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Now displaying: October, 2016
Oct 31, 2016

 

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 interview today comes to you live from Rome at the European Society of Cardiology, where I talk to authors of The STICH Trial, about their ten year outcomes that help to answer the question, "Is there such a thing as being too old for coronary artery bypass surgery in heart failure?" But first, here's your summary of this week's journal:

 
 
The first paper provides experimental evidence that hypertension may be a bone marrow disease. In this paper, first author Dr. Wang, corresponding authors Dr. Li and [Sia 00:00:50] from The First Affiliated Hospital of Dalian Medical University in China, recognize that recruitment of leukocytes from the bone marrow to the vascular wall is a key step in the development of hypertension. Numerous factors stimulate this leukocyte migration during inflammation, including chemokines, which are low molecular weight proteins of the cytokine family which activate g-protein coupled receptors and induce migration of neutrophils, monocytes, and macrophages to the damaged vascular wall.

 
 
In this study the authors focus on chemokine receptor CXCR2. Using mouse models with hypertension they found that aortic MRNA levels of CXCR2 and its ligand CXCL1 are elevated in these mice with hypertension. They elegantly demonstrated that mice lacking CXCR2 are protected from blood pressure elevation, vascular inflammation of inflammatory cells, fibrosis, reactive oxygen species formation, NADPH activation and vascular dysfunction in response to either angiotensin 2 or [dolcasalt 00:02:01].

 
 
These results were recapitulated using a novel, allosteric inhibitor of CXCR2. Importantly, they also showed in 30 hypertensive patients compared to 20 normatensive controls that hypertensive patients have increased numbers of circulating CXCR2-positive cells and that there is a correlation between blood pressure and the number of CXCR2-positive cells in the circulation.

 
 
In summary, these findings that CXCR2 inhibition prevents and reverses hypertension and vascular dysfunction in response to multiple hypertensive stimuli really help us to understand the mechanisms involved in CXCR2 action, but also point to a potential clinical use of CXCR2 inhibition for the treatment of hypertension. This is discussed in a beautiful accompanying editorial by Drs. [Montenel 00:02:56] and Harrison.

 
 
The next study suggests that the eyes provide a window to long-term cardiovascular risk. In this paper from first author Dr. [Seidelman 00:03:12], corresponding author Dr. [Solomon 00:03:13] and colleagues from the Brigham and Women's Hospital, authors investigated whether retinal vessel calibers are associated with cardiovascular outcomes in long-term follow-up, and whether they provide incremental value over the 2013 ACCAHA pooled cohort equations in predicting atherosclerotic cardiovascular disease events. They studied 10, 470 men and women from the [Eric 00:03:41] or Atherosclerosis Risk in Community Study who underwent retinal photography at their third visit, which occurred in 1993-1995.

 
 
During a mean follow-up of sixteen years, narrower retinal arterials, but wider retinal venules were associated with long-term risk of mortality and ischemic stroke in both men and women. Coronary heart disease in women was also related to narrower retinal arterials and wider retinal venules independent of the the pooled cohort equation variables. In fact, retinal vessel caliber reclassified 21% of low-risk women as intermediate-risk for atherosclerotic cardiovascular disease events.

 
 
In discussing the clinical implications of these findings, the authors noticed that identification of coronary heart disease is frequently delayed in women and this under-recognition may party be due to the fact that non-obstructive coronary artery disease is more prevalent in women and micro-vascular dysfunction may largely contribute to myocardial ischemia in women. Since the retinal vessels offer an insight into micro-vasculature, adding retinal imaging may be of incremental value to current practice guidelines in risk prediction in low-risk women. This, of course, deserves further study.

 
 
The next study challenges the traditional focus on macro-vascular disease in Type 2 diabetes, namely myocardial infarction, strokes, and peripheral artery disease, and causes us to focus on micro-vascular disease instead. In this paper from first author Dr. [Sorrenson 00:05:33], corresponding author Dr. [Stiehauer 00:05:36], and colleagues from the Maastricht University Medical Center in the Netherlands, authors hypothesized that micro-vascular dysfunction occurs in pre-diabetics, which may explain the increased risk of complications of micro-vascular origin in pre-diabetes and early Type 2 diabetes.

 
 
They studied 2,213 individuals in the Maastricht study, which is population-based cohort study enriched with Type 2 diabetes, and they determined micro-vascular function, measured as flicker-light-induced retinal arterial[inaudible 00:06:12] percentage dilatation, as well as heat-induced skin percentage hyperemia. They found impaired retinal and skin micro-vascular function in pre-diabetics with further deterioration in patients with Type 2 diabetes. Inverse linear associations were found between micro-vascular function and measures of glycemia such as HBA1C, fasting and two-hour post-op glucose levels. All associations were independent of cardiovascular risk factors.

 
 
The clinical implications are that micro-vascular dysfunction in pre-diabetes may at least partially explain the increased risk of complications that are known to be of micro-vascular origin such as retinopathy and albuminuria but also diseases such as heart failure and cognitive decline. The take-home message is that both early hyperglycemia and micro-vascular dysfunction may be considered potential targets for early preventive intervention.

 
 
Well, those were your summaries! Now, let's on to Rome.

 
 
Hello, I'm Dr. Carolyn Lam, associate editor of Circulation, and I am so delighted to be reporting from Rome this time at the European Society of Cardiology. We are discussing the 10-year followup paper on STICH that includes an age analysis that is being featured as a hotline session of clinical trials update. I'm here with the distinguished guest, the first author, Dr. Mark Petchey, from University of Glasgow, the corresponding author Dr. Eric [Moleskus 00:07:51] from Duke University, and the associate editor who managed this paper, Dr. Nancy [Scheitzer 00:07:56] from University of Arizona. Welcome! [crosstalk 00:07:59]

 
 
Right, let's get straight into this. Eric, remind us what it first showed and why there's a need to look at the effective age.

 
Dr. Eric M. :
Thank you Carolyn. Thanks to Circulation and to both of you for really helping us work through this paper. We are very excited that we're being able to feature this work in Circulation. So, a STICH trial is a reminder. Surgical treatment of ischemic heart failure trial has been a 15-year effort actually that started with the first patient enrolled in 2002, enrollment ending in 2007 and at the ACC with the simultaneous fabrication in the journal, we published the 10-year results of the STICH trial, combining medical therapy vs. cabbage plus medical therapy in patients with ischemic cardiomyopathy defined as an EF less than 35%. Coronary disease [inaudible 00:08:51] to cabbage was over 90% having class 2 or greater heart failure systems.

 
 
What we showed in our 10-year results was that cabbage, when added to guideline-directed medical therapy, led to a substantial reduction in all-cause mortality, cardiovascular mortality as well as all-cause plus cardiovascular hospitalization in those patients who were randomized to the cabbage arm. This translated to about an 18 months extension in survival for the cabbage patients over that time period, a 16% relative risk reduction in mortality and nearly a 10% after the risk reduction is all-cause mortality, with the number needed to be treated of approximately 14.

 
 
With those findings, the next question that we want to address rapidly was whether there was an impact by age. This is what we're here to talk about, mostly because everyone recognizes that age is, although something we can't control ... As we age, our risk for everything increases, and clearly heart failure, which is the field that we work in clinically, patients who are older in heart failure have more risks, and worse clinical outcomes in patients who are younger. Whether there would be a benefit that would persist in terms of the treatment in younger as well as older patients was really the subject of this analysis.

 
Dr. Carolyn Lam:
That's great. So maybe, Mark, you could tell us the highlights of the results. Give us an idea, first of all, of the age range that we're talking about, what you looked at. And then- this is definitely going to be an issue if we're talking about age- the relative risks vs. the absolute risk of the different types of outcomes.

 
Dr. Mark P:
Sure. So, the patients in the STICH trial were similar age to a normal heart failure trial. The median age was around 61. What we did to look at the patients we had in the trial, we looked at quartiles, first of all. So the lowest quartile was aged less than 54, and the highest quartile aged more than 67. So we had a fair spread of age. We didn't have many patients, we were very elderly or very old. So 65% were above age 75 and 1% above the age of 80. When we looked at the patients we saw a similar [inaudible 00:11:18] to a usual heart failure trial. The older patients had more co-morbidities, not surprisingly, and they had more... they basically died more often as they got older as we see in every other trial.

 
 
When we started looking at the results, the treatment effects of cabbage, obviously we were very eager to know if the benefits, which Eric's talked about already were seen across all age groups. I think clinicians, when they look at patients for bypass surgery have anxieties around sending older people for bypass surgery. We were thrilled is probably the word to say that we say benefits across all age ranges. So the point has been for us in terms of all-cause mortality were all [less than one 00:11:58]. We saw consistent benefit, or certain across-the-board benefit in terms of all-cause mortality.

 
 
What we did see that we were very interested about were the younger patients got more benefit in terms of all-cause mortality, [inaudible 00:12:12] quite strikingly more. The risk reduction was over 40% for the ... We saw upper age groups having benefits with [hazard issues 00:12:24], risk reductions of, roundabout, the [teens 00:12:28], as in the major overall trial results, the younger patients got particular benefit.

 
 
We then looked at cardiovascular mortality and we saw a slightly different pattern. We saw the benefit was actually quite similar across all age groups. The older patients were getting the similar reduction in cardiovascular mortality as the younger patients. So there's the main take-home findings.

