Fig 1.
Characteristics of CCh + burst pacing-induced tachyarrhythmia in C57BL/6 mice and in isolated hearts.
A and B: representative ECG and RA EG traces after 50 Hz burst pacing in vehicle-treated and CCh-treated (0.3 mg/kg, ip) mice, respectively. C: Right Atrial effective refractory period (RA ERP) in vehicle-treated and CCh-treated groups (n = 7 and n = 11, respectively). Each point indicates individual animal data, and lines represent mean ± SEM. D: % of total burst pacing stimulations that resulted in atrial tachyarrhythmias in each group. E: Cumulative atrial tachyarrhythmia time in vehicle and CCh groups (n = 7 and n = 11 respectively). Each point indicates individual animal data, and lines represent median ± IQR. F: Representative activation map during sinus rhythm before CCh treatment. LA activation starts from the lower right and propagates to the upper left. G: An activation map of the same heart after CCh and burst pacing. The LA shows an induced tachyarrhythmia with an activation pattern that is very similar to sinus rhythm, but with high and regular frequency (~50 Hz). Isolated heart ECG of self-terminated tachyarrhythmia is also shown. Similar observations were obtained from 5 out of 5 hearts.
Fig 2.
Heart phenotypes and burst pacing-induced tachyarrhythmia in TAC mice.
A: Heart weight / body weight ratio in sham and TAC mice (n = 6 and 10, respectively) at 16 weeks after surgery. Echocardiographic evaluation of EF (B) and LA diameter (C) in sham and TAC mice (n = 12 and 18, respectively) at 11 weeks after surgery. D: Representative images of fibrosis staining (Picrosirius red) of the sham and TAC surgery mouse atria at 16 weeks after surgery. E: LA fibrotic area in sham and TAC mice (n = 6 and 10, respectively) at 16 weeks after surgery. F: RA ERP in sham and TAC mice (n = 6 and 12, respectively) at 16 weeks after surgery. Each point indicates individual animal data, and lines represent mean ± SEM. G: % of positive atrial tachyarrhythmias from total burst pacing stimulations in sham and TAC groups at 16 weeks after surgery. H: Cumulative atrial tachyarrhythmia time in sham and TAC groups (n = 6 and 10, respectively). Each point indicates individual animal data, and lines represent median ± IQR.
Fig 3.
Heart phenotypes and burst pacing-induced tachyarrhythmia in Ang II mice.
A: Heart weight / body weight ratio in vehicle and Ang II infusion mice (n = 12/group). Echocardiographic evaluation of EF (B) and LA diameter (C) in vehicle and Ang II infusion mice (n = 12/group). D: Representative images of fibrosis staining of the vehicle and Ang II infusion mouse atria. E: LA fibrotic area in vehicle and Ang II infusion mice (n = 8/group). F: RA ERP in vehicle and Ang II infusion mice (n = 8/group). Each point indicates individual animal data, and lines represent mean ± SEM. G: % of positive atrial tachyarrhythmias from total burst pacing stimulations in vehicle- and Ang II-treated groups. H: Cumulative atrial tachyarrhythmia time in vehicle and Ang II groups (n = 8/group). Each point indicates individual animal data, and lines represent median ± IQR.
Fig 4.
ECG, heart histology and RA electrogram traces in Cardiac-LKB1 KO mice.
A: Representative ECG traces from telemetry-implanted control and Cardiac-LKB1 KO mice. B: Representative macro images control and Cardiac-LKB1 KO mouse hearts. Cardiac-LKB1 KO mouse had enlarged atria relative to control atria. C: Representative images of fibrosis staining of the control and Cardiac-LKB1 KO mouse atria. Cardiac-LKB1 KO mouse had increased red staining, indicative of collagen positive areas, in the atria relative to control atria. D: % of positive red stain area over entire LA and RA tissue in control and Cardiac-LKB1 KO mice (n = 8 for each group). Each point indicates individual animal data, and lines represent mean ± SEM. E: Control mice showed sinus rhythm, clear P waves and corresponding RA signal on RA EGs under anesthesia. F: Cardiac-LKB1 KO mice showed irregular RR intervals without P waves on ECG. RA EGs revealed independent and irregular atrial signals.
Table 1.
Echocardiographic parameters of control and Cardiac-LKB1 KO mice.
Fig 5.
Optical mapping of control and Cardiac-LKB1 KO mouse hearts.
A: Representative image of a perfused control mouse heart. LA excitation was detected, and the heart was in sinus rhythm. B: Representative images of perfused Cardiac-LKB1 KO mouse hearts. No atrial excitation was detected and ventricular excitation was confirmed (left). The right image shows a focal area close to atrial septum that was excited independently and irregularly. C: Representative activation map of control mouse atria. Excitation was initiated from the SAN, then propagated though the RA and LA and ended in the RAA and LAA. D: A representative activation map of Cardiac-LKB1 KO mice atria. Excitation was observed only at SAN area; the excitation did not propagate through the atria.
Fig 6.
mRNA expression level in right atria, left atria and left ventricles of Cardiac-LKB1 KO and control mice.
mRNA expression quantification for LKB1, TGFβ1 (transforming growth factor β1), COL1a1 (collagen type 1 α1), CTGF (connective tissue growth factor), SCN5a (voltage gated sodium channel α subunit 5) and CX40 (connexin 40). Each point indicates individual animal data, and lines represent mean ± SEM.