Gene linked to sudden cardiac death identified

Researchers in the University of California, San Diego (UCSD) Institute of Molecular Medicine (IMM) have cloned and identified the role of a regulatory gene that in the presence of underlying heart failure, appears culpable in the occurrence of cardiac arrhythmias, or irregular heart beats, that can lead to sudden cardiac death.

Although the UCSD studies were conducted in mice, the same gene, called KChIP2 (Kv Channel-Interacting Protein 2), is known to regulate critical electrical currents in the human heart that are vital to sustaining the normal rhythmic beating of the heart.

According to the UCSD study, when KChIP2 is defective, it appears to lead to diminished activity of a specific potassium current called Ito, that normally plays a key role in insuring a normal pattern of electrical activation throughout the heart.

There is a loss of KChIP2 during heart failure, so the KChIP2 deficient mice have a defect similar to human heart failure. The study suggests that this decrease in KChIP2 not only results in a loss of the specific electrical current Ito, but also a higher susceptibility to any external trigger that might cause the onset of potentially fatal heart arrhythmias.

To demonstrate this genetic link, the UCSD IMM team cloned KChIP2, then created mice which lacked the gene. While these mice had no physical signs of abnormalities of the heart and appeared to function normally, a single extra heartbeat induced a sustained malignant heart rhythm that would ordinarily lead to sudden death in humans. Normal mice receiving the same stimulation did not develop any arrhythmias.

In humans, arrhythmias are sometimes triggered by everyday events, such as exercise, drinking a beverage with caffeine, or the heart skipping a beat. In patients with heart failure, the KChIP2 gene is measurably down regulated, leading to increased vulnerability to arrhythmia. In order to block lethal arrhythmias in these patients, researchers said the next step will be to identify the molecular chain of events that trigger the switching off of the KChIP2 gene. Then, they hope to design an agent to block this pathway before it affects KChIP2 levels in the failing heart.

The investigators also found that in mice bred with only 50% of the gene, the Ito channel operated at exactly 50% capacity, with diminished electrical current flow. "This indicates that KChIP2 acts as a precise molecular switch that dials-up the activity of this current," said Ching-Feng Cheng, a physician researcher in the study.