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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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Nov 25, 2019

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

Dr Greg Hundley: And I'm Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature article really starts to look at micro-circulatory dysfunction and abnormal coronary perfusion during exercise that can be associated with myocardial ischemia. I hear you're anxious to hear about it, but why don't we go to your article first.

Dr Carolyn Lam: Here we go. This first paper I'd like to tell you about reports a novel cardiac kinase as a potential regulator in heart failure.

Dr Greg Hundley: Now remind me, Carolyn, I got to take me back a little bit. What are cardiac kinases?

Dr Carolyn Lam: Ah, I thought you would ask. Cardiac kinases are known to play a critical role in the development of heart failure and represent potential trackable therapeutic targets. Now to identify novel cardiac kinases involved in heart failure, the corresponding authors, Dr Hind Lal from University of Alabama at Birmingham and colleagues, employed an integrated transcriptomics and bioinformatics analysis and identified homeodomain-interacting protein kinase 2 or HIP kinase 2, as a novel candidate kinase. Now this is the first study to define the role of HIP kinase 2 in cardiac biology. In essence, they performed a series of mouse experiments that showed that cardiac HIP kinase 2 expression is elevated in adults compared to embryonal and neonatal stage of mouse experiments, but down regulated in failing hearts.

Deletion of HIP kinase 2 in the cardiomyocytes led to decreased cardiac function in adulthood. The cardiac effect of HIP kinase 2 correlated to its gene expression level and impaired ERK signaling was discovered as the main driver of HIP kinase 2 deficient phenotype by enhancing apoptosis. Taken together these findings really suggest that cardiomyocyte HIP kinase 2 is required to maintain novel cardiac function via ERK signaling.

Dr Greg Hundley: All right, Carolyn, my favorite question, what does this mean for us clinically?

Dr Carolyn Lam: Two points, first since HIP kinase 2 is protective in cardiomyocytes, gene therapy using HIP kinase 2 could be a potential therapeutic method of heart failure treatment in future. Secondly, because inhibition of HIP kinase 2 has been proposed as a therapeutic approach for certain cancers and for renal fibrosis, these results suggest that caution needs to be taken for the potential cardiotoxicity of HIP kinase 2 inhibition in the adult heart. Interesting.

Dr Greg Hundley: Yeah. Very nice. Well, I'm going to switch gears a little bit Carolyn and talk about ablation for atrial fibrillation. And the corresponding author of this paper is Jason Andrade from Vancouver General Hospital. In his study, they randomly assigned 346 patients with drug-refractory paroxysmal atrial fibrillation to A, contact force guided RF ablation, B, four-minute cryoballoon ablation or C, two-minute cryoballoon ablation and they followed the patients for 12 months. Now the primary outcome was time to first documented recurrence of symptomatic or asymptomatic atrial tachyarrhythmias, whether that be AFib, aflutter, atrial tachycardia, between days 91 and 365 after the ablation or a repeat ablation procedure at any time. And the secondary endpoints included freedom from symptomatic arrhythmia and AF burden.

Dr Carolyn Lam: Interesting clinical question. What did the results show?

Dr Greg Hundley: One-year freedom from atrial tachyarrhythmia defined by continuous rhythm monitoring, was 54, 52 and 52% with each of those therapies respectively. One-year freedom from symptomatic tachyarrhythmia defined by continuous monitoring was 79, 78 and 73% with those therapies respectively. No difference statistically in either.

Dr Carolyn Lam: Right. No significant difference in those outcomes but what about AF burden or side effects?

Dr Greg Hundley: Right, Carolyn. Well, compared to the pre-ablation monitoring period, AF burden was reduced by a median of 99%, 99.9% and 98.4% in each of the three therapies. No significant difference. And serious adverse events occurred in two patients in the CF-RF group, in six patients in Cryo with four minutes and in seven patients with Cryo in two minutes. Again, no significant difference between those groups.

Dr Carolyn Lam: Greg, were there any significant difference in these techniques?

Dr Greg Hundley: Well, Carolyn, that contact force RF group at a significantly longer procedure duration but a significantly shorter fluoroscopy exposure. And the P was 0.001 versus the cryoballoon group. In summary, in this multicenter, randomized, single blinded trial, contact force RF ablation, and two different regimens of cryoballoon ablation, resulted in no difference in one-year efficacy, which was 53% by time to first recurrence, but 98% burden reduction as assessed by continuous cardiac rhythm monitoring. A new study in patients with ablations looking at these new techniques and for many reasons they're very similar.

