Circulation November 7, 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.

In just a moment, we will take a deep dive into the issue of age and its association with outcomes of primary prevention ICDs in patients with non-ischemic systolic heart failure.

Yes, a long-awaited discussion from the Danish trial. That, in just a moment. First, here's your summary of this week's Journal.

The first original paper provides evidence of a true association between disturbed genetic imprinting and Preeclampsia. This paper is from co-first authors, Dr. Zadora, and Dr. Singh, and co-corresponding authors, Dr. Izsvak, from the Max Delbrück Center for Molecular Medicine; Dr. Hurst, from the University of Bath; and Dr. Dechend, from the Experimental and Clinical Research Center of Berlin.

These authors performed an unbiased analysis of genome-wide molecular data on raw characterized patient material, from normal controls, and patients with Preeclampsia, and identified DLX-5 as an imprinted target gene, with novel placental function in Preeclampsia. Due to loss of imprinting, DLX5 was upregulated in 69% of placentas from Preeclampsia patients. Levels of DLX5 correlated with the classical Preeclampsia markers.

DLX5 was expressed in human, but not in urine trophoblast, underlying the known human specificity of Preeclampsia. Finally, DLX5-induced overexpression if trophoblasts faithfully modeled Preeclampsia in a cell culture system. In summary, this paper shows that disturbed imprinting is common, and may play a causal role in Preeclampsia.

The next study affirms that stenosis severity is better discriminated using coronary invasive physiologic indices, than using coronary angiographic assessment. First author, Dr. Lee, corresponding author Dr. Koo, colleagues of Seoul National University Hospital, studied 115 patients with left anterior descending artery stenosis, who underwent both ammonia positron emission tomography, or PET, an invasive physiologic measurement.

Myocardial blood flow measured using PET, and invasively measured coronary pressures, were used to calculate microvascular resistance, and stenosis resistance. They found that both fractional flow reserve, or FFR, and instantaneous weight free ratio, or IFR, decreased as angiographic stenosis severity, resistance, and pressure gradient increased, and hyperemic myocardial blood flow decreased.

When the presence of myocardial ischemia was defined by both low hyperemic myocardial blood flow, and low coronary flow reserve, the diagnostic accuracy of FFR and IFR did not differ, regardless of cutoff values for hyperemic myocardial blood flow, and CFR. However, at any given stratum of a given stenosis, physiologic classification of stenosis severity using FFR or IFR showed better discrimination of a unique relationship between absolute myocardial blood flow, and pressure gradient, than anatomic classification using angiographic percentage.

In summary, by demonstrating coronary physiologic responses to coronary stenosis, these authors showed that stenosis severity is better discriminated, using invasive physiologic indices, than using angiographic assessment.

The next paper identifies a previously unknown angiogenic growth factor that can be enhanced therapeutically to repair the heart after myocardial infarction. This novel growth factor is endoplasmic reticulum membrane complex, Subunit 10, or EMC10, which the authors previously identified by bioinformatic secretome analysis in bone marrow cells.

In the current paper, from co-first authors Dr. [Rabel 00:04:35], and [Krof Clengobill 00:04:37], and corresponding author Dr. Wollert, from Hanover Medical Center, and colleagues, the authors investigated the angiogenic potential of EMC10, and its mouse homologue, in cultured endo fetal cells and infarcted heart explants. They found that EMC10 and its mouse homologue signal a virus, small GTAPases; p21-activated kinase; and p38 mitogen-activated protein kinase, to promote endothelial cell migration.

In mice with acute myocardial infarction, bone marrow derived monocytes and macrophages produced EMC10 endogenously, to enhance infarct vascularization, tissue repair, and heart function. Furthermore, subcutaneous treatment with recombinant EMC10 for one week, after myocardial infarction, augmented infarct vascularization and repair, and led to a sustained improvement in heart function and survival.

The next study is the first prospective randomized trial of screening for atrial fibrillation, with a smartphone-based, single-lead, electrocardiographic system in 1,001 patients, aged 65 years and above, with a CHA2DS2-VASc score of two and above, and without a history of atrial fibrillation.

In this paper, from first and corresponding author Dr. Halcox, from Swansea University Medical School, in the United Kingdom, and colleagues, patients were randomized, either to biweekly electrocardiographic recordings with the iPhone device, or to routine over a 12-month period.

