Circulation on the Run

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Circulation September 4, 2018 Issue Sep 04, 2018

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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. Current guidelines recommend measurement of one of the cardiac specific isoforms of cardiac troponin complex. However, what's the utility of combining measurements of troponins I and T in the early diagnosis of acute myocardial infarction? Well, you have to wait for our upcoming feature discussion, but it's coming right up after these summaries. The first original paper this week sheds light on the genetic basis and mechanisms of bicuspid aortic valve, the most common congenital heart defect in the population. We know that bicuspid aortic valve is an autosomal dominant trait with variable expression and incomplete penetrants suggestive of genetic and environmental modifiers. In the current study, first author Dr Gharibeh, corresponding author Dr Nemer from University of Ottawa, and authors of the Bicuspid Aortic Valve Consortium assessed cardiac structure and function in mice, lacking a GATA6 allele. They found that GATA6 heterozygous mice had a highly penetrant type of bicuspid aortic valve with right and left leaflet fusion, which is the most frequent type found in humans. GATA6 transcript levels were lower in human bicuspid aortic valve as compared to normal tricuspid valves. Mechanistically, GATA6 haploinsufficiency disrupted valve remodeling and extracellular matrix composition through dysregulation of the importance in the molecules including matrix metalloproteinase nine. Cell-specific inactivation of GATA6 reveal that an essential rule for GATA6 in secondary heart field myocytes. Thus, the study identifies a new cellular and molecular mechanism underlying bicuspid aortic valve. In the field of cardiac regeneration, c-Kit positive adult progenitor cells were initially reported to produce new cardiomyocytes in the heart. However, more recent genetic evidence suggests that such events are exceedingly rare. Today's paper provides insights into this discrepancy and it is from first author Dr Maliken, corresponding author, Dr Molkentin from Howard Hughes Medical Institute Cincinnati Children's Hospital Medical Center. The authors took a novel approach of deleting the necessary cardiogenic transcription factors, GATA4 and GATA6, from c-Kit expressing cardiac progenitor cells to determine whether true de novo cardiomyocyte formation would occur. They found that deletion of the necessary cardiogenic transcription factors, GATA4 and GATA6, from these c-Kit+ cardiac progenitor cells remarkably resulted in greater apparent cardiomyocyte derivation from the c-Kit+ cells. Deletion of GATA4 from c-Kit–derived endothelial progenitors altered the integrity of the endothelial cell network in the heart, resulting in greater c-Kit+–derived leukocytes entering the heart and fusing with cardiomyocytes. Thus, they demonstrated a new role for GATA4 in endothelial differentiation, specifically showing for the first time that GATA4 is essential for vascular development by the c-Kit lineage. The study shows that leukocyte to cardiomyocyte fusion is the primary basis for path lineage tracing results, incorrectly suggesting that c-Kit+ cardiac progenitor cells generated de novo cardiomyocytes in the heart. Lecithin–cholesterol acyltransferase, or LCAT, is the sole enzyme that esterifies cholesterol in the plasma. Its role in the supposed protection from atherogenesis remains unclear, because mutations in LCAT can cause more or less carotid atherosclerosis. Addressing this conundrum, co-first authors Drs. Oldoni and Baldassarre, co-corresponding authors Dr Kuivenhoven from University Medical Center Groningen, Dr Holleboom from Academic Medical Center Amsterdam, and Dr Calabresi from University of Milano in Italy hypothesized that genetic mutations causing complete LCAT deficiency versus partial LCAT deficiency would be differentially associated with carotid atherosclerosis in carriers of LCAT mutations. To study this, they looked at 74 heterozygotes for LCAT mutations who are recruited from Italy and the Netherlands and who were assigned to complete versus partial LCAT deficiency. These were also compared to 280 controls. Using carotid intima-media thickness as a measure of atherosclerosis, the authors demonstrated that carriers of LCAT mutations leading to complete LCAT deficiency exhibited less carotid atherosclerosis, indicating a reduced risk of cardiovascular disease. By contrast, however, carriers of LCAT mutations leading to partial LCAT deficiency showed marginally more atherosclerosis. The association of mutations in LCAT with subclinical atherosclerosis appeared to be related to the capacity of LCAT to esterify cholesterol on apoB-containing lipoproteins since the abnormal LCAT present in the partial deficiency was only active on this class of lipoproteins. These important findings bear relevance for pharmaceutical strategists that target LCAT. After a bioprosthesis aortic valve replacement, what is the incidence, correlates, and outcomes of hemodynamic valve deterioration? First author Dr Salaun, corresponding author Dr Pibarot from Quebec Heart and Lung Institute and their colleagues studied 1,387 patients who underwent bioprosthetic aortic valve replacement and found that hemodynamic valve deterioration identified by Doppler echocardiography occurred in one-third of patients and was associated with a 2.2-fold higher adjusted mortality. Diabetes and renal insufficiency were associated with early hemodynamic valve deterioration whereas female sex warfarin use and stented bioprosthetic valve versus the stentless ones were associated with late hemodynamic valve deterioration. These findings suggest that following bioprosthetic valve replacement, a systematic echocardiographic follow-up may be considered to ensure adequate detection and quantitation of hemodynamic valve deterioration. That wraps up on the summaries this week. Now for our feature discussion. We are recognizing the critical role that cardiac troponins play for the early diagnosis of acute myocardial infarction. We also know that there are different isoforms of cardiac troponins, the cardiac troponins T and I. Now, have you ever considered combining the two? How does that help the early diagnosis of acute myocardial infarction? Well, I am delighted to have with us the corresponding author of our feature paper today, Dr Christian Mueller from University Hospital Basel in Switzerland, a very familiar voice on this podcast. Welcome, Christian, and thank you so much for publishing yet another wonderful paper with us. Dr Christian Mueller: Thank you very much for highlighting this important work and allowing me to comment on it in the podcast. Dr Carolyn Lam: Christian, first of all, could you paint the background to help us understand what's the difference between the two isoforms, I mean, in terms of diurnal variation, the way that they may be released earlier or later, the way they may or may not be impacted by comorbidities like renal dysfunction or hemolysis? Could you help us understand why there may be rational to combine the two in looking at their impact on the diagnosis of acute myocardial infarction? Dr Christian Mueller: The measurement of cardiac troponin as a structural protein unique to the heart clear is a central piece in our early diagnosis of acute myocardial infarction, so both for the early rule out in patients who present with chest pain and are finally found to have more benign disease as well as the early ruling. In general, I think it's important to highlight that there are two isoforms exactly as you have mentioned, so there is cardiac troponin T and cardiac troponin I. So these two proteins are cardiac specific and are used in the diagnosis of acute myocardial infarction. Now with the development of high-sensitivity methods or measurements of both cardiac troponin T and cardiac troponin I concentrations, we have been able to get a little bit of a better understanding of in fact differences in the pathophysiology as well as analytical details between cardiac troponin T and I. Before I start highlighting the differences, I think it's important, I mean, both signals show a very strong correlation, so still very, very similar to each other. However, the small differences that have begun to emerge kind of allow to suggest that possible we could use them together as two pieces of information in the diagnosis. So, what are the differences? First, exactly as you have highlighted, that if in fact that diurnal rhythm with cardiac troponin T, which means that cardiac troponin T concentrations are higher in the morning hours as compared to the evening, we still have no clue why that's the case, but it's a relevant difference about 25% and it has been shown in two cohorts and a group from Maastricht who was the first one highlighting this. This rhythm has not been found for cardiac troponin I. The second difference is that, again, probably understood in many, many population studies cardiac troponin T concentrations are even stronger predictors of death as compared to cardiac troponin I concentration. Then the third difference it seems that if we measure it with high-sensitivity assays, for example high sensitivity, it seems to rise or if you released from injured cardiomyocytes even slightly earlier as compared to T and possibly even less injuries necessary to release I as compared to T. Then you mentioned renal function. Cardiac troponin T concentration shows slightly higher correlation with renal function as compared to I. Also, other pre-analytical issues, hemolysis seems to affect T and I concentration in a different way. So a lot of small tiny differences that have emerged and that underlie the hypothesis that possibly by combining the two signals we could be even more accurate in the diagnosis rather than relying on one on its own. Dr Carolyn Lam: That's good. That really sets up the rational very well. I think in and of itself is a learning lesson, because I think most clinicians sort of take the two equivalently. So could you tell us what you found? Dr Christian Mueller: I would like to of course thank the fantastic team that has allowed us to generate this data. It's a collaboration between the APACE investigators, the ADAPT investigators and experts in clinical chemistry from Maastricht University and Noreen Fandalin and Karen Villa of the first office. So we used two large diagnostic studies, APACE and ADAPT. We measured high-sensitivity cardiac troponin T and I and both of them and compared the diagnostic performance as compared to the final adjudicated diagnosis by two independent cardiologists who, of course, had all information, cardiac imaging and whatever you need to adjudicate. So, what we found is that in general if you look at diagnostic accuracy, overall is quantified by the area under the curve. Combining the two signals did not consistently increase overall diagnostic accuracy as compared to the individual isoforms. However, we were able to document some improvement for the rule out for the very early rule out of acute myocardial infarction. So the concept that is extremely attractive of course from a medical as well as from an economic perspective is to rule out the presence of acute myocardial infarction with a single blood draw. So, we can do this if we assess the ECG. The ECG doesn't show relevant changes. Then if the troponin concentration measured with a high-sensitivity assay is very low, then the likelihood that the patient would have an acute myocardial infarction again is extremely low or in scientific term sort of a negative predictive value approach is 99 to 100%. By combining very low concentration for high-sensitivity T and very low concentration for I, we were able to increase the efficacy of the early rule out and that seemed to be the most likely possible clinical utility of combining the two signals. Dr Carolyn Lam: Even that so-called neutral findings are very important. It's an important question to ask and important answer to get. Could you give us an idea for the rule-out part? How much do we gain? How much exactly do we gain by using both assays instead of just one? Dr Christian Mueller: So, the efficacy of the early rule-out depends to some extent on the assay used and the cut off applied. So the current you see algorithm uses cut-off that has been shown to be very safe. However, they are regarding their efficacy not very high. So the current you see recommended cut-offs and approach, allows the rule-out only in about perhaps 10 or 15% of patients. That number can be significantly increased, likely doubled or perhaps even increased threefold by using the combination approach. So this has been consistently showed both in the derivation and the validation cohort. Dr Carolyn Lam: Yeah. Do you think this is ready for prime time? I noticed a very balanced discussion actually calling for future studies, but perhaps you could state it better now. Dr Christian Mueller: The main limitation regarding prime time is the fact that currently manufacturers either of a high-sensitivity TSA or of a high-sensitivity high method, which means that the vast majority of hospitals at this point in time do only have one method available. It would require quite substantial investment in both hardware as well as changing of the logistics in the lab to implement measurement of both assays. So I think it's likely feasible, but it would be associated with relevant investment from a hospital perspective. In addition, I mean, also the rule-out approaches that use of only one assay also there are studies ongoing in trying to further increase the efficacy of the single marker approach. So I think it's the best tool marker strategy that we were able to come up with recently, because many of the other biomarkers that we had tested really didn't work out. Still, as you mentioned, I think it's also important to be very, very honest that it will be difficult to implement tomorrow in most institutions. Dr Carolyn Lam: Yeah, and perhaps a little bit more work needs to be done to sort first identify perhaps special situations where these may be particularly helpful. I supposed like you just said when we're thinking of the ESCs to review one-hour type algorithm, who knows maybe we should be having that extra insurance of the second test in those that test it negative in the first or something like that. Do you plan further work? I always ask you because you're always in the forefront of these things and we just love touching your work. Dr Christian Mueller: We have several additional analyses ongoing. Again, I think the main part is for just to go ... I go back from a clinical perspective. So I think for many hospitals that are using T at the moment, it's important to have I available for certain situations. So for example if you have a patient in whom you have evidence of chronic skeletal muscle disease, most of these disorders are rare but some of them have been shown to be associated with increasingly highly troponin T that do not seemed to be related for cardiac diseases but from skeletal muscle. This is rare but if you have a patient with that kind of history, then the dual mark measurement is I think mandatory. The same applies to iso that the other reasons to have false positive results for iso whenever you are ... If your hospital is using I, you should have the T method also available because once in a while you will identify patients in whom you have an I result that doesn't really match the clinical setting, then it's so easy and often so helpful to get the T result to decide on the most appropriate measurement of patient. For which patients are kind of a standard th…

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Circulation August 28, 2018 Issue Aug 27, 2018

