Circulation on the Run

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Now displaying: December, 2016
Dec 27, 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. Caroline Lam, associate editor from The National Heart Center and Duke National University of Singapore. Today we will be discussing the results of an individual level meta-analysis regarding venous thromboembolism and its risk factors, but first, here's your summary of this week's issue.

The first paper provides insights into paracrine signalling pathways that regulate epicardial adipose tissue formation. That is, referring to the adipose tissue located between the epicardium and underlying myocardium that is known to be strongly associated with coronary artery disease. In the current study from Dr. Lira of Icahn School of Medicine at Mount Sinai, New York, Dr. Pu from Boston Children's Hospital, Dr. [Chien 00:00:56] from Karolinska Institute and colleagues, the authors used a novel modified mRNA screening approach to probe the effect of individual paracrine factors on epicardial progenitors in the heart. Using two independent lineage tracing strategies in murine models, they showed that cells originating from the WT1-positive mesothelial lineage, which includes epicardial cells, differentiate into epicardial adipose tissue following myocardial infarction. This differentiation process required WT1 expression and was stimulated by insulin-like growth factor 1 receptor activation. Insulin-like growth factor 1 receptor inhibition significantly reduced its adipogenic differentiation and reduced WT1 lineage cell differentiation into adipocytes following myocardial infarction.

These results thus establish insulin-like growth factor 1 receptor signalling as a key pathway that governs epicardial adipose tissue formation in the context of myocardial injury. And it does this by redirecting the fate of WT1-positive lineage cells. The study also demonstrates the utility of a modified RNA based paracrine library screening to dissect signalling pathways in homeostasis and disease.

The next study brings us closer to understanding the mechanisms underlying diabetes-associated heart failure. In this study by first author, Dr. Wang, corresponding authors, Dr. Abel and Xiang from University of California, Davis and colleagues. High-fat diet feeding was used to induce obesity and diabetes in wild-type mice or mice lacking the beta-2 adrenergic receptor or beta-arrestin 2. High-fat diet feeding was found to selectively increase the expression of phosphodiesterase 4D in the mouse hearts in concert with the reduced phosphokinase A phosphorylation of phospholamban which contributed to systolic and diastolic dysfunction. The expression of phosphodiesterase 4D was also elevated in human hearts with diabetes. The induction of phosphodiesterase 4D expression was mediated by an insulin receptor and substrate as well as by beta-arrestin-2 dependent activation of a beta adrenergic receptor, ERK signalling cascade.

Genetic deletion of beta-2 adrenergic receptor or beta-arrestin-2 or pharmacological inhibition of beta-2 adrenergic receptor with carvedilol or G-protein receptor kinase 2 with paroxetine all significantly attenuated insulin-induced phosphorylation of ERK and phosphodiesterase 4D induction thus preventing diabetes-related systolic dysfunction. Thus, targeting the insulin beta-2 adrenergic receptor pathway may be a novel way to prevent diabetes-associated heart failure.

The next study addresses the gap in care pertaining to implantable cardioverter-defibrillator or ICD use among Medicare patients with low ejection fraction following myocardial infarction. Dr. Pokorny and colleagues from Duke University Medical Center examined rates of post-discharge ejection fraction assessment and ICD implantation among more than 10,280 Medicare-insured patients age 65 years above with an ejection fraction 35% and below during an index myocardial infarction admission in the ACTION Registry Get With the Guidelines. They found that the cumulative incidence of ejection fraction reassessment within one year of myocardial infarction was 66.8%. Within the first year of post-myocardial infarction, 11% of patients who had an ejection fraction reassessment underwent ICD implantation which was significantly higher than patients without an ejection fraction reassessment. After multivariable adjustment, ejection fraction reassessment remained significantly associated with a higher likelihood of ICD implantation within one year in both revascularized and non-revascularized patients. Based on these findings, the authors recommend that all patients who are potential candidates for ICD therapy be scheduled for follow-up outpatient ejection fraction assessment prior to hospital discharge to bridge these currently observed gaps in care.

The next study is the first multi-institutional study in Asia describing current treatment strategies for total anomalous pulmonary venous connection. This retrospective study of 768 patients with total anomalous pulmonary venous connection operated on between 2005 and 2014 is from first authors Dr. Shi, Zhu, and Chen, corresponding authors, Dr. Chen and Zhuang and colleagues from the Shanghai Children's Medical Center and Guangdong General Hospital in China. While most patients underwent conventional repair, a sutureless patient was technique was employed in 10% of patients. Over a median follow-up of 23 months, there were 38 intraoperative deaths and 13 late deaths. A younger age at the time of repair, next an infracardiac total anomalous venous connections, pre-operative pulmonary venous obstruction, prolonged cardiopulmonary bypass time and longer duration of ventilation were all factors associated with increased mortality. Among these 717 survivors, recurrent pulmonary venous obstruction was found in 15% or 111 patients. Risk factors for recurrent pulmonary venous obstruction included pre-operative pulmonary venous obstruction, infracardiac total anomalous pulmonary connection, mixed venous connections and prolonged cardiopulmonary bypass time, a sutureless technique was associated with a lower restenosis rate compared to conventional repair in patients with pre-operative pulmonary venous obstruction but not in newborn patients. Thus, this study provides an important data on the outcomes following surgical correction and risk factors for poor prognosis in total anomalous pulmonary venous connection in Asia.

The final study is the first systematic review and meta-analysis on the association of genetic polymorphisms and outcome of clopidogrel-treated patients with ischemic stroke or transient ischemic attacks. In this paper from first author, Dr. Pan, corresponding author, Dr. Wang and colleagues from Beijing Tiantan Hospital, Capital Medical University in Beijing, China. Authors looked at 15 studies of 4,762 patients with stroke or transient ischemic attack treated with clopidogrel and this included 3 studies from Europe and 12 studies from East Asia. They found that carriers of the CYP2C19 loss-of-function alleles were at increased risk of stroke compared to noncarriers. Composite vascular events were also more frequent in carriers compared to noncarriers while bleeding rates were similar. There was no evidence of statistical heterogeneity among the included studies for stroke but there was for composite vascular events suggesting that publication bias cannot be ruled out. Genetic variance other than CYP2C19 were not associated with clinical outcomes. The author suggested that their findings may justify genetic testing when clopidogrel is otherwise considered the preferred treatment modality, especially in East Asian patient populations in whom the prevalence of CYP2C19 loss-of-function allele is high.

In an accompanying editorial, Dr. Simon and [inaudible 00:10:11] suggest it maybe time to consider a prospective trial of personalized medicine using CYP2C19 genotyping in acute ischemic stroke and perhaps considering alternative medications in poor or intermediate metabolizers such as in the popular ongoing genetics trial in STEMI patients undergoing PCI. That wraps it up for the summaries this week. Now for our feature discussion.

Today's feature paper talks about the association of traditional cardiovascular risk factors with venous thromboembolism. And it is the first individual level meta-analysis of prospective studies. I am so delighted to have the first and corresponding author here with us, Dr. Bhaktawar Khan Mahmoodie from San Antonio's Hospital in the Netherlands. Hi Khan, thanks for being here.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for inviting me. Thanks a lot.

Dr. Carolyn Lam:              

And I am particularly delighted to have associate editor, Dr. Josh Beckman from Vanderbilt University joining us today as well. Welcome Josh.

Dr. Josh Beckman:          

Caroline, it is such a pleasure to be here with you. I've been listening to these podcasts and they have been incredible. I've been waiting to be able to jump in and today's paper is an awesome place to start.

