Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
In just a moment, we are going to be discussing the feature paper on results of the RE-LY trial in patients with valvular heart disease. Yes, you heard me right, this means dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. You need to listen to this discussion with first author Dr. Michael Ezekowitz, but first here is a summary of this week's issue.
In the first study, Dr. Norby and colleagues from the School of Public Heath University of Minnesota assessed trajectories of cardiovascular risk factors and the incidence of atrial fibrillation over 25 years in the ARIC study or the Atherosclerosis Risk in Communities Study. They first assessed the trajectories of cardiovascular risk factors in more than 2,400 individuals with incident atrial fibrillation and more than 6,400 matched controls. Next, they determined the association of those risk factor trajectories with the incidence of new atrial fibrillation among more than 10,500 individuals free of atrial fibrillation at baseline.
The main finding was that stroke, myocardial infarction and heart failure risk increase steeply during the time close to diagnosis of atrial fibrillation. All cardiovascular risk factors were elevated in atrial fibrillation cases compared to controls more than 15 years prior to the diagnosis. A trajectory analysis showed not only the presence of the risk factors such hypertension and obesity, but also their duration which was more informative in determining the risk of atrial fibrillation compared to a one time clinical measurement.
Finally, they identified diverse and distinct trajectories for the risk factors findings that carry implications for the different roles of different risk factors in the pathogenesis of atrial fibrillation. The findings of this very significant study also highlight the need to establish preventive strategies that address risk factors decades before atrial fibrillation diagnosis.
The next study is by first author Dr. van der Valk and corresponding author Dr. Strauss from the Academic Medical Center in Amsterdam. These authors aimed to better understand the underlying mechanisms responsible for atherogenicity of lipoprotein a or LPa. The authors achieved this aim by a combination of three approaches. First, in vivo magnetic resonance imaging using 18F-FDG PET/CT and SPECT to measure atherosclerotic burden, arterial wall inflammation and monocyte trafficking to the arterial wall. Secondly, ex vivo analysis of monocytes using facts analysis, inflammatory stimulation assays and trans endothelial migration assays. Third, in vitro studies on monocytes using an in vitro model for trained immunity.
Their main findings were that, firstly, individuals with elevated LPa had increased arterial wall inflammation in vivo. Secondly, that monocytes from these individual remain in a long lasting activated state ex vivo, and finally, that LPa elicited a pro-inflammatory response in healthy monocytes in vitro, an effect that was markedly attenuated by removing or inactivating oxidized phospholipids on LPa.
In summary, this study nicely shows that LPa induces monocyte trafficking to the arterial wall and mediates pro-inflammatory responses through its oxidized phospholipid content. The clinical implications are therefore, that oxidation's specific epitope targeted therapy using for example specific antibodies as single gene antibodies may bear clinical potential to modulate the arthrogenic impact of LPa.
The final study is from first author Dr. Mazen, and corresponding author Dr. Ouzounian from Toronto General Hospital and University of Toronto in Ontario, Canada. These authors sought to compare the long term outcomes of patients undergoing the Ross procedure compared to mechanical aortic valve replacement in a propensity match cohort study of 208 pairs followed for a mean of 14 years.
They found long term survival and freedom from re-intervention were comparable between the Ross procedure and mechanical aortic valve replacement. Of note however, the Ross procedure was associated with improved freedom from cardiac and valve related mortality, as well as a significant reduction in the incidence of stroke and major bleeding. This paper provides important evidence that supports continued used of the Ross procedure in properly selected young adult patients in specialized centers.
What this means is having experienced surgical teams dedicated to mastering the technique and committed to carefully following up the patients for possible late complications. This and more is discussed in a provocative editorial by Dr. Schaff from Mayo Clinic Rochester, Minnesota who provocatively entitled his editorial 'The Ross Procedure: Is it the Preferred Procedure or Double, Double Toil and Trouble?'
Those were all summaries, now for our featured paper.
I am so excited to be joined from all over the world to discuss the featured paper today, and that is on the comparison of dabigatran versus warfarin in patients with atrial fibrillation and valvular heart disease. To discuss this first we have, first and corresponding author, Dr. Michael Ezekowitz from the Sidney Kimmel Medical College at Thomas Jefferson University and Lankenau Medical Center in Philadelphia, as well as from the Cardiovascular Research Foundation in New York. Welcome Michael.
Thank you very much.
Michael, you're calling from South Africa aren't you?
I am indeed.
That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.
Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.
I love this and it is extremely exciting and the most global discussion that we have had so far, with calling in Japan and Singapore and South Africa. Indeed it's because we're discussing a very important problem globally. Michael first, when we talk about the RE-LY trial and the NOAC trials, we're always associating them with non-valvular atrial fibrillation, and yet your topic is discussing valvular heart disease from RE-LY. Can you please start by clarifying that?
I think the reason we wrote this paper is that there is a misunderstanding of the patient populations that was studied in all the NOAC trials because they were characterized as having non-valvular atrial fibrillation. That's only partially true because in all the trials, patients with mechanical heart valve and hemodynamically significant mitral stenosis were excluded, and yet there were many patients with valvular disease that were included. In the RE-LY trial which is the focus of this particular paper, 25% of the patients had some form of valvular disease that were recruited into the study. So the term non-valvular is misleading.
That is such an important clarification, and it's an issue that I see a lot in Singapore. Frankly, lots of patients with atrial fibrillation have some valve disease even if you exclude prosthetic valves, significant mitral stenosis or valvular heart disease requiring intervention. We're very clear not that this is the patient population you're referring to. Shinya, I want to bring you into this. I see lots of these patients, how about you?
The same. Majority of patients have valvular heart disease, small mitral regurgitation is very common. We are excluding only clinically overt mitral stenosis and basically mechanical heart valve in all the newest trials. As Michael pointed out, it is very important to correct misunderstanding. Non-valvular atrial fibrillation, we used in the clinical trial is all atrial fibrillation except clinical overt mitral stenosis and prosthetic for mechanical heart valve.
Exactly. A great foundation for us to get our understand right before we discuss the findings. Michael, could you please give us the top line result and tell us what do the results mean for your own clinical practice?
Basically, it means that the patients with valvular heart disease that were included in the trial, and these included patients with mitral regurgitation with was the most common lesion, mixed aortic valve disease, tricuspid regurgitation, and also it turned out that there were 192 patients that had mild mitral stenosis. Those with mitral stenosis were presumed to be rheumatic in ideology, and they did have a profile of having rheumatic heart disease, that there were more females, they were younger, there was a high incidence of heart failure and a high incidence of TIA and stroke.
The bottom line here is whether the patients had mild mitral stenosis or the other forms of valvular disease that I just mentioned, that they benefited in an identical fashion from the 150 milligram BID dose of dabigatran and the one 110 milligram BID dose of dabigatran as those patients without any valvular disease. The bottom line is that clinicians can use dabigatran with equal confidence in these patients with valvular disease as in patients without valvular disease.
Thank you Michael, that was very reassuring and something that is very clinically important. Shinya, I'm going to ask a different question. First, maybe your take on the findings, and secondly, what was it like handling this paper across the globe as the Associate Editor Managing this?
That is a very important point. The past as Michael pointed out, this paper is very important to remind the clinician of non-valvular atrial fibrillation is not really non-valvular atrial fibrillation, and there is no difference between valvular atrial fibrillation except mitral stenosis and prosthetic valve. The result is similar to non-valvular atrial fibrillation in regard to the effect of dabigatran or by warfarin. That is the one point I have to assure. As a part, it is very important. We are now including many patients not limited in that North America, Europe. We are participating a huge number of patients from Asia. The results is applicable to the global level. We are now leading in that global evidence-based world and RE-LY is one of the good example for the global trial testing the hypothesis with [inaudible 00:13:58] over warfarin.
Michael made a very good summary of that, not only limited to RE-LY, he talked about as our trial like ARISTOTLE and the ROCKET trial. All of the NOAC trial include patient who is valvular heard disease, and the exclusion criteria is a little bit different. Michael beautifully summarized that difference in the table, in his paper. There is a strong intention to publish this paper integration from all the editorial of old member. This is a very nice paper.
He's been very kind, that's very nice. That's true. In fact, the results in RE-LY were compared in an indirect fashion with the other trials, ROCKET and ARISTOTLE, through have published similar papers on patients with and without valvular heart disease. Just in summary, the bottom line is that this finding in RE-LY is highly reproducible in the other two trials so this is an important finding that is reproducible and true of the three novel agents that had looked at this in detail.
The other point that was raised is that there were differences in the exclusion criteria in these trials, but at the end of the day, the Europeans and the Americans in terms of guidelines, had fairly similar recommendation. For instance in the United States, it was felt that all patients with valvular disease could be anti-coagulated with the novel agent unless they had rheumatic mitral stenosis, mechanical or bioprosthetic heart valves, or patients that had undergone a prior mitral valve repair. The emphasis was that all other patients could be included.
The Europeans differed slightly and that they agreed that mechanical prosthetic valve and moderate to severe mitral stenosis should be excluded, but they were somewhat more global in recommending inclusions of all other valvular conditions. There is a slight difference then between the European and the American recommendations and guidelines.
On that note of looking across the world at the guidelines and what these results mean, it really leaves me to congratulate you Michael on such an excellent paper, and Shinya for just managing this paper so well.
Thank you very much for your invitation. Bye-bye.
You've been listening to Circulation on the Run. Thank you for joining us today.
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. Have you wondered which anti-platelet agent you should use in your patients with diabetes and coronary artery disease? Well, our feature paper deals with just this topic, so stay tuned, I'll be write back with it's author and associate editor. First, here's your summary of this week's journal: The first paper unravels novel peptides involved in atrial extracellular matrix remodelling in atrial fibrillation. This is work from first author Dr. Barallobre-Barreiro, corresponding author Dr Mayr from King's College London, and colleagues. They used novel mass spectrometry methods to analyze extracellular matrix in human atrial appendages from patients undergoing coronary artery bypass surgery.
Now, previous proteomic studies have examined the cellular proteome, but this is the first study to comprehensively characterize extracellular matrix proteins in human cardiac tissues, including the identification of glycosylation sites. They found extensive cleavage in the protein core of decorin which is a small leucine-rich proteoglycan that regulates collagen fibrillogenesis and a variety of other extracellular matrix cell signalling molecules. Decorin processing differed between human ventricles and atria and was altered in disease. It's C-terminus which is important for the interaction with connective tissue growth factor was predominantly detected in ventricles compared to atria. In contrast, atrial tissues from patients in persistent atrial fibrillation had higher levels of full length decorin, but also harbored a unique cleavage site that was not found in atrial appendages from patients in sinus rhythm. This unique cleavage site preceded the M-terminal domain of decorin and altered the binding capacity for myostatin, this altering muscle growth.
The cleaved decorin peptide antagonized myostatin, such that myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and in hearts of decorin-null mice. Furthermore, a synthetic peptide corresponding to this decorin region, those dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts. This is clinically important because mystatin inhibition has been implicated as a substrate for atrial fibrillation. This study therefore provides first evidence that peptides generated from the cleavage of extracellular matric proteins such as decorin, constitutes a local regulatory mechanism for growth factors in human cardiac tissue.
The next study looked at therapeutic hypothermia in patients with out of hospital cardiac arrest, and questioned if it may be most effective when induced early during cardiopulmonary resuscitation or CPR, in contrast to prior trials that looked at therapeutic hypothermia induced only after return of spontaneous circulation and hospital admission. This is the RINSE trial from Professor Bernard and colleagues from Ambulance Victoria Australia, which was a multi center randomized controlled trial which assigned adults with out of hospital cardiac arrest undergoing CPR to either a rapid intravenous infusion of up to two liters of cold saline, or standard care. The primary outcome measure was survival at hospital discharge. Secondary end points included return of spontaneous circulation.
The trial was unfortunately closed early at forty-eight percent of the recruitment target, due to changes in temperature management protocols at the major receiving hospitals. Still, a total of one thousand, one hundred and ninety-eight patients were randomized. Six hundred and eighteen to therapeutic hypothermia during CPR, and five hundred and eighty to standard pre-hospital care. Overall there was no difference in outcomes at discharge. In patients with an initial shockable cardiac rhythm there was lower rate of return of spontaneous circulation in patients who received cold saline compared with standard care. Thus, although this trial was stopped early, the data suggests that induction of mild therapeutic hypothermia using a rapid infusion of large volume intravenous cold saline during CPR did not affect outcomes at hospital discharge and may in fact cause harm in the subset of out of hospital cardiac arrest patients who present with shockable rhythm.
The last study provides the first generalizable risk score for sudden cardiac death among American adults from the general population without a history of cardiovascular disease. This large study from Dr. Deo of University of Pennsylvania, and colleagues, derived a sudden cardiac death prediction model using the Atherosclerosis Risk in Communities or ARIC cohort, and validated it in the Cardiovascular Health Study or CHS cohort. They found that the twelve independent risk factors in the ARIC study included age, male sex, African American race, current smoking, systolic blood pressure, use of [anti-hypotensive 00:06:00] medication, diabetes, serum potassium, serum albumin, HDO, estimated GFR, and QTC interval. Over a ten year follow up period this model combining these risk factors showed good to excellent discrimination for sudden cardiac death risk. In fact the model slightly outperformed that of the 2013 ACC AHA pooled cohort risk equations.
Finally, they also showed in the echocardiographic sub-cohort that a left ventricular ejection fraction less than fifty percent was present in only 1.1 percent of these participants and did not enhance sudden cardiac death prediction. This study importantly contributes to the distinguishing of sudden cardiac death risk across the general population, and the results can help target future strategies aimed at sudden cardiac death prevention for the highest risk subgroups in the American general population. That does it for the summaries. Now for our feature paper.
For our feature paper today we are discussing the super important issue of anti-platelet therapy in type 2 diabetes with coronary artery disease. Joining me today are the corresponding author, Dr. Dominick Angiolillo from the University of Florida College of Medicine - Jacksonville, as well as Dr. Gabriel Steg, Associate Editor from Paris, France. Welcome gentlemen.
Thanks for having us.
Dominick, I'd really like to start with you. Your paper entitled the OPTIMUS-4 Study, is really a study of the pharmacodynamic comparison of Prasugrel versus Ticagrelor in these patients with type 2 diabetes and coronary artery disease. The whole question is, what was the rationale to look at the pharmacodynamics?
As the title of the study says, OPTIMUS-4, it means that there was an OPTIMUS-1, 2 and 3 in the past, which means that there's a lot of thought that went into this and a lot of background information. The rationale for this specific study was that we're all well aware of the fact that patients with diabetes have high platelet reactivity, which may be one of the reasons why they have a higher risk of recurrent atherothrombotic events. Therefore, the need to define ways to optimize their anti-platelet effects, their levels of platelet inhibition. In this specific study we took an approach of looking at the novel, although we cannot call them novel nowadays, but the newer P2Y12 receptor inhibitors Prasugrel and Ticagrelor. Looking at them in a head to head comparison from a pharmacodynamic standpoint to see if one drug would be superior than the other, again, in terms of a platelet inhibitory effect.
This is the rationale, and just to expand a little bit on this, there's been a perception, again I want to underscore a 'perception' that based on subgroup analysis of the larger clinical trials, that Prasugrel is a superior drug for patients with diabetes. We do know that there's a benefit also with Ticagrelor compared with Clopidogrel, although the absolute risk reductions in the studies led to a perception that Prasugrel would be a better drug. We said to ourselves, "Well, we're never going to have a large scale head to head clinical comparison, why don't we do a head to head pharmacodynamic comparison to see if there are any differences?" This was the overall rationale for conducting this specific study.
That really sets a background perfectly. Tell us about the main findings.
The main finding was as follows, we conducted a very detailed pharmacodynamic study, this was a prospective randomized double-blind double-dummy crossover study, with all patients on the background of aspirin therapy. We looked at platelet reactivity, using a variety of assays, I like to say it in every possible salsa that you can imagine. The primary end point which is platelet reactivity at one week into two drugs, using an [ADP 00:10:00] specific assay, actually showed that Ticagrelor was superior to Prasugrel in terms of platelet inhibitory effects. That was the only time point where it was shown, but the study was actually designed to show the opposite, so it was a very interesting finding, while with all the other time points there were no differences between the platelet inhibitory effects between the two drugs.
The other thing that we did look at, which gives a little bit of a novelty to this study is, we went beyond just looking at ADP induced effects, which is the target for these two drugs, we looked at other signalling pathways which one would not believe to be necessarily affected by P2Y12 inhibitors, and we found these also to be reduced by both drugs to a similar extent.
Fascinating. I'm going to get to your second point a bit later. First, that first finding that surprisingly Ticagrelor appeared to perform better using one of the specific assays and so on, I'd really like Gabriel's opinion there. What do you think is the overall clinical implications or what was the message that the editorial board was hoping to get across to the audience? Because I noticed you invited an editorial as well, a beautiful one written by Dr. [Star-ee-an 11:36] Parker. What was the thinking behind that?
I think this is really a very important paper and I'm delighted that Dominick Angiolillo and his team submitted it to Circulation, in fact to be frank, we invited that paper after seeing his presentation at the ACC earlier this year. The reason that paper caught everybody's attention in the editorial board was that it's addressing a frequent and deadly disease, diabetes, that kills really patients with cardiovascular disease. There's a critical issue in the treatment because of the limitations of Clopidogrel because of the increased platelet reactivity in diabetics, and there's tremendous interest in the novel P2Y12 inhibitors Prasugrel and Ticagrelor, and of course any hint of differences between these agents has major clinical implications. In addition, I think I can state that Dominick's team is really one of the premiere international teams looking at this exact issue, platelet reactivity in diabetics. What they did was really state of the art rigorous clinical investigation by a highly skilled team, looking rigorously at a double blind crossover designed four different assays looking at platelet function and platelet response, looking both at the effect of a loading dose and the maintenance dose.
To me, the message is not a minute difference between the treatments, in fact I think that even though it's the primary outcome and it does show a slightly greater response with Ticagrelor than with Prasugrel, the overall most of the other assays at the other time points show a consistent good response with both agents. To us, and to me, the message is that the novel agents are clearly superior to Clopidogrel as we've seen in the clinical trials, but they are fairly consistent in their benefit, and it's reassuring to see this not in healthy volunteers but in actual patients with stable coronary artery disease. I think it was really important to show that. Certainly platelet reactivity doesn't summarize entirely the effects of any drug, and there might be platelet independent effects of Ticagrelor mostly and possibly Prasugrel, but I think on the platelet side, I think that this paper really nails it.
