Is enhancing cGMP-PKG signalling a promising therapeutic target for heart failure with preserved ejection fraction?

Á Kovács,N Hamdani,A Alogna,H Post

doi:10.1007/s12471-016-0814-x

Abstract

Heart failure with preserved ejection fraction, i.e. HFpEF, is highly prevalent in ageing populations, accounting for more than 50 % of all cases of heart failure in Western societies, and is closely associated with comorbidities such as obesity, diabetes and arterial hypertension. However, all large multicentre trials of potential HFpEF treatments conducted to date have failed to produce positive outcomes. These disappointing results suggest that a ‘one size fits all’ strategy may be ill-suited to HFpEF and support the use of tailored, personalised therapeutic approaches with specific treatments designed for specific comorbidity-related HFpEF phenotypes. The accumulation of a multitude of cardiovascular comorbidities over time leads to increased systemic inflammation, oxidative stress and coronary microvascular endothelial inflammation, eventually resulting in degradation of cyclic guanosine monophosphate (cGMP) via multiple pathways, thereby reducing protein kinase G (PKG) activity. The importance of cGMP-PKG pathway modulation is supported by growing evidence that suggests that this pathway may be a promising therapeutic target, evidence that is mainly based on its role in the phosphorylation of the giant cytoskeletal protein titin. This review will focus on the preclinical and early clinical evidence in the field of cGMP-enhancing therapies and PKG activation.

Highlights

Greater molecular understanding of cardiac mechano transduction in normal and failing hearts has provided novel perspectives on the role of cyclic guanosine monophosphate-protein kinase G (PKG) signalling in heart failure with preserved ejection fraction, i.e. HFpEF ([1,2,3,4,5]; Fig. 1).While initial descriptions of HFpEF focused on left ventricular (LV) diastolic dysfunction, it is clear that HFpEF involves a complex interplay of factors, including LV and vascular stiffness, left atrial impairment, chronotropic incompetence and decreased pulmonary vascular capacitance [6]
A further related finding was that the accumulation of a variety of cardiovascular comorbidities such as ageing, hypertension, diabetes, obesity and physical inactivity has been mechanistically linked to the classical hallmarks of LV stiffness and diastolic dysfunction, which include concentric LV remodelling and cardiomyocyte stiffening due to titin hypophosphorylation [1,2,3,4,5, 10, 12, 19, 22]. These findings suggest that PKG-mediated phosphorylation of titin could be a therapeutic target in HFpEF, the elements of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-PKG signalling network most critical to titin phosphorylation and stiffness still need to be elucidated
One explanation for the results described above was hinted at recently when it was reported that cGMP-specific PDE9A regulates cGMP signalling independently of NO and contributes to stressinduced cardiac disease

Summary

Introduction

Greater molecular understanding of cardiac mechano transduction in normal and failing hearts has provided novel perspectives on the role of cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signalling in heart failure with preserved ejection fraction, i.e. HFpEF ([1,2,3,4,5]; Fig. 1). One finding of potential clinical importance was the favourable reaction of slow LV relaxation and high diastolic LV stiffness in HFpEF to increased PKG activity following in vivo administration of the PDE5A inhibitor sildenafil, which facilitates increased myocardial PKG activity by inhibiting the breakdown of cGMP by PDE5A [1,2,3,4,5] This is significant, because relative to both aortic stenosis and heart failure with reduced ejection fraction (HFrEF) [5], HFpEF patients show reduced myocardial PKG activity and lower cGMP concentrations, both of which are associated with increased titin-based stiffness, titin hypophosphorylation and elevated myocardial nitrotyrosine levels, indicative of raised nitrosative/oxidative stress [5]. These findings suggest that PKG-mediated phosphorylation of titin could be a therapeutic target in HFpEF, the elements of the NO-cGMP-PKG signalling network most critical to titin phosphorylation and stiffness still need to be elucidated

Is PDE inhibition beneficial for HFpEF?

PKG activators and strategies to enhance cGMP

NO and nitroxyl donors

Findings

Summary and Conclusions