Dr. Carolyn Lam:              

It certainly is. Congratulations on managing such an important paper. Khan, maybe I could start with you. Venous thromboembolism versus arterial thromboembolism. We're very familiar with the latter. We know it comprises coronary heart disease, stroke, peripheral artery disease. We're very familiar with the risk factors such as hypertension, hyperlipidemia, diabetes, smoking. But here you're asking, are these same risk factors applicable in venous thromboembolism. That would include deep venous thrombosis, pulmonary embolism, where we traditionally classify it into provoked events that is triggered by things we know well like immobilization, surgery and so on. And then there are the unprovoked events that don't have any risk factors. So could you, first of all, point out ... you were looking at venous thromboembolism. What was your hypothesis with regards to the traditional cardiovascular risk factors?

Dr. Bhaktawar Khan Mahmoodie:            

Many researchers in the last 10, 15 years, they go questions whether there is connection between venous and arterial thromboembolism. Since then, several studies published on that with controversial results. So our hypothesis for this paper was to see whether there is real associations or are we looking at some kind of associations due to confounding factors such as age and overweight which are risk factors for both.

Dr. Carolyn Lam:              

Yeah. And yours is actually the first individual level meta-analyses of prospective studies dealing with this. Tell us what you found in ... Were you surprised by your findings?

Dr. Bhaktawar Khan Mahmoodie:            

What we found that actually traditional, modifiable, cardiovascular risk factors like hypertension, diabetes and hyperlipidemia were not risk factors for venous thromboembolism. The exception was smoking, current smoking, which was particularly associated with provoked venous thromboembolism which is probably pro its association with cancer. And cancer itself is a strong risk factor for venous thromboembolism. About whether I was surprised, I was not surprised at all. We saw in several cohort studies and well-defined cohort studies that the association disappeared after adjustment for age and body mass index which are important confounders in these [inaudible 00:14:06]. That's what I expected and we found it and it is confirmed with this large individual level meta-analysis.

Dr. Carolyn Lam:              

Great. But what did you think of the association of higher systolic blood pressure not with higher but with lower risk of venous thromboembolism?

Dr. Bhaktawar Khan Mahmoodie:            

That was a bit surprising for us too but I think the best explanation we can give at the moment is probably that we have some kind of competing risk. And one suggestion that we gave in the paper as well is that maybe what we already know is that higher blood pressure is a strong risk factor for atrial fibrillation. Most of these people they receive oral anticoagulants. That is subsequently probably a protective factor for venous thromboembolism. We probably deal with some kind of competing risk from another condition like the atrial fibrillation and use of anticoagulants which we could not unfortunately adjust for in this analysis.

Dr. Carolyn Lam:              

Sure. That makes sense. Josh, can I bring you into this? I mean I remember well our multiple and long discussions at the editors meetings. This is one of those papers that is extremely important for its negative, neutral associations isn't it?

Dr. Josh Beckman:          

I think this is one of the more important papers in this field in a long time. I am one of those people who has followed this literature and believed, based on the best previous publications, that there was a link between many of the arterial thrombosis or atherothrombotic risk factors and venous thromboembolism. In fact, Circulation published one of these meta-analyses, and I'm going to say only because this little paper is so large with only 21,000 patients demonstrating a clear association. So the first question I would have, we published that back at 2008, the first question I would have is can you describe for the general readership what such a large series of patients allows you to do that was not permitted by the other meta-analyses of say twenty to thirty thousand patients that have been previously in the literature.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you Dr. Beckman and thank you also for managing this paper. This is an important question and I think what we were able to do compared to the previous analysis in 2008, we were able to adjust for confounding risk factors. In the course, we included were all with validated venous thromboembolism events and also the events are temporal character, like all the risk factors were measured and then followed-up for event. While in that paper, there were many case-controlled studies added and the results were not adjusted for age and also not adjusted for body mass index. And if we do the same with what's done there, then we have the same results like in our [inaudible 00:17:14] associations, all of these risk factors were indeed positively associated with risk for venous thromboembolism.

Dr. Carolyn Lam:              

Let me just state, I mean, there were almost 245,000 participants in your study. With 4,910 thromboembolism events, so this is really huge and gives you a lot of power to look at this thing very carefully.

Dr. Josh Beckman:          

It was a 10-fold increase from any of the major publications in this area. It was almost geometrically larger in size which is why, I think its conclusion will be accepted differently than all the previous analyses. Now, let me ask one question about what you already identified in your discussion as a possible limitation. Is this study applicable to all populations around the globe or do you think it is a bit more focused?

Dr. Bhaktawar Khan Mahmoodie:            

I think it is focused at least. We don't have Asian population in these analyses and also the proportion of African-Americans were limited which was only limited to some U.S. cohorts so I think that there is a limitation which is results are probably only applicable for Caucasian population.

Dr. Josh Beckman:          

I guess my other question is, one of the reasons that people, I think, advance the argument that there may be overlap between the two kinds thrombosis is that there was evidence that the medication, statin, may ... to a much smaller degree, reduce venous thrombosis as well as reducing arterial thrombosis. Do you think that this is evidence of some common pathophysiology? Or is it like smoking, it's truly working separately from arterial disease?

Dr. Bhaktawar Khan Mahmoodie:            

Personally, I think that this association or the finding of statins reduce the risk of thromboembolism could be due to some pleiotropic effects of statins. Like even for stroke, we know that the association of cholesterol with stroke is not so clear-cut as it is with myocardial infarction but still it reduces risk of stroke. And also for venous thromboembolism, the risk reduction of venous thrombosis in the JUPITER trial was like 50%, which is very high, even better than aspirin. But I think that may not be directly related cholesterol levels but more to another pleiotropic effects of statins. It could influence levels of various coagulation [inaudible 00:19:56] in the endothelial stabilization which may be also important risk factors for venous thrombosis.

Dr. Josh Beckman:          

One of the reasons that this paper is very important is that we begin to look for therapies and risk factors based on what the disease is caused by. And so the fact that you guys were able to establish, in my opinion, quite clearly what does and what does not contribute to venous thrombosis allows us to begin to think about the disease differently and approach it differently. I would like to provide congratulations. My one little ask of you is that one of the things that I think this podcast is great for is to explain to the readership what goes into this kind of work. Everybody thinks that someone else's research is easier to do than their own, which of course is a ridiculous thing. But can you describe for us what it's like and how long it took from the study initiation to when you completed it? How much work went into trying to get all these studies together to create this individual patient level data?

Dr. Bhaktawar Khan Mahmoodie:            

Yeah. That was a great amount of work. Actually, I did a systematic review of the only PubMed publications back in 2014 and it took almost 2 years at least. I was not always active the whole 2 years but still I had to visit several PIs of the studies to get them so far to share their data. Eventually, I had to develop a code that will make it possible without sharing the individual level data by using the same definitions and the same categorization of variables so we call it a two-stage meta-analysis similar to one-stage if the definitions are similar. And eventually, I think that the real part of the analysis and inclusion of studies took like half a year or so. There was a lot of work.

Dr. Josh Beckman:          

I think this is a tremendous amount of work and for those members of our readership who do basic research, or translational work, or practice in the clinics, it really needs to be made clear that this is a heroic effort of hundreds and hundreds of hours. And that getting together all of these studies is just an enormous undertaking. And that even though, we can read the paper in 10 minutes and gleam the most important part. It is an incredible amount of work for which you guys are to be congratulated.

Dr. Bhaktawar Khan Mahmoodie:            

Thank you for acknowledging this. Thanks a lot.

