Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
RSS Feed Subscribe in Apple Podcasts
Circulation on the Run



All Episodes
Now displaying: April, 2018
Apr 30, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center of Singapore and Duke National University of Singapore. Our featured discussion today is a wake-up call because despite substantial efforts to promote cardiac rehabilitation in guidelines and performance measures only a small percentage of patients are receiving this and there is a remarkable regional variation. Lots of lessons to be learned here coming right up after these summaries.

                                                More children with congenital heart disease are surviving into adulthood, and congenital heart disease is associated with risk factors for dementia. But what is the actual risk of dementia in congenital heart disease adults? Well, in this first paper from first and corresponding author Dr. Bagge from Aarhus University Hospital in Denmark, the authors used medical registries and a medical record review of all Danish hospitals to identify more than 10,600 adults with congenital heart disease diagnosed between 1963 and 2012 and followed up until the hospital diagnosis of dementia or death, emigration, or the end of the study in the end of December 2012.

                                                For each individual with congenital heart disease the authors identified 10 members of the Danish general population matched on sex and birth year. They found that the risk of all-cause dementia was increased by about 60% in congenital heart disease adults compared with the matched general population. The risk was higher for early onset dementia, that is dementia at less than 65 years of age, in which the risk was more than double. The risk was also elevated for all levels of congenital heart disease complexity, including those with cyanotic potential. The relative risk remained increased for those without extra cardiac defect or acquired cardiovascular diseases.

                                                These results really underscore the importance of understanding the risk of adverse long-term neurologic outcomes in the growing and aging population with congenital heart diseases.

                                                The next paper suggests that patient outcomes after lower limb revascularization have improved in England over recent times. This paper from first and corresponding author Dr. Heikkila from London School of Hygiene and Tropical Medicine used individual patient records from hospital episode statistics to identify almost 104,000 patients who underwent endovascular or surgical lower limb revascularization for infrainguinal peripheral artery disease in England between 2006 and 2015. During this 10-year period the estimated one-year risks of major amputation and death reduced after both endovascular and surgical lower limb revascularization in England. These trends were observed for all categories of peripheral artery disease severity, with the largest reductions seen among patients with the most severe underlying disease.

                                                These encouraging trends coincided with a period of centralization and specialization of vascular services in England, although the current findings cannot be interpreted as resulting directly from this reconfiguration of services.

                                                The next paper presents experimental data showing that targeting the Janus kinase and signal transducer and activator of transcription or JAK-STAT pathway may represent a disease-modifying strategy in inflammatory vasculopathy. First author Dr. Zhang, corresponding author Dr. Weyand from Stanford University School of Medicine examined whether persistent vessel wall inflammation in giant-cell arthritis is maintained by lesional T cells and whether such T cells are sensitive to the cytokine signaling inhibitor tofacitinib, which is a JAK inhibitor that targets JAK3 and JAK1.

                                                To do this, vascular inflammation was induced in human arteries and grafted into immunodeficient mice that were reconstituted with T cells and monocytes from patients with giant-cell arthritis. Mice carrying inflamed human arteries were then treated with tofacitinib or vehicle. They found that tofacitinib suppressed T cell invasion into the artery, inhibited proliferation and cytokine production of vasculitogenic T cells and curbed survival of artery resident T cells. Tofacitinib treatment prevented neoangiogenesis and intimal hyperplasia in these inflamed arteries. Thus, inhibition of JAK-STAT signaling with tofacitinib effectively targeted multiple disease-relevant processes in inflammatory vasculopathy and thus represents a potential disease-modifying agent.

                                                The next paper provides important insights into how coronary artery calcification burden and cardiorespiratory fitness, which are actually two independent predictors of cardiovascular disease but may interact with each other to impact cardiovascular risk. First author Dr. Radford, corresponding author Dr. Levine from the Institute of Exercise and Environmental Medicine Texas Health Presbyterian Hospital and UT Southwestern Medical Center studied 8,425 men without clinical cardiovascular disease who underwent preventive medical examinations that included an objective measurement of coronary artery calcification and cardiorespiratory fitness between 1998 and 2007.

                                                They found that cardiovascular disease events increased with increasing coronary artery calcification and decreased with increasing cardiorespiratory fitness. Adjusting for coronary artery calcification levels for each additional MET of fitness there was an 11% lower risk of cardiovascular disease events. When both coronary artery calcification and cardiorespiratory fitness were considered together there was a strong association between continuous cardiorespiratory fitness and cardiovascular disease incident rates in all coronary artery calcium groups. Thus, the take-home message is for any baseline age and level of coronary artery calcification greater fitness is associated in a continuous fashion with lower risks of cardiovascular disease events.

                                                And that wraps up our summaries. Now for our feature discussion.

                                                We all know how cardiac rehabilitation is. It's strongly advocated in guidelines, it's very well highlighted in performance measures. But how well are we actually doing? Well, today's feature paper really gives us some very valuable information and really kind of holds a mirror in our face, doesn't it? I'm so pleased to have with us the first and corresponding author of the paper Dr. Alexis Beatty from VA Puget Sound Health Care System and University of Washington as well as Jarett Berry, our associate editor from UT Southwestern. Alexis, could you tell us what did you see when you looked at cardiac rehabilitation among the Medicare and VA populations?

Dr Alexis Beatty:               Overall participation in cardiac rehab after an MI or a PCI or a bypass surgery is pretty low, only about 16% of people in Medicare and about 10% of people on the VA actually participate in cardiac rehab. But the interesting thing is that we saw pretty wide variations from state to state in participation. So some states had pretty high participation, upwards of 40% of patients, and some states had only 1, 2, 3% of people participating.

Dr Carolyn Lam:                Were there any patterns to this, any factors that you teased apart?

Dr Alexis Beatty:               We did observe that some regions of the country appeared to be doing better than others. So for instance, the West North Central region of the United States, Nebraska, South Dakota area has high participation in both populations and other regions like the Pacific, California, Oregon, Washington, Hawaii, Alaska, have lower participation in both populations.

Dr Carolyn Lam:                And any postulations on why this may be the case?

Dr Alexis Beatty:               Yeah, I have some theories. We did try to look at whether it was due to patient characteristics, hospital characteristics, socioeconomic status, and it doesn't really seem to be any of those things that are driving the differences, which leads me to believe that it's actual practice variations. So I think that literally the systems are set up better in some areas of the country than others to get patients into cardiac rehab.

Dr Carolyn Lam:                And as you beautifully wrote in your paper, that means that there may be an opportunity here to identify best practices here, isn't it? Jarett, you've been thinking about this a lot. What do you think?

Dr Jarett Berry:                 Yeah, I was curious, Alexis, it is interesting that the hospital variation that you saw, the on-site cardiac rehab was fairly consistent across cardiac rehab participation rates in Medicare but there was quite a bit of variability in the access to an on-site cardiac rehab site in the VA patients. I thought that was an interesting observation because it does suggest perhaps that what's driving regional variability looks to be fairly complex as you point out in your paper. But I just wanted to have you speculate a little bit or think a little bit about strategies for how we might think about improving cardiac rehab participation given the fact that there doesn't seem to be one particular answer to this problem. And so as you think about this longstanding challenge, how would you think about the future, about how we could actually really move the needle in increasing cardiac rehab participation?

Dr Alexis Beatty:               There's a lot of different ways that I think that we can work to start moving the needle. And as you point out, not every VA location has a cardiac rehab center on-site and sites that do have cardiac rehab on-site do tend to do better at getting their patients into cardiac rehab. And I think it may just be that there are people there who are interested in cardiac rehab and are promoting it to patients. And then there probably are some access issues as well. But I think it's not just kind of an "if you build it they will come" sort of proposition. Having cardiac rehab centers is important but then having systems in place to get people into cardiac rehab and get people going to cardiac rehab are just as important.

                                                And so I've talked to a lot of the VAs that have centers, don't have centers, do a good job of getting people in, don't do a good job of getting people in. And even in these places that don't have cardiac rehab on-site, if they have a system in place that helps get patients into cardiac rehab they're still able to achieve pretty high rates. And so a lot of that is just doing kind of setting it up as an automatic order and having a nurse or exercise physiologist or somebody be a navigator for the patients through the process.

                                                And then the other thing I really want to stress is the importance of providers recommending it to patients. I think that's the strength with which the providers sell cardiac rehab can really make a big difference.

Dr Jarett Berry:                 It's interesting, I just took over cardiac rehab as a medical director here at Southwestern about a year and a half ago and I've been struggling with this. And one of the interesting things that I just would love to get your thoughts on that I noted, which doesn't seem to get a lot of attention in the literature to me, is the role of co-payments. I don't know if most physicians who aren't involved in this space appreciate that for most insurance and for Medicare, it may not be the case for VA, I can't speak to that, but the co-payment amount for each time you come, for each visit is between $30 and $50 per visit. That seems to me in some ways ... I know you didn't address it at all in your paper, but just keeping this conversational ... What do you think the role of some of these other less discussed factors are such as just co-payment amounts that might actually be having a bigger effect on participation? Because I know if I had to pay a 1,000 bucks to go to cardiac rehab I might think twice about it.

Dr Alexis Beatty:               Yeah, and I think the co-payment issue is a very real issue too and there's a lot of policy level things that makes cardiac rehab difficult. So one is this co-pay issue, there also then other changes to the way it's administered like where the location of the cardiac rehab can be and how hospitals get reimbursed for that. It has to be prescribed by a physician, it can't be prescribed by a nurse practitioner or a PA, it has to be supervised by a physician. There's a lot of restrictions on cardiac rehab that can just, practically speaking, make it difficult to deliver both from the patient and the provider and health system level.

