Simula Sakari, Laitinen Tomi P, Laitinen Tiina M, Hartikainen Päivi, Hartikainen Juha E K
Department of Neurology, Mikkeli Central Hospital, Mikkeli, Finland
Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
Physiol Rep. 2016 Sep;4(17). doi: 10.14814/phy2.12870.
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.
芬戈莫德是一种口服的1 -磷酸鞘氨醇（S1P）受体调节剂，用于治疗复发缓解型多发性硬化症（RRMS）。除了对淋巴组织和神经组织有治疗作用外，芬戈莫德还通过特异性调节S1P受体影响心血管系统。然而，S1P受体调节对心脏自主神经调节（CAR）内源性昼夜节律模式的影响尚不清楚。我们研究了芬戈莫德对CAR昼夜节律模式的影响。在27例RRMS患者服用芬戈莫德前（基线）、开始服用芬戈莫德当天（1D）和芬戈莫德治疗3个月后（3M）进行了24小时动态心电图记录。从白天和夜间的心电图记录中计算出两个连续R波峰之间的平均时间（RR间期）以及时域和频域中心率变异性（HRV）测量值的平均值。RR间期的平均夜间与白天比值在基线时为1.23±0.12，在1D时暂时降低（1.16±0.12；P<0.01），在3M时高于基线（1.32±0.11；P<0.001）。反映副交感神经心脏调节的HRV参数的夜间与白天比值在1D时降低，但在3M时恢复到基线水平（所有参数P<0.05）。另一方面，反映总体HRV的参数TP的夜间与白天比值逐渐降低，在3M时低于基线（P<0.05）。我们的研究结果表明，在芬戈莫德治疗期间，RR间期的昼夜节律模式与总体HRV以及副交感神经心脏调节之间的生理关系变得解耦。此外，芬戈莫德将CAR的昼夜平衡向总体HRV在白天占主导地位的方向转变。因此，S1P受体调节影响CAR的昼夜节律模式。
