Mysterious heart disease, atrial fibrillation (AF), affects millions worldwide and brings a complex puzzle. This disease can cause irregular hearts, lead to reduced heart function and greatly increase the risk of stroke. Although AF is well known to have a strong genetic component, the mechanism by which common genetic variants increase the risk of AF remains elusive. Recent research has begun to reveal how common genetic factors affect AF, laying the stages for innovative research to explain these mysteries.
In a pivotal study, Professor Jonathan Smith and Mina K. Chung from the Cleveland Clinic and their collaborative teams, as well as Gregory Tchou and Dan, from the Cleveland Clinic. The key contribution of Dr. Daniela Ponce-Balbuena has made significant progress in understanding the genetic basis of atrial fibrillation, the most common irregular heartbeat. Their study highlights the key role of the gene FAM13B in increasing the likelihood of developing this condition, paving the way for new personalized treatments.
Professor Smith shared: “Although many rare genetic variants that cause AF change the structure of proteins, most common variants associated with AF risk do not change the structure of proteins, but regulate the expression of nearby genes, thereby regulating the protein’s Expression, and thus produced proteins. We identified common variants that regulate the level of a gene called FAM13B, whereas the AF risk allele leads to decreased expression. We found that proteins encoded by this particular gene play a key role in cardiac function, Therefore, less expression leads to an increased sensitivity to AF. When the expression of this gene is reduced, it causes changes in the heart cells, affecting its electrical signaling and calcium processing, which is essential for routine heartbeats.” This insight marks a significant advancement in understanding this complex heart condition.
Their research focuses on how changes in this gene expression affect the heart’s electrical signaling and calcium processing, which is essential for maintaining a stable heartbeat. The team used advanced gene editing techniques, especially CRISPR-CAS9, to specifically alter this gene in human stem cells, which they then distinguished into cardiomyocytes. This innovative approach allows detailed study of the effect of the gene on cardiac function.
In addition, they conducted studies to examine the electroactivity in heart cells with reduced gene activity. They used a technique called plaque clips to study isolated heart cells with reduced gene activity. These studies are crucial to illustrate how gene changes affect the electrical signaling of the heart.
In addition, the team studied how these genetic changes affect calcium signaling in heart cells. They used a system called Ionoptix to measure calcium levels in cells after reducing gene activity, thereby further exploring its role in cardiac function.
Among the important components of their study, Professor Smith and Ponce-Balbuena studied genetically engineered mice lacking the FAM13B gene. Professor Smith noted: “These mice showed increased duration in certain heart wave patterns, and they were more likely to develop heart rhythm problems than normal mice.” This finding highlights the important role of the gene in maintaining normal heart rhythms,” he said. .
Together, their findings elucidate the critical role of FAM13B in atrial fibrillation. By determining genes that can alter cardiac function and demonstrate its effect on the heart, Professor Smith and colleagues have greatly improved our understanding of the genetic basis of AF. Their work opens new avenues for developing targeted treatments that have the potential to change the way this common heart disease is managed.
Journal Reference:
Tchou G, Ponce-Balbuena D, Liu N, Gore-Panter S, Hsu J, Liu F, Opoku E, Brubaker G, Schumacher SM, Moravec CS, Barnard J, Barnard J, Van Wagoner DR, Chung MK, Chung MK, Smith JD. The decrease in FAM13B expression increases the sensitivity of atrial fibrillation by regulating sodium current and calcium treatment. JACC Basic Transl Sci. July 26, 2023; 8 (10): 1357-1378. doi: https://doi.org/10.1016/j.rineng.2023.101425
About the Author
Dr. Jonathan Smithis a professor and chair of the Department of Molecular Medicine at the Western Reserve University of the Cleveland Clinic Reiner Medical College. He is also the director of the Molecular Medicine PhD Training Program. At the Cleveland Clinic Lerner Institute, Dr. Smith is a staff member of the Department of Cardiovascular and Metabolic Sciences, where he serves as the Chairman of Cardiovascular Research at Geoffrey Gund. Dr. Smith received a bachelor’s degree in biology from the University of California Santa Cruz and a doctorate in cellular and developmental biology from the Department of Medical Sciences at Harvard University. He conducted a postdoctoral study at Rockefeller University in Jan Breslow’s lab, examining mouse models of apolipoprotein gene expression, lipoprotein metabolism, and atherosclerosis. Dr. Smith was promoted as an assistant and associate professor at Rockefeller and joined the Lerner Research Institute in 2002. Lerner Institute. He has published nearly 200 peer-reviewed original research papers as well as other reviews and editorials. Dr. Smith’s research is currently funded by two NIH R01 grants and a program project grant led by Dr. Mina Chung. He is also the principal researcher for the T32 Training Grant Support Trainee. Dr. Smith trains many doctoral students, postdoctoral fellows, medical students, laboratory technicians, and high school and college students. He supports the entry of underrepresented minority students into STEM careers.
Greg Tchou is a leading technical expert in the laboratory of Dr. Jonathan D. Smith, Department of Cardiovascular and Metabolic Sciences at the Cleveland Clinic. Prior to joining the Smith Laboratory, he received his bachelor’s degree and doctorate in biochemistry and cell biology from the University of Michigan. PhD in cell biology from Rice University. His research focuses on the genetic basis of atrial fibrillation through CRISPR-CAS9 gene editing in human stem cell models. He likes football, cycling in many scenic subway parks in Cleveland when the weather allows, and (often) does not attend the meeting board.
Dr. Daniela Ponce-Balbuenacompleted BS and MS at the University of Benemérita. Puebla, Mexico. She received her PhD from Corrima University. In 2011, Colima, Mexico, then moved to the United States to work as a postdoctoral fellow at the Center for Research on Heart Rhythmia at the University of Michigan. In 2020, she joined the Department of Physiology and Cell Biology at Ohio State University, where Davis Institute of Heart and Lung serves as an Assistant Professor in Research. In 2023, she joined the Department of Cardiology and Vascular Medicine at the University of Wisconsin-Madison, School of Medicine, where she holds the current position of Scientist III. Daniela’s research focuses on the regulation of cardiac ion channels and arrhythmia mechanisms. The purpose of her research is to discover new virulent targets that can prevent and/or treat heart arrhythmia. Daniela enjoys the life of a scientist and attributes her success as a researcher to a team of outstanding scientists who have the right to work together.
