So, our next speaker is Dr. Greg Webster from Lurie Children's. He's going to be talking about what is the difference between sudden death and abortion sudden death. As Dr. Webster walks up here, I was sitting next to him just now, and he whispered in my ear, if you cut me off, my talk early, I'm going to get you drunk and shave your head tonight. So, I'm really looking forward to that. Go ahead, Greg. This is going to be the slowest talk you have ever heard. I was asked to talk about the difference between aborted sudden death and sudden death. And I'm going to try to approach this from four different directions, four hypotheses about how these two things might differ. And I think as a clinician, it's really important to recognize that there may just be an underlying proportion of people or population of people at risk for ventricular fibrillation, and the primary deciding factor regarding whether or not a patient survives is whether someone is standing nearby with a defibrillator. It's important not to miss that as we continue to talk. The cardiac chain of survival is the result of an enormous amount of data, both on the adult side and the pediatric side, that rapid activation of the response system, CPR, shock, transport, and arrival in an advanced cardiac care center decreases the number of deaths in the population. But what we're really here to talk about in this session is this idea of genetic separation. Is it possible to define two populations that are different genetically that end up with two different results in terms of their clinical outcomes? And at first glance, it seems like that might be the case. If you look at data from papers that looked at post-resuscitation evaluation, for example, you see a much higher rate of Brugada syndrome in those folks. But in post-mortem evaluations, you seem to see a much higher rate of CPVT, especially pathogenic and likely pathogenic variants in the ryanin receptor. And the question is whether this actually means something in clinical world. If you have Brugada syndrome, does it mean that you're more likely to be resuscitated? And the answer is we have no idea, and I'm going to walk through why that's the case using Brugada syndrome as an example. And one of the primary problems is an epidemiologic problem, not a genetic problem. There are asymmetric phenotype evaluations in these two populations. If you survive your cardiac arrest, over the next days to weeks to months, we have the opportunity to assay your phenotype and determine whether or not you have Brugada syndrome, with ECGs, with infusing of agents that are active on the sodium channels, and even after we've defined a population that has clinical Brugada syndrome, as most of the people know in this room, and it was taught to us by Dr. Bazzina a little bit ago, a very small number of them will apparently be genotype positive for a monogenetic cause of their Brugada syndrome. And that means there's a big gap between those people who have a phenotype for Brugada syndrome and those people who have a genotype. And I know that there's subtle structural defects in Brugada syndrome, but standard autopsy at least is not a good way to find them. And most autopsies of folks with Brugada syndrome are normal. And that means that in patients that are deceased, there's no phenotype to look at, and you're sampling with molecular autopsy this 20% that are genotype positive. And that means that post-mortem evaluation under-detects Brugada syndrome. Now if this is right, that means that if you pivoted from looking at decedents to looking at their family members, you should see an over-representation of Brugada syndrome in family members versus the decedents that you looked at in the first place. This is data from last year from Dr. Baer's group, and they looked at 303 families with 900 relatives after a sudden arrhythmia death. And they looked at these people comprehensively, but I'm going to focus on the Brugada data here. Fifteen percent of those relatives were diagnosed with Brugada syndrome, and most of those were on the basis of azomalene infusion. But importantly, a spontaneous type 1 pattern or clinically significant arrhythmia events occurred in 17% of the concealed Brugada cohort. In other words, they were not just seeing that giving azomalene to people changes their electrogram, but they were also demonstrating that in the long run as you follow them, they develop clinical features of real Brugada syndrome. So this is important. This suggests that postmortem evaluation is not sensitive for Brugada syndrome. And indeed, postmortem evaluation is not specific for Brugada syndrome either. And I'm going to pick on one particular gene, but it's not clear that every gene that has been associated with Brugada syndrome for the same reasons that Dr. Buzina talked about is a strong monogenetic cause of Brugada syndrome. So this was a look in 2018 across six international centers at a couple dozen SCN1B genotype positive cases. And what they found was that genotype correlated poorly with phenotype, and that there was a high frequency of these abnormalities in NOMAD, meaning that the estimated prevalence of these variants in NOMAD was almost a tenfold greater prevalence than the estimated prevalence of Brugada syndrome due to SCN1B. And what that suggests is that SCN1B is not a monogenetic cause of Brugada syndrome or sudden death. But if you send off postmortem molecular autopsy on a case where you have no other information