Carolyn Lam, MBBS, PhD

Circulation May 11, 2021 Issue

Circulation May 11, 2021 Issue

This week is a Double Feature Circulation on the Run. Please join authors Alexander Benz and Lars Wallentin as they discuss their article "Biomarker-Based Risk Prediction With The ABC-AF Scores in Patients With Atrial Fibrillation Not Receiving Oral Anticoagulation." Then, please join author Timothy McKinsey, editorialist Thomas Gillette and Associate Editor Sergio Lavandero as they discuss the article "HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling" and the editorial "HDAC Inhibition in the Heart: Erasing Hidden Fibrosis." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center and Duke National University of Singapore. Dr. Greg Hundley: I'm Dr. Greg Hundley, Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, I cannot get enough of our double features, and this one's really nice because it's a clinical feature and a preclinical feature, and both are just phenomenally interesting. The first is about the ABC-AF scores. In case you don't recognize it, well, then you just have to listen. Very, very important information on biomarker-based risk prediction in patients with atrial fibrillation, not receiving oral anticoagulation. Then we've got a really interesting paper talking about HDAC inhibition and diastolic dysfunction. Interested? Well, listen up. Dr. Carolyn Lam: First, let's talk about some of the papers in today's issue, shall we? I want to start, Greg. You grab your coffee. I need to talk about this first one, which really provides the first extensive genetic and phenotypic landscape of a very important condition, peripartum cardiomyopathy. This is from Dr. Arany and colleagues from Perlman School of Medicine, University of Pennsylvania. What they did is studied 469 women with peripartum cardiomyopathy, who were identified from several US and international academic centers. They acquired clinical information and DNA samples. Next-generation sequencing was performed on 67 genes and evaluated for the burden of truncating and missense variance. Dr. Carolyn Lam: What they found was that women with peripartum cardiomyopathy bear a significantly high burden of loss of function variants in a number of genes, including familiar ones like TTN, FLNC, DSP, and BAG3. The identity and relative abundance of these variants were remarkably similar to that seen in idiopathic dilated cardiomyopathy, indicating that the genetic predisposition to peripartum cardiomyopathy and dilated cardiomyopathy may be one in the same. Now, while peripartum cardiomyopathy patients with the TTN truncating variants presented with lower ejection fraction. No significant differences in the rates of recovery were seen. Dr. Greg Hundley: Really interesting, Carolyn. Clinically, what are the implications today as we see these patients? Dr. Carolyn Lam: Well, I think the most important one is that genetic counseling and testing should, perhaps, be considered for women with peripartum cardiomyopathy, following the guidelines for dilated cardiomyopathy. What about you, Greg? Dr. Greg Hundley: Very nice, Carolyn. Well, my paper evaluates the role of inflammation and outcomes in patients that sustain out-of-hospital cardiac arrest. It comes to us from Dr. Martin Meyer from Rigshospitalet. Carolyn, out-of-hospital cardiac arrest patients who remain comatose after initial resuscitation are at high risk of morbidity and mortality due to the ensuing post-cardiac arrest syndrome. Now, systemic inflammation constitutes a major component of the post-cardiac arrest syndrome and interleukin 6 levels are associated with this severity. The IL-6 receptor antagonists tocilizumab could potentially dampen inflammation after post-cardiac arrest. The objective of the present trial was to determine the efficacy of tocilizumab to reduce systemic inflammation after out-of-hospital cardiac arrest, A presumed cardiac cause, and thereby potentially mitigate organ injury. Dr. Carolyn Lam: Oh, wow. Interesting, Greg. what did they find? Dr. Greg Hundley: Carolyn, they had 80 comatose out-of-hospital cardiac arrest patients and they were randomized 1:1 in a double-blind, placebo-controlled trial to a single infusion of tocilizumab or placebo, in addition to standard of care, including targeted temperature management. The primary endpoint of the study was reduction of CRP response. This was achieved by tocilizumab, as there was a significant treatment-by-time interaction. Systemic inflammation was reduced by treatment with tocilizumab, as both CRP and leukocyte levels were markedly reduced. Now, myocardial injury was also reduced, documented by reductions in CK-MB and troponin T. However, there were no differences, Carolyn, in survival or neurological outcome. So Carolyn, it looks like for those that survive an out-of-hospital cardiac arrest and do experience neurological recovery, there could be cardiac benefits. Dr. Carolyn Lam: Wow, very interesting. I cannot imagine how difficult it must've been to perform such a trial. Thanks, Greg. Well, the next paper demonstrates a new mechanism underlying diastolic dysfunction, and provides theoretical and experimental evidence to explain, perhaps, the ineffectiveness of conventional nitric oxide enhancement trials for HFpEF. And you know, that's my favorite topic. Dr. Greg Hundley: Wow, Carolyn, really interesting. Can you summarize it for us? Dr. Carolyn Lam: Sure. Well, first of all, this comes from Doctors Eom and Kook from Chonnam National University Biomedical Research Center in Korea. These authors used two animal models of diastolic dysfunction, the salty drinking water, unilateral nephrectomy with aldosterone, or SAUNA, model, and a mild transverse aortic constriction model. They also looked at human heart samples from patients with left ventricular hypertrophy. Dr. Carolyn Lam: Together, in very, very elegant experiments, they showed that neuronal nitric oxide synthase was upregulated in diastolic dysfunction, which increases S-nitrosylation and cardiomyocytes, and its pharmacologic inhibition, as well as genetic ablation, alleviated diastolic dysfunction. Now, specifically, protein S-nitrosylation of histone deacetylase 2, or HDAC2, played a critical role in the development of diastolic dysfunction and nitric oxide reduction and the following protein denitrosylation may provide a novel therapeutic strategy for HFpEF. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes from Dr. William Pu from Boston Children's Hospital and looks at reactive oxygen species-mediated CaM kinase 2 activation, and how that contributes to calcium handling abnormalities and impaired contraction in the Barth syndrome. Carolyn, mutations in tafazzin, a gene required for biogenesis of cardiolipin, the signature phospholipid of the inner mitochondrial membrane, causes Barth syndrome. Carolyn, remember that Barth syndrome occurs primarily in males, is associated with cardiomyopathy, a low white count, and recurrent infections, and also skeletal muscle myopathy and short stature. Cardiomyopathy and the risk of sudden cardiac death are prominent features of the Barth syndrome, but the mechanisms by which impaired cardiolipin biogenesis causes cardiac muscle weakness and these arrhythmias are poorly understood. Dr. Carolyn Lam: Oh, Greg, thanks so much for not quizzing me on that one. I was trying to remember what Barth syndrome is, and thanks for the review. Okay, so what did they find? Dr. Greg Hundley: Right, Carolyn. The investigators identified a molecular pathway that links tafazzin mutation to abnormal calcium handling and decreased cardiomyocyte contractility. This pathway may offer therapeutic opportunities to treat Barth syndrome, and potentially other diseases with elevated mitochondrial reactive oxygen species production. Dr. Carolyn Lam: Thanks, Greg. Nicely summarized. Well, let's go through what else there is in today's issue. There is a Perspective piece by Dr. Singh, entitled The Morbidly Obese Patients with Symptomatic Atrial Fibrillation: Why are we Holding Back on Bariatric Surgery? There's an On My Mind piece by Dr. Wenger on the incremental change versus disruptive transformation: COVID-19 and the cardiovascular community. There's also a research letter by Dr. Phillip on cardiovascular evaluation after COVID-19 in 137 collegiate athletes, and it's the results of an algorithm-guided screening. A very interesting piece. Dr. Greg Hundley: Very nice, Carolyn. Well, Carolyn, in the mailbag, I've got an exchange of letters regarding the article Anti-Inflammatory Actions of Soluble Ninjurin-1 and the Amelioration of Atherosclerosis with Dr. Zheng, Jianmin, and Oh. Then finally, Dr. Rob Califf has an On My Mind piece, entitled Avoiding the Coming Tsunami of Common Chronic Disease: What the Lessons of the COVID-19 Pandemic Can Teach Us. Well, Carolyn, I'm really excited. Another double feature Tuesday. How about we turn our attention and move toward those articles? Dr. Carolyn Lam: Yep. Something for everyone in this one. Let's go. Today's feature discussion will sound somewhat familiar if we're talking about the ABC scores. Now, remember that stands for age, biomarkers, clinical history scores, and they're the scores that we use in patients with atrial fibrillation receiving oral