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Now displaying: September, 2016
Sep 26, 2016

 

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

 
 
Today we will be discussing the first multinational study looking at per-cutaneous device closure of peri-valvular leaks, a topic I'm certain you'll recognize as rapidly developing in cardiology, but first, let me fill you in on the highlights of this week's journal.

 
 
The first paper is a translational study telling us that when transfusing stored red blood cells for hemorrhagic shock, cold transfusing hemopexin and heptoglobin may be beneficial. This study is from first author Dr. Graw, and corresponding author Dr. Zapol and colleagues from the anesthesia center for critical care research at Massachusetts General Hospital and Harvard Medical School.

 
 
These authors reasoned that erythrocytes undergo progressive deleterious changes during storage. Such that, the transfusion of long-stored, packed red blood cells increases plasma levels of cell-free hemoglobin and heme. These are toxic breakdown products of hemolyzed erythrocytes.

 
 
Now, mammals usually synthesize the scavenger proteins: heptoglobin and hemopexin, which bind these toxic extracellular hemoglobin and heme, respectively. The authors therefore, tested the concept of cold transfusion of heptoglobin and hemopexin along with stored red blood cells in their murine remodel of hemorrhagic shock.

 
 
They first showed that resuscitation with long-stored, packed red blood cells produced a higher mortality, higher plasma hemoglobin levels, hemoglobinuria, kidney injury and diffused tissue inflammation, compared to resuscitation with fresh, packed red blood cells. However, when resuscitating hemorrhagic shock with stored red blood cells co-infused with either exogenous human hemopexin or heptoglobin, there was an increased survival and decreased tissue inflammation. Furthermore, co-infusion of heptoglobin with the stored red blood cells, prevented hemoglobinuria and kidney injury. These animal model data warrant further assessment in clinical conditions of severe hemolysis.

 
 
The next study suggests that sickle cell disease, although primarily a blood disease, may also be considered a vascular disease. This is a paper from co-authors Dr. Ranque and Menet from the University Paris Descartes in France, and describe results from the CADRE study. That is, the heart arteries and sickle cell study, which is the World's largest ongoing cohort of sickle cell disease that prospectively recruited more than 3,700 patients with sickle cell disease and 950 healthy controls from Cameroon, Ivory Coast, Gabon, Mali, and Senegal.

 
 
The authors found that mean carotid femoral pulse wave velocity was lower in patients with sickle cell disease, compared to controls and lower in specific hemoglobin phenotypes compared to others. Augmentation index, corrected for heart rate, also increased more rapidly with age in the patients with sickle cell disease, compared to controls, and was higher in patients than in controls. Both carotid femoral pulse wave velocity and augmentation index were independently associated with the glomerular filtration rate and osteonecrosis.

 
 
Augmentation index was also associated with stroke, pulmonary hyper-tension and priapism. Whereas, carotid femoral pulse wave velocity was also associated with microalbuminuria. These findings really under-score the association between sickle cell disease and vascular abnormalities and complications. The prognostic value of these vascular indexes will be assessed during the follow-up of these patients.

 
 
The next paper is a basic science paper suggesting that after sudden cardiac arrest, normalizing calcium cycling, may be a novel approach to improved post-arrest myocardial function. This paper is from co-corresponding authors Dr. Woods, from the Palo Alto Medical Foundation and Dr. Ashley from Stanford University in California.

 
 
These authors developed a rodent model of cardiac arrest using ECMO resuscitation. They used a genetically encoded calcium sensor in a novel fiber optic catheter imaging system to observe calcium-induced calcium release in-vivo before and after resuscitation. They then isolated cardiomyocytes from this model and assessed a mechanical load and calcium cycling simultaneously, using the micro-fiber carbon technique.

 
 
The main finding was of potentiation of calcium-induced calcium release in the post-arrest situation that began in-vivo and was mediated by activation of the calcium calmodulin kinase 2 or CaMKII. Since they also observed that oxidated stress and aldehydic adduct formation were high post arrest, they further tested a small molecule activator of aldehyde dehydrogenase type 2, known as Alda-1, which reduced oxidative stress, restored calcium and c CaMKII homeostasis and improved cardiac function in post-arrest outcomes in-vivo.

 
 
These findings are significant for their potential translational application in post-sudden cardiac arrest, a condition which is really known to have a high mortality.

 
 
The next study reports the results of the DOCTORS Study, standing for Does Optical Coherence Tomography Optimized Results of Stenting. This paper is from Dr. Meneveau from the University Hospital Jean Minjoz and colleagues. The DOCTORS Study is the first randomized control trial testing optical coherence tomography via OCT guided PCI to standard fluoroscopy guided PCI in 240 patients with non-ST-elevation and acute coronary syndromes.