 
Dr. Carolyn Lam:
OK, so by extrapolation then, the younger patients, a greater proportion of their deaths were probably cardiovascular, or there's a bit more of a competing risk, so to speak from non-cardiovascular deaths in the elderly, is that kind of the idea?

 
Dr. Mark P:
Carolyn, that's exactly right. Because the cardiovascular mortality was similar across all age groups, because all people, as we know, die more commonly of non-cardiovascular events, we saw that clearly in the trial the benefits in terms of all-cause mortality weren't quite as much. Just to emphasize, the cardiovascular reduction was consistent across all age groups.

 
Dr. Carolyn Lam:
With bypass compared to medical, yes.

 
Dr. Mark P:
Exactly.

 
Dr. Eric M. :
I think an important aspect to remember and I think STICH reminds us is that even in the oldest population- and although we did these analyses continuously, we described this in quartiles for the purpose of the paper- we have to remember in heart failure patients like these who have coronary disease, cardiovascular death is the most common cause of death, regardless if you're young or old. What happens is that as we get older, there is an increasing rate of non-cardiovascular deaths. It's not surprising to us, that of the findings we found, which is that as the risk of non-cardiovascular deaths increase in the ages, the impact on all-cause mortality is mitigated slightly, while the effect on cardiovascular mortality remains consistent because it's still by far the most common cause, I think more than double the cause even in the oldest group.

 
Dr. Carolyn Lam:
That's a great point. Now I've got to ask something though. What did you do about crossovers? Because this is a 10-year thing. The original results of STICH came out 5 years. You'd expect that there's quite a bit of crossover or no?

 
Dr. Eric M. :
I'll just comment on the effect of crossovers in STICH in general, and then we can focus on the age analyses. What's really interesting is that in STICH approximately over time, over the time period, there was approximately an 18% rate of crossovers. That actually led to, by the intention to treat analysis, a decrease in the effect [inaudible 00:15:15] intention to treat. But when you look at crossovers, the medical therapy patients who were randomized to medical therapy but received cabbage at some point, and the patients who were randomized to cabbage but never did receive cabbage. But actually when you look at as-treated analyses, by the treatment they received, not [inaudible 00:15:36] they were randomized, the effect of cabbage actually increases. The relative risk reduction is about 25% in that group. Thankfully, the effect of crossover into different age quartiles were [inaudible 00:15:51] different. We had the same, relatively the same effect, so there were no, we were [eventually knowing 00:15:57] to make sure that there was no increase in crossover rates in the older vs. the younger and we did not find that. I started the discussion, maybe you can complete it.

 
Dr. Mark P:
Thank you for hitting the nail on the head, Eric, that there weren't many crossovers, but if there were crossovers, if the crossover towards the cabbage, the benefits seemed the be greater and that was seen across all age groups. There was no differential between the older patients and the younger patients.

 
Dr. Carolyn Lam:
You know then, I just want to know what's your take-home message and then I'd really like to hear from Nancy the take-home message we wanted to convey in our journal.

 
Dr. Mark P:
I think for me the take-home message goes back to the fundamental approach to assessing a heart failure patient in a clinic. Over the years there's been a tendency for patients not to investigate and look for coronary heart disease. People tend to focus on medical therapy and device therapy but the coronary arteries have been the poorer cousin. I think we would urge people to think about revascularization by surgery, coronary artery bypass drafting's a treatment for  for heart failure, so certainly, my practice, we look for coronary artery disease more than we think about the patient and weigh out the pros and cons and certainly this analysis was done to give us [granularity 00:17:14] from the perspective of the older person and the young person and the relative benefits. Basically, it's steered me towards looking for coronary artery disease. Also you can inform the patient in the clinic and have discussions with the surgeons about the benefit in terms of the all-cause mortality across the age group, and the cardiovascular mortality as well.

 
Dr. Carolyn Lam:
Yeah, it's consistent. That's brilliant. Nancy, speak on behalf of our journal.

 
Dr. Nancy S.:
So at Circulation, we were very excited to get this paper because as heart failure clinicians, we all struggle with this issue in older patients in particular. When we look and find coronary disease, these tend to be patients with higher surgical risks. Our surgical colleagues are often hesitant to operate. The benefits are perhaps less apparent, and this data's very helpful to show us that in a patient in whom the heart disease is the primary morbidity, surgical revascularization has a clear benefit for these patients.

 
 
I do think that it's important to remember though, that STICH population is a selected population, and probably a little healthier than the average patient we see in clinic. As Mark rightly pointed out, the discussions with surgical colleagues I think can now occur with a greater level of data substantiation and understanding of the true benefits, and then competing risks and morbidities in this patients need to be considered with the reality that surgical revascularization benefits the patients. We're really excited to have worked with you, this fantastic group of authors to get this paper to a point where I think it's really going to have a clinical impact, and that's what we're trying to do. As you know, Carolyn, editorial board at Circ now has published really high-quality science that's going to impact the practice of clinicians seeing patients on a daily basis.

 
Dr. Carolyn Lam:
Thanks so much for that Nancy, and actually I was going to congratulate you gentlemen. In your paper you so humbly said that these are exploratory, I think, and I was actually thinking that we're never going to have a better trial than this and it's something I am personally taking to be clinically applicable in my heart failure patients so congratulations. I'm going to switch tracks a little bit... we're actually going to a simultaneous publication in Circulation from the European Society of Cardiology and I think that's really neat for our journal, Circulation. I want to ask each of you as author perspective and as associate editor who made this happen, what do you think of these simultaneous publications? Were there challenges, what was it like, and what was your experience like?

 
Dr. Mark P:
So I have to confess that usually when we submit papers for review, there is a mixture of trepidation, fear, generally quite negative thoughts. We submitted it, and I've got to say that it was the most interactive, positive experience I've had so far. It was quite clear that was interested in the data, and wanted to publish it in a way that informed the clinical community. They certainly worked with us to make sure the message was honed and as accurate as possible to reflect the results. We were really thrilled. It was a "breakneck pace" is also probably the best way to describe it. We worked day and night actually, but there was phone calls and emails happening in very rapid sequence and lots of responsiveness. I could almost describe it as "fun".

 
Dr. Carolyn Lam:
Kudos to you, Nancy! And from your point of view, was it fun?

 
Dr. Nancy S.:
It actually was fun.

 
Dr. Carolyn Lam:
(laughs)

 
Dr. Nancy S.:
You know, we've all had the experience of- on both sides- being an editor and being an author. Getting a paper, getting reviews, sending it back, getting the revision, it's not quite what you want, reviewing it again, sending it back, getting it back, it's not quite what you want, and then you feel obligated to publish a paper that's not really what you want. What we've decided to do is a much more interactive process to say "We're going to work with you to make this the paper we want to publish. We hope that as authors that's the paper you want to have written." We're doing this on a regular basis at Circulation but this was at hyperspeed, I would say.

 
Dr. Carolyn Lam:
[inaudible 00:21:34] how long?

 
Dr. Nancy S.:
We knew the paper was going to come in. We had been in contact with Eric. I identified reviewers before we even received the manuscript. I identified reviewers who would commit to a 72-hour turnaround. In fact, our reviewers did it in less than 24 hours. Then I looked at it, added to it, called Eric, and we talked it over. And then we sent it back with the formal replies. I think Mark then worked 24/7 to get it back to us very quickly. I worked with one of the senior associate editors; at that point we didn't involve the reviewers. We basically track-changed the paper to make the changes we really thought were necessary at the point. It wasn't a lot but I think they were critically changes. At that point, Mark and Eric were kind enough to accept those changes and the paper was on track for simultaneous publication. I do want to mention that we have simultaneous publication of five different presentations here at ESC in Circulation online which is certainly a record for Circulation and we're really proud of that.

 
Dr. Eric M. :
First of all, I want to think the journal. Really a remarkable, wonderful experience. I've been very fortunate in my career to be in a position to submit simultaneous publications previously, and this was a wonderful- I think it was a 14-day turnaround, it was remarkable. And the responses from the reviewers were outstanding even if they were reviewed in a very short time, and I think the paper definitely improved.

 
 
A general comment about simultaneous publications as you bring it up, I think it's an area of controversy. I think my perspective as a person who does clinical trials, as well as sees a lot of patients, there's an ethical mandate that exists to... Once you have information that you're putting out there, to be in a position, if we think it's clinically impactful, and we feel that the data is mature, to get that into people's hands, all of it, as soon as possible. There's a certainly a difference between what I can speak to in 8-10 minutes on stage with slides that will get distributed anyway across the world, and what, with Nancy's help, we are able to put into journal-wide circulation and really explain the story and give it a full [vetting 00:24:05]. I feel like, from the ethical perspective, being able to push forward with this simultaneous publication is in the best interest of our patients, and it's so exciting to see Circulation now doing this with the European Society, which is a remarkable achievement for this new editorial board, so thank you again.

 
Dr. Carolyn Lam:
You've been listening to Circulation on the Run. Tune in next week for more.

 
 

Oct 24, 2016

 

Carolyn:
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. We have such a special podcast for you today. The entire podcast is going to be a conversation with two very special guests, Dr. Marc Ruel from The University of Ottawa Heart Institute, the guest editor of the surgery themed issue this week. Hi Marc.

 
Marc:
Hello Carolyn. How are you?

 
Carolyn:
Very good. Especially because we also have Dr. Timothy Gardner, Surgeon, Associate Editor from Christiana Care Health System. Welcome back again, Tim.

