline. Furthermore, the adverse event profile of empagliflozin was similar across subgroups by renal function at baseline. Adverse events of particular concern in this population, such as urinary tract infection, acute renal failure, hypokalemia or fractures, lower limb amputations or hypoglycemia were not increased with empagliflozin compared to placebo.
The next study provides mechanistic insights into exercise intolerance in heart failure with preserved ejection fraction or HFpEF. First author, Dr. Houstis, corresponding author, Dr. Lewis and colleagues from Massachusetts General Hospital, investigated the mechanism of exercise intolerance in 79 patients with HFpEF and 55 controls referred for cardiopulmonary exercise testing who were also studied with invasive monitoring to measure hemodynamics, blood gases and gas exchange during exercise.
These measurements were used to quantify six steps of oxygen transport and utilization in each HFpEF patients, identifying the defective steps that impaired each one's exercise capacity. The authors then quantified the functional significance of each pathway defect by calculating the improvement in exercise capacity that a patient could expect from correcting the defect.
The authors found that the vast majority of HFpEF patients harbored defects at multiple steps of the pathway, the identity and magnitude of which varied widely. Two of these steps, namely, cardiac output and skeletal muscle oxygen diffusion were impaired relative to controls by an average of 27% and 36% respectively. Due to interactions between a given patient's defects, the predicted benefit of correcting any single defect was often minor. At the individual level, the impact of any given pathway defect on a patient's exercise capacity was strongly influenced by comorbid defects.
The authors concluded that a personalized pathway analysis could identify patients most likely to benefit from treating a specific defect. However, the system properties of oxygen transport favor treating multiple defects at once, such as, with exercise training.
What are the potential benefits or risks of intensive systolic blood pressure lowering in individuals with a low diastolic blood pressure? Well, the final paper today tells us. In this study by first and corresponding author, Dr. Beddhu, and colleagues from Salt Lake City in Utah, a post hoc analysis of the SPRINT trial was performed. Remember that the SPRINT trial was a randomized control trial that compared the effects of intensive versus standard systolic blood pressure control in older adults with high blood pressure at increased risk of cardiovascular disease. The current post hoc analysis examined whether the effects of the systolic blood pressure intervention differed by baseline diastolic blood pressure.
The authors found that there were U‐shaped relationships of baseline diastolic blood pressure with the primary cardiovascular disease outcome and all‐cause death. However, the beneficial effects of intensive systolic blood pressure lowering on the primary cardiovascular disease outcome in all‐cause death were not modified by baseline level of diastolic blood pressure.
Increased risk of kidney events and serious adverse effects of the intervention were consistent across baseline diastolic blood pressure quintals. Therefore, there was no evidence that the benefit of intensive systolic blood pressure lowering differed by baseline diastolic blood pressure levels.
These findings suggest that the reason for the observed associations of worse outcomes with lower diastolic blood pressure was due to underlying processes, such as increased arterial stiffness that lead to a decline in diastolic blood pressure, rather than the level of diastolic blood pressure per se. Furthermore, lower levels of diastolic blood pressure within the ranges examined in SPRINT, should not be an impediment to intensive treatment of hypertension, at least in those without diabetes or stroke.
Well, that wraps it up for our summaries. Now for our feature discussion. The ACC/AHA guidelines for the management of hypertension in adults has really been a hot topic. Just published this year, and it really updates the seventh JNC report, which was published in 2003. Well, today's feature paper deals directly with a comparison of these two guidelines and how it may impact our practice.
I'm so pleased to have with us today the first and corresponding author of this paper, Dr. Paul Muntner, from University of Alabama at Birmingham and a very familiar wonderful voice, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome!
Dr. Paul Muntner: Hi. Thank you for having me.
Dr. Wanpen Vongpatanasin: Hi, Carolyn.
Dr. Carolyn Lam: Paul, could I ask for you to start by painting the differences between the 2017 ACC/AHA guidelines and the JNC 7? We understand you were part of writing the guidelines, so who better than to draw our attention to the main differences.
