Effects of angiotensin receptor blockade on atrial electrical remodelling and the 'second factor' in a goat burst-paced model of atrial fibrillation.
Atrial fibrillation (AF) is self-perpetuating, via mechanisms of acute electrical remodelling and 'second factors' acting over a longer time course. Renin-angiotensin system (RAS) blockade may inhibit AF self-perpetuation. We evaluated the effects of RAS blockade with candesartan in a burst-paced goat model of lone AF in which both mechanisms are known to operate. Bioactivity of oral candesartan was demonstrated in 10 goats by inhibition of the pressor effect of angiotensin II. The effects of candesartan on electrical remodelling were assessed in 12 placebo and 12 candesartan-treated goats in a 28-day burst pacing protocol. To assess the effects of candesartan on second factors (structural remodelling), 16 goats underwent further 28-day periods of burst pacing (two periods in 16 goats, three periods in eight goats) each separated by periods of sinus rhythm sufficient for electrical remodelling to reverse. There was a progressive rise in angiotensin levels in both groups. Candesartan (0.5 mg/kg/day) achieved a 76% blunting of the pressor effect of angiotensin II and had no effect on electrical remodelling; the half time for fall of atrial effective refractory period (AERP) was 22.3 ± 4.9 h (placebo) and 22.0 ± 3.2 h (candesartan) (p = ns). Candesartan had no effect on AF stability, which progressively increased over successive 28-day periods (ANOVA p < 0.05). Candesartan had no effect on atrial electrical remodelling or the operation of 'second factors' in a goat model of lone AF. These findings suggest that any benefits of RAS blockade in patients with AF are unlikely to be due to direct effects on atrial remodelling.
Hall
Mark C S
MC
Liverpool Heart and Chest Hospital, Liverpool, UK. mark.hall@lhch.nhs.uk
Kirubakaran
Senthil
S
Choudhury
Rasheda
R
Abidin
Nik
N
Peters
Nicholas S
NS
Garratt
Clifford J
CJ
D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000503:physiopathology*; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005260:Female; D006041:Goats; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013777:Tetrazoles / Q000494:pharmacology*; D013997:Time Factors; D016276:Ventricular Function / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan