May 10, 2021

UCalgary researcher sheds light on 150-year mystery

Chen Lab discovers underlying molecular mechanism behind dangerous heart rhythm pattern
Wayne Chen
Wayne Chen

Cardiac alternans, the term used for a condition in which the heart alternates between a strong and weak beat, is associated with dangerous rhythm patterns in the heart, sudden cardiac death and heart failure. 

It was first discovered in 1872 by a German doctor who observed it in a patient who died one week after the anomaly was detected. Since then, scientists have come up with numerous theories — ranging from mechanical problems in the heart to problems with the heart’s electrical system — to explain this mysterious condition.

Over the past few decades, scientists have realized fluctuations in the amount of calcium (calcium alternans) released from the calcium storage site in muscle cells, the sarcoplasmic reticulum, play a primary role in the condition. More recent studies have drilled down even further, tracing the problem to the Type 2 Ryanodine Receptor (RyR2), which is the largest ion channel in the body and is essential for the heartbeat.

After years of experiments, a University of Calgary team, led by Dr. Wayne Chen, PhD, a professor at the Cumming School of Medicine who holds the Heart and Stroke Chair in Cardiovascular Research, has developed a new theory about the cause of cardiac alternans.

“We think that we have found a missing piece of the puzzle for a 150-year mystery,” says Chen, noting the work has been published in Circulation Research. “We think the real cause is the protein, calmodulin.”

Calmodulin is a naturally occurring, calcium-binding protein that is important in numerous signalling processes in the body. In the heart, calmodulin signals the RyR2 gateway to open or close, thereby regulating the flow of calcium in and out of the cytosol (the intracellular fluid), which keeps the heart’s beat steady.

Chen’s team discovered that too much calmodulin can cause inactivation of the RyR2, meaning the gateway was shut down too early, causing a weak contraction, followed by a strong contraction due to the lack of calmodulin inactivation of RyR2 in the following beat.

“This is a vicious cycle,” says Chen.

The study involved altering calmodulin and delivering it to living heart cells in mice using gene therapy. Scientists viewed the actions of calmodulin using confocal imaging, a powerful technology that allowed them to peer into the intact cells. They used computer modelling to provide further evidence supporting their conclusion. Many of the experiments were completed by the paper’s first author, Dr. Jinhong Wei, PhD.

“These are significant findings,” says Wei. “Knowing the root cause and progression of cardiac alternans offers potential for future therapy for dangerous arrhythmias.”

Libin Cardiovascular Institute Director, Dr. Paul Fedak, MD, PhD, a heart surgeon and researcher, agrees.

“Understanding the underlying mechanisms of disease is the first step towards therapy development,” he says. “This work is critical in solving a long mystery and improving outcomes for patients.”  

This work was supported the Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research to S.R.W. Chen (PJT-155940). The confocal imaging used in the research was supported in part by funds donated by Canadian Pacific Railway’s CP Has Heart Initiative and community donors.

Wayne Chen is a professor in the Department of Physiology and Pharmacology at the Cumming School of Medicine (CSM) and a member of both the Libin Cardiovascular Institute and Hotchkiss Brain Institute at the CSM.

Jinhong Wei is the recipient of the Libin Cardiovascular Institute and Cumming School of Medicine Postdoctoral Fellowship Award.

Paul Fedak is the director of the Libin Cardiovascular Institute, and the director of the Marlene and Don Campbell Family Cardiac Research Laboratory at the CSM.