Fingolimod initiation in multiple sclerosis patients is associated with potential beneficial cardiovascular autonomic effects

Abstract

Background: Fingolimod slows heart rate (HR) due to vagomimetic effects and might cause additional cardiovascular autonomic changes. While the time course of HR changes is well described, the extent and course of cardiovascular autonomic changes upon fingolimod initiation has not yet been evaluated. This study, therefore, intended to assess cardiovascular autonomic changes during the first 6 h after fingolimod initiation.

Methods: In 21 patients with relapsing-remitting multiple sclerosis (RRMS), we recorded respiration (RESP), electrocardiographic RR interval (RRI), systolic and diastolic blood pressure (BPsys, BPdia) at rest, before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. We calculated parameters of total autonomic modulation [RRI standard deviation (RRI-SD), RRI coefficient of variation (RRI-CV), RRI-total powers], mainly sympathetic cardiac modulation [RRI low frequency (LF) powers], sympathetic BP modulation (BPsys-LF powers), parasympathetic modulation [square root of the mean squared difference of successive RRIs (RMSSD), RRI high frequency (HF) powers], sympatho-vagal cardiac balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). We compared parameters between the eight measurements [analysis of variance (ANOVA) or Friedman test with post-hoc analysis; significance: p < 0.05].

Results: After fingolimod initiation, RESP, BPsys, and BPsys-LF powers remained unchanged while RRIs, RRI-CV, RRI-SD, RRI-total powers, RRI-LF powers, RMSSD, RRI-HF powers, and BRS increased after 1 h and rose to peak values occurring after 5, 1, 2, 2, 1, 4, 4, and 4 h, respectively. After 3 h, BPdia had decreased significantly and was lowest after 5 h. RRI-LF/HF ratios decreased to a nadir after 4 h.

Conclusions: The increases in parasympathetic and overall cardiac autonomic modulation and in BRS seen with fingolimod initiation are theoretically beneficial for the MS patient's cardiovascular system. However, long-term studies must show whether these effects persist or are attenuated (e.g. due to S1P1 receptor down-regulation upon continued fingolimod therapy).

Keywords: cardiovascular autonomic modulation; fingolimod; multiple sclerosis.

Figure 1.

RRI (panel A), BPsys (panel B) and BPdia (panel C) in 21 patients with RRMS before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. RRI increased (i.e. HR slowed), after fingolimod initiation, reached peak values at the fifth hour, and began to recover within 6 h. BPsys and BPdia increased slightly but not significantly 30 min and 1 h after fingolimod initiation. BPdia had significantly decreased 3, 4, 5, 6 h after fingolimod initiation, and was lowest 5 h after fingolimod initiation. Data are presented as mean ± SEM. Significant differences between before and after fingolimod initiation are highlighted as bold and italic numbers. The number of asterisks indicates the level of significance, with * indicating p < 0.05, ** p < 0.01, and *** p < 0.001. BPdia, diastolic blood pressure; BPsys, systolic blood pressure; RRI, electrocardiographic RR interval; RRMS, relapsing-remitting multiple sclerosis; SEM, standard error of the mean.

Figure 2.

RRI-CV (panel A), RRI-SD (panel B) and RMSSD (panel C) in 21 patients with RRMS before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. RRI-CV significantly increased only after the first hour, RRI-SD significantly increased after the first, second, third and fourth hour, and was highest after 2 h. RMSSD values were already significantly higher after 1 h than at baseline, reached peak values after 4 h, and remained increased until the 6 h. Data are presented as mean ± SEM. Significant differences between before and after fingolimod initiation are highlighted as bold and italic numbers. The number of asterisks indicates the level of significance, with *indicating p < 0.05, **p < 0.01, and ***p < 0.001. RMSSD, square root of mean squared differences of successive RR intervals; RRI, electrocardiographic RR interval; RRI-CV, coefficient of variation of RR intervals; RRI-SD, standard deviation of RR interval; RRMS, relapsing-remitting multiple sclerosis; SEM, standard error of the mean.

Figure 3.

RRI-HF powers (panel A), RRI-LF powers (panel B), RRI-LF/HF ratios (panel C) in 21 patients with RRMS before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. Parasympathetically-mediated RRI-HF powers were significantly higher than at baseline after 1, 2, 3, 4, and 5 h, with peak values after 4 h. Mainly sympathetically-mediated RRI-LF powers had slightly increased after 30 min and were significantly higher after 1 h than at baseline. RRI-LF/HF ratios showed a slight increase after 30 min, but then steadily decreased and were significantly lower after 4, 5, and 6 h than at baseline. Data are presented as mean ± SEM. Significant differences between before and after fingolimod initiation are highlighted as bold and italic numbers. The number of asterisks indicates the level of significance, with *indicating p < 0.05, **p < 0.01, and ***p < 0.001. HF, high frequency; LF, low frequency; RRI, electrocardiographic RR interval; RRMS, relapsing-remitting multiple sclerosis; SEM, standard error of the mean.

Figure 4.

RRI-TP (panel A), RRI-HFnu powers (panel B), RRI-LFnu powers (panel C), in 21 patients with RRMS before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. RRI-TP had slightly increased after 30 min, and was significantly higher after 1 and 2 h than at baseline. RRI-HFnu powers had significantly increased after 3, 4, 5, and 6 h, with peak values after 4 h. RRI-LFnu powers showed the mirror image of changes in RRI-HFnu powers, with a steady decrease reaching significance after 3, 4, 5, and 6 h and lowest values after 4 h. Data are presented as mean ± SEM. Significant differences between before and after fingolimod initiation are highlighted as bold and italic numbers. The number of asterisks indicates the level of significance, with *indicating p < 0.05, **p < 0.01, and ***p < 0.001. HF, high frequency; LF, low frequency; nu, normalized unit; RRI, electrocardiographic RR interval; RRMS, relapsing-remitting multiple sclerosis; SEM, standard error of the mean; TP, total power.

Figure 5.

BPsys-LF powers (A), BPsys-HF powers (B), and BRS (C) in 21 patients with RRMS before and 0.5, 1, 2, 3, 4, 5, and 6 h after fingolimod initiation. Sympathetically-mediated BPsys-LF powers and mechanically-mediated BP-HF powers did not change significantly upon fingolimod initiation; there was only a minor, nonsignificant increase in both parameters 30 min after fingolimod intake. BRS increased significantly after 1, 2, 3, 4, 5, and 6 h, with peak values after 4 h. Data are presented as mean ± SEM. Significant differences between before and after fingolimod initiation are highlighted as bold and italic numbers. The number of asterisks indicates the level of significance, with *indicating p < 0.05, **p < 0.01, and ***p < 0.001. BPsys, systolic blood pressure; BRS, baroreflex sensitivity; HF, high frequency; LF, low frequency; RRMS, relapsing-remitting multiple sclerosis; SEM, standard error of the mean.