Abstract
Galectin-3 is an inflammation biomarker associated with atrial remodeling which plays a role in the development of atrial fibrillation (AF). Atrial high-rate episode (AHRE) is related to development of clinically documented AF and stroke. The present study aimed to determine the relationship between the presence of AHRE and the coronary sinus (CS) serum sampling of galectin-3 levels in the long-term follow-up of cardiac resynchronization therapy (CRT) patients. A total of 108 consecutive CRT patients were included prospectively in the study. AHREs were defined as atrial tachyarrhythmia episodes lasting at least 6 min with atrial rate >190 beats/min detected by cardiac implantable electronic device. CS blood samples were drawn from the CS guiding catheter to perform galectin-3 measurements. Galectin-3 levels were measured via ELISA. During a mean follow-up 12.6±4.9 months, AHRE was observed in 31 (28.7%) patients and not observed in 77 (72.3%) patients. CS galectin-3 levels were significantly higher in patients with AHRE than those without AHRE (18.09±2.62 vs 13.17±3.17, respectively, p<0.001). Moreover, CS galectin-3 levels showed significant positive correlation with percent of time spent in total AHRE (r=0.436, p<0.001). Multivariate logistic regression analysis demonstrated that left atrium (LA) volume and CS galectin-3 levels were significant and independent predictors for AHRE (OR=1.127, 95% CI: 1.045 to 1.216; p=0.002, OR=1.799, 95% CI: 1.388 to 2.330; p<0.001, respectively). In this study, we determined that high CS galectin-3 levels were a predictor for the development of AHRE in CRT patients.
Significance of this study
What is already known about this subject?
It has been reported in the literature that galectin-3 plays a role in the development of atrial fibrillation (AF) by contributing to atrial remodeling.
The relationship of atrial high-rate episode (AHRE) episode duration over 5–6 min with the development of clinically documented AF has been reported.
Clinical AF, thromboembolic and cardiac adverse events have been reported in cardiac resynchronization therapy (CRT) patients with AHRE episodes.
What are the new findings?
CS galectin-3 levels were significantly higher in patients with AHRE than those without AHRE.
In the correlation analysis, in the patient group with AHRE, CS galectin-3 levels showed significant positive correlation with percent of time spent in total AHRE.
CS galectin-3 levels were a predictor for the development of AHRE in the long-term follow-up of patients undergoing CRT implantation.
How might these results change the focus of research or clinical practice?
Galectin-3 may be an important activator and marker of the fibrotic and inflammatory process, which forms the pathophysiological basis of AHRE development that is closely related to cardiovascular adverse events.
Introduction
Galectin-3 is a member of the β-galactoside-binding lectin family which binds matrix proteins such as cell surface receptors, collagen, elastin or fibronectin.1 Galectin-3 acts as a mediator in the conversion of fibroblasts into activated myofibroblasts and increases the release of matrix proteins involved in fibrogenesis.2 Studies have shown that galectin-3 is associated with atrial structural and electrical remodeling and plays a role in the development of atrial fibrillation (AF).3 4 Also it has been found that galectin-3 level is associated with poor prognosis in patients with AF and increases the risk of recurrence after ablation.5 6 A recent study by Gürses et al showed that levels of galectin-3 were associated with early AF recurrence following direct-current cardioversion in patients with persistent AF.7 Moreover, the relationship of galectin-3 levels with the presence and extent of atrial fibrosis has been reported.3
Atrial high-rate episode (AHRE) is commonly seen in patients with cardiac implantable electronic devices (CIEDs). In the follow-up of patients with CIEDs, AHRE has developed between 30% and 70% according to the definition and duration of AHRE and clinical features of the patients.8 9 The relationship of AHRE episode duration over 5–6 min with the development of clinically documented AF has been reported.10 In addition, it has been demonstrated that the development of AHREs is associated with increased risk of stroke and systemic embolism in large studies.11 12 Cardiac resynchronization therapy (CRT) is a well-established treatment option for patients with congestive heart failure (HF), widened QRS complex and signs of electrical dyssynchrony.13 There are limited number of studies in the literature that investigate the relationship between the presence of AHRE and clinical outcomes in CRT patients. In these studies, increased clinical AF, thromboembolic and cardiac adverse events have been reported in CRT patients with AHRE episodes.14 15
The aim of the present study is to determine the relationship between the presence of AHRE and the coronary sinus (CS) galectin-3 levels in the long-term follow-up of CRT patients.
