FIG. 12.
Progression of heart failure and the role of oxidative stress and peroxynitrite. The mechanisms leading to heart failure are of multiple origins and include acute and chronic ischemic heart disease, cardiomyopathies, myocarditis, and pressure overload just to mention a few. These diseases result in mismatch between the load applied to the heart and the energy needed for contraction, leading to mechanoenergic uncoupling. After initial insult, secondary mediators such as angiotensin II (AII), norepinephrine (NE), endothelin (ET), proinflammatory cytokines [e.g., tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6), in concert with oxidative stress and peroxynitrite, activate downstream effectors (e.g., PARP-1 or MMPs)], act directly on the myocardium or indirectly via changes in hemodynamic loading conditions to cause endothelial and myocardial dysfunction, cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation, and myocardial necrosis, leading eventually to heart failure. The adverse remodeling and increased peripheral resistance further aggravate heart failure. MMPs, matrix metalloproteinases; PARP-1, poly(ADP-ribose) polymerase. [Derived from Pacher et al. (995) with permission from Elsevier.]