Dr. Paul Muntner: I think that the new guideline, the ACC/AHA guideline, it was fairly comprehensive included 15 chapters, so there's a lot of new information in the guideline, everything from a dedicated section on the measurement of blood pressure to aspects of patient care.
The manuscripts featured in "Circulation" in this issue is focused on, in the past, there's different blood pressure thresholds in the guideline for defining hypertension, as well as recommendations for antihypertensive medication treatments, as well as blood pressure goals.
As everyone probably knows form JNC 7, hypertension was defined as a systolic blood pressure greater than or equal to 140 mmHg and/or a diastolic blood pressure greater than or equal to 90 mmHg, versus in the 2017 ACC/AHA guideline, these were lowered to 130/80.
In terms of treatment recommendations, there's really a fundamental shift with the new guideline, where the new guideline focuses not just on blood pressure levels, but also on overall cardiovascular disease risk. So going to the new guideline, people are recommended treatment if their blood pressure is above 140/90 but also there's a group with a blood pressure in the 130 to 139 range for systolic blood pressure, of 80 to 89 mmHg for diastolic blood pressure, who are recommended treatment if they have a high cardiovascular disease risk.
Finally, I'll just finish with this last note is that blood pressure control for people taking antihypertensive medication is now 130/80 so a goal blood pressure for people taking antihypertensive medication is systolic blood pressure less than 130 mmHg, and a diastolic blood pressure less than 80 mmHg.
Dr. Carolyn Lam: That was beautifully explained. Paul, I just really loved table 1 of your paper, and I want to refer our audience to it. It so nicely summarizes the differences between the 2017 guidelines and JNC 7. At risk of oversimplifying, when you compare the two in this approach, it's sort of comparing using a cardiovascular risk in conjunction with blood pressure‐type approach with a blood pressureonly number approach, isn't it?
Dr. Paul Muntner: Right. I think that's a key important piece of the new guideline and really CVD risk is used in conjunction with blood pressure levels to guide the recommendation to initiate antihypertensive medication. This decision was based on a wide variety of data from randomized trials, observational studies, as well as simulation or economic analyses that consistently showed the benefits of considering an individual's overall cardiovascular disease risk and providing effective and efficient treatment for lowering blood pressure.
Dr. Carolyn Lam: Right. And you analyzed the impact of this in the NHANES data in today's paper. Could you tell us a bit more about that?
Dr. Paul Muntner: The U.S. National Health and Nutrition Examination Survey, or NHANES, provides an opportunity to generate national representative point estimates on the prevalence of hypertension and treatment recommendations. So we're able to use data on about 9500 U.S. adults. Each person came in for a clinic examination where they had their blood pressure measured three times, and they were asked about their use of antihypertensive medication. What we found was the prevalence of hypertension, or the percentage of U.S. adults with hypertension according to the new guideline, is about 46%, which compares to 32% according to the JNC 7 guideline, so really a big increase in the prevalence of hypertension of about 14%. However, by using the combination of risk and blood pressure, we're not recommending treatment for everyone with hypertension but rather people with hypertension with very high blood pressure as well as those at high cardiovascular disease risk.
So antihypertensive treatment, pharmacological antihypertensive treatment, is now being recommended for about 36% of U.S. adults compared to 34% of U.S. adults according to JNC 7. The rest of the people with hypertension are recommended nonpharmacological therapies; exercise, diet, alcohol reduction, weight loss for people who are overweight and obese.
Really, it's an opportunity to treat people with pharmacological therapy if they're high risk. Then for people who aren't high risk, there's an opportunity for nonpharmacological therapies, so they can, hopefully, prevent the need for further treatment.
Overall, this equates to about 103 million U.S. adults with hypertension, so it's a very large number. However, only about 82 million of these individuals are recommended pharmacological antihypertensive treatment, so there's a big portion of the U.S. population who have hypertension, have high blood pressure, yet we think would benefit from nonpharmacological therapy.
