A new study reveals that autoantibodies have a direct impact on heart function in patients with lupus.
Cardiovascular disease is the primary cause of death for individuals with lupus, an autoimmune disorder where the immune system erroneously attacks the body’s own tissues and organs, including the heart, blood vessels, lungs, joints, brain, and skin. Lupus myocarditis, which is the inflammation of the heart muscle, can be particularly dangerous as it disrupts the rhythm and strength of the heartbeat. Unfortunately, the mechanisms driving this intricate disease remain largely unclear and challenging to investigate.
One ongoing question regarding lupus is why certain patients develop myocarditis while others do not, and what causes the vast differences in clinical symptoms—from absence of symptoms to severe heart failure—among those affected. Lupus involves a wide range of autoantibodies, which are immune proteins that mistakenly attack the body’s own tissues, varying widely in their specific targets. Similar to genetic differences, these variations may clarify why symptoms differ across individuals.
Researchers have long theorized that the distinct signatures of specific autoantibodies might explain the puzzling variations seen in lupus cases. However, pinpointing the autoantibodies responsible for heart damage has proven to be immensely difficult, mainly due to the lack of experimental models that accurately mirror cardiac diseases in lupus patients. The animal models currently in use do not adequately reflect human cardiac physiology, while cell cultures derived from humans fail to replicate the heart’s complexity and functionality.
Recent research indicates that autoantibodies significantly impact heart health in lupus patients
A recent study, published on August 15 in Nature Cardiovascular Research, features a collaborative research team from Columbia Engineering, Columbia University Vagelos College of Physicians and Surgeons, and Harvard University. They conclude that autoantibodies alone can directly impair heart function in lupus sufferers.
The researchers created small cardiac tissue samples from healthy adult human stem cells, enhanced their development using metabolic and electrical signals, and then exposed these tissues to autoantibodies extracted from the blood of lupus patients, both those with and without myocarditis. They discovered that how the autoantibodies bind to heart tissue varies based on the type and severity of the heart damage experienced by the patients. For instance, a group of patients with severe myocarditis exhibited unique populations of autoantibodies primarily targeting dying heart cells, while those with reduced heart pump efficiency had autoantibodies mainly affecting living heart cells. Notably, the autoantibodies attaching to living cardiac cells induced significant biological effects on the tissue, even in the absence of immune cells, which may unveil new potential mechanisms leading to heart failure in lupus patients.
Additionally, the study identified four specific autoantibodies that could directly influence the heart’s muscles. These discoveries could assist in identifying lupus patients who are at the highest risk of developing heart disease, guide the development of new treatment strategies, and have implications for other autoimmune conditions.
“This finding is the first to demonstrate that autoantibodies can actively cause myocardial injury in this intricate autoimmune disorder,” shared Gordana Vunjak-Novakovic, the project’s leading researcher and a distinguished university professor at Columbia specializing in biomedical engineering, medical sciences, and dental medicine. “It’s remarkable that these tiny heart tissues we engineered using human stem cells and ‘organs-on-chip’ technology can mimic organ-level functions tailored to individual patients, especially for such a multifaceted disease. We are now in an era where we can study disease progression and treatments using models that are both simple yet highly controllable and predictive of human organ behavior. It’s as if we’re living in the future.”
A collaborative effort between engineers and clinicians
Vunjak-Novakovic is a bioengineer renowned for her innovative approaches to creating functional human tissue for regenerative medical applications. For this study, she partnered with two physicians, Robert Winchester and Laura Geraldino-Pardilla, both specialists in rheumatology at NewYork-Presbyterian/Columbia University Irving Medical Center. The physicians supplied blood samples containing lupus autoantibodies and comprehensive clinical data from lupus patient cohorts, allowing the engineering team to evaluate the impact of patient-specific autoantibodies on heart function leveraging engineered tissues, and relate these findings to the patients’ clinical symptoms.
“Myocarditis can be challenging to diagnose and at times poses a significant clinical threat in lupus patients. The creation of this functional, mature cardiac tissue model is already paving the way for new approaches to enhance our understanding and eventual clinical treatment of this complex autoimmune condition,” remarked Winchester.
To delve deeper into potential therapeutic targets, Vunjak-Novakovic’s team also collaborated with Drs. Christine and Jonathan Seidman from Harvard University. They are now investigating ways to utilize their findings to better comprehend the fundamental mechanisms behind cardiac diseases in lupus patients, as well as to enhance diagnostic and therapeutic options for this intricate and demanding illness.
“What’s particularly exciting about this study is how we integrated our expertise in engineering and stem cell research to create models of the human heart, which allowed us to adopt a novel approach to resolving longstanding mysteries concerning heart disease in lupus patients,” stated Sharon Fleischer, the study’s first author and a postdoctoral scholar in Vunjak-Novakovic’s lab. “The innovative framework we developed for examining interactions between autoantibodies and human organs unlocks extraordinary opportunities for understanding organ damage, not just in lupus but across a broad range of autoimmune diseases.”
“It was truly a privilege to be part of such a collaborative team consisting of engineers, doctors, and biologists working in unison to tackle this challenging clinical issue,” expressed Trevor Nash, one of the study’s co-first authors, who recently graduated from the Vunjak-Novakovic lab and is an MD/PhD candidate in the Medical Scientist Training Program at the Vagelos College of Physicians and Surgeons.
