A Columbia University study published in Science Translational Medicine has uncovered a link between serotonin signaling and degenerative mitral regurgitation (DMR), the most common form of heart valve disease in the developed world. The findings implicate both genetic variation in the serotonin transporter (SERT) gene and SSRI antidepressant use as factors that may accelerate the progression of valve disease.
The clinical data
The researchers analyzed more than 9,000 patients who had undergone mitral valve surgery for DMR. They found that SSRI use was associated with younger age at surgery, suggesting that serotonin-modifying drugs may accelerate valve degeneration in patients who already have mitral valve disease.
The study also identified a specific genetic variant in the SERT gene promoter, the 5-HTTLPR “long-long” (LL) genotype, that was overrepresented among DMR patients requiring surgery. This variant reduces membrane localization of SERT in mitral valve interstitial cells (MVICs), the cells that maintain valve structure, leading to decreased serotonin clearance from the extracellular space.
Analysis of 122 human mitral valve biopsy samples confirmed that MVICs from LL-genotype patients showed increased collagen (COL1A1) expression and were more sensitive to the SSRI fluoxetine.
The mechanism
The paper delineates a signaling cascade: reduced SERT activity, from either the LL genotype or SSRI-mediated inhibition, leaves more serotonin in the extracellular space around valve cells. This enhances signaling through the HTR2B serotonin receptor on MVICs, which in turn upregulates transforming growth factor beta 1 (TGF-beta-1) and collagen production. The result is excessive collagen deposition that thickens and stiffens the mitral valve leaflets, accelerating the progression of regurgitation.
Three mouse models confirmed the causal direction: SERT knockout mice developed thickened mitral valve leaflets; wild-type mice treated with high-dose fluoxetine showed the same effect; and SERT gene silencing also produced thickened leaflets.
Caveats
The senior author, Giovanni Ferrari, cautions against over-interpretation: “A healthy mitral valve can probably stand low SERT activity without deforming. It is unlikely that low SERT can cause degeneration of the mitral valve by itself.” The risk appears to operate mainly in valves where degeneration has already begun, accelerating a pre-existing process.
The study’s clinical dataset is retrospective, and the association between SSRI use and earlier surgery does not establish causation. The findings identify HTR2B as a potential therapeutic target, but no HTR2B antagonist is currently approved for this indication.
The paper was originally published in January 2023; the recent attention follows a ScienceDaily feature and renewed interest in the serotonin-valve connection as a 2026 meta-analysis reported 2.76-fold higher odds of heart valve disease in people using SERT-modifying drugs.
Sources
[1] Castillero, E., Fitzpatrick, E., Keeney, S.J., et al. “Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.” Science Translational Medicine, Vol. 15(677) (2023). DOI: 10.1126/scitranslmed.adc9606
[2] ScienceDaily. “Columbia scientists discover surprising link between serotonin and heart valve disease.” July 11, 2026. https://www.sciencedaily.com/releases/2026/07/260711010131.htm