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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. Do we finally now have a simple, evidence-based way to make a diagnosis of heart failure with preserved ejection fraction? Well, today's feature paper certainly brings us closer to that goal and you must listen to the discussion coming right up after these summaries. Bleeding is commonly cited as a reason for stopping oral anti-coagulants. However, what is the prognostic significance of minor bleeding events, or so called nuisance bleeding, in patients with atrial fibrillation on oral anti-coagulants? First and corresponding author, Dr O'Brien from Duke Clinical Research Institute and her colleagues, identified 6771 patients with atrial fibrillation in the Orbit AF Prospective Outpatient Registry. They ascertained nuisance bleeding from medical records defined as minor bleeding that did not require medical attention. Overall, 20% had documented nuisance bleeding giving an incidence rate of 14.8 events per hundred person years. Nuisance bleeding was not associated with a higher risk of major bleeding, or a stroke and systemic embolism over the next six months. These findings therefore suggest that the occurrence of nuisance bleeding or minor bleeding should not lead to changes in anti-coagulant treatment strategies in patients treated with anti-coagulants. The next study sheds new light on mechanisms linking NLRP3 inflammasome activation to atherogenesis. Dr Westerterp from Columbia University, New York and colleagues studied mice with myeloid deficiency of ATP binding cassette transporters A1 and G1 and concomitant deficiency of the inflammasome components NLRP3 or caspase-111. They showed that cholesterol accumulation in myeloid cells activated the NLRP3 inflammasome. NLRP3 inflammasome activation enhanced neutrophil accumulation and neutrophil extracellular trap formation in atherosclerotic plaques thus accelerating atherogenesis. Patients with Tangier's disease, who had ATP binding at transporter A1 loss of function, had increased myeloid cholesterol content and showed markers of inflammasome activation. Thus, inflammasome activation may underline cardiovascular disease in these patients. The next study identifies TPX20 as a novel transcription factor regulating angiogenesis. TPX20 is a crucial transcription factor for embryonic development and its deficiency is associated with congenital heart disease. However, its role in angiogenesis has been not been previously described. At least until today's paper from co-first authors Dr Meng and Dr Gu and co-corresponding authors Dr Cooke and Dr Fang from Houston Methodist Research Institute. These authors use loss and gain function approaches to explore the role of TPX20 in angiogenesis both in vitro and in vivo. They showed that with VEGF stimulation, the transcription factor TPX20 upregulated PROK2 with is secreted from endothelial cells and gauges its receptor PROKR1 and thereby promotes angiogenesis in autocrine manner. This novel signaling pathway appeared to be highly conserved as it functioned in zebra fish vascular development and the angiogenic response to ischemia in a mouse model of peripheral disease. The authors furthered showed the selective role of TPX20 in endothelial migration but not proliferation. Furthermore, treatment with recombinant PROK2 the critical effector of TPX20, improved blood profusion and functional recovery in the mouse peripheral artery disease model. Thus, these data highlight the therapeutic potential of PROK2 in augmenting functional angiogenesis for diseases associated with this regulated angiogenesis. In patients with atrial fibrillation, left atrial appendage closure with the Watchman device, is known to prevent thromboembolism from the left atrial appendage. However, thrombus may still form on the left atrial face of the device, which then may potentially embolize. This next paper provides important data on the incidents, predictors, and clinical outcomes of device-related thrombus after left atrial appendage closure. First author, Dr Dukkipati and corresponding author Dr Reddy from Icahn School of Medicine at Mount Sinai, New York and their colleagues studied the device arms of 4 prospective FDA trials of patients undergoing the Watchman implantation. These were the PROTECT AF, PREVAIL, CAP, and CAP2 trials. They found that following percutaneous left atrial appendage closure with the watchman device, the incidence of device-related thrombus was 3.7% and this was associated with a more threefold higher risk of stroke and systemic embolism. Predictors of device-related thrombus were a history of trans- ischemic attack or stroke, permanent atrial fibrillation, vascular disease, a larger left atrial appendage diameter, and a lower left ventricular ejection fraction. Device-related thrombus was not associated with an increased risk of cardiovascular or all-cause mortality. Nearly 75% of patients that developed device-related thrombus did not experience a stroke. And ischemic strokes occurring in patients with device-related thrombus accounted for approximately 10% of all ischemic strokes, following left atrial appendage closure. Thus, given the ramifications of device-related thrombus, a judicious surveillance strategy using periodic transesophageal echo cardiography may be considered particularly when risk factors for device-related thrombus are present. Well, that wraps it up for our summaries. Now for our feature discussion. Heart failure with preserved ejection fraction or HFpEF, notoriously difficult diagnosis to make, but do we finally have a validated diagnostic algorithm for HFpEF? Oh, you have to listen to our conversation today. I am so proud and pleased and thrilled frankly to have with me today the corresponding author of the feature paper, and that's Dr Barry Borlaugug from Mayo Clinic in Rochester, Minnesota as well as editorialist Dr Walter Paulusus from VU University Medical Center in Amsterdam. Thank you so much both of you for making it here. I want to dive straight into it. So, Walter, maybe could you please paint the background to this because you wrote I think the most highly cited diagnostic guidelines of HFpEF, but that was in 2007. Tell us how does today's paper take us forward? Dr Walter Paulus: Thank you very much, Carolyn. It's quite an honor for me to give you comments about this paper, which I think is going to be a landmark event. Over the years we have seen multiple algorithms being proposed usually by professional societies like V and C or the American Society of Echocardiography for the diagnosis of HFpEF. The major drawback of all these algorithms is that they have never been validated in clinical practice. And the reason they have never been validated was that it was extremely difficult to establish a gold standard for HFpEF. And Barry was so clever to already invest in an establishing a gold standard for HFpEF ten years ago, and he very vigorously subjected all his patients in whom he suspected HFpEF to an invasive stress test and could establish the diagonals of HFpEF using this as a gold standard. And then he used all these consecutive patients with subsequently used to devise some form of an algorithm that was immediately validated against a gold standard. I think this has been a giant leap forwards. And again, I want to congratulate him with this unique endeavor. Dr Carolyn Lam: Barry, I want to echo Walter's words and congratulate you. Now, has it really been ten years in the making? Tell us about this, Barry. Dr Barry Borlaug: It has. In fact, it was 12 years ago when we started doing this, in 2006. But, yeah, these patients were examined in our laboratory between 2006 when I joined the staff at the Mayo Clinic to 2016. And really just doing this work up, we kind of started out doing it on a few patients and then we realized how powerful the methodology was. We did the invasive exercise testing with hemodynamics and a larger number of patients and just through accumulating a large number, as Walter points out, with a gold standard assessment this allowed us to then determine which less invasive attributes could be used to identify the likelihood that heart failure was the diagnosis. Dr Carolyn Lam: That's so great. But you know beyond just that it is such a precious data set and so on, your paper is just so beautifully written and so clinically applicable. You've got this HFpEF score now for diagnosis. Everybody's going to be talking about it. So tell us about it. What does HFpEF score? What makes you think it'll work? How do you apply it clinically? Dr Barry Borlaug: Thinking about diagnosis a lot, you really have to go back to [00:19:19] thinking, estimating the probability of disease, and when you're able to do that then you can find people where you need to perform really more invasive testing like the exercise testing. So really, we started like we need to have a better way to define who needs that more expensive and invasive evaluation. So we have this large cohort of patients, over 500 patients, 414 in the initial cohort, and then another 100 in the validation cohort. And they had all undergone this work up, they'd all undergone very detailed clinical evaluation and pheno typing. And we hypothesized which characteristics we thought would be most relevant. And then we did logistic regression to identify all the predictors. There were many things that are associated that you would expect with HFpEF, but there were only 6 factors in the end in a multi-variable model that were all independently associated. That provided the most parsimonious sort of model or score that we could develop. We included these six different variables. So there's two for letter H- heavy and hypertensive, and by heavy we define that as a body mass index above 30. Hypertensive is defined as two or more antihypertensive medicines. The F in the H2 HFpEF score is atrial fibrillation, either paroxysmal or persistence a. Fib. The P is for pulmonary hypertension as estimated by echo with an estimated PA systolic pressure on echocardiography of 35. We wanted all of these to be noninvasive criteria for this score. E is for elder. I specifically didn't call it elderly because that can be a pejorative term and its only 60 years which is not that old. So E is elder. And F is for filling pressures, again estimated by echo doppler cardiography as an EE prime ratio greater than 9. All of the scores are not one point each. They were arranged based on the strength of correlation in the logistic model. So being obese, having a BMI above 30 was awarded two points because it has a strong correlation. Being in atrial fibrillation or having a history of atrial fibrillation was even stronger at three points. If you tally these up, the score can range from 0-9, and based on that score you can then estimate a probability that HFpEF is present, if you're evaluating a patient that meets the entry criteria of the study, which is basically normal ejection fraction, and exertional breathlessness. Dr Carolyn Lam: Nice. Okay, Walter, I think I can safely say that you have been thinking about this syndrome longer than either Barry or I. So I'd love your perspectives on how do you think this will be put into practice clinically perhaps, and where is the key area that it will change practice compared to perhaps the old diagnostic algorithms were like? Dr Walter Paulus: I think this is a very important point, Carolyn. I think this score is so easy to handle and it is so well validated that we can now go to general practitioners and cause a general awareness for the disease. What vies me is that many patients are still unreported. The reason is that general practitioners and even general internal medicine people do not realize the [00:19:19] heart failure with preserved ejection fraction. Now with this score at hand, we can convince them that there needs to be an awareness when they see people that have value higher than six on the score, that they should be suspicious of heart failure being part of the symptomatology. I think this score mainly has its usefulness for general practitioners and general internal medicine. Apart from the score, and it's more up to Barry to comment on this, but I want to highlight also, that he did not only develop the score, but he also had these very beautiful nomograms which is more of a find than a score, where he treated the variables in a continuous way. I think this is fairly useful for cardiologists and especially for people who want to have acute patients into trials because here we now have a very refined scale that goes from 0-160 and that allows you again to see what type of population you are addressing, what type of patients you are seeing that eventually what type of patients you are recruiting. I think for me the HFpEF score is of importance for general practitioners, general internal medicine, and especially I think we should also promote the nomogram. The nomogram, I think, are so refined that it would be useful tool, I think an excellent tool, for includement into trials. Dr Carolyn Lam: Oh wonderful. Both of the simplicity and the cleverness, if I may, of this paper are precious to generalists and cardiologists. But Barry, I do have a couple of questions for you. Both you derivation and validation were in Olmsted if I'm not wrong. Now how am I supposed to apply it to my skinny HFpEF patients in Asia or elsewhere? Dr Barry Borlaug: That's an important point, Carolyn. And it's a limitation of the paper. The people in Olmsted County, MN are not the same as they are in other parts of the United States or other parts of the world. I think that additional evaluation and other cohorts are important. We did the best we could with what we had. We did look at the patients carefully at Mayo Clinic. People think of it as quaternary referral center, but a pretty substantial number of the patients are from the local area, I think about 2/3 of them were. And when we looked in a subset in a sensitivity analysis of the people that were more local practice rather than coming from large academic medical centers, the HFpEF score, or as Walter pointed out, the continuous HFpEF model performed equally well. When we looked at people with so-called advanced HFpEF so high hemopressures at rest versus people at so called early stage HFpEF the people that have normal hemodynamics at rest but elevation during exercise. The model also worked well in that cohort. But, like most studies that come out of where I work in southeastern Minnesota, it is mostly Caucasian people, the mean BMI was in the low 30s. So we need to look at other populations to make sure this works elsewhere as well. Dr Carolyn Lam: Barry, let it go on record that I am your biggest fan. So thank you so much for this. I was just thinking even in other populations where the mean BMI may be lower for example here in Asia, we still definitely see an association with a higher BMI albeit at a lower cutoff with the presence of HFpEF. So it does raise this issue of do we need to maybe calibrate the score differently in different geographies or ethnicities. But that's not by any way take away from the tremendous input that you've made. One other question is also the strength of atrial fibrillation in impacting the score. What are your thoughts on the possibility of misdiagnosis for example atrial fibrillation as HFpEF or the similar situation since they share symptomatology? Dr Barry Borlaug: This is a great point, Carolyn. People still sort of argue about this. Somebody has breathlessness and effort intolerance and atrial fibrillation. Some doctors say they have symptomatic atrial fibr…

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Circulation August 21, 2018 Issue Aug 20, 2018

