Nov 28, 2022
This week, please author Gemma Figtree and Associate Editor Nicholas Mills as they discuss the Frontiers article "Noninvasive Plaque Imaging to Accelerate Coronary Artery Disease Drug Development."
Dr. Greg Hundley:
Welcome listeners to this November 29th, 2022 issue of Circulation On the Run. I am one of your hosts, Dr. Greg Hundley, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.
Dr. Peder Myhre:
I am Dr. Peder Myhre from Akershus University Hospital and University of Oslo in Norway.
Dr. Greg Hundley:
Well, Peder this week's feature discussion very interesting. It is a state of the art review and it involves noninvasive plaque imaging and really how we might assess plaques to evaluate whether coronary artery disease is accelerating. Very important information by a large group of clinician scientists that will develop programs that, maybe, can be used in therapeutic drug development.
Dr. Peder Myhre:
That's so interesting, Greg.
Dr. Greg Hundley:
Right. A great group of individuals all put together, but before we get to that interesting feature discussion how about we grab a cup of coffee and start with some of the other articles in the issue? How about this week I go first?
Dr. Peder Myhre:
Go ahead Greg.
Dr. Greg Hundley:
Peder, these authors led by Marianna Fontana from University College London Medical School sought to characterize changes in the clinical phenotype of 1,967 patients with a diagnosis of transthyretin cardiac amyloidosis over the last 20 years enrolled and participating in the National Amyloidosis Center from 2002 to 2021.
Dr. Peder Myhre:
Oh yes, Greg, please. This cardiac amyloidosis we have to learn more about it. Please, tell me what did they find.
Dr. Greg Hundley:
Right, Peder.
First, there's been a substantial increase in the number of patients diagnosed with transthyretin amyloid in recent years. This is associated with greater proportions of patients referred following cardiovascular magnetic resonance imaging and bone scintigraphy scans. Second, transthyretin amyloid patients are often now being diagnosed much earlier in their disease process, as evidenced by a shorter duration of symptoms prior to diagnosis, milder stages of disease, and more favorable structural and functional echocardiographic changes at the time of diagnosis. Then, finally, mortality in these transthyretin amyloids patients has improved substantially in recent times aside from any potential benefits from disease modifying treatment or participation in clinical trials.
Dr. Peder Myhre:
Wow. Greg, over the course of 20 years we have seen some differences in the diagnosis or cardiac ATTR amyloidosis, so what would you say are the take home messages from this paper, Greg?
Dr. Greg Hundley:
Right, Peder.
Transthyretin amyloid is now often diagnosed earlier in the disease process with improved prognosis. I think, more data needed to guide decisions on in whom and when to initiate treatment and then which treatments should be used at each stage of the disease. Peder, along with this article there's an excellent editorial by Doctors Patel and Maurer entitled “The Future for Patients with Transthyretin Cardiac Amyloid is, It's Looking Brighter.”
Dr. Peder Myhre:
Okay. Greg, I'm going to continue in the field of clinical research and this paper actually describes a new ablation technique for ventricular tachycardia. Isn't that exciting?
Dr. Greg Hundley:
Absolutely.
Dr. Peder Myhre:
The paper comes to us from corresponding author Miguel Valderrabano from Houston Methodist Hospital in Texas and is entitled “Substrate Ablation by Multi-vein, Multi-balloon Coronary Venous Ethanol for Refractory Ventricular Tachycardia and Structural Heart Disease.” Ablation of ventricular tachycardia, VT, in the setting of structural heart disease often requires extensive substrate elimination, which is not always achievable by endocardial radiofrequency ablation and epicardial ablation is not always feasible. The left ventricle venous circulation allows vascular access to reach intramural substrates of VT in the context of myocardial infarction or non-ischemic scar, where radiofrequency ablation has limited success. Greg, in this study the authors enroll patients with ablation refractory VT and used phonography and epicardial mapping to perform a double balloon venous ethanol ablation. That is, by blocking flow with one balloon and injecting ethnol via this second balloon.
Dr. Greg Hundley:
Peder, what a beautiful description and very interesting strategy to address this situation.
What did they find?
Dr. Peder Myhre:
Greg, after the venous ethanol ablation vein maps and epicardial maps showed elimination of abnormal electrograms of the VT substrate an intracardiac echocardiography demonstrated increased intramural echodensity at the target lesions of the 3D maps and at one year of follow up VT recurrence occurred in seven patients, which translates into a success rate of 84%. The authors conclude that multi-balloon multi-vein intramural ablation by venous ethanol ablation can provide effective substrate ablation in patients with ablation refractory VT in the setting of structural heart disease over a broad range of left ventricular locations.
