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Circulation on the Run


Sep 7, 2021

This week's episode features special Guest Host Mercedes Carnethon, as she interviews author Sung-Min Cho and Associate Editor Marc Ruel as they discuss the article "Cerebrovascular Events in Patients with Centrifugal-Flow Left Ventricular Assist Devices: A Propensity Score Matched Analysis from the Intermacs Registry."

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:

And I'm Dr. Greg Hundley Associate Editor, Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, this week's feature, we're going to look at centrifugal flow, left ventricular assist devices and cerebrovascular events. But before we get to the feature, how about we grab a cup of coffee and jump into some of the other articles in the issue? And maybe how about I go first?

Dr. Carolyn Lam:

All right. I got my coffee.

Dr. Greg Hundley:

So my first paper comes from Professor Dali Luo from Capital Medical University. And it's pertaining to calsequestrin-1. So calsequestrin-1, and calsequestrin-2 isoforms buffer calcium and regulate its release from the sarcoplasmic reticulum of skeletal and cardiac muscle. Human inherited diseases associated with mutations of calsequestrin-1 or 2 include malignant hyperthermia and environmental heat stroke and catecholamingergic polymorphic ventricular tachycardia. However, patients with hypothermia, environmental heat stroke events often suffer from an arrhythmia for which the underlying mechanism remains unknown.

Dr. Carolyn Lam:

Wow. Okay. And what did the current paper do and find?

Dr. Greg Hundley:

Great, Carolyn. So what the authors found, calsequestrin-1, the skeletal isoform of it is indeed expressed in cardiomyocyte sarcoplasmic reticulum for mirroring in human hearts, mostly presenting as a polymeric form and interacting with the ryanodine 2 receptor in ventricles. Second, calsequestrin-1 deficiency cause sinus tachycardia in basal conditions. And this is a novel finding which may be associated with sinus beat regulation and ventricular arrhythmia as an independent arrhythmogenesis if a high concentration of volatile anesthetics are used. Next, these volatile anesthetics and heating to 41 degrees C can directly induce calsequestrin-1 oligomerization, thereby causing enhancement of diastolic calcium leak and premature calcium transience through a reduced regulatory effect of calsequestrin-1 on ryanodine 2 activity. And so Carolyn, this novel mechanism underlying the arrhythmia occurring in patients with malignant hypothermia or environmental heatstroke episodes may provide different strategies for heart disorders as an independent profile in these syndromes. And finally, the finding of calsequestrin-1 confirmational change induced by triggers in those with malignant hyperthermia and environmental heatstroke could lead to novel therapeutic approaches to prevent these types of episodes. And that may also very, very useful in treatment of heatstroke.

 

Dr. Carolyn Lam:

Wow. Thanks Greg. Well, moving from this preclinical world to a very common clinical question of the diagnosis of acute myocardial infarction. Now we know that in patients presenting to the emergency department with symptoms suggestive of an MI, the European Society of Cardiology zero and one hour algorithm is recommended by current ESC NSTEMI guidelines with a class one recommendation. Now, what this does is it combines a very high safety for early rule-out and high accuracy for rule-in allowing a definite triage of about 70 to 75% of patients using the zero in one hour sample.

Dr. Carolyn Lam:

However, what is the most appropriate management of the 25 to 30% of patients who remain in the gray observed zone? So this is the question that the current paper addresses. Now to answer this, we also need some more background that a single center pilot study previously of patients in the observed zone had derived a cutoff of seven nanograms per liter for a zero and three hour high sensitivity cardiac troponin T change to identify patients also eligible for early rule-out or rule-in of NSTEMI. So the current study that we're talking about in today's issue from Dr. Christian Mueller from Cardiovascular Research Institute in Basil, Switzerland, and colleagues, really aimed to externally validate that previously proposed seven nanogram per liter change cutoff, and if necessary derive and internally as well as externally validate some new criteria for these patients in the observed zone of the ESC zero in one hour algorithm.

Dr. Greg Hundley:

Wow, Carolyn, so we're learning a lot about cutoff values and also algorithms here with high sensitivity cardiac troponin T. So what did they find here? Very interested to hear.