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Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Can we get better at predicting clinical benefit of PCSK9 inhibition based on the severity and extent of coronary artery disease? Well coming right up after these summaries we have an important discussion of an analysis from the FOURIER trial, so stay tuned. The first original paper this week suggests that targeting visceral adiposity may be the crucial step to limit age-related cardiac remodeling and to promote healthy cardiac aging. Co-first authors Drs Sawaki and Czibik, corresponding author Dr Derumeaux, from INSERM France, and their colleagues, hypothesize that since aging induces cardiac structural and functional changes, linked to increase deposition of extracellular matrix proteins including osteopontin, well osteopontin may play a role in myocardial aging. To test this hypothesis, they studied osteopontin-deficient mice and their wild-type litter mates at two and 14 months of age in terms of cardiac structure, function, histology and key molecular markers. They found that during aging, visceral adipose tissue represented the main source of ostepontin and altered heart structure and function via its profibrotic secretome. Furthermore, interventions targeting osteopontin, such as visceral adipose tissue removal and osteopontin deficiency, rescued the heart and induced a selective modulation of fibroblast senescence. This work uncovers ostepontin's role in the context of myocardial aging and suggests that osteopontin may be a potential new therapeutic target for a healthy cardiac aging. The next study shows that higher triglyceride rich lipoprotein cholesterol may be a risk factor for cardiovascular disease and potential therapeutic target. First author Dr Vallejo-Vaz, corresponding author Dr Ray from Imperial College London, and their colleagues assess the relationship between triglyceride-rich lipoprotein cholesterol and cardiovascular risk and whether this risk was modifiable among patients receiving statins in the TNT trial. They found that higher levels of triglyceride rich lipoprotein cholesterol were associated with a significantly higher rate of cardiovascular events among coronary patients treated with statins. Statin therapy reduced triglyceride-rich lipoprotein cholesterol and to a greater extent among those treated with a higher statin dose. Based on their post hoc analysis of the TNT trial, they found that more intensive statin therapy with atorvastatin 80 milligrams, compared to atorvastatin 10 milligrams, resulted in a significantly greater cardiovascular risk reduction among patients with higher triglyceride-rich lipoprotein cholesterol. These results were consistent for higher triglycerides and directionally concordant for non-HDL cholesterol. A higher percentage reduction in triglyceride-rich lipoprotein cholesterol was associated with lower cardiovascular risk independent of LDL cholesterol reduction. Thus, these findings suggest that triglyceride-rich lipoprotein cholesterol is not only a cardiovascular risk marker, but also potentially a therapeutic target. Late gadolinium enhancement on cardiac magnetic resonance imaging represents fibrosis and is seen in 60% of adult patients with hypertrophic cardiomyopathy. However, what about in children and adolescents with hypertrophic cardiomyopathy? First author Dr Raja from University of Copenhagen in Denmark, corresponding author Dr Ho from Brigham and Women's Hospital in Boston, and their colleagues looked at cardiac magnetic imaging data from 195 children and adolescents with hypertrophic cardiomyopathy. Late gadolinium enhancement was present in 46% of patients with overt hypertrophy as opposed to 60% typically represented in an adult population of hypertrophic cardiomyopathy. On the other hand, late gadolinium enhancement was not seen in mutation carriers without left ventricular hypertrophy. In patients who underwent serial imaging, increases in late gadolinium enhancement, left ventricular mass, and left atrial size were detected over two and a half years. Thus these findings in children provide additional insights into the biology and natural history of hypertrophic cardiomyopathy and confirmed that fibrosis is a significant part of the disease process in both children and adults. Whether the adult mammalian heart harbors cardiac stem cells for the regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. This week's paper adds to the growing knowledge in this area. First author Dr Li, corresponding author Dr Zhou from Chinese Academy of Sciences and their colleagues developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, they assessed if non-myocytes generated any new myocytes during embryonic development, adult homeostasis and after myocardial infarction. Skeletal muscles were also examined after injury and acted as internal controls. By using this stem cell marker free and dual recombinases mediated cell tracking approach, the author showed that new myocytes arose from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive controls, the same lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. Thus, this study provides in vivo genetic evidence for non-myocyte to myocyte conversion in the embryonic but not the adult heart. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration. Well, that wraps it up for our summaries this week, now for our feature discussion. Are there subsets of patients that derive greater clinical risk reduction with the PCSK9 inhibitors? Well we're gonna find out about that right now with a discussion of our feature paper entitled the "Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease." So pleased to have with us Dr Marc Sabatine from the TIMI Study Group, who is the first and corresponding author of today's feature paper, as well as our editorialist, Dr Roger Blumenthal from Johns Hopkins University. And of course, we have a familiar voice, a very important editor of our digital strategies and that's Dr Amit Khera from UT Southwestern. Welcome everyone, I think I'd really like to start with maybe asking Roger to paint the background of the importance of this paper. Simply because I just love the title of your editorial, which is "Realizing the Value of PCSK9 Inhibitors: Are We Closer to Finding the Sweet Spot?" I think that really encapsulates it. So Roger, your thoughts? Dr Roger Blumenthal: As Amit Khera knows, I'm a golfer, so when you think about the sweet spot on the club, and we know that PCSK9 inhibitors are a great story of translation from bench to bedside, and we also know that the high cost of the therapy presents a challenge. So what Dr Sabatine and colleagues did was to try to identify the sweet spot for its most effective use and that was a pleasure to comment on Dr Sabatine's excellent study. Dr Marc Sabatine: I think taking a step back I would say from pure biologic perspective, we know that lowering LDL cholesterol will reduce events and that's true and primary and secondary prevention and so if you have therapies that were safe and inexpensive, then I think you wouldn't need to really look for that sweet spot cause it would be all sweet if you will to extend the analogy. But Roger's absolutely right that when you have therapies that are then expensive, then you have to decide, okay in which patients will I get the biggest bang for my buck? And that's a very legitimate question to ask. And so in FOURIER, overall the trial was positive but as we look for subgroups we say, "Can we find individuals who enjoy a greater absolute risk reduction?" Because therefore the benefit cost ratio is gonna be particularly favorable. And so we approach that in a couple different ways. First you can look for just predictors of baseline risk, so if someone has twice the baseline risk and the same relative risk reduction, you should get about twice the absolute risk reduction and therefore the number needed to treat would be cut in half. And so based on our experience from other TIMI trials and other datasets, we looked at three features that have identified patients with higher baseline risks. Amongst those with a history of MI which is in and of itself a heterogeneous group. And so those features were patients with a more recent MI, those with multiple prior MIs and those with known residual multivessel coronary disease. And all three features in the FOURIER dataset, not surprisingly, were predictors of risk with patients having an average about a 50% higher baseline risk. But what was particularly nice was that the subgroups also identified patients who had greater relative risk reduction. And so when you couple the two, the higher baseline risk with the greater relative risk reduction, that translated into greater absolute risk reduction then in each of these high-risk groups, the absolute risk reductions over three years or for CV death, MI, and stroke was around 3% versus around 1% for the low-risk groups. And so that changes the number needed to treat by a factor of three. Dr Carolyn Lam: Wow, that's so cool. Amit, do you think you could just give us a sneak peek into the editors' discussions when you saw this paper? Dr Amit Khera: This was an easy one, it's clearly a very important paper and if you step back 10,000-foot view, these drugs were initially approved based on LDL lowering and people were using them without knowledge of whether or not they actually lowered events. Marc's group and others have now shown us that certainly they do lower events, but really the next most important thing is application. Who should we use them in and when should they be used and where might they be most effective and I think it was said out in the introduction of this paper, this idea of personalized medicine. And I think this really is an important step forward, not just for PCSK9 field but in general, how we should be thinking about drugs, about balancing cost and benefits and who would benefit most. So maybe one analogy, I think PCSK9 was not prescribed as much as they had been predicted given costs and other considerations and maybe with analysis like this they've hit it out of the rough back on the fairway, I threw that in for you, Roger. And I do have one question for Marc, which is this is clearly important to better define who would benefit the most and I guess in terms of action abilities, the goal here to provide guidance for clinicians where, you know, if I'm seeing a patient this morning I would take this into account or is this something larger where we recently saw with alirocumab, they changed pricing based on sub-group analysis of a higher risk group. How do you think we should move forward with this type of information? Dr Marc Sabatine: I'll get back to the point I raised earlier, I do want to underscore that I think that the true biologic notion is that all these patients, sub-types of secondary prevention or primary prevention all benefit from LDL lowering. So I wouldn't want people to walk out with the notion that it's the only subset that would benefit and really from a population level, obviously Roger's in a better position to speak about this, but sort of shifting the population LDL lower in general would have a huge impact on the risk for cardiovascular disease. But to your question Amit, looking in for a patient in front of you, I think it's quite fair to say right now there's this kind of tug of war back and forth between payers and clinicians. Clinicians saying, "I have a patient in front of me, they have known atherosclerotic cardiovascular disease, I wanna lower their risk, I wanna manage their risk factors and I wanna get their LDL cholesterol lower and I have a bunch of great tools in front of me." Statin for sure is the foundation, maybe acetamide and PCSK9 inhibitors. And then payers saying, "Well wait a minute, these are expensive drugs and so we're gonna try to restrict that and create a lot of hoops for clinicians to jump through." And so I would rather than wasting all that time back and forth, I think it is logical to say, "What are the high-risk groups?" Where we can agree there's the large enough absolute risk reduction that for a given cost, that makes sense. Allow there to be alignment for that and have clinicians just be able to write a script and have it filled rather than wasting a lot of time with preauthorization and letters back and forth. Dr Amit Khera: That's a great point, maybe I'll just take one follow-up, which is now trying to sift through all the high-risk groups and they end up maybe becoming a bit of a Venn diagram. I know in Roger's editorial he talked about the other FOURIER analysis with PAD and there's more groups to come or do we have enough of a starting place where we think we have enough for decision making? Dr Marc Sabatine: I would say there are a variety of groups, there is some overlapping even in the paper then we looked at the union of those three high-risk features, which identified about two thirds of the patients who were enrolled in the trial with a history of MI. But you're right, the other slices of the data that will also identify high risk groups, PAD is a particularly good one because most of the therapy for those patients has focused on antithrombotic therapy, which always will have some downside for increased bleeding, whereas risk factor modification in this case has no downside. So that's a very high-risk group, it certainly is important to focus on. But I think within the MI subset, this is a great place to start the other analyses we're doing. And probably after we've sort of finished the series of, if you will, these kind of univariant slices, then we'll try to put that together into a more comprehensive picture. Dr Roger Blumenthal: We tried to say that we still need the formal cost-effective analyses in these specific high-risk groups, but it seems most reasonable to focus on engaging in shared decision making now with our patients about PCSK9 inhibitor use and those with a recent ACS and the basis of Odyssey Outcomes and we're awaiting the final publication of that. Symptomatic peripheral arterial disease, which Marc previously published in Circulation, and then looking at these high-risk features that was the subject of this article, those with a more recent MI within the past two years, multiple prior MIs and residual multivessel coronary disease. And one of the things that we especially found interesting was among the more than 8,000 individuals without a high-risk feature, the event rates were nearly unchanged in the evolocumab versus placebo groups. So I think that's very important, but one other point that we have to keep in mind is that the focus of the last set of guidelines and probably the next cholesterol guidelines that likely will be out in November, will have a large component of the shared decision making and we need to see where the cost comes down, whether these companies that make these medications will be able to significantly lower the cost in a reproduceable manner and patients and clinicians will have to jointly decide what to do, do we add acetamide? Do we add a PCSK9 inhibitor? But we finis…

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Circulation August 14, 2018 Issue Aug 13, 2018

