Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: July, 2018
Jul 31, 2018

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

                                                Does 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, but I think it's one additional piece of the puzzle.

Dr Carolyn Lam:                Yeah, I have to say too I mean, after reading this, after reading this awesome editorial, it's hard not to think I should be applying this clinically because it's going to be really hard and take a long time to prove this with more prospective data, for example. Although, external validation and other datasets may be better, this is the largest trial already to show this and show it so clearly with a significant interaction. I think that is striking to me.

                                                Torbjørn maybe I've put you on the spot with the last word, does this change your clinical practice?

Dr Torbjørn Omland:      I agree with Gregg. This will be one of maybe several other factors but I think it's ready for being taken into account when making this sometimes very difficult decision.

Dr Carolyn Lam:                Thank you so much Gregg and Torbjørn for joining me today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.


Jul 24, 2018

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. 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 normal weight was defined as a BMI of 18.5 to 24.9. I'm just thinking that if I were listening I'd want to know those cutoffs.

                                Now, can I ask a follow-up question, therefore to this dichotomy. As far as I understand you counted each of these risk factors equally, but did you try to do a weighted analysis by any chance? Did any one of them play a bigger role than others?

Dr Frank Hu:       That's an interesting mathematical question because it’s very difficult to assign different weights to different risk factors because we look at, not just total mortality but also cardiovascular mortality and cancer mortality. So, you would have to use different weights for different causes of mortality. That would make the analysis much more complicated. But we did calculate a different type of score using five categories of each risk factor and then using that score, we were able to rank people in more categories so for that score the range is from five to 25, and we categorized people into quintiles or even more categories and the contrast in life expectancy between the lowest and the highest group is even greater. So, it means that, the higher number of healthy lifestyle factors, the greater life expectancy. Also, with each category, each lifestyle factors a high degree of adherence to that factor, the greater health benefit people will get. So, I think it's really accumulative fact of multiple risk factors and also the degree of adherence to each of the factors.

Dr Carolyn Lam: Again, such an important public health message.

                                Jarett, how do you think this is going to be received by the public at large?

Dr Jarett Berry: Very well received. I mean this is a very important observation demonstrating some of these disconcerting observations about life expectancy in the United States and as we think about strategies for improving the public health, I think Dr Hu's group has really helped us outline, very clearly, what other bodies such as the American Heart Association have been saying for years now, that lifestyle factors are so important in influencing cardiovascular risk, and in this case, life expectancy. It really does put, once again, the right amount of emphasis on the role these lifestyle factors of improving the public health. I think it’s going to be very well received and really helpful and important observation that all of us need to hear.

Dr Carolyn Lam: Listeners, don't forget this important message and tell your friends about it, please.

                                Thanks for joining us today, don't forget to join us again next week.


Jul 17, 2018

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

                                                In this day and age of endovascular treatment for acute ischemic stroke, does time to treatment really matter? Well, we will be discussing results of the MR CLEAN Registry from real-world clinical practice, coming right up after these summaries.

                                                The first original paper this week describes the first mouse model of progerin-induced atherosclerosis acceleration. Progerin is an aberrant protein that accumulates with age, causes a rare genetic disease known as Hutchinson-Gilford Progeria Syndrome. Patients with Progeria Syndrome have ubiquitous progerin expression and exhibit accelerated aging and atherosclerosis, dying in their early teens mainly from myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part due to the lack of appropriate animal models. First author Dr Hamczyk, corresponding author Dr Andrews, and colleagues from CNIC in Madrid performed an elegant series of experiments and generated not only the first mouse model of progerin-induced acceleration of atherosclerosis, but also provided the first direct evidence that progerin expression restricted to vascular smooth muscle cells but not to macrophages was sufficient to induce premature atherosclerosis and death. Progerin-induced loss of vascular smooth muscle cells caused atherosclerotic plaque destabilization that led to myocardial infarction. Ubiquitous and vascular smooth muscle cell specific progerin expression increased LDL retention in aortic media, likely accelerating atherosclerosis.

                                                The next original paper implicates dysregulation of mitochondrial dynamics as a therapeutic target in human and experimental pulmonary arterial hypertension. Now, mitotic fission is increased in pulmonary arterial hypertension. The fission mediator, dynamin-related protein 1, or Drp1, must complex with adaptor proteins to cause fission. In the current paper from co-first authors Dr Chen and Dasgupta, corresponding author Dr Archer from Queens University in Ontario Canada, and colleagues, the authors examined the role of two recently discovered but poorly understood Drp1 adaptor proteins known as mitochondrial dynamics protein of 49 and 51 kilodalton. They found pathological elevation of these mitochondrial dynamic proteins in pulmonary artery smooth muscle cells and endothelial cells in both human and experimental pulmonary arterial hypertension that accelerated mitotic fission and supported rapid cell proliferation. Mitochondrial dynamics protein's expression was epigenetically upregulated by a decreased expression of microRNA-34a-3p. Circulatory microRNA-34a-3p expression was decreased in both patients with pulmonary arterial hypertension and preclinical models, silencing the mitochondrial dynamics proteins or augmenting microRNA-34a-3p regressed experimental pulmonary arterial hypertension, thus, proving to be potential new therapeutic targets for pulmonary arterial hypertension.

