Galectin-3 and heart failure: Prognosis, prediction & clinical utility

Abstract

Heart failure (HF) is a leading cause of mortality in the western world. Despite advances in the treatment of HF, like the use of angiotensin-converting enzyme (ACE) inhibitors, β-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), and implantable cardiac defibrillators, prognosis of HF patients remains poor. For clinicians dealing with HF patients, risk prediction in both acute, chronic, and new onset HF remains a challenge. Biomarkers might help in risk stratification and may guide the proper use of limited resources and therapy. Galectin-3 is an emerging biomarker which has been linked to tissue fibrosis, a hallmark in cardiac remodeling and HF. Galectin-3 can reliably be measured in the circulation, and several recent studies have shown the prognostic value of galectin-3 in acute and chronic HF, and its potential utility in the general population. The purpose of this review was to summarize the literature and explore the potential role of galectin-3 as a biomarker in HF.

Introduction

Heart failure (HF) is a major cause of morbidity and mortality in the western world. The 5-year mortality remains unacceptably high at around 50%, despite considerable improvements in HF therapy during the last decades [1], [2]. Furthermore, HF is very prevalent: the lifetime risk of acquiring HF is over 20% for people at the age of 40 in the western world [3].

HF imposes an enormous burden on health care costs, driven by a high number of HF rehospitalizations [4], [5]. It is expected that the prevalence of HF will rise in the future because of the aging population and, paradoxically, because we have succeeded to improve treatment, which “created” more HF [6], [7]. Therefore, better insight in the pathophysiological mechanisms underlying HF is warranted.

Biomarkers that reflect such pathophysiological mechanisms may assist in risk stratification of patients and may steer treatment of the individual patient [8]. The number of biomarkers has exploded, but most biomarkers are still under investigation as therapeutic consequence and their role in disease management remains unclear.

Current HF guidelines are primarily focused on B-type natriuretic peptide (BNP, or its stable precursor, NT-proBNP); this biomarker has established itself to be useful in diagnosis, prognosis, and disease management. Acutely decompensated patients with high cardiac wall stress have highly elevated BNP levels, which after unloading will drop rapidly [9], [10]. However, BNP has its drawbacks, and is influenced by the loading (fluid) status of the patient during presentation, but also by renal function, and obesity [11], [12], [13].

Galectin-3 has recently been linked to HF development and has shown to be associated with HF severity [14].

Galectin-3 is encoded by a single gene, LGALS3, which is located on chromosome 14, and consists of six exons en five introns [15]. Galectin-3 is a β-galactoside-binding lectin consisting of two domains, namely an atypical N-terminal domain and a C-terminal carbohydrate-recognition domain (CRD) (Fig. 1) [16]. Galectin-3 is predominantly released during differentiation of monocytes into macrophages [17], and is involved in many processes during the acute inflammatory response such as neutrophil activation and adhesion, chemoattraction of monocytes, opsonization of apoptotic neutrophils and activation of mast cells [18]. Chronic inflammation results in tissue damage and loss, which in turn results in fibrogenesis ( [19]), and as such, forms a bridge between inflammation and fibrosis.

Therefore, galectin-3 is a biomarker reflecting tissue damage, independent of cardiac loading conditions [20]. As such, it may supplement the currently used biomarker arsenal. This article will review the experimental and clinical data on galectin-3 in HF.