 
Timothy:
Thank you, Carolyn. Glad to be here.

 
Carolyn:
Marc, could you first give us an overview of the surgery themed issue from your perspective.

 
Marc:
This year as we have had on previous years, we are having a surgery themed issue which comprises what I would argue which is some of the very best cardiac surgical science can offer to the wide readership in the cardiovascular community that served by circulation. This year, we will have a total of ten articles that would be published in circulation, as a section of one of our regular issues and out of those ten, there are five original papers. There's one research letter which is an original research article but in a shorter format and we'll also have one invited perspective paper namely about coronary artery bypass grafting and its future with respect to multi-arterial grafts and the themed issue will be completed by three state of the art papers that deal in a very in depth comprehensive way with some important problems that the cardiovascular community faces from a clinical point of view.

 
Carolyn:
Thanks Marc. That was a beautiful summary of the issue. I couldn't help but notice that there was a theme of coronary artery bypass surgery covering at least four of the papers and I really like your thoughts on that. You covered everything from medical therapy, CABG versus PCI, on versus off-pump, emergency surgery in the setting of shock. Could you go through each of these four papers a little and tell us what was your take home message from each?

 
Marc:
As you said, there are three original research articles and one invited perspective that relate to coronary artery bypass grafting surgery and these encompass the number of clinical problems that are still controversial and certainly I believe they contribute a very, very significant [inaudible 00:02:31] with the wealth of knowledge that the cardiovascular community is looking for at this point. If I may go one by one, just with a very high level overview, if you will. The first one is a paper from the Leipzig Heart Center with first author, [Pieroz Adewalla 00:02:45], which looked at surgery for acute myocardial infarction but accompanied with cardiogenic shock. As you know, many patients undergo surgery in an acute MI context, but surgery for cardiogenic shock is often a very gruesome difficult decision.

 
 
Leipzig Heart Center looked at over 3,000 patients who had an acute MI prior to cardiac surgery for bypass surgery and of these, there were 508 patients who actually had cardiogenic shock due to [valve 00:03:15] failure with myocardial dysfunction and to give you an idea, these patients were quite sick. There's about 40% of the patients who were ventilated prior to surgery or very close to 40%. The timing was quite urgent, those patients were on inotrophes and on vasopressors to support their blood pressure prior to operation. Essentially, what they found is that first the outcomes got better over the last number of years, this is a series that dates back to about the 2000's, so the early 2000's.

 
 
They also favor an approach where they tried to avoid a cardioplegic arrest of the heart. Their favored overall approach is to do what we call on-pump beating heart type of surgery which would be a surgery where the cardioplegia would not be administered to stop the heart but the hemodynamics would be supported for the cardio coronary bypass. They also have over the years since the beginning of this year, is in 2000 ranging up to 2014 of increasing the use of the off-pump bypass surgery and certainly the outcomes have been better and the mortality although high has decreased significantly. It was as high as 40% in the early parts of the cohort if you will and in the latest third of the experience, therefore from 2010 to 2014, the mortality has been down to about 25%.

 
 
Again, these are patients who present with cardiogenic shock. What's also interesting to note is that patients who survive out of hospital still have a significant mortality burden and about 50% of them survive long term. What was interesting is the  Leipzig group is looking at some predictors of bad outcomes in those patients and they found that the serum lactate over four minimal per liter was actually a very robust and multi-variative predictor of a poor outcome after surgery.

 
Carolyn:
That was a great summary of that first paper. You mentioned beating heart surgery and so on. Would you like to comment on next paper that I think was the largest single institution European study comparing on versus off-pump bypass surgery?

 
Marc:
You're absolutely right. This is a paper from England, [inaudible 00:05:25] from Liverpool, where the patients were gathered from and with some contribution from Oxford as well from a statistical and methodological point of view and it's a retrospective cohort study of all isolated CABG patients in Liverpool between 2001 and 2015. These are bypass surgery patients and in total, there were over 13,000 patients who had CABG. About 6,000 patients had off CAB which is off-pump bypass surgery and more than 7,000 had bypass with cardiopulmonary bypass. The median follow up was 6.2 years. What's interesting in this paper is that they essentially found equivalent long term outcomes. As you know, there has been some debate regarding the completions of myocardial revascularization and the long term graft patency with off-pump surgery versus on-pump surgery. Also named conventional CABG.

 
 
What's interesting here is that the benefits of off-pump CABG appear to be seen early on with regards to antiemetic release as stroke rates, etc. Which does correspond to some of what has seen in the randomized controlled studies. However, the long term data is interesting. There's a a nice editorial about this paper written from a group from the Cleveland Clinic with Dr. Joe Sabik as the senior author and essentially it raised a number of good points, although this is an important series, it also shows that the surgeons who are very good at off-pump bypass surgery may overall be slightly technically more skilled at doing bypass surgery in itself and for instance, use more often arterial grafts and have more advanced techniques in their completion of bypass surgeries for their patients.

 
Carolyn:
Right. I'm so glad you mentioned the editorial. I was about to bring that up as well. Switching gears to you very kindly included a paper that talked about medications and the impact of here is the medical therapy on the comparative outcomes between CABG and PCI. Would you like to discuss that paper?

 
Marc:
This is a paper from the Care Registry which has generated some interesting publications in the past. The lead author is Dr. Paul Polinski and there's co-authors, Dr. Herbert Prince and Michael Mack from Dallas as well. This was presented at the science sessions in Orlando last November and it's an interesting paper. Essentially they have looked at large databases, again the Care Registry which comprises eight community hospitals and they look at six month period of performance of CABG and those eight community hospitals. They ended up with over 2,700 patients who were then systematically followed on a regular basis up to 2009 at which time the database was locked.

 
 
They look at various outcomes but also medication use in great detail over that period of time and the interesting perspective that this paper brings is that first, most patients at least in that period were not on optimal medical therapy. The authors used their own predefined definitions of what constitutes optimal medical therapy and this is with regards to adherence to aspirin use, lipid lowering agents, beta blockers and indicates of PCI, dual anti-platelet therapy. As expected but nicely documented in this paper, the outcomes of patients who were not on optimal medical therapy were much worse than those who were and CABG proved to be more robust in patients who were not on optimal medical therapy compared to PCI.

 
 
The differences between CABG and PCI in patients who were on optimal medical therapy tended to vanish. However, a number of caveats here is that only 25% of patients in fact in this cohort were on optimal medical therapy. The vast majority of patients were not considered to be on optimal medical therapy. Therefore, there are considerations of definitions that one has to be aware of and also considerations of statistical power because the group that was on optimal medical therapy was much smaller than the other group. Therefore, the effects, the superiority of CABG over PCI could only be firmly demonstrated in the group was not on optimal therapy, again comprising 75% of patients in this cohort.

 
Carolyn:
I love your summaries and they really show that these are true significant original contributions to that knowledge gaps in coronary artery bypass surgery. To round it all up, you also invited a perspective on novel concepts. Would you like to comment on that paper?

 
Marc:
This is an invited perspective in the view classifications that circulation has which is entitled, "The evolution of coronary bypass surgery will determine relevance as a standard of care for the treatment of multi-vessel CABG." It is authored by three leaders in the field, Dr. Gener, Dr. Gudino, and Dr. Grouw. Dr. Gener has been leading several of what I would call the advanced multi-vessel coronary re-vascularization trials looking for instance at multi-arterial grafts doing numerous anastomosis with two ventral mammary arteries in a wide fashion. He's been a leader of this movement certainly. Dr. Gudino recently published [inaudible 00:10:43] the 20 years of outcome of the radial artery graft and certainly has been one of the pioneers which use of this arterial graft for coronary artery bypass surgery. What the authors provide here is a very nice summary of what the trials have shown so far and they also report as many know that their rate of multi-arterial grafts use in SYNTAX, FREEDOM and I think we will soon see in EXCEL and NOBLE that will be presented this fall, has not been as high as it should have been.

 
 
In the US, it is estimated right now that the rate of use of more than one mammary artery is less than 10% across the nation, and other countries have not performed better than this either. This perspective is a call to improving the quality of multi-vessel coronary artery bypass mainly through the use of multiple arterial re-vascularization. There is also considerations around the hybrid coronary re-vascularization and as well as the use of off-pump versus on-pump surgery.

 
Carolyn:
I am really proud and privileged to have helped to manage one of the papers as associate editors in this issue as well and that is the paper from the group with corresponding author, Dr. Veselik, from Boston Children's Hospital and it centers around patients with congenitally corrected transposition of the great arteries but a management problem that is really increasingly encountered and really needs to be reviewed properly and that is the management of systemic right ventricular failure in these patients. Tim, you were so helpful in looking at this paper as well. Could you share some of your thoughts?

 
Timothy:
Well, this is a somewhat unique situation where a patient with this condition, congenitally corrected transposition of the great arteries may go through early life, in fact may end up as a young adult before this particular condition is identified because if there is no shunting or no cause for cyanosis and heart murmurs and so on early on, the circulations seem to work pretty well until the poorly prepared right ventricle which is the systemic ventricle, starts to fail after years of work carrying the systemic circulation and that is really the focus of the paper. There's been a lot of work and publications and attention to transposition syndromes but this particular one is a condition that may be first encountered by adult heart failure cardiologist who have not had this kind of exposure to congenital heart disease. It's a particularly apt paper to bring this condition to our attention and to demonstrate that really it's the adult heart failure cardiologist who may be managing these patients in their late 20's or 30's, when that systemic right ventricle fails because of a lack of formation to manage the systemic circulation.