I read that editorial and really agree that that puts everything in perspective really well. I particularly like the figure that accompanied the editorial. In case any of our listeners out there don't really remember all the different pathways and how Prasugrel and Ticagrelor and Clopidogrel are metabolized differently, I'd really refer everyone to that figure as well. Just want to pick up on one of the points that both of you mentioned, and that is the non ADP induced platelet reactivity that Prasugrel and Ticagrelor both seem to have an affect on and so on, and if they're so effective, Dominick, is there still a role for aspirin co-administration with these new anti-platelet agents?
The study clearly puts a little bit more beef, let's put it this way, to some of the ongoing clinical studies looking at whether we need aspirin in the patients treated with one of these newer P2Y12 receptor inhibitors. There are a series of ongoing studies out there. There's a laundry list, so I'm not going to go into the details. It does highlight that maybe when you have ultimate P2Y12 blockade, which is a key signalling pathway and blocks other responses by virtue of the fact that there's an interplay between this pathway and others, maybe you do not need this additional anti-platelet agent such as aspirin, which we know there's associated with potential bleeding particularly gastrointestinal side effects.
Having said that, this is not something that I'm advocating at time, but what I am saying is that we'll need to look into the results of the clinical trials. I believe that this study is an additional piece of evidence from an ex vivo standpoint to prior in vitro studies showing that aspirin is not associated with additional platelet inhibitory effects, at least not substantial platelet inhibitory effects. One can say that you may get away with just one of these newer agents. Again, this is based on pharmacodynamic findings, let's just wait for the clinical trial results.
I think that's so fairly put, and I learnt so much just listening to this conversation. Thank you so much for joining me today. Any last words from Gabriel?
Yeah, I'd like to make a couple of points as an Associate editor for Circulation. The first one is, this paper was picked up when we saw Dominick's team's presentation at the ACC, and I think it exemplifies that we really want to pick up the best science from the meetings, either before the meetings and publish it simultaneously as much as possible, but sometimes also at the meetings, so expect to see Circulation Editors at your presentations and maybe you'll seduce them enough with your science that we'll get good science submitted to the journal. The other aspect to it is also that I think with the new editorial board there's really a focus on trying to make the journal very international in it's approach, and I think it's fitting that I am Associate Editor from Europe and I think there's no more international a scientist than Dominick Angiolillo who's not only a good friend but also has been trained in Italy, has practiced in Spain, and now works in the US. I think he embodies how science transcends boundaries and borders. I think there's a definite international outlook to Circulation, and we're looking for great science from anywhere in the world, not solely the US.
Thank you so much Gabriel. Thank you so much Dominick. Thank you listeners for listening today, you've been listening to Circulation on the Run. Don't forget to join us next week for more summaries and highlights.
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 diving deep into issues of resistant hypertension, adherence to anti-hypertensive medication, and renal denervation. All this by looking closely at new data from the Renal Denervation for Hypertension trial. First, here are your summaries of this week's journal.
The first paper sought to answer these questions: How can we better re-stratify patients with long QT syndrome type 3? You will remember that as the type caused by a gain of function mutation in the SCN5A sodium channel, and the type that has a more lethal course than types 1 and 2. Another question is, are we sure that beta blockers are effective in type 3 long QT syndrome? Well the current study is by co-first-authors, Dr. Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from University of Rochester School of Medicine and Dentistry, which is the largest multi-center long QT type 3 syndrome cohort described to date.
This study was designed to identify the risk and therapeutic factors associated with cardiac events in patients. The risk factors evaluated included clinical features such as age, gender, ECG measurements, the mutation type, and the therapeutic effects of beta blockers, other medications, and ICD. In almost four hundred patients with type 3 long QT syndrome, 30% experienced at least one cardiac event; that is syncope, aborted cardiac arrest, or sudden death. The risk of a first cardiac event was directly related to the degree of QT prolongation. Each 10 millisecond increase in QTC up to 500 milliseconds was associated with a 19% increase in cardiac events. Prior syncope doubled the risk of life threatening events. Beta blocker therapy was associated with an 83% percent reduction in cardiac events in females, however the efficacy in males could not be conclusively determined due to low number of events. The take-home message is, in your patients with long QT syndrome type 3, recognize the very high risk sub-population with prolonged QTC and a history of syncope.
The next paper is a basic science paper that reveals a novel way in which mitochondrial dysfunction may be targeted in heart failure. This paper is from first author Dr. Li, corresponding author Dr. Tian, and colleagues from the Mitochondria and Metabolism Center at University of Washington. These authors previously found that elevation in the NADH to NAD ratio induces mitochondrial protein hyperacetylation, and renders hearts highly susceptible to stresses, and they showed this in a mouse model of primary mitochondrial dysfunction caused by genetic defects. In the current study they defined the molecular intermediaries linking specific NAD sensitive hyperacetylation targets to the development of heart failure, and further demonstrated the relevance of these mechanisms in human heart failure. Specifically, they identified that hyperacetylation of the regulators of mitochondrial permeability transition poor and malate-aspartate shuttle, mediates the increased susceptibility to cardiac stresses. Further, expanding the cardiac NAD pool via pharmacological or genetic approaches normalized the NADH to NAD ratio, and thereby normalized protein acetylation in hypertrophied and failing hearts. Importantly, these measures improved cardiac function and reduced pathological hypertrophy in mice. Thus, the clinical implication is that restoring the NADH to NAD ratio may be an effective and translatable strategy to treat mitochondrial dysfunction in heart failure.
The next study broadens our considerations of the benefits versus risks of intensive anti-platelet therapy in patients with a prior myocardial infarction, and really suggests that more intensive anti-platelet therapy should be considered, not only to reduce the risks of coronary events, but also to reduce the risk of stroke. This is a paper from Dr. Bonaca and colleagues of the TIMI study group from Brigham and Women's Hospital in Boston, Massachusetts, who investigated the efficacy of ticagrelor, 60 milligrams twice a day, for reducing stroke in patients with a prior myocardial infarction from the Pegasus-TIMI 54 trial.
You will remember that in the Pegasus-TIMI 54 trial, ticagrelor was already shown to reduce the risk of major adverse cardiovascular events when added to low-dose aspirin in stable patients with prior MI. Of more than 14,000 patients randomized to placebo or Ticagrelor, 213 experienced a stroke, 85% of which were ischemic. 18% of strokes were fatal, and another 15% led to either moderate or severe disability at 30 days. Ticagrelor significantly reduced the risk of stroke, with a hazards ratio of 0.75, and this was driven by a reduction in ischemic stroke. Hemorrhagic stroke occurred in nine patients on placebo and eight patients on ticagrelor. Furthermore, a meta-analysis of four placebo-controlled trials of more intensive antiplatelet therapy in more than 44,800 patients with coronary disease confirmed a marked reduction in ischemic stroke, with a combined hazards ratio of 0.66. Thus this study really broadens our considerations of benefits versus risks of intensive antiplatelet regimens for the long-term secondary prevention in patients with patients with prior myocardial infarction. It really highlights the broader benefits in reducing ischemic stroke, and not just coronary events. In summary, overall, for 1,000 patients initiated on ticagrelor 60 milligrams twice daily for three years, 13 primary endpoint events would be prevented, including approximately five ischemic strokes. This benefit would come at a cost of nine TIMI major bleeds, but no hemorrhagic strokes or fatal bleeds.
That wraps it up for our summaries! Now for our feature paper. Our feature paper today discusses a really important issue that we face everywhere around the world, and that is the management of resistant hypertension. We're taking a very interesting look at the Renal Denervation for Hypertension trial, because we're actually looking at the adherence to anti-hypertensive therapy, and what we've learned in this trial. I'm so excited because I am sitting right here with first and corresponding author Dr. Michel Azizi, from Georges Pompidou hospital in Paris, France. Hello Michel, thank you!
Hello, Carolyn. Thank you also for the invitation to discuss about the paper.
We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.
This whole issue of resistant hypertension, I'll tell you, to me that means someone who's adequately treated, and despite all the treatment that we can throw at them, they still have a blood pressure that is above a certain level, right?
But your study seems to tell us that that assumption, that everyone's receiving treatment and still having high blood pressure, may need to be questioned, so please tell us a little bit more about what you found.
This is a clinical trial where we compared the effect of renal denervation to medical treatment, optimal medical treatment. We standardized the anti-hypertensive treatment in the cohort of patients with resistant hypertension, and then we followed them on a monthly basis with home blood pressure monitoring. We also increased the intensity of the treatment every month after randomization between renal denervation against nothing, because this is a probe trial, it is not a double blind trial. We gave them the same treatment in both arms. At the end of the many study we demonstrated that there was 6 millimeter of difference, in terms of ABPM, in favor of renal denervation, against the same medical treatment alone.
However, because this trial was an open trial, it was open to a Hawthorne effect, and the possibility that patients or doctors behave differently in each arm of the study. Those having renal denervation may be more adherent to the treatment, and those not being given the new therapy, not being really adherent to treatment. This was an issue, so we specified analysis. We also measured drug levels in urine after six months of followup, and also assessed the exposure to each individual using a peptide in urine, which is N-acetyl-serylaspartyl-lysyl-proline (AcSDKP)/creatinine.
What we found after six months of followup in patients who really participated to this trial, they were willing to participate to the study, they signed an informed consent where it was written that, indeed, we will monitor drug levels. They knew that we would do this. They also knew that we will follow them very carefully every month, et cetera, that we'll provide them home blood pressure monitor for free. They had access to the same doctor, same nurse, same everything. They could arrive at the time they wanted in the morning for being investigated. After six months of followup we found that more than half of these patients did not take correctly their treatment, and even 15% of them, in reality, took zero medication over seven medications. This was a major, major surprise for us in this trial.
I think that's one of the most significant findings, even in a trial setting, that is such a lot of non-adherents, anti-habitants, of therapy. It really makes us question when we say someone has resistant hypertension, is it really that, or do we have just a very non-compliant patient?
Because it can only be worse in the real-world setting, isn't it? Congratulations, that was a very striking message to me as well. What was the other main finding that you wanted to ... ?
The other finding was that the rate of non-adherence was similar in both arms. That there was absolutely no influence of being randomized to the renal denervation group or the medical treatment group only. This means that the patients were not influenced, and other physicians behaved similarly in both arms. Because at the end you have exactly the same rate of non-adherence to treatment. This is also very important.
Yes, indeed. Wanpen, I was wondering what your thoughts were, and take-home messages from this paper. We definitely thought it was significant in the editorial board because you even commissioned a wonderful editorial by Dr. David Calhoun on this. What are your thoughts?
In the United States, using the same technique, we found as much non-adherence. I think there is a lot that we need to do and to understand what caused non-adherence. The patient should not be the only party that's to blame. I think that the doctor's as much of a culprit here to try to tease out what's the barrier to the treatment. Also, as pointed out by Dr. Calhoun, is that although the trials show improvement in blood pressure in both groups, at the end number of medications of patients in resistant hypertension, they require to take four to five drugs to get the blood pressure under control. I think this is going to be a lifelong continuing medication treatment that the physicians have to face, and to deal with the adherence problem as well. Just lastly, I think that although people believe that doing drug levels is only for research purpose, but many people don't realize that actually many drug levels for anti-hypertensive drugs actually is clinical available and can be ordered. It takes a little bit more effort to order it, but it can be done, and actually our center has been doing that already anyway.
Wow. I cannot say that my center has been doing that in Asia, but I really have to admit that this paper made me think about it. Especially the editorial when he highlights it, the very unique information that is provided by actually measuring the blood levels. Michel, you were nodding your head vigorously when Wanpen was saying that we should not just blame the patient. Tell me, what are your thoughts, and how does this affect your clinical practice?
I fully agree with Wanpen. We have to now integrate the fact that it's accessible, you can measure drug levels through technology, with mass spectrometry, et cetera. This is very important to integrate and to change our paradigm that we have to put in our brain. We have to monitor drug levels. Using this technology we have to establish a partnership with the patient.
I think the truth, also, is somewhere, as Wanpen said, we are also culprits. If patients do not take their treatment, okay, there may be some benefit and e have to look why they are not taking pill treatment, but also we are culprits because we don't listen to them, we don't take enough time, et cetera, et cetera. But I think patients should not be only blamed, so it opens a new possibility to discuss with the patient about the fact that we didn't find the drug in levels in their urine, et cetera.
However, taking into account that there will be this toothbrush effect, that is, "Patient, brush your teeth when you go to see the dentist," you'll take the pills when you go to see the doctor so you can be treated. This is one of the difficulties. However I think it's a new possibility to discuss with the patient of his or her difficulties in taking the pills. It gives us the opportunity to discuss, to take time with our patients.
It's really fascinating, you're talking from a system based in Europe. You're based in Paris.
Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?
Yes, yes, yes.
In the hospital we have these mass spectrometer platforms, so we have access to this, and we are working with the house authority to have the reimbursement. Because I think it's important, because if it's not reimbursed there is also a problem.
We are working to see how it could be reimbursed for labs doing these measurements.
But this is for maybe selected resistant hypertensive patients that are difficult to ... ?
Yes, absolutely. Those very difficult to manage. I think, as a rule of thumb, that after four or five drugs given to the patient, if the patient-
Yeah, we should start questioning, are they taking it.
If the patients do not have secondary hypertension, we should really start questioning ourself whether they are taking or not the treatment, even if they are looking right in your eyes and telling you, "Yes, doctor, I'm taking all the pills."
Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?
Actually the coding for doing drug levels, it's actually generic. It's the same coding for Digoxin or Cyclosporine. They actually don't care about what the name of the drug. Strangely, they're coded by the technique, so that's how we go with it, but we have to put in miscellaneous "other" for, we wanted to test for this. That's how we get around it.
Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?
Obviously we have to be selective, so we select from people who we would suspect are non-adherent, but they say they're taking it. But if they already came in and made that they're not taking the drug, there's no point doing that for the clinical purpose. We're doing it for people who we suspect it, and we use it the way ... Actually we shall describe very well, not only just to find what drug they're not taking, because when they're not taking, only about 30% are not taking everything, about 20% not taking one or two drugs. When we drill down to that drug they say, "I have side effects to beta blocker and I don't want to tell my physician that I have problems taking it, but I just not take it." I think that's what led us to pinpoint the problem a little bit better with this technique.
What a lot of practical advice, and congratulations once again for very, very meaningful findings. I learned a lot this time. I don't do this, and so I'm definitely going to think about this much more because of your work. Thank you very much Wanpen, Michel.
And thank you, listeners, for tuning in this time. Remember, you're listening to circulation on the run. Listen in again next week. Thanks.
Welcome to Circulation On The Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, associate editor from the national heart center and Duke National University of Singapore.
In just a while, we will be discussing patients with familial hypercholesterolemia after acute coronary syndrome, and the new data in this week's issue that suggests we still need to pay special attention to this group of patients even in the current era of the widespread use of high intensity satins. First here's your summary of this weeks issue.
The first paper suggests that we may need to look at thyroid function in our risk assessment sudden cardiac death in the general population. This paper is from co primary authors Dr. Chacker in Van Der Burgh and corresponding author Dr. Strecker and colleagues from the Erasmus University medical center in water dom.
The authors studied the association of thyroid function with sudden cardiac death in more than 10,000 participants of the population based Water Dom study. They found the higher levels of 3T4 were associated with an increased risk of sudden cardiac death even in the normal range of thyroid function. The estimated hazard ratio was 2.28 per one nano-gram per deciliter of 3T4, and these risk estimates did not change substantially even after stratification by age or sex or sensitivity analysis excluding participants with an abnormal 3T4. The absolute 10 year risk of sudden cardiac death increased in youth thyroid participants from 1 to 4% within increasing 3T4 levels.
Thus this study suggests that 3T4 and additive marker in risk stratifications for sudden cardiac death in the general population. Further research is needed to assess the possible additional benefit of using 3T4 levels to re stratify and prevent sudden cardiac death.
The next study reminds us that therapies to reduce ischemic events in patients undergoing percutaneous coronary intervention are still really important even in the current era of changing definitions of periprocedural myocardial infarction. This study is from first author Dr. Cavender of University of North Carolina chapel hill and corresponding author Dr. Bach Brigham women's hospital and colleagues.
The authors looked at more than 11,000 patients randomized to cangrelor or clopidogrel int the champion phoenix trial.
Cangrelor is an intravenous P2Y-12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention who are not pretreated with with a P2Y-12 inhibitor.
The authors explored the effects of cangrelor on myocardial infarction using different definitions of myocardial infarction and perform sensitivity analysis on primary endpoint.
They found that 4.2 percent of patients had a myocardial infarction defined by the second universal definition within 48 hours after undergoing PCI. When the sky definition of periprocedural MI was used, there were fewer total myocardial infarction, but the effects of cangrelor remain significant.
Finally similar effects were seen when MI's were restricted to those defined with large bio marker elevations or by symptoms of ECG changes. Very importantly patients who had an MI regardless of the definition, were at increased risk of death at 30 days.
In summary changes in the definition of MI used in the primary endpoint did not affect the overall findings from the champion phoenix trial. This study also reminds us that periprocedural MI remains an important clinical event in the current era. Being associated with increased risks of death at 30 days, and therefore reducing ischemic events in patients undergoing PCI remains very important.
The final paper describes experimental evidence of a novel treatment approach to hypertension using micro RNA's. This paper is from first author Dr. Lee and corresponding authors Dr. Chinn and Wang from Tong G medical college and Whadrom University of Science and Technology in Wuhan China.
Micro RNA's are a class of small non-coding RNA's that regulate gene expression at a post transcriptional level. These authors compared the expression of key neucler genoman coded and mitochondrial genoman coded genes involved reactive oxygen species production in spontaneous hypertensive rats and wistar rats. They then used bioinformatics to predict the micro RNA targets followed by biochemical validation using real time PCR and immunial precipitation.
They first found that there was down regulation of mitochondrial DNA encoded sitoca B in the spontaneous hyper intensive rats, which appeared to directly contribute to the increased mitochondrial reactive oxygen species.
Next they found that mere 21 a key micro RNA induced into hyper spontaneous rats, was able to trans-locate into mitochondria to counteract the mitochondria pseudonym B down regulation. Finally, they showed that exogenous mere 21 delivered by recombinant adeno associated virus was able to lower blood pressure and attenuate cardiac hypertrophy in the spontaneously hypertensive rat model.
