Fingolimod-Induced Heart Rate Slowing Tied to Parasympathetic Dominance in MS

Patients with preexisting parasympathetic predominance appear to experience persistent heart rate slowing after initiation of fingolimod (Gilenya; Novartis) therapy for relapsing/remitting multiple sclerosis (RRMS), a new report has found.

The study was published in Clinical Autonomic Research.¹

Patients who take fingolimod experience a transient decrease in their heart rate and blood pressure due to the sphingosine-1-phosphate (S1P) receptor modulator’s vagomimetic and vasodilating effects. According to authors, usually the therapy slows patients’ heart rates by 10 to 15 beats per minute, but the issue is usually resolved within 24 hours.

“Negative chronotropic and dromotropic fingolimod effects are usually transient and only occur upon fingolimod initiation or upon fingolimod reinitiation after a treatment pause, presumably because agonistic fingolimod effects on S1P1 receptors wane while S1P1 receptor desensitization and internalization starts several hours after fingolimod initiation,” the authors wrote.

Some patients, however, continue to experience a slowing of their heart rate months after fingolimod initiation. One possible reason is autonomic dysfunction, the authors said. A 2014 study assessed whether measures of parasympathetic function might be linked with bradycardia during the first 6 hours after therapy, and found a significant correlation.²

In this analysis, 34 patients with RRMS had their RR intervals tracked and blood pressures measured at rest and standing up prior to starting fingolimod., then at 6 hours at 6 months after starting the therapy. | Image Credit: © María Pilar Martínez - stock.adobe.com

“[T]he authors concluded that sinus bradycardia upon fingolimod initiation is associated with increased parasympathetic function while bradyarrhythmia is associated with reduced sympathetic function,” they explained. Yet, they wanted to know whether preexisting central autonomic dysfunction associated with MS might result in persistent heart rate slowing or enduring autonomic changes, even months after treatment initiation.

To find out, they recruited 34 patients with RRMS and tracked their RR intervals and blood pressures at rest and standing up prior to starting fingolimod. They then reassessed patients after starting therapy, at 6 hours and at 6 months.

After 6 hours, all the patients had increased heart rates, but also increased RRIs, RRI SD, root mean square of the successive differences (RMSSDs), RRI high-frequency powers (RRI-HF-powers), RRI total powers, and baroreflex sensitivity (BRS).

Of the 34 patients, 11 had prolonged bradycardia. Prior to taking fingolimod, the investigators said, those 11 patients did not decrease parasympathetic RMSSDs and RRI-HF-powers upon standing.

“After 6 months, all parameters had reapproached pretreatment values but the 11 patients with prolonged HR slowing had lower HRs while the other 23 patients had lower parasympathetic RMSSDs and RRI-HF-powers, and BRS than before fingolimod initiation,” the authors reported.

The findings, they said, support the hypothesis that both prolonged heart rate slowing after therapy initiation and long-term (6-month) persistent slowing might be tied to preexisting changes in central autonomic modulation.

The authors said that although previous studies suggested central autonomic modulation might contribute to persistent heart rate slowing, this study brings new clarity.

“[T]he current study seems to be the first to show that patients with RRMS and enduring heart rate slowing during long-term fingolimod treatment have a preexisting, autonomic dysfunction that was not present in the patients with RRMS with timely HR recovery after fingolimod initiation,” they said.

The investigators said the clinical effects noted in the 11 patients with prolonged heart rate slowing were minor.

“After 6 months, it had never resulted in any clinically manifest autonomic dysfunction or cardiac complications,” they wrote. “Still, autonomic testing of patients with MS is helpful to identify patients with central autonomic dysregulation prior to disease-modifying therapy and to thereby identify patients with a possibly increased cardiovascular risk upon treatment with an S1P receptor modulator.”

The investigators said additional studies are warranted to clarify if there are other parameters that might be associated with cardiovascular risk when taking S1P receptor modulators.

References

1. Hilz MJ, Canavese F, de Rojas-Leal C, Lee DH, Linker RA, Wang R. Pre-existing parasympathetic dominance seems to cause persistent heart rate slowing after 6 months of fingolimod treatment in patients with multiple sclerosis. Clin Auton Res. Published online October 9, 2024. doi:10.1007/s10286-024-01073-w

2. Rossi S, Rocchi C, Studer V, et al. The autonomic balance predicts cardiac responses after the first dose of fingolimod. Mult Scler. 2015;21(2):206-216. doi:10.1177/1352458514538885