anticoagulation, or at least that's the data we have so far. But, what are the utilities of these ABC scores in patients not receiving oral anticoagulation? Dr. Carolyn Lam: Well, guess what? That's what today's feature paper is all about. I'm so pleased to have with us today, the first author, Dr. Alexander Benz, from Population Health Research Institute, McMaster University in Canada, as well as Dr. Lars Wallentin, he's a senior author from Uppsala University in Sweden. Welcome, gentlemen. Alex, if I could start with you, please. A very interesting question and not so easy to answer, could you please tell us a little bit about the background to your study, what you did, and what you found? Dr. Alexander Benz: Sure. Thanks for the opportunity to speak here. The ABC scores have now been shown to outperform clinical risk scores in the setting of patients with AFib receiving oral anticoagulant therapy. But so far, nobody has ever looked at the performance of these scores in patients who are not treated with oral anticoagulant therapy. So here we validated the ABC stroke, bleeding, and death scores in patients with AFib who were not receiving oral anticoagulant therapy. We chose the ACTIVE A and AVERROES trials, where patients were randomized to receive antiplatelet therapy, so aspirin or aspirin plus clopidogrel, for the validation study. We ended up studying the scores and over 4,300 patients who were receiving either aspirin, which were over 3,195 patients, or aspirin plus clopidogrel in about 1100 patients, in these studies. Dr. Alexander Benz: Now, we found that the ABC stroke score was superior to the CHA2DS2–VASc score, yielding a C-index of 0.7. The ABC bleeding score was also better than the currently recommended HAS-BLED score for the assessment of the risk of bleeding, yielding an overall C-index of 0.73. And finally, the ABC-AF death score yielded a C-index of 0.78, which I think is remarkable. Dr. Alexander Benz: Now, as these scores were derived from patients receiving oral anticoagulant therapy, we're not surprised to see that the ABC stroke score underestimated the risk of stroke in this population. And very similarly, the ABC bleeding score overestimated the risk of bleeding in these patients receiving antiplatelet therapy. So these scores, the ABC stroke and bleeding scores, were recalibrated for our prediction of absolute event rates in the absence of oral anticoagulant therapy. Dr. Carolyn Lam: Thanks, Alex. That was a beautiful summary. Now, Lars, if I could ask you, please, could you really highlight to all of us, what is the key thing about validating these scores in patients with atrial fibrillation, but not receiving oral anticoagulation? Dr. Lars Wallentin: I think what people like to have is an estimate of the risk of stroke and the risk of bleeding. If you start them on oral anticoagulation and that has been difficult, we only knew this based on the risk scores on patients that were on treatment. But if we now are using this score, which are also well-calibrated, we can really estimate the absolute risk of a stroke. Let's say, 3% without oral anticoagulation, then how much is it lowered by oral anticoagulation down to 1%? And we can do this on an individual level, because there is a variability between patients and we can identify the risk for an individual patient without treatment, and the risk on treatment, and that can be balanced then against the risk for bleeding on treatment and without the treatment. And thereby, you can get the precise estimate on the risk-benefit ratio for the individual patients. Dr. Lars Wallentin: This is a precision medicine approach, which we think will provide a better treatment with better outcomes for the patients than we have had before. Also, death can be, of course, involved at the final net benefit, with and without treatment. Therefore, we think this is a great step forward, and this cannot be implemented in the real life because we have used biomarkers that now can be available in the routine laboratories. These are NTproBNP and troponin, which are available in all hospitals, and a new marker, GDF-15, a marker that's related to the bleeding risk and that is currently launched by Roche Diagnostics as a new tool. So I think this is a realistic future to improve treatments. Dr. Carolyn Lam: Dr. Lars, I have to tell you, all us editors fully agreed as well, that this is a great contribution, filling an important gap in the literature so far in a very clinically important question when we face the patient who hasn't started anticoagulation. So really, again, thank you both for this study and for publishing with us. A