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Gene Linked To Sudden Cardiac Death Identified By UCSD School Of Medicine Researchers

Date:
December 17, 2001
Source:
University Of California - San Diego
Summary:
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.

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.

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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. The findings are published in the December 14, 2001 issue of the journal Cell.

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.

“We knew that in all forms of heart failure, there’s a dramatic decrease in the Ito channel current, but we didn’t know why,” said co-first author Hai-Chien Kuo, Ph.D., who developed the genetically engineered mice which lack KChIP2 when she was an investigator in the lab of senior author Kenneth R. Chien, M.D., Ph.D., IMM director.

She added that “the mice without KChIP2 had normal heart structure and function. Following stimulation, however, we were able to see the direct relationship between the gene and the disruption of electrical current through the channel.”

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 percent of the gene, the Ito channel operated at exactly 50 percent 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, M.D., a physician researcher and the study’s other co-first author. “When less than 50 percent of the gene was available, the result was to shut down the electrical current 50 percent.”

He added that a defective Ito channel alone is not sufficient to induce arrhythmias by itself, but creates an electrical defect that makes the heart supersensitive to any other triggers for the disease. In the engineered mice lacking KChIP2, external stimulus was required to trigger the arrhythmia.

Senior author Chien noted that the findings published in Cell may account for the vast majority of lethal arrhythmias in heart failure patients leading to sudden cardiac death. “We now know that this gene is absolutely critical for the electrical current to be operative. This critical electrical switch is lost during heart failure, and it is likely that the loss of this particular current leads to malignant heart rhythms and sudden death in some heart failure patients,” he said.

He noted that sudden cardiac death accounts for nearly 400,000 deaths a year, with his team exploring various pathways that might cause the heart to spontaneously stop beating. Last year, his laboratory identified a transcription factor, HF-1b, a “genetic switch” that controls the expression of specific genes found in heart muscle tissue, and the conduction system, which contains the natural pacemaker cells of the heart. This finding, reported in the August 31, 2000 issue of Cell, points to another underlying cause of cardiovascular death due to arrhythmias, said Chien, who likened sudden cardiac death to cancer in that it may take several forms, with a wide spectrum of underlying mechanisms responsible for its onset. As noted by Chien, “the challenge is to identify the key molecular switches that lead to the disease, and to design new ways to treat complex human cardiac diseases.”

###Additional authors on the Cell article were Robert B. Clark, Ph.D. and Wayne R. Giles, Ph.D., Department of Physiology and Biophysics, University of Calgary; Jim J.-C. Lin, Ph.D. and Jenny L.-C. Lin, Department of Biological Sciences, University of Iowa; Masahiko Hoshijima, M.D., Ph.D., Van T.B. Nguyen-Tran, Ph.D., Yusu Gu, M.D., Yasuhiro Ikeda, M.D., and Po-Hsien Chu, M.D., post doctoral fellows in the UCSD’s IMM; and John Ross, Jr., M.D., professor of medicine, UCSD IMM.

The research was funded by the National Heart, Lung, and Blood Institute of the National Institutes of Health, the American Heart Association, and the Jean LeDucq Foundation.


Story Source:

The above story is based on materials provided by University Of California - San Diego. Note: Materials may be edited for content and length.


Cite This Page:

University Of California - San Diego. "Gene Linked To Sudden Cardiac Death Identified By UCSD School Of Medicine Researchers." ScienceDaily. ScienceDaily, 17 December 2001. <www.sciencedaily.com/releases/2001/12/011217083350.htm>.
University Of California - San Diego. (2001, December 17). Gene Linked To Sudden Cardiac Death Identified By UCSD School Of Medicine Researchers. ScienceDaily. Retrieved October 26, 2014 from www.sciencedaily.com/releases/2001/12/011217083350.htm
University Of California - San Diego. "Gene Linked To Sudden Cardiac Death Identified By UCSD School Of Medicine Researchers." ScienceDaily. www.sciencedaily.com/releases/2001/12/011217083350.htm (accessed October 26, 2014).

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