Mechanical Isolation Establishes and Maintains the Cardiac Pacemaker Cell Phenotype.

These impulses are produced by specialized heart cells known as cardiac pacemaker cells (CPCs). While the ionic mechanisms controlling CPC function have been studied for over a century, the upstream cellular events that shape and maintain the SAN's unique electrical properties are still not well understood.

We have discovered that abnormal activation of the core mechanotransduction pathways within CPCs leads to significant electrical dysfunction in the SAN. Mechanistically, our data shows that entire systems of ion channels essential for electrical oscillation, along with major transcription factor networks associated with CPC lineage commitment, are rapidly downregulated in response to cellular strain. These findings suggest that mechanical uncoupling and/or the suppression of mechanotransductive signaling pathways serve as a previously unrecognized critical regulatory mechanism necessary for supporting cardiac pacemaking.