Featured Research

from universities, journals, and other organizations

Scientists Discover New Genetic Pathway In Sudden Cardiac Death

Date:
September 1, 2000
Source:
University Of California, San Diego
Summary:
Researchers in the University of California, San Diego (UCSD) Institute of Molecular Medicine have discovered a new genetic pathway that plays a pivotal role in the onset of sudden cardiac death, a leading cause of cardiovascular mortality that affects 400,000 Americans each year.

Researchers in the University of California, San Diego (UCSD) Institute of Molecular Medicine have discovered a new genetic pathway that plays a pivotal role in the onset of sudden cardiac death, a leading cause of cardiovascular mortality that affects 400,000 Americans each year.

Reported in the Sept. 1, 2000 issue of Cell, their findings hold promise for the future development of biologically targeted therapies for lethal ventricular arrhythmias, or abnormal heart rhythms, and sudden cardiac death.

In a five-year effort, led by Van T.B. Nguyen-Tran, Ph.D. in the laboratory of Kenneth R. Chien, M.D., Ph.D., director of the UCSD Institute of Molecular Medicine, researchers have found clear evidence in mice that defects in the genes that guide the formation of the heart's pathway of critical electrical wiring may lead to ventricular arrhythmia and sudden death.

For the first time, research has shown that sudden cardiac death may involve a pathway that controls the formation of specialized pacemaker cells in the heart, according to Nguyen-Tran. These cells, which serve as electrical wires that control the heart rate, originate from neighboring cardiac muscle cells. Under the guidance of molecular switches, a panel of genes are turned on which are specific for pacemaker cells. Defects in these switches have now been identified as a direct cause of sudden death.

Even though sudden cardiac death is a major manifestation of heart disease, understanding of the precise molecular and cellular pathways that lead to its onset is very limited at present. Currently, sudden cardiac death is largely untreatable using drug-based approaches, and implantable defibrillators are the only accepted form of therapy. Tragically, most victims appear perfectly normal before they collapse and die from sudden cardiac arrest caused when the heart's electrical impulses become chaotic and the heart stops beating. In order to develop biologically targeted therapy, the identification of new pathways that lead to sudden cardiac death must be identified in experimental systems.

Despite the recent discovery of inherited mutations in potassium and sodium channel genes that can lead to sudden cardiac death, further research found that only 1% of the sudden death patients had the mutation, and only 20% of family members with the disease gene ultimately suffer from sudden cardiac death. This led the UCSD researchers to search for what they called the "second hit," or additional pathways that produce lethal ventricular arrhythmias.

To arrive at their findings, the researchers first identified a transcription factor, HF-1b, a "molecular 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. Then, they genetically engineered a mouse that was totally deficient in the HF-1b gene. Nguyen-Tran and her team determined that mice which cannot make HF-1b have a high incidence of sudden death (60%) and are highly susceptible to rhythm disturbances that are identical to those observed in the human population.

To study the cellular pacemaker function and capture naturally occurring sudden death in the surviving HF-1b mutant mice, Nguyen-Tran needed to accumulate an enormous amount of electrical recording data from a very small species that has a heart rate of more than 500 beats per minute. The team used miniaturized implanted radio telemetry technology similar to field technology used to track large species in the wild. They also modified their computer hardware to continuously capture and analyze the electrocardiogram (EKG) data 24-hours-a-day over several months.

"In readings accumulated for more than half a year, we found that every aspect of the conduction system was abnormal in these HF-1b deficient mice," Nguyen-Tran said. "Continuous heart recordings in these mutant animals clearly documented cardiac arrhythmias as the cause of death."

To determine if the widespread rhythm disturbances in the HF-1b mutant animals reflected structural defects in the cardiac conduction system, specific molecular markers were used to distinguish the conduction tissue from the heart muscle tissue. Results from these analyses revealed defects in the conduction tissue as well as in the cardiac muscle cells in mice that lack the HF-1b transcription factor.

In the Cell article, the researchers said "the present study provides several lines of evidence to support a critical role of HF-1b in the electrophysiological transition between ventricular and conduction system cell lineages."

In praising Nguyen-Tran and her team, Chien noted that "lots of science still needs to be done to determine the secreted factors that guide the formation of heart pacemaker and conduction cells. Using DNA array and other post-genome technology, we need to identify the genes upstream and downstream in the HF-1b pathway that may contribute to sudden cardiac death."

Within the next year, the researchers also hope to collect and test human tissue from tissue banks and patients who have survived life-threatening ventricular arrhythmias.

###

In addition to Nguyen-Tran and Chien, the study's co-authors include Susumu Minamisawa, Kai C. Wollert, Anne B. Brown, Pilar Ruiz-Lozano, Stephanie Barrere-Lemaire, Richard Kondo, Marc M. Rahme and Gregory K. Feld, UCSD; Celine Fiset, Robert B. Clark and Wayne R. Giles, University of Calgary; and Steven Kubalak, Lisa W. Norman and Robert G. Gourdie, Medical University of South Carolina, Charleston.


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. "Scientists Discover New Genetic Pathway In Sudden Cardiac Death." ScienceDaily. ScienceDaily, 1 September 2000. <www.sciencedaily.com/releases/2000/09/000901080116.htm>.
University Of California, San Diego. (2000, September 1). Scientists Discover New Genetic Pathway In Sudden Cardiac Death. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2000/09/000901080116.htm
University Of California, San Diego. "Scientists Discover New Genetic Pathway In Sudden Cardiac Death." ScienceDaily. www.sciencedaily.com/releases/2000/09/000901080116.htm (accessed July 31, 2014).

Share This




More Health & Medicine News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Health Insurers' Profits Slide

Health Insurers' Profits Slide

Reuters - Business Video Online (July 30, 2014) Obamacare-related costs were said to be behind the profit plunge at Wellpoint and Humana, but Wellpoint sees the new exchanges boosting its earnings for the full year. Fred Katayama reports. Video provided by Reuters
Powered by NewsLook.com
Peace Corps Pulls Workers From W. Africa Over Ebola Fears

Peace Corps Pulls Workers From W. Africa Over Ebola Fears

Newsy (July 30, 2014) The Peace Corps is one of several U.S.-based organizations to pull workers out of West Africa because of the Ebola outbreak. Video provided by Newsy
Powered by NewsLook.com
Weather Kills 2K A Year, But Storms Aren't The Main Offender

Weather Kills 2K A Year, But Storms Aren't The Main Offender

Newsy (July 30, 2014) Health officials say 2,000 deaths occur each year in the U.S. due to weather, but it's excessive heat and cold that claim the most lives. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile: iPhone Android Web
      Follow: Facebook Twitter Google+
      Subscribe: RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins