Abstract 17911: Mitochondrial Dysfunction in Heart Failure is Due to Reduced Complex Iii Activity and Can Be Reverted by Pharmacological Electron Chain Bypass
Background: Altered mitochondrial respiration has been involved in the pathophysiology of advanced heart failure although its molecular mechanisms and potential pharmacological treatments are not established.
Methods and results: Human mitochondria were isolated from the right atrial appendage from 95 patients undergoing cardiac surgery with cardiopulmonary bypass, 53 of them with heart failure (HF, NYHA functional class>1). HF was not associated with reduced mitochondrial yield, but was associated with a depressed mitochondrial ADP-stimulated O2 consumption (oxymetry) through all complexes, and with less citrate synthase (CS) activity (1.4±0.1 vs 1.7±0.1, p<0.01). Multivariate analysis including, age, sex, type of surgery and cardiovascular risk factors identified HF as independent predictor of CS activity. In a subset of 20 patients, analysis of the in vitro activity of each of the respiratory complexes (spectrometry) demonstrated a marked and selective reduction in compex III activity in patients with HF (n=10, 2.9±0.5 vs 7.4±1 nmol Cyt C/min*g, p<0.01). Pharmacological induction of alternative electron transfer from complex 1 to cytochrome c using 1 μg/mL methylen blue, bypassing complex III, significantly increased mitochondrial ADP-stimulated O2 consumption in patients with HF (from 78.7±9.4 to 89.9±9.7, p<0.01, paired t test).
Conclusions: These results demonstrate that 1) altered complex III activity contributes to mitochondrial dysfunction in patients with HF, even of moderate degree; 2) this alteration cannot be explained by loss of cytochrome c; and 3) respiratory chain bypass strategies could be useful to attenuate mitochondrial dysfunction in patients with heart failure.
- © 2013 by American Heart Association, Inc.