title: Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications.
abstract: Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator, was the first oral disease-modifying therapy approved for relapsing forms of multiple sclerosis; it reduces autoreactive lymphocytes' egress from lymphoid tissues by down-regulating S1PRs. Sphingosine-1-phosphate signaling is implicated in a range of physiologic functions, and S1PRs are expressed differentially in various tissues, including the cardiovascular system. Modulation of S1PRs on cardiac cells provides an explanation for the transient effects of fingolimod on heart rate and atrioventricular conduction at initiation of fingolimod therapy, and for the mild but more persistent effects on blood pressure observed in some patients on long-term treatment. This review describes the nontherapeutic actions of fingolimod in the context of sphingosine-1-phosphate signaling in the cardiovascular system, as well as providing a summary of the associated clinical implications useful to physicians considering initiation of fingolimod therapy in patients. A transient reduction in heart rate (mean decrease of 8 beats per minute) and, less commonly, a temporary delay in atrioventricular conduction observed in some patients when initiating fingolimod therapy are both due to activation of S1PR subtype 1 on cardiac myocytes. These effects are a reflection of fingolimod first acting as a full S1PR agonist and thereafter functioning as an S1PR antagonist after down-regulation of S1PR subtype 1 at the cell surface. For most individuals, first-dose effects of fingolimod are asymptomatic, but all patients need to be monitored for at least 6 hours after the first dose, in accordance with the label recommendations.
authors.affiliation: Cardiovascular Sciences Research Centre, Division of Clinical Sciences, St George's, University of London, London, United Kingdom. Electronic address: jcamm@sgul.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Camm
authors.affiliation: Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY.
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Bakshi
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
mesh_terms: D001283:Atrioventricular Node / Q000187:drug effects*; D002319:Cardiovascular System / Q000187:drug effects; D015536:Down-Regulation; D000068876:Fingolimod Hydrochloride; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy; D011409:Propylene Glycols / Q000494:pharmacology* / Q000627:therapeutic use; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine