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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: November, 2016
Nov 28, 2016

 

Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion today is about the validation of a novel biomarker-based stroke risk score for atrial fibrillation, the ABC stroke score. But first, here's your summary of this week's journal.

 
 
The first paper provides experimental insights into endothelial nitric oxide synthase uncoupling in endothelial dysfunction. In this paper by first author Dr. Lee, corresponding author Dr. Wong and colleagues from Qilu Hospital of Shandong University in China, authors assessed endothelial function in animal models of hyperglycemia, hyperhomocysteinemia, and a dyslipidemia. They demonstrated that GTP cyclohydrolase 1 is the target of the microRNA-133a and that it's a topic expression and endothelial cells mediates endothelial dysfunction.

 
 
Furthermore, Lovastatin up-regulated GTP cyclohydrolase 1 and tetrahydrobiopterin and re-coupled endothelial nitric oxide synthase in stress endothelial cells. These actions of Lovastatin were abolished by enforced micro RNA 133A expression and mirrored by a mir-133a-antagomir. Finally, the beneficial effect of Lovastatin in mice were abrogated by in vivo mir-133A over-expression or by GTP cyclohydrolase 1 knockdown. In summary, this paper offers a mechanistic basis for targeting micro RNA 133A as a therapeutic approach to correct endothelial nitric oxide synthase dysfunction. It also provides further support to the role of statins in combating endothelial dysfunction.

 
 
The next study shows us that in hypertrophic cardiomyopathy, calcium mishandling may be the potential link between the primary genetic cause and downstream signaling cascade that leads to hypertrophy and arrythmias. In this study, Dr. Helms and colleagues from University of Michigan analyzed gene expression, protein levels and functional essays for calcium regulatory pathways in 35 human hypertrophic cardiomyopathy surgical samples with and without sarcomere mutations and compared that with 8 control hearts. They found a marked reduction in circa2 abundance, which correlated with reduced circa2 function in hypertrophic cardiomyopathy compared to controlled hearts regardless of the underlying genetic etiology.

 
 
However, calcium calmodulin depend protein kinase type 2 or cam2, which is a calcium sensing kinase, was deferentially activated only in the sarcomere gene mutation positive samples. Activation of chem kinase 2 was associated with an increase in phospholamb and phosphorylation in hypertrophic cardiomyopathy. However, neither calcineurin MRNA nor MEF2 activity was increased, suggesting that calcineurin pathway activation was not an upstream cause of increased chem kinase 2 protein abundance or activation.

 
 
In summary, this paper demonstrated that calcium mishandling occurs through both genotype specific and common pathways in human hypertrophic cardiomyopathy. Post-translational activation of chem kinase 2 pathway is specific to sarcomere mutation positive hypertrophic cardiomyopathy. While Sarco 2 abundance and sarcoplasmic reticulum calcium uptake are depressed in both sarcomere positive and negative hypertrophic cardiomyopathy. Thus, chem kinase pathway inhibition may improve aberrant calcium cycling in hypertrophic cardiomyopathy. This is discussed further in an accompanying editorial by Dr. Jill Tardiff.

 
 
The third study suggests that in patients with a dilated aortic route and trileaflet aortic valve, a ratio of aortic route area to height provides independent and improved stratification for prediction of death. First author Dr. Masry, corresponding author Dr. Desai and colleagues from the Center for Aortic Disease, Heart and Vascular Institute of Cleveland Clinic, studied consecutive patients with a dilated aortic route of greater or equal to 4 centimeters who underwent echocardiography and gated contrast enhanced thoracic aortic computer tomography or magnetic resonance and geography between 2003 and 2007.

 
 
A ratio of aortic route area over height was calculated on tomography and a cutoff of 10 squared centimeters per meter of height was chosen as abnormal. In 771 patients with trileaflet aortic valve and concomitant aortopathy, there was incremental prognostic value for indexing aortic route or ascending aortic area to patient height rather than using an unindexed aortic diameter. Incorporation of the ratio significantly and independently reclassified the risk for death and at normal ratio was independently associated with higher long-term mortality while cardiovascular surgery was associated with improved survival. Importantly, a sizable minority of patients with aortic route diameters between 4.5 and 5.5 centimeters had an abnormal aortic route when indexed to height ratio. 78 percent of deaths in this subgroup occurred in those with an abnormal aortic route area to height ratio. Findings were similar when ascending aortic measurements were considered. The take home message is that an aortic route area to height ratio above 10 squared centimeters per meter of height has significant and independent prognostic utility and may be used to re-stratify patients with trileaflet aortic valve and a dilated aorta.

 
 
The final study provides pre-clinical data to show that Ticagrelor reduces cardio damage post myocardial infarction to a greater extent than Clopidogrel by an adenosine induced organ protective response. First author Dr. Villaher, corresponding author Dr. Bademan and colleagues from the Cardiovascular Research Center in Barcelona, Spain studied a close-chest swine model of ischemia reperfusion in which myocardial infarction was induced by 1 hour balloon occlusion of the mid-left anterior descending coronary artery followed by 24 hours of re-flow. Prior to occlusion, the animals were randomly assigned to receive either placebo, a loading does of Clopidogrel, a loading does of Ticagrelor or a loading does of Ticagrelor followed by an A1 A2 receptor antagonist. Edema infarc size left ventricular size and left ventricular function were assessed by three T cardiomagnetic resonance imaging. Inhibition of platelet aggregation was the same between the groups receiving a P2Y-12 inhibitor.

 
 
Yet, Ticagrelor reduced infarc size to a significantly greater extent than Clopidogrel, reducing it by a further 23.5 percent, an effect supported by troponin eye assessment and histopathological analysis. Furthermore, compared to Clopidogrel, Ticagrelor significantly diminished myocardial edema by 24.5 percent, which correlated with infarced mass. Administration of an adenosine A1 A2 antagonist abolished the cardio protective effects of Ticagrelor over Clopidogrel. At a molecular level, aquaporin 4 expression decreased and the expression and activation of AMP kinase cyclin and COX-2 increased in the ischemic myocardium of Ticagrelor versus Clopidogrel treated animals. In summary, this study shows that Ticagrelor exerts cardio protective effects beyond its anti-platelet efficacy by adenosine dependent mechanisms, which reduce necrotic injury and edema formation. This is discussed in an accompanying editorial by Drs. Gerbel, Jung and Tantry. That wraps it up for the summaries. Now for our feature discussion.

 
 
Today, we are going to be discussing the performance of the ABC score for stroke in atrial fibrillation. And as a reminder for all our listeners there, ABC stands for A for age, B for biomarkers, that's NT-proBNP and high-sensitivity troponin, and C for clinical history of prior stroke. And again as a reminder, this risk score was originally derived in the Aristotle trial. However, we have new results about its performance and validation today from first and corresponding author Dr. Jonas Oldgren from Uppsala Clinical Research Center in Sweden. Welcome, Jonas.

 
Speaker 2:
Thank you very much.

 
Carolyn Lam:
We also have today the associate editor who managed this paper, Dr. Sandeep Das from UT Southwestern. Hi Sandeep.

 
Speaker 3:
Hi Carolyn, thanks for having me.

 
Carolyn Lam:
So Jonas, could you start off by telling us why you did this study and what you found?

 
Speaker 2:
We did this study to validate the recently derived ABC stroke risk score. We have had risk scores for predicting stroke in patients with atrial fibrillation derived since the late 1990's and refined later on. But those risk scores have only used clinical markers for risk. We have for several years developed new risk prediction models with biomarkers and now we are combine them in a very simple biomarker based risk score, taking into account age as a clinical variable and the clinical history of prior stroke and only two common used biomarkers. And by that we can predict the risk of stroke with better precision than previous clinical risk scores.

