Did You Know?
Interesting Fact
The SCN5A gene, central to LQT3, encodes the alpha subunit of the cardiac sodium channel (Nav1.5). In the heart, this channel is responsible for the rapid influx of sodium that triggers each action potential. Mutations in SCN5A can cause sodium channels to stay open longer than they should, prolonging depolarization and lengthening the QT interval.
But Nav1.5 isn’t just in the heart. It’s also expressed in the interstitial cells of Cajal, the pacemaker cells of the intestine that generate slow waves to propel food forward. Dysfunction here can impair gut motility, leading to symptoms like constipation, bloating, or irregular bowel movements. For some patients, tummy troubles may be the earliest or most persistent manifestation of an SCN5A variant.
This overlap highlights the shared electrophysiology of excitable tissues: the same sodium current that determines whether a heartbeat resets on time also governs whether food moves efficiently through the intestines. Increasingly, researchers are finding that ion channel mutations create syndromes that cut across organs—the so-called “channelopathies.” LQT3 is a prime example: one gene, two rhythms—cardiac and intestinal—linked by a common molecular mechanism.
Long QT Syndrome Type 3
Long QT 3 is different to types 1 and 2 for a number of reasons: Firstly, it is a sodium channel malfunction rather than potassium. Secondly, it isn’t triggered by tachycardia but the QT actually prolongs at lower heart rates (bradycardia). Finally, it is a gain of function rather than a loss of function. The ECG in LQTS3 usually shows a delayed, pointed T wave and allows clear observation of the ST segment prolongation.
LQT3 mutations are more lethal but less common.
There is still a lot of debate around the efficacy of beta blockers for Long QT 3 patients, with the most recent research (2023) suggesting that betas do not have any protective effect for SCN5A mutations. Sodium channel blockers are often recommended for LQT3 patients with Mexiletine or Flecainide actually reducing the QT interval significantly due to blocking the late surge of sodium caused by the channel improperly inactivating.
These drugs however, especially Mexiletine, have numerous side effects which mean patient compliance with them long term is low.
The affected gene in LQTS3 is SCN5A, which codes for the Nav1.5 sodium channel. Defective inactivation of the channel from Phase 0 allows sustained input of Sodium up to phase 3 of the action potential, prolonging its duration. The late current is due to failure of the channel to remain inactivated and hence enter a bursting mode in which significant current can enter when it should not. As the sodium channel is not adequately inactivated, the membrane remains slightly depolarised by the slow leaking of sodium into the cell. This leads to instability of the membrane, and early after-depolarisations.
A SCN5A mutation causes a gain of function in the sodium channel.
The train‘s doors should be shut so it can depart. However, the door has been left a little open and some passengers without tickets, rush the train doors and sneak on board. They late arrivals mean that the train can’t leave on time.