Introduction

Despite the recent advances patients with ST-elevation myocardial infarction (MI) (STEMI) are still at significant early and late stage risk for cardiovascular adverse events (1,2). Although modern reperfusion therapies have been developed, adverse left ventricular remodeling (aLVR) is still common and a predictor of arrhythmic events following STEMI (3). Implantable cardioverter defibrillator (ICD) is recommended for the primary prevention of sudden cardiac death in patients with heart failure only if their left ventricular ejection fraction (EF) (LVEF) is <35%, and this practice is known to reduce cardiac mortality (4). However, many studies report that a significant proportion of cardiac arrests occurring outside the hospital is accompanied by EF >35% (5).

Microvolt T-wave alternans (MTWA) is defined by fluctuations of T-wave amplitude and morphology in the electrocardiography (ECG) trace. Positive MTWA is shown to be a significant and strong predictor of mortality due to arrhythmic events and all causes among ischemic cardiomyopathy patients (6). Premature ventricular complexes (PVCs) are common findings following MI; and patients with post-MI >10 PVCs/h upon Holter monitoring are at high risk of sudden cardiac death (7).

Galectin-3 (Gal-3) is a new biomarker with a regulatory role in fibrogenesis, tissue repair and inflammation (8). Myocardial fibrosis and aLVR are associated with increased levels of Gal-3 and arrhythmic event development. Increased levels of Gal-3 among hypertensive patients are reported to be associated with ambulatory ECG-based MTWA positivity (9).

Although guidelines recommend ICD as the primary prevention in patients with LVEF <35% following MI, no clear recommendation is present on how to prevent development of arrhythmic events and sudden cardiac deaths among patients with LVEF >35%. The aim of our study was to determine if Gal-3 levels are associated with MTWA positivity and frequent PVCs, known to predict arrhythmic events, among single-vessel patients with LVEF >35%, presented at the hospital with acute STEMI for the first time and underwent pPCI.

Materials and Methods

Study Population

The single-vessel acute STEMI patients successfully treated with pPCI from March 2019 through November 2019 were included in this prospective study. STEMI was defined according to current guidelines (10) and 141 STEMI patients were initially identified. Patients with a LVEF ≤35%, patients with severe valvular diseases, co-existing cancers, connective tissue diseases and cirrhosis were excluded. Patients who were not suitable or indicated for PCI and/or who did not have Gal-3 data at time of admission were also excluded. Consequently, the final study population consisted of 81 patients. In our study, Gal-3 median level was determined as 1.93 ng/dL. The patients grouped based on Gal-3 median level: low- (n=40) and high-Gal-3 (n=41) (≤ and >1.93 ng/dL, respectively) groups (11).

The study was approved by the Muğla University Ethics Committee (decision no: 02/07/2019-E24474).

Patients and Laboratory Measurements

Data about patient demographics, comorbidities, clinical and physical examination findings were recorded at the time of admission. Blood was sampled for routine biochemistry at the time of admission and within 48 h after pPCI for Gal-3 levels. Serum Gal-3 level was measured in duplicate, using a commercially available immunosorbent assay (Human Gal-3 platinum ELİSA BMS279/BMS279/4TEN). The intra-observer variability in the measurements of Gal-3 was also assessed and all of the mean intra-assay coefficients of variance were found to be less than 7.5%.

At 24 h to 72 h after revascularization, a transthoracic echocardiography was performed using a Vivid S5 probe 3S-RS (GE Healthcare). All patients treated according to the current STEMI guidelines (10) and angiographic data were recorded.

Ambulatory ECG-based MTWA

The analyses of MTWA were carried out from 12-channel records of the ambulatory Holter monitoring (DMS 300-7 Holter Reader; DSM, Stateline, Nevada, USA). The recordings were obtained for 24 hours in all patients and control participants. Before automatic analysis of tapes using the Holter program (CardioScan12.0 DM software; DSM), we performed the measurements of TWA  at maximum heart rates less than 120 beats/min. MARS PC Software (SPSS INC., Chicago, Illinois, USA) was used to identify the possible TWA periods according to the modified moving average algorithm. Data were edited manually when it was observed to be unsuitable due to noise or artifacts. The highest TWA value observed in either one of the channels was considered the maximum TWA value. TWA greater than or equal to 65 microV was considered positive in this study.

Premature Ventricular Complexes (PVCs)

More than 10 PVCs per hour during a 24-hour rhythm Holter examinations in ischemic heart patients was considered positive as it was reported to be associated with increased arrhythmic events.