 
Carolyn Lam:
Yeah, I like what you said. I mean it is literally as simple as ABC. So tell us how you validated it and what you found.

 
Speaker 2:
It was derived in a large cohort of patients participating in a clinical trial with new or relapsed coagulant compared to Warfarin and we now validated in almost a full size group participating it another clinical trial. So we have large data sets of very well described patients where we have good outcome data. Very solid data to rely on. Now we can see that the ABC risk score is now validated but the good precision and good collaboration of the discriminatory abilities is high and better than the previously used clinical risk scores.

 
Carolyn Lam:
Could you give us some numbers behind that that are clinically meaningful? Everyone's going to be wondering compared to the chads-vasc score for example, how does this ABC score perform in that validation test set?

 
Speaker 2:
We can adjust that by several different aspects. One is of course to calculate the C index which is a statistical method to see how good we can predict risk and the C indices for the ABC stroke score both in the duration and now in the validation cohort is higher than for the chads-vasc and atrial risk scores. But we can also look at what we have in this paper in circulation ... we can look at predicted outcome rates and observed outcome rates and can see that they clearly overlap both in the duration and validation court. So if you predict a risk that is less than 1 percent per year, it is observed also a risk that is less than 1 percent a year. Does this always ... the thing is when you derive risk or but when you validate it in another cohort, you need to show that it's a similar result.

 
Carolyn Lam:
Yeah, that's true. Sandeep, you are managing this paper. It's very important. How do you think that clinicians should be taking the results?

 
Speaker 3:
I think that clearly using anticoagulation and selected patients at high risk for stroke with atrial fibrillation is one of the best things we do in cardiology. You know in terms of reducing the risk of an important harm to patients. I think there's a fair bit of dissatisfaction out there with currently sort of standard, which is chads-vasc. Especially in people with a chads-vasc ... men with a chads-vasc of 1 or women with a chads-vasc of 1 to 2 where there's a bit of struggling over how to decide. So I think that one real advantage of this score in addition to the fact that it predicts better by the higher C statistic, which is fantastic and pretty uncommon, right? Lars sort of buried the lead a little bit by not emphasizing that it's relatively rare that we're able to move a c statistic by a point of 5 in the modern era.

 
 
But the other thing is that it helps give us an ability to come up with good estimates in people at low risk, which I think has been a challenge and something that people are a little concerned clinically. So I think that this is easily available, biomarkers that we routinely check all the time and it doesn't have the sort of gender challenge with chads-vasc where you're trying to figure out whether your low risk woman really needs to be on Warfarin or anticoagulation. So I think that it has a lot of clinical utility right out of the box, which is nice.

 
Carolyn Lam:
Actually, Jonas could you let us know is there any sex differences in the performance of the score?

 
[00:14:46]

Speaker 2:
 

There are no differences in the performance of the score. So we looked ... the advantage of this score is when we derived it in the original model, we looked at all important clinical and biomarker risk factors and we can see that these were the foremost interesting markers. So we only used those. So we can predict much better and as pointed out so nicely by Sandeep, for patients at the lower end of the risk spectrum, we can find patients or have higher or lower risk even within patients with chads-vasc 1 or chads-vasc 2. And I think it's also important to see what about patients at higher risk despite proper anticoagulation. We did not know how to treat them but in the future we might perhaps tailor treatment also for those patients with residual high risk of stroke despite proper anticoagulation treatment. For instance, if the left atrial appendage occluded devices are shown in the future to be a good option for those patients, we can find them also by this risk score. So both in the higher and lower end of the risk spectrum.

 
Carolyn Lam:
That's a really good point. On that note, I'm just curious. What do you think is in the future? What more knowledge do we need to address before we put this into practice or are you already using this? Or do you think it should enter guidelines for example? Maybe Sandeep, I could ask for your opinion first.

 
Speaker 3:
We see a lot of biomarkers associated with increased risk kind of studies come out in the literature. You know probably every week you see several of these things come out. So what's really interesting about this is that it's obviously methodologically extremely well done but its been derived and validated in two large cohorts, which is pretty much best practice right? You want to see people validate these risk scores in large and distinct cohorts of patients to build up sort of clinical validity to the reader or consumer. So I think, from my standpoint, this is ready for prime time. I'm really intrigued by the fact that biomarkers, especially troponin, are predicting stroke in this population and there have been some observational reports out there that have showed an association between troponin and increased risk of stroke or worse outcomes after stroke. So I'd be really curious as to what Jonas thinks about why troponin would be predictive of stroke in this population.

 
Speaker 2:
We were extremely intrigued by the finding when we first did those single observations of only troponin as a risk marker because we know that troponin is a very specific protein found in the myocardium. But the clinic predicts risk for stroke also and there are several explanations but they are mainly hypotheses about aging and myocardial function really to identify patients of risk. But the clear cut explanation is still not there.

 
Carolyn Lam:
It's likely that these biomarkers are incorporating aspects that we don't fully understand, which is why they are better predictors isn't it? I mean to your point Sandeep.

 
Speaker 3:
Yeah, no absolutely. And I think that's great.

 
Carolyn Lam:
Exactly. It really opens a lot of other questions that need to be answered in the meantime. Jonas, any other last words about how you may be applying this clinically in your own patients?

 
Speaker 2:
We have no solid data supporting the use of this clinical risk score and as already pointed out, which I think is very good, all clinic risk scores should of course be in the best world validated as useful decision support truth and really in clinics trial seeing that they improve outcomes. This is to my knowledge never been down with a clinical risk scores. We have never used them prospectively to guide treatment and to improve outcomes. Actually, we are aiming to do that. We hope to start a clinical trial next year with ABC score guided treatment compared to standard of care. But it's a very huge undertake of course to that we can improve treatment by risk or guided management.

 
Carolyn Lam:
That's excellent. So remember everyone, you heard it right here. A new trial that they're engaging. I really congratulate you first for this study, as well as this future efforts which are clearly going to be very important.

 
 
Thank you very much both of you for joining us today and thank you listeners for listening. Don't forget to tune in next week.

 

Nov 21, 2016

Carolyn:
Welcome to circulation on the run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. [Carolyn Nam 00:00:08], associate editor from the national heart center and Duke National University of Singapore ...

 
 
In just a moment we will be discussing the exciting new results of the [Prague 00:00:21] 18 study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. But first, here's your summary of this week's issue ...

 
 
The first study represents the largest published study on the association between PR interval and cardiac resynchronization therapy with defibrillator versus implantable cardioverter defibrillator and real world outcomes. Dr. Friedman and colleagues from Duke Clinical Research Institute studied 26,451 CRT eligible patients from the National Cardiovascular Data Registry ICD Registry. They found that a PR interval at or above 230 milliseconds was associated with increased rates of heart failure, hospitalizations, or death among CRTD but not ICD patients. The real world comparative effectiveness of CRTD versus ICD was significantly less among patients with a PR interval above 230 milliseconds compared to patients with a shorter PR interval.

 
 
The authors discuss that these findings may be due to the association between a prolonged PR interval and factors associated with lower rates of CRT response such as non-left bundle branch block morphology, ischemic heart disease, or atrial arrhythmias. It could also be due to the association between delayed AV conduction, disordered diastolic filling, and contemporary CRT reprogramming strategies. The take home message is: in CRT patients with a prolonged PR interval, recognize that they are at high risk for poor outcomes and merit close follow up and consideration of AV optimization ...

