Making Heads or Tails of the Large Mammalian Sinoatrial Node Micro-Organization.

The sinoatrial node (SAN) is endowed with protective mechanical and electrical properties that allow the pacemaking cardiomyocytes (PCMs) to sustain robust automaticity. The leading pacemaking site is known to be located at the superior (head) and inferior (tail) SAN1; however, it remains an enigma why these regions are the leading sites and how they are protected from a source-sink mismatch. Here, we discovered a unique micro-organization at the head and tail regions of the large mammalian SAN that may restrict the leading pacemaking sites to these origins through electrical and mechanical insulations, enabling intratissue and intertissue current source-sink balance. Our findings provide unique intratissue structural insights for the SAN head and tail, with an electrical and mechanical intertissue insulation formed by an ELN-rich border (Figure [F]). The PCMs in these sections are clustered among the fibroblast aggregates and expressed higher HCN4 and TBX18, distinct from the aligned midsectional PCMs. Collectively, the differential micro-organization and gene expression in the SAN are critical for restricting the pacemaking initiation to either the head or tail region and a faster pacemaking frequency at the superior SAN.