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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. I'm the one you usually hear chatting about all the papers in your weekly issue, however I am so delighted to be handing over the mic this week to two beloved colleagues, and they are Dr Greg Hundley and Dr Vlad Zaha, who will be taking us through this week's very special issue centered around cardio-oncology. Here they are. Dr Greg Hundley: My name is Greg Hundley. I'm a professor at VCU Health Sciences in Richmond, Virginia. We also have Vlad Zaha, who is an assistant professor at University of Texas Southwestern in Dallas. Dr Vlad Zaha: Hello, everybody. Dr Greg Hundley: We're going to be talking about the field of cardio-oncology today. As we all know, there have been many advances in the treatment of cancer lately, such that cancer is now becoming in some regards almost a manageable disease or a chronic disease for many individuals. But unfortunately we're seeing the emergence of cardiovascular disease in many patients, so much so that for some cancers, for example breast cancer survivors, cardiovascular events have supplanted the occurrence of cancer-related morbidity and mortality overall. And so emerging today is this new field of cardio-oncology, which is really a bridging discipline between oncologists and cardiologists that have been focused almost on examining the relationship between chemotherapies, radiation therapies, newer targeted immunologic therapies on the development of cardiovascular events. We as cardiovascular medicine specialists often become involved and then we are consulted to see a patient that might be scheduled to receive a cardiotoxic therapy and what should we do. Maybe they've already received, they're in the middle of the therapy, and we're asked to provide guidance to help the patient move through that therapy successfully. We're examining survivors now, those that have gone on the therapy and are experiencing increased cardiovascular risk. And then finally, a new emerging field that examines the association of risk factors that seem to be common between cancer and cardiovascular disease. In this issue of Circulation there are theories, really a miniseries of manuscripts, that are at this interface between cardiovascular and oncologic science and medicine. Following a similar miniseries that we published in 2015, this new block of manuscripts looks on some of the risk factors and mechanisms that may be common between these disorders. We're going to start today and look at this particular issue and examine the original manuscripts, look at the letters, and then talk a little bit about the review articles. I will walk through some of the introduction and then Vlad Zaha, who is working in cardio-oncology at University of Texas Southwestern, will help interpret for us some of the results and the meaning. The first study, an original manuscript by Simes et. al that's a subanalysis of the lipid study, and that's the Long-Term Intervention with Pravastatin in Ischemic Disease. The study is going to examine the relationship between D-dimer and the future development of cardiovascular events, but also importantly, cancer-related events. Remember, D-dimer is the degradation product of cross-linked fibrin markers of hypercoagulation and thrombosis. We use this a lot in the emergency department as an identifier of those at risk when we're suspecting one of CVT, pulmonary emboli, etc. This particular study focused on individuals aged 31 to 75 years that had experienced previously a myocardial infarction. The patients were randomized to receive 40 mg of pravastatin versus a placebo and as part of the study they were followed for six years to identify cardiovascular events. But at the end of the study another examination, an extended review, was enabled so that the patients or participants could be followed for another ten more years and in addition to looking at cardiovascular events, they also looked at all-cause mortality and etiologies of that mortality and specifically cancer. Vlad, can you tell us a little bit about some of the results and what did D-dimer predict? Dr Vlad Zaha: D-dimer has been considered a rather non-specific product that was first introduced in clinical practice in the 1970s for diagnosis of venous thromboembolisms. It is really interesting in this study that the others identified D-dimer that it is an independent predictor of not only long-term risk of arterial and venous events but all-cause mortality, cardiovascular disease mortality, cancer incidents and mortality and non-cardiovascular disease and non-cancer morality. It raises interesting questions that are further explored in an editorial in the same issue about what is a low and what is a high D-dimer and also what drives the D-dimer generation in these patients. Dr Greg Hundley: And so, it's interesting as well that one is identifying those at risk of cardiovascular disease but also cancer. Do the authors and the editorialists speculate on what that connection may be? Dr Vlad Zaha: The question that is discussed is a common area of etiology that is being more and more discussed nowadays as bridging the domains of heart disease and cancer, and that is information. Information resulting then in alteration of the clotting cascade and hypercoagulability that may then influence downstream both atherosclerosis and cancer processes. Dr Greg Hundley: Very good. It's interesting that we're bringing up this whole area of thrombosis because that really follows in the next study, which is a large population cohort assessment that is collected from a Danish registry of 6600 subjects that had experienced a lower extremity arterial, not venous, but arterial thrombosis. In that study what did they uncover, Vlad, in terms of an association with cancer and previously experiencing a lower extremity arterial thrombosis? Dr Vlad Zaha: Another interesting study where the patients uncovered an increased risk of cancer compared to the general population, especially during the first six months before, the investigators identified an association between lower limb arterial thrombosis and increased all-cause mortality in common especially for the smoking-related cancers. This is a very interesting study that brings up the possibility of opportunistic screening, again focused on cancer-related signs and symptoms during the diagnostic workup for lower limb arterial thrombosis. Dr Greg Hundley: And so, in these first two studies, both large in number, were identifying issues related to thromboembolic events and cardiovascular disease that also appear related or associated with the future development of cancer. The next couple of studies now switch and address issues related to mechanism. The first is a relatively large complex translational study by Meijers and associates that were examining the relationships between heart and vascular injury and the future development of colon cancer. In this particular study there were two separate experiments, one group performed in mice and the other performed in analyses of serum and plasma that were collected from human subjects that had experienced colon cancer. In the first series of experiments in mice, the mice were induced myocardial infarction and then they were a strain that were somewhat predisposed to development of colon cancer. What the investigators did is they examined in this strain predisposed to the development of colon cancer, the impact of inducing a myocardial infarction and promoting heart failure versus those that were not and they identified what looks to be some sort of association between an increased risk of development of colon cancer. Vlad, what were your observations and thoughts in terms of these particular findings and results? Dr Vlad Zaha: This is an interesting paradigm of bringing basic science observations and testing them in a translational fashion. It is a combination of really elegant studies in a mouse model that identifies potential targets of clinical relevance in a model of myocardial infarction. The authors evaluate the fact that such molecules in human cell line models and test the proliferation in that environment. The question is then: How does this reflect in a cohort of patients? That, I think, is really the strength of the study to be able to show that some of the biomarkers identified which events can have an implication at the bedside. Dr Greg Hundley: It was really interesting in that in the animals, independent of the hemodynamic compromise, so the hypotension, the reductions in EF, these circulating biomarkers that you identified seemed more associated with the development of colon cancer and then in the human study, examining similar factors were observed in patients with colon cancer and heart failure from the circulating blood of those individuals. Very interesting relationship identified in a very elegant translational study that involved both animal models and human subjects. The second mechanistic paper is by Li and associates and it's really addressing the issue of anthracycline-related cardiovascular injury. Remember, we still utilize anthracycline chemotherapy today as a fundamental curative component of the therapeutic regimen for lymphoma, leukemia and sarcoma, also in those with triple-negative breast cancer as an important component of that regimen for adjuvant treatment. In this particular study, the investigators were examining the implication of phosphoinositide 3-kinase. That is an important enzymatic regulator of tumorigenesis, but it also when it's expressed is up-regulated during cardiac stress and really impacts adverse remodeling and promotion of heart failure. In this particular study, the investigators in a mouse model were looking at blocking this particular enzyme and they had some really interesting results pertaining to the development of heart failure and cancer. Vlad, what did you see in this study that looked unique in that perspective? Dr Vlad Zaha: This is an especially interesting study for the perspective of the oncologists who still have to prescribe anthracycline, given the uncertainty of early toxicity that can manifest in some studies in five to ten percent of patients. Also, related to the late toxicity of anthracycline treatment in survivors of childhood cancer. What is particularly interesting about this isoform of phosphoinositide 3-kinase, the gamma isoforms, is that at the same time blocking this enzyme in macrophages increases the anti-tumor, I think it's the anthracycline therapy, and blocking it in the cardiomyocytes, suggests a potential cardioprotective mechanism. Having a target that can be used both to enhance the anti-cancer effect of anthracycline and to enhance the cardioprotective mechanism is really a potential ideal intervention that would help maximize the anti-cancer treatment and at the same time protect the heart. Dr Greg Hundley: Fantastic. Again, new research helping to come up with ways for those that continue to need anthracycline therapy that we may be able to attenuate some of the untoward cardiovascular effects, all the while preserving the antagonistic features associated with the treatment for cancer. Let's switch to the other sort of prospective original research format that we have in Circulation, and that's our letter format. Remember, our letters are addressing a specific point that can be readily appreciated in 800 words or less. The first is a letter by Anquetil et al that examines individuals recorded in the VigiBase World Health Organization database. This is basically a database organized around treatment of cancer and cancer therapeutics and it is examining those individuals that received sort of a newer class of agents called immune checkpoint inhibitors. Remember, that is modulation of our immune system to help attack cancer. In some rare circumstances, relatively infrequent, when these agents have been administered, the immune system has been unlocked and attacks the heart, promoting a myocarditis that if not recognized can be fulminant and lead to death. This particular group identified a new phenomenon that we need to be aware of and that's just frank myositis. Vlad, what are your thoughts on now perhaps these agents being associated with the development of myositis in the skeletal muscle? Dr Vlad Zaha: Often when adverse events, as you mentioned Greg, are an important concern for these new powerful tools for the oncologists and it has been pretty early in the process where some of the cases have demonstrated severe cardiovascular events. Fortunately it is a very low percentage, less than 1% of cases that can manifest with fulminant myocarditis, but this raises again a question of expanding the view towards other systems when we are applying one of these early novel molecular interventions. In this context, the recognition of myositis in another small percentage of patients is an important observation and increasing awareness of both cardiologists and oncologists towards this side effect is important as not all fatigue is equal and sometimes that can be due to manifestations of cardiomyopathy and sometimes it can be a manifestation of oxygen extraction in the peripheral tissue than muscle contractility. It is an important hypothesis-generating piece that will allow people to appreciate more of the complexity of addressing the intrinsic molecular mechanisms in cancer and heart disease. Dr Greg Hundley: It sounds that we need to be aware of another potential etiology of fatigue to put in an armamentarium of differential diagnoses for those patients that are not getting quite back to where they were from an exercise and activity level after treatment. The second research letter focuses on individuals that are receiving a Fontan procedure. Remember, Fontan procedures are surgical corrections for those primarily with single ventricles where we're diverting caval blood to the pulmonary circulation, since in some situations there's really no functional right ventricle. These patients over time experience chronic venous hypertension and have associations with liver disease. In this particular research letter, the authors are examining the relationship between really for the first report in an aggregate form of the relationship between undergoing a Fontan procedure and the development of hepatocellular carcinoma. Vlad, any quick comments to highlight on this particular procedure? I thought something that was interesting is that these individuals experienced these hepatocellular carcinomas in their 20s and 30s. Dr Vlad Zaha: That's right, Greg. This study confirms observations from previous case reports and the early occurrence of hepatocellular carcinoma is raising still important hypotheses for future clinical trials. On one hand, either there is an increased risk of hepatocellular carcinoma development in patients with non-cirrhotic livers after a Fontan operation, or the current screening modalities using imaging are insufficiently sensitive to identify early signs of cirrhosis in such patients and this stratifies them effectively at an early stage in their disease post-op Fontan procedure. Dr Greg Hundley: Lastly, let's just briefly discuss here, Vlad, some of the other editorials and review article formats that we have in Circulation. A particular one, a perspective that was written by Peter Libby and Ebert and associates that highlights this phenomenon potentially implicating inflammation and the link between cancer and atherosclerotic cardiovascular disease. The topic of this perspective is really on something called CHIP, which stands for clonal hematopoiesis of indetermi…

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Circulation August 7, 2018 Issue Aug 07, 2018

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Can proteomic biomarkers distinguish between subtypes of aortic stenosis even years before surgery? Well, to find out more, stay tuned. That's coming right up after these summaries.

The first original paper this week adds to the evidence that smoke-free policies are associated with a lower risk of cardiovascular disease. First and corresponding author, Dr Mayne from Northwestern University Feinberg School of Medicine, and her colleagues linked smoke-free policies to participants of the Coronary Artery Risk Development in Young Adults, or CARDIA study, which has a follow-up of up to 20 years. They found that smoke-free policies in workplaces were associated with significantly lower risk of incident cardiovascular disease after controlling for a wide range of covariants. Results were weaker for bar and restaurant bans, but in the same direction.

Preventive fractions range from an impressive 24 to 46%. Thus, smoke-free policies may improve cardiovascular health through reducing population exposure to tobacco smoke. However, we should remember that much of the US population remains unprotected by smoke-free policies. Thus, taken together with prior ecological work, these results support the continued expansion of smoke-free policies in indoor public places.

Most phase-3 randomized control trials feature time-to-first event end points for their primary analysis. In chronic diseases, however, a clinical event can occur more than once and recurrent event methods have been proposed to more fully capture the disease burden, as well as to improve statistical precision and power.

However, is this really the case? This question was examined by first author, Dr Brian Claggett, corresponding author, Dr Scott Solomon, from Brigham Women's Hospital in Boston, Massachusetts, and their colleagues, who sought to better characterize factors that influence the statistical properties of recurrent events and time-to-first event methods in the evaluation of randomized therapy.

They performed repeated simulated trials with 1:1 randomization of 4000 patients to active versus control therapy. Through simulation, they varied the degree of between-patient heterogeneity of risk as well as the extent of treatment discontinuation. They then compared their findings with those from the actual randomized control trials.

The authors found that the statistical power of both recurrent events and time-t- first event methods were reduced by increasing heterogeneity of patient risk, a parameter that's not usually included in conventional power and sample size formulae. Furthermore, data from real clinical trials were consistent with the simulation studies, confirming that the greatest statistical gains from the use of recurrent events methods occurred in the presence of high patient heterogeneity and low rates of study drug discontinuation.

The next paper uncovers a novel biomarker and therapeutic target of pulmonary arterial hypertension, and that is selenoprotein P. First author Dr Kikuchi, corresponding author, Dr Shimokawa, from Takaoka University Graduate School of Medicine in Japan and their colleagues performed micro-array analyses using pulmonary arterial hypertension, pulmonary artery smooth muscle cells, and found a 32-fold up regulation of selenoprotein P compared with controls.

Selenoprotein P promotes cell proliferation and apoptosis through increased oxidative stress and mitochondrial dysfunction. Using five strains of genetically modified mice, the authors demonstrated a pathogenic role of selenoprotein P in the development of hypoxia-induced pulmonary hypertension.

Furthermore, sanguinarine, which is an orally active small molecule identified by throughput screening reduced selenoprotein P expression and pulmonary arterial smooth muscle cell proliferation and ameliorated pulmonary hypertension.

In summary, this study shows that selenoprotein P plays a crucial role in the pathogenesis of pulmonary arterial hypertension and may be a useful and novel biomarker and therapeutic target in this disorder.

Familial hypercholesterolemia is known to be associated with a high risk of ischemic heart disease, including myocardial infraction, but what about the risk of ischemic stroke? Well, first author, Dr Beheshti, corresponding author, Dr Nordestgaard, from Copenhagen University Hospital and their colleagues examined the associations of familial hypercholesterolemia and high LDL cholesterol with ischemic stroke in both causal, genetic, and observational analyses using more than 106000 individuals from the Copenhagen General Population Study, and more than 10000 individuals from the Copenhagen City Heart Study.

They used a Mendelian randomization design to test whether high LDL per se had a causal effect on ischemic stroke risk using a combination of the familial hypercholesterolemia causative mutations and common genetic variants associated with high LDL.

The authors found that there was no association between familial hypercholesterolemia mutations and ischemic stroke risk. In the Mendelian randomization analysis, also including common genetic variants, there was also no causal effect of high LDL on the risk of ischemic stroke.

These findings imply that the predominant goal of targeting LDL lowering in those with and without familiar hypercholesterolemia is likely to reduce myocardial infractions, rather than ischemic stroke. Well, that wraps it up for our summaries. Now for our feature discussion.

Circulation publishes numerous papers regarding circulating biomarkers. We talk about biomarkers in the diagnostic, prognostic sense, but what about in a pathophysiologic sense, and especially in a disease as important as aortic stenosis? Well, that's what our featured paper this week is all about and I'm so excited to have with us corresponding author, Dr Stefan Söderberg, from Umeå University in Sweden, as well as our associate editor, Dr Peipei Ping from UCLA. We will be discussing the paper entitled "Proteomic Biomarkers for Incident Aortic Stenosis Requiring Valvular Replacement." Stefan, could you tell us a bit about what made you look at this very interesting question, and perhaps the unique resources you had in Sweden to look at this?

Dr Stefan Söderberg: I'm a practicing cardiologist, and I have been working a lot with aortic stenosis over the years. It's frustrating that we can't do anything to stop the process. In many cases, the patients are old and frail, and if you could find the means to stop the process long before they need surgery, it will be of great benefit for the human and for the society.

