Cardiovascular Sciences Research Centre, Division of Clinical Sciences, St George's, University of London, London, United Kingdom.
Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, NY.
Am Heart J. 2014 Nov;168(5):632-44. doi: 10.1016/j.ahj.2014.06.028. Epub 2014 Jul 11.
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.
芬戈莫德是一种鞘氨醇-1-磷酸受体（S1PR）调节剂，是第一种被批准用于治疗多发性硬化症复发型的口服疾病修正治疗药物；它通过下调 S1PR 来减少自身反应性淋巴细胞从淋巴组织中的流出。鞘氨醇-1-磷酸信号转导涉及多种生理功能，S1PR 在包括心血管系统在内的各种组织中表达不同。心脏细胞上 S1PR 的调节解释了芬戈莫德在开始治疗时对心率和房室传导的短暂影响，以及在长期治疗中一些患者观察到的血压轻度但更持久的影响。这篇综述描述了在心血管系统中鞘氨醇-1-磷酸信号转导背景下芬戈莫德的非治疗作用，并提供了与考虑开始芬戈莫德治疗的医生相关的临床意义的总结。一些患者在开始芬戈莫德治疗时观察到的心率短暂下降（平均每分钟下降 8 次），以及较少见的房室传导暂时延迟，这两种情况都是由于心脏肌细胞上 S1PR 亚型 1 的激活所致。这些影响反映了芬戈莫德首先作为一种完全的 S1PR 激动剂起作用，然后在细胞表面下调 S1PR 亚型 1 后作为 S1PR 拮抗剂起作用。对于大多数人来说，芬戈莫德的首剂量效应是无症状的，但所有患者都需要根据标签建议在首次剂量后至少监测 6 小时。
