Remodeling of the left atrium in pacing-induced atrial cardiomyopathy

Rapid atrial pacing produces atrial systolic and diastolic failure characterized by absent atrial booster pump function, increased atrial chamber stiffness, enhanced atrial conduit function, and atrial enlargement. However, the processes underlying these abnormalities are poorly understood. Therefore, we examined left atrial myocardium from dogs with rapid pacing-induced atrial failure (400 bpm for 6 weeks) and from control dogs. Western blotting was used to determine the levels of proteins involved in calcium homeostasis (SERCA 2A, phospholamban, Na⁺-Ca²⁺ exchanger). Matrix metalloproteinase (MMP) activity was measured using gelatin and casein zymography, and levels of tissue inhibitor of metalloproteinase-4 (TIMP-4) and the TIMP-4 complexed with MMPs were measured with Western blot analysis. There were no differences in SERCA 2A or Na⁺-Ca²⁺ exchanger protein levels, but phospholamban level was significantly decreased in atrial samples from rapidly paced dogs (51.2 ± 7.8 vs. 77.0 ± 10.0, p < 0.01). The activity of MMP-9 was selectively and significantly increased by 50%, and the level of complexed TIMP-4 protein was significantly decreased by 50% in samples from dogs with atrial failure. Thus, rapid pacing-induced atrial failure is associated with differential changes in MMP activity, an unchanged number of calcium pumps, and compensatory changes in the level of phospholamban.