                                                And what I tell my patients when I am trying to get them to go to cardiac rehab, and we do have co-payers in the VA too that are kind of on a sliding scale depending on patients’ means. And so I tell them that it's an investment. You are making this upfront investment of your time and money and effort to get yourself healthy and learn how to be healthy in the long term. So we know that people who attend cardiac rehab are less likely to be hospitalized and are less likely to die from their heart disease, and so it's an important investment to make and that's sometimes the hard message to sell and I wish it were easier to sell.

Dr Jarett Berry:                 I totally agree with you. My own patients and also the patients that I helped manage through cardiac rehab have received such benefit in many different areas from the participation. But yeah, it is an investment.

                                                I wanted to ask another question, if I may Carolyn, about the future. And you alluded to this in your paper, I know your work with Mary Whooley, you guys have done great work thinking about rolling out home-based cardiac rehab. And I think personally that the future of cardiac rehab for most patients, that we're really going to move the needle—I mean some of the policy issues are really important—but can you comment on just telling us what home-based cardiac rehab is and to what extent you think that is a potential solution to deal with these persistently low participation rates?

Dr Carolyn Lam:                Actually Jarett, if I may just butt in before Alexis answers, I was about to ask that because I was just placing myself in the patient's point of view. And I mean even me, I hate going to gyms now and much rather work with a home app instructing me what to do and I can just do it here, you know what I mean? So I think that's a great question. Alexis?

Dr Alexis Beatty:               I agree, the future is home cardiac rehab and using all the tools that we have at our disposal to make it easy to deliver home cardiac rehab. The evidence isn't quite as strong for home cardiac rehab but the existing evidence does suggest that it's equally effective to center-based cardiac rehab, it's just not reimbursed in the United States. So functionally it only exists in sort of integrated health systems like the VA.

                                                The VA, for instance, has started delivering home-based cardiac rehab programs. I think it's now at over 30 centers in the US. And this has basically started in the last five years. And the programs are pretty similar to a center-based cardiac rehab program in that patients come in and they get an in-depth assessment from cardiac rehab professionals. But then the difference is that they go and exercise on their own at home and they check in with the cardiac rehab professionals usually on a weekly basis over the telephone. And so it ends up being more of like a coaching relationship between the cardiac rehab professionals and the patients who are exercising on their own at home. And a lot of patients really like it because, as you pointed out, it's much more convenient for them, they don't like going to a gym, they'd rather be walking around in their neighborhood or going to their local community pool to swim. So it just sort of addressed a lot of these patient issues and they don't have to pay a co-payment. So it can take some of these other barriers that are there.

Dr Jarett Berry:                 Like a Peloton bike for cardiac rehab, right?

Dr Alexis Beatty:               Yeah. I mean you could even do that. For instance, in HF-ACTION they actually gave people exercise equipment for a HF-ACTION study for the home segment of the HF-ACTION study. So there certainly are models whereby we could just be giving exercise equipment. And in the VA I can mail people these little exercise paddlers that they can put on their floor or their table and you can use them with your legs or your arms. So certainly being able to send some of this exercise equipment to your patients may help them get them into doing things. But I think home cardiac rehab is the future.

                                                And then also I do work on using technology to help deliver home cardiac rehab and I view technology for this space not as the solution but as a tool to help you deliver home cardiac rehab. And now that technology is so ubiquitous, I think that we need to now learn how to use the technology to help us better deliver cardiac rehab in a way that meets the patients' needs.

Dr Carolyn Lam:                Wow. Jarett, I've actually got a question for you. You were just saying that you run the rehab unit there, so what messages did you take home from this paper?

Dr Jarett Berry:                 What I took home from this was exactly what we've been discussing, this issue of low uptake of cardiac rehab even in the scenario where you have a model where you're delivering this through Medicare or the VA we still see very low participation, albeit there is some variability. And so my interpretation after doing cardiac rehab here at Southwestern for the last year and half is exactly what Alexis is saying, is that we need to be really thinking more creatively about how we can deliver cardiac rehab where the patients are and not requiring them to participate in centers of cardiac rehab that are maybe 30, 40 miles from their home and in the middle of the workday, all of which just really makes such a model inefficient.

                                                So I just think what this paper does really solidify is that we really need to be thinking broadly and creatively about how to bring cardiac rehab to more patients because the way we're doing this now I think unfortunately is just ineffective.

Dr Carolyn Lam:                Anything to add, Alexis? This is great.

Dr Alexis Beatty:               So one other point that I would like to mention. I think about 10 years ago there was another paper that used a very similar method, and we based a lot of our methods off of that paper by Suaya about 10 years ago. And they found that the rate of participation in cardiac rehab was somewhere very close to ours, I think it was 18% and we observed 16%. And since that paper was published cardiac rehab got included in guidelines, included as a performance measure, and there has been a big push and a lot of attention to try to get people into cardiac rehab and we have moved the needle zero since that time. So I think clearly something new is needed to move the needle for cardiac rehab just as Jarett was pointing out. So we got to do something because what we're doing isn't working.

Dr Carolyn Lam:                That's a great call and thank you for showing that to us so clearly in your paper.

Dr Jarett Berry:                 Yeah, thanks Alexis and thanks for being so responsive in the revision process, it was a real pleasure to work with you all on this really important paper.

Dr Alexis Beatty:               Thank you so much for publishing this paper. I feel I've been working on this for like five years.

Dr Carolyn Lam:                Well you heard it here, listeners. Thank you for joining us today. Don't forget to tune in again next week.

Apr 24, 2018

Dr Carolyn Lam:                Welcome to "Circulation On The Run," your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor, from the National Heart Center, and Duke National University of Singapore. Our featured paper today is so important for cardiac surgeons and their patients. It answers a question of whether targeting a higher versus a lower blood pressure during cardiopulmonary bypass helps to prevent cerebral injury. Curious? Well, more soon right after these summaries.

                                                In the first original paper this week, MicroRNA-22 is shown to be a novel mediator of vascular smooth muscle cell, phenotypic modulation, and neointima formation. Co-first authors, Drs. Yang and Chen, co-corresponding authors, Dr. Zhang from Zhejiang University and Dr. Xiao from Queen Mary University of London and their colleagues used wire injury mouse models to show that MicroRNA-22 controls vascular smooth muscle cell phenotype and injury-induced arterial remodeling by modulating multiple target genes, including methyl-CpG-binding protein 2, histone deacetylase 4, and ecotropic virus integration site 1 protein homolog.

                                                The authors observed that MicroRNA-22 expression was suppressed in human femoral arteries with atherosclerotic plaques, and that there was an inverse relationship between MicroRNA-22 and its target genes in healthy and diseased arteries. Furthermore, local delivery of MicroRNA-2 in the injured arteries prevented adverse arterial remodeling, thus suggesting that site-specific delivery of MicroRNA-22 mimics may be a potential therapy for in-stent restenosis.

                                                The next paper adds to our understanding of the pathobiology of pulmonary hypertension related to left-sided heart failure and importantly adds histomorphometric evidence from human lung specimens at autopsy or surgery.

                                                First author Dr. Fayyaz, corresponding author Dr. Redfield, and colleagues from the Mayo Clinic studied patients with heart failure with preserved or reduced ejection fraction and pulmonary hypertension and compared these to normal controls, as well as patients with primary pulmonary veno-occlusive disease.

                                                They found that patients with heart failure and pulmonary hypertension had global pulmonary vascular remodeling with thickening of the media and intima in arteries and thickening of the intima in veins and small pulmonary vessels compared to normal control subjects.

                                                This venous and small-vessel intimal thickening was more severe than the arterial intimal thickening in heart failure with a pattern that was similar to patients with pulmonary veno-occlusive disease. In fact, the severity of pulmonary hypertension correlated most strongly with venous and small vessel remodeling rather than arterial remodeling.

                                                These findings expand our understanding of the pathobiology of pulmonary hypertension in heart failure. It also suggests that pulmonary venous remodeling in heart failure may predispose to worsening alveolar edema with pulmonary vasodilators as in primary pulmonary veno-occlusive diseases.

                                                Are there sex and race differences in the lifetime risk of HFpEF versus HFrEF? First author Dr. Pandey, corresponding author Dr. Berry from UT Southwestern Medical Center, and their colleagues used participant level data from two large respective cohort studies, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis to determine remaining lifetime risk estimates for heart failure with preserved and reduced ejection fraction at different index ages.

                                                They found that compared to women, men have a higher lifetime risk of HFrEF, heart failure reduced ejection fraction with a similar lifetime risk of HFpEF, or heart failure preserved ejection fraction. Compared with blacks, non-blacks have a similar lifetime risk of developing HFrEF but a higher risk of HFpEF.

                                                Lifetime risks of HFpEF and HFrEF were similar and substantially higher in those with versus without antecedent myocardial infarction.

                                                In summary, these findings provide novel insights on sex and race differences in the lifetime risks of HFpEF and HFrEF, and may help health policymakers in appropriate resource allocation for targeting HFpEF and HFrEF specific preventive therapies at the at-risk population.

                                                What are evidence-based blood pressure targets during pediatric cardiopulmonary resuscitation? Well, first and corresponding author Dr. Berg from Children's Hospital of Philadelphia and his colleagues studied a multi-center population of children with invasive arterial blood pressure monitoring during in-hospital ICU cardiac arrest, and the Collaborative Pediatric Critical Care Research Network Intensive Care Units, between 2013 and 2016.

                                                They found that a mean diastolic blood pressure greater or equal to 25 millimeters of mercury during cardiopulmonary resuscitation in infants, and greater or equal to 30 millimeters of mercury in children 1 year old or greater, was associated with a 70% greater likelihood of survival to hospital discharge, and a 60% higher likelihood of survival with a favorable neurologic outcome.

                                                On the other hand, survival rates were markedly lower with mean diastolic pressures less than 20 in infants and less than 25 in children 1 year or older. Thus, clinicians should consider targeting diastolic blood pressure of 25 or greater in infants, and 30 or greater in children 1 year old or older during cardiopulmonary resuscitation when invasive arterial blood pressure is monitored.