                                                Dyslipidemia guidelines currently recommend that non-HDL cholesterol and apolipoprotein B, or apoB, are secondary targets to the primary target of LDL cholesterol. However, how frequently does non-HDL cholesterol guideline targets change management, and what is the utility of apoB targets after meeting LDL and non-HDL targets?

                                                Well, answers are provided in the next paper from first author Dr Sathiyakumar, corresponding author Dr Martin, and colleagues from Johns Hopkins University School of Medicine. These authors analyzed more than 2,500 adults in the US National Health and Nutrition Examination Survey, as well as more than 126,000 patients from the Very Large Database of Lipids Study with apoB. They identified all individuals as well as those with high-risk clinical features, including coronary disease, diabetes, and metabolic syndrome who met the very high and high-risk guidelines targets of LDL cholesterol of less than 70 and less than 100 mg/dL, respectively, and this was measured using either the Friedewald estimation or a novel, more accurate method. They found that after using the more accurate method of estimating LDL cholesterol, guidelines suggested non-HDL targets could alter management in only 1 to 2% of individuals, including those with coronary disease and other high risk clinical features.

                                                However, using the Friedewald estimated LDL cholesterol gave a much higher percentage. Among all individuals with both LDL cholesterol less than 100 and non-HDL cholesterol less than 130 mg/dL, only 0-0.4% had an apoB above or equal to 100 mg/dL. Thus, the utility of current non-HDL targets appears to be contingent on the accuracy of LDL cholesterol estimation. When using a novel, more accurate estimation method to assess LDL cholesterol, the non-HDL cholesterol is infrequently above current guidelines' suggested targets after the LDL target is met. Current guidelines suggest that apoB targets also provide only modest utility after cholesterol targets are met. These findings were robust to high-risk clinical features, sex, fasting status, and presence of lipid-lowering therapies.

                                                The final paper tells us that HIV infection increases the risk of developing peripheral artery disease. Dr Beckman from Vanderbilt University Medical Center and colleagues studied almost 92,000 participants in the Veterans Aging Cohort Study from 2003-2014 over a median follow-up of nine years. They excluded participants with known prior peripheral artery disease or prevalent cardiovascular disease. They found that infection with HIV was associated with a 19% increased risk of incident peripheral artery disease beyond that explained by traditional atherosclerotic risk factors. Once peripheral artery disease had developed, HIV infection increased the risk of mortality compared to uninfected patients. Whereas for those with sustained CD4 cell counts above 500, there was no excess risk of incident peripheral artery disease events compared to uninfected people. Furthermore, worsening HIV infection as measured by CD4 cell count and HIV viral load was associated with increased incident peripheral artery disease and mortality. In summary, HIV infection increased the risk of developing peripheral artery disease and mortality. The findings also suggest that aggressive antiretroviral therapy to reduce viral load and increase CD4 cell counts may reduce the risk of developing peripheral artery disease. Furthermore, clinicians should solicit clinical complaints and physical signs consistent with peripheral artery disease to facilitate the diagnosis of peripheral artery disease in patients with HIV and ensure the addition of guideline-based anti-atherosclerotic therapies in these patients.

                                                Well, that wraps it up for our summaries. Now for our feature discussion.

                                                When it comes to acute ischemic stroke treatment, we've learned from trials of intravenous thrombolytics that time is brain. But what about the situation with endovascular treatment of strokes? Also, what's the situation like in the real world? Well, today's featured paper really provides precious data telling us about time-to-endovascular treatment and outcomes in acute ischemic stroke. I am so delighted to have with us the first and corresponding author of the MR CLEAN Registry, Dr Maxim Mulder from Erasmus University Medical Center, as well as our editorialist, Dr Micheal Hill, from University of Calgary, and our associate editor, Dr Graeme Hankey, from University of Western Australia, all here to discuss this hugely important topic.

                                                Maxim, could we start with you? So, MR CLEAN Registry means there was a MR CLEAN trial. Could you tell us a little bit more about your paper?

Dr Maxim Mulder:           Sure, well to start with, I think it's important to make sure all the people know the difference between the MR CLEAN trial and the registry since of course the trial was to show whether the intra-arterial treatment is effective when it comes to acute ischemic stroke treatments and then, of course, for people treated within six hours. When the MR CLEAN trial finished we continued in the Netherlands with all the participating centers from the trial to gather all the data from everybody who is treating in the whole country with the intra-arterial treatment, but they're not anymore in the light of the trial but in the clinical practice. We've had a lot of trials, but we don't have a lot of clinical practice date yet of the intra-arterial treatment, so that's where it all started.

