Circulation on the Run

Each monthly episode will discuss recent publications in the fields of genomics and precision medicine of cardiovascular disease.
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Now displaying: September, 2017
Sep 25, 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 Center and Duke National University of Singapore. Our featured discussion today centers on new data from the Framingham Heart Study that addresses the question of the prognosis of pre-hypertension among individuals who never progressed to hypertension as well as the role of early versus late onset pre-hypertension in this context. Well, more soon, right after your summary of this week's journal.

                                                The first original paper provides mechanistic insights on the relationship between low and oscillatory wall shear stress, together known as disturbed flow, and atherosclerotic arterial remodeling and stiffness. Co-first authors doctors Kim and Pokutta-Paskaleva, co-corresponding authors Dr. Brewster and Jo from Georgia Institute of Technology in Emory University in Atlanta, Georgia used a novel mirroring model of disturbed blood flow to stimulate arterial stiffening through collagen deposition in young mice. They discovered a critical role for Thrombospondin 1, or TSP1 in activating TGF beta and stimulating arterial stiffening, all of which was significantly attenuated in the TSP1 knockout animal.

                                                Blockade of TSP1 activation of TGF beta decreased the up regulation of pro-fibrotic genes that contributed to arterial stiffening. Furthermore, they show that TSP1 localized to regions of disturbed flow in arteries from patients with peripheral artery disease and these arteries had similar increases in collagen gene expression. Thus, this work links TSP1 up regulation to arterial stiffening and identifies TSP1 as an important promoter of pathologic arterial remodeling in peripheral artery disease.

                                                The next study provides international insights on the degree to which secondary prevention treatment goals are achieved in clinical practice among patients with diabetes and cardiovascular disease. First and corresponding author, Dr. Pagidipati from Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina, looked at 13,616 patients from 38 countries with diabetes and cardiovascular disease in the TECOS trial. They found that only 30 percent of patients met all 5 secondary parameters of aspirin use, lipid control, blood pressure control, angiotensin-converting enzyme-inhibitor, or ARBUs, and non-smoking status.

                                                Only 58 percent of individuals with diabetes and cardiovascular disease attained blood pressure control. Furthermore, the degree to which secondary prevention goals were met in this trial varied by the world region and country. In summary, patients with diabetes and cardiovascular disease are still being undertreated globally with respect to secondary prevention, and especially with regard to blood pressure control. These gaps in care provide clear opportunities for improvement in this high risk population.

                                                The next study is the first to directly compare data from an electronic data research network to a large cardiovascular disease cohort. First author Dr. Ahmed, corresponding author Dr. Allen from Northwestern University in Chicago and colleagues sought to evaluate the degree of agreement of electronic data research networks compared with data collected by standardized research approaches in a cohort study. To achieve this goal, authors linked individual level data from the multi-ethnic study of atherosclerosis, or MESA community based cohort with Healthlink, a 2006 to 2012 database of electronic health records from 6 Chicago health systems.

                                                They identified areas of agreement and disagreement between blood pressure, cardiovascular risk factor diagnosis, and cardiovascular events between the two data sources. The correlation was low for systolic blood pressure, compared with MESA, Healthlink overestimated systolic blood pressure by 6.5mm mercury. Conversely, there was a high correlation between body mass index in MESA and Healthlink. Healthlink underestimated body mass index by 0.3 kilograms per meters square.

                                                Using ICD-9 codes and clinical data, the sensitivity and specificity for Healthlink queries for hypertension were 82.4 percent and 59.4 percent. For obesity these figures were 73 percent for sensitivity and 89.8 percent for specificity and for diabetes they were 79.8 percent for sensitivity and 93.3 percent for specificity.

                                                Finally compared with adjudicated events in MESA, the concordance rates for myocardial infarction, stroke, and heart failure were at 41.7 percent, 61.5 percent, and 62.5 percent, respectively. These findings therefore illustrate the limitations and strengths of electronic data repositories compared with information collected by traditional standardized epidemiologic approaches for the ascertainment of cardiovascular risk factors and events.

                                                The next paper helps physicians and patients to make an informed decision about whether or not to stop low dose aspirin use. First and corresponding author Dr. Sundstrom from Uppsala University in Sweden and colleagues investigated whether long term low dose aspirin discontinuation increased the risk of cardiovascular events in a cohort study of more than 600,000 users of low dose aspirin for primary or secondary prevention in the Swedish prescription register between 2005 and 2009.

                                                They found that patients who discontinued aspirin had a 37 percent higher rate of cardiovascular events than those who continued, corresponding to an additional cardiovascular event observed per year in one out of every 74 patients who discontinued aspirin. The risk increased shortly after discontinuation and did not appear to diminish over time. Thus, in long term users, discontinuation of low dose aspirin in the absence of major surgery or bleeding seemed to be associated with a more than 30 percent increased risk of cardiovascular events, thus adherence to low dose aspirin treatment in the absence of major surgery or bleeding may be an important treatment goal.

                                                The final study raises the possibility of using Histone Methyltransferase Inhibitors for the treatment of heart failure. Dr. Papait from Humanitas Clinical and Research Center in Italy and colleagues focused on G9A, a histone methyltransferase that defines a repressive epigenetic signature. Using normal and stressed cardiomyocytes from a conditional cardiac specific G9A knockout mouse, and a specific G9A inhibitor, they showed that the histone methyltransferase G9A was important in defining the epigenetic landscape that maintained the transcription program of the cardiomyocyte. It was also important for the regulation of gene expression reprogramming during cardiac hypertrophy.

                                                Furthermore, impaired G9A function promoted cardiac dysfunction. Thus, these findings suggest that G9A may represent a therapeutic target for early stages of cardiac hypertrophy.

                                                That wraps it up for your summaries, now for our feature discussion.

                                                For today's feature discussion, we're talking about the very important topic of the prognosis of prehypertension without progression to hypertension. Now, we've always known that mild blood pressure elevations that we call prehypertension are associated with cardiovascular risk. However, this risk could be attributable to the fact that these patients with prehypertension eventually progress to overt hypertension. But, what happens to the patients with prehypertension who do not progress to hypertension, and what is the role of early versus late onset prehypertension?

                                                Well, we have some answers today and I am so pleased to have the first and corresponding author with us, Dr.  Teemu Niiranen, from Boston University's Framingham Heart Study. Welcome, Teemu.

Dr. Teemu Niiranen:       Thank you very much, great to be here.

Dr. Carolyn Lam:               And to help us along in this discussion, we have a familiar voice. Dr. Wanpen Vongpatanasin, associate editor from UT Southwestern. Welcome back, Wanpen.

Dr. Wanpen Vongpatanasin:       Thank you Carolyn. Happy to be here.

Dr. Carolyn Lam:               Teemu, you know, I sort of set the background that you so nicely articulated in this research letter, but could you tell us a little bit more of what you were looking at, how you did it, and what you found?

Dr. Teemu Niiranaen:     My boss, Dr. Vasan, was also a coauthor in this paper, he already showed some 15 years ago that prehypertension carries greater cardiovascular risk than perfectly normal blood pressure. However, it's pretty much unclear what happens to people who are prehypertension but never go on to develop hypertension because even the name suggests that if you have prehypertension you will get hypertension. We also looked at what effect does the age of developing prehypertension and hypertension have in this context.