The smartphone-based electrocardiographic approach was at least three times more likely to identify incident atrial fibrillation, than routine care, and at a cost of just over $10,000 per case identified, and was judged to be a highly acceptable approach in this group of patients. These results support consideration of evaluation in an appropriately-powered, event-driven randomized trial, to confirm the clinical and cost effectiveness of such an approach to stroke prevention in atrial fibrillation.

Well, that wraps it up for your summaries. Now for our feature discussion. The Danish trial really created a huge splash last year, when it was reported that a primary prevention ICD in patients with non-ischemic systolic heart failure, may not actually reduce all cause mortality. Something that we had, perhaps, taken for granted, and in fact, entered our guidelines.

Now, however, there was a pre-specified subgroup analysis at the time, that suggested a possible age-dependent association, between ICD and mortality, in the Danish trial. This week, we are so pleased to be discussing an in-depth analysis of the association between age and outcomes in the Danish trial.

I'm so pleased to have the first author of today's featured paper, Dr. Marie Bayer Elming, of Copenhagen, Denmark, as well as Dr. Sana Al-Khatib, who's not only an associate editor of circulation, but also the author of an accompanying, and she is from Duke, Durham, North Carolina. Welcome, ladies!

Dr. Bayer Elming: Thank you. Happy to be here.

Dr. Sana Al-Khatib: Thank you so much.

Dr. Carolyn Lam: Sana, could you start by framing why this paper is so important, and why we've been looking forward in anticipation to these results?

Dr. Sana Al-Khatib: Absolutely. As you know, data on the outcomes of primary prevention ICDs in patients with non-ischemic cardiomyopathy started emerging in the early 2000s, or so. Then in 2005, the sudden cardiac deaths and heart failure trial was published, that included a large number of patients with non-ischemic cardiomyopathy, and absolutely showed survival benefits from primary prevention ICDs in those patients. Of course, there were also patients with ischemic cardiomyopathy.

But really, that trial formed the basis of the guidelines, recommendations, that have informed our practice for the last 12 years, that basically tell us that we should consider implanting a primary prevention ICD in patients with non-ischemic cardiomyopathy, who have an EF of 35% or less, who have Class II or III heart failure symptoms. As long as they are on optimal care at the end, they have a reasonable life expectancy.

So that's what's we've been doing for years, and then, the Danish trial was published this past year, that really called into question the prior findings, and the current practice. Because Danish, as you stated, showed no survival benefit with primary prevention ICDs, but there are many aspects about the trial that people need to pay attention to, to put the results in perspective.

The fact that 58% of patients in the trial, in those arms, received cardiac resynchronization therapy ... the fact that the trial required that patients have an elevated NTproBMB level, to be considered for enrollment ... that may have biased the results toward a higher risk of non-sudden cardiac deaths, so on, so forth.

I think what was really interesting, and caught people's attention, when the paper was published, was this subgroup analysis that showed that younger patients may benefit more than older patients. I think, many of us, Carolyn, were really awaiting the results of a more dedicated analysis, looking at age in Danish, and Dr. Elming and her colleagues did a great job looking at this very closely in their paper, and showed great results, and probably will let Dr. Elming share those results with us.

Dr. Carolyn Lam: Yes, absolutely, Sana. Actually, I just wanted to echo how surprised everyone was, and the immediate thing was, "Oh, my goodness. What do we do with the guidelines?" Maybe we should get back to that later, and Marie, please share with us, what did you do, and what did you find this time?

Dr. Bayer Elming: The reason why we did this study was that, in this main Danish trial, age was the only one of the 13 pre-specified subgroups that had a significant treatment by a subgroup interaction. This suggested that a younger patient might have a survival benefit from ICD ... the implication, even though the overall study was neutral. So we wanted to further investigate this relationship between age and effective ICD implantation.

What we did was to look at the relation between age and effective ICD, and we found that there was this linear relation, for each year of younger age, that was associated with a reduction, a 3% reduction in the hazard ratio, for the benefit of ICD.

Also, we did this selection impact curve, which is a bit technical, but what it does is to describe the expected survival for the population, on as a whole, for the different age cutoffs for ICD treatments.

So, if we take into account, both the patients receiving an ICD, and those who did not, we could see why we would get the highest survival for the population as a whole. What we found was that, when no one in the population received an ICD, around 70% would survive.

If everyone in the population received an ICD, only 72% would survive, but if we chose 70 years as the age cutoff ... so, patients younger than 70 years received an ICD, and patients older than 70 years did not receive an ICD, we got the highest survival for the population, and 75% would survive.

