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A matter of the heart
APBN talks to Assoc Prof Philip Wong to get insights on a potential drug treatment for high-risk patients dying from sudden cardiac death.

Long QT syndrome (LQTS) affects approximately one in every 5,000 individuals, and those with a family history of LQTS are at a higher risk of being diagnosed with it. Such erratic electrical activity of the heart can be triggered by emotional or physical stress, exercise, or even the ringing of a door bell, and could lead to fainting spells, seizures or if prolonged, sudden cardiac death. Without treatment, more than half of those with inherited LQTS can die within 10 years.

The current therapy for such a condition is to have devices such as implantable cardioverter defibrillators (ICD) implanted in the patients to prevent sudden cardiac death. However, some local and regional studies have shown that the acceptance of device therapy is low due to possible barriers that include socio-cultural and demographic factors such as lack of knowledge on the life-saving advantages of these implantable devices, the unwillingness to have an unnatural object in their bodies, the fear of complications and age.

Researchers recently found a drug that can reverse the effects of LQTS type 2 (one of the most common genetic mutations that cause variations of LQTS), providing an alternative option for patients who are averse to having a foreign device implanted in them. We talk to Prof Philip Wong, who is part of the research team to understand more about LQTS.

1.Could you tell us a little bit about your background?

I joined SingHealth in 2001 and I’m currently a Senior Consultant at the Department of Cardiology at the National Heart Centre Singapore. I am also Deputy Director of the National Heart Research Institute Singapore, and my interest is in translational research, particularly in the areas of regenerative medicine, medical technology and digital health.

2. Can you tell us what is long QT syndrome?

The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle. A lengthened QT interval is a marker for potential arrhythmia (erratic fast heartbeats) and a risk factor for sudden cardiac death (SCD).

LQTS, where there is a prolongation of the QT interval, is an inherited condition, affecting approximately one in 5,000 people worldwide. There are different variants but the most common are LQTS type 1 and type 2, which are due to abnormalities in the transportation of important ions in and out of the heart cell, resulting in abnormal electrical instability of the heart. This electrical instability can trigger arrhythmia, and if left untreated, can be life-threatening.

LQTS is a well-known cause of SCD, especially in the younger population. Triggering factors of the heart’s erratic electrical activity include stressful physical activity, or even emotions such as anger. LQTS is often asymptomatic until an electrical event occurs and is usually discovered either through a routine electrocardiogram (ECG) or when a patient presents with loss of consciousness for an unknown reason.

LQTS type 2 usually occurs in families as it is an inherited condition, and thus screening for LQTS should be performed for the family if one of the family members presents with LQTS since the risk of inheriting the condition is high and the consequences of not treating it early can be dire.

3. What are the current treatments for long QT syndrome?

The current treatments, which are geared towards preventing a malignant arrhythmia, include drugs such as beta-blockers (which slow the heart rate down), and the implantation of an Implantable Cardioverter Defibrillator (ICD) in the chest wall, which detects cardiac arrhythmia and fires an electrical charge to ‘reset’ the heart to a normal rhythm.

Patients with LQTS are also advised to avoid all strenuous physical activities and limit their emotional extremes to minimise the triggering of serious arrhythmias.

4. What are some concerns and challenges that people with long QT syndrome face when dealing with their treatment?

Beta–blockers, which LQTS patients have to take for life, do not treat the underlying condition; rather, this medication aims at slowing the heart rate and in turn prevents SCD, but there is still a risk that the condition can occur despite being on the drug.

The other treatment option is an ICD, which is an invasive procedure. While having an ICD may prevent SCD, the use of devices carries some risks (e.g. patients with ICDs cannot swim, inappropriate shocks to the heart), complications and constraints (e.g. some patients are not suitable for ICD due to age or body size such as young children).

As LQTS can be a congenital condition, there is a possibility that the next generation or families/relatives will inherit it. Hence, genetic counselling is advised if either one in a couple has LQTS before they plan to have children.

5. What does it feel like for someone living with long QT syndrome?

A person who has been diagnosed with LQTS often live with the fear that his or her heart can suddenly develop cardiac arrhythmia anytime, leading to sudden collapse. There is little chance of doing any strenuous physical activity, regardless of age, without the possibility of experiencing SCD.

LQTS patients who have implanted ICDs need to go for regular checks to ensure that there is enough battery power in the ICD, especially if the ICD has been firing off shocks. Such patients would also experience the inconvenience of having to avoid situations that involve triggers which can set off erratic electrical activity of the heart, such as places with loud sounds.