 
 
The first finding was that OCT results directly impacted physician decision making, leading to a change in procedural strategy in half of the cases in the OCT guided group. The primary end-point of functional results of PCI, as assessed by post-PCI, FFR, was modestly improved in the OCT guided group compared to fluoroscopy alone. This improvement appeared to be explained mostly by optimization of the stent expansion. The benefit was obtained at the cost of a longer procedural and fluoroscopy time and more contrast use, but without an increase in peri-procedural myocardial infarction or kidney dysfunction.

 
 
These findings of the DOCTORS study add to the accumulating body of evidence supporting a potential benefit of OCT to guide PCI procedures in acute coronary syndrome. Additional prospective studies with clinical endpoints are warranted. These issues are discussed in an excellent accompanying editorial by Dr. Wijns and Dr. Pyxaras.

 
 
This brings us to the end of our summaries. Now for our feature paper.

 
 
Our featured paper today discusses a problem that we've actually created and that is para-valvular leaks following surgical valve replacement, and we're specifically discussing the role of percutaneous device closure exploring the first multi-national experience form the United Kingdom and Ireland and I'm here with first author, corresponding author as well, Dr. Patrick Calvert from Papworth Hospital in the United Kingdom. Welcome Patrick.

 
Dr. Calvert:
It's a great pleasure to be here, thank you for inviting me.

 
Dr. Lam:
Joining us also is Dr. Dharam Kumbhani, associate editor from UT Southwestern, hi.

 
Dr. Kumbhani:
Hi Carolyn, thanks for having me.

 
Dr. Lam:
Let's get straight into this. It's a problem we've created. How common is it? Why should we care about talking about perivalvular leaks?

 
Dr. Calvert:
You know Carolyn, this is actually quite a common problem. The series we know from previous publications around 5-17% of surgical valves develop leaks. We know in the early experience of TAVR that there was quite a problem with leak, although more recent iterations that's less of a problem. There's a lot of patients out there that have this problem. It's a difficult problem to treat because these are, by definition, high-risk patients and re-operation is not such an inviting thought for them to have. This is something that needs may be a different solution than re-operation.

 
Dr. Lam:
Could you tell us what makes your series special?

 
Dr. Calvert:
Yes, so let's talk about the other series first of all. We had a fabulous series published in 2001 from the Mayo Clinic. That was a single center of excellence where they are really great at doing the procedure, but they gave us great insight of a master class, really if you like, if I had to do the procedure. What is different about our paper is that it's like a real-world experience. It's all the centers that contributed in the United Kingdom and Ireland. It's 20 centers over an 11 year period, in total 308 procedures. It's, if you like, a warts-and-all approach to it. It think that's one way it's a little different.

 
 
I think another way that it definitely stands out is that we are fortunate enough in Europe to have licensed or CE-mark, a number of oblong devices that are a little different in shape. What we do know about these holes is, they tend to be crescentic in shape or at least longer then they are wide. The problem is, if you try to put a circular device in an oblong hole, it's not going to work.

 
Dr. Lam:
Which types of perivalvular leak are you talking about here?

 
Dr. Calvert:
We have approximately 50/50 split between the aortic surgical valve and the micro-surgical valve. Then, about 5% were TAVIs or TAVRs. Then we had a small number of pulmonic valves and one or two around angioplastic rings, so that's the proportions. We had about 57% mechanical valves and 37% bio-prosthetic valves.

 
Dr. Lam:
Wow, first congratulations. That is really important information. I can already imagine. I see those patients too. Dharam, as an interventional cardiologist. What is your take on it. Especially this mention of the oblong devices? They are not FDA approved, so they won't be in the United States, but what did you think of that, managing this paper?

 
Dr. Kumbhani:
I think this is a very tricky subset of patients to treat. As Patrick and his group have shown, that the rates of success can be very high. As you point out, we don't have all the devices that they have in the U.S. A lot of us who do this use more circular devices but they're flexible. The feeling is that they tend to fit in with whatever geometry of the leak is. I do think it would be interesting, and probably more appropriate to have devices that are shaped like these holes are. As Patrick mentioned, they're usually crescentic, or certainly not round.

 
Dr. Lam:
As a non-interventional cardiologist, I didn't realize it was very intricate. Tell us about your main findings.

 
Dr. Calvert:
Our principle findings, and what I think is the most important thing is that, if you're going to do this procedure, you have to achieve a leak at the end of the procedure, or at least in the months that follow-up, that is mild or less. In our series, we showed that those patients that had that, they were independently associated with less deaths and less major adverse cardiovascular events. It's a very clear dichotomy between those groups.

