Modulation of sphingosine receptors influences circadian pattern of cardiac autonomic regulation.
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.
Department of Neurology, Mikkeli Central Hospital, Mikkeli, Finland sakari.simula@esshp.fi.
Sakari
S
Simula
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Tomi P
TP
Laitinen
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Tiina M
TM
Laitinen
Neuro Center, Department of Neurology, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Päivi
P
Hartikainen
Heart Center, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Juha E K
JE
Hartikainen
D000328:Adult; D001341:Autonomic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology; D015716:Electrocardiography, Ambulatory / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006321:Heart / Q000294:innervation* / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D011446:Prospective Studies; D013110:Sphingosine / Q000378:metabolism*
D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
Autonomic nervous system; circadian rhythm; multiple sclerosis; sphingosine