                                                We used a case cohort setting in the Framingham Heart Study in the way that we only looked at 5 1/2 thousand decedents. These were people who had already passed away. Then we categorized those decedents into 5 categories, people who never got prehypertension or hypertension, people who developed prehypertension late in life, who never developed hypertension, and people who developed early onset prehypertension but never developed hypertension, and then people who went on to develop late or early onset hypertension. We used a cutoff of 55 years as the definition of early onset versus late onset.

                                                Then, in a case cohort setting, we estimated case versus controls, adjusted case versus control odds ratios, for the 4 prehypertension/hypertension categories versus those who died without ever developing prehypertension.

Dr. Carolyn Lam:               Teemu, could I just stop you here before you share the intriguing results. I just wanted to remark that it's so amazing how the Framingham Heart Study really enables analysis like this, simply because of the long follow up and just the great detail and the standardization of blood pressure measurements and so on. I mean, as I said, I worked at the Framingham Heart Center, and we were trained to do this in a standardized fashion.

                                                Define prehypertension and hypertension, just in case, and then please tell us your results.

Dr. Teemu Niiranaen:     Prehypertension was 120 to 135 systolic blood pressure, and a diastolic blood pressure of 80 to 89 millimeters mercury, and then hypertension was 140 over 90 millimeters mercury, or antihypertensive medication, and yes, your correct that the Framingham Heart Study provides a very unique setting. Especially for defining early versus late onset hypertension because we can define the age of hypertension or prehypertension or prehypertension onset objectively because these people have been followed up, they have attended so many exams, especially the original cohorts.

                                                But, to the results, so we observed that basically people who develop prehypertension, either early and especially late in life, but did not ever develop hypertension, their risk, or odds of dying of cardiovascular disease versus non-cardiovascular disease was pretty much similar to those who never develop prehypertension or hypertension, while conversely the people who went on to develop either late or especially early onset hypertension, or developed early onset hypertension they had considerably greater risk of cardiovascular death versus those who developed either prehypertension or hypertension. That's our main result. I won't go into conclusions yet.

Dr. Carolyn Lam:               Okay, but maybe at this point, I could ask Wanpen to share some thoughts. I mean, this is very striking findings. Curious what you think the clinical implications were, and especially as we discussed among the editors.

Dr. Wanpen Vongpatanasin:       It is very important study that, as Teemu outlined it, to look at the fate of people with prehypertension and I think that's the first time we had this kind of data to show whether the earlier versus late prehypertension and even hypertension itself. I don't think people have looked at in the large number in terms of outcome people who have early versus late onset hypertension. I found the result to be fascinating.

Dr. Carolyn Lam:               Yeah, what does this mean though when we see a patient with this sort of borderline hypertension, you know, falling in the prehypertension range. We don't know whether they're going to develop hypertension. What do you think the clinical implications are? Teemu?

Dr. Teemu Niiranaen:     Unfortunately a lot of the people who develop prehypertension as the name suggests they go on to develop hypertension, but there is still a considerably great part that never develop hypertension, and our study shows basically that if you are able as a doctor or a patient to prevent progression to hypertension you are much better off and this really hasn't been previously shown, so it just should motivate patients and also doctors to strive to, if they see a prehypertensive individual, try to through lifestyle and other interventions try to prevent the progression to hypertension.

Dr. Carolyn Lam:               Yeah, I think that was one of the take home messages for sure. Were there any other plans for future work you think that needs to be done?

Dr. Teemu Niiranaen:     There's the everlasting problem with observational studies, so definitely it would be great if our results could be taken into clinical trials or anything to test whether interventions, A, that preventing the progression from prehypertension to hypertension could then impact cardiovascular outcomes.

Dr. Carolyn Lam:               Indeed, and if I may comment, I've always wondered about ethnic differences when it comes to this. The one thing that Framingham, you know, it's difficult to see from there, is what happens in other ethnicities other than white ethnicities, isn't it? Still, very striking findings. Wanpen did you have any other comments or questions from Teemu?

Dr. Wanpen Vongpatanasin:       Well, I think that one thing also that's interesting to me is even the people who had early onset prehypertension, although the number of CHD deaths were not significant, but the odds still 28 percent higher than the control that will never have prehypertension so, I think that that the signal is there but perhaps because the number of people who had prehypertension but never really progress to prehypertension is relatively small. It could be underpowered to see the significance and I think that from this study, it tells me that the exposure to blood pressure to our life, I think is the blood pressure lowered on the cardiovascular system, I think that's the one that really determine the cardiovascular outcome the most. I think that we should not discount that this is not a truly benign phenomenon, I think hopefully they'll be some more data from the Framingham group or other group.

                                                Also, I think that this study also very important to show that early onset hypertension actually have the worst prognosis, and often time when people come to see a doctor when they're 30 and 40 years old, they don't really want to take medicine, and the physician often time are reluctant to prescribe the drug, and I think that this study say that we probably need to be a little bit more serious about it, because they actually have the most cardiovascular events.

Dr. Carolyn Lam:               What excellent points, and you know what? At this point I just want to highlight that beautiful figure that you have in your research letter, Teemu. I think it says it all. It highlights that point estimate for the prehypertension groups is not exactly 1. If anything, it is above 1, right? For the odds of poor outcomes, so I do take Wanpen's point as well. Beautiful figures, and I also actually want to use that to ask you a different question Teemu. You have 1 figure, because this is a research letter that only allows 1 figure and 800 words, and you've put so much important information into that space. I'd love for you to share that experience with our listeners too, of a research letter versus a full paper. Why did you choose to submit yours as a research letter, and how was that?

Dr. Teemu Niiranaen:     One of the important take home messages from this was the differences between early onset versus late onset hypertension that we'd been also recently publishing on, so we wanted to delve more in depth on this prognosis of prehypertension versus hypertension so we don't have to be repetitive too much. We decided to focus on this very small topic most intensively, therefore we decided that maybe a research letter would be the most effective way so we could communicate all the really novel stuff that we have in just one figure. Well, it has 3 panels, but it still counts as 1 figure.

                                                I just wanted to point out that maybe the early onset prehypertension, yeah the confidence intervals are somewhat wide, but the panels sees for coronary heart disease versus non-cardiovascular disease deaths, so that's maybe a bit more underpowered than the back panel B, so the CHD deaths are part of the CBD deaths, so with CBD deaths, the early onset prehypertension, the odds ration was 1.09, but still of course the confidence intervals reach up to 1.49. Just to clarify the difference between panel B and panel C, so B's better powered.

Dr. Carolyn Lam:               It's a very nice figure, and indeed, I think it works very, very well as a research letter, and I think the fact that we're discussing it right now shows that length doesn't dictate importance. Wanpen you had a few comments about that. What do you think of a research letter format?

Dr. Wanpen Vongpatanasin:       Yes, I think this research letter is a really important part of articles in Circulation. I think that all the others should be aware that we're trying to enter at submission if it's suitable, just like this one. It actually show up in the pub med exactly like the full article and gets cited as much and sometimes much more than a regular article because it capture the essence of one more focused problem and the figures and table allow to show only one or two at a time, so they really capture the essence or the guts of the article and the reader can go through that quickly and grasp the concept and learn within flipping through a few pages.

