May 2016

Seeking Serotonin-Connected Solutions to Heart Valve Disease

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The mitral valve is the most mechanically active part of our bodies, going through a range of motion unlike any other in the four-chambered heart. Each time its two leaflets snap closed, the resulting blood flow stoppage contributes to the “lub” sound of our “lub-dub” heartbeat. This continuous, persistent motion is our essential bass beat powering us through our lives, without our regular noticing.

Malfunctions of the mitral valve are fairly common without our noticing, too. At least 2.5 percent of the U.S. population has heart valve disease, affecting either the mitral or aortic valve, with most cases either discovered incidentally in the context of some other health issue or else going undetected until they cause severe illness. By the time people need surgical replacement of a faulty heart valve, there is often collateral damage to the rest of the heart from years of the valve’s persistent malfunction with each and every beat. No drug treatments are available for heart valve disease itself, only for the symptoms caused by the disease.

A research team at The Children’s Hospital of Philadelphia and University of Pennsylvania is working on a complex study of mitral valve disease that shows early potential to prevent long-term heart damage in young men and boys who are prone to a possible genetic subtype of mitral valve disease. The team recently received a grant from the National Heart, Lung and Blood Institute (NHLBI) to pursue research that could confirm the existence of this genetic subtype and explain its mechanism of disease, for which serotonin-related drugs could be an effective treatment approach.

“There’s a lot to be learned in terms of why serotonin systems are normally present in heart valve cells, and why they seem to go haywire in the disease state,” said study leader Robert Levy, MD, a cardiologist at CHOP and professor of Pediatrics at Penn’s Perelman School of Medicine, who specializes in heart valve disease.

Emerging Knowledge of How Serotonin Affects the Heart

Most people who are familiar with serotonin know it as a “happy” neurotransmitter because it has been most extensively studied in the brain in connection with depression. Common antidepressant drugs, such as fluoxetine (Prozac), work by blocking transport of serotonin back into cells and out of the synapse between neurons. As a result, more serotonin remains active in the synapse, engaged in more signaling, which helps to reduce depressive symptoms.

But serotonin influences the body in many more places than the brain. Spurred by clues that serotonin affects valve disease risk, including a popular weight-loss drug (fenfluramine/phentermine, or fen-phen) that acts on serotonin and was pulled from the market by the Food and Drug Administration in the 1990s for causing rapid-onset severe valve disease, Dr. Levy and other cardiac researchers have been working to determine what this hormone does in heart valves.

The picture is complex, and more unanswered questions remain than answered ones. They do know that in heart valves, as in the brain, serotonin can signal to receptor proteins on the heart valve cell’s surface, and it can enter the heart valve cells via serotonin transport proteins. When serotonin signals the receptors, it appears to set off reactions within heart valve cells that collectively lead to either maintenance of valve structure, or in valve disease, thickening of the leaflets. When it passes through the transport protein to a heart valve cell, it is broken down and not re-released.

In 2009, Dr. Levy led a team that identified how one of those diet drugs, fenfluramine (Fen), acts on serotonin in heart valves when it triggers risk of valve disease: It is analogous to Prozac in the brain, in that it shuts down the transporter protein and keeps more serotonin in an active signaling state.

Investigating a Gene Variant Affecting the Serotonin Transport Protein

Now Dr. Levy and colleagues are weaving together their growing knowledge about serotonin activity in heart valves with questions about a common gene variant that has largely been a focus of study in neuroscience.

The variant in question occurs in the gene for the serotonin transport protein, specifically in the promoter region that helps control the gene’s expression. About half the population is heterozygous, having one copy of the gene with its full-length promoter region, and one shorter variant copy of the gene with a 44-base-pair section deleted from the promoter region. Roughly a quarter of the population is homozygous with two full-length copies, and another quarter is homozygous with two copies of the shorter variant.

Dr. Levy and colleagues hypothesized that having two copies of the shorter gene variant could increase risk of earlier onset of severe valve disease; their idea was that having less transporter protein in heart valves in the first place would be a bit like taking the transporter-blocking drug Fen, which caused rapid-onset valve disease. So Dr. Levy and his co-investigator, Giovanni Ferrari, PhD, an assistant professor in the department of Surgery at Penn, decided to look at the damaged heart valves from cardiac surgery patients at Penn who were participants in a registry that Dr. Ferrari leads. They predicted that the younger surgery patients would be homozygous for the short form of the serotonin transport gene at above-average rates.

“What we found was actually the opposite of that,” Dr. Levy said. “That was really a pretty big surprise.”

Among the surgery patients whose heart valves they have examined so far, Dr. Levy and colleagues found that a group of younger patients (under age 55) was nearly twice as likely to be homozygous for the full-length form of the serotonin transport gene as they would have predicted from the variant’s distribution in the general population. Fewer of these patients than predicted were heterozygous for the gene variant, while about the typically expected proportion (one in four) was homozygous for the shortened form of the gene.

One other surprising thing stood out based on their early analysis of surgical samples: The effect they found was sex-specific, affecting only younger men in the study population. Both women of all ages and older men who needed mitral valve surgery had the gene variant at the usual expected distribution in the general population. Additionally, women were underrepresented in the surgical population, outnumbered two to one by men — even though women are generally twice as likely as men to experience mitral valve disease. These sex-related differences are so far unexplained.

Dr. Levy and his team are moving forward, working to confirm their early findings by establishing whether the individuals who are homozygous for the long form of the serotonin transport gene do indeed have more of the transport protein in their heart valves, as they expect. They also have more work to do using in vitro and animal models to explore the mechanism by which the long form of the transporter gene may cause damage. Their revised hypothesis is that, among individuals with two copies of the long form, serotonin is transported and dismantled within heart valve cells to a greater extent, releasing reactive oxygen species in the process and causing damage via oxidative stress.

“I think this genotype in the future will be used as a biomarker for looking at risk in patients with mitral valve prolapse,” Dr. Levy said. “Especially for males, it will be important to learn if they have the full-length form as their transporter polymorphism genotype.”

Looking Ahead

If Dr. Levy’s team confirms that this genotype puts boys and young men at elevated risk of serious valve disease, the good news is that researchers already have a head start on finding potential drug therapies — and this could mark the first general drug opportunity for heart valve disease. That is because serotonin-related therapies have been widely studied for decades in the context of neuroscience. Drug companies have large libraries of compounds that have been considered for potential use against depression and other mental and neurological health conditions. Many compounds that were rejected from consideration because they cannot cross the blood-brain barrier might still be candidates for keeping heart valves healthy.

“Mitral valve prolapse is detected in childhood,” Dr. Levy said. “Knowing about these diseases in childhood and starting treatment before there is chronic damage to the heart is really a great possibility, and it’s a very important reason to do these studies.”

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