 
Carolyn:
Exactly. Written by a group that has one of the most robust experiences in this field, so that also brings to mind another state of the art article in the issue that refers to the hypoplastic left heart syndrome and though it's entitled that and people may think it's rare, I think it's increasingly being seen in the adult cardiology world as well. You want to comment on that one?

 
Timothy:
That actually is one of the main points of this paper that this very, very difficult condition of hypoplastic left heart syndrome that requires staged operations beginning in the neonatal period has now reached the state of surgical accomplishment in medical management where many of these young children are surviving into young adulthood. Albeit, with having had two, or three, or four operations. In a community like ours here in Delaware, where pediatric patients transition to adult services and adult cardiologist sometime around their 20's, it's really important for the entire cardiology community to be aware of what has happened in terms of the successful staged treatment of children with hypoplastic left heart syndrome and that is brought out very nicely by the three authors who look at various accomplishments and different techniques for managing these staged repairs. It is very amazing to someone who has been observing this field for sometime as I have, that many of these children are in fact surviving into young adulthood and will require comprehensive cardiovascular treatment, not just by neonatal specialist but by specialist in adult congenital heart disease.

 
Carolyn:
Exactly, which is why such a timely state of the art articles both of them for this issue. There is another state of the art article that you were handling, Tim, "The Surgical Management of Infective Endocarditis Complicated by Embolic Stroke", now that's an important topic.

 
Timothy:
Absolutely, as we know up to a half or more of patients with infective endocarditis primarily on their left sided heart valves will have cerebral embolic problems and it has really been a dilemma for many of us in terms of optimal timing for the cardiac surgery with respect to the existence of cerebral injury from the embolism, from hemorrhage that may occur, from hemorrhage that may be exacerbated by placing the patient on the heart-lung machine, etc, and this paper really takes an extremely comprehensive, careful and judicious look at all of the evidence that has emerged and it has been a confusing field of evidence as to how to best optimally manage these patients with cerebral involvement from infective endocarditis.

 
 
I think this paper is going to have a big impact. It appears that there are a couple of messages that I took away from this paper. Number one, we really need to use the full panoply of diagnostic opportunities or diagnostic test for characterizing the nature and the extent of the cerebral involvement in these patients and then perhaps even more important, we need to convene what the authors called the infective endocarditis team and that has to include not just the surgeon, the cardiologist and the infectious disease specialist but also the neurologist, the neuro-interventional specialist, the neurosurgeon and so on because all of these specialist need to contribute to the assessment and choosing the optimal timing for these patients.

 
 
That is the central message of the paper. The authors also suggest that we may be getting to the point where we need to update and make sure that the guidelines that we're using are in fact current. Current in the sense that the experience now with advance imaging and with more aggressive management of the neurological or cerebral issues really need to be factored into how best to handle these patients, but I think this paper is going to have a big impact, it's very well written and very thorough.

 
Carolyn:
I agree. In fact all the content we just discussed is just so rich. Congratulations on such a beautiful issue. Marc, do you have any last highlights you'd like our audience to hear about?

 
Marc:
I'd like to also mention two other original research papers that will be featured in the surgery themed issue. One, in keeping with the congenital theme that we had talked about is about the modified [Straun's 00:19:08] procedure for palliation of severe Ebstein's anomaly and this is a series actually from Professor [Straun 00:19:16] himself mostly originating from Children's Hospital Los Angeles and essentially, the series here is that of 27 patients about equal in gender distribution who were operated at seven days of life, between 1989 and 2015.

 
 
It's very interesting that patients did well, the survival at ten years is 76% and most of them have undergone successful Fontan completion. I think this is a very important paper not only because it is an extremely vexing and difficult problem to deal with Esbtein's anomaly but it comes from the innovator of the operation himself with his team and it provides much needed data regarding the long term outcomes of these children with this very difficult solution. I think this will be of great interest and also as we commented before veering into the world of adult cardiology as well, because fortunately most of these patients survive into adulthood.

 
 
The other paper I wanted to touch upon which is also an original research paper that will be in this themed issue, is a paper from the CTSN Group looking at the impact of left ventricular to mitral valve are being mismatched on recurrent ischemic MR after ring annuloplasty and this paper used the free innovative and interesting methods. As some of you may know, there were two large files recently that were conducted by the CTSN looking at either moderate MR at the time of coronary artery bypass grafting or at severe ischemic mitral regurgitation. The randomizations were different when the moderate MR was CABG lone versus CABG post mitral valve repair and the severe MR was mitral valve repair versus mitral valve replacement.

 
 
These studies have led to interesting conclusions that several will know about but what's been interesting in the current study is that they have gathered all patients who underwent mitral valve repair from both studies, original randomized trials and they ended up with about 214 patients who underwent mitral valve repair. The others had moderate or severe MR and basically the point of this study is to look at predictors of failure of mitral valve repair and this is an extremely relevant problem, not only for the cardiac surgical community I would venture, but also for heart failure community and for JV General cardiology community. What the others found is that the most important predictor of recurrent mitral regurgitation after mitral valve repair was something called the left ventricular and systolic diameter to ring size ratio and they provide an algorithm which will have to be tested clinically with regards to whether it is applicable and indeed changes outcome, but this is a very important discovery in the field of ischemic MR and enabling us to hopefully better understand and improve outcomes for patients with this very difficult problem.

 
Carolyn:
I agree. Thank you so much, Marc and Tim for this most insightful discussion. Thank you very much and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next next week for more highlights and features.

 
 

Oct 17, 2016

Carolyn:
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 what the clinical implications of very brief episodes of device-detected atrial tachyarrhythmias are? Well, we will be discussing this with novel data from the RATE registry in just a moment. First, here's your summary of this week's journal.

 
 
The first study provides the first evaluation of the Sweden nationwide abdominal aortic aneurysm screening program. Of almost 303,000 men invited for screening, 84% attended. The prevalence of screening detected abdominal aortic aneurysm was 1.5%. After a mean of 4.5 years, 29% of patients with aneurysms had been operated upon with a 30-day mortality rate of 0.9%. The introduction of screening was associated with a significant reduction in aneurysm-specific mortality. The number needed to screen to prevent 1 premature death was 667, while the number needed to operate on to prevent 1 premature death was 1.5.

 
 
Furthermore, the authors showed that their screening program was highly cost-effective in the contemporary setting in Sweden. These findings confirm results from earlier randomized controlled trials in a large population-based setting, and may be important for future healthcare decision-making. This and the diverse requirements for efficient population screening for abdominal aortic aneurysm, from program management to maintaining skills in open repair are discussed in an excellent accompanying editorial by Dr. Cole from Imperial College London.

 
 
The next study looks at thoracic epidural anesthesia and suggests that caution may be needed in patients with or at risk for right ventricular dysfunction. You see, thoracic epidural anesthesia involves blockade of cardiac sympathetic fibers, which may affect right ventricular function and interfere with the coupling between the right ventricle and right ventricular afterload. Dr. Wink and colleagues from the Leiden University Medical Center therefore used combined pressure volume conductance catheters to study the effects of thoracic epidural anesthesia on right ventricular function and ventricular pulmonary artery coupling in 10 patients scheduled for lung resection.

 
 
Thoracic epidural anesthesia resulted in a significant reduction in right ventricular contractility, stroke work, dP/dt max and ejection fraction. This was accompanied by a reduction in effective arterial elastance such that ventricular pulmonary coupling remain unchanged. Clamping of the pulmonary artery increased right ventricular contractility but decreased ventricular pulmonary coupling. These effects of increased afterload were the same before and after thoracic epidural anesthesia. In conclusion, therefore, thoracic epidural anesthesia impaired right ventricular contractility but did not inhibit the native positive ionotropic response of the right ventricle to increase afterload. These findings are clinically relevant for daily practice in cardiothoracic surgery because pulmonary hypertension is frequently encountered, and right ventricular function is an important determinant of early and late outcomes.

 
 
The next study suggests that the use of point of care hemostatic testing may have a place in the management of patients undergoing cardiac surgery. Dr. Karkouti and colleagues of the Toronto General Hospital hypothesized that point of care hemostatic testing within the context of an integrated transfusion algorithm would improve the management of coagulopathy in cardiac surgery, thereby reducing blood transfusion. They therefore conducted a pragmatic multi-center stepped-wedge cluster randomized controlled trial of a point of care based transfusion algorithm in 7,402 consecutive patients undergoing cardiac surgery with cardiopulmonary bypass in 12 hospitals in Ontario, Canada. They found that the trial intervention reduced rate of red cell transfusion with an adjusted relative risk of 0.91 and a number needed to treat of 24.7.

 
 
The intervention also reduced rates of platelet transfusion and major bleeding but had no effect on other blood product transfusions or major complications. These findings that point of care testing improved management of coagulopathy in cardiac surgery support the consideration of their broader adoption in clinical practice.

 
 
The next study provides experimental evidence that brings us one step closer to therapeutic targeting of arterial leukocyte recruitment in the context of atherosclerosis. In this study from first author Dr. Ortega-Gómez, corresponding author Dr. Soehnlein and colleagues from LMU Munich, authors focus on cathepsin G, which is stored in neutrophil and azurophil granules and discharged upon neutrophil activation. They studied site-specific myeloid cell behavior after high-fat diet feeding or TNF stimulation in the carotid artery, the jugular vein, and cremasteric arterioles and venules in APOE E and Cathepsin G-deficient mice.

