Cardiac adrenergic control and atrial fibrillation

Abstract

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and it causes substantial mortality. The autonomic nervous system, and particularly the adrenergic/cholinergic balance, has a profound influence on the occurrence of AF. Adrenergic stimulation from catecholamines can cause AF in patients. In human atrium, catecholamines can affect each of the electrophysiological mechanisms of AF initiation and/or maintenance. Catecholamines may produce membrane potential oscillations characteristic of afterdepolarisations, by increasing Ca(2+) current, [Ca(2+)](i) and consequent Na(+)-Ca(2+) exchange, and may also enhance automaticity. Catecholamines might affect reentry, by altering excitability or conduction, rather than action potential terminal repolarisation or refractory period. However, which arrhythmia mechanisms predominate is unclear, and likely depends on cardiac pathology and adrenergic tone. Heart failure (HF), a major cause of AF, causes adrenergic activation and adaptational changes, remodelling, of atrial electrophysiology, Ca(2+) homeostasis, and adrenergic responses. Chronic AF also remodels these, but differently to HF. Myocardial infarction and AF cause neural remodelling that also may promote AF. beta-Adrenoceptor antagonists (beta-blockers) are used in the treatment of AF, mainly to control the ventricular rate, by slowing atrioventricular conduction. beta-Blockers also reduce the incidence of AF, particularly in HF or after cardiac surgery, when adrenergic tone is high. Furthermore, the chronic treatment of patients with beta-blockers remodels the atria, with a potentially antiarrhythmic increase in the refractory period. Therefore, the suppression of AF by beta-blocker treatment may involve an attenuation of arrhythmic activity that is caused by increased [Ca(2+)](i), coupled with effects of adaptation to the treatment. An improved understanding of the involvement of the adrenergic system and its control in basic mechanisms of AF under differing cardiac pathologies might lead to better treatments.

Figure 1. Arrhythmic electrical activity produced by adrenergic stimulation in human atrium

Action potentials recorded from human right atrial isolated tissue (a) and myocyte (b) in the absence (control) or presence of adrenaline or isoprenaline (ISO). Myocyte stimulated at 75 beats/min. Circles: spontaneous depolarisations; one occurring just before stimulus spike (←). Calibration bars: 50 mV (vertical), 200 ms (horizontal). Based on data in (Sleator et al. 1964) (a) and (Redpath et al. 2006) (b) with permission from American Physiological Society, and Elsevier, respectively.

Figure 2. Species- and cardiac chamber-dependent effects of adrenergic stimulation on action potentials and ion currents

a, Action potentials from dog (i) and human (ii) left ventricular myocyte, and from human right atrial tissue (iii) and myocyte (iv). C: control, ISO: isoprenaline, A: adrenaline, W: washout, HMR: HMR1556 (I_KS blocker), ET: endothelin. Calibrations: 25 mV, 100 ms. Based on data in (Stengl et al. 2006) (i), (Koumi et al. 1995) (ii), (Yeh et al. 1992) (iii), and (Redpath et al. 2006) (iv) with permission from Oxford University Press, American Society for Clinical Investigation, S. Karger AG, Basel, and Elsevier, respectively. b, Simulated time courses of main human atrial ion currents (defined in text) determining action potential (top trace) shape. Ordinate scales equalised for all currents <0.5 pA/pF. All traces derived from mathematical model (Courtemanche et al. 1998) using CESE Pro 1.4.8 software (Simulogic Inc., Halifax, Canada). Arrows indicate reported effect of ISO on currents.

Figure 3. Remodelling of atrial action potentials by chronic β-blocker treatment

a, Action potentials (dotted) in right atrium isolated from a rabbit not treated (control) or treated (chronic β-blocker) for 24 days with metoprolol. b, Action potentials and effective refractory period (↔) recorded in an atrial cell obtained from a patient not treated (upper panel) or treated (lower) with a β-blocker. Calibrations: 50 mV, 100 ms. Based on data in (Raine et al. 1981) (a) and (Workman et al. 2003b) (b) with permission from Wolters Kluwer Health/Lippincott, Williams & Wilkins, and Oxford University Press, respectively.