Abstract 20606: NADPH Oxidase 4-dependent Hydrogen Peroxide Production in Human Atrial Fibrillation: Relationship to Hypertension
Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia that is associated with increased risk of thromboembolism. Patients with AF often die of stroke caused by thrombi originated from left atrial appendage (LAA).
Hypothesis: LAA reactive oxygen species (ROS) production is increased in patients with AF.
Methods and Results: LAA ROS production was determined in patients undergoing cardiac transplant surgery. Among the total 35 patients recruited into the study (IRB approved at the U of Chicago and UCLA), 18 had AF and were older than those without (58.8±11.7 vs. 47.8±19.2, p=0.047). The gender distribution was not different. Systolic blood pressure (SBP) was not as well controlled in the AF patients (120.8±13.9 vs. 107.1±18.3 for AF vs. non-AF, p=0.033). ACEI was also less effective in SBP control in the AF patients (119.1±12.4 vs. 104.1.1±16.2, p=0.024). Whereas surprisingly we found that total superoxide production (detected quantitatively by electron spin resonance) from LAA was similar in patients with and without AF, hydrogen peroxide production was more than doubled in patients with AF (149.8±26.28 vs. 66.9±7.14 pmol/mg/min, p=0.0055), which correlated well with an intriguing upregulation in mRNA expression of NADPH oxidase 4 (NOX4). AF patients with co-existing hypertension had significantly higher hydrogen peroxide production compared to those without (239.0±125.1 vs. 83.6±51.3 pmol/mg/min, p=0.003). The mRNA expression of NOX1 and NOX2 however, were indifferent between the AF and non-AF groups. Superoxide production in the presence of the xanthine oxidase inhibitor Oxypurinol, or the eNOS inhibitor L-NAME, was indifferent between AF and non-AF groups.
Conclusions: Our data indicate that NOX4 is the primary oxidase responsible for the specific elevation in hydrogen peroxide production in patients with AF. Whereas AF makes SBP control more difficult, AF patients with co-existing hypertension have higher levels of hydrogen peroxide. These data represent the first evidence that NOX4-derived hydrogen peroxide may play an important role in the etiologies of AF and/or its thromboembolic complications.
- © 2010 by American Heart Association, Inc.