                                                That wraps up our summaries for this week. Now for our featured discussion.

                                                Does a higher versus a lower blood pressure target during cardiopulmonary bypass surgery reduce the risk of cerebral injury? Well, the feature paper today provides some answers, and we have the first and corresponding author, Dr. Anne Vedel from University of Copenhagen with us today, as well as our associate editor, Dr. Timothy Gardner, who's a cardiac surgeon from University of Pennsylvania.

                                                Thank you so much for being with us today and this was a terrific trial, a very difficult trial to carry out. Could you please tell us a bit more about it?

Dr Anne Vedel:                 Cerebral injury is an important complication after cardiac surgery with the use of cardiopulmonary bypass. Up to half of our patients suffer these perioperative silent strokes. Therefore, in Copenhagen we conducted a trial investigating the importance of two distinct blood pressure levels during cardiopulmonary bypass. Now, on this subject of optimal perfusion strategy during bypass, there are many opinions, but also a stunning lack of convincing evidence, for instance, when it comes to blood pressure management.

                                                Now, the question is whether normal physiological principles, such as cerebral autoregulation therapy, whether they apply during bypass, or if perfusion pressure indeed does play a less important role when blood flow is mechanically provided in an uncomplicated and sufficient way by the heart and lung machine.

                                                So, in a patient on the assessor-blinded randomized trial, we allocated patients to a higher or a lower MAP target, 70 to 80, or 40 to 50 millimeters of mercury, respectively, by titrating intravenous norepinephrine during bypass.

                                                Pump flow levels were set at 2.4 liters per minute per square meter of body surface, and our primary outcome was the total volume of new ischemic cerebral lesions, expressed as a baseline MRI, and opposed to the difference between the baseline MRI and the postop MRI on day three to six. Secondary outcomes were a number of new ischemic lesions and newer psychological test evaluations.

                                                Now among the 197 patients enrolled who were scheduled for coronary artery bypass, or heart valve repair surgery, or a combination of both, we found that 53% of patients in the low target group as opposed to 56 in the high target group had new cerebral lesions on their postop cerebral MRI.

                                                The primary outcome of volume of new cerebral lesions was comparable between groups, and so was the total number of newer lesions. No significant difference was observed in stroke rates in frequencies of postoperative cognitive dysfunction, or in severe adverse event rate.

                                                Therefore, we concluded that among patients undergoing on-pump cardiac surgery, targeting higher versus a lower mean arterial pressure did not seem to affect the volume or number of new infarcts.

Dr Carolyn Lam:                Wow, thank you so much, Anne. Tim, you think about these issues a lot more than I do as a non-surgeon. Could you tell me what your insights were?

Dr Tim Gardner:                You know, it's a very difficult study to do a randomized control trial in this environment, and they're really to be congratulated for doing it. As Anne acknowledges, this is not an area where randomized trials are very frequent.

                                                The first thing about the trial, I think, is a growing awareness among all of us that there seems to be a lot of imaging evidence of what we call injury or changes based on diffusion-weighted imaging in patients after cardiopulmonary bypass. This is not the first study that shows that.

                                                But the question is are these incidental, trivial lesions? I'd have to, again, ask Anne to clarify how many of the patients in either group, what percentage had what we would consider evidence of overt strokes?

Dr Anne Vedel:                 Well, overt strokes, as opposed to silent strokes, 1 patient in the lower target group had stroke and 6 patients in the high target group, which corresponds to 1 as opposed to 7%.

Dr Tim Gardner:                That was not quite statistically significant difference but headed in that direction with the assumption that if you have a larger sample size there might be, in fact, some association with overt stroke using the high target vasopressor approach, is that right?

Dr Anne Vedel:                 We can only speculate. But as you do, yes, I agree.

Dr Tim Gardner:                To go back to the original question, the significance of these, well, you were referring to as silent strokes. Can you comment on the clinical significance there? We hear of silent heart attack. What is a silent stroke and what are the implications of that long term for patients?

Dr Anne Vedel:                 In other fields of research on the silent strokes, it's been shown that they correlate to both frequency of postoperative cognitive dysfunction and also later development of mild cognitive impairment and dementia. But these kinds of results, there isn't enough research in the field of cardiac study for us to say the same. But those are the implications from other research fields.

Dr Tim Gardner:                But you can understand from the perspective of a cardiac surgeon, and this concern has been expressed and talked about in the literature for 20 years or more, the possibility that even what seems to be, with no injury apparent and no overt stroke, there may be some neurological consequence to cardiopulmonary bypass.

                                                So just to move on from that because I agree that we just don't have any reliable information that these silent strokes result in late or permanent injury, I think again the finding that manipulating the blood pressure, which seems to be intuitively beneficial in patients, especially elder patients, did not, in fact, show any benefit and, in fact, may have been associated with a slight increase in overt stroke. Is that a fair conclusion from your study? A summary of your study?

Dr Anne Vedel:                 I would say it is a fair conclusion, and surprisingly so. The question is whether it is the blood pressure or the means that we apply to have this increase in blood pressure that is the point of interest here.

Dr Tim Gardner:                You mean whether, in fact, using the norepinephrine, the vasoconstrictor, to increase the blood pressure whether that itself, it certainly didn't benefit, it may have been a problem.

Dr Anne Vedel:                 Exactly. That's what I speculate might be the case. But I also think it's fair to say at this point that this is somewhat artificial physiological scenario, the cardiopulmonary bypass.

Dr Tim Gardner:                I agree with that, that you're controlling blood flow and the patient is exposed to a lower hemoglobin and oxygen-carrying capacity and so on. But I think what struck me about your findings, or strikes me about your findings, is what appears to be in many of the patients, the low target patients, pretty effective autoregulation of the cerebral circulation, despite the artificiality of cardiopulmonary bypass.

                                                I think that's, again, something that has been not well known or well accepted by many people, thinking that if you lower body temperature, you lower hemoglobin, autoregulation may not be enough to maintain good cerebral perfusion. It looks like this study shows that in these patients, autoregulation worked fine. Is that fair?

Dr Anne Vedel:                 Yes. Or sufficient blood flow was delivered. All in all, what's new in our study, I think, is that hypertension per se shouldn't necessarily be considered a proxy for hyperperfusion during bypass.

Dr Tim Gardner:                Yeah, that's a very good qualification. So none of your patients, despite being in their mid to late 60s had evidence of carotid artery disease or whatever? Those patients were excluded from the trial, is that right?

Dr Anne Vedel:                 No, that's not correct. We didn't screen for carotid artery disease because we don't routinely do that in our institution. As we describe in our discussion, we included quite a heterogeneous study sample by enrolling the patients that came to us. We didn't screen and we didn't exclude these patients that you mention.

Dr Tim Gardner:                Do you know how does your group handle a patient that is known to have carotid artery disease, comes in with a known either prior endarterectomy or established disease? Do those patients, are they treated any differently either as a result of the study or just in general?

                                                Because that is a targeted group of patients, at least in my own experience, that we would be more concerned about allowing autoregulation to be the determinant, feeling that if there is a fixed stenosis in the carotid artery that we might need to increase the mean arterial pressure.

Dr Anne Vedel:                 I can certainly understand your point and, of course, it is a concern in our center, as well. But having said that, there were no patients in the PPCI trial that came to us with a history of carotid artery disease, so it wasn't a concern for us in this study.

Dr Tim Gardner:                That would be one point that I would make that we probably should pay attention to patients who do come for surgery and have known significant obstructive extracranial disease, but I understand that you didn't specifically have those patients or were aware of those patients.

                                                I think that this is a very useful study for us concerned about the possibility of inducing cerebral injury with cardiopulmonary bypass. To some people it's sort of counterintuitive that increasing perfusion pressure didn't improve the tolerance of patients to cardiopulmonary bypass but that's why you did the study. I think it's a very notable and important report that's going to be in circulation.

                                                The significance of these "silent infarcts" is merely something that we have to sort of sort out. I know you said that silent infarcts, as I agree, are associated with or presumed to be predictive of later cognitive dysfunction, dementia and so on. It really is a concerning message if that's the main message that comes out of these imaging studies. Because these are patients that, obviously, didn't have heart surgery for no reason, there was obviously a compelling indication for patients to have it.

                                                You would hate to re-ignite this concern as we had in and around year 2000 when the group at Duke was talking about writing about patients who had cognitive decline after cardiac surgery, were going to end up being demented five or 10 years down the line, so, that's from the perspective of a cardiac surgeon. Let's stick with the evidence but let's follow-up and see how predictive these silent infarcts are and what the consequences are long term. Do you think that's fair, Anne? Am I making a fair statement?

Dr Anne Vedel:                 I absolutely do think it's fair. And for a cardiac surgeon as yourself, I would find it very interesting to see that these kind of studies are also conducted in TAVR patients where you have sometimes a 200% incidence of these silent strokes.

                                                I mean you have a good taste as a cardiac surgeon if you only see them in 50% of your patients, understand me correctly, but I don't necessarily think that this high incidence, it's high, yes, but compared to other patient groups, such as TAVR patients, it's not necessarily that bad.

Dr Tim Gardner:                Right. Anne, I don't know whether you've seen the editorial that's going to accompany your paper, but it's very good. It's very supportive of your study and has some good comments. You'll be pleased with the editorial, I believe, if you haven't seen it.

Dr Anne Vedel:                 Thank you very much. I'm happy to hear that. I know we do things a bit controversially over here in Copenhagen, compared to many centers in the U.S.

Dr Tim Gardner:                That is not what the editorialists think. An anesthesiologist from Stanford and a neurologist from Penn, they have a very good commentary on your study and the whole field, so you'll be pleased.

Anne Vedel:                       I'm very happy to hear that. Thank you.

Carolyn Lam:      Well, listeners, I'm sure you learned a lot. Thank you for joining us today, and don't forget to tune in again next week.