Dr. Carolyn Lam: Wanpen, could I get you to chime in on what you think of the clinical implications of today's paper?
Dr. Wanpen Vongpatanasin: I think that this paper gives us at least reassurance that although we have 30 million more people with hypertension now, not all of them have to be started on medication right away. But it also put an emphasis on cardiovascular risk assessment, which we as the cardiologist are already doing this on a regular basis. It is a major step forward to incorporate cardiovascular risks as another way to gauge how people should be treated intensively, which we like that aspect of it.
Dr. Carolyn Lam: I agree. I think it's reassuring because most people think, "Oh, my goodness. We have got so much more hypertensives to manage." But then it tells us that a restratified approach really keeps it manageable, I suppose. But Wanpen, did you have some specific concerns or questions?
Dr. Wanpen Vongpatanasin: We look at the people who by JNC 7 calls prehypertension, which it's now some of them turn out to be a stage 1 hypertension. The question I have for Paul is that even though guidelines call for nonpharmacologic treatment first, the guidelines said give a try from three to six months, but what happens after that if they're still not reaching the goal?
Would people on the guidelines propose drug treatment eventually because, as you know, nonpharmacology treatment is easier said than done. Even though you might be able to tackle some aspect of it, but I doubt you can tackle everything; exercise, diet, sodium, weight loss all at the same time in a three to six month period.
Dr. Paul Muntner: It's a great question and it's something that the guidelines really spent a lot of time considering and reviewing the evidence. First, what the recommendation is that we recommend nonpharmacological intervention as you mentioned and the re‐evaluation. If the person's blood pressure remains in the stage 1 hypertension range and they're not a high cardiovascular disease risk, then they are recommended to continue attempts at the nonpharmacological interventions.
I've been asked several times since the guideline has been published, "What, are we supposed to just wait until people become high risk?" And my viewpoint on this is, it's hard enough to get people to adhere to their medications currently, let's be judicious about this, focus on the high‐risk people, and maybe if we can communicate with people that have high‐risk for cardiovascular disease, we can work with patients to improve medication adherence and really focus on the low‐risk people in preventing the need for lifelong therapy.
Dr. Wanpen Vongpatanasin: That's great, I think that's really helpful in clarifying this point. Because even if you say that 30 million doesn't need to be started on the drug right away, that eventually have to be started on drug in six months, I think that doesn't really give us a reassurance but, obviously, we still have to continue to
work on these patients who are on the fence of needing pharmacology intervention.
Dr. Paul Muntner: Right. I think what's interesting here is a lot of people since the guideline has been published have said to me, "Now this is done." I said, "No. Now we're really just starting. Now is the most important part of the guideline, which is implementation." And how are we going to implement the guideline, which, as we were just discussing, isn't just about initiating pharmacological therapy, but it's also about the nonpharmacological therapies as well as medication adherence and all these other issues that are in the guideline, proper measurement of blood pressure, etc.
I think that now is going to be the most important time to really have a big impact on our patients' lives by really using the evidence and now that it's in the guideline, we're using the evidence to direct treatment appropriately.
Dr. Carolyn Lam: Indeed, Paul. Just one thing. Along the lines of implementation, how about the issue of the lower target BP, to treat to? What did your study from NHANES show about that, numbers reaching targets, and do you see that as an issue?
Dr. Paul Muntner: It's an interesting question because the findings from our study found that it's currently over half of U.S. adults according to the new guideline, over half of U.S. adults on antihypertensive medication, have blood pressure above the goal in the new guideline. So in our study, 53% of U.S. adults taking antihypertensive medication had a blood pressure above 130/80. This represents an increase from the JNC 7 guideline of people with blood pressure above 140/90, of course, of about 14.4%. According to our estimates, there are about 8 million U.S. adults who are going to be recommended more intensive antihypertensive medication.
The blood pressure of less than 130/80 is a uniform goal for all people taking antihypertensive medication. This comes from several meta‐analyses that have consistently shown the cardiovascular and mortality risk reduction associated with achieving a blood pressure of less than 130/80. I think there's very firm evidence to stand on.
One interesting thing from the guidelines, it's in one of the tables, and I think it's a very important point to make, is that a lot of people who have above goal blood pressure, according to the new guideline, they're only taking one or two classes of antihypertensive medication. The vast majority of them are not taking multiple classes of antihypertensive medication, so we feel that these therapies can be optimized and we're not going to be pushing people into antihypertensive polypharmacy but rather they can receive substantial risk reductions without really giving them too many additional pills.
Dr. Carolyn Lam: Wow. Really about implementation. Wanpen, did you have any other comments before we close?
Dr. Wanpen Vongpatanasin: Yes, I think that is really interesting to see also with these guidelines how is this going to be embraced to the rest of the world. Actually, prior to this guideline, at least hypertension control rate in the U.S. is better than most countries, European countries, as well as in Asia. But now even lowering the bar, we use the same criteria for the rest of the world, that would be a lot worse control rate than now. I think it will be challenging, not only in this country but throughout the world.
Dr. Paul Muntner: That's a great point. Obviously, these guidelines are U.S. guidelines, however, new European guidelines should be coming out in 2018, is what I've heard. I think that even though these guidelines were developed by the American College of Cardiology and the American Heart Association, the data that we're using really comes from worldwide evidence. The evidence didn't stop at the borders. A lot of the evidence that was used in choosing the blood pressure levels to define hypertension, the blood pressure levels to recommend pharmacological interventions, as well as the blood pressure goals do come from other countries. A lot of data from Asia, Europe, Australia, so I think that the data used in these guidelines should be generalized when it's out of the United States.
I think there may be challenges with implementing these guidelines in different settings, and, obviously, a lot of things will have to be tailored to where they will be implemented. However, the overall goal is to reduce the burden of cardiovascular disease and renal disease related to hypertension and, hopefully, that can be a worldwide goal.
Dr. Carolyn Lam: What a great reminder. It is worldwide data, worldwide evidence for a worldwide problem. Well, listeners, you heard it right here on "Circulation on the Run." Thank you so much for joining us today and don't forget to tune in again next week.
Dr Carolyn Lam: (Music playing)...Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and his editors I'm Dr. Carolyn Lam associate editor from the National Heart Center and Duke National University of Singapore. Today is one of my favorite podcasts as always because it is the fellows in training podcast.
This is where the center stage and we’re so pleased to have two brilliant fellows with us today. Dr. Tom Ford from University of Glasgow and Dr. Kevin Shah from UCLA and of course joining us today as well is our editor for digital strategies, Dr. Amit Khera. Hi everyone.
Dr Kevin Shah: Hi Carolyn.
Dr Carolyn Lam: Hey Kevin. Since you're there in wonderful bright and sunny California and going to talk about one of my favorite topics HFpEF. Could you please tell yourself and then please tell us also about the paper you chose?
Dr Kevin Shah: I am a third-year general cardiology fellow at UCLA. I have a career interest in advanced heart failure and transplant cardiology. I'm going to be doing a one-year fellowship in that next year at Cedars Sinai in Los Angeles.
The article that I picked to discuss was the Reduced LAP Heart Failure I Trial and it was specifically testing a novel device in a small cohort of patients to see if the creation of intraatrial septal connection in patients with HFpEF can improve their filling pressures as well as their symptoms with exercise.
Dr Carolyn Lam: Yeah so Kevin what about this paper stood out to you?
Dr Kevin Shah: The two biggest things that were impressive to me and that really stood out were 1) this concept that keeps coming up more frequently in contemporary research, which is the idea of using a sham trial. Specifically, in this study they did perform a one-to-one randomized trial. With one of the arms, if they did not receive the actual device, they underwent a complete sham undertaking including headphones in music and blind folding the patient who were not sure if they received the device or not.
I think it's an important concept because it does speak to the placebo aspect of procedures. It tries to really control for that when a patient doesn't know if they received a novel device, and we can still test them and see how they feel after-the-fact. I think that's an important strategy in modern trials.
Dr Carolyn Lam: Kevin, that is such a good point and really quite novel too. So we've discussed this paper before but not quite the aspect that you point out and I couldn't agree more. The REDUCED LAP follows its pilot study results, which was open label single arm right published in the Lancet. So this is a very reassuring results since knowledge sham controlled.
I suppose the lesson comes from other device trials that were sham controlled and then gave maybe slightly different results), right when we're talking about the renal innervation trials before. But you said that there were two points that stood out to you so what was the second?
Dr Kevin Shah: The other will also be endpoints and what they chose to target. It was a small trial but I think it's important in a disease state such as HFpEF to select specific endpoint that really reflect the physiology and pathophysiology and the authors should be commended. I think for selecting primary and secondary endpoint that will primarily focus on hemodynamics as well as symptomatic relief.
I know that they are working toward their stage 3 trial and I think in the vein selection of these type of endpoint. Probably more so than endpoints such as mortality are going to favor this disease state in terms of trying to carve out some sort of therapy that actually make patients feel better.
Dr Carolyn Lam: Great great points. For me to just knowing that a hemodynamic endpoint makes sense, because if we look at the Champion Trial and look at the HFpEF subgroup of the champion trial it also seems to show that if people just treated patients with HFpEF according to a hemodynamic guide and in the champion trial that was the pulmonary artery pressure reading. That actually appeared to keep patients out of hospital. And I have to agree with you that sometimes we forget that has HFpEF is about pulmonary congestion and that the end of the day it is a hemodynamic disease. It is heart failure in other words.
Kevin one last thing what do you think about using this sort of strategy in HFREF?
Dr Kevin Shah: That's a good question I can't say I know at least this device has been studied in this trial like you mentioned in one prior trial that was not randomized. I'm sure it's been at least investigated. I can't say I've seen any literature on it. I like to think that it would make some sense from a physiological standpoint, but I don't know if anyone is actually gone to the task of seeing how the device performs in HFREF.
Dr Carolyn Lam: As I said I think at the end of the day I think they're all part of the same heart failure family. And left atrial hyper tension is kind of the final common pathway. So I agree with you that maybe it's worth considering in HFREF too, but then on the other hand of course and have friends HFREF you've got all this great medical therapy. Well Kevin I really, really appreciate your selection. May I now switch over to Tom? Tom would you like to tell us a little bit about yourself ,and which paper you chose.
Dr Tom Ford: Sure thing my name is Tom Ford. I'm very interested in interventional cardiology, and my career path has been a bit unusual because I did my basic cardiology training in Sydney. And then from there I got a great opportunity to pursue a research degree, a PhD, which I’m currently halfway through. That's what Prof. Colin Berry and Prof. Keith Oldroyd here in Glasgow and that’s a British Heart Foundation Fellowship so it's a great opportunity. I went out for recent WOSCOPS Trial from posthoc analysis. In this is a really interesting study a lot of the readers and listeners will be familiar with the original publication. It was actually published 22 years ago. Published in the New England Journal of Medicine.
The WOSCOPS was a landmark trial that looked at statins for primary prevention. And this is the present analysis that looked at just over 2500 Mills with LDL-cholesterol above hundred and 190 mg/dL. So for those of you listeners in the UK 4.5 mmol per liter so quite the high LDL. They looked at these gentlemen without pre-existing vascular disease. There's guideline recommendation for this group but not much evidence. And what they showed was over a five-year period of follow-up that there was a reduction in cardiovascular death and all cause mortality with this treatment. That wasn't just for the period of the trial because of the study design we were able to get a legacy effect which was noted over 20 years of follow-up. So in summary a trial will show the benefits of statins and primary prevention mortality benefit for people without very high LDL to start with.
