Abstract 15021: Energetic and Functional Abnormalities in Human Heart Failure are Associated with Increased Ventricular and Skeletal Muscle Mitochondrial Uncoupling Protein-3 Levels
Heart failure patients have decreased cardiac phosphocreatine/ATP (PCr/ATP) ratios and skeletal muscle PCr recovery rates, suggesting mitochondrial dysfunction, but the cause is unknown. Plasma non-esterified fatty acid (NEFA) concentrations increase in heart failure and regulate the transcription of mitochondrial uncoupling protein-3 (UCP3), a protein expressed in heart and skeletal muscle that uncouples oxidative phosphorylation and decreases mitochondrial efficiency. We hypothesised that increased UCP3 levels underlie the energetic abnormalities, thereby providing a unifying mechanism of mitochondrial dysfunction in heart failure.
Methods: Following ethical approval and informed consent, cardiac surgery patients underwent pre-operative cardiac and gastrocnemius 31P magnetic resonance spectroscopy, cardiac MRI, echocardiography (TTE) and gastrocnemius near-infrared spectroscopy. Intra-operatively, ventricular and skeletal muscle biopsies were obtained for immunoblotting. Correlation coefficients are Pearson's r (ratio data) and Spearman's rho (rS) (ordinal data).
Results: Forty seven patients (44 men and 3 women) were recruited. Subjects presented a mixture of systolic and diastolic impairment (ejection fraction (MRI) range 31-83%, E/E' (TTE) range 4-35). Plasma NEFAs correlated negatively with ejection fraction (r = -0.33, p < 0.05). Energetic abnormalities (cardiac PCr/ATP rS = -0.42, p < 0.05; skeletal muscle PCr recovery time constant rS = 0.28, p < 0.05) and ventricular (rS = 0.37, p < 0.05) and skeletal muscle (rS = 0.39, p < 0.01) UCP3 levels increased with heart failure severity. Tissue levels of UCP3 correlated negatively with cardiac PCr/ATP (r = -0.31, p < 0.05) and skeletal muscle PCr recovery rates (r = -0.33, p < 0.05), and correlated positively with skeletal muscle oxygen consumption during exercise (r = 0.33, p < 0.05).
Discussion: Uncoupling of heart and skeletal muscle mitochondrial oxidative phosphorylation via UCP3 in human heart failure may underlie the observed mitochondrial dysfunction and energetic abnormalities, which in turn may result in further contractile impairment.
- © 2011 by American Heart Association, Inc.