These findings are striking because they provide experimental support for developing micro RNA based treatments for hypertension.
Those were your summaries of original papers but before I go, I just have to highlight this in depth review paper in this week's issue, and it is regarding sodium glucose co transported to inhibitors or SLG2 inhibitors in the treatment of diabetes, discussing the cardiovascular and kidney affects potential mechanisms and clinical applications.
It is a beautiful review article written by first author Dr. Heresphink of the University Medical Center Groningen, corresponding author Dr. Churney from Toronto general hospital and colleagues. Truly a must read, but now here is our featured paper.
Our featured paper today is on patients with familial hypercholesterolemia after acute cornery syndromes. Today I have with us the first and corresponding author David Nan chin university of Lausanne in Switzerland.
Hi David, thanks for joining us.
Hi, I'm very happy to be here.
As the associate editor who managed this paper we have Dr. Amat Kira and you will recognise him as the digital strategies editor as well from UT Southwestern. Welcome back Amat.
Thank You Carolyn, happy to be here.
I am really curious about this paper because it speaks of familial hypercholesterolemia that most of us would assume is very rare.
Now David, I know that you actually published prevalence in a prior paper last year, but could you maybe start by telling us why we should, how common is this in our patients with acute coronary syndrome?
In fact we studied patients who is hospitalized with acute coronary syndrome in several university hospitals in Switzerland. Of course we try our best to include all classifications in the study in order to be very protective of the acute coronary syndrome population.
We found that among patients with acute coronary syndrome, familial hypercholesterolemia was not a rare disease. We found a prevalence of 2-5% which is in fact 10 times higher than what is thought to be in the general population.
The important point here is that we use very simple clinical catatonia to assist the prevalence of adage. This catatonia includes unbelievable[inaudible 00:08:50] and the family of Bethany of coronary heart disease. This criteria are very easy to use and implement in a clinical practice in the sitting in acute coronary syndrome to detect patients with familial hypercholesterolemia.
Exactly. You did not use molecular diagnosis in your paper, but yet, with these simple criteria there was a very important clinical take home message. Could you tell us about those findings?
The question we wanted to answer here is wanted to know what happened to this patient with familial hypercholesterolemia after hospital discharge. We found that patients with familial hypercholesterolemia were an increased risk of recurrence of cornea events within the year after discharge, and this is despite the use of idol science.
In fact, one year after the coronary syndrome, 7 people found a patient with adage were still using idle studies, which is very good we were quite impressed by these numbers, but they mean[inaudible 00:09:57] one year after the acute coronary syndrome, with one in twenty become affected later.
Most of these patients were not able to decrease their added cholesterol to lower evens.
I really think there is clear room for infestation of leamington therapy among these patients. In any of those drugs available from my seeing and very effective to decrease and [inaudible 00:10:25] to substance, but they are very expensive.
Maybe the best initial strategy, to prescot these drugs, is to target patients with familial hypercholesterolemia after acute coronary syndrome. Because these patients are at high risk of recurrence and most of them cannot achieve their cholesterol level with our studies.
Congratulations for being really the first to show that. This is common and it affects recurrent events. I think actually the first step is to recognize this in our patients which very few of us really do I think.
Amat from your point of view, knowing the results of this paper how has it changed your clinical practice?
Absolutely Carolyn. First I congratulate Dr. Nan chin and his colleagues. This was an incredibly important paper, and I think as you pointed out, one of the first to really show us why it is irrelevant to show us why it is relevant to identify FH at the time of an ACS.
Generally even when I work with my trainees when we talk about FH, everyone is thinking, "Well, we'll just put everyone on statins," and it's well appreciated. We can think about cascades swinging and why it's important to their offspring, but what Dr. Nan chin and his colleagues have certainly highlighted, is that these patients are at higher risks for recurrent ACS and recurrent events, and that's incredibly important as mentioned that tells us that maybe the routine treatment post ACS with high dose statins is not sufficient.
What's next is the tricky part, do we initiate PCS canine initially, do we add a zedemi upfront. Sort of the next step is the part that's a little bit more tricky, but I certainly see a potential for augmented therapy in these patients up front.
I like the way you said tricky, and that's usually when we call for an editorial isn't it?
That is correct as we will see with this article.
I really like the title of it, "Diagnosis and Management of Petra Zygas familial hypercholesterolemia too little and too late."
That was very interesting, but are there any other take home messages from your end David?
Maybe one thing we can add ... We are currently trying to change our practice regarding these reasons that we have now. We have now implemented in our casualty department a system that's explaining strategy to identify this patient, to identify patient with asage.
We have a prevention team that can provide very early during hospitalization additional information for this patient about asage. That's one very important point is to encourage family testing especially for the children of the patient and also to provide concerning for other cardiovascular risk factors. Because we also found that half of these patients with asage were smokers in fact and 40% of them had hypertension.
Certainly to address the other cardio risk factor in patients with asage so certainly very important. At the end part of what we are doing is we are assured of the patient will an appropriate medical follow up in the primary care setting because it's also very important for management of asage and circular prevention in the primary care setting after discharge.
Wow. Those are excellent points. Very practical advice on screening, management, and really just applying the results of what you found. Congratulations once again.
Amat I'm going to switch tracks a little bit now. Since we've got you online I really have to ask you a couple of things with your hat as a digital strategies editor.
Has it been two months since we first chatted even about this podcast which is part of the digital strategies. Let's take stock of it. How are things going?
Well, so far I think excellent and frankly one of the highlights of our digital strategies is your podcast. It's gotten rave reviews and certainly appreciate all your enthusiasm and your unique take on how to do this. We've also had some excellent work with our social media. We have a revised website which has a lot more real estate for some novel offerings, and I think we certainly can't rule out traditional print media, but those articles that come out online.
It's been really an exciting time and thinking of novel ways to share new information in a modern era.
Right. Thanks to you really Amat and I would really want to bring out one of the strategies that we may have not talked about so often yet, and that's the "on my mind" vlogs.
The reason I'm going to bring it up is because last week I was struck by the on my mind article by Milton Packer and it's entitled, "Heart Failure's Dark Secret. Does anyone really care about optimal medical therapy?" That's just awesome. Could you tell us a bit more about this vlog.
I think you hit the nail on the head there it certainly an edgy and controversial title, and if you think about it that's the purpose of this in most of our academic writing. It's a little bit stiff in following certain para dines, and more formal para view. The purpose here for the on my mind was literally that for someone who is a thought leader to free associate various ideas they have that would be controversial or edgy or may not be accepted down the main stream.
That's a bit on purpose because we hope to create a dialog around that. If you look on our webpage, there's actually a place where people can add comments or start a dialog saying whether they agree or disagree, or begin an important conversation around these edgy topics.
I think that's the really cool part when we can actually start interacting with our readers and listeners online that way.
Thank you to my wonderful guests and thank you listeners for listening this week. Don't forget to tune in next week for more highlights and features.
Welcome to "Circulation on the Run", your weekly podcast summary and backstage pass to the journal and its editors. I'm Doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. In just a moment, we will be discussing the very topical subject of wearable cardioverter defibrillators in patients at high risk of sudden cardiac death. Yes, this is the topic of our feature paper which really builds on prior US data using these devices and extends it, now, to a healthcare system outside the United States. First, here's the summary of this week's journal.
The first paper describes a novel class of mediators that may revolutionize the nonsurgical treatment of limb ischemia. This paper from first author Doctor Jung from University of Louisville School of Medicine and corresponding author Doctor Spite from Harvard Institute of Medicine and colleagues looked at resolvents. Resolvents are a family of lipid mediators synthesized from Omega-3 polyunsaturated fatty acids that promote the resolution of inflammation and have been shown to regulate the transition from inflammation to repair. Now, this is very relevant to limb ischemia because most other mediators that promote revascularization also exacerbate inflammation, thus potentially limiting their therapeutic use in chronic inflammatory diseases such as diabetes.
To assess the role of resolvents in revascularization and resolution of inflammation, the authors using a Murine model of hindlimb ischemia coupled with Laser Doppler profusion imaging, micro-computed tomography and targeted mass spectrometry. They identified that resolvent D2 is produced in the skeletal muscles of their Murine model of limb ischemia as well as in skeletal muscle biopsies of patients with peripheral artery disease. They showed that resolvent D2 increases tissue profusion by promoting arterial genesis that is collateral artery growth and, importantly, that it rescues defective revascularization in diabetic mice. These findings are important because they could inform the development of novel strategies for the clinical management of limb ischemia.
The next paper addresses food fortification with folic acid, which we all know prevents neural tube defects but may now even prevent congenital heart defects. This paper is from Doctor [Mule 00:02:53] and colleagues from The Center for Chronic Disease Prevention, Public Health Agency of Canada who studied approximately six million Canadian births from 1990 to 2011 and compared the prevalence rates and temporal trends in congenital heart disease sub-types before and after 1998 when folic acid fortification was mandated in Canada. They quantified the effects of folic acid fortification on the birth prevalence of specific non-chromosomal congenital heart disease sub-types, after controlling for concomitant changes in maternal age, pre-pregnancy diabetes, preterm pre-eclampsia, multiple birth and pregnancy termination. They found that there was an eleven percent reduction in non-chromosomal congenital heart defects following folic acid fortification. Specifically, folic acid fortification was associated with a twenty-seven percent reduction in conotruncal defects, a twenty-three percent reduction in coarctation of the aorta, a fifteen percent reduction in ventricular septal defects and an eighteen percent reduction in atrial septal defects. This large ecological study, therefore, provides evidence of a modest protective effect of folic acid fortification on congenital heart defects.
The last study suggests that in patients with ischemic cardiomyopathy and right ventricular systolic dysfunction, we should perhaps be taking a look at the mitral valve. This is work from first author Doctor Seib from the Beth Israel Deaconess Hospital and Harvard Medical School, corresponding author Doctor Kwon from the Heart and Vascular Institute of Cleveland Clinic Foundation and colleagues, who looked at over five hundred and fifty patients with ischemic cardiomyopathy, all of whom underwent cardiac MRI. They found that mitral regurgitation, as measured by effective orifice area, was a significant independent predictor of right ventricular ejection fraction. They further found that the relationship between right ventricular ejection fraction and mortality may be affected by mitral valve surgery in that a reduction in right ventricular ejection fraction was associated with increased mortality in non-repaired patients but not in patients who had undergone mitral valve repair.
The clinical take-home messages are that right ventricular function should be carefully assessed in patients with ischemic cardiomyopathy and if systolic dysfunction is found, patients should be assessed carefully for significant mitral regurgitation as well as other known risk factors such as right bundle branch block, right ventricular scar or a decreased left ventricular ejection fraction. The study suggests that mitral valve surgery may mitigate the relationship between right ventricular rejection fraction and mortality, however further studies are clearly needed.
Those were the summaries. Now, for our feature paper discussion.
I am thrilled to be joined by three guests today to discuss the feature paper on wearable cardio defibrillators in patients at high risk of sudden cardiac death. This is a real world experience all the way from Germany. Joining us today we have two authors of the paper, the first and corresponding author Doctor Nadine Visnic as well as author Doctor Ruth Strasser, both from the University of Dresden and Heart Center Dresden in Germany. Welcome, ladies.
Hello, how are you?
Very good, thank you.
We have Doctor Mark Link, Associate Editor from UT Southwestern. Thank you for joining us, Mark.
You're very welcome.
Mark, let's start with a behind the scenes look. We have data from the United States describing the wearable cardio defibrillator. We have ample data on the implantable cardio defibrillators. What made the editorial board decide that this particular paper from Germany was so important?
There are a number of aspects that we looked at for this paper. This is exciting new technology that is beginning to impact the daily lives of all the physicians in the states, the wearable defibrillator. This is a very nice prospective study from Germany that looked at a very large group of patients with this wearable defibrillator, gave us real world experience and it also fits in with the circulation mission of becoming a world wide cardiac journal, not just United States journal. We were very interested in the topic. We're very interested in the international collaboration and we're very excited to publish this paper.
I love that. Practicing in a non US system, as well, I found this particularly special about this paper.
Nadiene, we're all wondering, could you describe the patient population, just so we know the kind of patients that your results are applicable to.
The patients included in the register were regular patients we meet in clinic in every day life. No specific selection was made. For legal reason, of course, to analyze the data, they signed informed consent for the register. From April 2010 through October 2013, in total six thousand forty-three patients were using the wearable cardioverter defibrillator in Germany. All of these patients were registered into the life vest network, the registry to record demographic such as gender and age. Also, the cardiovascular indications and defibrillation treatments and daily wear time. The German population consisted of seventy-eight male and twenty-two female patients with median age of fifty-seven years.
Great. What were the indications for the wearable defibrillators?
Most of the patients had to reduce the ejection faction by below thirty-five percent or even had experienced ventricular tachycardia as an indication. The largest group we had in our analysis was thirty-seven percent where those with newly diagnosed dilatative cardiomyopathy and ischemic cardiomyopathy accounted for twenty-seven of patients, especially forty days after myocardial infarction or after a high risk PCI or cabbage. Also, in total, we had twelve percent of patients that had an ICD explantation mostly due to infection situation. What is very special on that paper is that ten percent of all our patients had myocardidas as a diagnosis and was reason to use the WCD.
Wow. That does sound very representative of the real world patients that we would put wearable defibrillators on, as well.
Ruth, could you tell us, what were the main results? Were there any differences by sub-groups?
Perhaps, we should first go on the compliance because this is very important to the daily wear time. This was more than twenty-two hours in ninety-four percent of the patients. Many patients who complained about the inconvenience but understanding that this life vest is a potentially life saving and only temporary treatment strategy made it acceptable to ninety-eight percent of the patients. As to the [inaudible 10:52] there is a difference, the younger patients, patients younger than forty-eight years of age or younger, they wear the life vest longer, sixty-six days. While the older patients, older than sixty-eight patients, this was statistically significant, wore it only forty-nine days. This difference was not used to compliance, because you do the description based on the cardiac diagnosis.
We also observed that the longer the cumulative wear of the life vest was, the longer day hours the patient had the life vest on. They were somewhat accustomed to it. One thing which is very, very important is, that in more than twenty-five percent of the patients, we could save the implantation of a permanent ICD due to the recovery of the ejection fraction. This was especially important for those patients who had the life vest, for example after myocardidas or after myocardial infarction, which is a very large population.
Also, which is important is that [full 12:06] shock treatment for reasons other then VT occurred only in point four percent, of less than one percent. Whereas those patients were successfully treated, this was one point six percent. They were treated in response to VT and VF. This means the incidence rate was eight point four per hundred patient years. This was even higher in those patients who had the life vest for the explantation. The life vest is very effective. It's a very effective strategy for general patient population with above indications. It can save the implantation, as I said already, in more than twenty-five percent in the population in Dresden itself. We could observe even a reduction of the need of implantation of permanent ICD more than thirty-five percent due to the recovery of the ejection. This is a very important treatment, especially for those patients who have an acute illness.
The German cohort is the first large cohort outside the US healthcare system. It confirms the overall value of the life vest and treatment pathways in Germany. Also, the cohorts analysis uncovered over two hundred forty-two sustained but self-terminated episodes of VT among seventy life vest patients, so that you have safely not treated because they were still conscious and could still press the response button. We found out that some of the self terminated VT episodes were even longer than eight minutes in duration time. All in all, we could see that the life vest is a device which is safe and which can prohibit shocks, as well.
Thanks, Nadine. [Ruth 14:12]
Mark, though, for the readers, I'm sure we need to put in perspective, as well, because there are still patients where perhaps an implantable cardio defibrillator is still more important. Could you share some thoughts about that?
Yeah. I think this is a very interesting, important study, for a number of regards.
One, is that there was a very high rate of compliance with using the life vest. To leave it on for twenty-three hours a day, for a mean of sixty days, is really quite impressive patient compliance. The data showed that it did recognize and treat VF in a small percentage, but in a important percentage, of people. This data does need to be put in perspective and the randomized trial is currently ongoing. The vest trial, which will randomize people, probably similar population to what the German study did, and look at the life vest performs in that population.
We look forward to further data from the vest trial and from other trials, that are looking at what the place of the wearable defibrillator will be in the future.
Thank you, Mark and that's perfect take home message for all us out there.
Thank you, once again, Nadine, Ruth, Mark. It has been wonderful chatting with you.
To all of you out there, you've been listening to Circulation on the Run.
Thank you for joining us.
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. I am so pleased to be joined this week by Dr. Judd Hollander and Dr. Deborah Diercks to discuss a problem that all of us, as cardiologists and emergency department physicians will recognize. This is a feature paper on the state of the art approach to the patient presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome, but first here are the highlights of this weeks issue.
The first study is from first author's Dr. Wing and Dr. August from Grand Valley State University in Michigan who investigated whether social and physical neighborhood characteristics are related to progression of sub clinical atherosclerosis measured by coronary artery calcium. They studied this in almost six thousand adult participants of Mesa, a multi-ethnic study of atherosclerosis, followed over twelve years. The main result was that increases in density of neighborhood healthy food stores were associated with decreases in coronary artery calcium. This was significant even after adjusting for time varying demographic confiders, time varying behavioral risk factors and depression.
The next study from Dr. Hess and colleagues from the University of Colorado School of Medicine characterized rates of implantable cardioverter defibrillator or ICD counseling and ICD use among more than twenty-one thousand potentially ICD eligible hospitalized heart failure patients in the Get With the Guidelines heart failure program. This study had several notable findings. First, only twenty-two point six percent of patients received ICD counseling. This means that up to four out of five hospitalized heart failure patients, eligible for ICD counseling, did not receive it. Women were counselled less often than men and racial or ethnic minorities were counseled less frequently than white patients.
Among counseled patients, a totally of sixty-two point six percent of patients received an ICD or had a documented plan for ICD placement. Women were just as likely as men to receive an ICD, however, ICD used differences by race and ethnicity persisted. The clinical implications of this study are that future quality improvement initiatives should incorporate culturally competent ICD counseling and elevating ICD counseling to a full performance measure and publicly reporting it by sex or race or ethnicity may need to be considered.
The next paper is from first author Dr. Resconey and corresponding author, Dr. Catalucci and colleagues from the Institute of Genetic and BioMedical Research in Milan, Italy. These authors looked at the voltage dependent [inaudible 00:03:31] calcium channel which is a key mediator of interest [inaudible 00:03:34] calcium entry associated with various cardiovascular conditions such as hypertrophy, atrial fibrillation, hypertension and diabetic cardio myopathy. The author's aim to address the problem that [inaudible 00:03:47] approaches aimed at enhancing calcium current and inotropism in heart failure have also frequently been found to favor arrhythmogenesis and diastolic dysfunction. Thus, limiting their clinical use.
