Niels Voigt

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

Background— The molecular mechanism of increased background inward rectifier current (IK1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated IK,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 IK,ACh blocker tertiapin was used for inhibition of IK,ACh. Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated IK,ACh was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced IK,ACh in a concentration-dependent manner with greater potency in cAF than in SR (−logIC50: 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 IK,ACh to basal current. In single-channel recordings, constitutively active IK,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, IK1 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 IK1 activity and constitutively active IK,ACh. Blockade of IK,ACh may represent a new therapeutic target in AF.

Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation

This study was designed to establish the pathology‐specific inhibitory effects of the IKur/Ito/IK,ACh blocker AVE0118 on atrium‐selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF).

Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation

Inward rectifier potassium currents IK1 and acetylcholine activated IK,ACh are implicated in atrial fibrillation (AF) pathophysiology. In chronic AF (cAF), IK,ACh develops a receptor-independent, constitutively active component that together with increased IK1 is considered to support maintenance of AF. Here, we tested whether class I (propafenone, flecainide) and class III (dofetilide, AVE0118) antiarrhythmic drugs inhibit atrial IK1 and IK,ACh in patients with and without cAF. IK1 and IK,ACh were measured with voltage clamp technique in atrial myocytes from 58 sinus rhythm (SR) and 35 cAF patients. The M-receptor agonist carbachol (CCh; 2u2009µM) was employed to activate IK,ACh. In SR, basal current was not affected by either drug indicating no effect of these compounds on IK1. In contrast, all tested drugs inhibited CCh-activated IK,ACh in a concentration-dependent manner. In cAF, basal current was confirmed to be larger than in SR (at −80xa0mV, −15.2u2009±u20091.2xa0pA/pF, nu2009=u200988/35 vs. −6.5u2009±u20090.4xa0pA/pF, nu2009=u2009194/58 [myocytes/patients]; Pu2009<u20090.05), whereas CCh-activated IK,ACh was smaller (−4.1u2009±u20090.5 pA/pF vs. −9.5u2009±u20090.6xa0pA/pF; Pu2009<u20090.05). In cAF, receptor-independent constitutive IK,ACh contributes to increased basal current, which was reduced by flecainide and AVE0118 only. This may be due to inhibition of constitutively active IK,ACh channels. In cAF, all tested drugs reduced CCh-activated IK,ACh. We conclude that in cAF, flecainide and AVE0118 reduce receptor-independent, constitutively active IK,ACh, suggesting that they may block IK,ACh channels, whereas propafenone and dofetilide likely inhibit M-receptors. The efficacy of flecainide to terminate AF may in part result from blockade of IK,ACh.

Impaired Na+-dependent regulation of acetylcholine-activated inward-rectifier K+ current modulates action potential rate dependence in patients with chronic atrial fibrillation

Shortened action-potential duration (APD) and blunted APD rate adaptation are hallmarks of chronic atrial fibrillation (cAF). Basal and muscarinic (M)-receptor-activated inward-rectifier K(+) currents (IK1 and IK,ACh, respectively) contribute to regulation of human atrial APD and are subject to cAF-dependent remodeling. Intracellular Na(+) ([Na(+)]i) enhances IK,ACh in experimental models but the effect of [Na(+)]i-dependent regulation of inward-rectifier K(+) currents on APD in human atrial myocytes is currently unknown. Here, we report a [Na(+)]i-dependent inhibition of outward IK1 in atrial myocytes from sinus rhythm (SR) or cAF patients. In contrast, IK,ACh activated by carbachol, a non-selective M-receptor agonist, increased with elevation of [Na(+)]i in SR. This [Na(+)]i-dependent IK,ACh regulation was absent in cAF. Including [Na(+)]i dependence of IK1 and IK,ACh in a recent computational model of the human atrial myocyte revealed that [Na(+)]i accumulation at fast rates inhibits IK1 and blunts physiological APD rate dependence in both groups. [Na(+)]i-dependent IK,ACh augmentation at fast rates increased APD rate dependence in SR, but not in cAF. These results identify impaired Na(+)-sensitivity of IK,ACh as one potential mechanism contributing to the blunted APD rate dependence in patients with cAF. This article is part of a Special Issue entitled Na(+) Regulation in Cardiac Myocytes.

Application of the RIMARC algorithm to a large data set of action potentials and clinical parameters for risk prediction of atrial fibrillation

Ex vivo recorded action potentials (APs) in human right atrial tissue from patients in sinus rhythm (SR) or atrial fibrillation (AF) display a characteristic spike-and-dome or triangular shape, respectively, but variability is huge within each rhythm group. The aim of our study was to apply the machine-learning algorithm ranking instances by maximizing the area under the ROC curve (RIMARC) to a large data set of 480 APs combined with retrospectively collected general clinical parameters and to test whether the rules learned by the RIMARC algorithm can be used for accurately classifying the preoperative rhythm status. APs were included from 221 SR and 158 AF patients. During a learning phase, the RIMARC algorithm established a ranking order of 62 features by predictive value for SR or AF. The model was then challenged with an additional test set of features from 28 patients in whom rhythm status was blinded. The accuracy of the risk prediction for AF by the model was very good (0.93) when all features were used. Without the seven AP features, accuracy still reached 0.71. In conclusion, we have shown that training the machine-learning algorithm RIMARC with an experimental and clinical data set allows predicting a classification in a test data set with high accuracy. In a clinical setting, this approach may prove useful for finding hypothesis-generating associations between different parameters.