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Now displaying: January, 2017
Jan 30, 2017

Dr Carolyn Lam:                Welcome to Circulation On the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke-National University of Singapore. Our featured discussion today relates to 20 year outcomes after mitral valve repair versus replacement for severe degenerative mitral regurgitation.

                                                But first, here's your summary of this week's issue. The first paper suggests that agonistic angiotensin receptor autoantibodies may be biomarkers of adverse outcomes. In this study from first author Dr. Abadir, corresponding author Dr. Fedarko, and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland, authors developed a quantitative immunoassay for measuring agonistic angiotensin AT1 receptor autoantibodies in the serum.

                                                They then assessed its operating characteristics in a discovery group of 255 community dwelling adults from Baltimore and validated these findings in a second group of 60 individuals from Chicago. They found that AT1 receptor autoantibody levels were significantly associated with higher levels of inflammatory cytokines, weaker grip strength, slower walking speed, higher risk for frailty, more falls and increased mortality.

                                                Furthermore, chronic treatment with angiotensin receptor blockers, it attenuated the AT1 receptor autoantibody association with decline in grip strength and increased mortality. These results therefore suggest that followup studies and intervention trials in chronic inflammatory diseases should test whether AT1 receptor autoantibody levels can be used to stratify patient risk and whether they can be used to identify patients who may benefit from angiotensin receptor blocker treatment.

                                                The next paper suggests that baseline target mismatch on CT perfusion imaging may predict the response to tenecteplase in ischemic stroke. Dr. Bivard and colleagues from John Hunter Hospital University of Newcastle in Australia pooled two clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke.

                                                Baseline CT perfusion was analyzed to assess if patients met the diffused two target mismatch criteria. These criteria are absolute mismatch volume of more than 15 mL, mismatch ratio of more than 1.8, baseline ischemic core less than 70 mL and volume of severely hypoperfused tissue less than 100 mL.

                                                Among 146 pooled patients, 71 received received alteplase and 75 received tenecteplase. Overall tenecteplase treated patients had greater early clinical improvement by NIH Stroke Scale change and less parenchymal hematoma, but did not show a significant difference in three month patient outcome by the Modified Rankin Scale.

                                                74 of the 146 patients met target mismatch criteria. It was only among these patients with target mismatch that treatment with tenecteplase result in greater early clinical improvement and better late independent recovery than those treated with alteplase. In summary, tenecteplase may offer an improved efficacy and safety profile versus alteplase, benefits that are possibly exaggerated in patients with baseline CT perfusion defined target mismatch.

                                                The next study is the first to provide a comprehensive analysis of circulating metabolite levels and relate these to clinical outcomes in patients with pulmonary arterial hypertension. First author Dr. Rhodes, corresponding author Dr. Wilkins and colleagues from Imperial College London conducted a comprehensive study of plasma metabolites using ultra-performance liquid chromatography mass-spectrometry in 365 patients with idiopathic or heritable pulmonary arterial hypertension and 121 healthy controls.

                                                They found that increases in circulating modified nucleosides originating from transfer RNAs, energy metabolism intermediates, tryptophan and polyamine metabolites and decreased steroids, sphingomyelins and phosphatidylcholines independently discriminated pulmonary arterial hypertension from controls and predicted survival. Furthermore, correction of metabolite levels overtime was linked to better clinical outcomes and patients who responded well to calcium channel blocker therapy had metabolic profiles comparable with healthy controls, thus these findings suggest that monitoring plasma metabolites overtime could be useful to assess disease progression and response to therapy in pulmonary arterial hypertension. Therapeutic strategies targeted against metabolic disturbances, particularly translational regulation and energy metabolism, may merit further investigation in pulmonary arterial hypertension.

                                                The final study takes a contemporary look at age associated changes in left ventricular diastolic function. Dr. Shah and colleagues from Brigham and Women's Hospital in Boston, Massachusetts related diastolic measures including tissue Doppler E prime, E to e prime and left atrial size, to the risk of heart failure hospitalization or death in 5801 elderly participants in the ARIC study. They further defined sex-specific 10th percentile limits in 401 participants free of cardiovascular disease or risk factors. They found that each diastolic measure was robustly associated with incident heart failure hospitalization or death. Reference limits for E to e prime and LA size were generally in agreement with existing guidelines, whereas limits for tissue Doppler E prime were substantially lower at 4.6 for septal E prime and 5.2 for lateral E prime in the ARIC study compared to 7 and 10 respectively in international guidelines. Compared to the guideline cut points, the ARIC base limits improved risk discrimination and reclassified over one-third of the study population as having normal diastolic function. These findings were further replicated in the Copenhagen City Heart Study.

                                                In summary, this study suggests that a decline in left ventricular longitudinal relaxation velocity occurs maybe as part of healthy aging and is largely prognostically benign. This supports the use of age-based normative values when considering an elderly population.

                                                Well, that wraps it up for the summaries, now for our featured discussion.

                                                Today we are discussing the very important result of the mitral regurgitation international database and we have with us today no other than the corresponding author Dr. Jean-Louis Vanoverschelde, and he is from University of Louvain in Brussels. Welcome Jean-Louis, I made it.

Dr Jean-Louis Vanoverschelde:  Hey, how are you?

Dr Carolyn Lam:                Thank you so much for joining us. Also joining us today is Dr. Victoria Delgado, associate editor from Leiden University Medical Center in the Netherlands. Welcome Victoria.

Dr Victoria Delgado:        Hello. Thank you very much for having me in this podcast.

Dr Carolyn Lam:                So, severe degenerative mitral regurgitation with flail leaflets, a very important condition and your study, Jean-Louis, really provides important clinically applicable information. Could you please address our clinicians out there with a take home message from your paper.

Dr Jean-Louis Vanoverschelde:  Well, the take home message is very easy, once this condition needs to be operated on, there are really two options, one which is to repair the valve and keep the native tissue and the other is to replace the valve and trash the native tissue if I can say so. The results of the study are really clear. There is a major survival advantage by repairing the valve as opposed to replacing it. So for everyone of those who have degenerative mitral regurgitation with flail leaflets, the best treatment option is mitral repair.

Dr Carolyn Lam:                Now these results came from a multi-center registry of thousands of patients. I was really struck with the duration of the study. I think that's something that's really novel. You had a 20 year follow up but also patients were recruited from 1980 all the way to 2005, am I right? So could you expand a little bit about the possibility of techniques changing during that period?

Dr Jean-Louis Vanoverschelde:  Although there has been subtle changes in the practice, the basic principle have remained the same. So we have not really accounted for these changes in the practice over time, with regard to what happened to mitral valve replacement, clearly the prostheses that were there 30 years ago are not the same as the ones that are currently implanted to the patients, but none the less when we performed an analysis, a sensitivity analysis to look at whether the results were different from 20 years ago compared to those that were more recent, we found exactly the same result.

Dr Carolyn Lam:                Yes, I thought that was a very important sensitivity analysis. Tell us a bit more about the propensity score matching as well because another thing people will be thinking is, you know, this is a registry, huge numbers very important but obviously there would be differences in indication for repair versus surgery.

Dr Jean-Louis Vanoverschelde:  For sure, the fact is that there are statistical means that allow you to mimic not to be the exactly the same as, but to mimic randomization and it is the propensity score matching. That means that you perform a prior analysis that will identify similar patients in the two cohorts and match them so that you are basically having the same kind of patients that are treated with two different ways. So it's not randomization but it’s getting close to randomization when you use cohorts like the one from the MIDA registry.

Dr Carolyn Lam:                Perfect. Victoria, did you take the same take home messages and are you applying this clinically? I noticed that you invited an editorial, a lovely editorial on this paper as well, so please share your thoughts.

Dr Victoria Delgado:        Yeah, I share the same take home message that Dr. Vanoverschelde has outlined. I think that this is very important article, it's a landmark article highlighting one of the most important things that mitral valve repair should be probably the standard of care for patients with severe mitral regurgitation without degenerative cause with a flail and the article basically what it does is also endorsing the recommendations of current guidelines highlighting the value of mitral valve repair. Of course that mitral valve repair should be performed in centers with experience and with good durability of these repairs, so the centers need to have a good heart team where they can analyze their results in such a way like the MIDA registry has done demonstrating a good durability of the repair.

Dr Carolyn Lam:                And do you have anything to add to that Jean-Louis?

Dr Jean-Louis Vanoverschelde:  No, I think basically Victoria very well summarized the basic features not only of the paper itself but also of the condition and what currently is in the guidelines. In fact, the guidelines have already said that we should be preferring mitral valve repair over replacement, but the data on which this was based were probably not as conclusive as the one that are provided by this analysis of our registry, so I think it's really reinforcing the idea that we should go ahead and try to perform repair as much as possible, now with a caveat of course that the surgeons need to be skilled enough to perform that. But with the type of differences that we see in survival between the two cohorts I think that if a surgeon does not feel comfortable with repairing the valve and would rather replace it, he might refer the patient to another surgeon that is capable of repairing the valve. The impact and outcome is such that I think this really supports the idea that the patient should be referred to high volume and skilled centers.

Dr Carolyn Lam:                Could you give us an idea of what kind of impact you're talking about, what kind of numbers that you see?

Dr Jean-Louis Vanoverschelde:  It's the same in all the analysis, whether it's in the overall population or in the matched cohorts by 20 years, we have something like 20 to 25% survival difference, absolute survival difference between the two groups. So it's a reduction of mortality approximately by half if you perform repair compared to replacement, and it is increasing with time, so it's not something that is only present in the first years but is increasing with time, so it's about 20 to 25% absolute difference between the two cohorts.

Dr Carolyn Lam:                That truly is remarkable. Congratulations again on such a landmark paper like Victoria said. Now to either of you, question that's a bit left field maybe, but what do you think the role is now for percutaneous techniques of mitral valve repair or replacement then?

Dr Jean-Louis Vanoverschelde:  That's an interesting question. I think that if you really look far away into the future probably everything at some point in time will be percutaneous. At this stage I’m not sure that the percutaneous technique able to mimic what we can do with surgery in terms of mitral valve repair. So, it's an alternative to surgery in patients who are inoperable. In those who can undergo a surgical mitral repair, my first choice will certainly be to go surgically rather than percutaneously, at least right now.

Dr Carolyn Lam:                Victoria?

Dr Victoria Delgado:        I also agree with those comments. I think that now we have a lot of possibilities to treat these patients but the most important thing is to have the entire clinical picture of the patient, to see the pros and cons of preparing the patient for surgery or for percutaneous valve. There should be also an integration of imaging to know which is the cause of the valve dysfunction and to see whether the anatomy could be easily repaired by surgery or instead if the patient has contraindication for surgery, if it could be repairable as well with transcatheter therapy. But then for that I think that is really important and this is what the editorial also highlights, the role of the heart team, where there are different specialist surgeons, clinical cardiologists, heart failure specialists, imaging specialists that can integrate the entire information of the patient in order to select the most appropriate therapy. But still for patients who do not have contraindications for surgery who have repairable valve and as you can see from this registry, the percentage of repairability is quite high, I would still refer the patient as well for surgical valve repair.

Dr Carolyn Lam:                You heard it right here. Thank you so much for joining us today and please don't forget to tune in next week.


Jan 23, 2017


Dr Carolyn Lam:               

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke-National University of Singapore. In just a moment, we're going to be discussing new results of the pioneer trial, and the patient with atrial fibrillation who undergoes intracoronary stenting, a familiar conundrum. What's the role of NOACs? Is there still a role for full-dose triple therapy with warfarin? First, here's your summary of this week's journal.

The first paper tells us about the clinical impact of left atrial appendage closure. Dr. Melduni and colleagues from the Mayo Clinic in Rochester, Minnesota, studied 9,792 patients undergoing bypass or valve surgery between 2000 and 2005. They used propensity score matching to estimate the association of left atrial appendage closure with early post-operative atrial fibrillation- defined as atrial fibrillation within 30 days of surgery- ischemic stroke, and mortality. They found that after adjustment for treatment allocation bias, left atrial appendage closure during routine cardiac surgery was significantly associated with an increased risk of early post-operative atrial fibrillation, and did not influence the risk of stroke or mortality.

They therefore concluded that it remains uncertain whether prophylactic exclusion of the left atrial appendage is warranted for stroke prevention during non-atrial-fibrillation-related cardiac surgery.

The next study provides pre-clinical evidence that genes on sex chromosomes may contribute to the sexual dimorphism of abdominal aortic aneurysms. That is, we well know that abdominal aortic aneurysm is a male-predominant disease. Now, in this paper, by first author Dr. Alsiraj, corresponding author Dr. Cassis and colleagues from the University of Kentucky, female LDL-receptor-deficient mice, with an XX or XY sex chromosome complement, were infused with angiotensin II for 28 days to induce abdominal aortic aneurysms. DNA microarrays were performed on the abdominal aortas, and to mimic the males, the female mice were administered a single dose of testosterone.

They found that an XY sex chromosome complement, in phenotypic females, profoundly influenced aortic gene expression profiles and promoted abdominal aortic aneurysm severity. When XY females were exposed to testosterone, aneurysm rupture rates were striking. The mechanisms for augmented abdominal aortic aneurysm severity in XY females included increased inflammation, augmented matrix metalloproteinases, and oxidative stress. These results, therefore, demonstrate that genes on the sex chromosomes regulate aortic vascular biology and contribute to sexual dimorphism of aortic abdominal aneurysms. Sex chromosome genes may therefore serve as novel targets for sex-specific abdominal aortic aneurysm therapeutics.

The next two studies shed light on the mechanism of action of PCSK9 monoclonal antibodies on lipoprotein metabolism. In the first study, Dr. Watts and colleagues from University of Western Australia carried out a two-by-two factorial trial, of high-dose atorvastatin versus evolocumab on stable isotope tracer kinetics in 81 healthy, normal lipidemic, non-obese men.

They found that both atorvastatin and evolocumab independently accelerated the fractional catabolism of VLDL apoB, IDL apoB, and LDL apoB. On the other hand, evolocumab, but not atorvastatin, also decreased the production rate of IDL apoB and LDL apoB. The reduction of LDL apoB and LDL cholesterol was significantly greater with a combination versus either mono-therapy. In summary, they found that in healthy, normal lipidemic men, evolocumab decreased the concentration of atherogenic lipoproteins, particularly LDL, by accelerating their catabolism, and by reducing IDL and LDL production. The latter effects are incremental to statins.

