Good morning, everyone. My name is Lucilia Giammarino and I'm a postdoc in Dr. Ackermann's team. Today I'm happy to give you this presentation entitled Identification of Calcium-Released Channel Deficiency Syndrome among Patients Diagnosed with Adiopathic Ventricular Fibrillation. So, what is Calcium-Released Channel Deficiency Syndrome, or CRCDS? It's a newly described inherited channelopathy caused by either biogenic or biophysical loss of functional pathogenic variants in the cardiac RYR2 and called the ryanodine receptor. The ryanodine receptor is the largest intracellular calcium channel forming homotetramer localized on the sarcoplasmic reticulum. This protein plays an essential role in the intracellular calcium handling, ensuring proper excitation-contraction coupling. Now, dysfunctional ryanodine receptors are instead associated with abnormalities in the calcium handling that can lead to contractile and electrical dysfunctions. So, as I mentioned, RYR2 plays a crucial role in excitation-contraction coupling in cardiomyocytes. Indeed, during a cardiac action potential, the depolarization of the membrane potential triggers the opening of the L-type calcium channel, allowing a small entry of calcium. Now, this is insufficient to trigger cardiomyocyte contraction, however, can induce conformational change in the ryanodine receptor, allowing, therefore, the opening of this channel and the release of calcium from the SR to the cytoplasm. So, in this moment, we will observe a transient increase in the intracellular calcium level that now will act on the tropomyosin complexes inducing cardiomyocyte contraction. Now, this level will instead drop after muscle contraction ends, thanks to the return of calcium to the SR, related via the serca pump, but also thanks to the extrusion of calcium through the sodium and calcium exchanger, or NCX, through the sarcolemma. A substantial number of RYR2 pathogenic variants have been identified so far and functionally characterize as either gain-of-function mutation or loss-of-function mutation. Now, gain-of-function mutation in RYR2 are causing an increased SR calcium leak and are associated with the catecholaminergic polymorphic ventricular tachycardia type 1. Clinically, CPVT1 patients manifest an abnormal stress test CCG, characterized by bidirectional progressive ventricular ectopy with increasing workload, and overall, an increased risk for beta-adrenergic-mediated arrhythmias. But then, instead, on the other hand side, loss-of-function mutations are instead causing an impaired SR calcium release and are associated with CRTDS. Now, unlike CPVT, where stress tests can reveal arrhythmias, now these patients, they present a normal resting but also stress CCG, so very often these patients, the first manifestation in those patients is sudden cardiac arrest or sudden cardiac death. Idupanic ventricular fibrillation, or IVF, is a diagnosis of exclusion that is made when structural ischemic or primary electrical genetic disease can account for the arrhythmia event. As you can see, over the last decades, our understanding and therefore our ability to diagnose cardiac arrhythmia syndrome have largely improved. So therefore, the percentage of IVF patients reduced over the years, however, still many patients are classified and fall into the category in the IVF umbrella. So therefore, raising an important question, could some of these IVF cases actually stem from under-recognized CRTDS? So in this study, we perform a retrospective review of 169 patients that were evaluated and treated at the Mayo Clinic between January 2000 and July 2024 and received a diagnosis of IVF. At the same time, also an RYR2 genetic test performed. And here, we consider as putative CRTDS cases each patient that presented a clinical phenotype different from the classical CPVT1, but also presented an ultra-rare non-synonymous VUS or loss-of-function RYR2 variant. Overall, among 169 IVF patients, we identified six patients with putative CRTDS. All of them experienced sudden cardiac arrest associated with exertional or recreational activity, but presented normal stress and resting ECG. The test revealed six different RYR2 variants among the six patients. And overall, all of them received treatment with an implantable cardioverter defibrillator. Five patients were treated with nadolone, while only one patient had also a left cardiac sympathetic denervation and was treated with flaconide. So our cohort consisted of 40% females with an average age of a sudden cardiac arrest of 31 years old. 24% of them had a history of syncope or seizure, and 18% of them presented a history of sudden cardiac death. 60% of these patients manifested cardiac event during rest. And overall, echocardiographic and electrocardiographic findings were pretty much normal. The biggest majority, so 97% of them, received treatment with an ICD implantation. So now, when we are considering the six CRDC, CRTDS patients that we identified here, so their demographic characteristics are pretty much similar to our overall cohort. However, very interestingly, they all experienced the sudden cardiac arrest during exertion. So what is the clinical presentation of these patients? So the first case is a male patient that had a swing-related sudden cardiac arrest at the age of 14, and later on he received recurrent appropriate VTEVF terminating ICD shocks. The second patient was, again, a male patient and had a recreational sudden cardiac arrest at the age of 8. The third case was represented by a female patient that had exertional sudden cardiac arrest at the age of 40, but also presented a family history of sudden cardiac death. The fourth case was a female patient that had post-coital sudden cardiac arrest at the age of 31, and also presented a childhood onset of mild biventricular cardiomyopathy with recovered left ventricle ejection fraction. The fifth case was a female patient that had exertional sudden cardiac arrest at the age of 38, and also in her stress test we could see that there was short-coupled PVC triggering polymorphic ventricular tachycardia, but she also underwent the EP study that manifested the T ballooning. The last case was represented by a male patient that had recreational sudden cardiac arrest at the age of 8, and later on he received