Loss of natriuretic peptide receptor C enhances sinoatrial node dysfunction in aging and frail mice

Heart rate is controlled by the sinoatrial node (SAN). SAN dysfunction is highly prevalent in aging; however, not all individuals age at the same rate. Rather, health status during aging is affected by frailty. Natriuretic peptides regulate SAN function in part by activating natriuretic peptide receptor C (NPR-C). The impacts of NPR-C on HR and SAN function in aging and as a function of frailty are unknown. Frailty was measured in aging wildtype (WT) and NPR-C knockout (NPR-C -/-) mice using a mouse clinical frailty index (FI). HR and SAN structure and function were investigated using intracardiac electrophysiology in anesthetized mice, high-resolution optical mapping in intact atrial preparations, histology and molecular biology. NPR-C -/- mice rapidly became frail leading to shortened lifespan. HR and SAN recovery time were increased in older vs. younger mice and this was exacerbated in NPR-C -/- mice; however, there was substantial variability among age groups and genotypes. HR and SAN recovery time were correlated with FI score and fell along a continuum regardless of age or genotype. Optical mapping demonstrates impairments in SAN function that were also strongly correlated with FI score. SAN fibrosis was increased in aged and NPR-C -/- mice and was graded by FI score. Loss of NPR-C results in accelerated aging due to a rapid decline in health status in association with impairments in HR and SAN function. Frailty assessment was effective and often better able to distinguish aging-dependent changes in SAN function in the setting of shorted lifespan due to loss of NPR-C.