The novel hypothesis addressed in this study is that a peptidome emetic therapeutic approach may overcome the arrhythmogenic limitations of current channel activator inotropes. To test this hypothesis, the author's used a whole host of methods to dissect new regulatory pathways modulating the [inaudible 00:04:24] tight calcium channel life cycle. This included yeast, two hybrid screenings, biochemical and molecular evaluations, protein interaction essays, fluorescence, microscopy, and structural molecular modeling and functional studies. Having uncovered a novel mechanism involving the [inaudible 00:04:44] tight calcium channel, calcium beta two chaperon, the author's then generated a mimetic peptide that specifically targets this calcium beta two chaperon. Thereby controlling the channel assembly and density of the plasma membrane while preserving its physiological channel function.
Finally, they showed that delivery of this mimetic peptide into a mouse model of diabetic cardiomyopathy restored calcium balance and recovered cardiac function. This study is so significant because it provides the proof of concept for the exploitation of novel therapy based on mimetic peptide technology. Really opens the field to mimetic peptides being used as innovative therapeutic tools for the treatment of cardiac disease.
The last study is from Dr. Cammel from the Feil Family Brain and Mind Research Institute in New York and colleagues who studied the association between pregnancy and aortic complications such as dissection or rupture. They used data on all emergency department visits and acute care hospitalizations at nonfederal health care facilities in California and New York between the period of 2005 to 2013. This was a cohort crossover study where they authors defined the period of risk as six months before delivery until three months after delivery. Compared each patient's likelihood of aortic complications during this high risk period to an equivalent control period of two hundred and seventy days exactly one year later.
Among more than six and a half million pregnancies in almost five million women, they identify thirty-six cases of aortic dissectional rupture during the high risk pregnancy period and nine cases during the control period. This gives the rate of aortic complications a five point five per million patients during pregnancy compared to one point four per million during the equivalent period one year later. Thus, pregnancy was associated with a significantly increased risk of aortic dissectional rupture with an incidence rate ratio of four compared to the control period one year later.
Furthermore, absolute risks were particularly elevated in those with a documented diagnosis of hypertension or a connective tissue disease. These findings have clinical implications for the counseling of patients at high base line risk of aortic complications and they also further suggest that clinicians may need to have a lower threshold for initiating diagnostic testing for symptoms of a possible aortic dissection or rupture in pregnant or postpartum patients and especially in those with connective tissue disorders or hypertension.
Our feature paper this week discusses a problem that impacts twenty million patients in North America and Europe every year. What am I talking about? These are patients presenting to the emergency department with symptoms and signs suggestive of an acute coronary syndrome. Who am I talking with? Well, today we have first author Dr. Judd Hollander from Thomas Jefferson University and Dr. Deborah Diercks associate editor from UT Southwestern. Welcome Judd and Deborah.
Let's start with a behind the scenes look at this paper. It's an in depth review that was invited by the editorial team. Deborah, can you tell us how this idea came about?
I think one of the goals of the editorial board of circulation is really to provide great clinical reviews that really could benefit the members. I have a unique aspect in that I'm an emergency physician. This idea was really brought about by discussion of really what can we merge cardiology and emergency medicine with. What would be the most clinically issue we're challenged with right now? You can't get two emergency physicians in a cardiologist's room together without some discussion and challenge around the [inaudible 00:09:11].
There's been so many changes in the last decade and so much more information about how we can use these in a clinically relevant way. It really fit nicely into a really great review article and I am really happy that we are able to invite Judd who's well known to the US and one of the leaders in the United States in this area and also an international group inviting a cardiologist from Europe and also an emergency physician from New Zealand to participate in it.
Judd, what is the take home message of this in depth review from your point of view?
I think the biggest take home message is we have known for decades and decades that if we rely on our clinical judgement we miss too many patients. We send home people that will be having acute coronary syndromes and acute myocardial infraction and the challenge over the last decades of trying to find ways where we're not going to spend a ton of money over admitting people to the hospital because of a fear of missing an event that may happen five percent of the time.
The beauty of the advances in troponins is we now have troponins that now have increasing sensitivity whether they be the non high sensitivity troponins used in the US or the high sensitivity troponins that are actually used in Europe and the rest of the world. We can use those better [inaudible 00:10:29] and combine them with clinical decision rules to create accelerated diagnostic pathways which is a big term. For now, if we put a blood test together with a structured clinical decision rule, we can, with more than ninety-nine percent negative predictor value, find patients who are safe to send home.
Judd, I really have to congratulate you on such a beautiful paper. You really did cover all of that but what I love most is the way that you've managed to summarize very clearly a whole wealth of information because when you talk about biomarkers, there's so many out there and there's zero hour, one hour, two hours, this score and that score. I'm actually looking at table one now where you show a summary of the biomarkers strategies and then, in table two, you show a summary of the risk scores and then the performance measures of each of these scores. That must have taken quite a lot to put together.
I think that's why Deb was very smart and invited authors from around the world. We have Christian Muller from Switzerland and Martin Tann from New Zealand which, literally, means we're all on different time zones and we were able to work around the clock to do that. There as always somebody awake. Getting more series, the nice thing is that my colleagues on this paper are some of the leaders in doing this kind of research. In fact, they are the leaders in doing this kind of research.
What I think is very challenging for the average cardiologist or the average emergency physician is there have been so many different approaches and many of them actually work. The challenge for us was to try and make it relatively simple so you can choose the approach at your institution and put it into a structured pathway and pick the one that works best for you. You can get a ninety-nine percent negative predicted value using the right essays with samples that the time of presentation and one hour later, you can get a ninety-nine percent negative predictor value at zero and two hours. You can combine it with an accelerated diagnostic pathway and do that at zero and two hours and zero and three hours.
I think the important thing is you need to figure out what will your clinicians use? Certain clinicians may be very comfortable with one risk score and not another and then they need to combine the timing of testing with the risk score their comfortable with in order for us to achieve the great possibilities we have with these new tasks. I think when you try and do a one size fits all, there are going to be people who push back because they don't like one component of the risk score. Really what we're trying to do and we didn't say everybody should do A, B or C but we present the data on five or six different options and let people choose what is most feasible for them.
How wonderful. Deborah, what were you thinking when you were reviewing this paper and trying to structure it for the clinician out there who wants to use this information?
I think that, overall, we were really impressed by the clarity and the ease that a reader can take this information home. There is so much information out there and there are so many different ways to apply it that we're really impressed how the authors put it in a really pretty clear manner so you can actually see the risk stratification tools that are out there, what they're used with and what type of troponins. Think about your own clinical practice and what you can adapt really based on the evidence that is out there.
I couldn't agree more. Judd, how about this issue of the coronary CT angiogram and where that falls?
That's really an interesting question because there's been a lot of publicity and a lot of editorializing in recent years that maybe you can make a decision with your two troponins and your biomarkers and decrease the number of people that need downstream testing. One of the dilemma with this, like I said before, is we know we're not really good at predicting who has acute coronary syndrome based on clinical things and for that reason the European Society guidelines as well as the American AHAACC guidelines have always said you need to do two things. You need to rule out acute myocardial infraction and you need to risk stratify patients for underlying coronary disease. When a patient comes into the emergency department, if I'm going to be guideline compliant with the recommendations in the world, I need to do both things.
The paper, we summarize really clearly ways you can get out of the woods with biomarket testing and clinical pathways but then you still want to risk strategy for coronary disease. There are sometimes where you might not need that downstream testing but what coronary CTA really lets us do is it makes us more efficient than a stress test. A stress test I like to say is a next day test; although there is data that you can do it when the patient's in the emergency department rapidly. It certainly is not the standard practice.
There are people afraid of putting people on the treadmill too soon in case they have unstable angina but a coronary CTA lets me look at the coronary arteries, immediately, when they're in the emergency department. There's very few areas in emergency medicine where there are three large randomized control trials that all give the same results. It doesn't say coronary CTA is better than a next day stress test but it does say you can avoid admission and, hence, save some dollars. It says you can send patients home sooner and, hence, save some angst that the patients may feel while they're in that diagnostic indecision area.
That's such a practical summary and, in fact, it really reflects the entire paper which is really so clearly presenting the information. Judd, one last thing, could I check is this correct, in my understanding, that the main difference between this and say the guidelines that you just measured is that what you do here is really give the readers all the information? As you say, allow the readers to choose what suits them best. This is not making recommendations, it's summarizing all the information. Is that right?
Yeah, that's exactly right. If you look, I think it's table number four, where we go through each one of the decision aids and how many or what percent of patients actually fit into that decision aid and what the negative predictive value is for that decision aid combined with troponin. Then what type of troponin was used to achieve those results, you'll see that about half the studies are done with, what we call, the contemporary troponin or just the regular sensitivity troponin that we use in the United States. The other half of the data we show is with high sensitivity troponins. It would not be a good idea for somebody creating their quality program in their emergency department to take something that was tested with a high sensitivity troponin and validate it there and then apply it in an emergency department in the United States where we don't have those [inaudible 00:17:18].
We thought it was critically important to lay out the data and as the high sensitivity troponins come on the market, hopefully in the next year in the US, people can begin with something now and switch to something else later if they want. If we made a recommendation that was firm, the world changes too fast. I don't think we would be doing the best for our patients.
That is such a great statement to end this on. Thank you so much Judd and Deborah. This was an excellent discussion.
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week for more exciting cardiology needs from all over the world.
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 National Heart Center and Duke National University in Singapore. Joining me today will be Dr. Katherine Mills and Dr. Andrew Moran to discuss the very striking findings of a new study on global disparities of hypertension prevalence and control, but first, here's the summary of this week's original papers.
In a study by first author, Dr. [Lu 00:00:42], corresponding author, Dr. Denny, from the Harvard TH Chan School of Public Health in Boston, Massachusetts and colleagues, authors aimed to investigate how the risk of cardiovascular disease is distributed among whites and blacks in the United States and how interventions on cardiovascular risk factors would reduce these racial disparities. To achieve these aims, the authors used a nationally representative sample of more than 6,000 adults, age 50-69 years of age, in the United States and developed a risk prediction model that was calibrated separately for blacks and whites.
The main results were that were substantial disparities in the risk of fatal cardiovascular disease; 25% of black men and 12% of black women were at high risk of fatal cardiovascular disease compared to only 10% of white men and 3% of white women, respectively. A large proportion of these fatal cardiovascular events among blacks were concentrated among this small proportion of the population. Now, whereas, population wide and interventions focused on single risk factors did not reduce black/white disparities in fatal cardiovascular risk and intervention that focused on high-risk individuals and reduced multiple risk factors simultaneously could indeed reduce black/white disparities in fatal cardiovascular disease by a quarter in men and a third in women.
These results really emphasize that focusing preventative interventions on the high-risk individuals has a large potential to improve overall cardiovascular health and reduce racial disparities in the United States.
The next paper is from first author, Dr. Lee, corresponding author, Dr. Federer, from Ohio State University Wexner Medical Center in Columbus Ohio and colleagues who looked at the issue of adenosine-induced atrial fibrillation and aimed to elucidate the molecular and functional mechanisms that may underlie this problem. To achieve this aim they integrated panoramic optical mapping and regional immunoblotting to allow them to resolve the protein expression of the two main components of the adenosine signaling pathway, mainly the A1R and GIRK4. They found that these signaling pathways were 2-3 times higher in the human right atrium compared to the left atrium leading to a greater right atrial action potential duration shortening in response to adenosine.
Furthermore, they showed that sustained adenosine-induced atrial fibrillation is maintained by re-entrant drivers localized in the lateral right atrial regions with the highest A1R and GIRK4 expression. Finally, the authors demonstrated that selective GIRK channel blockade successfully terminated and prevented atrial fibrillation. Thus, suggesting that the arrhythmogenic effect of adenosine in human atria may be mediated by activating GIRK channels. The take-home message, therefore, is that specific blockade of the GIRK channels may offer a novel mechanism to prevent adenosine mediated atrial fibrillation in patients.
The next study is from Dr. Nielsen and colleagues from the Copenhagen University Hospital of Bispebjerg in Copenhagen, Denmark, who aimed to assess the optimal blood pressure in patients with asymptomatic aortic valve stenosis. To achieve this aim, the authors used data from the simvastatin, ezetimibe in aortic stenosis or SEAS trial of 1,767 patients with asymptomatic aortic stenosis and no manifest atherosclerotic disease. Outcomes that were studied included all-cause mortality, cardiovascular death, heart failure, stroke, myocardial infarction, and aortic valve replacement. The main findings were that an average diastolic blood pressure above 90 and a systolic blood pressure above 160 millimeters mercury were associated with a poor outcome.
Furthermore, low systolic blood pressure was also related to adverse outcomes while low average diastolic blood pressure was harmful in moderate aortic stenosis. In summary, the optimal blood pressure, which was associated with the lowest risk of adverse outcomes, were the systolic blood pressure between 130 and 139 and a diastolic blood pressure between 70 and 90 millimeters mercury. The clinical take-home message is that in the scarcity of randomized controlled evidence, these results may assist clinicians in their decisions in blood pressure measurements in patients with aortic stenosis, meaning that a blood pressure above 149D may be treated while a blood pressure lower than 120 systolic or 60 diastolic may be recognized as a warning signal for poor outcomes.
That was the summary of this week's original papers. Now for a discussion of our feature paper.
I am so excited to be joined by two guests today to discuss our feature paper entitled Global Disparities of Hypertension Prevalence and Control, a systematic analysis of population-based studies from 90 countries. We are so pleased to have the first author, Dr. Katherine Mills, from Tulane University School of Public Health and Tropical Medicine in New Orleans. Welcome, Katherine.
Thank you. Good morning.
And a very special occasion indeed, we have an editorialist joining us, as well, in none other than Dr. Andrew Moran from Columbia University Medical Center in New York. Welcome, Andrew.
Good morning. Thank you, Carolyn.
It's wonderful to have you discuss this. This paper has so many key findings that really struck me. If you don't mind, I am just going to summarize some of these. For example, Katherine, you reported globally more than 30% of the adult population, amounting to almost 1.4 billion people have hypertension in 2010, and the prevalence of hypertension was higher in low and middle income countries than in the high income countries, making it, therefore, that approximately 75% of people living with hypertension live in the low and the middle income countries. Yet, hypertension awareness, treatment, and control were much lower in the low and middle income countries compared to the high income countries. That is really striking. Katherine, I'd really love for you to share with us what was the inspiration to look at this and what do you think was the most striking finding?
We know that hypertension is a very important risk factor for cardiovascular and kidney disease. It's the leading cause of cardiovascular disease in the world and for premature death. A previous study in our research group found that about 26% of the world's adult population had hypertension in 2000, but since then there really hasn't been any global estimate made. Basically, since 2000, a lot of studies from individual countries and high income countries have shown a leveling off or decrease of hypertension prevalence, but studies from individual low and middle income countries have actually shown an increase in hypertension prevalence.
Given these trends in individual countries and the importance of hypertension prevalence and treatment and control, to prevent cardiovascular disease, we really wanted to look and see what the disparities were in high income compared to low and middle income countries. I think the most striking findings to me was that we found that over 75% of adults with hypertension globally are in low and middle income countries, and that's over a billion people. We also found that only 7.7% of those people with hypertension and low and middle income countries have controlled hypertension. That represents a huge global public health problem that could lead down the road to a large burden of cardiovascular and kidney disease if it's not effectively addressed.
Katherine, I could not agree with you more because it's actually a living reality that I'm seeing where I come from in Asia. We have just so much hypertension, and what struck me was that from 2000 to 2010, while the prevalence increased here, it decreased in high income countries. Yet, this is where the greatest need is and where the control is the lowest. That was striking. Can you just articulate a bit further how your data now add to the knowledge that was there before your paper?
Basically, this is the first paper to show that the prevalence of hypertension is higher in low an middle income countries compared to high income countries. It's the first paper since 2000 to quantify the global burden of hypertension, and it's the first paper to really compare rates of awareness, treatment, and control comparing high income to low and middle income countries.
That is fantastic and really striking. I think that's why the Circulation Editorial Board to invite an editorial by Andrew to discuss this. Andrew, your editorial was entitled Still on the Road to Worldwide Hypertension Control, and even in the first sentence of your editorial, you mention that hypertension is a preventable risk factor, and that's why this is so important. I really like that your first subheading has this big word, action. Maybe you could tell us a bit more. What are the implications of these findings for worldwide hypertension control and actions that we can take?
There's a growing attention to noncommunicable diseases worldwide as a lot of maternal and fetal deaths, those rates have improved worldwide, and so really as the world population ages, problems like hypertension and related noncommunicable diseases are becoming a bigger and bigger health problem for people around the world, not just in high income countries. As a matter of fact, recently the World Health Organization set a 25 by 25 goal, meaning to reduce deaths from noncommunicable diseases by 25% by the year 2025. A big part of that effort is going to be an effort to control hypertension. The World Heart Federation has set a goal of improving hypertension control by 25% as part of that overall effort.
Yes. You mentioned that I think in the editorial, as well, but are there some action steps that we could take globally as a community?
Yes. It's striking to me as a practicing physician that something so basic as measuring blood pressure and recommending treatment for people with elevated blood pressure, which is so integral to our daily practice in medicine, that we still have so far to go in achieving control both in high income settings and low and middle income country settings. One of the most basic cornerstones of achieving control is proper measurement of blood pressure. I think one of the goal efforts has to involve making sure that primary care settings and even community centers have available well-calibrated and validated blood pressure measurement devices and that people know how to measure blood pressure accurately.
The other problems that come up with controlling hypertension are for people who have a diagnosis that is accurately made, are they able to follow up with a primary care provider to monitor their blood pressure, and do they have medications available to them that are affordable? It's important to note that especially in low and middle income countries, most people have to pay for their medications out of their own pockets, so the affordability and availability of medications is a really important part of achieving our goals. I think it's important to see that low and middle income countries, even though it can seem like a daunting setting in which to implement improvements in the quality of healthcare delivery, there also important places to experiment with improving the quality of care delivery worldwide.
For example, the concept of having a community health worker make home visits and reach out into the community was something that was developed in low and middle income countries and now is becoming a popular and effective method of delivering care in all countries worldwide.
