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Circulation on the Run: April 25

  • Carolyn SP Lam, MBBS, PhD orcid
  • W. Gregory Hundley, MD orcid
  • Peder L. Myhre, MD, PhD orcid
Originally published 10.1161/podcast.20230421.342161

Dr. Greg Hundley:

Welcome listeners to this April 25th issue of Circulation on the Run. I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Peder Myhre:

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

Dr. Greg Hundley:

Peder, today's feature, very interesting. It goes into the world of pediatric friends and explores infantile dilated cardiomyopathy. It's really going to discuss some of the basic preclinical science pertaining to impairment of the organization of the centrosome and how that might be related to children with dilated cardiomyopathy.

But before we get to that feature, how about we grab a cup of coffee, and we discuss some of the other articles in the issue. Would you like to go first?

Dr. Peder Myhre:

Yes, please. Greg, we have a very interesting article regarding AAA to begin with. Concerns have been raised about the long-term performance of aortic stent grafts for the treatment of abdominal aortic aneurysms, in particular, unibody stent grafts.

Only limited data sets are available to evaluate the long-term risks related to these devices. In this retrospective cohort study, named SAFE-AAA, which comes to us from corresponding author Eric Secemsky, from Beth Israel Deaconess Medical Center in Boston, it describes the longitudinal assessment of the safety of unibody aortic stent grafts among Medicare beneficiaries from 2011 to 2017. They used inverse probability weighting to account for imbalances in observed characteristics, and the composite primary outcome was aortic re-intervention rupture and mortality.

Dr. Greg Hundley:

Wow, Peder. It sounds like a really interesting study on abdominal aortic aneurysm. What did they find?

Dr. Peder Myhre:

This is a large study, Greg, and of the 87,163 patients who underwent aortic stent grafting at more than 2,000 U.S. Hospitals, 13.7% received a unibody device. The primary endpoint occurred in 73% of unibody device-treated patients versus 65% of non-unibody device-treated patients during a median follow up of 3.4 years. That use has a ratio of 1.19 with the non-inferiority P-value of 1.00. The authors conclude that unibody endografts fail to meet non-inferiority when compared to non-unibody endografts with respect to aortic re-intervention, rupture and mortality.

Dr. Greg Hundley:

Wow, Peder. So beautifully described and important therapeutic interventional data pertaining to those with AAA.

Well, Peder, my article comes to us from the world of dilated cardiomyopathy. Peder, the Dilated Cardiomyopathy Precision Medicine Study developed Family Heart Talk, and that is a booklet designed to help dilated cardiomyopathy probands communicate genetic risk and the need for cardiovascular screening to their relatives.

Contacting others potentially at risk within a family by probands has traditionally been difficult. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in this multi-center, open-label, cluster-randomized control trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after the probands were enrolled.

Dr. Peder Myhre:

Oh, okay, Greg. This is really a tool to facilitate communication with the hopes of down the road increasing screening for heritable diseases. What did they find?

Dr. Greg Hundley:

Right, Peder. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm. It's 19.5% versus 16%. The odds of screening completion among these first degree relatives were higher in the Family Heart Talk arm after adjusting for proband randomization pertaining to their stratum, sex, and their age quartile. And so Peder, Family Heart Talk, a booklet that can be provided to dilated cardiomyopathy patients by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of patients with dilated cardiomyopathy.

And so now how about we dive into that mail bag, and perhaps I'll go first. There's a nice exchange of letters between Professors McAvoy, Zu, and [Anand] regarding the prior publication entitled Influence of Age on the Diagnosis of Myocardial Infarction.

Dr. Peder Myhre:

Nice, Greg. we also have a research letter by Dr. Paratz with a very clear title, “No Association Between Adult Multiple Cardiac arrest and COVID-19 Vaccination.”

And then finally we have highlights from the circulation family of journals by our own Molly Robbins. In first, she describes the one-year results of a novel variable loop by phasic pulse field ablation catheter on paresis small atrial fibrillation as described in Circulation: A & E (Arrhythmia and Electrophysiology).

Then the hemodynamic profiles of amyloid cardiomyopathies are reported in Circulation: Heart Failure, and then a randomized trial shows the potential impact of community health workers on hypertension control as published in Circulation: Cardiovascular Quality and Outcomes.

And then the association of pericoronary adipose tissue with features of plaque vulnerability is reported in Circulation: Cardiovascular Imaging. Finally, the association of coronary flow reserve among patients with coronary microvascular dysfunction with events as described in Circulation: Cardiovascular Interventions.

Dr. Greg Hundley:

Fantastic, Peder. Well, how about we get on to that feature discussion and learn a little bit more about the relationship between the centrosome and infantile dilated cardiomyopathy.

Dr. Peder Myhre:

Let's go.

