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 this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries.
The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis.
The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension.
Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets?
Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features.
However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies.
The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients.
Well, that wraps it up for our summaries. Now for our feature discussion.
When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic.
Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper?
Dr Maxim Mulder: Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started.
So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data.
So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice.
Dr Carolyn Lam: Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael?
Dr Micheal Hill: I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data.
I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging.
Dr Carolyn Lam: True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree?
Dr Micheal Hill: Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging.
Dr Carolyn Lam: Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands?
Dr Graeme Hankey: I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data.
We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they’re assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue.
So, although, generally time is an important prognosticator as we've learned here, there are probably other factors that need to be considered and accounted for. But this certainly takes us a step forward, and, in answer to your question, I think we have confidence in its generalizability.
Dr Carolyn Lam: Thank you Graeme. Maxim, in line with that, are there any next steps you plan?
Dr Maxim Mulder: In light of the most recent trials, the DAWN and DEFUSE 3 trial about 6 to 25-hour, 24-hour window, I think that both of the trials are very exciting, and they shine a new light into a new set of patients that are still able to offer a great benefit intra-arterial treatment. In my opinion, the most important thing, especially in those two trials, those are highly selective patients, especially selected on all the extra imaging parameters, and I guess that there's a whole larger population that could still benefit in this time window and that's also one of the things we're currently studying in one of our new trials in the Netherlands in the MR CLEAN-LATE trial, and that is randomizing patients who are having a large vascular occlusion 6 to 24 hours, and the only extra criteria they should meet is they should have at least a little bit of collateral circulation on the ischemic brain side.
Dr Carolyn Lam: Michael and Graeme, what do you think are the priorities for next steps in research.
Dr Micheal Hill: I guess overall in the field, I don't think there's any doubt that faster treatment is better. What we need to do across the world is make sure that everybody's receiving it on a system-wide basis. Right? I think there needs to be a lot of more careful work done on getting systems of care in place to make sure that patients are getting the treatment they can get. We have very many weaknesses. Some are related to lack of accreditation. Some are related to the resources required to get people treated quickly. Some are related to continuing resistance in some specialties to even giving intravenous thrombolytic drugs. So, I think faster treatment in general for acute stroke is a theme; it's not just limited to endovascular treatment. It's treatment for patients for intravenous thrombolysis. It's also actually true for TIA and minor stroke. We've had recent data on fast antiplatelet therapy, so, it's not an emergency in the same way in terms of minutes, but it's still a general theme of acute stroke care.
We need to be like the Ferraris and the Formula One, right? And get ourselves moving. That's a big challenge for people. Right? It's a big stress on systems. But, I think there are other examples in medicine. We've seen this evolution in acute coronary care, and we've seen the evolution in acute trauma care. In many ways, the next things that need to really continue to happen are publications like this and getting the message out that people need to start changing their mind. The biggest thing that I find when I talk to people or talk at meetings or talk to administrators is that they say, "Well, we can't do this many CTs that fast. We can't respond that fast." And the answer is actually that you can't change the biology of the disease, so if you decide you wanna treat stroke patients, you better figure out how to change your systems. It's a question of will here rather than trying to bend the disease to the system.
Dr Carolyn Lam: Wonderfully put. Can't change the biology so we better change the systems. How about you, Graeme? Any last words?
Dr Graeme Hankey: Just to concur with Michael’s comments there and Max's underlying theme that time is very important. And as Michael alludes to, it's not just acute ischemic stroke due to large vascular disease, it's also acute intracerebral hemorrhage. We're learning now really if we're gonna have an effect in the bleeding brain probably we have to do that within the first three hours and maybe not be waiting so late. And as Michael alludes to, someone with a minor ischemic stroke who's had a hot volcano gone off in their neck, as you know, ruptured atherosclerotic plaque, it's like those volcanoes in Hawaii, they're gonna keep going off again. And the risk is 5% in the next two days and 10% in the next week. So, a TIA and a mild ischemic stroke, it is a medical emergency to find the cause and to get it treated, and that's why the synopsis of this message from Max's study is that people, if they do avail themselves of acute assessment early, even if they don't have a large vessel occlusion causing an ischemic stroke, they may actually have their intracerebral hemorrhage treated quickly or, more evidence based at the moment, their TIA or mild ischemic stroke have the cause ascertained and treated emergently and reduce that early risk of recurrence should they survive.
Dr Carolyn Lam: Excellent points. Thank you so much, gentlemen. This has been an amazing podcast.
Thank you so much for joining us today. Don't forget to tune in again next week, listeners.
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 for the National Heart Center, and Duke National University of Singapore.
How do resuscitation teams at top-performing hospitals for in-hospital cardiac arrest actually succeed? Well, to learn how, you have to keep listening to the podcast, because we will be discussing this right after these summaries.
The first original paper this week tells us that recent developments in RNA amplification strategies may provide a unique opportunity to use small amounts of input RNA for genome wide-sequencing of single cells. Co-first authors, Dr Gladka and Molenaar, corresponding author, Dr van Rooij, and colleagues from Hubrecht Institute in Utrecht, the Netherlands, present a method to obtain high-quality RNA from digested cardiac tissue, from adult mice, for automated single-cell sequencing of both healthy and diseased hearts.
Based on differential gene expression, the authors were also able to identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cells subpopulations.
For example, they identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlated with known myofibroblast markers, in both mouse and human cardiac tissue. This paper raises the exciting possibility for new biology discovery using single-cell sequencing that can ultimately lead to the development of novel therapeutic strategies.
Myeloid-derived suppressor cells are a heterogeneous population of cells that expand in cancer, inflammation, and infection, and negatively regulate inflammation. However, their role in heart failure was unclear, at least until today's paper in this week's journal. Co-first authors Dr Zhou, Miao, and Yin, and co-corresponding authors, Dr Wang and Li, from Huazhong University of Science and Technology, measured the myeloid-derived suppressor cells by flow cytometry in heart failure patients and in mice with pressure overload–induced heart failure, using isoproterenol infusion or transverse aortic constriction.
They found that the proportion of myeloid-derived suppressor cells was linked to heart failure severity. Cardiac hypertrophy, dysfunction, and inflammation were exacerbated by depletion of myeloid-derived suppressor cells but alleviated by cell transfer. Monocytic myeloid-derived suppressor cells exerted an antihypertrophic effect on cardiomyocyte nitric oxide, but monocytic and granulocytic myeloid-derived suppressor cells displayed antihypertrophic and anti-inflammatory properties through interleukin 10.
Rapamycin increased accumulation of myeloid-derived suppressor cells by suppressing their differentiation, which in part mediated its cardioprotective mechanisms. Thus, these findings revealed a cardioprotective role from myeloid-derived suppressor cells in heart failure by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin 10 and nitric oxide. Pharmacological targeting of myeloid-derived suppressor cells by rapamycin constitutes a promising therapeutic strategy for heart failure.
In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL cholesterol and cardiovascular risk in patients with stable atherosclerotic disease. However, was the efficacy of evolocumab modified by baseline inflammatory risk?
While Dr Bohula from the TIMI Study Group and colleagues explored this question by examining the efficacy of evolocumab stratified by baseline high sensitivity CRP. They also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL concentrations. They found that the relative benefit of evolocumab for the prevention of adverse cardiovascular events was consistent, irrespective of baseline high sensitivity CRP. However, because patients with higher high sensitivity CRP levels had higher rates of adverse cardiovascular events, they also tended to experience greater absolute benefit with evolocumab.
In an analysis of baseline high sensitivity CRP in achieved LDL cholesterol, the authors found that at first cardiovascular event rates were independently associated with both LDL cholesterol and high sensitive CRP. Event rates were lowest in patients with the lowest hsCRP and LDL cholesterol, supporting the relevance of both inflammatory and residual cholesterol risk.
The next paper provides further evidence that residual inflammatory risk, as measured by on-treatment high sensitivity CRP, remains an important clinical issue in patients on combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from Brigham and Women's Hospital and colleagues, evaluated the residual inflammatory risk among patients participating in the SPIRE-1 and -2 cardiovascular outcome trials, who are receiving both statin therapy and the PCSK9 inhibitor bococizumab, according to on-treatment levels of high sensitivity CRP and LDL cholesterol measured 14 weeks after drug initiation.
They found that among high-risk stable outpatients treated with moderate or high-intensity statins and PCSK9 inhibition, roughly one in two had residual inflammatory risk defined by an on-treatment high sensitivity CRP level of 2 or more mg per liters, and roughly one in three had values above 3 mg per liter.
PCSK9 inhibition was associated with a 60% mean reduction in LDL cholesterol but little change in high sensitivity CRP. Levels of high sensitivity CRP above 3 mg per liter were associated with a 60% greater risk of future cardiovascular events, corresponding to a 3.6% annual event rate, even after accounting for on-treatment LDL cholesterol.
Thus, PCSK9 inhibition, added to statin therapy in stable outpatients, does not lower high sensitivity CRP. Persistent elevations of CRP is associated with future cardiovascular risk in these patients, even after low levels of LDL cholesterol are achieved. If corroborated, these data suggests that inflammation modulation may yet have a role in the primary and secondary prevention of cardiovascular disease when LDL cholesterol is already controlled. Well, that wraps it up for our summaries. Now, for our future discussion.
In-hospital cardiac arrests are common worldwide and they're so important because they represent opportunities for us to improve survival. Now, yet, overall rates of hospital survival after in-hospital cardiac arrests remain poor and there is substantial variation across facilities. This may be surprising because we all seem to follow or should follow the same ACLS algorithms across the world and yet, there are different outcomes.
How do resuscitation teams, at top performing hospitals, for in-hospital cardiac arrest, how do they succeed? Pleased to be discussing this with a real star team in today's podcast. We have first and corresponding author of our feature paper, Dr Brahmajee Nallamothu. We also have Dr Steven Kronick, who is the chair of the CPR committee and both are from University of Michigan Medical School. We also have Dr Sana Al-Khatib, who is a senior associate editor of Circ, from Duke University. So, welcome everyone! Let’s go straight into it. Maybe starting with you Brahmajee, could you tell us what inspired you to perform this study?
Dr Brahmajee Nallamothu Thank you, Carolyn, for giving us the opportunity to talk about this study. I'm an interventional cardiologist here at the University of Michigan and typically, this isn't an area that interventional cardiologists are really greatly involved with. I became interested because I also, at times, I round in the cardiac intensive care unit, and that's a place where a lot of patients often times end up after they've had an in-hospital cardiac arrest at our institution and what I've noticed over the years, is the variability in care that would be occurring out there, and then also lots of gaps in the literature.
Over a decade or so ago, I started partnering with a close friend and colleague, Paul Chan, from the Mid America Heart Institute and we started to do a series of studies on how in-hospital cardiac arrest care varies across institutions in the United States and we published a number of articles that have been in really high-profile journals over the last 10 years, but the problem has always been that even though we could describe really well what was happening, we had very little understanding of why it was happening or how certain hospitals were seeming to outperform others in this really challenging situation.
We wanted to dive a bit deeper into the questions and reasons behind top performers doing so well and that's what brought us on to doing this study.
Dr Carolyn Lam: Great. You want to tell us a little bit about it? It's really very different from the other CPR studies I've seen. Could you tell us about it and what you've found?
Dr Brahmajee Nallamothu: Sure, so in the broader framework, it's a qualitative study and what I mean by qualitative is, we didn't really collect data either through surveys or through outcome assessments. What we did was, we actually went out and talked to people.
The study though was really focused on what people call a mixed methods approach. We didn't just randomly talk to different hospitals, we actually focused on hospitals that were at the top-performing levels. We also focused on some hospitals that were non-top-performing as well, to get some contrast between the two and when I said we talked, we did this in a very systematic and pretty rigid way.
We always had four interviewers go out to nine hospitals. We split them up, so we had two content experts and then two methodologic experts in qualitive studies, and we started to interview a bunch of people. In fact, we interviewed almost 160 people across these nine hospitals.
We interviewed everyone from CEOs and hospital leadership, down to boots on the ground, including both clinical providers and even non-clinical providers, such as spiritual care, security. We tried to get this comprehensive view of what was actually happening during an in-hospital cardiac arrest across these nine hospitals, and really the results were quite fascinating to us.