One thing I would add is that I think we really need collaborations from the international level because so many of these low and middle income countries have very limited healthcare resources, and there still dealing with a lot of infectious diseases, so I think it really is going to take an international effort to address this problem in low and middle income countries.
Thank you so much for joining us for another episode of Circulation on the Run. Tune in next week for more summaries and highlights.
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Joining on me in just a moment are two guests to discuss a very exciting new category of papers, known as the white paper. The topic for today is an evolution within the field of current day percutaneous coronary intervention that of the treatment of higher risk patients with an indication for revascularization. But first, here is your summary of this week's journal.
The first study is from first author doctor Jolis and corresponding author doctor Grainger, from the duke clinical research institute in Durham, North Carolina. These authors describe the American Heart Association Mission: Lifeline, STEMI Systems Accelerator. This exciting project represents the largest effort ever attempted in the United States to organize ST segment elevation myocardial infarction care across multiple regions, including 484 hospitals, 1,253 emergency medical services across sixteen regions and involving more than 23,800 patients.
Indeed, this project aims to organize coordinated regional reperfusion plans so as to increase the proportion of patients treated within guideline goals, that is a first medical contact to devise time of less than 90 minutes for STEMI patients directly presenting to PCI capable hospitals and less than 120 minutes for transferred patients.
The authors observed that during the study period of July 2012 to December 2013, there was a significant increase in the proportion of patients meeting these guideline goals, including an increase from 50% to 55% of STEMI patients directly presenting via emergency services and from 44% to 48% of those transfer patients. The authors concluded that these improvements, while modest, suggest the potential for reductions in total ischemic time and happily observe corresponding trends towards lower in-hospital mortality compared with the national data towards the end of the measurement period. Indeed, the tickle message is that the findings support continued efforts to implement regional STEMI networks.
The next study is by first author doctor Hidari and corresponding author doctor Kuang from the Brigham and Women's Hospital in Boston, Massachusetts. They describe the OMEGA-REMODEL randomized clinical trial. This is a multi-center, double-blinded, placebo control trial of 358 participants presenting within acute myocardial infarction who are randomized to six months of high dose omega-3 fatty acids at four grams daily versus placebo.
Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and following therapy with the primary study in point being a change in left ventricular systolic volume index. Indeed, the authors reported that compared to placebo, patients who received four grams daily omega-3 fatty acids experienced significant improvements in both left ventricular and systolic volume and surrogate measures of non-infarct myocardial fibrosis during the six months of treatment.
These remodeling benefits further followed a dose response relationship with the rise in the in vivo omega-3 fatty acid levels as quantified by your red blood cell index. They concluded that four grams daily of omega-3 fatty acid is a safe and effective treatment in improving cardiac remodeling in patients receiving current guideline based post-myocardial infarction therapies. Indeed, this does warrant perspective clinical studies.
The third study is by first author doctor Liu and corresponding author doctor Sia from University of Texas, Houston Medical School and Colleagues, who sought to understand the molecular basis underlying adaption to high altitude hypoxia. By conducting both human high altitude and most genetic studies, the authors identified a novel functional role of CD73-dependent elevations in extracellular adenosin signolin in response to high altitude hypoxia.
This led to sequential activation of a readthrough site AMP-activated protein kinase, which in turn resulted in increased 2,3-bisphosphoglyceric production and enhanced oxygen release capacity to peripheral tissues. Thus, reducing tissue hypoxia, inflammation and pulmonary injury. These findings have significantly added to our understanding of the molecular mechanisms underlying adaption to hypoxia. Thereby, opened novel therapeutic possibilities for the prevention and treatment of hypoxia related conditions.
The final study is from first author doctor Yen and corresponding author doctor Chen from the National Taiwan University and Colleagues, who aimed to determine the effect of betel nut chewing and paternal smoking on the risks of early metabolic syndrome in human offspring. The author studied more than 13,000 parent-child trios identified from more than 238,000 Taiwanese aged 20 years or older screened in two large community based screening cohorts.
The main finding was that pre-fatherhood habits of both betel nut chewing and cigarette smoking led to a 77% and 27% increase in risk of early metabolic syndrome in their offspring respectively. In fact, they even observed a dose-response relationship where the risk was higher with an increase in duration of exposure as well as with earlier age of starting exposure. These findings interestingly suggest that genetic or epigenetic changes due to exposure to both betel nut and cigarette smoking before birth can contribute to early occurrence of metabolic syndrome in offspring. In fact, these findings really support education for avoidance of these habits or cessation of these habits.
That was your weekly summary. Now, for our feature paper. Our feature paper this week is a white paper regarding the treatment of higher risk patients with an indication for revascularization and evolution within the field current-day percutaneous coronary intervention. To join me in this discussion, I'll have the first and corresponding author doctor Ajay Kirtane from Colombia University Medical Center, New York Presbyterian hospital, as well as doctor [Manus Brelaques 00:08:22], associate editor from UT Southwestern. Welcome, Ajay and Manus.
Thanks so much for having us.
Great. Manus, I would love if we could start by talking about the concept of the white paper and what circulation is looking in these white papers.
Of course. It is a very exciting part of the new circulation which is for topics that are very timely and important, but at the same time there's not enough populous data and populous literature to be able to address it in a more formal systematic review way. The concept is that establish the leaders in the field. I'm going to provide their perspectives which have derived through their clinical practice and be able to inform us of what the current issues are, how can they best be addressed and what are the next steps forward.
That's great, and what a great example to start with with this paper by Ajay. Ajay, maybe I could just start by asking you to make it crystal clear to us the kind of patients you're referring to in this higher risk and the context and the scope of the problem that you're talking about in your paper.
Absolutely. First of all, I'm honored that you would consider that's both timely and important and that this will be one of the new papers in the series on behalf of all the [cohorts 00:09:44] is we're really pleased to be able to discuss it. I think the reason that we find this really critical at this juncture is because what we're sort of saying is an evolution in current-day [catlab 00:09:53] practice. There are many patients now who were seen that have either been turned down for cardiac surgery of have highly complex disease that we know merit revascularization.
In other words, medical therapy has failed for them either from the symptomatic standpoint or because it puts them at too high risk given the complexity of their coronary anatomy and where these lesions are located. Yet at the same time, in order to be able to treat these patients effectively, we need to grasp not only advanced techniques in terms of how to do it, but also need to be able to select the patients appropriately so that they can undergo these procedures safely and to drag the benefit that we'd like to be able to offer them.
Just one brief thing to mention is that we certainly know that over the past 10 years or so, there's been a lot of criticism of the PCI procedures they could perform, particularly here in the United states. Some of them were perhaps unnecessary or some of them were not necessarily benefiting patients. The good news is we've curtailed a lot of that, but yet at the same with that curtail we've sort of seen a decline in these types of cases that we refer to in the paper where patients really could benefit from revascularization, but for whatever reason or not being offered it.
Listeners might be wondering though, what is the difference between what you're talking about high risk, and we read a lot of papers about complex procedures and complex PCI, you want to make that differentiation just slightly clearer?
Sure. I think that complex PCI has been something that carries the historical definition and usually involves lesion subsets like the left main, chronic total occlusion, bifurcations, that require more than just a simple predilatation stent implantation. The concept of procedural risk though while it overlaps with complexity, to some extent actually has other inputs. For instance, the ventricular function of the patient whether or not the other circulation is also compromised, so it's a larger ischemic territory, and similarly some things that were previously complex with an evolution of techniques actually don't offer or confer that much greater risk on patients.
I would say when I did my fellowship training, left main was something that my heart rate got up for and we were worried about the patient in that respect. Now when we do left mains, it's actually something where we view it as one of the more simple things that we do relative to for instance the retrograde approach to a CTO revascularization. There's been an evolution and there's an overlap of what's complex and what's high risk.
Very nicely put. Could you tell us a little bit about how your paper is structured? I really like for example the way your tables are laid out and so on, but maybe just give an overview?
Absolutely. I think we start off with just setting the scope of the problem. Basically, looking at coronary heart disease and the fact that there are subsets of coronary diseases for which has prognosticked the importance to revascularize. For instance, the publication of this ten-year result for the first trial [inaudible 00:12:45] revascularization as a whole. We talk a little bit about the assessment of procedural risk and then we sort of move on in the end to the various areas that interventionalists need to become better trained in order to deal with these types of patients. I have to give credit where credit is due. The tables that you like so much were actually the suggestion of the editors.
Because of the new theory, Manus had a lot to do with this. I think it's very important for people to understand, at least for this paper the role, the back-and-forth conversation between not only us, but also the editors and the reviewers play in bringing this manuscript to its final form. I really give them credit for it. What's in the tables are not only descriptions of the types of multidisciplinary teams that are needed in order to [affect 00:13:27] that we take of these patients. Also, the techniques that would be useful for interventionalists to know how to use and be [inaudible 00:13:33] to take care of these patients. Finally, a table looking at future directions because it's all good and fine for us to say this is a new area and we're moving into it, but we need to sort of generate the research and the evidence base to really support the treatment that we're trying offer or saying we can offer in the manuscript.
Manus, you have to this describe some of this back-and-forth conversation that went on.
Ajay, I wish that every author took the comments as well as you did because that's definitely not the case. I must admit that it was a pleasure working with you because again you were so open to all the comments and suggestions even though some were tough ones. I think the interaction and being so open I think made the paper better and we're very, very appreciative for your response to those.
I think at the end of the day when you have a new editor team taking over, there are going to be changes and some changes you learn how to grow through and other changes you basically adopt what the previous editors were doing. At least my experience, not to [despair 00:14:29], is the prior circulation editors at all, I actually had a great experience with them as well, but this was novel, and I think it's something that for many authors will find quite nice to experience because there was a lot of back and forth. Some parts were contemptuous, but these were all resolved. I wrote in my response back to the reviewers I really do feel the paper was better as a result.
I think that's the idea that [inaudible 00:14:51] the language and the whole editorial team is trying to enforce and we're very happy with it and enjoyed.
I couldn't agree more. Actually, Manus I was also going to ask the title is provocative. It says this is an evolution and even in the conclusion of the paper that this could be a new field of coronary interventional procedures. I really love your thoughts. Is this a beginning of a whole new field?
I personally do believe and many people I think do believe that there's a tremendous evolution that is going on right now, continue to go on in the field compared to the early days of [inaudible 00:15:26] where we did simple angioplasty I think it has come a long way. But I think there is gap between what can be done right now in terms of technical possibilities, in terms of equipment we'll have and improved patients' quality and quantity of life.
Actually, what is being done because as you heard from Ajay, many of those patients who could benefit do not. Within the environment of trying to stop in a [inaudible 00:15:51] procedure, which is very appropriate, what happened exactly is that those more complex and high risk cases because of the fear of complications or sub-optimal outcomes led to offering less treatment to those complex patients.
I do believe it's an evolution in the field. I do believe that having access to these techniques, equipment and offering options to the patients and explaining there is benefit ratio can bring the patient's life, make them better and bring the field forward to the next step.
Ajay, do you think you could elaborate a little bit more then on what those next steps you think are and what are the future areas of research?
Yeah, I'd certainly be happy to do so. I couldn't agree with Manus more. I know he and I share a lot of beliefs in terms of this. One of the things that's important to recognize is while we can all assess procedural risk, some of these advanced techniques are not commonly shared by all interventionalists here in the United States, particularly if you look at the overall case volumes of many interventionalists in the United States, there are folks who are just not going to have the requisite volume to be able to do complex CTO revascularization with a retrograde approach. For instance, they would bring procedural success rates up around 90%.
I think that some of this is education. You have to sort of understand what can and cannot be done, what can and cannot be done [faithfully 00:17:08] and what techniques you use or are necessary in order to be able to improve this rate of success. If for instance I can't do the procedure myself, then I need to be familiar with somebody who actually can because if the patient merits revascularization, in other words they could benefit from having a procedure done, they're not a surgical candidate and they could be helped by PCI, then rather than saying, "We should just do medical therapy because I can't do the procedure." The appropriate thing to do is to actually refer the patient to somebody who actually could do the procedure in a safe way and therefore ensure benefit for the patient.
That's an educational aspect. Some of it relates to training, but I think conceptually we do need to start understanding now that there is a sub-specialization within coronary intervention of interventionalists who are able to offer things that many interventionalists cannot. That's somewhat of a fundamental step many people have to take, but I think it's time to take that step and that was the whole point in writing this paper.
I think that is a very effective first step that now you've brought it to light and we're so proud and privileged to be publishing this paper. Thank you so much Ajay, thank you so much Manus.
Thanks so much for having us.
And thank you listeners. You've been listening to Circulation on the Run. Please tune in next week for more highlights and discussions.
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 Centre and Duke National University of Singapore. I am so excited to be joined in just a moment by Dr. Andrea [inaudible 00:00:21] and Dr. Wendy Post to discuss the feature paper this week about leisure-time physical activity and the risk of coronary heart disease in young women. First, here's the summary of this week's issue.
The first paper, by Dr. Bohula and colleagues at the TIMI Study Group at Brigham and Women's Hospital in Boston, Massachusetts, aim to test the hypothesis that an atherothrombotic risk stratification tool may be useful to identify high-risk patients who have the greatest potential for benefit from more intensive secondary preventive therapy such as treatment with Vorapaxar following a myocardial infarction. As a reminder, Vorapaxar is a first-in-class anti-platelet agent that inhibits thrombin-mediated activation of platelets via the protease activator receptor 1. The authors studied almost 8,600 stable patients with a prior myocardial infarction followed for a median of two and a half years.
In the thrombin receptor antagonist and secondary prevention of athrothrombotic ischemic events, TIMI 50 trial. They identified nine independent risk predictors which were age, diabetes, hypertension, smoking, peripheral artery disease, prior stroke, prior coronary bypass grafting, heart failure and renal dysfunction. A simple integer-based scheme using these predictors showed a strong graded relationship with the rates of cardiovascular death, myocardial infarction or ischemic stroke. Moreover, the net clinical outcome was increasingly favorable with Vorapaxar across the risk groups.
In summary, this paper provides a practical strategy that could be used by clinicians to assist with risk stratification and therapeutic decision-making regarding Veropaxar use for secondary prevention after myocardial infarction.
The next paper is by first author Dr. [inaudible 00:02:40] and corresponding authors, Dr. [Gerstein 00:02:43] from the Beth Israel Deaconess Medical Center and Dr. [Carr 00:02:47] from the Broad Institute of Harvard and MIT, who look at aptamer-based proteomic profiling. Now DNA aptamers are [alu 00:02:57] nucleotides of approximately 50 base pairs in length selected for their ability to bind proteins with high specificity and affinity. They therefore holds considerable promise for biomarker and pathway discovery in cardiovascular diseases.
These authors applied a novel technology that uses single-stranded DNA aptamers to measure over 1,100 proteins in a single blood sample. They applied this to a model of planned myocardial injury and that is patients undergoing septal ablation for hypertrophic cardiomyopathy, and they found that 217 proteins were significantly changed in the peripheral vein blood after planned myocardial injury in this derivation cohort. They validated 79 of these proteins in an independent cohort. Furthermore, among 40 validated proteins that increase within one hour after myocardial injury, 23 were also elevated in patients with spontaneous myocardial infarction.
Finally, the authors applied this to archive samples from the Framingham heart study and showed 156 significant protein associations with the Framingham risk score. This study is so exciting because it highlights any merging proteomics tool that captures a large number of low abundance analytes with high sensitivity and precision, thus providing important proof of principle for future clinical applications and this is discussed in an excellent editorial that accompanies this paper by doctors Graham [Malini 00:04:37], [Lau Enleui 00:04:39] from the University of Ottawa Heart Institute.
The next paper is by Dr. [Anter 00:04:51] and colleagues from the Beth Israel Deaconess Medical Center in Boston, Massachusetts, who looked at post infarction, reentrant ventricular tachycardia and addressed the problem that in vivo descriptions of ventricular tachycardia circuits are currently limited by insufficient spatiotemporal resolution. The authors therefore utilize a novel, high resolution mapping technology to characterize the electrophysiological properties of these reentrant circuits in 15 swine.
The main finding was that the zones of slow conduction within the reentrant circuits with the inward and outward curvatures while conduction velocity in the comment channel isthmus itself was nearly normal. The authors further demonstrated that entrainment mapping over estimated the true size of the isthmus. Thus, the conclusion was that high resolution activation mapping of ventricular tachycardia may better guide ablation therapy and ablation at zones of high curvature may be an attractive target for ablation.
The final papers from first author, Dr. [Tang 00:06:08] and corresponding author Dr. [Fitzgerald 00:06:10] from the University of Pennsylvania Perlman School of Medicine in Philadelphia. These authors studied the cardiovascular consequences of prostanoid I-receptor deletion in microsomal prostaglandin E synthase-1 deficient hyperlipidemic mice. The clinical background to this research question is that inhibitors of cyclooxygenase-2 or Cox-2 are well-known to relieve pain, fever and inflammation by suppressing biosynthesis of prostacyclin and prostaglandin E2.
However, suppression of these prostaglandins particularly prostacyclin by Cox-2 inhibitors or deletion of the I-prostanoid receptor for prostacyclin is known to accelerate atherogenesis and enhance thrombogenesis in mice. In contrast, deletion of the microsomal prostaglandin E synthase1 has been shown to suppress PGE2 but increase biosynthesis of prostacyclin. It therefore confers analgesia while attenuating atherogenesis and does not predispose mice to thrombogenesis. Therefore, possibly contributing to cardiovascular efficacy.
In this particular study, therefore, the authors sought to determine the relative contribution of suppressing PGE2 versus augmenting prostacyclin to the impact of depletion of microsomal prostaglandin E synthase-1 in hyperlipidemic mice. The main findings were that augmentation of prostacyclin is the dominant contributor to the favorable thrombogenic profile of microsomal prostaglandin E synthase-1 depletion in these atherosclerotic mice while suppression of PGE2 accounted for the protective effects in atherosclerosis and the exciting clinical take-home message is that inhibitors of the microsomal prostaglandin E synthase-1 may be less likely to cause cardiovascular adverse effects than NSAIDS or specific inhibition of Cox-2. Those were the highlights of this week. Now for our feature paper.
