Circulation September 12, 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 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.

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