Dr Carolyn Lam: Carolyn awesome Tom. I love that she began saying that your into interventional cardiology but you chose an article about medical therapy and the importance of it, the statins. I fully agree with you. Amit did you have some for Tom?
Dr Amit Khera: Sure. First I want to commend you both I don't think you did this on purpose but Carolyn's heart failure HFpEF expert. I'm sure she loved the other trial and I'm a preventative cardiologists. So we certainly love you choices this week. Tom, thanks for the summary. It's an important article and one that we did highlight on the previous podcasts. You know there's so many things to talk about but certainly remind you that we have great data sets around that can answer unique questions that maybe are unanswerable today and I think this is an example of that.
Can you speak to this ideal of pulling an old 22-year-old child as you mentioned and how that provides insights and kind of as a PhD student ways to think about ways to be creative and research?
Dr Tom Ford: One of the reasons I chose this child because it's close to my heart looking at a population in the west of Scotland. Sadly over here we've got too high prevalence of cardiovascular morbidity and mortality. So what this trial speaks to is the benefits of a really carefully planned procedure. I mean these were outstanding researchers that thought ahead of their time, and as a result of their analysis. Over two decades later they are still multiple publications and there's kind of open approach where there's different research groups that have used this data set for number of different outputs.
I think a real outstanding example of what can be done with well-planned study.
Dr Amit Khera: Sounds like were in agreement about how to use a fruitful database and continue to learn from it as time goes on. The thing about this as you pointed out is the LDL above 190 component and what the authors say this is sort of the first clinical trial evidence for treatment. In your view, does this change practices or guidelines? Was this already what we were doing? Does this support what we were already doing, or how does this impact clinical care and guidelines currently?
Dr Tom Ford: I think it's a good point. People will say we were doing this anyways. I think now it's going to be helpful and practical inside the clinic. If you can say to a patient well actually look I know we’re asking you to take this tablet you've not actually had an event but, ultimately we know the natural history of people in your position may well be unfortunately that they’re high-risk, and that there is actually a mortality benefit to be had from these tablets that you don't necessarily want to take but definitely the benefit’s there.
Dr Amit Khera: The neat part as you pointed out also was dual components when they're looking at the on treatments during the trial. We see an improvement in events. What the WOSCOPS investigators have done so creatively over the years is this idea of a legacy affect.
The long-term impact in preventive cardiology – certainly a space for where were going was just looking beyond the short-term. There's obviously problems there too because that was not pre specified people were necessarily on assigned therapies. Tell me when you look at this long-term legacy effect what does that mean to you? How does that add be it the way you counsel patients or how you think about this treatment in patients with high LDL?
Dr Tom Ford: The effect of the statin assumes that all the patients are actually taking the drug. I think there has to be an analysis of these patients in this trial and obviously not everyone was compliant. So I think we can maybe extraopolate that for the that there might be in even bigger effect for those patients that were actually taking the drug. And I think if you were to take it for five year period. Obviously we don't know what happens after that. What we do know is the solid mortality data.
What it speaks to me is that if you take the drug and you are at high risk to begin with then potentially it's plaque stabilization, the pleiotrophic effects of statins that we know are beneficial and the hard endpoints are definitely reduced. That persists over 20 years of follow-up. So I think that’s really a great victory for preventive cardiology as you said.
Dr Amit Khera: That's a great point about biasing towards the know when you have people crossing over and that this may be conservative of what was seeing in the long term. I think that's a really important point. One last question for you. The West of Scotland trial - generations have changed and back then obviously part of it was trial design but LDLs on average were higher. The median or mean in the group was around 192.
If you look when they look above or below that 190. The people below were 178 or so - still pretty high LDL. So it does beg the question you know we have this paradigm of LDL above 190 should be treated regardless. You wonder if that should be 160 or whether the number should be lower. What are your thoughts about that?
