Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Rhode Island Hospital studies uncover keys in sudden cardiac death

18.01.2012
First-of-its-kind genetic animal models allow researchers to identify triggering conditions and direct link to sex hormones

Researchers in Rhode Island Hospital's Cardiovascular Research Center have published two new studies focusing on the causes of arrhythmia and sudden cardiac death (SCD) when a genetic disorder is present.

The studies use a first-ever genetic animal model the researchers developed in 2008 to further their understanding of a genetic disorder known as Long QT Syndrome (LQTS). The first study identified differential conditions and cellular mechanisms that can trigger SCD when LQTS is a factor, and the second study, for the first time, directly links sex hormones and the incidence of arrhythmia and SCD. Their findings are published in the Journal of Physiology and the HeartRhythm Journal.

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.

In 2008, Gideon Koren, M.D., a physician researcher and director of the Cardiovascular Research Center at Rhode Island Hospital, 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.

In a new study published in the Journal of Physiology, the researchers used this animal model to identify differential conditions and cellular mechanisms that trigger arrhythmia in LQT1 or in LQT2 syndrome. In this study, Koren and the researchers studied early afterdepolarizations (EADs), an abnormal depolarization during the plateau phase of the heart electrical activity (action potential) that can initiate arrhythmia, and a hallmark of LQTS. The focus was on mechanisms underlying different high-risk conditions that trigger EADs.

Their findings indicate that the conditions required for EAD to occur in the animal models are genotype specific. For LQT2, the researchers found that conditions such as a slow heart rate or a slightly lower potassium ion concentration outside the heart cells (as seen in hypokalemia) can cause a dramatic prolongation of action potential and produce triggered activity (EADs). In LQT1, however, these conditions result in relatively limited prolongation and no EADs. In contrast, isoproterenol that mimics cardiac stimulation by the sympathetic system causes arrhythmias in single cells only in LQT1 heart cells.

Koren summarizes, "This study takes single cells out of the heart and reveals how arrhythmias are being initiated. 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."

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.

Surge is a sudden rise of the sympathetic tone. That surge is very important in triggering arrhythmia in LQT2. As Koren explains, "In LQT2, you need the startle response -- like an alarm clock. 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."

In a second study, published in the HeartRhythm Journal, Koren 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.

Koren explains, "Quite simply, we demonstrate that estrogen promotes major cardiac events – such as polymorphic ventricular tachycardia (pVT) and SCD – while progesterone prevents them when LQT2 is a factor. Estrogen has a pro-arrhythmic effect."

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."

Koren explains that this finding suggests that high progesterone levels during pregnancy likely account for the reduced risk of SCD in LQT2 patients during pregnancy. 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.

He concludes that while further studies are needed in clinical trials, 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.

The National Institutes of Health provided funding for these studies. Koren's principal affiliation is Rhode Island Hospital, a member hospital of the Lifespan health system in Rhode Island. He is also a professor of medicine at The Warren Alpert Medical School of Brown University. Other researchers with Koren involved in the study published in the Journal of Physiology include Gong-Xin Liu, Bum-Rak Choi, Ohad Ziv, Weiyan Li also of Rhode Island Hospital and Alpert Medical School as well as Enno de Lange and Zhilin Qu of the David Geffen School of Medicine at the University of California. Other researchers involved in the study in HeartRhythm Journal include Katja Odening, Bum-Rak Choi, Gong-Xin Liu, Kathryn Hartmann, Ohad Ziv, Leonard Chaves, Lorraine Schofield and Jason Centracchio, all of Rhode Island Hospital and Alpert Medical School, Manfred Zehender and Michael Brunner of the University Medical Center Freiburg, in Germany, and Xuwen Peng of the Pennsylvania State University College of Medicine.

About Rhode Island Hospital

Founded in 1863, Rhode Island Hospital in Providence, R.I., is a private, not-for-profit hospital and is the principal teaching hospital of The Warren Alpert Medical School of Brown University. A major trauma center for southeastern New England, the hospital is dedicated to being on the cutting edge of medicine and research. Last year, Rhode Island Hospital received more than $55 million in external research funding. It is also home to Hasbro Children's Hospital, the state's only facility dedicated to pediatric care. For more information on Rhode Island Hospital, visit www.rhodeislandhospital.org, follow us on Twitter @RIHospital or like us on Facebook www.facebook.com/rhodeislandhospitalpage.

Nancy Jean | EurekAlert!
Further information:
http://www.lifespan.org

More articles from Studies and Analyses:

nachricht Multi-year study finds 'hotspots' of ammonia over world's major agricultural areas
17.03.2017 | University of Maryland

nachricht Diabetes Drug May Improve Bone Fat-induced Defects of Fracture Healing
17.03.2017 | Deutsches Institut für Ernährungsforschung Potsdam-Rehbrücke

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Northern oceans pumped CO2 into the atmosphere

27.03.2017 | Earth Sciences

Fingerprint' technique spots frog populations at risk from pollution

27.03.2017 | Life Sciences

Big data approach to predict protein structure

27.03.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>