Dr. Carolyn Lam:

So in two large prospective multicenter diagnostic studies, they found that the proposed zero and three hour high sensitivity cardiac troponin T change of seven nanogram criteria, unfortunately provided suboptimal safety for ruling out NSTEMI in patients remaining in the observed zone of the ESC zero and one hour algorithm. So this had a sensitivity of only 33% and missed 80 patients with NSTEMI. So they derived their own novel criteria based on zero and three hour samples. And these novel criteria combined a three hour high sensitivity cardiac troponin T concentration of less than 15 nanograms per liter and a zero and three hour absolute change cutoff of four nanograms per liter.

Dr. Carolyn Lam:

And that combination provided a high safety for ruling out NSTEMI in these patients in the observed zone and with a sensitivity of 99% missing only one patient with NSTEMI. Another further thing they found was at a zero and three hour cardiac troponin T absolute change of greater or equal to six nanograms per liter triage, 63 patients, or 11% towards rule-in thus resulting in a specificity of 98%. So in summary, this novel criteria based on zero and three hour sample seemed to balance safety and efficacy well for the further decision making in patients who are remaining in the observed zone after the zero and one hour cardiac troponin T algorithm. Internal validation of these novel criteria and external validation in an independent international cohort showed robustness of performance metrics and further strengthen its possible clinical use.

 

Dr. Greg Hundley:

Very nice, Carolyn. Lots of data there, and hopefully very important clarification on both the zones as well as the cutoff values for using cardiac troponin T. Well, Carolyn, my next paper again comes from the preclinical science world and it's from Dr. Anne Eichmann at Yale University School of Medicine, and it pertains to activin receptor-like kinase 1. And we're going to call that ALK1.

 

Dr. Greg Hundley:

Kinase 1 and we're going to call that ALK1. And it's an endothelial transmenbrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. And loss of function mutations of the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasias, a devastating disorder that leads to arteriovenous malformations.

Dr. Carolyn Lam:

Oh, okay. And what did the authors find?

Dr. Greg Hundley:

Dr. Carolyn Lam, ALK1 mutants displayed defective polarization against the direction of blood flow in capillary and venous endothelium as well as increased integran VEGF receptor 2 mediated P13K activation of YAP/TAZ signaling.

Dr Carolyn Lam:

Okay, Greg, that was super summarized but what are the clinical implications?

Dr. Greg Hundley:

Carolyn, pharmacological integrin inhibition using cilengitide or ATN-161, or YAP/TAZ inhibition using verteporfin, prevented AVM malformation in ALK1 mutant mice. And therefore for this study, the authors revealed that integrin and YAP/TAZ were novel affectors of ALK1 signaling in AVM pathogenesis that might be targeted for AVM treatment in patients with hemorrhagic telangiectasias.

Dr. Carolyn Lam:

Thank you, Greg. Well, let's review what else is in today's issue. There's an exchange of letters between Doctors Amadio and Valentine on cell-free DNA to detect heart allograph acute rejection. There's an AHA Update paper by Dr. Churchwell on preemption, a threat to building healthy, equitable communities. There's a Research Letter by Dr. Merkler on the association between cervical artery dissection and aortic dissection.

Dr. Greg Hundley:

And Carolyn, I've got a paper from Professor Daniels regarding the Clinical Implications of Basic Research getting inside the engine, the myosin modulation of hypertrophic cardiomyopathy and systolic heart failure. And then finally, there's an In Depth piece from Dr. Viskin entitled, “Polymorphic Ventricular Tachycardia: The Terminology, mechanism, diagnosis and Emergency Therapy.”

 

Dr. Carolyn Lam:

Nice. Well, let's go on to our feature discussion. Can't wait.

Dr. Greg Hundley:

You bet.

 

Dr. Mercedes Carnethon:

Welcome to this episode of Circulation on the Run, our podcast where we have an opportunity to talk with the authors of some of the top articles within our journal for a given week. And we've chosen today to focus on a set of articles, one of which is led by Dr. Sung-Min Cho from the Johns Hopkins University. And I'm really excited to have you with us today, Dr. Cho and joining us as well as the associate editor, Dr. Marc Ruel who handled the paper. And my name is Mercedes Carnethon from the Northwestern University's Feinberg School of Medicine. I guess without further ado, welcome to you both and we'll just jump right into it.

Dr. Mercedes Carnethon:

Dr. Cho, I'd love to hear a little bit more about your paper today. What made you choose to pursue this particular topic and what really inspired you?

