Chronic heart failure and the substrate for atrial fibrillation.
OBJECTIVE
We sought to define the underlying mechanisms for atrial fibrillation (AF) during chronic heart failure (HF).


RESULTS
Preliminary studies showed that 4 months of HF resulted in irreversible systolic dysfunction (n = 9) and a substrate for sustained inducible AF (>3 months, n = 3). We used a chronic (4-month) canine model of tachypacing-induced HF (n = 10) to assess atrial electrophysiological remodelling, relative to controls (n = 5). Left ventricular fractional shortening was reduced from 37.2 +/- 0.83 to 13.44 +/- 2.63% (P < 0.05). Left atrial (LA) contractility (fractional area change) was reduced from 34.9 +/- 7.9 to 27.9 +/- 4.23% (P < 0.05). Action potential durations (APDs) at 50 and 90% repolarization were shortened by approximately 60 and 40%, respectively, during HF (P < 0.05). HF-induced atrial remodelling included increased fibrosis, increased I(to), and decreased I(K1), I(Kur), and I(Ks) (P < 0.05). HF induced increases in LA Kv channel interacting protein 2 (P < 0.05), no change in Kv4.3, Kv1.5, or Kir2.3, and reduced Kir2.1 (P < 0.05). When I(Ca-L) was elicited by action potential (AP) clamp, HF APs reduced the integral of I(Ca) in control myocytes, with a larger reduction in HF myocytes (P < 0.05). I(CaL) measured with standard voltage clamp was unchanged by HF. Incubation of myocytes with N-acetylcysteine (a glutathione precursor) attenuated HF-induced electrophysiological alterations. LA angiotensin-1 receptor expression was increased in HF.


CONCLUSIONS
Chronic HF causes alterations in ion channel expression and ion currents, resulting in attenuation of the APD and atrial contractility and a substrate for persistent AF.
Sridhar
Arun
A
Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, USA.
Nishijima
Yoshinori
Y
Terentyev
Dmitry
D
Khan
Mahmood
M
Terentyeva
Radmila
R
Hamlin
Robert L
RL
Nakayama
Tomohiro
T
Gyorke
Sandor
S
Cardounel
Arturo J
AJ
Carnes
Cynthia A
CA
D000111:Acetylcysteine / Q000494:pharmacology; D000200:Action Potentials; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016279:Atrial Function, Left; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling; D002304:Cardiac Pacing, Artificial; D002908:Chronic Disease; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005355:Fibrosis; D006329:Heart Conduction System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010865:Pilot Projects; D015221:Potassium Channels / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012032:Refractory Period, Electrophysiological; D013997:Time Factors; D016277:Ventricular Function, Left
D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D044140:Receptor, Angiotensin, Type 1; D000111:Acetylcysteine