For someone, like myself, that's been in this space for ten years, I tell people I learn more talking to these nine hospitals than I have in the last ten years of looking at numbers on a spreadsheet. I really started to understand, for the first time, what was really going on, how these hospitals were dealing with these challenging situations because there's no bigger emergency in a hospital, and Steve, who we're going to hear from, we talk about this, but Steve has a great line about how when an in-hospital cardiac arrest occurs, that patient automatically becomes the sickest person in an institution and yet, we haven't set up systems that really build on how to handle that in the most consistent and positive way.
Dr Carolyn Lam: Oh, my goodness, I just love that line! Now, you have to tell us, so what's the secret? What's the secret of the succeeding hospitals?
Dr Brahmajee Nallamothu: What we found in general was, that resuscitation teams at top-performing hospitals really demonstrated the following features. They had dedicated or designated resuscitation teams. They really included the participation of diverse disciplines as team members during the in-hospital cardiac arrest. There were really clear roles and responsibilities of the team members that were set up right from the front.
There was better communication and leadership, actually, during these events and finally, in the training aspect, one of the unique things we found was, the top-performing hospitals seem to have a high rate of in-depth mock codes, that they used as strategies for getting their clinicians ready for these events.
Dr Carolyn Lam: As you were speaking I was just thinking through the experiences of in-hospital cardiac arrests that I've encountered, and you're right. These elements, though we don't talk about them much, make a huge difference. Steve, I am so curious about your outlook. I mean you must have attended a kajillion CPRs as chair of the CPR committee. Tell us, what do you think is the take home message for clinicians and hospitals?
Dr Steven Kronick: My field is in emergency medicine and as chair of the CPR committee, I have responsibility of overseeing how we respond to cardiac arrests in our hospitals. I think that many institutions spend a lot of time and effort looking at in-hospital cardiac arrests are managed, and how to improve on it. We're able to use data to help compare ourselves to similar institutions, but beyond the bottom line of either ROSC or survival to discharge, we've most relied on process measures to figure out what we're doing.
We're essentially flying blind, or at least not flying in any sort of formation when we do that. I think that this study validates some of the operational aspects of the arrest response, for those centers who use those and can help other decide where they want to direct their efforts. I think a good example that Brahmajee brought up, is this distinction we found between the use of dedicated teams, designated teams, or not having any organized team, and the impact that has on survival.
The use of these teams can mean significant use of resources but showing that it's associated with better outcomes help provide support for that concept and for those centers who might already use one of those models, it helps them to steer their efforts to improving the delivery or the efficiency of that model.
Dr Carolyn Lam: Yeah, and indeed. Congratulations to both of you, Steve and Brahmajee. I do think that these are novel contemporary data, at least the first that I know of. Sana, you handle the paper and recognize this. Could you tell us a little about what you think are the novel and important aspects?
Dr Sana Al-Khatib: I really have been a fan of this paper from the get go and yes, it doesn't have the quantitative analysis that the statistical modeling, most of us are used to. It is a qualitative study, but I think that gives it strength. It makes it unique. This type of research, it can really only be effectively done through a qualitative study that really has all the important aspects of a good qualitative study, so I do want to congratulate them. Clearly, a lot of work went into this, and I appreciate all their efforts.
In terms of the main findings, some of us might look at this data and say, well it's not surprising that those are the characteristics, or the features, of the top performing hospitals, but I felt like it was great, in terms of how the data were presented. Encouraging hospitals to adopt this. Giving them almost like a checklist of what they need to be doing to improve the outcomes of their in-hospital cardiac arrests, in terms of ensuring that they have designated resuscitation teams.
The whole idea about diversity of participants in these arrests, and making sure everyone has a clear role and responsibility. The whole idea of making sure that somebody takes leadership and you have clear and very good communication among the different people who are doing this and great training. In fact, these people were doing in-depth mock codes. I think that spells it out very nicely and gives a lot of the hospitals, hopefully, action items that they can implement to improve the outcomes these patients. I love this paper.
Dr Carolyn Lam: Sana, I love the way you put that. Checklist, and you know what I was thinking as Brahmajee and Steve were talking earlier? I was thinking blueprint, almost, of the things that we should have. So Steve, could I ask your thoughts. I mean, are you going to put some of these things into practice in your own committee and how?
Dr Steven Kronick: There are a variety of things we can do. Some of these things are a pretty high-functioning place, but still looking at recommendations that have been laid out and how we help modify those things. Though the example is the roles that people play at an arrest. We can certainly improve on assigning those roles, how people work together as a team, and then also, getting to work more as a team, so that when they are called upon to perform those duties, they can do it in a more coordinated way.
Dr Carolyn Lam: How beautifully put. I'm going to steal a couple of minutes at the end of this podcast. I really have to because it's so rare to have Brahmajee on the line today and he's the Editor-in-Chief of Circ: Cardiovascular Quality and Outcomes. Brahmajee, could I ask you to say a few words to our worldwide audience about your journal?
Dr Brahmajee Nallamothu: We are a kind of daughter journal to Circulation. We are a bit more unique than the others, in the sense that we aren't disease or subspecialty focused. We deal with, broadly, the issues around outcomes research, health services research, quality of care research, and really health policy. We publish an issue once a month. We have a broad interest in things that are really relevant to the community around outcomes research and health services research.
I will say that I really appreciate this because of the worldwide audience and reach, one of the big issues we've been very interested in is expanding our reach, from the United States to other parts of the world, and in fact, last fall, we had a global health issue, which was well received, and we received papers from across the world.
In fact, every paper in that issue was a non-US-based paper, and it touched on a number of things from issues around healthcare utilization in Asia to demographics and disease registries in Africa, and it was a wonderful experience, so I think it's a journal that we're excited about.
It was first launched by Harlan Krumholz, who has set a high bar and standard for us, and I think that my editorial team, which has been fantastic, has continued with that work. We would love to see papers from your readers and your listeners from across the world and excited about what that journal is going to be doing in the next five years.
Dr Carolyn Lam: Oh wow! That's so cool! Well listeners, you heard it right here, first time on Circulation on the Run. Thank you so much 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. This week features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries.
The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women.
Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study.
The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter.
Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing.
The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression
and the ensuing increase in angiotensin II, which acted on smooth muscle cells
in the vessel walls to regulate basal activity and blood pressure in a circadian
fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen
in the perivascular adipose tissue resulted in a superdipper phenotype with
exacerbated hypotension during the resting phase. These findings imply that it
is possible that obesity could alter the perivascular adipose tissue peripheral
clock, thus promoting abnormal dipper phenotypes and increasing
cardiovascular risk. The results therefore inform the design of novel therapeutic
approaches for hypertension by targeting the perivascular adipose tissue
What is the net clinical benefit of oral anticoagulation for very elderly patients
with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding
authors, Dr Chen from Taipei Veterans General Hospital and Dr
Lip from University of Birmingham, addresses this question. These authors use a
nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and
intercerebral hemorrhage between patients with and without atrial fibrillation,
all aged 90 years and above, from 1996 to 2011, and they also compared
patients treated with warfarin and non-vitamin K antagonists oral
anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan.
They found that even among these very elderly patients aged 90 years and
above, atrial fibrillation was associated with an increased risk of ischemic stroke
compared to patients without atrial fibrillation. Warfarin use was associated
with a lower risk of ischemic stroke, with no difference in intercerebral
hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was
associated with a positive net clinical benefit compared to being untreated or to
antiplatelet therapy. Compared to warfarin, NOX were associated with a lower
risk of intracerebral hemorrhage, with no difference in the risk of ischemic
stroke. Thus, oral anticoagulation may still be considered for
thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX
being a favorable choice
The final paper provides insights into the mechanisms linking obesity and
cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from
Peking University Health Science Center and colleagues use a combination of
animal models and human adipose biopsies to characterize a new adipokine
named family with sequence similarity 19, member A5 or FAM19A5. This novel
adipokine was capable of inhibiting post injury neointoma information via
sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling.
Thus, down regulation of FAM19A5 during obesity and loss of its vascular
protective function may trigger cardiometabolic diseases.
Well, that wraps it up for our summaries. Now for our feature discussion.
I'm just so excited about today's feature discussion, because we're talking about
Circulation going global. And I am just absolutely delighted to have with us, our
Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior
Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you
start by telling us a little bit more about your vision for the global outreach of
Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global
journal with a global footprint. We have editors distributed around the world in
16 countries and 10 time zones. And importantly, those editors all have an
equivalent role at the leadership table. Part of the reason for this is because
cardiovascular disease is now, as we are all aware, a global scourge. There are
no more final frontiers for cardiovascular disease. That said, the manifestations
of cardiovascular disease differ in different parts of the world. In the developed
world, and the developing world, for example, the way cardiovascular disease
manifests itself can be very different. And at the same time, the way in which
the disorders are tackled are different. The way we tackle heart disease in the
West can be different than it is in the East, for example. And there are
important initiatives that have emerged in different pockets of the world, best
practices that we need to understand better. What can we all learn from the
way in which cardiovascular disease manifests itself around the world and it's
being addressed around the world?
Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in -
Chief and I heard you say this, I was just floored, because coming from
Singapore and all our listeners out there in Japan and China, we just really
appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit
more about this new initiative then for the journal.
Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from
Canada, who is a household name in the cardiovascular world, he and I cooked
up a scheme that Paul will describe, where we will reach out on a regular basis
for insights from various different countries, ultimately, circling the globe
progressively over time. And I will defer to Paul to tell us more about the
Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but
still believing that you can teach an old dog new tricks, I would point out that
Circulation is almost 70 years old, and it has staying power. And one of the
reasons that it has staying power is because it is capable of reinventing itself,
and so I was attracted to help out again, from the editorial process, given Joe's
vision and leadership and the excitement around the reinvention that you've
described, to get involved with this initiative. And I was inspired, of course, by
the fact that those of us who do clinical trials appreciate that a lot of different
ideas, a lot of different cultures and perspectives are brought to a collaborative
table. And I'm thinking back now, Carolyn to three years ago, when you and I
first met enjoying courses as part of a trial in heart failure, which involves 43
countries, 800 sites, it will be 5000 patients centers, we've traveled separately
and together around the world, convincing people that there are unmet needs
in heart failure and other parts of cardiovascular disease, we learned that the
approach to standard of care, the rigor which is applied, the exquisite
sensitivities around differences that are meaningful, and the tricks that some
investigators and countries use that we can all I think, learn from has been very
So I think in this initiative, we want to have thought leaders. And we've already I
think, commenced and have two outstanding leaders from Japan and India to
come forward in the first two quarters of this initiative. Tell us about the
regional epidemiologic features, cardiovascular disease in their regions, what
the most important challenges are, what their best practices are, that you're
alluded to, who provides cardiovascular care and what the impediments are to
progressing because we think if we listen and learn as essentially knowledge
brokers, because welcome to Circulation, we can facilitate raising the level of all
of the boats in the water and potentially make new partnerships and do a better
job. So I'm excited about this. I'm delighted that Joe was receptive and really
look forward to working with him and some of these terrific people around the
world, you included who brings such a unique and important perspective from
which we can all learn.
Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International
knowledge brokers, that's what we hope to be. Isn't that fabulous, just an
opportunity to learn from each other, everybody having stuff to bring to the
table? Tell us a bit more though, what are you looking for in these papers?
Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic.
We're going to allow diversity of approaches. We're going to invite a thought
leader and hope that that thought leader might invite one or two others, we
want to limit it to three co-authors. We want obviously some insights into how
cardiovascular health professionals are being trained, what research
infrastructure exists, and how they access the literature, how do they read
Circulation, how do they read other journals, and are there collaborative ideas
that they've developed to their neighbors to the East and West that may be
could be broadened? Are there unmet needs that they've indicated similar or
different from those in Western Europe, South America? We've got about seven
or eight points of light that we hope to illuminate in the course of this exercise.
And the prospectus that's laid out in an editorial that Joe and I collaborated on
that I believe, Joe, is going to come out in early July.
Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just
the opposite of a formulaic, cookie cutter approach. We want to leverage the
beautiful diversity of our world. The different approaches that people take to
attack this scourge that is keeping a humble approach to tackle instead of the
visas that is humbling bar none. There is nothing that is more globally important
than the continued growth and expansion of cardiovascular disease. And
importantly, we can all learn from each other. There are exciting initiatives that
I've learned about in South America and in pockets of Europe and in Asia, and in
the Middle East that we can all benefit from, and we want to shine a bright light
on that. These pieces will be relatively short. They will be in our Frame of
Reference section, so 1200 words or so, so that they are accessible so that
people, you know, feel that they can carve out, you know, four minutes in their
busy day to read what cardiovascular disease looks like, as Paul said, our first
ones will be from Japan and India, and we plan to reach out to South America
and to the Middle East, and just continue on around until over the course of the
next number of years, we've touched virtually every country in the world.
Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that
you might be looking to focus on?
Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is
that in the West, in the developed world, cardiovascular disease increasingly has
become a chronic disorder where more and more people, over the course of the
last six years are surviving their acute coronary syndrome, their tachyarrhythmia
events, and they are developing chronic disorders like heart failure, whereas in
the East, it is the atherothrombotic manifestations that have both MI and stroke
that are expanding rapidly. So given that the face of cardiovascular disease is
different in different parts of the world, different strategies have to be
leveraged to address that, and we want to learn about that.
Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these
papers and just reflect on the things that we're learning. Paul, did you have
anything else that you wanted to add?
Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes
and obesity and the expanding epidemic that seems to effect some regions such
as India, in the Middle East, even more than other areas, but I think this is going
to be great. We're gonna have some fun and learn and exciting and hopefully it
will catalyze better care and better thinking around this enemy that we all face.
Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited
as I am about this. You have to read the editorial. It's a fantastic read.
Thanks 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. And I am joined today by our Editor of Digital Strategies, Dr. Amit Khera from UT Southwestern, as well as three wonderful fellows in training. Yes, you've guessed it, it's our FIT Podcast and I'm just so thrilled to be here again.
Dr Carolyn Lam: Amit, any words of introduction before we start?
Dr Amit Khera: Thank you Carolyn. I think, for both of us, this is our favorite podcast, or two podcasts, that we do, a year. It reminds us of how bright the future is, with superb cardiology fellows in training around the country, and it really is a testament to how important we find fellows in training, to Circulation, to our mission, and how much we learn from them.
So we're really excited about this group, today, and thank them for participating.
Dr Carolyn Lam: Absolutely. So, why don't we start, now, with ladies first? Let's hear from Dr. Elizabeth Hill.
Dr Elizabeth Hill: Thanks for having me today. My name is Beth Hill, and I'm a first year cardiology fellow at Scripps Clinic, in La Jolla, California. I've a particular interest in sports and exercise cardiology, which brings me to the article I picked today about sudden cardiac death and hypertrophic cardiomyopathy, hot topics in the field and in general.
And so, today, I'm excited to be discussing the EVIDENCE HCM study, looking at the hypertrophic cardiomyopathy of risk, sudden cardiac death model.
Dr Carolyn Lam: Nice. So tell us a little bit about what really struck you about the paper and, perhaps, how that may apply to where you practice?
Dr Elizabeth Hill: What I really liked about the paper is that, when I see patients in clinic with hypertrophic cardiomyopathy, prior to having this risk stratification tool, we didn't really have a way to objectively risk stratify our patients with hypertrophic cardiomyopathy and really guide the discussion about who may benefit from an implantable cardiac defibrillator or ICD. And so, I've been using this a little bit with my patients. While it hasn't made it fully into the AHA or ACC guidelines yet, I'm using it as a tool.
Dr Carolyn Lam: Great. You know, these are seven risk factors, isn't it? I'm always struck by that survival curve that really shows that those with a predicted 6% risk stand out. Is that what you use, as well, to guide your decisions?
Dr Elizabeth Hill: Yeah. I think, as the authors noted, they picked this somewhat arbitrarily so that they could study their risk model. But I think what they found is that it seemed to fit well with the observed high risk of sudden cardiac death cohort, such that those that were seen and observed, about 9% risk of sudden cardiac death in five years, were in that greater than 6% cohort. So I think that population should receive ICDs, and that is one factor that I used to guide my decision making as well.
Dr Amit Khera: Beth, this sort of interest that you've had for a long time, in sports cardiology, I've noted you've done some prior work in EKG screening and other screenings. In terms of this article specifically, as you pointed out, this is a really helpful tool because I still remember back when I was a fellow in training, there was, sort of, this thought that everyone was high risk with hypertrophic cardiomyopathy, and I think we realized that's not true at all. The overall incidence of sudden death was only 2.4% in this cohort.
The question I have for you, in terms of application, is, as Carolyn pointed out, these are reasonably simple variables, but as we sometimes are now using cardiac MRI and genetics and other more advanced tools, where do you think they fit in, in the current paradigm, since this is a bit of a more simplistic score?
Dr Elizabeth Hill: The seven risk factors they put into this tool were noted to be independently associated with an increased risk of sudden cardiac death, and those are well known factors, entricular tachycardia, maximum wall thickness. But I really do think that other factors will come into play soon and are part of my discussion, and colleagues' discussions, including the late gadolinium enhancement on MRI, genetic factors, and I really think this may be a place for tools like machine learning. These authors, O'Mahoney and colleagues, they really did, kind of a tour-de-force, going back to the 1970s, but there is still a decent amount of data missing. So maybe we can partner with the machines and help them go back into these records, a little bit more effortlessly, and look at genetics, maybe some wearable device data, and really refine our risk stratification tool moving forward. But that's definitely something I use in risk stratification in some of my intermediate risk patients.
Dr Amit Khera: Those are great points. I think your point about machine learning and novel algorithms will definitely take foot in the future.
Maybe a follow-up, again, given your background interest, I think it's a trade-off where we're trying to, of course, avoid sudden death, but you also don't want to overtreat. Especially, when you think about athletes getting ICDs and how that changes, or anyone, for that matter, about maybe telling someone they're at high risk, or giving them an ICD when perhaps they don't need it. I guess that comes to, what's the threshold? Here they use 6%, but that ends up being a bit arbitrary, in terms of what threshold we use. And how do we decide, when we talk to our patients, about what threshold's a right threshold to apply an ICD?
Dr Elizabeth Hill: Yeah. That's a great question. Like you mentioned, these devices come with inherent risks, such as unnecessary shocks, increased risks for infection, and sometimes there's restrictions with athletic sport, although that's been changing recently.
But, I think that's where the shared decision-making process comes into play, where you put current data on the table with the patients and, perhaps, their families as well, and have a risk-benefit discussion. Perhaps gather a little bit more data about the patient, maybe follow them over time, but I guess I wouldn't jump to put an ICD in, in every patient and, especially, the lower-risk cohort. And what number that is, I'm not quite sure. Here they say maybe less than 4%, but, again, somewhat arbitrary, I think.
Dr Carolyn Lam: Thanks Beth. I mean, as Amit said, it's just so inspiring to see how the papers are being used in practice. Really loved those perspectives.
Now, from sunny San Diego all the way to snowy New Zealand. We have Dr. Mesfer Alfadhel. And Mesfer, tell us a little bit about yourself, and the paper that you've chosen?
Dr Mesfer Alfadhel: Thank you very much. I'm thrilled to be part of this podcast. I'm a second-year cardiology fellow-in-training at the Needham Hospital, in Needham City, New Zealand, where it's snowing at the moment. I'm also a clinical lecturer at the University of Otago School of Medicine. I do have great interest in general cardiology, as the rest of my colleagues, but also am passionate about interventional cardiology and structural heart disease.
The paper I've chosen is really quite relevant to everyone in cardiology, and perhaps extends to other colleagues in other health professions impacted by automated external defibrillator use on survival and functional outcomes in shockable observed public cardiac arrest. The aim of the study was to determine the association of bystander automated external defibrillator use, the survival and function of outcomes in shockable observed out of hospital cardiac arrests. The study was from 2011 to 2015 and the Resuscitation Consortium prospectively collected detailed information on all cardiac arrests at nine regional centers, six in the United States and three in Canada.
They also found that among nearly 50,000 out of hospital cardiac arrests, 8% were observed public out of hospital cardiac arrest, of which 61% were shockable. Overall, a remarkable one in five of shockable observed public out of hospital cardiac arrest were bystander shocked. Now the bystander automated external defibrillator observed, shockable observed public out of hospital arrests were associated with increased odds of survival and full or near full functional recovery almost 2.6 and 2.7 odds ratio than when compared to emergency medical service defibrillation. What's also interesting is that the longer the wait for the emergency services, the higher the benefits from a bystander observed shock.
Dr Carolyn Lam: You know, Mesfer, I appreciate that you chose this one as well. What struck out to me immediately was that more than 60% of out of hospital cardiac arrests were shockable. And when we think about the number of lives that could potentially be saved, therefore, that's quite astounding, isn't it? But can I ask you something? So these are in the US and Canada, how applicable do you think this is to New Zealand?
Dr Mesfer Alfadhel: We do have a small population, just over four million. The number of cardiac arrests here is around 2,000 out of hospital cardiac arrests. And I think probably half of them in the latest reports were shockable. The emergency response time in the urban areas is around six minutes, which I think is acceptable, but we have about 20% of population living in rural areas. And the emergency response time exceeds 10 minutes almost all the time. I think that probably a group that we need to direct intervention to in New Zealand.
Dr Amit Khera: It's really an important article. I should say that June for the American Heart Association is AED and CPR month so great choice to remind us of the value of these and especially, the one thing that was amazing, obviously this is an observational study, but the absolute change, not relative, was about 14% meaningful recovery and so that's quite impressive in terms of the number needed to treat if you will. Maybe an adjunct to Carolyn's question is, when we think about strategies to enhance bystander AED use for strategies, essentially get the AED there faster. As you know if the EMT time was not delayed it wasn't necessarily better for the bystander.
We had a paper in Circ sometime last year looking at drones and then also geocoding and other people in some countries have looked at apps where you essentially can train a group of people and then they can be texted for a sudden cardiac arrest in their area. I'm curious about any creative things, there's always training and AEDs, I think in this place it was public areas in industry, but what do you think are some creative things or things that we need to be doing to help enhance the ability for bystander or early AED use.
Dr Mesfer Alfadhel: I think this is one area in medicine in general that where technology is really going to advance how we deal with this problem. There's an app that's available, it was launched in the UK a few years ago and it’s become available in New Zealand in the last two weeks called, the Good SAM. SAM stands for smartphone activated medics. And it's become available in New Zealand two weeks ago and I downloaded it and still yet wait for it to be activated. And the way it works is you can activate a medical emergency using the app and it dials the emergency response but what it also does is it activates the nearest three people with CPR training nearest to you and it tells you how far they are from the emergency. Now if you don't have the app and you call 911 or the equivalent, the operator can activate it to the nearby personnel who have that experience. And I think it's going to reduce the time markedly.
Now the other end of the question where some of what strategies could be used I think we had a good report from Denmark where they made changes in 2007 in Denmark and then followed by the rest of the country in 2010 where they made CPR or resuscitation education as compulsory at school but also when getting a driving license they made courses available for free that increased the number of defibrillators available in public places and they shared that information with public. They’ve redone, audited their work, and compared to prior to intervention prior to 2007 and after that and they found an increase number of using the AEDs increased from somewhere around 2% to 15%, which is really encouraging. I think we are following Denmark in that regard probably at slower rate.
Dr Amit Khera: Thank you those are excellent insights.
Dr Carolyn Lam: Amit, don't you see that I just love learning from these fellows during these podcasts. We should do more of these. This is awesome.
Dr Amit Khera: I completely agree.
Dr Carolyn Lam: Thank you Mesfer, enjoy the skiing. But now from snowy New Zealand we're going all the way to Nashville Tennessee. Welcome Dr. Vineet Agrawal. So tell us a bit about yourself and your paper.
Dr Mesfer Alfadhel: So my name is Vineet Agrawal. I'm a second-year cardiology fellow at the Vanderbilt University Medical Center. My background is as a physician scientist and as a general cardiologist. My long-term goals are in understanding mechanisms underlying heart failure with preserved ejection fraction.
With that in mind I was really taken by an article that was recently by Margaret Redfield's group from the Mayo Clinic in Circulation, titled “Global Pulmonary Vascular Remodeling and Pulmonary Hypertension Associated with Heart Failure and Preserved or Reduced Ejection Fraction.” I found this article to be a very interesting, hypothesis-generating article.
In a nutshell what they did was they took an autopsy cohort of patients in the Mayo Registry and those who had heart failure with both preserved and reduced ejection fraction, normal controls, and those who had a primary pulmonary venous occlusive disease, and looked at the lung specimens of these patients. And interestingly what they found was there was a significant amount of pulmonary venous remodeling that had occurred in patients who had both preserved and reduced ejection fraction. This correlated not only with their right heart cath findings, so those who had elevated pulmonary pressures and elevated transpulmonary gradients, but also differed from the primary pulmonary venous occlusive disease in the sense that the histologic appearance of these vessels was quite different.
