Hey everyone, this is a pre-roll announcement. It's going to take exactly 5 minutes and because I really want to get the word out, it's in front of almost every episode. Now you know because I value your time, in my intros I always give you time stamps, so you could jump forward in the episode to whatever interests you most. But if you're listening to this message, it means there's 5 minutes that I inserted in front of it. So add 5 minutes to whatever I said in the intro and it should take you there. If you've heard this announcement, feel free to skip ahead, but if you have not, I promise you're going to want to listen. Here we go. Hey everyone, it's Ryan from The Poison Lab with an announcement I am beyond excited to share. After ages of tinkering, testing, and refining, my poisonous mushroom card game is finally here. Gotta pick 'em. You can get your copy at gottapickum.com and click the link that says "buy gotta pick 'em". The game is so much fun and it's actually pretty educational. The name of the game itself got to pick 'em is a pneumonic to help remember the poisonous mushrooms and you can find a podcast episode about that at thepoisonlab.com. Check out the episode "A NUMONIC FOR POISON OF SMUSHRUMES WITH DR. ROB BASS IT TO LEARN MORE". But we're talking about the game, which contains 58 individual poisonous mushrooms as well as 19 different antidotes or modifier cards. You get dealt to hand of different mushrooms and antidotes and you can forage one of them. Then you pass your hand to the next player and get a new hand from someone else. You score points by collecting mushrooms within the same toxin class, grabbing their antidotes, or modifiers that make the mushrooms more or less toxic. So as you forage, you can build strategies to get more points from the same mushrooms in the next rounds. It's a bit of an engine builder meets sushi go. And because I'm a huge nerd, the scoring systems actually complement the toxins, where the things that cause late toxicity get you points later, chronic toxicity builds up over time, which actually 15 different ways to score, it's really fun. And it's endlessly replayable. Not only do you get different hands every game, which might change your strategy, but in between rounds you change up how things are scored by drawing bonus cards, which might get you extra points for say a mushroom that has a ring on this type, or mushrooms with a certain color spore print, or a certain toxin class. All in all, there are 34 different bonus cards. On top of that, at www.gottapicum.com, you can find multiple rule variations to change up the way you play, and you can experiment and find the way you like the most. And at gottapicum.com, you can find several different links to companion blogs that will help you learn while you play. Click Learn the Numeric to learn about the gottapicum numeric and how it characterizes the different toxic mushrooms. Or click Learn Basics about Identification to find the blog that will run you through mushroom anatomy and ID to help you understand what features are listed on the card. And most importantly, definitely check out the Learn the Mushrooms link to find the companion blog with pictures of all of the mushrooms from the cards and a detailed explainer for each toxin class where they're found, the toxic syndrome that they create, how they're treated, real case reports of poisoning from those mushrooms and expert insights. Because this game about poisonous mushrooms was made by people who treat poisonous mushrooms. So whether you're a poison nerd, a mushroom nerd, or a board game enthusiast, this game is made for you. Head over to gottapicum.com and you can get a copy of it for yourself. I cannot wait for you to play this and please nothing would make me happier to see a picture of you playing your first round. So please snap a photo and send it to Tox Talk 1, T-O-X-T-A-L-K-1 at gmail.com. I'm really excited for you to check this out. I know I have a blast playing it and I think you will too. And remember buying this game is not the only way you can show support for the show. This is a totally unfunded production and it exists because of support from listeners like you to help pay for website hosting, audio production software, sound engineers, all sorts of hidden costs that are associated with putting on an educational show like this. So you can help support the show at www.thepoisonlab.com/support and you'll get something back. Not only will you have no ads while you're listening as well as bonus content but supporting members actually had early access to buying this game at a discounted price. And they're enrolled for things like giveaways of this game or merch when we have it available. So if you want ad free episodes, bonus content, updates as soon as possible and access to things like giveaways or discounts when they're available, head over to www.thepoisonlab.com/support. For as little as a dollar a month you can help us keep the show going. But you don't have to pay anything to support the show. I'm just happy you're here listening. Thank you for being part of the community that makes this show so much fun. Welcome to the mini episode. If you're here it's because you're interested in learning more about the actual cellular mechanisms of the arrhythmia torsaud the point or torsaud depointase. This version of the episode is directed at those with a little bit of scientific understanding of how the heart works. We're going to assume you know a little bit about cardiac action potentials and the cardiac de-plorization cycle. This is a really content heavy and jargon heavy topic. So if you have no