 
 
The next study is the first adolescent study of serum lipidomics that identifies a new panel of serum glycerophosphocholines that are associated with cardiovascular risk. First author Dr. [Sine 00:02:29], corresponding author Dr. [Palsova 00:02:31], and colleagues from Hospital for Sick Children in University of Toronto recognize that atherogenic dislipidemia is traditionally assessed with high abundance lipids, such as cholesterol and triacylglycerols, which accumulate at millimolar levels in blood. Current advancements in mass spectrometry now allow the discovery and study of new low abundance lipids, which circulate at micro- or nanomolar blood levels. And one such example are the glycerophosphocholine metabolites.

 
 
They studied a population based sample of 990 adolescents with age range 12-18 years using liquid chromatography electrospray ionization mass spectrometry. They identify several novel glycerophosphocholines that were associated with multiple cardiovascular disease risk factors. Mediation analysis revealed that these novel glycerophosphocholines mediated their respective relationships between visceral fat and cardiovascular disease risk factors. Furthermore, a particular glycerophosphocholine shown recently to predict incident coronary heart disease in older adults was already associated with several cardiovascular disease risk factors in these adolescents.

 
 
The clinical implication is that the development of a lipidomics signature that could facilitate early intervention or treatment of those at high risk of cardiovascular disease or monitor response interventions could help triage limited healthcare resources. Furthermore, future research on glycerophosphocholines might improve biological understanding of disease and identify potential drug targets to impede cardiovascular disease development ...

 
 
The next study also describes plasma lipidomic profiles but this time in patients with type 2 diabetes. This study is from first author Dr. [Elchuri 00:04:35], corresponding author Dr. [Meekly 00:04:37], and colleagues from the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. These authors performed a targeted lipidomic analysis using liquid chromatography electrospray ionization tandem mass spectrometry in a case cohort of 3,779 patients with type 2 diabetes and one or more additional cardiovascular risk factors from the advance trial.

 
 
They found that sphingolipids, phospholipids, cholesterol esters, and glycerol lipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model of 14 traditional risk factors and medications improved the prediction of cardiovascular events. The prediction of cardiovascular death was also improved with the incorporation of 4 lipid species to the base model. These results were further validated in a subcohort of type 2 diabetes from the lipid trial. In summary, this important study demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes ...

 
 
The last study sheds new light on the optimal ablation method for atypical atrioventricular nodal reentrant tachycardia or atypical ARNVT. Dr. [Catrisis 00:06:10] and colleagues from Beth Israel Deaconess Medical Center, Harvard Medical School in Boston, Massachusetts study 2,079 patients with AVNRT subjected to slow pathway ablation. In 113 patients, atypical AVNRT or coexistent atypical and typical AVNRT without other concomitant arrhythmias was diagnosed. Ablation data and outcomes were compared to a group of age and sex matched control patients with typical AVNRT. The authors found that in the atypical group slow pathway ablation was accomplished from the right septum in 110 patients and from the left septum in 3 patients. There was no need for additional ablation lesions at other anatomical sites and no cases of AV block were encountered.

 
 
In summary AVNRT, regardless of the type, appears to be successfully ablated by targeting the anatomic area of the slow pathway. When a right septal approach is not successful, the anatopic area of the slow pathway can be ablated from the left septum and so it seems the slow pathway participates in both typical and atypical AVNRT. The take home messages are that catheter ablation at the anatomical area of the slow pathway from the right or left septum may be the treatment of choice for atypical AVNRT. The approach is not associated with an increased risk of inadvertent AV block. The recurrence rate following ablation of atypical AVNRT may not be significantly higher than that seen following the ablation of typical AVNRT.

 
 
Those were the highlights from this week's issues. And now for our feature paper ...

 
 
We're so pleased to have with us today for our podcast interview first and corresponding author of the Prague 18 study, Dr. [Zuzana Motovska 00:08:12] from Charles University in Prague. Welcome Zuzana.

 
Zuzana:
Thank you for having me.

 
Carolyn:
We're also so lucky to have Dr. [Gabriel Stig 00:08:21], associate editor from Paris, and I understand you're even traveling at the moment. Thank you, Gabriel for making the time.

 
Gabriel:
Yes, hello Carolyn, hello Zuzana.

 
Carolyn:
So let me start by congratulating you Zuzana on this first head-to-head comparison study of prasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary or cutaneous coronary intervention. And what a lovely study acronym of course, Prague 18. Could you maybe start by describing, in the Czech Republic before your study, how were clinical decisions being made between prasugrel and ticagrelor in these patients?

 
Zuzana:
The current guidelines prefer newer P2Y12 inhibitors over clopidogrel for patients with acute coronary syndromes. Prasugrel and ticagrelor are being increasingly used in patients [with just 00:09:15] primary PCI in Czech Republic. Analysis of our registry documented that doctors did not view these two drugs as interchangeable and prasugrel is a drug associated with a high risk of bleeding. Our data show that safety in terms of bleeding risk was the most important aspect under consideration when choosing one of new agents for an individual patient. The same observation has been reported from other contemporaries from other countries and according to the published subgroup analysis of [stratum 00:09:54] and other studies we have also perceived prasugrel to be a more effective agent for primary PCI. We prefer this drug in patients with a high thrombotic risk.

 
Carolyn:
Could you, maybe now, clearly describe what you did in this study and what were your findings?

 
Zuzana:
The Prague 18 study truly [inaudible 00:10:19] was designed to test the hypothesis on whether one of the newer drugs, prasugrel or ticagrelor, is more effective and safer than the other one in acute myocardial infarctions, which is the primary [treatment 00:10:36] strategy. We randomized the total 1,230 in 14 participating sites. I highlighted hemodynamic instabilities, was not an [excluding 00:10:52] criterion for study participation. The patients were randomized for prasugrel or ticagrelor immediately on hospital arrival and the recommended dosing regiments were used for both drugs. The prasugrel dose was reduced during the maintenance phase in patients over 75 and [reduced vein 00:11:12] was the [sixth 00:11:14] feature around presence of both these parameters was an exclusion criterion.

 
 
So, what we find. Fewer [unsourced 00:11:23] primary endpoint composed of all cause of death or reinfarction show serious bleeding or urgent vessel revascularization within 7 days after randomization or discharge if prior to the seventh day. They did not differ between groups, either for in 4 person prasugrel group and in 4.1 person in ticagrelor group. The appearance of key secondary end point composed of cardiovascular death, nonfatal MI, or nonfatal stroke. Within 30 days did not show any significant difference between prasugrel and ticagrelor, furthermore no significant difference was found in any of the components of the primary and secondary endpoints and also no significant difference was observed in the appearance of definite vein thrombosis [inaudible 00:12:17] days after randomization.

 
 
So the study did not show any difference between ticagrelor and prasugrel in the early phase of a mild [treatable 00:12:26] primary PCI. Because of small sample size the confidence for the estimation of the [interval 00:12:35] of either were quite high, however we identify differences, which are very low in absolute numbers and [inaudible 00:12:45]

 
Carolyn:
That was very nicely explained Zuzana, thank you. Now could you share a little bit more about, were you powered for this analysis and the decision to stop early.

 
Zuzana:
Oh yes, the power analysis was computed for primary endpoint difference of 2.5 person and the needed sample size was estimated at 2,500 patients. The interim analysis led to a decision to terminate the study prematurely because of futility. No significant difference in primary endpoint was found between the two study drugs in the course of the entire randomization process, moreover the difference in appearance of the primary endpoint between the compare groups was declining with a growing number of randomized patients and analyzed on the different 0.1% and this was the decision why we stopped the trial prematurely.

