The Role of the Atrial Neural Network In Atrial Fibrillation: The Metastatic Progression Hypothesis.

With the advent of catheter ablation of atrial fibrillation (AF) there has been acceleration in our understanding of the mechanisms underlying the etiology of this common clinical arrhythmia. In this regard, the role of the intrinsic cardiac autonomic nervous system in the initiation and maintenance of AF began to receive attention in numerous experimental and clinical investigations. Up to now, the focus has been on the large ganglionated plexi (GP) which are located in the posterior left atrium mainly at the pulmonary vein-atrial junctions. As long term outcomes have been reported and single procedures have indicated diminished success rates particularly for persistent/long standing persistent AF, emphasis has begun to shift away from the pulmonary vein isolation (PVI) alone as well as GP ablation with or without PVI. An understanding of the atrial substrate represented by the extensions of the intrinsic cardiac autonomic system constituting the atrial neural network is beginning to evolve. In this review, the contribution of the intrinsic cardiac autonomic nervous system to the etiology of AF is addressed, particularly in regard to the greater prevalence of AF in the elderly. In addition, we emphasize the involvement of the atrial neural network in the "metastatic" progression of paroxysmal to persistent and long standing persistent forms of AF.

Mechanism of alpha-adrenergic regulation of expressed hKv4.3 currents.

The transient outward potassium current (I(to)) is an important repolarizing current in the mammalian heart. I(to) is regulated by adrenergic stimulation; however, the effect of agonists on this current, and consequently the action potential duration and profile, is variable. An important source of the variability is the difference in the channel genes that underlie I(to). There are two subfamilies of candidate genes that are likely to encode I(to) in the mammalian heart: Kv4 and Kv1.4; the predominance of either gene is a function of the species, stage of development, and region of the heart. The existence of different isoforms of the Kv4 family (principally Kv4.2 or Kv4.3) further complicates the effect of alpha-adrenergic modulation of cardiac I(to). In the human ventricle, hKv4.3 is the predominant gene underlying I(to). Two splice variants of human Kv4.3 (hKv4.3) are present in the human ventricle; the longer splice variant contains a 19-amino acid insert in the COOH-terminus with a consensus protein kinase C (PKC) site. We used heterologous expression of hKv4.3 splice variants and studies of human ventricular myocytes to demonstrate that alpha-adrenergic modulation of I(to) occurs through a PKC signaling pathway and that only the long splice variant (hKv4.3-L) is modulated via this pathway. Only a single hKv4.3-L monomer in the tetrameric I(to) channel is required to confer sensitivity to phenylephrine (PE). Mutation of the PKC site in hKv4.3-L eliminates alpha-adrenergic modulation of the hKv4.3-encoded current. The similar, albeit less robust, modulation of human ventricular I(to) by PE suggests that hKv4.3-L is expressed in a functional form in the human heart.

Probing the interaction between inactivation gating and Dd-sotalol block of HERG.

Potassium channels encoded by HERG underlie I:(Kr), a sensitive target for most class III antiarrhythmic drugs, including methanesulfonanilides such as Dd-sotalol. Recently it was shown that these drugs are trapped in the channel as it closes during hyperpolarization. At the same time, HERG channels rapidly open and inactivate when depolarized, and methanesulfonanilide block is known to develop in a use-dependent manner, suggesting a potential role for inactivation in drug binding. However, the role of HERG inactivation in class III drug action is uncertain: pore mutations that remove inactivation reduce block, yet many of these mutations also modify the channel permeation properties and could alter drug affinity through gating-independent mechanisms. In the present study, we identify a definitive role for inactivation gating in Dd-sotalol block of HERG, using interventions complementary to mutagenesis. These interventions (addition of extracellular Cd(2+), removal of extracellular Na(+)) modify the voltage dependence of inactivation but not activation. In normal extracellular solutions, block of HERG current by 300 micromol/L Dd-sotalol reached 80% after a 10-minute period of repetitive depolarization to +20 mV. Maneuvers that impeded steady-state inactivation also reduced Dd-sotalol block of HERG: 100 micromol/L Cd(2+) reduced steady-state block to 55% at +20 mV (P:<0.05); removing extracellular Na(+) reduced block to 44% (P:<0.05). An inactivation-disabling mutation (G628C-S631C) reduced Dd-sotalol block to only 11% (P:<0.05 versus wild type). However, increasing the rate of channel inactivation by depolarizing to +60 mV reduced Dd-sotalol block to 49% (P:<0.05 versus +20 mV), suggesting that the drug does not primarily bind to the inactivated state. Coexpression of MiRP1 with HERG had no effect on inactivation gating and did not modify Dd-sotalol block. We postulate that Dd-sotalol accesses its receptor in the open pore, and the drug-receptor interaction is then stabilized by inactivation. Whereas deactivation traps the bound methanesulfonanilide during hyperpolarization, we propose that HERG inactivation stabilizes the drug-receptor interaction during membrane depolarization.

Modulation of HERG potassium channels by extracellular magnesium and quinidine.

Torsades de pointes is a polymorphic ventricular arrhythmia resulting from congenital or drug-induced (acquired) QT prolongation. Pharmacologic suppression of repolarizing potassium currents is one mechanism causing the acquired long QT (LQT) syndrome. Recent studies have linked mutations in a gene encoding a potassium channel subunit (HERG) to the LQT syndrome. Clinical experience indicates that intravenous magnesium sulfate is effective in reversing torsades de pointes, but the molecular basis of this effect is not understood. This study was designed to investigate the effects of extracellular magnesium (Mg2+) on HERG potassium currents. HERG potassium channels were expressed in Xenopus oocytes and in a human cell line and were examined by voltage-clamp methods. Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent shift in the membrane-potential dependence of HERG channel opening, causing a reduction in K+ current. This effect was much greater than that observed in another human delayed rectifier K+ channel, hKv1.5, suggesting a specific interaction with the HERG channel. Quinidine is an antiarrhythmic drug that also causes torsades de pointes under certain conditions. Quinidine (3 microM) inhibited HERG currents expressed in oocytes by 32.1 +/- 3.2% (n = 5), whereas 1 microM quinidine inhibited HERG currents in tsA201 cells by 75.8 +/- 2.4% (n = 12). Increasing extracellular Mg2+ did not relieve the inhibition by quinidine, but caused additional suppression. These results indicate that extracellular Mg2+ exerts a direct action on HERG potassium channels, resulting in suppression of outward repolarizing potassium current. It is concluded that modulation of this important K+ current is not the mechanism by which intravenous magnesium terminates drug-induced LQT and torsades de pointes. Potent suppression of HERG channel current by quinidine, compared with that of I(Ks) and I(Na), is a likely contributor to torsades de pointes arrhythmias.