                                                I think we should have many more interesting research letter like this.

Dr. Carolyn Lam:               Congratulations again Teemu for a beautiful paper, a very important one. Thank you Wanpen for shepherding this one.

                                                And thank you listeners for joining us today. Don't forget to tune in again next week.


Sep 18, 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 Center and Duke National University of Singapore.

                                Today we will be discussing the cost effectiveness of statin use guidelines for the prime and prevention of coronary heart disease and stroke. Comparing the 2013 American College of Cardiology American Heart Association guidelines with the adult treatment panel three guidelines. A very important and current discussion that you don't want to miss. All coming up right after these summaries.

                                The first original paper in this week's journal is the largest study yet reported that assessed the long term outcome of Takayasu's Arthritis. First author, Dr. Comarmond, and corresponding author Dr. Saadoun and colleagues from Hospital Pitie-Salpetriere in Paris performed a retrospective, multi-centered study of 318 patients from the French Takayasu network including patients with Takayasu Arthritis fulfilling the American college of Rheumatology and/or Ishikawa criteria. They found that, firstly, 50% of  Takayasu arthritis patients relapse and experienced a vascular complication at ten years. Secondly, male sex, elevated CRP, and carotidynia were independently associated with relapse and with a two-fold higher risk of relapse. And thirdly, patients at high risk for vascular complications could be identified according to presence of two or more of the following risk factors: progressive clinical course diagnosis, thoracic aortic involvement, and or retinopathy. In summary, these factors identify patients with a high risk of relapse or vascular complications and may therefore serve to adjust more aggressive management and close follow up in Takayasu's Arthritis.

                                The next study provides experimental evidence for a pathogenic role of the transcription factor interferon regulatory factor five or IRF-5 in atherosclerosis. In this study from co-first authors, Dr. Seneviratne and Dr. Edsfeldt, corresponding author Dr. Monoco from Kennedy Institute of Rheumatology in Oxford, United Kingdom, and colleagues. The authors showed that atherosclerosis prone apple-E negative mice who were also deficient in IRF-5 showed reduced atherosclerosis lesions and necrotic core formation. They found that the development of the lesion necrotic core was controlled by IRF-5 through impairment of macrophage dead cell removal, or spherocytosis. They further demonstrated that the CD-11C gene was a direct target of IRF-5 in macrophages and that IRF-5 was important in maintaining CD-11C positive macrophages in atherosclerotic lesions. In summary IRF-5 was shown to be a potential therapeutic target since its inhibition could reduce plaque inflammation and necrotic core size, thus potentially promoting a stable plaque phenotype with a lower risk of acute clinical complications.

                                The next study is the first to assemble a transcriptomic framework of multiple cardiac cell populations during post natal development and following injury, thus enabling comparative analysis of the regenerative or new natal state, compared to the non regenerative or adult state. In this study from first author Dr. Quaife-Ryan and co- corresponding authors Dr. Porrello from the Royal Children's Hospital and Dr. Hudson from the University of Queensland, Australia. The authors isolated cardiomyocytes, fibroblasts, leukocytes and endothelial cells from infarct and non infarct neonatal and adult mouse hearts. The then performed RNA sequencing on these cell populations to generate the transcriptome of the major cardiac cell populations during cardiac development, repair and regeneration. They further, surveyed the epigenetic landscape of cardiomyocytes during post natal maturation by performing deep sequencing of assessable chromatin regions. This comprehensive profiling of cardiomyocytes and non myocyte transcriptional programs uncovered several injury responsive genes across regenerative and non regenerative time points. The majority of transcriptional changes in all cardiac cell types resulted from development maturation from neo natal stages to adulthood. Rather that activation of a distinct regeneration specific gene program. Furthermore, adult leukocytes and fibroblasts were characterized by the expression of a proliferative gene expression network following infarction, which mirrored the neonatal state.

                                But in contrast cardiomyocytes failed to reactive the neonatal proliferative network following infarction which was associated with loss of chromatin accessibility around cell cycle genes during post natal maturation. In summary these findings are significant because they defined a regulatory program underpinning the neonatal regenerative state and identified chromatin modifications in adult myocytes that could restrict cardiac regenerative potential after birth and may need to be overcome to facilitate cell cycle re entry in adults.

                                The final study reports results of two studies investigating the pharmicokinetic and clinical outcomes of a new drug coated balloon to treat femoral popliteal disease. The first study is the Illuminate pivotal study in which 300 symptomatic patients were randomized to stellarex drug coated balloon or standard angioplasty. The primary safety outcome was freedom from device and procedure related death through 30 days and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness endpoint was primary patency through 12 months. The second study was the illuminate pharmicokinetic study in which paclitaxel plasma concentrations were measured after last balloon deployment and at pre specified times until no longer detectable. In this report my first in corresponding Dr. Krishnan from Mount Sinai Medical Center in New York. In the pivotal study the primary safety endpoint and the primary patency rate was significantly higher with the drug coated balloon. The rate of clinically driven target lesion revascularization was significantly lower in the drug coated balloon cohort. pharmicokinetic outcomes showed that all patients had detectable Placitexal levels after drug coated balloon deployment that declined within the first hour.

                                In summary these findings demonstrate the safety profile and superior patency of the stellarex drug coated balloon for femoral popliteal disease compared to standard angioplasty. This therefore suggests that this drug coated balloon may be a valuable treatment option for patients with superficial femoral and popliteal artery disease.

                                Well those were your summaries now for our feature discussion.

                                Today we are discussing the highly relevant and also highly controversial issue of Statins for primary prevention of cardiovascular disease and when do we start a statin. How cost effective is it, and of course all this discussion really began with the 2013 ACC/AHA guidelines that expanded the recommended statin use. I am so pleased because this week’s journal actually provides, for the first time, some cost effectiveness data that may help us in making this decision and in facing our patients. I can't tell you the number of times I've had an individual patient come to me and just want to discuss all the pros and cons of starting a statin for primary prevention and I'm sure, listeners out there you identify with this. Well hang because today we have the corresponding author of today's feature paper Dr. Kirsten Bibbins-Domingo from University of California, San Francisco  as well as the editorial list on this wonderful paper, Dr. Rodney Hayward from University of Michigan and VA Ann Arbor. Welcome Kirsten and Rod.

Dr. Kirsten Bibbins:          Thank you.

Dr. Rodney Hayward:     Great to be here.

Dr. Carolyn Lam:               Kirsten, could you please tell us the top line results of what you found in this paper, it's such an important paper.

Dr. Kirsten Bibbins:          We use simulation modeling to compare three approaches to giving Statins for primary prevention. The older guideline in the US called ATP-3, the one that you mentioned in your introduction the ACC/AHA guideline that broadened the use of Statins to many many more people and then an even broader strategy where we don't look at cardiovascular risk, and in each of these approaches we found that the use of Statins for primary prevention was very effective and in fact cost saving, when we did a cost effectiveness analysis. And regardless of the assumptions that we made about more side effects then we had known from the literature or could anticipate or regardless of the parameters that we put into the model we found that, pretty much that the broad use of these medications is effective and, in fact, cost saving.

