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Abstract #1332

Assessment of Cardiac Function and Pulmonary Edema by MRI Following Pharmacological TRPV4 Channel Blockade in a Murine Heart Failure Model

Hasan Alsaid1, Stephen C. Lenhard2, Weike Bao2, Mary V. Rambo, Alan R. Olzinski2, Gregory A. Logan3, Mark E. Burgert4, James R. Tunstead5, Hilary S. Eidam2, Krista B. Goodman2, Mui Cheung2, Robert N. Willette2, Kevin S. Thorneloe2, Beat M. Jucker2

1Preclinical & Translational Imaging, GlaxoSmithKline, King of Prussia, PA, United States; 2Heart Failure DPU, Metabolic Pathways and Cardiovascular Therapy Area Unit; 3Respiratory Therapy Area Unit; 4Discovery Analytics; 5Platform Technology & Science

Activation of TRPV4 increases lung permeability, leading to the formation of lung edema. GSK2193874A is a novel TRPV4 channel blocker that inhibits TRPV4 Ca2+ flux (in-vitro, IC50 =2nM). In this study, we tested whether GSK2193874A could prevent and/or reverse pulmonary edema and improve pulmonary function assessed by 1H-MRI in a murine heart failure model. MRI results revealed GSK2193874A significantly reduced lung water signal intensity, lung volume and edema. However, no effect was observed on cardiac function and remodeling. These results suggest MRI may be used to assess the therapeutic benefit of TRPV4 channel blockade on pulmonary edema in heart failure.