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Abstract
Fingolimod is an oral sphingosine‐1‐phospate (S1P) receptor modulator for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In addition to therapeutic effects on lymphoid and neural tissue, fingolimod influences cardiovascular system by specific S1P‐receptor modulation. The effects of S1P‐receptor modulation on the endogenous circadian pattern of cardiac autonomic regulation (CAR), however, are not known. We examined the effects of fingolimod on the circadian pattern of CAR. Ambulatory 24‐h ECG recordings were undertaken in 27 RRMS patients before fingolimod (baseline), at the day of fingolimod initiation (1D) and after 3 months of fingolimod treatment (3M). The mean time between two consecutive R‐peaks (RR‐interval) and mean values for measures of heart rate variability (HRV) in time‐ and frequency domain were calculated from ECG recording at daytime and nighttime. The mean night:day‐ratio of RR‐interval was 1.23 ± 0.12 at baseline, decreased temporarily at 1D (1.16 ± 0.12; P < 0.01) and was higher at 3M (1.32 ± 0.11; P < 0.001) than at baseline. The night:day‐ratio of HRV parameters reflecting parasympathetic cardiac regulation (pNN50, rMSSD, HFnu) decreased at 1D but recovered back to baseline at 3M (P < 0.05 for all). On the other hand, the night:day‐ratio of TP, a parameter reflecting overall HRV gradually decreased and was lower at 3M than at baseline (P < 0.05). Our findings suggest that physiological relation between the circadian pattern of RR‐interval and overall HRV as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment. In addition, fingolimod shifts the circadian equilibrium of CAR toward greater daytime dominance of overall HRV. Accordingly, S1P‐receptor modulation influences circadian pattern of CAR.
Highlights
Fingolimod is a sphingosine analogue used for the treatment of relapsing-remitting multiple sclerosis (RRMS) (Cohen et al 2010; Kappos et al 2010; Calabresi et al 2014)
Our findings suggest that physiological relation between the circadian pattern of RR-interval and overall heart rate variability (HRV) as well as parasympathetic cardiac regulation becomes uncoupled during fingolimod treatment
Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society
Summary
Fingolimod is a sphingosine analogue used for the treatment of relapsing-remitting multiple sclerosis (RRMS) (Cohen et al 2010; Kappos et al 2010; Calabresi et al 2014). Fingolimod and Circadian Pattern of Cardiac Autonomic Regulation itself does not bind to S1P2-receptors, and its affinity for the S1P3-receptor is considerably weaker than that of physiologically secreted (endogenous) sphingosine (Brinkmann et al 2002; Mandala et al 2002). Acquisition of continuous electrocardiogram (ECG) by ambulatory 24-h recording allows identification of nighttime and daytime signals and circadian pattern in cardiac autonomic regulation can be obtained. In this prospective study, we evaluated the effect of fingolimod on the circadian pattern of cardiac autonomic regulation in RRMS patients. Cardiac autonomic regulation was assessed from HRV at night and by day before fingolimod initiation, during the first 24-h after fingolimod initiation and after 3 months of continuous fingolimod treatment
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