TNFα in myocardial ischemia/reperfusion, remodeling and heart failure

TNF alpha is crucially involved in the pathogenesis and progression of myocardial ischemia/reperfusion injury and heart failure. The formation and release of TNF alpha and its downstream signal transduction cascade following activation of its two receptor subtypes are characterized. Myocardial TNF alpha and TNF receptor activation have an ambivalent role in myocardial ischemia/reperfusion injury and protection from it. Excessive TNF alpha expression and subsequent cardiomyocyte TNF receptor type 1 stimulation induce contractile dysfunction, hypertrophy, fibrosis and cell death, while a lower TNF alpha concentration and subsequent cardiomyocyte TNF receptor type 2 stimulation are protective. Apart from its concentration and receptor subtype, the myocardial action of TNF alpha depends on the duration of its exposure and its localization. While detrimental during sustained ischemia, TNF alpha contributes to ischemic preconditioning protection, no matter whether it is the first, second or third window of protection, and both TNF receptors are involved in the protective signal transduction cascade. Finally, the available clinical attempts to antagonize TNF alpha in cardiovascular disease, notably heart failure, are critically discussed.