Characterization of inwardly rectifying K+ channel in human cardiac myocytes. Alterations in channel behavior in myocytes isolated from patients with idiopathic dilated cardiomyopathy.

BACKGROUND

Little is known about the characteristics of the inwardly rectifying K+ channel (IK1) and the influence of preexisting heart disease on the channel properties in the human heart.

METHODS AND RESULTS

We studied the characteristics of cardiac IK1 in freshly isolated adult human atrial and ventricular myocytes by using the patch-clamp technique. Specimens were obtained from the atria and ventricles of 48 patients undergoing cardiac surgery or transplantation and from four explanted donor hearts. The action potential in ventricular myocytes exhibited a longer duration (391.4 +/- 30.2 milliseconds at 90% repolarization, n = 10) than in atrium (289.4 +/- 23.0 milliseconds, n = 18, P < .001) and had a fast late repolarization phase (phase 3). The final phase of repolarization in ventricle was frequency independent. Whole-cell IK1 in ventricle exhibited greater slope conductance (84.0 +/- 7.9 nS at the reversal potential, EK; n = 27) than in atrium (9.7 +/- 1.2 nS at EK; n = 8, P < .001). The steady-state current-voltage (I-V) relation in ventricular IK1 demonstrated inward rectification with a region of negative slope. This negative slope region was not prominent in atrial IK1. The macroscopic currents were blocked by Ba2+ and Cs+. The channel characteristics in ventricular myocytes from patients with congestive heart failure after idiopathic dilated cardiomyopathy (DCM) exhibited distinct properties compared with those from patients with ischemic cardiomyopathy (ICM). The action potential in ventricular myocytes from patients with DCM had a longer duration (490.8 +/- 24.5 milliseconds, n = 11) compared with that for ICM (420.6 +/- 29.6 milliseconds, n = 11, P < .01) and had a slow repolarization phase (phase 3) with a low resting membrane potential. The whole-cell current slope conductance for DCM was smaller (41.2 +/- 9.0 nS at EK, n = 7) than that for ICM (80.7 +/- 17.0 nS, n = 6, P < .05). In single-channel recordings from cell-attached patches, ventricular IK1 channels had characteristics similar to those of atrial IK1; channel openings occurred in long-lasting bursts with similar conductance and gating kinetics. In contrast, the percent of patches in which IK1 channels were found was 34.7% (25 of 72) of patches in atrium and 88.6% (31 of 35) of patches in ventricle. Single IK1 channel activity for DCM exhibited frequent long-lasting bursts separated by brief interburst intervals at every holding voltage with the open probability displaying little voltage sensitivity (approximately 0.6). Channel activity was observed in 56.2% (18 of 32) of patches for DCM and 77.4% (24 of 31) of patches for ICM. Similar results were obtained from atrial IK1 channels for DCM. In addition, channel characteristics were not significantly different between ICM and explanted donor hearts (donors). IK1 channels in cat and guinea pig had characteristics virtually similar to those of humans, with the exception of lower open probability than that in humans.

CONCLUSIONS

These results suggest that the electrophysiological characteristics of human atrial and ventricular IK1 channels were similar to those of other mammalian hearts, with the possible exception that the channel open probability in humans may be higher, that the whole-cell IK1 density is higher in human ventricle than in atrium, and that IK1 channels in patients with DCM exhibited electrophysiological properties distinct from IK1 channels found in patients with ICM and in donors.