A potent​ial cure for long QT syndrome (LQTS)

In September 2013, researchers at National Heart Centre Singapore (NHCS) made a breakthrough – a world first. They discovered a potential cure for long QT syndrome (LQTS), in a petri dish.

The 10-member team from NHCS’ Research and Development Unit was working on Long QT Syndrome 2 (LQTS 2), one of 13 types of LQTS, when they made the discovery.

All 13 types of LQTS look the same on echocardiogram (ECG) readings. Types 1, 2 and 3 are the most common. LQTS 2 is caused by mutation in the hERG (human ether-a-go-go related gene), which affects the electrical system that controls heartbeats.

Dr Ashish Mehta, Senior Research Scientist, Research and Development Unit (RDU), NHCS, a member of the SingHealth group, who led the study, said the team used existing stem cell research to identify a drug compound that could reverse the effects of this mutation. “The drug compound allows the faulty proteins to bypass the cell’s ‘quality control check’, which then results in an increase in the inflow and outflow of potassium and corrects the effects of LQTS 2,” said Dr Mehta.

How they did it

The breakthrough occurred when the team used stem cells from a young patient with LQTS to mimic the disease in a petri dish. In two to three weeks, they generated human-induced pluripotent stem cells. They spent six weeks maturing the cells, then reprogrammed them into beating heart cells (real heart cells beating in a petri dish). ECG readings of these cells mirrored the patient’s heart condition, giving researchers a cellular model with which to understand how LQTS 2 develops in the human body.

The team then tested various drugs on the cellular model. Doing this in the petri dish allowed them to test without any risk to the patient, and to continuously monitor how the cells were reacting to the drugs. After a year of rigorous testing, they saw on ECG readings that a compound known as ALLN could correct the heart cells’ prolonged QT.

The research findings earned the team a best poster prize in 2013 at the prestigious European Society of Cardiology Congress – a large international cardiology meeting with about 30,000 participants.

Clinical trials ahead

The team’s task now is to test for toxicity and safety in similar conditions before finding partners to bring these drugs to clinical trials. Conventional drug testing can be a long and laborious process; it can take about 15 years to progress from a discovery to a commercially available drug.

The breakthrough is expected to quicken the quest for a cure. Prof Wong said, “Using this platform we can potentially halve the time required for drug testing by doing away with multiple drug screenings. We were able to focus our search for drugs that only affect the hERG mechanism instead of testing multiple drugs. Previously, we used computer simulations, but now we can show what happens during drug testing on actual live cells that mimic the disease. Results can be seen right there in the petri dish.”

There are other advantages. Dr Winston Shim, Scientific Director, RDU, NHCS, a member of the SingHealth group, said that making such drugs commercially available will involve partnering with pharmaceutical companies,drug discovery incubators and others, to test the compounds. The likelihood of these partnerships forming is high, as the team’s research in proving the efficacy of the drug has lowered the risks of testing, which can be very expensive.

“With our current knowledge of the drug and LQTS 2 manifestation, we were able to cherry-pick drugs likely to be out on the market for testing. Selecting these drugs means we know where to look for side effects,” said Dr Shim.

Associate Professor Philip Wong, Director, Research and Development Unit (RDU), National Heart Centre Singapore (NHCS), a member of the SingHealth group, explained that people with LQTS 2 will have to be on the drug for life, to manage the effects of the disease and reduce the risk of sudden cardiac death.

Long QT syndrome (LQTS) symptoms: Do you have it?

Since LQTS has no signs or symptoms, many people are unaware they have it. See a doctor if:

  • A parent, sibling or child has been diagnosed with LQTS. The condition may be inherited.
  • You suddenly faint during physical exertion or when you experience intense emotions.
  • You have seizures. A continually erratic heartbeat deprives the brain of oxygen – this condition is what causes seizures.

Long QT syndrome (LQTS): Treatment

Studies have shown that if left untreated, more than 50 per cent of people with inherited Long QT Syndrome (LQTS) die within 10 years.

To manage LQTS, patients are advised to avoid competitive sports. Treatment includes the following:

Medication: Drugs like beta blockers slow the heart rate by blunting the heart’s reaction to adrenaline in times of stress, fear or exertion, making dangerous rhythms in a patient with LQTS less likely.

Medical procedures: An Implantable Cardioverter Defibrillator (ICD) is implanted under the skin of the patient’s chest, where it continuously monitors his heartbeat. It will deliver electrical shocks to restore a normal heart rhythm when necessary.

See previous page to find out what exactly is Long QT Syndrome (LQTS).

Ref: R14