Lymphatic Dysfunction Drives Heart Valve Disease

Dysfunction in the lymphatic system has been identified as a hidden driver of life‑threatening heart valve disease in patients with Marfan syndrome, according to a new Northwestern Medicine study published in The Journal of Clinical Investigation.

Marfan syndrome, a genetic condition caused by mutations in the FBN1 gene, weakens connective tissue throughout the body. One of its most dangerous complications is myxomatous degeneration of the mitral valve (MDMV), which can lead to mitral valve prolapse, severe blood leakage and even sudden cardiac death.

While scientists have long understood that abnormal TGF-b signaling plays a role in the disease, the biological steps linking gene mutation to valve failure have remained unclear.

In the new study, investigators discovered that lymphatic vessels — tiny channels responsible for draining interstitial fluid and regulating immune responses — play a critical role in maintaining the health of the mitral valve.

“We discovered that normal lymphatic vessel growth is blocked in the mitral valves of Marfan syndrome mice,” said the study’s first author Can Tan, MD, PhD, research assistant professor of Medicine in the Division of Cardiology. “While multiple cell types including valvular endothelial cells and immune cells actively drive inflammation in the mitral valve, we are testing drugs to target and reverse these specific problems.”

The team found that lymphatic vessels normally develop in the mitral valve shortly after birth. But in Marfan Syndrome mice carrying the FBN1 mutation, this process is disrupted.

The mutant mice had fewer and more underdeveloped lymphatic vessels, impaired fluid drainage, structural defects in lymphatic endothelial cells and a buildup of inflammatory immune cells. Together, the changes created a harmful environment that accelerated the mitral valve’s degeneration.

“If the lymphatic vessels are dysfunctional and cannot drain interstitial fluid, the valve’s connective tissue becomes softer and thicker, a condition known as myxomatous degeneration,” said Tsutomu Kume, PhD, professor of Medicine in the Division of Cardiology and of Pharmacology, who was senior author of the study.

The new findings build on earlier work in the Kume laboratory.

“In our earlier work, we for the first time showed that lymphatic vessels are present within the adult murine mitral valve and that lymphatic function is critical for maintaining its structural integrity,” Kume said.

Before that earlier study, it was unclear and even neglected whether lymphatic vessels were present in the mitral valve and, if so, how they would function there. That insight prompted the team to investigate whether lymphatic dysfunction might also explain mitral valve disease in Marfan syndrome.

The latest findings represent a significant shift in how scientists understand mitral valve disease, Tan said.

“Our research shifts the paradigm in the field by revealing a previously overlooked driver of heart valve failure: lymphatic dysfunction,” Tan said. “We show that lymphatic dysfunction actively drives mitral valve disease in Marfan syndrome.”

Next, the team tested potential treatments. By stimulating lymphatic growth using a targeted molecule, vascular endothelial growth factor C (VEGFC), the team was able to improve lymphatic vessel density and valve health in mice. Another treatment, fingolimod, helped reduce inflammation, restore lymphatic structure and improve drainage.

“These strategies are designed to rebuild the valvular structure by promoting healthy lymphatic vessels and preventing inflammation,” Tan said.

Currently, many people with severe mitral valve disease — especially those with Marfan syndrome — ultimately require open-heart surgery. The new study could pave the way for more treatment options, Tan said.

“This matters because Marfan syndrome patients often face high-risk, traumatic open-heart surgeries as their only option,” Tan said. “By providing a potential pharmaceutical alternative, our work could fundamentally change how we treat these diseases and prevent heart failure before it even starts.”

Moving forward, Kume said that the team has filed a provisional patent related to the use of fingolimod in this context, highlighting its translational potential. The investigators are now working to translate their findings beyond animal models.

“Our next step will involve examining human mitral valve samples from Marfan syndrome patients,” Tan said. “We will also evaluate treatments in mouse models to determine if we can safely and effectively translate our findings to help patients.”

Additional Feinberg co-authors of the study included Luisa Iruela-Arispe, PhD, the chair and Stephen Walter Ranson Professor of Cell and Developmental Biology; Ziyou Ren, ‘20 PhD, assistant professor of Dermatology and of Preventive Medicine in the Division of Epidemiology;, Xianpeng Liu, PhD, research assistant professor of Surgery in the Division of Thoracic Surgery; and Zhi-Dong Ge, MD, PhD, research associate professor of Pediatrics.

The study was supported by National Institutes of Health grants R01HL159976 and R01EY034740, as well as a National Cancer Institute Cancer Center Support Grant awarded to the Robert H. Lurie Comprehensive Cancer Center.