Statistical Analysis

Statistical analyses were carried out using SPSS software version 20 (SPSS Inc., Chicago, Illinois, USA). Chi-square (x²), Student’s t-test, and Mann-Whitney U tests were used where appropriate. We evaluated the levels of possible factors (age, male, hyperlipidemia, Diabetes Mellitus, hypertension, anterior MI, LVEF, peak troponin level, LAV, and Gal-3 class) by univariable analyses, and factor found to be significant predictors were evaluated by multivariable logistic regression to determine independent predictors of TWA and PVCs.

Results

This study includes 81 consecutive patients with LVEF >35%, who presented at our emergency polyclinic with STEMI and had a single vessel stent placement via pPCI. Of 81 patients with STEMI, 39 had left anterior descending artery obstructive coronary artery disease, 28 had right coronary artery disease, and 14 had left circumflex artery disease. A total of 12 bare-metal stents and 70 drug-eluting stents were used to treat obstructive coronary artery lesions. TIMI grade flow 3 could be established in all patients.

The mean age of low-Gal-3 patients was 51.7±11.3 years and 90% of the participants were males, whereas the corresponding values were 50.5±12.3 years and 80.5% within in high-Gal-3 group (Table 1). No statistically significant difference was observed between the low- and high-Gal-3 groups with respect to diabetes, hypertension and hyperlipidemia history, and blood levels of creatinine, hematocrit and cardiac enzymes. As the only statistically significant difference between two Gal-3 groups was that LAV was higher in high-Gal-3 patients (55.7±18 vs 40.6±13.7 mL, p<0.001).

Predictors of PVCs

Univariable logistic regression analysis showed significant relationships between the presence of PVCs and LAV, age, and high Gal-3 group were detected (p=0.003, p=0.026, p<0.001, respectively) (Table 2).

Multivariable logistic regression revealed that age, increased  LAV and high Gal-3 group were significant and independent factors in predicting PVC positivity [Odds ratio (OR) (95% confidence interval (CI)): 1.083 (1.023-1.140), p=0.005; OR (95%CI): 1.042 (1.002-1.083), p=0.04; OR (95%CI): 10.576 (2.295-48.726), p=0.002, respectively] (Table 2). The strongest predictor among these was high Gal-3 group (Table 2).

Predictors of MTWA

The univariable logistic regression model for MTWA positivity yielded that LVEF and high Gal-3 group were the statistically significant independent variables (p=0.05, p=0.001, respectively); while only high Gal-3 was a significant predictor of MTWA positivity [OR (95%CI): 6.734 (2.149-21.101), p=0.002] on multivariable logistic regression (Table 2).

Galectin-3 and Arrhythmic Events

The predictive value of Gal-3 levels on arrhythmic events is presented in Figure 1. Among the MTWA positive patients, the T-wave positive cases were 12.5% in low-and 48.4% in high-Gal-3 subgroups (p<0.001) (Figure 1). Regarding PVC positivity, 7.5% low-Gal-3 patients were PVC positive, while it was 46.3% in high-Gal-3 group (p<0.001) (Figure 1). Furthermore, in a receiver-operating characteristic curve analysis, Gal-3 cut-off ≥3.44 ng/dL had AUC of 0.867 for distinguishing MTWA positivity with a 81.8% sensitivity and 83.0% specificity (Figure 2).

Discussion

This study showed that Gal-3 levels of STEMI patients are independently related to PVC and MTWA positivity that can predict arrhythmic mortalities. LAV is observed to be higher in high-Gal-3 group compared to the low-Gal-3 patients. Independent predictors for ECG-based MTWA positivity were found to be age, LAV, and Gal-3, of which, Gal-3 was the strongest. The only independent predictor of PVC positivity was also Gal-3.

In STEMI cases, heart failure and arrhythmic events are the most significant causes of mortality, and aLVR has a significant role in this process (12). aLVR occurs rapidly after STEMI and progressive post-infarction re-modelling is the most significant predictor of poor clinical outcomes (12-14). Fibrotic tissue in the heart forms a substrate for ventricular arrhythmias which leads to formation of ventricular tachycardia/ventricular fibrillation (15-17).

