Understanding heart failure with preserved ejection fraction: where are we today?

Abstract

Heart failure with preserved ejection fraction (HFpEF) represents a complex and heterogeneous clinical syndrome, which is increasingly prevalent and associated with poor outcome. In contrast to heart failure with reduced ejection fraction (HFrEF), modern heart failure pharmacotherapy did not improve outcome in HFpEF, which was attributed to incomplete understanding of HFpEF pathophysiology, patient heterogeneity and lack of insight into primary pathophysiological processes. HFpEF patients are frequently elderly females and patients demonstrate a high prevalence of non-cardiac comorbidities, which independently adversely affect myocardial structural and functional remodelling. Furthermore, although diastolic left ventricular dysfunction represents the dominant abnormality in HFpEF, numerous ancillary mechanisms are frequently present, which also negatively impact on cardiovascular reserve. Over the past decade, clinical and translational research has improved insight into HFpEF pathophysiology and the importance of comorbidities and patient heterogeneity. Recently, a new paradigm for HFpEF was proposed, which states that comorbidities drive myocardial dysfunction and remodelling in HFpEF through coronary microvascular inflammation. Regarding the conceptual framework of HFpEF treatment, emphasis may need to shift from a 'one fits all' strategy to an individualised approach based on phenotypic patient characterisation and diagnostic and pathophysiological stratification of myocardial disease processes. This review will describe these novel insights from a pathophysiological standpoint.

Keywords: Diastole; Endothelial dysfunction; Heart failure; Inflammation.

Fig. 1

Cardiomyocyte cAMP and cGMP signalling pathways involved in myofilament regulation and titin-based stiffness. Stimulation of β-ARs activates Gs -AC-mediated generation of cAMP, which stimulates PKA activity. cGMP is generated from activation of sGC by NO and from activation of pGC by NPs. cGMP stimulates PKG activity. Both PKA and PKG induce lusitropic effects through phosphorylation of TnI, and lower cardiomyocyte stiffness through phosphorylation of the titin N2B segment. Circled P’s indicate phosphorylatable sites. AC adenylyl cyclase, βAR beta-adrenergic receptor, cAMP cyclic adenosine monophosphate, G G-stimulatory protein, NPR natriuretic peptide receptor, PEVK unique sequence rich in proline, glutamic acid, valine and lysine

Fig. 2

Mechanisms explaining downregulation of myocardial cGMP-PKG signalling in HFpEF. PDE5 phosphodiesterase type 5, PDE9 phosphodiesterase type 9, SR sarcoplasmic reticulum, RGS2/4 regulator of G-protein signalling 2 and 4

Fig. 3

Comorbidities drive myocardial dysfunction and remodelling in HFPEF. IL-6 interleukin-6; sST2 soluble ST2; TNF-α tumour necrosis factor alfa; VCAM vascular cell adhesion molecule. Modified with permission from [28]

Fig. 4

HFpEF represents a heterogeneous syndrome, characterised by multiple cardiovascular and non-cardiovascular comorbidities

Fig. 5

Distinct stages of structural myocardial disease in HFpEF. a–c, histological images of LV myocardium from HFpEF patients, demonstrating minor (a), moderate (b) and severe (c) interstitial fibrosis