Cardiovascular fingolimod effects on rapid baroreceptor unloading are counterbalanced by baroreflex resetting

Mao Liu,Ralf A. Linker,Max J. Hilz,Francesca Canavese,Katharina M. Hoesl,Klemens Winder,Carmen de Rojas Leal,Sankanika Roy,Ruihao Wang,De-Hyung Lee

doi:10.1007/s10072-020-05004-1

Abstract

Background and purposeInitial cardiovascular fingolimod effects might compromise baroreflex responses to rapid blood pressure (BP) changes during common Valsalva-like maneuvers. This study evaluated cardiovascular responses to Valsalva maneuver (VM)-induced baroreceptor unloading and loading upon fingolimod initiation.Patients and methodsTwenty-one patients with relapsing-remitting multiple sclerosis performed VMs before and 0.5, 1, 2, 3, 4, 5, and 6 hours after fingolimod initiation. We recorded heart rate (HR) as RR intervals (RRI), systolic and diastolic BP (BPsys, BPdia) during VM phase 1, VM phase 2 early, VM phase 2 late, and VM phase 4. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. To assess cardiovagal activation upon baroreceptor loading, we calculated Valsalva ratios (VR) between maximal and minimal RRIs after strain release. Analysis of variance or Friedman tests with post hoc analysis compared corresponding parameters at the eight time points (significance: p < 0.05).ResultsRRIs at VM phase 1, VM phase 2 early, and VM phase 2 late were higher after than before fingolimod initiation, and maximal after 4 hours. Fingolimod did not affect the longest RRIs upon strain release, but after 3, 5, and 6 hours lowered the highest BPsys values during overshoot and all BPdia values, and thus reduced VRs. BRG was slightly higher after 3 and 5 hours, and significantly higher after 4 hours than before fingolimod initiation.ConclusionsVR-decreases 3–6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Stable and at the time of HR nadir significantly increased BRGs indicate improved responses to baroreceptor unloading. Thus, cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting.

Highlights

Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, approved for treating patients with relapsing-remitting multiple sclerosis (RRMS) [21], has an initially vagomimetic effect on the heart [13, 22, 32, 33]
While we previously observed that fingolimod initiation is associated with a significant increase in spontaneous baroreflex sensitivity (BRS) under resting conditions [20], it is still unclear whether and to which extent fingolimod affects cardiovagal activity during the aforesaid rapid blood pressure (BP) challenges, during the first 6 hours after fingolimod initiation
In the group of 21 RRMS patients enrolled in our previous study [20], we analyzed the changes in electrocardiographic RR intervals (RRIs), systolic and diastolic blood pressures during Valsalva maneuvers (VM) that were performed before and 0.5, 1, 2, 3, 4, 5, and 6 hours after the first dose of fingolimod

Summary

Introduction

Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, approved for treating patients with relapsing-remitting multiple sclerosis (RRMS) [21], has an initially vagomimetic effect on the heart [13, 22, 32, 33]. Using linear regression analysis between decreasing BPsys and RRI values during VM phase 2 early, we determined baroreflex gain (BRG) reflecting vagal withdrawal and sympathetic activation upon baroreceptor unloading. Conclusions VR-decreases 3–6 hours after fingolimod initiation are physiologic results of fingolimod-associated attenuations of BP and HR increases at the end of strain and do not suggest impaired cardiovagal activation upon baroreceptor loading. Cardiovascular fingolimod effects do not impair autonomic responses to sudden baroreceptor loading or unloading but seem to be mitigated by baroreflex resetting

Methods

Results

Discussion

Conclusion