Dr Tom Ford: I agree with you. I think it's always a challenge to kinda pass off dichotomous endpoints when you’ve got continuous variable like LDL. It's just a continuum of risk and divided using the figure 190 in the study. In fact the patients with LDL less than 190 they couldn't show statistically significant reductions in all cause mortality. But I think it's again personalization of meds and we may have to discuss the risk with individual patient.
Ultimately we do have to have a firm conclusion. I think in this study the data is quite clear that 190 does seem to be quite robust as the predictor who's gonna get the most benefit.
Dr Amit Khera: Listen I think protection article that you pointed out was close to home and you certainly discuss it very well and provided lots of important insights. And again I think it was an excellent choice and one that was really highlighted in the media as well. I think there was a broad allure to this article. If we make change gears now little bit we've heard about the science part know we want to talk about what it means to be a fellow in training.
I just want to say on behalf Circulation also speak for myself. It's so important for us to involve fellows in training into our activities and you're one of our major targets in terms of impact and goals for the journal. We're so delighted to do this twice a year and were always thinking about other ways we can get FITs involved. I mentioned just a couple of things the American Heart Association has of fellows in training program where people can sign up for free and get online access to the journal.
So I hope all fellows are taking part in that. We're starting a new initiative called FAVES where just like you both submitted articles of interest of the fellows can do the same. On Fridays we’ll post those on social media so these are a few ways that were getting FITS more involved and we really hope to continue that. Let me start by maybe asking Kevin to have a chat with you as much.
Kevin in terms of journals there's some me now we're getting inundated with information. I think that's a good thing. How do you consume the medical literature? There's old print journals; there's the online journal; there's a table of contents your social media tell us a little bit about how you consume the medical literature.
Dr Kevin Shah: I agree. We’re kinda getting to a space where now the amount of information that's coming out is tremendous. I think that finding a strategy to help filter out what appeals to your clinical and research interest is becoming more challenging. For me I'll say print journals are slowly kind of falling off. I don't subscribe to too many of them but they still do come to my doorstep. The main way that I would say I'm getting access to or at least becoming aware of articles that are kinda relevant to where I am in my training and what I'm doing is the social media. Some primarily at least for me is Twitter.
I'll say it's a helpful tool and that I can follow a group of individuals that have a similar professional interest as me and you can almost always rely on the fact that somebody will post an article that becomes relevant to a common interest. So between sharing on social media I think that's the primary way that I'm really catching my eyes to a major journal articles.
Aside from that I still subscribe by email to a couple larger journals and see their weekly or biweekly updates about what's being published. And the last at least in my institution our division chief Dr. Gregg Fonarow; he goes out of his way to send to the fellows and faculty new articles that are kind of pertinent to clinical practice. Which is very helpful for us.
Dr Amit Khera: That's so helpful and you know everyone has their own way of consuming the literature but I certainly appreciate your interest in social media. You know there are some luddites out there that think of it literally as just social and it really has a professional bent to it. Well rapidly you can figure out the most cutting-edge important articles in your field so I certainly appreciate your comments. Tom let me ask you now, at your stage of training. You've had an interesting training path as you said you sort of started as an interventional cardiologist and now you are doing a PhD. There so many different articles in Circulation. We have original research, state-of-the-art reviews. We have these opinion pieces and on my minds and different ones. Tell us a little bit about what articles appeal to you and which other novel formats maybe you'd be interested in seeing.
Dr Tom Ford: I think that the original research articles are great if it's in your chosen field. Obviously this is where we're going to a great deal of detail on specific topics but outside of that I think that the review articles are great form if it's something that’s a common clinical topic to kinda brush up on. Your On My Mind section I think is great because it gives you an opportunity to hear from key opinion leaders in the field. I think it was Morton Kern discussing invasive coronary physiological assessment.
So I think there’s different types of articles that can be quite helpful. To start with the original research ones. I’ll skim through the contents. I'll tend not to read the details if it's not in my chosen field.
