Spatial heterogeneity of APD under long QT conditions: characterisation and relationship to sinus activation sequence.

AIMS: Enhanced spatial variation in ventricular action potential duration (APD) is known to contribute to arrhythmia development under long QT conditions, although the causes of APD variation are unclear. Specifically, between-individual variation in the locations of pro-arrhythmic long APD islands and associated repolarisation gradients is difficult to explain in the context of established regional variation in electrophysiology. This study aimed to explore the mechanisms underlying the spatial heterogeneity of ventricular APD under baseline and long QT conditions. METHODS AND RESULTS: New Zealand White rabbit hearts (n = 26) were Langendorff-perfused with oxygenated Tyrode's solution and loaded with blebbistatin and FluoVolt. Optical mapping of transmembrane voltage from the anterior epicardial surface of the right (RV) and left ventricles (LV) during sinus rhythm revealed a strong inverse relationship between activation time and APD90 in all hearts (linear regression slope: -0.85 ± 0.17, r2: 0.60 ± 0.12, p < 0.0001), despite considerable between-heart variation in the activation sequence. Lengthening of the pacing cycle length (350 to 1000 ms) and dofetilide-induced IKr blockade each induced greater AP prolongation in ventricular sites with earlier sinus activation, contributing to increased spatial heterogeneity of APD90. Optical measurement of APD90 from cardiomyocytes isolated after optical mapping of the intact heart indicated that myocytes from ventricular sites with earlier sinus activation had longer intrinsic APD90. Isolated RV myocytes also exhibited shorter average APD90 than LV myocytes. Measurement of the mRNA levels of 22 genes encoding cardiac ion channel, transporter and regulatory proteins demonstrated that ventricular sites with distinct sinus activation times exhibit different gene expression profiles. With increasing sinus activation time, the mRNA levels of Scn5a and most repolarisation genes decreased while that of Kcnip2 increased. CONCLUSION: Ventricular sites with distinct sinus activation times exhibit different electrophysiological properties which contribute to enhanced spatial heterogeneity of APD under long QT conditions.