couple of questions, though. It does require these extra biomarkers that come with some, what can I say, cost of needing to measure them if they're not already measured. Could you give us some idea of how much the scores add to what we're used to, the CHA2DS2–VASc and the HAS-BLED score? I don't know, maybe Alex? Dr. Alexander Benz: Sure. I think one downside of the widely-accepted and also often useD clinical scores is that they rely on Arbitrary categorization and dichotomization of clinical variables, and with biomarkers, we have the great advantage of having a continuous tool to assess the risk of outcomes here. And as Lars mentioned, these are mainly the cardiac biomarkers NTproBNP and cardiac troponin, as well as the GDF-15, or growth differentiation factor 15. We think that biomarkers reflect a powerful tool to also reflect underlying subclinical disease, which is very important, I think, in this stratification, and this is probably where much of the superiority of the biomarker-based tool stems from. Dr. Carolyn Lam: Right, thanks. Back to what Lars had said about more precision, which is exactly what the whole of cardiology is, I think, moving towards as well, but it was very, very clever to look for the studies ACTIVE and AVERROES. Hard to think of the population in which you tested this. But weren't the blood samples in these studies very old? Did you then have to remeasure those biomarkers? Were they reliable? Dr. Lars Wallentin: Yes. These were old samples that were taken at entry into the ACTIVE and AVERROES trial. The investigators in Canada were really very clever to save the sample, but the samples have been saved for a decade or more since then. But fortunately, these assays are very stable over time, so all of them, and therefore the results are reliable. The levels are very similar to the ones we get in the real-life setting for samples as the one we have in ARISTOTLE and RE-LY, where the scores were derived. So this seems to be, I think, also an advantage that this can be used for stored samples, and fresh samples. Dr. Carolyn Lam: Thank you for addressing that so nicely. We're running out of time sadly, but I would love to hear, maybe as final remarks, what you think are the overall clinical implications and perhaps the next steps for important studies that need to be done. Maybe I could ask Alex to start first and then Lars can finish? Dr. Alexander Benz: Well, I think the next steps in the ABC score program will depend on potential integration or a combination of scores, which then may guide physicians in whom to treat or even whom not to treat. Withholding anti-platelet therapy in certain very low-risk patients, that's what comes to mind. I know that Lars and his colleagues are performing a randomized controlled trial in Sweden where they're testing the ABC scores in clinical practice against the usual care with the clinical scores. Maybe, Lars, you want to elaborate on this. Dr. Lars Wallentin: Yeah, I think the final step is, of course, a prospective randomized trial showing which are the real benefits. We are randomizing 6,000 patients to conventional care versus precision medicine-based care using the ABC risk scores. Outcomes are death and stroke and bleeding. I hope that we will find usefulness of this also in a prospective trial, which will be the final piece of evidence, of course. Dr. Carolyn Lam: Wow, Lars, that is amazing. Thank you so much for sharing that with us. First time on Circulation on the Run. Well, audience, I'm sure you enjoyed that. Thank you so much, Lars and Alex. Now, hold on tight, we're going on to our next feature discussion. Dr. Carolyn Lam: Oh, I can't wait to get onto this feature discussion. You see, it's actually going to reveal a potential new way to target diastolic dysfunction. My absolute favorite topic. It's a basic science paper. It is incredible. You're going to hear all about its clinical translational potential and significance, and from none other than the corresponding author, Dr. Timothy McKinsey from University of Colorado School of Medicine, and editorialist of a beautiful accompanying editorial, Dr. Thomas Gillette from UT Southwestern, and Dr. Sergio Lavandero, our Associate Editor from University of Chile, San Diego. Thank you so much for being here. Tim, could I get you started off? Recognizing there are a lot of clinicians listening out there, this is an incredible paper. HDAC, I think for some, it will be the first time you've been hearing such a word. Please, please, could you break it down for us what you did and what you found? Dr. Timothy McKinsey: Sure. Thanks, Carolyn, and thanks for inviting me to