And while as an autopsy study this is not necessarily an article that would immediately change practice, what I think it does do though is it forces us to think about these conditions in a different context and particularly with an eye towards future therapeutics. Heart failure with preserved EF as a disease, as I'm sure we all know, is sorely missing therapies that could alter the disease progression and potentially even alter mortality in these patients. And this article in my opinion really sheds light on at least anatomically a new location for us to think about as a therapeutic target when we try to better understand this disease and find therapies for these patients.
Dr Carolyn Lam: Vineet, can I just say you're singing to the choir here. I'm such a fan of this work as well for obvious reasons. But hey, could I ask you, in your clinical practice, do you see a lot of these patients with HFpEF and pulmonary hypertension and wonder how to treat them? And along those lines, how has this paper helped you think about these patients more?
Dr Mesfer Alfadhel: I would say when I first started residency as a medical student this was not necessarily a condition that was really something that I had learned much about or felt like I had been exposed to; however, as a resident I felt like most of the patients, or at least half of the patients, I was seeing with heart failure had a component of diastolic heart failure or they had a preserved EF but very symptomatic from the standpoint of heart failure. And I struggled to treat them, particularly in some part due to the fact that many of the risk factors that contribute to HFpEF, diabetes, uncontrolled hypertension, obesity, are chronic problems that are difficult to manage as a clinician regardless.
And second because I feel that there just weren't any data to support any treatments that we were pursuing at the time and so we would try and apply what we had learned in other types of heart failure to these patients with limited results. If I could talk about what I think this article may change in terms of my practice today, one thing that we've always thought about in terms of pulmonary vascular remodeling in heart failure is that it's just a passive process that as fluid builds up you back up into the lungs and as the fluid builds up and backs up into the lungs you get remodeling.
I think one thing that this article shows is that it may actually be a bidirectional process, which would suggest that perhaps we may need to reconsider looking at pulmonary-specific therapies in this population. But more importantly I think it does confirm that chronic elevating filling pressures do have an effect and a deleterious effect on the pulmonary vasculature. Particularly when you look at other trials such as the CardioMEMS trial, the CHAMPION trial in which the data pretty convincingly showed that as clinicians we don't do the best job of reducing left-sided filling pressures in our patients with heart failure as much as we think we do. This article really drives home the point to me that I really need to make sure that when I see these patients that I'm doing everything I can to reduce their left-sided filling pressures because the consequences of not doing so can affect the lungs, which can then in turn affect the heart as well.
Dr Carolyn Lam: Vineet, that's really words of wisdom. Couldn't agree more. And these are the first sort of autopsy, histological evidence that we have, which is so important. I think if I could just add a couple of perspectives too, it makes me think about making sure that I rule out PVOD in these patients sometimes. We now keep thinking about HFpEF we forget that we need to also rule out PVOD and the other thing much as we now think about not just the filling pressures but the remodeling it's good to note that they found it more in the venous than the arterial system, which also comes therefore with a warning message that we can't just extrapolate I suppose all the PAH therapies that we know about. What do you think about that?
Dr Mesfer Alfadhel: I absolutely agree with that. It's really interesting that all of our therapies from heart failure standpoint and from a PAH standpoint have focused on the myocardium, the neural hormonal cascade, and then the arterials. The pulmonary main artery and arterials. I don't think anyone really understands the biology of pulmonary veins and yet they're actually a pretty significant part of our everyday practice in cardiology. Pulmonary veins are thought to be the source of atrial fibrillation. We look at pulmonary vein inflow when we evaluate patients with echoes. And yet we understand so little about the biology and the mechanisms by which pulmonary veins are affected in both diseased and healthy patients.
I think this article for that reason raises a number of very interesting questions and may potentially change the way we think about these patients.
Dr Carolyn Lam: I keep learning, Amit, this is awesome. I could go on forever so you better stop me.
Dr Amit Khera: I should probably just be a fly on the wall. You must know Carolyn is a HFpEF, HFrEF aficionado and you guys should have a side call for another hour after this. But I do have one, maybe orthogonal question which is, it's interesting because if you look at how insights were made, they're made off areas I would argue at least that we don't, modern environment uses much which is the autopsy and probably to a large degree hemodynamics as much as probably in the old days although that's changing. I'm curious in a fellowship training program your exposure to autopsy and kind of current in-depth hemodynamic-type training, what's your experience?
Dr Mesfer Alfadhel: Our experience with looking at pathological slides, getting under the microscope, seeing tissue first hand, is somewhat limited in our fellowship training program. I would say in certain subspecialties like our heart failure, advanced heart failure subspecialties we do get a chance to see more myocardial biopsy specimens, but I think increasingly the focus has been on noninvasive methods by which we can assess some of these same things that we used to do, use the microscope for. Invasive hemodynamics I think similarly we get a lot of experience in terms of spending time in the cath lab but I do kind of wonder if we don't have the same in-depth training that we used to have in understanding all the nuances of hemodynamics that used to exist in the past.
Certainly, I think that while that's partially a reflection of the way and the direction in which medicine is heading, there is a little bit that's potentially lost there. That said, while we have the benefit of manuscripts like this that does do in-depth hemodynamics and looks at autopsy samples from a clinical standpoint, if we were to ever try and understand this in a larger population I think we would be required to try and find a way to noninvasively or maybe through potentially invasive hemodynamics better study this in live patients.
Dr Amit Khera: Appreciate that answer and I'm just for all of you, this has been outstanding. You all have served as incredible expert discussants. I know Carolyn already said it multiple times but we've learned a ton about each of these articles and great to see how they come alive and are used in practice and how they're applied in your own thinking and specifically as fellows in training with these have meant to you. We thank you all for joining us and it's really been a fantastic experience.
Dr Carolyn Lam: Amit, I can only echo your thanks and thank you listeners for joining us today. Fellows out there you are so important to us. Please, please apply to join us on the next FIT podcast as you can see it's really fun.
Don't forget to join us 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 issue is so special. It is an autopsy issue. I think it's actually the first of its kind in the history of Circulation. I am so pleased to have with me today Dr Jeffrey Saffitz from Beth Israel Deaconess Medical Center, who's the content editor for Pathology for Circulation and the guest editor for this entire autopsy issue. Welcome, Jeff.
Dr Jeffrey Saffitz: Thank you.
Dr Carolyn Lam: We also have Dr Lee Goldman from Columbia University Medical Center who wrote a beautiful perspective piece on autopsy. Thank you and welcome, Lee.
Dr Lee Goldman: Morning.
Dr Carolyn Lam: Jeff, could you start us off? I mean, an autopsy issue. How in the world did this come about?
Dr Jeffrey Saffitz: I think it really began by coincidence. The journal received submissions from several authors, each involving studies of autopsies, and the editors approached me and asked if we might consider grouping them together in a special issue focused on the role of the autopsy and cardiovascular medicine. I thought that would be a very interesting idea and this evolved into actually something much greater. Two additional papers came in focusing on the autopsy and I think looking at these papers in the aggregate, they represent what we can now consider to be the contemporary utility of the autopsy in understanding the way cardiovascular disease works. So I was particularly pleased that the editors agreed to group these papers into a single issue focused on the autopsy. We were really delighted that Lee Goldman agreed to write a perspective. He has had a longstanding history of studying the role of the autopsy and I hope the readers will find this to be a really interesting and useful issue which will, I hope, chart the course for future discovery.
Dr Carolyn Lam: Just listening to you, I love the way you say it's a contemporary look at autopsy. I mean, we covered things like molecular genetic, proteomic, autopsies, even like electronic autopsies using device. That's really cool. Lee, thank you again for sharing your time and incredible perspectives with us. The long history of autopsy. Do you think it's still necessary now?
Dr Lee Goldman: Maybe give some perspective. I first got involved in this a number of decades ago, when as a junior faculty member, I was assigned to be on the medical audit committee of the hospital where I saw patients as a cardiologist. And two of the senior people in the committee got into a debate about whether autopsies were still important given the advent of CT scans and other modern diagnostic technology. And to listen to them debate for 15 or 20 minutes, I finally had the temerity to pipe in and say we can actually study this, and so we did. We looked at autopsies in three different decades: 1960, 1970, 1980, and much to everyone's surprise, I think found, A. that the rate of which autopsies found diagnoses that doctors had missed and for which treatment would almost certainly have prolonged life was about 10 percent, and it was 10 percent, 1960, 10 percent, 1970, 10 percent, 1980.
But the difference was that doctors were missing different diagnoses. The things that got missed in 1960, and where autopsies showed there were being missed led to better diagnostic approaches and those things were rarely missed in 1980. But since people stayed alive longer, they got new things that we didn't really know much about in 1960. A big difference, fewer people missed heart attacks, pulmonary emboli, and things of that sort, but far more people had missed infections, especially fungal infections that were complication of multiple antibiotics or immunosuppressive therapies.
And so, as I followed this in 1980, if you will, to now, 2018, we find this gets recapitulated over and over again. Medicine moves forward, things we used to miss, we no longer miss, but people still die, and they still die from things that we don't always diagnose. We've done statistical analyses to show that probably the rate of misdiagnosis is going down a little bit, but it's still substantial and we still estimate that thousands of people each year die in the U.S. from things that are not what the doctors thought they had, and if that diagnosis had been made, the patient would have lived longer.
Dr Carolyn Lam: Lee, I just love that perspective. I have to say, it's really humbling. I mean, 1960s and so on would predate me as well, so I'm really humbled, and I love that reminder. Jeff, in fact, quite a number of our papers illustrate exactly what Lee said. We have four papers just dealing with sudden cardiac death, and that is still what diagnosis was struggled with. Could you tell us a little bit more about those?
Dr Jeffrey Saffitz: Yes, of course. I think we all recognize that sudden death remains a huge public health issue. We also realize that most people who die suddenly and unexpectedly don't do so in the hospital when they're being followed and monitored; rather, they die out in the community, and in many cases, these are individuals in whom major risk for coronary disease or other potentially lethal cardiovascular conditions was really not known. So I think it remains a major public health issue, and we still have a great deal to learn. So perhaps it's not surprising that four of the five papers involved autopsy studies of sudden death victims of individuals who died out in the community. A couple of them focused on sudden death in young people.
We know that these individuals often will have familial diseases, and the autopsy has been one mechanism for studying these individuals, so one of the papers from Michael Ackerman at Mayo Clinic, advanced the concept that they started many years ago, the so-called molecular autopsy in which they apply a whole exome sequencing in cases of sudden unexpected death in young people defined here as age under 40, and they identified some rare variants which were likely to be of potential pathogenic significance in sudden death. A related paper from Junttila et al in Finland looks at the finding of myocardial fibrosis in young victims of sudden death. They identified several cases in which that was the only structural change in the myocardium, and when they applied next gen sequencing, the identified variance that we typically associate with the familial non-ischemic cardiomyopathies, arrhythmogenic, dilated, and hypertrophic cardiomyopathy. But the key insight here is that we traditionally think of these diseases as having rather characteristic structural changes which we can recognize at autopsy. What they showed is that those structural changes might be limited to nothing more than some fibrosis. And so the key here is that this expands our potential opportunity to recognize these familial cardiomyopathies, and the overarching idea is we use the autopsy to serve the living. This is a way to gain information at autopsy that we can then use to help family members and other individuals by virtue of the insights gained at autopsy.
Dr Lee Goldman: When we did the estimates in my editorial, and I estimated that roughly 28,000 people die each year in America with diagnoses that doctors missed and for which treatment would have been different if they hadn't missed it, that's really based on, I'll call traditional autopsy methods, which are anatomical, include microscopic evaluation, include culture, but it's not historically included genetic testing. I believe, as these articles show, that the advent of genetic testing, which you could argue could have been done while the patient was alive, but we're not quite there yet in terms of testing everyone's genome, now help you autopsies find even more things that might've been missed. And as you just heard, also can have important information for the family. So, one of the issues you often get into in autopsies is what's in it for the family, and one of the problems here is that the pathologists don't get paid. For the family members, it's mostly an aggravation. The doctors are worried they're going to get sued if something that gets found. And so, to make this work you need to bring in some incentives. Doctors not getting sued if they find things because they should get credit for trying to learn more, some way to reimburse reasonably pathologists and hospitals who do the autopsies, and the understanding of family members that they not only will perhaps be more reassured about what happens to the loved one, but also may learn things that will affect their future, because certainly, these cardiomyopathies, instead of them being diagnosed, are familial and oftentimes will lead to testing and hopefully interventions in family members that'll be to their benefit.
