Genetic mutations in ARVC typically affect the function of desmosomes, which are structures that attach heart muscle cells to one another. Desmosomes provide strength to the heart muscle and play a signalling role between neighbouring cells. Without normal desmosomes, the heart muscle cells will detach from one another and die, particularly when the heart muscle is placed under stress (such as during vigorous exercise). The damaged heart muscle is gradually replaced by fat and scar tissue. These changes also disrupt the electrical signals that control the heartbeat, which can lead to dangerous arrhythmia and sudden cardiac death.
The team discovered that key characteristics of the disease, such as abnormal "fatty changes" and altered distribution of proteins involved in cell-cell connections (called desmosomal proteins) are reproduced in the heart cells. This new cellular model for studying the disease could help to improve understanding on how these mutations lead to arrhythmias and clinical manifestations of ARVC.
The human heart cell model was developed using patient-specific induced pluripotent stem cells, converting skin samples from an ARVC patient into heart muscle cells on a petri dish outside the body. This technique is based on the induced pluripotent stem cells (iPSC) technology of transforming skin cells into stem cells developed by Professor Shinya Yamanaka, winner of the 2012 Nobel Prize in Physiology/Medicine - bypassing the ethical concerns (and political hype) of human embryonic stem cells. They developed a key clinical application for iPSC technology by replicating patients' own heart cells outside the body for the study of genetic cardiovascular diseases. Heart cells from patients with inherited heart muscle disease can now be studied in a petri dish without risk to patients, including the possibility of testing new treatments.
ARVC occurs in an estimated 1 in 2,000 to 1 in 5,000 people. The disorder may be under-diagnosed as it can be difficult to detect in people with mild or no symptoms. ARVC is a rare condition, more commonly detected in younger individuals, in their 20s and 30s, particularly males, and is more lethal in that age group. Common symptoms if they do occur include palpitations, light-headedness and fainting. Those with family history of sudden cardiac death are at higher risk.
Associate Professor Philip Wong, Director, Research and Development Unit, National Heart Centre Singapore (NHCS)said, "For the first time, we have created a 'crystal ball' of the disease outside the body, to look into the patient's detailed genetic makeup and its relationship to the manifestation of disease. There would be significant opportunities now to safely study the effects of environmental factors and treatments, including gene and drug therapy, on such diseases as they do not have to be tested on patients in the first instance."
The team has also been successful in using the iPSC technology to replicate other inherited heart rhythm diseases such as long QT syndrome (LQTS) and Brugada Syndrome. These diseases are caused by mutations in genes coding for proteins that control the electrical activity of the heart which can lead to ventricular arrhythmias, blackouts and sudden cardiac death.
"Our success in using iPSCs as a platform for the study of genetic cardiovascular diseases was made possible with the clear and cohesive networking between the research scientists, clinicians and bio-medical engineers. The collaborative efforts with other leading research institutions in Singapore, including Duke-NUS, NUS and A*STAR, has allowed NHCS to take a lead globally in this area and enhance Singapore's reputation as a leader in translational cardiovascular research," said Wong. "The next stage is for us to use this ARVC model to understand more about the disease and to specifically use such models to risk stratify patients with risk of cardiac arrhythmias. Such models will allow us to measure risk in individuals safely and tailor individual preventive programmes and treatments to patients in a more precise manner, i.e. the practice of 'stratified and personalised' medicine."
Published in the European Heart Journal.
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