Abstract-Previous studies have postulated an important role for the inwardly rectifying potassium current (I K1 ) in controlling the dynamics of electrophysiological spiral waves responsible for ventricular tachycardia and fibrillation. In this study, we developed a novel tissue model of cultured neonatal rat ventricular myocytes (NRVMs) with uniform or heterogeneous Kir2.1expression achieved by lentiviral transfer to elucidate the role of I K1 in cardiac arrhythmogenesis. Kir2.1-overexpressed NRVMs showed increased I K1 density, hyperpolarized resting membrane potential, and increased action potential upstroke velocity compared with green fluorescent protein-transduced NRVMs. Opposite results were observed in Kir2.1-suppressed NRVMs. Optical mapping of uniformly Kir2.1 gene-modified monolayers showed altered conduction velocity and action potential duration compared with nontransduced and empty vector-transduced monolayers, but functional reentrant waves could not be induced. In monolayers with an island of altered Kir2.1 expression, conduction velocity and action potential duration of the locally transduced and nontransduced regions were similar to those of the uniformly transduced and nontransduced monolayers, respectively, and functional reentrant waves could be induced. The waves were anchored to islands of Kir2.1 overexpression and remained stable but dropped in frequency and meandered away from islands of Kir2.1 suppression. In monolayers with an inverse pattern of I K1 heterogeneity, stable high frequency spiral waves were present with I K1 overexpression, whereas lower frequency, meandering spiral waves were observed with I K1 suppression. Our study provides direct evidence for the contribution of I K1 heterogeneity and level to the genesis and stability of spiral waves and highlights the potential importance of I K1 as an antiarrhythmia target. Key Words: Kir2.1 Ⅲ inwardly rectifying potassium current Ⅲ reentry Ⅲ spiral waves Ⅲ ventricular tachycardia Ⅲ ventricular fibrillation V entricular fibrillation (VF) is the leading cause of cardiac arrest and sudden cardiac death in the industrialized world. 1 Studies in the 1970s suggested that the heart could sustain electrical activity that rotated around a functional obstacle. 2,3 These reentrant waves are believed to be the unitary components of fibrillation. Several other studies that focused on understanding the mechanisms of initiation and maintenance of VF concluded that the stability of spiral waves (functional form of reentrant waves) depends on the abbreviation of action potential duration, as well as the reduction of wavefront-wavetail interactions, at fibrillation frequencies. 4 -6 In addition, ionic heterogeneity may be a key factor in the initiation of spiral waves and their transition to the irregular spatiotemporal pattern seen in VF. [7][8][9] Numerous studies pioneered mainly by Jalife and colleagues have indicated that I K1 plays an important role in determining cardiac excitability and arrhythmogenesis and that I K1 block has a significa...

Patterns of cellular organization in diverse tissues frequently display a complex geometry and topology tightly related to the tissue function. Progressive disorganization of tissue morphology can lead to pathologic remodeling, necessitating the development of experimental and theoretical methods of analysis of the tolerance of normal tissue function to structural alterations. A systematic way to investigate the relationship of diverse cell organization to tissue function is to engineer two-dimensional cell monolayers replicating key aspects of the in vivo tissue architecture. However, it is still not clear how this can be accomplished on a tissue level scale in a parameterized fashion, allowing for a mathematically precise definition of the model tissue organization and properties down to a cellular scale with a parameter dependent gradual change in model tissue organization. Here, we describe and use a method of designing precisely parameterized, geometrically complex patterns that are then used to control cell alignment and communication of model tissues. We demonstrate direct application of this method to guiding the growth of cardiac cell cultures and developing mathematical models of cell function that correspond to the underlying experimental patterns. Several anisotropic patterned cultures spanning a broad range of multicellular organization, mimicking the cardiac tissue organization of different regions of the heart, were found to be similar to each other and to isotropic cell monolayers in terms of local cell–cell interactions, reflected in similar confluency, morphology and connexin-43 expression. However, in agreement with the model predictions, different anisotropic patterns of cell organization, paralleling in vivo alterations of cardiac tissue morphology, resulted in variable and novel functional responses with important implications for the initiation and maintenance of cardiac arrhythmias. We conclude that variations of tissue geometry and topology can dramatically affect cardiac tissue function even if the constituent cells are themselves similar, and that the proposed method can provide a general strategy to experimentally and computationally investigate when such variation can lead to impaired tissue function.