Materi̇als and methods
Study population
A total of 108 consecutive patients between February 2017 and February 2019 who underwent CRT (Protecta-Medtronic and Dynagen, Inogen-Boston Scientific, USA) implantation according to the CRT indications determined by ESC Acute and Chronic Heart Failure guideline16 were enrolled in this prospective study. At baseline, demographic characteristics and medical conditions including comorbidities and medications were recorded for all of the patients. The CHA2DS2-VASc were calculated using the baseline patient profile as follows: HF, hypertension, age ≥75 years (2 point), diabetes mellitus, previous stroke/transient ischemic attack (2 point), vascular disease, age 65–75 years, female sex. Patients with <3 months of follow-up after CRT implantation, those with a history of AF, the development of documented AF during follow-up, patients with AF ablation and exitus patients were excluded from the study.
Device implantation
At the time of device implantation, baseline CS blood samples were drawn from the CS guiding catheter prior to delivering the CRT left ventricular (LV) lead to perform galectin-3 measurements. Then, the LV lead was implanted in the CS to achieve permanent epicardial stimulation as described previously by Pitzalis et al.17 A lateral and posterolateral site were chosen as the primary area if it was accessible, pacing threshold was sufficient and phrenic nerve stimulation was absent. The right ventricular (RV) lead was implanted in the RV apex or septal wall and right atrial lead was implanted in the right atrial appendage. The CRT devices and leads used were manufactured by Medtronic (Model Protecta, USA) and Boston Scientific (Model Dynagen-Inogen, USA). The pacing mode was set as DDD (dual chamber pacemaker), which was programmed to maximize biventricular pacing. Non-responsiveness to CRT was defined as the absence of improvement in the patients’ symptoms, New York Heart Association (NYHA) functional class and/or their echocardiographic parameters (<15% decrease in the LV end-systolic volume) and hospitalization due to decompensated HF despite optimal medical therapy at least 3 months after the implantation of the CRT devices.
Atrial high-rate episodes detection and evaluation
AHREs were defined as atrial tachyarrhythmia episodes lasting at least 6 min with atrial rate >190 beats/min detected by CIEDs, enabling the exclusion of most noise from non-cardiac origin.18 19 The accurate diagnosis of AHRE was evaluated by experts from cardiac electrophysiology team. Per cent of time spent in total AHRE, duration of the longest AHRE, number of total AHRE, time to detection of first AHRE were calculated separately for every patient during the follow-up period. The follow-up duration was defined as the time period from the date of device implantation to last date of hospital visit (including device clinic visit and specialist clinic visit). The device diagnostic information was interrogated to assess whether patients had developed AHRE or not at 1-3-6 months and thereafter every 6 months since the time of CIEDs implantation.
Standard echocardiography
All patients underwent conventional two-dimensional transthoracic echocardiography evaluations before CRT implantation. Echocardiographic examinations were performed by an experienced cardiologist with GE Vingmed Vivid 7 (GE Vingmed Ultrasound, Horten, Norway) echocardiography device in the left lateral decubitus position. Parasternal long-axis, short-axis, apical four-chamber and two-chamber images were taken and the evaluation was made according to the criteria of the American Society of Echocardiography using M-mode, two-dimensional, continuous wave Doppler, pulse wave Doppler method.20 The ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) was calculated and used as an index of LV diastolic function. Left atrium (LA) volume was measured from standard apical two-chamber and four-chamber views at end-systole. LA volumetric analyses were performed using the biplane Simpson’s method and subsequently indexed to body surface area for left atrial volume index (LAVI) measurements.