 
 
Their studies revealed a crucial role for Cathepsin G in arterial leukocyte adhesion, an effect that was specific for the arteries and not found during venular adhesion. Consequently, Cathepsin G deficiency attenuated atherosclerosis but not acute lung inflammation. Mechanistically, Cathepsin G was immobilized on arterial endothelium, where it activated leukocytes to firmly adhere, engaging endocrine clustering, a process of crucial importance to achieve effective adherence under high-sheer flow.

 
 
Therapeutic neutralization of Cathepsin G specifically abrogated arterial leukocyte adhesion without affecting myeloid cell adhesion in the microcirculation. Repetitive application of Cathepsin G-neutralizing antibodies really allowed the inhibition of atherogenesis in the mice. Taken together, these findings presented evidence of an arterial-specific recruitment pattern centered on Cathepsin G adhesion, thus representing a potential novel strategy and target for the treatment of arterial inflammation. Well, that wraps it up for the summary of this week's journal. Now, for our featured discussion.

 
 
Our feature paper for today discusses the clinical implications of brief device-detected atrial tachycardias and really novel findings from the RATE registry. I'm so happy to be here with the first and corresponding author, Dr. Steven Swiryn from Feinberg School of Medicine, Northwestern University. Hi, Steven.

 
Steven:
Good morning.

 
Carolyn:
We also have with us Dr. Mark Link, associate editor from UT Southwestern. We all know that prolonged episodes of atrial tachycardia or atrial fibrillation are associated with increased risk and that if we anticoagulate those with a high CHA2DS2–VASc score, we can lower the risk of stroke. Now, the European Society of Cardiology guidelines also say that recent data reinforced the assumption that even brief episodes of silent atrial fibrillation may convey an increased risk of stroke. We also know that prior studies have looked at device-detected atrial fibrillation. Steven, I'd really love if you could start by telling us what makes your study different. What was the main thing you were trying to look at?

 
Steven:
Well, one reason it's attractive to use the device population, patients with pacemakers or defibrillators, to look at these issues is because devices have a very high likelihood of detecting episodes of atrial fibrillation whereas symptoms or single 12 EKGs miss a lot of atrial fibrillation, so the sensitivity is much higher, although not perfect. The problem is that very brief episodes of atrial fibrillation are very poorly detected by devices. The specificity of automatic detection is very low, such that all previous studies until the RATE registry have excluded any episode of atrial fibrillation detected by a device less than 5 minutes in duration because they're unreliable. A lot of them turn out to be false positive detections. Our study was designed to evaluate whether even very brief episodes of an atrial tachyarrhythmia might also be associated with risk of clinical events and might or might not warrant anti-coagulation.

 
Carolyn:
Ah, that's interesting, so you really helped to answer how brief is "brief" when we need to talk about device-detected atrial fibrillation. Could you expand on how you actually defined "short episodes" here?

 
Steven:
Right. A short episode for the purpose of the RATE registry was defined as an episode where the electrogram that we scrutinized had both the onset and the offset of the episode within the same electrogram tracing, so although we can't put a specific time duration on it because that wasn't part of the criterion, it's typically less than 20 seconds or so, although not always, whereas a long episode was defined as an electrogram where either the onset and/or the offset was not captured by the device memory and therefore we don't know the duration. Some of those may not have been very long, and some of those may have been extremely prolonged episodes. That allows us to actually scrutinize the electrogram. We looked at 37,530 individual electrograms using 8 teams of adjudicators, each with a physician and a field clinical engineer from the device company so that we could actually say definitively, "Yes, this was atrial fibrillation," or, "No, it wasn't."

 
Carolyn:
This is the first study to really look under that 5-minute limit of atrial tachycardias. What did you find?

 
Steven:
Well, we found that in contrast to prolonged episodes, short episodes of atrial tachyarrhythmias were not associated with an increased risk compared to those without atrial fibrillation of pre-defined clinical events, including death from any cause, heart failure, stroke, hospitalization for atrial fibrillation, and a few other smaller events.

 
Carolyn:
This was over a 2-year follow-up period, is that right?

 
Steven:
The median follow-up was slightly less than 2 years, that's right.

 
Carolyn:
What I really was struck with was also the second finding, the propensity to develop longer episodes. Could you expand on that?

 
Steven:
We reasoned that in the clinic, one might be faced with a short episode was we defined them, and then you don't know what's going to happen for the next 2 years to bring to bear the results of our study. We looked at if your first episode was short, what was your likelihood over the full follow-up of the study of progressing to longer episodes. About 50% of patients who had their first episode as only a short episode progressed to a longer episode over the full follow-up and therefore were in the long category for the rest of the results. Half of them never got a longer episode.

 
 
It was, as one might imagine, if you had your first short episode very early in the study and had a longer follow-up, you were more likely to end up in the long category, and if you had very frequent short episodes, you were also more likely to end up in the long category by the time the full follow-up was over with. Having an initial short episode is not a guarantee that you're never going to get a long episode and that you'll never acquire a consideration of anti-coagulation.

 
Carolyn:
That was a very important message to me as well because it meant that although I can be secure or reassured by these data for very short episodes, I needed to look out for the development of longer episodes, at least that's what your registry showed over 2 years of follow-up. I'm curious, Mark, what were your take-home messages because that leaves us with a bit of a conundrum. What do we do about anti-coagulation in these patients?

 
Mark:
I think this study is a big help to the practicing electrophysiologist and practicing cardiologists. It's a very ledger number of patients with a lot of episodes of afib. It's reassuring to me that the shorter episodes of afib as defined by the study, the individuals did not have a higher incidence of stroke compared to those with no episodes, so it's reassuring and very important clinically as I go through my practice.

 
 
I do look forward to more analyses and more data from this study because although now we know that episodes less than 20 seconds are in all likelihood not going to need anti-coagulation, we still don't know about those from 20 seconds to 5 minutes. Hopefully with more analysis of this study we'll get that answer also.

 
Carolyn:
Steven, do you agree with that?

 
Steven:
We would love to have that. At first glance, you would think that devices would give you all of the data you needed because after all, they're monitoring the patient 100% of the time, but there are difficulties with that because device memory is limited, and you don't get electrograms that go on until the termination of atrial fibrillation even if the device were accurate in determining when that termination was because depending on how the device was programmed and depending on whether it was a more modern device later in the trial or earlier and had more or less memory, it cuts off after a limited amount of time, and you don't see necessarily how long the duration is.

 
 
Now, you can use device-based data. The device gives you its estimate of how long the episode is, but those are not as reliable as adjudicating the electrograms and actually looking at them. Those data would be a little softer than the main results if we get there.

 
Mark:
That was the data that was used for all of the other studies, was [transassert 00:14:51]. It would be comparable to those other studies. I still think it would be very important data that I'd love to see.

 
Steven:
Okay, well, I agree. I think it would be very interesting to look at that and a number of other things. We have a number of other things we could do with this database. There are a number of substudies that are in progress. For example, one interesting one is there were some instances we found, because we actually looked at these electrograms, there's something that we termed "competitive atrial pacing," where the device will pace at times when we as clinicians would not want to pace. For example, pacemaker-mediated tachycardia would be an instance of that, but then you can pace in the atrium inappropriately. There's a rhythm called repetitive non-reentrant ventricular atrial systole, which, although it's exotic to all of us, actually turned out to be fairly common where there's pacing in the atrium that occurs for various reasons when we want it to.

 
 
We actually saw instances where the device itself induced atrial fibrillation. It wasn't that common, but we did see it. We have a substudy that we're working on about the subjective competitive atrial pacing to see how much of that there was and of what, if any, consequence that was. That's one of the things that's been done. Because we scrutinized these so carefully, we tracked morphology and atrial rate at least as a crude estimate, and we have those data, so we could actually evaluate whether if something looks very, very rapid and disorganized as opposed to more organized electrograms at a slower rate, did that make any difference. We don't have any results for those analyses yet. I agree with Mark that the intermediate durations would be interesting to look at.

 
Carolyn:
I agree too, and I'm really grateful for you sharing those thoughts. Very grateful for both of you for your time today. I just have to congratulate you. I completely agree this paper fills an important knowledge gap, and congratulations once again.

 
Steven:
Thank you very much.

 
Mark:
Thank you.

 
Carolyn:
Thank you for listening. You've been listening to Circulation on the Run. Please tune in next week.

 
 

 

Oct 10, 2016

 

Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, Associate Editor from the National Heart Center and Duke-National University of Singapore. Today's featured discussion deals with the perspective piece entitled, What I Wish Clinicians Knew About Industry and Vice Versa. Intriguing, isn't it? I can tell you it is one of the best papers I have ever read, so stay tuned. First, here's your summary of this week's journal.

 
 
The first study takes a step towards understanding atrial fibrillation on a more fundamental level by demonstrating that some patients have altered left ventricular myocardial energetics even in the absence of other comorbid diseases. First author, Dr. [Veejay Surendra 00:00:50], corresponding author, Dr. [Cassidy 00:00:53] and colleagues from the University of Oxford studied 53 patients with lone atrial fibrillation undergoing catheter ablation and compared them to 25 matched controls without atrial fibrillation. They did this using sequential studies of cardiac function with magnetic resonance imaging as well as energetics with phosphorus-31 magnetic resonance spectroscopy.