 
Carolyn:
Right. Gabriel could you comment a little bit as the associate editor managing this paper, how do you think it's going to impact practice?

 
Gabriel:
First of all, let me start by congratulating Zuzana and the team of the Prague 18 trial for this academic trial. I think it's really important that we have a clinically led effort to investigate optimal treatments in modern cardiology in general and specifically in acute coronary syndromes. We've known for several years now, through large randomized trials, that the novel P2Y12 agents, ticagrelor and prasugrel, are clearly superior to clopidogrel but we don't know which of the two agents to choose and we know that comparison across trials are fraught with major methodological problems. So with evidence that prasugrel is superior to clopidogrel for PCI treated ACS patients, there was evidence that ticagrelor was superior to clopidogrel for ACS patients in general but we didn't have any rational data on which to base a rational selection process between the two agents.

 
 
Really, I think it's an important issue and often people state that these are delicate differences between agents, and we shouldn't expect that this is going to impact clinical outcomes. Actually it does impact clinical outcomes because we know that those novel agents have had a roughly 20% reduction in major heart outcomes compared to clopidogrel so this is not a moot point. It's not a minute difference, it's a huge difference and it's an important clinical issue. That's my first point, I think it's an important question and I really want to commend the investigators for launching this trial despite not having the support of industry.

 
 
The second point I want to make is I think that the results from the trial are not yet complete because we don't have the one year follow-up and I know that this is planned and the investigators are continuing follow-up of their patient cohort, which I think is going to be important because it's conceivable that differences may emerge over time as was, in fact, the case in some of the previous trials. In [plato 00:15:49] there was a modest difference early on but the curves diverged over time between clopidogrel and ticagrelor so it's conceivable that differences that are absent at 30 days might emerge over time.

 
 
In fact, I have a question for Zuzana. One of the interesting features and important issues that needs to be addressed is ... I know that in some sites in the Czech Republic, because of the out of pocket expenses related to the cost of the novel agents, it was allowed for patients to be switched back to clopidogrel after hospital discharge. Do you have any sense of what is the proportion of patients who are scaled back to clopidogrel instead of prasugrel or ticagrelor after initial index submission?

 
Zuzana:
Thank you Gabriel, it's true the study ... a lot of patients who are unable to bear the cost associated with long term treatment with the study medications and switch to clopidogrel. Therefore, a second goal of the study was to assess the rate, the reason, and also the consequences of switching from a study drug to clopidogrel after the acute phase in the course of 12 months follow-up. We are not focusing on the study completion and analysis that are related to the second study. There are, of course, patients who switch from prasugrel or ticagrelor to clopidogrel also in first 30 days and this proportion was about one third of patients.

 
Gabriel:
The other point I want to make really relates to the power issues and Zuzana already pointed out herself this important issue. The paper is actually accompanied by an excellent and very cogent editorial by Steve [Webiok 00:17:31], who discusses explicitly and in great detail the issue of sample size. We know that the relative difference between the novel agents and clopidogrel is in the range of 20% so we might expect that the difference between the two novel agents themselves, when we compare prasugrel and ticagrelor, might be less. Yet the study was powered for actually a greater relative risk reduction than what was seen in the pivotal trials of prasugrel and ticagrelor compared to clopidogrel. So the study is really on the low end of the power spectrum and I think, as you pointed out Zuzana, it's important to keep in mind that the confidence interval for the relative risk between ticagrelor and clopidogrel both act together on prasugrel, both for the primary endpoint, which is a combination of efficacy and safety, as well as for the key secondary endpoint of efficacy.

 
 
It's really very wide and we can't rule out a major benefit or a major detrimental effect of one agent versus the other. I think this is important to keep in mind because many people equate a neutral result of a trial, a non-significant result, particularly in the [secondary 00:18:36] trial, with lack of difference or clinical equivalence or non-inferiority and I think it's important to remember the readers that this is not a non-inferiority trial, it's not a clinical equivalence trial, it's superiority trial that is actually with a neutral result. It's really and important issue.

 
 
Yet, because it's the first head-to-head comparison, because it's an academic effort independent, and because it's going to report one year outcomes, I think this is a critical effort and the investigators need to be lauded for that. Even if this study isn't powered, it will be able to be pulled in further meta-analysis with other upcoming studies that are similar that also may be underpowered and provide us with a hint of evidence of what might be the best agent to use, which is an every day clinical question. This is a very, very common condition and any unbiased evidence we can get from randomized trials is very valuable ...

 
Carolyn:
Thank you, everyone, for listening to this episode of circulation on the run. Tune in next week ...

 

Nov 14, 2016

Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In today's podcast interview we will be discussing the ruling in and ruling out of myocardial infarction with the European Society of Cardiology 1-hour algorithm. Stay tuned for a discussion of new data and controversies on this hot topic. Now, here's a summary of this weeks issue.

 
 
The first paper brings us one step closer to the ultimate goal of cardiac tissue engineering. That is to replicate functional human myocardium in vitro. In this study, by first author Dr. Ruan, corresponding authors Dr. Murry and Regnier from the Institute for Stem Cell and Regenerative Medicine and University of Washington, authors recognize that human-induced pluripotant stem cells, or iPSC-derived cardiomyocytes, really provide a cell source for cardiac tissue engineering. However, their immaturity limits their potential applications. Hence, they sought to study the effect of mechanical conditioning and electrical pacing on the maturation of iPSC-derived cardiac tissues.

 
 
They found that after two weeks of static stress conditioning, the engineered myocardium demonstrated increases in contractility, tensile strength, construct alignment, cell size, and SERCA2 expression. When electrical pacing was combined with static stress conditioning the tissue showed an additional increase in force production and further increases in expression of RyR2 and SERCA2. These studies really demonstrate that electrical pacing and mechanical stimulation promote the maturation of the structural, mechanical, and force generation properties of iPSC-derived cardiac tissues and constitute a really important contribution to cardiac tissue engineering.

 
 
The next study is the first large-scale, nationwide, population-based investigation of the association between congenital heart defects and any placental measure. This study by Dr. [Matheson 00:02:27] and colleagues from Aarhus University Hospital in Denmark, included all 924,422 live-born Danish singletons from 1997 to 2011. Congenital heart defects was present in 7,569 newborns. The authors compared the mean differences in placental weight between newborns with and without congenital heart defects and found that only three specific subgroups of congenital heart defects were associated with measures of impaired placental growth. These included Tetralogy of Fallot, double outlet right ventricle, and major ventricular septal defects. In these subgroups, the mean deviations from the population mean head circumference and birth weights were reduced by up to 66%, with adjustment for placental weight. In other words, up to two thirds of the deviations in fetal growth, including fetal cerebral growth, may be related to the impaired placental growth. The present work provides an important contribution to the existing knowledge on the association between congenital heart defects and placental anomalies as well as the possible importance for fetal growth in this population.

 
 
The next study provides an up-to-date evaluation of the cost effectiveness of antibiotic prophylaxis in the prevention of infective endocarditis. In this study by first author Dr. Franklin, corresponding author Dr. Thornhill, and colleagues from the University of Sheffield, the cost effectiveness of antibiotic prophylaxis, namely single dose amoxicillin or clindamycin, in patients at risk of infective endocarditis. They did this using, firstly, recent estimates of the effect of antibiotic prophylaxis on infective endocarditis in the English population; secondly, rates of antibiotic adverse drug reactions; and thirdly, estimates of the probability of developing infective endocarditis following dental procedures derived from French data. All this as foundation for analysis of cost and health benefits.

