Study explains how genetic mutations lead to an inherited heart condition linked to sudden death
An international team of researchers co-led by University of Toronto professor Michael Gollob has uncovered the mechanism driving a unique form of short QT syndrome, an inherited condition that can cause sudden cardiac death in otherwise healthy young individuals.
The study, published recently in the European Heart Journal, provides an explanation for how genetic mutations in the SLC4A3 gene can lead to this uncommon heart condition.
“Short QT syndrome is an electrical condition of the heart that has nothing to do with cholesterol, blood pressure or blocked arteries,” says Gollob, who is a professor of physiology and medicine at U of T’s Temerty Faculty of Medicine.
“It’s a genetic condition that can make the heart vulnerable to a dangerous arrhythmia, and many people do not know they have it until suddenly, a tragedy occurs.”
He estimates that short QT syndrome, which was first described in 2003, affects roughly one in 20,000 people.
In 2017, researchers studying two Danish families identified the SLC4A3 gene as a new genetic cause of short QT syndrome. The gene encodes a transporter protein that facilitates the exchange of chloride and bicarbonate ions in and out of the cell, a key process to maintain pH balance in the cellular environment.
Gollob says they were motivated to study how a pH imbalance could trigger irregular heartbeats, or arrhythmias, and lead to short QT syndrome because it represents a previously uncharacterized form of the condition.
To answer this question, the researchers used skin cells from a patient with SLC4A3-driven short QT syndrome, which they reprogrammed into stem cells and later differentiated into heart muscle cells and miniature 3-D heart organoids.
These models allowed the researchers to confirm clinical observations by showing that lab-grown heart muscle cells and heart organoids with SLC4A3 mutations had more arrhythmia-like events than those with a normal version of the gene.
The researchers found that these mutations made the transporter protein less stable, resulting in more proteins being degraded and fewer functional proteins at the cell barrier. Loss of the transporter protein led to a higher pH inside the heart muscle cells, which disrupted calcium currents and produced an irregular heartbeat. The researchers also used gene editing to correct the SLC4A3 mutations and restore normal cell pH, calcium flow and heart rhythms.
Collectively, these findings provide strong evidence that these mutations are a cause — and not a correlate — of heart malfunction in people with this subtype of short QT syndrome.
“What makes this form of short QT syndrome so interesting is that it’s caused by a pH imbalance in heart cells, and that change in pH has secondary effects on electrical activity,” says Gollob.
He notes that almost all other known cases of short QT syndrome are caused by genetic mutations in proteins that form channels to regulate the flow of potassium or calcium, two elements that work in tandem to allow heart cells to relax and contract.
Gollob is hopeful that studies like this one will lead to more targeted and less toxic therapies for people affected by short QT syndrome.
“Once you understand the mechanism of disease, you can now start hypothesizing about novel drug treatments that may be more effective,” he says.
Currently, the main treatment for people with short QT syndrome who survived a cardiac arrest is an implantable defibrillator. Gollob says that while medications are also available — the most commonly used drugs are quinidine and sotalol — they have severe side effects and many patients cannot tolerate the necessary doses.
Gollob and his collaborators are also trying to understand how to risk stratify people who have a genetic mutation associated with short QT syndrome but do not exhibit any symptoms.
He says that currently in his clinic, he sees about 15 families affected by the condition. Many individuals were referred to his clinic after a family member experienced a cardiac arrest or other serious cardiac-related event.
“Can we learn more about who’s at highest risk in our families and who isn’t? Can we identify genetic modifiers that may predict risk?” he asks.
Gollob’s research is supported by the Ian Copland Arrhythmia and Sudden Death Research Fund at the University of Toronto.