Circulation September 5, 2017 Issue

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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!

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