S1P receptor modulators and the cardiovascular autonomic nervous system in multiple sclerosis: a narrative review

Abstract

Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators have a complex mechanism of action, which are among the most efficient therapeutic options in multiple sclerosis (MS) and represent a promising approach for other immune-mediated diseases. The S1P signaling pathway involves the activation of five extracellular S1PR subtypes (S1PR1-S1PR5) that are ubiquitous and have a wide range of effects. Besides the immunomodulatory beneficial outcome in MS, S1P signaling regulates the cardiovascular function via S1PR1-S1PR3 subtypes, which reside on cardiac myocytes, endothelial, and vascular smooth muscle cells. In our review, we describe the mechanisms and clinical effects of S1PR modulators on the cardiovascular system. In the past, mostly short-term effects of S1PR modulators on the cardiovascular system have been studied, while data on long-term effects still need to be investigated. Immediate effects detected after treatment initiation are due to parasympathetic overactivation. In contrast, long-term effects may arise from a shift of the autonomic regulation toward sympathetic predominance along with S1PR1 downregulation. A mild increase in blood pressure has been reported in long-term studies, as well as decreased baroreflex sensitivity. In most studies, sustained hypertension was found to represent a significant adverse event related to treatment. The shift in the autonomic control and blood pressure values could not be just a consequence of disease progression but also related to S1PR modulation. Reduced cardiac autonomic activation and decreased heart rate variability during the long-term treatment with S1PR modulators may increase the risk for subsequent cardiac events. For second-generation S1PR modulators, this observation has to be confirmed in further studies with longer follow-ups. The periodic surveillance of cardiovascular function and detection of any cardiac autonomic dysfunction can help predict cardiac outcomes not only after the first dose but also throughout treatment.

Plain language summary: What is the cardiovascular effect of S1P receptor modulator therapy in multiple sclerosis? Sphingosine 1-phosphate (S1P) receptor (S1PR) modulators are among the most efficient therapies for multiple sclerosis. As small molecules, they are not only acting on the immune but on cardiovascular and nervous systems as well. Short-term effects of S1PR modulators on the cardiovascular system have already been extensively described, while long-term effects are less known. Our review describes the mechanisms of action and the short- and long-term effects of these therapeutic agents on the cardiovascular system in different clinical trials. We systematically reviewed the literature that had been published by January 2022. One hundred seven articles were initially identified by title and abstract using targeted keywords, and thirty-nine articles with relevance to cardiovascular effects of S1PR therapy in multiple sclerosis patients were thereafter considered, including their references for further accurate clarification. Studies on fingolimod, the first S1PR modulator approved for treating multiple sclerosis, primarily support the safety profile of this therapeutic class. The second-generation therapeutic agents along with a different treatment initiation approach helped mitigate several of the cardiovascular adverse effects that had previously been observed at the start of treatment. The heart rate may decrease when initiating S1PR modulators and, less commonly, the atrioventricular conduction may be prolonged, requiring cardiac monitoring for the first 6 h of medication. Continuous therapy with S1PR modulators can increase blood pressure values; therefore, the presence of arterial hypertension should be checked during long-term treatment. Periodic surveillance of the cardiovascular and autonomic functions can help predict cardiac outcomes and prevent possible adverse events in S1PR modulators treatment. Further studies with longer follow-ups are needed, especially for the second-generation of S1PR modulators, to confirm the safety profile of this therapeutic class.

Keywords: S1P receptor modulator; autonomic nervous system; cardiovascular effect; multiple sclerosis.

Figure 1.

Short- and long-term effects of S1P receptor modulators on blood pressure regulation. S1P signaling pathway plays an essential role in vasoreactivity and vascular permeability. Blood flow exerts shear stress on the vessel’s endothelial wall, which activates the S1P endothelial pathway signaling through G protein–coupled S1P receptors. The nitric oxide (NO) produced by endothelial NO synthase (eNOS) after S1P/S1PR1 activation cascade is critical for blood pressure homeostasis by generating vasorelaxation. Initially, S1P receptor modulators (S1PR-Ms) act as potent agonists on S1PR1 that induce transient endothelium-dependent vasodilation. S1PR1 downregulation consecutive to S1PR overstimulation converts S1PR-M in functional antagonists. Pharmacological inhibition of S1PR1 decreases the eNOS/NO activation in response to shear stress and reduces flow-mediated vasodilation. Concomitantly, there is an increase in S1PR2 and S1PR3 expressions in vascular smooth muscle cells that generates sustained vasoconstriction via PKC/Rho/ROCK signaling pathway activation. Therefore, S1PR modulators can shift to a higher-than-normal blood pressure value due to impaired endothelial-dependent vasodilation and predominant S1PR2- and S1PR3-mediated vasoconstriction. Source: Created with BioRender.com. Akt, Akt kinase; eNOS, endothelial nitric oxide (NO) synthase; PKB, protein kinase B; PKC, protein kinase C; ROCK, rho-associated kinase; S1PR-M, sphingosine 1-phosphate receptor (S1PR) modulator; SPNS2, spinster homolog 2, S1P transporter; stress fibers, contractile actomyosin bundles.

Figure 2.

Transient vagomimetic effect of S1P receptor modulators on cardiac cells after treatment initiation. S1P receptor modulators are competitive antagonists with S1P binding to S1P receptor subtype 1 (S1PR1) generating via GIRK channels activation and downstream signaling a transient vagomimetic effect. This is represented by a decrease in heart rate and delay in atrioventricular conduction. Overstimulation of S1PR1 is transient due to β-arrestins activation, which generates receptor internalization and S1PR1 downregulation. S1PR desensitization determines the functional antagonist effect of S1PR modulators, which imposes a reduction of S1PR1 on the cell’s surface and leads to a change in S1P homeostatic signaling. Source: Created with BioRender.com. GIRK, G protein–coupled inwardly rectifying potassium channel; M2 receptor, muscarinic type-2 receptor; S1PR-M, sphingosine 1-phosphate receptor (S1PR) modulator.

Figure 3.

Short- and long-term changes of heart rate, blood pressure, and cardiac autonomic modulation during fingolimod treatment. Immediately after fingolimod initiation, a negative chronotropic effect on the sinus node is observed, with a maximal drop of the heart rate after the fifth hour post-dose, associated with a slight and transient decrease in systolic and diastolic blood pressures. A significant parasympathetic activation revealed by increasing values for RMSSD (root mean square of successive RR interval differences), or pNN50 (percentage of successive RR intervals that differ by more than 50 ms), was correlated to the moment of maximal heart rate drop after fingolimod initiation. A reduction in the LF/HF ratio, based on the augmented HF (high frequency) values, another parasympathetic marker, is also observed. After the nadir point for the heart rate and heart rate variability parameters displaying the cardiac autonomic regulation, there is a recovery toward baseline values starting after 5 h, which continues for the next several hours, corresponding to the downregulation of S1P receptors in the myocytes. Diastolic and systolic blood pressure values also recover to baseline starting after 5 h. Long-term treatment is associated with a mild blood pressure increase and a decrease in parasympathetic cardiac modulation, reflected in RMSSD and pNN50 values. The LF/HF ratio reduction is due to the impairment of both sympathetic and parasympathetic modulations, which is correlated to a decrease in baroreflex sensitivity. BL, baseline; H1, H2, H3, H4, H5, and H6, the first, second, third, fourth, fifth, and sixth hour after fingolimod intake.