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Early down-regulation of K+ channel genes and currents in the postinfarction heart
1Department of Medicine, State University of New York Health Science Center, Brooklyn 11203, USA.
Insights
Early down-regulation of potassium (K+) channel gene expression and currents in the post-myocardial infarction (post-MI) heart occurs before significant hypertrophy. These molecular changes may contribute to early cardiac arrhythmias in post-MI patients.
Area of Science:
- Cardiovascular Physiology
- Cardiac Electrophysiology
- Molecular Cardiology
Background:
- Down-regulation of potassium (K+) channel gene expression and currents is a hallmark of cardiac hypertrophy.
- This phenomenon is observed in the remodeled heart following myocardial infarction (MI).
Purpose of the Study:
- To investigate if K+ channel gene and current down-regulation occurs early post-MI, preceding significant myocardial hypertrophy.
- To determine the correlation between these changes and the incidence of ventricular tachyarrhythmias (VT).
Main Methods:
- Induction of VT in 3-day post-MI rat hearts.
- Assessment of action potential (AP) characteristics in isolated left ventricular (LV) myocytes.
- Quantification of outward K+ currents (Ito-fast and I(K)) and K+ channel subunit expression (Kv2.1, Kv4.2, Kv4.3) at 3 days and 4 weeks post-MI.
Main Results:
- Sustained VT was induced in 60% of 3-day post-MI rats, but none in sham controls.
- AP duration was prolonged, and Ito-f and I(K) densities were significantly reduced in 3-day post-MI LV myocytes.
- Reduced K+ channel expression (Kv4.2/Kv4.3 and Kv2.1) correlated with decreased Ito-f and I(K) currents, respectively.
Conclusions:
- Early down-regulation of K+ channel gene expression and currents post-MI occurs independently of significant hypertrophy.
- These early electrophysiological changes may be a key factor in the arrhythmogenesis observed in the post-MI heart.
Introduction:
Down-regulation of key K+ channel subunit gene expression and K+ currents is a universal response to cardiac hypertrophy, whatever the cause, including the postmyocardial infarction (post-MI) remodeled heart.
Methods And Results:
We investigated the hypothesis that down-regulation of K+ channel genes and currents post-MI occurs early and before significant remodeled hypertrophy of the noninfarcted myocardium could be detected. We investigated (1) the incidence of induced ventricular tachyarrhythmias (VT) in 3-day post-MI rat heart; (2) action potential (AP) characteristics of isolated left ventricular (LV) myocytes from sham-operated and 3-day post-MI heart; (3) time course of changes in outward K+ currents Ito-fast(f) and I(K) in isolated myocytes from 3-day and 4-week post-MI noninfarcted LV and compared the changes with sham-operated animals; and (4) changes in the messenger and protein levels of Kv2.1, Kv4.2, and Kv4.3 in the LV and right ventricle of 3-day post-MI heart. Sustained VT was induced in 6 of 10 3-day post-MI rats and in none of 8 sham rats. The membrane capacitance of myocytes isolated from 3-day post-MI noninfarcted LV was not significantly different from control, whereas membrane capacitance 4-week post-MI was significantly higher, reflecting the development of hypertrophy. AP duration was increased and the density of Ito-f and I(K) were significantly decreased in 3-day post-MI LV myocytes compared with sham. The reduced density of Ito did not significantly differ in 4-week post-MI LV myocytes, whereas the density of I(K) was decreased further at 4 weeks post-MI. The changes in Ito-f and I(K) correlated with decreased messenger and protein levels of Kv4.2/Kv4.3 and Kv2.1, respectively.
Conclusion:
These results support the hypothesis that down-regulation of K+ channel gene expression and current in the post-MI LV occurs early and may be dissociated from the slower time course of post-MI remodeled hypertrophy. These changes may contribute to early arrhythmogenesis of the post-MI heart.