Abstract 13021: Regional Electromechanical Heterogeneity in the Rabbit Wild-Type and Long-QT-Syndrome Heart

Abstract

Introduction: Long-QT-syndrome type 2 (LQT2) has been linked to heterogeneities on a whole-heart scale. Here, we systematically investigated regional electromechanical function in wild-type (WT) and transgenic LQT2 rabbits. Methods: Rabbits (n=7 WT, 6 LQT2) were examined by phase-contrast magnetic resonance imaging (MRI) to assess cardiac wall movement velocities. A novel data-processing algorithm was developed to calculate regional contraction-like profiles. Using patch clamping, action potentials (AP) were recorded from cardiomyocytes isolated from the left ventricular (LV) apex and LV, septum, and right ventricular base. Cav1.2, KCNQ1, Kv1.4, Kir2.1, Nav1.5, SERCA, RyR2, Phospholamban (PLB) and NCX expression were quantified by western blot. Results: AP was longer in WT LV apex than in all three base regions (APD90 median 291 vs. 202, 209, 196ms; p<0.01, 0.05, 0.05). MRI revealed an earlier, longer and stronger contraction in LV apex than LV base (fig. 1) in both genotypes and an additional relaxation impairment in LQT2 LV apex (fig. 1B). In WT, 5 proteins were downregulated in LV apex vs. LV base (KCNQ1, p=0.07; Cav1.2, p<0.01; Kv1.4, NCX, PLB, p<0.05). In LQT2 no similar profile was present. Instead, NCX and PLB were upregulated apically compared to WT (p<0.05). An in silico model integrating the quantitative WT differences reproduced a contraction and AP prolongation in apex vs. base. Conclusions: Electromechanical heterogeneity is not exclusive to the arrhythmogenic heart: we demonstrate the presence of an electromechanical, in silico reproducible apico-basal gradient in healthy rabbit hearts with an associated regionally heterogeneous expression of 5 key proteins. This pattern can be explained logically as apical mechanical dominance reduces outflow resistance and increases efficiency. LQT2 rabbits show increased intra-cardiac heterogeneity with diastolic asynchrony that can be determined non-invasively and might have prognostic value.