Dr. Carolyn Lam:              

Josh, I couldn't agree with you more and I truly couldn't have said it any better. Thank you both of you for making this just one of the best discussions we've had on this podcast. I'm sure the listeners all agree what a wonderful time we've had.

You've been listening to Circulation on the Run. Please remember to tune in next week.


Dec 19, 2016

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. We have such a special issue today. You see, it's entirely focused on resuscitation and I am delighted to have with me today, Associate Editor, Dr. Mark Lane from Puffs Medical Center, who really put this issue together. Welcome, Mark.

Dr. Mark Lane:                  Thank you Carolyn.

Dr. Carolyn Lam:               Mark, maybe you could start by telling us why the focus on resuscitation? I do believe this is the first time we've done this at Circulation.

Dr. Mark Lane:                  Yes, this is the first time we've done this at Circulation. It really was a confluence of a couple things coming together. Once is that over the spring and summer, we had a very high volume of high quality resuscitation papers come to Circ. This was not something that we actually asked for but we noted that there were a number of these. Also, it's an important time in resuscitation because a number of the resuscitation counsels across the world have called for improvements in the survival rate, noting that we already have the tools that we need to increase survival and we have to better apply these tools. The HA has provided a goal of doubling resuscitation and resuscitation counsels in Europe, New Zealand and Australia have also echoed that call.

Dr. Carolyn Lam:               That's great, so this is a really important issue. I just echo your words about their being a remarkable number of original papers. We have seven and they're just such high quality. Let's chat through them, shall we? I'm going to go by pre-hospital setting to the out of hospital setting and finally end up in the in-hospital setting. Shall we do that?

Dr. Mark Lane:                  That sounds great.

Dr. Carolyn Lam:               The first paper is really about identifying patients at risk for pre-hospital sudden cardiac death at the early phase of myocardial infarction. You want to tell us a bit about that one?

Dr. Mark Lane:                  This is a study coming from the emergency medical services in the greater Paris area, where they looked at their cardiac arrest and STEMIs over the last seven or eight years. What they were specifically looking at is, can you identify STEMI patients who are at risk for having a cardiac arrest, because if you could identify those patients, you'd want to get there very quickly because if you know they're going to arrest or they're going to have a cardiac arrest, then having a defibrillator there would be very important.

                                                What they found, is that you can actually identify STEMI patients who are higher likelihood of arrest and those STEMI patients are those with younger age, they're not obese, they don't have diabetes. They have shortness of breath in addition to their chest pain and they have a very short delay from the time of chest pain to their call EMS. That is they're very concerned about their chest pain. You could use these characteristics to predict which STEMI patients, which chest pain patients were at highly likelihood of having a cardiac arrest. There was as much as a 19-fold difference between individuals without any of these factors and individuals with several of these factors.

Dr. Carolyn Lam:               What I like about this, is that simplicity of that score. Age, symptoms and kind of the absence of diabetes, absence of obesity and that short time frame. It's something that could be asked on a routine questionnaire by EMS dispatchers, for example.

Dr. Mark Lane:                  Right. It highlights the importance of the dispatch system. That simple questions, you can really stratify risk and it's not just getting an ambulance out there. Truly stratifying risk in order to get there quicker.

Dr. Carolyn Lam:               There are two papers that deal with out of hospital cardiac arrest. One of them interestingly focusing on the neuro-protective effects of Glucagon-Like Peptide-1 analog Exenatide. Thoughts about that one?

Dr. Mark Lane:                  This is a randomized study from Denmark. Notable that there are very low number of randomized trials in resuscitation so the fact that they did this is remarkable. What they did, is this glucagon-like peptide analog is a type II diabetic medicine and there is some reason to believe that that may protect the brain after resuscitation and ROSP. They had two goals in this trial. One was to see if it was feasible to administer a drug within six hours of a cardiac arrest and the other was to get any sort of outcome measure of whether this could provide some benefit. They randomly assigned 120 comatose patients and half of them got the peptide analog and the other half did not. What they showed, it is feasible to give IV administration of a drug within six hours of a cardiac arrest. Unfortunately, the drug they used did not appear to have any clinical benefit and this was both a composite end-point of death in neurologic function but also an evaluation of a brain neuron specific amylase, which was actually brain damage so they didn't see any biological or clinical neuro-protective effects of this drug.

Dr. Carolyn Lam:               I didn't realize it until you said it, it is very difficult to do a randomized control trial. This is very significant just for that. The next study about the out of hospital arrest, really talks about bystander CPR and I think seeks to answer to what degree bystander CPR remains positively associated with survival with increasing time to potential defibrillation. Important question, what do you think of that?

Dr. Mark Lane:                  It's an important question that surprisingly has not been evaluated that closely. Most either studies either look at bystander CPR or EMS arrival times but don't look at the interaction between the two. This study looks at the interaction between bystander CPR and EMS response time and that's the critical thing in this paper that's very interesting.

                                                What they did is, they split bystander CPR with or without and then EMS response times five minutes, 10 minutes and longer. If EMS responds within five minutes and you had bystander CPR, the survival rates with good neurological outcome were 14.5%, which is really a remarkable number. If there was no bystander CPR and the EMS arrived within five minutes, it dropped to 6.3%. There was 2.3-fold higher likelihood of good neurologic survival with bystander CPR with EMS within five minutes.

                                                They also looked at the 10 minute response time of EMS and if you had bystander CPR and EMS arrived within 10 minutes, the survival rate was 6.7% and without bystander CPR, it was 2.2%. With bystander CPR and EMS arrival within 10 minutes, there was a three-fold higher likelihood of survival with bystander CPR. It's interesting that by 13 minutes, there really was essentially no difference in those individuals who had bystander CPR or not, suggesting that at that point it's taken so long for EMS to arrive, it really doesn't make really much difference between whether you have bystander CPR.

                                                A really important paper showing that bystander CPR is critical, but so is EMS arrival within five minutes especially, but even 10 minutes.

Dr. Carolyn Lam:               I like that paper and I really like the way you crystallized the findings so clearly like that. What I'm also liking is the way, even though these papers weren't invited or anything, there is this nice flow because from bystander CPR we now talk about duration of resuscitation. There's one regarding adults and followed by one in pediatric population so very nice set of papers. Could we start by maybe talking about the adult one? The one looking at the association between duration of resuscitation and favorable outcomes after out of hospital cardiac arrest from North America.

Dr. Mark Lane:                  The reason that these two papers are important is really the futility issue. When is it futile to continue a CPR and that's a very important question. This adult paper is from the ROC Consortium. The ROC is a North American Seer NIH Sponsored consortium that's been going on over the last 10 or so years. What they looked at was outpatients and they had a very large number of greater than 11,000 subjects and of those 8% survived with a good outcome. That's 8% of those 11,000. If you looked at those 8% that survived, 90% of those had return of spontaneous circulation with 20 minutes. You really wanted to get their blood pressure back within 20 minutes.

                                                If you went beyond 20 minutes to the return of spontaneous circulation, you still could get good outcome. It was less likely but it was more likely if you had initial shockable rhythm, you had a witnessed cardiac arrest or you had bystander CPR. If you had some of those features, then you would argue to continue CPR for a longer time period. Actually a very nice important paper that if you had those other three features, you could still get good neurologic functioning, even with resuscitation attempts up to 40 minutes.

Dr. Carolyn Lam:               Exactly. I thought I saw 47 minutes somewhere, but it gives us a bit of a guidance when we're making these really tough decisions and talking about tough decisions and futility, I think it's even more amplified in the pediatric population, isn't it? This next paper from Japan talks about the duration of pre-hospital CPR in the pediatric population. What are your thoughts on that one?

