Good morning, everyone, welcome. Just a few announcements, so obviously welcome to HRS 2025. If you've not already done so, please download the HRS mobile app, and then of course scan the QR code so you can participate in the Q&A session, which will be at the end of all of our speakers. I'd like to welcome you to this, you know, very interesting session on LV non-compaction. My name is Karen Austin. I'm from UCSF. And I'm Stephanie Chandler, and I'm from Lurie Children's in Chicago. So I have the pleasure of introducing our first speaker, Lisa De La Fave-Castillo, from Northwestern University, and she'll be discussing the genetics of LV non-compaction. All right, I'd like to thank the organizers for asking me to talk at this session. I'm excited. I think it's going to be fun. All right, so I just have like two brief slides on LV non-compaction and what it is because these people are the experts in it, but I'm the first speaker, so I feel like I have to say something about it. So it's morphologically characterized by prominent tuberculations in the left ventricle. If we, if there's a ratio of non-compact to compacted layers of 2.3, then that's considered to be diagnostic, but they'll have way more to say about it. And it can occur in conjunction with other cardiac disease or in isolation, and I think this is what they're going to get at most is it's currently under debate, discussion in terms of how to characterize it and what to do with it. So moving on to the genetics, which I can talk a lot about. So there are numerous guidelines, statements in terms of genetic testing for inherited cardiovascular disease, specifically for cardiomyopathies. The guidelines say that genetic testing should be offered to all patients diagnosed with all recognized forms of cardiomyopathy. And in terms of LVNC, most of the guidelines, they use a panel appropriate for the cardiomyopathy that's been identified in association with the LVNC phenotype. These are more recommendation practice statements that, again, it says if LVNC is present with cardiomyopathy, yeah, you should consider genetic testing. If you don't have the cardiomyopathy component of LVNC, then maybe let's learn a little bit more, take a family history, figure out if there is some other cardiomyopathy going on in the family. So that's what the practice guidelines say. I will say on the clinical side, yeah, we might do it with or without cardiomyopathy, just saying. So we really do want to learn more about what the instances are when LVNC is occurring. So it's, from a genetic counseling standpoint, we always do a three-generation family history. Again, assess what other forms of cardiomyopathy might be going on in the family, because in about 17% to 50% of patients who have an LVNC phenotype, you're actually going to find a family member with cardiomyopathy. And then, obviously, if you find that, then that's going to steer you more towards probably looking at something genetic going on. So I'm going to give an overview of LVNC genetics. These are, it actually occurs with many different conditions. I'll go into some in more detail. The inheritance is kind of everything all over the place. We can get autosomal dominant, autosomal recessive, X-linked, mitochondrial, you name it, you got it. It can be seen in some neuromuscular disorders, congenital heart disease, chromosomal abnormalities, most common being just nonsyndromic LVNC, cardiovascular only. When we're looking at LVNC in neuromuscular disorders, some of the cases where we can see it is with Barth syndrome, which I'll go into more on the next slide. In some of the more general conditions, we can see it in Duchenne and Becker muscular dystrophy. And, in fact, if you see LVNC in combination with Duchenne, then those boys typically, we can see an increased association with a rapid deterioration of LV dysfunction and higher mortality. Lamin, for amyotrophic muscular dystrophy, for the dominant form, and holdorum. So LVNC in Barth, for those of you who don't know Barth syndrome, it's caused by pathogenic variance in the TAS gene, or the tefazin protein, it's X-linked recessive. Typically these neonates have very severe onset of dilated cardiomyopathy, poor prognosis. They can get transplanted, in which case then you have kind of resolved that cardiac phenotype, but really aggressive management of their cardiomyopathy can greatly improve survival. And typically if these kiddos can get out of that neonatal period, then they tend to have a much better prognosis. Along with the cardiomyopathy, they can also have a skeletal myopathy, dysmorphic faces, learning difficulties. These can be pretty sick kiddos. LVNC can also go with a lot of different congenital heart defects, which I'm not going to name them all. There have been some reports that if people have LVNC in combination with a congenital heart defect post-surgery, they can actually have a poor prognosis, increased post-operative length of stay, adverse outcomes after surgery. So something to consider. It can also go with chromosomal defects. 1p36 deletion syndrome is the most common. LVNC is present in about 23% of these cases. PRDM16, a deletion of that gene, is kind of a newer gene coming on the horizon. That can also go with LVNC, and I'll talk more about that gene in a bit. And then some, what do we see with non-syndromic LVNC? So where we're just seeing that LVNC phenotype. If we do a cardiomyopathy panel, the yield of testing is somewhere around 17% to 41% in those cases. Sarcomere genes are the most prevalent form or the most prevalent cause of non-syndromic LVNC. And Van Waning did a really nice study in 2018 where they looked at 327 non-compaction patients. So they looked at both adults and peds, and 32% of them, they found a pathogenic variant. You'll also see that about 16% were gene negative but have a positive family history. So right, that gets at some of the other genes that haven't quite been identified yet. And then about half were considered to be sporadic. But you'll see as I show later on, those sporadic cases actually still might have an underlying genetic cause. And in this study, the age of diagnosis was certainly younger for those with pathogenic variants. For if we see some of the most common genes, we're talking about sarcomere genes. So the sarcomere is the main kind of component of our muscle cells. That's what causes our muscles to contract and relax and all those proteins that are