Background: The mechanisms responsible for atrial electro-anatomic remodeling during the development of atrial fibrillation (AF) are not known. Mitochondria determine atrial myocyte cell survival and function by regulating cellular oxidative and metabolic stress. We therefore postulated that mitochondria play a central role in the remodeling of atrial myocardium and the pathogenesis of AF.
Methods: Our hypothesis was tested in a novel murine model (cardiac specific LKB1 knockout (KO)) where there is a high rate of sinus rhythm progressing to AF (95% of mice). Structural and electrophysiological properties of atria were studied in sinus rhythm and AF. Multiple parameters including the ECG, cardiac MRI, echocardiography, histopathology and immunoblotting in KO mice were compared with age- and gender-matched wild type controls.
Results: LKB1 KO mice developed biatrial enlargement while in sinus rhythm that progressively increased as persistent AF developed. Apoptotic and necrotic myocyte death produced a substantial reduction in atrial cardiomyocytes (44%) that was replaced by fibrosis (34% vs 4.9%, p<0.05) and non-myocyte cells. In KO atria, there was a 6 fold increase in TUNEL positive nuclei and significant elevations of caspase 3 (10.4±1 vs 3.6±0.5 AU, p<0.05) and caspase 9 (1.4±0.1 vs 0.7±0.06 AU, p<0.05) activity. Mitochondrial reactive oxygen species were increased in KO atria (13.6±0.7 vs. 4.2±1 AU, p<0.05). In addition to extracellular matrix remodeling, cell-to-cell coupling was disrupted in KO atria with reduced gap junction proteins such as connexin 40 (0.24±0.03 vs 0.82±0.01 AU, p<0.05) and connexin 43 (1.4±0.1 vs 14.4±1 AU) (p<0.05). Electron microscopy showed impaired ultrastructure of mitochondrion and myofibrils in atrial myocytes.
Conclusions: We conclude that mitochondria play a pivotal role in the genesis of AF. Mitochondrial ROS generation and caspase activation lead to progressive cardiomyocyte loss and the transition of sinus rhythm to paroxysmal and persistent AF. These findings raise the possibility that therapies directed at maintaining atrial mitochondrial function may prevent the development of chronic AF.