Background: Increased circulating leptin is present in human heart failure, and leptin deficiency is linked to worse outcomes in chronic ischemic injury. In the present observational study, we tested the hypothesis that cardiac leptin production and signaling are increased in the failing human heart, and that mechanical unloading with a ventricular assist device (VAD) reverses these changes.
Methods and results: All studies were performed using human cardiac tissue obtained from (1) hearts not matched for transplantation (nonfailing), (2) at the time of cardiac transplant (failing), or (3) paired samples at the time of VAD implant (pre-VAD) and removal (post-VAD). The expression of brain naturetic peptide, leptin, leptin receptor, and tumor necrosis factor alpha mRNA was measured, and the protein expression of leptin and its receptor was examined by Western blot and immunofluorescent staining of cardiac sections. The assessment of leptin signaling was performed by measuring the phosphorylation state of the leptin receptor. The phosphorylation state of signal transducer and activator of transcription-3 and AMP-activated kinase proteins were also measured. All data are expressed as mean+/-SEM with a statistical significance in failing relative to nonfailing groups determined by Student independent t test, and the significance between pre- and post-VAD groups determined by paired t test. In failing human hearts, the mRNA expressions of leptin and its receptor were increased 5.4+/-0.3-fold (P<0.05) and 4.5+/-0.3-fold (P<0.05), respectively, with similar changes in protein. The phosphorylation state of both the leptin receptor and signal transducer and activator of transcription-3 proteins were increased 1.4+/-0.1-fold (P<0.05), and the level of phosphorylated AMP-activated kinase protein was increased 1.9+/-0.2-fold (P<0.05). Mechanical unloading of the failing human heart with a VAD resulted in no change in tumor necrosis factor alpha expression but a marked decrease in leptin production to 1.7+/-0.1% (P<0.05) and leptin receptor expression to 3.0+/-0.2% (P<0.05) of pre-VAD levels. Phosphorylation of the leptin receptor, signal transducer and activator of transcription-3, and AMP-activated kinase were also decreased to 45+/-7%, 75+/-8%, and 58+/-8% of pre-VAD values, respectively (P<0.05 for all values).
Conclusions: These results indicate that the failing human heart increases expression of leptin and its receptor and that mechanical unloading downregulates this increase. Further, a cardioprotective role for leptin in the failing human heart is suggested through the activation of signal transducer and activator of transcription-3 and AMP-activated kinase signaling.