Atrial electrophysiological remodeling in the CS-CREM mice The representative ECG and the RR interval distributions were shown in Figure 3A and Supplementary Figure 2, respectively. Monthly ECG tests revealed a significantly lower P-wave amplitude in the heterozygous mice compared to the wildtype mice, while the P-wave duration showed no statistical differences (Figure 3B-C). At 12 weeks of age, the heterozygous animals exhibited a significantly increased burden of atrial premature beats compared to the wild-type mice (P = 0.0128, Figure 3D). Furthermore, at 8 weeks of age, one heterozygous mouse experienced an AF event during the routine ECG examination, and the incidence of AF at 16 weeks was 20% (9/41). As mice aged, the prevalence of AF increased in the heterozygous CS-CREM mice. By 28 weeks, 60% (25/41) of the heterozygous mice developed AF. The log-rank 13 test demonstrated a statistically significant difference between the two AF-free survival curves (P ＜ 0.0001, Figure 3E). Additionally, to further explore the electrophysiological properties of spontaneous atrial fibrillation in CS-CREM animals, we performed multi-channel matrix electrophysiological mapping on the atria of 20- week-old wild-type (wt) and heterozygous (ki/wt) mice. The results showed that the atria of ki/wt mice exhibited heterogeneous electrical conduction such as reentrant under spontaneous rhythm and 8Hz pacing (Figure 3F).

Figure 3. Atrial electrophysiological remodeling of CS-CREM mice. (A) Typical electrocardiogram (ECG) of CS-CREM mice. Top: representative figure of normal ECG in wild-type mice (wt). Middle: representative figure of atrial premature beats of ECG in heterozygous mice (ki/wt). Bottom: representative figure of AF event in heterozygous mice (ki/wt). (B) Comparison of P-wave duration between heterozygous mice (red, ki/wt) and wild-type mice (blue, wt) at the age of 4, 8, and 12 weeks. (C) Comparison of P-wave amplitude between heterozygous mice (red, ki/wt) and wild-type mice (blue, wt) at the age of 4, 8, and 12 weeks. (D) Comparison of atrial premature beats burden between heterozygous mice (red, ki/wt) and wild-type mice (blue, wt) at the age of 4, 8, and 12 weeks, *P < 0.05, **P < 0.01, ***P < 0.001, estimated by two-sample t-test. (E) Kaplan-Meier AF-free survival curve in heterozygous mice (red, ki/wt) and wildtype mice (blue, wt) (P ＜ 0.0001). (F) Representative activation maps obtained from spontaneously beating and 8Hz pacing hearts from heterozygous and wild-type mice. (G) Conduction velocity of atria under spontaneously beating and (H) 8Hz pacing. (I) Atrial effective refractory period (AERP) calculated by S1S2 stimulation in heterozygous and wild-type mice. n = 3, P = 0.0268

Translational Research

https://doi.org/10.1016/j.trsl.2024.01.001