Circulation July 10, 2018 Issue

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.