Dr. Carolyn Lam:               Could you give us an idea of what you used in that simulation model, what population was it, how applicable is it to people outside the US, for example.

Dr. Kirsten Bibbins:          Simulation modeling is a way to take the evidence that we have from multiple types of studies and to try to synthesize that evidence and apply it to, in this case, the population of the US. So our simulation model uses the demographics of the US and takes the primary studies and the effect rises that we know from those studies and using that model we found that each of these three approaches had both health benefits and cost saving benefits. It's applicability might be somewhat variable if this were applied to a different population, but the effects are pretty substantial and so it suggests that Statins are likely to be beneficial using these approaches in a broad array of populations.

Dr. Carolyn Lam:               Could you give us an idea of the estimated effect size, you know, when you say cost effective, for example, how, how much and for what. Give us everyday clinician some kind of take home of numbers that would make sense for them.

Dr. Kirsten Bibbins:          One way to think about these types of cost effectiveness analysis is that often times they give us numbers that suggest that we have to pay a certain amount to get the type of health benefit that we want. In this case because we found that they were cost savings, it actually suggests that the amount that we pay for Statins, to give Statins to a broad population of individuals actually saves us money. It saves us money in terms of the heart attacks that are avoided, and the other types of health care costs that are avoided and probably a number that might be relevant to your audience might be that the number that one would need to treat in order get one additional year of life, through using these Statins for primary prevention, is on the order of about 35 individuals and so that's a small number that we would be treating in a primary care practice in order for an additional quality adjusted year of life.

Dr. Carolyn Lam:               I thought that was really one of the most remarkable figures, you know, that the ATP-3 guidelines would result in 8.8 million more statin users than the status quo and that was an entity of 35 per quality of life. Was that correct?

Dr. Kirsten Bibbns:           That's exactly right.

Dr. Carolyn Lam:               Whereas the ACC/AHA guidelines could potentially result up to 12.3 million more statin users than the ATP-3 guidelines with a marginal number needed of 68 per quality of life. So very, very useful figures, but you know, I began by saying my individual patient. These feel like population bases statistics, you know, and my individual patient kind of wants to know but for me, what's a long term risk and so on. And these are issues that you have discussed so elegantly, Rod, in your editorial. Could you enlighten us a bit on these considerations.

Dr. Rodney Hayward:     Sometimes decisions that we have to make in policy are inherently population based decisions, like putting fluoride in the water, in which the average benefit of cost for population is what you have. Cause you can't treat individual separately with that type of intervention, but with a statin, the average that a population gets is not the important thing to our patients across the room. And it's sort of the number needed to treat for them, how likely are they to benefit. And what I think this paper establishes very well, and I think it's important to start with why the areas of agreement here, this establishes that the new guidelines are a great idea. There's no assumptions in this model that would change that starting people on a statin between 7.5 and 10 % ten year risk isn't a good idea. And that aspect of the paper even some of the issues I have about some of the assumptions are not going to be relevant, where it starts to become concerning, and will always be controversial is how low of risk to start it at. Do we go from 7.5 to a 5% risk? Do we start putting everyone at age forty on a statin?

                                And at that case, certain elements of this simulation model are very important, the likelihood of an individual benefiting becomes very, very small. And even a small dislike of the medicine, would outweigh that. But also you have to assume in this model that we know all the bad things of a statin at 20-25 years, because you're starting to put people on a daily medicine that's biologically active for 30 years. And it's impossible statistically, epidemiologically, to know with any degree of certainty whether or not being on these medicines for 20-30 years would have unheard effects. We don't have that ability, currently, even if we had the databases so how should individuals think about that, well my feeling is that is part of the shared decision making of how much a patient worries about unknowns, about being on a medicine long-term versus they worry more about the potential for a heart attack prevention which are likely there. I want to emphasize again these are not relevant concerns when we're talking about the current guidelines, these are only concerns when we start pushing it down to a 5% risk or everyone over 40 where you're extending to tens of millions more people, in which the population benefits would be substantial.

                                As long as people don't mind taking a pill every day at those ages and we know all of the harms being on a statin for 20 years. And that's something that no one knows.

Dr. Carolyn Lam:               Rod that was just so eloquently stated, and listeners out there, you just have to read this editorial. It states these things very clearly, and I think it's really helpful in our thinking of what to tell patients when we do see them. Kirsten, I'd love to invite your thoughts on what Rod just said, you acknowledge this, fully in your paper. Curious, any steps you took to maybe address this and what you would say as a take home message for clinicians?

Dr. Kirsten Bibbins:          I think that Rod's bringing out exactly the point. And, I think, we have seen the shift from the earlier guideline to the most recent guideline in putting more people on Statins and these medications certainly have the benefit, but as you bring more and more people on who have lower overall cardiovascular risk, their likelihood of benefiting while there, is always smaller. And so then other things do come in to play, and I think the thing that probably was most surprising to us as we put this work together, was how sensitive our results were to, essentially, a patients preference as we moved down into including more of these lower risk individuals. That means that an individual who's lower risk may not directly benefit or their likelihood of benefiting in terms of avoiding a heart attack is lower, and so therefore the facts that their tolerance for taking a daily medication is in fact, then becomes relevant in to their particular trade off for taking this medication. And I think that is clinically important as we think about including more and more lower risk people into these types preventative guidelines, the threshold for any given individuals tolerance for taking a daily medication and of course, as Rod said, if you're doing this over many years and decades the fact that we don't actually know what will happen over the long term, also becomes relevant.

Dr. Carolyn Lam:               Just maybe one last question for both of you. What do you think our next step is here, what more do we need?

Dr. Kirsten Bibbins:          I just think we still want to continue to expand our understanding of what the long term effects and side effects of daily use of statin therapies are, again I'd want to emphasize as you said it's always important to understand patients preference, but, as Rod said, our current guidelines which really have focused on higher risk individuals, I wouldn't want it to be lost that these medications are in fact very effective and so I think having an understanding of the long term use of these medications and what the potential side effects when used over a long period time are, I think that's a critically important area. As well as really developing continuing to develop the tools that can help doctors and patients together engage in the conversation about the trade off for given individual.

Dr. Rodney Hayward:     I would definitely agree with that, but I would focus on three bits of science. That are critically important for refining this issue. The one is something we currently don't have and that's post marketing surveillance of medicines long term. That when you look at the data we have, that, most of them follow patients either a short period of time and don't have enough continuity or their smaller studies in which outcomes that are long term might be found. And this is a place where big data, but also combining and sharing data across health systems could really help us monitor. This is not just an issue for Statins but as more medicines are recommended for younger individuals with life expectancy we need to work on that. Two the results are insensitive meaning that it always looks good, for people in the current guidelines but two elements of the model for people at a 5% risk or starting people at age 40 are assumptions that are being made with the best available data now, but have some considerable concerns and could be improved.

