Recently, many reports have indicated that Gal-3 is a novel biomarker of heart disease and a prognostic indicator of patients with heart failure.

Clinical studies suggest that serum and myocardial Gal-3 levels in patients with heart failure reflects cardiac inflammatory condition and can be considered as a useful biomarker for both cardiac inflammation and fibrosis, depending on the pathophysiological mechanisms of heart failure [93]. In the general population, a high concentration of plasma Gal-3 correlates with clinical outcomes of heart failure [94,95]. The increased serum levels of Gal-3 are associated with adverse clinical events in both patients with acute [62,63] and chronic [64,65] heart failure with preserved or reduced ejection fraction.

Some practical guidelines have indicated the utility of established or recommended biomarkers in diagnosis and risk management of heart failure. In fact, American College of Cardiology Foundation (ACC)/American Heart Association (AHA), Heart Failure Society of America (HFSA), and European Society of Cardiology (ESC) have established the natriuretic peptides (NPs), circulating hormones of cardiac origin that play an important role in the regulation of intravascular blood volume and vascular tone, as useful diagnostic biomarkers in the patients suspected of heart failure [96,97,98,99]. However, the utilities of novel biomarkers other than NPs are less established in clinical practice. The recommendations on the clinical assessment and analytical perspectives of novel biomarkers in diagnosis and management of heart failure were prepared by the National Academy of Clinical Biochemistry (NACB) [100]. In these criteria, novel biomarkers need to be able to recognize fundamental causes of heart failure, assess its severity, and foresee the risk of the disease progression. The ACC/AHA guidelines recommended the use of Gal-3 as a biomarker for assessment of myocardial fibrosis in heart failure, however, the ESC has not recommended the clinical use of Gal-3 [101].

Myocardial fibrosis is tightly implicated in the pathophysiological mechanisms for ventricular remodeling of heart failure. As a potential key factor in pathophysiology of heart failure, US Food and Drug Administration has approved Gal-3 as soluble biomarkers for myocardial fibrosis to detect ventricular remodeling [96]. Thus, the serum levels of Gal-3 are associated with ventricular remodeling and cardiac function. However, whether and how Gal-3 plays a pathophysiological role in cardiac remodeling remains unclear, especially in clinical settings. In fact, the serum levels of Gal-3 was not related to left ventricular remodeling defined by cardiac MRI in patients with acute myocardial infarction and left ventricular dysfunction, although certain biomarkers involved in extracellular matrix turnover, such as matrix metalloproteinase-3 and monocyte chemoattractant protein-1 at baseline (mean 46 h), were highly associated [66]. In addition, Srivatsan et al. conducted a study that found that Gal-3 could not predict mortality, while other biomarkers could be used as a predictor of mortality [102].

As mentioned above, the roles of Gal-3 in heart failure and cardiovascular disease are still controversial clinically, however, many animal models clearly demonstrate the possibility of Gal-3 as a novel biomarker of heart disease. Overexpression of myocardial Gal-3 during early pre-symptomatic stages of heart failure has been well documented in several studies using animal models. Intrapericardial injection of recombinant Gal-3 in healthy rats significantly increased the degree of myocardial fibrosis with ventricular remodeling, and the induction of heart failure [80,81]. And Gal-3 was indicated to colocalize with activated myocardial macrophages [80]. On the other hand, cardiac remodeling and dysfunction induced by Gal-3 was prevented by a pharmacological inhibitor of Gal-3, N-acetyl-seryl-aspartyl-lysyl-proline [80]. In a rat model of heart failure, increased Gal-3 was detected at hypertrophied hearts, prior to the development of heart failure [81]. These findings imply that Gal-3, at the early stages of inflammatory responses, may be a potential therapeutic target in the treatment of heart failure. A rat model of right ventricular heart failure, created by banding of the pulmonary artery, demonstrated that Gal-3 was significantly increased in both right and left ventricles and that protein kinase C promoted cardiac fibrosis and heart failure by modulating Gal-3 expression [82]. In order to clarify the important role of myocardial Gal-3 expression during the early stage of heart failure, the time-course analysis of cardiac and serum Gal-3 in viral myocarditis, which was induced at 12, 24, 48, 96 h, 7 and 10 days after specific virus-inoculation, was performed using an animal model [31]. Gal-3 was indicated as a useful histological biomarker of cardiac fibrosis in acute myocarditis following viral infection and serum Gal-3 levels might be an early diagnostic method for detecting cardiac fibrotic degeneration in acute myocarditis [31].

However, the clinical data has not shown that circulating Gal-3 levels reflect myocardial Gal-3 levels or myocardial fibrosis, although circulating Gal-3 has been demonstrated as a potential predictor for clinical outcome in several cohort studies, as mentioned earlier [94,95]. In clinical settings, since various stages and degrees of myocardial inflammation and fibrosis may be present in a patient with heart disease, serum Gal-3 levels may reflect a sum of different pathophysiological conditions [93]. Thus, it may be that the circulating Gal-3 levels in a patient with various stages of heart disease will not adequately reflect myocardial inflammation and fibrosis.

Endomyocardial biopsy is widely used as a diagnostic tool for patients with heart diseases, such as myocarditis and other cardiomyopathies, which are often difficult to diagnose by conventional radiological imaging methods [103]. The histologic examination of endomyocardial biopsy is still the gold standard for final diagnosis, such as for myocarditis and other cardiomyopathies like cardiac fibrosis, despite the continuous advancements in diagnostic and therapeutic approaches [104,105,106].

Unlike uniform materials from experimental animals, there are many variables in human biopsy materials by its nature. Human biopsies are usually obtained under different conditions, e.g., variable time periods between biopsy and processing, as well as variation in disease onset or severity. In contrast, the serum levels of Gal-3 reflect myocardial Gal-3 expression or cardiac fibrosis by using a sophisticated animal model for time-course histological examination [31]. It is possible that the difference between experimental data and clinical findings is due to a wide variability in clinical settings with differences in sample collection and disease stages. Since experimental animal data clearly indicate that serum Gal-3 might be an early diagnostic biomarker for cardiac degeneration or fibrosis in acute myocarditis [31], further studies are thus needed to investigate whether such findings are also applicable to cardiac degeneration or fibrosis in humans. Gal-3 can be used as a predictive biomarker for the early stage or new-onset of heart failure, especially if it is only the first single pathological factor. In addition, Gal-3 can also be used as an additional indicator for detecting worse prognosis, mortality, and readmission.