Dr. Greg Hundley:
Very nice, Peder. What a beautiful description. Excellent.
Well, this next paper Peder comes to us from the world of preclinical science and these authors led by Professor Christine Sideman from the Harvard Medical School evaluated alpha-kinase 3. Now, alpha-kinase three is a muscle specific protein in which loss of function variants cause cardiomyopathy with distinctive clinical manifestations in both children and adults. At presence the muscular functions of alpha-kinase 3 remain poorly understood, so to address this dilemma these investigators explored the punitive kinase activity of alpha-kinase 3 and the consequences of damaging variants using isogenic human induced pluripotent stem cell derived cardiomyocytes. Mice and human patient tissues.
Dr. Peder Myhre:
Okay, Greg.
This sounds like impressive basic science work, so what did the authors find.
Dr. Greg Hundley:
Right, Peder.
Damaging variance in alpha-kinase 3 encoding an abundant muscle specific protein caused both neonatal and adult onset cardiomyopathies and led to both ventricular dilation and hypertrophy. Now, although alpha-kinase three contain an alpha kinase domain the team showed that it lacks catalytic activity and is really a pseudo kinase. Then finally, Peder, alpha-kinase 3 localizes to both the nuclear envelope of cardiomyocytes and the M-band of the sarcomere where it regulates the expression and localization of myomesins, myomesin 1 and myomesin 2, and additional M-band proteins important for sarcomere protein turnover.
Dr. Peder Myhre:
That is a beautiful summary, Greg. Since you did so well at summarizing this difficult topic, I'm not going to ask you what a clinical implications, but rather to take home messages here.
Dr. Greg Hundley:
Very nice. Glad you asked Peder.
First, alpha-kinase 3 cardiomyopathy may cause impaired contractility and ventricular dilation due to miss localization and dysregulation of myomesin proteins which are critical for force buffering in cardiomyocytes. Next, alpha-kinase 3 cardiomyopathy may cause hypertrophy due to dysregulation of key M-band proteins, which are important for sarcomere protein turnover. Then finally, therapeutic strategies to restore cardiomyocyte force buffering functions and sarcomere protein turnover may ameliorate disease phenotypes in patients with alpha-kinase three cardiomyopathy.
Dr. Peder Myhre:
Thank you Greg.
The next paper is also from the field of preclinical science and it is about the Hippo-YAP signaling pathway which maintains sinal atrial node homeostasis. It comes to us from the corresponding author Jun Wang from the University of Texas Health Science Center at Houston. Greg, this paper is not about hippos, but it is about the Hippo signaling pathway, which is known to control organ size and growth in animals and humans. These authors sought to investigate this pathway in relation to the sinal atrial node, i.e. The sinus node. As you know Greg, the sinal atrial node functions as the pacemaker of the heart initiating rhythmic heartbeats. Despite its importance the sinal atrial node is one of the most poorly understood cardiac entities, because of its small size and complex composition and function. To uncover the function of Hippo signaling in sinal atrial node the authors use knockout mice and a series of physiological and molecular experiments including telemetry, electrocardiogram recording, echochoreography, calcium imaging, immunostaining, ANA scope, quantitative real time PCR, and western blotting.
Dr. Greg Hundley:
Wow, Peder, that sounds like quite an extensive series of experiments. What did they find?
Dr. Peder Myhre:
Deletion of essential Hippo kinases caused increased fibroblast proliferation and fibrosis in the sinal atrial node. They also found evidence suggesting that Hippo signaling regulates calcium hemostasis in pacemaker cells and that may be partially mediated by the regulation of genes and coding key calcium handling proteins such as RYR2. Finally, the demonstrated that deletion of Hippo effectors in the sin atrial node can rescue the defect previously described.
Greg, the take home messages is that Hippo signaling was found to be an important regulator of the sinal atrial node homeostasis and that this provide insights applicable to the treatment of patients with sinus node dysfunction.
Dr. Greg Hundley:
Ah, beautifully done Peder. Beautifully done.
We've got some other articles in this issue. Let me tell you about a Research Letter. It's from Professor Nazer entitled “Targeted Screening for Transthyretin Amyloid Cardiomyopathy in Patients with Atrial Fibrillation.” Then Tracy Hampton has a whole series of cardiology news highlighting first that primary cilia are critical for exercise induced muscle hypertrophy. This is from the proceedings of the National Academy of Sciences. Next, there's a discussion of whole body reperfusion techniques to restore function in pig organs after death, that comes to us from nature. Then lastly, there's a final article scientists identify diverse pathogenic gene variants that lead to heart failure from the journal science.
