Researchers find association between serotonin, heart valve disease

According to a recent study, serotonin can damage the heart’s mitral valve, potentially speeding up a condition known as degenerative mitral regurgitation. The findings of the multicenter trial, co-led by Columbia’s Giovanni Ferrari, PhD, and CHOP’s Robert J. Levy, MD, and funded by the National Heart, Lung, and Blood Institute, were just published in Science Translational Medicine. Mitral regurgitation due to ageing.

One of the most frequent types of heart valve disease is degenerative mitral regurgitation (DMR). The mitral valve is placed between the heart’s left atrium and left ventricle. When the heart contracts, it closes tightly to prevent blood from flowing back into the left atrium.

The shape of the mitral valve gets deformed in DMR, preventing the valve from entirely shutting. This causes blood to seep back into the lungs (regurgitation), decreasing the quantity of oxygen-rich blood that can travel via the heart to the rest of the body.
As a result, DMR can cause symptoms such as weariness and shortness of breath. Because of the decreased efficiency of circulation, the heart needs to work harder, causing lasting damage over time. This can result in a variety of significant and life-threatening cardiac problems, such as atrial fibrillation and heart failure.
There is currently no treatment for mitral valve degeneration.

“Certain medications can ease the symptoms and prevent complications, but they do not treat the mitral valve,” says Ferrari, scientific director of the Cardiothoracic Research Program at Columbia. “If the degeneration of the mitral valve becomes severe, surgery to repair or replace the valve is needed.”

Serotonin’s Function

Serotonin is involved in many bodily functions, including emotional mood, digestion, sleep, memory, and blood coagulation. Serotonin’s action as a neurotransmitter aids in mood regulation; low levels of serotonin are linked to anxiety and sadness.

Serotonin attaches to certain receptors on the surface of a cell, signalling the cell to act. The serotonin transporter (SERT or 5-HTT) protein transports serotonin into the cell to be reabsorbed and regenerated, a process known as serotonin reuptake.

Selective serotonin reuptake inhibitors (SSRIs) bind to the SERT and limit serotonin reuptake, allowing serotonin to be accessible for longer periods of time. This enhanced serotonin availability may aid in the treatment of mood disorders. SSRIs are a class of antidepressants that includes well-known drugs such as fluoxetine (Prozac) and sertraline (Zoloft).

Design of the Study

The researchers reviewed clinical data from almost 9,000 individuals who had undergone DMR valve repair or replacement surgery, as well as 100 mitral valve biopsies. “Studying the data of these patients, we found that taking SSRIs was associated with severe mitral regurgitation that needed to be treated with surgery at a younger age than for patients not taking SSRIs,” Ferrari explained.

The researchers also used normal mice and transgenic mice lacking the SERT gene to study in vivo mouse models. They discovered that mice without the SERT gene had thicker mitral valves, and that normal mice given high dosages of SSRIs also had thickened mitral valves.

The researchers used genetic analysis to identify genetic variants in the SERT gene region 5-HTTLPR that alter SERT function. They discovered that a “long” variation of 5-HTTLPR inhibits SERT activity in mitral valve cells, especially when there are two copies (one maternal and one paternal). Patients with DMR who had the “long-long” form required mitral valve surgery more frequently than those with other variants.

Mitral valve cells from DMR patients with the “long-long” variation were more likely to respond to serotonin by generating more collagen, causing the mitral valve to change shape. Furthermore, mitral valve cells expressing the “long-long” variation of 5-HTTLPR were more susceptible to fluoxetine than other variants.
Implications for Mitral Valve Disease Patients.

According to the findings, using SSRIs reduces SERT activity in the mitral valve in DMR patients with the “long-long” type. The researchers recommend checking DMR patients for decreased SERT activity by genotyping them for 5-HTTLPR, which can be easily identified from a blood or mouth swab DNA sample.

“Assessing patients with DMR for low SERT activity may help identify patients who may need mitral valve surgery earlier,” said Ferrari. “Promptly fixing a mitral valve that is very leaky would protect the heart and could prevent congestive heart failure.”

The researchers did not find a negative effect with normal doses of SSRIs or the “long-long” variant in cells from healthy human mitral valves. “A healthy mitral valve can probably stand low SERT activity without deforming,” said Ferrari. “It is unlikely that low SERT can cause degeneration of the mitral valve by itself. SSRIs are generally safe for most patients. Once the mitral valve has started to degenerate, it may be more susceptible to serotonin and low SERT.”