science background or maybe even if you do I will not be surprised if your eyes start to glaze over. For a more entertaining way to learn at least the cardiac action potentials I recommend listening to the other mini episode where we explain all of this but we use kind of a more fun story to really break down all the steps of cardiac de-plorization and provide an easier way for people to remember the steps. It still might get a little complicated and we don't go as in depth into arrhythmia propagating mechanisms but it's at least a little more fun to listen to. However if you found the other episodes maybe a little bit too simple this could be the episode you're waiting for where we're going to go more in depth into the actual cellular mechanisms, the physiology and the proposed theories for how torsauds is propagated. So without further ado let's jump in. This is the cardiac de-plorization cycle and how lopairamide or any potassium channel blocking agent can cost your sods. So if you think of your heartbeat like a light turning on if it only ever turned on once that would be a problem. We need it to be able to turn on, have a heartbeat and then turn off again so that we can turn it back on and have a second heartbeat. And we do this by moving ions through the cell in very specific sequences which lead to secondary cellular changes that cause cardiac contraction and the subsequent resetting up of the cellular machinery to contract again. Those ions are sodium, potassium and calcium and they move through the cell in a specific sequence. Before we understand how those move through the cell we have to understand the cell's basic nature. Cardiac cells are polarized and depolarizing them allows them to send their signal. Your cells have special pumps on their membranes called sodium potassium ATPase pumps and they use chemical energy in the form of ATP to move three sodium outside the cell and pump two potassium inside the cell, three out to in. This means that there is always more positively charged sodium outside the cell than there is positively charged potassium inside the cell. This relatively larger amount of positive charges outside the cell compared to the relatively smaller amount of positive charges inside the cell means that inside the cell there is less of a positive charge or aka a relative negative charge. This is called the transmembrane potential and since there is a negative relative charge it means the cell has a charge or is polarized. For a ventricular myocytes that charge is about negative 90 millivolts. In order to depolarize the cell we let all the sodium which is built up outside, flood into the cell and change that transmembrane potential back down to zero meaning there is an equal amount of positive charges inside and outside the cell. So phase zero or the first step of cardiac depolarization is allowing sodium to follow its concentration gradient and flood back into the cell when sodium channels open up. This occurs when the myocytes receives a stimulus to open up the sodium channels and as the sodium floods in it actually raises the transmembrane potential from about negative 90 to about positive 10 millivolts. Now the positively charged potassium in the cell was hanging out in part due to the large negative membrane potential. And now that that has been abolished by allowing sodium to flood into the cell, potassium follows its concentration gradient and floods out of the cell. This is phase one of the cardiac depolarization cycle and it's the initial movement of potassium out of the cell which is an outward flow of positive ions. Since no more sodium is coming in we get a more negative charge in our cell because we have positive ions leaving and we go down to about zero millivolts from positive 10. Another thing that occurs with the change of the transmembrane potential from a negative number to a more positive value is a conformational change in L-type calcium channels. They now open up allowing calcium to flood into the cell. As calcium is flooding in and potassium is flooding out the membrane potential remains at zero because positive charges are entering and exiting. Calcium moves to the rannidine receptor and stimulates the sarcoplasmic reticulum to release calcium. This is called calcium-dependent calcium release and it is phase two of the cardiac depolarization cycle. As calcium is released from the sarcoplasmic reticulum it binds to tropomycin on top of the active actin binding site which lets actin bindamycin create crossbridge formation and signal for cardiac contraction. these steps, the sodium channels are closed and the calcium currents are
relatively small, but potassium continues to leave the cell. So the predominant movement of ions is positive charges leaving the cell. And this is called phase 3 of the depolarization cycle, and it is repolarization, where the efflux of positive charges leads to a more negative membrane potential, and it's potassium dependent. Sodium potassium ATPase pumps continue to pump sodium out of the cell and potassium in the cell, reestablishing the high amount of extracellular sodium and intracellular potassium that creates the trans-membrane potential, and allowing for the cycle to be repeated over and over. Now there's two ways that lopairamide actually affects the arrhythmogenicity of the heart based on prolongation of the acypotential. So lopairamide blocks the human-eather-related ogo-go or herg potassium inward rectifying channel. So during repolarization of phase 3, that potassium efflux takes quite a bit longer. And when we look at the overall trans-membrane potential, it has to do with the