The myocardium has limited options for responding to an injury sufficient to cause decreased global contractile function. Myocardial pump performance can be quickly stabilized by increased adrenergic drive, which through ß-adrenergic mechanisms increases cardiac output via positive chronotropic and inotropic effects. In a kinetic sense, the next available option for stabilizing pump function is the Frank-Starling mechanism, whereby volume expansion places the ventricles at a higher position in the preload-performance relationship. The renin-angiotensin and ß-adrenergic systems appear to exert most of the signaling in this regard. The third and slowest-to-develop option is to create more contractile elements through a hypertrophic response involving new synthesis of sarcomeres in individual cardiac myocytes. The first two compensatory adjustments are very powerful in humans and have probably evolved as protective responses to trauma and blood loss. The hypertrophic response may also be considered in this context but in more of a wound-healing paradigm that incorporates features of a generalized inflammatory response. As such, a host of proinflammatory cytokines have been shown to be increased systemically or in the myocardium of subjects with heart failure. The first of these was tumor necrosis factor-α (TNF-α), 1 a 17-kD protein that acts through two distinct receptors, TNFR1 and TNFR2. TNF-α produces a series of powerful biological effects that include immunostimulation, mediation of host resistance to bacteria, activation of protein kinase C, and activation of the expression of a wide variety of genes generally involved in inflammation or cell growth. 2 In an acute or subacute setting, most of these biological effects of TNF-α are helpful in combating infection or responding to injury.