Researchers co-author study published in ‘Cell’A study, published in the Sept. 1 issue of Cell, on the discovery of a new genetic pathway that plays a pivotal role in the onset of sudden cardiac death is co-authored by three MUSC research scientists.Headed by the University of California, San Diego, Institute of Molecular
Medicine, the multi-center research study, identified the new genetic pathway
as a leading cause of cardiovascular mortality that affects 400,000 Americans
each year.
In the 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 electric 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 special 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 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 percent of the sudden death patients had the mutation, and only 20 percent of family members with the disease gene ultimately suffer from sudden cardiac death. This led to 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 percent) 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.” 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.” In addition to contributing to the Cell article, MUSC workers were also responsible for laying the groundwork for this breakthrough, identifying the potential for myocytes to convert between ventricular and conduction lineages during development of the heart. This crucial insight was reported by Drs. Cheng Gang, Wanda Litchenberg and Gourdie in the top journal, Development, last year. Gourdie and Kubalak noted that a good deal of credit must go to the excellent Moleclular Cell and Biology graduate program at MUSC and its ability to attract top students. Litchenberg, Gang and Norman are all alumni of this MUSC program, presently the only Ph.D. training course available in Charleston. Within the next year researchers also hope to collect and test human tissue from tissue banks and patients who have survived life-threatening ventricular arrhythmias. The study also included co-authors at the University of Calgary, Canada. To access the study, “A Novel Genetic Pathway for Sudden Cardiac Death
via Defects in the Transition between Ventricular and Conduction System
Cell Lineages, visit Cell's Web site at
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