                                One is, we don't know the impact of a non fatal heart attack on future outcomes, my personal opinion is the assumption in this model, is probably an overestimate. Unimportant for the current guidelines but would be critically important for these younger risk people and ways to really understand the impact of non fatal events on future risk are epidemiologically tricky and it's very easy to pick up things that are markers that aren't causal and then when you run your models you think you're extending life years where you really aren't. And the other is we still don't know how much a Statins relative benefit varies by a persons LDL level, that might seem astounding but there's evidence on both sides. That it is related to baseline LDL and it's not. This is a completely solvable question, the CTT group has the data and we really need them to publish and tell us how much the relative risk of a statin varies by that. The current assumption in the ACC/AHA guidelines is that it is not correlated, the assumption in Kirsten's model is that it is.

                                Either could be correct, my personal opinion is it's probably in between, those two, but that would help us in terms of thinking of extending to the lower people. If LDL is a partial factor that probably should be considered, if it's not then only risks should be considered. That is completely answerable for those that have access to the RCT data and I'm hoping that this paper may encourage that publication.

Dr. Carolyn Lam:               Wow, those were such insightful comments, I can't thank you enough, Rod and Kirsten for joining us today.

                                Listeners I'm sure you enjoyed that and learned so much just like I did. Don't forget to join us again next week.

Sep 11, 2017

Dr. Carolyn Lam:               Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and it's editors. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Our feature paper this week contains novel data from the TOPCAT trial, this time relating physical activity to prognosis in patients with heart failure and preserved ejection fraction. A great discussion coming right up after this weeks' summaries.

                                                Our first paper tells us that pericarditis may be a marker of occult cancer and augurs increased mortality following the cancer diagnosis. Authors, Dr. Sogaard and colleagues from our host university hospital in Denmark used the Danish medical databases to conduct a nationwide cohort study of all patients with a first-time diagnosis of pericarditis from 1994 to 2013. Among 13,759 patients with acute pericarditis, 1,550 subsequently were diagnosed with cancer during followup.

                                                Patients with newly-diagnosed pericarditis had higher risks than age and sex match members of the general population of being diagnosed with lung cancer, Non-Hodgkin lymphoma, and myeloid leukemia during the first three months following a pericarditis diagnosis, but increased risks for lung cancer and Non-Hodgkin lymphoma and bladder cancer persisted beyond one year following a pericarditis diagnosis. The increased cancer risk was not restricted to patients with pericardial effusion.

                                                Furthermore, pericarditis was a prognostic factor for survival after lung cancer, breast cancer, and bladder cancer. Thus, the clinical take-home message is that patients with pericarditis, particularly when complicated by pericardial effusion, may need to be considered for workup targeted at diagnosing or ruling out cancer.


The next paper provides insights into mechanistic processes leading to stent thrombosis in the largest contemporarily available series of patients undergoing optimal coherence tomography, or OCT imaging, during stent thrombosis presentation. The first author, Dr. Adriaenssens, corresponding author, Dr. Byrne from Munich, Germany, and colleagues of Prestige Consortium, performed a prospective multicenter study to evaluate OCT findings in consecutive patients presenting with stent thrombosis enrolled in a registry that was using a centralized registration system.

                                                In 231 patients with stent thrombosis undergoing OCT, uncovered and malapposed struts were frequently observed, with the incidents of both decreasing with longer time intervals between stent implantation and presentation. The most frequent dominant observation varied according to the time intervals from index stenting. Uncovered struts and stent underexpansion were the most common observations in acute or subacute stent thrombosis, whereas neoatherosclerosis and uncovered struts were the most common findings in late or very late stent thrombosis. The impact of dedicated clinical strategies for the prevention and treatment of mechanisms underlying stent thrombosis should be investigated in future clinical studies.

                                                The next study identifies a new type of capillary malformation, arteriovenous malformation. Now, we know that most arteriovenous malformations are localized and occur sporadically. However, they also can be multifocal in autosomal dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation arteriovenous malformation or CMAVM. RASA1 mutations have been identified in 50% of patients with CMAVM.

                                                In the current study, first author, Dr. Amyere, corresponding author, Dr. Vikkula from Brussels, Belgium and colleagues studied non-RASA1 patients and found that EphB4 mutations occurred in patients with multifocal capillary malformations associated with arteriovenous malformations. This phenotype named CMAVM2 mimicked RASA1-related CMAVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120-RasGAP was a direct effector of EphB4. Furthermore, the study implicated EphB4-RAS-ERK signaling pathway as a major cause of arteriovenous malformations. Thus, patients with multifocal capillary malformations need to be screened, not only for an inherited RASA1 mutation, but also for EphB4.

                                                The final study identifies a novel potential therapeutic target in the treatment of atherosclerosis, and that is Dickkopf-related protein 3, or DKK3, a secreted protein previously known for its involvement in the regulation of cardiac remodeling and vascular smooth muscle cell differentiation, but very little studied in atherosclerosis. In the current study, first author is Dr. U.N. [inaudible 00:05:51], corresponding authors, Dr. Qu from Capital Medical University in Beijing, and Xu from Kings College London used both epidemiological and experimental approaches to test the hypothesis that DKK3 was atheroprotective.

                                                In the prospective population-based Bruneck study, they found that the level of plasma DKK3 was inversely related to carotid artery intimal medial thickness and five-year progression of carotid atherosclerosis independently from standard risk factors for atherosclerosis. Experimentally, they demonstrated that DKK3 promoted re-endothelialization in murine models of atherosclerosis and wire-induced femoral artery injury, thus revealing its atheroprotective role.

                                                They further explored the mechanism of DKK3-induced endothelial cell migration, which was via noncanonical Wnt signaling pathways.  The study, therefore, provides the evidence for a role of DKK3 in the protection against atherosclerosis involving endothelial migration and repair with potential therapeutic implications.

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

                                                For today's feature discussion, we are talking about physical activity and prognosis in heart failure with preserved ejection fraction, or HFPEF. To discuss this paper, which contains really neat results from the TOPCAT trial, we have none other than the first author, Dr. Sheila Hegde, corresponding author, Dr. Scott Soloman, both from Brigham and Women's Hospital, as well as Dr. Jarett Berry from U.T. Southwestern, who was the editorialist on this paper. Welcome, everyone.

Dr. Scott Solomon:          Thanks, Carolyn.

Dr. Sheila Hegde:             Thank you.

Dr. Jarett Berry:                Thank you, Carolyn.

Dr. Carolyn Lam:               Hey, Scott. Could you set the background a little bit and let us know what was the rationale of looking at physical activity in TOPCAT?

Dr. Scott Solomon:          As you well know, heart failure with preserved ejection fraction is a disorder in which we don't currently have a therapy, or for which we currently don't have a therapy, and we know that people would also have a lot of comorbidities. Sheila has been extremely interested in the role of physical activity in heart failure and patients with heart failure, has studied this in the atherosclerosis risk in community studies, and we thought TOPCAT would be a great overall trial dataset to understand the importance of physical activity in HFPEF patients and the relationship with outcomes.

                                                As you know, TOPCAT is a study that was funded by the NIH in patients with heart failure, preserved ejection fraction. Patients were randomized to spironolactone or placebo and then followed for outcomes, and it was a very rich dataset for which we have a lot of physical activity information.

