Temporal alterations and cellular mechanisms of transmural repolarization during progression of mouse cardiac hypertrophy and failure

Aim The remodelling of transmural dispersion of repolarization (TDR) in human heart failure (HF) and in different animal models of cardiac hypertrophy or HF remains a controversial topic. We hypothesize that TDR may exhibit temporal alterations, depending on the stage of the disease. Methods We systematically investigated the temporal alterations of TDR during the development of cardiac hypertrophy and HF in the mouse pressure-overload model using electrophysiological and molecular biology techniques. Results A progressive prolongation of QT interval and changes in the amplitude of the J wave at 2, 5, 9 and 13 weeks were found in anesthetized aorta-banded mice. Action potential duration (APD) at 90% repolarization (APD90) in subendocardial myocytes of the left ventricular free wall remained unchanged at the hypertrophic stage (2 and 5weeks), but was significantly prolonged in HF mice at 9 and 13weeks. However, APD90 in subepicardial myocytes exhibited a significant prolongation at 2weeks and did not progressively extend from 2weeks to 13weeks in banded mice. Thus, non-parallel prolongation of APD in subendocardial and subepicardial myocytes led to a reduction in TDR at hypertrophic stage and an amplification of TDR at HF stage. Further experiments revealed that asynchronous down-regulation of voltage-dependent potassium currents (Ito,f, IK,slow and Iss) and L-type calcium currents (ICa-L) in subendocardial and subepicardial myocytes may contribute to the dynamic remodelling of transmural APD. Conclusion The two distinct TDR modes were revealed during the progression of mouse cardiac hypertrophy and failure, indicating that the remodelling of TDR depends on the stage of the disease.