Dr. Sung-Min Cho:

Thank you so much for the invitation and opportunity to talk today. During my training as a neuro person, I'm a neurointensivist by training and neurologist. I noticed that we are getting a lot of consults for LVAD associated strokes. When I took a closer look at the ENDURANCE trial, very showed really 29.7% stroke rate at two years and a few years later, we had this MOMENTUM 3 trial, which showed HeartMate 3 device had 10% stroke rate at two years. And we realized that a stroke is a major issue in this population and I wanted to study the incidence respecters and outcome of this strokes in LVAD population. However, despite the many observational studies in the past, we were really interested in looking at device specific stroke risk for current continuous flow LVADs and we wanted to look at the device specific risk and prevalence of these patients balancing co-morbidities each cohort. And that's why we conducted this study.

Dr. Mercedes Carnethon:

Great, well Sung-Min, it's not often that as an epidemiologist and cardiovascular epidemiologist that I actually get to talk with neurointensivists and get their insights on the importance of their work. Can you tell me a little bit about what you found and whether it surprised you?

Dr. Sung-Min Cho:

Population, we used the Intermacs registry database. This is well established database as all cardiologists and cardiothoracic surgeons know, and we defined a neurologic adverse event as stroke plus TIA, transient ischemic attack. We used a propensity score matching analysis to assess the association of HVAD with stroke risk, to balance for pre-implant risk factors. And basically after performing propensity score matching, we found that hazard of stroke was higher for patients with HVAD device compared to HeartMate 3. We kind of expected this based on the randomized control trials in the past but there was no head to head comparison between these two cohorts. This study really confirmed our suspicion that HeartMate 3 actually had lower hazard of a stroke compared to HeartMate 3.

Dr. Mercedes Carnethon:

Well, thank you so much. It's a really great explanation. And for those who haven't had a chance to dig into the issue yet, I really encourage you to read the piece. I found it to be very instructive. And I'm interested as well, Mark in your take about what excited you about this piece.

Dr. Marc Ruel:

Well, thank you very much Mercedes and Sung-Min it's really a pleasure to have you with us today. As you know, this has been a very impactful paper and you were very kind to share with us the study around your idea as to why you wanted to evaluate this question but even more than your idea and what led to the completion of the paper are the implications of your paper. And I think it would be great if you shared with us a little bit, what has been the path that your paper has led to and including amongst others, very likely a decision by the Medtronic to pull the HVAD out of market. It's interesting that your data, to my knowledge, correct me if I'm wrong, were presented first at the annual meeting of the Society of Thoracic Surgeons in January, 2021. And again, I want to reiterate that Circulation's very thankful that you chose to send your paper to our journal and we feel that it will give it full justice, like many other journals of would have had but we're really excited to have received your paper and give it the fullest consideration.

Dr. Marc Ruel:

Can you tell us a little bit about the implications and for lack of a better word, the storm that your paper has created in the field and your take on it?

Dr. Sung-Min Cho:

Right. That's a great question. Thank you for that. Like I said, as a neurologist, we see these patients after complication, patients having stroke and then we see these patients and we always wanted, cardiologists and cardiothoracic surgeons and neurologists, we always wondered which device carried more risk for stroke and TIA. And really our group actually worked on many papers in the past looking at single institutional data and also systematic review meta-analysis looking at this topic, but really HeartMate 3 came along a couple years ago, more recent device so we didn't have a lot of data.

Dr. Sung-Min Cho:

So intermex registry really helped since we didn't have a lot of data. So, INTERMACS Registry really provided opportunity for us to look at this specific question, really balancing those two chords to look at the risk of stroke in this HeartMate 3 and HVAD. And when we did that two years ago, we submitted a proposal to INTERMACS, and Dr. Kirklin from UAB, he really helped us to look at this data closely with his statistical team. And we had really a thorough statistical method to perform a propensity matching analysis. And we finally finished the analysis and presented in annual STS meeting in January, and it did really trigger a lot of attention to a lot of academic institutions and people who are practicing LVAD, and after that, when we finally submitted this paper to Circulation, we had to have a lot of discussion in between FDA and the Medtronic and discussing this implication of this paper. When it was finally published in Circulation, we are happy that there's a lot of attention and we made it through.

Dr. Marc Ruel:

Well, thank you, Dr. Cho, and maybe for the listener of this podcast, I would like to reiterate some of the salient points of your paper essentially, and correct me if I'm wrong, over 6,200 patients were included, about roughly 3,000 patients per group comparing the HeartMate 3 versus the HVAD.

