Show notes
This week, join authors Maryjane Farr and Josef Stehlik as they discuss their Perspective article "Heart Xenotransplant: A Door That Is Finally Opening." 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 in 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. Dr. Greg Hundley: Well, Carolyn, this week's feature, very interesting, xenotransplantation, where organs from other species are transplanted into humans. And it's a perspective piece. And so, we're going to get a weighted conversation from two different individuals that have a different perspective on the topic. Dr. Greg Hundley: But, before we get to that, how about we grab a cup of coffee, and start with some of the other articles in the issue? Would you like to go first? Dr. Carolyn Lam: Absolutely, Greg. Although man, that is a big hook you just gave us. Xenotransplantation is seriously, seriously, a hot topic. Can't wait to learn more. Dr. Carolyn Lam: But, for this first paper I want to talk about, well, we know that sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing, can identify carriers of pathogenic, or lightly pathogenic, variants. However, to what extent do these variants associate with clinically meaningful phenotypes, and what do we know about variants of uncertain significance? Dr. Carolyn Lam: So to answer this question, Dr. Dan Roden, from Vanderbilt University, and his colleagues, looked at 10 arrhythmia susceptibility genes, that were sequenced in more are than 20,000 participants without an indication for arrhythmia genetic testing in the eMERGE III study, which is a multi-center prospective cohort. Variants, previously designated pathogenic, or likely pathogenic, were identified in 120 individuals, or 0.6% population. And electronic health records revealed an over-representation of arrhythmia phenotypes. Some variants of uncertain significance were also found in individuals with arrhythmias and patch clamping, confirmed reclassification, to likely pathogenic. Dr. Greg Hundley: Really interesting results from this eMERGE III study, Carolyn. So what's the take home message? Dr. Carolyn Lam: As genetic testing becomes more common, the combination of electronic health records and in vitro testing, will help classify variant pathogenicity. Population screening has the potential to identify patients with undiagnosed Mendelian rhythm disorders. However, we need to consider the pros and cons of such an approach. And this is discussed in an accompanying editorial by doctors, Walsh, and Bezzina, and Wilde, from Amsterdam University Medical Center. Dr. Greg Hundley: Very nice, Carolyn. Well, my first paper comes to us from Professor Karl Heusler from the University of Wurzburg. Carolyn, this study was a pre-specified analysis of the anticoagulation using the direct factor Xa inhibitor, apixaban, during atrial fibrillation catheter ablation comparison to vitamin K antagonist therapy, or the AXAFA–AFNET 5 trial. And it randomized 674 patients with atrial fibrillation, in a one-to-one fashion, to uninterrupted apixaban, or vitamin K antagonist therapy, prior to first time ablation, with a goal to assess the prevalence of magnetic resonance imaging detected ischemic brain lesions, and their association with cognitive function, three months after first time ablation, using the continuous oral anticoagulation in patients with paroxysmal atrial fibrillation. Dr. Carolyn Lam: Huh. Nice. So what did they find, Greg? Dr. Greg Hundley: Right, Carolyn. They found that brain MRI detected chronic white matter damage, as well as, acute ischemic lesions, were frequently found after first time ablation for paroxysmal atrial fibrillation, using uninterrupted oral anticoagulation. Including, 27.2% of those receiving apixaban, and 24.8% of those receiving the vitamin K antagonists. So Carolyn, no difference there. MRI detected acute ischemic brain lesions were not associated with cognitive function at three months after ablation. And then, Carolyn, the lower Montreal Cognitive Assessment scores, both before and after ablation, were associated with older age only, highlighting the safety of atrial fibrillation ablation on uninterrupted oral anticoagulation. Dr. Carolyn Lam: Oh, thank you, Greg. Well, my next paper talks about basilar artery occlusion, which we know is a devastating condition without definitive evidence to guide treatment. Now, while we do know that faster treatment times with endovascular therapy is associated with better outcomes in the anterior circulation of the brain. What about this relationship for basilar artery occlusion? See? So that's the question that this paper sought to answer, and it's led by Dr. Smith from University of Calgary in Alberta, Canada, and colleagues. They used individual level patient data from the Get With The Guidelines-Stroke nationwide US registry, prospectively collected from January 2015 to December 2019, and identified 3015 patients with basilar artery occlusion treated with endovascular therapy. Dr. Greg Hundley: Ah, Carolyn. And so what did they find here? Dr. Carolyn Lam: So, here are the results. Treatment of basilar artery occlusion with endovascular therapy, within