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A2445 - Leptin and Leptin Receptor in PAH and the Right Ventricle
Author Block: M. Talati1, A. Trammell2, E. Brittain3, N. Fortune1, Y. Su4, J. D. West1, A. Hemnes1; 1Division of Allergy Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States, 2Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, Atlanta, GA, United States, 3Vanderbilt University, Nashville, TN, United States, 4Cardiovascular Medicine, Vanderbilt University, Nashville, TN, United States.
Background: Pulmonary arterial hypertension (PAH) is a fatal cardio-pulmonary disease, which causes right ventricular (RV) dysfunction and failure. Leptin, a neuroendocrine hormone released by adipose tissue has a complex relationship with cardiovascular diseases including PAH. Leptin is thought to be an important factor linking obesity, the metabolic syndrome, and cardiovascular disorders. Given the published link between insulin resistance, PAH and RV dysfunction, we sought to determine if there is an association between leptin and RV dysfunction in PAH. We hypothesized that in PAH, leptin can influence metabolic changes via leptin receptors. Methods: Oral glucose tolerance testing was done on 9 PAH patients (4 female, 5 male) at Vanderbilt University Hospital (VUH)(IRB#130712). Immunohistochemical analysis was performed in RV tissue from donors and PAH patients at VUH (IRB#130712) and transgenic mouse model of PAH with RV failure before and after metformin treatment using leptin receptor antibody (GTX37636). Results: The average BMI for the PAH patients was 29.39+2.78. Baseline plasma leptin levels in 7/ 9 patients were higher than normal levels. Leptin levels were higher in females (45.97+15.41 ng/ml) than males (12.69+7.5 ng/ml) (p=0.004). Following oral glucose challenge, leptin levels significantly decreased (p=0.01) but remained higher than the normal levels (Females- 40.49 +15.03, Males-11.65+6.8). The TG/HDL-c ratio, which is surrogate for insulin resistance was higher (4.1+1.12) compared to normal levels (females - 4.78+1.26, males - 3.55+0.7). By immunofluorescence we demonstrated the presence of leptin receptors in human RV. In control RV cardiomyocytes, the leptin receptor was predominantly localized to cytoplasm whereas in PAH RV cardiomyocytes leptin receptor was present both on the plasma membrane and in the cytoplasm. As metformin is known to improve insulin sensitivity, we quantitated the expression and localization of leptin receptors in RV cardiomyocytes from transgenic mouse model of PAH with RV failure following metformin treatment. At baseline, RV tissue from transgenic mice demonstrated 50% increase (p=0.0004) in the immunostaining for leptin receptor with a striking localization to the plasma membrane compared to controls. Metformin treatment significantly reduced immunostaining for leptin receptors in transgenic mice (p=0.0002) but did not change leptin receptor immunostaining in controls. Conclusions: Taken together, our results suggest that PAH patients may have higher levels of plasma leptin, leptin receptors are enriched in human and rodent PAH RVs and that metformin may improve cardiomyocyte leptin expression. These pilot studies requires further investigation to understand the role of leptin and its receptor in PAH RV cardiomyocytes.