BACKGROUND: Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown. METHODS AND RESULTS: We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively, P<0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P<0.01). CONCLUSIONS: The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.