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.

Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

“…A gradual dose titration regimen to minimize first-dose effects of ponesimod In humans, activation of S1P 1 receptors on cardiomyocytes during initiation of treatment with an S1P 1 R modulator leads to transient HR decreases and infrequently AV conduction delays [Peters and Alewijnse, 2007;Camm et al 2014]. These effects initially observed with the nonselective S1PR modulator fingolimod were later found to occur also with selective S1P 1 R modulators in humans.…”

“…Initial studies in rodents suggested that modulation of S1P 3 R on cardiac myocytes by fingolimod was associated with a reduction of heart rate (HR) by activation of G-protein-coupled inwardly rectifying potassium channels (GIRK) that regulate pacemaker frequency, and the shape and duration of action potentials [Koyrakh et al 2005;Camm et al 2014]. Modulation of S1P 2 R and S1P 3 R on myofibroblasts by fingolimod was also shown to stimulate extracellular matrix synthesis [Sobel et al 2013].…”

Fingolimod: therapeutic mechanisms and ocular adverse effects

“…This same mechanism is responsible for Mobitz type 1 s-degree AV nodal block observed in 0.2% of those patients treated with fingolimod. 6,7 An increase in blood pressure is observed in patients treated with fingolimod. This increase is, on average, +2 mm Hg systolic and +1 mm Hg diastolic.…”

Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways

“…Data are representative of at least 3 independent experiments. 4 0 9 0 jci.org Volume 126 Number 11 November 2016 in the heart (22,27,28). The conformationally constrained FTY720 analog SH-BC-893, in contrast, could be used therapeutically, as it does not activate S1P 1 in reporter cells ( Figure 1, A and B).…”

“…Targeting cancer metabolism by simultaneously disrupting parallel nutrient access pathways despite their activity in vitro and in animal models (21,22). Even if sphingolipids with acceptable drug properties were developed, lysosomal nutrient generation from macropinosome and/or autophagosome degradation could afford resistance, particularly in tumors with activated Ras, in which these pathways are upregulated (9,23).…”