Complexity of signaling in heart failure. Following an insult (e.g., a myocardial infarction), there are many changes in cellular and molecular signals and structure that occur as a primary consequence of that disturbance. Each of the signals and structural changes generated by the sequelae of the insult has many targets, including some earlier in the cascade. These changes in signaling and structure continue to propagate through secondary and later pathways. It is thus possible for therapeutic benefit to arise from interrupting (or augmenting) one of the pathways in the cascade, but it is equally possible for that same change to produce deleterious effects. The left red arrow represents the initial insult. The right red arrow represents a therapeutic intervention The X indicates that the therapeutic intervention may be a functional knockout or an augmentation of the function. Given the complexity of the pathways, the upstream and downstream sense of signaling may not be clear.