Elsevier

Pharmacological Research

Volume 140, February 2019, Pages 33-42
Pharmacological Research

Review
Serotonin contribution to cardiac valve degeneration: new insights for novel therapies?

https://doi.org/10.1016/j.phrs.2018.09.009Get rights and content

Abstract

Heart valve disease (HVD) is a complex entity made by different pathological processes that ultimately lead to the abnormal structure and disorganization of extracellular matrix proteins resulting to dysfunction of the leaflets. At its final evolutionary step, treatments are limited to the percutaneous or surgical valve replacement, whatever the original cause of the degeneration. Understanding early molecular mechanisms that regulate valve interstitial cells remodeling and disease progression is challenging and could pave the way for future drugs aiming to prevent and/or reverse the process. Some valve degenerative processes such as the carcinoid heart disease, drug-induced valvulopathy and degenerative mitral valve disease in small-breed dogs are clearly linked to serotonin. The carcinoid heart is typically characterized by a right-sided valve dysfunction, observed in patients with carcinoid tumors developed from serotonin-producing gut enterochromaffin cells. Fenfluramine or ergot derivatives were linked to mitral and aortic valve dysfunction and share in common the pharmacological property of being 5-HT2B receptor agonists. Finally, some small-breed dogs, such as the Cavalier King Charles Spaniel are highly prone to degenerative mitral valve disease with a prevalence of 40% at 4 years-old, 70% at 7 years-old and 100% in 10-year-old animals. This degeneration has been linked to high serum serotonin, 5-HT2B receptor overexpression and SERT downregulation. Through the comprehension of serotonergic mechanisms involved into these specific situations, new therapeutic approaches could be extended to HVD in general. More recently, a serotonin dependent/ receptor independent mechanism has been suggested in congenital mitral valve prolapse through the filamin-A serotonylation. This review summarizes clinical and molecular mechanisms linking the serotonergic system and heart valve disease, opening the way for future pharmacological research in the field.

Introduction

Heartvalve diseases (HVD) include various disorders that result from the genetic or environmental disruption of leaflet function. These pathologies are divided into two main clinical entities: stenosis, in which pathological leaflet thickening and narrowing inhibit valve opening, and regurgitation or insufficiency, in which the improper coaptation of valve leaflets allows blood backflow. Regardless of the etiology, these valvular pathologies progress slowly and subclinically through molecular and cellular mechanisms, including fibromyxoid or fibrocalcific remodeling (cellular migration, followed by cellular differentiation and extracellular matrix remodeling), which result in symptomatic diseases that require surgical intervention. Of the numerous factors that lead to valvular pathologies (the genetic, inflammatory, and cardiovascular risks that mediate conditions to degenerative pathologies), the contribution of the serotonergic system in these pathologies may be advanced through two clinical contexts: the carcinoid heart and drug-induced valvulopathy. It is surprising to observe that the similar fibromyxoid lesions are induced by benfluorex, a fenfluramine derivative, in both mitral and aortic tissues [1] or in both mitral and tricuspid tissues [2], whereas the valvulogenesis, anatomical and hemodynamic features of each lesion are different. The common macroscopic and histological characteristics shared by drug-induced valvulopathy and acute rheumatic fever make difficult the establishment of the imputability of these drugs in HVD [3] and suggest a similar serotonergic mechanism involved in HVD. The aim of this review is to highlight the contribution of serotonin in HVD. Clinical presentations including carcinoid heart, drug-induced valvulopathy and the degenerative mitral valve disease in the dog, in which serotonin is clearly involved, will be deeply analysed. Cellular and molecular mechanisms will be discussed to underline possible new targets in serotonergic valvulopathies and other kinds of degenerative valve processes.

Section snippets

Serotonin synthesis, metabolism and effectors in cardiac valve tissues

Serotonin (5-hydroxytryptamine or 5-HT) is an endogenous monoamine neurotransmitter /hormone that regulates central (mood, appetite, memory, anxiety, sleep, pain, aggression, and cognition) and peripheral (platelet aggregation, gastro-intestinal motility, cardiac function and blood pressure homeostasis) functions. Over the last decade, several reports emphasized the role of 5-HT in the early phase of wound healing and tissue repair and its major contribution to fibrogenesis. Mechanisms are

Clinical data

The pathogenesis of carcinoid heart disease (CHD) and the development of carcinoid plaques remain incompletely understood; however, an increasing body of evidence points toward 5-HT playing a key role. CHD occurs in more than 50% of patients with carcinoid syndrome associated with neuroendocrine tumors secreting 5-HT. The carcinoid heart is characterized by the development of right-sided valvular dysfunction. The echocardiographic features include the thickening, retraction and regurgitation of

Involvement of mechanical stress to serotonin valve effects

Most of studies are performed on cultured valvular cells but in fact the valve tissue is subjected to considerable mechanical strain. During an average human life span, heart valves open and close approximatively 3 billion times in response to different gradient pressures (more than 200 mmHg). Cardiac valves are living tissues with the ability to repair and remodel in response to damage. Valve biology must be modeled in these extreme hemodynamic conditions. Several laboratories have developed

Discussion

Serotonin and serotonergic 5-HT2 receptors, 5-HT2A and/or 5-HT2B, have been shown to induce the pathological remodeling of cardiac valves (Fig. 2). 5-HT2B receptor stimulation is a common feature of drug-induced valvulopathy. In the field, an important issue is now to identify drugs (old, new or future) at risk for heart valve degeneration. Huang and colleagues screened 2200 compounds that were FDA approved and identified 5-HT2B receptor agonism using calcium-based high-throughput screening [83

Conflicts of interest

None.

Acknowledgements

This study was supported by the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the University Pierre and Marie Curie of Paris, the University of Strasbourg, the Centre Hospitalier et Universitaire de Strasbourg, and by grants from the Fondation de France, the French Ministry of Research, and the Agence Nationale pour la Recherche [ANR-12-BSV1-0015-01].

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