HCN4 and heart failure: Isl1 and Tbx18 are also potentially involved: both Isl1 and Tbx18 were significantly downregulated in the sinus node in heart failure (Supplementary Fig. 4) and downregulation of Isl1 has been shown to downregulate HCN440,41 and Tbx18 has been shown to upregulate HCN445; however, Tbx18 is a transcriptional repressor63 and is unlikely to affect HCN4 directly.