Platelet activation and arterial peripheral serotonin turnover in cardiac remodeling associated to aortic stenosis

Abstract

Peripheral serotonin (5-HT) has been involved in adverse cardiac remodeling and valve fibrosis. The peripheral levels of 5-HT mainly depend on its release from activated platelets and degradation by monoamine oxidase A (MAO-A). The SERAOPI study investigated the relationship between arterial serotoninergic system, degree of platelet activation and cardiac remodeling, in patients with aortic valve stenosis (AS). Thirty patients with severe AS and 15 control subjects underwent transthoracic echocardiography, radial, and aortic arterial blood sampling. Measurements of 5-HT and its MAO-Adependent degradation product, 5-HIAA, were performed by HPLC. Arterial platelet activation was assessed by flow cytometry analysis of platelet surface expression of P-selectin and activated integrin GPIIb/IIIa. Activated platelets and arterial plasma 5-HT increased in AS patients as compared to control subjects (P-selectin 1.08 6 0.2MFI vs. 0.49 6 0.1MFI, P 5 0.04; GPIIb/IIIa 0.71 6 0.1MFI vs. 0.35 6 0.1MFI; P 5 0.0015 and arterial plasma 5-HT 11.55 6 1.6 nM vs. 6.18 6 0.7 nM, P 5 0.028, respectively). Moreover, 5-HT was strongly correlated to left ventricular hypertrophy assessed by echocardiography. The correlation was independent of cardiovascular risk comorbidities and others echocardiographic AS parameters. Finally, plasma 5-HIAA increased in AS patients (74.64 6 9.7 nM vs. 37.16 6 4.1 nM; P 5 0.0002) indicating a higher 5-HT degradation rate by MAO-A. Platelet activation, arterial circulating serotonin, and serotonin degradation increased in patients with AS. These observations suggest that the serotoninergic system may contribute to the pathogenesis of AS including valve fibrosis and adverse ventricular remodeling.

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

“…Although MR has been shown to result in a chronic state of platelet activation 27,28 , 5HT levels have not been studied in MR patients. However, aortic stenosis also results in enhanced platelet activation, and increased 5HT levels have been documented in a clinical study comparing aortic stenosis patients to those without valvular heart disease 30 . In our platelet studies, SSRI administration resulted in enhanced ADP induced platelet activation accompanied by increased 5HT levels (Figure 4).…”

“…The importance of platelets in 5HT mechanisms related to heart valve disease has been explored to a limited extent 27,28,30,38 . Platelets are the primary carriers of 5HT in blood.…”

“…Fluoxetine, a representative SSRI, enhances plat activation, and increases platelet secretion of 5HT thus enhancing HTR signaling ( Figure 3A-C). Asp administration inhibits platelet activation ( Figure 3) and thus, could mitigate MR progression by reducing plat activation associated 5HT release from platelets ( Figure 3D-F Age range (years) (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)…”

“…It is also noteworthy that MR is associated with a chronic state of platelet activation 27,28 , that correlates with the severity of valvular regurgitation 27 . Since platelets release 5HT when activated 29 , MR patients over time would hypothetically have more 5HT exposure than subjects without MR. Aortic stenosis has also been shown to result in increased platelet activation, and elevated plasma 5HT levels as well 30 . Thus, the present studies investigated the hypothesis that 5HT and related SLC6A4 mechanisms contribute to the pathophysiology of MR.…”

Monoamine Oxidases, Oxidative Stress, and Altered Mitochondrial Dynamics in Cardiac Ageing

“…Physiological ageing is also characterized by SNS dysfunction as shown by the increase in circulating catecholamine levels in old compared to adult individuals [35]. Concerning serotonin, a correlation was found between plasmatic serotonin and the degree of hypertrophy in aortic stenosis patients [36]. In another study, higher serotonin levels were associated with worse HF symptoms and systolic dysfunction [37, 38].…”