Dr. Mark Lane:                  This was a study from Japan, using their nation-wide Japanese data base. Actually, in many ways mirrored the adult experience. The number of patients analyzed with roughly the same. This was nearly 13,000. They looked at 30 day survival both overall and 30 day survival with good neurologic function and 30 day survival overall were 9% so similar to the 8% in adults and good neurologic function were 2.5%, which wasn't quite as good as in the adults and that the duration of CPR also was very important. Once CPR went out to 42 minutes there was less than 1% chance that that individual was going to survive with any significant neurologic outcome. If you had bystander CPR you could increase that time by four to five minutes but again showing very similar numbers to the adult population that once you start hitting that 40 to 45 minute time frame, if there's no return of spontaneous circulation then the odds of survival are really quite low.

                                                The time frame may be extended a bit by CPR, maybe be extended by a bit if you had a shockable rhythm. Again, very similar features to what were found in the adult study.

Dr. Carolyn Lam:               What a nice pair of papers. You know, the pediatric paper was paired by yet another, wasn't it? This one now addresses very importantly conventional versus compression only CPR in the pediatric population. Again, from Japan. I know both the pediatric papers were of great interest because you invited an editorial on this as well. You want to comment on those?

Dr. Mark Lane:                  This issue of compression only CPR versus standard CPR, which includes compression and ventilation is a very hot one because we know that if you can do compression only CPR, the individuals willing to do that type of CPR are much greater than the individuals willing to do mouth to mouth. In the adult population, there's been a number of very good retrospective registries and also randomized trials that showed that compression only CPR may be very similar ... In fact some studies better, some studies a little worse than compression-ventilation CPR.

                                                Whether this applies to the pediatric population is not clear. There is more asphyxial arrest in the pediatric population whereas in the adult it's more cardiac so there is concern that compression only CPR will not be as good in children. This group of investigators used the same registry. A little shorter time-frame. They looked at it for two years and thus only had 2,000 patients in this registry. Of these 2,000 patients 400 received conventional CPR, 700 received compression only CPR and 1,000 did not receive any CPR. The important findings in this study was that any CPR increases survival so if you did not get any CPR, your survival was 3.7%. If you got conventional CPR your survival was 25.9% and if you got compression only CPR your survival was 9.3%.

                                                When you compared unadjusted survival with compression only versus the standard CPR, the odds ratio were 3.42 that standard CPR was better than compression only CPR. However when you did multi-variable adjustment, that big difference decreased and was no longer statistically significant between conventional CPR and compression only CPR. The same was true when you did propensity score matching which is an attempt to randomize to match groups. There was really no difference between conventional CPR and and compression only CPR.

                                                From this study, it's clear that any CPR is better than no CPR. There was a hint here that standard CPR was better than compression only CPR but because that improvement disappeared with multi-variable adjustment and propensity score matching both the authors and the editorialists have called that it's time for a randomized trial of compression CPR in kids.

Dr. Carolyn Lam:               Very nice. That brings us already, to the last original paper. Into the in-hospital setting and it talks about time to epinephrine. That's nice. We've got time to balloon and time to door and and now we've got time to epinephrine. Tell us about this one.

Dr. Mark Lane:                  This was a very nice study from the guidelines database. This is a data base that the HA is using to evaluate resuscitation in hospitals. In this database, the investigators looked at times to the epinephrine administration and then overall patient survival for the hospitals. What they found is that there was wide variability in the time to first epinephrine dose. The HA and other counsels have recommended that it be given as soon as possible or early-on in resuscitation and in this database 12.7% of patients had delays greater than five minutes to epinephrine.

                                                What importantly they showed, when you looked at the hospital's overall time to epinephrine administration and the hospital's overall resuscitation survival rates, they were inversely proportional. That is, the longer that hospitals took to give the first dose of epinephrine, the lower their survival rate. This really leads to a very important question, is it the delay in epinephrine administration that makes the difference between these good functioning hospitals and poor functioning hospitals, or is it that the delay to epinephrine administration is really a surrogate for poor CPR performance. I suspect that both of them could be true, although I suspect the second one is probably a higher likelihood.

Dr. Carolyn Lam:               Congratulations again on this amazing issue with extremely important take-home messages just from the original papers. Were there other papers you wanted to highlight in this issue?

Dr. Mark Lane:                  Yeah, there were three research letters and this is a newer type thing for SERP. These are original manuscripts but in a very succinct fashion in that they're making a single point. I actually thought these three research papers were very interesting also. One was on the mechanical CPR in the cares database and in this paper they actually showed that mechanical CPR was associated with poor outcomes in resuscitation so a paper well worth reading. In another paper from France looked at pulmonary embolism related to sudden cardiac death and what they found is that PEs were present in a significant percentage of people who had sudden cardiac arrest and again if you had a non-shockable rhythm, female, prior thromboembolism or absence of heart disease you were more likely to have a pulmonary embolism.

                                                The final research letter looked at ticagrelor versus clopidogrel in comatose patients undergoing PCI, a randomized study. Succinct paper well worth reading. In addition to those three research letters, there were four frames of reference. These are more a personal perspective on resuscitation and resuscitation signs over time and interesting reading, all four of them.

Dr. Carolyn Lam:               Mark, that was a beautiful summary and I am sure you've whet the appetites of all the listeners to just grab hold of this issue. Thank you so much for joining me today. Thank you listeners for tuning in and don't forget to tune in next week.

Dec 12, 2016

Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Today we will be discussing the pooled analysis results of the 10 ODYSSEY Trials with important implications for the reduction of lipids in major cardiovascular events. But first, here's your summary of this week's journal.

The first paper provides experimental data on vascular disease that brings into focus the critical roles of transcription factors such as GATA2 in the maintenance of endothelial cell function, as well as the role of selected microRNAs as a novel player of vascular regulation. In this study by first author Dr. Hartman, corresponding author Dr. Thum from Hanover Medical School, and colleagues, authors used GATA2 gain and loss of function experiments in human umbilical vein endothelial cells to identify a key role of GATA2 as a master regulator of multiple endothelial functions, and this via microRNA-dependent mechanisms.

Global microRNA screening identified several GATA2-regulated microRNAs, including miR-126 and miR-221. GATA2 deficiency led to vascular abnormalities, whereas supplementation with miR-126 normalized vascular function. In a mouse model of carotid injury, GATA2 was reduced and systemic supplementation of miR-126-coupled nanoparticles enhanced miR-126 availability in the carotid artery and improved reendothelialization of injured carotid arteries in vivo.

In summary, GATA2-mediated regulation of miR-126 and miR-221 has an important impact on endothelial biology. Thus, modulation of GATA2 and its targets miR-126 and miR-221 represents a promising therapeutic strategy for the treatment of vascular diseases.

The next study is the first to show that current smokers from the general population have lower levels of circulating cardiac troponin I, a seemingly paradoxical observation given the known detrimental cardiovascular impact of cigarette smoking.

First author Dr. Lyngbakken, corresponding author Dr. Omland, and colleagues from the University of Oslo used data from the large population-based HUNT study, in which cardiac troponin I was measured in 3,824 never smokers, 2,341 former smokers, and 2,550 current smokers. Current smokers had significantly lower levels of cardiac troponin I than never smokers and former smokers, an association that remains significant even after adjustment for potential confounders.

The authors also found an association between increasing concentrations of troponin I and clinical endpoints, namely acute myocardial infarction, heart failure, and cardiovascular death in the total cohort. However, this association was attenuated in current smokers and was significantly weaker than in never or former smokers with a p for interaction of 0.003. The prognostic accuracy of troponin I as assessed by C-statistics was lower in current smokers than in never smokers. Troponin I provided no incremental prognostic information to the Framingham Cardiovascular Disease risk score in the current smokers.

Together, these results suggest that mechanistic pathways other than those involving subclinical myocardial injury may be responsible for the cardiovascular risk associated with current smoking. Future studies are needed to determine whether a lower cardiac troponin I threshold should be considered for exclusion of myocardial infarction in smokers or whether prognostic tools other than measurement of cardiac troponins should be utilized when evaluating risk of future events in current smokers.

The next study contributes to our understanding of cardiomyocyte signaling in response to ischemic injury. In the study by first author Dr. [Wool 00:05:04], corresponding author Dr. [Ju 00:05:04] from Tongji University School of Medicine in Shanghai, and colleagues, authors sought to understand the role of low-density lipoprotein receptor-related proteins 5 and 6 as well as beta-catenin signaling in the heart. They did this using conditional cardiomyocyte-specific knockout mice who had surgically induced myocardial infarction. They found that deletion of lipoprotein receptor-related proteins 5 and 6 promoted cardiac ischemic insults. Conversely, deficiency of beta-catenin, a downstream target, was beneficial in ischemic injury. Interestingly, although both insulin-like growth factor-binding protein 4 and Dickkopf-related protein 1 are secreted beta-catenin pathway inhibitors, the former protected the ischemic heart by inhibiting beta-catenin, whereas the latter enhanced the injury response mainly through inducing lipoprotein-related protein 5 and 6 endocytosis and degradation.

These findings really add to our understanding of the beta-catenin signaling pathway in ischemic injury and suggests that new therapeutic strategies in ischemic heart disease may involve fine-tuning these signaling pathways.

The next paper from the International Consortium of Vascular Registries is the first study allowing an assessment of variations in repair of abdominal aortic aneurysms in 11 countries over 3 continents represented by the Society of Vascular Surgery and European Society for Vascular Surgery. Dr. Beck from University of Alabama-Birmingham School of Medicine, and colleagues, looked at registry data for open and endovascular abdominal aortic aneurysm repair during 2010 to 2013, collected from 11 countries. These were Australia, Denmark, Hungary, Iceland, New Zealand, Norway, Sweden, Finland, Switzerland, Germany, and the United States.

Among more than 51,000 patients, utilization of endovascular aortic repair for intact aneurysms varied from 28% in Hungary to 79% in the United States, and for ruptured aneurysms from 5% in Denmark to 52% in the United States. In addition to the between-country variations, significant variations were present between centers within each country in terms of endovascular aortic repair use and rate of small aneurysm repair. Countries that more frequently treated small aneurysms tended to use the endovascular approach more frequently. Octogenarians made up 23% of all patients, with a range of 12% in Hungary to 29% in Australia. In countries with a fee for service reimbursement systems, such as Australia, Germany, Switzerland, and the United States, the proportion of small aneurysms and octogenarians undergoing intact aneurysm repair was higher compared to countries with a population-based reimbursement model.

In general, center-level variation within countries in the management of aneurysms was as important as variation between counties. Hence, this study shows that despite homogeneous guidelines from professional societies, there is significant variation in the management of abdominal aortic aneurysms, most notably for intact aneurysm diameter at repair, utilization of endovascular approaches, and the treatment of elderly patients. These findings suggest that there is an opportunity for further international harmonization of treatment algorithms for abdominal aortic aneurysms. This is discussed in an accompanying editorial entitled, Vascular Surgeons Leading the Way in Global Quality Improvement, by Dr. Fairman.

The final paper from Dr. Gibson at Beth Israel Deaconess Medical Center and Harvard Medical School and colleagues, presents the results of the apoAI event reducing in ischemic syndromes I, or AEGIS-I, trial, which was a multicenter, randomized, doubleblind, placebo-controlled dose-ranging phase 2b trial of CSL112, which is an infusible, plasma-derived apoAI that has been studied in normal subjects and those with stable coronary artery disease, but now studied in the current study in patients with acute myocardial infarction.

The trial showed that among patients with acute myocardial infarction, four weekly infusions of a reconstituted, infusible, human apoAI, CSL112, was associated with a dose-dependent elevation of circulating apoAI and cholesterol efflux capacity without adverse hepatic or renal outcomes. The potential benefit of CSL112 to reduce major adverse cardiovascular events will need to be assessed in an adequately powered phase 3 trial.

Now for our future discussion. Today I am delighted to have with us Dr. Kausik Ray from Imperial College London, who's the first and corresponding author of a new paper regarding the pooled analysis of the 10 ODYSSEY Trials. To discuss it with us is Dr. Carol Watson, associate editor from UCLA. Kausik, just let me start by congratulating you on this paper. I believe this is the first data that allows us to look under the 50 mg/dL mark of LDL and really ask if the LDL MACE relationship extends below this level.

Dr. Kausik Ray: Yes, the reason for looking at this is that the IMPROVE-IT trial really looked at people down to an average LDL cholesterol of about 54, and with the new PCSK9 inhibitors, which instead of giving you a 20% further reduction LDL, they give you the opportunity for a further 50 to 60% reduction. We actually get the chance to get people down to levels like 25 mg/dL, and the question is, does the benefit continue at that level?

We did a pooled analysis of 10 of the ODYSSEY Trials, really in some ways to try and help predict what you might see in ODYSSEY outcomes, what you might see in the [Fuliay 00:12:00] trial, and to also manage expectations as well, because there's probably been a lot of hype around the two New England Journal papers about 50, 60% reductions of all potential reductions based on small numbers of events. So the question is, if you reduce LDL by 39 mg/dL, how might that reduce your risk, and is the relationship continuous? So those were the aims.

Dr. Carolyn Lam: That's great, and maybe could you give us an idea of the number of patients you are looking at and the number of events?

Dr. Kausik Ray: Yeah. In the 10 pool studies, we had just under 5,000 individuals, and we had just about 6,700 person years' worth of followup. In total, we had 104 first MACE events. To put this into context, it's about one third of the number of events that the first [framing 00:12:53] of analysis had. It's an observation analysis rather than randomized trial data, so you got to bear that in mind with the usual caveats that go with observational data. But the same endpoints that were adjudicated, this is [inaudible 00:13:10] heart disease death, non-fatal MI, ischemic stroke, and unstable angina requiring hospitalization. This is the same endpoint that is in the ODYSSEY Outcomes Trial, so it's interesting in that regard.

Dr. Carolyn Lam: Yeah, it sure is. So what's the bottom line? What did you find?

Dr. Kausik Ray: What we found was that there was a continuous relationship all the way down to LDL cholesterol levels of about 25 mg/dL, that every 39 mg/dL lower on treatment LDL, your risk went down by about 24%. If you looked at [apo-like 00:13:48] approaching be on non-HDL cholesterol, again, you found the same continuous relationship with a similar point estimate for a similar standardized difference in LDL cholesterol. We also looked at many of the guidelines, talk about percentage reduction. We actually looked at percentage reductions. If you start with a baseline LDL of X and you achieve a 50% further reduction in LDL, how much further benefit does that give you? A 50% further reduction gave you a 29% further lower risk of MACE. So we didn't find any threshold or limit all the way down to LDLs of about 25.

Dr. Carolyn Lam: That's really a key, novel finding that you contributed, so congratulations once again. I suppose the question will always be, you're talking about relative risk reductions here. At such low levels, can you give us an idea of the absolute risk reductions?

Dr. Kausik Ray: Yes. You've got to remember that the relative risk reductions are what you can apply to population differences. If you pick a high-risk patient population, you would expect to see a much bigger absolute risk reduction than maybe this study or another study. Similarly, if you pick a low-risk group, you are going to see a much smaller absolute benefit. I always try to advise a little bit of caution that if you basically look at the range ... If you start with let's say an LDL of 150 and you go down to let's say an LDL of 25, you are talking about a 1.25% absolute risk reduction. Remember, these patients are possibly going to be a slightly lower risk than the ones that are recruited into the ODYSSEY Outcomes and into the [Fuliay 00:15:46] trial, for example.

Dr. Carolyn Lam: I think you mentioned what I was going to just ask you about. This is observational. You had 104 events, and I suppose another limitation might be that your followup was two years at max, if I'm not wrong? What do you say about that, and are there plans for future analyses?

Dr. Kausik Ray: Within the context of these studies, I think that the whole of this data will eventually become dwarfed by what we see with the big CDOTs, because you've got 18, 27,000 people, 3 years' worth of exposure and followups, so you are going to have many, many more events. That is a limitation, but I think what is interesting is that we know that the baseline LDL cholesterol level is around about 90 mg/dL. We don't actually know what the actual baseline ... because the baseline [characters 00:16:43] haven't been published for ODYSSEY Outcomes, but the [Fuliays 00:16:46] around about 89. What it tells you is what the point estimate is likely to be. It's likely to be in the 24 to 32% ballpark because that's what your baseline LDL is and that's what we'd predict in the regression lines that we observed here.

I think that we're not going to get many more events in these studies because largely the randomized period of followup is now over. Many of these people are now into open labels, extensions for safety, so we won't get many more events from this. In terms of, I think, the way people should maybe look at this is possibly as a taster for what's to come in the next 18 months or so. I think for the time being it answers two questions. Is lower likely to be better? And it is. I think the other question it tells is how might you get people down to LDLs below 50?

One of the important things was that if you were just on statins, in this population, if you were recruited on the basis of a high baseline LDL, you got no additional people down to LDLs below 50. You got under 10% with add-on [inaudible 00:18:05], but you got around about 50% when you used the PCSK9 inhibitor as an add-on to existing therapy. It tells you about how to get to such low levels as well. I think that's the other key thing that it actually gives you.

We did an analysis of safety [inaudible 00:18:23], and I think that's really important. Once you see the efficacy, or if you see the MACE events continue to go down ... If you looked at treatment-emergent adverse events ... and I completely take the fact that it's every side effect reported altogether, which may or may not be linked to LDL levels specifically, but when we did that, the relationship actually was just a horizontal line, so there was no relationship with percentage reduction or on treatment LDL, so it gave us a nice idea of both safety and efficacy that we might experience in the big outcome studies.

Dr. Carolyn Lam: All right. Obviously the big outcome studies are going to be game changers, and I'd really love to invite [Carol Scotts 00:19:09] here, because there's a whole lot of other things that need to be considered if this becomes the case, isn't it? Carol, I really appreciated that you invited an editorial, and the editorial is by Neil Stone who entitles it, Looking Beyond Statins: Will the Dollars Make Cents? Please tell us about the discussions about this paper that occurred.

Dr. Carol Lam: I would again like to congratulate Dr. Ray on a fantastic paper, and I would like to reiterate exactly what he said. I think it really does give us some comfort about this class of medication and its relative safety. I think that's very important, because I can't tell you how many patients I get and how many referring physicians I get who worry when their patients come back with LDLs of 20 or below. I think that gave us some comfort, and I do also think it was very important to show that this would fall along the same regression line that statins perhaps would fall.

As with all the caveats that Dr. Ray said, I agree with all of them, but I do say this is a tasty little taster, and I appreciate and congratulate you for publishing this. The editorial by Dr. Neil Stone was quite interesting. As you said, he subtitled it, Will the Dollars Make Cents? C E N T S or S E N S E, sort of a play on words there. Will the relative benefits that we can achieve with this class of medications make sense for the cost of these drugs?

That's obviously a very separate issue from what was discussed in the manuscript, but it's something to think about. We understand that there are additional patients that will be helped if they can get their LDL down, and we hope that that will translate into the outcomes. Again, just as Dr. Ray mentioned, we will have to wait for the cardiovascular outcomes trials to be completed. When they are, if they do show the benefits that we hope, will their price point make them accessible to enough patients for this to be a widely applied, utilized therapy? Or will they not? That's part of what was discussed in Dr. Stone's editorial.

Dr. Kausik Ray: When we were writing the manuscript and stuff like that, and we were doing this and everybody's like, "Oh, wow, look at the graphs." I said, "Look, we need to balance all of these bits and reassure ... We've got an opportunity." So I suggested them giving those additional analyses, and you saw how big the online supplement was. There was a ton of work that we put into this, and to format it into a concise ... I really want to just thank the editorial board for giving us the chance and actually being able to help us and work with us on this, because it's really important. I hope people look at all of those things because it will help people also that question the LDL. They all talk about the hypothesis and the safety of really low LDLs, and people come off statins as a result. I think this will help.

Dr. Carolyn Lam: You're listening to Circulation on the Run. Thank you so much for being with us, and don't forget to tune in next week.

Dec 5, 2016

Dr. Carolyn Lam:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Our feature discussion is regarding the exciting results of the masked hypertension study showing that clinical blood pressure underestimates ambulatory blood pressure, but first here's your summary of this week's issue.

The first study reviews the largest clinical experience so far with pulmonary vein stenosis following ablation for atrial fibrillation. First author Dr. Fender, corresponding author Dr. Packer and colleagues from Mayo Clinic Rochester, Minnesota evaluated the presentation of 124 patients with severe pulmonary stenosis between 2000 and 2014 and examined the risk for re-stenosis after intervention utilizing either balloon angioplasty alone or balloon angioplasty with stenting. All 124 patients were identified as having severe pulmonary vein stenosis by CT in 219 veins. 82% were symptomatic at diagnosis with the most common symptoms being dyspnea, cough, fatigue and decreased exercise tolerance. 92 veins were treated with balloon angioplasty, 86 with stenting and 41 veins were not intervened on. The acute procedural success rate was 94% and did not differ by initial management. Overall, 42% of veins developed re-stenosis, including 27% of veins treated with stenting and 57% of veins treated with balloon angioplasty.

The three-year overall rate of re-stenosis was 37% with 49% of balloon angioplasty treated veins compared to 25% of stented veins developing re-stenosis. This was a difference that remained significant even after adjusting for age, CHADS2 VASC score, hypertension and time period of the study with an adjusted [inaudible 00:02:30] ratio of 2.46 for risk of re-stenosis with balloon angioplasty versus stenting. In summary, this study shows that the risk for pulmonary vein re-stenosis is significant following atrial fibrillation ablation. The diagnosis is challenging due to non-specific symptoms and while there is no difference in acute success by type of initial intervention, stenting significantly reduces the risk of subsequent pulmonary vein re-stenosis compared to balloon angioplasty.

