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      Vagomimetic Effects of Fingolimod: Physiology and Clinical Implications

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          Abstract

          Fingolimod is a sphingosine 1-phosphate (S1P) receptor modulator approved to treat relapsing-remitting multiple sclerosis (MS). Initiation of treatment with fingolimod has been found to produce transient bradycardia and/or slowing of atrioventricular impulse conduction in a small proportion of patients. This effect is thought to be due to the interaction of fingolimod with S1P receptors on the surface membrane of atrial myocytes causing a vagomimetic effect, similar to the action of acetylcholine on muscarinic receptors. As a precaution, patients are under electrocardiogram (ECG) monitoring for 6 h after receiving their first dose. Fingolimod is contraindicated in patients with overt or concealed cardiac diseases. However, the Fingolimod Initiation and caRdiac Safety Trial (FIRST), which was designed specifically to investigate the cardiac profile of fingolimod, did not show an increased risk of clinically relevant cardiac events with fingolimod. This review examines the electrophysiology and pathophysiology of cardiac impulse formation in the context of fingolimod. It concludes that these vagomimetic effects should be considered benign and should not prevent the effective use of fingolimod in the treatment of patients with MS.

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          Most cited references 65

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          Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators.

          Experimental evidence suggests that autonomic markers such as heart-rate variability and baroreflex sensitivity (BRS) may contribute to postinfarction risk stratification. There are clinical data to support this concept for heart-rate variability. The main objective of the ATRAMI study was to provide prospective data on the additional and independent prognostic value for cardiac mortality of heart-rate variability and BRS in patients after myocardial infarction in whom left-ventricular ejection fraction (LVEF) and ventricular arrhythmias were known. This multicentre international prospective study enrolled 1284 patients with a recent ( 105 ms, BRS >6.1 ms per mm Hg). The association of low SDNN or BRS with LVEF below 35% carried a relative risk of 6.7 (3.1-14.6) or 8.7 (4.3-17.6), respectively, compared with patients with LVEF above 35% and less compromised SDNN (> or = 70 ms) and BRS (> or = 3 ms per mm Hg). ATRAMI provides clinical evidence that after myocardial infarction the analysis of vagal reflexes has significant prognostic value independently of LVEF and of ventricular arrhythmias and that it significantly adds to the prognostic value of heart-rate variability.
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            The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009--a World Society of Arrhythmia's project.

            A worldwide cardiac pacing and implantable cardioverter-defibrillator (ICD) survey was undertaken for calendar year 2009 and compared to a similar survey conducted in 2005. There were contributions from 61 countries: 25 from Europe, 20 from the Asia Pacific region, seven from the Middle East and Africa, and nine from the Americas. The 2009 survey involved 1,002,664 pacemakers, with 737,840 new implants and 264,824 replacements. The United States of America (USA) had the largest number of cardiac pacemaker implants (225,567) and Germany the highest new implants per million population (927). Virtually all countries showed increases in implant numbers over the 4 years between surveys. High-degree atrioventricular block and sick sinus syndrome remain the major indications for implantation of a cardiac pacemaker. There remains a high percentage of VVI(R) pacing in the developing countries, although compared to the 2005 survey, virtually all countries had increased the percentage of DDDR implants. Pacing leads were predominantly transvenous, bipolar, and active fixation. The survey also involved 328,027 ICDs, with 222,407 new implants and 105,620 replacements. Virtually all countries surveyed showed a significant rise in the use of ICDs with the largest implanter being the USA (133,262) with 434 new implants per million population. This was the largest pacing and ICD survey ever performed, because of mainly a group of loyal enthusiastic survey coordinators. It encompasses more than 80% of all the pacemakers and ICDs implanted worldwide during 2009. ©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.
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              Chronotropic incompetence: causes, consequences, and management.

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                Author and article information

                Journal
                CNS Neurosci Ther
                CNS Neurosci Ther
                cns
                CNS Neuroscience & Therapeutics
                Blackwell Publishing Ltd (Oxford, UK )
                1755-5930
                1755-5949
                June 2014
                16 May 2014
                : 20
                : 6
                : 496-502
                Affiliations
                [1 ]Cardiology Section, Department of Molecular Medicine, University of Pavia Pavia, Italy
                [2 ]Cardiovascular Department, IRCCS Multimedica Sesto San Giovanni, Italy
                [3 ]Electrophysiology Section, Department of Cardiology, Sant'Anna Hospital Como, Italy
                Author notes
                Emilio Vanoli, M.D., Cardiology Section, Department of Molecular Medicine, University of Pavia, Pavia, Italy. Tel.: +39 0382 526061; Fax: +39 0224 209339; E-mail: emivano@ 123456gmail.com
                Article
                10.1111/cns.12283
                4204275
                24836740
                © 2014 The Authors. CNS Neuroscience & Therapeutics Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                Categories
                Review Articles

                Neurosciences

                fingolimod, atrioventricular block, bradycardia, cardiac electrophysiology

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