Mitochondrial respiratory abnormalities in patients with end-stage congenital heart disease

Nitric oxide (NO) binds to mitochondrial cytochrome oxidase to decrease myocardial oxygen consumption (M vo 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). M vo 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 M vo 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 ω-nitro- l-arginine methylester ( l-NAME). eNOS agonists caused a smaller decrease in M vo 2 in CHD compared with CMP patients. Changes in M vo 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 M vo 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. Abnormal regulation of M vo 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.