The next paper shows that the index of microvascular resistance, which is a novel invasive mreasure of coronary microvascular function, has emerging clinical utility as a test for the efficacy of myocardial re-perfusion in invasively managed patients with acute ST elevation myocardial infarction. In this study by first author Dr. [Carrick 00:03:30], corresponding author Dr. Barry and colleagues from the University of Glasgow in Scotland, index of microvascular resistance and coronary flow reserve were measured in the culprit artery at the end of percutaneous coronary intervention in 283 patients with ST elevation myocardial infarction. Authors found that compared with standard clinical measures of the efficacy of myocardial re-perfusion, such as ischemic time, ST segment elevation and angiographic blush grade, the index of microvascular resistance was more consistently and strongly associated with myocardial hemorrhage, microvascular obstruction, changes in left ventricular ejection fraction and left ventricular end diastolic volume at six months as well as all caused death of heart failure during the median follow up of 845 days.

In fact, compared with an index of microvascular resistance greater than 40, the combination of this index and coronary flow reserve less than two did not have incremental prognostic value. The take-home message is therefore that an index of microvascular resistance above 40 represents a prognostically validated reference test for failed myocardial re-perfusion at the end of primary percutaneous coronary intervention. This study supports further research into microvascular resistance based therapeutic strategies in these patients.

The next study provides experimental data regarding molecular mechanisms underlying calcific aortic valve disease. First author, Dr. Haji, and corresponding authors Dr. Matthew and [Bose 00:05:24] from the Quebec Heart and Lung Institute in Canada performed genomic profiling and in-depth functional assays in human aortic valves. They demonstrated for the first time that the promotor region of the long non-coding RNA H19 is hypomethylated in patients with calcific aortic valve disease. This hypomethylation in turn increases H19 expression in the valve interstitial cells where it prevents Notch 1 transcription by blocking or out-competing P53’s recruitment to the Notch 1 promotor. Thus, H19 appears to be the missing link connecting Notch 1 to idiopathic calcific aortic valve disease. It may therefore represent a novel target in calcific aortic valve disease to decrease osteogenic activity in the aortic valve.

The next paper describes the largest cohort of mycotic abdominal aortic aneurysms to date and is from Dr. [Sorelias 00:06:37] and colleagues of Uppsala University in Sweden.  These authors identified all patients treated for mycotic abdominal aortic aneurysms in Sweden between 1994 and 2014. Among the 132 patients, they noted that the preferred operative technique shifted from open repair to endovascular repair after 2001 with the proportion treated with endovascular repair increasing from 0% in 1994 to 2000 to 60% in the 2008 to 2014 period. Survival at three months was lower for open repair compared to endovascular repair at 74% versus 96% respectively with a similar trend present at one year. A propensity score adjusted analysis confirmed the early better survival associated with endovascular repair. During a median follow up of 36 months for open repair and 41 months for endovascular repair. There was no difference in long-term survival, infection-related complications or re-operation. The take-home message is that endovascular repair appears to be a durable surgical option for treatment of mycotic abdominal aortic aneurysms.

The final study provides insights into the molecular mechanisms by which aldosterone triggers inflammation and highlights the particular role of NLRP3 inflammasome, which is a pivotal immune sensor that recognizes endogenous danger signals and triggers sterile inflammation. Authors Dr. Bruden [Esimento 00:08:32], Dr. [Tostes 00:08:33] and colleagues from the University of Sao Paulo in Brazil analyzed vascular function and inflammatory profiles of wild-type NLRP3 knockout, caspase-1 knockout and interleukin-1 receptor knockout mice, all treated with vehicle or aldosterone while receiving 1% saline. They found that mice lacking the interleukin-1 beta receptor or lacking inflammasome components such as NLRP3 and caspase-1 were protected from aldosterone-induced vascular damage. In-vitro, aldosterone stimulated NLRP3-dependent interleukin-1 beta secretion by bone marrow derived macrophages. Chimeric mice reconstituted with NLRP3 deficient hematopoietic cells showed that NLRP3 in immune cells mediated the aldosterone-induced vascular damage.

In addition, aldosterone increased the expressions of NLRP3, caspase-1 and mature interleukin-1 beta in human peripheral blood mononuclear cells. Finally, hypertensive patients exhibited increased activity of NLRP3 inflammasome. Together these data demonstrate that NLRP3 inflammasome via activation of interleukin-1 receptor is critically involved in the deleterious vascular effects of aldosterone, thus NLRP3 is a potential target for therapeutic interventions in conditions with high aldosterone levels.

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

On today’s podcast we are going to be discussing the very important issue of masked hypertension. This is an issue that gets a lot less attention than I think compared to white coat hypertension. I’m so pleased to have the first and corresponding author of the masked hypertension study, Dr. Joseph Schwartz, from Stony Brook University and Columbia University in New York. Welcome to the show, Joe.

Dr. J. Schwartz:
My pleasure. I’m delighted to join you.

Dr. Carolyn Lam:
We have a regular on the show today as well, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back Wanpen.

Dr. Wanpen V.:
Thank you so much. Happy to be here.

Dr. Carolyn Lam:
Joe, I want to start by addressing the common misperception that ambulatory blood pressure is usually lower than clinical blood pressure. That seems to make a lot of sense to us clinically because, for example, I always use ambulatory blood pressure to diagnose white coat hypertension and so the assumption there is that my clinically measured blood pressure is higher than what I’m going to be finding if this patient measures the blood pressure on an ambulatory 24-hour basis. It’s also from the cutoffs that we use. For example, ambulatory blood pressure we use a 24-hour cutoff of 130/80 to make the diagnosis whereas with clinical blood pressure we use a cutoff of 140/90 so all of this kind of reinforces that ambulatory blood pressure is usually lower. Your study, though, tells us otherwise so please fill us in here.

 Dr. J. Schwartz:
You're right that in the doctor's office there are a certain set of people who probably get anxious when they're around a doctor and with that anxiety may cause a temporary increase in their blood pressure, a temporary elevation, and that's the basis of where we think white coat hypertension comes from. That's a very widespread belief among doctors and it's even been in previous guidelines, there have been statements to that effect. When I talk to people out in the general public and tell them I'm doing a study comparing blood pressure out in the real world compared to blood pressure in the doctor's office, all of them tell me, "Well, usually when I'm in a doctor's office that's a relatively calm period for me unless there's really something wrong with me and out in the everyday world I have to face a variety of stressors. I have deadlines. I have places I need to get to. Sometimes I have people yelling at me. Sometimes I'm just in a hurry."

All these things elevate your blood pressure out in the real world and so when we were trying to recruit people for the study, and we were very agnostic in recruiting them, telling them that we were interested in the differences in blood pressures between the doctor's office and the ambulatory blood pressure and they might go in either direction. When I told them about the fact that their ambulatory blood pressure or real world blood pressure might be higher than in the doctor's office, the vast majority of people nodded affirmatively and said, "It wouldn't surprise me at all."

Dr. Carolyn Lam:
Could you define masked hypertension compared to white coat hypertension and tell us a little bit about the population you studied.

Dr. J. Schwartz:
Sure. First with the definition. I'm going to say something a little bit different from something you said before. You mentioned cutoffs that we typically used for ambulatory blood pressure of 130/80 and those are the cutoffs that are used if you compute an average blood pressure over the entire 24 hours. What many people do, and what we did for this study, was compare the average blood pressure when people were awake to their blood pressure in the doctor's office because obviously in the doctor's office everybody is awake. The typical cutoffs there are 135/85, recommended by numerous guidelines in this country and with our international collaborators. The definition of masked hypertension is having a blood pressure in the clinic setting that's below 140/90 but having an ambulatory blood pressure where either the systolic blood pressure is above 135 or the diastolic is above 85 millimeters of mercury.