Dr. Carolyn Lam: Thank you, Marie. What important results. So, maybe, still consider ICDs for primary prevention ... in our non-ischemic systolic heart failure, patients were less than 70 years old. Is it as simple as that, Sana? You wrote a beautiful editorial. Tell us, what are the clinical implications?

Dr. Sana Al-Khatib: This is an important question. Danish was an important trial, but in my mind, it truly doesn't refute the role of primary prevention ICDs in patients with non-ischemic cardiomyopathy. As I mentioned earlier, the majority of patients enrolled in Danish received a CRT device. And so, you end up questioning, what does that actually mean, for those patients who are not eligible for cardiac resynchronization therapy?

So, I actually believed that, and as you know, Carolyn, and maybe Marie knows, as well, there have been several meta analyses that have been published, combining data on patients with non-ischemic cardiomyopathy only, and excluding patients with cardiac resynchronization therapy from Danish, that have actually now shown, consistently, a significant improvement in survival, with a primary prevention ICD ... including one that was done by our group.

So, no, I don't think that, based on the results, we should say, "No, we shouldn't be offering primary prevention ICDs to patients with non-ischemic cardiomyopathy," and this beautiful analysis that was done by Marie and her group actually shows that, at least for those patients who are 70 years of age and younger, I think we should absolutely continue to consider them for the therapy, and offer them the therapy, if they're appropriate candidates.

Then, of course, if the patients are older than 70,, and they meet criteria for cardiac resynchronization therapy, I think it will be important for us to be talking to the patients about ... is the RTD with a defibrillator, versus a CRTP only, with a pacemaker, and talking about the pros and cons, and everything else? But in those patients who are older than 70, who don't meet criteria for CRT, I think more research is needed, to really understand the role of primary prevention ICDs in those patients. We definitely need more data there.

Dr. Bayer Elming: I definitely agree that, of course, for the patients older than 70 years were not candidates for CRT treatment. These patients, we do not know very much about 'em, and this study that we did, do not answer that question. Based on the Danish study, and this further analysis of the age inspection, the guidelines in Denmark also state that patients younger than, we say, 68 years, because that was the age cutoff used in the '08 Danish trial, you should definitely think of giving patients with non-ischemic cardiomyopathy an ICD.

But for the older patients, it depends on a variety of co-factors, such as co-morbidity, or frailty, and it should be an individual assessment of the patient. So, I agree with you, Sana.

Dr. Carolyn Lam: That's wonderful. Hey, just one more question. Sana, I'd like you to put on your AE hat, now, and sort of think with me. In circulation, we don't ... well, we're careful about publishing subgroup analyses, so to speak, right, of results. You articulated, in your editorial, reasons why this, perhaps subgroup analysis, may be different from others. Could you elaborate on that a bit?

Dr. Bayer Elming: Yeah, and absolutely, that's a great question. As you pointed out, I mean, you really ... the conventional wisdom in clinical research is to be careful, interpreting subgroup analyses. I think there are some strengths in this particular analysis, as Marie stated: "Here's what we specified." The other thing is, I believe that Marie and her group then came, and did their very robust statistical methods, and really, probably most importantly, if you look at their findings, they actually really align well, and support their main conclusion.

For example, looking at the fact that older patients had the higher presence of co-morbidities, that they had a higher level of [Co-BMP 00:17:00], they had had a longer duration of heart failure ... I mean, all those things most likely had an impact on their mode of death, really making it more likely for those patients to succumb to non-sudden cardiac death. I think the whole story makes a lot of sense.

Dr. Bayer Elming: If I can elaborate a bit on this, I think one of the important findings from the study is that we show that mode of death varied according to age. So, the rates of sudden cardiac death were almost similar, between the younger and the older part of the population. But the rates of non-sudden death were almost twice as high in the older part of the population. This is a really good explanation why the ICD implantations have less impact in the older patients.

Dr. Carolyn Lam: Yeah, because ICDs would definitely not be expected to reduce non-sudden cardiac deaths. Really, really, well put. Oh, thank you so much, Marie. We're so proud to be publishing your beautiful paper, as well as your editorial, Sana, and thank you for this great conversation.

Well, listeners, I'm sure you enjoyed that as much as I did. Thank you for joining us this week, and don't forget to tune in next week.

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