recurrent ICD shocks. So as I mentioned to you, all of them overall manifested pretty normal stress ECG, as you can see also from this original recording, obtained a peak exercise. And last, considering that we know from the literature that RYR2 pathogenic variants of RYR2, so associated with genetic cardiac arrhythmias, typically cluster in specific genes, cluster from 1 to 4, we also wanted to localise this mutation. And we observed that the six variants, the first one was localising in the cluster number 1, corresponding to the N terminal of the protein, 4 were instead localised in the transmembrane domain of the protein, corresponding to the cluster 4, but also an additional mutation was localised in the cluster 4. And among all of this, two mutations occurred de novo, and only one of these RYR2 variants had been previously functionally characterised and resulted as a loss of function mutation. So in conclusion, in this project we determined the prevalence of potential CRCDS causing RYR2 variants in a large unrelated cohort of patients diagnosed with IVF, and we observed that as much as 3% of these patients, so diagnosed with IVF, may actually represent unrecognised cases of RYR2-related CRCDS. But considering that all of our potential CRCDS cases had an exertion-triggered sudden cardiac arrest, we believe that as much as 9% of patients with exertion-related IVF may be potential CRCDS cases. We believe that identification of these patients and their underlying RYR2 variants are critical for both tailoring clinical management, but also for getting genetic counselling for the affected patient and also their families. And in conclusion, we believe that this study highlights the importance of expanding our understanding of CRCDS to refine and improve diagnostic, but also therapeutic strategy. And now I would like to thank everyone who contributed to this work, and I would like to thank my supervisor, Professor Ackermann, and you for your kind attention this morning. Thank you so much. While we wait for questions from the audience, I have a question in terms of the mechanism. Do we know more about why the stress test would be negative, and yet all of these patients seem to have exertional events? Unfortunately, I believe that there is still much to be done here. It's not exactly clear what are the mechanisms, like what beta-adrenergic is doing. Normally, we know that in CPVT, we will have this leak of this channel, however, despite the fact we will have a reduction of the function or of the protein in RYR2 in this patient, probably there could still be some abnormalities in the gating of the channel, however, there is still much to do. There's one more question from the audience. Did any of these patients have atrial tachycardia, any neurodevelopmental delay? I think that's still alluding to some of our CPVT patients. As far as we know, no. But thank you very much for the question. Can I do that? Can I speak to make the questions? Yes. Okay. So my first question is that it's true that CPVT exercise stress test was performed without the therapy? Mm-hmm. And the second question would be to be able to make this kind of diagnosis, I used to be able to make a functional evaluation of the variances. And the third question, did you perform the clinical test that has been recognized? Thank you. So thank you. Thank you. Thank you very much for the question. So probably, I don't remember the order, but I remember the question. So, yes. So this is very important to underline. For CRCDS cases, it's important to functionally characterize these variants. So probably, we need to team up in general, overall, to increase the number of studies that would then lead to a better understanding of the mutation, but also of the disease in general. Talking about the clinical aspects, so the stress ECG, the stress test, yes, it was performed without treatment. Yes. However, regarding the clinical CRCDS EP study that you could perform, as you remember, maybe, only one of those, yeah, only one of those patients that I presented here actually underwent the EP study and presented this T-wave balloon. And why that? Because very often these patients, they are treated with beta blockers and for undergoing the study they will need to stop completely and they are very afraid of removing the therapy. So we need probably to show more evidence that this study is important. However, I know that some of our colleagues, in particular Dr. Judy Chessie, is also teaming up for increasing the number of proof that this EP study is essential. I think we may need to move on in the interest of time, but I'm sure she'll be available for questions after the session. Thank you so much. So the next speaker is Dr. Chelsea Boyd, and she will be talking about short QT intervals associated with increased all-cause mortality, but rarely reported. All right. Thank you very much. All right. Let me just get us started. All right, everybody. Hello. I'm a pediatric cardiology fellow at Texas Children's, and it's my honor today to talk about our work on short QTC intervals in children. All right. So our investigation was initiated following a sentinel case that highlighted a potential gap in our ECG reporting practices. This case involved a 17-year-old male who presented to our institution after a prolonged VF cardiac arrest. His initial post-arrest cardiac evaluation was normal, including a normal QTC of 404 milliseconds. Though, in hindsight, this QTC might be considered relatively short for the immediate post-arrest period. Subsequent ECG demonstrated a QTC of 348 milliseconds, which was neither flagged by the automated algorithm nor documented by the interpreting physician in the impression. The patient was ultimately diagnosed with short QT syndrome, secondary to SLC4A3. Cascade screening identified multiple affected family members, all of whom were recommended for ICD. This case prompted the central question that inspired our investigation. In clinical practice, how often do physicians explicitly document a short QTC interval in written ECG interpretations? Automated ECG algorithms routinely flag prolonged QTCs, and clinicians are trained to recognize and report them. But the same clinical practice does not apply when the QTC is abnormally short. From there, a broader question