For this episode of the podcast, we discussed magnificent magnesium. In particular, we reviewed why it is so effective at treating torsades de pointes and other seemingly unrelated conditions like asthma and eclampsia.
Torsades de pointes was first described by a French physician named Francois Dessertenne in 1966, after he observed the characteristic EKG findings on a patient of his in the hospital. He described it as “ventricular tachycardia with two variable foci”. This is actually a reasonable description, as torsades is a type of polymorphic ventricular tachycardia. In the paper Dessertenne called the arrhythmia “torsades de pointes” or, in English, twisting peaks.
Importantly, torsades de pointes only arises in the context of a prolonged QT interval. Although there is a congenital long QT syndrome, most commonly the QT interval becomes prolonged from exposure to certain medications, myocardial ischemia, or electrolyte derangements. There is a specific sequence of events that leads to torsades:
- Following a normal sinus beat the ventricles repolarize. In the setting of a prolonged QT interval this repolarization process takes longer.
- If a ventricular ectopic beat occurs during this repolarization period, torsades can be triggered. This event is referred to as an early after-depolarization (or EAD) and it sets off a re-entrant circuit in the ventricle.
- The up and down morphology, or the “twisting of peaks” that Francois Dessertenne noted, is actually the circulation of this re-entrant circuit that’s been triggered.
Magnesium for the win!
To understand why magnesium is an effective treatment for torsades de pointes, we must review the mechanics of cardiac myocyte repolarization.
- Sodium influx drives depolarization.
- This is followed by repolarization, which has 4 phases.
- Phase 1 involves potassium efflux from the myocyte
- Phase 2 involves both potassium efflux and calcium influx
- Phases 3 and 4 involve more potassium efflux
Potassium efflux repolarizes by driving positive charge out of the cell, making the membrane potential more negative. During phase 2, calcium influx temporarily balances the flow of charge so that repolarization stalls. This is represented by the plateau phase we are used to seeing on the membrane potential vs time graph. The early-after depolarizations that trigger torsades occur during phase 2 with calcium influx into the cell.
A case series published in 1984 from the American Journal of Cardiology was the first description of the use of magnesium sulfate infusions to treat torsades. They successfully treated three patients, all of whom had acquired prolonged QT intervals from different medications. At the time the standard treatments for torsades were overdrive pacing or isoproterenol.
All of the patients in the case series had normal serum magnesium levels. So why did they use it? The authors cited another case series from 1968 where two patients were treated for what was thought to be ventricular fibrillation induced by hypomagnesiemia and long QT. The authors from the 1984 report correctly re-interpreted the 1968 tracings as actually having been torsades, and then seem to have made the connection between low magnesium levels in those patients and using magnesium to treat torsades in the patients in front of them. Fortunately, their hypothesis was correct.
How does magnesium work? Magnesium functions physiologically as a calcium channel blocker. This makes sense because they both form divalent cations and sit right on top of each other in the second column of the periodic table, in the group known as the alkaline earth metals. By blocking calcium channels during repolarization, magnesium suppresses the early afterdepolarizations that lead to torsades.
This was first shown to be the case in an experiment from the 1980s involving dogs that had EADs induced by cesium infusions. Magnesium terminated the arrhythmias and stopped the EADs.
This calcium channel blocking mechanism helps explain why magnesium is an effective treatment for other conditions. One example is bronchospasm during asthma exacerbations. By blocking calcium channels, magnesium both decreases calcium influx into bronchial smooth muscle cells and competes with calcium for binding to calmodulin, blocking calcium’s ability to activate actin-myosin cross bridge cycling. This leads to relaxation of smooth muscle cells and bronchodilation.
Another example is eclampsia. Magnesium is the drug of choice for seizure prevention in severe pre-eclampsia and eclampsia. While there are a number of explanatory theories, the primary mechanism is thought to be that magnesium inhibits excitatory NMDA receptors. NMDA binds glutamate but the ion that conducts across the receptor is calcium. And, unsurprisingly, magnesium is able to block calcium flow through NMDA and block neuro-excitation. It’s though that cerebral vasoconstriction may also play a role in eclamptic seizures and magnesium, via its calcium channel blocking effects, would be helpful there as well.
One final condition where magnesium may work via its calcium channel blocking effects: atrial fibrillation with rapid ventricular response. Magnesium has been shown help with rate control of rapid atrial fibrillation, probably via a similar mechanism as a calcium channel blocker (sort of like diltiazem).
Take Home de Pointes
- Torsades de pointes is a ventricular, re-entrant arrhythmia that occurs exclusively in the setting of a prolonged QT interval.
- Early afterdepolarizations, which are mediated by calcium influx, trigger torsades.
- Magnesium acts as a calcium channel blocker when treating torsades. This same mechanism treats bronchospasm in asthma and prevents seizures in eclampsia.
- Understand the pathophysiology and risk factors for torsades de pointes
- Learn about the mechanism of action of magnesium when treating torsades
- Understand the mechanism of action for magnesium’s therapeutic role in asthma and eclampsia
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Listen to the episode
Credits & Citation
◾️Episode written by Avi Cooper
◾️Audio edited by Clair Morgan of nodderly.com
◾️Show notes by Tony Breu and Avi Cooper
Cooper AZ, Abrams HR, Breu AC. Why does magnesium treat torsades de pointes? The Curious Clinicians Podcast. October 28, 2020. https://curiousclinicians.com/2020/10/28/episode-11-why-does-magnesium-treat-torsades-de-pointes/(opens in a new tab)
Image credit: https://jetem.org/torsades_depointes/