Key result
Computational modeling of rabbit ventricular myocytes suggests that during ischemia, inhomogeneous accumulation of metabolites may alter KATP channel opening and cause differential action potential shortening.
A computational model of rabbit ventricular myocytes suggests that transmural heterogeneity in K_ATP channel activation during ischemia leads to differential action potential shortening across myocardial layers.
May explain ischemia-related repolarization heterogeneity; hypothesis-generating and requires in vivo validation before any clinical consideration.
To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for Ca(2+) and Mg(2+) buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K(+) channel and L-type Ca(2+) channel, Na(+)-K(+)-ATPase, and sarcolemmal and sarcoplasmic Ca(2+)-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 min of ischemia, the three regions were characterized by different I(Na), I(to), I(Kr), I(Ks), and I(Kp) channel properties. The results indicate that the ATP-sensitive K(+) channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, P(i), total Mg(2+), Na(+), K(+), Ca(2+), and pH diastolic levels are normal. The model predicts that only K(ATP) ionophore (Kir6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the K(ATP) channel opening through metabolic interactions with the endogenous PI cascade (PIP(2), PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes.
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Michailova et al. (2007) studied Ischemia. Computational modeling of KATP current was evaluated on KATP channel activation and action potential shortening. Computational modeling of rabbit ventricular myocytes suggests that during ischemia, inhomogeneous accumulation of metabolites may alter KATP channel opening and cause differential action potential shortening.
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