B-po01-052 atrial-specific lkb1 knockdown represents a novel mouse model of atrial cardiomyopathy with spontaneous atrial fibrillation

AF is one of the most common cardiac arrhythmias, with > 37 MM patients worldwide. To develop more effective therapies for AF, it is essential to comprehend its underlying mechanisms using better models. Large animal models are more similar to humans, but their availability and cost are big drawbacks. Mice can be genetically manipulated and offer affordable phenotyping platforms. Liver kinase b1 (Lkb1) knockout mice develop spontaneous AF by 8 weeks of age. One of the main limitations of this model, however, is that they also develop ventricular dysfunction and heart failure, complicating the understanding of mechanisms because of the confounding effects of ventricular dysfunction on AF. To develop an effective model of spontaneous AF without confounding ventricular effects. We used the atrial-specific AAV9-ANF-Cre to drive atrial-specific Lkb1-knockdown (Lkb1-aKD) following injection into 5-day-old LKB1FL/FL mice. Starting at week 5, 24-hours ECGs were obtained once/week via subcutaneously implanted telemeters. AF was defined by a lack of P-waves and irregularly irregular R-R intervals for more than 1 second. Lkb1-aKD mice exhibited 100% AF incidence at 6 weeks and an age-dependent increase in the duration of spontaneous AF episodes. Atrial Doppler/echocardiography revealed increased atrial size and diminished mitral valve function, indicating increased atrial cardiomyopathy. No change was seen in left ventricular ejection fraction and end-diastolic dimensions in 12 weeks old LKB1-aKD mice. qRT-PCR and western blot analyses revealed significant Lkb1 downregulation in atrial but not in ventricular tissue, consistent with atrial-restricted Lkb1 knockdown. Picrosirius-red staining and qRT-PCR analysis showed increased collagen content in the atria of LKB1-aKD mice, indicating prominent atrial fibrosis. AAV9-mediated knockdown of Lkb1 produces a novel mouse model of AF and cardiomyopathy without genetic or phenotypic alterations in the ventricles. Lkb1-aKD mice represent a practical atrial-specific mouse model of spontaneous AF, ideally suited for mechanistic studies aimed to uncovering the molecular basis of spontaneous AF without confounding influences from ventricular remodeling.