emerged. Given the rarity of congenital short QT syndrome, is there value in routinely flagging short QTC intervals in the general pediatric population? Should documentation of this finding be reserved for those with clinical features suggesting short QT syndrome? Or should it be systematically reported whenever identified on a pediatric ECG? To address these questions, we had four primary objectives. First, we aimed to determine the prevalence of short QTC measurements in our single-center pediatric ECG database. Second, we assessed how often the computer algorithm reported in an automated short QTC measurement, whether that was concordant with the final QTC measurement, meaning that the QTC on the final ECG also measured short. And additionally, how often physicians revised an automated normal QTC to short. Third, when a short QTC measurement was in fact present on the final ECG, we evaluated how often physicians explicitly recognized and documented this finding in their formal ECG interpretation. And fourth, although rare, short QTC syndrome carries a high risk of sudden death, prompting us to investigate whether any short QTC interval, akin to a prolonged QTC, is independently associated with all-cause mortality. For this analysis, we included all ECGs recorded between November 2004 and October 2024, with QTC intervals calculated using Bizette's formula. To ensure inclusion of physician modifications, we selected this time frame to exclude ECGs that were obtained prior to the implementation of electronic ECG reporting. Additionally, ECGs with paced rhythms were excluded from the analysis. A short QTC was defined as 250 to 360 milliseconds, with the lower boundary chosen to reflect the threshold below which artifact was considered likely, based on existing literature on short QTC syndrome. We further defined an extremely short QTC as 250 to 300 milliseconds, based on adult literature demonstrating decreased survival in this cohort. Mortality status was obtained from our institutional electronic medical record, and patients without identifiable records were excluded. For comparison, we also assessed the mortality rate and age at death among all patients in our ECG database without a short QTC interval. All-cause mortality was compared across these groups using both univariate analyses and multivariable logistic regression. A total of 708,970 ECGs were identified in our institutional MUSE database during the study period. Of the full dataset, 2,882 ECGs, representing 0.4% of the ECG database, had a short QTC on automated analysis. Of these, 883 were remeasured and found to fall outside the short QTC range, and therefore were excluded. On the other hand, 1,999 of the ECGs flagged by the computer retained a final short QTC measurement after confirmation by a physician and were included in the analysis. To this cohort, we added the 1,226 ECGs that were not identified by the automated system as having a short QTC, but were remeasured by a physician and found to meet criteria for short QTC. In total, 3,225 ECGs met inclusion criteria with a final short QTC, representing 0.5% of the overall ECG database consistent with previously reported prevalence in adult cohorts. Of the 3,225 ECGs included in our study, only 171, or 5.3%, included explicit documentation of a short QTC interval in the written ECG interpretation, all obtained after the initial description of short QTC syndrome in 2000. This highlights a sizable discrepancy between objective QTC measurements and clinical documentation, representing a clear opportunity to improve recognition and reporting of short QTC intervals during routine ECG interpretation. We then turned our attention to evaluating all-cause mortality among individuals with a short QTC. Our analysis began with the 3,225 ECGs identified as having a final short QTC measurement. This corresponded to 2,866 unique patients, excluding those who could not be identified in our EMR. This resulted in 2,607 unique patients with a short QTC, comprising the primary cohort for our mortality analysis. Within this cohort, we found that 9.2% of patients with short QTC intervals, shown here in blue, were documented as deceased, a strikingly high figure. As a comparator, we evaluated all patients in our total ECG database without a short QTC, shown here in red, among whom only 1.5% were identified as deceased. We then examined whether multiple short QTC measurements conferred additional mortality risk compared to a single short QTC measurement. To account for the possibility that sicker patients might undergo more ECGs, we adjusted for the total number of ECGs per patient in addition to standard patient demographics in our regression analysis. We found that patients with multiple short QTC measurements had approximately twice the odds of mortality compared to patients with a single short QTC measurement. This suggests that recurrent short QTC measurements may represent a higher risk phenotype in the general pediatric population. We next evaluated age at death using median values for comparison due to the non-normal distribution of our patient population, which included a higher number of infants relative to older children. The median age of death in the patients with a short QTC was 2.2 years, significantly younger than the median age of death of nearly 10 years observed among those without short QTC. Based on adult studies showing decreased survival in individuals with a QTC of 300 milliseconds or less, we subdivided our short QTC cohort into patients with a QTC greater than 300 milliseconds, shown in green, from those with what we will call an extremely short QTC, 300 milliseconds or less, shown in blue. We observed a trend towards increased mortality in individuals with an extremely short QTC with a mortality rate of 15% compared to 9% in the group with a QTC 300 to 360. The lack of statistical significance is likely attributable to the relatively small size of the extremely short QTC group, which included 80 patients, 12 of whom were deceased. There are several important limitations to note here. Due to the size of our cohort, we were not able to independently verify every QTC value. However, we have conducted an interim validation, and full verification remains an important next step. We had limited ability to assess