working together. And so the most common genes are MYH7 titan and MYBPC3 going with LVNC. And then, of course, I talked about PRDM16 as kind of a newer gene on the horizon in association with LVNC. I've also listed out some of those non-sarcomere contributing genes, which there are lots of different types of cardiomyopathy that go with them. I'm going to go into a couple more of these in more detail in another couple slides. So some of the correlations of genetics and adverse cardiac events, again, out of this Van Waning study, they showed that in kids, when you're testing them, if they actually have a cardiomyopathy phenotype in combination with LVNC and a pathogenic variant, those ones are the highest risk for adverse cardiac outcomes. If they don't have a pathogenic variant and the non-compaction is just found incidentally, which can certainly happen, somebody does not go for some reason and they see the LVNC, then those have the lowest risk for adverse cardiac outcomes. In adults, if you have a pathogenic variant, then again, that's more correlating if you have LV dysfunction as having a higher risk for adverse cardiac outcomes. And then if they didn't have a pathogenic variant, it was kind of like, well, there's really no association with LV dysfunction or not. It's just kind of you have this LVNC phenotype of the heart. But the interesting thing that I wanted to come back to is, of the people who had LVNC, a third of those people who didn't report a family history actually have a pathogenic variant. So I don't feel like we can absolutely say no family history, no testing, because we're missing out on a third of those people. So just something to consider. This, I really like this kind of picture from this study that I've been talking about, because it really shows some of the different, can I do this? No. Okay. I don't know how to get the pointer, but some of the different genes that they had focused on and looked at, MYH7 actually had, like, those pathogenic variants had the lowest risk for major adverse outcomes, so I thought that that was interesting. So this is something that you might want to look more at. Other genes that have come on the horizon, which are ones that I would not have thought about, are ion channel genes. Typically we think of, and especially as EPs, right, you think of ion channel as it doesn't associate with cardiomyopathy, although we know that for some ion channels that's not the case, but these two genes are another case where it's proving that point. HCN4 and RYR2 have actually had some association with LVNC, and HCN4, those people who had LVNC and pathogenic variants certainly had more bradycardia. So we're seeing that HCN4 can go with bradycardia, but now we're seeing the LVNC phenotype coming out too. So it's starting to get really interesting in terms of where all these genetics are playing out. Again, this is a different study, but you'll see very similar genes that they were finding in association with LVNC, and about 31 percent had those ion channel genes of HCN4 and RYR2. And then a list of, they were finding even a couple other newer genes that the other study didn't show either. So it's interesting. This was a totally different study where they were starting to assess rare variant burden, and so MYH7, you heard that gene, I was talking about that the last time. This study actually showed that truncating variants in MYH7 are actually having a bit of a higher preponderance in LVNC. Typically truncating variants in MYH7 have not been associated with cardiomyopathy, but now we're starting to see, well, maybe truncating variants are predisposing to LVNC. Same kind of goes for truncating variants in ACTN2 and PRDM16 again. So starting to learn more and more about some of these genes and some of this variant burden. And then this is just a nice graph all the way at the end to show that those truncating variants in MYH7, PRDM16, and ACTN2 have not been associated with any of the other forms of cardiomyopathy except LVNC. So kind of interesting. And then this I actually thought was a really nice summary of all the genes that have had some affiliations with LVNC. So as you can see, there's a lot of them. Typically doing a broad cardiomyopathy arrhythmia panel is going to get you a really nice yield or the highest yield that we have at this point in time of these LVNC genes, and so it's certainly something to consider. And then lastly, I just want to put in one quick plug for those of you who don't do a lot of cardiovascular genetics. If you want to learn more about how to do cardiovascular genetics, myself and a few others at Northwestern University, in combination with Jackson Labs, developed three genetics modules to teach you about genetics and genetic testing, identifying red flags to learn patterns of inherited cardiovascular disease, and then how to interpret positive results, negative results, and variants of uncertain significance. These are free CME, CNE modules that you can take online at your will and learn more about it. And then we also did a cardiogenomic database to give you some guidelines. And that is all I have. This is our fantastic team at Northwestern University of Medicine doing cardiovascular genetics. Thank you so much, Lisa. We're going to save questions for the end, so don't forget to write into the QR code if you have questions or come up to the speaker, to the microphone at the very end. Moving on, it is now my pleasure to welcome Shiraz Muscati from Stanford University, who will be talking about imaging pearls for LV non-compaction. When is it more than hypertrabeculation? Thank you so much. It's a huge honor to be here. It's my first time at HRS. For those of you who don't know me, my name's Shiraz. I'm a cardiologist and imager at Stanford. So this is my first HRS meeting, but it's very impressive. And thank you for having me. I have no significant disclosures. I'll start off the conversation here with a few cases. This first case is a 17-year-old male with no past medical history, referred to cardiology for a murmur. He was an elite athlete and no symptoms with peak exercise. And this is his echo. And as you can see, he certainly has dilated atria. He has an LV which is hypertrabeculated and mildly dysfunctional. You can't see the RVL too well in this particular case. Our second case is a 9-year-old male with a strong family history of non-compaction cardiomyopathy, referenced to the previous