Genes previously known to be essential to the coordinated, rhythmic electrical activity of cardiac muscle -- a healthy heartbeat -- have now also been found to play a key role in thyroid hormone (TH) biosynthesis, according to Weill Cornell Medical College researchers.
The authors' findings, published online this week by the peer-reviewed journal Nature Medicine, suggest that mutations of either of two gene products -- proteins called KCNE2 and KCNQ1 -- already known to be involved in human cardiac arrhythmias, could also cause thyroid dysfunction.
"It has long been known that the thyroid influences cardiac function and cardiac arrhythmias," says study senior author Dr. Geoffrey W. Abbott, associate professor of pharmacology in medicine at Weill Cornell Medical College, "but our findings demonstrate a novel genetic link between inherited cardiac arrhythmia and thyroid dysfunction."
Additionally, it is the authors' suggestion that assessment of the thyroid status of patients with KCNE2- and KCNQ1-linked cardiac arrhythmias could in some cases reveal a potential endocrine component to their cardiac arrhythmias that may not have been previously determined. This, in turn, could indicate treatment of the thyroid condition, with potentially beneficial effects on cardiac function.
KCNQ1 and KCNE2 were each recognized more than a decade ago as forming potassium channels in cardiac muscle that help end each heartbeat in a timely fashion. Inherited mutations in KCNQ1 and KCNE2 cause ventricular and atrial cardiac arrhythmias, previously presumed to be due entirely to the role of these proteins in cardiac muscle. The researchers have now discovered that KCNQ1 and KCNE2 also form a potassium channel in the thyroid gland.
"When the thyroid does not produce enough TH, a person may experience symptoms such as fatigue and a lowered heart rate, but there is also a more complex interplay between thyroid function, cardiac structure and cardiac arrhythmias. Our new findings may begin to explain some of these interrelationships," explains Dr. Abbott.
While studying mice that had the KCNE2 gene removed from their genome, the researchers observed that the animals developed symptoms of hypothyroidism, especially during pregnancy, and gave birth to pups with dwarfism, alopecia (baldness) and cardiomegaly (enlarged heart).
After allowing the mouse pups to drink milk only from mothers without the genetic alteration, the pups' symptoms were alleviated. The healthy mothers' milk contains normal levels of TH -- essentially acting as a TH replacement therapy. The symptoms were also treated by direct TH supplementation of pups or mothers.
"We then wanted to test what the mechanism was in the mice that caused deletion of the KCNE2 gene to have negative consequences for the thyroid," says Dr. Abbott.
Using micro positron emission tomography (microPET), Dr. Abbott and his team visualized the accumulation in the mouse thyroid of an iodine radioisotope in real-time. They found that absorption of the radioisotope in the thyroid was greatly impaired in mice lacking the KCNE2 gene. They believe that, normally, the KCNQ1-KCNE2 potassium channel helps another protein (the sodium/iodide symporter) to transport iodide into the thyroid.
Without the KCNQ1-KCNE2 potassium channel, the efficiency of iodide absorption by the thyroid is greatly reduced. Because iodide is an essential component of TH, this means that KCNE2 deletion also impairs TH production.
Future studies will now center on determining how applicable the research team's findings in the mouse are to the human population.
"While we have identified KCNQ1 and KCNE2 in both mouse and human thyroid, much additional work is required before we can fully understand how inherited mutations in the genes coding these proteins affect human thyroid function, how this in turn influences the health of human heart and other tissues, and how useful our discoveries will be in developing therapies to treat thyroid and thyroid-related human disease," explains Dr. Abbott.
Cardiac arrhythmias affect up to three million people in the United States. The majority of these suffer from atrial fibrillation, a chronic arrhythmia most often observed in the aging population. Ventricular arrhythmias account for the large majority of the 300,000 cases of sudden cardiac death annually in the United States. Thyroid dysfunction is estimated to affect one to four percent of the world's population.
Additional co-authors include Torsten K. Roepke, Elizabeth C. King and Kerry Purtell from Weill Cornell; Daniel J. Lerner from CV Ingenuity, San Francisco, CA; and Andrea Reyna-Neyra, Monika Paroder,Wade Koba, Eugene Fine and Nancy Carrasco from the Albert Einstein College of Medicine, The Bronx, NY.
The study received support from the National Institutes of Health and the American Heart Association.
Weill Cornell Medical College
Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in areas such as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, transplantation medicine, infectious disease, obesity, cancer, psychiatry and public health -- and continue to delve ever deeper into the molecular basis of disease and social determinants of health in an effort to unlock the mysteries of the human body in health and sickness. In its commitment to global health and education, the Medical College has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, the Medical College is the first in the U.S. to offer its M.D. degree overseas. Weill Cornell is the birthplace of many medical advances -- including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, the first indication of bone marrow's critical role in tumor growth, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. For more information, visit www.med.cornell.edu.
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