Differential activation of signal transduction pathways in human hearts with hypertrophy versus advanced heart failure

Background-Left ventricular failure is commonly preceded by a period of hyp ertrophy. Intriguingly, many of the signaling pathways that have been impli cated in the regulation of hypertrophy, including the 3 mitogen-activated p rotein kinases (MAPKs: extracellular signal-regulated kinase, stress-activa ted protein kinase, and p38), protein phosphatase, calcineurin, and the pro tein kinase Akt and its target glycogen synthase kinase-3 (GSK-3), also reg ulate the apoptotic response. Methods and Results-To understand the mechanisms that might regulate the pr ogression of heart failure, we analyzed the activity of these signaling pat hways in the hearts of patients with advanced heart failure, patients with compensated cardiac hypertrophy, and normal subjects. In patients with hype rtrophy, neither the MAPK nor the Akt/GSK-3 pathways were activated, and th e dominant signaling pathway was calcineurin. In failing hearts, calcineuri n activity was increased but less so than in the hypertrophied hearts, and all 3 MAPKs and Akt were activated (and, accordingly, GSK-3 beta was inhibi ted), irrespective of whether the underlying diagnosis was ischemic or idio pathic cardiomyopathy. Conclusions-In the failing heart, there is a clear prohypertrophic activity profile, likely occurring in response to increased systolic wall stress an d neurohormonal mediators. However, with the activation of these hypertroph ic pathways, potent proapoptotic and antiapoptotic signals may also be gene rated. Therapies directed at altering the balance of activity of these sign aling pathways could potentially alter the progression of heart failure.