Tetrahydrobiopterin depletion and NOS2 uncoupling contribute to heart failure-induced alterations in atrial electrophysiology

Yoshinori Nishijima, Arun Sridhar, Ingrid Bonilla, Murugesan Velayutham, Mahmood Khan, Radmila Terentyeva, Chun Li, Periannan Kuppusamy, Terry S. Elton, Dmitry Terentyev, Sandor Gyröke, Jay L. Zweier, Arturo J. Cardounel, Cynthia A. Carnes

Research output: Contribution to journalArticlepeer-review

57 Scopus citations


AimsHeart 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.Methods and resultsA 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.ConclusionChronic 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.

Original languageEnglish (US)
Pages (from-to)71-79
Number of pages9
JournalCardiovascular Research
Issue number1
StatePublished - Jul 1 2011
Externally publishedYes


  • Arrhythmia mechanisms
  • Heart failure
  • Nitric oxide
  • Oxygen radicals

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)
  • Physiology


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