Not All Hypertrophy Is Created Equal

C ardiac hypertrophy is the natural response of myocardi- um to various stressors, including neurohormonal stimuli, hemodynamic overload, and injury. In the face of continued stress, pathological hypertrophy progresses to a loss of cardiomyocytes, the development of fibrosis, and, ultimately, heart failure. Emerging evidence has shown that glycogen synthase kinase-3 (GSK-3) is an important negative regulator of cardiomyocyte hypertrophy, yet inhibition of GSK-3 has been shown to reduce cell death after ischemia reperfusion. Therefore, it has been difficult to predict what the consequences of chronic inhibition of GSK-3 in the heart would be because it might be a balance between the potential for the aggravation of cardiac hypertrophy versus antiapoptotic effects. In this issue of Circulation Research, Hirotani and colleagues report that sustained inhibition of GSK-3 in postneonatal hearts results in well-compensated "physiologic" cardiac hypertrophy and, most intriguingly, exerts protective effects against the development of "pathological" hypertrophy and heart failure with pressure overload. 1 Although there are a number of concerns that need to be addressed before targeting GSK-3 for the treatment of heart failure, this "best of both worlds" outcome provides an interesting and favorable rationale for such intervention.