The second paper to deal with this topic comes from Dr. Ginsberg and colleagues from Columbia University in New York, who studied 18 participants, this time 10 of whom were women, who completed a placebo-controlled two-period study, receiving two doses of placebo followed by five doses of alirocumab. These authors found that alirocumab decreased LDL cholesterol and LDL apoB by increasing IDL and LDL apoB fractional clearance rates, and by decreasing LDL apoB production rates. These results were consistent with increases in LDL receptors available to clear IDL and LDL from the blood during PCSK9 inhibition. These two papers are discussed in a beautiful accompanying editorial by Dr. Chris Packard from University of Glasgow. In his editorial entitled "Unpacking and Understanding the Impact of PCSK9 Inhibitors on Apolipoprotein B Metabolism." Those were your highlights! Now for our feature discussion.

Today we are going to be discussing one of the most common conundrums in all of cardiovascular medicine, and that is the care of patients with atrial fibrillation who also need percutaneous coronary intervention. Of course, both dual antiplatelet therapy and oral anticoagulation therapy would be indicated to reduce the risk of stent thrombosis and thromboembolism in atrial fibrillation, respectively. However, with the intensification of the anti-thrombotic regimen, there is the inevitable trade-off with more bleeding. Now, to discuss this, we have the first and corresponding author on a very novel study of the pioneer trial, and that is Dr. Michael Gibson, from Harvard Medical School and Beth Israel Deaconess Medical Center. We also have the editorialist for this very exciting paper, Dr. Deepak Bhatt from Brigham and Women's Hospital, and finally, we have Dr. Dharam Kumbhani, associate editor from UT Southwestern. Welcome, gentlemen!

Dr Deepak Bhatt:           Thank you.

Dr Michael Gibson:          Thanks.

Dr Dharam Kumbhani:   Thank you.

Dr Carolyn Lam:                So, Michael, could I start with you? This is a sub-study of the pioneer study. Could you tell us how this is different from the primary results, what were you looking for, and what you found?

Dr Michael Gibson:          As you know, as [inaudible 00:07:40] said, we have a lot of bleeding with conventional triple therapy, and we used two regimens to try and reduce that bleeding. One was a reduced dose of rivaroxaban, 15 milligrams, plus thienopyridine. The other strategy was baby dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we found in the overall study was a significant reduction in bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's the baby dose plus DAPT- and down to 16.8% for the 15 milligrams of riva plus the thienopyridine.

You'd have to treat about 11 to 12 patients to prevent one significant bleeding event. That's the mainstay. What we found in this very, very important sub-study is that that was associated with reduction in hospitalization. All-cause hospitalization was reduced, and cardiovascular hospitalization went down from 28.4% to about 20% for the two regimens. Bleeding with hospitalization went down, from 10.5% to about 6%. At the end of the day, you'd only have to treat 10 to 15 people to prevent one hospitalization, so from a health economic perspective, and from a patient viewpoint and hassle perspective, this was very important.

Dr Carolyn Lam:                In fact, Michael, I would say from a clinician-cardiologist perspective, these results are really very applicable. In fact, I really like, in the accompanying editorial, what Deepak wrote, that it may be one of those rare occasions where a sub-study provides very clinically meaningful information compared to the primary study. Deepak, would you like to elaborate a little bit more about that?

Dr Deepak Bhatt:             Sure. A really great point that you've raised. It wasn't, in fact, a sub-study we're talking about in Circulation. It was an analysis from the overall trial, looking at a different endpoint than the primary endpoint, the hospitalization, and the composite of hospitalization and mortality. I think that's a very important endpoint. If it were a heart failure trial, for example, that's the endpoint everyone would hone in on- mortality and hospitalization. The fact that that was significantly reduced, I think, is very clinically meaningful. Mike mentioned the economic implications, which for sure are there, by reducing hospitalizations and re-hospitalizations.

The impact on cardiovascular hospitalizations- the reduction there- I find particularly remarkable. The reduction in bleeding, of course, is good, and in its own right has a great deal of value, but the additional reduction in cardiovascular hospitalizations, I think, is quite reassuring for those that are worried about the efficacy of the two experimental regimens that he and his colleagues studied. Sure, the trial's not powered in each individual sub-group for rare events like stroke, but the fact that CV hospitalizations are not increased, and in fact reduced, tells me that this is a winning strategy or strategies.

Dr Carolyn Lam:                Right. Michael, another issue, though- this is open label, and I suppose one of the criticisms could be that there is a bias for clinicians managing patients on the traditional Vitamin K antagonist to maybe hospitalize patients more for some reason. What is your response to that?

Dr Michael Gibson:          That is always the criticism of an open label trial, but again, the events were adjudicated, and for the heart events, that's done in a blinded fashion, so it's reassuring that there was a blinded assessment of the heart events.

Dr Carolyn Lam:                True. How about comments on generalizability? I mean, what do you think? Trial setting, real world ...

Dr Michael Gibson:          Yeah, I think that's one of the advantages. This was very much a real-world kind of study. It was truly done throughout the world. We had a very broad entry criteria. Anyone who was getting a stent put in- you didn't have to have ACS, although about half the patients did. The only real exclusive criteria was you couldn't have any bleeding or be profoundly anemic. You couldn't have a stroke or [TIA 00:11:58] in the past. Other than that, it made real-world practice in a lot of ways.

Dr Dharam Kumbhani:   This is Dharam. If I may ask both the other people on the call, is ... Rivaroxaban is not FDA approved, in these doses, for use. I'm wondering if they might provide some comment, given the benefit that we see in this trial, overall, what their thoughts are and what the next steps might be.

Dr Carolyn Lam:                Sure. Maybe Michael, then Deepak?

Dr Michael Gibson:          Yeah, that's a good point. It is important to point out that you'd need to check the prescribing information in your country. In some countries- I think it's about 54 countries- the 2.5 milligram dose is available. It is approved for ACS, but is not approved for a-fib. Then, you have a dose of 20 milligrams that's approved worldwide for a-fib, but there are some countries- it's important to note, in some countries, 15 milligrams is the full dose that's approved- say, in Japan and Taiwan. There are Japanese studies showing that 15 milligrams was not only safer than warfarin, but more efficacious than warfarin in a trial like J-ROCKET. You're right, the 15 milligram dose is available in the US- it's approved for renal insufficiency, but at this time, it's not labelled for the ACS or stented patient.

But again, physicians are at liberty to look at this data, which is the first real data that we have to guide decision-making in this setting, and they're at liberty to make their own choices.

Dr Deepak Bhatt:             Yeah, I would agree with that assessment, and emphasize ... Like Mike said, it's an international audience for Circulation, so I would say, look in your own country, and in many parts of Europe, the 2.5 milligram rivaroxaban dose is available and approved for ACS, and could therefore be used for this purpose, though not strictly falling within the label indications. In the US, there's the 15.

I think, if I just answer the previous question, the results are very generalizable, and for doctors that critique that point, I'd say, "Why didn't you enroll your patients in the trial?" There's the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS with apixaban, and I'm missing one that's also ongoing as well, I think, but there are four different trials that are out there. The Pioneer was the first to report ...

