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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.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/248187 doi: bioRxiv preprint first posted online 3 Impaired responsiveness to catecholamines is a hallmark of the failing heart and is detectable both in vivo and in isolated ventricular myocytes 1, 2 . The mechanisms responsible for the attenuated catecholamine effects in heart failure (HF) are varied and include reduced adenylate cyclase activity and enhanced G protein receptor kinase and intracellular phosphatase activity which together lead to a decrease in cAMP dependent signaling and impaired PKA-dependent target phosphorylation 1,3,4 . Given the functional distribution of β-adrenergic receptors (β-ARs) and G-proteins across the surface sarcolemma and transverse tubule (TT) membrane 5, 6, 7 a further factor contributing to impairment of the β-adrenergic signalling cascade in HF is the reduction of transverse tubule (TT) density seen in many pre-clinical models and human HF 8,9,10,11 .In addition to the classical cAMP-dependent process, the myocardial response to catecholamine stimulation is also regulated by the cGMP-PKG signaling axis consisting of the β3-AR / soluble guanylate cyclase (sGC) and natriuretic peptide / particulate guanylate cyclase (pGC) pathways (reviewed by Tsai & Kass, 2009). The outcome of cGMP dependent activation depends on the source of activating cGMP; that activated by sGC inhibiting the β-AR response whereas pGC derived cGMP has no effect 13,14 .Furthermore, the cGMP pools are differentially regulated by PKG and PDEs suggesting highly compartmentalized regulation of cGMP and PDE5 localisation within the healthy ventricular myocardium 15,16 .Given the negative impact of acute PDE5 inhibition on the inotropic and lusitropic response to catecholamines and the established loss of catecholamine reserve in HF it is somewhat surprising ...