                                                So, what we found is we consider our data, so with the least possible selections or the only selection was basically to treat within six and a half hours and have patients that had a proven large vessel occlusion that were treated in the Netherlands and of course as we also know from when intravenous therapy was introduced that what happens in clinical trials doesn't necessarily happen when a new treatment is introduced into clinical practice. There are less strict criteria for patients to get treated, and you know everybody, of course, there is a lot of debate about which patients should be treated. In clinical trials it is very strictly coordinated, but in clinical practice there's a lot more room to have an interpretation and also treat a different population. So, we also see that our population is somewhat older and has more comorbidities than in all the trials. Also what we found, of course, our most important finding was that when compared to all the trials or the large trials combined together in the Emberson analysis about time that when we look at the influence or the association of time with functional outcome of intra-arterial treatment that this association is clearly stronger than we found in the previous, the trial data.

                                                So, I think that's a very important finding. Also, for everybody who's now treating this patient in clinical practice.

Dr Carolyn Lam:                Exactly. I mean this is really stunning results. If I could paraphrase from your paper, every hour delay in time from stroke onset to the start of endovascular treatment resulted in a 5.3% decreased probability of functional independence and a 2.2% increase in mortality. This is stunning. Thank you, thank you for publishing these results with us in Circulation. I would like to ask Michael, I love the point you made in the editorial that time of stroke onset is really quite a difficult thing to determine. Could you tell us your thoughts about that, Michael?

Dr Micheal Hill:                  I mean, it's something like 15-20% of the time stroke is unwitnessed, either because stroke occurs in sleep and the patient is discovered with their stroke symptoms on awakening. Or the patient is simply alone and has their stroke unwitnessed by any bystander. Even in so-called witness stroke, there are probably significant errors in determining the exact time of stroke onset because it's an emergency, and everybody's flustered and time anchors are not necessarily well known. And, so, I think it's an important point that the actual measurement of time is challenging, yet it's still an easier clinical tool for us to use in gauging the extent or evolution of stroke. That's the most important thing to point out here is that this population effect that Max has observed in the MR CLEAN registry is certainly concordant with clinical trial data.

                                                I certainly think it's correct, and, as you pointed out in your comments, dramatic, but a really important issue is that for the individual patient, there's quite a lot of variance in the evolution of stroke. So, whereas, on a population basis, it's absolutely true that the average time from estimated time of stroke onset to treatment initiation is absolutely critical; in some patients, the individual might be still a good candidate for treatment even in late time windows, and some patients, even after a couple hours, the damage is already extensive, and they may not be good candidates for treatment. It still requires individual decision making, and it still leaves a lot of room for clinical judgment largely based on imaging.

Dr Carolyn Lam:                True, and I think you've really succinctly put that solid take-home message in the title really, which is acute ischemic stroke biology really demands fast treatment. I think that's the one thing that we'd really like clinicians to come away with. You agree?

Dr Micheal Hill:                  Absolutely. Especially, I think, the advantage of looking at whole populations and large, I mean this is a large registry, the MR CLEAN registry, and the group should be congratulated because it's clearly the biggest registry in the world right now of available data, and it's only getting larger week by week as they carry on with their work. You know the whole Netherlands group, the MR CLEAN group, are a fantastic group, but absolutely right, on a population basis, we absolutely have to get our systems in place so that on average we're treating patients incredibly fast. On an individual basis, the clinicians and the teams treating an individual patient still need to make judgments about that patient's eligibility for treatment. It's easy when the times are fast, so if you're an hour and a half from onset, nearly everybody's gonna be a good candidate for treatment, but as time elapses you need to make judgements on the basis of imaging.

Dr Carolyn Lam:                Well put. You know, Graeme, you're over there in Australia. What are your take-home messages about how generalizable these findings are to places outside perhaps of the Netherlands?

Dr Graeme Hankey:        I think you're asking about the external validity. I think the internal validity is certainly there. As Michael said, this is the largest registry that we have that's been published data on this before. It's certainly novel, and we're very confident that the results are valid, although this is an observational study and not a randomized trial. The association between time and outcome seems to be independent of the major patient factors that may influence time to endovascular therapy. For example, younger people who are less frail and they're alert and they're mobile can get to treatment earlier. So, you might say, well of course they're gonna have a better outcome. But these factors were adjusted for. And, of course, there are procedural factors that could influence the association between time and outcome, but we're very confident in the results and the novelty of them in supporting and building on the randomized trial data.

                                                We're also very confident in the registry and the nature of the population. The results are likely to be generalizable beyond the Netherlands population where this was conducted in routine clinical practice, certainly across Caucasian populations that are similar and with similar stroke interventional and assessment protocols, and I would hope to see this sort of study validated externally in other populations. But, also, as Michael said, I think this study not just highlights the importance of time as a factor and its implications for systems of care and recognizing people with disabling stroke and ensuring they’re assisted urgently to the appropriate imaging but also to acknowledge that time isn't the only factor. And as Michael has alluded to, our brain tissue has different collateral circulations and different probable genetic factors and metabolic factors. So, someone with a stroke at one hour, it might be all over for them. Whereas, another person with a stroke at 24 hours ago, they might have salvageable tissue.

                                                So, although, generally time is an important prognosticator as we've learned here, there are probably other factors that need to be considered and accounted for. But this certainly takes us a step forward, and, in answer to your question, I think we have confidence in its generalizability.