Dr Carolyn Lam:                I think you're thinking of the Entrust AF-PCI with Edoxaban.

Dr Deepak Bhatt:             The most recent one, yes. I forgot the acronym, there. If people are really thinking that the results don't apply to their patients, well, there are trials that are ongoing. Enroll your patients. But to say, "Oh, my patients, I'm not going to enroll them in the trial," and then say, "The results aren't generalizable," I always find that an odd thing. I think the results are very generalizable. The one word of caution I would say, though, is to make sure to renally dose, as was done in the trial. That is, there was a downward adjustment in dose from the 15 milligrams to the 10. In real life, we've seen in registries with NOAC use, whether it's rivaroxaban or any of the others, a lot of times, the renal function is not carefully monitored in those patients that are on the fringe in terms of their renal function, and that's the one situation NOACs can backfire, where the dose isn't corrected for their degree of renal dysfunction. Other than that one caveat, I think the results are quite generalizable.

Dr Carolyn Lam:                Excellent comments. We should wrap up soon, but not before I want to ask Dharam. Thank you for managing this beautiful paper. What, to you, is the take-home message for clinicians out there?

Dr Dharam Kumbhani:   Yeah, it was an absolute honor and delight to manage this, and I think the paper's great. The editorial's great. It's gotten a great response. I think the take-home message is that this is a very clinically relevant question, and a very clinically relevant trial, and it shows that the needle will be moving towards using non-VKA-based agents, especially in patients such as this, who have both a-fib and PCI. I think this is very exciting space, a very important space. This trial suggests that if you use the strategy rivaroxaban low dose, with or without a DAPT, that it is safer, both in terms of mortality and bleeding, compared with what is traditionally being used with warfarin plus DAPT. I think this was a very, very exciting trial.

Dr Carolyn Lam:                Indeed, and congratulations to all three of you. Thank you so much for joining me on Circulation On The Run. Thank you, listeners, for joining us too, and don't forget to tune in next week.


Jan 16, 2017


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

                                                In today's episode, we are discussing very important new data regarding stroke risk stratification in patients with atrial fibrillation. First though, let me give you the highlights of this week's journal.

                                                The first paper provides mechanistic evidence that endothelial-derived microparticles may play a key role in the development of endothelial dysfunction following acute coronary syndrome. In this paper from first author, Dr. Abbas, co-corresponding authors, Dr. Toti and Morel from the University of Strasbourg in France, authors expose core sign coronary artery endothelial cells to microparticles shed from senescent cells, or circulating microparticles from patients with acute coronary syndrome.

                                                They showed that exposure to these microparticles induced increase senescence-associated beta-galactosidase activity, oxidative stress, and early phosphorylation of MAP kinases and AKT, and upregulation of p53, p21 and p16. Depletion of endothelial-derived microparticles from acute coronary syndrome patients reduced the induction of senescence.

                                                On the other hand, pro-senescent microparticles promoted endothelial cell thrombogenicity. These microparticles exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and ACE in endothelial cells. Losartan and AT1 receptor antagonist and inhibitors of either MAT kinases or PI3-kinase prevented the microparticle-induced endothelial senescence. 

                                                In summary, these findings indicate that endothelial-derived microparticles from acute coronary syndrome patients induce premature endothelial senescence and thrombogenicity suggesting that targeting endothil-derived microparticles and their bioactivity may be a promising therapeutic strategy to limit the development of endothelial dysfunction post-acute coronary syndrome.

                                                The next study is the first large and prospective study showing that NT-proBNP is associated with cardiovascular events in patients with adult congenital heart disease independent of multiple clinical and echocardiographic variables.

                                                This is a study from first author, Dr. Bekan; and corresponding author, Dr. Roos-Hesselink and colleagues from the Erasmus University Medical Center in Rotterdam, the Netherlands. The author studied 595 clinically stable patients with adult congenital heart disease who attended the outpatient clinic between 2011 and 2013.

                                                All patients underwent clinical assessment, electrocardiography, echocardiography and biomarker measurement, including NT-proBNP, high-sensitivity troponin T and growth differentiation factor 15. Patients were prospectively followed over a median of 42 months for the occurrence of cardiovascular events including death, heart failure, hospitalization, arrhythmia, thromboembolic events and reintervention.

                                                They found that of the three evaluated biomarkers, NT-proBNP was most strongly associated with cardiovascular events. Importantly, patients with a low-risk of death and heart failure could be accurately identified with a high negative predictive value.

                                                In patients with elevated NT-proBNP, elevations of high sensitivity troponin T and growth differentiation factor 15 identified those patients at highest risk of cardiovascular events.

                                                In summary, these biomarkers may play an important role in the monitoring and management of patients with adult congenital heart disease.

                                                The next study describes heart failure stages among older adults in the community. Dr. Shah and colleagues from the Brigham and Women's Hospital in Boston Massachusets classified more than 6,000 participants in the atherosclerosis risk and community study into heart failure stages. These were stage A; asymptomatic individuals with heart failure risk factors, but no cardiac structural or functional abnormalities. Stage B; asymptomatic individuals with structural abnormalities such as left ventricle hypertrophy, dilation, dysfunction, or valve disease. Stage C1; clinical heart failure without prior hospitalization. Stage C2; clinical heart failure with prior hospitalization.

                                                They found that only 5% of examined participants were free of heart failure risk factors or structural heart disease. 52% were categorized as stage A, 30% stage B, 7% stage C1, and 6% stage C2. Worst heart failure stage was associated with a greater risk of incident heart failure hospitalization or death at a median follow up of 608 days.

                                                Left ventricular ejection fraction was preserved in 77% of stage C1 and 65% of stage C2 respectively. In corporation of longitudinal strain measurements and diastolic dysfunction into the stage B definition, reclassified 14% of the sample from stage A to B.

                                                Abnormal LV structure, systolic function, whether based on ejection fraction of longitudinal strain, and diastolic dysfunction, were each independently and additively associated with the risk of incident heart failure hospitalization or death in stage A and B participants.

                                                The authors concluded that the majority of older adults in the community are at risk of heart failure, appreciably more compared to previous reports in younger community-based samples. The study also highlighted the burden of heart failure with preserved ejection fraction in the elderly and provided evidence that left ventricular diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and ejection fraction in identifying patient at risk of heart failure hospitalization or death.

                                                The next study sheds light on the association of the LPA gene, ethnicity and cardiovascular events. First author, Dr. Lee; corresponding author Dr. Tsimikas and colleagues from University of California San Diego studied 1,792 black, 1,030 white, and 597 Hispanic subjects all enrolled in the Dallas Heart Study. They measured LPA snips, apolipoprotein A isoforms, LP(a) and oxidized phospholipids on apolipoprotein B100.

                                                These individuals were also followed for a median of 9.5 years for major adverse cardiovascular events. The authors found that the prevalence of LPA snips and apolipoprotein A isoforms were very different across ethnic groups. LPA snips that were associated with elevated LP(a) in whites were associated with low LP(a) in Hispanics mainly due to differences in apoliproprotein A isoforms size.