six hours of last known well, is associated with better outcomes, compared to treatment after six hours. Including, lower odds of mortality and higher odds of reperfusion, independence, and discharge home. Dr. Carolyn Lam: There was a non-linear association between, faster treatment with endovascular therapy for basilar artery occlusion, and better outcomes, with the greatest per hour improvement in outcomes seen within six hours of the last known well. In summary, results indicate that, faster treatment with endovascular therapy may improve outcomes in basilar artery occlusion. Efforts should therefore be made, to optimize workflow, including pre-hospital, inner-hospital, intra-hospital processes, to achieve rapid treatment with endovascular therapy in acute stroke with basilar artery occlusion. Dr. Greg Hundley: Very nice, Carolyn. Well, my next paper comes to us from the world of pre-clinical science. And Carolyn, as we know, pulmonary hypertension can be caused by chronic hypoxia, leading to hyperproliferation of pulmonary arterial smooth muscle cells, and apoptosis-resistant pulmonary microvascular endothelial cells. And then, upon re-exposure to normoxia chronic hypoxia induced pulmonary hypertension in mice, is reversible. So in this study, the authors led by Dr. Christine Veith, from Justus Liebig University in Giessen, aimed to identify novel candidate genes involved in pulmonary vascular remodeling, specifically, in the pulmonary vasculature. Dr. Carolyn Lam: Ah, a very interesting and important topic. So what, or how, did they do this, Greg? Dr. Greg Hundley: Right, Carolyn. So following a microarray analysis, the investigative team assessed the role of secreted protein, acidic, and rich in cysteine, or SPARC, using lung tissue from idiopathic pulmonary arterial hypertension patients, as well as from chronic hypoxic mice. In this experiment, the mice were exposed to normoxia, chronic hypoxia, or chronic hypoxia with subsequent re-exposure to normoxia, at different time points Dr. Carolyn Lam: Okay, so what were the results? Dr. Greg Hundley: Okay, Carolyn, the big drum roll. So the microarray analysis of the pulmonary vascular compartment, after laser micro dissection, identified SPARC as one of the genes down-regulated at all reoxygenation time points that were investigated. Intriguingly, SPARC was vice versa, up-regulated in lungs, during development of hypoxia induced pulmonary hypertension in mice, as well as in idiopathic pulmonary hypertension. Although, SPARC plasma levels were not elevated in pulmonary hypertension. Dr. Greg Hundley: Transforming growth factor, or TGF-beta 1, or hypoxia induced factor to a signaling pathways, induced SPARC expression in human pulmonary arterial smooth muscle cells. In loss of function studies, SPARC silencing enhanced apoptosis, and reduced proliferation. And so Carolyn, in conclusion, these authors provide evidence for the involvement of SPARC in the pathogenesis of human pulmonary hypertension, and chronic hypoxia induced pulmonary hypertension in mice, most probably, by affecting vascular cell function. Dr. Carolyn Lam: Wow. Thanks for that, Greg. Well, let me give a tour of what else there is in today's issue. There's a letter from Dr. Ng on could cardiologists support, improve, the cardiovascular risk of GnRH agonists. There's a Case Series, by Dr. Blumer, on [entitled] Hemophagocytic Lymphohistiocytosis Associated with Endocarditis: A Case Years in the Making." There's a Perspective piece by Dr. Hillis on [entitled], Is Asymptomatic Severe Aortic Stenosis Still a Waiting Game?" Dr. Greg Hundley: And Carolyn, from the mailbag, we have a Research Letter, from Professor McFadyen entitled, Inherited Thrombophilias are Associated with a Higher Risk of COVID-19 Associated Venous Thromboembolism, a Prospective Population Based Cohort Study. Dr. Greg Hundley: Well, now onto that perspective and discussion from two viewpoints on xenotransplantation. Dr. Carolyn Lam: Xenotransplantation. Cool. Let's go. Dr. Greg Hundley: Well welcome everyone, to this feature discussion. And today, we're taking a little bit of a, different tact, and we are going to discuss a perspective piece. As you know, usually we will discuss an original article, but we have a perspective. And we have with us, the two authors that created this perspective. Dr. Jane Farr from UT Southwestern, in Dallas, Texas, and Dr. Josef Stehlik, from University of Utah. Welcome to you both. Dr. Greg Hundley: And listeners, our discussion today is on cardiac xenotransplantation, taking a heart from another species and implanting it in a human subject. So Josef, we'll start with you. Could you tell us a little bit about the history of cardiac xenotransplantation, and what are some of the obstacles that have to be overcome, if we're considering performing this procedure in a patient? Dr. Josef Stehlik: Greg, thank you for that question. The concept of xenotransplantation has been around for a long time, with the biggest attraction being, a large and ideally safe source of organs for our patients. As far as cardiac xenotransplantation, the first human art xenotransplant was done in 