Adenoviral Expression of I _Ks Contributes to Wavebreak and Fibrillatory Conduction in Neonatal Rat Ventricular Cardiomyocyte Monolayers

Abstract

Abstract-Previous studies have shown that the gating kinetics of the slow component of the delayed rectifier K ϩ current (I Ks ) contribute to postrepolarization refractoriness in isolated cardiomyocytes. However, the impact of such kinetics on arrhythmogenesis remains unknown. We surmised that expression of I Ks in rat cardiomyocyte monolayers contributes to wavebreak formation and facilitates fibrillatory conduction by promoting postrepolarization refractoriness. Optical mapping was performed in 44 rat ventricular myocyte monolayers infected with an adenovirus carrying the genomic sequences of KvLQT1 and minK (molecular correlates of I Ks ) and 41 littermate controls infected with a GFP adenovirus. Repetitive bipolar stimulation was applied at increasing frequencies, starting at 1 Hz until loss of 1:1 capture or initiation of reentry. Action potential duration (APD) was significantly shorter in I Ks -infected monolayers than in controls at 1 to 3 Hz (PϽ0.05), whereas differences at higher pacing frequencies did not reach statistical significance. Stable rotors occurred in both groups, with significantly higher rotation frequencies, lower conduction velocities, and shorter action potentials in the I Ks group. Wavelengths in the latter were significantly shorter than in controls at all rotation frequencies. Wavebreaks leading to fibrillatory conduction occurred in 45% of the I Ks reentry episodes but in none of the controls. Moreover, the density of wavebreaks increased with time as long as a stable source sustained the fibrillatory activity. These results provide the first demonstration that I Ks -mediated postrepolarization refractoriness can promote wavebreak formation and fibrillatory conduction during pacing and sustained reentry and may have important implications in tachyarrhythmias. Key Words: I Ks , postrepolarization refractoriness Ⅲ wavebreak Ⅲ gene expression D uring ventricular and atrial fibrillation, conduction of the electrical wavefront is characterized by complex patterns of propagation, including reentry, wavefront fragmentation (wavebreak), and wavelet formation. 1 A wavebreak occurs if the stimulatory efficacy of a wavefront does not suffice to excite all the tissue downstream. The free shoulder of a broken wave is then prone to curl and give rise to a rotor. 2 To date, the molecular mechanisms of wavebreaks leading to fibrillatory conduction remain poorly understood.Studies in single guinea pig myocytes showed that slow recovery of excitability during diastole was, in part, a consequence of the slow gating kinetics of the delayed rectifier potassium outward current I K . 3,4 Shortly after these studies were published, I K was found to be the result of the activation of 2 outward currents: I Kr and the I Ks . 5 Given the large amounts of I Ks present in guinea pig myocytes 6,7 and the slow deactivation kinetics of this current, 8 we surmise that I Ks is a likely candidate to have an important role in regulating excitability during the diastolic interval, ie, postrepolarization refractorin...

Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia

“…Color-coded signals in Fig. 10A indicate the phase in the excitation-recovery cycle at each pixel location (3,17,18). Stable reentry was present in all monolayers, and in each, there was a single stationary rotor.…”

“…Calcium-tolerant ARVMs were isolated from hearts of Sprague-Dawley rats (200 g) as previously described (3,17,18) for single rotations from representative optical mapping movies of monolayers infected with Ad-GFP, Ad-Na V 1.5, Ad-Kir2.1, or Ad-Kir2.1 + Ad-Na V 1.5. The color bar indicates the phase in the excitation-recovery cycle.…”

In Humans, Chronic Atrial Fibrillation Decreases the Transient Outward Current and Ultrarapid Component of the Delayed Rectifier Current Differentially on Each Atria and Increases the Slow Component of the Delayed Rectifier Current in Both

“…The increase in these inward rectifier currents seems to play a critical role in shortening the atrial APD and ARP and in promoting AF maintenance and recurrence (18). Because I Ks accumulates at high frequencies due to its slow deactivation, the I Ks increase would also contribute to CAF-induced shortening of APD and to further promote fibrillatory conduction (19). It is reasonable to speculate that a frequency-dependent inhibition of I Ks , such as that produced by propafenone (20), is useful in the CAF context, thus converting I Ks in a putative antiarrhythmic target (19).…”

A Method to Replicate the Microstructure of Heart Tissue In Vitro Using DTMRI-Based Cell Micropatterning

“…The main limitation of current cardiac monolayer cultures, other than their 2D nature, is that they are generally comprised of either randomly aligned cells (isotropic structure) 4,10,20,31 or cells aligned in a single direction (uniformly anisotropic structure). 5,7 In contrast, natural cardiac tissue consists of fibers and sheets that continuously change direction, twisting and turning throughout the heart wall at both micro-and macroscopic spatial scales.…”