Battling Sudden Arrhythmic Death in Hearts

In cardiology, arrhythmia, a type of irregular heartbeat due to electrical abnormalities, is a serious condition that needs quick attention. Currently, the only type of treatment are antiarrhythmic drugs, such as sodium channel blockers and beta-blockers. However, these drugs have the potential to worsen the arrhythmia that led them to take the medication and worsen chances of survival.

The heart runs on the contraction and relaxation of muscles, but more specifically, the electrical signals in the heart. A healthy heart requires the electrical signal to originate from the correct place - the AV node - and for the signal to conduct. Arrhythmia occurs when the signal originates in the wrong place, is blocked, or erratically traveling signals. The act of creating electrical signals is based on the movement and release of calcium. This production is caused by RyR2, a gene that provides instructions for a protein that acts as a calcium channel in muscle cells, letting calcium in and out of the cell's storage area. The ability of the muscles to create force is based on the amount, timing of release, and magnitude of calcium released.

It was found that a Reactive Oxygen Species or ROS-mediated oxidation (unstable product of metabolism that are able to steal electrons from other molecules). These species have the ability to chemically modify the calcium channel. Because the channel is destabilized, the channel is set halfway between being closed and open, letting calcium leak out. Calcium dribbles out into the jelly-like substance in the cell.

However, when the amount of calcium rises, the cell attempts to get rid of the unwanted molecule. Therefore, it uses a sodium and calcium channel, which moves 3 ions (you can think of it as "pieces") of sodium into the cell for each calcium ion that leaves. The more sodium enters the cell, the more positively charged the cell becomes, because each individual ion of sodium is positively charged. This is when a Delayed Afterdepolarization (DAD) occurs. Because electrical signals are caused by a big spike in positively-charged ions entering the cell, this is a case of a wrongly conducted electrical signal.

Since an extra heartbeat is produced (and it can be assumed that as the RyR2 continues to leak, more wrong heartbeats are produced), it can lead to dangerous arrhythmias. So, scientists have been looking to find something to inhibit the RyR2 and this answer is Dantrolene.

In Joshi et. al, scientists tested whether a molecule that could block the calcium channel could stop calcium leaks. They found that it was possible and that it prevented electrical instability and help the heart pump well.

Results

Joshi et. al gave guinea pigs arrhythmias (Premature ventricular contraction (PVC), Ventricular tachycardia, ventricular fibrillation, etc.). Scientists treated guinea pigs with Dantrolene and found that it drastically reduced the rate of PVCs in the animal.

It was also found that it also prevented the thinning of the ventricle walls and lowered the amount of fibrotic tissue. Thin heart walls do not beat as steadily as healthy heart muscle, which makes it easier for arrhythmias to start. Fibrotic tissue is scar tissue that replaces damaged heart tissue and because it is stiff, it cannot conduct electricity well and cannot contract well, leading to possible arrhythmias. Therefore, not only does Dantrolene reduce arrhythmias through fixing stray electrical signals, it prevents them through mending heart tissue.

Dantrolene has many exciting possibilities for the future of fighting irregular heart rhythms, which continue to be a big cause of illness and possible death. I am excited to see how this field progresses!