Dr. Peder Myhre:
Thank you, Greg.
Finally, there is one Perspective piece by Dr. Rajiv Agarwal from Indiana University School of Medicine entitled “Hydrochlorothiazide versus Chlorthalidone: What is the difference?”
Now, let's move on to the feature discussion that I know you are very excited about, Greg, to learn more about the non-invasive plaque imaging in our frontiers of medicine.
Dr. Greg Hundley:
You bet.
Well listeners, welcome to this feature discussion today on November 29th and we have with us Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills from Edinburgh, Scotland. Welcome to you both. Listeners, this is a really interesting feature discussion. It's one of our Frontiers articles that combines where we are in the past, but also where we want to move in the future and a very nice comprehensive review with many articles.
Gemma, can you describe for us the genesis really of this article and what you've been working on?
Dr. Gemma Figtree:
Thanks so much, Greg. Look, I think it's very exciting times at the moment and it's a really important time for all of our community to actually get together in this space. We are driven by trying to make a more efficient process for drug discovery and translation to occur and to basically move into humans in the space of coronary artery disease. We've actually known, obviously, for a long time that the underlying process driving heart attack, but we've not been able to image and treat the actual underlying disease. What this article focuses on is how we actually merge top current technology with policy and approval of drugs. We are very excited about the team of over 20 different institutes around the world trying to work on the best measures of corona artery disease as the disease itself.
Dr. Greg Hundley:
Very nice. Now, help us understand different techniques and why is this a frontier?
Dr. Gemma Figtree:
Look, I think it's a mixture of the fact that, obviously, we're getting great advances in noninvasive imaging techniques that allow us to actually measure plaque burden, but also plaque characteristics. In the case of drug translation this is an absolutely fundamental piece. You can transform a clinical trial where you can look at the underlying pathology and be able to enrich trials or be able to look at the effect of trials of a new drug in humans.
It's really important to acknowledge the fact that humans are really the only animal on the planet that get corona artery disease itself. To be able to translate some of the exciting new drugs that target the plaque itself and work synergistically with some of our agents on cholesterol, and blood pressure, et cetera, we really need to have these measures of coronary artery disease itself. It's a combination of the technology, but also how we apply it to a clinical trial and then how do we work with our regulatory authorities and policy advisors around getting this into humans. We really aiming to try to accelerate the development of drugs that can try to tackle our greatest burden of cardiovascular disease around the world.
Dr. Greg Hundley:
I'm hearing cardiovascular disease, I also heard in their imaging and lots of different modalities, and then I heard regulatory bodies. Are you thinking maybe we need standards?
Dr. Gemma Figtree:
That's exactly right. I think, importantly, whilst there's a lot of exciting technology and a lot of us are pursuing potentially different avenues of this we also need to be able to coordinate and develop a simple and harmonized approach that's able to be applied across the world in an equitable fashion. Whilst we, obviously, have developing exciting new toys we have to make sure that a measure that we want to work with regulatory authorities is able to be applied in all of our countries around the world to make sure that the drug development is applied in an equitable fashion.
Dr. Greg Hundley:
Very nice. Well listeners, next we're going to turn to our associate editor, Dr. Nick Mills. Nick, you evaluate many manuscripts. What attracted you to this particular paper? Also, help us put it in the context of why you think it's a new frontier that is emerging or needs to emerge in cardiovascular disease.
Dr. Nick Mills:
Yeah, thanks Greg.
Three things, the expertise of this group, the focus and novelty of the topic, and the fact that it's a really timely issue Gemma just outlined. Gemma a phenomenal job bringing together people from all over the world to tackle this area that includes imaging expertise, drug development expertise, industry that gives it a very balanced and diverse range of views and marks it out from other reviews that focus on particular imaging modality. Novelty's really important, but timeliness as well. We've seen in the last five years major breakthroughs in the treatment of diabetes and heart failure. But, drug development of coronary heart disease is stalling. I cannot remember the last time I went to a really exciting late breaking trial on a new development for coronary heart disease that has changed the outcomes for patients. We do need to rethink.
Gemma's absolutely right, that requires us to work with regulators to stimulate industry involvement in drug discovery, and delivery, and testing. This is occurring at a time where we've got more fabulous imaging modalities then we've ever had before. Critically, they're noninvasive. They're easy for patients, they're easy for serial testing, and that really opens up many opportunities. It's the fact that it's timely, novel, great expertise, and also really exciting area for cardio of medicine.
