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ORIGINALLY PUBLISHED September 5, 2023

Circulation on the Run: September 5, 2023

  • Carolyn S.P. Lam , MBBS PhD
  • W. Gregory Hundley , MD
  • Peder L. Myhre , MD, PhD

This week, please join Guest Host Pishoy Gouda, author Kiran Khush, and Associate Editor Maryjane Farr as they discuss the article "Left Ventricular Dysfunction Associated with Brain Death: Results from the Donor Heart Study."

Transcript

Dr. Greg Hundley:

Welcome listeners. Now, we turn a chapter and move into the month of September and we are so delighted to be with you here at Circulation on the Run on this September 5th. I am one of your co-hosts, Dr. Greg Hundley, associate editor director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

I'm Dr. Peder Myhre, a social media editor from Akershus University Hospital, and University of Oslo in Norway.

Dr. Greg Hundley:

Well, Peder, we have a really interesting feature discussion today entitled Left Ventricular Dysfunction and its Association with Brain Death, and it's really the results from the Donor Heart Study, very interesting as we seek organ transplant survival, a very interesting article to address today. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? Perhaps, starting with this September 5th, maybe I could go first. What do you think?

Dr. Peder Myhre:

Sounds great, Greg. Go ahead.

Dr. Greg Hundley:

Very good. Peder in patients with hypertrophic cardiomyopathy, myocyte disarray and microvascular disease have been implicated in adverse events, and recent evidence suggests that these may occur early before the phenotypic expression of the disease. As novel therapy provides promise for disease modification, detection of phenotype pre-development is an emerging priority, so to evaluate their utility as early in disease specific biomarkers, this team led by the senior author, Dr. George Joy from the University College London measured myocardial microstructure and microvascular disease in three hypertrophic cardiomyopathy groups.

The first, was overt disease, either genotype positive and LVH positive. Or genotype negative, the second group, and LVH positive, and subclinical HCM demarcated by being genotype positive and LVH negative. In the three groups, they really explored the relationships of electrical changes in genetic substrate. Peder, all individuals underwent 12 lead ECGs, quantitative myocardial perfusion by CMR, measuring myocardial blood flow, profusion reserve and profusion defects. And then also a very advanced technique entitled cardiac diffusion tensor imaging, measuring a feature entitled fractional anisotropy. In fractional anisotropy, lower values are expected when there's more disarray within the myocardium. Lastly, mean diffusivity reflecting myocyte packing and interstitial expansion. Finally, they measured second eigenvector angle, and that measured the sheet lit orientation within the sheets of the myocardial wall.

Dr. Peder Myhre:

Oh, what an important study within the field of HCM, looking at both these different groups and also using all these measures of microvascular disease and microstructural disease. Very interesting. What did they find?

Dr. Greg Hundley:

Right, Peder, several things. First, using the diffusion tensor imaging in hypertrophic cardiomyopathy, they found evidence of myocardial disarray would be detectable in pathogenic sarcomere mutation carriers, even in the absence of the phenotypic expression of myocardial hypertrophy. Next, these DTI, diffusion tension imaging parameters suggestive of myocardial disarray related to EKG abnormalities in subclinical as well as overt hypertrophic cardiomyopathy. In those with avert disease, the presence versus absence of sarcomere mutation had differing effects on the microstructure and the microvascular function. Peder, in summary, microstructural alteration and microvascular disease occurs in overt hypertrophic cardiomyopathy, but are different in genotype positive and genotype negative patients, both also occur in the absence of hypertrophy and sarcomeric mutation carriers where changes associate also with ECG abnormalities. Peder, very interesting study where this team identified measurable changes in myocardial microstructure and microvascular function are early phenotype biomarkers in this emerging era of disease modifying therapy.

Dr. Peder Myhre:

Oh really, really interesting, all of that. Thank you so much. Now, we're going to move into clinical science and we're actually going to get the results of a randomized clinical trial entitled the CAMEO-DAPA trial. Greg, sodium-glucose co-transporter-2, the SGLT-2 inhibitors reduce risk in patients with heart failure and preserved ejection fraction HFpEF, but the hemodynamic mechanisms underlying these benefits remain unclear. In this study, which was a single center double-blinded randomized placebo controlled trial at the Mayo Clinic sought to determine if treatment with dapagliflozin affects pulmonary capillary wedge pressure, PCWP, at rest and during exercise in patients with HFpEF.

Dr. Greg Hundley:

Wow, Peder. A randomized clinical trial testing the hemodynamic effects of SGLT-2 inhibitors in HFpEF. As you know, boy, Carolyn would love to be here for this. A very hot topic. How did they conduct this study, and what did they find?

