Determinants of CREB degradation and KChIP2 gene transcription in cardiac memory.

BACKGROUND: Left ventricular pacing (LVP) to induce cardiac memory (CM) in dogs results in a decreased transient outward K current (I(to)) and reduced mRNA and protein of the I(to) channel accessory subunit, KChIP2. The KChIP2 decrease is attributed to a decrease in its transcription factor, cyclic adenosine monophosphate response element binding protein (CREB). OBJECTIVE: This study sought to determine the mechanisms responsible for the CREB decrease that is initiated by LVP. METHODS: CM was quantified as T-wave vector displacement in 18 LVP dogs. In 5 dogs, angiotensin II receptor blocker, saralasin, was infused before and during pacing. In 3 dogs, proteasomal inhibitor, lactacystin, was injected into the left anterior descending artery before LVP. Epicardial biopsy samples were taken before and after LVP. Neonatal rat cardiomyocytes (NRCM) were incubated with H(2)O(2) (50 micromol/l) for 1 hour with or without lactacystin. RESULTS: LVP significantly displaced the T-wave vector and was associated with increased lipid peroxidation and increased tissue angiotensin II levels. Saralasin prevented T-vector displacement and lipid peroxidation. CREB was significantly decreased after 2 hours of LVP and was comparably decreased in H(2)O(2)-treated NRCM. Lactacystin inhibited the CREB decrease in LVP dogs and H(2)O(2)-treated NRCM. LVP and H(2)O(2) both induced CREB ubiquitination, and the H(2)O(2)-induced CREB decrease was prevented by knocking down ubiquitin. CONCLUSION: LVP initiates myocardial angiotensin II production and reactive oxygen species synthesis, leading to CREB ubiquitination and its proteasomal degradation. This sequence of events would explain the pacing-induced reduction in KChIP2, and contribute to altered repolarization and the T-wave changes of cardiac memory.

Left versus right atrial difference in dominant frequency, K(+) channel transcripts, and fibrosis in patients developing atrial fibrillation after cardiac surgery.

BACKGROUND: The development of atrial fibrillation (AF) after cardiac surgery is associated with adverse outcomes; however, the mechanism(s) that trigger and maintain AF in these patients are unknown. OBJECTIVE: The purpose of this study was to test our hypothesis that postoperative AF is maintained by high-frequency sources in the left atrium (LA) resulting from ion channel and structural features that differ from the right atrium (RA). METHODS: Forty-four patients with no previous history of AF who underwent cardiac surgery consented to LA and RA biopsies. Histologic sections evaluated fatty infiltration, fibrosis, and iron deposition; quantitative reverse transcription-polymerase chain reaction (RT-PCR) assessed ion channel expression. In a subset of 27 patients, LA and RA unipolar recording leads were also placed. In patients who developed AF, the dominant frequency (DF) for each lead was calculated using fast Fourier transform. RESULTS: DFs during AF were LA 6.26 +/- 0.8 Hz, RA 4.56 +/- 0.7 Hz (P <.01). RT-PCR revealed LA-to-RA differences in mRNA abundance for Kir2.3 (1.8:1) and Kir3.4 (2.3:1). While LA fibrosis was greater in patients developing AF compared with those remaining in normal sinus rhythm (10.8% +/- 11% vs. 3.8% +/- 3.5%; P = .03), the amount of LA fibrosis inversely correlated with the LA DF. CONCLUSIONS: This is the first demonstration of LA-to-RA frequency differences during postoperative AF, which are associated with LA-to-RA differences in mRNA levels for potassium channel proteins and LA fibrosis. These results strongly suggest that sources of AF after cardiac surgery are located in the LA and are stabilized by LA fibrosis.