Dr Carolyn Lam: Lee, what great comments about bringing this into the clinical perspective and I just love what you said, Jeff, about autopsy for the living. That is just a quotable quote. That's so cool. I noticed that you did ask Dr Judge to write an editorial specifically about bringing autopsies into the molecular genetic era. So I just want to encourage all our listeners to make sure you read that as well. But Jeff, back to you about the other two papers.
Dr Jeffrey Saffitz: Well, I think one that I found particularly significant is this idea that nowadays, patients come to autopsy with implantable cardiac electronic devices, and the point of this paper is that interrogation of these devices postmortem can provide really important information about the cause and timing of those deaths. I think the reality is that most pathologists who do these autopsies are entirely unprepared or ill equipped to do such interrogations, and so I think the point of this paper is simply to encourage pathologists who do these autopsies to develop partnerships and relationships with cardiologists who are able to get this type of information from these devices. And again, it not only provides information about what happened to that one individual and what the death was all about, but it provides important information to the family and potentially information that allows the family to recognize particular risks that might impact the living members. So I thought this was just another really interesting example of how information that is potentially available at autopsy may not be fully utilized, and I hope that this paper will have an impact in that regard.
Dr Carolyn Lam: That's great. Lee, did you have any perspectives on devices and its role in autopsy now?
Dr Lee Goldman: I guess that the point that I would just reinforce would be that diagnostic technologies, including the ability to monitor someone's heart rate, have helped us diagnose things that were missed in previous eras, but medicine is always pushing the frontier forward, and as long as we develop new therapies, develop new devices, there'll be new things to learn. I want to make one other point about what I'll call overconfidence in diagnoses. The published statistics for the accuracy of most diagnostic tests are based on what doctors think the diagnosis ends up being, not the autopsy, which is the ultimate gold standard. So, if you actually go through some not-so-complicated arithmetic, you'll find that many of the tests that we think are almost perfect at finding things really aren't because the people who die with those things found that autopsies that the test missed. There's something called a virtuous circle, there's also a vicious cycle. There's a bit of a vicious cycle here that if you don't do autopsies to be sure you aren't missing things, you become overconfident in the tests that you think are finding them, and therefore think you already know everything and don't need to do an autopsy. To me, in some ways, that's the most perverse result of the plummeting autopsy rate, which, by the way, can be linked directly to changes in how hospitals get accredited, that in prior years there was a minimal autopsy rate required for accreditation. When that was removed, not surprisingly, autopsy rates plummeted, and now, most autopsies done in the US are not done in hospitals because doctors aren't sure what's going on. They've done by medical examiners as part of the laws for autopsies least being considered and people who die without having had a medical attention to some degree.
Dr Jeffrey Saffitz: You are exactly right on all of these points. I'll just say this is the point of one of the other papers from Tseng et al. This was a prospective autopsy study of sudden death in the city and county of San Francisco, and what they showed here is that only about half of the deaths that were considered to be sudden cardiac deaths as defined by the conventional criteria actually turned out to be deaths due to a rhythmic disorder. So Lee's point is exactly right. Doctors think they know a lot of things, but they're not always right about that, and the autopsy is probably one of the best ways to bring some quality control to this, and to really provide, I think, objective data that often is the case flies in the face of what the previous thinking was, and I think this paper in this issue of Circulation really brings that point home very clearly.
Dr Carolyn Lam: Yikes. OK, so here I am, I practice in Asia, and I think the autopsy rates are even lower, so this is a great wake up call for me just listening. Let's switch gears a little bit. How about the paper by Dr Herrington? Now this goes to a proteomic bisection almost of maybe preclinical disease and atherosclerosis. Would you like to comment on that on, Jeff?
Dr Jeffrey Saffitz: In the perspective that I wrote with Gaetano Thiene, in addition to looking at the history of the autopsy, we looked to the future and just considered briefly what role will the autopsy play going forward, and I think the paper by Herrington is a great example of how we can use the autopsy to learn so much more about the way human disease works. The basic idea here is that something like coronary artery disease or atherosclerosis, we think of as being a disease that only involves the blood vessels, and we tend not to recognize it until it is rather advanced and clinically manifest, but we recognize that these diseases begin decades before they become clinically manifest. We really don't know how to identify the earliest antecedents, and without knowing that we really, I think, very much limit our ability to identify the disease way early before it becomes clinically manifest, and then be able to practice preventive measures and intervene to prevent the disease from occurring.
So, what this paper showed is that it's an application of high-throughput proteomics looking at coronary artery and aortic samples obtained at autopsy, and these authors identified particular changes in proteins that they then were able to show in a prospective independent clinical cohort were able to predict the development of coronary artery disease. So I think going forward, we are going to redefine our understanding of human disease by learning about its earliest expressions and its full systemic distribution, and in doing so, we'll be much better prepared to diagnose earlier and intervene and prevent disease. So I think this was a great example of how the autopsy can help in that effort.
Dr Carolyn Lam: I feel like we are going full circle in history and going back to learn about how to go forward. I don't know if I expressed that well, but I am just in awe of what I've learned from both of you. Thank you so much, Jeff, for putting together this amazing issue, and thank you so much, Lee, for sharing your perspectives. Thank you, audience, for joining us this week. 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. Today's feature discussion revolves around important hemodynamic and echo data from the reprise three trial, comparing the lotus and core valve transcatheter aortic valves in patients with high surgical risk. Can't wait? Well it's coming right up after these summaries.
The first original paper this week provide experimental data showing that the endothelium controls cardiomyocyte metabolism and function via notch signaling. Corresponding author, Dr. Fischer, from German Cancer Research Center in Heidelberg, Germany, and colleagues, studied fatty acid transport in cultured endothelial cells and transgenic mice with endothelial specific notch inhibition, or wild type mice treated with neutralizing antibodies against the Notch ligand. They showed that notch signaling in the endothelium controlled blood vessel formation and fatty acid transport in the adult mouse heart. Inhibition of Notch signaling in the vasculature led to expansion of the cardiac vasculature and impairment of fatty acid transport to cardiomyocytes. This resulted in metabolic reprogramming and heart failure.
Together, these data provide compelling evidence for a central role of Notch signaling at the coordination of nutrient transport processes in the heart. These findings help to explain how pharmacological inhibition of Notch signaling, for example, in oncology could lead to heart failure. The findings also help to identify the signals and molecules involved in endothelial transport capacity and show how these could offer new targets for the treatment of heart failure.
The next paper raises the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure. Ischemic injury to the myocardium is known to trigger a robust, inflammatory response, which is an integral part of the healing process, although much effort has been directed at tempering the inflammatory response in hopes of achieving clinical gain. Major efforts have focused on individual cytokines, the complement cascade, and antibodies to adhesion molecules preventing leukocyte invasion.
In contrast, relatively little effort has focused on macrophages. Although macrophage transformation is known to be crucial to myocardial repair, the events governing this transformation are poorly understood. In today's paper, co-corresponding authors of the trial in Hill, from UT Southwestern Medical Center, performed an elegant series of experiments and showed that release of DNA from necrotic tissue during myocardial infarction, triggered in macrophages a recently described innate immune response known as the GMP-AMP synthase-stimulator of interferon genes pathway or cGAS-STING pathway.
This response in turn promoted an inflammatory macrophage phenotype. Suppression of the pathway promoted emergence of reparative macrophages, thereby mitigating pathological ventricular remodeling. These results therefore reveal for the first time, that the cytosolic DNA receptor, GMP-AMP synthase, functions during cardio ischemia as a pattern recognition receptor in the sterile immune response.
Furthermore, this pathway governs macrophage transformation, thereby regulating post injury cardiac repair. As modulators of this pathway are currently in clinical use, these findings raise the prospect of new treatment options to combat ischemic heart disease and its progression to heart failure.
Cigarette smoking is a well-known risk factor for atherosclerotic cardiovascular disease. However, less is known about the risk for heart failure. First author, Dr. Kamimura, corresponding author, Dr. Hall, from University of Mississippi Medical Center, and their colleagues investigated 4129 black participants without a history of heart failure or coronary heart disease at baseline in the Jackson Heart Study.
They examined the relationship between cigarette smoking and left ventricular strength and function by using cardiac magnetic resonance imaging. They found that current cigarette smoking status, smoking intensity in terms of cigarettes per day, and smoking burden in pack-years, were independently associated with higher left ventricular mass, lower left ventricular strain, higher brain natriuretic peptides, higher BNP levels and higher risk of incident heart failure hospitalization in blacks.
These relationships were significant after adjustment for coronary heart disease, suggesting mechanisms beyond atherosclerosis may contribute myocardial dysfunction and increased risk of heart failure in smokers. In summary, these findings suggest that smoking is associated with structural and functional left ventricular abnormalities that lead to heart failure in blacks and that smoking cessation should be encouraged in those with risk factors for heart failure.
What happens to the risk modifying effects of exercise in individuals with increased genetic risk of cardiovascular disease. Drs. Tikkanen, Gustafsson, and Ingelsson from Stanford University School of Medicine performed the study in about 500,000 individuals from the UK Biobank and reported and compared the association's objective and subjective measures of fitness and physical activity with prospective cardiovascular disease events and all-cause death.
They found consistent and robust inverse association, particularly between objective measures of fitness and physical activity and six cardiovascular outcomes and total mortality. Using genetic risk scores for coronary heart disease and atrial fibrillation, they showed that these inverse associations were present in each genetic risk category, suggesting that elevated genetic risk for these diseases can be compensated for by exercise.
The knowledge that lifestyle choices have substantial effects on disease risk could encourage individuals to initiate a healthier lifestyle to reduce their overall risk. In the longer term, identifying subgroup space on genetic risk that benefit most from lifestyle interventions, could help personalize preventive strategies for chronic diseases.
Well, that wraps it up for our summaries, now for our feature discussion.
Today's featured paper deals with transcatheter aortic valve replacement, which we are all going to recognize has rapidly emerged as a treatment of choice in inoperable patients and, it's a reasonable alternative to surgical aortic valve replacement in high- and intermediate-surgical-risk patients. However, the success of this technology is in large part due to the rigor with which quantitative echocardiography by core laboratories has been used to assess the native and prosthetic aortic valve function.
Today's feature paper gives us such important data from the REPRISE III trial, which compares the Lotus and the CoreValve transcatheter aortic valve in patients with high and extreme surgical risk. I'm so pleased to have the corresponding author, Dr. Federico Asch, from MedStar Washington Hospital Center, as well as our associate editor, Dr. Dharam Kumbhani from UT Southwestern. All right Federico, please help me here, so as a noninterventionist and a person who doesn't deal with all these different types of valves every day, please tell us what was the motivation of looking so closely at the echocardiographic data from REPRISE, because the REPRISE III trial results were already published?
Dr Federico Asch: The most interesting aspect of this analysis is really that there is a very methodic, blinded comparison of two different valves. The valve that is being tested and that the reason why Boston Scientific has sponsored the study, is the Lotus valve, the Lotus System is, if you want, a new valve that is not clinically approved in the United States yet, that basically, it's a completely repositionable bovine pericardial valve that comes in different sizes.
The three sizes that were tested in here are what we would call the small, or 23 millimeters, the medium, 25 millimeters, and the large, 27 millimeters. Each patient, at the moment of randomization, or at the moment of inclusion, were randomized to the small, medium, or large Lotus valve vs the clinically approved CoreValve, which is a Medtronic product. Obviously, this is taken as the control group because this is one of the valves that is widely clinically available nowadays in the United States and worldwide.
This is exactly the motivation here. On one side, to prove whether this valve was as good as CoreValve or not and whether it was as safe as the CoreValve as well, and that, the study was about. Every three patients that were randomized, two were randomized to the new valve, the Lotus, and one was randomized to the CoreValve.
An important note to make here is because the control arm included clinically available valves at the beginning of the study, the previous generation of CoreValve was used and then about halfway through the trial, the Evolut valve was the one being used, so there's two different valves on the CoreValve system that were tested in this trial while Lotus was a single earlier generation valve.
We focus here on the hemodynamic implications, that meaning, the gradients and the degree, if you want, of obstruction that these valves could have over time, and the amount of regurgitation that these two valves and how they compare to each other.