Dr Carolyn Lam:                Thank you Graeme. Maxim, in line with that, are there any next steps you plan?

Dr Maxim Mulder:           In light of the most recent trials, the DAWN and DEFUSE 3 trial about 6 to 25-hour, 24-hour window, I think that both of the trials are very exciting, and they shine a new light into a new set of patients that are still able to offer a great benefit intra-arterial treatment. In my opinion, the most important thing, especially in those two trials, those are highly selective patients, especially selected on all the extra imaging parameters, and I guess that there's a whole larger population that could still benefit in this time window and that's also one of the things we're currently studying in one of our new trials in the Netherlands in the MR CLEAN-LATE trial, and that is randomizing patients who are having a large vascular occlusion 6 to 24 hours, and the only extra criteria they should meet is they should have at least a little bit of collateral circulation on the ischemic brain side.

Dr Carolyn Lam:                Michael and Graeme, what do you think are the priorities for next steps in research.

Dr Micheal Hill:                  I guess overall in the field, I don't think there's any doubt that faster treatment is better. What we need to do across the world is make sure that everybody's receiving it on a system-wide basis. Right? I think there needs to be a lot of more careful work done on getting systems of care in place to make sure that patients are getting the treatment they can get. We have very many weaknesses. Some are related to lack of accreditation. Some are related to the resources required to get people treated quickly. Some are related to continuing resistance in some specialties to even giving intravenous thrombolytic drugs. So, I think faster treatment in general for acute stroke is a theme; it's not just limited to endovascular treatment. It's treatment for patients for intravenous thrombolysis. It's also actually true for TIA and minor stroke. We've had recent data on fast antiplatelet therapy, so, it's not an emergency in the same way in terms of minutes, but it's still a general theme of acute stroke care.

                                                We need to be like the Ferraris and the Formula One, right? And get ourselves moving. That's a big challenge for people. Right? It's a big stress on systems. But, I think there are other examples in medicine. We've seen this evolution in acute coronary care, and we've seen the evolution in acute trauma care. In many ways, the next things that need to really continue to happen are publications like this and getting the message out that people need to start changing their mind. The biggest thing that I find when I talk to people or talk at meetings or talk to administrators is that they say, "Well, we can't do this many CTs that fast. We can't respond that fast." And the answer is actually that you can't change the biology of the disease, so if you decide you wanna treat stroke patients, you better figure out how to change your systems. It's a question of will here rather than trying to bend the disease to the system.

Dr Carolyn Lam:                Wonderfully put. Can't change the biology so we better change the systems. How about you, Graeme? Any last words?

Dr Graeme Hankey:        Just to concur with Michael’s comments there and Max's underlying theme that time is very important. And as Michael alludes to, it's not just acute ischemic stroke due to large vascular disease, it's also acute intracerebral hemorrhage. We're learning now really if we're gonna have an effect in the bleeding brain probably we have to do that within the first three hours and maybe not be waiting so late. And as Michael alludes to, someone with a minor ischemic stroke who's had a hot volcano gone off in their neck, as you know, ruptured atherosclerotic plaque, it's like those volcanoes in Hawaii, they're gonna keep going off again. And the risk is 5% in the next two days and 10% in the next week. So, a TIA and a mild ischemic stroke, it is a medical emergency to find the cause and to get it treated, and that's why the synopsis of this message from Max's study is that people, if they do avail themselves of acute assessment early, even if they don't have a large vessel occlusion causing an ischemic stroke, they may actually have their intracerebral hemorrhage treated quickly or, more evidence based at the moment, their TIA or mild ischemic stroke have the cause ascertained and treated emergently and reduce that early risk of recurrence should they survive.

Dr Carolyn Lam:                Excellent points. Thank you so much, gentlemen. This has been an amazing podcast.

                                                Thank you so much for joining us today. Don't forget to tune in again next week, listeners.


Jul 10, 2018

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

                                                How do resuscitation teams at top-performing hospitals for in-hospital cardiac arrest actually succeed? Well, to learn how, you have to keep listening to the podcast, because we will be discussing this right after these summaries.

                                                The first original paper this week tells us that recent developments in RNA amplification strategies may provide a unique opportunity to use small amounts of input RNA for genome wide-sequencing of single cells. Co-first authors, Dr Gladka and Molenaar, corresponding author, Dr van Rooij, and colleagues from Hubrecht Institute in Utrecht, the Netherlands, present a method to obtain high-quality RNA from digested cardiac tissue, from adult mice, for automated single-cell sequencing of both healthy and diseased hearts.

                                                Based on differential gene expression, the authors were also able to identify multiple subpopulations within a certain cell type. Furthermore, applying single-cell sequencing on both the healthy and injured heart indicated the presence of disease-specific cells subpopulations.

                                                For example, they identified cytoskeleton-associated protein 4 as a novel marker for activated fibroblasts that positively correlated with known myofibroblast markers, in both mouse and human cardiac tissue. This paper raises the exciting possibility for new biology discovery using single-cell sequencing that can ultimately lead to the development of novel therapeutic strategies.

