summary: Taking an SSRI and having the “long” SERT serotonin genetic variant reduces SERT activity in the mitral valve, leading to degenerative mitral regurgitation, one of the most common valvular heart diseases.
The neurotransmitter serotonin can negatively affect the mitral valve of the heart, contributing to a heart condition known as degenerative mitral regurgitation, according to a new multicenter study involving researchers from the Children’s Heart Valve Center at Children’s Hospital of Philadelphia.
The study, which was co-led by CHOP’s Robert J. Levy, Columbia University MD’s Giovanni Ferrari, and also involved collaborators at the University of Pennsylvania and Valley Hospital Heart Institute, was recently published in Translational Medicine Sciences.
Degenerative mitral valve regurgitation is one of the most common heart valve diseases. A healthy mitral valve tightly closes the opening between the left atrium and left ventricle when the heart contracts. With degenerative mitral regurgitation, the mitral valve becomes deformed, and the valve can’t close completely when the heart contracts, allowing some blood to leak backward into the left atrium. This abnormal flow of blood is called regurgitation.
Although patients initially do not have symptoms, over time the mitral valve becomes thickened and deformed, and patients gradually feel tired and short of breath. Because the pumping becomes less efficient due to this leakage, the heart needs to work harder. This extra work of the heart eventually leads to congestive heart failure.
Some medications can relieve symptoms and prevent complications, but they do not treat the underlying cause. If mitral valve prolapse becomes severe, surgery to repair or replace the mitral valve is required.
To better understand the factors that contribute to disease progression, CHOP researchers and collaborators analyzed data from more than 9,000 patients who underwent surgery for degenerative mitral valve disease and evaluated 100 human mitral valve biopsies, in addition to studying mouse models.
Researchers found that taking selective serotonin reuptake inhibitors (SSRIs) — the most commonly prescribed antidepressant — was associated with severe mitral valve regurgitation, which required surgery at a younger age than those not taking SSRIs.
In animal models, they found that normal mice treated with high doses of SSRIs developed thickened mitral valves. They also found that mice lacking the serotonin transporter (SERT) gene, the target of SSRIs–which transport serotonin into cells, where it can’t bind to receptors and transmit signals–developed thicker mitral valves.
Through genetic analysis, the researchers identified genetic variants in a region of the SERT gene (5HTTLPR) that affect the extent of SERT activity. Patients with two copies of the “long” variation of the gene that makes SERT less active — one copy from the mother and the other from the father — had much lower SERT activity and required surgery more often.
Patients with this “long” type were more likely to react to serotonin in a way that could alter the shape of the mitral valve. In addition, ‘long’ mitral valve cells were more sensitive to SSRI treatment than cells from other variants.
The authors note that they did not find an adverse effect of normal doses of SSRIs and that a healthy mitral valve may tolerate a low SERT level without deformation, as it is unlikely that a low SERT level would cause mitral valve degeneration by itself. They suspect that once the mitral valve begins to deteriorate, it may be more susceptible to serotonin and lower SERT.
Levy, a cardiologist at the Heart Center and chair of the William J. Children’s Hospital of Philadelphia.
“We suggest that assessing patients with degenerative mitral regurgitation known to have potentially low SERT activity by genotyping them for 5HTTLPR may help identify patients who may need mitral valve surgery early.”
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“Decreased serotonin transporter activity in the mitral valve contributes to the development of degenerative mitral regurgitationWritten by Estibaliz Castillero et al. Translational Medicine Sciences
Decreased serotonin transporter activity in the mitral valve contributes to the development of degenerative mitral regurgitation
Degenerative mitral valve regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that decreased serotonin transporter (SERT) activity accelerates MV remodeling and progression to MR.
Through studies of a cohort of patients with MRI, we show that selective serotonin reuptake inhibitors (SSRIs) are used and Sirte The 5-HTTLPR LL inducible polymorphism has been associated with MV surgery at a younger age.
Functional characterization of 122 human MV samples, in conjunction with in vivo studies Sirte– / – Mice and wild-type mice treated with SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to MRI pathophysiology through enhanced serotonin receptor (HTR) signaling.
SERT activity was decreased in LL MVICs in part due to decreased membrane localization of SERT. In rats, or fluoxetine treatment Sirte Knockdown resulted in thick MV leaflets.
Likewise, the silencing Sirte in normal human MVICs led to up-regulation of transforming growth factor-β1 (TGFB1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity, but also decreased Sirte expression and increase HTR2B expression.
It was also associated with increased fluoxetine treatment and the LL genotype COL1A1 In the presence of serotonin in MVICs, these effects were attenuated by HTR2B inhibition.
These findings suggest that assessment of both 5-HTTLPR genotype and SERT inhibitor therapies may be useful tools for the classification of patients with MV disease to estimate the likelihood of rapid disease progression.