In terms of the sample, for years I've had a particular strategy for trying to recruit participants. I do worksite-based studies and so I identify large organizations that will allow me to recruit their employees and then what we did for this study is go to individual departments, both here at Stony Brook University, at Columbia University, at a residential veterans' home that's affiliated with Stony Brook University and then also at a local private hedge fund management company. We would go to these sites, I talk to the head of a department and tell them a little bit about masked hypertension and what the study was about and ask them if they would be willing to have their employees participate in the study. Once I had the okay from the department head then we would conduct public health screenings, blood pressure screenings. My staff and I would go into the department for multiple days and invite anybody who was interested to have their blood pressure taken on site and while we were taking those blood pressures carefully.

The proper way to take those is to take three readings and leave a minute or two interval between them and rather than just have silence then between the readings we would tell them a little bit about our study. At the end of the study if they didn't have extremely high blood pressure and were not taking blood pressure medication we would ask them if they might be interested in participating in the study that we just described. That's how we identified potential participants and about 2/3 of the people that we talked to who looked eligible indeed chose to participate.

Dr. J. Schwartz:
The one other thing I might mention that I think we mentioned, I hope we mentioned as a limitation of the study, is that everybody in the study had health insurance and at least until recently there were very large portions of the population that didn't have health insurance, everybody by virtue of their employment by the organizations that participated in the study, did have employer-based health insurance.

Dr. Carolyn Lam:
Thanks for clarifying the population so well. Could you just give us the top line of your findings. How big a difference did you find, which direction and that intriguing effect of age?

Dr. J. Schwartz:
Sure. The first thing we found is that on average the systolic blood pressure is seven millimeters mercury higher out in everyday life than it is in the clinic setting where we take our clinic readings. I should mention that unlike most studies, and all studies at the time that we began our study, we brought people in three separate times to take the clinic blood pressure. Up until that, almost all of the studies of ambulatory blood pressure monitoring only had clinic blood pressures from a single visit. I think we have a very reliable measure of the clinic blood pressure as well as reliable measure of ambulatory blood pressure. We see a seven millimeter difference in the systolic blood pressure and a 2 millimeter difference, again the ambulatory being higher for diastolic blood pressure.

What's more remarkable is if you think about what's a sizable difference. If you think if we perhaps somewhat arbitrarily say 10 millimeters of systolic blood pressure is a large difference. More than 35% of the population has an ambulatory blood pressure that is more than 10 millimeters higher than their clinic blood pressure whereas only 3% of our sample had that large a difference in the opposite direction, what many people would call a white coat effect. It's more than a 10 to 1 difference in numbers of people who have elevated ambulatory versus elevated clinic.

You asked me to mention something about the age difference. When you look at how that difference in systolic blood pressure varies by age, it's quite a bit larger for people who are younger. If you're under 30 the difference is, on average, 10 millimeters rather than seven millimeters and if you go up as you approach 60 years of age or so the difference becomes relatively small, perhaps in the neighborhood of two millimeters. We don't have enough people because it's a working population over 65 to say very much about what would happen. In fairness to prior research, which often is on older populations and particularly hypertensive populations, the studies that have historically shown that ambulatory blood pressure tends to be lower than clinic blood pressure are in these older populations and populations that have elevated blood pressure to start with.

My speculation there, and you haven't asked me to mention it but I will, is that older people and those with hypertension have a reason to be more nervous or more anxious when they go to the doctor than people who are not taking medication and probably don't even know that they have hypertension. People who are just being screened perhaps during a routine physical for the possibility of hypertension, because the doctors take a blood pressure reading every time you go in, they're doing that in order to see whether you might have hypertension, but most people who are going in for what we call a well patient visit are not nervous about their blood pressure being high.

Dr. Carolyn Lam:
I have to say, the take-home message for me when I read this was, I am not paying enough attention to masked hypertension and then another thing was, maybe I need to think about more white coat hypertension in the older and masked hypertension in the younger. Wanpen, do you think it's as simple as that? What were your take-home messages?

Dr. Wanpen V.:
I think this is a very important study that examines this in a systematic way. I'm not surprised that Joe found as much masked hypertension here. I think that he's absolutely right. We looked at this in Dallas Heart Study as well recently and we found that in the population-based sample in Dallas almost 20% of people have masked hypertension and white coat we found only like 3% and the average in the Dallas Heart Study was very close to those samples, about mid-40s. I think that's a very important finding in that the people with masked hypertension would not be suspected otherwise to have problems. Also, in the Dallas Heart Study they used home readings but Dr. Schwartz used ambulatory blood pressure monitoring. Unless extra out of office monitoring is being done we will totally miss these people who are more likely to have target organ damage from high blood pressure. I think that's absolutely important.

Dr. Carolyn Lam:
Actually, Wanpen you brought up something I was going to bring up as well. Where does home blood pressure fit in with this? Do you think it's home blood pressure versus ambulatory blood pressure?

Dr. Wanpen V.:
The US Preventive Services Task Force has issued a little bit of recommendations recently that we need to either use ambulatory blood pressure monitoring or home blood pressure monitoring to confirm diagnosis of hypertension in the office. If someone shows up with elevated blood pressure in the office either home blood pressure or ambulatory blood pressure needs to be done. If we just followed that guidelines we're still going to miss people with masked hypertension because by definition they don't have elevated blood pressure in the office. I think that from these findings and Dr. Schwartz' study I think to catch these people we really need to pay attention to people with pre-hypertension type of blood pressure because it seems like those are the group that has the most probability to have elevated ambulatory blood pressure so anyone with borderline blood pressure in the clinic, those are the ones who the doctor needs to tell the patient to monitor blood pressure at home or order ambulatory blood pressure themselves if that's available in their facility.

Dr. Carolyn Lam:
Wanpen, I fully agree. What an important message. Joe, I'd like to give you the final word but I'd love to hear how you have maybe taken this into your own practice.

Dr. J. Schwartz:
I think we mostly focused on and indeed the paper mostly focuses on the difference between clinic blood pressure and ambulatory blood pressure. When we talk about the young people, the young people have a bigger difference but those differences are for the most part all in the normal range. You might see a 10- or a 12-point difference but it might be that the ambulatory is 124 and the clinic is 112 and no doctor is going to worry about that very much. There are really always two things that we're trying to look at simultaneously: The first is what is that difference between the ambulatory and the clinic, but the second is for whom does the clinic stay under the threshold for diagnosis of hypertension but the ambulatory is over? That's the diagnosis of masked hypertension.

We haven't said it today so I'll say it: Of those people who had normal clinic blood pressures averaged across three repeated visits, 15.7% of them had elevated ambulatory blood pressure and would have been diagnosed as having hypertension based on their average daytime ambulatory blood pressure reading. That's one message.

The last message is unfortunately there is almost no research yet telling us what we should do in terms of treating people with masked hypertension. We are now at the point where we can identify these people and we're also at the point where we now know that there are a lot of such people and we don't even have any research to base guidelines on for deciding what we should do with them. The most obvious thing is to recommend lifestyle changes. If they're overweight we could suggest that they lose weight. We could suggest that they exercise more. We might think about treating some of those people, especially if their ambulatory blood pressure is well above 140/90. There are no statements out in the literature by any of the organizations, and in fact there's no research examining whether there's a benefit or not a benefit to perhaps putting some of those people on medications. I think that's a big question that future research needs to address.

Dr. Carolyn Lam:
Joe, thank you so much. I think your last statements just really emphasize how important this paper is. It increases awareness and it's going to open the door to much more needed research in this area. Thank you so much. Thank you Joe and Wanpen for being on the show today.

Thank you listeners for joining us. Don't forget to join us next week for even more news and exciting discussions.