Biochemical measurements
Biochemical and hematological parameters were measured from peripheral venous blood samples. Biochemical parameters were measured on Abbott ARCHITECT c8000 (Abbott Laboratories, Illinois USA) autoanalyzer using commercial kits. Hematological parameters were studied with Abbott Cell Dyn 3700 (Abbott Laboratories) device by laser and impedence method. Galectin-3 levels were measured from CS blood samples. Galectin-3 in EDTA-serum samples were stored at −80°C until ELISA analysis was made. Serum galectin-3 levels were determined using Multiwash (TriContinent Scientific, USA) and Synergy 4 Microplate Reader (Biotek, USA) devices and Human Galectin-3 Platinum ELISA kit (eBioscience, San Diego, USA) by working according to the manufacturer’s instructions with ELISA method. The standard curve was created by applying the five-parameter curve fit method and the results were calculated as ng/mL according to this curve. High-sensitive C reactive protein (hs-CRP) (CardioPhase) was measured quantitatively in BN II System Nephelometer (Dade Behring, Marburg, Germany) by immunonephelometric method from patients’ serum and the results were reported in ng/mL.
Statistical analysis
Statistical analysis was carried out using Statistical Package for the Social Sciences for Windows V.15.0 (SPSS, Chicago, Illinois, USA). Descriptive statistics were given as mean, SD and percentage. The distribution of the data was analyzed with the Kolmogorov-Smirnov test and logarithmic transformation was applied to the data that did not have normal distribution. Independent samples t-test was used for continuous variables and χ2 test was used for categorical data. Any correlation between data was tested with the Spearman’s correlation analysis. Univariate and multivariate logistic-regression analysis (Forward Stepwise) were also performed and potential confounders (age, CHA2DS2VASC score, coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), left ventricular ejection fraction (LVEF), LA volume, hs-CRP, galectin-3) were included for the model. Receiver-operating characteristic (ROC) curves analysis was performed to evaluate the potential of galectin-3 for prediction of AHRE. P values <0.05 were considered to be statistically significant.
Results
Baseline patient characteristics
We included 108 consecutive patients undergoing CRT implantation. Baseline characteristics of patients were shown in table 1. During a mean follow-up 12.6±4.9 months, AHRE was observed in 31 (28.7%) patients, and not observed in 77 (72.3%) patients. Age (p=0.032), CAD (p=0.038), COPD (p=0.020) were significantly higher in patients with AHRE than those without AHRE. Serum hs-CRP values were significantly higher in patients with AHRE compared with patients without AHRE, whereas glomerular filtration rate (GFR) values were significantly lower. In patients with AHRE, the CHA2DS2VASC score was significantly higher than those without AHRE (5.0±1.5 vs 3.8±1.3, respectively, p<0.001). LA volume, LA diameter, LAVI and E/e' ratio were significantly higher in patients with AHRE than those without AHRE. Also, LVEF and CRT biventricular pacing rates were significantly lower in patients with AHRE. Non-response to CRT was detected in 8 (25.8%) patients with AHRE while non-response to CRT was detected in 15 (19.5%) patients without AHRE (p=0.527). ACE/angiotensin receptor blocker and antiplatelet treatment use were significantly higher in patients with AHRE. According to the NYHA functional classification, the majority of patients were class III (75%). During the follow-up, hospitalization for worsening of HF was significantly higher in patients with AHRE than in patients without AHRE (29.0% vs 13.0%, respectively, p=0.047).
Atrial high-rate episode parameters during follow-up
In patients with AHRE, per cent of time spent in total AHRE was 0.107%±0.053%, duration of the longest AHRE was 2.17±2.43 hours, number of total AHRE was 7.77±5.67 and time to detection of first AHRE was 5.42±3.37 months during the follow-up (table 2).