Dr. Greg Hundley:

Welcome, listeners, to this April 25th feature discussion, and today we have with us Dr. Chaz (Charles) Hong from the University of Maryland and our own associate editor, Dr. Gabriele Schiattarella from Charité University in Berlin. Welcome, gentlemen.

Well, Chaz, could you describe for us some of the background information that went into your preparation of your study on infantile dilated cardiomyopathy and what was the hypothesis that you wanted to address?

Dr. Chaz Hong:

Thank you very much, first of all, for inviting me here. Infantile dilated cardiomyopathy is a relative rare condition, but among pediatric dilated cardiomyopathy is the most prevalent and has the worst prognosis. While genetic etiology has been suspected, in much of the studies, we really didn't know much about the etiology of infantile dilated cardiomyopathy as an entity on its own. The idea here was that we would use the recently described induced pluripotent stem cell as a patient-derived platform to identify the causal mutations behind infantile dilated cardiomyopathy.

The underlying hypothesis was that even though these have not been previously shown to be clearly genetic, that underlying hypothesis was that there was an underlying contributing factors to this central.

Dr. Greg Hundley:

Chaz, I see you're going to focus on the centrosome. Could you describe for us just a little bit, what is the centrosome?

Dr. Chaz Hong:

It's actually interesting because as a cardiologist I rarely paid attention to centrosome. I didn't even know it existed in cardiomyocytes because, for practical purposes, I thought that heart cells did not need centrosome.

As a background, centrosome, you might have learned it in college biology, where it say, it's the mitotic spindle formation centers. During mitosis, as the chromatids are being separated during mitosis, it serves as a microtubule organizing center that pulls the chromosomes apart during cell division.

And then what happens is that at the end of mitosis, they form a paired organelles. It's comprised of hundreds of proteins that then functions as an organelle zone. In certain organelles, it can also serve as a basal body as a signaling node for primary cilium.

Centrosome is what we think of as vital for cell division, but we're beginning to realize that it has a role in other parts of human biology. In cardiomyocytes, very little is known. There's actually one paper prior showing that centrosome actually breaks apart as cardiomyocytes mature. Early cardiomyocytes, as you know, fetal cardiomyocytes do proliferate, and they do have centrosome that functions as a mitotic spindle organizing centers.

But once the cell division stops, centrosome actually breaks apart and certain components disappear, but certain other components actually go to the perinucleus. That was described as a centrosome reduction, and that is also thought to happen in skeletal muscles as well, but very little was known about that process.

Dr. Greg Hundley:

Very nice. And so, Chaz, what we're going to do here is investigate the role of the centrosome in these patients with infantile dilated cardiomyopathy. Could you describe for us, Chaz, your study design?

Dr. Chaz Hong:

We had a IRB ready for infantile dilated (cardiomyopathy) cases. I worked with Dr. David Bichell at Vanderbilt. He's a pediatric cardiac surgeon. We had an IRB that was ready in case such patient arrived. These are unfortunately very rare, but Vanderbilt was a very large pediatric cardiac surgical center.

I think it was a July 4th the child presented for transplantation. And so we had all the subjects ready, we had all the tools to generate IPS cells from the child's heart. The study design was such that when the heart was ex-planted, we would extract cardiac fibroblasts from these heart tissue. The infants are very small, so we thought that it'd be hard to draw enough blood from each children during surgery.

The study was designed to take the ex-planted heart, dissect it, and start to grow cardiac fibroblasts out from these tissues. These are actually generated from cardiac tissues themselves. And then we reprogrammed them using Yamanaka factors into induced pluripotent stem cells. And then subsequently, we actually turned them into cardiomyocytes so that we could study them and study their structure and function.

Dr. Greg Hundley:

Very nice. And so, Chaz, what did you find?

Dr. Chaz Hong:

We found that the cardiomyocytes generated from this child who had been dying of infantile dilated cardiomyopathy did not shorten as well, so we had an advantage of that. We actually had an EM and the histopathological samples. We knew that this child did not have a functioning Z-disc, and the mitochondrial are very bizarre looking. When we actually generated the IPS cells from this child and compared to wild-type cardiomyocytes, they did not shorten well, and in a lawn of cells they didn't contract at all. They had a predominant loss of Z-disc in the sarcomere.

Sarcomere structure was very disrupted, and the mitochondria were very bizarre looking rather than a very nice kind of meshwork that we see normal mitochondria from normal IPS cells. IPS cells from the child actually had these globular look that we saw also on his heart biopsy.

Dr. Greg Hundley:

Chaz, just to recapitulate here, so you had fibroblast and then converted them to pluripotent stem cells and then differentiated them to cardiomyocytes. Is there a chance that just going through that process would have promoted some of the results that you found as opposed to the fact that we're ascribing your finding to this differentiated cardiomyocyte in and of itself?