 
 
At baseline, there was subtle but significant left ventricular dysfunction and abnormalities in ventricular energetics in patients relative to controls. Following ablation of atrial fibrillation, left ventricular function measured by ejection fraction and peak systolic circumferential strain improved rapidly with a switch to sinus rhythm but remained at normal at 6 to 9 months. Although pulmonary vein isolation effectively eliminated atrial fibrillation in all the patients in the study, the hearts continued to express an energetic profile consistent with a myopathic phenotype meaning that the ratio of phosphocreatine to adenosine triphosphate was lower in the atrial fibrillation compared to controls irrespective of recovery of sinus rhythm and freedom from recurring atrial fibrillation.

 
 
The clinical implications of these findings are that apparently lone atrial fibrillation may actually be a consequence rather than a cause of an occult cardiomyopathy and that this cardiomyopathy is unaffected by ablation. Of course, future studies are needed to prove this and to examine whether therapeutic strategies that target the adverse cardiometabolic phenotype could reduce atrial fibrillation recurrence. These important issues are discussed in an accompanying editorial by Doctors Hyman and Callans.

 
 
The next study provides experimental evidence that suggests we may finally have an answer to heart failure preserved ejection fraction or HFpEF, and that is the modification of titin. Titin is a sarcomeric protein that functions as a molecular spring and contributes greatly to left ventricular passive stiffness. The spring properties can be tuned through post-transcriptional and post-translational processes and their derangement has been shown to contribute to diastolic dysfunction in patients with HFpEF. The current paper by first author, Dr. Methawasin, corresponding author, Dr. Granzier and colleagues from University of Arizona provide important proof of principal investigation of the effects of manipulation of titin isoforms as a treatment for a transverse aortic constriction murine model of progressive left ventricular hypertrophy leading to HFpEF.

 
 
Conditional expression of a transgene with deletion of the RNA recognition motif for one of the splicing factor, RBM20 alleles, resulted in reduced splicing and a substantial increase in larger more compliant titins that were named super compliant titin. The result was normalization of passive stiffness of isolated muscle strips as well as normalization of left ventricular diastolic function and chamber stiffness as assessed by echocardiography and pressure volume analyses. There were no effects on extracellular matrix stiffness. The authors also showed that other spliced targets of RBM20 did not contribute to the results and thus, the beneficial effects were almost certainly entirely related to the changes in titin isoforms.

 
 
Furthermore, treadmill exercise was used to show that treated animals displayed improved exercise tolerance. In summary, the study showed that increasing titin compliance in this murine model resulted in marked improvement in multiple measures of diastolic function and performance, thus suggesting that titin holds promise as a therapeutic target in HFpEF. This is the discussed in an excellent accompanying editorial by Dr. LeWinter and Dr. Zile.

 
 
The next study adds importantly to evidence that heavy physical exertion and anger or emotional upset may act as triggers of first myocardial infarction. In this paper by first author, Dr. Smith, corresponding author, Dr. Yusuf, and colleagues from the Population Health Research Institute Hamilton Health Sciences and Master University, authors explored the triggering association of acute physical activity, anger, and emotional upset with acute myocardial infarction. They did this in the inter-heart study which was a case control study of first acute myocardial infarction in 52 countries. In the current analysis, the authors used a case crossover approach to estimate odds ratios for acute myocardial infarction occurring within 1 hour of triggers.

 
 
Of 12,461 cases, 13.6% engaged in physical activity and 14.4% were angry or emotionally upset in the case period referring to the 1 hour before symptom onset. Physical activity in the case period was associated with an increased odds of acute myocardial infarction with an odds ratio of 2.3 and a population attributable risk of 7.7%. Anger or emotional upset in the case period was associated with an increased odds of acute myocardial infarction of more than 2.4 odds ratio and a population attributable risk of 8.5%. Importantly, there was no effect modification by geographic region, prior cardiovascular disease, cardiovascular risk factor burden, prevention medications, time of day, or day of onset of acute myocardial infarction.

 
 
Interestingly, the authors did find an interaction between heavy physical exertion and anger or emotional upset with an additive association in participants with exposure to both in the 1 hour prior to the acute myocardial infarction. The take home message, these findings suggest that clinicians should advice patients to minimize exposure to extremes of anger or emotional upset due to the potential risk of triggering an acute myocardial infarction. While heavy or vigorous physical exertion may also be a trigger, this did not refer to just any physical activity and the authors cautioned that this must be balanced against the known well-established benefits of regular physical activity over the long term and clinicians should continue to advice patients about the life-long benefits of exercise.

 
 
The last study provides insights in the molecular mechanism in pulmonary hypertension. First author, Dr. Lee, corresponding author, Dr. Stenmark, and colleagues from the Pediatric Critical Care Meds and CVP Research University of Colorado Denver hypothesized that metabolic reprogramming to aerobic glycolysis may be a critical adaptation of fibroblast in the hypertensive vessel wall, an adaptation that drives proliferative and pro-inflammatory activation through a mechanism specifically involving increased activity of the NADH sensitive transcriptional corepressor, C-terminal-binding protein 1.

 
 
The authors assessed glycolytic reprogramming and measured NADH to NAD+ ratio in bovine and human adventitial fibroblast as well as mouse lung tissues. They found that expression of the C-terminal-binding protein 1 was increased in fibroblast within the primary adventitia of humans with idiopathic pulmonary arterial hypertension and animals with pulmonary hypertension. Furthermore, treatment of fibroblast from the pulmonary hypertensive vessels of hypoxic mice with a pharmacological inhibitor of C-terminal-binding protein 1 led to a normalization of proliferation inflammation and the aberrant metabolic signaling.

 
 
In summary, these result showed that C-terminal-binding protein 1, a transcription factor that is activated by increased free NADH acts as a molecular linker to drive the proliferative and pro-inflammatory phenotype of adventitial fibroblast within the hypertensive vessel wall. Thus, this metabolic sensor may be a more specific target for treating metabolic abnormalities in pulmonary hypertension. Those were your summaries. Now for our feature paper. Our feature today is special on so many levels, and because it's so special, I actually have Dr. Joe Hill, editor-in-chief of circulation from UT Southwestern here today with me. Hi Joe.

 
Joe:
Sure. As always, it's a pleasure to be here with you. This is a new type of content where we solicit thought leaders from a variety of vantage points around the cardiovascular space to provide their perspective on the future of cardiovascular Science in medicine. Rob Califf, the FDA Commissioner, provided his perspective on the regulatory role interfacing with cardiovascular medicine and Science. Victor Dzau who presides over the National Academy of Medicine in the United States did the same, provided a very insightful perspective from his vantage point now, formerly in academia, but now overseeing this advisory board to the policy makers in Congress. Today, we're going to talk about a perspective that emerges from industry, from someone who also has a strong and long history in academia.

 
Carolyn:
That is a perfect lead up. The title of the paper; What I Wish Clinicians Knew About Industry and Vice Versa. Here is the amazing guest that we have today, it's Dr. Ken Stein, Chief Medical Office of Rhythm Management at Boston Scientific. Hi Ken. It is a very, very intriguing title and I'd like you to first describe to us what makes you the person who can talk about being a clinician and going over to the dark side of industry and vice versa?

 
Ken:
Thanks Carolyn and Joe. I think right now just get over my embarrassment at being called a thought leader and being mentioned in the same as Rob Califf and Victor Dzau. I met both of them but I don't think I've ever been mentioned in the same sentence as either them and probably never will be again. Why me to do this? Again very gracious of Joe to invite the submission. My history, I've been in industry now at Boston Scientific for 7 years, and prior to that was an unreformed academic faculty at Cornell. Ever since I did my training, eventually becoming co-director of the EP Lab there for many years. Then 7 years ago, the opportunity came up to leave the cloistered ivory towers of academia and to join industry. It's been a very interesting and I think very productive ride ever since.

 
Carolyn:
I have to tell you that your article is just one of the most well-written pieces I have ever read and I mean that sincerely. You began with the story that everybody asked you this question. Why did you do it? What did you learn? I'm going to ask that of you today. Tell us.

 
Ken:
In the 7 years, I get 2 questions all the time. One is, do you miss practice? The answer is, there are things about practice that I miss very deeply and that is really the engagement that you get with patients and families. I think we always have to remember as caregivers, we're privileged to be able to do what we do. On the other hand is, but I do get an opportunity to participate in decisions now that rather than affect one patient at a time, for better or for worse, affect hundreds of thousands of patients at a time.

 
 
The other question is, what surprised you? What have you learned? What didn't you know about industry? As I thought about it, it's 2 things. It's one that I think in retrospect I was and I think many of us are way too cynical about the motivations of industry, how industry operates. The other shock, if you will, was that it goes 2 ways and there's a lot of cynicism in industry about physician motivations and how physicians operate on a day to day basis.

 
Carolyn:
Really? Do you have any examples of that?

 
Ken:
I'll give you a couple of examples. First, from the point of view of how does industry work and what are the motivations in industry. One of the first decisions that I had to make 7 years ago after joining the company was to issue a recall on one of our products. It actually was a recall that had not yet failed in the field but we had some bench testing that suggested that there was a particular risk to some patients and novel to the industry and the whole thing. This is not go over well with the CEO, but in fact, really the only question people ask is, is this the right decision for patients? That was a really gratifying piece of education to me.