 
 
Of course there's all sorts of reasons why you might be able to achieve a good result in a patient, but we know that if you can do it, those patients will be very much better than the others. In our paper we achieved that in around 75% of patients and they did much better than the others. That is a principle finding. There were another of other factors that were associated independently with death and those also included NYHA classification at follow up, but also creatinine baseline. As I've already eluded to, this is a high-risk chord of patients and there are conventional risk factors that will pre-dispose whether someone's going to do well or not. That's what came out in the multi-variable analysis.

 
Dr. Lam:
Very important clinically. Take home message from your point?

 
Dr. Kumbhani:
I think one of the interesting findings was that only 16% of these PVLs were closed for hemolysis. The vast majority of them were done for symptomatic causes. That probably speaks to the dictum that it's the smaller PVLs that cause hemolysis. I don't know if you have a handle, based on your experience, on that?

 
Dr. Calvert:
When we designed the series, a number of years ago ... When you design a registry you look at the things you're going to collect. Then when you've written the paper you think, "I just wish I had collected some more data." That's one of those things we really wish we looked ... It's fascinating. We do this procedure together and one of the things we're terrified about is taking a big leak, getting rid of heart failure and creating hemolysis.

 
Dr. Kumbhani:
Exactly.

 
Dr. Calvert:
We all have had personal experiences of that happening.

 
Dr. Kumbhani:
Yes.

 
Dr. Calvert:
The data we collected, collected patients who had new hemolysis, requiring transfusion. Therefore, all I can tell you from our series is, that was really quite a small ... It was only 2 or 3% of people who had new hemolysis.

 
Dr. Kumbhani:
After the closure?

 
Dr. Calvert:
After the closure. Of course, about 16 or 17% had hemolysis going into it. It doesn't really tell us any information about what happened to those, unfortunately.

 
Dr. Kumbhani:
One other interesting thing that I wanted to point out. If you look at the PCIs registry, all of, there are about 120 hospitals in it. Is that correct?

 
Dr. Calvert:
That's approximately correct, yes.

 
Dr. Kumbhani:
You had 20 centers that were doing this?

 
Dr. Calvert:
Yes.

 
Dr. Kumbhani:
1 in 6 is doing these in a competent fashion, the PVL closures. I think, as you pointed out, the series are usually single institutions that really specialize in this in the U. S. I think the experience may be a little more consolidated. If you want to just comment on that finding alone?

 
 
The second thing is, is there something different about the intervention training procedure in the U.K. that allows for more interventionists to be comfortable doing this?

 
Dr. Calvert:
I think that's a really great question. I think there's a little to pick apart behind that. I think the first thing to say is that, although there were 20 centers that contributed cases, some of those centers would have definitely had proctors come in to do the cases. This is the entire learning curve. This is every case that has contributed in the U.K. It's watching our learning curve and the lot. There will be a number of centers that have been heavily proctored coming in.

 
 
One thing that's really nice about the U.K., it's a small country. Particularly in this structural community, most people know each other. If you've got a problem, you ring up your friend down the road and say, "You've done a few of these, come and give us a hand." We get that and I do that too, so that's great.

 
 
I think the second thing to say, and I think it's important to say this, our cousins in America are fantastic at doing this procedure. I think they have to be because although the devices are malleable, and they will squash because as we both know, it doesn't matter what the device looks like at the end provided it plugs the hole and is not interfering with the leaflets and it's not falling out. That's fine. I do believe that the oblong devices are more likely to get a good closure. I think therefore, you're less likely to be having to put in 2 or 3 devices in the same sitting. I think that's technically demanding for ... I think it probably is a little more straight forward with the oblong devices.

 
 
I think it is important to say for the record, that there's nothing in this paper that is scientifically proven the oblong devices are better. They trend in their right but, it is a fact of the series of oblong devices. Once they're available, it was 72% and for the total it's about 2/3. It's not a scientific comparison but, we've got these good results with these devices.

 
Dr. Kumbhani:
It would not be a fair comparison but in your database, are you able to do some kind of propensity analysis looking at the oblong versus the other devices? Comparing ventricle leak for example or hemolysis?

 
Dr. Calvert:
We don't have enough breakdown data on hemolysis unfortunately. I think I just need to be careful what I say because a lot of the authors came up with hypotheses about things. I looked at the data and I think when we subgroup too much, it became too small to read to give any careful answers.

 
Dr. Kumbhani:
I see.

