Abstract
Introduction and hypothesis: Genetic abnormalities close to the Pitx2 gene correlate more strongly with atrial fibrillation (AF) than any other genetic modification. It is known that Pitx2c mRNA is expressed in the adult left atrium (LA), but its relevance for the electrical integrity of cardiomyocytes throughout the atria remains unresolved. We therefore compared regional action potential (AP) morphology in PITX2c +/- and wild type (WT) littermate mice. Methods: Transmembrane (T) and optical (O) APs were recorded from superfused intact, isolated LA paced at 100ms. TAPs were recorded from three distinct regions on the LA epicardium: 1) the junction with the interatrial septum (S), 2) the medial muscular dome (M) and 3) the lateral wall (L). OAPs were recorded using a custom murine atrial optical mapping system using the Hamamatsu ORCA flash 4 and Di-4-Anepps. Results: OAPs were shorter in Pitx2c deficient LA (AP duration (APD70); WT 13±2ms, n=4 LA vs Pitx2c +/- 9±1ms, n=4 LA, all data as mean±SEM, p<0.05). Simultaneous recordings of OAPs from multiple LA regions showed an AP gradient with longer OAPs at the septum than at the lateral wall, in both genotypes. In WT LA, TAPs were longer and of greater amplitude at the septum than in the other two regions (APD90; S 26±1ms, M 19±1mV and L 19±1ms, APA; S 81±1mV, M 76±2mV and L 76±2mV, n=6 LA, p<0.05). In Pitx2c +/- , TAPs were shorter than WT in all three regions tested and exhibited the same regional patterning (S 20±1ms, M 15±1ms and L 16±1, n=7 LA, p<0.05). The regional AP amplitude gradient was not apparent, or at least shifted more towards the lateral wall, in PITX2c +/- atria (APA; S 77±2mV, M 76±3mV and L 74±2mV, n=7 LA, ns). Conclusion: Partial depletion in Pitx2c mRNA expression causes a uniform APD shortening throughout the LA and loss of regional changes in AP amplitude. Identification of the targets downstream of Pitx2 accounting for these changes will help to better understand the mechanisms conveying AF due to reduced Pitx2 function.
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