Also, knowing that the interventions on the statins, for example, have been unsuccessful, we thought that there must be better ways or other biomarkers. Furthermore, that many of these studies, the phenotype of aortic stenosis has been very poorly described and there is probably much more behind just aortic stenosis than just, for example, calcium deposits in an X-ray, et cetera, et cetera.

Dr Carolyn Lam: You used some very unique resources in Sweden to therefore look at the proteomic signatures of aortic stenosis. Could you describe that and simplify perhaps the results so we can understand it?

Dr Stefan Söderberg: First of all, I got this idea from other studies done up in northern Sweden. If you have an absolutely unique setting, the combination of huge population-based studies in 30 years back, we have a huge biobank with examples of extraordinary good quality from each of these participants. For example, for each participant, the blood has been spun and put into freezer, deep freezer, within one hour for 30 years, and they are now, as I said, about 100000.

Furthermore, I'm working as a cardiologist at a university, and up here, you do all of the aortic surgery for the whole northern Sweden. That is, we can combine the names of the person undergoing surgery together with these population-based surveys and we can get details from all those who have participated in the surveys long before they did the surgery, and they can go and retrieve samples from cases and match controls from the freezers. It's a unique setup. Then, when we were designing the study, we got the chance to get these analyses done by our friends at the university to get the proteomic analysis via a unique data technique.

Dr Carolyn Lam: Wow. Could you describe your results?

Dr Stefan Söderberg: The results that we found in the first set of 334 patients who underwent surgery is 10 years after their first sampling, we found six proteins. Then, we got the question back from Circulation to establish a validation cohort, and we were able to do so to include all those new cases in the last 2 years, and there we could replicate five of these proteins.

The interesting thing that the pattern is completely different between those having coronary artery disease from those without. That kind of phenotyping has not been done throughout other aortic stenosis studies. Therefore, this study is unique. We have had two papers in the last year in the Journal of American Heart Association from the cohort, as well, showing the thing that happened.

For example, lipoprotein little A is only associated with future aortic stenosis valve replacement only in those with concomitant coronary artery disease. There are many unique things, the prospective design, and the phenotype differentiating those with and without coronary artery disease.

Dr Carolyn Lam: Yeah, and if I may just reiterate that the population base that you work with is just enviable and just so that the audience realizes, these are biomarkers that were collected 11 years before the aortic stenosis surgery, isn't it? You really had a long follow-up.

Also, just to let everyone know, it was a proximity extension assay that you used for the discovery, and the six proteins were growth differentiating factor 15, or GDF15, galectin-4, von Willebrand factor, interleukin 17 receptor A, transferrin receptor protein 1, and PCSK9, so very interesting. Peipei, you have a way of putting things into context so beautifully. Could you tell us your thoughts when you saw this paper?

Dr Peipei Ping: I thought this is a very high-quality study that actually benefited from the long-term established, well-controlled cohort in northern Sweden, as Dr Söderberg just shared with us. On the other end, it married a technology platform that's very well-established and -validated, and this situation targeted proteomics platforms using multi-proximity extension assays with carefully controlled markers and screened 92 cardiovascular candidate markers.

This is the kind of approach that provides semi-quantitative as well as quantitative outputs and is capable to offer validated screens on large population clinical subsets. A study of such with a high value cohort combined with a validated and well-controlled technology platform offered results that clearly have clinical significance, as well as setting up examples for other studies to follow. The enthusiasm from the editorial boards, as well as the reviewers, have been substantially high and supportive.

Dr Stefan Söderberg: Fantastic. I'm very glad to hear this.

Dr Carolyn Lam: Stefan, you also mentioned that a very unique element was the separation of aortic stenosis with and within coronary artery disease, or at least established or visible coronary artery disease. Could you explain how that provided pathophysiologic insights?

Dr Stefan Söderberg: First, I should say we were very, very strict. Our routine is that everyone was 100% undergoing, aortic valve replacement, they undergo a coronary angiogram before. If we saw any sign of atheromatosis, it was not enough that they had the significant stenosis, but any signs, they were put into the group of coronary artery disease. Those without, we couldn't see anything there. Radiograph here reported absolutely clean coronary arteries. Of course, we cannot exclude if there were aortic changes within them all, of course.

We believe that this is a very important message that in order to further study aortic stenosis, we should be very careful in phenotyping the disease. We hope the growing cohort will be able to do this further. For example, cuspid versus tricuspid valves, women versus men, et cetera.

My answer in short is phenotype. Let me take one example which I found very, very exciting. That is the finding of PCSK9, which is closely related not only to cholesterol symptoms, but also to lipoprotein little A emphasis. As you know, the first strong finding in aortic stenosis was the LP little A. This is related to that genetic finding, and that was in the huge study from Canada. They did not have the same phenotyping, so we had information to his important findings. That's one example.

Another example is the transferring receptor, where data has shown that bleeding acutely in the valvular tissue causes damage, and this relates iron metabolism to the formation of the aortic valve. Obviously, it seems that the process in the aortic valve is very much similar to the vessel arteriosclerosis. It seems to be different. This is the indication that when we formulate new studies or new drugs on aortic stenosis, we must be very careful to use the right drug for the right type of valvular disease.

Dr Carolyn Lam: Those are great points. Peipei, do you think that's the main clinical take-home message, beyond that great comment you made earlier that this paper's just a great example of the use of tools, modern tools, that we have in proteomic characterization like the proximity extension assay to provide pathophysiologic insights when you have a really well-phenotyped cohort? What's the critical take-home message, though? Is there one now?

Dr Peipei Ping: The take-home message is marriage of amazing high value cohort's data sets with that of the well-controlled clinical study using target proteomics approaches. In this particular study, one main critical innovation is the study is capable of providing insights regarding molecular signatures that have predicted values. As stated in the manuscript, the circulating proteins that found critically important, their alterations took place years before the surgery were associated with aortic stenosis. That is of value, clinical value, to many other clinical studies to follow.

Dr Carolyn Lam: Wow. That's wonderful. Thank you so much for putting these findings in context for us. Thank you, listeners, for joining us today. Don't forget to tune in again next week.

Circulation July 31, 2018 Issue Jul 31, 2018

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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 measuring baseline BNP add prognostic information in patients undergoing revascularization for left main coronary artery disease? Well, to find out the answers, you have to stay tuned and listen up for our feature discussion coming right up, after these summaries. The first original paper this week reports a new role for bone morphogenetic protein 9, or BMP9, as an endogenous inhibitor of cardiac fibrosis. Now, we are familiar with transforming growth factor beta-one, or TGF-β1, as a promoter of cardiac fibrosis. TGF-β1 also activates counterregulatory pathways that serve to regulate TGF-β1 activity in heart failure. BMP9 is a member of the TGFβ family of cytokines and signals via the downstream effector protein Smad1. In the current paper from first author Dr Morine, corresponding author Dr Kapur, from Tufts Medical Center in Boston, and their colleagues. The authors examined BMP9 expression and signaling in human cardiac fibroblasts and human subjects with heart failure. They utilized the thoracic aortic constriction–induced model of heart failure to evaluate the functional effect of BMP9 signaling on cardiac remodeling. The authors' results identified a novel functional role for BMP9 as an endogenous inhibitor of cardiac fibrosis due to LV pressure overload. They further showed that treatment with either recombinant BMP9 or inhibiting a high affinity receptor for BMP9 known as endoglin promoted BMP9 activity and limited cardiac fibrosis in heart failure. Thus, this provides a potential novel therapeutic approach for patients with heart failure. The next paper shows that endothelial C-type natriuretic peptide, or CNP, regulates microcirculatory flow and blood pressure. First author, Dr Špiranec, corresponding author Dr Kuhn, and colleagues from University of Würzburg in Germany analyzed whether vasodilating response to CNP changed along the vascular tree. In other words, whether the guanylyl cyclase–B receptor was expressed in microvascular types of cells. The authors used novel gene-modified mouse models to show that guanylyl cyclase–B cyclic GNP signaling in parasites diminished microcirculatory resistance and arterial blood pressure. In contrast, endothelial, or macrovascular smooth muscle cell guanylyl cyclase–B signaling was not involved. This indicated that CNP participated in the local cross talk between endothelial cells and parasites, thus playing an important role in the maintenance of normal microvascular resistance and blood pressure. Thus, pharmacological augmentation of endogenous CNP signaling in parasites may provide a useful therapeutic tool to combat increased vascular resistance and hypertension. Has the rapid and exponential growth in transcatheter aortic valve replacement, or TAVR, demand overwhelmed capacity, thus translating to inadequate access and prolonged wait times? Well, the next paper provides some answers. First author, Dr Elbaz-Greener, corresponding author Dr Wijeysundera, from University of Toronto, evaluated temporal transient TAVR wait times and the associated clinical consequences in their population-based study of all TAVR referrals from April 2010 to March 2016 in Ontario, Canada. Their study cohort included 4,461 referrals, of which 50% led to a TAVR, 39% were off-listed for other reasons, and 11% remained on the wait list at the conclusions of the study. For patients who underwent a TAVR, the estimated median wait time in the post reimbursement period stabilized at 80 days and has remained unchanged. The cumulative probability at 80 days of wait-list mortality was 2% and of heart failure hospitalization, 12%, with an increase in events with increased wait times. Thus, post reimbursement wait time has remained unchanged for patients undergoing a TAVR procedure, suggesting that the increase in capacity has kept pace with the increase in demand. The current wait time of almost 3 months is associated with important morbidity and mortality, suggesting a need for greater capacity and access. The final paper shows that patients with type 2 diabetes and a history of heart failure are particularly likely to benefit from treatment with the SGLT2 inhibitor canagliflozin. First author, Dr Rådholm, corresponding author Dr Figtree, from Royal North Shore Hospital in Australia, and colleagues, studied more than 10,000 participants with type 2 diabetes and high cardiovascular risk in the CANVAS Program who were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. Participants with a history of heart failure at baseline constituted 14.4% of the study population and were more frequently women, white, and hypertensive, with a history of prior cardiovascular disease. The benefit of canagliflozin on cardiovascular death and hospitalized heart failure was greater in patients with a prior history of heart failure compared to those without heart failure at baseline with a p for interaction of 0.02. The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in patients with and without heart failure at baseline. Effects were apparent across a broad range of participant subgroups, including those using established treatments for the prevention of heart failure, such as renin-angiotensin-aldosterone system inhibitors, diuretics, and beta-blockers. Thus, patients with type 2 diabetes and a history of heart failure may be particularly likely to benefit from treatment with canagliflozin. The beneficial effects of canagliflozin on heart failure outcomes unlikely to be accrued on top of other therapies for heart failure management. And that brings us to the end of this week's summaries, now for our feature discussion. In patients with left main coronary artery disease who are undergoing revascularization, could BNP assessment be that precision medicine tool to aid us in our clinical decision making? Well, I am just so excited to discuss this very topic with the corresponding author for this feature paper, Dr Gregg Stone from Columbia University Medical Center, as well as our associate editor and editorialist for this paper, Dr Torbjørn Omland from University of Oslo. Gregg, it was a super smart idea to look at circulating BNP and how this may associate with outcomes, as well as therapies in the EXCEL trial. Please tell us what inspired you to do this and please tell us what you found. Dr Gregg Stone: As everybody knows, BNP has been identified as an important prognostic factor in patients with heart failure and ischemic heart disease. It correlates with both cardiovascular and noncardiovascular mortality. Patients with left main disease are among the highest-risk patients that either interventional cardiologists or cardiac surgeons treat because of the amount of myocardium at risk, they often present in heart failure, and even if they're not in overt heart failure, they can be prone to large severe left ventricular dysfunction. So first we wanted to establish the prognostic utility of BNP in this patient population and then we were interested to see if it might have a role in helping differentiate which patients might have a better prognosis with either PCI or coronary artery bypass graft surgery. EXCEL is the largest trial to date of left main PCI versus CABG in a randomized format with 1905 enrolled patients. And overall, we found that PCI and CABG had similar rates of deaths, large myocardial infarction, or stroke in 3 years. But of course, there are high risk-patients and low-risk patients buried within those overall aggregate outcomes, and BNP was an important prognostic predictor of overall mortality in the trial. Both cardiovascular and noncardiovascular, but not of any other ischemic end points interestingly. Not myocardial infarction, stent thrombosis, graft occlusion, bleeding, revascularization. But definitely, mortality. Even independent of left ventricular ejection fraction and heart failure status. Now, when we looked at the outcomes of PCI versus bypass surgery, we actually found a very powerful interaction, such that at relatively lower BNP levels, patients who underwent PCI had a better prognosis and tended to have lower mortality. Where patients with high baseline BNP levels tended to have a better prognosis after surgery. Dr Carolyn Lam: You know, Torbjørn, I love your editorial where you contextualize these findings so nicely. Could you do that for us now? Dr Torbjørn Omland: First, I would like to congratulate Gregg and his team with this very interesting and very well-done study, and I think Circulation is very fortunate to be able to publish papers like this. We have known for quite a long time that BNP is a strong prognostic indicator across the spectrum of cardiovascular diseases and it seems to be particularly strongly associated with risk of heart failure events, cardiac arrhythmias, and risk of death. And, as shown in the EXCEL trial, the association with left ventricular ejection fraction is actually quite weak, and also the association with ischemic events. So, these findings fit very well with previous observations. The really novel and intriguing finding of this study is the very strong interaction between procedural BNP levels and the effect of the randomized therapies and, as you alluded to, all the investigators have tried to look at this in other more low-risk populations like in the LIPID trial but actually failed to find any significant interaction. It's really a novel and important finding. Dr Carolyn Lam: That's true. Does it bring up the question are the natriuretic peptides just a better EF measurement? You mentioned that there was a correlation, what do you think, Gregg? Dr Torbjørn Stone: Well, you know, there was a weak correlation between BNP and ejection fraction and history of heart failure but the prognostic utility of BNP in this study and its ability to differentiate between the outcomes of PCI versus CABG in patients with low versus high BNP was actually strongly independent of both congestive heart failure history and acute left ventricular ejection fraction. So, I think the BNP is giving a useful independent information. It's a strong reflector of both atrial and ventricular pressures and volume status, but it also reflects myocardial hypoxia, it may be involved in glycolysis and lipid peroxidation, and other mechanisms that we don't fully understand. There may be elements of diastolic dysfunction that we have not measured in this study and other mechanisms related to prognosis in these patients. So, while EXCEL was not set up to truly differentiate and delve deeply into the mechanisms of our observations, statistically these were strong associations that may prove clinically useful. Dr Carolyn Lam: Right, I thought that was so intriguing as well, just the points that you brought up. First, let's just clarify for the audience that when you say low and high you were using a cutoff of 100. Dr Gregg Stone: We did use a cutoff of 100 pg per mL as is common, but we also modeled BNP as a continuous measure. And actually the relationships were even stronger when modeled as a log hazard ratio continuous measure, both for mortality and for the primary end point. Dr Carolyn Lam: Yeah, that's so cool. And Torbjørn, you talked about this in your editorial as well and I thought your point about the distributions of the ejection fraction versus the distribution of natriuretic peptide, that was very revealing, too. Would you like to explain your thoughts there? Dr Torbjørn Omland: I found it very interesting that all of this is clearly a high-risk operation overall. More than 90% actually had what we regard a normal, or at least not a reduced ejection fraction. Whereas the distribution of BNP values were more widely distributed so that actually about 40% of participants had BNP levels above this ratio of 100 pg per mL. And that probably shows that in this population, BNP provides additional and independent information about the status of the myocardium that is not revealed by angiography or ejection fraction measurements. Dr Carolyn Lam: That's true, and that's an important point because it added above the SYNTAX score, too, right Gregg? Dr Gregg Stone: That's right, it was an independent predictor, and in fact the SYNTAX score and the severity of left main coronary disease did not vary, according to BNP levels, that is. High versus low BNP were equally distributed, not related to the anatomic extent and complexity of coronary artery disease. So, BNP is clearly reflecting a different state of the myocardium in a way that we can't measure with any other available test and that makes it quite a useful biomarker. Dr Carolyn Lam: Exactly, so I think I'd like to wrap up with asking you both, you can already see what the potential clinical implications are, right? Which means that perhaps in a similar type of patient where there's equipoise of the revascularization method and has left main disease, maybe we should be using natriuretic peptides to guide our clinical decision making. What do you think are next steps before this is prime time? Dr Gregg Stone: Well I can mention that when one makes a decision of the best revascularization modality for patients with extensive multi-vessel or left main coronary artery disease, there are many factors that go into that determination, both clinical, anatomic, is the patient a good candidate for one versus the other revascularization modality, what are the patient's preferences, what's the surgeon's or interventionalist's likelihood of being able to safely get the patient through the procedure and achieve complete revascularization. The SYNTAX score makes a difference, as does gender and age and kidney disease and COPD and ejection fraction and many other factors. So I think we can now add to that list BNP, although I will say this was a post-hoc study, we only had BNP available in approximately 60% of the patients, and while the outcomes were similar in the patients who we did not versus who we did have BNP, this has to be looked at as hypothesis-generating analysis, and we would love to also see this type of finding replicated in other large datasets. That being said, there are no other large left main or new multi-vessel disease trials that are planned right now to my knowledge, and I think given the breadth of this dataset and its size and scope, I do think that these findings are robust enough to use BNP as one of the clinical factors to consider in revascularization decisions. Dr Torbjørn Omland: I actually agree with that and I think ideally, we would, of course, like to see external validation in another dataset and even retrospective randomized study comparing conventional versus BNP-guided strategy but that may not be realistically undertaken. So, I think these are clearly the best data we have and as clinicians need to integrate this in our overall evaluation in making this important decision. Dr Carolyn Lam: Yeah, I mean Gregg, could I ask you, do you apply this clinically already? Dr Gregg Stone: We have not been before this, although I believe we will now. I believe BNP should be a biomarker that we more routinely measure in patients with ischemic heart disease as well as those with overt congestive heart failure. And again, use as one of the factors of many when making revascularization decisions. And I think it's important to note also that the PCI patients tended to preferentially benefit, in fact with even lower mortality when BNP was lower. Where the surgical patients tended to benefit when BNP was higher. So, it's one factor, not the only factor, b…

