Pre-existing parasympathetic dominance seems to account for heart rate slowingafter six months of Fingolimod-treatment in patients with multiple sclerosis

Abstract

Abstract Purpose: Vagomimetic Fingolimod effects cause heart-rate (HR) slowing upon treatment-initiation but wear off with Sphingosine-1-phosphate-receptor downregulation. Yet, prolonged HR-slowing may persist after months of Fingolimod-treatment. We evaluated whether cardiovascular autonomic modulation differs before and six months after Fingolimod-initiation between RRMS-patients with and without initially prolonged HR-slowing upon Fingolimod-initiation. Methods: In 34 RRMS-patients, we monitored RR-intervals (RRI) and blood-pressure (BP), at rest and upon standing-up before Fingolimod-initiation. Six hours and six months after Fingolimod-initiation, we repeated recordings at rest. At the three time-points, we calculated autonomic parameters, including RRI-standard-deviation (RRI-SD), RRI-total-powers, RMSSD, RRI-high-frequency-[HF]-powers, RRI- and BP-low-frequency-(LF)-powers, and baroreflex sensitivity (BRS). Between and among patients with and without prolonged HR-slowing upon Fingolimod-initiation, we compared all parameters assessed at the three time-points (ANOVA with post-hoc testing; significance: p< 0.05). Results: Six hours after Fingolimod-initiation, all patients had decreased HRs but increased RRIs, RRI-SDs, RMSSDs, RRI-HF-powers, RRI-total-powers, and BRS; 11 patients had prolonged HR-slowing. Before Fingolimod-initiation, these 11 patients did not decrease parasympathetic RMSSDs and RRI-HF-powers upon standing -up. After six months, all parameters had re-approached 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. Conclusion: Our patients with prolonged HR-slowing upon Fingolimod-initiation could not downregulate cardiovagal modulation upon standing-up already before Fingolimod-initiation, and six months after Fingolimod-initiation still had more parasympathetic effect on HR while cardiovagal modulation and BRS were attenuated in the other 23 patients. Pre-existing autonomic dysregulation may cause prolonged HR-slowing upon Fingolimod-initiation.