Apr 17, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Does NT-proBNP-guided therapy improve outcomes in acute decompensated heart failure? Well the Prima II trial results are coming right up after these summaries.

                                Is hospital volume a good structural metric assessing the quality of care in heart failure? Well, in the first original paper this week from Dr. Kumbhani and colleagues at UT Southwestern Medical Center, authors determined the relationship between admission volume, process of care metrics, and short and long-term outcomes admitted with acute heart failure in the Get With the Guidelines-Heart Failure registry, which has linked Medicare in patient data at 342 hospitals.

                                They found that lower volume hospitals had worse adherence to important heart failure process measures, than higher volume hospitals. There was no association between risk adjusted in-hospital mortality and hospital heart failure admission volume among older adults.

                                After adjusting for adherence with process measures at discharge, annual heart failure admission volume had a minimal association with mortality, and readmissions up to six months post-discharge. Thus, rather than focusing solely on hospital volume, hospital profiling efforts should perhaps focus more on participation in quality improvement initiatives, adherence to process metrics, and risk standardized outcomes.

                                The next study describes the association between air pollution and heart disease mortality in the United States, with a focus on whether the association differs by race and ethnicity. First and corresponding author Dr. Jennifer Parker from the National Center of Health Statistics Centers of Disease Control and Prevention and her colleagues use data from the 1997 to 2009 National Health Interview Survey linked to mortality records through December 2011 and the Annual Estimates of Fine Particulate Matter or PM2.5 as an index of air pollution.

                                They found that the association between air pollution and heart disease mortality in this national sample was elevated and similar to estimates found in prior studies. After controlling for social demographic and geographic factors, the associations between air pollution and heart disease mortality for non-Hispanic black and Hispanic adults were not statistically significantly different from that of non-Hispanic white adults.

                                Thus, this study supports the application of findings from prior studies of air pollution and mortality, albeit largely from non-Hispanic white adults, but to other races and ethnicities in the United States.

                                The next study suggests that large cardiac muscle patches engineered from human induced pluripotent stem cells may be a reality. First author Dr. Gao, corresponding author Dr. Zhang from University of Alabama at Birmingham generated human cardiac muscle patches of clinically relevant dimensions of 4 x 2 centimeters and they did that by suspending cardiomyocytes, smooth muscle cells, and endothelial cells that had been differentiated from human-induced pluripotent stem cells in a fibrin matrix and culturing this construct on a dynamic platform.

                                The results from in vitro assessments of calcium transience, action potential propagation, and forced generation, as well as the presence of intercalated disc-like structures, suggested that cardiomyocytes matured in these human cardiac muscle patches. During the 7-day dynamic culture period. When transplanted onto infarcted swine heart, measurements of cardiac function, infarct size, wall stress all improved with no increase in arrhythmias.

                                Changes in the expression profile of myocardial proteins indicated that the human cardiac muscle patch transplantation partially reversed abnormalities in sarcomeric protein phosphorylation. Collectively, these observations indicate that human cardiac muscle patches can be successfully generated and may improve recovery from ischemic myocardial injury.

                                Does a second arterial conduit improve outcomes after multivessel coronary artery bypass grafting? Well, in the next study from first author Dr. Goldstone, corresponding author Dr. Woo, from Stanford University and their colleagues used a clinical registry including all 126 non-federal hospitals in California to compare all-cause mortality, and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score matched cohorts, who underwent primary isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit or a venous conduit between 2006 and 2011.

                                The authors found that receipt of a second arterial conduit was associated with lower mortality, and at first cardiovascular events, compared with receipt of a venous conduit. The survival benefit associated with the use of a second arterial conduit extended to patients up to 78 years old. As a second arterial conduit, the right internal thoracic artery offered no benefit, compared with the radial artery, but it was associated with an increased risk of sternal wound infection.

                                These findings therefore suggest that surgeons should perhaps consider lowering their threshold for using arterial grafts and that the radial artery may be the preferred second conduit.

                                That wraps it up for our summaries. Now for our future discussion.

                                NT-proBNP and natriuretic peptides in general, have really become mainstay in management of heart failure, in the diagnosis, in the prognostication, but questions still remain regarding NT-proBNP-guided therapy. We heard about the guided trial in chronic heart failure just reported last year, and this year, in fact this week, in this week's journal, we're about to hear about PRIMA II trial in acute heart failure.

                                And how NT-proBNP was tested as a potentially guiding strategy for the management of acute heart failure. I'm so pleased to have the corresponding author with us, Dr. Wouter Kok, from University of Amsterdam, as well as our Senior Editor Dr. Biykem Bozkurt from Baylor College of Medicine. So welcome both of you, and Wouter may I just jump straight in it?

                                PRIMA II means that there was a PRIMA I trial, so could you just briefly tell us a bit about PRIMA I and the rationale for PRIMA II?

Dr Wouter Kok: Well the PRIMA II was an in-hospital guiding therapy that was preceded by the PRIMA II, it was a chronic heart failure patient population and one of things that we noticed in PRIMA I was the lack of effect of trying to reach a percentage drop in chronic heart failure patients. Why is that? Is that because there is a long time before you can achieve a therapy adjustment? Or is it something else? And shouldn't we start before patients are discharged from hospitals?

                                So the idea was born to do an in-hospital guiding study instead of chronic heart failure patients study.

Dr Carolyn Lam:                Interesting. And could you tell us briefly, the design of PRIMA II and your findings?

Dr Wouter Kok: So the PRIMA II was designed based on the previous publication of several authors indicating that a 30% reduction in NT-proBNP would be a good target for heart failure therapy. Now, we first asked ourselves the questions, whether we should put this target in front of the hospital admission, so in the first 2 days or perhaps at the end of the hospital admission? And the 30% reduction was validated only for discharge purposes, so but we also tried to establish whether we could precede this date a little bit before discharge, but it appears that you cannot precede it too much.

                                So you cannot do it at day 3 or day 4, when patients are not stable. Because then you may expect a rise in proBNP again before discharge, and then you already ran the rise patients to discharge. So we decided to do it at discharge. At least 1 or 2 days before discharge, when patients would be clinically stable. And this definition of clinical stability was important because there should be one guideline for doctors to say, OK this patient has been treated well, or not.

Dr Carolyn Lam:                Interesting. And so patients were randomized only after clinical stabilization, though in hospital after an acute decompensation, right? And then maybe the randomization arms, and the results please?

Dr Wouter Kok: Yeah, so the patients were randomized about day 7 or 8 after clinical stabilization, and day 3, but also patients at day 9, but when they were stable, they were randomized. And then the proBNP was measured, and when it was not reduced more than 30% they were guided. And when they were reduced more than 30% they were not guided but they were made ready for discharge.

                                So this was the randomization group. And the conventional group, the NT-proBNPs were measured at the randomization, and also at discharge, but nothing was revealed to the doctors. So it was only as a comparison for example, in the number of days necessary to wait before discharge, if this would influence the results.

                                The main finding is that the end point was negative for total mortality after 6 months, in combination with heart failure readmissions. So there were about 36% end point in both groups.

Dr Carolyn Lam:                Yeah Wouter, you know, we've just come from the guided trial that was so soon neutral and infect, ended early and that was in the chronic heart failure setting so very different from what you tested in PRIMA II. Congratulations first of all for a beautifully done study.

                                But may I just ask, because in guided it was mentioned repeatedly that perhaps even the control arm was treated so well because these were such specialized centers. So what kind of centers took part in PRIMA II?

Dr Wouter Kok: We started at centers in Amsterdam, they were all very well educated in heart failure treatments, and all were using proBNP before the study started, so they were experienced in interpreting proBNPs. Because we had too little centers, and the inclusion rate was not so fast, then we asked other centers to participate, and we asked 2 for instance in Barcelona and Porto in Portugal, which helped us to complete the trial.

Dr Carolyn Lam:                Oh that's really nice. And the design is really quite special, and I'm so appreciative that you took the time to explain that they were randomized only when stabilized.

                                Biykem, what do you think of that?

Dr Biykem Bozkurt:         It's a fascinating trial, I have to congratulate Wouter and his colleagues. The number one very important finding I think is, about two-thirds of the patients before randomization are able to achieve reduction of NT-proBNP more than 30%. So subsequent to that in the guided therapy we're able to achieve maybe an incremental additional 15% adding to about, I think 80% of the patients initially randomized to the NT-proBNP arm. Achieving a reduction more than 30%. So overall, if the patient's naturally before randomization, achieve a reduction NT-proBNP, two-thirds of the time, pushing it further, trying to achieve a further dry state, by randomization does not appear to make any changes in readmission rates, or mortality at six months.

                                So this very important finding is the majority of the patients on conventional strategies are able to be decongested and achieve clinical stability. Now the other important finding is, I think about 17-20% of the patients regardless of what we do, do not demonstrate this significant drop in their NT-proBNP levels. Which I call as a non-responder team, which is a fascinating group of individuals. So we have the yin-yang, individuals may actually demonstrate that they're responsive. And when they're responsive, then the majority of the patients do demonstrate a reduction by more than 30%, and even if we push it further by targeted therapies, don't make a difference in outcomes.

                                About 17-20% regardless of what we do, do not respond, and from former studies we know that those patients are associated with worse outcomes. The other important finding I think, is what changed in the study? What medications, what therapies were changed? It was fascinating from Wouter's group to recognize that there was a little, significant, but a little increase in the ACE admission prescription. But there was also an interesting finding in the guided therapy, that the beta blocker used was slightly lower.

                                That raises a question of if we were to just chase the numbers, meaning try to just target therapies according to the NT-proBNP levels, whether we would see some unintended consequences such as reduction in medications, just because the numbers may be going in one way or the other. This is acknowledged in Lynne Warner Stevenson's editorial that will be accompanying the paper. And the editorial is very nicely titled "Getting to Dry". So I found that fascinating to recognize that the therapies, when especially the conventional arm is treated well, did not differ.