Dr Carolyn Lam: Very interesting. My next paper also has to do with atrial fibrillation. Now we know that numerous skills exist for classification of major bleeding events in patients with atrial fibrillation who are anticoagulated. Now there are limited data comparing the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. And so Dr Bergmark from the TIMI study group and colleagues analyzed bleeding outcomes according to the ISTH, TIMI GUSTO and BARC bleeding scales in the ENGAGE AF-TIMI 48 trial of edoxaban versus warfarin. And they found that among patients with atrial fibrillation at risk for stroke, there was an approximately four-fold difference in the frequency of the most severe bleeding events across these commonly used bleeding scales. Further, the relative safety of edoxaban as compared with warfarin tended to increase with greater severity of bleeding.

Dr Greg Hundley: Interesting Carolyn. Tell me, what's the take home message from this study?

Dr Carolyn Lam: This analysis reminds us that the currently available and commonly used bleeding scales differ in important ways. The analysis shows us that one size does not fit all and that the most appropriate bleeding scale really depends on the clinical setting and the intervention being investigated. For patients particularly concerned about bleeding, these results should provide additional reassurance about the safety of the DOX. Finally, this analysis also illustrates how the differential effect of edoxaban compared to warfarin on bleeding, impacts the assessment of net clinical benefit. Now this is discussed in an editorial by John Alexander and Adam Nelson who highlight that one of the most interesting findings was the statistically significant and graded amplification of edoxaban safety compared to warfarin with more severe bleeding.

Greg, perhaps now's a good time, tell us what else is in this issue of the journal?

Dr Greg Hundley: Happy to do so. Ben Freedman from the University of Sydney discusses in a white paper concurrent thoughts from the AF, another atrial fibrillation paper, AF screen international collaboration, which summarizes existing evidence and knowledge gaps on searching for an AFib post-stroke using ECG monitoring. And Carolyn, our own James de Lemos suggests in an on my mind piece that subdividing type two MI into different based on etiology could lead to improved forecasting of events. In a perspective article, Tommy Wang from Vanderbilt revisits the polypill and discusses why we need population-based approaches in the precision medicine era.

Dr Carolyn Lam: Wow. Super interesting. And how about letters? What's in the mailbox?

Dr Greg Hundley: Oh gosh, Carolyn. It's really full this week. There are multiple letters ranging from science, to responses, to prior inquiries. It is really interesting to read these responses and the authors going back and forth and having that open discussion for us. And so Brody Slostad first has his own research letter that reviews unicuspid aortic valves, the demographics, comorbidities, and echocardiographic features and long-term outcomes. Darren Casteel from UC San Diego discusses blood pressure lowering by the antioxidant resveratrol is counterintuitively mediated by oxidation of the cyclic GMP dependent protein kinase. And there's a nice response by Dr Joseph Burgoyne from Kings College London. Finally, there's a letter by Daxin Wang and his associates from Yangzhou University regarding the article targeting filament A reduces macrophage activity in atherosclerosis and there's a corresponding response from Levent Akyürek event accurate from the Institute of Biomedicine. Great mailbox this week, Carolyn. How about now we go on to our feature discussion?

Dr Carolyn Lam: Oh boy, I can't wait. Thanks Greg.

How does coronary microvascular dysfunction relate to exercise physiology or inducible myocardial ischemia? Well, we are going to be talking all about that in the next few minutes and that's because our feature paper this week is the first study to really directly assess coronary blood flow during exercise in patients with microvascular dysfunction. And to compare these changes with high resolution perfusion imaging. We're really pleased to have with us the first and corresponding author, Dr Divaka Perera from Kings College London, as well as our associate editor Dharam Kumbhani from UT Southwestern. Welcome gentlemen and Divaka. Could you start by telling us what makes your study unique? What did you do? What did you find?