 
 
A decision analytic cost effectiveness model was used based on the decision model by the National Institute for Health and Care Excellence, or NICE, that was used to inform the 2008 guidelines. The authors found that antibiotic prophylaxis was less costly and more effective than no antibiotic prophylaxis for all patients at risk for infective endocarditis. In fact, if antibiotic prophylaxis was reinstated in England for those at moderate or high risk of infective endocarditis, it could save 5.5 to 8.2 million pounds and result in health gains of more than 2,600 quality-adjusted life years. Antibiotic prophylaxis was even more cost effective for those at high risk of infective endocarditis, being cost effective even if only on 1.44 cases of infective endocarditis was prevented per year. In summary, these updated findings really support the cost effectiveness of guidelines recommending antibiotic prophylaxis use, particularly in high risk individuals.

 
 
The last study provides data on long term cardiac mortality among survivors of cancer diagnosed in teenagers and young adults in the largest population-based cohort to date. Furthermore, the study provided, for the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 to 39 years. For example, survivors of Hodgkin lymphoma, lung cancer, acute myeloid leukemia, non-Hodgkin lymphoma, and CNS tumors experience 1.3 to 3.8 times the population-based mortality rates. This study provides important insight into the cardiotoxicity of the treatments given in the past to teenagers and young adults with each individual type of cancer and importantly, provides an initial basis for developing evidence-based follow up guidelines.

 
 
Those were you summaries. Now for our feature interview.

 
 
Our feature paper today discusses the hot and controversial topic of ruling in and ruling out myocardial infarction with the European Society of Cardiology 1-hour algorithm. I'm so excited to have with us the corresponding author of the paper that really represents the first multi-center external validation of these ESC guidelines for MI and the first multi-centered direct comparison of the performance of the algorithm with high-sensitivity troponin I and high-sensitivity troponin T assays. This would be Dr. Martin Than from Christ Church Hospital in New Zealand. Welcome Martin.

 
Martin:
Thank you very much. It's a great pleasure for me to be able to join everybody and talk here.

 
Carolyn:
It's great to have you. We also have with us the editorialist on this paper, Dr. Allan Jaffe from Mayo Clinic, Rochester, Minnesota. Allen, it's so good to hear your voice again.

 
Allan:
Good to talk to you again too, Carolyn.

 
Carolyn:
Finally, we have Dr. Deborah Diercks, Associate Editor from UT Southwestern. Welcome Deb.

 
Deborah:
Oh, it's good to be here and I'm looking forward to the conversation and what we're going to learn from these two gentlemen.

 
Carolyn:
Absolutely. You know what? I'm going to start with Martin. I love the way to set up your paper. You very correctly pointed out that there's a tension in that ED physicians require really high sensitivity to confidently rule out MI and send patients home, whereas cardiologists do not want high proportion of false positives because we don't want false high risk to lead to invasive testing. I just love, if you could start by telling us how the ESC 1-hour algorithm fits into all this and what you were trying to do in your study.

 
Martin:
I heard Deb Diercks on the phone as well, who's a very respected emergency physician in this area, and I think we would both say that we have a certain bias in our perspective on this, which is of course we are the people at the end of the day that have to send people home when they present with chest pain and possible myocardial infarction. We are also, of course, the people that take the fall if there are any mistakes made. Historically, people have not been very kind to emergency physicians who miss such a diagnosis. It's an extremely high source of medical legal action in the United States and, in fact, worldwide. So we're somewhat paranoid as a speciality about missing cases of myocardial infarction because at the end of the day, the worst thing that can possibly happen is for you to send someone home who comes to harm from the very clinical complaint for which they came to you for help. We want to avoid that at all costs and that was the basis behind us trying to put together this paper.

 
 
Soon after the ESC guidelines come back and I returned from London, where they were announced at the conference, to New Zealand, I received quite a lot of phone calls and correspondence saying, "Okay, we see these new ESC guidelines are out. When are we going to start introducing them?". I immediately wanted to say, "Well, the key thing is to understand how they would work, how they would be implemented, and whether they'd work in my own setting" because if we want to implement them in New Zealand or Australasia, we would want to double-check on that first. That's the basis and the philosophy behind the manuscript.

 
Carolyn:
Tell us what you found.

 
Martin:
As Allan will be the first to point out, I think there are a number of flaws in the data we had available to us that allowed us to do this analysis, but based on the concept that when we've surveyed emergency medicine physicians, the sensitivity that was wanted was at least 99% if not higher. We found that neither of the algorithms produced that level of sensitivity, although the algorithm based on hsTnI was very close. I think it's 98.8%, so that was very good. Reasonably wide confidence intervals on that. The hsTnT algorithm performed slightly less well with a sensitivity around 97%. I guess, if I was to start with an a priori question, which is did we reach a standard of 99%, then our answer to this was, in one case, not quite, and the other case, no, we probably didn't. We said that if you wanted to use a metric of negative predictive value, which I know a lot of people do, then there was actually very good negative predictive value in the high 99 percentage range for both pathways.

 
Carolyn:
Do you mind if I stretch you a little bit and ask you to describe exactly what you did in the cohorts? You were saying that there were some imperfections. Maybe you'd like to tell us a little bit about that.

 
Martin:
Absolutely. As always, when you're writing a paper, you look back and you always feel there are far too many imperfections, but I guess the principle one I would say that's been noted is that we had samples done on arrival and the algorithm itself specifies a [inaudible 00:11:43] one-hour second sample. We didn't have those specimens, so we had to base our data analysis on samples done either at 90 minutes afterwards or two hours afterward. It's clearly not being tested exactly as it was written, although one could argue that that slightly delayed sampling is potentially reflective of real life, where it's very hard to hit a one hour mark in a busy emergency department, and two, where the slight delay in getting the samples would actually allow more time for a troponin to rise and therefore give a chance of providing a better sensitivity.

 
 
I think the other I guess key flaw is that of course, the people present to emergency departments at different time frames following the onset of their symptoms. There's been some valid concern raised that algorithms may not necessarily perform as well in very early presenters. In fact, that is something that's being emphasized now in the ESC guidelines.

 
Carolyn:
Right. Allan, I loved your editorial. You did mention a couple of these points. Would you like to maybe clarify your view of this?

 
Allan:
I think that there are two or three terribly important issues. We all would like to have very facile algorithms. Particularly given removing the high sensitivity, the idea would be gee, wouldn't it be nice to have something really simple that works perfectly? If you look at the validation and the way the algorithm has been put together, immediately there are some concerns that people ought to have and that at least we tried to point out, that were important. One of them Martin has already discussed a little bit, which is one looks at most of the validation studies. There are very few patients who are evaluated very early after the onset of their symptoms. That's a potential problem because the overlap, since they use very low values or very small change, that there could be, with people who have real disease, is in those very early presenters. The initial algorithm from the ESC used both a very low level troponin and a set of change criteria. Actually when they published those criteria, they changed that and eliminated, at least for the first three hours, the very low values. If one looks at Martin's study, it was again, the very early patients who potentially may have been missed. I think we need more data before we go ahead and acknowledge that this will be working for those early presenters.

 
 
There are two other problems with the population that we need to be careful about. It's been well known that when you have a negative troponin at six hours all the way back to [Chrisann's 00:14:26] original article in the '90s, that you're pretty safe. The population that you'd like to look at really are the patients who, after two hours in Martin's study, since he took a little bit longer given the logistics that were there in New Zealand and Australia, is the patient who came in at four hours because by six, they're actually meeting that six-hour criteria. When you have a large number of other such patients, you simply add noise and it makes you sensitivity look better, but it's not necessarily the case that that give you that same degree of reassurance that ED physicians would like.