Our feature paper today is entitled "The frequency, [type 00:08:41] and volume of leisure time physical activity and risk of coronary heart disease in young women" and I am so excited to be joined by two lovely ladies today to discuss this paper. First, the first and corresponding author Dr. Andrea [Comastick 00:08:58] from the School of Public Health of Indiana University Bloomington and Dr. Wendy Post, associate editor from the Johns Hopkins University. Welcome Andrea and Wendy.
Thank you so much for having us.
I am just so excited that we are talking about a paper about women being discussed by women. What more could you ask for? I have to say this is a first for Circulation on the Run, which is why I’m just so excited, so let’s get straight into it.
Andrea, maybe I could just ask you to start by sharing the story of how you and your team came up with some new questions and new data because I’m sure a lot of listeners are thinking there’s a lot of data on exercise and how good it is for cardiovascular health in women already.
Yeah, that's a great question. When we started talking about conceptualizing this paper, the first thing was to focus on younger women. Most of the previous work on physical activity and heart disease has been in older adults and that's primarily because it's older adults that have heart attacks. It’s hard to get a large enough study of young women that has enough coronary heart disease events to be able to study this. We were fortunate where we had a large cohort in the nurses health study too of women and because it’s been followed for over 20 years, we had enough events to be able to examine this association.
We did want to think about, "Okay, what can we add?" because there’s a lot of information about just overall physical activity and health, so what can we do differently? I’m pretty familiar with the physical activity guidelines and really tried to look at what in the guidelines currently and then what could we add? What could be of interest when they start revising the guidelines which is actually going to happen very soon.
That was when we started focusing on, "Okay, instead of looking at just overall activity, look at intensity, comparing moderate and vigorous." We also wanted to look at frequency of physical activity and looking at frequency but also adjusted for a total time or total amount of physical activity that somebody does. Then we are also, the third thing was that we thought was important was looking at adolescent physical activity.
We know that kids, unfortunately as they get older and get into their teenage years, their activity declines quite a bit. Looking at how this physical activity during adolescence earlier life impact coronary heart disease risk in adulthood. Those were the three main things that we were focusing on when we first conceptualized the paper.
Nice. Tell us, what did you find?
We did find that exercise is just as beneficial in younger woman as it is in older adults, which is great. We also found that moderate intensity exercise is just as beneficial as vigorous intensity exercise, which I think is a really important message to get out there. I think a lot of people, especially those that are really inactive to begin with are completely intimidated about the fact of trying to think about going to a gym or trying to jog or run a marathon or something like that.
I think really emphasizing that moderate intensity activity is beneficial and we found that walking was actually the most beneficial activity that we looked at in our study, that brisk walking was really really good for everybody and really lowered risk of coronary heart disease.
Yeah, and the other thing we found which might be of interest for those that are also extremely busy, especially this target population where a lot of people are moms and working was that frequency didn't seem to matter, that as long as people were exercising for a couple hours a week that they should be that they could accumulate it in a couple times a week or they could do it more frequently, four or five times a week. It didn't seem to matter.
That’s cool. You know what? I think a lot of these things we'll also discuss at the Editorial Board when we're looking at this paper. Wendy, we promised that we would give a backstage pass to the Editorial Board and The Journal, so could you share a little bit about what we talked about there?
Well, the Editorial Board was really excited about this paper. We loved the emphasis on young women and the important public health message about how we need to get out there and move and exercise to reduce our risk for cardiovascular disease. As was mentioned, there have been previous studies that also show the benefit of exercise but the Editorial Board especially liked the large sample size, the long duration of follow-up, the number of events that had been accrued that allowed for sophisticated analyses, adjustment for confounders and the very rigorous study design and excellent statistical methods that have been used in this study and so many other studies from the nurses health study, but I think we particularly just loved the message. The message was great.
We need to get out there and move. We need to tell our patients, especially young women, that now we have data that if you start exercising now, it will help in the future but also the study showed that if you hadn't exercised much in early life that’s starting to exercise more proximal to the event was also important as well.
Thank you Wendy. I also remember that we talked about the lack of interaction with body mass index, and I thought that was a great message. Andrea, could you maybe share a little bit about that?
Yeah, this is something that previous investigators have looked at the interaction between body mass index and exercise. Unfortunately, we’ve all found the same thing so it doesn’t seem to matter whether women are normal weight or overweight or obese that they still get benefit when they exercise, and I think that’s really encouraging. I know a lot of people might start to exercise because they really want to drop some weight but just trying to emphasize even if the numbers on the scale aren't changing, that exercise still has all these really great benefits for heart disease and also for many other diseases.
Exactly. Can I just ask both of you and maybe I’ll start with Andrea, what will you do different now both as a woman and as a clinician seeing women now that you know what you do from your data?
Well, I’m not a clinician. I’m an epidemiologist so unfortunately I don’t get to see patients and counsel them although I do try to talk to community members as a public health person and really get in the community on board with what we’re talking about. I just try to tell people, I actually talked to a group of people last week, and just trying to say, "Anything is better than nothing and just trying to even start with some short walks." Again, just emphasizing you don’t have to go to a gym or you don’t have to be doing anything that's super strenuous but just do stuff that feels good and just try to get your heart rate up a little bit like going out for a brisk walk. I think that's my main message that I try to tell everybody is at least start with something and get moving a little bit.
I love that. Wendy?
I like to emphasize the data about brisk walking. I thought that was great because many of our patients don’t want to join a gym, don’t have the time to join a gym so just getting out and walking is fabulous exercise and now we have the data here that in young women that after 20 years of follow-up, brisk walking was associated with I think it was a 35% reduction in risk for cardiovascular disease during follow-up.
In addition, I liked the message about the total amount of time that you spend exercising in a week is what’s important. It doesn’t matter whether you divide that into seven days a week to get to that same amount of time or whether you do it in bursts of three days a week, and I think that’s particularly important for the many women who have so many different responsibilities and may not have time every day to go out and exercise. The days that you do have time, just exercise a little bit more those days, so lots of really important messages for our patients and for ourselves.
I really couldn’t agree more and just from my point of view, because I see a lot of patients in Asia and I do acknowledge just like you did, Andrea, in your paper that your data are predominantly in white populations. Still one of the messages I like to get out to the women I see is we have very skinny women and when I see younger women, and I really like emphasizing that, "Hey, just because you’re not struggling with an obesity issue or just because you’re young, it doesn’t mean you don’t need to exercise and that we all should just get moving." Thank you very, very much for that Andrea.
Oh, no. It's my pleasure and thank you for having me come on today and talk about this.
Thank you too, Wendy. Do you have any other comments?
No, but congratulations on your publication, Andrea.
Oh, thank you so much, Wendy. I was really happy to get the message that guys were excited about it. Thank you so much.
You’ve been listening to Circulation on the Run. Thank you for joining us this week and please tune in next week.
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. Joining me in just a moment are Dr. James Gammie and Dr. Timothy Gardner to discuss our feature paper this week describing the first-in-human clinical experience with a novel transapical beating heart mitral valve repair.
First, here are the highlights of this week's journal. The first paper is from co-primary authors doctors Yoon, [Tsue 00:00:49], and [Cha 00:00:50] as well as corresponding authors Dr. [Che 00:00:55] and Dr. Kim from the Seoul National University College of Medicine. These authors examine mechanisms underlying diabetes-induced microvasculopathy, testing the hypothesis that Notch signaling in endothelial cells may play an important role in this condition.
The authors tested this hypothesis by inducing diabetes in eight-week-old adult mice using intravenous streptozotocin. They then modulated endothelial Notch signaling using chemical inhibitors in both wild type and transgenic mice. Results showed that the Notch ligand called Jagged-1 was markedly increased in endothelial cells of diabetic mice. Using endothelial specific Jagged-1 knocked down mice, they found that blocking Jagged-1 prevented diabetic microvaculopathy. Furthermore, using the induceable endothelium-specific Jagged-1 knocked down mice, blocking Jagged-1 even at four weeks after the establishment of diabetic microvaculopathy could reverse the condition.
In summary, these findings show that diabetes induces Jagged-1 over expression and suppresses Notch signalling in endothelial cells leading to diabetic microvaculopathy in adult mice. The clinical implications are that dysregulated intercellular Notch signalling may therefore represent a novel molecular target in the treatment of diabetic retinopathy.
The next study by Dr. Smith and colleagues at the Leiden University Medical Center in the Netherlands evaluated the association between LDL cholesterol variability and four cognitive domains at 30 months in the 4428 participants of the prosper study.
Results showed that a higher LDL cholesterol variability was associated with lower cognitive test performance for intermediate and delayed memory-related tasks, selective attention, and processing speed. Higher LDL cholesterol variability was also associated with lower cerebral blood flow and greater white matter hyperintensity load in an MRI substudy of 535 patients.
In addition to being independent of the mean LDL cholesterol levels and of clinically overt cardiovascular diseases, these associations were present both in the placebo and pravastatin treatment [inaudible 00:03:43] of the prosper trial suggesting that the findings did not mearly reflect pleiotropic effects of statins or of nonadherence.
The study importantly provides the first observational evidence that lipid variability, not just absolute or mean values, but the variability, maybe of importance to neurocognitive function and thus contributes while understanding potential pathways of neurocogniticve decline.
The next study is by first author, Dr. [Huh 00:04:19], and corresponding author, Dr. Ralph, from the Menzies School of Health Research Charles Darwin University in Australia. These authors aimed to investigate the long term outcomes from acute rheumatic fever and rheumatic heart disease.
They achieved this aim by using linked data between the rheumatic heart disease register, hospital data, and death register for residents of the northern territory of Australia, and examined 1248 patients with rheumatic heart disease as well as 572 patients with acute rheumatic fever in the period 1997 to 2013.
The main findings were that in the first year after an acute rheumatic fever episode, the incidents of progression to rheumatic heart disease was 10 times higher than acute rheumatic fever recurrence; 10% of rheumatic heart disease patients had severe disease at diagnosis. The presence of comorbidities was associated with higher incidence of rheumatic heart disease complications and mortality. In particular, comorbid renal failure and hazardous alcohol use accounted for 28% of the access indigenous mortality.
These findings have global relevance for settings with high acute rheumatic fever, rheumatic heart disease rates and really emphasized the need for integrated chronic disease management strategies for these patients.
The final paper is by first author Dr Bettencourt, corresponding author Dr. Blankstein, and colleagues from Brigman and Women's Hospital in Boston, Massachusetts. These authors sought to answer the question what is the most appropriate score for evaluating the pretest probability of obstructive coronary artery disease?
To answer the question, the authors compared the Diamond-Forrester score with the two CAD consortium scores recently recommended by the European Society of Cardiology, and they did this in 2274 consecutive patients without prior CAD referred for coronary CT angiography. CT angiography findings were used to determine the presence or absence of obstructive CAD defined as 50% or more stenosis.
Here's a refresher of the different probability scores. The Diamond-Forrester score is calculated based on chest pain type such as non-anginal, atypical or typical angina, gender, and age. The first CAD consortium model score called CAD consortium basic is also based on these factors, but was developed using more advanced statistical modeling strategies which were not available when the Diamond-Forrester model was derived. Additionally, the population had a lower prevalence of disease than the original Diamond-Forrester derivation cohort.
The second CAD consortium score called CAD consortium clinical included the same characteristics as CAD basic, but also included the following clinical risk factors; diabetes, smoking status, hypertension, and dyslipidemia. Moreover, the presence of typical chest pain was weighted less in diabetics compared to nondiabetics in the CAD clinical score. Results showed that among symptomatic individuals referred for coronary CT angiography, the CAD consortium clinical pretest probability score demonstrated improved calibration and discrimination for the prediction of obstructive CAD compared to the Diamond-Forrester classification.
Driving home the clinical implications of this, the authors applied these observed differences in pretest probability of obstructive CAD to guidelines-based patient management algorithms and projected that the use of the newest score could decrease the proportion of individuals in whom testing would be recommended and increase the yield of diagnosing obstructive CAD.
Those were the highlights of these weeks issue. Now, for our feature paper. Our feature paper today is about the first-in-human clinical experience with the transapical beating heart mitral valve repair using a expanded polytetrafluoroethylene chordal insertion device. We're really lucky today to have the first and corresponding author, Dr. James Gammie from the University of Maryland Medical Center as well as Dr. Timothy Gardner, associate editor from Christiana Care Health System to discuss this exciting paper. Welcome, both of you.
James, may I start with you? What an exciting title, a first-in-human experience, and this is really sounding very reminiscent of our experience with TAVR and aortic stenosis valves. Could I ask you, with so many exciting things, what is it about the results that excited you most?
This is an exciting project in that we believe it affords a new treatment option for patients with degenerative mitral regurgitation. We believe that this is a less invasive way of achieving surgical grade reduction of mitral regurgitation. This is a project which has involved a great number of people on our team both within the university and then within Harpoon Medical, as well as our colleagues in Europe to bring this device from an idea which was asked more than a decade ago into a clinical experience.
It really rose out of our recognition in particularly my own practice that virtually, every patient with degenerative mitral regurgitation could be fixed with ePTFE or Gore-Tex neo-chords, and the question became how can we place neo chords on a prolapsed mitral leaflets without doing open heart surgery?
We begin working on that in the laboratory a number of years ago and went through a variety of prototypes, and ultimately, came up with this idea where we could use a 3 millimeter shafted instrument with a specially designed wrap of Gore-Tex on a 21-gauge needle such that we could land on the underside of the mitral leaflet, deploy device, and create a specially designed knot on the atrial surface of the leaflet, and that would anchor the ePTFE on the leaflet. We could repeat that a few times transapically and then adjust the length of those chords in real time using transesophageal echo guidance.
We got this to work in the laboratory and we had hoped that we would have some modest success in humans, but we've been quite pleasantly surprised that it has just worked and we've outlines this initial clinical experience in the manuscript.
First of all, I'd just like to pick up on the point that this is degenerative mitral regurgitation, so this is limited to the primary mitral regurgitation, not secondary?
That's correct and we know that right now, at least in North America, that two-thirds of mitral valve operations are done for degenerative disease. That's correct.
I think a lot of the audience out there is going to be wondering how this new technique compares to the MitraClip. Could you tell us a little bit more about that?
I do MitraClip as well, so I think I'm well positioned to comment on the differences. The Harpoon device right now is still in operation. It does require a small one or two-inch incision. We anticipate it's going to be a thoracoscopic approach in the very near future and then, beyond that, we would hope to extend it to a transcatheter approach. That's one difference.
The MitraClip now is certainly across the world. It's used predominantly for functional mitral regurgitation. In our own experience, it seems to work best for functional mitral regurgitation and as you know, there are anatomic limitations for MitraClip in degenerative disease. The MiraClip replicates the LCRA surgical approach and I think what we've learned from all the less invasive approaches to treat mitral valve disease is that we have to respect what we've learned from our surgical experience, and we know that the LCRA approach works best when it's combined with an annuplasty ring, and certainly, the MitraClip, again, is mostly this perfunctional MR.
Another point I'd bring up is that the experience with MitraClip has been that when you place a MitraClip, you get a fairly strong fibrous reaction and in most of the series, it's not been possible to then go back and surgical repair the valve, but you have to do a replacement because you've compromised the leaflets. Our own approach were simply putting Gore-Tex sutures in the leaflets and we believe that one advantage is that we're not burning any bridges, and that you can go back and do an open repair of you had to.
In our experience, you asked about our results, we had great results in 10 out of 11 of our patients. One patient did require a reoperation. Actually, one of the chords had come untied on the surface in that patient. We were able to go ahead and do a repair and we saw as we had anticipated it based on our animal experience, there was not much compromised to the leaflets.
One of the advantages of our approach is that we can titrate the length to the Gore-Tex chords to optimize the amount of coaptation and maximize the quality of the repair, and that's something that we can't do an open cardiac surgery, and one of the challenges of mitral valve repair is that you have to figure out how long to make those chords while the heart is arrested and placid, and that's one of the challenges in why mitral valve repair is certainly some degree of an art to doing that.
What we've found is that the imager is incredibly important, and so we've teamed up with our echocardiography colleagues, and they really provide essential input into the procedure, and it's done not looking directly at the valve, but looking up at the screens. I think as surgeons, with this procedure, we're moving more into almost becoming interventionalists.
Thank you, James. That was so exciting. Tim, I have to bring you into this now. Now that James has said they're becoming like the interventionalist. Back to my original comment of TAVR and aortic stenosis, are we witnessing history in the making now? You invited an editorial by Dr. Michael Mack and his title was very provocative, Transcatheter Treatment of Mitral Valve Disease. Is it deja vu all over again? What are your thoughts?
I think this is an exciting report and I think that this is the wave of the future. I agree completely with Michael Mack that we are beginning to see interventions for mitral valve disease that are effective, less invasive, in some instances catheter based, but this is just the beginning. In fact, mitral valve disease is somewhat more complex even than aortic stenosis, but this type of experience and the ingenuity and the technical prowess, and the ability to do this minimally, invasively, and so on really portend a whole new era.
I agree with Jim. This is sort of the common ground between the interventional structural cardiologist and the surgeon, and we're becoming even more entwined, more collaborative, and more mutually supportive. We are in a new era and I think over those next decade or so, we're going to see this and similar, and even different procedures tried and proven to be useful for the variety of mitral valve disorders that we encounter. Perhaps the era of the full sternotomy for fairly straightforward, single, focused operations will become something of a thing of the past.
That's beautifully put. James, with that comment, what are the next steps?
As we said in the manuscript, this isn't barely experience and we're continuing to learn as we move [inaudible 00:17:07] to the clinical arena. We are currently in the midst of a CE Mark trial in Europe. We rolled it out to eight separate centers. As we approve clinical experience, we will learn more about precisely which patients work best with this approach and we will accrue longer term data. We now have a number of patient out to a year with stable results and so, as the numbers go up, we'll do that, and then we anticipate a randomized trial in the United States in the early to mid portion of 2017 where we'll compare this approach to conventional open cardiac surgery.
That's fantastic. Thank you so much to both of you, gentlemen, for joining me on our podcast today.
You've been listening to Circulation on the Run. Thank you for joining us this week and don't forget to tune in next week.
Dr. Lam: Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the Journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center, and Duke National University of Singapore.
Dr. Sanjay Kaul and Darren McGuire will be joining me in just a moment to share their perspectives on the EMPA-REG OUTCOME trials. Are the results with empagliflozin in diabetic patients at high risk, are they too good to be true. First, here are the highlights from five original papers in this week's issue.