current of positively charged ions flowing in and the current of positively charged ions flowing out. Well, if you have a cell with a particularly strong calcium inward current and you blockade your potassium efflux current, you can actually make the cell more positive again. And this can actually trigger an action potential. If the outward flow of potassium is so slow, such as in the presence of a potassium channel blocker, that the inward influx of calcium actually predominates, we can get a triggered action potential because we're becoming more positive in our trans-membrane potential. And this is called an early after depolarization. And it functions as, well, a full depolarization that occurs during phase 2 or phase 3 of the cardiac action potential. And it's an ectopic beat that can spread a depolarizing signal. This is why there's even been some studies that hypothesize using calcium channel blockers to reduce the inward calcium flow and prevent early after depolarization's intorsod. This is also one of the proposed mechanisms of magnesium's efficacy intorsods. Magnesium being a divalent cation sort of takes the place of calcium at the cellular membrane and can reduce the inward flow of calcium, thus reducing the likelihood of getting an early after depolarization or reducing the amplitude of the early after depolarization. Now some have suggested that early after depolarizations alone are not enough to propagate torsods. I've read some studies that suggest because torsods is so susceptible to electricity, it's unlikely to be purely from early after depolarizations. As making all the tissue refractory at once doesn't really affect an early after depolarization since it occurs during repolarization. It's more likely that a reentrant rhythm around an area of slowly repolarizing tissue propagates the depolarizing signal that was started from the early after depolarization. And since low paramide creates conditions where cells take longer to repolarize, it might create a heterogeneous field of ventricular tissue where some areas aren't in a refractory state for longer because of their prolonged repolarization. And when we have areas that are not able to conduct ions in the depolarizing action potential, we create substrate for reentrant rhythms. So low paramide increases the likelihood that we'll have substrate to conduct a reentrant rhythm. And reentrant rhythms are particularly susceptible to defibrillation as making all the tissue refractory at once leads to termination of the rhythm. I'm not going to review reentrant rhythms because I think we covered them in the original episode. But basically, it's a self-propagating electrical depolarization signal that moves around in a ring around an area of non-conductive tissue, either because it's refractory due to having a prolonged repolarization phase or because it is dead tissue like saying a myocardial infarction. The second proposed mechanism of torsodes is that there are multiple ectopic pacemakers at a fixed width from each other so that they're beating off sync and not terminating each other's pacemaking activity. The pacemakers are likely reentrant rhythms surrounding areas of tissue with prolonged repolarization and are thus refractory. And of course, a paramide prolongs repolarization so it could create multiple heterogeneous areas of refractory tissue for which reentrant rhythms can propagate around. And in electrical studies where they implant two different pacemakers at a given width, it has reliably produced the same waveform or twisting of points as torsodes. Lastly, one other final hypothesis for how torsodes could be propagating through the ventricle is called the spiral theory where there's an area, maybe a cylinder of repolarizing tissue that is going much slower than the rest of the ventricle. And you get a reentrant rhythm that sort of spirals around the cylinder, going up and down the heart, but also moving around the circumference of the cylinder. And the waves of depolarization that this sort of spiral effect sends out has been shown in computer models to create the twisting of points in torsodes that we're so familiar with. I'm going to post a great article that reviews the possible propagation mechanisms of torsodes and the physiologic theories behind it in the show notes of this episode. That's it for today's episode. I hope maybe you learned a little bit about early after depolarizations or the types of mechanisms that propagate torsodes. There's still a lot to know, but it was kind of fun chewing into some of the details. Don't forget to check out the other many episodes which takes these concepts and distills them down into a more entertaining way to listen, albeit still rather complicated. And as always, thanks for listening. Don't forget to follow the show at whatever social media you use. That lab poison on Twitter, my Twitter is @enpoisonfarmd. We have an Instagram, talks_talk, and you can always reach out to us at
[email protected]. Thanks so much for listening. Until next time, talk so. Can you play us out? The information on this show is for educational purposes only and should not be interpreted as medical advisor treatment recommendations. Please contact your doctor for any health questions or call your local poison center at 1-800-222-1222 for poison-related questions. The opinions expressed on this podcast do not represent those of our employers. This show is poorly written and shotally produced by Ryan Feldman. Subscribe for future episodes and don't forget to share with your nerdy friends. See you next time. Bye-bye.
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