                                                After multi-variable adjustment, LP(a) and oxidized phospholipids on apolipoprotein B were both predictors of major adverse cardiovascular events. Conversely, LPA snips and apolipoprotein A isoforms did not add predictive value to models and did not show clinical utility in this study.

                                                These data suggests that much of LP(s) mediated major adverse coronary events is driven by oxidized phospholipids. Importantly, elevated LP(a) and oxidized phospholipids on apolipoprotein B must be recognized as important predictors of major adverse cardiovascular events across racial groups.

                                                The final study addresses the question of the optimal antithrombotic regimen for longterm management of patients with symptomatic peripheral artery disease, or PAD, with a history of limb revascularization. To answer this question, Dr. Jones and colleagues from Duke Clinical Research Institute looked at the EUCLID trial, or examining use of ticagrelor in PAD trial, which randomized patients with PAD to treatment with ticagrelor 90 milligrams twice daily, or clopidogrel 75 milligrams daily.

                                                As a reminder, patients in EUCLID were enrolled based on a normal ankle-brachial index of less .8, or a prior lower extremity revascularization. The current paper really focus on the subset of 7,875 patients who were enrolled based on a prior lower extremity revascularization criterion.

                                                The authors found that after adjustment for baseline characteristics, patients enrolled based on prior revascularization for PAD had higher higher rates of myocardial infarction and acute limb ischemia with similar composite rates of cardiovascular death, myocardial infarction and stroke when compared with patients enrolled based on the ankle brachial index criterion.

                                                Overall, there were no significant differences between ticagrelor and clopidogrel for the reduction of cardiovascular or acute limb events.

                                                Those were your highlights. Now, for our featured discussion.

                                                On today's podcast, we are discussing the very, very important issue of stroke risk in patients with atrial fibrillation. Most of us use the international guidelines for anticoagulation in atrial fibrillation that mostly suggest that we use the CHADS VASc scoring system to determine the stroke risk in a particular patient and then determine whether or not this patient meets the threshold for anticoagulation.

                                                This assumes that the CHADS VASc score corresponds to a fixed stroke rate. Today, in our journal, we have very, very interesting results from a paper with corresponding author, Dr. Daniel Singer who really suggest that we may need to rethink that. Dr. Daniel Singer joins us today from Massachusets General Hospital.

                                                Welcome Daniel.

Dr. Daniel Singer:             Thank you for having me.

Dr. Carolyn Lam:               Great. Today, we also have Dr. Sana Al-Khatib who's the associate editor from Duke University who managed this paper. Welcome Sana.

Dr. Sana Al-Khatib :         Thank you Dr. Carolyn, I'm happy to be here.

Dr. Carolyn Lam:               Daniel, could we start by you letting us know what you sought to do in your study and what you found?

Dr. Daniel Singer:             We all know that anticoagulants are extraordinarily effective at preventing stroke in patients with atrial fibrillation, but they also raise the risk of bleeding, and sometimes that bleeding could be quite serious and even fatal. As a result, for that past 10, 15 years, we have used a risk-based approach to the decision about whether to start a patient on anticoagulation, and that risk is the stroke risk that a patient faces if they weren't taking anticoagulants. Then we figured that anticoagulants will reduce it by about two-thirds.

                                                There are formal decision analysis and then a more informal sense that a patient has to face an anticoagulated risk of stroke of about 2%, some people might say 1% to 2% before anticoagulation results in an expected net clinical benefit that the effect in reducing ischemic stroke will exceed the risk of increasing bleeding.

                                                While the CHADs VASc score has been widely accepted as the basis for estimating that risk, it became apparent to us as we looked across the studies that were underlying that assumption, that the risk that were associated with various CHADs VASc scores were extremely variable. Many of these risks actually were less than that 1% or 2% threshold for anticoagulation.

                                                What I mean is that the stroke risk associated with CHADs VASc score of one, or two, which is the basis for the guideline threshold for anticoagulation actually corresponded to risk less than 1% in many of these very large studies. We have conducted a systematic review just to be sure that we were capturing the overall evidence base for this, and that's what we report in our paper.

Dr. Carolyn Lam:               Perhaps you could start by letting us know exactly how far off are we in our stroke risk estimation.

Dr. Daniel Singer:             We looked at 34 studies that were quite large and then we zeroed in on the largest one. If you looked at the rate for stroke overall, they varied enormously in terms of the overall stroke rate. Then when we focused down on CHADs VASc score of 1, or 2, we found that the majority of these studies, actually, for CHADs VASc 1, was less than 1% per year. For CHADs VASc 2 score was in the majority these studies less than 2% per year.

                                                Both of those stroke risks have raised us the question where are these patients could gain in that clinical benefit from being anti-coagulated, because those stroke risk, if they were reduced by two-thirds, would really be a very small reduction in risk and yet they'd still face the bleeding risk.

                                                Among the most interesting findings actually is that we found that a Swedish national database and the large Danish national database came up with threefold difference in their estimate of stroke rates. The Swedish database produced lower risk, and the Danish database produced substantially higher risk.

                                                If you think about it, there are probably no two countries in the world that are more similar in terms of gene, social environmental, medical care systems, and that raises the specific question of, "Is it underlying rates that vary across different cohorts and different geographies, or is it a different in methodology?"

                                                We think a lot of the differences are due to methodologic difference, and that we need to standardize these differences together, better handle on what the real stroke rate is among patients with these low CHADs VASc scores.

Dr. Carolyn Lam:               The variability that you pointed on your paper is really striking, but another possibility, do you think, is that maybe stroke risk isn't static.

Dr. Daniel Singer:             Yeah. If that's the case, we face a great difficulty in developing predictions rules of what the stroke risk could be. I think most people feel it's the function of their age, and whether they've had a prior stroke, and whether they have the comorbidity, hypertension, and diabetes, and so on, that are incorporated into the various stroke risk scores, in particular, CHADs VASc.

                                                We tend to think that that's pretty fixed until you get older or until you accumulated another comorbidity. I think the striking difference is that, one, that we actually anticipated in the beginning, was that the stroke rates in people with atrial fibrillation were also coming down. The stroke rates in general have been dramatically decreasing for decades now.

                                                One issue is whether that applies as well to atrial fibrillation associated stroke. There is a suggestion of that, but the variability across the cohorts is so great that you can't pick up a strong signal in terms of calendar time. Although I suspect that there is a strong calendar effect. Exactly why that is, we could speculate. I suspect a lot of it is control of blood pressure, but that's speculation.

Dr. Carolyn Lam:               Daniel, congratulations again for that fascinating and really very sobering findings.

                                                Sana, you managed this paper. It's very important paper. In fact, important enough that you invited an editorial. Could you please share some of your thoughts?

Dr. Sana Al-Khatib :         Oh, yeah. Absolutely. First, I'd like to start by congratulating Daniel and his team on conducting this really important study. I enjoyed reading it and managing it. Definitely, congratulations.

                                                A couple of thoughts that I have. I completely agree with this really important finding, that there is a lot of variability in the rates of stroke that come from different patient populations and databases. As you pointed out Daniel, I think this is indeed largely due to differences in methodology in terms of how the information was selected, how certain things were defined.

