Purpose: Many clinical trials have reported that right ventricular apical (RVA) pacing increases the risk of heart failure and atrial fibrillation, but the mechanism remains unknown. Using thallium 201 (Tl)/iodine 123-labeled beta-methyl iodophenyl pentadecanoic acid (BMIPP) single photon emission computed tomography (SPECT), we assessed the hypothesis that RVA pacing has a direct undesirable effect on myocardial metabolism. Methods: We reviewed the Tl/BMIPP SPECT studies that were performed more than one month after implantation of permanent pacemaker or implantable cardioverter defibrillator in our hospital. The ventricular pacing lead was located in right ventricular apex. Patients with ischemic heart disease, congenital heart disease and specific cardiomyopathy were excluded. All images were analyzed qualitatively in a blind manner. A positive finding was defined as reduced uptake on the BMIPP image compared with the Tl perfusion image. In quantitative analysis, a polar map was divided into 17 segments. Each segment was graded on a 5-point scale and mismatch score was calculated from the %uptake differences between the Tl and BMIPP. Results: Seventy one patients were included (mean age 65 years). Indications for device implantation were atrioventricular block (AVB) (n=31), sinus node dysfunction (SND) (n=22), both AVB and SND (n=1), ventricular tachyarrhythmia (n=10) and brady atrial fibrillation (n=2). Mean duration of pacing was 3369 days. Myocardial fatty acid metabolic dysfunction defined as a mismatch between Tl uptake and BMIPP uptake were detected in 39 patients mainly in inferior and apical segments. On multivariate analysis, percent ventricular beats that were paced (%VP) was identified as only independent factor for Tl/BMIPP mismatch, however, duration of pacing and pacing threshold were not. Cutoff value of %VP was determined (40%) by ROC analysis. Conclusions: RVA pacing leads to regional myocardial metabolic dysfunction, which may be the main cause of unfavorable clinical outcomes associated with RVA pacing.