Dr. Carolyn Lam:               Indeed, and I wasn't even aware of the extent of the physical activity information in TOPCAT. Sheila, could you explain a bit how physical activity was captured and graded, and tell us about your findings?

Dr. Sheila Hegde:             Each participant’s physical activity was assessed by self report. Subjects were asked about the amount of heavy, medium, and light exercise in the preceding two weeks. They were given some examples of what those might be and what we did was, we converted these to AHA, American Heart Association categories of poor, intermediate, and ideal activity. As you know, the ideal activity category corresponds to 150 minutes of moderate intensity activity per week or 75 minutes of vigorous activity per week. What we found, using these categories, was that the majority of subjects actually met criteria for poor activity, so at least 75%. Also, a majority were New York Heart Association Class II heart failure.

                                                Those with poor activity were more likely to be women, have diabetes, chronic kidney disease, and a previous history of heart failure hospitalization. Interestingly, there was no significant difference in history of myocardial infarction, stroke, atrial fibrillation, or COPD. The median follow-up time for this group was 2.4 years, and we did sort of focus on the first two years because there was an interaction with times and randomization and, using Cox regression models, we found that those with poor or intermediate activity had approximately a two-fold higher risk of a primary composite outcome, which was heart failure hospitalization, cardiovascular mortality, or aborted cardiac arrest.

Dr. Carolyn Lam:               Wow! You know what the question is? Chicken or egg? Does this mean those who were exercising had better outcomes or they were just better and, therefore, they could exercise?

Dr. Sheila Hegde:             That's a very good question. This is a post hoc analysis, so it will be difficult to say, but we did sort of look at excluding those with a history of stroke or MI and found that the same two-fold increased risk of outcomes existed for those with poor intermediate activity.

Dr. Scott Solomon:          This is always the problem, as you know, Carolyn, with observational data. We don't know if the patients who are exercising more are doing better because they're exercising more or is it that the people who feel better can exercise more? You try to adjust as much as you can, but I don't know that there's any way to determine that for sure without doing a randomized trial of exercise in patients with HFPEF.

Dr. Carolyn Lam:               Certainly and, in fact, I thought that was one of the good messages, that it's time that we do a proper trial of that, don't you think? Jarett, would you have some questions for Sheila and Scott, too?

Dr. Jarett Berry:                I was really interested in your figure 3, this dose response analysis. In figure 3, you divided the exposure into deciles. You don't begin to see a decremented risk until you begin to see the ninth and tenth decile of exercise. If you look at other observational data, you really see this different pattern where just getting off the couch seems to be beneficial in other observational data for preventing coronary disease events but, both in our work and also in this paper here, particularly your figure 3, you see that this higher dose of physical activity was required to see a reduction in risk. I don't know if you could comment a little bit on that.

Dr. Sheila Hegde:             I agree that there is a difference in what appears to be a dose response at lower levels of activity. In this analysis, we actually included amount of light intensity of activity since the majority of people had no moderate or vigorous intensity activity to account for. In that sense, there's even sort of a higher threshold, perhaps, required to achieve benefit and reduction of risk, and it may be that heart failure has a different mechanism for physical activity in terms of achieving those benefits.

Dr. Jarett Berry:                I'm wondering, I guess getting back to Carolyn's original point there about, and Scott's comments, as well, about the need for a trial. If you look back at HF-ACTION where we saw some relatively modest benefit for exercise training and heart failure with reduced ejection fraction. Some of our prior work would suggest that, actually, the benefit of exercise is much more apparent in HFPEF patients. When you train HFPEF patients, they tend to improve much more dramatically with regard to VO2 peak, compared to heart failure with reduced ejection fraction. I'm just wondering what your thoughts were about the next steps. It seems like a trial of some type would be of great interest. What are your thoughts about that?

Dr. Scott Solomon:          I agree with you 100%. It would be a great idea for a trial. There have been small trials, as you know. Dalane Kitzman did a trial and Frank Edelmann and Burkert Pieske did a trial, and I think they're actually even doing another one now. The relatively small numbers of patients do show improvement in myocardial oxygen uptake, improvement in quality of life, and some improvement in some measures of echocardiographic measures of diastolic function, as well, with exercise training which is, frankly, more than we've gotten with drug therapies, so I agree 100%.

                                                It's also important to note that it's actually hard to get our patients with HFPEF in the United States into cardiac rehab because it's currently not paid for by Medicare, and I'm hoping that will change, as well.

Dr. Carolyn Lam:               You know, that's so well put, Scott. I've got a question, though. Every time you think TOPCAT, you think regional variation, right? How did this look in the different regions, in the U.S. versus elsewhere?

Dr. Scott Solomon:          First of all, let me just tell the audience that TOPCAT was a study in which we enrolled patients both in the Americas, which was the U.S., Canada, Argentina and Brazil, and in Russia and the Republic of Georgia. As you know, when we unblinded the trial, we found that the event rates in Russia and the Republic of Georgia were considerably lower, about five-fold lower than they were in the Americas. We believe that many of these patients may not have had heart failure.

                                                We've also recently found that many of these patients probably weren't taking spironolactone, as well. For many of our TOPCAT analyses now, including this one, we excluded the patients in Russia and Georgia and just focused on the Americas. Sheila, did you happen to look at the results in Russia and Georgia, just as a tweak?

Dr. Carolyn Lam:               I can tell you that the majority of patients were active, so very much different than our majority in active patients in the Americas region.

Dr. Jarett Berry:                This is an amazing study that really puts forward an important hypothesis that needs to be tested. Before, I know we've discussed that a couple of times already, but I really believe that we are exercising the wrong heart failure patients. As the Director of Cardiac Rehab here at Southwestern, we are including a lot of heart failure with reduced ejection fraction but, as Scott points out, there aren't currently funding available or billing is not allowable for patients who have heart failure with preserved ejection fraction.

                                                I think it's only studies like this that are going to move the field for it and how we can begin to think about caring for these patients and treating their comorbidities and treating their disease process through what we believe is probably one of the most important therapeutic strategies we have that we're not using, and that would be the exercise training, so I think this is a fantastic study and a wonderful contribution as we begin to think more about the future of treatment for patients with HFPEF.

Dr. Carolyn Lam:               Thank you so much, everyone. Listeners, I'm sure you enjoyed that conversation as much as I did. Don't forget to tune in again next week.


Sep 5, 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 Center and Duke National University of Singapore. Today's feature paper looks at the early use of N-Acetyl Cysteine with nitrate therapy in patients undergoing primary PCI for STEMI. More soon right after this week's summary of original articles.

                                                The first paper identifies a novel association between Phosphatidyl Choline Transfer Protein, or PCTP expression, in the blood, and death or myocardial infarction in patients with cardiovascular disease. Now, PCTP regulates intermembrane transfer for phosphatidyl choline. Platelet PCTP expression has been shown to be associated with increased platelet responses upon activation of protease-activated receptor four thrombin receptors. In today's paper, first authors Dr. Mao and Songdej, corresponding author Doctor Rao, and colleagues from the Temple University School of Medicine in Philadelphia used DNA protein binding studies and human erythroleukemia cells, as well as luciferase reporter studies to show that PCTP is a direct transcriptional target of RUNX1, a major hematopoietic transcription factor that regulates platelet production and function. Furthermore, in 587 patients with cardiovascular disease, the authors showed that PCTP expression in the blood correlated with RUNX1 expression and was independently associated with future death or myocardial infarction. Thus, regulation of PCTP by transcription factor RUNX1 may play a role in the pathogenesis of platelet-mediated cardiovascular events.