for confounding variables that may otherwise explain the differences between groups, including but not limited to medication use, underlying illnesses, electrolyte abnormalities, and acidosis. We also did not specifically evaluate depolarization or repolarization abnormalities, and we did not account for bradycardia, though we used Bizette's formula, which may underestimate the QTC in this setting. Additionally, deaths occurring outside of our institution may not have been captured, potentially leading to underestimation of patient mortality. As a single center study, generalizability may also be limited. And finally, further characterization of the short QTC cohort, particularly with respect to the patient mortalities, is warranted to clarify the clinical meaning of these findings. To conclude, short QTC intervals are rarely explicitly documented in written ECG interpretations despite their potential significance, both for patients with short QTC syndrome and for the general pediatric population. While our analysis was not designed to identify patients with short QTC syndrome, though some may be included, it revealed a signal that a short QTC interval alone may be associated with increased all-cause mortality in children. These findings suggest that increased attention to short QTC intervals in routine ECG interpretation may be warranted despite the rarity of short QTC syndrome as a clinical diagnosis. Again, I thank you for your time and extend a very special thank you to the whole team at Texas Children's Hospital. Thank you. That must have been tremendous work trawling through all those ECGs. There's one quick question from the audience. If your S-short QT cohort was younger than average, do you worry that the formula or range was inadequate for these young patients? The formula or range for the QTC? Yeah, there are certainly multiple ways to come at a QTC measurement, and there are concerns with each formula. And I think based on prior literature, we chose Buzet's formula, but there are certainly concerns that it may not be accurate in all portions of our population. Okay, thank you so much. Yeah. So our next speaker is Dr. Philip Segar. He will be talking about the new drug SGK1 inhibition with long LQT1213, significantly reducing the QT interval in our long QT patients. Sorry, I'm a Mac person who's struggling here with a IBM computer, but I think I figured it out. I got it. That's where we're set. Listed here are my disclosures, and the slides will come up in a moment. Thank you, Dr. Asaki. Ladies and gentlemen, it's a real – I'm excited to be here today to discuss the results of the Wave 1 Part 2 study of SGK1 inhibition with LQT12-13 in patients with the congenital long QT syndrome. All authors are either employees or consultants of Thrive Therapeutics, who is the study sponsor. Long-term glucocorticoid kinase 1, or SGK1 inhibition, reduces the late inward sodium current. In LQT type 3, the primary defect is an increase in the late inward sodium current, and SGK1 inhibition reduces the late inward sodium current and subsequently reduces the action potential duration. In LQT type 2, the primary defect is a reduction in HERG loss of current due to decreased HERG loss of function and a decrease in IKR. Secondarily, and importantly, there's an increase in the late inward sodium current largely due to SGK1 activation. Subsequently, like in LQT3, in LQT2, SGK1 inhibition shortens the action potential duration and would be expected to reduce the QTC interval in patients who have LQT type 2. Thrive's compounds are potent and selective SGK1 inhibitors, and we'll focus today on LQT1213, an experimental compound which is orally bioavailable. It's a small molecule, and it has no meaningful direct or off-target effects on any of the major cardiac ion channels shown on this slide. Multiple experiments have shown that SGK1 inhibition reduces the action potential in long QT syndrome patient-derived iPSC cardiomyocytes, and shown here is data from Michael Ackerman's laboratory demonstrating that LQT1213, either in iPSC cardiomyocytes from patients with LQT3 or LQT2, significantly reduces the action potential duration compared to control, and does this to either a greater or similar degree than high-dose myxilatine. Importantly, in cardiomyocytes without LQT mutations, either from CRISPR isogenic corrected iPSC cardiomyocytes and LQT3, or in normal cardiomyocytes, SGK1 inhibition does not result in overshortening of the action potential duration. The purpose of this safety study was to evaluate the effects of SGK1 inhibition with LQT1213 on the QTc interval in adult patients with genetically confirmed long QT syndromes types two or type three after short-term dosing for two and one-third days. The patients were, there were 12 patients, and they all had genetically confirmed LQT2 or LQT3 mutations, and a baseline QTcf interval greater than 480 milliseconds. They were admitted to a clinical pharmacology unit for the duration of the study, and on day one were started on placebo three times a day. Thereafter, they were initiated on either high-dose LQT1213, 16 milligrams TID, or lower dose of 7 milligrams TID for seven doses with the last dose on day four in the morning. Triplicate ECGs were collected and analyzed by a core ECG laboratory pre-dose and an eight post-dose time points on days one, two, and four. And the endpoints evaluated were the changes of the QTcf, the other ECG parameters, safety, and pharmacokinetics. Several methods were used to evaluate the QTcf analysis. The time-matched change in the AUC of the QTcf on days two and days four versus day one placebo at the same time intervals was evaluated at the time period shown on the slide, and the methodology is illustrated in the figure. The QTcf AUC is a measure of the effect over time and reduces variability. In addition, time-matched delta QTcf values on days two and days four versus day one placebo at individual time points were assessed, both in the whole patient population and in those who had QTcf intervals particularly prolonged to baseline greater than 500 milliseconds. In addition, a post hoc analysis was performed examining the maximal pre-dose QTcf on day two versus the minimal QTcf on days two and days four at zero to four hours post-dosing. This was done