Dr. Marc Ruel:

Now, as you alluded to the HVAD is the more ancient device, if you will. So there's a slightly longer follow-up, around 12 months on median, versus nine months with the HeartMate 3. And there's adjustment that has been made for this. And I think to me, really the key finding is that in the early acute phase around implantation, there is no real difference with regards to the risk adjusted incidents of neuro adverse events. However, once you pass the early implantation acute phase, in the chronic stable phase, there starts being really a signal that is detrimental to the performance of the HVAD versus the HeartMate 3. And I think your hazard ratio, correct me if I'm wrong, it's around 5.7 for neuro adverse events.

Dr. Marc Ruel:

So this is a very compelling hazard ratio, even coming out of an observational study with all the careful attention that you provided to adjust for residual confounding, et cetera.

Dr. Marc Ruel:

So obviously this is a very strong finding, but I would like you to perhaps comment on this, the patients are not the same. There's some indication that the HVAD patients may have been a little sicker, more RV dysfunction, more tricuspid regurgitation, higher INTERMACS-1 incidents more often on ECMO prior to an implant. What are your thoughts about this?

Dr. Marc Ruel:

Obviously, you've been very careful and the reader will note in the paper that many attempts have been made to account for those. But please give us your take around that 5.7 hazard ratio for neuro adverse event that you found.

Dr. Sung-Min Cho:

Right? In fact, we were really being careful adjusting those compounders. So we did a propensity matching has a primary analysis, but as you pointed out, as a secondary analysis, we wanted to look at multi-variable logistic regression analysis, looking at multi-hazard analytics. And when we did the secondary analysis, as you said, in the beginning early hazard period, the risk was similar, as time went on in the constant hazard period, the hazard ratio was 5.7 for HVAD compared to HeartMate 3, which gives a much higher risk of stroke and TIA for those patients with HVAD compared to HeartMate 3.

Dr. Sung-Min Cho:

So, that was really convincing to us. Confirming the findings from propensity matching analysis, showing that same findings were consistent throughout the different analysis. As we pointed out, HVAD patients actually were sicker, they had more ECMO, and they had more ventilation requirement or sicker patients INTERMACS level. Those are all carefully balanced in both propensity matching analysis and also multi-hazard analytics. And both of these analysis consistently showed that HVAD carried more risk of TIA and stroke compared to patients with HeartMate 3.

Dr. Mercedes Carnethon:

Thank you so much Sung-Min. You know what excites me as I think about choosing articles for journal clubs, when we're working with our trainees, the propensity matched approach and comparing it directly with what you're getting from multi-variable regression really provides an excellent methodological strategy to be able to generate results from these real world studies where it's not a randomized trial of who received which device, but we're able to yield practical conclusions that are actionable based on these findings when we have these well done analyses. And Marc alluded earlier to the actions that were taken in response to the findings from your study. Can you expand on those just a little bit more?

Sung-Min Cho:

Of course. So I guess, I don't know the real backstory, what was going on behind the scene, but I know for sure that STS leadership and INTERMACS leadership, they had a lot of discussion with the company who made HVAD device and also FDA, and I know that this study, the results of this study contributed to the decision they made back in June, pulling up HVAD device from the market.

Sung-Min Cho:

So I'm glad that this study could contribute to the science and hopefully this will help the patients in the future for device selection. So yeah.

Dr. Marc Ruel:

Sung-Min, I think it's fair to say that your study is probably, if not the most impactful in the field of ventricular assist devices, and I probably would personally think that it is, if not the single most impactful, certainly one of the two or three that are the most impactful. So congratulations to you and your team.

Dr. Marc Ruel:

If you still have a minute or two, I had a couple of more secondary questions?

Dr. Marc Ruel

In your analysis I noted that in the early acute phase, there are some protective predictors, such as performing the LVAD implant by sternotomy, which essentially results in about half of the neuro adverse events that you would otherwise observe. So I was a little intrigued by that. And high volume centers had about 1.8 hazard ratio. I suspect that's probably reflective of baseline risk and more acute illness in those patients coming. But if you have a chance, I'd love to hear your thoughts around this?

