Cardiovascular disease is the leading cause of death in patients suffering from lupus, an autoimmune disease in which our immune system attacks our own tissues and organs, the heart, blood, lung, joints, brain, and skin. Lupus myocarditis—inflammation of the heart muscle—can be very serious because the inflammation alters the regularity of the rhythm and strength of the heartbeat. However, the mechanisms underlying this complex disease are poorly understood and difficult to study.

A long-standing question about lupus is why some patients develop myocarditis while others remain unaffected. And why the clinical manifestations of affected patients range so dramatically, from no symptoms at all to severe heart failure. Lupus is characterized by a large number of autoantibodies, immune proteins that mistakenly target a person’s own tissues or organs, with different specificities for various molecules. Like our genes, they may explain why different individuals experience different symptoms.

Researchers have long suspected that specific autoantibody signatures could hold the key to the puzzling clinical variations they observe in lupus patients. Thus far, identifying autoantibodies involved in heart damage has been incredibly challenging due to the lack of experimental models that can replicate the cardiac disease in lupus patients. The currently used animal models fall short because of differences in cardiac physiology, while human cell cultures simply cannot capture the complexity and function of the human heart.

Study shows that autoantibodies can directly affect heart disease in lupus patients

In a new study, published August 15 in Nature Cardiovascular Researcha team of researchers from Columbia Engineering, Columbia University Vagelos College of Physicians and Surgeons, and Harvard University report that autoantibodies alone directly affect heart function in lupus patients.

The researchers engineered millimeter-sized cardiac tissues from healthy adult human stem cells, matured them using metabolic and electromechanical signals, and then incubated them with the autoantibodies found in the blood of lupus patients with and without myocarditis.

The team found that the binding patterns of the patients’ autoantibodies to heart tissue depend on the type and severity of their myocardial damage. A subset of patients with severe myocarditis had unique autoantibody populations that primarily targeted dying cardiac cells, whereas patients with weakened heart pump function had autoantibodies that mostly targeted the surface of live cells.

Interestingly, the team discovered that the autoantibodies that were binding to live cardiac cells were able to exert potent biological effects on the tissues in the absence of immune cells, revealing potentially new mechanisms that could contribute to heart failure in lupus patients.

The study also identified four such autoantibodies that may directly affect the heart muscle. These findings may help identify lupus patients with the greatest risk of developing heart disease, inform the development of new therapeutic strategies, and allow extension to other autoimmune diseases.

“This finding is the first demonstration that autoantibodies can directly mediate myocardial injury in this complex autoimmune disease,” said the team’s leader Gordana Vunjak-Novakovic, University Professor and the Mikati Foundation Professor of Biomedical Engineering, Medical Sciences, and Dental Medicine at Columbia.

“It’s astonishing that these tiny heart tissues we’ve engineered using human stem cells and ‘organs-on-chip’ technology have the ability to emulate organ-level functions in a patient-specific way, and for such a complex disease. We now live in the era of studying the progression and treatment of diseases using apparently simple yet highly controllable and predictive models of human organs.”