Abstract 17079: Tetrahydrobiopterin (NOS Cofactor) Treatment Improves Atrial Electrophysiology in Chronic Heart Failure.
Heart failure (HF) is a common antecedent to atrial fibrillation (AF). Atrial oxidative stress is known to contribute to the substrate for AF. We examined whether manipulating NOS activity by administration of NOS substrate (Arginine-ARG) and cofactor (tetrahydrobiopterin, BH4) altered HF-induced abnormalities in atrial electrophysiology.
Methods: We used a 4 month model of tachypacing induced canine HF (n=12) to evaluate NOS (NOS) function in the left atrium, relative to a matched ARG-BH4 treated HF group (n=9, 6 week treatment), and a control group. Left atrial appendage myocytes were studied using perforated patch whole cell techniques to elicit action potentials (T=36 ± 0.5°C).
Results: Final LV fractional shortening was 37 ± 0.8% in controls, 15.0 ± 1.9% in HF, and 17.7 ± 1.7% in ARG-BH4 treated HF. HF reduced atrial [BH4] (p<0.05) while atrial [ARG] was unchanged. ARG-BH4 treatment, reduced inducibility of atrial fibrillation (p<0.05) and increased atrial effective refractory period (p<0.05). Treatment with ARG-BH4 restored atrial [BH4] (p<0.05), while [ARG] was unchanged, and improved atrial NOS coupling as indicated by increased atrial [BH4], increased NO and reduced O2•−. EPR spectroscopy indicated that ARG-BH4 reduced HF-induced atrial oxidative stress (p<0.05). Atrial action potentials in the HF group were shorter and triangulated compared to controls (p<0.05). Treatment with ARG-BH4 resulted in normalization of the APD at both 50% and 90% repolarization (see figure; 1 Hz). No adverse events were detected with ARG-BH4 treatment.
Conclusion: These data suggest that modulation of atrial [BH4] and NOS activity may be antiarrhythmic during chronic heart failure.
- © 2010 by American Heart Association, Inc.