do this. It's really a pleasure. HDAC, that stands for a class of enzymes called histone deacetylases, and those are also known as erasers of acetyl marks on chromatin. So they're really famous for the regulation of epigenetics or gene expression. But we found that HDACs do a lot of other things in the heart too, by deacetylating both histone and non-histone proteins, and we're just really interested in the therapeutic potential of inhibiting HDAC enzymes for the treatment of heart failure. And, in so doing, we assess their ability to reverse existing diastolic dysfunction in a mouse model of kidney disease and hypertension. Dr. Carolyn Lam: You know what, Tim, I really liked the way you very carefully said that. A mouse model of diastolic dysfunction with preserved ejection fraction, that I think, previously, a lot of people with just very loosely used the word HFpEF for such a model, but I really, really appreciate how carefully you worded that. Could you tell us a little bit about the model and what you found? Dr. Timothy McKinsey: Sure. Yeah, we've been really careful not to call it a model of HFpEF, because it isn't a model of heart failure. It really is a model of isolated diastolic dysfunction and preserved ejection fraction. It's a model that's been used in the literature in the past, where you perform a uninephrectomy in mice, so remove one kidney, and then implant something called DOCA, which is an aldosterone memetic. And over time, these animals develop systemic hypertension that results in cardiac hypertrophy and diastolic dysfunction. Dr. Timothy McKinsey: We were perplexed because we couldn't see any fibrosis in the model. But when we did a deep dive into fibrosis using more sensitive methods than are traditionally used, we did uncover what we're calling hidden fibrosis. We believe that HDAC inhibitors, our data suggests that HDAC inhibitors, can actually block the formation of hidden fibrosis that leads to diastolic dysfunction. Dr. Carolyn Lam: Very nice. If you could just give us a one-line on how will you find this hidden fibrosis? Dr. Timothy McKinsey: We got stuck on that for years, because we did all the traditional assays to measure cardiac fibrosis, mainly picrosirius red stain, and we didn't see anything. But we were fortunate to team up with some really talented collaborators, including Maggie Lam here at the University of Colorado, who is an expert at using mass spectrometry to study cardiac remodeling, and also Luisa Mestroni and Brisa Peña who use atomic force microscopy to look at tissue stiffness. When we teamed up with those investigators, first with Maggie we found that, sure enough, when we used her sensitive mass spec assay to look at extracellular matrix protein expression in the heart, there was really a profound increase in ECM protein expression in this mouse model, even though the staining for fibrosis was negative. That told us that there was this underlying hidden fibrosis. Dr. Carolyn Lam: Oh, that is really interesting. And so it is that form of fibrosis that was actually reversed, perhaps, by the HDAC inhibition, and that's what you showed. Would that be accurate to say? Dr. Timothy McKinsey: Yeah. So the HDAC inhibitor really had this profound ability to block that ECM remodeling, the hidden fibrosis, to the point where initially we thought it was an artifact. We thought maybe there was a mix-up of samples. It wasn't a mix up. It's just that the compound, this inhibitor of HDAC enzymatic activity, really has this amazing ability to block the formation of hidden fibrosis. Dr. Carolyn Lam: Oh, wow. Wow, Tom, I really, really loved your editorial where you put all of this in context and talked a little bit about the translational and clinical potential. Could you maybe share your thoughts here? I love the title by the way, Erasing Hidden Fibrosis. Dr. Thomas Gillette: Thanks. Thanks for that. Yeah, first of all, Tim, it was a really great piece of work, and it's actually really exciting because when we think of this diastolic dysfunction, and really it's the development of HFpEF, I think, that a lot of people are... It's the single most critical unmet need in cardiovascular medicine, is the treatment for HFpEF. That diastolic dysfunction, it's really that stiffness that Tim was measuring with his atomic force microscopy and those changes in ECM that really seemed to be critical, at least in that model. Dr. Thomas Gillette: And we know from other models as well that these underlying changes in fibrosis and stiffness, perhaps in the ECM, play a really important role, not only in the diastolic dysfunction, but also if you think about in strain