                                                Myeloid-derived suppressor cells are a heterogeneous population of cells that expand in cancer, inflammation, and infection, and negatively regulate inflammation. However, their role in heart failure was unclear, at least until today's paper in this week's journal. Co-first authors Dr Zhou, Miao, and Yin, and co-corresponding authors, Dr Wang and Li, from Huazhong University of Science and Technology, measured the myeloid-derived suppressor cells by flow cytometry in heart failure patients and in mice with pressure overload–induced heart failure, using isoproterenol infusion or transverse aortic constriction.

                                                They found that the proportion of myeloid-derived suppressor cells was linked to heart failure severity. Cardiac hypertrophy, dysfunction, and inflammation were exacerbated by depletion of myeloid-derived suppressor cells but alleviated by cell transfer. Monocytic myeloid-derived suppressor cells exerted an antihypertrophic effect on cardiomyocyte nitric oxide, but monocytic and granulocytic myeloid-derived suppressor cells displayed antihypertrophic and anti-inflammatory properties through interleukin 10.

                                                Rapamycin increased accumulation of myeloid-derived suppressor cells by suppressing their differentiation, which in part mediated its cardioprotective mechanisms. Thus, these findings revealed a cardioprotective role from myeloid-derived suppressor cells in heart failure by their antihypertrophic effects on cardiomyocytes and anti-inflammatory effects through interleukin 10 and nitric oxide. Pharmacological targeting of myeloid-derived suppressor cells by rapamycin constitutes a promising therapeutic strategy for heart failure.

                                                In the FOURIER trial, the PCSK9 inhibitor evolocumab reduced LDL cholesterol and cardiovascular risk in patients with stable atherosclerotic disease. However, was the efficacy of evolocumab modified by baseline inflammatory risk?

                                                While Dr Bohula from the TIMI Study Group and colleagues explored this question by examining the efficacy of evolocumab stratified by baseline high sensitivity CRP. They also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL concentrations. They found that the relative benefit of evolocumab for the prevention of adverse cardiovascular events was consistent, irrespective of baseline high sensitivity CRP. However, because patients with higher high sensitivity CRP levels had higher rates of adverse cardiovascular events, they also tended to experience greater absolute benefit with evolocumab.

                                                In an analysis of baseline high sensitivity CRP in achieved LDL cholesterol, the authors found that at first cardiovascular event rates were independently associated with both LDL cholesterol and high sensitive CRP. Event rates were lowest in patients with the lowest hsCRP and LDL cholesterol, supporting the relevance of both inflammatory and residual cholesterol risk.

                                                The next paper provides further evidence that residual inflammatory risk, as measured by on-treatment high sensitivity CRP, remains an important clinical issue in patients on combination statin and PCSK9 inhibitor therapy. Dr Pradhan, from Brigham and Women's Hospital and colleagues, evaluated the residual inflammatory risk among patients participating in the SPIRE-1 and -2 cardiovascular outcome trials, who are receiving both statin therapy and the PCSK9 inhibitor bococizumab, according to on-treatment levels of high sensitivity CRP and LDL cholesterol measured 14 weeks after drug initiation.

                                                They found that among high-risk stable outpatients treated with moderate or high-intensity statins and PCSK9 inhibition, roughly one in two had residual inflammatory risk defined by an on-treatment high sensitivity CRP level of 2 or more mg per liters, and roughly one in three had values above 3 mg per liter.

                                                PCSK9 inhibition was associated with a 60% mean reduction in LDL cholesterol but little change in high sensitivity CRP. Levels of high sensitivity CRP above 3 mg per liter were associated with a 60% greater risk of future cardiovascular events, corresponding to a 3.6% annual event rate, even after accounting for on-treatment LDL cholesterol.

                                                Thus, PCSK9 inhibition, added to statin therapy in stable outpatients, does not lower high sensitivity CRP. Persistent elevations of CRP is associated with future cardiovascular risk in these patients, even after low levels of LDL cholesterol are achieved. If corroborated, these data suggests that inflammation modulation may yet have a role in the primary and secondary prevention of cardiovascular disease when LDL cholesterol is already controlled. Well, that wraps it up for our summaries. Now, for our future discussion.

                                                In-hospital cardiac arrests are common worldwide and they're so important because they represent opportunities for us to improve survival. Now, yet, overall rates of hospital survival after in-hospital cardiac arrests remain poor and there is substantial variation across facilities. This may be surprising because we all seem to follow or should follow the same ACLS algorithms across the world and yet, there are different outcomes.

                                                How do resuscitation teams, at top performing hospitals, for in-hospital cardiac arrest, how do they succeed? Pleased to be discussing this with a real star team in today's podcast. We have first and corresponding author of our feature paper, Dr Brahmajee Nallamothu. We also have Dr Steven Kronick, who is the chair of the CPR committee and both are from University of Michigan Medical School. We also have Dr Sana Al-Khatib, who is a senior associate editor of Circ, from Duke University. So, welcome everyone! Let’s go straight into it. Maybe starting with you Brahmajee, could you tell us what inspired you to perform this study?