1964, in a man with terminal heart failure, who received a chimpanzee heart at the University of Mississippi. Dr. Josef Stehlik: The patient didn't survive the surgery, and the way it was done back then, brought up a number of ethical issues, and other issues as well. And so, the next xenotransplant was not done until 1984, in a neonate with hypoplastic left heart syndrome, at Loma Linda University. You might have heard the term, Baby Fae, before. And this infant survived about 20 days, and so we couldn't consider it, long term success. However, these two first xenotransplant brought up some important issues that would be studied for years to come. And I think, that the biggest lesson was that, the intra-species immune barriers were a formidable obstacle, and that really, new technologies, and then new medications, would probably have to come into the clinical arena, before we could do it again. Dr. Greg Hundley: Very nice. Well listeners, now we're going to turn to our second author on this particular paper. And Jane, can you describe some of the circumstances pertaining to this most recent cardiac xenotransplantation? What transpired, and what's been the outcome with that individual? Dr. Maryjane Farr: Thanks, Greg. And thanks for having us here on this program today. So the circumstance around this particular groundbreaking transplant was such that, there was a critically ill patient. This man who was in cardiogenic shock. Both sides of his heart were not working. He was on life saving temporary mechanical support with VA ECMO. And he unfortunately, despite his cardiogenic shock, he was not eligible for standard allotransplantation. Dr. Maryjane Farr: Part of that story was really about, not meeting standard criteria for organ transplantation, probably just about anywhere, in terms of a long history of, maybe not taking his meds, or taking care of himself. And there's, certain criteria that he didn't fit into. And he actually had been assessed, as I understand it, by a number of programs, before the University of Maryland approached him with this possibility. Dr. Maryjane Farr: One other option that could have been taken, was a mechanical circulatory assist device. But as I say, both sides of his heart were not working, and so really, total cardiac replacement was really his only option. Dr. Greg Hundley: And so Jane, do we know anything about what happened? How did the surgical procedure go? Do we know anything about the outcomes? Dr. Maryjane Farr: This is of course, patient privacy. So what we know is really, what's in the public arena. And it's actually, there's been a lot of transparency, which has been terrific, by the patient, and the family, and the doctors, because this is such groundbreaking information. But this patient was truly critically ill. There was some paperwork done to try to get FDA approval for emergency experimental surgery, with xenotransplantation. And of course, all the research at University of Maryland, and in many other centers, nationally, and internationally, have been done over the years. And so finally, there was an approval to do this, and it was basically a scheduled surgery. Dr. Maryjane Farr: And as I understand it, it went just like any other transplant surgery. There was obviously, a procurement team for the genetically modified pig. There was cold storage of the device. Transport, at least as far as to the next operating room, or however it went. And then, standard implantation, and release of cross clamp, and perfusion. And at least by what you can read about, the heart started to work almost immediately. And then of course, I think that's the easy part. It was really all the intense and multi blockade immunosuppressive therapy, which is really, the challenge of this type of therapy. Dr. Greg Hundley: Very nice. Well, Josef, Jane's alluded to this a little bit, but who would be a candidate for this therapeutic, this form of therapy? Dr. Josef Stehlik: Greg, so that's an excellent question. And I would like to address it. Before I do that, maybe we should also mention, very briefly, a little bit of the science behind the genetically engineered pig, that Jane mentioned. Dr. Josef Stehlik: There were three main things that have been done, and what enabled that is gene editing. And here, I would like to actually mention Dr. Mario Capecchi, who received a Nobel Prize in 2007, for his groundbreaking work at the University of Utah, by describing mouse gene knockout. That has been part of what has been used for engineering, of course, in newer approaches, like CRISPR. Dr. Josef Stehlik: Some of the things that have been done is that, the highly antigenic carbohydrates that pigs have on their cell surface, have been edited out. There have been genes that have been edited out and in, connected to coagulation and compliment, to prevent clotting and bleeding in the organ and the recipient after transplant. Dr. Josef Stehlik: And of course, one thing that it's very relevant also to our COVID pandemic, there has always, with xenotransplantation, been a question. Could there be trans-species infection? And p…
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