title: Mitochondrial respiratory abnormalities in patients with end-stage congenital heart disease.
abstract: BACKGROUND
  Nitric oxide (NO) binds to mitochondrial cytochrome oxidase to decrease myocardial oxygen consumption (MVO(2)). This regulation is disrupted in heart failure (HF) due to reduced NO. The present objective was to evaluate NO-mediated regulation of mitochondrial respiration in the myocardium of patients with congenital heart disease (CHD) and cardiomyopathy (CMP).
  
  
  METHODS
  MVO(2) was measured in vitro in explanted human myocardium obtained at transplantation. Seven patients had CHD (5 cyanotic, 2 acyanotic), and 11 had non-ischemic CMP. The effects of the following on MVO(2) were measured: kinin-dependent endothelial NO synthase (eNOS) agonists, bradykinin, ramiprilat and amlodipine; NO donors, nitroglycerin and S-nitroso-N-acetylpenicillamine (SNAP) (10(-7) to 10(-4) mol/liter); and NOS inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME).
  
  
  RESULTS
  eNOS agonists caused a smaller decrease in MVO(2) in CHD compared with CMP patients. Changes in MVO(2) at the highest dose in CHD vs CMP were, respectively: bradykinin, -22 +/- 7% vs: -30 +/- 5% (p < 0.05); ramiprilat, -17 +/- 8% vs -26 +/- 2%, (p < 0.001); and amlodipine, -5 +/- 7% vs -29 +/- 6% (p < 0.001). L-NAME attenuated the effect of bradykinin, ramiprilat and amlodipine in both groups, confirming that the drug effect was secondary to eNOS activation. Nitroglycerin and SNAP also caused smaller decreases in MVO(2) in CHD vs CMP (NTG -16 +/- 6% vs -37 +/- 4%, SNAP -37 +/- 4% vs -49 +/- 3%, [p < 0.01]), suggesting altered mitochondrial function in CHD.
  
  
  CONCLUSIONS
  Abnormal regulation of MVO(2) in end-stage CMP may be secondary to reduced endogenous NO availability and can be reversed by the use of NO agonists. In end-stage CHD, this abnormality may be related in part to abnormal mitochondrial function.
authors.affiliation: Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York, USA. sm364@columbia.edu
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
authors.forename: Kit E
authors.initials: KE
authors.lastname: Loke
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Chen
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Mosca
authors.forename: Jan M
authors.initials: JM
authors.lastname: Quaegebeur
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Addonizio
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hintze
mesh_terms: D000293:Adolescent; D000328:Adult; D002311:Cardiomyopathy, Dilated / Q000151:congenital / Q000378:metabolism; D002648:Child; D046508:Culture Techniques; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006321:Heart / Q000187:drug effects; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000503:physiopathology*; D016027:Heart Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010101:Oxygen Consumption
chemical_list: D009569:Nitric Oxide; D003576:Electron Transport Complex IV