Galectin-3 levels and atrial high-rate episode parameters
CS galectin-3 levels were significantly higher in patients with AHRE than those without AHRE (18.09±2.62 vs 13.17±3.17, respectively, p<0.001) (figure 1). In the correlation analysis, in patients with AHRE, CS galectin-3 levels showed significant positive correlation with percent of time spent in total AHRE (r=0.436, p<0.001) (table 3). There was no significant correlation between CS galectin-3 levels and duration of the longest AHRE, number of total AHRE and time to detection of first AHRE.
Predictive parameters of atrial high-rate episodes
Simple logistic regression analysis revealed that age (OR=1.052, 95% CI: 1.004 to 1.103; p=0.034), CHA2DS2VASC≥2 score (OR=1.909, 95% CI: 1.346 to 2.707; p<0.001), CAD (OR=3.245, 95% CI: 1.024 to 10.283; p=0.045), COPD (OR=3.190, 95% CI: 1.169 to 8.710; p=0.024) LVEF (OR=0.874, 95% CI: 0.792 to 0.964; p=0.007), LA volume (OR=1.142, 95% CI: 1.079 to 1.209; p<0.001), hs-CRP (OR=1.259, 95% CI: 1.027 to 1.544; p=0.027) and CS galectin-3 levels (OR=1.787, 95% CI: 1.415 to 2.257; p<0.001) showed an association with the presence of AHRE. These variables were entered into a backward stepwise multivariable logistic regression model. Multivariate logistic regression analysis demonstrated that LA volume and CS galectin-3 levels were significant and independent predictors for AHRE (OR=1.127, 95% CI: 1.045 to 1.216; p=0.002, OR=1.799, 95% CI: 1.388 to 2.330; p<0.001, respectively) (table 4).
The ability of CS galectin-3 levels to differentiate patients with AHRE from those without AHRE was assessed by ROC curve analysis. ROC curves for the occurrence of AHRE had an area under curve (AUC) of 0.881. The optimal cut-off value of CS galectin-3 levels for the prediction of AHRE was 15.1 ng/mL. CS galectin-3 levels cut-off value of 15.1 ng/mL had sensitivity of 87.1% and specificity of 71.4% for the presence of AHRE (figure 2).
Discussion
In our study, we determined that CS galectin-3 levels were a predictor for the development of AHRE in the long-term follow-up of patients undergoing CRT implantation. Moreover, CS galectin-3 levels were significantly correlated with per cent of time spent in total AHRE episodes.
Galectin-3 is an inflammation biomarker released from activated macrophages that causes cardiac fibrosis through fibroblast proliferation, collagen storage and myocyte dysfunction.21 It has been reported in the literature that galectin-3 plays a role in the development of AF by contributing to atrial remodeling.22 In meta-analyses, high galectin-3 levels were also found to be an independent predictor for AF recurrence after ablation.23 In the Atherosclerosis Risk in Communities study, high plasma galectin-3 level was shown to be closely related to the development of CAD and HF with an increase in the incidence of AF.24 In the Cardiac Resynchronization in Heart Failure study, baseline serum galectin-3 levels were reported to be associated with death and hospitalization for HF in CRT patients.25
Atrial high-rate episodes detected by CIEDs (atrial rate >190 beats/min, >6 min and <24 hours) without prior diagnosis of AF with ECG or Holter monitoring was defined as subclinical AF in the European Heart Rhythm Association consensus document published in 2017.18 In the Asymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial (ASSERT) study, AHRE (atrial rate >190 beats/min with >6 min) developing in CIEDs patients was described as new-onset AF, and subclinical AF development rate was found to be 34.7% at 2.5-year follow-up.19 In another large-scale study, TRENDS (A Prospective Study of the Clinical Significance of Atrial Arrhythmias Detected by Implanted Device Diagnostics), the development rate of AHRE (atrial rate >175 beats/min with >5 min) was observed as 30% at 1.1±0.7 years follow-up.12 In our study, CRT patients were followed for 12.6±4.9 months and the rate of AHRE (atrial rate >190 beats/min with >6 min) was determined as 28.7% like previous studies. Although it has been revealed in many studies that AHRE episodes with a duration of ≥5–6 min increase the risk of developing stroke and thromboembolism (TE), there is still uncertainty regarding the minimum duration of device-detected AHRE that increases TE risk.26