Dr. Sung-Min Cho:

Yeah, that's exactly what we thought actually is, initially we thought, hypothesized that surgical volume, the center volume will be associated with lower risk of stroke, but it was the other way around. But as you said, probably higher volume centers were getting sicker patients, so that's the association probably we were getting in the analysis. And we wanted to adjust for surgical techniques, sternotomy versus thoracotomy, and even after adjusting for that, HVAD remained a significant hazard per stroke, which showed in the table two and three, I think in the manuscript.

Dr. Sung-Min Cho:

And if I may, I want to say these couple of things. In the raw number, in the 6.4% of patients actually had TIA and strokes, neurological adverse events in HeartMate 3, at one year based on our study. And the risk goes up with a longer follow-up time of course. Moment3 trials had two-year follow-up, about 10% had stroke. And this is still, after HVAD is taken off the market, still there's a significant risk for stroke in these patients and based on autopsy and MRI studies although there is a very small studies--MRI studies, although they're a very small series, studies looking at MRI'd brains after explantation of LVAD. And it shows actually more than 95% of patients have cerebral micro bleeds, which is a marker for small vessel disease in the brain. I think this is an important issue, and although we show that one device had a lower risk of stroke, still question remains, are these patients have a high risk of stroke? And there is a need for improving biomedical engineering aspect, and I'm sure cardiologists and cardiothoracic surgeons know much better than I do regarding hemo-compatibility, especially for stroke.

Dr. Sung-Min Cho:

There is also a dire need for early detection and intervention for these events to improve the outcome for these patients, because once you have a stroke, the outcome is devastating, right? So I think there needs to be better medical management, neuroprotective agent, as well as neuro- monitoring methods, maybe biomarkers to predict stroke or TIA to come so we can intervene and prevent these really devastating complications.

Dr. Marc Ruel:

Mercedes, if I'm so allowed, I do have one final comment and question.

Dr. Mercedes Carnethon:

Most definitely. This has been delightful, so yes.

Dr. Marc Ruel:

Wonderful. So, first, Sung-Min, I want to thank you for working with us. We at Circulation were interested in your paper. You may recall you and I spoke on the phone offline when the decision to revise was made, and we went carefully over what the editors were anticipating would make your paper even better. And you were very responsive. You and your co-author's team were tremendous. And I think the paper that we have before us is absolutely very, very insightful and very important. And obviously tremendously impactful. So I want to thank you again for that.

Dr. Marc Ruel:

And my question is probably the very difficult question which is in everybody's mind at this point and I would like your take as a neurointensivist. You have someone who you have to care for who has a well-functioning HVAD, two years post implant. What would you recommend in terms of optimization for the prevention of neural adverse events? I realize we don't have all the information, but you are one of the few experts in the world who can probably provide us with a very valid take on this very difficult question.

Dr. Sung-Min Cho:

Yeah, it is indeed a difficult question. And that's what I am, including me a lot of neurointensivists, they are very interested in this topic. I think really, as I alluded before, only detection is really important, but it's really tough because either patients, they cannot get MRI. There's no way to know who's going to have stroke or not.

 

Dr. Sung-Min Cho:

We know that a bacteremia is a huge risk factor for these patients. Whenever they have device infection, dry valve infection, bacteremia, their stroke risk goes up quite a bit. We have a lot of data on that. So we can carefully monitor these patients, follow these patients. There is some data that, within six days from infection, their stroke risk goes quite high up for these patients.

Dr. Sung-Min Cho:

But really, neuro-monitoring and biomarker study, there's so little data on this, but patients who are sick like this, not just LVAD patients but ECMO patients or ICU patients, are close neurologic monitoring and some markers to predict occurrence of a stroke or vascular event. I think that's something we really need to study and look into.

Dr. Sung-Min Cho:

Of course, we have a lot of biomarkers we can pick up from the brain, brain injury markers that we can study, and that has not been done in this space. And there are a lot of opportunities, I think, to look at that. And there's some signal based on Cleveland Clinic data that Randall Starling actually looked into, use of PDE5 inhibitor in this patient population, some protection against the ischemic stroke, and I think that's something also we should look into for neuroprotective agent.

Dr. Mercedes Carnethon:

Thank you so much! This has been such a delightful discussion this morning with Sung-Min Cho, the lead author of the study and the Associate Editor, Marc Ruel who handled it.

Dr. Mercedes Carnethon:

I really appreciate your attention. I hope the listeners enjoyed this episode of Circulation on the Run. Please join us again next time.

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 ahajournals.org.