title: Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling.
abstract: OBJECTIVE
  Chronic beta-adrenoceptor antagonist (beta-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with beta-blockers and other cardiovascular-acting drugs.
  
  
  METHODS
  Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca(2+) current (I(CaL)), transient (I(TO)) and sustained (I(KSUS)) outward K(+) currents, and input resistance (R(i)) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant.
  
  
  RESULTS
  In atrial cells from patients treated chronically with beta-blockers, the APD(90) and ERP (75 beats/min stimulation) were significantly longer, at 213+/-11 and 233+/-11 ms, respectively (n=15 patients), than in cells from non-beta-blocked patients, at 176+/-12 and 184+/-12 ms (n=11). These cells also displayed a significantly reduced action potential phase 1 velocity (22+/-3 vs. 34+/-3 V/s). Chronic beta-blockade was also associated with a significant reduction in the heart rate (58+/-3 vs. 69+/-5 beats/min) and in the density of I(TO) (8.7+/-1.3 vs. 13.7+/-2.1 pA/pF), an increase in the R(i) (214+/-24 vs. 132+/-14 MOmega), but no significant change in I(CaL) or I(KSUS). The I(TO) blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic beta-blockade, in cells from non-beta-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n=11-13 patients) was not associated with any significant changes in atrial cell electrophysiology.
  
  
  CONCLUSIONS
  The observed atrial cellular electrophysiological changes associated with chronic beta-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of beta-blockade.
authors.affiliation: Section of Cardiology, Division of Cardiovascular and Medical Sciences, University of Glasgow, Royal Infirmary, 10 Alexandra Parade, G31 2ER, Glasgow, UK. a.j.workman@clinmed.gla.ac.uk
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Workman
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Kane
authors.forename: Julie A
authors.initials: JA
authors.lastname: Russell
authors.forename: John
authors.initials: J
authors.lastname: Norrie
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Rankin
mesh_terms: D000200:Action Potentials / Q000187:drug effects*; D000222:Adaptation, Physiological; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D002478:Cells, Cultured; D001026:Coronary Artery Bypass; D005260:Female; D006325:Heart Atria; D006801:Humans; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000150:complications / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects*; D012044:Regression Analysis
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002121:Calcium Channel Blockers; D007473:Ion Channels