to a commercial lab, all of the commercial labs include SCN1B. And this means that these postmortem evaluations that we're doing in the case of Brugada syndrome are neither sensitive nor specific for detecting the disease that we care about. And what that means is when we're trying to figure out are there two genetic populations between these two groups that are the same or different, we're not evaluating the same population characteristics. In survivors, we're primarily evaluating phenotype, but in decedents, we're primarily looking at genotype. And that means that the epidemiologic hurdles outweigh the genetic hurdles. It is challenging to compare genetics if you can't define the disease in the same way in both populations. Now, I'm not declaring that this is the end of the game on this. There are a bunch of methods that maybe allow us to bridge this gap. But so far, those populations haven't been assembled and analyzed that allow us to say whether there's a subtle genetic difference between people who are resuscitated and people who die of sudden death. Pivoting a little bit to look at external factors, are there components that interact with the genome that cause you to either have an aborted event or to have sudden death? This is data from Denmark, where they looked at 1,300 deaths, and one of the advantages of Denmark is they have a central pharmacy system. So the records are available backwards for decedents in the 90 days prior to death. And if they looked at, in this group where they looked at pharmacotherapy prescribed within 90 days, people who had been prescribed rugotigenic drugs, people who had been prescribed one or more QTC-prolonged drugs, the odds ratio of those events being associated with people who had sudden arrhythmia death were two to three times higher, the odds were two to three times higher, of those who had an explained cardiac death. Now, most people who are clinicians in this room have seen cases of VF due to secondary drug effects, but this data suggests that the same phenomenon that we see in rare cases also occurs at a population scale. Similarly, myocarditis, which is another disease that interacts with the myocardium and increases your risk for sudden death, has an interaction with genetic components. This was a study from 2017 out of New York that looked at 42 patients with acute myocarditis, and they did whole exome sequencing for rare variants that cause disruptions in the protein structures in cardiomyopathy and arrhythmia genes. And what they found is that in a dominant model, heterozygous changes, there was no difference between healthy controls and acute myocarditis, but that there was a vast increase in both homozygous and compound heterozygous variants among people who had myocarditis when compared with healthy controls. Now, neither of the last two external factor sides demonstrated a difference between aborted sudden death and sudden death. However, both drug effects and myocarditis are heterogeneous disease states, and there's a gradient between mild disease and severe disease. And because dying of ventricular fibrillation requires initiating VF, sustaining VF, and if you terminate VNF, reinitiating VF in order to have a lethal event, the fact that mild alterations may allow for patients to exit that cycle and have aborted sudden death may be different than severe alterations that may continue or reinitiate arrhythmia after spontaneous termination. We see this clinically, and the fact that this exists in the population is a suggestion that it may happen across a broader scale. And finally, I want to talk briefly about susceptibility to ventricular fibrillation. There's been extensive work on initiation and propagation of ventricular fibrillation that started in the 1930s with the Uyghur sages, led to this model of leading circle reentry and then the rotor model and the 3D scroll model. And in animal work, there's been extensive documentation that changes in the genetic milieu allow you to change those cycles of initiating VF, sustaining VF, and if you terminate VF, reentering into VF. And some of those have been in Connexin 43, inward rectifying potassium channels, and spatial dispersion in the HERG protein. The thing that's important about this is we are entering a phase where we are starting to understand that there is a coupling between the pathophysiology that happens in atrial fibrillation and the pathophysiology that happens in ventricular fibrillation. And I am hopeful that as we continue to fund atrial fibrillation at a high level, we'll start to understand some of these mechanisms and be able to apply them to clinical work, which has not been a big crossover so far. So in summary, does defibrillating people turn people who may have sudden death into aborted sudden death? Unquestionably, yes. That's the overwhelming data. Is there a genetic separation between these two populations? We don't know yet. Part of that's because we haven't had the ability to assemble an epidemiologic population that allows us to discriminate that. And then, are there external factors, and are there intrinsic susceptibilities to VF? There are both genetic and population models that suggest that this is strongly the case, but we have not yet had the data that says that it discriminates in a way that demonstrates that it's between the two of them. Thank you guys very much. I appreciate it. Thank you.

sudden death

aborted sudden death

genetic separation

external factors

research