Background: A large calcium-insensitive transient outward current (I(to)) has been recorded in atria, left ventricular (LV) free wall, and right ventricular septal subendocardium of the human heart. Recent studies suggested a major contribution of this current to the electrical heterogeneity of the heart. However, no data have been reported on the distribution of I(to) density within the LV septal wall from compensated human LV hypertrophy.
Methods and results: Microelectrode and patch-clamp techniques were used to record action potentials and I(to) in myocytes isolated from superficial (<3 mm deep) and deep (3 to 6 mm deep) layers of LV septum from patients with aortic stenosis and compensated LV hypertrophy. Subendocardial specimens were also obtained from undiseased donor hearts. In none of the superficial subendocardial cells from diseased hearts was a macroscopic I(to) recorded (n=42), whereas in cells from the same location from donor hearts, a typical I(to) was clearly present, with a peak density of 5.88+/-0.78 pA/pF at +60 mV (n=4). However, in deep layers from patients with compensated LV hypertrophy, macroscopic I(to) was present, with a peak density of 10.50+/-2.58 pA/pF at +60 mV (n=4). The absence of I(to) in superficial septal cells from hypertrophied hearts was not due to a divalent cation-related shift of the current kinetics. Instead, extracellular Ca2+ removal induced an I(to)-like current, possibly carried by K+ ions, with a peak density of 30.7+/-2.6 pA/pF at +60 mV (n=29). However, its magnitude, kinetics, and pharmacological characteristics did not allow identification of this current as the usual I(to).
Conclusions: Both topography and pathology can be major modulating factors of the regional distribution of I(to) density in human LV septum. Therefore, they may play a prominent role in determining electrical gradients within this region from which the early depolarization vectors start and the left-to-right activation sequence of the interventricular septum proceeds.