Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology
Open Access
- 1 April 2011
- journal article
- research article
- Published by Oxford University Press (OUP) in Cardiovascular Research
- Vol. 91 (1), 71-79
- https://doi.org/10.1093/cvr/cvr087
Abstract
Heart failure is a common antecedent to atrial fibrillation; both heart failure and atrial fibrillation are associated with increased myocardial oxidative stress. Chronic canine heart failure reduces atrial action potential duration and atrial refractoriness. We hypothesized that inducible nitric oxide synthase 2 (NOS2) contributes to atrial oxidative stress and electrophysiologic alterations. A 16-week canine tachypacing model of heart failure was used (n= 21). At 10 weeks, dogs were randomized to either placebo (n = 12) or active treatment (n = 9) with NOS cofactor, tetrahydrobiopterin (BH4, 50 mg), and NOS substrate (l-arginine, 3 g) twice daily for 6 weeks. A group of matched controls (n = 7) was used for comparison. Heart failure increased atrial NOS2 and reduced atrial BH4, while l-arginine was unchanged. Treatment reduced inducible atrial fibrillation and normalized the heart failure-induced shortening of the left atrial myocyte action potential duration. Treatment increased atrial [BH4] while [l-arginine] was unchanged. Treatment did not improve left ventricular function or dimensions. Heart failure-induced reductions in atrial [BH4] resulted in NOS uncoupling, as measured by NO and superoxide anion (O2·−) production, while BH4 and l-arginine treatment normalized NO and O2·−. Heart failure resulted in left atrial oxidative stress, which was attenuated by BH4 and l-arginine treatment. Chronic non-ischaemic heart failure results in atrial oxidative stress and electrophysiologic abnormalities by depletion of BH4 and uncoupling of NOS2. Modulation of NOS2 activity by repletion of BH4 may be a safe and effective approach to reduce the frequency of atrial arrhythmias during heart failure.This publication has 56 references indexed in Scilit:
- P Wave Duration and Risk of Longitudinal Atrial Fibrillation in Persons ≥60 Years Old (from the Framingham Heart Study)The American Journal of Cardiology, 2011
- Duration of heart failure and the risk of atrial fibrillation: different mechanisms at different times?Cardiovascular Research, 2009
- Chronic heart failure and the substrate for atrial fibrillationCardiovascular Research, 2009
- Atrial cellular electrophysiological changes in patients with ventricular dysfunction may predispose to AFHeart Rhythm, 2009
- MicroRNAs: Target Recognition and Regulatory FunctionsCell, 2009
- Reversal of Cardiac Hypertrophy and Fibrosis From Pressure Overload by TetrahydrobiopterinCirculation, 2008
- Myocardial ischemia results in tetrahydrobiopterin (BH 4 ) oxidation with impaired endothelial function ameliorated by BH 4Proceedings of the National Academy of Sciences of the United States of America, 2007
- Cardioprotection by Sulfaphenazole, a Cytochrome P450 Inhibitor: Mitigation of Ischemia-Reperfusion Injury by Scavenging of Reactive Oxygen SpeciesThe Journal of pharmacology and experimental therapeutics, 2007
- Oxidative Stress Markers Are Associated with Persistent Atrial FibrillationClinical Chemistry, 2007
- n-3 (omega-3) polyunsaturated fatty acids prevent acute atrial electrophysiological remodelingBritish Journal of Pharmacology, 2007