Dr. Greg Hundley:
Very nice. Well listeners, we're going to go back to Gemma. Gemma, what do you think are some of the next research studies that we need to perform to support what we're trying to indicate today in this Frontiers article?
Dr. Gemma Figtree:
Yeah. Thanks very much, Greg.
I think, ultimately, the features that need to be taken into consideration for a surrogate endpoint to be approved by our regulatory authorities need to be considered. There are many drug companies, but also individual investigators with ideas of drugs to take forward. What we need to do is make sure for all those studies that we're actually working together and ideally having a harmonized endpoint for use there. I think, working early with regulatory authorities is going to be key.
I think, if you actually, within the tables that are presented in the paper we demonstrate very clearly that these measures of plaque, particularly, the CT coronary angiography measures of low attenuation plaque are pretty ready for consideration by regulatory authorities. I think, agents that we already know work to reduce mortality, such as statins, we know that they actually have direct effects on plaque both from a pathophysiological perspective, but also from these imaging studies. We know that that change in the plaque characteristics and volume predict the outcomes.
In a sense, we've got a fabulous array of data already. In fact, new agents that have come through have also demonstrated effects on these measures. I think, by bringing all of this together in this article we're already in a position to work with regulatory authorities to see what is needed next. I think, listening to that's going to be very important. I do think that the next steps are really going to be working with effectively, I guess, our colleagues to make sure that we don't continue to rapidly advance the measures whilst losing the opportunity to work with regulatory authorities.
In answer your question about the research side of things, I think, as we gather more and more information about this we have to make sure that phase two studies are then linked and we can retrospectively see how they predict the outcomes in phase three studies, but I firmly believe that we're in a position that over the next couple of years we should be able to do harmonized approaches at phase two studies and then as a whole community be able to look at how that predicts outcome and work with our regulatory authorities to get more confidence in these endpoints as key. This is all driven by my clinical observations and interest in people who look up and say, "Why me" when they're having a heart attack? In our community where we're getting very good primary prevention we see up to 25% of our heart attack patients having plaque events and catastrophic heart attacks without those traditional risk factors that would've worn them.
Part of this is also opening up avenues for driving new diagnostic tools that can pick up the disease itself. Picking up... Treating coronary disease as the disease and using that for diagnostic and therapeutic purposes, I think, is a great opportunity to tackle this great burden that we're currently not winning with.
Dr. Greg Hundley:
With the group that you had assembled were there any primary suggestions on how to unite some of these efforts on a global scale? I really liked, very early in our conversation today, you mentioned that and I wondered what this collective you assembled may have suggested.
Dr. Gemma Figtree:
Yeah. Look, I think at the moment it is a collection of experts. I haven't quite figured out the name for such a thing, but we are also working with some of the leading organizations now to try to also make sure we get their auspicing of the concepts and how to best do that. I think, by not coming out of one particular organization and evolving from the members itself, and in particular, having industry and regulatory authorities involve and drug discovery experts right from the beginning has been fantastic. Also, making sure that we have that pragmatic approach and that consideration of equitable access. Particularly, making sure that any phase two trial can be done or enrichment for phase three trial can be applied right around the globe and make sure we get diversity of patients enrolled in these studies.
Dr. Greg Hundley:
Very nice. Coming back to you, Nick, any additional thoughts to build on Gemma's comments here?
Dr. Nick Mills:
Well, to say as someone who's worked in the field of cardiac biomarkers for many years and felt that we could tackle this with the regulators and drug delivery, but I've seen inflammatory biomarkers, lipoproteins come and go without changing. I think, it's just a really exciting opportunity that we now have the ability to phenotype an image, coronary artery disease noninvasively, but a highly specific surrogate endpoint that we've never had before. It's why I'm starting to do research into DT.
Dr. Greg Hundley:
Very nice. Well listeners, we want to thank Dr. Gemma Figtree from Sydney, Australia and our own associate editor, Dr. Nick Mills for bringing us this really provocative Frontiers article highlighting a new strategy. Bringing together regulators, leading researchers, and industry to advance new methodologies and trying to tackle globally how we might address atherosclerosis.
Well, on behalf of Peder, Carolyn, and myself we want to wish you a great week and we will catch you next week on The Run.
This program is copyright of the American Heart Association 2022. 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, please visit ahajournals.org.