Figure 1. Mechanism of Ang II–induced SND.

Normally, the small volume of excited tissue in the SAN (source) depolarizes the neighboring quiescent atrial tissue (sink). In conditions with increased Ang II, NADPH oxidase is activated, leading to oxidation of two methionine residues of CaMKII, rendering the enzyme autonomously active. Elevated activity of CaMKII leads to SAN cell death, reducing the threshold volume of automatic cells of the SAN and increasing non-excitable tissue in the form of fibrosis. This increased electrotonic loading produces a source-sink mismatch (explained in detail in the text), slows the beating rate, and causes SND. CT, crista terminalis; IAS, inferior atrial septum.