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Circulation July 24, 2018 Jul 24, 2018

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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. Did you know that despite being one of the wealthiest nations in the world, the United States population has a shorter life expectancy compared to almost all other high-income countries in the world? Well, stay tuned to learn what Americans could do to narrow the life expectancy gap between the United States and other industrialized nations. Coming right up after these summaries. Are microRNAs involved in nitrate tolerance? Well, the first original paper this week provides some answers. This is from co-corresponding authors Dr Bai and Zhang from Central South University in Changsha, China. Nitrate tolerance develops when there's dysfunction of the prostaglandin I2 synthase and prostaglandin I2 deficiency. These authors hypothesize that prostaglandin I2 synthase gene expression may be regulated by a microRNA-dependent mechanism in endothelial cells. They induce nitrovasodilator resistance by nitroglycerin infusion in Apoe deficient mice and studied endothelial function in both the mouse models as well as human umbilical vein endothelial cells. They found that nitric oxide donors induced atopic expression of microRNA 199a/b in endothelial cells, which was required for the nitrovasodilator resistance via repression of prostaglandin I2 synthase gene expression. Targeting this axis effectively improved nitrate tolerance. Thus, the atopic expression of microRNA 199 in endothelial cells induced by nitric oxide may explain prostaglandin I2 synthase deficiency in the progression of nitric tolerance. Thus, microRNA 199a/b may be a novel target for the treatment of nitric tolerance. What are the long-term outcomes of childhood left ventricular noncompaction cardiomyopathy? Well, the next paper presents results from the National Population-Based Study in Australia. First author, Dr Shi, corresponding author, Dr Weintraub, from Royal Children's Hospital in Melbourne, looked at the National Australian Childhood Cardiomyopathy Study, which includes all children in Australia with primary cardiomyopathy diagnosed at less than 10 years of age between 1987 and 1996. Outcomes for left ventricular noncompaction patients with a dilated phenotype will compare to those with a dilated cardiomyopathy. There were 29 patients with left ventricular noncompaction with a mean annual incidence of newly diagnosed cases of 0.11 per hundredth thousand at risks persons. Congestive heart failure was initial symptom in 83%, and 93% had a dilated phenotype. The median age at diagnosis was 0.3 years of age. Freedom from death or transplantation was 48% at 10 years after diagnosis, and 45% at 15 years. Using propensity score inverse probability of treatment-weighted Cox regression, the authors found evidence that left ventricular noncompaction with a dilated phenotype was associated with a more than two-fold greater risk of death or transplantation. The next paper reports the first application of multiomics and network medicine to calcific aortic valve disease. Co-first authors Dr Schlotter and Halu, corresponding author Dr Aikawa from Brigham and Woman's Hospital and Harvard Medical School in Boston, and their colleagues examined 25 human stenotic aortic valves obtained from valve replacement surgeries. They used multiple modalities, including transcriptomics and global unlabeled and label-based tandem-mass-tagged proteomics. Segmentation of valves into disease stage–specific samples was guided by near-infrared molecular imaging. Anatomic-layer specificity was facilitated by laser capture microdissection. Side-specific cell cultures was subjected to multiple calcifying stimuli, and the calcification potential and basil or stimulated proteomics were evaluated. Furthermore, molecular interaction networks were built, and their central proteins and disease associations were identified. The authors found that global transcriptional and protein expression signatures differed between the nondiseased, fibrotic, and calcific stages of calcific aortic valve disease. Anatomical aortic valve microlayers exhibited unique proteome profiles that were maintained throughout disease progression and identified glial fibrillary acidic protein as a specific marker of valvula interstitial cells from the spongiosa layer. In vitro, fibrosa-derived valvular interstitial cells demonstrated greater calcification potential than those from the ventricularis. Analysis of protein-protein interaction networks further found a significant closeness to multiple inflammatory and fibrotic diseases. This study is significant because it is the first application of spatially and temporarily resolved multiomics and network systems biology strategy to identify molecular regulatory networks in calcific aortic valve disease. It provides network medicine–based rational for putative utility of antifibrotic and anti-inflammatory therapies in the treatment of calcific aortic valve disease. It also sets a roadmap for the multiomic study of complex cardiovascular diseases. The final paper tackles the controversy of antibiotic prophylaxis for the prevention of infective endocarditis during invasive dental procedures. This is from a population-based study in Taiwan. First author, Dr Chen, corresponding author, Dr Tu from Institute of Epidemiology and Preventive Medicine College of Public Health in National Taiwan University aimed to estimate the association between invasive dental treatments and infective endocarditis using the health insurance database in Taiwan. They chose 2 case-only study designs. First a case-crossover, and second, self-controlled case series. Both designs used within-subject comparisons such that confounding factors were implicitly adjusted for. They found that invasive dental treatments did not appear to be associated with a larger risk of infective endocarditis in the short period following invasive dental treatment. Results were consistent from both study designs. The authors also did not find any association between invasive dental treatments and infective endocarditis even among the high-risk patients, such as those with a history of rheumatic disease or valve replacement. In summary, these authors found no evidence to support antibiotic prophylaxis for the prevention of infective endocarditis before invasive dental treatments in the Taiwanese population. Whether antibiotic prophylaxis is necessary in other populations requires further study. Alright, so that wraps it up for our summaries, now for our feature discussion. The United States is one of the wealthiest nations worldwide, but Americans have a shorter life expectancy compared with almost all other high-income countries. In fact, the US ranks only 31st in the world for life expectancy at birth in 2015. What are the factors that contribute to premature mortality and life expectancy in the US? Well, today's feature paper gives us some answers. And I'm just delighted to have with us the corresponding author, Dr Frank Hu from Harvard T.H. Chan School of Public Health, as well as our dear associate editor, Dr Jarett Berry, from UT Southwestern. Frank, could you begin by telling us a bit more about the inspiration for looking at this, what you did, and what you found? Dr Frank Hu: So, we look at the impact of healthy lifestyle habits, life expectancy in the US as a nation. As you just mentioned, Americans have a shorter life expectancy compared with almost all other high-income countries, so in this study we wanted to estimate what kind of impact of lifestyle factors have, premeasured that and life expectancy in the US population. What we did is to combine three datasets. One is our large cohort, Nurses' Health Study, and Health Professionals Follow-Up Study. We use this large cohort to estimate the relationships between lifestyle habits and mortality. And the second data set we use is to get age and sex to specific mortality rates in the US as a nation. This is the CDC WONDER dataset. And the third dataset we used is the NHANES dataset, this is the National Health and Nutrition Examination Survey. We used this dataset to get the prevalence of healthy lifestyle factors in the general US as a nation. So, we used the three datasets to create age-specific, sex-specific life tables and estimated life expectancies. At age 50, according to the number of healthy lifestyle habits that people would follow, what we found is that following several lifestyle factors can make a huge difference in life expectancies. Here we talk about five basic lifestyle factors: not smoking, maintaining a healthy weight, exercise regularly—at least a half hour per day—and eating a healthy diet, and not drinking too much alcohol. No more than one drink per day for a woman, no more than two drinks per day for men. What we found is that, compared with people who did not adapt any of those low-risk habits, we estimated that the life expectancy at age 50 was 29 years for woman and about 26 years for men. But for people who adapted all five healthy lifestyle habits, life expectancy at age 50 was 43 years for women and 38 years for men. So, in other words, a woman who maintains all 5 healthy habits gained, on average, 14 years of life, and the men who did so gained 12 years life compared with those who didn't maintain healthy lifestyle habits. So I think this is a very important public health message. It means that following several bases of healthy factors can add substantial amount of life expectancy to the US population, and this could help to reduce the gap in life expectancy between the US population and other developed countries. Dr Carolyn Lam: Thank you, Frank. You know that is such an important public health message that I am going to repeat it. Adhering to five lifestyle risk factors mainly, don't smoke, maintain a healthy weight, have regular physical activity, maintain a healthy diet, and have moderate alcohol consumption, AND a woman could increase her life expectancy at age 50 by 14 years and a man could do that by 12 years more. That is absolutely amazing. Okay so Frank, actually, I do have a question though. These are remarkable datasets obviously, but they also go back to the 1980s. So did you see any chief risk factor that may have played more predominant apart with time? Dr Frank Hu: We didn't specifically look at the changes in risk factors life expectancy, but among the five risk factors, not smoking is certainly the most important factor in terms of improving life expectancy. The good news is that prevalent smoking in the US has decreased substantially in the past several decades. However, the prevalence of other risk factors has actually increased. For example, the prevalence of obesity has increased two- or three-fold and the prevalence of regular exercise remained at a very low level, and also the diet quality in the US population is relatively poor. So, the combination of those risk factors have contributed to relatively low life expectancies in the US population. Dr Carolyn Lam: Right. Obesity, not smoking, I hear you. I just wanted to point out to all the listeners too, you have to take a look at Figure 1 of this beautiful paper, it's just so beautifully illustrated in it. Jarett, you helped to manage and bring this paper through. What are your thoughts? Dr Jarett Berry: Yeah, I just want to echo your comments, Carolyn, and Dr Hu. This is a fabulous paper, and a very important contribution characterizing these important associations in the US population. And I think, and the discussion thus far has been really helpful in putting all of this into context. I do want to ask you, just a couple of, I guess more, philosophical questions about some of the observations in the paper. And one of them is the prevalence of the low-risk factor, those with a large number of low-risk factors, for example, in both the Nurses Health and in the Health Professional Follow-Up Study, you observed that the presence of five lifestyle factors was less than 2%. And it's interesting you see this in a large number of datasets and I think important, maybe for our readers to realize that there's two sides to the coin here. One, the benefit of these low risk factors, but also, unfortunately, the low prevalence of these collections of healthy lifestyle factors that you've outlined. Could you comment a little bit on that, and what that means, both maybe from a scientific point of view of perhaps, more importantly, from a public health stand point? Dr Frank Hu: Yeah and this is very important observation and the number of people or the percentage of people who maintained all the five low-risk lifestyle habits is quite low in our cohort, even the nurses and health professionals, they are more health conscience in the general population. They have much better access to health care and also better access to healthy foods and have physical activity facilities. Despite all this potential advantages, and these more percentage of people who are able to maintain all five lifestyle risk factors. On the other hand, about 10 to 15% of our participants did not adopt any of the five low-risk lifestyle habits. So it means that we still have a lot of work to do in terms of improving the lifestyle habits that we discussed earlier. The five risk lifestyle factors and in the general population, I think the percentage of people who adapt all the five lifestyle factors, probably even lower than 2%. And so that means that we have a huge public health challenge in front of us and have to improving the five lifestyle risk factors. One of the most important public health challenges as mentioned earlier is obesity because currently we have two-third of the US population is overweight or obese. So that's something I think is major public health challenges for us. Dr Jarett Berry: Right, and it's interesting looking at your Table 1, and those individuals who have all five low risk factors. It's interesting that the prevalence of physical activity was incredibly high. I have a great interest of impact of exercise on these types of outcomes and it's interesting that in both cohorts, six or seven hours a week of exercise was the mean physical activity level in those with five risk factors. So, it's interesting and in some ways, these lifestyle factors, they do tend to congregate or covary with one another such that those individuals who do spend that kind of time, albeit unfortunately more rare than we would like to see it, the increase in physical activity does tend to have a positive impact, not only on the weight, but also on healthy lifestyle or healthy diet choices. Dr Frank Hu: Right, yeah this is a very good observation that what I do want to point out that our definition of regular exercise is pretty cerebral to put it in terms of the definition. So we define moderate to vigorous physical activity in our cohorts. We included not just running, playing sports, but it was also walking in a moderate intensity. So it means that people can incorporate physical activity into their daily life. For example, by walking from a train station and with climbing stairs in their workplace and so on and so forth. So here physical activity means both recreational activity and also moderate intensity activities such as graceful walking. Dr Carolyn Lam: Frank, I think both of us listening are breathing a sigh of relief there and just for the listeners to understand too. These factors were dichotomized, right, and so you were describing the type of exercise and actually you used a three and a half hour per week limit to define healthy or not. Similarly, just for reference the alcohol intake was 5 to 15g a day for women, or 5 to 30g a day for men. And norm…