as well, because I know in our models of HFpEF and this mouse model of HFpEF, we have the two-hit model published that Gabrielle, a Allie developed with Dr. Hale in Nature. It's that strain that we could measure that really seems to correlate well with the heart failure phenotype. And so it begs the question, has he caught a very early change in the ECM that's really critical to the development of this pathology? And is there a way that we could detect it early on in patients? Is there a way we could measure that in patients and really get a sense of who's progressing and how they're progressing? Dr. Thomas Gillette: Then there's a second point, and I mentioned a little bit in the editorial, I didn't go into it too deeply, and that is, it's really intriguing what this might mean for the development of the disease, because the matrix not only is involved in stiffness, but it's also a reservoir for growth factors, it helps recruit inflammatory cells, and inflammation plays a huge role in HFpEF. And so it begs the question, how many of those changes may proceed a lot of that pathology as well? Dr. Carolyn Lam: Wow, Tom, I really couldn't agree more. I made a big deal earlier about agreeing with Tim, calling this a diastolic dysfunction model rather than HFpEF, but I completely agree with you that the implications are for the development of HFpEF, and it needed the begs, the question of how many patients actually have this hidden fibrosis? And we know that in patients with HFpEF, there is a stage of advanced fibrosis where we feel patients don't respond to treatment as well. So have we caught an early phase that may be clinically applicable? I really loved the way you worded that. But finally, with Sergio, could you put it all together and what the editors thought of this paper? Why you invited Tom to write this editorial? And perhaps what next steps are? Dr. Sergio Lavandero: Okay, Tim, this is really a fascinating work. I have a long road, because in Italy, you develop the most important new concept. The new concept, the hidden fibrosis. The second important, originally, most of the HDAC inhibitors were developed for other diseases, originally for cancer. So now we have more data that, probably, this compound can apply to other diseases like cardiovascular disease. It was difficult to convince at the beginning some reviewers about the concept of hidden fibrosis, because it's not traditional. But finally, we asked to another expert to, "Okay, why don't you explain, please, this new technique?" For the future, Tim, what do you think? How can we evaluate hidden fibrosis in patients? Dr. Timothy McKinsey: Ideally, and you would have a non-invasive approach to assessing hidden fibrosis in patients. Obviously I know myocardial biopsies could be analyzed using the mass spec approach and atomic force microscopy, but not everyone is going to want to get a myocardial biopsy. So ultimately, we would like to correlate data that we obtain with biopsies, with circulating factors to see if there is a non-invasive surrogate circulating factor that correlates with the existence of hidden fibrosis. I think that would be very powerful clinically. Dr. Sergio Lavandero: What do you think the specificity of this research, because maybe it's too broad? What do you think? Dr. Timothy McKinsey: Yeah, that's a great point. There's a negative impression of general HDAC inhibition, because people just can't believe that you could inhibit a large number of HDAC enzymes throughout the body and not kill someone. But you can. And in our models you can use pretty low doses of these HDAC inhibitors and see efficacy. But obviously, the holy grail in this field would be to identify specific HDAC isoforms that regulate specific disease processes. So we have an active area of investigation where we're trying to tease apart the roles of different HDACs in the heart, with the ultimate goal of finding the HDAC or a subset of HDACs that regulate in fibrosis. Then you could selectively inhibit those and perhaps have a safer drug than a general HDAC inhibitor. Dr. Carolyn Lam: Thank you, once again. This is an amazing discussion and really, really an example of just the kind of papers we love publishing at Circulation. So novel and with such translational potential. Thank you, Tim, again, and Tom and Sergio. Thank you, audience, for joining us today. From Greg and I, you've been listening to Circulation on the Run. Don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own, and not necessarily those of the editors or of the American Heart Association. For more, visit  

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