Author + information
- Vittorio Racca, MD∗ (, )
- Marco Rovaris, MD,
- Emanuele Vaini, MSc,
- Rosella Cavarretta, MD,
- Maurizio Ferratini, MD,
- Anastasia Toccafondi, BMSc and
- Marco Di Rienzo, MSc
- ↵∗Cardiology Rehabilitation Centre, Santa Maria Nascente Institute IRCCS, Fondazione Don Carlo Gnocchi, Via Capecelatro 66, 20148 Milan, Italy
Fingolimod, the first oral agent for treatment of multiple sclerosis (MS), exerts its main action through the engagement of sfingosine-1-phosphate receptors (S1Pr) (1) at the lymphocyte level. However, S1Pr are also expressed in the atrial myocytes and endothelial cells, and their activation may frequently cause a nonharmful bradycardia following the first dose. The drug is generally well tolerated, although some cardiovascular adverse effects have been reported, including first- or second-degree atrioventricular blocks (1) and a moderate reduction in the left ventricular systolic function (2). In a very limited number of patients, major cardiovascular events also have been signaled (1). The influence of fingolimod treatment on the autonomic cardiac control over time is still not fully clarified. In this observational longitudinal study, we investigated the effect of fingolimod on the sympathetic and parasympathetic heart control and on the arterial baroreflex function after 6 months of treatment.
We consecutively recruited 21 subjects, 11 men and 10 women, affected by the relapsing remitting form of MS and beginning the treatment with fingolimod (single daily oral dose of 0.5 mg) in compliance with the Helsinki Declaration. Patient characteristics were: age 41.9 ± 7.8 years, body mass index 23.3 ± 2.9 kg/m2, time from MS onset 12.4 ± 7.2 years. The Expanded Disability Status Scale median score was 5.0 (range 1.0 to 6.5). Exclusion criteria were history of cardiac, renal, and respiratory diseases, and use of drugs interacting with cardiac function within the last 4 weeks.
Continuous finger arterial blood pressure (BP) was recorded for 10 min before the first dose (T0) and after 6 months of treatment (T6m) in supine position. Systolic and diastolic BP were measured in each beat, and the beat length was estimated by the pulse interval (PI) (i.e., the time period between consecutive systolic peaks). Heart rate (HR) was derived by the formula HR = (1,000/PI) · 60.
From the analysis of the PI beat-to-beat series, the percentage of normal beats differing for >50 ms from the preceding normal beat (PNN50) and the root mean square of successive PI differences (RMSSD) were computed. The fast Fourier transform estimated the PI spectral characteristics. From each spectrum, the power density was integrated over the low-frequency (LF) (0.04 to 0.15 Hz) and the high-frequency (HF) (0.15 to 0.4 Hz) bands. The LF/HF power ratio was also calculated. PNN50, RMSSD, and the HF power have been associated with the parasympathetic control of the heart, the LF power with the sympathetic control and the LF/HF ratio with the sympathovagal balance (3). The sequence and the alpha coefficient techniques estimated the spontaneous baroreflex sensitivity (BRS) (4).
The results of the analysis are reported in Table 1. With reference to T0, after 6 months of treatments, the PI mean value was unchanged, whereas the PI SD decreased (−30%). All the PI-derived indexes of parasympathetic heart control significantly lowered: pNN50 (−64%), RMSSD (−32%), and power in the HF band (−68%). The PI power in the LF band also decreased (−66%).
Concerning the baroreflex function, the gain of the baroreflex markedly decreased either when estimated by the sequence technique (−7.8 ms/mm Hg, with a drop of −43.7%) or the alpha coefficient technique (−13.2 ms/mm Hg, with a drop of −65%).
Thus, at T6m, we observed a consistent reduction in the baroreflex sensitivity and in all indexes of the sympathetic and parasympathetic heart control. A reduction in the vagal drive to the heart was already reported after 3 months of fingolimod treatment (5). In our study, we show that this reduction is still present after 6 months and, importantly, for the first time, we document a concomitant impairment of the baroreflex function and of the sympathetic drive to the heart over this time window.
To discriminate whether this midterm autonomic dysfunction might either depend on the drug treatment or on the progression of the disease, we evaluated in a matched group of 17 MS patients under another drug treatment (natalizumab), the same autonomic variables 6 months apart. In this control group, no significant change was observed in any autonomic parameter. This finding supports the hypothesis that the changes in the autonomic indexes observed in the fingolimod-treated patients over the 6-month timespan might mostly depend on the drug effect and not be a consequence of the disease evolution during this time frame.
From the clinical perspective, our study suggests that a periodic surveillance of the autonomic heart control may be appropriate in MS patients treated long term with fingolimod.
Please note: The study was funded by a “Ricerca Corrente 2014-2015” grant from the Italian Ministry of Health and the Don Gnocchi Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Racca V.,
- Di Rienzo M.,
- Cavarretta R.,
- et al.
- Task Force of the ESC and the NASPE
- Simula S.,
- Laitinen T.,
- Laitinen T.M.,
- et al.