Heart failure is one of the most important causes of mortality and morbidity and ischemic heart disease is the most common cause of heart failure.1,2 In the advanced stages of ischemic heart disease-related heart failure, the frequency of arrhythmic episodes increases. Ventricular arrhythmias can cause fatal outcomes in these patients.3,4 In order to reduce mortality, an implantable cardioverter-defibrillator (ICD) is recommended for selected patients, subject to certain indications. However, studies have shown that when these indications are taken into account, only one third of patients receive appropriate ICD therapies. Also, a high percentage of patients who do not fulfill these indications and do not have an ICD are resuscitated from sudden cardiac death. Therefore, additional parameters are needed in patients with ischemic cardiomyopathy to improve the indications and risk stratification.

Human studies have shown an independent relationship between myocardial fibrosis and arrhythmia episodes.5,6 Magnetic resonance imaging (MRI) studies have shown a relationship between myocardial fibrosis load and ventricular tachycardia episode frequency and prognosis.7,8 However, MRI is not suitable for use as a screening test. Also, the load and distribution of fibrosis after ICD implantation cannot be assessed using MRI.

Galectin-3 (Gal-3) is a beta-galactosid binding protein that has been shown to be associated with cardiac fibrosis9,10 and also with mortality in acute and chronic heart failure.11

In this study, we aimed to assess the association between ventricular fibrillation/ventricular tachycardia (VF/VT) and the quantity of left ventricular fibrotic tissue assessed using blood Gal-3 levels in ischemic cardiomyopathy patients with a VVI-ICD.

This was a cross-sectional study including adults treated in the cardiac arrhythmia outpatient clinic of a university hospital between January and April 2017. Patients diagnosed with ischemic dilated cardiomyopathy and who underwent VVI-ICD implantation for primary or secondary prevention were included in the study after their informed consent was obtained. Patients who had had a myocardial infarction (MI) in the previous year, patients with renal insufficiency (creatinine clearance<60 ml/min/1.73 m2 calculated by the 4-variable Modification of Diet in Renal Disease or Cockcroft-Gault formulas), those with inappropriate shocks, or those with a VVI-ICD for non-ischemic dilated cardiomyopathy, arrhythmogenic right ventricular dysplasia (ARVD), Brugada syndrome, long or short QT syndrome, or hypertrophic cardiomyopathy, were excluded from the study.

Healthy volunteers with no known medical problems were selected from hospital staff as controls. Data on age, gender, type of MI, comorbidities (including diabetes, hypertension and chronic obstructive pulmonary disease), smoking and medications were recorded for all participants. ICD interrogation was performed in 32 patients and all arrhythmia episodes in the previous three years were recorded, as were patients’ medical histories from the outpatient clinic files. Arrhythmic events were analyzed retrospectively.

Blood samples to measure Gal-3 levels were taken from all participants between 8 a.m. and 9 a.m., after 8-12 hours fasting. Blood was placed in ethylenediaminetetraacetic acid tubes and centrifuged for 15 min at 3500 rpm and serum samples were obtained, which were stored at -80°C until the day of study. Plasma Gal-3 levels were measured by enzyme-linked immunosorbent assay (ARCHITECT i2000SR, Abbott Diagnostics, Abbott Park, IL, USA). The manufacturer's recommended limit was 4-114 ng/ml.

Treatments from intracardiac electrograms were reviewed from outpatient clinic records and the appropriateness of shocks was assessed. Patients with untreated lead malfunction or excessive inappropriate shocks were excluded from the study. Patients were divided into three groups: the first group included patients who had received no treatment, the second included patients with arrhythmia who received appropriate therapies but did not meet the criteria of arrhythmia storm, and the third included patients who had sustained VT or VF requiring three or more separate ICD therapies within 24 hours.

In the present study we evaluated Gal-3 as a potential predictor of sustained VT/VF in ICD patients. Gal-3 levels were significantly higher in the patient groups than in healthy controls and in patients requiring ICD therapies than in those not requiring therapies, and were associated with the presence of arrhythmias that required ICD therapies. There was a significant negative correlation between EF and Gal-3 levels in the patient groups.

An ICD is recommended in patients with dilated cardiomyopathy, symptomatic heart failure (New York Heart Association class II or III) and EF ≤35% despite ≥3 months of optimal pharmacological therapy who are expected to survive for >1 year with good functional status. In a post-hoc analysis of the MADDIT II trial, only 35% of ICD patients received appropriate ICD therapies in a three-year follow-up.12 In another study, a significant proportion of patients resuscitated from sudden cardiac death had EF>35%.13 This suggests that some ICDs implanted in accordance with the current guidelines may be unnecessary, and that some patients who did not receive an ICD may have died from sudden death. Given the complications and financial burden of ICD use, additional parameters are needed to improve the indications for implantation.

Ventricular arrhythmias are thought to arise due to the heterogeneous structure of scar tissue and healthy peri-infarct tissue. This heterogeneous structure gives rise to slow and fast pathways that provide the basis for the reentry circuit and thus maintains the arrhythmia.14 Scar tissue in homogenous structures was shown to constitute less arrhythmia risk than in heterogeneous structures.15–19

The gold standard non-invasive imaging technique for detecting myocardial scar tissue is MRI. Wu et al. reported an eight-fold increase in hospitalization for heart failure, appropriate ICD firing and cardiac death in ischemic dilated cardiomyopathy patients with scar tissue as revealed by late gadolinium enhancement on cardiac MRI compared to those without scar tissue.8 This finding was supported by a study by Assomull et al. and in other studies.7,20 A study by Scott et al. showed that the magnitude of scar tissue, as demonstrated by late gadolinium enhancement on cardiac MRI in patients with coronary artery disease, increases the risk of ventricular arrhythmias independently of EF.17

In the damaged area, Gal-3 plays an important role in the fibrotic process by converting inactive fibroblasts to active myofibroblasts that produce collagen and glycoprotein.9,20,21 Gal-3 was shown to be secreted from myocardial scar tissue and to promote myocardial fibrosis and cardiac dysfunction. It has been associated with remodeling in patients with heart failure9 and Gal-3 levels secreted from fibrotic tissue have been identified as the best independent predictor of mortality in heart failure.10,22 Pietro et al. found that Gal-3 levels were a predictive marker for VT/VF in patients with heart failure who received an ICD, with sensitivity and specificity of 60% and 65%, respectively, for predicting VT/VF in patients with Gal-3>17 ng/ml.23

Some limitations should be considered when interpreting these data. The main limitation is the small number of patients. Secondly, cardiac structure and arrhythmic burden were not assessed for the control group. Third, it is not possible to exclude non-cardiac causes that could increase plasma Gal-3 concentrations. Finally, arrhythmia is not solely caused by fibrosis. It may also occur due to ischemia and other electrophysiological causes.

Gal-3 may be an inexpensive and easily accessible parameter to predict arrhythmia risk in patients with ischemic dilated cardiomyopathy. Gal-3 may further improve risk stratification in ischemic cardiomyopathy patients who are more prone to developing life-threatening arrhythmias. However, large-scale prospective studies including efficacy and safety studies are needed to determine the role of this biomarker in predicting arrhythmias and sudden cardiac death in clinical practice.

The authors received no financial support for the research, authorship, or publication of this article.

The authors have no conflicts of interest to declare.