                                                The next paper provides molecular insights into cardiac fibrosis and shows that bone marrow cells are involved in cardiac fibrosis during pathological stress. Drs. Kishore, Verma and colleagues from Lewis Katz School of Medicine and Temple University of Philadelphia hypothesize that interleukin-10 inhibits pressure overload-induced homing of bone marrow fibroblast progenitor cells to the heart, and inhibits their trans-differentiation to myofibroblasts, thus attenuating cardiac fibrosis. To test this hypothesis, the authors used pressure-overload in wild-type and interleukin-10 knockout mice by transverse aortic constriction, and used chimeric mice to determine bone marrow origin. They further isolated fibroblast progenitor cells from mouse bone marrow for mechanistic studies.

                                                They found that, in addition to resident cardiac fibroblasts, bone marrow-derived fibroblasts significantly contributed to progression of pathological cardiac fibrosis, and that pliotropic antiinflammatory interleukin-10 inhibited the recruitment and trans-differentiation of bone marrow fibroblast progenitor cells in the pressure-overloaded myocardium. At a molecular level, they showed that interleukin-10 inhibited TGFβ SMAD2-3 signaling in activated bone marrow fibroblast progenitor cells. Furthermore, inhibition of TGFβ SMAD2-3 signaling mediated micro-RNA21 maturation was a novel mechanism by which interleukin-10 inhibited bone marrow progenitor cells-mediated cardiac fibrosis. Thus, selective inhibition of bone marrow cells homing to the heart and of fibrotic signaling using interleukin-10 or selective RNAs might inhibit the transition of physiological hypertrophy to heart failure, and may be a potential therapeutic target to treat or prevent the development of hypertrophic remodeling.

                                                The next study looks at the risk of major bleeding in patients receiving ticagrelor compared to Aspirin after a TIA or Acute Ischemic Stroke in the SOCRATES study. As a reminder, the SOCRATES trial was the first outcome study with ticagrelor in patients with Acute Ischemic Stroke or TIA, who were given ninety days of monotherapy with ticagrelor, 90 milligrams, twice daily and compared with those given aspirin 100 milligrams daily. The trial found that ticagrelor was not superior to aspirin in reducing the primary composite endpoint of stroke myocardial infarction or death. In today's study, Dr. Easton and colleagues from University of California San Francisco aimed to describe the bleeding profile of monotherapy with ticagrelor versus aspirin in this population of patients with Acute Ischemic Stroke and TIA, to characterize major bleeding based on the PLATO, TIMI and GUSTO bleeding definitions, and to identify factors associated with major bleeding.

                                                They found that PLATO major bleeds occurred in 0.5% of patients on ticagrelor and 0.6% of patients on aspirin. The most common locations of major bleeds were intracranial and gastrointestinal. Intracranial hemorrhage was reported in 12 patients, or 0.2%, on ticagrelor and 18 patients, or 0.3%, in aspirin. Independent of bleeding classification, PLATO, TIMI or GUSTO, the relative difference between treatments for major or severe bleedings was similar. However, non-major bleeds were more common on ticagrelor. Thus, this paper contributes important data on the bleeding profile of ticagrelor in patients with acute cerebral ischemia, provides some reassurance that there's no increased risk of major bleedings with ticagrelor compared to aspirin, including intracranial bleeds, however, a numerical increase in minor bleedings with ticagrelor.

                                                The next paper tells us that single 24-hour urine collections may be useful for estimation of average sodium intake in populations. However, for a reliable estimation of cardiovascular and renal risk, multiple 24-hour urine collections may be needed. First author, Dr. Olde Engberink, corresponding author, Dr. Vogt and colleagues from Academic Medical Center Amsterdam selected 574 adults with EGFR above 60, an outpatient 24-hour urine sample, and at least one collection during a seventeen year follow-up. Sodium intake was estimated using a single baseline collection, and the average of samples that were collected during a one, five, and fifteen year follow-up.

                                                They found that estimates of daily sodium intake changed more than 0.8 grams in half of the subjects when using multiple follow-up collections instead of a single baseline collection. The way of estimating sodium intake significantly affected the observed relationship between sodium intake and long-term outcome. Hazard ratios for cardiovascular and renal outcomes changed up to 85% when multiple follow-up 24-hour urine collections were used, instead of a single baseline collection. Thus, in summary, relative to a single baseline, the use of subsequent 24-hour urine samples resulted in different estimations of an individual's sodium intake, while population averages remained similar. This had significant consequences for the association between sodium intake and long-term cardiovascular and renal outcome.

                                                That wraps it up for your summaries this week. Now to our featured discussion.

                                                Today for our featured discussion, we are talking about approaches to cardio protection. Now, we all know that the mortality rates in STEMI has improved over the last few years, because we've gotten better at reperfusion therapy with primary PCI, as well as effective secondary prevention therapy. However, the incidents and severity of heart failure following STEMI has been rising and thus, cario-protective therapies are of great interest to prevent heart failure and improve overall clinical outcomes following STEMI, following primary PCI. Over the years, a number of cardio-protective therapies have been tried, but have either been unable to reduce MI size or improve clinical outcomes following STEMI, but in this week's journal, we have an exciting trial, very interestingly of two old cardio-protective therapies showing a lot of promise in this area. And to do discuss this, I am so pleased to have the corresponding author, Dr. John Beltrame from University of Adelaide in Australia, as well as associate editor from Brigham and Women's Hospital in Boston, Massachusetts, Dr. Laura Mauri.

                                                John, you know, in my introduction I said this is very interesting. You're actually combining two old therapies, N-acetylcysteine and nitroglycerin in your approach in this trial. Now, both these drugs have been around for a long time. Please share with us what led you to think that a combination would work, what made you test the combination, and what makes your trial different from the other reperfusion studies before.

Dr. John Beltrame:           So, nitroglycerin, of course, has been utilized to treat myocardial infarctions for many years, has been shown to reduce the chest pain in that scenario, but little reward in perhaps reducing infarct size. And one of the main benefits of that people don't know is the vasodilation effect that it has on the coronary arteries, as well as reducing the wall stress. So, what we thought to combine it with N-acetylcysteine, which potentiates nitroglycerin effects, but also is a free radical scavenger. So therefore it would actually also work on reperfusion injuries. So these have a very synergistic effect, and therefore we expected to have good benefits.

                                                The ... because we're also looking at an anti-ischemic therapy with a reperfusion protective therapy, we wanted to introduce it as soon as possible. And so this drug was initiated in the emergency department as patients arrived, and then taken off to the cath lab where it was continued. We also began to ensure that we had adequate N-acetylcysteine, which I'll probably refer to as NHC from now on, as much on board as possible before we actually opened the artery. We gave high dose N-acetylcysteine at 20 milligrams in the first thirty minutes, and then at a slower rate for the next twenty-four hours. So for the first hour we gave it at 20 milligrams a minute, and then thereafter 10 milligrams a minute. And then, the actual study. We had patients randomized and double-blind placebo control trial, multiple sites here within South Australia with the primary endpoint being myocardial infarct size on early cardiac MRIs.