Dr. Peder Myhre:

This trial was conducted by corresponding author Barry Borlaug and coworkers at the Mayo Clinic, where they did extensive hemodynamic assessments including right heart catheterization with cardiac hemodynamics measured at rest and during exercise using high-fidelity micromanometers at baseline, and then again, following 24 weeks of treatment with either dapagliflozin 10 milligrams or placebo. In total, Greg, they enrolled and followed 37 patients with a median age of 68 years. 66% were women and 71% were obese. Treatment with dapagliflozin resulted in reduction in the primary endpoint of change in pulmonary artery wedge pressure at rest and during exercise at 24 weeks related to treatment with placebo. The mean difference was 3.5 millimeters of mercury at rest, and 5.7 millimeters of mercury at maximal exercise. Body weight and plasma volume was also reduced with dapagliflozin, so that's the mean 3.5 kilograms reduction and a mean 285 milliliters reduction. However, there were no effects on red blood cell volume or oxygen consumption. Greg, this data provide new insight into the mechanisms of benefit for SGLT-2 inhibitors in HFpEF, showing favorable hemodynamic effects both at rest and during exercise.

Dr. Greg Hundley:

Very interesting Peder, so really discovering that there are hemodynamic effects that may go along with some of these marked findings we've seen, related to the treatment of heart failure, very interesting. Well, we do have also some other articles in the issue. Maybe I can describe a few first, there's an exchange of letters by Professors Aronson and Hong, regarding the article “Disruption of Phosphodiesterase 3A Binding to Circa 2 and How That Increases Circa 2 Activity and Reduces Mortality in Mice with Chronic Heart Failure.”

Dr. Peder Myhre:

Nice. There is a Perspective piece by Dr. Turakhia, entitled “The Epidemic and Data Freezone of Non-Sustained Ventricular Tachycardia, an Unintended Consequence of Digital Monitoring and a Path Forward.” Next, there is the ECG Challenge by Dr. Xiao entitled “Chest Pain, Bundled Branch Block and Wide Complex Tachycardia: is Three a Company or a Crowd?” Finally, Molly Robbins gives us Highlights from the Circulation Family of Journals during July where she will cover, first, the experience with ablations of atrial arrhythmias in patients with atrial switch for transposition of great arteries presented in Circulation: A&E. Next, predictors of stroke among patients with HFpEF but without atrial fibrillation evaluated in Circulation: Heart Failure. Third, the risk associated with an AI-based analysis of biological age derived from ECG with outcomes is reported in circulation, cardiovascular quality and outcomes. And then there's a paper on the impact of diabetes on myocardial fibrosis assessed by cardiac MRI in patients with hypertension, which is explored in Circulation: Cardiovascular Imaging. Finally, Greg, reasons for improvements in TAVR outcomes over time are explored in Circulation: Cardiovascular Interventions.

Dr. Greg Hundley:

Wow, Peder, lots of information in this issue, and of course, Molly does a fantastic job with those summaries. Well, how about now we jump to that feature discussion and review left ventricular dysfunction, associated brain death and results from the Donor Heart Study?

Dr. Peder Myhre:

Let's go.

Dr. Pishoy Gouda:

Hello and welcome to another episode of Circulation on the Run. My name is Dr. Pishoy Gouda and I'm an interventional fellow at the University of Alberta in Edmonton, Canada. I'm very excited to be joined today with Dr. Kiran Khush from the Stanford University School of Medicine and Dr. Maryjane Farr from the University of Texas Southwestern Medical Center. We've got a very exciting paper to share with you today, and it's titled, The Left Ventricular Dysfunction Associated With Brain Death, the Results from the Donor Heart Study. Now, to place this all into context, we're all aware of the incredibly long wait list for heart transplantation and the high mortality that these patients face while waiting for a lifesaving transplant. Despite this, only a third of all potential donor hearts are actually used for heart transplantation.

One of the most common reasons for a potential donor heart being declined is LV dysfunction, which is what we'll be discussing today. Now, to put this in a little bit more context, we're joined with Dr. Farr, who's one of our heart transplant physicians. I was hoping you can share with some of our listeners who might not be familiar with the process. Now, let's imagine you're on service for the heart transplant team and get a call about a potential donor heart. An echocardiogram has been completed that showed moderate LV dysfunction with an ejection fraction of 40 to 45%. Before gleaning additional insights from this paper, what's been your current practice on how to proceed from there?

