550 FINGOLIMOD IN MULTIPLE SCLEROSIS: BRADYCARDIA, ATRIOVENTRICULAR BLOCKS AND EFFECT ON THE QT-INTERVAL. A PROSPECTIVE STUDY.
Authors: Amati Francesca , Vetrano Saverio Danilo , Paolicelli Damiano , Ciccone Marco Matteo 
Published: December 2022

Abstract
Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) that is mainly characterized by inflammatory demyelination, leading to severe neurological disability. MS typically affects young adults and usually arise with acute relapses, followed by partial or complete remission period. Currently, there is no definite treatment for MS. However Sphingosine-1-phosphate receptor modulators (S1PRMs), a class of disease-modifying treatments (DMTs), have shown a positive effect of the S1P pathway and S1PRMs on immune cell trafficking and neuroprotection, leading to the approval of 3 drugs (Fingolimod (Gilenya®), Siponimod (Mayzent®), and Ozanimod (Zeposia®)) for MS treatment [1]. Since S1PR have extensive expression on cardiomyocytes and vascular endothelial cells, cardiovascular effect, such as atrioventricular block (AVB), sinus bradycardia, orthostatic hypotension or hypertension, are expected [2]. At present, the approved S1PRMs require 6-h continuous cardiac monitoring after first dose and after every up titration. Nevertheless, so far no study has investigated the risk of cardiovascular adverse events in MS patients treated with S1PRMs.
The aim of the present study was to define the incidence of cardiovascular adverse events (AEs) in relapsing-MS patients, without cardiac pre-existing conditions, treated with Fingolimod 0.5 mg/die.
We enrolled 9 consecutive patients (mean age 34 years) admitted to the Neurology Department at University of Bari, between February and May 2022. All patients underwent 12 lead ECG, trans-thoracic Echocardiogram and BP evaluation. A six hours continuous monitoring of heart rate and blood pressure by telemetry started immediately after Fingolimod administration. A 12 lead ECG was obtained at the 5th and 6th hour of monitoring. During six hours monitoring blood pressure did not change significantly. As regards the entity of the HR changes, we found a decrease of 12 ± 8 bpm especially between the 2nd and the 3rd hour of monitoring; at the 3rd hour of monitoring, two of our youngest patients experienced a second degree type 1 AVB but normal atrio-ventricular conduction restored during the 5th hour of monitoring. All patients remained asymptomatic and were discharged in good clinical conditions after the end of six hour monitoring.
Given the higher incidence of cardiovascular AEs in patients with MS receiving S1PRMs, a comprehensive assessment of patient conditions is recommended. During Fingolimod treatment, heart rate, brady-arrhythmias, and blood pressure should be monitored via active electrocardiography recording for at least 6 h after the first dose; monitoring could be potentially prolonged according to patient situation, although in our cohort the maximal conduction delay occurred within 3 hours. Our perspective is to obtain a long-term follow-up (1–3 years) focusing on heart rate and blood pressure variations, in order to elaborate a prediction model of cardiovascular risk in patients receiving S1PRMs.
[1] Zhao Z, et al. Front Immunol. 2021 Dec 7;12:795574.
[2] Paolicelli D et al. J Clin Pharmacol. 2015 Oct;55(10):1131-6.