The first paper is from Dr. Gilboa, from the National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention in Atlanta, Georgia, and Dr. Marelli from the McGill Adult Unit for congenital heart diseases in Montreal, Quebec, and colleagues. These authors recognize that because of advancements in care there has been a decline in mortality from congenital heart defects over the last several decades. However, there are still no current empirical data documenting the number of people living with congenital heart defects in the United States.
These authors address this gap in knowledge by using prevalence data from Quebec, Canada, in the year 2010, as a foundation for a mathematical model, and estimated that in the United States in the year 2010, approximately 2.4 million people, including 1.4 million adults, and 1 million children were living with congenital heart defects. This estimate is significant, because it corresponds to a 63% increase in the estimated size of the adult population with congenital heart defects in the United States since the year 2000. This has significant implications for resource allocation for health services delivery that will need to account for this growing population of adults with congenital heart defects.
The second paper is from first author Dr. Tabot, and corresponding author Dr. Liao, from the University of Chicago, and colleagues who aim to understand better the common complication of angiodysplasia leading to nonsurgical bleeding in patients with left ventricular assist devices. The authors studied 101 patients with heart failure, left ventricular assist devices, or orthotopic heart transplants. They found that compared to patients with heart failure, or transplant patients, patients with left ventricular assist devices had elevated serum levels, and endothelial expression of angiopoietin-2, which is a potent angiogenic mediator.
Elevated levels of angiopoietin-2 in these patients increase angiogenesis in vitro, and were associated with bleeding events. Furthermore, they found that increased thrombin levels in left ventricular assist device patients were associated with elevated angiopoietin-2 levels. In aggregate, therefore, the results indicate that high levels of thrombin induced endothelial angiopoietin-2 expression, which may then contribute to angiodysplasia and non-surgical bleeding in patients with left ventricular assist devices. The clinical implications are that clinical studies angiopoietin-2, and factor 12 inhibitors may therefore be indicated to prevent nonsurgical bleeding in patients with left ventricular assist devices.
The third paper is Dr. Gordon from Hasbro Children's Hospital in Rhode Island, and Dr. Kieran from the Dana Farber Cancer Institute in Boston, Massachusetts, and colleagues who addressed the Hutchinson Gilford Progeria Syndrome. An extremely rare, fatal segmental premature aging syndrome, where without specific treatment, death usually occurs at an average age of 14 1/2 years from an accelerated atherosclerosis.
A PRIA single arm clinical trial has demonstrated that the protein farnesyltransferase inhibitor, Lonafarnib, ameliorates some aspects of cardiovascular and bone disease in this syndrome. The current trial sought to further disease outcomes by additionally inhibiting progerin prenylation using pravastatin and zoledronic acid on top of Lonafarnib in 37 participants with the Progeria syndrome. Results showed that the composite primary study outcome of increased rate weight gain and decreased carotid artery echodensity was achieved. Overall, participants experienced increased bone density, size, and structural properties. However, unlike the PRIA single arm Lonafarnib monotherapy trial, mean carotid-femoral pulse wave velocity and mean carotid artery adventitial echodensity were not improved. In addition, rates of carotid and femoral artery plaques and extraskeletal calcifications all increased.
In summary, compared PRIA Lonafarnib monotherapy treatment, additional bone mineral density benefit, but likely no additional additional cardiovascular benefit was obtained with the addition of pravastatin and zoledronic acid. The authors concluded that since increased bone fracture is not a disease feature, the addition of a combination of statin and biphosphonate to Lonafarnib therapy is not recommended for clinical treatment of Progeria syndrome. However, it is reasonable to consider statins if concurrent lipid abnormalities need to be treated.
This paper is accompanied by an excellent editorial by Dr. Francis Collins, who describes our journey in seeking a cure for this rare disease of Progeria.
The fourth paper is by first author, Dr. Grisenti and corresponding author Dr. Tilley from Lewis Katz School of Medicine, Temple University in Philadelphia, and colleagues who aimed to better understand the role of leukocyte expressed beta-2 adrenergic receptors in regulating immune cell responses to acute cardiac injury. The authors achieved this aim by studying wild type mice who were irradiated, and then transplanted either with isoform specific beta adrenergic receptor knock out bone marrow, or wild type bone marrow. These chimeric mice, after full reconstitution then underwent myocardial infarction surgery.
Results showed that immune cell specific beta-2 adrenergic receptor expression was essential to the repair process following myocardial infarction. In the absence of beta-2 adrenergic receptors, vascular cell adhesion molecule-1 expression was increased in leukocytes, inducing their splenic retention following injury, and leading to impaired scar formation, followed by rupture and death. Splenectomy partially restored the beta-2 adrenergic receptor deficient leukocyte infiltration into the heart, but gene therapy to rescue the leukocyte beta-2 adrenergic receptor expression completely restored all injury responses back to normality.
This study is clinically important because it highlights a bit of a tension that we're facing. On the one had, beta adrenergic receptors are known to regulate cardiac function and remodeling following myocardial injury, by their effects through cardiomyocytes. That's why we use beta blockers to prevent, at first, cardiac remodeling. However, the current studies now indicate that inhibition or deletion of the immune cell expressed beta-2 adrenergic receptor causes leukocyte dysfunction, and impaired immunomodulatory responses to myocardial injury.
These results may, therefore, have implications on the use of beta blockers around the time of acute myocardial injury, such as myocardial infarction, or perioperatively. This is really an area that needs further research and understanding.
The fifth paper is by Dr. Herman, from the hospital of the University of Pennsylvania, and colleagues who report on the one year clinical outcomes of SAPIEN 3 transcatheter aortic valve replacement in high risk and inoperable patients with severe aortic stenosis. Now, as a refresher, in the initial partner trial of transcatheter aortic valve replacement for high risk and inoperable patients with severe symptomatic aortic stenosis, there was a demonstration of marked survival advantage compared to medical management ... But a high one year mortality of 24% in the high risk, and 31% in inoperable patients.
More recently, the lower profile SAPIEN 3 prosthesis system has become available. Which has a balloon expandable cobalt chromium frame, with bovine pericardial leaflets, and an external fabric seal. The early 30 day outcomes of this system have been reported, and show a very low rate of adverse events.
The current study now reports the one year survival, and showed that all cause survival was more than 85% for all patients, above 87% in the high risk, and above 82% in the inoperable subgroups. Furthermore, there was a high rate of transfemoral access at 84%, and a high all cause and cardiovascular one year survival in the high risk transfemoral subgroup of 89% and 93%, respectively. Between 30 and 365 days, the incidence of moderate perivalvular aortic regurgitation did not increase. There was no association between mild perivalvular leak and one year mortality. Although, a small increase in disabling stroke occurred.
These results, which likely reflect device iteration and procedural evolution, support the use of Taver as a therapy to consider in high risk and inoperable patients with aortic stenosis.
Those were the highlights from this week's issues, and now for our feature paper. We will be discussing the perspective paper entitled "Is the Mortality Benefit With Empagliflozin in Type 2 Diabetes Too Good to be True?". To discuss this, we have two very special guests. First, Dr. Sanjay Kaul, writer of this paper, and from Cedars-Sinai Medical Center. Second, Dr. Darren McGuire, deputy editor of circulation from UT Southwestern. Welcome, Sanjay and Darren.
Dr. McGuire: Thanks, Carolyn.
Dr. Kaul: Thank you, Carolyn.
Dr. Lam: To start us off, I'd really love if Darren could please introduce this new content category of circulation. Frame of reference section, of which this is one of the papers, a perspective article.
Dr. McGuire: Sure, so we envisioned, as we're evolving circulation to our new editorship, an opportunity for authors, luminaries in the field, to give us in a very encapsulated form, a laser focus perspective on a specific topic. These come in two flavors, the perspectives piece, which this is, is a little more evidence and scientific quantitatively based. Then we'll also have a section called on my mind, which is more of a free-flowing opinion editorial targeting possibly a contentious or controversial issue. These are going to be very short, and hopefully very entertaining, and kind of teasers for the readership of the Journal.
Dr. Lam: Sanjay, you made it very personal, and I like that, too. Share with us how this idea came about.
Dr. Kaul: Well, I was very impressed at the reception that the results of the EMPA-REG outcome trial received at the EAST meeting at Starcom last year. While I was witnessing the applause, I had polar reactions. On one hand, I thought that after nearly five decades of trials with checkered history, with regards to cardiovascular outcomes, here we have for the first time a trial demonstrating not only cardiovascular benefit, but a mortality benefit. I thought maybe it's time to take the trumpets out and sort of herald this holy grail, which we had failed to achieve. On the other hand, realizing that we had been fooled before many times by trials, yielding implausibly large treatments actually, that were never replicated at subsequent trials.
I had a skeptical response to it, and sort of asked this question rather tongue-in-cheek, or maybe used as a rhetorical tool to address whether this mortality benefit was too good to be true.
Dr. Lam: You know, you didn't just question it. You examined the data, and provided even more evidence. That's what I was impressed with in your paper. That table where you provided base factor, as well as a Bayesian analysis. Could you break that down for us, and explain what you found?
Dr. Kaul: Yes, I was trying to sort of examine the strength of the evidence, in terms of the quantitative aspect. Yes, the effect size for the cardiovascular benefit was quite impressive. For the primary endpoint, which was a compositive cardiovascular, death, non-fatal MI, and non-fatal stroke, the p-value was not very robust. It was .04. The p-value tends to overestimate the strength of evidence. I utilized base factor, which basically is a metric that allows the two competing hypotheses to predict the data. Using the base factor, I was able to demonstrate that the alternative hypothesis was stronger than the null hypothesis by eight-fold. The p-value of .04 translated into a base factor of .13. Which is not strong evidence against the null hypothesis. It requires independent confirmation and subsequent trials.
A p-value of .04, while meeting the superiority criteria, would not be sufficient enough to meet the FDA's requirement of substantial effectiveness. Substantial effectiveness just basically means that the FDA requires two trials, each with a p-value less than .05. In 1998, they modified their regulatory requirement, and accepted that one single trial would be sufficient, provided that there would be a persuasive p-value. Persuasive basically is defined as a p-value less than .001.
The base factor allows us to sort of interpret the strength of the evidence, with respect to the primary composite endpoint was not strong enough to meet this requirement. With respect to cardiovascular mortality, as well as all cause mortality, which trumps all other endpoints, it was persuasive enough.
Dr. Lam: What's your conclusion on that?
Dr. Kaul: What is controversial about that was that in the three specified statistical plan, the so-called hierarchical testing strategy, the non-inferiority for three point MACE, followed by non-inferiority for four point MACE, and followed by superiority of three point MACE, and lastly, superiority of four point MACE. Because the p-value of four point MACE superiority was .08, one can argue purely from a statistical perspective that you stop your testing strategy, and any analysis beyond that would be deemed exploratory. Even though cardiovascular mortality and all cause mortality was prespecified, the purist would argue that since you failed superiority for four point MACE, you really can't proceed further. You can analyze, but it will be considered an exploratory analysis.
I sort of wept and said that because Christopher Columbus had prespecified that he will be discovering the route to India, the fact that he stumbled upon America does not mean it doesn't exist because he had not prespecified it. I think all cause mortality is the most meaningful endpoint, and the least subjective measurement error. It meets the key attributes of regulatory decision making. Which it's prespecified, it's highly persuasive, therefore, it meets the replication criteria, and the p-value is so robust that even if you adjust for nearly 100 multiple comparisons, the p-value would still hold. It meets all the regulatory criteria for approval.
Dr. McGuire: Sanjay, let me just chime in here. I think it's also important, not only were these prespecified, but it's important, I think, for readers of these diabetes programs to realize that hospitalization for heart failure ... Although it's not part of the primary outcome ... In virtually every one of these trials, it is prospectively collected, chartered to find, and essentially adjudicated by blind endpoint adjudicators. You know, death is death. Cardiovascular death in these programs are all adjudicated, as well. I think the prospective collection and central adjudication also adds legitimacy to the hospitalization for heart failure are above and beyond the analytic issues.
Dr. Lam: Darren and Sanjay, I hear both of you kind of saying it does look like, even looking at it from different angles, the data do look strong. At the end of the day, Sanjay, you concluded that it does need another trial. Results do need to be replicated. That was your conclusion. I'd love to hear Darren's take on this.
Dr. McGuire: I think what Sanjay is saying there, and I think what we all believe, was we would really love to see this observation with another member or members of the class. We're learning a lot in hindsight based on these observations, and people are exploring potential mechanistic underpinnings. We're learning a lot about the mechanisms of these medications, above and beyond their glucose uric effects. There's a lot of implication about renal physiology and hemodynamics, and altered myocardial metabolism. I think as Sanjay points out in the paper, some of this looks like a possible arrhythmic effect. We have a lot to learn about this mechanism of action, and whether or not this will be unique to impact gliflozin.
It has been publicly announced, Boehringer Ingelheim is planning, they're in the planning phases for heart failure trials with empagliflozin to further explore this signal. I think they will address Sanjay's desire to have some replication in a different patient population. Still, we would love to see these extended into other patient populations. To both extend the use of the medications if they're found, but also provide further confirmation of the observations from EMPA-REG outcome.
Dr. Kaul: Carolyn, let me also add, I used the title as a rhetorical tool, as I stated earlier. I do conclude that the mortality data is not likely to be spurious. In the back of my mind, I still have that 1% skepticism that I would like to eliminate, because the findings were totally unexpected, and unprecedented, as we discussed earlier. If all the pathways, including the mechanistic pathways are aligned, I would have substantial reassurance, beyond any reasonable doubt that the findings are true. That's why I'm asking for replication. Not necessarily by empagliflozin in other trials, but by another molecule within the same class. I think that would be sufficient.
Dr. McGuire: Yeah, and I think it's really interesting to note there, is that I was involved in the early days of some of these drugs as they're being developed. When the other two members of this class went to the FDA, dapagliflozin and canagliflozin, they provided FDA's requirement and meta analysis from all of the phase 2B and 3 trials that had been completed to date. The meta analysis of the cardiovascular outcomes. Both dapagliflozin and canagliflozin had point estimates of cardiovascular death reduction of 30%, and 35%, respectively. When we saw those data, they were based on 25 to 40 total events. We chuckled, thinking this is spurious, from small events being analyzed. That there's no way they would prevent cardiovascular death. Sure enough, you know, you could almost superimpose those point estimate plots from the phase 2B-3 meta analysis, with the ultimate outcomes from EMPA-REG. There's some promising, although again, very statistically imprecise estimates that this may well be a class effect. As many of the listeners will know, there are ongoing cardiovascular outcomes trials for all of these medications. That will come some time in the next year or two.
Dr. Lam: That's fantastic. Thank you both for sharing those perspectives. I mean, I learned so much. I really think, Sanjay, your paper achieved exactly what you had meant for it to achieve, and exactly what circulation was hoping to create the discussion, as well.
Dr. McGuire: Thank you, Carolyn.
Dr. Kaul: Thank you very much.
Dr. Lam: You've been listening to Circulation on the Run. Thank you for listening. Don't forget to join us next week for more highlights and discussions.
Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm doctor Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore.
I am excited to be joined today by 2 guests and we will be discussing the feature paper on phenotype specific treatment of heart failure with preserve ejection fraction but first here are the highlights from 5 original papers in this week's issue.
(0:42) The first paper by first author doctor Haas, corresponding author Dr. Bidinger and colleagues from Boston Children's Hospital aim to investigate the role of PCSK9 in nephrotic syndrome associated hypercholesterolemia. The authors did this by first looking at 50 patients with nephrotic syndrome and showing that resolution of nephrotic syndrome was associated with a decrease in their plasma cholesterol, as well as a decrease in their plasma PCSK9 levels. They then looked at two mouse models of nephrotic syndrome. One using nephrotoxic serum to induce immune mediated damage of the kidney podocytes. The second, a model of genetic ablation of the kidney podocyte.
In both these models nephrotic syndrome produced hypercholesterolemia and a 7 to 24 fold induction of plasma PCSK9 levels. The authors then went on to look at the effect of knocking out PCSK9 both in the whole body as well as specifically in the liver in these mice. They showed that mice lacking PCSK9 no longer showed the increase in LDL cholesterol with nephrotic syndrome induced by nephrotoxic serum. Thus in summary, podocyte damage triggered mocked inductions in plasma PCSK9 and conversely knocking out PCSK9 in ameliorated this lepodimia in a mouse model of nephrotic syndrome. The cool thing about this data is that they now opened the door to the consideration of PCSK9 inhibitors in patients with nephrotic syndromes associated hypercholesterolemia.
(2:45) The second paper by Dr. Fortis and colleagues from Duke Clinical Research Institute aimed to address an important knowledge gap that has not yet been addressed in the pivotal noac trials or large registries. Which is whether outcomes differ among atrial fibrillation papers with worsening renal function compared with those with stable renal function while taking a noac versus warfarin. The authors looked a this by studying more than 12,600 patients who were treated with rivaroxaban compared to warfarin in the ROCKET AF trial. On treatment worsening renal function was defined as a decrease of more than 20% from screening creatinine clearance measurement any time point during the study.
The main finding was that among patients with on treatment worsening renal function, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin without an increase in the composite leading end point. This is really encouraging to all of us who treat these patients, knowing that it is possible to safely anti-coagulate patients with worsening renal function without excessive bleeding and to know that rivaroxaban may be an alternative to warfarin in these patients. This paper is accompanied by a beautiful editorial on the multifaceted dilemma of renal function and atrial fibrillation by doctors Hijazi and Wellington.
(4:30) The third paper by doctor [inaudible 00:04:32] and colleagues from Massachusetts Journal Hospital describes a randomized controlled trial of an advanced care planing video decision support tool in 246 patients with advanced heart failure. Patients were randomized to an intervention arm which consisted of a six minute video as well as an advanced care planning checklist or to a control arm where patients received only a verbal description of the goals of care. This video began by first introducing to the patient the concept of advanced care planning and then using images to depict the three part goals of care namely, life prolonging care, limited medical care and comfort care. Patients in the intervention arm who were showed the video, were more likely to be informed, to select a focus on comfort and less likely to desire CPR and intubation compared to patients receiving the verbal information only. The clinical application of this finding is that advanced care planning video decision needs can stimulate and supplement patient decision communication. Indeed we need such tools to enhance patients understanding of their goals of care options and to ensure that our patients get care that reflects their well-informed wishes.
