A Regional Reduction in Ito and IKACh in the Murine Posterior Left Atrial Myocardium Is Associated with Action Potential Prolongation and Increased Ectopic Activity

Abstract

BackgroundThe left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.MethodsWe used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.ResultsSpontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.ConclusionsThe murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.

PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers

“…Our findings are relevant to AAD therapy even if the presumed link between PITX2 expression and genetic variants on chromosome 4q25 proves elusive. The mechanisms by which reduced PITX2 mRNA concentrations shorten the LA action potential at high heart rates remain to be fully elucidated 8 , 20 . Validating our findings in patients is desirable but will be challenging because access to fresh LA cardiomyocytes and LA tissue is limited.…”

“…LA cell isolation was performed as previously reported (20) . Standard I Na and I K1 currents were recorded as previously published 18 , 19 , 20 .…”

“…LA cell isolation was performed as previously reported (20) . Standard I Na and I K1 currents were recorded as previously published 18 , 19 , 20 . Background K + (TASK-like) currents sensitive to high Ba 2+ (10 mM) were measured 21 , 22 , 23 .…”

Dynamic monitoring of single-terminal norepinephrine transporter rate in the rodent cardiovascular system: A novel fluorescence imaging method

“…Rodent cardiac chambers (LAA, left atrial appendage; RAA, right atrial appendage; LV, left ventricle; RV, right ventricle) and mesenteric arteries (MA) were dissected free as described (Holmes et al, 2016;Hansen et al, 2019), transferred to the imaging chamber and securely pinned down as flat as possible onto a Sylgard-lined base. Tissues were continuously superfused at 2 ml·min −1 with warmed (35-37°C), oxygenated KH solution for at least 20 min prior to ex vivo studies.…”

PITX2‐dependent gene regulation in atrial fibrillation and rhythm control

“…; Holmes et al . ). Given the crucial role of PITX2 in left–right asymmetry, it is probable that loss of PITX2 in some cases of heritable AF causes incomplete suppression of pacemaker activity in the left heart.…”