S1PR1 and Bradycardia: Bradycardia has been associated with S1P receptor modulators and is thought to be mediated by S1P1 and S1P3 receptor binding in cardiac myocytes.16 The risk of bradycardia has been shown to be largely mitigated with gradual dose escalation,16 which was implemented over the course of 7 days in True North and the subsequent OLE.