Effect of simvastatin and antioxidant vitamins on atrial fibrillation promotion by atrial-tachycardia remodeling in dogs.
BACKGROUND
There is evidence for a role of oxidant stress and inflammation in atrial fibrillation (AF). Statins have both antioxidant and antiinflammatory properties. We compared the effects of simvastatin with those of antioxidant vitamins on AF promotion by atrial tachycardia in dogs.


RESULTS
We studied dogs subjected to atrial tachypacing (ATP) at 400 bpm in the absence and presence of treatment with simvastatin, vitamin C, and combined vitamins C and E. Serial closed-chest electrophysiological studies were performed in each dog at baseline and 2, 4, and 7 days after tachypacing onset. Atrioventricular block was performed to control ventricular rate. Mean duration of induced AF was increased from 42+/-18 to 1079+/-341 seconds at terminal open-chest study after tachypacing alone (P<0.01), and atrial effective refractory period (ERP) at a cycle length of 300 ms was decreased from 117+/-5 to 76+/-6 ms (P<0.01). Tachypacing-induced ERP shortening and AF promotion were unaffected by vitamin C or vitamins C and E; however, simvastatin suppressed tachypacing-induced remodeling effects significantly, with AF duration and ERP averaging 41+/-15 seconds and 103+/-4 ms, respectively, after tachypacing with simvastatin therapy. Tachypacing downregulated L-type Ca2+-channel alpha-subunit expression (Western blot), an effect that was unaltered by antioxidant vitamins but greatly attenuated by simvastatin.


CONCLUSIONS
Simvastatin attenuates AF promotion by atrial tachycardia in dogs, an effect not shared by antioxidant vitamins, and constitutes a potentially interesting new pharmacological approach to preventing the consequences of atrial tachycardia remodeling.
Department of Medicine, Montreal Heart Institute and University of Montreal, Montreal, Quebec, Canada.
Akiko
A
Shiroshita-Takeshita
Gernot
G
Schram
Joel
J
Lavoie
Stanley
S
Nattel
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000627:therapeutic use*; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000209:etiology; D020746:Calcium Channels, L-Type / Q000096:biosynthesis / Q000235:genetics; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D007249:Inflammation; D018384:Oxidative Stress; D012032:Refractory Period, Electrophysiological / Q000187:drug effects; D019821:Simvastatin / Q000008:administration & dosage / Q000627:therapeutic use*; D014810:Vitamin E / Q000008:administration & dosage / Q000627:therapeutic use*
D000975:Antioxidants; D020746:Calcium Channels, L-Type; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C419385:L-type calcium channel alpha(1C); D014810:Vitamin E; D019821:Simvastatin; D001205:Ascorbic Acid