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Circulation July 17, 2018 Issue Jul 17, 2018

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Dr Carolyn Lam: Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. In this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries. The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis. The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension. Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets? Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features. However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies. The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients. Well, that wraps it up for our summaries. Now for our feature discussion. When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic. Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper? Dr Maxim Mulder: Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started. So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data. So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice. Dr Carolyn Lam: Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael? Dr Micheal Hill: I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data. I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging. Dr Carolyn Lam: True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree? Dr Micheal Hill: Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging. Dr Carolyn Lam: Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands? Dr Graeme Hankey: I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data. We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they're assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue. So, although, generally time is an important prognosticator as we've learned here, there are probably…

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Circulation July 10, 2018 Issue Jul 10, 2018

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Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor for the National Heart Center, and Duke National University of Singapore. How do resuscitation teams at top-performing hospitals for in-hospital cardiac arrest actually succeed? Well, to learn how, you have to keep listening to the podcast, because we will be discussing this right after these summaries. The first original paper this week tells us that recent developments in RNA amplification strategies may provide a unique opportunity to use small amounts of input RNA for genome wide-sequencing of single cells. Co-first authors, Dr Gladka and Molenaar, corresponding author, Dr van Rooij, and colleagues from Hubrecht Institute in Utrecht, the Netherlands, present a method to obtain high-quality RNA from digested cardiac tissue, from adult mice, for automated single-cell sequencing of both healthy and diseased hearts. Based on differential gene expression, the authors were also able to identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cells subpopulations. For example, they identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlated with known myofibroblast markers, in both mouse and human cardiac tissue. This paper raises the exciting possibility for new biology discovery using single-cell sequencing that can ultimately lead to the development of novel therapeutic strategies. Myeloid-derived suppressor cells are a heterogeneous population of cells that expand in cancer, inflammation, and infection, and negatively regulate inflammation. However, their role in heart failure was unclear, at least until today's paper in this week's journal. Co-first authors Dr Zhou, Miao, and Yin, and co-corresponding authors, Dr Wang and Li, from Huazhong University of Science and Technology, measured the myeloid-derived suppressor cells by flow cytometry in heart failure patients and in mice with pressure overload–induced heart failure, using isoproterenol infusion or transverse aortic constriction. They found that the proportion of myeloid-derived suppressor cells was linked to heart failure severity. Cardiac hypertrophy, dysfunction, and inflammation were exacerbated by depletion of myeloid-derived suppressor cells but alleviated by cell transfer. Monocytic myeloid-derived suppressor cells exerted an antihypertrophic effect on cardiomyocyte nitric oxide, but monocytic and granulocytic myeloid-derived suppressor cells displayed antihypertrophic and anti-inflammatory properties through interleukin 10. Rapamycin increased accumulation of myeloid-derived suppressor cells by suppressing their differentiation, which in part mediated its cardioprotective mechanisms. Thus, these findings revealed a cardioprotective role from myeloid-derived suppressor cells in heart failure by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin 10 and nitric oxide. Pharmacological targeting of myeloid-derived suppressor cells by rapamycin constitutes a promising therapeutic strategy for heart failure. In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL cholesterol and cardiovascular risk in patients with stable atherosclerotic disease. However, was the efficacy of evolocumab modified by baseline inflammatory risk? While Dr Bohula from the TIMI Study Group and colleagues explored this question by examining the efficacy of evolocumab stratified by baseline high sensitivity CRP. They also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL concentrations. They found that the relative benefit of evolocumab for the prevention of adverse cardiovascular events was consistent, irrespective of baseline high sensitivity CRP. However, because patients with higher high sensitivity CRP levels had higher rates of adverse cardiovascular events, they also tended to experience greater absolute benefit with evolocumab. In an analysis of baseline high sensitivity CRP in achieved LDL cholesterol, the authors found that at first cardiovascular event rates were independently associated with both LDL cholesterol and high sensitive CRP. Event rates were lowest in patients with the lowest hsCRP and LDL cholesterol, supporting the relevance of both inflammatory and residual cholesterol risk. The next paper provides further evidence that residual inflammatory risk, as measured by on-treatment high sensitivity CRP, remains an important clinical issue in patients on combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from Brigham and Women's Hospital and colleagues, evaluated the residual inflammatory risk among patients participating in the SPIRE-1 and -2 cardiovascular outcome trials, who are receiving both statin therapy and the PCSK9 inhibitor bococizumab, according to on-treatment levels of high sensitivity CRP and LDL cholesterol measured 14 weeks after drug initiation. They found that among high-risk stable outpatients treated with moderate or high-intensity statins and PCSK9 inhibition, roughly one in two had residual inflammatory risk defined by an on-treatment high sensitivity CRP level of 2 or more mg per liters, and roughly one in three had values above 3 mg per liter. PCSK9 inhibition was associated with a 60% mean reduction in LDL cholesterol but little change in high sensitivity CRP. Levels of high sensitivity CRP above 3 mg per liter were associated with a 60% greater risk of future cardiovascular events, corresponding to a 3.6% annual event rate, even after accounting for on-treatment LDL cholesterol. Thus, PCSK9 inhibition, added to statin therapy in stable outpatients, does not lower high sensitivity CRP. Persistent elevations of CRP is associated with future cardiovascular risk in these patients, even after low levels of LDL cholesterol are achieved. If corroborated, these data suggests that inflammation modulation may yet have a role in the primary and secondary prevention of cardiovascular disease when LDL cholesterol is already controlled. Well, that wraps it up for our summaries. Now, for our future discussion. In-hospital cardiac arrests are common worldwide and they're so important because they represent opportunities for us to improve survival. Now, yet, overall rates of hospital survival after in-hospital cardiac arrests remain poor and there is substantial variation across facilities. This may be surprising because we all seem to follow or should follow the same ACLS algorithms across the world and yet, there are different outcomes. How do resuscitation teams, at top performing hospitals, for in-hospital cardiac arrest, how do they succeed? Pleased to be discussing this with a real star team in today's podcast. We have first and corresponding author of our feature paper, Dr Brahmajee Nallamothu. We also have Dr Steven Kronick, who is the chair of the CPR committee and both are from University of Michigan Medical School. We also have Dr Sana Al-Khatib, who is a senior associate editor of Circ, from Duke University. So, welcome everyone! Let's go straight into it. Maybe starting with you Brahmajee, could you tell us what inspired you to perform this study? Dr Brahmajee Nallamothu Thank you, Carolyn, for giving us the opportunity to talk about this study. I'm an interventional cardiologist here at the University of Michigan and typically, this isn't an area that interventional cardiologists are really greatly involved with. I became interested because I also, at times, I round in the cardiac intensive care unit, and that's a place where a lot of patients often times end up after they've had an in-hospital cardiac arrest at our institution and what I've noticed over the years, is the variability in care that would be occurring out there, and then also lots of gaps in the literature. Over a decade or so ago, I started partnering with a close friend and colleague, Paul Chan, from the Mid America Heart Institute and we started to do a series of studies on how in-hospital cardiac arrest care varies across institutions in the United States and we published a number of articles that have been in really high-profile journals over the last 10 years, but the problem has always been that even though we could describe really well what was happening, we had very little understanding of why it was happening or how certain hospitals were seeming to outperform others in this really challenging situation. We wanted to dive a bit deeper into the questions and reasons behind top performers doing so well and that's what brought us on to doing this study. Dr Carolyn Lam: Great. You want to tell us a little bit about it? It's really very different from the other CPR studies I've seen. Could you tell us about it and what you've found? Dr Brahmajee Nallamothu: Sure, so in the broader framework, it's a qualitative study and what I mean by qualitative is, we didn't really collect data either through surveys or through outcome assessments. What we did was, we actually went out and talked to people. The study though was really focused on what people call a mixed methods approach. We didn't just randomly talk to different hospitals, we actually focused on hospitals that were at the top-performing levels. We also focused on some hospitals that were non-top-performing as well, to get some contrast between the two and when I said we talked, we did this in a very systematic and pretty rigid way. We always had four interviewers go out to nine hospitals. We split them up, so we had two content experts and then two methodologic experts in qualitive studies, and we started to interview a bunch of people. In fact, we interviewed almost 160 people across these nine hospitals. We interviewed everyone from CEOs and hospital leadership, down to boots on the ground, including both clinical providers and even non-clinical providers, such as spiritual care, security. We tried to get this comprehensive view of what was actually happening during an in-hospital cardiac arrest across these nine hospitals, and really the results were quite fascinating to us. For someone, like myself, that's been in this space for ten years, I tell people I learn more talking to these nine hospitals than I have in the last ten years of looking at numbers on a spreadsheet. I really started to understand, for the first time, what was really going on, how these hospitals were dealing with these challenging situations because there's no bigger emergency in a hospital, and Steve, who we're going to hear from, we talk about this, but Steve has a great line about how when an in-hospital cardiac arrest occurs, that patient automatically becomes the sickest person in an institution and yet, we haven't set up systems that really build on how to handle that in the most consistent and positive way. Dr Carolyn Lam: Oh, my goodness, I just love that line! Now, you have to tell us, so what's the secret? What's the secret of the succeeding hospitals? Dr Brahmajee Nallamothu: What we found in general was, that resuscitation teams at top-performing hospitals really demonstrated the following features. They had dedicated or designated resuscitation teams. They really included the participation of diverse disciplines as team members during the in-hospital cardiac arrest. There were really clear roles and responsibilities of the team members that were set up right from the front. There was better communication and leadership, actually, during these events and finally, in the training aspect, one of the unique things we found was, the top-performing hospitals seem to have a high rate of in-depth mock codes, that they used as strategies for getting their clinicians ready for these events. Dr Carolyn Lam: As you were speaking I was just thinking through the experiences of in-hospital cardiac arrests that I've encountered, and you're right. These elements, though we don't talk about them much, make a huge difference. Steve, I am so curious about your outlook. I mean you must have attended a kajillion CPRs as chair of the CPR committee. Tell us, what do you think is the take home message for clinicians and hospitals? Dr Steven Kronick: My field is in emergency medicine and as chair of the CPR committee, I have responsibility of overseeing how we respond to cardiac arrests in our hospitals. I think that many institutions spend a lot of time and effort looking at in-hospital cardiac arrests are managed, and how to improve on it. We're able to use data to help compare ourselves to similar institutions, but beyond the bottom line of either ROSC or survival to discharge, we've most relied on process measures to figure out what we're doing. We're essentially flying blind, or at least not flying in any sort of formation when we do that. I think that this study validates some of the operational aspects of the arrest response, for those centers who use those and can help other decide where they want to direct their efforts. I think a good example that Brahmajee brought up, is this distinction we found between the use of dedicated teams, designated teams, or not having any organized team, and the impact that has on survival. The use of these teams can mean significant use of resources but showing that it's associated with better outcomes help provide support for that concept and for those centers who might already use one of those models, it helps them to steer their efforts to improving the delivery or the efficiency of that model. Dr Carolyn Lam: Yeah, and indeed. Congratulations to both of you, Steve and Brahmajee. I do think that these are novel contemporary data, at least the first that I know of. Sana, you handle the paper and recognize this. Could you tell us a little about what you think are the novel and important aspects? Dr Sana Al-Khatib: I really have been a fan of this paper from the get go and yes, it doesn't have the quantitative analysis that the statistical modeling, most of us are used to. It is a qualitative study, but I think that gives it strength. It makes it unique. This type of research, it can really only be effectively done through a qualitative study that really has all the important aspects of a good qualitative study, so I do want to congratulate them. Clearly, a lot of work went into this, and I appreciate all their efforts. In terms of the main findings, some of us might look at this data and say, well it's not surprising that those are the characteristics, or the features, of the top performing hospitals, but I felt like it was great, in terms of how the data were presented. Encouraging hospitals to adopt this. Giving them almost like a checklist of what they need to be doing to improve the outcomes of their in-hospital cardiac arrests, in terms of ensuring that they have designated resuscitation teams. The whole idea about diversity of participants in these arrests, and making sure everyone has a clear role and responsibility. The whole idea of making sure that somebody takes leadership and you have clear and very good communication among the different people who are doing this and great training. In fact, these people were doing in-depth mock codes. I think that spells it out very nicely and gives a lot of the hospitals, hopefully, action items that they can implement to improve the outcomes these patients. I love this paper. Dr Carolyn Lam: Sana, I love the way you put that. Checklist, and you know what I was thinking as Brahmajee and Steve were talking earlier? I was thinking blueprint, almost, of the things that we should have. So Steve, could I ask your t…

