(CHICAGO) — Rush University Medical Center researchers have identified the underlying mechanism of calcium-triggered cardiac arrhythmias, or irregular heartbeats. The discovery, described in the Jan. 19 issue of Nature Medicine, has major implications for the development of molecularly designed drugs specifically targeted at this form of arrhythmia.
The study was led by Wayne, Chen, PhD, professor of molecular biophysics and physiology at Rush and professor of physiology and biochemistry at the University of Calgary-Libin Institute. Michael Fill, PhD, professor of molecular biophysics and physiology at Rush, collaborated on the research.
Cardiac arrhythmias can cause dizziness and fainting, or in severe cases, sudden death. While many factors, including genetics, contribute to the development of arrhythmias, research has shown that a common cause of cardiac arrhythmias is calcium overload. Calcium overload disrupts the finely controlled electrical activity governing contraction of heart muscle.
Calcium is stored inside cardiac cells, much like skeletal muscle cells, in preparation for contraction. The protein responsible for release of calcium is known as the cardiac ryanodine receptor (RyR2), or the calcium release channel, which acts like a safety valve that prevents calcium overload.
“This is a very important protein because naturally occurring mutations in the gene have been linked to many cardiac diseases, including atrial fibrillation and sudden cardiac death,” Chen said.
“The problem with mutations in the ryanodine receptor is that it lowers the threshold for the calcium release, leading to another phenomenon called spontaneous calcium release. Large spontaneous calcium release events can cause life-threatening cardiac arrhythmias,” he said.
Using a combination of molecular biological, electrophysiologic and genetic engineering techniques, the Rush scientists, in working with researchers at the University of Calgary's Libin Institute, showed that the ryanodine receptor contains a calcium sensor that recognizes the concentration of calcium within the heart cells. When the calcium level is too high, the sensor opens the channel. Using a genetically modified mouse model, the research group was able to manipulate the sensor and prevent calcium-triggered arrhythmias.
"The calcium-sensing gate mechanism discovered here is an entirely novel concept with potential to shift our general understanding of ion channel gating, the molecular mechanisms of cardiac arrhythmias and the treatment of calcium-triggered arrhythmias,” Chen said.