Serotonin pathway tied to faster damage in some leaky heart valves

A Columbia-led research team has reported evidence that serotonin signaling may hasten damage in some patients with degenerative mitral regurgitation, a common form of heart valve disease. The finding matters because it points to a possible reason some patients reach surgery earlier, especially if they use SSRI antidepressants and carry a particular genetic variant.

Columbia University Irving Medical Center said the work was led by researchers in its Department of Surgery with collaborators at the Children’s Hospital of Philadelphia, the University of Pennsylvania and the Valley Hospital Heart Institute. The main study, supported by the National Heart, Lung, and Blood Institute, was published in 2023 in Science Translational Medicine.

Degenerative mitral regurgitation occurs when the mitral valve, which separates the heart’s left atrium and left ventricle, no longer seals properly. Columbia said the leak can force blood backward, strain the heart and, as the disease advances, contribute to fatigue, shortness of breath, atrial fibrillation and heart failure.

Medication can help symptoms and complications, Columbia said, but it does not repair the deteriorating valve. Severe cases may require surgery to fix or replace the valve.

Patient data pointed to earlier surgery

The researchers reviewed records from more than 9,000 patients who had mitral valve repair or replacement for degenerative mitral regurgitation, along with 100 valve tissue samples. According to Columbia, SSRI use was associated with patients needing surgery for severe mitral regurgitation at a younger age than patients not taking SSRIs.

The team said the patient findings showed an association, not proof that SSRIs caused faster valve disease. Observational data cannot exclude other differences between patients that may affect when surgery occurs.

The researchers then tested the biology in mice and human valve cells. Columbia said mice lacking the serotonin transporter gene developed thickened mitral valves, and normal mice given high SSRI doses also showed valve thickening.

The serotonin transporter, also called SERT or 5-HTT, helps move serotonin back into cells after signaling. SSRIs, including fluoxetine and sertraline, reduce that transporter’s activity, leaving serotonin active for longer.

Genetic variant may raise vulnerability

The study also focused on 5-HTTLPR, a region of the SERT gene that affects transporter activity. Columbia said patients with two copies of a “long” variant had lower SERT activity in mitral valve cells and underwent mitral valve surgery more often than patients with other variants.

In laboratory work, valve cells from patients with the “long-long” variant responded more strongly to serotonin and produced more collagen, Columbia said. Excess collagen can make valve tissue thicker and less flexible, changing how the valve moves.

The same cells were more sensitive to fluoxetine than cells with other variants, according to the researchers. The team proposed that people with degenerative mitral regurgitation and low SERT activity could be candidates for closer monitoring, though genetic testing for this purpose is not part of standard valve care.

Findings do not mean patients should stop antidepressants

Columbia said the researchers did not see harmful effects from normal SSRI doses or the “long-long” variant in cells from healthy human mitral valves. The work does not show that SSRIs damage healthy valves or that patients should change antidepressant treatment without medical advice.

Later studies have expanded the serotonin link, according to journal reports cited by Columbia. A 2024 mouse study connected SERT deficiency with fibrotic changes in cardiac valves and heart muscle, while 2025 and 2026 studies examined serotonin signaling in aortic stenosis, another valve disease.

A 2026 systematic review reported an association between drugs that modify SERT activity and heart valve disease, with an odds ratio of 2.76. The review did not prove causation, and Columbia said more research is needed to assess individual drugs, doses, treatment duration and preexisting valve disease.

For now, the researchers said routine cardiology care, imaging and individualized decisions remain central for patients with degenerative mitral regurgitation. The serotonin findings offer a possible biological clue, but clinical trials would be needed before genetic testing or serotonin-targeted treatments become part of regular care.

This story draws on original reporting from ScienceDaily.