Abstract 1529: Chamber-specific Differences of IK,ACh Remodelling in Patients with Atrial Fibrillation
Background: Left (LA) to right atrial (RA) IK,ACh gradients are implicated in rotor dynamics and wavelet formation during atrial fibrillation (AF). Lines of evidence suggest impaired IK,ACh function in RA of AF patients. However, clinical AF is most frequently induced in the LA. This study compared function and expression of IK,ACh in LA and RA from patients with sinus rhythm (SR) and chronic AF (cAF).
Methods: IK,ACh was measured with whole-cell voltage-clamp in isolated human RA and LA myocytes. Competitive RT-PCR and Western blot (GAPDH-controlled) were used to quantify GIRK1 (Kir3.1) subunit mRNA and protein, respectively.
Results: Basal current of RA and LA myocytes was similar in SR (- 16.5±1.2 pA/pF [n=16/10] RA vs −16.7±3.3 pA/pF [n=10/3] LA) and increased in cAF by 58% and 129%, respectively. In cAF, basal current was 47% larger in LA than in RA. Carbachol (CCh, 2 μM)-activated IK,ACh current was 82% lower in LA than in RA myocytes of SR patients (Figure⇓). In cAF IK,ACh was reduced by 38% in RA only. These findings point to a RA-LA gradient of IK,ACh in SR and cAF patients. In RA tissue from cAF, mRNA and protein levels of GIRK1 were downregulated by 38% and 68%, respectively, whereas LA GIRK1 mRNA was unchanged. Despite unaltered LA IK,ACh, corresponding GIRK1 proteins were decreased by 39% pointing to compensatory posttranslational changes in LA IK,ACh.
Conclusions: IK,ACh is larger in RA than in LA myocytes of both SR and cAF patients. In cAF IK,ACh decreases in RA myocytes only. We provide novel information about RA-LA gradient and chamber-specific mechanisms of IK,ACh remodelling in the human atrium, with potential implications for AF promotion and maintenance.