Dr Amit Khera: Yeah great point. Obviously they are topical depending on what your main interest area and we always say reading around your field to get a broader perspective in cardiovascular medicine. I think you hit on the point about on my mind ones. We really want people be able to free associate and original article are sometimes more stiff and linear. So we really like those pieces as well. Carolyn we’ll give you second set ask a question or two to for today.
Dr Carolyn Lam: Actually Amit I just wanted to comment. Isn't it so encouraging to hear the variety of approaches and you know Circulation has enough that we’re meeting various different needs. I really wanted to take the opportunity to thank you as editor of digital strategies for just doing so many of these initiatives for Circulation. I think it’s just incredibly important for the Journal to keep up with the times in that sense. Amit, may I be cheeky ask you how do you consume the literature?
Dr Amit Khera: Carefully. You know the neat part in being on the editorial board of Circulation and one of the associate editors we get to see so many amazing papers that come through and I think obviously I get to see, essentially and also my digital strategies role I essentially see every paper that comes through that we end up publishing.
Obviously I get wide exposure to Circulation but obviously beyond that I get all the e-Table of Contents for almost every major cardiovascular Journal. Certainly looking at social media and I tend to find hotspots interventions and other areas and podcasts – let’s not forget podcasts. So there's some great podcasts out there. I know of one.
Dr Carolyn Lam: Oh I love it. All right but just one last question for both Tom and Kevin from me. I honestly would love to know what do you think we could do better or what would you like to see more from Circulation?
Dr Kevin Shah: I guess the question I have for Circulation is there any role or have fellows ever gotten involved in the review process for articles?
Dr Amit Khera: Listen that's really important because you learn a lot from doing that and obviously in institutions similar to ours where if you asked to review a paper you have a fellow contribute. I think you might be asking something sort of more formal and systematic with Circulation. I will say that one of our Circulation journals I believe it's Circ Heart Failure or Quality and Outcomes I'll check. It has a formal program where fellows essentially can be assistant editors if you will.
We have our cardiology fellows here at UT Southwestern involved in that process. And I think part of that process is just an IT issue of how to maintain confidentiality of our papers for our authors but yet still let fellows contribute meaningfully. And also timing because you know papers have cycles where you decide if he should go out for review but it'll come back and you never know when that happens you have to make the next level decision.
Then it goes potentially to a meeting and so being able to make sure that fellows can participate at every level, cause that's where the value comes in. We are certainly interested in learning from what our other Circulation of family journals is doing in that space and definitely an area that we've thought about some fellows contribute but need to do more.
Dr Carolyn Lam: And Tom how about you?
Dr Tom Ford: Just picking up on your point on what the sister journals are doing you know I see the Outcomes Journal is looking at more visual abstracts and video abstracts. You know I think it's really important that we increase the efficiency of learning. What's your take on that?
Dr Carolyn Lam: That is the greatest suggestion. I like first of all your phrase of increasing the efficiency of learning. Amit, I'm going to turf it to you again.
Dr Amit Khera: I'll tell you what's amazing you know when I started this role a bit ago. Both of you are obviously contributing to research and everyone on this call is and I think we forget that in the social media space we don't have a lot of data. Some things sound good or feel good. At Circulation my predecessor Carolyn Fox did a randomized trial called intention to tweet if you haven't read it. And there's a follow-up to that that was published. And essentially by randomizing articles to social media or not there was no increase in the views if you will of the article.
There's always limitations to every study but the point is, as you think about novel offerings, something we struggle or something we’ve seen as an opportunity, what works we tried a few things we tried certain videos and we look at what's the uptake and interestingly some things we thought that would be widely of interest really weren’t. Then other avenues we’ve tried have been.
I love what you said, and as Carolyn also felt, the idea of efficiency of learning. I think we need to do frankly in the social media and journal spaces is to continue not just to innovate but to study and figure out what works and what doesn't to help different learners.
Dr Carolyn Lam: (Music playing)....Thank you very much audience for listening today as well. You've been listening to Circulation on the Run. Don't forget to tune in again next week.
Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke-National University of Singapore. 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.
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.
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.
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.