PDE5 inhibition improves symptom-free survival and restores transverse tubule loss and catecholamine responsiveness in heart failure

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.