                                                So they got to see the opportunity to have a smaller sample size than many of the conventional infarct studies, and the key finding was in that early MRI, we saw an absolute 5% reduction in infarct size, which was an exciting find for us and this we expect to translate to a significant reduction in cardiovascular events and that's where I guess we're going in the future, is that we need to now undertake a study where we show that the combination of these two drugs also impacts on cardiac events.

Dr. Carolyn Lam:               How beautifully summarized, John. And really, congratulations on such an impactful and elegantly done study. I like the way you highlight it, though. Basically, you gave this drug earlier than most other trials of reperfusion therapies, because you gave it even before the primary PCI procedure as most cardio-protective strategies were tried within the cath lab. Would that be accurate?

Dr. John Beltrame:           Exactly right. So, whereas a number of the studies would take the patient with the STEMI to the cath lab, undertake the diagnostic angiogram and the diagnostic angiogram would then confirm that this was occluded, then they would introduce the cardio-protective agent and then proceed on to open up the artery. Whereas we had an opportunity for sort of ... at least twenty to thirty minutes before the artery was opened to actually have those drugs on board. And so, in a number of cases, we improved the patency of the vessel when we got to the diagnostic angiogram. So it's a two-point strategy, one anti-ischemic and one cardio-protective in terms of reperfusion injury. And we think that future trials in this area need to address both those conditions.

Dr. Carolyn Lam:               I can think of no better person to comment on being able to do these trials and the future of these trials than Laura. Laura, what are your thoughts?

Dr. Laura Mauri:               Thanks Carolyn. John, that was a great summary and I think you're really to be commended, because this is just such a challenging area to be doing trials in, but that's really what we need. And you know, most of the trials have focused on early procedure success for therapies that we currently use, rather than showing documented benefit in longer-term endpoints. But as you mentioned earlier, Carolyn, we really do still have patients who would benefit from therapies that may reduce infarct size. I think it's really remarkable, John, that your study was able to intervene early in the emergency room, as we know as clinicians that's not easy to do, not only to activate the quick pathways of care that we need for STEMI, but then on top of that to lay on a randomized trial, but I think it's incredibly important.

                                                What are you foreseeing as the challenges? As you think about your next steps in rolling this out to a ... potentially a larger trial and implementing such a study?

Dr. John Beltrame:           As with many trials, it's ways of recruitment, because a study like this is not gonna be funded by industry, you need to be looking at ... here within Australia, be looking at government authorities to put in an application for funding and then, it's a matter of recruiting. That's one of challenges we came across in doing this particular study, and this relates particularly, I guess, to the MRI endpoint, is the number of patients that were claustrophobic and therefore we couldn't actually perform the cardiac MRI, and so your primary endpoint ... you missed out. And so again, there's going to be frustrations like that and a much larger trial, which will need to involve even more centers. But funding that's ... for much of the research, I guess, it will be the challenge, because we've got two agents as Carolyn mentioned in the beginning that have been around for a long time and are certainly unlikely to attract any industry funding.

Dr. Carolyn Lam:               John, I have a question about the design as well. Of the current and maybe a future trial, because I'm left with the question, was it your early intervention? Was it the outcome you chose? Or was it one drug or the combination? And so, you did not do a factorial design in this trial. Are there plans to look at that, or do you the combination ... it's so obvious that two separate drugs don't need to be tested?

Dr. John Beltrame:           Very good question. So, you're quite correct, we can't be absolutely confident in terms of the mechanism, because we had one opportunity, I guess, to do the study and so we wanted to keep a simplified design, and that's what we gave everyone; a background of nitroglycerin and then just randomized the N-acetylcysteine. But we think it's actually the combination of the two that makes the benefits, because as you would be aware, the synergistic benefits is that the N-acetylcysteine potentiates the effect of the nitrates, potentiates the vasodilating properties, potentiates it's anti-platelet properties also. And so we think it's a combination of the two.

Dr. Laura Mauri:               John, it's interesting ... the use of the cardiac MRI endpoint, as we've all seen, it's being used more and more frequently, but at the same time, it's new for us, right? So you've raised some of the challenges and the practical execution of getting patients who can tolerate it, especially after an acute hospitalization. But the classical endpoint has been SPECT imaging as a surrogate endpoint for mortality in myocardial infarction. Of course, that's based on very large trials showing correlation, but the MRI should really give much better resolution, so I think that's really a very logical next step. But I think the more data that we get across multiple different trials, the better we can validate that endpoint and see how it might differ from the classical surrogate endpoints that we've had for myocardial infarction.

                                                Other than the efficiency of looking at MRIs, do you have other observations when you look at MRIs at endpoint compared with some of the traditional endpoints like SPECT?

Dr. John Beltrame:           Not SPECT so much, but to follow on exactly what she was saying, we all also measured serum creatine kinase, so CK, values. And because of the larger spread of the data and therefore the need to have a larger sample size, although we certainly saw a trend of improvement in CKs as a marker of infarct size, we didn't achieve statistical significance, but with the MRI because we had more precise measurements, that gave us a smaller margin of error and therefore, we were able to see a difference between the two treatments. So certainly I think in the future, the MRI is certainly a very good way to evaluate agents in this particular area.

Dr. Laura Mauri:               It's nice to see the consistency that you saw across the different endpoints.

Dr. Carolyn Lam:               That's true, but I do have a question though, as an Echo cardiologist here, your three-month assessment of the ventricular remodeling, if I read it right, there was no change detected at three months. Would you like to comment on that?

Dr. John Beltrame:           What we saw in terms of the infarct size, we still saw a difference. I think what you might be referring to, the infarct size was a little bit smaller, so that's just ... over time the we feel like the scar contracts down. But I'm not sure if you're also referring to the ...

Dr. Carolyn Lam:               LV dimensions and injection fraction.

Dr. John Beltrame:           The injection fraction's interesting, because when we looked at that ... because we found no difference in the injection fraction. Now, if you take a look at the actual values, they're almost normal and I think that says something to where we are in terms of the management of acute STEMIs, because we preserved the left ventricular function, because there were normal ejection fractions, so we couldn't make them better than what we had in placebo, so that is something to primary PCI, I think.

Dr. Carolyn Lam:               That's a great answer. Thank you, John. And Laura?

Dr. Laura Mauri:               John, your group is really to be commended for conducting such a high-quality trial in this very challenging area. We've been victims of our own success, I think, in this space because the mortality rates have obviously declined after MI, infarct size is on the decline with early reperfusion. Getting in there with attempted therapies is a race when you're also trying to achieve fast door-to-ballon times, but it's still an important area and one we can only address with careful, randomized trials with important therapies. So I want to congratulate you and your group, it's really a step in the right direction.

Dr. Carolyn Lam:               You've been listening to "Circulation On The Run", thank you so much for joining us, and don't forget to tune in next week!