Dr Carolyn Lam: That's great. Could I ask if you had any hypothesis going in, because as I recall, the Lotus valve actually met the non-inferiority comparison, but it did have significantly higher rates of new pacemaker implantation and valve thrombosis, right? So, was that perhaps a hypothesis going in and what did you find?
Dr Federico Asch: So, the initial hypothesis of the trial overall was that this new valve was one that was designed to have less paravalvular regurgitation, which is something as you probably know, has been of significant concern in the cardiology world ever since the initial clinical trials for Tyler with Partner and CoreValves.
Patients with more significant paravalvular leak did have worse outcome over time, so, one of the main goals of this valve itself, was to prevent that paravalvular regurgitation. So, that was the initial idea behind this product I would say, not just the clinical trial and obviously, this clinical trial tried to prove that, indeed, as I mentioned before, the primary effectiveness end point was mortality, disabling stroke, and paravalvular leak, the main driver on the difference between the two valves there was indeed a much lower paravalvular regurgitation on the Lotus valve compared to CoreValve.
There was also lower stroke rate, but the most important difference was on the paravalvular aortic regurgitation. Of course, when you think of any of these devices, for them to be able to prevent paravalvular leak, they have to have some kind of skirt or cushioning around the valve, an adaptive seal, which in the case of the Lotus valve, that would prevent any flow around the stent, but one of the risks of that of course is that by trying to seal the valve, you're actually, you may be decreasing a little bit the effective orifice area, so it was actually very important to understand whether gradients with this valve were higher and whether the potential differences in the gradients did turn into any difference in clinical outcomes.
Dr Carolyn Lam: That is super clear now. What did you find?
Dr Federico Asch: I would say, the findings from a hemodynamic standpoint, we can briefly summarize them in two aspects of it. No surprise, the paravalvular leak was significantly lower for Lotus compared to CoreValve, and that was true for any of the three sizes, for the small, medium, and large size in all of them, the rate was significantly lower for Lotus. It was actually under 1% of the patients with moderate or higher paravalvular leak, as opposed to an average of 6.7% on the CoreValve, but on the other side of the spectrum, the gradients and the effective orifice area, and the dimensional index were all significantly better on the CoreValve compared to the Lotus.
The bottom line is, we have two valves that each of them has a specific strength. On one side, Lotus has less paravalvular leak. On the other hand, CoreValve has a better gradient profile than Lotus. I would say in two lines, that's the findings of this study. We did take these findings further and compared among different valve sizes and we saw that these differences were consistent at each of the valve size, so if we would compare the small Lotus with the small CoreValve or the large Lotus with CoreValve, the findings were very similar.
They were always significant, and what is important is that while there was a difference, both for paravalvular leak and for gradients and other hemodynamic parameters, the reality is that when it came to clinical outcomes, there was no significant difference among the two.
Dr Carolyn Lam: Dharam, you have to weigh in now as an interventional cardiologist, what does this mean to you.
Dr Dharam Kumbhani: First of all, Federico, congrats to you and Ted and the rest of the group. I think this is obviously a very important trial and I think this hemodynamics paper, I think definitely moves, helps understand the differences a little bit better, so I think this is a very valuable contribution. I think you said it exactly right. I think what is really interesting is that you have a significant introduction into the paravalvular leak, but yet you have, because of difference in valve design, one being annular vs the other being super annular, you have higher gradients with the Lotus valve compared with the CoreValve, so you wonder if the two differences can cancel themselves out in some way, because you don't see any difference in clinical end points at one year, and also, I guess, what we've learned from the Partner data and other CoreValve data is it would be really helpful to see how this evolves over time, whether there will be any late separation of the curves or just a long-term follow-up, whether that will still be important.
I think that is the really interesting insight that we glean from this analysis. I want to make two other points. I think the other interesting thing about the design of the Lotus valve, and probably having such a great seal for the paravalvular leak reduction and having higher radial strength, I would think, at the annulus, I suspect that that's probably also the reason why the pacemaker rate is higher with this, compared with CoreValve, so it's almost 30% in this trial. About 20%, 18% already had an existing pacemaker, so particularly I guess, as we move to lower-risk population, I think that will certainly, balancing the two and deciding probably one valve doesn't fit everybody and we may have to have strategies to figure out which may be the best valve for a given patient based on this.
The other point I'd like to make is the question about stents or valve thrombosis and I know that your group has been heavily invested in that research, because I know in the JAMA paper, there was a report of few valve thrombosis events and you also bring that home here in this hemodynamics paper. Is there anything you want to elaborate on that or any insights that you feel would be helpful for the next set of trials and next generation of the Lotus valve?
Dr Federico Asch: Yeah, you're bringing two very, very important points. Let me address the thrombosis one first. As you very well described, we have been working a lot on multiple different valves and understanding why this is happening. It's clearly something of concern. In this study in particular, we did not have data collected to detect subclinical thrombosis, which is what most of us have been talking mostly about over the last few years. The diagnosis of thrombosis here was not so clinical. These were patients that mostly, because gradients were going up, were detected. They were image ... there was one or two cases with TE and the other ones with CTs and then they were given anticoagulation and those results, and based on that is that the diagnosis of thrombosis was made. All those cases, nine cases, indeed, happen on the Lotus group. The CoreValve is one in that overall has shown to have lower rates of thrombosis in general and I'm not just talking about our own report. Our report was consistent with that.
That may be something related to the fact that it's a super annular valve and the flow through the valve may be better, if you want, but we don't know that. The rate of thrombosis, again, clinical thrombosis, in this case, for the Lotus valve was 1.5%, which is still low, but it's impossible to compare to all those new reports that are coming out because those are mostly subclinical, which is not the case here.
One could argue that if would have done CTs on every patient here at 30, 45 days, we would have found much higher rates in both valves, but we don't know that. We don't have the data to address that.
Dr Dharam Kumbhani: As I remember, almost all of them, I think seven out of eight of those reported, were in the 23 valve, right? They were not ... I think the larger valves ...
Dr Federico Asch: Exactly. There were nine cases overall, eight of them were on the small valve, on the 23 millimeters, and one was in the middle size, on the 25 millimeters. You are completely right.
Dr Dharam Kumbhani: I don't know what to make of that, but that was an interesting observation as well.
Dr Federico Asch: Yeah. It's interesting because when you look at reports of subclinical thrombosis, actually some of the reports suggest that this is more common in bigger valves than in smaller valves. Registries, I'm talking about, but that didn't seem to be the case here, but again, we need to understand the limitations. This was not a study geared towards detecting sub clinical thrombosis or thrombosis overall. These are just clinically reported cases that were analyzed thoroughly but they were triggered by some kind of clinical event, what's mostly an increase in the gradient.
That's all that I would make out of the thrombosis. I think there is definitely more that we need to learn about it. We know that both CoreValve and Lotus have been reported to have cases of thrombosis, but in general, CoreValve seems to be of all the type of devices, the one with the lowest incidents.
Dr Dharam Kumbhani: Maybe your studies will help in understanding the influence of hemodynamic profile, patient-prosthesis mismatch, to the risk of thrombosis. I think the interactions are not well understood. I think that will be very interesting going forward.
Dr Federico Asch: Exactly. And the other comment that I wanted to make, Dharam, regarding your first impression about the pacemakers and the gradients, a couple of observations that I want to make out of that, one is that the difference in gradients between Lotus and CoreValve seem to be the highest early and then over months, that difference seemed to get smaller and smaller, still significant though, even at one year, but one could argue that if, as we continue following up these patients, maybe the difference starts getting smaller and smaller to the point that to become irrelevant, but we don't know that. That is just the impression that we get at looking at the curves over time.
The pacemaker, obviously, as you can imagine, this is something that is of concern for everybody. It's a high rate, the newer Lotus generations are geared towards having lower paravalvular leak, like the head Lotus Edge and so we would expect that in the future that would be the case, but we don't know. The same way that it is important to mention that CoreValve has been addressing their initial concern, which was paravalvular leak.
I mentioned before that the control arm in this clinical trial included CoreValve classic, earlier generations from roughly half of the patients, and the paravalvular leak in that group was a little bit over 10%, while the second group, which was the Evolut R had already a much lower rate of paravalvular leak, but was still significantly higher than Lotus, but was definitely better.
I think what this points out to, is that all these devices are so early in their life, in their history, that all the efforts that each of these companies are making into fixing the specific problems that each of them have, really turn into a next generation that addresses more aggressively all these things. In the case of CoreValve, definitely the paravalvular leak is one and they are making very good progress in the care of Lotus, the permanent pacemaker is one and we expect in subsequent generations to improve as well.
Dr Carolyn Lam: It's been very enlightening for me and I'm sure for all our listeners. Thank you for joining us today 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'm Dr Carolyn Lam, associated editor from the National Heart Center and Duke National University of Singapore. This week's feature paper reports results of the SWAP-4 study, which is the first study to evaluate the pharmacodynamic impact of the timing and dosing of clopidogrel administration when de-escalating from ticagrelor therapy. Extremely important take-home messages for clinicians looking after patients with coronary artery disease and a must listen to. Coming up right after these summaries.
In the first original paper this week, chondroitin sulfate, well known in the context of the monogenic disease mucopolysaccharidosis type 6 may actually represent a novel therapeutic approach for the treatment of general heart failure. First author Dr Zhao, corresponding author Dr Foo, from Genome Institute of Singapore studied changes in myocardial chondroitin sulfate in non-mucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. They found that failing human hearts display an abundant accumulation of chondroitin sulfate proteoglycans in the extracellular matrix largely localized to fibrotic regions.
The main component of chondroitin sulfate glycosaminoglycan chains in human hearts was chondroitin 4 sulfate. TNF alpha was a direct binding partner of glycosaminoglycan chains rich in chondroitin 4 sulfate. Modification of the chondroitin sulfate chain with the recombinant human arylsulfatase B, which is an FDA-approved treatment for mucopolysaccharidosis type 6 that targets chondroitin 4 sulfate, actually ended up reducing myocardial inflammation and overall fibrosis in vivo. In two independent rodent models of pathological cardiac remodeling, this recombinant human arylsulfatase B treatment prevented cardiac deterioration and improved functional recovery. Thus, targeting extracellular matrix chondroitin sulfate represents a novel therapeutic approach for the treatment of heart failure.
The next paper focuses on the subcutaneous ICD, which is an entirely subcutaneous system that does not require intra-procedural vascular access or endovascular defibrillator leads or coils. Now the subcutaneous ICD has a novel mechanism of defibrillation and is associated with an increased energy requirement for defibrillation when compared to traditional transvenous ICDs. Thus, ventricular fibrillation or VF conversion testing at the time of subcutaneous ICD implantation is a class 1 recommendation.
Yet, what is the current adherence to this recommendation? Well, today's paper addresses this question from first and corresponding author Dr. Friedman from Duke Clinical Research Institute. He and his co-authors studied first time subcutaneous ICD recipients between 2012 and 2016 in the National Cardiovascular Database Registry ICD Registry to determine the predictors of use of conversion testing, predictors of an insufficient safety margin during testing and in-hospital outcomes associated with the use of conversion testing.
Results show that use versus non-use of VF conversion testing after subcutaneous ICD implantation in the US was more related to physician preference than patient characteristics. The study also identified several patient characteristics associated with an insufficient defibrillation safety margin. That included increased body mass index, severely decreased ejection fraction, white race, and ventricular pacing on the pre-implantation ECG. Use of VF conversion testing after subcutaneous ICD implantation was not associated with a composite of in hospital complications or death. These data may inform ICD system selection and a targeted approach to conversion testing.
We know that elderly patients are at elevated risk of both ischemic and bleeding complications after an acute coronary syndrome and display higher on clopidogrel platelet reactivity as compared to younger patients. Does prasugrel at five milligrams compared to clopidogrel reduce ischemic events without increasing bleeding in the elderly? Today's paper addresses this question from corresponding from corresponding author Dr Savonitto from Manzoni Hospital Italy and his colleagues.
These authors performed a multicenter randomized open label blinded end point trial comparing a once daily maintenance dose of prasugrel five milligrams with the standard clopidogrel 75 milligrams in patients more than 74 years old with acute coronary syndrome undergoing percutaneous coronary intervention. The primary end point was a composite of mortality, myocardial infarction, disabling stroke and re-hospitalization for cardiovascular causes or bleeding within one year. Enrollment was interrupted due to futility for efficacy according to pre-specified criteria after a planned interim analysis when 1,443 patients had been enrolled with a median follow-up of 12 months.