Dr. Chaz Hong:

Actually that's a very important point because early on at that time, most of the normal cardiomyocytes, a normal IPS cells would derived from peripheral blood and other tissues. Source of tissue could have been an contributing factor. We didn't know at the time, so to account for that, what we did is that we made IPS cells from this child in three different clones, so three different time points, independent clones. And then we also made normal IPS cells from a variety of individuals to make sure that this wasn't just a technical artifact.

And then what we did was that we used a CRISPR/Cas9 genomic editing technology, and once we found a gene, we knocked out the rotated gene in normal cardiomyocyte from healthy donors, and we showed that now the cardiac function, the sarcomere, and mitochondria disrupted in normal wild-type cardiomyocytes.

And then we also did a gene correction using homology directed repair to correct the mutant gene in this child's IPS cells. We showed that it could correct all the defects of the child's IPS cell-derived cardiomyocytes.

Dr. Greg Hundley:

Beautiful work, Chaz. I mean... Wow, listeners, this just sounds so highly innovative, both from the clinical perspective but also the technical perspective.

Well, Gabriele, in the discussion at the editorial board, many papers come across with innovative preclinical science. What attracted you and all the other editors to this particular paper? And then how do you put these results really in context for describing preclinical science as it pertains to working with patients that have infantile dilated cardiomyopathy?

Dr. Gabriele Schiattarella:

Thank you, Greg. Exactly. Among the many papers that we receive a circulation, Chad's work really struck out for many reason. The first is it addressed a fundamental clinical need, which is infantile dilated cardiomyopathy for which has been said the only option is cardiac transplantation. Chad's work is able to really shed the light on the pathophysiological mechanism, the syndrome, which also at the end of the paper tease upon the possibility of a pharmacological approach in this kind of syndrome, in this kind of disease, which is unprecedented. This was really one of the major strength of the paper.

In addition to that, Chad, and the coworkers and collaborators need to be congratulated with because of the highly investigative approach that they use. They really ask the question, what is the cause of this dialectic cardiomyopathy in this child? They drilled down using a number of mechanisms including IPS-derived cardiomyocyte, as well as lower organisms such as zebra fish and resophilia to identify the causative mutation of this condition in this baby, in this infant.

This is of extreme value, of course, and provides a number of pathophysiological and mechanistic finding that can be exploited for a number of dilated cardiomyopathy of unknown etiology. In finding cardiomyopathy, of course, but also a number of DCM, dilated cardiomyopathies, for which we don't know what kind of gene is caused. Through this kind of approach from cell to organism to human and vice versa can be solved.

Dr. Greg Hundley:

Very nice. Well, Chaz, what do we see is the next study in your arena that you and your group is going to try and address here?

Dr. Chaz Hong:

Thank you, Greg. There are actually two areas that I'd like to pursue. First is how does defects and essential zone protein cause all of the defects we see in this dialectic cardiomyopathy? Namely, we've shown that it may be mediated in part through microtubule network formation. It turns out that we know very little about how microtubule organizes the part cell structure and function.

I'd like to do a very fundamental basic science investigation into how centrosome microtubule network is involved in normal cardiac structure and function. And the second point is that we believe that this is actually just a tip of the iceberg in terms of causes of pediatric dialectic cardiomyopathy.

In fact, we found few more mutations than centrosomes that may be associated with infantile dilated cardiomyopathy. Those, those are the areas that we want to pursue, which suggests that the centrosomes and central components may have a fundamental role in structure and function of heart cells, and mutations or defects in that role can cause pediatric heart failure.

I think that's exciting, and we do have a small molecule that can recover, restore much of the function in this child's structure and function, and to develop those compounds into potential therapeutics would be another area that we would like to pursue.

Dr. Greg Hundley:

Wow, Chaz, absolutely beautiful. Gabriele, what are your thoughts here?

Dr. Gabriele Schiattarella:

I believe, and I think that as Chad has mentioned, investigating the role of centrosome, this so far pretty obscure organelle which serves as the main station of the railway track in the myocytes such as microtubules, can help identify other myocardial disease that pertain not exclusively to genetic cardiomyopathy.

We know the microtubule network is fundamental also for non-genetic form of heart failure. An investigation in this sense addressing what are the major drivers of microtubule disruption, which of course in cardiomyocyte in many form of cardiovascular disease can really be helpful for the whole cardiovascular field, I would say.

Dr. Greg Hundley:

Well, listeners, we want to thank Dr. Chaz Hong from the University of Maryland and Dr. Gabriele Schiattarella from Charité University in Berlin for bringing this elegant preclinical science and really the first study to demonstrate a case of human disease caused by a defect in centrosome reduction. Perhaps future studies aimed at identifying variants in centrosome components may uncover additional contributors to human cardiac disease.

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 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.

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