Abstract 32: Mitral Valve Interstitial Cells With the Serotonin Transporter (SERT)-LL Polymorphism are More Efficiently Activated by Serotonin
Prolapse of the Mitral Valve (MV) leaflet is a hallmark of several cardiac disorders such as Myxomatous MV Disease (MMVD) or ischemic MV regurgitation (MR), and is only treated surgically. Elevated levels of serotonin (5HT) have been associated with valvulopathies. Ongoing studies in our laboratory suggest that 5HT signaling plays an important role in the progression of MMVD. In addition, a 44 base polymorphism in the promoter region of the 5HT transporter (SERT) gene, designated as short (S) or long (L) allele, has been reported with Mendelian distribution, with LL resulting in increased 5HT reuptake compared to SS.
We hypothesized that patients with MMVD have enhanced 5HT signaling due to a high frequency of SERT-LL. DNA was extracted from 152 MMVD surgical patients, genomic fragment analysis performed to determine allelic frequencies, and a chi-square statistical test completed. We show that surgical patients with MMVD have a higher than expected frequency of SERT-LL (34% (52 of 152) vs. 25%). Notably, the frequency of SERT-LL is particularly enhanced (51% (21 of 41) vs. 25%) (p=0.009) in MMVD patients under 60 years old.
Based on these findings, we tested whether MV interstitial cells (MVICs) expressing SERT-LL have increased susceptibility to 5HT-mediated activation. We demonstrate that SERT-LL MVICs respond to 5HT with a 4-fold increase in smooth muscle actin (SMA) mRNA expression, a marker of VIC activation, compared to a less than 1-fold increase in SERT-LS and SERT-SS cells. The SMA response is abrogated by specific pharmacological inhibitors of the 5HT receptors 5HTR2A and 5HTR2B, and SERT, as well as siRNA knockdown. Studies of 5HTR expression in cells of each genotype are in progress.
Due to the enhanced frequency of the SERT-LL genotype among MMVD patients, particularly within the younger subset, and increased susceptibility of SERT-LL MVICs to 5HT, we postulate that the SERT-LL genotype may contribute to an increased risk of rapid disease progression by increasing the efficiency of 5HT signaling and uptake in MVICs resulting in extracellular matrix production leading to prolapse and impaired valve function. The SERT-genotype may constitute a novel means of identifying patients who may benefit from pharmacotherapy that alter 5HT-related mechanisms.
Author Disclosures: K.H. Driesbaugh: None. J.B. Grau: None. J.E. Bavaria: None. F. Alkhaleel: None. E.K. Lai: None. R.E. Shaw: None. R.C. Gorman: None. J.H. Gorman: None. R.J. Levy: None. G. Ferrari: None.
- © 2015 by American Heart Association, Inc.