Electrical remodeling in rapidly stimulated atrial myocytes occurs very early (within 90 minutes), likely driven by proteolysis rather than transcriptional changes, which follow a more variable and delayed time course.
Early atrial APD shortening precedes transcription in models; hypothesis-generating for proteolysis in AF, not yet informing practice.
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. The arrhythmia is associated with electrical (reduced action potential duration [APD] and ICa) and structural remodeling that increases future AF susceptibility. The time course of the molecular events that initiate this remodeling are not currently known, and is the focus of this investigation using rapidly stimulated atrial myocytes. In rapidly stimulated isolated canine atrial strips, APD90 was reduced within 1.5hr (APD90, ?24.3%, P(0.05) indicative of remodeling. This time course was confirmed in atrial myocytes (HL‐1 cells) subjected to rapid stimulation in culture (APD90, ?36.1%, P(0.01), with an associated reduction in ICa‐L and ICa‐T. Real time quantitative RT‐PCR results revealed no significant change in Ca2+ channel (‐subunit mRNA at this time point, indicating that proteolysis was most likely responsible for reduced ICa. The time course of transcriptional remodeling was variable, with some genes regulated very early (0–3hr: Hspa1a, Aqp4 & Prkci), others gradually over 18hr (Map2k3 & Gucy1a3), and others much later (18hr: Nppa, Nppb & Tgfb1). Thus, the remodeling produced by rapid stimulation of atrial myocytes is complex. Electrical remodeling is achieved within 90 min, while the time course of transcriptional remodeling is highly variable and likely pathway‐specific.
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Mace et al. (2008) studied this question.
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