Heart Online First, published on March 8, 2018 as 10.1136/heartjnl-2017-312865 Review Phosphodiesterase-5 inhibitors and the heart: Heart: first published as 10.1136/heartjnl-2017-312865 on 8 March 2018. Downloaded from compound cardioprotection? David Charles Hutchings, Simon George Anderson, Jessica L Caldwell, Andrew W Trafford Unit of Cardiac Physiology, ABSTRACT recently reported that PDE5i use in patients with Division of Cardiovascular Novel cardioprotective agents are needed in both type 2 diabetes (T2DM) and high cardiovascular Sciences, School of Medical risk was associated with reduced mortality.6 The Sciences, Faculty of Biology, heart failure (HF) and myocardial infarction. Increasing Medicine and Health, The evidence from cellular studies and animal models effect was stronger in patients with prior MI and University of Manchester, indicate protective effects of phosphodiesterase-5 was associated with reduced incidence of new MI, Manchester Academic Health (PDE5) inhibitors, drugs usually reserved as treatments of raising the possibility that PDE5is could prevent Science Centre, Manchester, UK erectile dysfunction and pulmonary arterial hypertension. both complications post-MI and future cardio- PDE5 inhibitors have been shown to improve vascular events. Subsequent similar findings were Correspondence to observed in a post-MI cohort showing PDE5i use Dr David Charles Hutchings, contractile function in systolic HF, regress left ventricular Institute of Cardiovascular hypertrophy, reduce myocardial infarct size and suppress was accompanied with reduced mortality and HF 7 Sciences, The University of ischaemia-induced ventricular arrhythmias. Underpinning hospitalisation. Potential for confounding in these Manchester, Manchester, M13 these actions are complex but increasingly understood observational studies is high, however, and data 9NT, UK; david. hutchings- 2@ were not collected on partner status or activity manchester. ac. uk cellular mechanisms involving the cyclic GMP activation of protein kinase-G in both cardiac myocytes and the levels, both of which link to greater life expec- Received 14 December 2017 vasculature. In clinical trials, PDE5 inhibitors improve tancy. Nevertheless, growing evidence from animal Revised 8 February 2018 symptoms and ventricular function in systolic HF, and models support a cardioprotective action of PDE5is, Accepted 12 February 2018 accumulating epidemiological data indicate a reduction including improving contractile function in HF with 8 9 in cardiovascular events and mortality in PDE5 inhibitor reduced ejection fraction (HFrEF), regressing 4 users at high cardiovascular risk. Here, we focus on the left ventricular hypertrophy (LVH), reducing 10 11 translation of underpinning basic science to clinical infarct size in myocardial infarction (MI) and 12 studies and report that PDE5 inhibitors act through a suppressing ventricular arrhythmias (VAs). number of cardioprotective mechanisms, including a PDE5is have consistently improved patient exer- cise capacity and ventricular function in trials of direct myocardial action independent of the vasculature. 13–16 We conclude that future clinical trials should be designed HFrEF ; yet, outcomes in HF with preserved ejection fraction (HFpEF) have been mixed with with these mechanisms in mind to identify patient http://heart.bmj.com/ the largest study to date failing to demonstrate subsets that derive greatest treatment benefit from these 17 18 novel cardioprotective agents. clinical benefit. Two factors may underlie these discrepant findings. First, PDE5is exerted an effect on left ventricular (LV) remodelling in HFrEF INTRODUCTION which was not observed in HFpEF, and second, Progression of heart failure (HF) is driven in part PDE5is acutely reduce contractile function at both by maladaptive responses of cardiac muscle to 1 cellular and in vivo levels, which may further limit pathological stress. There is growing evidence 19 their use in HFpEF. Thus, it is likely that PDE5is on September 30, 2021 by guest. Protected copyright. that stimulation of a signalling pathway within have differing efficacy according to HF subtype cardiac myocytes, the cyclic GMP (cGMP)–protein (HFrEF vs HFpEF). kinase-G (PKG) axis, dampens these cardiac stress Although there is additional interest in PDE5is responses, and its activation can attenuate patho- in treatment of congenital heart disease, chemo- logical hypertrophy, protect against ischaemic therapy cardiotoxicity and hypertension, here we injury and enhance cell survival.2 One means of outline evidence behind PDE5i cardioprotection in potentiating cGMP–PKG is by inhibiting the degra- HFrEF, HFpEF and MI. In particular, we highlight dation of cytosolic cGMP by phosphodiesterase-5 the direct