Dr. Maryjane Farr:

Hi, Pishoy. Hi everybody. This is a hard one because if you've been doing this long enough, you know that probably hearts in the 45 to 50%, even 40% range will probably turn around and be okay for transplant, but it depends on a lot of different factors of the donor. Young donors, traumatic brain injury. We know this from clinical experience that there's probably many of these hearts that we can use, but every now and again, you'll take one of these hearts and it doesn't work all that well. This is a very important clinical question for which there has been very little data about over the years and it meaningfully changes lives If we can get answers to this particular question.

Dr. Pishoy Gouda:

Absolutely. Thanks for joining us. Welcome Dr. Kush.

Dr. Kiran Khush:

Pleasure to be here.

Dr. Pishoy Gouda:

I was hoping you could tell us a little bit about the Donor Heart Study and about this analysis.

Dr. Kiran Khush:

Thank you very much. It's been a saga over many years. This is a study that was funded by the National Institutes of Health, that was conducted from 2015 up through 2021. What we did was, we enrolled over 4,300 donors being considered for cardiac donation at eight organ procurement organizations across the United States. The overall aim of the Donor Heart Study was to establish evidence-based criteria for donor heart selection. As you may know, right now, the process of donor heart acceptance is not standardized, it varies a lot from one center to another, even from one cardiologist or surgeon to another, and so I think that leads to a lot of inconsistencies and a lot of underuse of available donor hearts. In the setting of a national shortage of organs for transplantation, I think we really need to do our best to develop criteria to standardize donor heart selection so that we're using more of the available organs in a safe manner.

One of the first goals of the Donor Heart Study was to take a deep dive into left ventricular dysfunction because we know that LV dysfunction is one of the main reasons why available hearts are not used for transplant. We also know that this is a very common phenomenon that can occur in the setting of traumatic brain injury or neurocardiogenic injury where we get a huge sympathetic surge that occurs in the donor after brain death, that can cause transient cardiac stunning. Previous studies have shown that this process is often reversible, and small case series and anecdotes have shown that these hearts are acceptable to be used for transplant. Previous studies showed that the incidence of LV dysfunction after brain death ranged from about 10 to 45%. One of the main areas of focus of this study was to say, what is the real incidence of left ventricular dysfunction after brain death?

How common is it, and how often is it reversible during the time of donor management? That's why we took very detailed echocardiograms of all the donors enrolled in the Donor Heart Study, and we determined that 13% of donors do indeed have LV dysfunction after brain death. In the donors that had LV dysfunction, we did serial echocardiograms during donor management to look at reversibility, and we found that over 50% of these donors demonstrated significant improvement in LV function just within 24 hours, so from this study, we know that LV dysfunction is common after brain death and it's largely reversible. And then we looked at the outcomes of the recipients of the donors who had LV dysfunction, and we found that they had very good survival after transplant equivalent to the recipients of donors with normal LV function. This suggests that these hearts are perfectly safe to use for transplant.

Dr. Pishoy Gouda:

That's amazing. It's incredibly difficult to do studies in critical care and in the heart transplant setting, so to be able to get this many patients and this quality of data has led us to get some really important answers. Now, what I want to ask is, well, where do we go from here? What's the next question that you have?

Dr. Kiran Khush:

Yeah, I'm hoping that with this data, transplant centers will feel reassured in using donor hearts with LV dysfunction, especially as Jane mentioned, if these hearts come from young donors without a previous cardiac history, the likelihood is that the donors have neurocardiogenic injury, which is highly reversible. Our next step is to actually look at predictors of reversibility of LV dysfunction. If we have a donor with low LV function, can we actually predict which hearts are going to get better during the donor management period? I think that will really inform our decisions about whether to use these hearts for transplant. We're working on developing the prediction models, and then after that, the next step will be to tie in the predictors of how the recipient is going to do after the transplant. If we have the donor characteristics and we have the potential recipient characteristics, can we model the outcomes after transplant? Hopefully, these kinds of models can be used real time by transplant centers to then make decisions about which donor heart to accept for transplant, and ultimately improve and standardize donor heart utilization.

Dr. Pishoy Gouda:

Well, thank you very much, Dr. Kush. Congratulations, this was an excellent paper. I want to bring on Dr. Farr again. You see, many papers come across your desk and I just wanted to ask you first off, what made this paper stand out to you?