Many studies have demonstrated that myocardial fibrosis, detected by late gadolinium enhancement (LGE) in cardiovascular magnetic resonance (CMR), is strongly associated with ventricular arrhythmia/arrhythmic events (18-21). A large meta-analysis study has shown that detection of ventricular fibrosis via LGE-CMR is a strong predictor of ventricular arrhythmia/arrhythmic events among both ischemic and non-ischemic cardiomyopathy patients, especially for those with LVEF ≤30% (20). Another study reported that the presence of midwall LGE showing myocardial fibrosis in CMR, in patients with dilated cardiomyopathy with LVEF ≥40%, was associated with increased risk of sudden cardiac death and that this patient group may benefit from ICD implantation (21).

Ambulatory ECG-based MTWA reflects a temporal dispersion in intra-cardiac repolarization that may contribute to re-entrant arrhythmias. Although MTWA is often used as a predictor of arrhythmia development and sudden death in patients with low LVEF, some studies also reported that it was a predictor of sudden cardiac death and total mortality in patients with preserved LVEF as well (22,23). In a study with 1037 normal LVEF patients who were recommended an exercise stress test on the basis of clinical assessments, MTWA was determined to be a predictor of mortality (24).

Post-MI PVCs which often develop through infarct scar, are common among patients with LV dysfunction (25). In patients with structural heart disease, PVC increases the risk of mortality and patients with >10 PVCs per hour are considered to have a marker for increased risk of sudden cardiac death (10).

Gal-3 has a central role in development of fibrosis in heart and kidneys and tissue re-modelling (26,27). In recent studies, Gal-3 is reported as a potent prognostic marker for major adverse cardiovascular events in heart failure patients (28,29). Moreover, de Boer et al. (30) reported that Gal-3 is an independent predictor of cardiovascular mortality in the general population. In another study, patients with obstructive sleep apnea syndrome were shown to present with a significant association between Gal-3 levels and coronary atherosclerosis (31).

Increased levels of Gal-3 are shown to be predictive of atrial fibrillation (AF) development in patients with both preserved and impaired left ventricular function (32,11). The largest of these studies, ARIC study also found that increased Gal-3 levels were associated with increased AF risk (33). In another study, high Gal-3 levels were associated with new-onset AF at higher rates among patients treated for the first time with MI and treated with pPCI (34). A study in hypertensive patients also reported that elevated levels of Gal-3 were associated with MTWA positivity (35).

The role of Gal-3 has been assessed in relation to post-MI outcomes (33-36). In patients with anterior STEMI treated with pPCI, high Gal-3 levels in early acute phase (within 48 hours) were found to be associated with 6-month aLVR (36) and was also reported to be a strong independent predictor of long-term outcomes (37).

We demonstrated here that increased levels of Gal-3 were associated with both PVCs and MTWA positivity, known predictors of arrhythmic events. The association was thought to be due to the relationship of aLVR and myocardial fibrosis with Gal-3 levels following STEMI. LAV values were higher in the high-Gal-3 group. Following cardiac ischemia, re-modelling and left atrium enlargement process, led by the profibrotic mediator Gal-3 in the left atrium as well as in the left ventricle, eventually play a role in the development of heart failure. This mechanism may explain the relationship between high Gal-3 level and LAV observed in our study. The relationship between increased Gal-3 levels and increased LAV was not explored directly in this study but it can explain the relationship between Gal-3 levels and AF, observed in prior studies.

Study Limitations

There are some limitations of this study. First of all, the single-center, non-randomized nature of the study may have led to subject selection bias. Second, the post-STEMI serial changes in the Gal-3 levels circulating in the blood were not evaluated, resulting in an inability to identify the best time for peak value measurement of Gal-3 following STEMI. Third, CMR imaging that is a good indicator of myocardial fibrosis was not performed in our patients. Fourth, we included single-vessel patients and patients with EF >35%, which makes the results unsuitable for gener-alization to all STEMI patients. Finally, the most important limitation of our study is that we did not follow the patients for a long period of time, and therefore could not observe the development of arrhythmic events and sudden cardiac death.

Conclusion

Gal-3 levels at the time of admission of patients presenting with STEMI and treated via pPCI are significantly related to PVC and MTWA positivity that are predictors of arrhythmic events. This relationship can be used for risk classifications in this patient group.

Ethics

Ethics Committee Approval: This study was approved by Muğla Sıtkı Koçman University Rectorate Building, Dean’s Office of Faculty of Medicine Clinical Researches Ethics Committee (no: 72855364-050.01.04-E.24474).

Informed Consent: Informed consent was obtained from the patients.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: İ.B., H.P., Concept: İ.B., Design: İ.B., H.P., Data Collection or Processing: İ.B., H.P., Analysis or Interpretation: İ.B., Literature Search: İ.B., H.P., Writing: İ.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.