Our main findings are that (i) chronic infusion of the non-selective β-adrenergic agonist ISO results in compensated cardiac hypertrophy with slightly improved cardiac function, (ii) ISO withdrawal stops transient catecholamine-induced adaptation and unmasks the chronic maladaptive features resulting in cardiac dysfunction, and (iii) the drop in cardiac function is associated with a strong reduction of PKA activity and the loss of cardioprotective HDAC4-NT production (Fig 7). The gene discussed is HDAC4; the disease is cardiac hypertrophy.