Dr Divaka Perera: As you said, microvascular dysfunction is being recognized as quite a common cause of angina. In fact, about 40% of patients who present to the Cath lab for a diagnosis of angina are found to have nonobstructive coronary artery disease, and a significant proportion of these are thought to have microvascular dysfunction. The definition of microvascular dysfunction has been based on demonstration of impaired coronary flow reserve, but what we haven't known is whether the Cath lab measurements that are made actually correlate with exercise maladaptation. Bearing in mind that these patients experience symptoms during exercise and whether there's actually demonstrable ischemia in these patients who don't have obstructed coronary artery disease. Our study's unique in that we were able to measure directly exercise physiology during cardiac catheterization and we were able to stratify patients upfront on the basis of their coronary flow reserve and then in a blinded fashion assess whether these patients who did or didn't have augmentation of flow reserve had ischemia.

Dr Carolyn Lam: Divaka, could you give us a detailed picture of what that meant? These patients were sitting with catheters and then riding bikes or give us a picture of what you did.

Dr Divaka Perera: Right. This is a setup we've been working on for the last 10 years or so to make sure that we have a reproducible and safe protocol that can be carried out in a Cath lab. A patient who was referred for diagnostic angiography, this may have been the first investigation they were having, or they may have had some form of noninvasive testing beforehand. These patients would undergo angiography via the right radial artery with their arm extended out to the side. And then during angiography when the time was right to assess this condition, they would carry out supine bicycle exercise. And that was a bike that was mounted onto the Cath lab table. During all of this, we would measure intracoronary pressure and flow velocity using this combo tipped wire which could give us distal coronary pressure and Doppler flow velocity and we were able to do this throughout the condition of exercise.

Dr Carolyn Lam: That's cool, but then how did the MRI come in then?

Dr Divaka Perera: Right. The MRI was actually done at a different visit and in that situation, we only carried out vasodilator testing. We also do exercise patients in the MR scanner, but we haven't included any of those data in this current paper. Patients would have two visits at least as part of this research protocol.

Dr Carolyn Lam: Maybe now with that background, tell us what you found.

Dr Divaka Perera: The first and most important finding was that patients are classified in the Cath lab on the basis of a coronary flow reserve below 2.5. The flow reserve threshold of 2.5, actually have demonstrable ischemia on a stress profusion myocardial magnetic resonance imaging scan. 82% of patients in the MVD group, the microvascular dysfunction group had inducible ischemia compared to just 22% of controls. This was mirrored by quantitative myocardial profusion reserve data as well, where the ability to augment overall myocardial blood flow was significantly diminished in patients with MVD. And perhaps most interestingly, their exercise pathophysiology was dramatically different to that of controls.

In the healthy heart, the heart actually becomes more efficient during exercise. We were able to quantify the proportion of accelerating and decelerating waves by carrying out a technique called wave intensity analysis on the data I've just described, on the physiology data that I've just described. And by doing that we were able to quantify the proportion of accelerating waves to decelerating wave energy. In the healthy heart, as we exercise the proportion of accelerating wave energy increases and we've termed that profusion efficiency. Now in stark contrast when you have MVD, the heart actually becomes less efficient and the profusion efficiency decreases. This is a normal finding and really told us that cath lab measurement based on the response to vasodilators seems to identify a population who have maladaptation during exercise and demonstrable ischemia on scanning.

Dr Carolyn Lam: Wow. Dharam, could I now ask you to help frame these results in the context of what's known or not known about microvascular disease?

Dr Dharam Kumbhani: I want to congratulate the Divaka and his group. I think this is very interesting analysis. It's really a new paradigm about what is now understood to be more and more of a common issue. It seems like a lot of work, even for the patient population that was enrolled. And I think done in an incredibly thoughtful way. Having said that, I guess what I'd like to understand as a card carrying interventionalist myself, I imagine that some of this may be perhaps in need of validation. And so do you think that this study and in some of the two distinct phenotypes that you describe that this will need to be demonstrated in other labs and other situations?

Dr Divaka Perera: Absolutely. I think we have demonstrated is a proof of concept that we can assess these patients in the Cath lab and then shown that firstly, the measurement of CFR and the classification of patients on the basis of CFR does identify a group with distinct pathophysiology, but that that doesn't tell the whole story because your CFR can be diminished for one of two broad reasons. That there's an abnormality of resting flow or an abnormality of hyperemic or flow at maximum stress. Now, the traditional paradigm of microvascular dysfunction has been that these patients will all have, or the majority will have, diminution of stress flow. Or that they might have an inability to reduce their microvascular resistance during stress.