because this is an analysis procedure that is sometimes used by clinicians and some reports in the literature. Statistics use paired t-test and mean values with the standard errors reported. The baseline characteristics included nine females and three males. The nine had LQT2 type genotypes and the mean QTcf duration was 521 milliseconds and 11 were on beta blockers. The drug levels at three hours post-dosing are shown here with the median values and the first to third interquartile ranges. Drug accumulation is evident between days two and days four in both dose cohorts. And the plasma levels were significantly higher in those with the 16 milligram TID cohort and only on day four in the 16 milligram cohort were concentrations resulted in 90% SGK1 inhibition reached in at least some patients. There was no meaningful effect on the QTcf interval in the seven milligrams TID cohort and thus on subsequent slides we'll just focus on the higher dose cohort. In addition, as expected based upon preclinical data, there was no effects on heart rate, PR, or QRS intervals. Shown here is the QTc AUC data time matched between days two and four versus day one placebo demonstrated on day four there's statistically significant meaningful reductions in the AUC of the QTcf at all three examined time intervals. The AUC is a measure of a mean effect over time and if the AUC is divided by the number of hours of the individual time intervals, one can calculate the average effect over that time period which for the three to six hours is 10.8 milliseconds. On day two there were no meaningful effects on the QTcf intervals. This is likely due to both lower drug concentrations as well as the concept that it may take more time for a drug that does not directly affect ion channels but rather alters kinase activity to exert its full effect. And thus going forward we'll focus on the day four data. Shown here are the time match values at the individual time points of day four versus day one placebo. And as you can see, there's statistically significant reductions at day three at hour three of 16.1 milliseconds, hour six of 10.7 milliseconds and a trend towards a reduction at the four hour time point. The 10 and 12 hour bars are great since they would be at subtroph levels as only a single morning dose was given on day four. When we then examine the subjects who had higher QTcf baseline intervals greater than 500 milliseconds in these four subjects, there appears to be a greater reduction in the QTcf interval. And these reductions would be consistent with a possible greater reduction in ventricular repolarization with SGK1 inhibition in patients with longer QTcf baseline intervals. The methodology of the post hoc analysis examining the day two maximal baseline predose values to the post dose values on day four minimum values as shown on this slide. And this resulted in a 37.7 millisecond reduction. From a safety standpoint, oral administration of LQT1213 appeared to be well tolerated without meaningful drug related adverse events including severe or serious adverse events, ventricular arrhythmias or changes in any of the objective measurements listed on the slide. So in summary, in this initial small study, in adult patients diagnosed with confirmed long QT syndromes type two or type three receiving LQT1213 dosing of 16 milligrams TID for two and one third days, oral administration appears to be well tolerated. Significantly meaningful and significant reductions in the QTcf were observed. The QTcf AUC and time match QTcf individual values were reduced compared to placebo and time match analyses demonstrated reductions of up to 16 milliseconds compared to placebo. These results support future development of SGK1 inhibition for patients with LQT type two and LQT type three. And these are the acknowledgements and I'd like to thank you all for your attention. Happy to answer questions. There were some very promising results. I have a quick question. How far are we from having this a bit clinically available for our long QT patients and what are the next steps? The next steps are a much larger study which we hope will lead to approval for this orphan drug. There's a question from the audience. Any known drug interactions such as Laconide or Mexilatine? No. So far there's no known drug interactions. There's a question from the audience. It's very hard to say with four LQT2 and two LQT3. It wasn't clear that there was really a difference in response. Maybe small trends for LQT3 but I wouldn't want to really read anything into that with such small numbers. Thank you for the question. Thank you so much. Thank you. We'll move on to the next speaker. So the next speaker is Dr. Matthias Müller from Germany. He will be giving an update on the long QT2 international registry. Thank you very much. It's a great honor for me to present the preliminary data on the QT long QT2 study. It starts. Our preliminary results of an international registry study belongs long QT2 syndrome type QT2 in the young. The background and objectives. Data on long QT2 is limited in children and adolescents particularly with regards to efficacy of beta blocker therapy, additional antiarrhythmic medication like Mexilatine, impact of left cardiac sympathetic denervation, usefulness of an ICD, participation in school sports. To improve our knowledge on pediatric long QT2, a retrospective international registry study was set up to establish contemporary data on symptoms and diagnosis, management and outcome. The inclusion criteria for this study was long QT disease specific genetic mutation and diagnosis age younger than 18 years. Data were enrolled using a web-based case report form and managed by a custom-made database. By February 2025, 222 persons were enrolled from 14 participating centers all over the world. Now the baseline characteristics. At this time, 60% of the patients were female, 30 male and in one patient the gender was unknown. The median age at diagnosis was 8 years, the median body weight 26 kg and the median QTc 480 ms. At diagnosis, which symptoms present the patients at diagnosis, 30% had cardiac specific symptoms and most patients, 40-43 patients had cardiac arrest or syncope during rest. Cardiac arrest or syncope was evident in near 30% during physical exercise, auditory stress