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Snapshot Science: Does Serotonin Contribute to Heart Valve Disease Progression in Patients With Low Serotonin Transport Activity?
The neurotransmitter serotonin can affect the heart's mitral valve and potentially accelerate a cardiac condition known as degenerative mitral regurgitation (DMR) in people with a particular genetic variant that lowers serotonin transporter (SERT) activity, according to a multicenter study supported by a grant from the National Heart, Lung and Blood Institute.
Why it matters
DMR is a common heart disease that requires surgery in severe cases. A healthy mitral valve tightly closes the opening between the left atrium and the left ventricle when the heart contracts. But for patients with DMR, the mitral valve becomes thickened and deformed, and the valve cannot close completely when the heart contracts, allowing blood to leak backward into the left atrium.
Initially, patients are asymptomatic, but over time they progressively feel tired and short of breath. As pumping becomes less efficient due to this leak, the heart needs to work harder, and this extra work eventually leads to congestive heart failure. Certain medications can ease symptoms and prevent complications, but they do not treat the underlying cause of the disease. If the degeneration of the mitral valve becomes severe, surgery to repair or replace the mitral valve is needed.
Who conducted the study
Robert Levy, MD, director of Cardiology Research at CHOP and professor of Pediatrics at Perelman School of Medicine at the University of Pennsylvania, and Giovanni Ferrari, PhD, of Columbia University, co-led the study. Additional researchers at the University of Pennsylvania and Valley Hospital Heart Institute also collaborated.
How they did it
To better understand factors that contribute to the progression of the disease, CHOP researchers in the Pediatric Heart Valve Center and their collaborators analyzed data from more than 9,000 patients who had undergone valve repair or replacement surgery for DMR and evaluated 122 mitral valve biopsies. Studying the data of these patients, the researchers found that taking selective serotonin reuptake inhibitors (SSRIs) — the most commonly prescribed types of antidepressants — was associated with severe mitral regurgitation that needed to be treated with surgery at a younger age than for patients not taking SSRIs. The researchers noted that they did not find a negative effect with normal doses of SSRIs and that a healthy mitral valve may tolerate low SERT without deforming, as it is unlikely that low SERT can cause degeneration of the mitral valve by itself. They suspect that once the mitral valve has started to degenerate, it may be more susceptible to serotonin and low SERT.
The research team found high doses of selective serotonin reuptake inhibitors (SSRIs) developed thickened mitral valves in animal models. They also found that models lacking the SERT gene — the target of SSRIs — developed thicker mitral valves.
Through genetic analysis, the researchers identified genetic variants in a region of the SERT gene (5-HTTLPR) that affect SERT activity. They found that a "long" variant of 5-HTTLPR makes SERT less active in the mitral valve cells, especially when there are two copies (one from the mother and one from the father). Patients with DMR and the "long-long" variant were more likely to react to serotonin in a way that could change the shape of the mitral valve causing a need for mitral valve surgery more often than those with other variants. Additionally, "long-long" mitral valve cells were more sensitive to SSRI treatment than cells from other variants.
"Our study shows that taking SSRIs and having the 'long-long' SERT genetic variant lowers SERT activity in the mitral valve," said Dr. Levy, who is also an attending cardiologist in the Cardiac Center and the William J. Rashkind Endowed Chair in Pediatric Cardiology. "We suggest that assessing patients with known degenerative mitral regurgitation for potential low SERT activity by genotyping them for 5-HTTLPR may help identify patients who may need mitral valve surgery earlier. Ongoing research is exploring the idea that SERT and related serotonin mechanisms may represent therapeutic targets for the medical therapy of heart valve disease."
Where the study was published
The study appeared in Science Translational Medicine.