A few studies have assessed the clinical impact of device-detected AHRE in patients with HF and CRT. Witt et al 15 concluded that the risk of clinical AF development increased in CRT patients with AHRE and over 24 hours AHRE was closely related to TE. In the study by Borleff et al,14 shock therapy (appropriate or inappropriate) and all cardiac hospitalizations were reported more frequently in CRT patients with AHRE compared with the patients with sinus rhythm. Moreover, this study showed that recipients of CRT who developed new-onset AF showed less echocardiographic response to CRT. Similarly, in our study, patients with AHRE had higher non-response to CRT than patients without AHRE. Santini et al 27 followed up 1193 patients with CRT for a median of 13 months in their study and found that death and HF hospitalizations were higher in patients with device-detected AT/AF. In a study by Shanmugam et al, 28 TE, AF, HF and cardiovascular death were significantly higher in patients with AHRE burden cut-off point 3.8 hours over 24 hours. Likewise, in our study, CRT patients with AHRE were found to have significantly higher hospitalization for worsening of HF during follow-up than those without AHRE. In the literature, studies also investigated the relationship between serum galectin-3 level and atrial thrombogenicity. In a study by Koçyiğit et al, serum galectin-3 levels were found to be associated with LA appendage (LAA) located spontaneous echo contrast and thrombus formation and also LAA flow velocity decreased in high serum galectin-3 levels.29 Another study revealed that serum galectin-3 levels were significantly correlated with LAA remodeling and high levels of galectin-3 were also a predictor for LAA thrombus formation in patients with AF.30 Considering the relationship between atrial fibrosis and the development of LA/LAA located thrombus,31 32 high CS galectin-3 levels may lead to the development of LAA thrombus formation by contributing to atrial fibrosis and remodeling. Therefore, CS galectin-3 levels were associated with the development of AHRE in CRT patients as well as it may be an effective biomarker as an indicator of increased atrial thrombogenicity in patients with AHRE. In the light of the studies mentioned above, clinical and laboratory parameters that can be predictors for the development of AHRE, which is closely related to cardiac adverse events, are important in the follow-up of CRT patients.
Tissue injuries detected in atrial fibrosis cause galectin-3 synthesis and secretion which advance AF progression via by atrial extracellular matrix production. Therefore, increased galectin-3 levels may contribute to the mechanism of ‘atrial fibrillation begets atrial fibrillation’.33 In their cardiac magnetic resonance study, Yalcın et al 3 stated that serum galectin-3 levels showed significant correlation with the extent of left atrial fibrosis. The degree of atrial fibrosis was predictive for AF recurrence after AF catheter ablation. In the study by Berger et al,34 it was concluded that changes in serum galectin-3 level reflected the changes in the arrhythmogenic atrial substrate. Galectin-3 plays a role in cardiac fibrosis, and in lung, liver, kidney and vascular fibrosis.35–38 On account of this, in our study, CS galectin-3 levels may be more accurate and specific than peripheral venous strategies for predicting AHRE episodes in the follow-up period of the patients undergoing CRT.