Dr Brahmajee Nallamothu            Thank you, Carolyn, for giving us the opportunity to talk about this study. I'm an interventional cardiologist here at the University of Michigan and typically, this isn't an area that interventional cardiologists are really greatly involved with. I became interested because I also, at times, I round in the cardiac intensive care unit, and that's a place where a lot of patients often times end up after they've had an in-hospital cardiac arrest at our institution and what I've noticed over the years, is the variability in care that would be occurring out there, and then also lots of gaps in the literature.

                                                Over a decade or so ago, I started partnering with a close friend and colleague, Paul Chan, from the Mid America Heart Institute and we started to do a series of studies on how in-hospital cardiac arrest care varies across institutions in the United States and we published a number of articles that have been in really high-profile journals over the last 10 years, but the problem has always been that even though we could describe really well what was happening, we had very little understanding of why it was happening or how certain hospitals were seeming to outperform others in this really challenging situation.

                                                We wanted to dive a bit deeper into the questions and reasons behind top performers doing so well and that's what brought us on to doing this study.

Dr Carolyn Lam:                Great. You want to tell us a little bit about it? It's really very different from the other CPR studies I've seen. Could you tell us about it and what you've found?

Dr Brahmajee Nallamothu:          Sure, so in the broader framework, it's a qualitative study and what I mean by qualitative is, we didn't really collect data either through surveys or through outcome assessments. What we did was, we actually went out and talked to people.

                                                The study though was really focused on what people call a mixed methods approach. We didn't just randomly talk to different hospitals, we actually focused on hospitals that were at the top-performing levels. We also focused on some hospitals that were non-top-performing as well, to get some contrast between the two and when I said we talked, we did this in a very systematic and pretty rigid way.

                                                We always had four interviewers go out to nine hospitals. We split them up, so we had two content experts and then two methodologic experts in qualitive studies, and we started to interview a bunch of people. In fact, we interviewed almost 160 people across these nine hospitals.

                                                We interviewed everyone from CEOs and hospital leadership, down to boots on the ground, including both clinical providers and even non-clinical providers, such as spiritual care, security. We tried to get this comprehensive view of what was actually happening during an in-hospital cardiac arrest across these nine hospitals, and really the results were quite fascinating to us.

                                                For someone, like myself, that's been in this space for ten years, I tell people I learn more talking to these nine hospitals than I have in the last ten years of looking at numbers on a spreadsheet. I really started to understand, for the first time, what was really going on, how these hospitals were dealing with these challenging situations because there's no bigger emergency in a hospital, and Steve, who we're going to hear from, we talk about this, but Steve has a great line about how when an in-hospital cardiac arrest occurs, that patient automatically becomes the sickest person in an institution and yet, we haven't set up systems that really build on how to handle that in the most consistent and positive way.

Dr Carolyn Lam:                Oh, my goodness, I just love that line! Now, you have to tell us, so what's the secret? What's the secret of the succeeding hospitals?

Dr Brahmajee Nallamothu:          What we found in general was, that resuscitation teams at top-performing hospitals really demonstrated the following features. They had dedicated or designated resuscitation teams. They really included the participation of diverse disciplines as team members during the in-hospital cardiac arrest. There were really clear roles and responsibilities of the team members that were set up right from the front.

                                                There was better communication and leadership, actually, during these events and finally, in the training aspect, one of the unique things we found was, the top-performing hospitals seem to have a high rate of in-depth mock codes, that they used as strategies for getting their clinicians ready for these events.

Dr Carolyn Lam:                As you were speaking I was just thinking through the experiences of in-hospital cardiac arrests that I've encountered, and you're right. These elements, though we don't talk about them much, make a huge difference. Steve, I am so curious about your outlook. I mean you must have attended a kajillion CPRs as chair of the CPR committee. Tell us, what do you think is the take home message for clinicians and hospitals?

Dr Steven Kronick:           My field is in emergency medicine and as chair of the CPR committee, I have responsibility of overseeing how we respond to cardiac arrests in our hospitals. I think that many institutions spend a lot of time and effort looking at in-hospital cardiac arrests are managed, and how to improve on it. We're able to use data to help compare ourselves to similar institutions, but beyond the bottom line of either ROSC or survival to discharge, we've most relied on process measures to figure out what we're doing.

                                                We're essentially flying blind, or at least not flying in any sort of formation when we do that. I think that this study validates some of the operational aspects of the arrest response, for those centers who use those and can help other decide where they want to direct their efforts. I think a good example that Brahmajee brought up, is this distinction we found between the use of dedicated teams, designated teams, or not having any organized team, and the impact that has on survival.

                                                The use of these teams can mean significant use of resources but showing that it's associated with better outcomes help provide support for that concept and for those centers who might already use one of those models, it helps them to steer their efforts to improving the delivery or the efficiency of that model.

Dr Carolyn Lam:                Yeah, and indeed. Congratulations to both of you, Steve and Brahmajee. I do think that these are novel contemporary data, at least the first that I know of. Sana, you handle the paper and recognize this. Could you tell us a little about what you think are the novel and important aspects?

