In the course of daily life, the heart reacts to alterations in workload demand with changes in contractility and beating rate; over time, robust changes in ventricular volume and mass take place.1 In the context of organism development, athleticism, or pregnancy, the cardiac growth response is normal and adaptive. In the context of pathological triggers, however, cardiac remodeling is ultimately maladaptive and a discrete milestone in disease pathogenesis. The end result is heart failure, a syndrome with ≈50% 5-year mortality, rivaling the most lethal cancers. Article see p 2392 Plasticity of any tissue entails the complex interplay of protein synthesis, degradation, and posttranslational modification. In general, both anabolic and catabolic pathways are activated, and intricate cascades of protein modifications and protein degradation are triggered. The importance of reversible protein acetylation, a dynamic regulator of function that rivals protein phosphorylation in terms of ubiquity and importance, has come to the fore. Acetylation-dependent regulatory circuits are robust, operating in concert with pathways controlled by other posttranslational modifications to govern homeostasis and stress responsiveness. In the case of histones, acetylation of the e-NH 2 group of lysine residue side chains leads to relaxation of chromatin structure, enhanced accessibility to DNA-binding proteins, and consequent activation of transcription. Protein acetylation is regulated by histone acetyltransferases and histone deacetylases (HDACs). These HDACs, in turn, are categorized into 4 classes. Class I HDACs (1, 2, 3, 8) are expressed ubiquitously, and consist mainly of a deacetylase domain that catalyzes hydrolytic release of the acetyl group. Members of class IIa (4, 5, 7, 9) and class IIb (6, 10) are highly expressed in cardiac and skeletal muscle and brain. In addition to a highly conserved catalytic domain, these HDACs have an extended N terminus that facilitates interaction with the transcription factor, MEF2. Class III HDACs, the mammalian …