Exploring the Genetics of Heart Arrhythmia
The heart's regular rhythm depends on the electrical signals that cycle through it. At the most basic level, these signals are created by the movement of charged particles within the heart tissue. Anything that alters the electrical balance of this process can give a person an irregular heart beat, or arrhythmia, which can be life threatening.
Ali Nekouzadeh, D.Sc., a newly named Children’s Discovery Institute Fellow, is studying the heart's electrical system by taking a technologically enhanced look at some of the pore-like structures that help transmit the charged particles, called ions, across the cardiac cell membrane to generate the electrical signals. Abnormalities in these minute pores have been linked to irregular heart rhythms in children and adults.
Nekouzadeh’s unusual approach makes use of mathematical models that simulate the properties of the molecular-sized pores. These pores, called ion channels, consist of one or more proteins. They let ions travel in and out of heart muscle cells, and through careful controlling of the timing and amplitude of the ion flow, generate and conduct the heart’s electrical impulses. Tiny changes in the delicate structure of ion channels can alter the timing and the amplitude of the ion flow and consequently disturb the heart’s well-coordinated operation.
Nekouzadeh, a postdoctoral research associate in biomedical engineering, will use biophysical principles and mathematical equations that describe the motion at the molecular level of the internal movements of these flexible pores as they open and close to transmit electrical currents. He hopes to find out how particular variations in ion channel genes cause changes in the heart's electrical signals and ultimately lead to arrhythmias.
With funding from the Children’s Discovery Institute, Nekouzadeh will study genetic mutations known to cause Long QT syndrome, an inherited disorder in which the heart muscle takes longer than normal to recharge between beats. In people with a particular type of Long QT syndrome, physical or emotional stress can trigger rapid, erratic heartbeats, which may lead to fainting, seizures and sudden death.
The syndrome affects about 1 in 5,000 people and results in 3,000 deaths in the United States each year. About half of patients with the syndrome have their first symptoms before age 12.
Using computer-based mathematical models that replicate the shape and action of ion channels, Nekouzadeh will simulate the motion of the normal and mutant ion channel proteins to learn about the effect of different genetic mutations. So far, scientists have found mutations in at least nine genes associated with Long QT syndrome, with mutations in three genes accounting for about 75 percent of cases.
“There are thousands of biochemical units, or amino acids, that make up these ion channels, and if you change one or two of them, you can get a totally different behavior,” he said. “The result can be that the electrical signals responsible for the heart’s contractions are altered, as they are in Long QT syndrome.”
While there have been a few small research projects in a similar area, Nekouzadeh said his approach is unique because he examines the movement of substructures within ion channels.
“If this is successful, it will provide, for the first time, a mechanistic link between the molecular structure of ion channels, their modifications by mutations, disease or drugs and the resulting function at the cell and tissue levels,” he said.
Those discoveries could lead to the development of therapeutic treatments for Long QT syndrome as well as for other diseases related to electrical signals, including other heart-related diseases and neuromuscular diseases such as Parkinson’s disease.
“These electrical signals are a very important physiological feature of many types of cells because they help cells communicate with each other,” he said. “What we learn from this research could also be important for other electrically excitable cells, which include muscle cells and nerve cells.”
Nekouzadeh said he is grateful for the support from the Children’s Discovery Institute that has enabled this research. “The research is novel and untested, but the high risk could lead to a high reward,” Nekouzadeh said. "I hope that I can develop some framework for understanding ion channels that helps many different areas of science.”
-Ali Nekouzadeh, Ph.D.