Cardiovascular disease is the leading cause of morbidity and mortality in developed countries. Preventing cardiovascular events and the subsequent progression of heart failure is a major clinical issue. Biomarkers play an important role in the diagnosis and decision-making of a variety of disease entities. Recently, various biomarkers, such as brain natriuretic peptide, have been introduced in our daily clinical practice. Among cardiovascular biomarkers, Galectin-3, and suppression of tumorgenicity 2 protein (ST2) have been well validated to predict cardiovascular prognosis, and provide useful information for management of heart diseases.

Galectin-3, a β-galactoside-binding lectin, is primarily secreted by macrophages and is expressed in a variety of tissues, including the heart, kidney, lung, and vascular tissues. Its production is significantly increased on cell injury, and it plays a critical role in cell adhesion and inflammation. Galectin-3 induces the differentiation of fibroblasts into myofibroblasts, and synthesize collagen types I and III, leading to fibrosis and scar formation. Thus, Galectin-3 is considered as a key molecule in cardiovascular remodeling. Several studies have shown that Galectin-3 levels predict the risk of mortality in patients with heart failure [1].

ST2 is a member of the interleukin-1 (IL-1) receptor superfamily and has transmembrane (ST2L) and soluble (sST2) isoforms [2]. ST2L, a functional IL-33 receptor, is expressed not only in Th2-type immune cells but also in endothelial cells, smooth muscle cells, fibroblasts, and cardiomyocytes. The biological function of IL-33 is that it is constitutively expressed in the nuclei of vascular endothelium and released into the extracellular space as an “alarmin” signal in response to cell injury and necrosis. IL-33 binds to the heterodimeric complex of ST2L and IL-1 receptor accessory protein on the cell surface, activating downstream signaling pathways, leading to the transcription of inflammatory genes, the production of inflammatory cytokines, and subsequent immune responses. IL-33 functions as a pro- or anti-inflammatory cytokine depending on several co-stimulatory factors. In heart failure and atherosclerosis, it is known to exert protective effects through its anti-inflammatory and anti-fibrotic effect (Fig. 1) [3,4,5,6]. On the other hand, sST2 released into the circulation acts as a “decoy” receptor for IL-33 and inhibits the beneficial effect of IL-33/ST2L axis, which are associated with the suppression of cardiac hypertrophy, remodeling, and atherosclerosis. Like Galectin-3, ST2 has been reported to be a clinically useful marker of heart failure. IL-33 and its receptor sST2 are independent predictors of poor HF prognosis. Unlike NT-proBNP, ST2 is not affected by age, BMI, renal function, or HF etiology. In addition, ST2 measurement at admission in acute HF patients has been shown to be superior to NT-proBNP in predicting 1-year mortality [7].

Fig. 1
figure 1

Role of IL-33/ST2 axis on heart failure and coronary atherosclerosis. IL-33 binds to the heterodimeric complex of ST2L and IL-1 receptor accessory protein on the cell membrane, activating downstream signal transduction. In the context of heart failure, IL-33 has shown to attenuate the activation of the MAPK pathway and NF-κB, which are responsible for fibrosis and inflammation [3]. Additionally, IL-33 also reduces the expression of HMGB1 and inhibits the release of Th1 cytokines (IL-6, TNF-β, INF-γ), preventing cardiomyocytes from hypertrophy and apoptosis [4]. In coronary atherosclerosis, IL-33 increases Th2 cytokines and cholesterol efflux gene expression, resulting in reduction of foam cells [5, 6]. A fraction of the IL-33 released as an “alarmin” signal from necrotic cell is neutralized by soluble ST2 (“decoy” receptor), which inhibit cardiovascular protective effect of IL-33/ST2 axis. ST2L ST2 transmembrane ligand, IL-1RAcP Interleukin-1 receptor accessory protein, HMGB High-mobility group box 1, SMC smooth muscle cell, Mφ macrophage

Full size image

Regarding the mechanism of atherosclerosis progression, the “inflammatory hypothesis” proposes that inflammatory signaling promotes the progression and unstabilization of plaques, which then become a substrate for thrombus formation, leading to acute coronary syndrome. In the arterial wall, the binding of IL-33 with ST2L directs the immune response toward T helper 2 and macrophage 2 phenotype, limiting plaque inflammation and progression. In contrast, sST2 inhibits the protective effect of IL-33 on atherosclerotic plaques by capturing IL-33. Besides IL-33/ST2 axis in atheroma evolution, Galectin-3 is also upregulated in vulnerable plaques and is known to attract monocytes and exacerbate inflammation [8]. Clinically, higher Galectin-3 values have been identified in patients with AMI than those with unstable angina and, in turn, higher values than stable angina [9]. In addition, Galectin-3 expression has been observed to be elevated in patients with multivessel coronary artery disease, reflecting the severity of coronary artery disease [1]. With regard to ST2, Zhang et al. [10] found that plasma sST2 levels were significantly higher in ACS patients with complex lesions than those with simple lesions, suggesting that sST2 may be useful biomarker for evaluating the stability and complexity of coronary plaques. Recent investigation by Luo et al. [11] also demonstrated that elevated serum sST2 levels correlated with plaque vulnerability assessed by coronary CT angiography in non-STEMI patients. In contrast to these clinical studies of Galectin-3 or sST2 concerning advanced stages of atherosclerosis, the role of these biomarkers in early stages of atherosclerosis have not been fully investigated.

In this issue of Hypertension Research, Takahashi et al. [12] revealed that elevated sST2 values contribute to the development of coronary atherosclerosis (coronary artery stenosis of 50% or more by CCTA) in hypertensive patients. In addition, sST2 values in the CAD group were significantly higher than those in the non-CAD group in both the non-hypertensive and hypertensive groups. It should be emphasized that this study was conducted on patients who underwent coronary CT for screening purposes (patients with clinical suspicion of coronary artery disease or patients with one or more cardiovascular disease risks i.e. patients with primary prevention for CAD), demonstrating that a significant increase in sST2 was observed even at early stage of coronary atherosclerosis. Previous reports have mainly focused on data obtained at advanced stages of atherosclerosis or after cardiovascular events. The results of this study suggest that ST2 may be involved in the early stages of CAD, adding new insights to the existing data. Furthermore, they assessed the extent of coronary artery calcification and atherosclerosis using the Agatston score and Gensini score, respectively. The results showed that sST2 was correlated with the Gensini score, whereas Galectin-3 was associated with the Agatston score. These findings suggest that the roles of sST2 and Galectin-3 in the progression of atherosclerosis may be different, and that sST2 may have a stronger anti-atherosclerotic effect against the progression of coronary atherosclerosis as compared to Galectin-3. Long-term follow-up of the cohort of this study will provide valuable data to improve the early diagnosis of coronary atherosclerosis.

Prevention of cardiovascular events plays an important role in the subsequent development of heart failure. Preemptive therapeutic intervention at the risk stage of heart failure, such as in the setting of hypertension, diabetes, and chronic kidney disease, will become increasingly important in the era of the “heart failure pandemic”.

It is expected that advances in atherosclerosis biomarkers, including the findings from this study, will enable efficient early diagnosis and management of coronary atherosclerosis in the future.