RT Journal Article
SR Electronic
T1 PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 248187
DO 10.1101/248187
A1 Michael Lawless
A1 Jessica L. Caldwell
A1 Emma J. Radcliffe
A1 George W.P. Madders
A1 David C. Huthchings
A1 Lori S. Woods
A1 Stephanie J. Church
A1 Richard D. Unwin
A1 Graeme J. Kirkwood
A1 Lorenz K. Becker
A1 Charles M. Pearman
A1 Rebecca F. Taylor
A1 David A. Eisner
A1 Katharine M. Dibb
A1 Andrew. W Trafford
YR 2018
UL http://biorxiv.org/content/early/2018/01/17/248187.abstract
AB Heart failure is characterized by poor survival, a loss of catecholamine reserve and cellular structural remodeling in the form of disorganization and loss of the transverse tubule network. Indeed, survival rates for heart failure are worse than many common cancers and have not improved over time. Tadalafil is a clinically relevant drug that blocks phosphodiesterase 5 with high specificity and is used to treat erectile dysfunction. Using a sheep model of end-stage heart failure we show that tadalafil treatment results in a marked improvement in symptom-free survival, reverses transverse tubule loss and restores the hearts chronotropic and contractile response to catecholamines. We propose that the molecular switch for the loss of transverse tubules in heart failure and their restoration following tadalafil treatment involves the BAR domain protein Amphiphysin II (BIN1). Thus, the phosphodiesterase 5 inhibitor tadalafil dramatically improves symptom-free survival in heart failure and our findings are consistent with this being via restoration of lost catecholamine reserve.