Inhibition and down regulation of the serotonin transporter contribute to the progression of degenerative mitral regurgitation

Abstract

Aims: Heart valve disease attributed to serotonin (5HT) has been observed with 5HT-secreting carcinoid tumors and in association with medications, such as the diet drug, Dexfenfluoramine, a serotonin transporter (SLC6A4) inhibitor and 5HT receptor (HTR) 2B agonist. HTR2B signaling upregulates TGFβ-1 resulting in increased production of extracellular matrix proteins. SLC6A4 internalizes 5HT, limiting HTR signaling. Selective 5HT reuptake inhibitors (SSRI), widely used antidepressants, target SLC6A4, thus enhancing HTR signaling. However, 5HT and SLC6A4 mechanisms have not been previously associated with degenerative mitral regurgitation (MR). The present studies investigated the hypothesis that both dysregulation of SLC6A4 and inhibition of SLC6A4 contribute to the pathophysiology of MR. Methods and Results:Here we report SLC6A4 related studies of 225 patients with MR requiring surgery. A multivariate analysis showed that SSRI use in MR patients was associated with surgery at a younger age, indicating more rapidly progressive MR (p=0.0183); this was confirmed in a national dataset (p<0.001). Aspirin use by MR patients was associated with surgery at an older age (p=0.0055). Quantitative reverse transcriptase PCR of MR leaflet RNA from 44 patients, and 20 normal mitral leaflets from heart transplant recipients, demonstrated down regulation in MR of both SLC6A4 and vesicular monoamine transporter-2 (SLC18A2), that packages 5HT (p<0.001). Human mitral valve interstitial cells cultivated with Fluoxetine, a SSRI, demonstrated down regulation of SLC6A4 and upregulation of HTR2B, compared to untreated, in cells from both normal and MR leaflets. Platelet 5HT studies in healthy subjects without heart disease used ADP-induced activation to model MR-associated activation. Fluoxetine significantly increased platelet activation and plasma 5HT levels, while Aspirin inhibited ADP platelet activation.Conclusions: Down regulation and inhibition of SLC6A4 influences MR through enhanced HTR signaling. SSRI may further influence MR through inhibition and down regulation of SLC6A4, upregulation of HTR2B, and increased platelet release of 5HT. Translational PerspectiveDegenerative mitral valve regurgitation (MR) affects millions, and there is no medical therapy for this disease. MR becomes progressively worse, and for severe MR, the only option is cardiac surgery. Serotonin (5HT) is best known as a neurotransmitter. However, 5HT secreting carcinoid tumors cause a cardiac valve disorder in many cases, and 5HT related medications, such as the diet drug Fenfluoramine, have been associated with the development of cardiac valve disease. The present paper presents evidence that diminished serotonin transporter (SLC6A4) expression and inhibition, lead to increased 5HT receptor signaling, contributing to the progression of MR.

First quantitative dosages: Strong correlations between non-5-HT2Rs serotonin receptors on normal human heart valves

“…Another recent study, using also qPCR in patients ( n = 44) with MV prolapse, has shown no up-regulation of 5-HT 2A R, while 5-HT 2B R was even down-regulated: (−1.4x), 5-HT 2C R (−3.9x), 5-HT 1B R (−5.5x), 5-HT 1D R (−3.1), 5-HT 7 R (−3.2x), and SERT (−5.2x). In this study, TPH1 has been shown to be down-regulated (−2.3x) but 5-HT 1A R and 5-HT 4 R were not significantly changed ( 5 ) (see Figure 4 ). TGF-β2 was again increased (2.3x), especially BMP4 (+2.0x), but not BMP3 (−2.7x) or BMP5 (−4.9x).…”

“…TGF-β2 was again increased (2.3x), especially BMP4 (+2.0x), but not BMP3 (−2.7x) or BMP5 (−4.9x). The blockers of SERT in vitro increased the 5-HT 2B R on VIC ( 5 ).…”

“…Ref. references for this figure/ 1) Levy et al ( 5 ); 2) Driesbaugh et al ( 2 ); 3) Hulin et al ( 25 ); 4) Roy et al ( 27 ); 5) Sainger et al ( 28 ). See also for review: Ayme-Dietrich et al ( 3 ) and Barnes et al ( 11 , 23 ).…”

“…Over-expression of mRNA for 5-HT 2A R (x12) and 5-HT 2B R (x28) has been observed on human heart valves in prolapses (2). However, another study using qPCR has not confirmed an increase in 5-HT 2B R in human valvular prolapse (5). 5-HT 2B R may also play a crucial role in the propensity of valvular tissue to develop calcification.…”

“…A secondary effect observed was the valvular toxicity of serotoninergic receptor drug agonists ( 3 ). More recently, its role has been reported in myxoid valvular degeneration and mitral prolapse (MVP) ( 2 , 3 , 5 ). The common macroscopic and histological characteristics shared by drug-induced valvulopathy and acute rheumatic fever make it difficult to determine the involvement of 5-HT agonists in heart valve diseases (HVD) and to suggest the possibility of a similar serotoninergic mechanism.…”