Modulation of Cardiac Autonomic Function by Fingolimod Initiation and Predictors for Fingolimod Induced Bradycardia in Patients with Multiple Sclerosis

Abstract

Objective: It is well-known that initiation of fingolimod induces a transient decrease of heart rate. However, the underlying cardiac autonomic regulation is poorly understood. We aimed to investigate the changes of autonomic activity caused by the first dose of fingolimod using a long-term multiple trigonometric spectral analysis for the first time. In addition, we sought to use the continuous Holter ECG recording to find predictors for fingolimod induced bradycardia.Methods: Seventy-eight patients with relapsing-remitting multiple sclerosis (RRMS) were included. As a part of the START study (NCT01585298), continuous electrocardiogram was recorded before fingolimod initiation, and until no <6 h post medication. Time domain and frequency domain heart rate variability (HRV) parameters were computed hourly to assess cardiac autonomic regulation. A long-term multiple trigonometric regressive spectral (MTRS) analysis was applied on successive 1-h-length electrocardiogram recordings. Decision tree analysis was used to find predictors for bradycardia following fingolimod initiation.Results: Most of the HRV parameters representing parasympathetic activities began to increase since the second hour after fingolimod administration. These changes of autonomic regulations were in accordance with the decline of heart rate. Baseline heart rate was highly correlated with nadir heart rate, and was the only significant predicting factor for fingolimod induced bradycardia among various demographic, clinical and cardiovascular variables in the decision tree analysis.Conclusions: The first dose application of fingolimod enhances the cardiac parasympathetic activity during the first 6 h post medication, which might be the underlying autonomic mechanism of reduced heart rate. Baseline heart rate is a powerful predictor for bradycardia caused by fingolimod.

Cardiac Autonomic Dysfunction in Multiple Sclerosis: A Systematic Review of Current Knowledge and Impact of Immunotherapies

“…Relations between autonomic function, fatigue and cognition in MS patients are worth further study. Existing CAD may be a predictor of the well-documented first-dose cardiac effects of fingolimod [68][69][70][71]101], while rare cases of takotsubo cardiomyopathy in MS patients and life-threatening cardiac complications in those treated with fingolimod demonstrate the potential importance of CAD [13,14,[19][20][21].…”

“…Conversely, significant negative correlations were found between measures of sympathetic function and fingolimod-induced PR-interval increase [68]. A sub-study (n = 78) of the START study found that low baseline HR was a powerful predictor of fingolimod-induced bradycardia, while another study in 114 patients reported that body mass index, optic nerve involvement, baseline HR and T-peak-T-end interval were independent predictors of greater HR reduction on initiation of fingolimod [69,101]. In a study in 625 patients initiating fingolimod, normalised spectral power in the high-frequency band (marking vagal modulation) and previous annualised relapse rate were independently correlated with the probability of requiring extended monitoring (45 [7.2%] patients) [70].…”

A Comprehensive Monitoring Study on Electrocardiographic Assessments and Cardiac Events After Fingolimod First Dose—Possible Predictors of Cardiac Outcomes

“…The results of an analysis of the heart rate variability of 81 patients suggest that enhanced parasympathetic activity is a potential mechanism for the decline in heart rate. Baseline heart rate therefore was considered to predict the risk for bradycardia caused by fingolimod ( 11 ). In fact, the cardiovascular effects of fingolimod observed after first dosing resemble the effects of parasympathetic signaling of the autonomous nervous system ( 15 ).…”

“…The first dose of fingolimod was found to result in an increase in parasympathetic activity. It was suggested that this effect is responsible for an initial heart rate decline ( 11 , 12 ) and measures of parasympathetic activity could be a predictive marker of first dose events ( 13 , 14 ). Furthermore, cardiac autonomic tone at baseline was found to predict the magnitude of heart rate decrease ( 15 ).…”

An Innovative Technique to Assess Spontaneous Baroreflex Sensitivity with Short Data Segments: Multiple Trigonometric Regressive Spectral Analysis

“…However, because of their short wavelengths, oscillations in the HF band or ultra-high frequency (UHF) band can slightly change in frequency and amplitude using a local data segment of 25 s. Therefore, there is always a compromise in the selection of the local data segment length. We have applied different lengths of local and global data segments according to the research conditions (Wright et al, 2009 ; Friedrich et al, 2010 ; Reimann et al, 2010 , 2012 , 2013 ; Gasch et al, 2011 ; Viehweg et al, 2016 ; Li et al, 2017 ). The most commonly used lengths of local and global data segments were 30 s and 2 min, respectively, but shorter lengths have also been applied.…”