New treatment reduces heart scarring and abnormal heart rhythms, offering a possibility for future therapies
In a study led by Baylor College of Medicine and University of Oxford, researchers found that blocking a specific molecular interaction reduced atrial fibrosis scarring in mouse models and cells from human patients with atrial fibrillation (AF), reduced fibrotic responses in human cells, and in the mouse models reversed established atrial fibrosis and reduced abnormal heart rhythms.
The study, published in the latest edition of Nature Cardiovascular Research, points to the potential for a treatment for AF that up until now has not existed.
“Atrial fibrillation (AF) is the most common arrhythmia, affecting more than 10 million adults in the United States. It substantially raises the risk of ischemic stroke, heart failure, myocardial infarction and even can increase the risk of dementia and kidney disease,” said Dr. Xander Wehrens, professor and director of the Cardiovascular Research Institute at Baylor and co-senior author on the paper. “There are current treatments that help improve heart rhythm but nothing that stops and reverses progression. Our findings open the door to the potential for an effective treatment.”
Dr. Svetlana Reilly, associate professor of cardiovascular science at the University of Oxford and co-senior author on the paper says the findings address a gap in treatment options.
"Atrial fibrosis is a major unmet clinical problem in atrial fibrillation, and currently we have no therapies that directly target the scarring process itself,” Reilly said. “Our findings identify a promising therapeutic pathway and suggest that targeted interventions may offer a new strategy for preventing or reversing the structural remodeling that underlies disease progression."
Atrial fibrillation, commonly called AFib, is when the heart’s upper chambers beat irregularly, causing the buildup of scar tissue that changes the heart’s structure and makes abnormal heart rhythms more likely to develop.
Researchers focused on a small molecule called microRNA-31-5p (miR-31-5p), which helps regulate gene activity inside cells. Patients with AF have elevated levels of this molecule in atrial fibroblasts.
The molecule reduces the production of a protein known as the calcitonin receptor (CTR), which helps control fibroblasts, the cells responsible for producing materials that support heart tissue. When CTR levels fall, fibroblasts can become overactive leading to scar tissue.
Targeting this process, researchers designed a selective locked nucleic acid target-site blocker to prevent miR-31-5p from interacting with the CTR. In human atrial fibroblasts from patients with AF and in mouse models, this treatment restored CTR levels. In mouse models, it prevented the development of atrial fibrosis, reversed established atrial fibrosis (with fibrosis regressing by approximately 30% relative to baseline while untreated controls progressed), and reduced the duration and burden of abnormal heart rhythms.
“We have worked on this line of research for some time and anticipated the outcomes; however, we were surprised to see this treatment led to a reversal of some of the damage,” Wehrens said. “More work is needed to understand how this treatment would work in humans, but our findings suggest that targeting this molecular interaction will help prevent further scarring and reduce tissue damage.”
Others who contributed to the research include: Jasha Trompf, Kathryn Cox, Mohit Hulsurkar, Lucia M. Moreira, Chi Him Kendrick Yiu, Aaron M. Johnston, Satadru K. Lahiri, Shuai Zhao, Paul Robinson, Roddy Hiram, Mozhdeh Mehdizadeh, Lorena Perez Carrillo, Rana Sayeed, George Krasopoulos, Vivek Srivastava, Nicholas Walcot, Shakil Farid, Antonios Kourliouros, Priya Sastry, David A. Menassa, Benjamin Davies, Rita A. Schack, Robia G. Pautler, Keith M. Channon, Craig Lygate and Stanley Nattel. Affiliations include University of Oxford (where the project originated), Baylor College of Medicine, University of Montreal, University of Glasgow, McGill University, University Duisburg-Essen, and Fondation Bordeaux Université.
Funding is from the British Heart Foundation Intermediate (multiple awards), National Institutes of Health (R01HL174510, R01HL160992, R01HL180477), Clarendon and Commonwealth Scholarships, the American Heart Association’s Career Development Award, Canadian Institutes of Health Research and Heart and Stroke Foundation of Canada. (For detailed list of affiliations and funding sources see publication.)