talk, a normal ECG. And his echo is not as significant. Normal systolic function, maybe a little bit hypertrophied and hypertrabeculated. And so with those two cases as an introduction, this talk is really going to be focusing on what is abnormal. And so it's a bit of a philosophical talk. And so with that, I'll present to you this piece of philosophy from one of the great philosophers of our time, Obi-Wan Kenobi, that many of the truths we cling to depend greatly on our point of view. So how do we define abnormal? Well, much of the time, we use something like this, a bell curve, right? So we all know that two standard deviations away from normal is what we define arbitrarily as abnormal. Now, that works really well. That works really well in cases where you have a continuum. And at the extremes of that continuum, we'll arbitrarily define something as abnormal. For example, with obesity, with secondary hypertrophy from essential hypertension, et cetera, et cetera. So these sorts of normal states, we're at the extremes of one of these states, you become a disease. That's very clear. And it works really well. However, when we're looking at primary cardiomyopathies, our goal as cardiologists, as electrophysiologists, as imagers, our goal is to identify these abnormalities of inborn genetic molecular myocardial abnormalities. Our goal is to identify these based on the endpoint. So we're playing detective, right? We got to look at the heart. We have to look at their EKG, and we have to somehow intuit whether what we're seeing at the endpoint is worthy of an evaluation to identify an inborn genetic structural problem. And that's a very different thing than going from a continuum to identify a disease. For example, with HCM, you can see here in this study in 2008, the majority of adults with this is actually adults and children with HCM did have abnormal LVMI, abnormal LV mass index. That being said, there's a considerable number of people with HCM who have normal LV mass. They still have HCM. They still have an inborn genetic problem, but they have a normal LV mass. And so this just highlights the challenge that we're faced with. So when we're faced with this challenge, we have to look at not only the measurements and findings of the actual imaging study, but also the indication and the population that we're studying. And then finally, the interpretation and action taken as a result of that imaging study. Each of these two things are just as important as the study itself. So to highlight that point, the other way to say this is that in a gene-positive first-degree family member of someone with a cardiomyopathy, our ability to identify disease in that individual is very good. The positive predictive value of that test is very high because the disease prevalence in that population is quite high. However, if someone is walking in off the street, case number two, innocent, or sorry, case number one, innocent murmur, a kid walks in off the street, the disease prevalence in that population is quite low, ergo the positive predictive value will be quite low, although the negative predictive value will be quite high. And so you have to take these into account when interpreting these imaging studies. Looking at HCM as a comparison to LVNC, HCM genetic disease, genetic diagnosis is as high as 60% in these cases. There's a known pattern of progression of disease, and there's large multi-center, there's a wealth of data looking at the indications for an ICD, looking at outcomes in these disease populations. We know what the classic risk factors are, we know what the atypical risk factors are. There's a wealth of knowledge in that population. By contrast, in LVNC, you've already heard about the genetics in LVNC, maybe up to 40% of cases are positive, but many of those genes are also related to HCM or dilated cardiomyopathy. Very difficult, there's an undulating phenotype in LVNC. So a kid can come in with LV dilation, or hypertrophy, with normal function, with varying degrees of hypertrabeculation, and that phenotype can change over time, and that's been documented in multiple studies. The incidence of arrhythmia and factors associated with outcome are difficult, and I would posit that that difficulty is not just in studying outcomes of that population, but because the baseline diagnosis can oftentimes be in question. It's very clear that LVNC can be associated with an increased mortality when there's abnormal LV ejection fraction when there's standard burden of LVNC. However, if you have apical LVNC, if you have normal ejection fraction, those patients can have a normal lifespan. So these are the three most common criteria. You've all heard of these. The Chin Criteria, the Jenny Criteria, the Stolberger Criteria. In the Chin Criteria, they've described prominent trabeculations that increase from base to apex, a compact to total ratio of less than 0.5. Typically these are measured in diastole, but I will point out that this initial description of the Chin Criteria, there was exactly eight cases of LVNC in that report. So that's what we're making these criteria based off of, eight cases. Well, as you get further on in the criteria, it must get better, right? In the Jenny Criteria, these are typically measured in the parasternal short axis plane. And similarly, they look at the non-compact to compact ratio. They also look at the communication in the intratrabecular space as documented on color Doppler. However, in this report, there was also only eight cases of LVNC. And finally, the Stolberger Criteria, which were published even later, also reports the trabecular to compact ratio, also looks at three prominent trabeculations, looking for perfused intratrabecular spaces, and they looked at actually 50 cases, so a substantially larger cohort, but still only 50 cases of LVNC. They also pointed out that there was actually a high degree of disagreement, or low intra-observer agreements, particularly in cases where image quality was poor. So these criteria exist, they're out there, but they're far from perfect. So since we've discussed poor image quality and criteria for higher levels of imaging, we could look at the MR Criteria, and these were already mentioned. This is a landmark paper published in 2005 from Peterson et al. And in this study, they described a non-compact-to-compact ratio of greater than 2.3 as associated with the clinical diagnosis of LVNC, which sounds