The G Protein–Gated Potassium Current I _K,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation

Abstract

Background— The molecular mechanism of increased background inward rectifier current ( I K1 ) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I K,ACh contributes to enhanced basal conductance in chronic AF (cAF). Methods and Results— Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I K,ACh blocker tertiapin was used for inhibition of I K,ACh . Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I K,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I K,ACh in a concentration-dependent manner with greater potency in cAF than in SR (−logIC 50 : 9.1 versus 8.2; P <0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at −100 mV: cAF, −6.7±1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, −1.7±0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I K,ACh to basal current. In single-channel recordings, constitutively active I K,ACh was prominent in cAF but not in SR (channel open probability: cAF, 5.4±0.7%, n=19/9 versus SR, 0.1±0.05%, n=16/9; P <0.05). Moreover, I K1 channel open probability was higher in cAF than in SR (13.4±0.4%, n=19/9 versus 11.4±0.7%, n=16/9; P <0.05) without changes in other channel characteristics. Conclusions— Our results demonstrate that larger basal inward rectifier K + current in cAF consists of increased I K1 activity and constitutively active I K,ACh . Blockade of I K,ACh may represent a new therapeutic target in AF.

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…Migotanie przedsionków wywołuje skrócenie okresu refrakcji w przedsionkach oraz długości cyklu AF w pierwszych dniach trwania arytmii, głównie z powodu zmniejszenia dokomórkowego prądu wapniowego i zwiększenia dokomórkowego prostowniczego prądu potasowego [94,95]. Natomiast strukturalna choroba serca powoduje na ogół wydłużenie okresu refrakcji w przedsionkach, co ilustruje niejednorodny charakter mechanizmów wywołujących AF u różnych pacjentów [96].…”

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

“…94,95 Structural heart disease, in contrast, tends to prolong the atrial refractory period, illustrating the heterogeneous nature of mechanisms that cause AF in different patients. 96 Hyperphosphorylation of various Ca 2+ -handling proteins may contribute to enhanced spontaneous Ca 2+ release events and triggered activity, 97,98 thus causing ectopy and promoting AF.…”

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

“…When high-frequency atrial activation is maintained for at least 24 h, ion-channel remodelling changes the electrophysiologic substrate, promoting perpetuation of re-entry and increasing the activity of triggers, further contributing to AF permanence. 494 Atrial fibrillation itself leads to remodelling, causing electrophysiological (electrical), contractile, and structural changes. 495,496 Although AF can typically be reversed in its early stages, it becomes more difficult to eliminate over time due to such remodelling.…”