Molecular and Functional Remodeling of Superior and Inferior SAN in a Rat Model of HCM

Recently, our laboratory presented functional and molecular evidence for the presence of 2 competing sinoatrial node (SAN) pacemakers in healthy human and rat hearts. Anatomically localized near the superior vena cava and inferior vena cava, the superior and inferior SANs (sSAN and iSAN, respectively) preferentially control fast and slow normal heart rates. However, only 1 dominant pacemaker, primarily the sSAN, was functional in the failing rat heart with hypertrophic cardiomyopathy. This study aimed to determine the transcriptional basis of functional silencing of 1 of 2 dominant pacemakers in failing rat hearts. Ascending aortic constriction was performed on 1-week-old male Sprague-Dawley rat pups to induce left ventricular hypertrophy and heart failure. The dominant pacemaker was anatomically mapped in adult (10-12 weeks old) healthy and failing rat hearts using optical mapping in isolated right atrial tissue preparations. RNA sequencing was used to identify regional sSAN/iSAN gene expression differences between healthy and failing rat hearts. In all failing rat hearts optically mapped in this study (n = 4), only the sSAN pacemaker was functional, while the iSAN was silent. Compared to healthy rat hearts, a total of 3,640 genes were downregulated, and 4,518 genes were upregulated in failing rat hearts. The functional quiescence of the iSAN in these failing rat hearts may be explained by their downregulation of sodium, potassium, and calcium ion channels as well as their downregulation of specific structural genes, including ankyrin, titin, and myosin heavy chain. Moreover, the iSAN showed predominant downregulation of several key transcription factors such as Tbx5, Tbx3, Shox2, and Smad9. Pressure-overload–induced heart failure resulted in significant downregulation of critical transcription factors, ion channels, and structural transcripts of the iSAN, which could explain the functional silencing of the iSAN in failing rat hearts.