                                As was the case in the guided trials. When you treat the patients very well, as was seen in this trial, there was not much of a difference. But again trying to treat a number by targeted therapies may not result in all the optimization that as we envisioned to see. And the third concept is the length of stay, of course in the U.S. is a major issue, and I do realize when we're trying to treat a number, sometimes the length of stay may end up being longer. And I do realize that perhaps in the targeted therapy group, the length of stay was a little bit longer, maybe Wouter can comment on that.

                                But overall it didn't result in any change in outcomes, or was not associated with any of the outcomes. So that was also an interesting finding. Because we tend to focus a lot on length of stay, but interestingly I guess by secondary analysis, there was no association with the clinical outcome.

Dr Carolyn Lam:                Wouter, would you want to comment the length of stay concept?

Dr Wouter Kok: Well it's indeed in the guided group, and the randomized group who were trying to attain the 30% NT-proBNP reduction, the length of stay was longer. Something about 11 days, compared to those who did not need guiding was about 8 days. Still long compared to U.S. standards, but it was the same in the conventional group, so about 9 days is respective of whether they reached a 30% reduction or not.

                                So here is the clinical experience. So the patient cannot tell whether he is reduced more than 30%, and the doctor isn't able to tell either. Because then the admission would have been longer probably. But trying to lower the 30% more, has some effect. There's little effect, but it has some effect. And then they have to do a sort of economic analysis, is 3 days longer in hospital, is it worthwhile to do that compared to for example reduction in admissions that you receive? This is a small population, only one-third of the patients who need guiding, and more than half of them you will reach somewhat more reduction than if you don't try at all.

                                So for us, that is the main result of the trial, if there is a signal, then it is still possible to do something, and the other remark about whether you increase or decrease medication, that's something that was discussed in the guided study too. So what is the best for the patient, is that the maximum medication or not, and we see for example, that if we reduce beta blockers, in some patients then some will improve in their functioning and also in the BNP.

                                So it's not always necessary to increase and increase medication. So that was also some signal that we tried to do some more research in. What is the target? Is the target a guideline, saying that more medication is better? Or is the target itself for proBNP a possibly better target than that?

Dr Biykem Bozkurt:         And the other interesting finding for that, there were no differences in chemo concentration levels in the guided versus non-guided groups. And last point that I wanted to make is the larger BNP reduction was amongst the individuals who did not require any guidance in successfully guided versus unsuccessfully guided, compared to those who did not need the guidance.

                                Those who were able to achieve the more than 30%, when you look at the magnitude, meaning amongst the individuals who are going to naturally respond to therapy, the natural responders, the decrement, or the decrease in the BNP levels are larger, than those ones we're trying to push. So that was another interesting, fascinating ... I was almost thinking whether that in the future we should look at responsiveness of patients, if we see they're responders then try to target their therapy or not.

                                So in a sense the non-responders, they now respond regardless of what we do. Responders may be gaugeable or titratable, or maybe with the precision respond to targeted therapies that almost have a dichotomous approach. What do you think about that Wouter?

Dr Wouter Kok: I say yeah we made a big mistake in thinking that more than 30% for patients who still needed guiding would be the same as rating the more than 30% without guiding. But the difficulty you have in reaching the 30% is already indicative somewhat less increase in prognosis than you will reach it spontaneously.

                                So we have to adapt our numbers for the trial, so it is recalculation that how many patients we would need to be successful in our trial, and that would be 600 patients in every arm, and then even then, you have to recalculate some of the effects that you will have to reach them. Perhaps the mid-range risk group is a better risk group to target than the highest risk group. That's something that we have to think about too.

Dr Biykem Bozkurt:         I think we will probably need to focus on individualization, I almost feel as though we will need to learn from the cancer trials, and see whether we could try to target rather than you know the population based clinical trials, trying to do the targeted therapies. Maybe fine tune the ability to precisely target, and of course that requires a little bit more layering of the markers and or a signal that we're going to be profiling in the individual.

                                So I don't think it's the end of targeted therapies, perhaps requiring a little bit of a more precision, and maybe individualization. But I am fascinated by first realizing it's a responder, and then maybe trying to accelerate and or optimize therapy, perhaps especially when we are forced or driven by administrative concepts such as length of stay or others. So making sure that maybe these variables, these biomarkers may help us recognize that maybe we haven't achieved that appropriately dry state yet.

                                But those all need to be determined, of course, by future trials, so far targeted therapies both in the acute and in the chronic does not seem to result in implementing outcomes.

Dr Wouter Kok: Well and the next step for us is to try and think how can reduce proBNP in all patients, we tried it with medication, but didn't do that much of catheterizations for those who were ... there were 50% of patients who were ischemic so why don't we do much of these catheterizations now days. So that's something we're thinking about how can we improve these patients? What are we missing?

Dr Carolyn Lam:                Yeah, if I could add my two cents. So Wouter mentioned finding the right therapies that can effectively reduce NT-proBNP safely, and well you mentioned choosing the right patients to use this in. And if I may, you know, just adding perhaps the right settings as well. Because it's well known that not all of us take care of heart failure patients the same way. And maybe there are settings where having a number to guide us may be more useful than others. But what do you do? You know, we wait for more data, but in the meantime, just congratulations. Heartfelt, heartfelt congratulations Wouter for a beautiful study, thank you so much for the privilege of publishing it in Circulation.

                                Thank you for being on this podcast, and listeners don't forget to tune in again next week.

Apr 9, 2018

Dr. Carolyn Lam:               Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I am Dr. Caroline Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Can we reverse the cardiac effects of sedentary aging? Well if you're curious, you have to read the feature paper in this week's journal, as well as listen to the upcoming discussion of a trial that addresses this issue. All coming right up, after these summaries.

                                                Desmond mutations are known to cause skeletal and cardiac muscle disease, and also recently has been described in patients with inherited arrhythmogenic right ventricular cardiomyopathy or dysplasia. In today's first original paper, however, authors identified a novel Desmond mutation in a large Spanish family with inherited left ventricular arrhythmogenic cardiomyopathy or dysplasia, and a high incidence of, at first, cardiac events.

                                                First in corresponding author, Dr. Bermudez Jimenez from Granada, Spain, describe for the first time the largest family to date with a single Desmond mutation with a phenotype of left dominant arrhythmogenic dysplasia in the absence of skeletal myopathy symptoms and atrioventricular conduction disorders and supported by strong clinical and functional data. In a series of elegant experiments using explanted cardiac tissues and mesenchymal stem cell derived cardio myocyte from the family members, the author showed that the pathogenic mechanism probably corresponds to alteration in Desmond dimer and oligomer assembly and its connection with membrane proteins within the intercalated discs, thus Desmond mutations should be suspected in patients presenting with a cardiomyopathy characterized by mild left ventricular systolic dysfunction and/or dilatation, fibrosis, ventricular arrhythmias and a family history of sudden death.

                                                The next study is the first large scale report examining the incremental risk of surgical aortic root enlargement in patients undergoing aortic valve replacement.

                                                First author Dr. Rocha, corresponding author Ouzounian from University of Toronto and their colleagues sought to evaluate the early outcomes of patients undergoing aortic valve replacement with or without surgical aortic root enlargement.

                                                Now aortic root enlargement allows for larger prosthesis implantation and maybe an important adjunct to surgical aortic valve replacement in the transcatheter valve in valve era.

                                                Among more than 7,000 patients undergoing aortic valve replacement at a single institution from 1990 to 2014, the authors observed no incremental risk in post-operative mortality or adverse events following surgical enlargement of the aortic root as compared to aortic valve replacement alone. They therefore concluded that surgical aortic root enlargement appears to be a safe adjunct to surgical aortic valve replacement in the modern era.

                                                The next study suggests that in patients with acute coronary syndrome and an LDL cholesterol above 50 milligrams per deciliters, health care providers should consider adding ezetimibe to statins, particularly in two patient subgroups.

                                                First in corresponding author Dr. Giugliano from the TIMI study group at Harvard Medical School in Boston, Massachusetts and his colleague explored outcomes stratified by diabetes in the "improve it" trial where patients with a recent acute coronary syndrome were randomized to ezetimibe versus placebo on top of backgrounds in the statin.

                                                They found that patients with diabetes derived significantly greater relative and absolute benefit with the addition of ezetimibe relative to patients without diabetes. This enhanced benefit was driven by reductions in acute ischemic events including myocardial infarction and ischemic stroke in diabetics, while non-diabetic patients who were more than 75 years of age or who had a high risk score also significantly benefited from the addition of Ezetimibe to Simvastatin.

                                                These benefits of Ezetimibe were achieved without an increase in safety events compared to placebo. Thus, the two patient subgroups of acute coronary system who are likely to achieve greater benefits with the addition of ezitimibe include: one, patients with diabetes, and two, patients without diabetes who have a high risk score.

                                                The final study provides insight into sudden cardiac arrests in the young and the potential contribution of standard cardiovascular risk factors to this risk, even in the young.

                                                First author, Dr. Reshmy Jayaraman, corresponding author Dr. Chugh from Cedars-Sinai Medical Center in California and their colleagues, prospectively ascertained 3,775 individuals who suffered sudden cardiac arrest between the ages of 5 and 34 years in the Portland, Oregon Metropolitan area and who were also followed up for 13 years. They found that 5% of cases occurred in young residents between the age of 5 and 34 years.

                                                Among the young, there was an unexpectedly high prevalence of classical cardiovascular risk factors, such as obesity, diabetes, hypertension, hyperlipidemia and smoking. In fact, one or more risk factor was observed in 58% of cases, with obesity being the most common.

                                                Less than a third had warning symptoms prior to their lethal event and sports activity was a trigger in only 14% of young cases. Thus, standard cardiovascular risk factors, especially obesity, may play a larger role in sudden cardiac arrests in the young than previously recognized. This suggests the potential role of public health approaches that screen for cardiovascular risk factors at earlier ages.

                                                And that wraps it up for our summaries, now for our feature discussion.

                                                Oh boy, today's featured discussion is gonna make everyone listening fall in love with exercise and seriously get off your chair right now as you listen to this discussion.

                                                It's about how exercising may reverse cardiac aging and I am so delighted to have with me none other than the corresponding author, Dr. Ben Levine from the institute of exercise and environmental medicine at Texas Health Presbyterian and UT Southwestern, as well as Dr. Jarett Berry, and he's our dear associate editor from UT Southwestern.

                                                Ben, I have been dying to have you on this show, so welcome and please, tell us what you did.

Dr. Ben Levine:                 Thank you very much, it's a pleasure to be here Carolyn, thanks for inviting me to talk about it. As you know, our lab has been particularly interested in the components of aging that are related to senescent versus those that are related to senescence activity.

                                                Perhaps the most dramatic reason that we're interested in this, I'm just gonna give you a little bit of background, if you don't mind, comes from one of the most important studies ever done in our field, that was done in Dallas in the mid-1960s. It's called the Dallas Bedrest and Training Study.

                                                At that time, my mentors, G Blomqvist, Jerry Mitchell, Bengt Saltin, took five young men, put them to bed for three weeks and then trained them for two months and virtually everything we know about the adaptive capacity of the circulation to exercise starts without study.

                                                I was only ten years old, so I really had nothing to do with it, but 1996, 30 years later, we found those same five guys and brought them back to Dallas to study them again.

                                                Now, these are the most intensively studied humans probably in the history of the world. 78 pages of circulation in 1968. What we found was quite amazing. We found that not a single one of those five guys was in worse shape 30 years later, than they were after three weeks of bed rest when they were in their 20s.

                                                So, three weeks of bed rest was worse for the body's ability to physically work than 30 years of aging. And so, we sort of launched off that in a series of experiments, trying to figure out when in the aging process does the shrinking and stiffening of the heart develop, that is the sine qua non. if you will, of the cardiac aging. So, when does it start? How much exercise do you have to do to prevent that?

                                                We did one interesting study where we compared a group of very highly selected seniors, all aged around 70, who were healthy, but did no exercise, compared to a group of elite Masters Athletes. Amazingly, the healthy seniors, their hearts got smaller and it shrunk and they got stiffer and the athletes had hearts that were indistinguishable from healthy 30 year olds.

                                                So, a lifelong training at the level of being an elite athlete completely prevented that aging response, which is really interesting scientifically, but not a very good public health measure.

                                                So, we then asked how much exercise do you need to do over a lifetime to preserve the compliance, the youthfulness, if you will, of the circulation, and at times, they act like you need to do about 4 or 5 days a week over a lifetime. 2 to 3 days a week didn't do anything. 4 to 5 days a week did almost as much as being an elite competitive athlete. So, now we've got the dose. 4 to 5 days a week.

                                                We said, "okay, if we do that, can we reverse cardiac aging once it's occurred?" So, we took our healthy sedentary people and we also looked at a group of HFpEF patients and we trained them for a year, at the right dose, using high intensity exercises. We made them fitter, but we couldn't touch their cardiac or vascular stiffness. Quite disappointing actually.

                                                Last thing then, we said "okay, this leads up in to our current study maybe, just maybe, if we pick the right sweet spot in time, when the heart is just beginning to stiffen in that late middle age period and deal the right dose at the right time for a long enough period, we could reverse the effects. And, that's what we did. We took 60 people, healthy, middle aged, 45-64, mean age around 50. We randomly assigned them to two years of exercise training or two years of yoga, balance, flexibility, and we did 2 light heart caths. We measured their cardiac compliance directly invasively and we showed that our 2 year training program, which included high intensity intervals, reversed the effects of decades of sedentary aging.

Dr. Carolyn Lam:               Wow, Ben, you know, no one tells the story like you and I have to tell you, I've been a fan of your work, citing it since I was 10. Thank you so much for this amazing contribution to the Journal this week. I just know everybody's asking questions like "So, you've given us when to start, you given us the dose, but we want to understand a bit better, what do you mean high intensity, how many minutes and what exactly." Could you give us an idea?

Dr. Ben Levine:                 Sure. There are multiple different ways to go about doing HIIT or High Intensity Interval Training. And there's no magic to intervals. Intervals just allow you to do something for a shorter period of time and harder than you could do for a longer period of time. That is the strategy that athletes use to go faster and stronger and higher, because the body adapts to the load that's placed on it.

                                                Interval training, what I like, is based on an old Norwegian ski team workout. It's called the "4x4". What that means is 4 minutes at 95% of your maximum followed by 3 minutes of recovery, active recovery, repeated 4 times. So, basically, you go as hard as you can go for 4 minutes and at the end of those 4 minutes, you should be ready to stop. Typically, your heart rate will drift up towards 95% of maximum or so. Then, at the end of the 3 minutes of recovery, you should be ready to do the next interval.

                                                As it turns out, that's extremely effective training stimulus. Not just for healthy people or athletes, for the patients with hypertension and with heart failure.

Dr. Carolyn Lam:               I noticed that you have to screen over 260 individuals to finally get your 60, so how doable is this and what was the compliance?

Dr. Ben Levine:                 Right. You have to remember that out of those 260 individuals that we screened, the majority of them were excluded up front because they had hypertension or if they were obese or they already had heart disease. So, the first round of screening was making sure we're getting people of the right age and were healthy. And, then another fraction, say 40 of them or so, didn't wanna undergo two light heart catheterizations. And, I get that. We were pretty pleased that somebody volunteered to do it, but you know, it's an intense commitment. People have to be willing to be randomized. So, they couldn't say "Well, I wanna do your study, but only if I get randomized to exercise", that was not acceptable.

                                                So, everybody had to be prepared to be randomized to either yoga or the fitness training and the yoga, it makes people feel better, it's relaxing. I think it provided that clinical equipoise and it ensured that even the controlled patients had close contact with our research team.

                                                Then, what we had was, on average 88% of the prescribed sessions were followed by our exercisers and a fraction of them, 15 or 20%, actually did 100% of their prescribed sessions over two years, didn't miss a single one.

Dr. Carolyn Lam:               So, Jarett, have you started doing that yourself now?

Dr. J Berry:                          I tell you, I pried my kids out of bed last summer, to go do 4x4s and get them ready for cross country. I talked all about Ben Levine and told my kids that we were doing what Dr. Levine recommended. That didn't help too much, they found it rather challenging. It was interesting that the VO2 plateaus a little bit at that 10 month mark, when you guys backed off on that additional interval training. Do you think that the plateau is just a limitation of the training effect or do you think that something that has to do with the lower level of interval training at that time?

Dr. Ben Levine:                 You know Jarett, I think that's a fascinating question and it's one of the things that really surprised me. So, Jarett pointing to the fact that at that 10 month mark, we measured VO2 max, we didn't cath them, but we did an Echo, and it showed that from 10 months to 2 years VO2 max didn't increase very much.

                                                There was a dramatic increase from baseline to 10 months. It took 3 months at that peak dose. But then, when we dropped one interval and did the same thing every week for 2 years, there wasn't an influence of time. The heart didn't continue to get bigger, the stroke volume didn't continue to enlarge.

                                                I think it highlights a critical part, an essential element, to that exercise training and that is, doing the same thing, over and over again doesn't get you fitter. If you wanna get fitter than you are, you have to change things around, you have to increase the load. So, I think that if we had wanted to make them even fitter than they were at 10 months, we'd have had to either kept that second interval or added another one or increase the duration of some of the base training sessions.

                                                It's really interesting to me, that they didn't continue to improve simply on the basis of time. That surprised me.

Dr. Jarett Berry:                Yeah, cause you wonder. You think about, the guidelines suggest moderate intensity exercise, which is obviously much lower intensity than what you're talking about with this interval training, but very little guidance with regard to interval training.

                                                Your data here obviously suggests that it's not just getting off the couch and doing something, and not just doing a decent amount, it seems to suggest that the interval training component may be a secret ingredient that might be most helpful, at least for those patients who can tolerate that level of training.

Dr. Ben Levine:                 Yeah, I think that maybe it's the secret sauce, Jarett, but I think, you do have to ask yourself, what is the goal of training and what is your objective outcome? What you want is to reduce cardiovascular mortality. I think we would all agree that you get the biggest bang for your buck by going from sedentary to active. And, the mechanism of that is uncertain, but could relate to autonomic function or clotting or improving stabilization of endothelium or other risk factors, inflammation, who knows, there's a lot of different candidates. So, I think that particularly for people who are at the highest risk for heart failure, either from their family history or other risk factors, like hypertension and diabetes, those are the ones who were likely to get in a special benefit on altering cardiac structure.

                                                That's why I think our data is still an important poll. We didn't really know why do you get the biggest bank for your buck with a little training, but if you really wanna prevent heart failure, you gotta do more.

                                                In our data that we did partnered with the Cooper Clinic and looked at people who had done the same number of exercise sessions over 25 years. None, 2-3, 4-5 or 6-7, over 25 years, we saw virtually no effect of 2-3 days a week of what we call casual training on anything we could measure, related to cardiac structure. Their vascular stiffness was the same as people who were sedentary, their cardiac stiffness was the same as people who were sedentary. They were a little fitter and perhaps there were other important differences that are related to just improving immortality, but you have to get past that low to moderate dose to have the structural effects on the circulation.

Dr. Jarett Berry:                These are really great points here, Ben. I want for our listeners to hear you comment a little bit more on the primary outcome and how you guys measured stiffness, because I think in addition to the level of training, it's also the approach and the phenotype that you collected to measure this and I think it would be helpful for you to walk us through that a little bit and how you guys measured stiffness.

Dr. Ben Levine:                 We used an old physiological technique called "Lower Body Negative Pressure". We first let the subject settle down, we measure a variety of cardiovascular variables, cardiac output, and we do an advanced ECHO imaging and some arterial stiffness measures and after about 40-45 minutes or so, we'll measure the pulmonary capillary wedge pressure, that's what we use as an index, and plus ventricular and diastolic pressure. We'll do 3D ECHO volumes and then we unload the heart by doing Lower Body Negative Pressure. We basically seal the subject in a box at the iliac crest and turn on a vacuum cleaner and suck blood into their venous capacitance. It's a very simple way to unload the heart.

                                                In contrast to people who do put in conductants or reflectant catheters and occlude the IVC and do pressure volume rudes, we have taken a little bit of a different approach. I do steady state and diastolic pressure volume curves. So that means, we look at the pressure and volume in the heart at baseline at two different unloading levels. So, let's say the baseline ledge is 10. The first level of LBNT of minus 15 will get it down to 6 or 7. The next level of minus 30 gets it down to 2 or 3. And, so we get a nice unloading of the heart and we're able to establish a steady state, which is probably more afunctional than a release of an IVC occlusion.

                                                Then, we let go of the suction, everything returns to normal. We repeat our baseline measures and then we give the rapid saline infusion. When I say rapid saline, I mean 15 and 30 mls per kilogram, that's at 200 mls a minute. That's a big volume infusion, but we'll give those doses and we'll raise the ceiling pressure from 10 at baseline to 15 and then 19, 18, 19. So, we get a large physiologic range of the diastolic pressure volume curve, and then we'll fit that to an extremely widely accepted exponential equation, which allows us to calculate the overall stiffness of the heart, the diastolic component, and then we'll do a few other things, we'll measure distensibility , which is the volume at any given pressure and DPDV, the change in pressure for a given volume, which is the hansen float to the exponential curve fitting.

Dr. Jarett Berry:                Can you comment a little bit about what this means for how this is distinguished perhaps from maybe more conventional non invasive measurements of cardiac stiffness?

Dr. Ben Levine:                 I think the most important thing to realize is that, cardiac compliance is dynamic. It depends on the volume at which you're making that measurement. So, as you unload the heart, any heart, even the stiff heart, it gets more compliant, and as you load the heart, even a compliant heart, it gets stiffer. Part of that is a function of pericardial constraint, as well as myocardial stiffness.

                                                The whole idea that there is a measure of diastolic function that you can measure by ECHO that is load independent is frankly an oxymoron, because, diastole is load dependent. I think the ECHO measurements are interesting and useful, depending on what you're trying to find out, because there are many different aspects of feeling and diastolic suction and diastolic stiffness. All of which influence how well the heart feels at rest and during exercise.

Dr. Carolyn Lam:               I have to ask you one last question. I am so pleased that you included at least 52% women. Were there any differences by sex?

Dr. Ben Levine:                 Of course, Carolyn, it's critical to include women, since they're 50% of the population. We've been very interested in their training responses in men and women at different age groups in many of our other studies. What's interesting is that in premenopausal women, there's a quite clear distinction in how women respond to training. They don't hypertrophy as much, even for the same stimulus, heart beats a heart beat, over a year, there's a much less hypertrophic response to premenopausal women than young men.

                                                We didn't see anywhere near that difference in our mostly postmenopausal middle aged men and women. We didn't have enough power to clearly be confident that there was no difference, but when we tried to test that hypothesis, whether there was a different response in men or women, we could not detect a difference.

Dr. Carolyn Lam:               That is a good thing. So, women out there, you heard it from Dr. Levine. We got to exercise too. High intensity. All the time.

                                                Thank you audience, for listening today. Don't forget to tune in again next week.


Apr 2, 2018

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.

                                                Today's feature paper is about statins, and it's the first population-based study to show a dose-dependent benefit on amputation and survival in peripheral artery disease. Very important data and a very important discussion coming right up after these summaries.

                                                The first original paper this week indicates for the first time that the natural history of coronary stenosis is better predicted by physiologic information by FFR, or fractional flow reserve, than by anatomic information from angiography. First author, Dr. Ciccarelli, corresponding author, Dr. DeBruyne, from OLV Hospital in Belgium compared the values of angiographic diameter stenosis and of fractional flow reserve in predicting the natural history among 607 patients from the FAME 2 trial who had documented stable coronary disease and in whom no revascularization was performed. The primary end point was defined as vessel oriented clinical end point at two years, and this was a composite of prospectively adjudicated cardiac death, vessel-related myocardial infarction, vessel-related urgent and non-urgent revascularization.

                                                The overall results showed that FFR predicted the natural history better than diameter stenosis. In addition, among the stenosis with mismatch between diameter stenosis and FFR, more than half had a low FFR in the presence of an angiographically mild stenosis and the rate of primary outcome was higher in those with reduced FFR regardless of whether diameter stenosis was significant or not. The take-home message is, therefore, that measurements of FFR should be considered not only an angiographically intermediate stenosis but also perhaps a mild or severe stenosis by visual evaluation.

                                                The next study provides population-based data on cardiovascular outcomes and risks after initiation of a sodium glucose cotransporter-2 inhibitor, or SGLT2 inhibitor. First and corresponding author, Dr. Udell, from University of Toronto, and his colleagues, performed population-based cohort study among type 2 diabetes patient with established cardiovascular disease and newly initiated on antihyperglycemic agents within the US Department of Defense Military Health System between 2013 and 2016. After propensity matching, more than 25,250 patients were followed for a median of 1.6 years. Initiation of SGLT2 inhibitors was associated with a lower all-cause mortality, lower hospitalization for heart failure events, lower major adverse cardiovascular events, but higher below-knee amputation risk. Findings underscore the potential benefits and risks to be aware of when initiating SGLT2 inhibitors. Importantly, it remains unclear whether the risk of below-knee amputation extends across a class of medications as the study was not powered to make comparisons among individual treatments.

                                                The next paper reports results of the redefined trial, which is the first trial to study the effects of renin-angiotensin-aldosterone system inhibitors in adults with tetrology of Fallot and mild right ventricular dysfunction in the absence of severe valvular lesions. First author, Dr. Bokma, and corresponding author, Dr. Bouma from Academic Medical Center Amsterdam, and their colleagues, studied 95 patients in the redefined trial and found that 150 mg of losartan daily did not significantly improve the primary outcome of right ventricular ejection fraction change compared to placebo. There were no significant treatment effects on secondary outcomes of left ventricular ejection fraction, peak aerobic exercise capacity or NT-proBNP. However, in a post hoc analysis, losartan was associated with improved right ventricular ejection fraction in a subgroup of 30 patients with nonrestrictive right ventricles and incomplete remodeling. The conclusion is, therefore, that losartan had no significant effect on right ventricular dysfunction or secondary outcome parameters in repaired tetralogy of Fallot. Future larger studies may determine whether there might be a role for losartan in specific vulnerable subgroups.

                                                The final study reinforces that vesicle trafficking plays an essential role in the signal regulation of pathologic hypertrophy and identifies a novel potential target in this process. This novel target is the transmembrane BAX inhibitor motif containing 1, or TMBIM1. First author, Dr. Deng, corresponding author, Dr. Li, from Wuhan University in China, and their colleagues, found that TMBIM1 expression levels were substantially decreased in both clinical and experimental hypertrophic hearts. Mechanistically, TMBIM1 interacted directly with tumor susceptibility gene 101 and accelerated the formation of multivesicular bodies to degrade activated toll-like receptor 4. Toll-like receptor 4 degradation in turn was essentially for the progression of cardiac hypertrophy. Importantly, expressing TMBIM1 in monkeys via lentivirus protected their hearts from aortic banding induced cardiac hypertrophy. In summary, these findings shed light on the role of vesicle trafficking in signal regulation during cardiac hypertrophy and provide a novel therapeutic target for treating hypertrophy.

                                                That wraps it up for our summaries. Now for our feature discussion.

                                                Peripheral artery disease, a disease that affects more than 200 million individuals worldwide and associated with a high risk of cardiovascular events and death and, of course, the much feared amputations. Yes, statin guidelines for peripheral artery disease are largely based on coronary artery disease or stroke data. Well, today's feature paper really addresses an important knowledge gap between statins, doses, amputation survival in peripheral artery disease. I'm delighted to have the first and corresponding author, Dr. Shipra Arya from Stanford University School of Medicine and, of course, our favorite, Dr. Josh Beckman, Associated Editor from Vanderbilt University.

                                                Now, Josh. I understand there's a bit of a back story of how this paper came to circulation. Want to share?

Dr Josh Beckman:            Oh, absolutely. First of all, I have to say that one of the jobs of an associated editor is someone who kind of goes antiquing in every single store. Every place I am where people are presenting really good science, I'm kind of scoping it out. I'm interested. I want to see what's going on. I like to talk to the people who are doing the work to see how they're thinking about it, and I was lucky enough to see Dr. Arya's presentation. I think it was at an ATVB meeting, wasn't it?

Dr Shipra Arya:                  That's right.

Dr Josh Beckman:            I thought that this is an incredibly cool piece of work, and I basically hoped, I prayed, I asked. I said, "You know, maybe you should send this to us because we would really like to see the full manuscript," because inside I hoped that it would be just as impressive when it was written out as a full manuscript as it was when she was discussing it at the meeting. And, lo and behold, we were lucky enough that she submitted it to us and you can see the results online right now.

Dr Carolyn Lam:                Indeed! Well put. Shipra, with that kind of lineup, please, tell us about your study and what you found.

