Hypertrophic preconditioning: short-term tricks for long-term gain.

N early 3 decades ago, this journal reported the seminal discovery by Murry et al 1 of ischemic precondition-ing, a phenomenon in which several episodes of brief isch-emia followed by reperfusion protected cardiac muscle cells from a subsequent prolonged ischemic insult. Since then, a similar protective effect of ischemic preconditioning has been observed in many organs, including brain, liver, and kidney, supporting the notion that ischemic preconditioning is a fundamental property shared by different cell types. Given the obvious clinical implications, intense research efforts have been devoted to dissecting the mechanisms and identifying the putative mediators underlying the short-term or long-term cardioprotective effects induced by preconditioning. 2 Different forms of nonischemic preconditioning have been demonstrated in the heart, including mechanical stretch, heat stress, metabolic challenge, and pharmacological agents. 3,4 The cardioprotective effects have also been extended beyond myocyte viability to pathological hypertrophy and remodel-ing. However, the vast majority of studies investigating preconditioning have focused on the protective effects of ischemic preconditioning against subsequent ischemia/reper-fusion injury–induced myocyte death. In contrast, other non-ischemic types of preconditioning have received relatively little attention, 7 and whether the principles of precondition-ing can be applied to other pathological cardiac states remains unexplored and nonischemic preconditioning remains a vastly underexplored area in cardiac biology. A report in this issue of Circulation by Wei et al 8 proves a bold hypothesis that, similar to mechanisms of ischemic preconditioning, transient hypertrophic stimulation to the heart would make the heart more resistant to the development of pathological hypertrophy against sustained hypertrophic stress. In this body of work, Wei et al, in elegant experiments, provide proof of concept of hypertrophic preconditioning as a mechanism to decrease pathological hypertrophy in the presence of sustained hypertrophic stimuli. 8 Both in vitro and in vivo systems were used in the study. In vitro, pretreatment of cultured cardiomyocytes with norepinephrine for 12 hours followed by 12 hours of withdrawal resulted in a significant reduction in the subsequent hypertrophic responses at both the morphological and molecular levels with decreased expression of fetal myocyte genes such as β-myosin heavy chain and atrial natriuretic peptide. In vivo, the authors first used 2 cycles (1 and 2 days) of mini-pump–mediated phenylephrine administration before a final 4-day phenylephrine treatment. Comparing this group with the simple 4-day treatment group, they observed a significant attenuation in cardiac hypertrophy by phenylephrine pretreatment, although in this model cardiac fibrosis was not significantly reduced. Next, …