(6:10) The fourth paper is by first author Dr. [inaudible 00:06:12] and corresponding author Dr. Lloyd Jones and colleagues from the Northwestern University Feinburg school of medicine in Chicago. These authors provided the first prospective evaluation of atherosclerotic cardiovascular disease outcomes in adults with heterozygous familial hypercholesterolemia in the US population. They did this by using individual pool data from 6 epidemiologic cohorts including more than 68,500 baseline person exams and 1.2 million person years of follow up. They confirmed substantially elevated long term, meaning up to 30 year risks of coronary heart disease and total atherosclerotic cardiovascular disease including stroke in US adults with a familial hypercholesterolemia phenotype defined as LDL cholesterol above 190 milligrams per deciliter. This was associated with an acceleration of coronary heart disease risk by up to 20 to 30 years. These findings were independent of other risk factors and were consistent using various definitions of the familial hypercholesterolemia phenotype.
What are the clinical implications of these findings? This was discussed by Dr. Rodriguez and Dr. [inaudible 00:07:47] in an editorial, the take home message is that there is likely an important long term burden of atherosclerotic cardiovascular disease in phenotypic but unrecognized familial hypercholesterolemia patients in the United States. Current efforts to identify patterns and gaps in the diagnosis and management are well justified. The findings also have implications for risk communication to patients.
(8:20) Finally, the fifth paper is by Dr. [inaudible 00:08:25] and colleagues of the TIMI study group from Brigham and Women's Hospital. These authors looked at the impact of renal function on outcomes with edoxaban and oral factor 10 A inhibitor with 50% renal clearance compared to warfarin in the ENGAGE AF-TIMI 48 trial. In the pre-specified subgroups of granting clearance 30 to 50 and more than 50 ml per minute. The higher dose edoxaban regiment was comparable to warfarin for preventing stroke or systemic embolism and resulted in significantly less major bleeding. In further exploratory analysis, there was a suggestion of lower relative efficacy for prevention of stroke or systemic embolism with the high dose edoxaban regiment, compared to warfarin in the upper range of creatinine clearance beyond 95 ml per minute. Due to lower rates of major bleeding, the net clinical benefit was more favorable with the higher dose edoxaban regiment across the range of creatinine clearance.
In summary, edoxaban demonstrated superior safety and comparable efficacy to warfarin for the prevention of thromboembolic events in many patients with atrial fibrillation. However the authors were careful to note that there was insufficient evidence to allow definitive conclusions to be drawn in patients with normal renal clearance above 95 ml per minute. The authors called for further investigation of optimal dosing of edoxaban in the higher range of creatinine clearance.
(10:14) Those were our highlights now for our feature paper of the week. Phenotype specific treatment of heart failure with preserved ejection fraction, a multi-organ road map. The first author is Dr. [inaudible 00:10:31] from Northwestern University Feinberg School of Medicine in Chicago and colleagues. To discuss this very special paper today I have two guests, one is a corresponding author, Dr. Walter Paulus from the VU, University medical center in Amsterdam as well as Dr. Jarett Berry, associate editor from UT Southwestern. Welcome Walter and Jarett.
Jarett Berry: Thanks Carolyn.
Walter Paulus: Thank you very much Carolyn.
Carolyn Lam: To start us off this is an in depth review paper and it is a really very special type of paper that it's new to Circulation. Jarett could you tell us a little bit about these reviews and how this paper came to be?
Jarett Berry: As we think about the new Circulation and our goals to really make the content of Circulation as clinically relevant as possible, as we think of the different circumstances and clinically challenges faced by practicing physicians, many different topics come to mind and one in particular, therapeutic area heart failure with preserved ejection fraction is one particular type of cardiovascular disorder that has been very difficult to find novel treatments for. As we all know there has been a number of large scale clinical trials that have failed to improve clinical outcomes in these patients, in situations like this what we really need is wisdom and a guide from those with expertise in this area so we can take that wisdom and that perspective and incorporate it into our approach to caring for these patients in a way that can provide a road map moving forward.
This particular review addressing heart failure with preserved ejection fraction was timely in that sense and the choice of author, of course, Walter and his colleagues are leaders in the field in terms of the research and our understanding of HFpEF. With that goal, we're really trying to reach out to these types of investigators for these types of reviews to provide us with a framework to help us think about charging our way forward and we couldn't think of a more appropriate choice to lead that effort other than Walter Paulus.
Carolyn Lam: Thank you so much Jarett, that's so well put and I couldn't agree more. I mean HFpEF is one of those disease syndromes were guidelines haven't changed in years and basically the first sentence is that we don't have outcome improving treatments available. Walter this must have been particularly challenging and I really congratulate you because one of the central figures that I'm so impressed with in this review is actually a clinical application figure and I'm referring to figure 2. Do you think you could tell the readers a little bit more about this?
Walter Paulus: I would like to thank first the editors of Circulation for having given us the opportunity to write this in-depth review. I must admit before answering Carolyn's question that I really enjoy this [inaudible 00:13:37]. We have a very challenging team of co-authors and the most difficult part of the enterprise was to have all the noses directed in the same direction. You have to align very many ideas and it has been a very challenging in-depth but I think it will be teamed out with a, not a compromise but something, a paper where everybody is still happy with its content. This is somehow also reflected in the figure 2 to which Carolyn is alluding.
When we start speaking about the phenotypic diversity, it's very difficult to [inaudible 00:14:13] with a conceptual theme on how we're going to organize therapy when there are many different phenotypes around. I think this is what this figure is all about, it tries to organize the phenotypic diversity and come up with a type of personalized medicine for each phenotype in a very comprehensive way. This figure, in fact, orders the phenotypes, presentation phenotypes and pre-disposition phenotypes with presentation phenotypes on the abscissa and the pre-disposition phenotypes on the ordinate. Then you get a matrix configuration, you start out in the matrix in the left hand corner for the most common phenotype which is metabolic risk combined with [inaudible 00:14:59] congestion. Then you go on and you see that you can have [inaudible 00:15:04] hypertension, then you have additional measures that need to be taken. You can go downwards in the graph and then you'll find out that it might be renal dysfunction and then you find specific measures that have to be taken when renal dysfunction is present.
By combining the ordinate and the abscissa in the matrix, you find a very personalized type of therapy for the individual phenotype. I think this to me what makes the figure that feeling is that it's structured, it's organized, it's something very complex in something which is easily comprehensible.
Carolyn Lam: Walter, I have not seen a figure like this that it's so novel and I know that clinicians will really welcome this because as Jarett so nicely put, it's wisdom and some sort of simplification and yet with in-depth understanding that we so need in the management of this syndrome. Another thing that I thought was very special about your paper is that you tackled head on the divergent results of several recent trials. You described the low nitric oxide, low cyclic guanosine monophosphate cycle that's present in HFpEF but also try to put into context the need trial, the relax trial, top cat and even mention Socrates preserved in all of this. Do you have any quick top line comments, not to give the whole story away because I'm sure readers are now encouraged to look at the paper but on how all of this actually falls into place in your schema.
Walter Paulus: I think how everything falls into place is illustrated in the figure 1. Figure 1 shows a very broad perspective on the problems of HFpEF as it shows HFpEF to be the result of systemic inflammatory state but so far we have focused only on the project manifestations of the systemic inflammatory state [inaudible 00:17:08] cardiac manifestations, which is the stiffness of the myocardium, and the [inaudible 00:17:12] of the myocardium. There are also things going in the pulmonary [inaudible 00:17:16], there are things going on in the skeletal muscle and there are things going on in the kidney. I think that if you do not take these other organs into perspective, then the image you will have from the results of your trials is getting blurred. For instance, we have so many trials about look at the exercise [inaudible 00:17:35] in terms of elevation of [inaudible 00:17:37].
It's my feeling that many patients with HFpEF just get treated diabetic. You see them afterwards again in your [inaudible 00:17:46] patient clinic and they have symptoms of nasal fatigue. They no longer being hindered by the elevation of [inaudible 00:17:52] probably because of the administration of the diabetic but they're still highly symptomatic and they have moved over to another board and that limits the [inaudible 00:18:01] mainly the skeletal muscle. It's of course nicely illustrated already for years by the work of Dalane Kitzman which is one of the co-authors, but still these issues, the same goes for the hypertension, a field in which Carolyn has been very active. There are some patients who are persistent [inaudible 00:18:18] hypertension, I'm intrigued by our classification.
It's clear that these patients have moved to a [three catalyst 00:18:24] type of hypertension and we should pay attention to this and we should try to treat it in a very specific way. Again [inaudible 00:18:33] the failure of our trials is also comprehensible. He have two, [inaudible 00:18:38] focus on the myocardium and we should try to keep a very broad perspective and look at [inaudible 00:18:43] in major broader way. Just to support this point is the result of the Socrates reserve trial which I was very intrigued by it, just listen to the results couple of days ago at the European Heart Failure Society meeting in Florence. Turns out if you give this very [inaudible 00:19:01] patients that there is no change in nature at [inaudible 00:19:05], no change in left atrial dimension, there's no single argument that something is changing in the myocardium. Nevertheless the effort tolerance of the patients was greatly increased and the question is in quality of life, how that has drastically improved? What I think is going on, is that maybe on the dose of the [inaudible 00:19:23] you are using this very [inaudible 00:19:24].
The main effect might be going on the [inaudible 00:19:27] and you just took the wrong end point, you are again focusing very narrowly on the myocardium. I think most of the patients have entered such a trial are relatively stable. You're not going to put in a trial a patient who is unstable, they must be all be treated with diabetics and you shift symptoms from the myocardium to the other organs. I think that the index review which we provide, I think has 2 main issues, that you should have a broad perspective on HFpEF with inclusion of the other organs and secondly, that we provide a matrix configuration for phenotypes specific treatment.
Carolyn Lam: Walter that is beautifully put and Jarett I think I'm speaking on behalf of you too that this paper has really accomplished what our in-depth reviews were aiming to do, which is to provide a clinical perspective and really insightful comments regarding the syndrome. Is there anything else you'd like to add Jarett?
Jarett Berry: Yeah, I just wanted to echo your congratulations and just to really highlight the importance of this figure 2. I think it is an important step for us to begin to take the concept of the heterogeneity the phenotype, whether it's something happening centrally or peripherally and take that heterogeneity and try to incorporate that into our practice pattern. I think that's obviously been discussed in length in literature before but has not been put together in a practical way for practicing clinicians. I just want to echo your comments that Walter and his coauthors have done an important service for all of us as we think about how to take care of our patients with HFpEF.
Carolyn Lam: That's awesome, I think anyone listening is really going to want to take hold of that journal and have a look at both figures, 1 and 2 and read this beautiful paper. Thank you very much Jarett and Walter for your time, today.
Jarett Berry: Thanks Carolyn.
Walter Paulus: Thank you very much Carolyn, [good night 00:21:20].
Carolyn Lam: You've been listening to Circulation on the Run, thank you for listening and don't forget to join us next week for more highlights.
Carolyn: Welcome to Circulation on the Run. You're weekly podcast summary and backstage pass to the journal. I'm Dr. Carolyn Lam from the National Heart Center in Duke National University of Singapore. I am thrilled to be your host every week. Joining me today to introduce our podcast are two very very special guests. Dr. Joseph Hill from UT Southwestern is editor and chief of Circulation. Hi Joe.
Joe: Pleasure to be here, Carolyn. Carolyn: Thanks, and your second guest, Dr Amit Kara is also from UT Southwestern and the associate editor for digital strategies of Circulation. Hi Amit.
Amit: Hi, Carolyn. Happy to be here. Carolyn: No Joe and Amit, if you don't mind I'm going to start the ball rolling by sharing my little story of how these podcasts came to be. Now do you guys remember when we first talked about this? All right well I do. Joe: Absolutely. Carolyn: Ha ha because frankly, and I don't know if you know this Joe, it wasn't a very good day for me. I had just landed very early in the morning from a long trip and I was battling jet lag while trying to get a million things done such as unpack, clear my mail, get ready for work. You know, the usual. Of course the thing I needed most was to learn that I also needed to do weekly podcasts for Circulation right. So after our chat I did I suppose what a lot of us do when things seem a little bit overwhelming. I dropped everything and I headed for a run in the gym. But in the gym as always I was trying to multitask as well, so I brought my mobile device for my jog so that I could read my mail at the same time, you know. I can already see the smiles of everyone listening because I know you've done this before. Anyone who's done it will know what a pain it is trying to read while you're bouncing up and down on the treadmill. It was just at this point when I was about to go cross-eyed that the radio in the gym started to play the morning news and the news headlines. I remember thinking to myself, oh wow, how I wish I could have someone read my mail or at least the headlines of the mail to me so that I could get the gist of everything even while I was literally on the run. That's how the Circulation podcast idea came to me and hence it's name, Circulation on the Run. To me it's an audio summary of the headlines of the journal so that you the listener can in 15 minutes get caught up literally on the run or drive or whatever it is you're doing when you'd rather listen than read. Just so you know you haven't missed the big things. But in addition to getting an overview of the issues contents every week, you get main take home messages as a clinician. Because it will be dull to talk to myself every week I will be inviting an author, an editor, of a featured article of particular clinical significance so that we can give you a behind the scenes look of the paper. That is the idea of the Circulation podcast. Joe, how does this fit with your vision of the journal? Joe: Carolyn, I love your story behind the scenes on how this all got started and I really, truly appreciate your energy and leadership here. This is such an important endeavor for where we want to take the journal. In fact, your leadership here illustrates one of the major initiatives that we have started and that is a global footprint of editorial oversight for Circulation. We are afforded an extraordinary privilege here to see the best science as it emerges from all around the world and we want to do everything we can to make sure that the journal meets the needs of the clinicians, the practitioners, and the investigators everywhere in the world. Here you are leading this important initiative from your home base in Singapore. That's exactly what we're looking to foster and develop going forward. Carolyn: Oh Joe thanks so much for that. I really so appreciate this privilege of doing this and it's true that I'm a living example of the journal going global so to speak. I also really like the way you say that with this overwhelming knowledge that we're facing, we do need help to synthesize and synergize that information. Especially in the clinically oriented way. I think you made that very clear to us in your leadership of our editorial board. Thanks for that. Maybe speaking of trying to reach the world, social media and digital strategies play a big roll. Amit maybe you could tell us a little bit more about how the podcasts fit in your larger scheme for the journal. Amit: Absolutely and I just want to echo Joe's comments and thank you, Carolyn, for taking the lead of this important endeavor. We couldn't think of a better person to do so. When we look digital strategies we have to remember that the journal is producing so much valuable content. The authors are working very hard and creating such an immense amount of new knowledge. We have to appreciate that people consume knowledge in different ways. In the current era there's so many different ways to do that. One hand we still have the traditional print journal which is incredibly valuable and important. Has depth of information that certainly many and most people would want to investigate. But the other end of the spectrum we have our bite sized information which is Twitter and Facebook and so forth which certainly helps people sort of prioritize or are able to glean what's exciting that week and then they can go back and do a deeper dive. The podcast fits somewhere in between. I love what you said, Circulation on the Run, you're example was a great one for people who are wanting to consume this information but perhaps in a different way. The audio component and also a time component where they have 10 to 15 minutes to take in this information. Your vision for this is a great one. We'll have a brief component where you will review the weekly articles and people can then learn what's in the journal and what's the most important findings and content that week. Similarly they have the opportunity to really get to know an author and get to know some editors and to really get behind the scenes. This backstage pass if you will. We finally have to remember that we're appealing to a broad audience. People of different ages and around the world. People like to consume information in different ways. We really like to have this as an important part of our offering towards helping people consume this information. Carolyn: Oh Amit. I couldn't have said it better. Thank you so much. Just to be true to ethos. Let me remind everyone that it's going to be a 15 minute podcast and we're going to do our very best to compress all that you need to know into those 15 minutes. I just want to echo what you said that this is only part of the broader strategy and it doesn't mean that the print journal is dead in any way. In fact I am so excited to see the new journal. I don't know about you. It's got a whole new look. It is really really quite good looking, if I might say so. Everyone out there, you're going to expect this new journal on June 29th, 2016. Look out for it. Trust me. You won't be disappointed because there's also a very special little part of the cover that I'd like to discuss before we sign off. That is the doodle. Joe could you tell us a little bit more about the doodle? Joe: As you say the journal look I think is fantastic. It has a clean and modern look to it. The judicious use of color to highlight the different types of content, which as before spans a spectrum of basic science, the definition going forward is vertebrate models, pre clinical models, and disease oriented questions. Starting there, traversing through clinical science, population sciences, health services research, the entire spectrum. Again we are afforded an extraordinary privilege here to help frankly shape the future of cardiovascular medicine. We take that responsibility very seriously. That's why we've recruited an extraordinary team of editors from literally around the world. At the same time, we want to have a little fun. We want to make it fun and engaging as well as very very serious. As part of that, we've launched something that we're calling the Circulation Doodle. That is an idea that leverages the google.com website where I think everyone is familiar with. They, based on an event that occurred that day or week or month, they play around with the visual depiction of the word Google. We're going to do the same thing with Circulation. Every month we will reach out and solicit doodles from artists all around the world. Everyone who's listening to this podcast, I encourage you to think about this. Every month there will be a doodle theme. The first one for July will be Texas. Commemorating the fact that the journal headquarters is moving back to Texas after having been in Boston for 12 years. Previous to that it was under the leadership of Jim Willerson. It's coming back to Texas and the first Circulation doodle depicts a Texas theme. In fact, if you're interested you can find this in the April 25th issue of the journal where in the third of four notes from the incoming editor in that third one on April 25th, we show the first doodle. We're asking people to submit doodles according to monthly themes. The month of August will be vacation. I can tell you start thinking about ways in which you might incorporate a vacation theme in the depiction of the world Circulation for August and the one that comes in that's the best, that the editors like the most, it will be placed on the cover of the print journal and on the website for a full month. We've also conceived themes for the rest of the year all the way through to June of 2017, and in the first issue that comes out from our team, we will list those themes and you'll have plenty of time to start thinking about what you would like to submit. Then in subsequent years, those monthly themes will also evolve. We'd like to get people's ideas about issues that come up related to holidays or national heritage months. Things that we might not know about from our base in the US. We want to do that around the world. It's an opportunity to be creative at the level of themes, and again artistic depiction of the word circulation. Carolyn: I love that. Thank you so much Joe and that just exemplifies that we are all about science and all about having fun at the same time. That was a brilliant introduction to what our podcasts are going to be like as well. Thank you so much Joe and Amit for joining me today. Again, everyone, this was Circulation on the Run. Don't forget, first issue coming out 29th June, 2016.