Abstract 3496: Time-Dependent and Regional Differences in Myocardial Nitric Oxide-Redox State in Atrial Fibrillation
Human atrial fibrillation (AF) is associated with myocardial oxidative damage and increased atrial NADPH oxidase activity. However, it is unclear whether these findings are early events in AF or a consequence of AF-induced remodeling. We evaluated the time-course and sources of superoxide (O2−) production in the right (RA) and left (LA) atria of a goat model of pacing-induced AF. 14 days after the onset of AF, LA O2− release (by lucigenin-enhanced chemiluminescence -and HPLC 2-OH ethidium) was increased (Fig.1⇓). Inhibition of NADPH oxidases normalized O2 production in LA-AF but had no effect in RA (Fig.2⇓) or in sinus rhythm (SR). Atrial NO synthesis (HPLC) and nNOS protein levels were reduced (by 62±27% and 66±31%, respectively, P<0.05), but BH4 levels (HPLC) and arginase activity remained unchanged. After 6 months of AF, O2− release was enhanced in both atria (Fig 1⇓). NADPH oxidase inhibition did not affect O2 production, whereas inhibition of NOS or mitochondrial oxidases decreased O2− by 31±5% and 55±16%, respectively (Fig 2⇓). Arginase activity was increased whereas BH4 levels, NO synthesis, eNOS and nNOS protein were reduced (eNOS: 24±11%, nNOS: 89±3%). Mitochondrial SOD was decreased in both atria, other antioxidant proteins remained unchanged. An increase in LA NADPH oxidase activity and a reduction in nNOS expression are early events in AF. In contrast, mitochondrial oxidases and uncoupled NOS account for the increased O2− production in late AF. These changes may play an important role in AF-induced myocardial remodeling by altering [Ca2+]i handling and promoting interstitial fibrosis.