The rapid delayed rectifier K+ current, I-Kr, plays a key role in repolarisation of cardiac ventricular action potentials (APs). In recent years. a novel clinical condition denoted the short QT syndrome (SQTS) has been identified and, very recently, gain in function mutations in the gene encoding the pore-forming sub-unit of the I-Kr channel have been proposed to underlie SQTS in some patients. Here, computer simulations were used to investigate the effects of the selective loss of voltage-dependent inactivation of I-Kr upon ventricular APs and on the QT interval of the electrocardiogram. I-Kr and inactivation-deficient I-Kr were incorporated into Luo-Rudy ventricular AP models. Inactivation-deficient IKr produced AP shortening that was heterogeneous between endocardial, mid-myocardial, and epicardial ventricular cell models, irrespective of whether heterogeneity between these sub-regions was incorporated of slow delayed rectifier K+ current (I-Ks) alone, or of I-Ks together with that of transient outward K+ current. The selective loss of rectification of I-Kr did not augment transmural dispersion of AP repolarisation, as AP shortening was greater in mid-myocardial than in endo- or epicardial cell models. Simulated conduction through a 1 D transmural ventricular strand was altered by incorporation of inactivation-deficient I-Kr and the reconstructed QT interval was shortened. Collectively, these results substantiate the notion that selective loss of I-Kr inactivation produces a gain in I-Kr function that causes QT interval shortening. (C) 2004 Elsevier Inc. All rights reserved.