Dr Sana Al-Khatib:            I really have been a fan of this paper from the get go and yes, it doesn't have the quantitative analysis that the statistical modeling, most of us are used to. It is a qualitative study, but I think that gives it strength. It makes it unique. This type of research, it can really only be effectively done through a qualitative study that really has all the important aspects of a good qualitative study, so I do want to congratulate them. Clearly, a lot of work went into this, and I appreciate all their efforts.

                                                In terms of the main findings, some of us might look at this data and say, well it's not surprising that those are the characteristics, or the features, of the top performing hospitals, but I felt like it was great, in terms of how the data were presented. Encouraging hospitals to adopt this. Giving them almost like a checklist of what they need to be doing to improve the outcomes of their in-hospital cardiac arrests, in terms of ensuring that they have designated resuscitation teams.

                                                The whole idea about diversity of participants in these arrests, and making sure everyone has a clear role and responsibility. The whole idea of making sure that somebody takes leadership and you have clear and very good communication among the different people who are doing this and great training. In fact, these people were doing in-depth mock codes. I think that spells it out very nicely and gives a lot of the hospitals, hopefully, action items that they can implement to improve the outcomes these patients. I love this paper.

Dr Carolyn Lam:                Sana, I love the way you put that. Checklist, and you know what I was thinking as Brahmajee and Steve were talking earlier? I was thinking blueprint, almost, of the things that we should have. So Steve, could I ask your thoughts. I mean, are you going to put some of these things into practice in your own committee and how?

Dr Steven Kronick:           There are a variety of things we can do. Some of these things are a pretty high-functioning place, but still looking at recommendations that have been laid out and how we help modify those things. Though the example is the roles that people play at an arrest. We can certainly improve on assigning those roles, how people work together as a team, and then also, getting to work more as a team, so that when they are called upon to perform those duties, they can do it in a more coordinated way.

Dr Carolyn Lam:                How beautifully put. I'm going to steal a couple of minutes at the end of this podcast. I really have to because it's so rare to have Brahmajee on the line today and he's the Editor-in-Chief of Circ: Cardiovascular Quality and Outcomes. Brahmajee, could I ask you to say a few words to our worldwide audience about your journal?

Dr Brahmajee Nallamothu:          We are a kind of daughter journal to Circulation. We are a bit more unique than the others, in the sense that we aren't disease or subspecialty focused. We deal with, broadly, the issues around outcomes research, health services research, quality of care research, and really health policy. We publish an issue once a month. We have a broad interest in things that are really relevant to the community around outcomes research and health services research.

                                                I will say that I really appreciate this because of the worldwide audience and reach, one of the big issues we've been very interested in is expanding our reach, from the United States to other parts of the world, and in fact, last fall, we had a global health issue, which was well received, and we received papers from across the world.

                                                In fact, every paper in that issue was a non-US-based paper, and it touched on a number of things from issues around healthcare utilization in Asia to demographics and disease registries in Africa, and it was a wonderful experience, so I think it's a journal that we're excited about.

                                                It was first launched by Harlan Krumholz, who has set a high bar and standard for us, and I think that my editorial team, which has been fantastic, has continued with that work. We would love to see papers from your readers and your listeners from across the world and excited about what that journal is going to be doing in the next five years.

Dr Carolyn Lam:                Oh wow! That's so cool! Well listeners, you heard it right here, first time on Circulation on the Run. Thank you so much for joining us today. Don't forget to tune in again next week.