great. However, you'll notice, again, only seven patients in this cohort with actually diagnosed LVNC. The other thing that you'll notice is that the non-compact-to-compact ratio in the LVNC cohort went as low as 1.5. And so these criteria, which are designed to be sensitive, right? These criteria are designed to rule out patients without cardiomyopathy and not necessarily rule in everyone with cardiomyopathy, which sounds pretty good. So if you have a high non-compact-to-compact ratio, at least you can be sure that that patient has LVNC in comparison to the patient with the low ratio. However, that's actually not true. So this is one of my favorite papers out there. If there's one paper you're going to look at from this presentation, please take a look at this one. As a result, this came out of the MESA study. As you all may know, the MESA study is this massive cohort of thousands and thousands of patients who are followed continuously across decades. It's actually sort of an update to the Framingham population. And what they found, this is just an offshoot of that cohort, but it's a really interesting study. What they found in that cohort, so patients without hypertension, without other cardiac disease, and who didn't meet any sort of MACE, any sort of outcome, 43% of patients in that cohort met criteria for LVNC in one of eight segments, and 8% in two of eight segments. So even if you're going to say, well, I'm just not going to call it if it's only in one segment, I'm only going to call it in two segments, you're still going to be calling 8% of normal patients with LVNC. So the proposed criteria we've already demonstrated are definitely not sensitive, but they're also not specific for the diagnosis of LVNC. So what do we do? Well, people are leveraging higher level imaging to try to make the diagnosis of LVNC better. This is a study out of Stanford, and what they did is they actually used a semi-automatic algorithm to measure the chamber, the non-trabeculated chamber, the trabeculated chamber, and also the compact myocardium, and say, well, if we have a volumetric understanding of the heart, maybe we can then finally take a step towards identifying disease. And what they found is actually that's true. So when you look at the trabeculated area to non-trabeculated cavity ratio, there was high intra-observer reproducibility and high intra-observer reproducibility. The problem is none of this has actually been correlated with outcome or with a genetic diagnosis of LVNC. So the potential is out there. There potentially is this approach that could be taken, but has yet to be proven clinically. Similarly, the group out of Texas Children's looked at a semi-automatic algorithm to trace the surface of the trabeculated myocardium and the compact myocardium. And this is very different than the previous – this and the prior study are very different than the standard criteria that we use in clinical practice, because they really leveraged the volumetric understanding, the volumetric data that we have in MR. And what they found is that when you look at the total mass ratio of trabeculated to compact myocardium, you're able to distinguish between people with and without cardiac dysfunction. So again, very preliminary work, has yet to be correlated with genetic diagnoses, has yet to be correlated with clinical outcomes, more importantly, but promising. So going back to our first case. This 17-year-old male with no past medical history, so low positive predictive value of the test. But if you look at his echo, if you look at his MR, you can see he has very dilated atria, some degree of systolic dysfunction, and a high trabecular to compact ratio. So in this case, with the addition of MR – with the corroboration of MR, we can probably say this is somebody who's going to end up with LV non-compaction. With our second case, this is a 9-year-old male with a strong family history, but the echo looked pretty normal. And in fact, when we looked at the myocardial deformation indices, these were also quite normal. When you look at the relaxation, this was also quite normal. So this kid, we're just continuing to follow as we would with any kid with a family history of cardiomyopathy. Even more important than everything we've talked about are the implications of the diagnoses that are made. So I'll step a little bit outside of my instructions in giving this talk and just relay the impact of these diagnoses – that these diagnoses can have. We all know that exercise restriction can have serious psychological – can cause serious psychological trauma to children and to adults. That's true of patients with ICDs in place. That's true of patients with diagnoses of cardiomyopathy. That's true of patients who have a proposed diagnosis on MR. We also know that obese children become obese adults. And so these diagnoses aren't just – we sort of tend to think of making the diagnosis as the safer alternative, that we just want to be safe, we just want to do the right by the kid and make sure they don't die, so we're going to give them this diagnosis. When in fact, we're potentially causing harm when we do that. So what do we do? What's abnormal? Well, I would posit – and these are my opinions – but I would posit that isolated hypertrabeculation, where you have an increased trabecular layer with normal function and compact layer thickness, no significant family history associated syndrome or structural disease. Those patients, regardless of the compact to compact ratio – non-compact to compact ratio – regardless of how prominent their trabeculations are, we would just continue to monitor them and not make a diagnosis of LVNC. Hypertrabeculation that's associated with LV systolic dysfunction, which is associated with diastolic dysfunction, with a markedly thin compact layer, with abnormalities on baseline ECG arrhythmia, those are the patients that we would ultimately diagnose with LVNC. But I would posit this is a clinical diagnosis. Imaging can help to define the degree of hypertrabeculation and help to make that diagnosis, but ultimately it's up to the clinician. We have to be concerned about those high prevalence situations, right? So again, family history, obviously patients who are gene positive, you have to have a really high suspicion, and even the question of an LVNC diagnosis can push you to make that diagnosis because of the high positive predictive value in that population, particularly in syndromes like Anderson-Fabry and Dannen disease, but also in neonates. We have to have particular caution in patients with congenital structural heart disease. Those patients are not included in any of the studies that we've discussed today, but as the previous lecturer discussed, there is a high incidence of LVNC in those structural heart diseases, so we just have to have caution in those cases. In my view, LVNC should not be diagnosed purely on the basis of an imaging study because there's an unacceptably high number of healthy individuals who meet criteria for LVNC. Cases with cleared cardiomyopathy and hypertrabeculation may not meet the published criteria. So it's incumbent on us and imagers to report the extent and the degree of hypertrabeculation, but then combine those with other clinical criteria. Finally, in a talk on echo and MRI, you've seen no images of delayed enhancement, and that's because LVNC can be associated with late gadolinium enhancement, but the implications of that are far from clear. And then ultimately, I just wanted to mention that MR can help to identify thrombus for which these patients are at risk, and you'll hear more about in the next study. Thank you very much for your time. Thank you so much. As always, we're going to save the questions for the end, so please use the HRS app to submit them or come up to the central microphone. I have the pleasure of introducing our next speaker, Massimo Silvetti, from Bambino Gesu Children's Hospital. He's going to be talking about the clinical management of LV non-compaction in children. Good morning, everyone, dear chairman, dear colleagues. First of all, I want to thank the organizer for having invited me to this congress. Secondly, I want to apologize for my poor English pronunciation. This is Middle Italian pronunciation. It's not very nice, but you will excuse all my mistakes. So LV non-compaction phenotypes, usually it's typically a non-isolated phenotype or associated with cardiomyopathy with mixed phenotype, congenital disease, malformation syndrome, metabolic disorder, neuromuscular disease, and this is the association with cardiomyopathies, isolated, dilated, hypertrophic, mixed, and restrictive, and they have the worst prognosis, and also with congenital disease. These are the most common concomitant congenital disease. So it has clinical, a variable clinical manifestation, and children with non-isolated LV non-compaction present with symptoms of their disease, and the symptoms are congenital failure, chest pain, thromboembolism due to blood stasis and clots formation in the honeycomb-like myocardial structure, atrial, ventricular arrhythmia, up to sudden cardiac death. This is the graph of presentation, congenital failure, asymptomatic, arrhythmia or syncope, and other. As I'm an electrophysiologist, I will focus more on arrhythmias. The electrophysiological phenotyping, according to these authors, shows some cases of sinusoidal dysfunction, ventricular arrhythmia, and abnormalities involving heavy nodes and interventricular septum as a heavy block, bundle-branch block, and also WPW and other tachycardia and flutter. The possible explanation, according to those authors, can be the presence or more jagged discontinuous distribution of conductive ventricular fibers. Ventricular arrhythmias have a broad arrhythmia spectrum, from asymptomatic, sporadic, to clinically asymptomatic and life-threatening arrhythmias, and also with the progression of arrhythmogenicity. Also, they reported the high incidence of arrhythmia coming from cardiac apex. There is a common area of non-compatition. What are the predictors of fatal arrhythmia events? There are not many in children, because in children, only late gadolinium enhancement was associated with ventricular tachycardia, fibrillation, cardiovascular mortality, and heart transplantation. Non-sustained VT was recorded only in patients with normal EF, rather than those with abnormal EF. And on the contrary, PBC were more frequent in patients with mild ventricular dysfunction than in normal function. So, we can say that these are the risk factors for children. At the ECHO, the presence of lower ventricular systolic function, greater ventricular dimensions, the presence of left ventricular posterior wall non-compactation, and also lower radial and longitudinal strain. At CMR, the presence of late gadolinium enhancement. And ACG, the abnormal T wave, hypertrophy, WPW, and all other diseases, the coexistence of congenital heart disease or other phenotypes of cardiomyopathies. And the mixed phenotypes, as I already said, are the worst prognosis. And other factors, that is the congestive heart failure diagnosis and the younger age diagnosis, as already said by the other speakers. This is a larger study, 242 children, followed for nearly 20 years in a group of Texas. And they found that the risk was due to the presence of congestive heart failure and mixed phenotype or dilated phenotype. They also had ablation, ICD, and 6% of sudden cardiac death. But we have to underline that there was a high incidence of death or transplantation in infantile left ventricular non-compactation, as high as 25%. But again, we have to underline that a patient with normal ACG did not die. A patient with normal cardiac dimension and function without preceding arrhythmia did not die suddenly. This is our experience that was published last year as 140 pediatric patients followed for 10 years. It's quite unusual because we had the most isolated left ventricular non-compactation. Well, in this patient, we have nearly 25% arrhythmia, nearly 10% of supraventricular tachycardia, 10% of ventricular arrhythmia, PVC, ventricular tachycardia, and 5% of bradycardia. No cases of sudden cardiac death, some devised implantation, some ablation. But the most important finding of our studies was that the genetic testing was significantly more frequently positive in arrhythmic patients than in non-arrhythmic patients. These are the genes involved, as we saw in the first presentation. But this result may suggest that arrhythmia are related to the underlying disease of genetic cardiomyopathy and known to the presence of trabeculation per se. This is one of our patients, ACG, CMR, and the ICD. You can see the sustained monomorphic ventricular tachycardia was successfully terminated by anti-tachycardia pacing. Management. There is no specific treatment of left ventricular non-compactation. But all the drugs that we use for left ventricular dysfunction are useful to obtain a favorable remodeling. And also, we can use anti-coagulation, anti-platelet therapy, anti-arrhythmic drug, ablation device. And remember that efficacy and complication are related to the associated phenotypes and auto-transplantation. Ablation. This study reported an experience with WPW, left ventricular non-compactation. 11% of patients, most of these patients have a dilated phenotype, left ventricular systolic dysfunction. Related to the precipitation or related to left ventricular non-compactation is not clear. But the efficacy of the ablation was 80%. It's something less than usually in normal children. But left ventricular adjustment fracture improved in most of the dysfunction in patients that were ablated. You can see that without WPW and with WPW, there is a significant more frequent presence of dysfunction. This is one of our patients that was successfully ablated for a MIME, supraventricular tachycardia, with an ablation in the posterolateral tricuspid annulus. So ventricular arrhythmia. There are no data in children. We had this data from this group of Spanish in adults. And they found that the ventricular arrhythmia subset is heterogeneous, coming from right ventricular outflow tract, Purkinje system, or scarce induced regional ischemic dilated cardiomyopathy. So what is the relationship within right ventricular outflow tract and arrhythmia in left ventricular non-compactation? It's not clear. Subendocardial fibrosis, airless, electromanifestation, or left ventricular non-compactation? We don't know. It's not clear that in Purkinje system, because they are more frequent in isolated left ventricular non-compactation, due to the involvement of Purkinje network of trabeculae or papillary muscles. This is one of our patients that was ablated for PVC and ventricular tachycardia. This was ablated in the right ventricular outflow tract in the posterior region. It was successfully ablated. Then we had devices. For devices, we had to follow guidelines. The most recent guidelines on 2021 PACE is the first consensus statement. I was honored to participate. And also the 2022 European Society of Cardiology guidelines on managing a patient with ventricular arrhythmia and the prevention of sudden cardiac death. For device recommendation, there are the usual recommendations, according to age, weight, pacing system, pacing mode. Because neonate infants and children below 15 kilograms for pacemaker, below 20 kilograms for defibrillator should receive an epicardial device. Children more than 15 kilograms for pacemaker, more than 20, 30 kilograms for defibrillator should receive a transvenous device, pacemaker, or a transvenous or epicardial ICD. Adolescents should receive transvenous devices or, for defibrillator, subcutaneous ICD. The outcome of ICD in pediatric cardiomyopathy, we published this data two years ago when we didn't have data on non-compactation. But we found that for the three main cardiomyopathies, arrhythmogenic, dilated, hypertrophic, we found no difference in the incidence of ICD complication. This is an example of a patient who was implanted for congenitally blocked ventricular septal defect that was repaired, and left ventricular compactation at born, and seven years later. An example of epicardial ICD with the coil, you can see in the pericardial space. So what are the disadvantages of epicardial devices? Rid of lead stretching, of course, for every children. They grow more frequent insulation bridge and lead fractures. So dichotomous anatomy required, so that is also higher infective risk. And growth-induced displacement, ICD can, or coil, can change the defibrillation vector and cause ineffective defibrillation. So it may require some time during the follow-up to perform a defibrillation testing to see if the system is still properly working. And peculiar to devices, epicardial device, the risk of strangulation is not so rare. Trasvenous spasmag or ICD, this is an example, one of our patient that was implanted after a resuscitated cardiac arrest. She had VSD, left ventricular compactation, and this is the implantation. This is seven, 12 years later, and you can see that the device is still properly functioned and probably working. Again, for trasvenous systems, they have a risk of lead stretching, of course, but also risk of lead fracture, less than epicardial ones. But the peculiarity is risk of venous occlusion, of course, tricuspid valve damage, endocarditis, or thrombosis, although very rare. But also, in hypertrophic cardiomyopathy, you can see that you can have a very small right ventricle cavity, as in this case. You can see that the defibrillator lead, the coil, is as long as the long axis right ventricle. So, reaching the tricuspid annulus, and this is the final lead location, but it's okay, but we would like to go further, deeper in the right ventricle. An example, lead stretching due to body growth. This was implanted two years after implantation. It's quite straightened, but not so straightened. After other seven years, you can see how the lead is dislodged by the growth, but it's still properly functioning, and this patient, later on, underwent transplantation. An example, lead fracture close to the device. That's why we can have a third weapon, that is subcutaneous SED. This is some example of subcutaneous SED. The advantages, it doesn't have intravascular components, but the contraindication is relatively bulky, is unsuitable for patient requiring cardiac pacing or anti-tachycardia pacing up to now, and also, they need ECG screening that can be fulfilled in nearly 80% of young patient of congenital disease patient. This is one of our patients that was successfully resuscitated in primary prevention, the first episode saved her life. Sorry, previous, and this is an overview of pediatric SED literature from the first studies from the group of London, from Germany, from Netherlands, some Italian study, and the multicenter North American study, and our multicenter European study. You can see that the mean of all this data tell us that there is 18% of appropriate success, 15% in appropriate shocks, and 12% complication. This is the SEDICA project, our European registry, I am the PI, the participating country, the participating center, our results are very good with two incision, twin incision, BMI more than 20, intermuscular location. We know from adults that subcutaneous SED in blue had better results, less complication than transvenous SED, this is a praetorian trial, but adults, not many data in pediatrics, this meta-analysis show that the subcutaneous SED show significantly less inappropriate shock and less lead-related complication, while they have marginally significant, more-related, frequent-poker-related complication. So in conclusion, eventual compensations show variable cranial manifestation, from asymptomatic to severe congestive failure or malignant arrhythmias. Therefore, the treatment varies from none to medication, but the prognosis strongly depends on the prevalent phenotype. Pre-statification in this patient is challenging, follow recommendation for associated disease or phenotype. We have to underline again that asymptomatic, isolated eventual compensation with normal ECG, normal eventual dimensional function, and no arrhythmia is a low risk. Arrhythmias may be considered a red flag for a genetically determined cardiomyopathy. TAPS, the electrophysiological study, can be recommended. Medical treatment to avoid adverse remodeling, antiarrhythmic drug, and invasive electrophysiology and cardiac stimulation has to be performed according to current guidelines and recommendation. We proceed on results and risk that are related to the associated disease or phenotype. So ablation, as in the other patients, and bradyarrhythmia, ICD, as in the other patient. Thank you for your attention. I was 15, perfect. Thank you. Thank you so much to those three great speakers. We have one question from the audience. I believe it's intended for anyone, because it's not specific. But it says, for the neonate, as diagnostic criteria are imperfect, what is your approach to genetic testing? How and when do you offer it in the neonate? Okay. Is this on? Yeah. Yeah, and I'm probably not the best person to ask, because I do all adults. But. Yeah. We do. Okay, go. Yes, we do. Yeah, go. We do, but they have a serious clinical setting that we do. Yeah, we're pretty aggressive with genetic testing in neonates, particularly if there's systolic dysfunction, if there's a high trabeculated burden, if they're patients who look clinically as though they have cardiomyopathy. Our cardiomyopathy colleagues will be pretty aggressive about recommending genetic testing as they feel it can really help with counseling, with prognostication, and with testing for the family members, with, I forget the word I'm looking for, but with counseling of family members. In addition to that, I do have to mention, when we diagnose cardiomyopathy sort of as a general rule, in fetal life, we're also quite aggressive, particularly if it's still within the window where all the treatment options can be offered, particularly termination. We're pretty aggressive in that cohort, particularly, again, if there's dysfunction, if the heart muscle looks significantly abnormal, we'll be looking for syndromic disease, for genetic disease, because it can really affect counseling and their decision making. Yeah. Thank you. A little bit to piggyback on that. For the gene-elusive, non-syndromic family, how do you counsel them on the risk to a subsequent pregnancy? It's very difficult, yeah, I don't know. It's a great question. So are you talking about somebody who clearly has, the fetus clearly has a cardiomyopathy? Or just if they have another child who has a clinical phenotype, and we don't really have a genetic etiology, how do we counsel them on the risk of a subsequent child also having LV non-compaction? Yeah, it's very difficult. I think you have to make a lot of extrapolations, but yeah, I don't know if there's a clear answer. I don't have a great answer for you. Yeah, I mean, it's probably not the answer that they want, but I would say it could be up to 50%, because most of these are autosomal dominant, and when we don't have an underlying genetic cause, I always do that it could be up to 50%. Now, it doesn't mean, I do the clarification, it doesn't mean that they will absolutely have non-compaction, it means that they are at risk, it predisposes them, and therefore, it could be up to 50% that they would have the gene, may or may not have the disease. And it could, again, be any combination of LVNC, DCM, HCM, you name it, because I have multiple families where it's LVNC in one, but DCM in another, and HCM in another, you pick, same family. Yeah, such a challenging situation. Our next question is for Dr. Silvetti. Are there specific complications and ablation for these groups of patients? Are there specific complications and ablations for LV non-compaction patients? As I said, it depends on the phenotype, because if you are ablating a dilated cardiomyopathy, you have some risk, if you ablated a hypertrophic cardiomyopathy, you have other risk, and so it depends on the substrate. If we ablate an isolated epithelial non-compactation, we have this same, absolutely the same risk of abnormal child, but if they have more severe damage or more severe involvement of the heart chambers, we may find more difficulties. For instance, a hypertrophic cardiomyopathy can be more difficult to ablate an accessory pathway because it can be very deep in our, so it depends, it depends, it's variable. It depends on the peculiarity of the child. Usually, it's not so different from normal structural heart patients, in my opinion, in my experience. We have another question from the audience, also for Dr. Silvetti. Considering the difficulties in making the diagnosis and determining risk factors, and I'm gonna make this question a little bit harder, what are the indications for primary prevention, ICD, not secondary prevention, which is obvious? Yes, just follow the guidelines. I mean, it doesn't add more risk if it has a mixed phenotype with hypertrophic cardiomyopathy. We have to follow the guidelines of the hypertrophic cardiomyopathy. If it has a dilated cardiomyopathy, the same. So we have to follow the general guidelines because there are no guidelines for isolated leventrional compactation. And also, as I showed, the study of Chosex demonstrated that the presence of non-sustained VT or PVC seems not to add any more risk. It is the contrary in the adults, but in children, we don't have this data. So we can stratify also with the electrophysiologist study, but it's not very clear. It's not very, and we have to tailor our decision to every patient, to every