Oxidation of myofibrillar proteins causes contractile dysfunction in human heart failure

Background: Previous studies in microembolized pig hearts (Eur. Heart. J. 27, 875-881, 2006) demonstrated that augmented intracellular accumulation of reactive oxygen species causes oxidative modifications at the level of the contractile machinery. This study was aimed at investigating the role of myofibrillar protein (MP) oxidation\nitrosylation and the relationship between MP oxidation and contractile impairment in human failing myocardium (NYHA class IV). Methods and Results: As compared to samples from non-failing donor hearts (NF-group, n = 15), left ventricular biopsies from explanted failing hearts (NYHA class IV, HF-group, n = 33) displayed a 2.3 ± 0.29- and 2.6 ± 0.53-fold increase in actin and tropomyosin (Tm) carbonylation respectively, and a 2.2 ± 0.47-fold higher level of high-molecular-mass complexes of Tm due to disulphide cross-bridge formation. MP were also modified by reactive nitrogen species. The extent of S-nitrosylation was 1.3 ± 0.15-fold higher in the HF-group. Interesting, actin and Tm carbonylation along with Tm oxidation significantly correlated with both loss of viability (r2 = 0.646, P = 6.16E-12; r2 = 0.453, P = 1.58E-07; r2 = 0.221, P = 0.001, respectively), as indicated by plasma TnI levels and contractile impairment (r2 = 0.599, P = 6.88E-112; r2 = 0.457, P = 1.37E-07; r2 = 0.646, P = 6.16E-12, respectively), as shown by reduced left ventricular ejection fraction (LVEF). Conclusion: This study demonstrates that HF-related oxidative and nitrosative stresses induce covalent changes of MP and that these MP changes play a relevant role in contractile impairment as suggested by the inverse correlation between MP oxidation and LVEF.