 
 
The flip side of the coin, we did introduce a new battery technology in our fibrillators and CRT devices just before I joined the company that basically doubled the amount of battery capacity that we have in the devices. It's one of the funny things. There are still editorials being written in journals other than circulation, I'll say, that still say that industry will never increase battery longevity of their devices but cost us money because we lose money on device replacements. We've done it and a lot of our competitors are in the process of doing it.

 
 
When I got to the company, what I found is there was a tremendous amount of angst within the leadership of the company. Do doctors do this or are they afraid in a fee-for-service environment to give up what they get doing battery replacements on short-lived devices. Of course that cynicism is unfounded. That doctors have embraced longer, better battery life technology.

 
Joe:
Ken, to hear you say this is interesting and frankly inspiring. You can't pick up a copy of the New York Times right now and not read about some issue around drug pricing and some of the companies that have done the wrong thing with. They've increased prices hundreds of percentage, 400%, even more. To know from your perspective that those are perhaps the exceptional circumstances and that there are many, many companies who of course have to keep a business running but at the same time they truly have the patient at heart. You have said and you said in your piece that as the Chief Medical Officer, you're the voice of the patient at your organization.

 
Ken:
I aim to be. That was the lesson I learned from Don Baim who really ... Don passed away very shortly after I joined the company, who's really a giant in cardiology. I wish that I had been able to spend more time with him as a mentor but that was very important statement he made. Say he's right, there are bad actors, there are bad actors in industry, there are bad actors among physicians, there are bad actors among academics, but that's not generally true. I also want to be careful not to be misconstrued. Skepticism and doubt are important. Cogito ergo sum, it's not just I think, therefore I am, it's probably better understood that I doubt, therefore I think, therefore I am. Skepticism is fundamental to scientific process, but there's this border that you cross over where constructive skepticism turns into destructive cynicism. I'm afraid gets in the way of our ability to work together to better the outcomes, better welfare of patients.

 
Carolyn:
Do you think we've swung from the United States maybe you could give me your opinion to the wrong end of that balance between constructive skepticism and destructive cynicism? Joe, what do you think?

 
Joe:
As someone who has not worked in my own research closely with industry, sometimes I think that we have. I mean, there are certainly many examples. We all know where people have crossed the line and that is profoundly unacceptable, but at the same time, I worry that we've thrown the baby out with the bathwater and some of the things that are uniquely done in academia and some of the things that are uniquely done in industry, a synergy between them across the divide is essential to move this field forward. I think sometimes the boundaries and the bright lines separating them are so distinct and defined that it prevents those source of synergies.

 
Carolyn:
Thank you for that paper that really provides that balanced perspective. The beautiful thing, it's just so personal almost. It feels like we're sitting with you, having a conversation when we're reading that paper. Like now, it's just been an amazing experience having you on this podcast. Do you have any last messages?

 
Ken:
My last words. I again just want to thank you and thank Joe. Has the pendulum swung too far? Thing about pendulums are that they oscillate and I think what's needed is a willingness to watch out that it doesn't swing too far. Is there cynicism? I'll admit, I was flabbergasted and I still flabbergasted that you allowed me to write this piece but I think the fact that you welcomed the piece from someone in industry within the intent of bringing this out, that is the pendulum not going too far. As long as there are voices, editors, journals who are willing to help us articulate points like this, I think that's at least what keeps us in a reasonable balance.

 
Joe:
As Carolyn said, you brought a uniquely human conversational element to this piece. Not everybody would publish a piece in circulation and acknowledge that you are intimated and embarrassed walking into Don Baim's office. That brought us right into your living room and that was powerful.

 
Ken:
Honestly, I wasn't looking for the job. I was more interviewing them to find out what I can about the company, but I did not want to make an ass of myself in front of them. I felt like I was [pieing 00:19:53] for fellowship. I walked in the door and honestly I'm still standing with my hand on the doorknob and he looks up at me and I have to remember his voice, he had that deep sort of growly voice. He said, "Stein, you have no idea what Chief Medical Officer does, do you?" I'm just thinking, do I try to BS my way out of this or do I just give him the God honest truth and turn around and go back to work. I said, "No, Dr. Baim." I couldn't call him [inaudible 00:20:22] and to the end, I told him, "Dr. Baim," I said, "I had no idea." That's when he said, "Your job is to be the voice of the patient within Boston Scientific." He said after that, "You don't need to know anything about business. We know you don't know anything about business. We've got a lot of MBAs and hopefully they do."

 
Carolyn:
Thank you once again for the paper, for this discussion. Thank you both for being here. For all of you who are listening, thank you for joining us again on Circulation on the Run.

 
 

Oct 3, 2016

Carolyn:
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, we will be discussing an interesting Danish nationwide cohort study on the return to the workforce following first hospitalization for heart failure, but first here's your summary of this week's journal.

 
 
The first paper addresses a common question asked by patients who have survived an aortic dissection. Will this happen to me again? First author, Dr. Isselbacher, and corresponding author, Dr. Lindsay, and investigators of the International Registry of Aortic Dissection investigated this in the largest systematic analysis to date of patients presenting to hospital with a recurrent aortic dissection.

 
 
In this large registry, the authors identified 204 patients with recurrent aortic dissection and compared these to 3624 patients in the registry with an initial aortic dissection. They found that patients with recurrent dissection were more likely to have Marfan syndrome, but not bicuspid aortic valve. Descending aortic dimensions were greater in those with recurrent dissections than those with only an initial dissection, and this was independent of the sentinel dissection type. In multivariable analysis, the diagnosis of Marfan syndrome was independently predictive of a recurrent aortic dissection with a hazards ratio of 8.6.

 
 
Furthermore, they found that the patient's age at the time of first dissection correlated with the anatomic pattern of aortic involvement. In younger patients, dissection of the proximal aorta tended to be followed by dissection of the distal aorta, whereas the reverse was true among older patients suggesting divergent mechanisms of disease.

 
 
In summary, therefore, this study shows that recurrent aortic dissection while in common does occur and in fact affected 5% of those in this registry. The data really illustrate the importance of syndromic forms of aortic dissection and suggest that occurrence of a recurrent dissection should raise suspicion of a genetic etiology of aortic disease.

 
 
The next study provides pre-clinical data suggesting that counteracting increased hepcidin may be a therapeutic target for treatment of intracerebral hemorrhage. In this study from first author, Dr. Xiong, corresponding author, Dr. Yang, and colleagues from Xinqiao Hospital, the Third Military Medical University in China, parabiosis and intracerebral hemorrhage mouse models were combined with in vitro and in vivo experiments to investigate the roles of hepcidin in brain iron metabolism after intracerebral hemorrhage. Hepcidin in an important iron regulatory peptide hormone that controls cellular iron efflux.

 
 
The authors found that increased hepcidin-25 was found in the serum and astrocytes after intracerebral hemorrhage. In hepcidin-deficient mice with intracerebral hemorrhage, there was improvement in brain iron efflux and protection from oxydative brain injury and cognitive impairment, whereas, the administration of human hepcidin-25 peptide in these mice aggravated the brain injury and cognitive impairment.

 
 
In vitro studies showed that increased hepcidin inhibited intracellular iron efflux in  brain microvascular endothelial cells, but this phenomenon was rescued by a hepcidin antagonist. Additionally, toll-like receptor 4 signally pathway increased hepcidin expression, whereas, a toll-like receptor 4 antagonist decrease brain iron levels and improve cognition following intracerebral hemorrhage.

 
 
In summary, the study showed that increased hepcidin expression caused by inflammation prevented brain iron efflux and aggravated oxidative brain injury and cognitive impairment, thus, counteracting increased hepcidin maybe a mechanistic target to promote brain iron efflux and attenuate oxidative brain injury following intracerebral hemorrhage.

 
 
The next basic science paper provides fascinating insights into the similarities between advanced atherosclerotic lesions and tuberculous granulomas, both of which are characterized by a necrotic lipid core and a fibrous cap. First author Dr. Clement, corresponding author Dr. Mallat, and colleagues from the University of Cambridge Addenbrooke's Hospital in United Kingdom looked at the C-type lectin receptor 4E which has been implicated in the events leading to granuloma formation in tuberculosis.

 
 
The authors hypothesized that the same C-type lectin receptor 4E may be involved in the formation of atherosclerotic lesions as well. They addressed this hypothesis by examining the impact of receptor activation on macrophage functions in vitro and on the development of atherosclerosis in mice. They showed that C-type lectin receptor 4E was expressed within human and mouse atherosclerotic lesions and was activated by necrotic lesion extracts. The receptor signaling in macrophages inhibited cholesterol efflux and induced endoplasmic reticulum stress responses leading to the induction of proinflammatory mediators and growth factors.

 
 
Furthermore, repopulation of LDL receptor-deficient mice with C-type lectin 4E receptor-deficient bone marrow reduced lipid accumulation, endoplasmic reticulum stress, macrophage inflammation, and proliferation within developing arterial lesions that's significantly limiting atherosclerosis.

 
 
In summary, this paper shows that C-type lectin receptor 4E orchestrates major pathophysiologic events during pluck development and progression, and thus, provides a mechanistic explanation for the close association between necrotic lipid core formation and the development of inflammatory advanced atherosclerotic lesions.