situation. So we don't have guidelines just for leventrional compactation. We have to follow the general cardiomyopathy guidelines. That's what we did in Rome. Thank you. For Dr. Muscatia, I'm sure you get this question a lot. Echo versus MRI and sort of the series of events, or if you feel like there's a gold standard for diagnosis. Yeah, there certainly is not a gold standard. I mean, I think that's quite clear. I think if you use the published criteria that are out there for either Echo or MR, you're gonna be at risk for overdiagnosis and missing patients. So it certainly has to be put in the clinical context of the patient, for sure. That being said, I think both have their benefits. Each one has their benefit. In the kid who does not need to be sedated, over 10, over 12 years of age, we're very quick to go to MR because even patients with good windows, you can miss pretty extensive hypertrabeculation. And if that's your question, then it's worth going after. There also are, it's rare, but you do see some patients with late gadolinium enhancement. And with those patients, they are at increased risk for developing systolic dysfunction. So in somebody who's, you know, does not need to be sedated, and you're quite concerned for a cardiomyopathy, whichever cardiomyopathy, we're very quick to use MR. With the side benefit that you can identify clots that you might miss on Echo as well. Now, if you have to sedate a kid, we're much more reticent, particularly because, you know, there's cost and risk associated with sedating any kid with a cardiomyopathy. So only if there's a particular concern, if it's gonna really make a clinical decision, management change, will we do so. I actually, oh, go ahead. Oh, the presence of late gadolinium enhancement is certainly a risk factor we have to considerate. Yeah. I did wanna follow up, actually, on the presence of clots and anticoagulation. I think this is a real sticking point in terms of management. From a general practice perspective, do you only anticoagulate with the presence of non-compaction and dysfunction, or is there something about the features on imaging that also prompt you to anticoagulate empirically? So the imaging tool, before, you said about the imaging tool before the procedures? So I think what I'd be interested in sort of hearing about is your approach to when you anticoagulate a patient with LV non-compaction. Do they always have dysfunction in addition to the sort of imaging features, or is there something else about their clinical history other than, of course, the presence of a clot? No, we follow with usual non-invasive examination, and regularly, once or twice a year, they are following our cardiomyopathy center, and they follow out in that way. And sometime, they send to our AP lab or AP center to have another evaluation, just to see if there are risk, or they can fulfill the risk for something more, a procedure or a device or something like that. Of course, the dysfunction is one of the main indication, of course. Yeah, I don't clinically manage LVNC at our center. They're managed by our cardiomyopathy group, but my understanding is that they're fairly, if there is a diagnosis of LVNC, if the clinicians, if the imagers, everyone agrees that this patient has LVNC, even with normal systolic function, they'll put them on antiplatelet therapy. And then with dysfunction, especially if they've had a prior clot, they'll be on true anticoagulation. But with just isolated hypertrabeculation, we haven't really called it LVNC, we'll just treat them as a normal kid. One additional question from the audience. What kind of ambulatory monitoring do you use in your practice to assess for arrhythmias, to risk stratify for LVNC, ventricular arrhythmias, and sudden cardiac death? Ventricular arrhythmias? How do you approach to, what's your approach to ambulatory monitoring in these patients? Well, as I said before, it depends of the associated phenotype. Because if it's hypertrophic cardiomyopathy or dilated cardiomyopathy, or congenital disease with ventricular arrhythmia, either non-sustained or PBC, we may go on in the examination and we may perform an electrophysiological study. For normal heart and arrhythmia, then we perform certainly the CMR, because we have to rule out the presence of ligand reenhancement. And if we have suspicious of risk, we do the electrophysiological study. Thank you. Lisa, you talked a little bit about how your recommendation would be a broad cardiomyopathy panel for patients. If, let's say we've had a patient who was tested five or 10 years ago, do you ever recommend a repeat testing? And at what point do you make that recommendation? Yes, yes, and yes. So actually, I used to just do a cardiomyopathy-only panel, and then I switched about three years ago to do a combination cardiomyopathy and arrhythmia panel. I kind of get as big as I can get. That was actually based off of a study that I was involved with that showed an increased sensitivity or pickup rate for even doing a combined cardiomyopathy and arrhythmia panel. I typically tell patients to recontact me every three to five years to see what the panels look like. There have been some key genes that continue to get added over the years, right? And so I'll always assess what genes are there now versus what genes were there. Are there key genes that were missing that we should retest? And so I do end up retesting quite a bit. It depends on the diagnosis, depends on what genes you're looking for, and if they were on the panel back 10 years ago versus now. I mean, really, anything, like if we're talking anything beyond eight years ago, I would say the panels are significantly changed, and so definitely retest. But then again, some people just had a very small panel, even five years ago, and I'm like, yeah, that still didn't capture what we want now, and so if we go broad, we're gonna get a lot more. So it really depends on what they had and what was found. And I will sometimes even retest if there was a suspicious variant of uncertain significance back then to get current updated classification now with a bigger panel. So there's lots of cases where I will retest, yeah. We are at time. Thank you all very much, and thank you so much to the speakers. Thank you.

Left Ventricular Non-Compaction

LVNC

genetics

imaging

clinical management

cardiomyopathies

diagnostic criteria

treatment strategies

genetic testing

device implantation