 
Dr. Calvert:
I think what would be really fascinating, is when we pool data with other countries because I know there are other countries that are looking at this as well. We might get more information, but that's something we have on the horizon so what this space.

 
Dr. Kumbhani:
That's good.

 
Dr. Lam:
That is fantastic. Thank you Patrick. Thank you Darrin. Seriously, I'm floored. I learned so much from this and I really enjoyed this conversation.

 
 
Thank you very much, and to the listeners out there, don't forget you've been listening to Circulation on the Run. Join us next week for more highlights and features.

 
 

Sep 20, 2016

 

Carolyn:
Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn 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.

 
Michael:
Thank you very much.

 
Carolyn:
Michael, you're calling from South Africa aren't you?

 
Michael:
I am indeed.

 
Carolyn:
That's wonderful. We're very honored to have Dr. Shinya Goto Sensei, Associate Editor of Circulation from Tokai University Japan. Hello Shinya.

 
Shinya:
Hello Carolyn, thank you very much for your invitation to such an excited podcast. I enjoy podcast every week.

 
Carolyn:
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?

 
Michael:
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.

 
Carolyn:
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?

 
Shinya:
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.

 
Carolyn:
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?

 
Michael:
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.

 
Carolyn:
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?

 
Shinya:
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.

 
Michael:
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.

 
Carolyn:
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.

 
Michael:
Thank you.

 
Shinya:
Thank you very much for your invitation. Bye-bye.

 
Carolyn:
You've been listening to Circulation on the Run. Thank you for joining us today.

 
 

Sep 20, 2016

 

Carolyn:
Welcome to Circulation on the Run. Your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from The National Heart Center and Duke National University of Singapore. 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.

 
Dominick:
Thanks for having us.

 
Gabriel:
Hello.

 
Carolyn:
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?

 
Dominick:
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.

 
Carolyn:
That really sets a background perfectly. Tell us about the main findings.

 
Dominick:
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.

 
Carolyn:
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?

 
Gabriel:
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.

 
Carolyn:
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?

 
Dominick:
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.

 
Carolyn:
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?

 
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.

 
Carolyn:
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.

 
 

Sep 19, 2016

 

Carolyn:
Welcome to Circulation On The Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn 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!

 
Michel:
Hello, Carolyn. Thank you also for the invitation to discuss about the paper.

 
Carolyn:
We're also so lucky to have the associate editor who handled the paper, Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome, Wanpen.

 
Wanpen:
Hi, Carolyn.

 
Michel:
Hi, Wanpen.

 
Carolyn:
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?

 
Michel:
Yes.

 
Carolyn:
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.

 
Michel:
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.

 
Carolyn:
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?

 
Michel:
Yes.

 
Carolyn:
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 ... ?

 
Michel:
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.

 
Carolyn:
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?

 
Wanpen:
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.

 
Carolyn:
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?

 
Michel:
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.

 
Carolyn:
It's really fascinating, you're talking from a system based in Europe. You're based in Paris.

 
Michel:
Yes.

 
Carolyn:
Wanpen just said that she's doing it, and she's based in the US. Do you now routinely, maybe, monitor these medication levels?

 
Michel:
Yes, yes, yes.

 
Carolyn:
Wow.

 
Michel:
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.

 
Carolyn:
Of course.

 
Michel:
We are working to see how it could be reimbursed for labs doing these measurements.

 
Carolyn:
But this is for maybe selected resistant hypertensive patients that are difficult to ... ?

 
Michel:
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-

 
Carolyn:
Yeah, we should start questioning, are they taking it.

 
Michel:
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."

 
Carolyn:
Wanpen, how about the reimbursement issues and things like that in the United States? How are you getting it done in your institution?

 
Wanpen:
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.

 
Carolyn:
Do you do that again routinely, or in selected patients that are difficult to manage hypertensive?

 
Wanpen:
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.

 
Carolyn:
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.

 
 

Sep 5, 2016

Carolyn:
Welcome to Circulation On The Run, your weekly podcast, summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Nam, 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.

 
David:
Hi, I'm very happy to be here.

 
Carolyn:
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.

 
Amat:
Thank You Carolyn, happy to be here.

 
Carolyn:
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?

 
David:
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.

 
Carolyn:
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?

 
David:
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.

 
Carolyn:
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?

 
Amat:
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.

 
Carolyn:
I like the way you said tricky, and that's usually when we call for an editorial isn't it?

 
Amat:
That is correct as we will see with this article.

 
Carolyn:
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?

 
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.

 
Carolyn:
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?

 
Amat:
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.

 
Carolyn:
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.

 
Amat:
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.

 
Carolyn:
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.

 
 

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