At this point of interruption, there was no difference in the primary end point between reduced dose prasugrel and standard dose clopidogrel. The results of this Elderly ACS 2 study therefore could not show overall clinical benefit of prasugrel five milligrams versus clopidogrel in elderly ACS patients undergoing early PCI.
The final study is the first to define the cellular and molecular mechanisms of cardiac valve inflammation and fibrosis occurring in the setting of systemic inflammatory disease. First author Dr. Meier, corresponding author Dr Binstadt from University of Minnesota used T-cell receptor transgenic mice which spontaneously developed systemic auto antibody associated autoimmunity leading to fibro inflammatory mitral valve disease and arthritis.
They identified a critical population of CD301b/MGL2 expressing mononuclear phagocytes that orchestrated mitral valve inflammation and fibrosis in this mouse model. They further demonstrated an analogous cell population was present in human inflammatory cardiac valve disease. Finally, they defined key inflammation molecules that drove mitral valve disease in this model, thus providing multiple potential therapeutic targets that are required for mitral valve inflammation and fibrosis.
Dr Carolyn Lam: That wraps it up for your summaries. Now for our feature discussion.
Searching between different classes of P2Y12 inhibitors including de-escalation from ticagrelor to clopidogrel commonly occurs in clinical practice. However, what are the pharmacodynamic profiles of this strategy? Well, today's feature paper is going to provide a lot of insights. I am so pleased to have the corresponding author of the SWAP-4 study, Dr. Dominick Angiolillo from University of Florida College of Medicine Jacksonville, as well as our associate editor Dr. Gabriel Steg from Hôpital Bichat in Paris, France. Dominick, now this is SWAP-4. That means there was a SWAP 1, 2, 3. Could you just paint the background and rationale for SWAP-4 and tell us what you found?
Dr Dominick Angiolillo: We performed this study on the background of a line of research that we've been conducting over the past number of years of switching antiplatelet therapies. There's so many different types of switches that can occur and one of them is that which is defined as a de-escalation which is that from a more potent P2Y12 inhibitor to a less potent and one of those that occur frequently in clinical practice is the switching from a ticagrelor to clopidogrel and this was essentially the rationale for conducting the SWAP-4 study.
Now I want to start off with saying that the reason for doing this study is not to advocate switching because we always recommend that individuals follow guideline recommendations but we performed this study because we wanted to provide clinicians with some additional insights that if you're going to switch particularly from ticagrelor to clopidogrel, which would be the modality which is associated with, put it this way, with the smoothest transition one drug to another.
This is the rationale. What we did was do a pharmacodynamic, conduct a pharmacodynamic study taking patients who were on standard treatment with dual antiplatelet therapy aspirin and clopidogrel and they had a run-in phase with ticagrelor. And the reason why we took patients on the back part of aspirin and clopidogrel is because we then wanted to look at the effects after switching to compare it with a baseline. There have been some discussions about drug-drug interactions. And patients were randomized to either continue with treatment with ticagrelor to switch with a loading dose of clopidogrel, 600 milligrams 12 hours after last dose of ticagrelor. 24 hours after last dose of ticagrelor or directly switch with a maintenance dose. So, the randomization was into four groups.
Essentially to keep a long story short, what we observed was that when de-escalating from ticagrelor to clopidogrel we did see an increase in platelet activity obviously as expected. But the use of a loading was not able to mitigate this increase but there were no differences according to timing of administration of the loading dose clopidogrel 12 or 24 hours. We had anticipated in our study design that with the administration of the loading dose 24 hours after last maintenance dose we could have achieved a smoother transition, but this was not the case.
Nevertheless, the overall conclusions of our study are supported by the pharmacodynamic data in terms of you still achieve a better transition when you give a loading dose than without a loading dose. I was also want a little bit cautious and I think during the review process of the journal and feedback from the editors we kind of phrased in a very cautious way the suggestion for a drug-drug interaction, in fact we suggested because there are other ways to look into this phenomenon in more detailed manner. For example, doing some specific pharmacodynamic analysis which was not done in this study. Nevertheless, the take-home message from a clinical perspective remains unchanged.
Dr Carolyn Lam: Thanks so much, Dominick. That was a very important framing of the paper that you gave us at the start that this trial was not designed to try to say who should be de-escalated or not and that should be in line with the guideline recommendations and yet such an important just take-home message that if there is a need that the 600-milligram loading dose of clopidogrel should be used. You know, Gabriel, you've thought a lot about this and especially the drug-drug interaction question. What are your thoughts there?
Dr Gabriel Steg: Yeah, well first of I think this is an extraordinary, important study even though it's a pharmacodynamic study, which many clinicians might look at and then quickly read the abstract and turn the page I think this is actually one of the most interesting papers we've published in recent months. The reason for this is this is tackling a very common clinical scenario, which is having or desiring or wanting to de-escalate the intensity of platelet therapy after a PCI or ACS from a potent agent such as ticagrelor to a less potent agent such a clopidogrel. And as nicely explained in the paper, there are multiple reasons why this can occur.
A common clinical scenario is that cost is a major issue. Because of the cost patients or physicians may want to switch to clopidogrel, a generic drug as opposed to a branded drug. Another scenario which is fairly common is side effects. Either nuisance bleeding or maybe dyspnea with ticagrelor may prompt some physicians and patients to want to deescalate to clopidogrel. To a less intensive therapy which may not have dyspnea or may not cause as much nuisance bleeding. And finally, sometimes it's done on purpose because some believe that within a few weeks or months following PCI or ACS the benefits of more intensive patient therapy is less, the risk remains the same and therefore maybe we could proposedly de-escalate therapy to clopidogrel and get away with it and there have been a number of randomized studies and observational studies that suggested that this might be feasible although these studies have weaknesses. They're often open label. They're often fairly small and somewhat underpowered.
So, we don't have a definitive answer. Nevertheless, this happens on an everyday basis in most large clinical centers and we don't know exactly how to do it and what the best way to do it and I really want to credit Dominick's team for doing a rigorous series of investigations, including this one, which is the latest one but not the only one in trying to really map out how exactly we should as clinicians manipulate these agents to achieve the best safety and efficacy for our patients. And I think the message here is very clear. Yes, you can de-escalate but you have to be careful on how you do it. And I think you really need to use a loading dose, a 600-milligram loading dose of clopidogrel if you're going to deescalate from ticagrelor to clopidogrel to avoid a gap in protection that might be deleterious to patients.
That does not address all of the questions that are raised by de-escalation and as I pointed out I think outcome trial data are really of paramount importance here, but I think this really important because it has major practical implications for clinicians worldwide on how to do this. So, I think this is a great study. I really want to congratulate Dominick.
Dr Dominick Angiolillo: Thank you.
Dr Carolyn Lam: You looked at the genetic status as well. Could you tell us about your findings there?
Dr Dominick Angiolillo: We in the spirit of trying to perform the most comprehensive possible assessment we have also looked at the genetic background of our patients and in particular looking whether the presence of a loss of function allele for CYP2C19, which is involved with clopidogrel metabolism, could have affected the outcomes. And the reason why we did this there've been a lot of studies clearly showing that if you have a loss of function allele for CYP2C19 you do have higher levels of platelet reactivity. Therefore, we want to see if those carriers would have had even a greater increase in platelet reactivity. And again, we did all this in the spirit of really trying to define again this from a pharmacodynamic standpoint, if there could be any potential safety hazards with such an increase in platelet reactivity with the de-escalation.
When we did our analysis, we did not find any impact of a CYP2C19 on our data. However, I think it's important to underscore that we did not have too many patients with a loss of function allele so clearly the study was not designed or nearly closely powered to look into this assessment. So, I think that aspect does need to be interpreted with caution.
Dr Carolyn Lam: Thanks so much, Dominick. Were there perhaps caveats that clinicians listening in should pay attention to? For example, this study was conducted in stable patients with coronary artery disease. What about patients with recent acute coronary syndrome?
Dr Dominick Angiolillo: That's a great point. The reason why we conducted this study in a more stable setting was largely driven by two aspects. Well first of all, we wanted to have a run-in phase of patients switching from clopidogrel to ticagrelor to have some sort of baseline to reference to after the switch. And this would have been mostly ACS patients that would be less likely to be on clopidogrel. The second is purely a safety issue. We know that patients with acute coronary syndromes are associated with higher levels of platelet reactivity and in the context of a study where we do not know the pharmacodynamic profiles associated with de-escalation or better off we don't know the details.
And so, there was a safety consideration there which is why we did it in stable patients. But what we can say is tied with Gabriel's comment before in all the studies out there are not powered or do not have the rigor of a mega trial. Although we give our suggestions and recommendations, practical recommendations on how to switch, there is an increase in platelet reactivity and we stress in our manuscript that if you are going to switch, please try to delay this as much as possible because those increases in platelet reactivity for example, in a patient with an ACS for example, immediately after PCI, something that we probably would not want for our patients. I'm very happy actually that we conducted the study in the more stable cohort because we had less confounders. This is kind of the reason behind all this.
Dr Gabriel Steg: The last question maybe I would ask Dominick is whether he believe that results would be different if we had the patients on a maintenance therapy for longer with clopidogrel, do you believe that the risk of rebound or drug-drug interaction are the same early on after institution of therapy or later on? Is there any reason to expect a difference?
Dr Dominick Angiolillo: That's a great question. My personal opinion would be that with longer duration the platelet reactivity would have gone back down to baseline. We actually continue to study out up to around 10 days following the switch which we thought would have been sufficient time to get back to baseline and it was not the case particularly in the patients whose switch was a 75 milligram. The answer's probably yes. Probably yes. To redesign the trial again maybe having that 30-day time point as well would have been obviously of added value.
Dr Carolyn Lam: Thank you so much, Gabriel and Dominick. This has been extremely insightful. Fun as always.
You've been 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.
What do salty, Chinese meals, neurotransmitters, cancer, and pulmonary arterial hypertension have in common? Well, you are not going to want to miss this week's feature discussion. It's going to reveal a new therapeutic approach to pulmonary arterial hypertension that may just surprise you, coming up right after these summaries.
Do congenital heart defects signal a familial predisposition to cardiovascular disease? Well, this question was addressed in this week's first original paper from first and corresponding author, Dr. Auger, from University of Montreal Hospital Research Center in Quebec, Canada. Dr. Auger and colleagues aimed to determine whether the risk of cardiovascular disorders later in life was higher in women who had newborns with congenital heart defects. To answer the question, they studied a cohort of more than one million women who had delivered infants between 1989 and 2013 in Quebec. They showed for the first time that congenital heart defects in offspring were associated with increased risk of maternal cardiovascular morbidity later in life, including atherosclerotic disease, cardiac hospitalization, and cardiac transplantation. The association with subsequent cardiovascular morbidity risk was present for both critical and noncritical congenital heart defects. Thus, women who have given birth to offspring with congenital heart defects may benefit from early attention to traditional cardiovascular risk factors and more aggressive primary prevention strategies.
Acute myocardial infarction, or AMI, is a major cardiovascular complication of non-cardiac surgery, but what are the outcomes following perioperative AMI? This question was answered in the next paper from co-corresponding authors, Dr. Smilowitz and Berger, from New York University School of Medicine. The authors identified more than 8,000 patients who were diagnosed with AMI during hospitalization for major non-cardiac surgery using the 2014 US Nationwide Readmission Database. They found that perioperative AMI after non-cardiac surgery was associated with a high in-hospital mortality and a 19% risk of 30-day hospital readmission among survivors. The majority of hospitalizations after perioperative AMI were because of infectious, cardiovascular, or bleeding complications. Recurrent AMI occurred in 11% of patients re-hospitalized after perioperative AMI. At six months after perioperative AMI, more than 36% of patients were re-hospitalized, and the overall risk of in-hospital deaths was almost 18%. Thus, hospital readmissions and mortality among patients with perioperative AMI pose a significant burden to the healthcare system. Strategies to improve outcomes of surgical patients early after perioperative AMI are warranted.
What is the recent status of hypertension in China? Co-corresponding authors, Dr. Wang and Gao, from Fuwai Hospital, Peking Union Medical College, and Chinese Academy of Medical Sciences in China used a stratified, multistage, random sampling method to obtain a nationally representative sample of more than 450,000 residents from 31 provinces in mainland China from 2012 to 2015. The authors found that more than 23% of Chinese aged 18 years or old had hypertension, and that's equivalent to an estimated 284.5 million individuals. The prevalence of hypertension was similar in rural and urban settings, whereas three municipalities, mainly Beijing, Tianjin, and Shanghai had the highest prevalence of hypertension. Almost half the hypertensive population was aware of their hypertension. About 41% were treated, and only 15% achieved a blood pressure control. Among treated patients, barely 32% were prescribed two or more antihypertensive medications. Thus, this study revealed a considerable prevalence of hypertension in Chinese adults, as well as low awareness and control rates, representing an urgent public health message in China.