                                                I agree with you there. You called for standardization of this, and I wonder if you have any thoughts about how we can go about doing that. I also want to bring up some of the newer studies now that are showing some significance in terms of biomarkers. Is that really adding significantly to the predictive ability of risk prediction models? I wanted to get your thoughts on that as well.

Dr. Daniel Singer:             Let me address your last question, which is simply you state that the CHADs VASc score, the CHAD score and so on, are based on very simple clinical features, and it would be unusual for them to be highly predictive. In fact, they're only mediocrely predictive, and the addition of biomarkers high-sensitivity troponin proBNP, now, people have suggested the imaging biomarkers like magnetic resonance to asses fibrosis in the left atrium. These are all very, very promising in terms of getting better models.

                                                The problem is to do that on a very scale such that we can get precise and well-calibrated predictions. We've found when we're analyzing to pair risk scores, we found that the most important issue is the underlying risk, so that, yes, you can get a great model, but if you have high variability in the underlying rate, you can have a problem specifying an individual with a stroke risk.

                                                We have to standardize and improve the quality of bringing people into these cohorts, and of interrogating the cohorts and databases and making sure that we have the same approach to assessing outcomes.

                                                This could probably be best done in very big scientific prospective registry studies, but it's tough to get all that information. There are some registry studies now ongoing, the ORBIT registries, the GARFIELD registries that may help us a lot with specifying stroke risk, but they don't have the biomarkers embedded in them. I'm hopeful that with better message, and large studies, and incorporating biomarkers, that we'll really get down to very accurate and generalizable stroke risk.

                                                I think the CHADs VASc and similar simple stroke risk scores will be in the rear-view mirror.

Dr. Sana Al-Khatib :         That's great. Can I ask one other question, because I completely agree with you looking at your numbers and the data that you presented, is that when you look, especially at the CHADs VASc score 1 patient, the risk seems to be pretty low.

                                                As you very well know, the guideline documents don't really ... At least, for the American AHA/ACC guideline document, they don't really verbalize very definitively the need to anticoagulate patients with a CHADs VASc score of 1.

                                                If you look at the numbers related to a CHADs VASc score of 2, I'm not sure that I completely agree that the risk is very low. Certainly, there was 33% of the studies reported stroke rates of greater than 2% per year. I think maybe different people have different thresholds. While I completely agree with you on the CHADs VASc score of 1 patients, I find that the findings on patients with a CHADs VASc score of 2 a bit more concerning.

                                                In fact, if anything, I would want based even on your data, not on the guidelines to offer anticoagulation to patients with CHADs VASc score of 2. What would you say to that?

Dr. Daniel Singer:             I'm looking at our table that has this, and a lot of the CHADs VASc 2 scores are under 2%, but they're in mid 1%. In the North American cohorts in particular, the rates tend to be lower. That said, I think the heart of the problem here is that we have focused on the threshold for anticoagulation. I think there's an argument to be made that you lay out the risks and benefits to the patients and engage them in a decision, particularly with regards to these lower CHADs VASc scores.

                                                At least you make a lot of, perhaps, even more emphasis on being sure that the higher CHADs VASc scores, that anticoagulation is the net benefits of anticoagulation are made very clear to the patient, and that we don't have large fractions of patients who can take anticoagulants not taking them.

                                                We know from the pinnacle registry and other registries, that even at high CHADs VASc scores, we have 40% plus of atrial fibrillation patients who are not getting anticoagulants. I think that's where we have a lot more assurance that the net benefit is positive and that we can make a different both in terms of a patient in front of us, and in terms of the overall public health aspects of atrial fibrillation and stroke.

Dr. Sana Al-Khatib :         I do believe that this is really important, but it is also important to keep in mind that with the novel novel oral anticoagulants, I think the whole landscape has changed. Not only do patients have different options to consider, but certainly, the risk of bleeding, which is the other part of this equation, has gone down significantly with the novel agents.

                                                I think as we engage in shared decision making with patients, I think it is really important to highlight these really very remarkable features about the agents that have really changed the care of patients with atrial fibrillation.

                                                One thing to add to this whole topic is, really, all the new advances that we're seeing in this field that has been really life-changing for us and for our patients.

Dr. Carolyn Lam:               Indeed Sana. I was about to bring up the bleeding risk part, the flip side of the coin as well. Also, the point that most of my patients with atrial fibrillation, they really strongly value the avoidance of stroke even more than avoidance of bleeding. Someone, that needs to be taken into consideration as well.

                                                Daniel, I'd love to give you the last words. You mentioned that you like to highlight, maybe, some more of the implications of your findings.

Dr. Daniel Singer:             I guess I would say there's a scientific implication, which is what we've ben discussing, which is the importance of trying to get these rates down correctly and accurately, and maybe we have to get people together to say how they're doing these studies.

                                                The second is, for the individual patient, that we should engage them in this discussion. Maybe patients who are perfectly willing to a novel anticoagulant and CHADs VASc score of zero. That would come out of a discussion with the patient. That our emphasis at this point since we're a little unsure about the threshold level, our emphasis both at the individual patient level, and then from the public heath perspective should be on the higher CHADs VASc scores where we know that we can expect a net clinical benefit from the vast majority of patients with AF.

                                                I agree with Dr. Al-Khatib, that the novel anticoagulants post an important advantage in the sense not so much in their overall bleeding, but particularly in terms of their intercranial bleeding, which is the lethal bleeding we most want to avoid.

Dr. Carolyn Lam:               Thank you both for joining us. Thank you listeners for joining us. Don't forget to tune in next week.


Jan 9, 2017

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 and Duke National University of Singapore. This episode marks the six month milestone of our run together, a run that has taken us around the world from the United States to Europe, South Africa, and Asia, and one that is shared by listeners all over the world.

                                                On behalf of the editors, and from the bottom of my heart, I want to thank you for your support and request that you please subscribe to our podcast and share it with your friends and colleagues. We commit to bringing you the best of cardiovascular science in the most accurate and digestible way possible, thus suiting the busy cardiologist on the run.

Dr. Lam:                               All right, here are your highlights of this week's issue.

                                                The first paper looks at tissue plasminogen activator, or TPA treatment in ischemic stroke, addressing two aspects that are still unclear. Number one, the degree of additional benefit accrued with treatment in the first 60 minutes after onset of ischemic stroke; and number two, the shape of the time-benefit curve through 4.5 hours. First author, Dr. Kim, corresponding author Dr. Saver and colleagues from UCLA stroke center analyzed more than sixty-five thousand acute ischemic stroke patients treated with intravenous TPA within 4.5 hours of onset from the "Get With the Guidelines" Stroke U.S. National Program.

                                                They found that 878 of these over sixty-five thousand patients were treated within the first 60 minutes after onset, a ten-fold increase over previously available data. Thrombolytic treatment within the first 60 minutes was associated with the highest rates of favorable discharge outcomes. The shape of the time-benefit curve throughout the first 4.5 hours was non-linear for some outcomes. Discharge to home and discharge free of disability decayed more rapidly in the first hundred to a hundred and seventy minutes after onset than later. While independent ambulation at discharge and in-hospital mortality declined in a steady fashion through the time window.

                                                These findings reinforce the importance of quality improvement programs to accelerate door to needle time for thrombolytic therapy in acute ischemic stroke.

Dr. Lam:                               The next study sheds light on mechanisms underlying red blood cell mediated hypoxic vasodilation. A highly conserved response coupling oxygen delivery to metabolic demands of the tissues, and very clinically relevant in states of systemic hypoxemia and impairment in oxygen delivery, such as in patients suffering from cardiovascular, pulmonary, or hemolytic diseases.

                                                In this paper, Dr. Bailey and colleagues from University of British Columbia Okanagan in Canada studied ten healthy participants who were randomly assigned to a normoxic, or 21% oxygen, and hypoxic, or 10% oxygen trial with measurements performed at rest and following 30 minutes of cycling at 70% of maximal power output. Blood was sampled simultaneously from the brachial artery, internal jugular, and femoral veins with plasma and red blood cell nitric oxide metabolites measured. Cerebral and femoral venous blood flow were determined by transcranial doppler ultrasound and constant infusion thermodilution respectively.

                                                The authors found that hypoxia was associated with a mild increase in both cerebral and femoral blood flow, with further more pronounced increases observed in femoral blood flow during exercise. Plasma nitrite gradients reflecting consumption were accompanied by red blood cell iron nitrosyl hemoglobin formation at rest in normoxia, during hypoxia and especially during exercise, with the most pronounced gradients observed across the femoral circulation. In contrast, there were no gradients consistent with S-nitrosohemoglobin consumption.

                                                Collectively, these findings suggest hypoxia, and to a far greater extent exercise, independently promote arteriovenous delivery gradients of intravascular nitric oxide with deoxyhemoglobin mediated nitrite reduction, identified as the dominant mechanism underlying hypoxic vasodilation. This is as opposed to the competing hypothesis of S-nitrosohemoglobin formation.

                                                In summary, by distinguishing between the two competing mechanisms that underpinned endocrine nitric oxide vasoregulation, that is, the S-nitrosohemoglobin hypothesis versus the nitrite reductase hypothesis, these data help us to understand the dynamic interplay that takes place between nitric oxide metabolites as a function of oxygen demand in vivo, and will help to establish the most specific and sensitive prognostic markers of vascular health and therapeutic interventions that optimize tissue oxygenation.

Dr. Lam:                               The next study addresses the controversial issues of thrombus aspiration during percutaneous coronary intervention, or PCI, for the treatment of ST elevation myocardial infarction, or STEMI.

                                                Dr. Jolly and colleagues from Hamilton General Hospital in Ontario, Canada performed an individual patient meta-analysis of three eligible large randomized trials that is the TAPAS, TASTE and TOTAL trials including more than eighteen thousand patients who underwent PCI for STEMI. They found that as a routine strategy thrombus aspiration did not reduce cardiovascular mortality for STEMI patients undergoing primary PCI, and that exploratory analysis of patients with high thrombus burden suggested that thrombus aspiration may improve cardiovascular mortality but at the price of an increased risk of stroke or transient ischemic attack.

                                                In summary, these data suggest that thrombus aspiration should not be used as a routine strategy in patients with STEMI, however in patients with high thrombus burden, further large randomized trials are needed to determine if improved forms of thrombus aspiration can reduce cardiovascular mortality and to determine its safety with regards to stroke.

Dr. Lam:                               The next paper is the first study to look at coronary artery calcium imaging as a tool to personalize systolic blood pressure treatment goals.

                                                Dr. McEvoy and colleagues from Johns Hopkins University School of Medicine in Baltimore, Maryland studied 3,733 participants from the multi-ethnic study of atherosclerosis with systolic blood pressure between 120 to 179 millimeters of mercury. Within subgroups categorized by both systolic blood pressure and estimated ten year atherosclerotic cardiovascular disease risk, they compared multi-variable adjusted hazards ratios for the composite outcome of incident atherosclerotic cardiovascular disease or heart failure after further stratifying by coronary artery calcium.

                                                The authors found that combining coronary artery calcium imaging and assessment of global atherosclerotic cardiovascular disease risk had potential to guide personalized systolic blood pressure goals, particularly among adults with an estimated risk between five to fifteen percent, and pre-hypertension, or mild hypertension.

                                                For example, among those with an atherosclerotic cardiovascular disease risk of less than fifteen percent and who had systolic blood pressure between 140 and 159, those with a coronary artery calcium score up to 100 were at two times the risk, while those with a coronary artery calcium score more than 100 were at 5.7 times the risk of events, all compared to a coronary artery calcium score of zero. Thus, information on coronary artery calcium burden may be considered when making personalized treatment decisions about blood pressure targets, particularly among patients with an estimated cardiovascular risk between five and fifteen percent, and who have either pre-hypertension or mild hypertension.

                                                In summary, information on coronary calcium burden may be considered when making personalized treatment decisions about blood pressure targets, for example, choosing a traditional goal of 140 or a more intensive goal of 120 millimeters of mercury. The authors ended by calling for a precision medicine clinical trial evaluating risk-based blood pressure treatment goals, preferably incorporating coronary artery calcium.

                                                Well, those were your highlights, now for your feature discussion.

Dr. Lam:                               On today's episode we are going to be discussing the very important issue of type-two myocardial infarction, very important yet usually neglected compared to type-one myocardial infarction. As a reminder to our listeners, type-two MIs are the ones where there is myocardial demand-supply mismatch whereas type one is the usual acute coronary artery plaque rupture and thrombosis. To discuss this I am really honored to have two James' on the podcast. The first is Dr. James Januzzi from Massachusetts General Hospital, the second is Dr. James de Lemos, executive editor of Circulation from UT Southwestern.

                                                Welcome to you both.

Dr. Januzzi:                         Thank you very much Carolyn, really great to be speaking with you.

Dr. de Lemos:                    Thanks Carolyn, it's great to be on.

Dr. Lam:                               Dr. Januzzi, could you please let us know what you found in this paper, it's really extraordinary. Just give us a top line of the results.

Dr. Januzzi:                         Basically we set out to examine the question of how frequent type-two myocardial infarction is in a population of patients followed longitudinally after they have taken a trip to the cath lab for one reason or another. Really with the goal to better understand the type-two MI syndrome. It was our hypothesis that type-two MI was perhaps more common than people may have recognized, and that type-two MI would be higher risk in terms of the likelihood for ischemic complications than what people had previously recognized. As you point out, type-two MI is often neglected from a management perspective.

                                                What we found, basically, was among a cohort of patients, 1,250 patients coming through the cath lab at the Massachusetts General Hospital Heart Center, in follow up over a several year follow up period with a maximum of eight years of follow up, with a mean of about 3.4, a median of 3.4 years follow up. Out of the 1,251 patients that we enrolled and followed, 152 actually had an incident type-two myocardial infarction during follow up. Additionally, type-two MI was actually quite recurrent in many patients, and in each of the cases whether individual or in most patients with recurrent type-two MI, the mortality risk was really quite striking. Patients that had a type-two MI, partially because they were more complicated medically speaking, as one might have expected, they were older and had lower blood pressure, more coronary disease, heart failure and other medical comorbidities. The likelihood for a major adverse cardiovascular event was more than doubled in patients that suffered an incident type-two MI, the risk for mortality was actually remarkably almost ten-fold higher with a cardiovascular death rate that was around nine-fold higher, heart failure was tripled.