6. Most people do not understand the psychological impact of living and dealing with long QT syndrome. Your team has discovered a new drug that can reverse the effects of LQTS type 2, providing an alternative option for patients who are averse to having a foreign device implanted in them. Can you elaborate on the mechanism of this drug?

The NHCS research team, which comprises Dr Ashish Mehta, Dr Chrishan Ramachandra and Dr Winston Shim, discovered this drug using a unique drug discovery platform. Traditional methods of drug discovery which include the use of computer modelling, bio-informatics and animal models were not utilised in this discovery. The team used heart muscle tissue, derived from skin cells and blood of LQTS patients to create the disease entity in a petri dish in the laboratory, using Induced Pluripotent Stem Cell (iPSC) technology.

In the iPSC platform, mature cells such as blood cells or skin cells are re-programmed into primitive stem cells, from which a continuous lineage of heart tissue can be created in a petri dish for testing. This is a unique form of ”personalised medicine” as the tissues created from such cells have the same features (phenotype) and genetic makeup of the patients, along with the characteristic prolonged QT instability, but in the form of heart tissue in the ”petri dish”. Different drugs are then tested safely in the petri dish (and not on patients) and the outcomes observed.

A defect in the hERG gene in LQTS type 2 patients causes problems in the transportation of important ions within the cell during heart muscle contraction, which leads to electrical instability within the heart. Using the iPSC-derived heart tissues from five LQTS patients, the team reproduced these similar abnormalities and characterised the electrical instability in these heart cells. They found that a drug, which has been approved by USA’s FDA for use to treat cystic fibrosis of the lung (which, like LQTS, is also an inherited condition that affects the transportation of important ions but in the lung), completely reverses the condition of prolonged QT in the petri dish.

With clinical trials to test if this drug can remove the risk of arrhythmia, especially under stress, it represents a potential treatment for LQTS patients to reverse the effects of LQTS and to go on to lead normal lives, without the fear of developing life-threatening arrhythmia and SCD.

7. Your team’s findings were shared at the European Society of Cardiology Congress at Barcelona, Spain, what are the next steps for this drug?

This important finding has been published in the European Heart Journal, a prestigious journal of the European Society of Cardiology. We are currently seeking potential collaborations with industry partners, including the manufacturer of the drug, to conduct clinical trials to develop this new treatment modality for LQTS patients based on our research findings.

This interview was conducted by Lim Guan Yu.

About the Author

Assoc Prof Philip Wong
MBBS, MRCP(UK), FRCP, FAMS, FACC(USA)
Senior Consultant at the Department of Cardiology at the National Heart Centre Singapore
Deputy Director of the National Heart Research Institute Singapore

Associate Professor Philip Wong’s sub-specialty interest is in interventional cardiology with research interest in pre-clinical discovery and development work in health-tech and digital technologies.

Prof Wong founded Asia’s first GLP-certified pre-clinical medical device CRO, Innoheart Pte Ltd in 2008. He has been the study PI for more than 100 of its highly complex implantable device projects. Innoheart’s ability to create specialised disease models for testing medical device implants and new drugs is also well-known. He is the recipient of A*STAR Programme Leaders Award for Cardiology, a programme to promote med-tech innovations between hospitals, academia and industry. He is also Adjunct Professor, School of Materials Science, NTU, where he teaches development of medical devices and digital technologies. He has published more than 70 peer-reviewed publications and is Associate Professor at Duke-NUS Graduate Medical School. In 2009, Prof Wong also founded WEB Biotechnology Pte Ltd, a company that makes the Spyder ECG, a wearable ECG sensor which transmits medical grade data wirelessly using a smartphone from the patient to the physician continuously and almost instantaneously across the world.

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APBN Editorial Calendar 2017
January:
Healthcare Focus: LUNGS
February:
War on CANCER
March:
Get to Know TCM
April:
Diabetes: The Big Picture
May:
The Piece of Your Mind - Brain Health/Science
June:
Advocacies in Support of Rare Disease Patients
July:
Food Science & Technology
August:
Eye – the Window to your Soul
September:
Infectious Diseases
October:
A change of heart — Cardiovascular diseases
November:
Diseases threatening our Children
December:
Skin Diseases/Allergic Reactions
Editorial calendar is subjected to changes.
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