‘AF-induced atrial remodeling’ has been tried to be explained by various mechanisms such as oxidative stress, atrial dilatation, calcium-overload, inflammation, TRCP channel-mediated myofibroblast activation in persistent AF. This shows us the contribution of AF duration to atrial remodeling.39 AHREs of longer duration are a predictor for the development of clinically documented AF and the increased risk of TE. Also, increased duration of AHRE may be attributed to increased atrial structural and electrical remodeling.18 Recently, Lenarcyk et al 40 analyzed device-collected data on AF episodes during 24 months in a randomized CRT trial and reported that each additional per cent of time spent in AF was moderately sensitive but highly specific in predicting mortality, increasing its risk by 5%. For this reason, the patients’ cumulative duration of AHRE is important. In our study, we detailed AHRE parameters and made correlation analysis with CS galectin-3 levels. While the CS galectin-3 levels were significantly higher in the group with AHRE, it showed a significant correlation with ‘per cent of time spent in total AHRE episodes’. However, it did not correlate with ‘duration of the longest AHRE episode’, ‘number of total AHRE episodes’ and ‘time to detection of first AHRE episode’. In the light of these results, we are in the conclusion that the time spent in total AHREs in the follow-up of CRT patients reflects atrial fibrosis and remodeling better and is more important for development of clinical AF. Another striking point of our study was that CS galectin-3 levels were an independent predictor for AHRE development in multivariate analysis. According to this result, we think that galectin-3 is a potential mediator in the fibrotic and inflammatory ‘atrial substrate’, which forms the patholophysiological basis of AHRE development. CS galectin-3 levels which were closely related to AHRE as a predictor for both cardiac adverse events and documented AF, might be of clinical importance in the follow-up and in the management of treatments in patients with CRT. Although there are many studies in the literature that reveal the relationship between galectin-3 and AF, our study is the first prospective long-term follow-up study which examines the CS galectin-3 levels and the development of AHRE in CRT patients.
Although the CHADVASC score is used as a risk predictor for TE in patients with AF, it has been reported that the CHA2DS2-VASC score may also be predictive for the risk of new-onset AF.41 In our study, the CHA2DS2-VASC score was significantly higher in the group with AHRE than those without AHRE. Moreover, CHA2DS2-VASC ≥2 showed an association with the presence of AHRE. This result might be explained by the fact that the components of the CHA2DS2-VASC score contribute to the development of AF as well as to the development of AHRE. CAD has been shown to play an important role in the onset and progression of AF. CAD can lead to LV dysfunction and elevate left atrial pressure that may contribute to structural changes within the atrial myocardium, providing the arrhythmogenic substrate for AF.42 Patients with COPD, often suffer from atrial tachycardias and AF. Multiple pathophysiological mechanism can contribute to AF in COPD, including hypoxia, hypercapnia and inflammation.43 We think that the mechanisms mentioned above that contribute to AF development in CAD and COPD patients, may also affect AHRE development in these patients. Similarly, in our study, CAD and COPD were significantly higher in patients with AHRE than those without AHRE. However, CAD and COPD were not an independent predictor for the presence of AHRE in the long-term follow-up of patients undergoing CRT implantation. The relation between LA dimension and atrial arrhythmia has been well known. Atrial dilatation alters the effective refractory period in different atrial regions creating the perfect substrate for atrial arrhythmias.44 In a study, high LAVI values were associated with worse LV remodeling, poor diastolic dysfunction and high incidence of AF in patients with HF with severely impaired LV systolic function.45 Xu et al 46 found that left atrial volume index was higher in CRT-D patients who developed AHRE and LAVI was an independent predictor for the development of newly detected, post-CRT-D AHRE. Similarly, in our study, it was observed that the LA volume was an independent predictor for AHRE development.
The present study had some limitations. First, this was a single-center study, where only a small study population was analyzed. Second, we were not able to completely evaluate the prognostic value of CS galectin-3 levels on cardiovascular outcomes in CRT patients with AHRE.
Conclusion
In this study, we determined that high CS galectin-3 levels were a predictor for the development of AHRE in the long-term follow-up of patients undergoing CRT implantation. In CRT patients, galectin-3 may be an important activator and marker of the fibrotic and inflammatory process, which forms the patholophysiological basis of AHRE development that is closely related to cardiovascular adverse events. The CS galectin-3 levels, which we found to be closely associated with AHRE, might play an important role in determining the treatment modalities and follow-up frequency in CRT patients.
Footnotes
Contributors Conception and design: GA, AY, OCY. Data collection and processing: GA, AY, OCY, UA. Analysis and interpretation: GA, UA, KS, ÖG. Literature review: GA, ÖG, UA, KS. Writer: GA. Critical review: AY, UA, ÖG, OCY, KS.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Samsun Education and Research Hospital ethics committee (approval number: GOKA/2017/9/7). The study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from all patients.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request.