Full show notes at the publisher

Circulation July 3, 2018 Issue Jul 02, 2018

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Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. This week features Circulation Global Rounds, a brand-new series of papers from all across the world that you are going to want to hear about, coming right up after these summaries. The first original paper this week tells us that community trends and acute decompensated heart failure may differ by race and sex. Dr Patricia Chang from University of North Carolina in Chapel Hill and colleagues examine the 10-year rates and trends of hospitalized acute decompensated heart failure in the Atherosclerosis Risk in Communities or ARIC study, which sampled heart failure–related hospitalizations in four US communities from 2005 to 2014, using ICD-9 codes. They found that acute heart failure with reduced ejection fraction was more common in black men and white men, whereas acute heart failure with preserved ejection fraction was most common in white women. Rates of hospitalized acute decompensated heart failure increased over time, with higher rates in blacks, and rising cases of preserved ejection fraction heart failure. Mortality rates were 30% at one year with a more pronounced decrease over time in blacks but generally did not differ by heart failure types. Whether racial differences may be related to age of onset comorbidities, or other community level and social economic factors, deserve further study. The next paper is a population-based study identifying long-term outcomes and risk factors and children with hypertrophic cardiomyopathy. Dr Alexander from Boston Children's Hospital and colleagues examine the National Australian Childhood Cardiomyopathy Study, a long-term national cohort study with a median follow-up duration of 15 years. They found that the greatest risk of death or transplantation for children with hypertrophic cardiomyopathy was in the first year after diagnosis, with 14% of patients achieving this combined end point compared to 0.4% per year thereafter. Risk factors for death or transplantation included symmetric left ventricular hypertrophy at diagnosis, Noonan syndrome, increasing left ventricular free wall thickness, and lower fractional shortening during follow up. The majority of surviving patients had no symptoms. Thus, children with hypertrophic cardiomyopathy who are alive one year after diagnosis have a low long-term rate of death or transplantation. Deaths from heart failure usually occur soon after diagnosis, whereas the risk of sudden cardiac death is ongoing. The next paper is the first demonstration of a peripheral clock in the perivascular adipose tissue that could contribute to the homeostatic regulation of circadian blood pressure variation. Co-corresponding authors Dr Chang and Chen from University of Michigan and their colleagues used a novel brown adipose specific aryl hydrocarbon receptor, nuclear translocator-like protein 1 or Bmal1 and angiotensinogen knockout mouse model to demonstrate that local Bmal1 in perivascular adipose tissue regulated angiotensinogen expression and the ensuing increase in angiotensin II, which acted on smooth muscle cells in the vessel walls to regulate basal activity and blood pressure in a circadian fashion during the resting phase. In fact, deletion of Bmal1 or angiotensinogen in the perivascular adipose tissue resulted in a superdipper phenotype with exacerbated hypotension during the resting phase. These findings imply that it is possible that obesity could alter the perivascular adipose tissue peripheral clock, thus promoting abnormal dipper phenotypes and increasing cardiovascular risk. The results therefore inform the design of novel therapeutic approaches for hypertension by targeting the perivascular adipose tissue peripheral clock. What is the net clinical benefit of oral anticoagulation for very elderly patients with atrial fibrillation? Well, the next paper by first author Dr Chao, cocorresponding authors, Dr Chen from Taipei Veterans General Hospital and Dr Lip from University of Birmingham, addresses this question. These authors use a nationwide cohorts study in Taiwan to compare the risks of ischemic stroke and intercerebral hemorrhage between patients with and without atrial fibrillation, all aged 90 years and above, from 1996 to 2011, and they also compared patients treated with warfarin and non-vitamin K antagonists oral anticoagulants, or NOX from 2012 to 2015 when NOX were available in Taiwan. They found that even among these very elderly patients aged 90 years and above, atrial fibrillation was associated with an increased risk of ischemic stroke compared to patients without atrial fibrillation. Warfarin use was associated with a lower risk of ischemic stroke, with no difference in intercerebral hemorrhage risk compared to nonwarfarin treatment. The use of warfarin was associated with a positive net clinical benefit compared to being untreated or to antiplatelet therapy. Compared to warfarin, NOX were associated with a lower risk of intracerebral hemorrhage, with no difference in the risk of ischemic stroke. Thus, oral anticoagulation may still be considered for thromboprophylaxis in very elderly patients with atrial fibrillation, with NOX being a favorable choice The final paper provides insights into the mechanisms linking obesity and cardiovascular diseases. Co-corresponding authors, Dr Kong and Wang from Peking University Health Science Center and colleagues use a combination of animal models and human adipose biopsies to characterize a new adipokine named family with sequence similarity 19, member A5 or FAM19A5. This novel adipokine was capable of inhibiting post injury neointoma information via sphingosine-1-phosphate receptor 2 and downstream G12/13-RhoA signaling. Thus, down regulation of FAM19A5 during obesity and loss of its vascular protective function may trigger cardiometabolic diseases. Well, that wraps it up for our summaries. Now for our feature discussion. I'm just so excited about today's feature discussion, because we're talking about Circulation going global. And I am just absolutely delighted to have with us, our Editor-in-Chief himself, Dr Joe Hill from UT Southwestern, as well as our Senior Advisory Editor, Dr Paul Armstrong from University of Alberta. So Joe, could you start by telling us a little bit more about your vision for the global outreach of Circulation? Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global journal with a global footprint. We have editors distributed around the world in 16 countries and 10 time zones. And importantly, those editors all have an equivalent role at the leadership table. Part of the reason for this is because cardiovascular disease is now, as we are all aware, a global scourge. There are no more final frontiers for cardiovascular disease. That said, the manifestations of cardiovascular disease differ in different parts of the world. In the developed world, and the developing world, for example, the way cardiovascular disease manifests itself can be very different. And at the same time, the way in which the disorders are tackled are different. The way we tackle heart disease in the West can be different than it is in the East, for example. And there are important initiatives that have emerged in different pockets of the world, best practices that we need to understand better. What can we all learn from the way in which cardiovascular disease manifests itself around the world and it's being addressed around the world? Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in - Chief and I heard you say this, I was just floored, because coming from Singapore and all our listeners out there in Japan and China, we just really appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit more about this new initiative then for the journal. Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from Canada, who is a household name in the cardiovascular world, he and I cooked up a scheme that Paul will describe, where we will reach out on a regular basis for insights from various different countries, ultimately, circling the globe progressively over time. And I will defer to Paul to tell us more about the specifics. Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but still believing that you can teach an old dog new tricks, I would point out that Circulation is almost 70 years old, and it has staying power. And one of the reasons that it has staying power is because it is capable of reinventing itself, and so I was attracted to help out again, from the editorial process, given Joe's vision and leadership and the excitement around the reinvention that you've described, to get involved with this initiative. And I was inspired, of course, by the fact that those of us who do clinical trials appreciate that a lot of different ideas, a lot of different cultures and perspectives are brought to a collaborative table. And I'm thinking back now, Carolyn to three years ago, when you and I first met enjoying courses as part of a trial in heart failure, which involves 43 countries, 800 sites, it will be 5000 patients centers, we've traveled separately and together around the world, convincing people that there are unmet needs in heart failure and other parts of cardiovascular disease, we learned that the approach to standard of care, the rigor which is applied, the exquisite sensitivities around differences that are meaningful, and the tricks that some investigators and countries use that we can all I think, learn from has been very revealing. So I think in this initiative, we want to have thought leaders. And we've already I think, commenced and have two outstanding leaders from Japan and India to come forward in the first two quarters of this initiative. Tell us about the regional epidemiologic features, cardiovascular disease in their regions, what the most important challenges are, what their best practices are, that you're alluded to, who provides cardiovascular care and what the impediments are to progressing because we think if we listen and learn as essentially knowledge brokers, because welcome to Circulation, we can facilitate raising the level of all of the boats in the water and potentially make new partnerships and do a better job. So I'm excited about this. I'm delighted that Joe was receptive and really look forward to working with him and some of these terrific people around the world, you included who brings such a unique and important perspective from which we can all learn. Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International knowledge brokers, that's what we hope to be. Isn't that fabulous, just an opportunity to learn from each other, everybody having stuff to bring to the table? Tell us a bit more though, what are you looking for in these papers? Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic. We're going to allow diversity of approaches. We're going to invite a thought leader and hope that that thought leader might invite one or two others, we want to limit it to three co-authors. We want obviously some insights into how cardiovascular health professionals are being trained, what research infrastructure exists, and how they access the literature, how do they read Circulation, how do they read other journals, and are there collaborative ideas that they've developed to their neighbors to the East and West that may be could be broadened? Are there unmet needs that they've indicated similar or different from those in Western Europe, South America? We've got about seven or eight points of light that we hope to illuminate in the course of this exercise. And the prospectus that's laid out in an editorial that Joe and I collaborated on that I believe, Joe, is going to come out in early July. Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just the opposite of a formulaic, cookie cutter approach. We want to leverage the beautiful diversity of our world. The different approaches that people take to attack this scourge that is keeping a humble approach to tackle instead of the visas that is humbling bar none. There is nothing that is more globally important than the continued growth and expansion of cardiovascular disease. And importantly, we can all learn from each other. There are exciting initiatives that I've learned about in South America and in pockets of Europe and in Asia, and in the Middle East that we can all benefit from, and we want to shine a bright light on that. These pieces will be relatively short. They will be in our Frame of Reference section, so 1200 words or so, so that they are accessible so that people, you know, feel that they can carve out, you know, four minutes in their busy day to read what cardiovascular disease looks like, as Paul said, our first ones will be from Japan and India, and we plan to reach out to South America and to the Middle East, and just continue on around until over the course of the next number of years, we've touched virtually every country in the world. Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that you might be looking to focus on? Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is that in the West, in the developed world, cardiovascular disease increasingly has become a chronic disorder where more and more people, over the course of the last six years are surviving their acute coronary syndrome, their tachyarrhythmia events, and they are developing chronic disorders like heart failure, whereas in the East, it is the atherothrombotic manifestations that have both MI and stroke that are expanding rapidly. So given that the face of cardiovascular disease is different in different parts of the world, different strategies have to be leveraged to address that, and we want to learn about that. Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these papers and just reflect on the things that we're learning. Paul, did you have anything else that you wanted to add? Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes and obesity and the expanding epidemic that seems to effect some regions such as India, in the Middle East, even more than other areas, but I think this is going to be great. We're gonna have some fun and learn and exciting and hopefully it will catalyze better care and better thinking around this enemy that we all face. Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited as I am about this. You have to read the editorial. It's a fantastic read. Thanks for joining us today. And don't forget to tune in again next week.

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