 
 
The third population-related issue is that you'd like to do this in all-comers. The protocol was developed for chest pain patients, but there are a variety of patients in whom we evaluate myocardial infarction in, who may not qualify for that. The patients who are critically ill, for example, who may have Type 2 infarctions. The individuals who may come in who are very elderly, who often don't have chest pain so we don't identify them necessarily as a rule out. Interestingly, if you start thinking about those groups, they tend to have much higher troponin, so they may well skew the cut-offs that are used and change the algorithm.

 
 
In truth, we don't want more than one way of defining myocardial infarction. We only want one algorithm for ruling in and ruling out. Having an all-comers study, in my way of thinking, would be important. In that same regard, let me point out that you can rule out myocardial infarction because you don't have an acutely changing pattern of troponin elevations, but what we really rule in myocardial infarction? You rule in acute cardiac injury. Could be myocarditis, could a apical ballooning. There are a whole variety of other types of disease entities that could be involved and the arbitrary value of 52 that was put in the algorithm really, I think, is much too low for two reasons. One reason, because it didn't include all-comers. A second reason is because of the way in which the comparison between troponin T and I were done. I'll talk about that in just a moment. I would point out that using a different assay, the troponin I assay, in another set of studies, another group from Hamburg has suggested that very different metrics would be much better.

 
 
The final thing to say about extrapolation between the assays, and then I have some suggestions about what would make this better if you want to go there now or we can wait, is the comparison and the way in which the metrics for troponin I were developed really weren't by using troponin I as a gold standard. It was by taking and using troponin T as the gold standard for the diagnosis, then thawing samples many years later, running troponin I, and then extrapolating from the gold standard of troponin T to troponin I. Well, there's several problems with that. Number one is that appropriate comparisons should be fresh samples. Fresh samples. In addition, we believe, from the way in which we think about high sensitivity, which may not be correct, that the troponin I assay should be more sensitive and in [inaudible 00:18:05] fact, in the papers that were done validating this approach or attempting to describe the approach, troponin T was wildly more sensitive than was troponin T. We're extrapolating some data that doesn't sort of fit the way in which the information we have, it would mean all of the troponin I validation studies are incorrect.

 
 
That's where those numbers came from and even more problematic are the change numbers, which are very low. For the troponin T assay, they're three in five between ruling in and ruling out, which if you look at the assay imprecision, is something the assay can't do. Now you're extrapolating them in a very, very loose manor to troponin I and making them even lower. Those are not doable sorts of things. There's a real problem with the way in which the metrics for troponin I, even though it performed well in this circumstance, ended up being developed. I think all of those things need to be taken into account when we look at the results of the study. The results that Martin and his group got are very similar to the other validation studies that have been done because they've all done it pretty much that same way. There's not a surprise that their validation is similar, but I think unfortunately, we didn't have an opportunity to unmask, in a data-driven way, the problems that I just described.

 
Carolyn:
Thank you Allan. Deborah, if you could share your thoughts on this.

 
Deborah:
Martin raises some valid issues. That if something goes out as an algorithm, people want to use it. That use needs to be predicated on does it work in their patient population and is it feasible in the time frame and can it be adopted safely and what the indications are. In the emergency department, the value really is the negative predictive value because we want to be able to safely send people home. That's where rapidity of an evaluation is very important.

 
 
The other issue raised was exactly what Dr. Jaffe talked about. Does the algorithm itself reflect what we really need? Can you validate something that was created by the scientific way, but really a combination of a lot of information? Are the thresholds really valid themselves? That's the challenge with it. I think what you heard here are kind of two issues we struggle with it. We have a very respectable organization putting out an algorithm that is scientifically based and we want to adopt early, but there are questions on both sides of the issue on whether it can be adapted into real-world clinical practice on a global nature where prevalence of disease is different and the patients it'll be applied to vary, whether it's been on time of presentation or overall demographics.

 
 
Also on the scientific side, on the assays itself, are we using the right cutoff? Especially when we're looking at deltas and looking at such a rapid change. It's very nice to hear both of those points so eloquently described today during the discussion.

 
Carolyn:
Thanks Deb. I fully agree. Hence, again, the importance of this paper. Martin, I'd love to hear your responses to Allan's comments and then also share with us, what's the take-home message for you as a clinician? How are you applying what you just found?

 
Martin:
The guidelines are good on the right line, it's just as I said, they may not necessarily translate to all other environments. I guess that's my take-home message to myself, which was if I were to look at my own data from my own center, in Christ Church, and the way it's applied here, if I had applied the ESC guidelines and it had met the metrics which I was satisfied with, which I guess would be a very high sensitivity for me in terms of rule out, then I would actually seriously consider implementing it in my own center. It didn't reach that threshold so now I want to try and refine or explore further how I could allow the guidelines to do that. For example, one way that, and this is in the guidelines, but not necessarily in the flow chart, is the importance of applying clinical judgment and clinical findings with the results of the algorithm. I think that's a very important step in it. For example, if I was going to apply this in my own center, I'd want to be setting out clearly for the doctors concerned, how one would incorporate clinical judgment rather than it being a very subjective thing, which might vary significantly between a junior doctor or a far more experienced one.

 
 
I guess the take home message for me is this. The ESC guidelines are a very important piece of work. They've been robustly developed. For people who want to implement them, I'm no saying don't use them at all. I'm just saying that, you know, just think about carefully how you would use them and check whether you think they're appropriate for your setting.

 
Carolyn:
That's great. Allan, what about you? What are your thoughts on how this may be applied in clinical practice and what more needs to be done?

 
Allan:
I think we need to have a real trial where patients are managed based on the results of these approaches rather than more observational studies. I would argue that those management trials that involve an all-comers sort of population, so we are comprehensive, and should also interrogate whether or not the protocol itself is adequate or whether or not it requires follow-up to meet the metrics that have been proposed. I would point out that in the past, in the studies from the group from New Zealand and Martin Than particularly, have had very, very good follow-up. One at least needs to ask the question whether or not the algorithms that are proposed work perfectly without any follow-up or whether or not follow-up is an important component. We don't know that yet.

 
Carolyn:
Thanks Allan. I'd love to give the final words to Deb. Take home messages?

 
Deborah:
You know, I think that we need to look at this as a positive in that we're looking at time frames that provide a rapid evaluation and the discussion is around safety. As long as we keep focused on appropriate evaluations for the patients and applying the right algorithm to the right patient, we're going to benefit the care of those we're really concerned about. I appreciate the work that both Martin and Allan both have done on really pointing out how we can do that in a great manor.

 
Carolyn:
Thank you, all of you, for joining us today. I mean, it's been such an enlightening conversation. I'm sure the listeners have enjoyed it and thank you listeners for tuning in. Don't forget to tune in again next week.

 

Nov 7, 2016

 

Dr. Carolyn Lam:

 

 

 

 

 

 
Welcome to circulation on the run. Your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam associate editor for the National heart center and Duke National University of Singapore. Our podcast is really going around the world, and today's feature interview comes to you live from China. Where we will be discussing the prediction of ten year risks of cardiovascular disease in the Chinese population. So now to all our Chinese colleagues out there: Chinese dialect

 
 
First here's your summary of this week's journal. The first study challenges the assumption that all patients with vascular disease are at high risk of recurrent vascular events. First author Dr. Kasenbrud corresponding author Dr. Viceren and colleagues form the University Medical center Utric in the Netherlands, provide new data on the estimation of ten year risk of recurrent vascular events and a secondary prevention population. In other words, in patients with established cardiovascular disease they applied the second manifestations of arterial disease or 'smart' score for the ten year risk prediction of myocardial infarction, stoke or vascular death in more than six thousand-nine hundred Dutch patients with vascular diseases ranging for coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm and poly-vascular disease. Predictors included in the SMART risk score included age, sex, current smoking, diabetes, systolic blood pressure, total cholesterol, HGL cholesterol, presence of coronary artery disease, cerebral-vascular disease, peripheral artery disease, abdominal aortic aneurysm, estimated glomariaol fruition rate, high sensitivity CRP and years since the first manifestation of vascular disease. They further externally validated the risk score in more than eighteen thousand four hundred patients with various types of vascular disease fro the TNT ideals Sparkle and Capri trials.

 
 
The overall findings was that the external performance of the SMART risk score was reasonable apart from over-estimation of risk in patients which a ten year risk of more than forty percent. What was striking was the substantial variation in the estimated ten year risk. The median ten year risk of a reoccurring major vascular event was 17 percent but this varied for less than 10 percent in 18 percent to more than 30 percent in 22 percent of patients.

 
 
The authors further estimated residual risk at guideline recommend targets by applying the relative risk reductions form meta-analysis to estimated risks for targets for systolic pressure, LDL, smoking, physical activity and use of anti-thrombotic agents. They found that if all modifiable risk factors were at guideline recommend targets only half of the patients would have ten year risk of less than 10 percent. Even with optimal treatment many patients with vascular disease appear to remain at more than a 20 percent or even more than 30 percent of a ten year risk.

 
 
The take home message is that a single secondary prevention strategy for all patients with vascular disease may not be appropriate. Instead novel risk stratification approaches may be helpful to individualize secondary prevention by identifying high risk patient which may derive the greatest benefit from novel interventions.

 
 

 

 

 

 

 

 

 

 

 
The next study provides experimental evidence that an indigenous-gastro transmitter hydrogen sulfide may potentially be a therapeutic target in diabetic patients with cardiovascular diseases. In this paper by first author Dr. Chen, corresponding author Dr.Kisher and Colleagues from the Louis Cat's school of medicine Temple University in Philadelphia. Authors aim to evaluate the role of hydrogen sulfide deficiency in diabetes induced bone marrow cell dysfunction and to examine the therapeutic effects of restoring hydrogen sulfide production in diabetic bone marrow cells on ischemic high limb injury in diabetic DBDB mice. They further specifically investigated the effects of hydrogen sulfide deficiency on the nitric oxide pathways under conditions of high glucose. They found that bone marrow cells for diabetic DBDB mice had decreased hydrogen sulfide production and lower levels cystathonine gamma lyaze which is the primary enzyme that produces hydrogen sulfide in the cardiovascular system. Administration of a stable hydrogen sulfide donor and over expression of cystathonine gamma lyaze in diabetic bone marrow cells restore their functional and restorative properties. Further more they demonstrated that the therapeutic actions of hydrogen sulfide were mediated by nitric oxide pathway involving endothelial nitric oxide synthase PT495.

 
 
In summary these results support the hypothesis that hydrogen sulfide deficiency plays critical role in diabetes induced bone marrow cell dysfunction and suggests that modulating hydrogen sulfide production in diabetic bone marrow cells may have transformational value in treating critical limbs ischemia.

 
 
The next study reinforces the importance of hypertension as a critical risk factor for inter-cerebral hemorrhage, and suggests that Blacks and Hispanics may be a particularly high risk. In this study by DR. Walsh and colleagues for the University of Cincinnati, authors conducted the largest case controlled study to date on treated and untreated hypertension as a risk factor for inter-cerebral hemorrhage. They also investigated whether there was variation by ethnicity. The ethnic racial variations of inter-cerebral hemorrhage or eriche study is a prospective multi-center case controlled study of inter-cerebral hemorrhage among Whites, Blacks and Hispanics. Cases were enrolled from 42 recruitment cites, controls were matched cases one to one by age, sex, ethnicity and metropolitan area. A total of 958 white, 880 black and 766 Hispanic cases of inter-cerebral hemorrhage were enrolled. Untreated hypertension was more highly prevalent in Blacks at almost 44 percent and Hispanics at almost 47 percent compared to whites at 33 percent. Treated hypertension was a significant independent risk factor and untreated hypertension was substantially greater risk factor for all three ethnic groups and across all locations. There was a striking interaction between ethnicity and risk of inter-cerebral hemorrhage, such that untreated hypertension conferred a greater risk of inter-cerebral hemorrhage in Blacks and Hispanics relative to Whites.

 
 

 

 

 

 

 

 

 

 

 

 
The nest study provides the first prospective multi-centered data on mortality and morbidity in rheumatic heart disease from low and middle income countries. First author Dr. Zulky, corresponding author Dr. Mayoci and authors from Gertrude hospital and University of Cape Town in South Africa present the results of two year follow up of the global rheumatic heart disease registry or remedy study in 3343 children and adults with rheumatic heart disease from 14 low and middle income countries. They found that although patients were young with a median age of only 28 years the 2 year case fatality rate was high at almost 17 percent. The median age at death was 28.7 years. Mortality was higher in low income and low middle income regions compared to upper middle income countries. Independent predictors of death was severe valve disease, more advanced functional class, atrial fibrillation and older age. Where as post primary education and female sex were associated with a lower risk of death. The authors carefully noted that apart from age and gender the independent risk factors for mortality such as severity of valve disease heart failure, atrial fibrillation and low education were all modifiable and thus they called for programs focused on the early detection and treatment on clinical rheumatic heart disease.

 
 
Well that's it for the summaries, now lets go over to China

 
 
For our feature interview today we are going all the way to Beijing at the great Wall meeting where we will be meeting authors as well as editors. So here we have first and corresponding author Professor {Dong Fen Gu} and co-author Professor {Sherliang} both from {Fu Y} hospital Chinese academy of medical sciences in Beijing. Welcome

 
Dr.Gu:
Welcome we are so delighted to be interviewed by you

 
Dr. Carolyn Lam:

 
Thank you so much we are so excited to be talking about your paper predicting the ten year risks of cardiovascular disease in the Chinese population. And here we have as well editor in chief Dr. Joe Hill as well as Dr. Amid Kira digital strategies editor and associate editor. Gentlemen how is it in Beijing? And I hear that you have a Chinese greeting for everyone as well.

 
Joe Hill:
{Ni how} and {nuchme and senchmen}

 
Amid Kira:
I can't top that but I agree with what Joe said

 
Dr. Carolyn Lam:
Dr. Gu, could you please tell us what is it that is so different about cardiovascular disease in China compared to what we heard about in the western world.

 
Dr.Gu:
Okay cardiovascular disease is both leading cause of death in China and in United States as well in European countries. However the patterns for components of cardiovascular disease including coronary arteries and stroke are still quite different in the Chinese populations compared united states. For example there are coronary arteries mortality rate in the united states is along the 100 thousand per year and this is the first leading cause of death in the united states. And for stroke the annual mortality rate is along 36 per 100 thousand in the united states populations. However in china the stroke mortality rate among Chinese populations is around the 160 per 100 thousand, so that almost 3.5 to 4 as high as in untied states. Obviously for our lifestyle in including battery behavior quite different you can easily identify one kind of difference in the united states and the Europe restaurants from Chinese restaurants and some western style restaurants you can figure it out.