Jul 2, 2018

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. 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
Dr Joe Hill: Thank you, Carolyn. As I hope our readers are aware, Circulation is a global
journal with a global footprint. We have editors distributed around the world in
16 countries and 10 time zones. And importantly, those editors all have an
equivalent role at the leadership table. Part of the reason for this is because
cardiovascular disease is now, as we are all aware, a global scourge. There are
no more final frontiers for cardiovascular disease. That said, the manifestations
of cardiovascular disease differ in different parts of the world. In the developed
world, and the developing world, for example, the way cardiovascular disease
manifests itself can be very different. And at the same time, the way in which
the disorders are tackled are different. The way we tackle heart disease in the
West can be different than it is in the East, for example. And there are
important initiatives that have emerged in different pockets of the world, best
practices that we need to understand better. What can we all learn from the
way in which cardiovascular disease manifests itself around the world and it's
being addressed around the world?
Dr Carolyn Lam: Joe, you had me at hello. I remember that when you first took over as Editor-in -
Chief and I heard you say this, I was just floored, because coming from
Singapore and all our listeners out there in Japan and China, we just really
appreciate that global outlook. So thank you, on behalf of us all. Tell us a bit
more about this new initiative then for the journal.
Dr Joe Hill: I will tell you in broad strokes, that Paul Armstrong, a noted clinical trial is from
Canada, who is a household name in the cardiovascular world, he and I cooked
up a scheme that Paul will describe, where we will reach out on a regular basis
for insights from various different countries, ultimately, circling the globe
progressively over time. And I will defer to Paul to tell us more about the
Dr Paul Armstrong: Carolyn, it's an exciting initiative and as someone a little long in the tooth, but
still believing that you can teach an old dog new tricks, I would point out that
Circulation is almost 70 years old, and it has staying power. And one of the
reasons that it has staying power is because it is capable of reinventing itself,
and so I was attracted to help out again, from the editorial process, given Joe's
vision and leadership and the excitement around the reinvention that you've
described, to get involved with this initiative. And I was inspired, of course, by
the fact that those of us who do clinical trials appreciate that a lot of different
ideas, a lot of different cultures and perspectives are brought to a collaborative
table. And I'm thinking back now, Carolyn to three years ago, when you and I
first met enjoying courses as part of a trial in heart failure, which involves 43
countries, 800 sites, it will be 5000 patients centers, we've traveled separately
and together around the world, convincing people that there are unmet needs
in heart failure and other parts of cardiovascular disease, we learned that the
approach to standard of care, the rigor which is applied, the exquisite
sensitivities around differences that are meaningful, and the tricks that some
investigators and countries use that we can all I think, learn from has been very
So I think in this initiative, we want to have thought leaders. And we've already I
think, commenced and have two outstanding leaders from Japan and India to
come forward in the first two quarters of this initiative. Tell us about the
regional epidemiologic features, cardiovascular disease in their regions, what
the most important challenges are, what their best practices are, that you're
alluded to, who provides cardiovascular care and what the impediments are to
progressing because we think if we listen and learn as essentially knowledge
brokers, because welcome to Circulation, we can facilitate raising the level of all
of the boats in the water and potentially make new partnerships and do a better
job. So I'm excited about this. I'm delighted that Joe was receptive and really
look forward to working with him and some of these terrific people around the
world, you included who brings such a unique and important perspective from
which we can all learn.
Dr Carolyn Lam: Oh, I love that so much Paul. Thanks for putting it that way. International
knowledge brokers, that's what we hope to be. Isn't that fabulous, just an
opportunity to learn from each other, everybody having stuff to bring to the
table? Tell us a bit more though, what are you looking for in these papers?
Dr Paul Armstrong: We have some guidelines. But as Joe insists we're not going to be formulaic.
We're going to allow diversity of approaches. We're going to invite a thought
leader and hope that that thought leader might invite one or two others, we
want to limit it to three co-authors. We want obviously some insights into how
cardiovascular health professionals are being trained, what research
infrastructure exists, and how they access the literature, how do they read
Circulation, how do they read other journals, and are there collaborative ideas
that they've developed to their neighbors to the East and West that may be
could be broadened? Are there unmet needs that they've indicated similar or
different from those in Western Europe, South America? We've got about seven
or eight points of light that we hope to illuminate in the course of this exercise.
And the prospectus that's laid out in an editorial that Joe and I collaborated on
that I believe, Joe, is going to come out in early July.
Dr Joe Hill: That's exactly right, Paul. And I would just echo exactly what you said that just
the opposite of a formulaic, cookie cutter approach. We want to leverage the
beautiful diversity of our world. The different approaches that people take to
attack this scourge that is keeping a humble approach to tackle instead of the
visas that is humbling bar none. There is nothing that is more globally important
than the continued growth and expansion of cardiovascular disease. And
importantly, we can all learn from each other. There are exciting initiatives that
I've learned about in South America and in pockets of Europe and in Asia, and in
the Middle East that we can all benefit from, and we want to shine a bright light
on that. These pieces will be relatively short. They will be in our Frame of
Reference section, so 1200 words or so, so that they are accessible so that
people, you know, feel that they can carve out, you know, four minutes in their
busy day to read what cardiovascular disease looks like, as Paul said, our first
ones will be from Japan and India, and we plan to reach out to South America
and to the Middle East, and just continue on around until over the course of the
next number of years, we've touched virtually every country in the world.
Dr Carolyn Lam: And that's huge. And are there any specific types of cardiovascular disease that
you might be looking to focus on?
Dr Joe Hill: You know, I don't think so. One of the points that I have made and learned is
that in the West, in the developed world, cardiovascular disease increasingly has
become a chronic disorder where more and more people, over the course of the
last six years are surviving their acute coronary syndrome, their tachyarrhythmia
events, and they are developing chronic disorders like heart failure, whereas in
the East, it is the atherothrombotic manifestations that have both MI and stroke
that are expanding rapidly. So given that the face of cardiovascular disease is
different in different parts of the world, different strategies have to be
leveraged to address that, and we want to learn about that.
Dr Carolyn Lam: I would love to have you both come talk again, when we receive some of these
papers and just reflect on the things that we're learning. Paul, did you have
anything else that you wanted to add?
Dr Paul Armstrong: I think, Carolyn that hits the high spots. I suppose we should mention diabetes
and obesity and the expanding epidemic that seems to effect some regions such
as India, in the Middle East, even more than other areas, but I think this is going
to be great. We're gonna have some fun and learn and exciting and hopefully it
will catalyze better care and better thinking around this enemy that we all face.
Dr Carolyn Lam: Listeners. You heard it right here, Circulation on the Run. I'm sure you're excited
as I am about this. You have to read the editorial. It's a fantastic read.
Thanks for joining us today. And don't forget to tune in again next week.