or emotional stress. Unspecific symptoms were syncope with seizures, neosyncope or palpitations even in 30%. Near all patients had antiarrhythmic medication at or after diagnosis, near 90% had non-selective beta-blockers like narolol in 60% or propranolol in 27%. Selective beta-blockers like bisoprolol for example or mexilitin were not often prescribed and 4 patients had non-medication. Selective devices were implanted in 28% of the 222 patients, near 50% had an ICD, one-third had an IED and one-third a pacemaker. Now we have a look at the patients with ICD and AED and so the ICD was implanted for secondary prevention in the most patients and for an AED was prescribed in the most cases for primary prevention. During the median follow-up of 5.5 years from diagnosis to the last clinical visit, 20% of the patients experienced symptoms under medication. The most symptom was syncope followed by neosyncope, palpitations and appropriate ICD discharge and cardiac arrest and it's remarkable the most symptoms were at rest. Now have a look at patients with ICD, 8 patients with ICD received an appropriate ICD discharge and as shown before, 30% had an ICD discharge and appropriate ICD discharge at rest and only 25% under exercise. Very low appropriate ICD discharge were under sleep or non-medication compliance or emotional stress. School sports is important, near 60% of the individuals participated in school sports, one-third with restrictions, one-third with grades and one-third without grades. During school sports there were no cardiac events. If cardiac sympathetic denervation was very low represented in our collective, only 4% had an LCSD, 2 patients for primary and 2 patients for secondary prevention. Two patients had no medication after LCSD and one patient had not allowed and one patient had proper allow and 3 patients had ventricular tachyarrhythmias after LCSD. Two patients VT and one patient VF. Coming to the outcome, it's a good outcome, 99% of the patients were alive at the last follow-up visit. One newborn baby died from sepsis after pacemaker implantation, after bradycardia and lung cutie. And one 23-year-old female died suddenly while on low-dose NADLOL. Working together, contemporary data demonstrate in our young LungQT2 patients mortality on effective beta-blocker therapy was very low during mid-term follow-up. ICD contributed significantly to patient survival. Benefits of LCST in preventing sudden cardiac death and VT or VF in LungQT2 remains to be determinate. Participation in school sports wasn't associated with increased risk of cardiac events or sudden cardiac death. And most cardiac events occurred at rest. Thank you very much for your attention. It was interesting to see that there really wasn't many patients on myxilatine or who have had left cardiac sympathectomy. There's a question from the audience. How about the gender difference in the cause of cardiac arrest? I'm not sure at the moment. You haven't looked into the difference? Yes. Any other questions from the audience? It seems like the mortality rate was low with only two patients but there were quite a lot of breakthrough events. Have you looked at what these patients were on, whether they were on myxilatine or whether there was any non-compliance, low dose of beta-blockers? These patients were on effective beta-blocker therapy. No patient had myxilatine, I think so. And the compliance, I don't know. There's another question. When saying rest, did you assess if they were playing video games, for example? It's a good question. We don't know. We only asked in the chart in which situation was it and it was asked for rest. So I don't know if the child plays video games or like a Fortnite phenomenon or something. I don't know. I think there was one more question. So none of your high-risk patients were on the tribal therapy, leptargy, asympetic innervation, myxilatine, and beta-blockers? Because I think that the conclusion that leptargy, asympetic innervation, is not effective. We cannot control this data. There are tons of data on leptargy, asympetic innervation. And in our experience, those at higher risk should be treated with tribal combination of myxilatine and leptargy. At the moment, I know only from two patients. They were on the tribal therapy. And I'm not really sure, but one patient had throughout phenomenon under the tribal therapy. Excuse me? Thank you very much. Thank you very much. So our last speaker is Dr. Carlos Lodeiro, again from Texas Children's. He will be talking about Pediatric Out-of-Hospital Cardiac Arrest Survival to Hospital Admission. Good morning, everyone. My name is Carlos. I'm also a cardiology fellow at Texas Children's. And today, I'm happy to talk to you about Pediatric Out-of-Hospital Cardiac Arrest Survival to Admission and in-hospital evaluation and outcomes. So as you all know, Pediatric Out-of-Hospital Cardiac Arrest survival rate is poor, anywhere from 7% to 10%. For those that do survive to admission, limited data is available about the in-hospital evaluation. More specifically, although the AAP and PACES have described an ECG and echocardiogram as important elements of such evaluation, no study has reported how often this happens. In addition, no protocol currently exists or institution for evaluation of these patients, which further increase our curiosity in learning what exactly happens when these patients make it to admission. So with that in mind, our goal was to describe a cohort of pediatric out-of-hospital cardiac arrest survivors that were admitted to Texas Children's Hospital, including their in-hospital evaluation, final diagnosis, and survival to discharge. With this information, we were hoping to then identify areas of improvement that could improve the evaluation of these patients while admitted and also guide the development of an institutional protocol. We completed a single-center, retrospective, descriptive study from 2006 to 2023. Through a partnership with the Houston Fire Department, we used their database to identify all 911 calls received for pediatric out-of-hospital cardiac arrest that were transferred to Texas Children's and survived to admission. We included all children aged less than 18 years of age that survived to admission and had complete information on their EMR. And we excluded those diagnosed with trauma, whether accidental or non-accidental, suicide, or home ventilator malfunction. For our data collection, we looked at patient demographics, medical history, initial rhythm of an EMS arrival, in-hospital evaluation, which included cardiac, neurologic, and genetic. For the purpose of this study, we defined basic cardiac evaluation as patients that had both ECG and an echocardiogram done. And lastly, we looked at survival to discharge. In total, the Houston Fire Department received 980 calls for pediatric out-of-hospital cardiac arrest, of which 336 survived to the Texas Children's Emergency Department. Of those, 218 had available data, and 51 survived to admission. Of those 51, 41 met our inclusion criteria. And of those 41 that survived to admission, only 15 survived to discharge. I do want to highlight this in that of those 41 that survived to admission, 63% died during admission and did not survive to discharge. Looking at the demographics for those that survived to admission, 66% were male, 38% were infants, 44% were non-Hispanic black, and 39% were Hispanic. We also found that half had a known underlying medical condition, including 10% with congenital heart disease, 10% with genetic disease, and 20% with a known seizure disorder. Transitioning to their in-hospital evaluation from a cardiac standpoint, we found that 20% had an ECG only, 7% had an echo only, 56% had an ECG and an echo, which was our definition of basic cardiac evaluation. 34% had a cardiology consult, and 17% had an EP consult. Now I do want to clarify that the EP consult is accounted in that 34% of the cardiology. We just wanted to highlight which ones were seen by the EP team, as those are two different teams in our institution. From a neurologic standpoint, 70% had an EEG, 36% had a brain MRI, and 73% had a neurology consult. If we compare the two, there is a significant difference between the amount of patients that get a neurology consult compared to those without a cardiology consult. Going into those that had a cardiac evaluation of those that had an electrocardiogram, 39% were abnormal, which included prolonged QTC, ventricular hypertrophy, peak T waves, atrial flutter, and ventricular tachycardia. And similarly, those that had an echocardiogram, 54% were abnormal, which included depressed function, LVNC, congenital heart disease, and ventricular hypertrophy, and hypertrophic cardiomyopathy. Now with more than a third of EKGs that were done being abnormal, and 50% of the echocardiograms being abnormal, and knowing that not all 41 patients had a cardiac evaluation, we then wondered, what was the initial rhythm of an EMS arrival for these kids? And we found that 46% had pulsed electrical activity, 15% had a systole, 5% had bradycardia, and 27% had ventricular arrhythmia. Looking at those without ventricular arrhythmia, 7 patients required shock, 3 patients required both shock and an antiarrhythmic, 2 in the form of amiodarone, and 1 in the form of amiodarone and lidocaine, and 1 patient, none of those. We then wanted to focus on these 11 with ventricular arrhythmias and see what their cardiac evaluation was like. So we found 9% had an ECG only, 9% had an ECHO only, 54% had an ECG and an ECHO, 54% had a cardiology consult, and 36% had an electrophysiology consult. And I will remind you that these EP consults are included in those 54% of the cardiology consult. We then, knowing that cardiac arrests often have a genetic ideology, also looked at whether a genetic evaluation was part of the inpatient diagnostic process of the patients that did not already carry a genetic diagnosis prior to arrest. And we found that 65% had a documented family history, 16% had a three-generation pedigree, 29% had genetic testing, of which I'll say 6 actually led to a diagnosis, and 24% had a genetic consult. Moving on to outcomes and diagnosis, we wanted to know what percentage of these patients get a diagnosis, and we found that 56% had a final diagnosis, of which 20% were cardiac ideology, 17% were infectious, 15% with SIDS, and 5% were non-traumatic intracranial hemorrhage. Now having these four different categories as diagnosis, we then wanted to know what did their cardiac evaluation look like, and more importantly, where were those patients that did not get a cardiac evaluation? Thankfully, all of those that had a cardiac ideology, all had an EKG, all had an echo, and all had a cardiology consult. Those with an infectious, 43% had an ECG, 43% had an echo. Those with SIDS, 83% had an ECG, 50% had an echo, and those with intracranial hemorrhage both got an ECG and an echocardiogram. I will mention that none of the kids that fall in the infectious, SIDS, or intracranial hemorrhage categories had a cardiology consult. We then wanted to focus on the eight that had a cardiac ideology. We found that four survived, and four died during admission. The diagnosis for those that survived, including CPVT, restrictive cardiomyopathy, hypertrophic cardiomyopathy, congenital heart disease of those that died during admission, two had congenital heart disease, one was diagnosed with Pompe disease, and one was diagnosed with hypertrophic cardiomyopathy. I will mention that of these eight, three had unknown diagnosis prior to their arrest, five were newly diagnosed, of which four of these were diagnosed through genetic testing, which included a patient with CPVT, restrictive cardiomyopathy, Pompe disease, and hypertrophic cardiomyopathy. And then lastly, of these eight, four of these patients belonged to the group that had initial rhythm as ventricular arrhythmias upon EMS arrival. The three that survived all got ICDs placed. Lastly, going back to our 41 patients, then we wanted to know, okay, which ones do not have a diagnosis? And we found that 44% of patients had an unknown cause of arrest. So then, this being one of the particular groups that interest us, wanted to see what their cardiac evaluation looked like. And to do this, we also added those with SIDS. SIDS is a diagnosis, we don't consider that an identifiable cause of cardiac arrest. So we ended up with 24 patients of those 41, which is 59%, and we found that 8% had an ECG only, 29% had an echo only, 46% had a basic cardiac evaluation, 25% had a cardiology consult, and 8% had an EP consult. Again, that EP consult is included in those 25%. So in summary, of those patients that survived to admission after a pediatric out-of-hospital cardiac arrest, 64% died during admission, and 59% did not have an identifiable etiology of their cardiac arrest. A majority of those that survived to admission don't get a cardiology consult, including some of those that had ventricular arrhythmias documented upon EMS arrival. Of those 59% that did not have an identifiable cause of arrest, less than a half get basic cardiac evaluation, and less than a third get a cardiology consult. And lastly, less than a third of patients get genetic testing, and of those that do get genetic testing, more than 50% got a diagnosis. I do want to recognize the limitations of this study. In addition to being a single-center study, there was the inability to find data on our EMR, inability to identify these patients or an EMR based on the information that we got from the Houston Fire Department, and then how much practice has changed during their study period. To conclude, the in-hospital evaluation of patients that survived to admission after a pediatric out-of-hospital cardiac arrest is inconsistent and requires development of protocols to help guide diagnostic process and management of these patients. We believe that a cardiology consult is warranted in patients with a concerning history, either personal or family, those with an abnormal cardiac evaluation, those with documented ventricular arrhythmias, and those with unknown etiology of cardiac arrest, including those with SIDS. Now, I would argue that those that have a history of seizures that are difficult to control should also be seen by cardiology. Lastly, a detailed history and genetic evaluation remain a critical part of this evaluation, not only because they can help guide management for their patients, but also their families. With that, I would like to acknowledge the entire electrophysiology team at Texas Children's for their guidance and support, and thank you for your time. Thank you. That was very sobering data showing a very poor outcome in these patients. I think there were only 14 patients surviving with very limited cardiology assessment, despite many guidelines and statements recommending comprehensive evaluation. What do you think are some of the barriers towards a proper cardiology consult in these significantly affected patients? I think there's multiple factors. I think the lack of a protocol plays a big role. Lack of understanding between the multiple teams that see these patients, so from the emergency department, those that go to the PICU and those that go to the CVICU. On Thursday, when there was a sudden cardiac death session, one of the critical care doctors from our institution was saying how in the CVICU, everybody thinks about the heart, but when they're in the PICU, nobody thinks about the heart. I think also the lack of documenting of a family history plays a role. I think it's critical for everybody to understand that having a good understanding of what happened with this patient, the family history and the risk factors, that would also lead to a more thorough evaluation. I think understanding that for those that do not have a clear ideology, which includes some of those that we excluded from our study, whether that is trauma, suicide, a mechanical ventilator case or choking or asthma, things like that, if the story doesn't make sense, I think the cardiology team should be involved. I think a big argument would be those with infectious causes. But from our side, for example, arrhythmogenic cardiomyopathy is known to be a two-hit mechanism. You have a predisposed genetically, and then you have an infection, and that's how you can present Brugada patients. You can present them with ventricular fibrillation and fever, which would be technically infectious. I think a protocol would be the main way to try to help these outcomes. There are several questions from the audience. Could you tell if the neuroevaluation was prompted for a decision in terms of direction of care, as opposed to ideology? And a similar question, why do you think the neurological assessment was much higher than the cardiac assessment? That's a great question. A lot of the patients, while I was going through the charts, the console would be for brain death, so assessment of whether they had brain death. I think that accounts for a big percentage of those patients. I did speak with the neurology team from our institution, in terms of EEGs and MRIs, which I think the brain MRI was pretty low as well. From their standpoint, they recommend everybody to get a brain MRI within five days of the cardiac arrest. So I think that these numbers are also concerning from their side. Do you have any data on how many got an autopsy? We do have those numbers. Unfortunately, a lot of patients actually, the families get offered autopsies and they deny. We do have some that I looked into. For example, one of the patients that fell in the infectious group, that was not consulted by cardiology. The autopsy showed concerns for myocarditis, cardiology should be involved. There are some results that we have not been able to find, so we're still working on those things. One last question. I think everyone is thinking about this similar question, but with this result, is there a move of changing the management, or has there been any plan to develop a protocol to evaluate these patients? This definitely sparked an interest in developing a protocol and making sure that this is a multidisciplinary effort and having not only cardiology, neurology, the ICUs, both cardiac and the PICUs, as well as the emergency department teams, so there's a clear understanding of who should be a red flag, who should get a more thorough evaluation. Thank you so much. That was interesting. So I think we might finish this session. Thank you, everyone, for attending. There's a good turnout considering it was the last day in an early morning session. I hope you enjoy the rest of the Heart Rhythm Society meeting.

arrhythmia syndromes

Calcium-Released Channel Deficiency Syndrome

ryanodine receptors

pediatric cardiology

out-of-hospital cardiac arrest

standardized protocols

LQT1213

SGK1 inhibitor

Long QT Syndrome Type 2

cardiac evaluation