RI Hospital: Estrogen Linked to Sudden Cardiac Death
Friday, January 20, 2012
The second study identifies differential conditions and cellular mechanisms that can trigger SCD when a genetic disorder known as Long QT Syndrom (LQTS) is a factor. Both studies use a first-ever genetic animal model the researchers developed in 2008 to further their understanding of LQTS. Their findings are published in the Journal of Physiology and the HeartRhythm Journal.
Sex hormones and Sudden Cardiac Death
In the first study, published in HeartRhythm Journal, Gideon Koren, M.D., a physician researcher and director of the Cardiovascular Research Center and his colleagues furthered their understanding of arrhythmias by studying the impact of sex hormones, and confirming for the first time a direct link between the hormones and SCD.
Higher risks for women
Sex differences in long-QT-related arrhythmias with a higher risk of pVT and SCD have been well-documented in the clinical setting, and the risk is higher in women than in men, particularly during the postpartum period. In this study, Koren says, “We show for the first time a direct link between sex hormones and the incidence of arrhythmias and sudden cardiac death. Through our research in our animal models, we have demonstrated that progesterone significantly reduces triggers for polymorphic ventricular tachycardia. At the same time, we were able to show that progesterone is protective and prevents SCD when LQT2 is present.”
The finding suggests that high progesterone levels during pregnancy likely account for the reduced risk of SCD in LQT2 patients during pregnancy, Koren said. The marked reduction in progesterone during the postpartum period, however, likely promotes arrhythmias and SCD in these patients. Their findings also indicate that estrogen increases both trigger and sustainability of pVT, and thereby promotes major cardiac events.
A genetic link
It is known that genetic mutations can predispose individuals to arrhythmia and/or SCD, a leading cause of death in the United States. Between one in 2,500 and one in 5,000 individuals are born with mutations that cause LQTS, a disorder of the heart’s electric system, and a determining factor in the development of arrhythmia and/or SCD. Ninety percent of the known mutations cause loss of function of ion channels responsible for LQTS types 1 and 2 (LQT1 and LQT2).
LQTS leads to a prolonged “QT interval” on electrocardiograms. The QT interval refers to the time it takes the chambers of the heart to “repolarize” themselves so that the heart is ready for another contraction cycle. When this timeframe is lengthened, it is associated with triggering irregular arrhythmia that can cause sudden cardiac arrest.
A new model from RIH
In 2008, Koren and his colleagues developed a first-of-its-kind genetic rabbit model to study arrhythmia and SCD that mirrors what happens in individuals who have mutations of the LQT1 or LQT2 genes.
“This study takes single cells out of the heart and reveals how arrhythmias are being initiated," Koren said. "What we are showing in this study is that single cells are responsible for generating an arrhythmia. Further, we found that different types of increased autonomic nervous system activity play a critical role in the cause of arrhythmias and sudden cardiac death, but it differs based on genotype.
Fight or flight
"The autonomic nervous system is what controls “fight or flight” response. In their research, Koren and his colleagues found that sympathetic “surge” activity was responsible for triggering arrhythmia in LQT2. In LQT1, however, an increased steady sympathetic tone was associated with arrhythmias. Further, we found that different types of increased autonomic nervous system activity play a critical role in the cause of arrhythmias and sudden cardiac death, but it differs based on genotype.”
Surge is a sudden rise of the sympathetic tone. That surge is very important in triggering arrhythmia in LQT2. “In LQT2, you need the startle response -- like an alarm clock," Koren said. "However, in LQT1, we found the increased steady sympathetic tone is very important in inducing arrhythmia, like in patients swimming for an extended period of time. So there are different ways that arrhythmia will be induced depending on the genotype.”
While further studies are needed in clinical trials, Koren said the clinical implications of this study will impact on the standard treatment of patients who are diagnosed with LQT2. Specific hormone-based therapies may be prescribed to protect them from arrhythmia and potentially avoid sudden cardiac death.
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