(Philadelphia, PA) - Genetic testing is a powerful diagnostic tool that is increasingly being used for the diagnosis of dilated cardiomyopathy, a disease in which the heart becomes enlarged, making it difficult to pump blood. Cardiomyopathy affects more than 3.5 million people in the United States. African Americans are at especially high risk but have been underrepresented in genetic studies, often due to socioeconomic barriers and other health disparities.
Now, after years of work, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) have identified four variations in a gene known as BAG3 that are linked to a poor outcome. The study, published online August 22 in the journal JAMA Cardiology, is the first to describe genetic variants that are almost exclusive to African Americans that impact outcome in dilated cardiomyopathy patients.
"Few research groups have examined genetic causes of dilated cardiomyopathy or genes that might predict disease outcome in patients of African ancestry," explained senior investigator Arthur M. Feldman, MD, PhD, Laura H. Carnell Professor of Medicine at LKSOM. Moreover, few studies have focused on therapy of heart failure in African Americans; heart failure constitutes a set of signs and symptoms that complicate dilated cardiomyopathy.
To better understand the role of genetic factors in patients of African ancestry, Dr. Feldman and colleagues accessed DNA samples originally obtained from patients enrolled in previous clinical studies that had included the collection of DNA. In total, they were able to obtain genomic DNA for 509 African American patients.
Through genomic sequencing analyses, the researchers discovered four BAG3 variants that were significantly associated with dilated cardiomyopathy outcome. "When we looked at the relationship between the variants and heart failure outcomes, we found that individuals carrying BAG3 mutations had a nearly two-fold increase in risk of dying or being hospitalized with heart failure," said Dr. Feldman. Out of the study population, about 10 percent of patients carried at least one of the mutations.
According to Dr. Feldman, the variants identified in BAG3 previously were thought to be benign or likely benign. However, when expressed in vitro in human heart muscle cells stressed by oxygen deprivation followed by reoxygenation - recapitulating events in heart failure - each variant was found to produce pathogenic effects. The effects included an increase in programmed cell death, or apoptosis, and a reduction in autophagy, the mechanism by which cells clear out damaged cellular components and potentially harmful debris.
Similarly, when one of the mutations was put into mice with half the genetic map for BAG3, the mice developed worsening heart failure. By contrast, insertion of a normal strand of BAG3 DNA cured the mouse of heart failure.
"Normally BAG3 functions to protect and preserve heart muscle cells by blocking apoptosis and helping cells clear out misfolded proteins and damaged organelles,"explained Dr. Valerie Myers, whose doctoral thesis encompassed the research and who is the lead author of the new paper. Mutated BAG3, on the other hand, facilitated the death of heart muscle cells. Importantly, replacing mutated BAG3 with wild-type or normal BAG3 via gene therapy restored normal or near-normal function to the mouse heart.
Dr. Feldman and colleagues now are in the process of developing a treatment specifically for patients with BAG3 deficiency. "BAG3 protein levels can potentially be restored in patients with loss of BAG3 alleles through gene therapy," he added.
Other researchers contributing to the study include Valerie D. Myers and Joseph Y. Cheung, Department of Medicine, LKSOM; Glenn S. Gerhard, Department of Human Genetics and Molecular Biochemistry, LKSOM; Dennis M. McNamara, Bonnie S. Lemster, Karen Hanley-Yanez, and Charles F. McTiernan, Vascular Medicine Institute, University of Pittsburgh Medical Center; Dhanendra Tomar and JuFang Wang, Center for Translational Medicine, LKSOM; Muniswamy Madesh, Department of Cell Biology, University of Texas - San Antonio; Scott M. Kaniper, Richard Sheppard, Jeffrey D. Alexis, and Douglas G. Tilley, LKSOM; Frederick V. Ramsey, Susan G. Fisher, Department of Clinical Sciences, LKSOM; Roxann G. Ingersoll, McKusick-Nathans Genetic Institute, Johns Hopkins University; Laura Kasch-Simenza, Genetic Resources Core Facility, Johns Hopkins University; Jessica A. Schwisow, Amrut V. Ambardekar, Seta H. Degann, and Michael R. Bristow, Department of Medicine, University of Colorado; Christopher D. Kontos, Department of Medicine, Duke University; Joseph M. McClung, Department of Physiology, East Carolina University; Anne L. Taylor, Office of the Dean, Vagelos College of Physicians and Surgeons, Columbia University; Clyde W. Yancy, Department of Medicine, Northwestern University; Kamel Khalili, Department of Neuroscience and Center for Neurovirology, LKSOM; Jonathan G. Seidman, Department of Genetics, Harvard Medical School; and Christine E. Seidman, Brigham and Women's Hospital, Division of Cardiology.
The research was funded in part by National Institutes of Health grants HL91799, HL123093, and MD009118 and by American Heart Association grant 17POST33660251.
About Temple Health
Temple University Health System (TUHS) is a $2.1 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University, and Temple University Physicians, which is Temple Health's physician practice plan comprised of more than 500 full-time and part-time academic physicians in 20 clinical departments.
The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation.
Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. Each TUHS member organization is owned and operated pursuant to its governing documents.