 
 
The last paper examined the impact of optimal medical therapy in the dual antiplatelet therapy or DAPT study. In this paper from first author, Dr. Resor, corresponding author, Dr. Mauri, from the Brigham and Women's Hospital in Boston and colleagues, authors sought to assess the impact of optimal medical therapy use on long term patient outcomes and on the treatment benefit and risk of continued dual antiplatelet therapy, and they did this using data from the DAPT study which was a randomized placebo control trial comparing 30 versus 12 months of final prudent therapy on the background of aspirin after coronary stenting.

 
 
Optimal medical therapy was defined as a combination of statin, beta blocker, and angiotensin-converting enzyme inhibitor or angiotensin receptor blocker used in patients with an ACC/AHA class 1 indication for each medication. Endpoints included myocardial infarction, major adverse cardiovascular and cerebral vascular events or MACE, and GUSTO moderate or severe bleeding events.

 
 
Of 11,643 randomized patients with complete medication data, 63% were on optimal medical therapy. Between 12 and 30 months, continued final prudent therapy reduced myocardial infarction compared to placebo in both groups and had consistent effects on the reduction in MACE, and an increased bleeding regardless of the optimal medical therapy status. In other words, the P for interaction was nonsignificant for these comparisons.

 
 
Importantly, patients on optimal medical therapy had lower rates of myocardial infarction, MACE, and bleeding compared to patients not on optimal medical therapy. Rates of stent thrombosis in death did not differ. The take home message is therefore, that more emphasis on the use of optimal medical therapy after coronary stenting is needed, but the decision to continue dual antiplatelet therapy beyond 12 months should be made irrespective of the optical medical therapy status.

 
 
Those were your summaries. Now, for our feature paper.

 
 
Our feature paper today discusses a really important, but frankly, often neglected outcome in heart failure, and that is return to the workforce following first hospitalization for heart failure, and I'm really pleased to have the first and last author of this really special Danish paper, Dr. Rasmus Rorth and Dr. Soren Kristensen, both from the University of Copenhagen, here to join me today. Hello, gentlemen.

 
Soren:
Hello and thank you for having us, Carolyn.

 
Rasmus:
Hello.

 
Carolyn:
As a very special third guest, we actually have editorialist, Dr. Martin Cowie from Imperial College London as well. Hi, Martin.

 
Martin:
Hi, Carolyn. Nice to be part of the conversation.

 
Carolyn:
This is going to be so fun. Let's get straight into this. Rasmus, maybe you could start by telling us. This return to work concept is hardly addressed in guidelines, it's so important, and yet, you are one of the first if not the first to take a look at it. What inspired you to do this?

 
Rasmus:
First of all, we are very inspired to work with heart failure because heart failure is a common costly, disabling, and deadly disease, and furthermore, information on young patients with heart failure is vast.  We know that they have a high hospitalization rate and a low mortality rate compared to all the patients. We also know from some of the big trials that young heart failure patients report low quality of life. Therefore, we wanted in this study to examine return to work for a number of reasons.

 
 
First of all, it gives off some information of the patient's performance basis and we get some information of their quality of life and mental status, and one more reason that is not that common for us as clinicians to think about is also for society, the economic burden these patients play in the society, and all of these reasons inspired us to get into this exciting field.

 
Carolyn:
I really appreciated that you did this because the patients that I see here in Asia are on average 10 years younger than the heart failure patients that have been seen in other European registries and so on, so it is a very, very important aspect because my heart failure patients are often the sole breadwinners of families here. Could you, maybe, Soren, share with us what are those unique resources that you manage to look at this in such detail in the Danish registries?

 
Soren:
The unique quality in Denmark is that you have the unique identifying numbers for all the citizens of Denmark and these numbers are not only used in the health systems. They're also used for administrative registries for tax paying and for state funds and pensions. We were able to link information from the hospital discharge registries with information on tax paying and whether or not people are getting pensions. In that way, we could follow all patients who stayed in Denmark at least to see whether or not they were receiving any funds, any pension, or sick leave money, or things like this from the state, or whether they upheld a position. That's what makes the Danish system a bit unique, that we have this ability to track the patients across all the fields of society and also that we have a public health system which all patients are included in, and the private sector is negligible in Denmark.

 
Carolyn:
Wow. Listening to that is making all epidemiologist everywhere really drool. That is such a precious system to look at this. What were your main findings, Rasmus?

 
Rasmus:
Maybe I should explain a bit about the setting. This is a nationwide-based study starting where we identify the patient with the first heart failure hospitalization, 18 to 60 years in the period from 1997 to 2012, and we followed them onwards. In our primary analysis, we only included patients in the workforce, that means either employed or available for the labor market at time hospitalization. That is the setting of the study.

 
Carolyn:
Could you share your main findings and your take home messages?

 
Rasmus:
Our primary outcome of this study is that after one year, 25% of the patients did not return to the workforce and we had a low mortality, only 7% died.

 
Carolyn:
Twenty-five percent didn't return to the workforce?

 
Rasmus:
Yeah, and keeping in mind, Carolyn, these are patients in the workforce at their first hospitalization and also young patients. Our take home patient from this paper is that patient in the workforce at heart failure hospitalization had a low mortality for the high risk of [inaudible 00:13:41] from the workforce at one year of followup. Furthermore, we look at some association effect associated with returning to work, and we found that young age, male sex, and high level of education were associated with high likelihood of returning to work.

 
Carolyn:
Martin, you wrote just a beautiful editorial. I have to say I was chuckling and enjoying it as I read it. I could hear your voice in it. What do you make of these results in the interpretation?

 
Martin:
I was really pleased to see something published by this really important topic that is largely ignored, and as you said in your introduction, the guidelines, if you read them you'll think that nobody of working age ever develops heart failure. There's no mention at all about return to work. There's no mention of the kind of urgent need to be able to provide people with the counseling about the heart failure and how it might impact their work, and also, no interaction, no mention of interaction with employers to tell them, "Yes, this person have this condition, but actually, could do their job or stay in the same job," or "How we can help support them?"

 
 
I think this article which is so good to see graded publish in Circulation and I think we have to see it in the context of other occupational rehabilitation work which shows that if you don't get people back to work quite quickly after a major event in their lives, then you'll never get them back, and that's got huge consequences for them in their mental health, their economic, social, family, and never mind the healthcare system. It's really nice to see this work and I hope many people read it and quote it.

 
Carolyn:
Martin, you've been to Asia. You know that our patients are strikingly young, but I wonder, do you think these results are extrapolatable outside of Denmark?

 
Martin:
I think this comment and not an editorial, Denmark, of course, is a relatively small country. It's wealthy. It's different from the states, but it's very different from Asia as you say, so lots of heart failure patients in Asia are young, of working age, and quite often, their families depend on them.

 
 
I think the tactics may have to be different to different countries, but the general principles are the same that we, as a heart failure team, as heart failure doctors, have to think about the person not just in terms of the left atrium and left ventricle, or even of the whole body function, but actually, what is their role in their family, what are they trying to achieve in life, how can we support them about way, because otherwise, we're really failing our patient.

 
 
I think, in Asia even more than in some wealthy, rich countries where there's a lot of safety nets, it's really important. I'd be interested in your comment, Carolyn, on what you think we can do to improve right across the world in terms of occupational rehab.

 
Carolyn:
First, I think it begins with awareness and that's why I just wanted to tell Soren and Rasmus how much I enjoyed this paper and I will be citing it because I think it's so important especially in the younger heart for the community, but can I ask you, Soren or Rasmus, have these findings changed your practice in any way or to be even more provocative, do you think that maybe return to work should be a benchmark to evaluate heart failure programs?

 
Rasmus:
Martin also points out that, first of all, we need to shed light on this hidden fact of heart failure, and afterwards, I think it's also a very good policy metrics to use in the future to see how our patients do.

 
Carolyn:
Are there efforts in Denmark to improve this as a yardstick?

 
Soren:
I'm quite sure that, by large, it's not really registered who is working, who is not working there. There's not much attention to it. We're all focusing very much on the performance of the patient of the NYHA class and so on, so I think we should put more emphasis on this issue and we should, as Martin also added, that we should discuss with the patients if they could change their job or their positions in some ways to better cope if they lost some of their performance, because we're both think and we both agree with Martin that it's a huge quality of life to be able to maintain your job in one way or the other, and we should definitely put more focus on that, but I'm afraid to say that I don't think we put much focus on it in Denmark at this time, but hopefully, we will.

 
Martin:
I think you're right, the attitude have to change across the world, don't they, and they start with the heart failure team and the patients because I think most doctors and nurses and patients assume diagnosis of heart failure, that means really nothing can be the same again, but we really should be trying to return people to their optimal function, and I'm sure we can do a lot more, but perhaps, we need to upscale the workforce and knowing about the key things about occupational counseling, and maybe also [inaudible 00:18:30] interact with employers a little bit more without patient's permission to give them the confidence to have this person re-enter the workforce in a supported way because I'm sure the employers value many of these people and would be pleased to see them still in the workforce.

 
Rasmus:
Exactly. I even think that could be like a fair way of trying to help the patient by relieving them from their job, which is actually will be a big mistake for some patients [inaudible 00:18:54] as a physician to help them with making sure they don't have to return to their job and fill out the statements and everything, but this may not be the best for the patient.

 
Martin:
Exactly.

 
Carolyn:
Gentlemen, I have enjoyed this conversation so much. Thank you for taking the time to discuss this very important paper.

 
 
You've been listening to Circulation on the Run. Tune in next week for more.

 

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