 
 

 

 

 

 
And another example, smoking rate is major component for risk of cardiovascular disease it is very high in Chinese adult men. It over 50 percent right now but in the united states in the past 50 years it declined immensely. And around maybe less than around 20 percent and from the previous experiment from studies by Dr. Liu Chin from and my colleague Dr.WU they used the questions for predictions of coronary arteries compared to equations and also use the similar prediction model compares that its chemical cardiovascular disease from the united states population and the Chinese population. That to over estimation if we use the united states produced this kind of equation. So based on this kind of scenario we based on Chinese long term larger scales cohort to precede and study our own prediction model.

 
Dr. Carolyn Lam:
Wow that is really fascinating Dr. Gu and I really could not agree with you more because I sort of trained in the united states for quite some time and then I moved back to Singapore and saw for myself in Asia the tremendously high rates of stroke. I was also very struck by the relative youth of the patients suffering cardiovascular disease and the differences in risk factors, the smoking but not just that, obesity is almost defined on a different scale in our relatively sized smaller Chinese population compared to that in the western. Congratulations to you and your team for a successful amazing effort. Could you or Dr. Yang now just let us know what are your main findings.

 
Dr. Yang:

 

 

 

 

 
Well I think there are 2 major finding for our work. First we developed a new prediction risk model you know after analysis is for high risk score or equations released by AJ and ACC and is some other risk scores. We included 6 conditional risk factors in combination with our previous knowledge that included age, treated or untreated ISBP, total classical, HDLC current smoking and diabetes. So this traditional risk factors were set up as a base model and then we use the predefined statistical to include new additional variables they were Chinese special elements. Finally in our model there were rates as constraints and geographic region which means northern part versus the southern part in China and also organization is rural or urban area. And finally the forth one is family history as a CVD so this for additional variables in our model suggest that we maybe as a Chinese prediction and equations has something special. For example we feel more attention for central obesity in primary prevention in Chinese populations and also you know the norther part and the southern part there are large differences in the risk profiles. And so maybe according to our risk prediction model we pay more attentions for the residence living in northern part in China.

 
 
And then for the second points I think we found that PCE equation which shows for equations was not appropriate to predict ten year risk of in Chinese populations. For example in our revelation cohort we found that our model just slightly over predicts severity risk by 17 percent in Chinese man but when we use the PCE models released form AHA the over-estimation come to 50 percent so maybe equations from western populations are not appropriate to Chinese populations.

 
Dr. Carolyn Lam:
Thank you so much Dr. Yang I mean those are just such important findings applicable to a huge population in china, like you said. And just as important as the second point that the pooled equations derived from western populations may not be the most appropriate for certain other ethnic populations. I think that a very important message and that why we are so proud to be publishing this in Circulation. Could I ask then are you applying these new equations in your personal clinical practice?

 
Dr.Gu:

 
Risk assessment is a fundamental components for prevention of ASSVD. In Chinese we question {turn the PA on} provide a valuable to identify high risk individuals in Chinese populations. And not with just complicated [inaudible 00:18:02] for further analysis. And propose three levels of groups of risk stratification could be identified by cut off 5 percent and 10 percent. So lower risk individuals with predicted activity risk of less than 5 percent should be offered lifestyle wise to maintain the lower risk status. While the moderate risk individual is predicted risk of 5 to 10 percentage for intensive therapeutic lifestyle change wit drug therapy if necessary. For the high individual risk high or large 10 percent teheraph of clinical aliment taken account for physicians recommendation should be required with therapy for the lifestyle modification. Then annually clinic up, including an echocardiographic information for carotid artery back and even for outer [inaudible 00:19:09] CT examinations for coronary artery are recommended. Also blood pressure, lipids, glucose measurement if necessary are suggest according to Chinese guideline. While cardiovascular disease prevention as well as for the epidemic of this kind a lines. For ACVD patients those are different kinds of risk assessment we could know whether their risk profile had been improved or be progressed so that appropriate clinical elements should be taken in clinical practice.

 
Dr. Carolyn Lam:
Thank you very much Dr. Gu so that just show that these findings are immediately clinically applicable and I trust that means you're suing it in your clinics too, and once again were so happy to be publishing this in Circulation so in the rest of the time in going to now direct questions at Joe and Amid.

 
 
How's China been? How are your chopstick skills and any word on how Circulation is being received there?

 
Joe Hill:
Well Carolyn its a delight to be here this is a bustling media that get better and better every year. In about 2 hours we have our first ever Circulation session, we brought several editors here to discuss the types of content that we are looking to publish, the type of work across prevention and population and electrophysiology of heart failure. This is an extraordinary media that is now internationally acclaimed and as we've heard here, the face of cardiovascular disease in Asia is changing. And as you pointed out 60percent of the human race lives in Asia and we want to do everything we can to be here on the ground, in Asia trying to address this curve that is already present and is worsening by the day.

 
Dr. Carolyn Lam:
Amid, you know you've seen the latest statistic on our podcasts and you highlighted that we have quite a number of listeners over there as well. Would you like to tell me how this is all blending it to the digital strategies and anything else you might want to highlight?

 
Amid Kira:
Sure its been an incredible meeting and we get to meet great colleagues like our colleagues today on this podcast and learning so much from this meeting. Our podcast as you pointed out quite a sizable and growing cadre of people in Asia and Japan and China who are listening and we truly want to enhance that as Joe mentioned with the large splurge of cardiovascular disease and the great science that is going on here. Want to make sure that we are able to be apart of that conversation and interact with researcher and clinitions here. In addition to podcast, we are exploring some other options involving social media, specifically in China so stayed tuned in how those develop but we certainly appreciate the importance of being her and interacting where so much of cardiovascular disease and cardiovascular science is occurring.

 
Dr. Carolyn Lam:
That's so great. Joe or Amid now there's a specific we would like to highlight to our listeners the doodle, either of you want to pick that up a bit about blipping the doodle?

 
Amid Kira:
So there is as you know Circulation now has this doodle where we change it periodically and its sort of a fun themed thing. Right now I think it Halloween and we've had several other ones that people have designed to sort of keep thing fresh and light and interesting. There's a new app called blippar which you can download from iTunes or android stores and you can essentially scroll that over with your phone with the doodle and that will take you to new content either table of contents of videos, different kinds of content that it can navigate you to. So I hope people will not only enjoy the doodle kind of anticipate what's next in terms of seasons but will take the time t blip the doodle when they get a chance.

 
Dr. Carolyn Lam:
That great and that blippar- B l I P P A R. You really c should check it out, anyone who is listening to this really check it out you'll be floored. Joe could I just turn the mic to you for any last words about the global outreach of Circulation, I mean its just so amazing that you're there in China

 
Joe Hill:
Well heart disease Carolyn knows no boundaries nor does Circulation. There was a day when cardiovascular disease was largely an issue in the developed world that is long since gone and that's why the study that we are talking about today with these authors is so important because the face of cardiovascular disease is different than in the west, the ways in which it is  evolving id different here than in the west and I like many others foresee an increase a significant increase in the types and prevalence of heart disease here in Asia. for all the reasons that we have been talking about, hypertension, obesity, type two diabetes, smoking the environment all of these challenges I fear are going to lead to a substantial increase in the prevalence of heart disease in Asia and that why we're here on the ground with Circulation in Asia that's why we have one of our major leaders Chong Shong Ma who is here in Beijing. Circulation is in China everyday, it’s in Beijing everyday to try and address this problem.

 
Dr. Carolyn Lam:
And you heard it from our editor and chief, so thank you everyone for listening to this episode of Circulation on run. Tune in next week.

 
 

 

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