University of Calgary scientists have increased our understanding about the role of genetics in serious heart arrhythmias with a groundbreaking discovery: enhanced function in a gene (ITPR1) widely associated with movement disorders and seizures is also linked to cardiac arrhythmias that can lead to sudden cardiac arrest; one of the most devastating cardiac conditions.
"These findings have significant implications for diagnosing, managing and treating cardiac arrhythmias," says Dr. Wayne Chen, PhD, a professor at the Cumming School of Medicine, and principal investigator on the study.
Wayne Chen in his lab at the Cumming School of Medicine. Photo Credit: Britton Ledingham, iEvolve Media
The research, published in Circulation, reveals how gain-of-function (GOF) mutations in ITPR1 disrupt how the heart manages calcium, a critical part of keeping the heartbeat steady.
According to Chen, the discovery is an important first step in decreasing the risk of sudden cardiac death for individuals with the defective ITPR1 gene.
"These findings have significant implications for diagnosing, managing and treating cardiac arrhythmias," says Dr. Chen.
The Role of ITPR1 in the Heart
Calcium plays a critical role in cellular functions such as muscle contraction and electrical signaling. In the heart, proper calcium regulation is essential for maintaining a regular heartbeat.
The ITPR1 gene encodes a calcium release channel found in various tissues, including the brain and the heart's Purkinje fibers, specialized muscle fibers that facilitate the heart's ability to pump blood effectively.
Chen's study reveals that GOF mutations on this gene increase spontaneous calcium release in Purkinje cells, triggering arrhythmias under stress conditions, such as during periods of vigorous activity or emotional stress.
The research, conducted in mice, included international collaborators. Together they identified 21 GOF mutations in ITPR1. To assess the potential role of these mutations, the team used data from a UK Biobank to find seven mutations associated with cardiac arrhythmias in humans.
According to Chen, the discovery is an important first step in helping patients with ITPR1-related cardiac arrhythmias.
"Early identification of GOF ITPR1 mutations could guide personalized treatment strategies, potentially saving lives," he says. "Now clinicians can include this gene in genetic panels for diagnosing unexplained arrhythmias."
Dr. Robert Rose, PhD, deputy director of the Libin Cardiovascular Institute, says Chen's work has potential to improve patient outcomes.
"This work has important implications for personalized or precision medicine in the area of inherited cardiac arrhythmias," he says. "Understanding mechanisms is essential as it can lead to new strategies for treatment as well as for diagnostic screening in arrhythmia patients."
The Heart and Stroke Foundation estimates about 60,000 cardiac arrests occur outside of hospitals in Canada, with only 10 per cent of individuals surviving.
This work was supported by research grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Canada, the National Natural Science Foundation of China, the National Institutes of Health, and the Spanish Ministry of Science Innovation and Universities.