What we have found in contrast is that actually two thirds of patients who have impaired flow reserve have impaired flow reserve because of an abnormality of rest perfusion. One third only conform to that traditional paradigm, and this, as you've rightly pointed out, is something that's going to need further investigation. It's very exciting and it might mean that we have a basis on which to try different therapies, for instance. That those therapies might be pathophysiologically stratified, but it needs a lot of work and I'm sure you won't be surprised to know that we've already embarked on that next stage of work to validate and take this forward.

Dr Dharam Kumbhani: Let's say you were able to validate this paradigm and you indeed are able to stratify patients with microvascular disease. What you have defined as a functional and a structural endotype. Do you believe that if this were validated and established further from a diagnostic standpoint in labs across other places, what kind of diagnostic testing do you imagine that this would require?

Dr Divaka Perera: At the most basic level Dharam, I think we need to get interventional cardiologists and any cardiologist doing diagnostic angiography to realize that the finding of unobstructed coronary artery disease isn't the final answer. It actually begins a whole chapter of investigation and if we can at least get people to think about doing a physiology study in a way analogous to what's happened when we find equivocal amounts of coronary artery disease that you'd reach for a pressure wire and do a functional test. If we can introduce that paradigm once we find normal or unobstructed coronary arteries in a patient with classical symptoms, that would be step number one. The next step will be that we'll have across the board a harmonized means of classifying these patients and by looking at microvascular resistance as well as coronary flow reserve, we might be able to identify endotypes that behave differently and need different forms of therapy. Once we've got that in place, then we have a basis to carry out large registries and large trials in a systematic fashion.

Dr Dharam Kumbhani: Let me just clarify that. You don't envision that let's say this all gets validated. Do you envision that labs that do CFR measurements would then in addition need to have the ability to do exercise testing as well?

Dr Divaka Perera: No, I don't think so. I think exercise testing requires a really carefully evolved set up and it's not practical to unleash this onto world at large. But it generates hypotheses and examines concepts which can then be translated. I think routine use of microvascular function testing will rely on response to vasodilators and these will be endothelium independent techniques such as an adenosine and possibly as a second stratum, endothelium dependent methods as well. Perhaps using graded acetylcholine infusions. But it would be vasodilator testing in the Cath lab rather than exercise.

Dr Dharam Kumbhani: Got it.

Dr Carolyn Lam: Fascinating. Wait, Divaka, just to be sure that the audience got this. You talked about the two endotypes, a structural and functional and the structural one is the one that has a low flow to begin with. The functional is the one that the hyperemic flow is the one that's mainly impaired. Is that correct? Just checking.

Dr Divaka Perera: Let me just clarify. Those patients that we've termed to have functional MVD have elevated resting flow, but actually essentially normal flow at stress. In contrast, those who have structural MVD have essentially normal resting flow but have an inability to augment their peak flow. The net result appears to be the same in the sense that they all have demonstrable ischemia on noninvasive testing, but the mechanisms are different and therefore the therapies that we direct towards these patients may also need to be different.

Dr Carolyn Lam: Very nicely put. Thank you. And if the audience, you still didn't get that, pick up the paper and read it. But say, one last question because you kind of teased us just now and said, actually we are going on with next steps and so on. What are the next steps? Maybe from you and then Dharam.

Dr Divaka Perera: I think the next step is to assess whether this sort of stratification allows us to treat patients more efficiently. To deliver subtype stratified therapy. And we need to assess this with reference to meaningful clinical outcomes, so quality of life, exercise-based indices, et cetera, before we get onto looking at large numbers and then looking at cardiovascular outcome data.

Dr Carolyn Lam: Great. And Dharam, maybe I'll let you have the closing words.

Dr Dharam Kumbhani: We're understanding a lot more about what is always been an enigma for clinicians as far as having patients who present with very typical symptoms, either stable or unstable symptoms and have no coronary artery disease. I want to congratulate the authors on really trying to dig deeper into this and helping us with this very difficult patient population.

Dr Carolyn Lam: Thank you, Dharam. Thank you Divaka. And thank you listeners for joining us today. You've been listening to Circulation on the Run. Don't forget to tune in again next week.

This program is copyright American Heart Association 2019.

 

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