Patients with systemic sclerosis-associated pulmonary arterial hypertension have a far worse prognosis than those with idiopathic pulmonary arterial hypertension. But why is this the case? In the next paper, from co-corresponding authors, Dr. Hsu and Dr. Kass, from Johns Hopkins University School of Medicine, these authors tested whether the disparity involved underlying differences in myofilament function. They studied cardiac myocytes isolated from the right ventricular septal endomyocardial biopsies from patients with systemic sclerosis-associated pulmonary arterial hypertension, idiopathic pulmonary arterial hypertension, or systemic sclerosis with exertional dyspnea but without pulmonary arterial hypertension. They also looked at control right ventricular septal tissue obtained from non-diseased donor hearts.
They found that right ventricular myofilaments isolated from humans with systemic sclerosis-associated pulmonary arterial hypertension exhibited diminished contractile force and abnormal calcium sensitivity versus control myofilaments. This is in sharp contrast to the hypercontractile compensation in idiopathic pulmonary arterial hypertension. Systemic sclerosis patients with dyspnea and only exercise-induced pulmonary hypertension exhibited an intermediate right ventricular myocardial filament phenotype. These myofilament contractile abnormalities correlated strongly with in vivo right ventricular function at rest and right ventricular contractile reserve during exercise, suggesting a central role of right ventricular myofilament dysfunction in systemic sclerosis-associated pulmonary arterial hypertension.
In summary, these findings uncover key deficiencies in the right ventricles of systemic sclerosis-associated pulmonary arterial hypertension, and these findings suggest that therapies targeted at right ventricular myofilament contractile dysfunction may prove particularly useful for this vulnerable subpopulation. That wraps it up for our summaries. Now, for our feature discussion.
Today's feature paper promises a new therapeutic approach in pulmonary arterial hypertension. We know that pulmonary arterial hypertension is a rare disease, but nonetheless it casts a large shadow because it most commonly afflicts young women and remains a disabling disease. Despite treatment advanced in the last 20 years, high-risk patients still succumb at a rate of 15% annually. Moreover, our most effective therapy is a continuous infusion of parenteral prostacyclin, which is both cumbersome and expensive. Thus, there remains an urgent need for better therapies to improve survival and quality of life. Today's feature paper introduces a novel approach to this.
I'm so pleased to have the corresponding author, Dr. Sylvia Cohen-Kaminsky, from Inserm, Paris, France, as well as associate editor Dr. Charlie Lowenstein, from University of Rochester, to discuss today's special paper. You know, I'm gonna start with Charlie, because you have a way of explaining things and just putting the background to mechanistic papers so well. Could you do that for us, please?
Dr Charlie Lowenstein: Sure. When I started in research, I worked in a neuroscience laboratory. One of the things we studied was glutamate and its class of receptors. Glutamate, as you know, is one of the major neurotransmitters in the brain. The brain releases small amounts of glutamate, which acts as a messenger, neurons talking to other neurons. But when there's a stroke, the brain releases huge amounts of glutamate, and it's actually toxic and can cause damage, and mediate neuronal damage and cell death. Glutamate is a hot topic in the world of neuroscience. But in the cardiovascular field, people don't know much about glutamate. They don't appreciate glutamate as being important at all. So, I have a question for you, Sylvia. How did you start to get interested in glutamate and its family of receptors?
Dr Sylvia Cohen-Kaminsky: It started around 2000, and since 2000 we are having some clues about peripheral glutamate receptor in different cells in different organ. But basically, for vascular cells and for the topic of PAH, there was two things that make me thought about it. First of all, it was shown that the NMDA receptor contributes to the proliferation of different cancer cell types. Human tumor cells express the NMDA receptor, then an NMDA-receptor antagonist may inhibit cancer cell growth and migration. We know that pulmonary vascular cells from PAH patients have cancer-like properties. They are also proliferative and resistant to apoptosis, and they have several properties of cancer cells, such as metabolic shift and so on.
In addition, not only neurons in the brain express the NMDA receptor, but also brain microvascular endothelial cells that respond to an NMDA receptor activation by gross production, disruption of endothelial cell barrier, and monocyte transmigration. All these three processes are relevant to PAH development. That's why I thought that perhaps an NMDA receptor is expressed on microvascular cells from the lung, and perhaps we could have a process involving an NMDA receptor in this vascular remodeling.
Dr Charlie Lowenstein: As you know, there are three flavors of glutamate receptors. How did you discover that there was one particular kind, the NMDA receptor, that was really important for smooth muscle cells?
Dr Sylvia Cohen-Kaminsky: You are right. We did analysis of mRNA expression, and most of the known receptor in the brain, either metabotropic or ... ionotropic, sorry, indeed expressed in vascular cells and they may cooperate to activate this NMDA receptor exactly as it happens in the brain. We didn't work that on these other receptor, but we are pretty sure they are at work in cooperation with the NMDA receptor. Why though an NMDA receptor? Because it's an ion channel permeable to calcium, and the calcium is an event which can be important in cell proliferation. In addition, the first thing we have shown in these remodeled vessels when we did mass spectrometry imaging was increased level of glutamate and glutamine, its precursor. That was also an additional element that makes us think about this NMDA receptor.
Dr Charlie Lowenstein: I want to go from the receptor to glutamate. There are three or four amazing things about your paper. One of them is that you suggest that cells in the vascular are releasing glutamate, which is a neurotransmitter. Do you think those are the smooth muscle cells that are talking to other smooth muscle cells by releasing these messenger molecules?
Dr Sylvia Cohen-Kaminsky: Yes. Smooth muscle cells are talking to other smooth muscle cells. But we also did some work on endothelial cells, and they are also able to release this glutamate. So we think that vascular cells in the vascular wall are discussing together through glutamate, although we don't know yet the normal function of this NMDA receptor in the vascular system. However, in the pathology it's very clear that there is this release. What is very interesting is that this release can be triggered by pathways which are already down-regulated in PAH, such as the endothelin-1 pathway.
Dr Charlie Lowenstein: Another remarkable part of your observation is that the signaling with glutamate and glutamate receptors is hyperactivated in the setting of a major human disease, pulmonary artery hypertension. How did you figure out that glutamate is so important in this special disease?
Dr Sylvia Cohen-Kaminsky: Because we showed, as I already told you, this glutamate accumulation in the remodeled vessel. We used this mass spectrometry imaging which allows analysis of metabolites directly in the remodeled vessels from sections performed from extended lengths. We saw this glutamate accumulation together with glutamine accumulation, so the ligand was overexpressed. In addition, when doing western blots from these remodeled tissue dissected from ongoing arteries, we have shown that we have a particular phosphorylation of this receptor which is very well-known in the CNS. This phosphorylation is involved in sending the receptor to the membrane and stabilizing the receptor to the membrane. Having this phosphorylation means that NMDA receptor is engaged, activated in the remodeled vessels in situ.
Dr Charlie Lowenstein: In an experimental model, you explored the role of glutamate in two very nice, complementary ways. One is with a genetic approach, the NMDA receptor deficiency. The other is using drugs. What were the drugs, what were the pharmacology that you used to block glutamate's transmission, and how did that affect the mice?
Dr Sylvia Cohen-Kaminsky: We used drugs that are very well known in the CNS. We used two drugs. One is memantine, which is already commercialized for the treatment of Alzheimer's disease. The other one is MK-801, which has been produced initially as a potential pharmacological drug but it was too potent to be used in the CNS. Therefore, this drug is only used in research at the moment. But these two drugs were able to act on this vascular remodeling and a number of PAH parameters. We have explored at least 12 parameters involved in this animal model of PAH, and hemodynamic stable parameters of hemodynamics including intra-arterial pressure, vascular remodeling, right ventricular remodeling with different parameters that shows a certain index. The cardiomyocyte hypertrophy, the fibrosis, the inflammation inside the right heart and around remodeled vessels, all these parameters were modified by the drug.
In addition, in vivo we have shown the destruction of the NMDA receptor glutamate axis with decreased engagement of the NMDA receptor in pulmonary arteries by following this phosphorylation I mentioned, decrease of apoptosis resistance and also proliferation. This was shown also after the treatment with the drugs, and also decrease of endothelial cell dysfunction that could be followed in the blood through selecting those H.
Dr Charlie Lowenstein: Your results with this drug were really impressive. I love that part of your study. You showed when you block glutamate signaling, first of all, the blood vessels looked much better in a model of pulmonary artery hypertension. In an experimental model, blocking glutamate transmission really improved the way the vessels look. But secondly, what was really amazing was, normally in humans one of the big problems with pulmonary artery hypertension, as you said, is the right ventricle gets inflamed and fibrotic, and a lot of patients die from complications of right ventricular dysfunction. In your model, when you treat with MK-801, blocking glutamate receptor, the right ventricle looks a lot better. It was really an impressive part of your study.
Dr Sylvia Cohen-Kaminsky: I think that this is view on the effect of the vessels themselves, then the right heart can recover. But we may have a direct effect in the heart. If you remember this Chinese restaurant syndrome, when you eat too much Chinese food, which is full of glutamate, you have some cardiac involvement, arrhythmia, and so on. Initially, toxicologists thought that it passed through the central nervous system. But then they realized that maybe the NMDA receptor is expressed in cardiac cells, and indeed it is expressed and is colocalized with the ryanodine receptor, meaning that it could have a function in the heart as well. But this has, of course, to be explored precisely. We know from the transplantation that, when we transplant on with the lung, the heart can recover very well. We may have these two effects. One due to the relief on vascular remodeling, and the other perhaps a direct effect on the heart.
Dr Carolyn Lam: You know, I have to chime in now. That cuts too close to home with the Chinese food and glutamate. First and foremost, I just really have to say, Charlie and Sylvia, it's people like you who make basic science come alive and simply extraordinarily exciting. Taking glutamate, something that we've talked about in the context of Chinese food and neurotransmitters, and therefore showing the potential to even repurpose perhaps some drugs for pulmonary arterial hypertension. So let me just round up by asking you, what do you think our next steps, how far are these findings away from clinical application? Perhaps, Charlie, your thoughts?
Dr Charlie Lowenstein: While I think that the use of MK-801 to treat excess monosodium glutamate during a Chinese meal, maybe that's a little bit premature. I'm much more excited about the idea of using glutamate-receptor antagonists to treat or prevent or even reverse pulmonary artery hypertension, both its vascular and cardiac complications. I'd love to ask Sylvia, do you think these medications in this class, do you think NMDA-receptor antagonists are ready for clinical trials?
Dr Sylvia Cohen-Kaminsky: In fact, they are not ready as they are. We have a program in which we have designed hypothesized new NMDA-receptor antagonist that do not go to the brain, because we want that treating PAH has to be safe, and we don't want to interfere with brain system. So we created this new NMDA-receptor antagonist that do not go to the brain. At the moment, we are in the process of the documentation. We have two patents for two series of molecules, and we expect the drug conjugate by the end of this year. To reconjugate means that we have a number of properties on this drug, the pharmacokinetics, metabolism, selectivity profile, toxicity, and so on. We are doing all this physical chemical properties, and of course validation of these new molecules in the animal models as therapy alone and also as add-on therapy with existing therapies, such as these vasodilators. We hope that we can have an additive effect between an NMDA-receptor antagonist and current PAH drugs.
Dr Charlie Lowenstein: Sylvia, as you know, drug companies about 10 or 20 years ago invented all these amazing glutamate-receptor antagonists to treat central nervous disease like stroke. One of the amazing things about your discovery is you're suggesting that glutamate receptors in the periphery are great targets as well. The exciting thing about your observation is you're really opening up new therapeutic approaches for targeting neurotransmitters in the periphery. I think your discoveries are tremendously exciting and could open up new avenues in treatment of a disease, pulmonary artery hypertension, for which there really aren't effective therapies right now.
Dr Carolyn Lam: I couldn't have said it better. Thank you so much, Charlie. Thank you so much, Sylvia.
See, listeners? Aren't you glad you heard it here right on Circulation on the Run? Don't forget to tune in again next week.
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.