                                                Really just illustrates the very morbid nature of the type-two myocardial infarction, and illustrates the fact that studies are urgently needed to better understand how we should manage these patients.

Dr. Lam:                               Dr. Januzzi when I manage patients I find this diagnosis of type two-MI to be a very dirty one to make, if you know what I mean. It's hard to really be sure what's happening, and what to attribute rises in troponin to, and so on. Could you tell us a little bit more about how difficult it was to adjudicate the events, and what's the risk of misclassification in your study?

Dr. Januzzi:                         It's a challenge, and that's something that came up during the peer-review process. We really wanted to make sure that we got this right, so in fact we went back and did a cross-sectional re-review of cases to make sure that our adjudication process was accurate. It's not a very straightforward thing to judge, obviously. A rise and/or fall in troponin may be from a type-one myocardial infarction. There's increasing interest in a syndrome of myocardial injury in the absence of a classical myocardial infarction. Then lastly, we recognized that troponin may rise and fall, for example, in patients with heart failure, possibly due to non-coronary mechanisms. You are correct, it may be a challenge to classify these patients solely on the basis of the presence of a rise or fall of troponin.

                                                What we did was classify them utilizing the Universal Definition of MI Task Force criteria, which includes symptoms and signs, as well as a rise and/or fall of troponin, plus evidence for loss of myocardial function on non-invasive testing. We were pretty strict, actually, in terms of how we judged them, and when we went back and re-reviewed ten percent of the cases, we actually found that all of the fifteen cases that we went back and re-reviewed met the criteria that we had articulated in the front end. We feel pretty confident that we got the diagnosis correct, but obviously it's a challenge in every day practices, as you rightfully point out.

Dr. Lam:                               It does certainly sound very rigorous, indeed. Dr. de Lemos, you managed this. He mentioned reviewers giving him a hard time, what was it like managing this paper?

Dr. de Lemos:                    It was fascinating because the Universal Definition that introduced type-two MI into the classification scheme is only a decade old. It's remarkable how little we know about the problem, and how much we struggle in clinical practice. We thought this paper was one of the first and most comprehensive evaluations to put some construct around the problem. As you pointed out, Carolyn, it is a messy diagnosis. Even when you do it in an organized, researched fashion this reflects what we all deal with in clinical practice where it's not so easy to define myocardial infarction even when given the criteria of the Universal Definition. The challenge really is that only a minority of the troponin elevations that are the classic type-one MIs that we know what to do with. The rest of them are either these troponin elevations NOS, type-two MI, or something on a continuum on this spectrum that's really hard to differentiate.

                                                This paper's important because it really highlights that these non-type-one MIs whatever they are, are common and associated with really high risk, and it's sort of a call to arm that we better start to understand and sub-classify these if we're going to be able to reduce risk in this very high risk population. That's really why we were so interested in the paper, and why we worked so closely with Jim and his team to address some of the issues that you just raised.

Dr. Lam:                               I completely agree, in fact it's beginning to remind me of the world of HFpEF when we first started realizing that people with heart failure, even though ejection fraction's normal are definitely not doing well. James Januzzi, if you don't mind, what do you think are the implications for treatment, what are the things that you think need to be examined going forward?

Dr. Januzzi:                         Carolyn I laughed when you mentioned HFpEF because at one of the recent Universal Definition of MI Task Force meetings, I actually said that type-two MI is the HFpEF of the myocardial infarction world. To answer your question, I have approached this question very much the way we do in the heart failure space relative to heart failure with preserved EF. In order to develop a strategy for treatment for type-two MI, we need considerable advances still in our understanding of just what exactly is a type-two MI, what types of patients have type-two MI, and on an individual level, the treatment strategies may follow.

                                                The problem here is if you look just at all comers who suffered a type-two MI in our study, the majority were actually taking statins, they were taking aspirin, they were more likely to be taking beta-blockers. So the patients themselves were actually on the very treatments that we might think about prescribing in those folks that have a type -wo MI, and yet they still suffered the MI, and they had worse outcomes. One might think about coronary disease and revascularization, and indeed one of the nice things about our study is we enrolled patients at the time of coronary angiography, and then followed them subsequently, so we actually had detailed coronary angiograms on every one. Those suffering an incident type-two MI certainly had more coronary disease, so one might argue revascularization might either be protective if done prior to the onset of type-two MI, or at the time of type-two MI a revascularization-driven strategy might be a logical approach.

                                                I think more fundamentally, bringing it back to heart failure and to the HFpEF analogy, I think that in order to better understand treatment we need to better understand just who these patients really are. So much like has been done in the heart failure space we're now doing cluster phenotype analyses where we're looking at the various phenotypes of patients with type-two MI using network analyses, which is one way to approach a problem when you've got a mix of various diseases that fall under the same title. So in those patients with preserved ejection fraction heart failure, there are patients that are younger obese patients, there are the patients with advanced diabetes, et cetera.

                                                Our hypothesis for our present research is to examine this question within the type-two MI diagnosis to see if we can identify specific clusters of phenotypes that might be treated in specific ways. The coronary patients might deserve revascularization, the heart failure patients might deserve a different approach for their care. That, I think, might be the way forward, exactly taking a page from the playbook that you just mentioned with respect to preserved ejection fraction heart failure.

Dr. Lam:                               Wow, how terribly exciting. Congratulations again for this paper, I really think it's a landmark and will open the door to many more important papers. I would like to switch tracks a little bit at the moment. We are coming to six months into the new Circulation editors that have been under the leadership of Joe Hill and James de Lemos, and I'd actually like to start by asking you, Dr. Januzzi, what was it like working with our new Circulation team? Then handing the mic over to Dr. de Lemos to tell us a little bit more about what the journey has been so far in the last six months.

Dr. Januzzi:                         Thanks for asking, it was an absolute pleasure. I trained with Dr. Hill and with Dr. de Lemos in one degree or another during all of our respective residency and/or fellowship training, so I've known these guys for a long long time. I think that the most important aspect in the peer review process is a collaborative and collegial process where the division between author and editor can allow for communication. In this experience with this manuscript, it was a very easy-going and collaborative process where the paper from beginning to end grew in its quality, and ultimately landed in the journal, and the way that it did was, I think, a substantial likelihood for heavy citation. That says a lot about the editors who really help us to bring it to this final product.

Dr. Lam:                               Dr. de Lemos?

Dr. de Lemos:                    We're now six months in to the new Circulation editor team's tenure, and I think all of us are having a blast. I think we've put together this team of diverse international experts that build off each other and thrive off each other, so from the team perspective, we're just having great fun, working hard, learning a great deal. We hope that those of you out there that are listening and reading, and submitting papers, and using our journal for your own research, are noticing the changes that we've made and think we're headed in the right direction. We'd love to hear from you about the things you like, and those things you don't like. We do think we've, in many ways, modestly changed the focus of the journal. There's so many new content categories that are designed to speak to the global burden of cardiovascular disease, the international aspect of cardiovascular research, and new clinically relevant problems, translating basic science so that clinicians can understand it. We hope that clinically active, as well as basic investigators are finding these changes useful in their own daily lives.

Dr. Lam:                               Thank you both so much for spending time with me on Circulation on the Run. Thank you everyone, don't forget to tune in next week.