myocardial actions of these novel cardi- (PDE5, figure 1). PDE5 inhibitors (PDE5is) such as oprotective agents, with a focus on translation of sildenafil (Viagra), tadalafil (Cialis) and vardenafil cellular mechanisms to clinical actions. (Levitra) have proven efficacy in treating erectile dysfunction and pulmonary arterial hypertension 3 (PAH). Underlying their utility in both conditions BaSIC MYOCARDIAL ACTIONS OF PDE5IS is a well-defined action on the vasculature through To understand the effects of PDE5is on cardiac enhancement of cGMP derived from nitric oxide function, we must first address the processes linking (NO), leading to relaxation of vascular smooth excitation of the surface membrane (the action muscle and vasodilatation. With discovery that potential) to mechanical contraction of the cardiac To cite: Hutchings DC, PDE5 is also expressed in cardiac muscle and upreg- myocyte, termed ‘excitation–contraction coupling’ Anderson SG, Caldwell JL, 4 20 et al. Heart Epub ahead of ulated in hypertrophy and failure, attention has (figure 1B). Briefly, depolarisation of the cell print: [please include Day shifted towards direct myocardial effects of PDE5is. membrane during the action potential opens volt- Month Year]. doi:10.1136/ PDE5is have proven safety profiles with low age-gated Ca channels, causing the influx of a small heartjnl-2017-312865 5 2+ incidence of adverse cardiovascular events. We quantity of Ca into the cell (ICa-L). This triggers a Hutchings DC, et al. Heart 2018;0:1–7. doi:10.1136/heartjnl-2017-312865 1 Copyright Article author (or their employer) 2018. Produced by BMJ Publishing Group Ltd (& BCS) under licence. Review Heart: first published as 10.1136/heartjnl-2017-312865 on 8 March 2018. Downloaded from http://heart.bmj.com/ on September 30, 2021 by guest. Protected copyright. Figure 1 Cyclic nucleotide signalling in cardiac myocytes and its relation to contraction and arrhythmias. (A) Competing effects of cyclic GMP (cGMP) and cyclic AMP (cAMP) within the cardiac myocyte. Sildenafil (left side) inhibits phosphodiesterase-5 (PDE5) leading to the accumulation of cGMP within the cell. cGMP activates protein kinase-G (PKG) resulting in phosphorylation of the L-type Ca2+ channel and cardiac troponin I (cTnI). These effects are negatively inotropic. cAMP (right), for example, following stimulation of β1-adrenoceptors and β2-adrenoceptors by epinephrine, activates PKA leading to positive inotropic and proarrhythmic actions. In addition, there is also potential for crosstalk between the two axes; cGMP can inhibit phosphodiesterase-3 (PDE3) to increase cAMP. (B) Excitation–contraction coupling in the cardiac myocyte. Opening of L-type Ca channels (LTCC) during the action potential lead to influx of Ca and stimulation of Ca release from the sarcoplasmic reticulum (SR), initiating myofilament contraction. (C) Overload of the SR, as occurs in HF and under β1-adrenergic and β2-adrenergic stimulation, leads to spontaneous Ca waves, which activate Na+–Ca2+ exchanger (NCX) channels to cause after depolarisations and triggered arrhythmias. larger release of Ca from its intracellular store, the sarcoplasmic size of triggering ICa-L or (2) changing SR Ca content. The latter reticulum (SR), giving rise to an increase in cytosolic Ca termed is determined largely by rate of Ca uptake via the sarcoplas- the ‘Ca transient’, which activates myofilament proteins and mic-endoplasmic reticulum Ca ATPase pump (SERCA). While elicits contraction. Ca transient amplitude is a major determi- cellular Ca is tightly controlled in healthy myocytes via elegant nant of cardiac inotropy and can be modified by (1) changing the feedback mechanisms,20 in disease (eg, HF) the SR can become 2 Hutchings DC, et al. Heart 2018;0:1–7. doi:10.1136/heartjnl-2017-312865 Review Heart: first published as 10.1136/heartjnl-2017-312865 on 8 March 2018. Downloaded from Figure 2 Competing effects of the cyclic GMP–protein kinase G (PKG) and cyclic AMP–protein kinase A (PKA) axes in the heart. Left panel: sildenafil increases cGMP and activates PKG, leading to phosphorylation of (1) L-type Ca channel (LTCC) to reduce Ca influx and (2) cardiac troponin I to reduce myofilament Ca sensitivity. Both effects are negatively inotropic. Right panel: β1-adrenergic and β2-adrenergic stimulation increases cAMP to activate PKA, leading to phosphorylation of (1) L-type Ca channel, increasing Ca influx and (2) phospholamban (PLB) to activate sarcoplasmic-endoplasmic reticulum Ca ATPase pump (SERCA) and increase Ca uptake into the sarcoplasmic reticulum (SR). These actions lead to a greater Ca content within the SR, increased force of contraction and greater propensity to arrhythmias. overloaded, giving rise to spontaneous releases of Ca and the stimulates