Dr Shipra Arya:                  Thank you for that invitation to submit to Circulation because initially I wasn't sure if Circulation would be interested in my work, so it was really great to hear when Josh said that this is something that it would certainly consider. The basic premise was to try and find out whether high-intensity statins as defined by the 2013 lipid guidelines, they would also have limb protective effects for PAD along with reduction mortality. As you said in the introduction, most of the data comes from either coronary data or comes from small groups of PAD patients, but never from such a large population.

                                                We identified about 150,000 veterans in the National VA database from 2003 to 2014 and excluded people who didn't have a diagnosis of PAD before 2003, and why this was such a labor of love was also to figure out how to identify the certainty that people had PAD and then getting into their pharmacy files and trying to parse out whether they were on high-intensity, low, moderate, or no statin. Initially, I had done the analysis of no statin, but then after review and discussion, it became clear that we needed a control group, which was people who were also on some guideline-directed therapy and not just no statin because they could be patients who were the noncompliant patients and who don't show up to the doctor's visits, and that's why they do poorly.

                                                That's why we chose a control group which were on antiplatelet therapy, at least aspirin or Plavix, any other antiplatelet agent. Even in that comparison, we find that after risk adjustment, patients who are on high-intensity statin had a more than 30% risk reduction of amputation as well as about a 24, 25% risk reduction of mortality compared to people who did not take a statin but at least took an aspirin. Low to moderate intensity statins were also effective, about 20%. Risk reduction in both amputation and mortality, but high-intensity statins when directly compared to the low to moderate intensity statins outperformed them.

                                                Just to be sure of our findings, we did it so many different ways. We did the Cox modeling. Then we did propensity matching that which person is more likely to receive the statin versus the other. Then we did subgroup analyses where we put people in different subgroups that people who had coronary artery disease as an indication, maybe that's why they were on these statins. But, people without coronary artery disease also same association [stack 00:11:12]. We were pretty confident in our findings, and that's why we sent it to Circulation.

Dr Carolyn Lam:                Wow. You know, Josh, you are the best at putting papers like this into context and really expounding on the significant. Tell us, why did this catch your attention so much?

Dr Josh Beckman:            Every time I think that statins have become just a standard part of therapy for patients with atherosclerosis, the first thing I noticed in this paper was that there were so many people who were still not on any statins or people who were on homeopathic doses of statins, and I can't understand how that happens. I think the mortality data was nice and consistent, but the amputation data is what really made a big difference. I'll ask Dr. Arya, but in my impression, the literature has been sort of back and forth as to whether or not statins really reduced limb outcomes. Your paper, I think, was clearly the largest sample that had taken a look at that question. Can you sort of separate out your papers from some of the previous work in that area?

Dr Shipra Arya:                  Sure. I would add that a lot of work about amputations has been coming out from vascular surgery data, and a lot of that work just focuses on short term outcome for limb loss. They look at 30 days. Maybe they'll go look up to six months to a year, but actually patency of bypasses, patency of vessels is a long-term phenomenon. Much like mortality that can happen years later, your amputation risk can happen years later, too. I think what separates us is the lifetime followup for these patients, and we are looking in a cohort of patients who are in this veterans' healthcare system so the data is automatically getting captured even if they get their care outside. Records do make it back and diagnoses do make it back. It's the VA [inaudible 00:13:03], and we did some sensitivity analysis to show that, yes, most of the veterans we have in [inaudible 00:13:09] actually get their care and have data being added continuously into the corporate data warehouse.

                                                That was something I think that lent to the power of making the [sure 00:13:20] conclusion and that's where previous studies have not been able to show a significant association with amputation. The studies, if they are single center or they are focused from electronic medical records or perspective followup, either the patients get lost to followup or go see other doctors or other healthcare systems, and that information doesn't get back to the researchers, while mortality data you can get from Social Security Death Index or other sources. I think that's what makes the study different than other studies in this similar field in terms of followup.

Dr Josh Beckman:            I don't think you're giving yourself enough credit. There's a whole bunch of things that make the study unique. One of the things that I was most taken with right upfront was the way that you defined peripheral artery disease for this population. There has been, as far as I know, at least seven or eight different definitions that people have used with administrative data to try and ferret out who has PAD, and in contrast to coronary disease and stroke, it's a much more complicated endeavor to do that. So, when I saw the way that you did it ... I'm going to say this in a way that I know is going to sound funny, but you made the complicated look really simple. Your definition is not something that required 3,000 lines of ICD-9 codes within inclusion and exclusion criteria and speaks, in my opinion, to the power of the large sample because, basically, they needed one ICD-9 code and either two ABIs, a visit to a vascular surgeon or procedural code. Now, I know that this definition comes from some of your work, so can you tell us how you derive this and then let's talk about what that means.

Dr Shipra Arya:                  Absolutely. We looked at practice patterns for patients with vascular disease across the VA, and most patients who undergo procedures for PAD, we can confidently say that they do have PAD. When we look at the specificity of just that occurrence, it's pretty high, like [90% 00:15:23]. Then what we did was we did some random sampling in the VA data, about 300 patients, and used different codes to see if patients came back to the vascular surgeon within ... We used 14 months because it's usually one year followup that most people prescribe, so whether they went two months before or after because the appointment hours. We found that that was again a high specificity of about 80%. Then, when you look at patients who come back with ABI followup. So, we looked at CPT codes for ABI. We found out it's like a 99% specificity. If you have ABI followup within a year, and we relaxed it to 14 months, you could be 99% confident that this patient does have PAD.

                                                We just combined all those three together, and this is ... If Circulation is interested, I can send you this, too. We are working on this manuscript where we are giving researchers different algorithms that they could use to identify PAD because I wanted a more specific sample because I was looking at PAD outcomes. I wanted the PAD definition to be tight. Our specificity is greater than 80% combining all these three together, about 84%. We are fairly confident in this that, yes, these patients truly have PAD, so when we follow them up for outcomes, we can be confident in our results. If researchers wanted a more relaxed definition of PAD, they could use other algorithms that we are putting in that paper where they could say, "We will only use one ABI measurement, or we would use a combination of these."

Dr Josh Beckman:            That brings up two points. You talk about this brings up the power of large data and the ability to tone down on people who really, truly, absolutely have PAD without any question. So, number one, are you worried that you're missing people that probably do have PAD and would benefit from therapy, and number two, do you worry that you're basically concentrating on the sickest right end of the curve of the group of PAD patients?

Dr Shipra Arya:                  Right. That's a great point, and I discussed that with my coauthors and mentors and we wanted to be sure about our outcomes and not want to include people who did not have PAD, and then we are kind of including the effect size of what we may find, but yes, these are truly what we are calling a symptomatic PAD, and I think I mentioned that in the manuscript somewhere, that we probably would be missing people who are asymptomatic and not really being followed up. If we extended this analysis to people who are not regularly being followed or being under surveillance for their PAD, the results could be different. So, yes, it does not generalize the whole of that population. If we had gone that route and relaxed our inclusion, my worry was that we would get ... Because of large data setting up, as you say, if we include a bunch of people who are truly not PAD, we would be a [threading 00:18:17] risk in non-PAD patients.

Dr Carolyn Lam:                Josh and Shipra, I loved the paper, but after this discussion I'm even more in love with the paper and impressed, so I think I just have a question for both of you. Is there any excuse not to give statins now? Do we actually think a trial is going to come on this topic? Is this the best data that we have? Is it going to enter guidelines? What do you think?

Dr Josh Beckman:            I can give you my opinion first, if you want, because you're the person who actually has control of all the data. I would say this. I think it's been well known that statins should be used in all the patients with PAD for their cardiac outcome. My guess is that there are two things that are going to happen that are going to make people consider statins for limb outcomes.

                                                One, data like this and there's never going to be a trial, a prospective randomized trial at this point, I mean unless you disagree, but there's no way people will randomize to not statin. I think the second reason is the recent data on the PCSK9 inhibitor, evolocumab, which showed that on top of statins in PAD patients, there was a further reduction in limb events. I think we're heading towards getting the LDL to zero. It may take a couple more steps, but that's basically what's going to happen.

Dr Shipra Arya:                  I agree. I think there has been time and time again data that shows, especially those already data supporting the mortality benefit for larger cohorts of patients with cardiovascular disease including PAD. I think this study really nails down the limb protector effects of statins, and doing a trial of this magnitude would be very difficult to do because to get that would be effect size that you have. You would need a huge cohort of patients, and you probably won't find statin-naïve patients because you have already half the patients with PAD have coronary artery disease, as well. So, not every study needs a trial. Not every question needs a trial, in my opinion. I think that's the power of large data sets. I think the evidence is overwhelming, and I would agree with Josh.

Dr Josh Beckman:            I have always had a hard time explaining to people who came to see me for legs problems that they have to take a drug for their heart. It's sort of a weird two-step that people have a hard time accommodating. Do you think by telling them that this drug will also save their leg that they're going to be more likely to take the medicine by the end of the year?

Dr Shipra Arya:                  Yes, absolutely. That's what I tell my patients who come and see me, that this medication works on arterial plaques, and it stabilizes them. It's not just the same plaque that you have in your heart is the one you have in your leg. Maybe a little different, but to oversimplify, yes. This is not just a heart medication, and this is not just a cholesterol medication. This is a medication for your plaques, for your blockages. That's how I explain it to them, and I think the uptake would be more if we explain to them that, yes, this will help you keep your leg, stay ambulatory and stay at home and not end up in assisted living or nursing home.

Dr Josh Beckman:            Carolyn, this is so much fun, especially when we get to talk to the people that do so much hard work to put stuff in circulation, so I just want to say thanks again to Shipra and her coauthors.

Dr Shipra Arya:                  Thank you so much, and thank you for giving us the opportunity. I think the comments from Circulation really made our paper better, so thank you for doing that.

Dr Carolyn Lam:                I wish that we could just keep going on and on because I just know that Josh has even more great questions up his sleeve. See, Shipra, I told you, he's amazing. But, there you go. You're amazing, too. Your paper is amazing. Thank you so much for joining us today.