Dr. Maryjane Farr:

Well, I remember when it was announced at one of the international transplant meetings that Kiran had been awarded an NIH grant for the Donor Heart Study, and we were all very, very excited for her because this is really, really hard research to do. It's one thing to do database analysis, that's hard and that's important, but to actually get in involved with organ procurement organizations across the country to do a prospective observational study with all this data and all this turmoil. When I looked at the concert diagram for this paper, I immediately understood the inclusions and exclusions and I went boom, boom, boom, and I was right there at the study cohort, but some of the more senior editors looked at this and said, what kind of consort diagram is this?

It just spoke to the complexity of donor management and donor recovery and what transplant clinicians face. Number one, I was really looking forward to it, and then when I saw that it came through to circulation and I was asked to handle it, I was so excited because I actually just really wanted to know the answers. First of all, I read the paper, I was like, so what happened? Well, this is the first I know of many papers that will come from the Donor Heart Study, and so we were pretty delighted to get this one.

Dr. Pishoy Gouda:

That's awesome. Thanks Dr. Farr. Now, I want to ask, now that you've read it, you've seen the results, you've had some time to digest. How is this going to change your practice, and how should this change the heart transplant community as a whole?

Dr. Maryjane Farr:

This is a really, really important question. There is so much donor organ shortage, and part of that shortage, as Kiran has mentioned, is that it's the physicians and surgeons that are turning down these organs, because we don't want to do the wrong thing, we want to make sure that we are giving our potential recipients the best opportunity for a long life, and so we don't want to get this wrong coming out of the gates. To really better understand what donors you can take and what donors you should probably not take is absolutely deserving of intensive study in a longitudinal fashion, with all these opportunities to look at, not just who the donors are and who the recipients are, but then the next question will be donor management. Well, what can you do? What kind of management is both possible? And then important to predict outcomes.

The other thing that's important is, there's 137 adult heart transplant programs across the country, and some of those programs are enriched with very, very experienced transplant physicians and surgeons who've been doing donor selection for a very long time, but some of those centers have very, very junior people who are incredibly smart but don't have 10 years behind their belt or 10 years of mentorship to know what they should take and what donors they shouldn't take. Guidance is absolutely essential here, to say, this is okay to do, to be backed up by guidelines and make this kind of stuff get into the guidelines is really important work and very difficult to do.

Dr. Pishoy Gouda:

Absolutely. Well, thank you very much, Jane, Kiran, and now I'll open it up for any final comments. Do any of you have any other final thoughts or concluding remarks?

Dr. Kiran Khush:

Sure. I really appreciate what Jane said about the difficulty of doing donor research. This is a really complex topic where there's very little oversight of donor research in the US. There's no central body that oversees donor research, so you're often making it up as you go. The OPOs are focused on clinical donor management, which is what they should be focused on. A lot of OPOs don't have dedicated staff to do research, and donors are managed at hundreds if not thousands of donor hospitals around the country.

Implementing a research study in such a broad network is very difficult. And then finally, how do you truly get consent, both from the donor families and also from the potential recipients of these donors for research? I think it's an incredibly complicated space to be doing research. I certainly faced many obstacles along the way with this study, which was observational, but to do an interventional study in donors is even that much more difficult, so I really applaud the people who are actually, as Jane mentioned, doing studies, especially interventional studies during donor management, I think we need a lot more of them, and I hope that over time we'll figure out how to do this and do it right.

Dr. Pishoy Gouda:

Well, thank you again very much, Kiran. Dr. Farr, I'll turn it back to you.

Dr. Maryjane Farr:

Yeah, I wanted to... At the end of the paper, Kiran, in her acknowledgements acknowledged all the donor families out there who not only donated organs of their loved ones, but also participated in the research. I think what's so important here is that we have the highest regard, respect and confidentiality for donors and recipients and to honor their gifts, and while we want to do research and we want to intervene, donor families want to donate and they want to know that they are also participating in the act of saving lives, and so I think it just cannot be understated that all of this research is held with the highest moral intent to respect the confidentiality and the purpose of what's trying to be achieved here in transplantation.

Dr. Pishoy Gouda:

Absolutely, I completely agree. Well, thank you very much for joining us for another episode of Circulation on the Run. We had a great time with Kiran and Maryjane. We'll see you next week. Have a great day, guys.

Dr. Kiran Khush:

Thank you.

Dr. Pishoy Gouda:

Well, thank you for joining us for another episode of Circulation on the Run. We had a great time with Dr. Maryjane Farr and Dr. Kiran Kush. As always, we'll see you next week. Have a great day.

Dr. Greg Hundley:

This program is copyright of the American Heart Association 2023. 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.

Circulation on the Run

Information

Cite As

"Circulation on the Run: September 5, 2023", September 5, 2023.

DOI: 10.1161/podcast.20230905.6639