Researchers have successfully diminished scar tissue and enhanced heart functionality in mouse models of heart failure through monoclonal antibody treatment, a similar approach to those already approved by the FDA for other medical issues. This opens up the potential for developing similar immunotherapies for individuals with heart failure following a heart attack or similar heart-related trauma.
A recent study conducted by scientists at Washington University School of Medicine in St. Louis indicates that a specific type of immunotherapy—similar to those sanctioned by the FDA for inflammatory diseases like arthritis—might also serve as a viable treatment option for heart failure.
The findings of the study were published on October 23 in the journal Nature.
Following a heart attack, viral infection, or other forms of heart damage, scar tissue commonly develops within the heart muscle. This scar tissue disrupts the heart’s regular contractions and is a significant contributor to heart failure, a condition characterized by the gradual decline in the heart’s capability to adequately pump blood throughout the body. This ongoing issue creates a cycle that can only be managed with existing treatments, as there is currently no complete cure.
Investigating samples of human heart tissue, the research team pinpointed a type of fibroblast cell within the heart as the primary factor responsible for scar tissue development in heart failure cases. To explore ways to prevent this scarring, the researchers employed mouse models of heart failure that contained the same fibroblasts. They utilized a therapeutic protein known as a monoclonal antibody, which inhibits the creation of these detrimental fibroblasts, effectively reducing scar formation and improving heart function in the mice.
“Once scar tissue forms in the heart, its ability to heal significantly diminishes or is completely lost,” explained Kory Lavine, MD, PhD, a cardiologist and the study’s senior author, as well as a professor of medicine in the Cardiovascular Division at WashU Medicine. “Heart failure is an increasing concern in both the U.S. and around the globe, impacting millions. While current treatments can ease symptoms and slow disease progression, there is an urgent need for improved therapies that can actually halt the disease’s progression and prevent further scar tissue formation that impairs heart function. We are optimistic that our research will lead to clinical trials exploring this immunotherapy approach for heart failure patients.”
Fibroblasts play various roles in heart function, and distinguishing among their different types has proven difficult. Some fibroblasts contribute to the structural soundness of the heart and ensure that blood flows well through its vessels, while others drive inflammation and promote scar formation. With the advent of advanced single-cell sequencing technologies, researchers are now able to differentiate between these cell groups.
“The distinct types of fibroblasts present new possibilities for developing treatment strategies that specifically inhibit the fibroblasts contributing to scarring while safeguarding the ones that help maintain the heart’s structure to prevent rupture,” Lavine remarked. “Our findings indicate that the fibroblasts responsible for scarring in injured hearts are quite similar to those involved in cancer and other inflammatory conditions, paving the way for immunotherapies that could potentially diminish inflammation and subsequent scar formation.”
Co-led by Junedh Amrute, a graduate student in Lavine’s lab, the research team employed genetic techniques to show that a signaling molecule known as IL-1 beta played a crucial role in the process that drives fibroblasts to generate scar tissue in heart failure cases. With this in mind, they examined a mouse monoclonal antibody that blocks IL-1 beta and observed beneficial outcomes in the mouse’s heart conditions. The mouse monoclonal antibody was supplied by Amgen, whose scientists also contributed to the research. Monoclonal antibodies are lab-created proteins that influence the immune system. This treatment lowered scar tissue formation and enhanced heart pumping efficiency, as evaluated using echocardiograms.
At least two FDA-approved monoclonal antibodies—canakinumab and rilonacept—can inhibit IL-1 signaling. These immunotherapies are authorized for treating inflammatory diseases such as juvenile idiopathic arthritis and recurrent pericarditis, which is inflammation of the heart’s protective sac.
One of these antibodies has also undergone evaluation in a clinical trial for atherosclerosis, characterized by plaque buildup that hardens arteries. The study, known as CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study), found benefits for participants dealing with atherosclerosis.
“While this trial wasn’t designed to specifically assess this treatment for heart failure, the data suggests that the monoclonal antibody might provide benefits to those with heart failure,” Lavine noted. “Secondary analyses indicated that this treatment was connected to a significant decline in heart failure hospitalizations compared to standard care. Our recent study could help clarify why.”
Nevertheless, the IL-1 antibody used in the CANTOS trial was associated with some side effects, such as an elevated risk of infection. Researchers believe that a more precisely targeted antibody blocking IL-1 signaling specifically in cardiac fibroblasts could mitigate these risks.
“We are hopeful that the convergence of evidence, including our investigations into the IL-1 beta pathway, will pave the way for designing a clinical trial that specifically examines targeted immunotherapy in heart failure patients,” Lavine stated.
