Relationship of inflammatory indices with left atrial appendage thrombus or spontaneous echo contrast in patients with atrial fibrillation

Abstract

BACKGROUND

Inflammatory indices derived from complete blood tests have been reported to be associated with poor outcomes in patients with atrial fibrillation (AF). The data about the relationship between inflammatory indices and left atrial appendage thrombus (LAAT) or dense spontaneous echo contrast (SEC) are limited.

AIM

To explore the value of inflammatory indices for predicting the presence of LAAT or dense SEC in nonvalvular AF patients.

METHODS

A total of 406 patients with nonvalvular AF who underwent transesophageal echocardiography were included and divided into two groups based on the presence (study group) or absence (control group) of LAAT or dense SEC. Inflammatory indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet–to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR), were calculated from complete blood analysis. The associations of inflammatory indices with LAAT/dense SEC were analyzed using logistic regression.

RESULTS

LAAT and dense SEC were detected in 11 (2.7%) and 42 (10.3%) patients, respectively. The PLR only showed an association with LAAT/dense SEC in the univariate model. Elevated NLR (odds ratio [OR] = 1.48, 95% confidence interval [CI]: 1.11-1.98, P = 0.007) and reduced LMR (OR = 0.59, 95%CI: 0.41-0.83, P = 0.003) were found to be independent risk factors for the presence of LAAT/dense SEC. The areas under the NLR and LMR curves for predicting LAAT/dense SEC were 0.73 (95%CI: 0.66-0.80, P < 0.001) and 0.73 (95%CI: 0.65-0.81, P < 0.001), respectively, while the cutoff values were 2.8 (sensitivity: 69.8%; specificity: 64.0%) and 2.4 (sensitivity: 71.7%; specificity: 60.6%), respectively.

CONCLUSION

Increased NLR and decreased LMR may predict LAAT/dense SEC in patients with nonvalvular AF.

Key Words: Nonvalvular atrial fibrillation, Left atrial appendage thrombus, Spontaneous echo contrast, Neutrophil–lymphocyte ratio, Lymphocyte–monocyte ratio

Core Tip: Atrial fibrillation (AF) increases the risk of ischemic stroke. One of the most powerful risk factors for ischemic stroke is the development of a thrombus and spontaneous echo contrast (SEC) in the left atrial appendage (LAA). Inflammatory state increases the propensity for thrombosis in AF patients. Therefore, we explored the value of inflammatory indices for predicting the presence of LAA thrombus or dense SEC. The results showed that some inflammatory indices derived from complete blood tests, including the neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio, may predict LAA thrombus or dense SEC in patients with nonvalvular AF.

INTRODUCTION

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the clinical setting[1]. AF increases the risk of ischemic stroke by 4-5-fold, accounting for approximately 15% of all ischemic strokes[2,3]. One of the most powerful risk factors for ischemic stroke is the development of left atrial (LA) thrombus and spontaneous echo contrast (SEC)[4]. The majority of atrial thrombi originate in the LA appendage (LAA)[5].

Currently, the prevention of thromboembolic events is the main concern for the management of AF. Transesophageal echocardiography (TEE) is not only the most reliable and sensitive method to verify the presence of thrombotic mass in the LAA but also an important tool in decision-making with both therapeutic and prognostic implications. The presence of echocardiographic mass is an important factor in treatment decisions regarding cardioversion and catheter ablation despite the fact that effective anticoagulation is considered to be one of the most important prerequisites of these interventions. Various factors, including the thrombotic state, activation of the acute phase response, and inflammatory state, are among the significant factors that increase the propensity for thrombosis in AF patients[6,7].

Previous investigations have demonstrated the relationship between inflammation and thrombus formation in patients with nonvalvular AF. Katoh et al[8] reported that Toll-like receptor 4 signaling may play a role in atrial thrombogenesis in AF patients with heart failure. The study of Pfluecke et al[9] showed that the content of monocyte-platelet aggregates and the CD11b expression on monocytes and granulocytes are increased in AF patients with proven thrombus formation and seem to be appropriate biomarkers for stratification of thromboembolic risk in patients with AF. However, the above-mentioned biomarkers are not usually available in routine clinical settings. Complete blood count (CBC) is an easy and reproducible test performed at the bedside or by emergency services. Thus, the present study was conducted to explore whether CBC-derived inflammatory indices could be used to predict the presence of thrombus or dense SEC in the LAA in patients with nonvalvular AF.

MATERIALS AND METHODS

Study population

Nonvalvular AF patients who underwent TEE between March 2015 and February 2019 were reviewed. The demographic and clinical data, including age, sex, and comorbidities, were collected. Serum creatinine levels were recorded, and the estimated glomerular filtration rate was calculated by the CKD-EPI equation[10]. The CBC parameters (including the number of neutrophils, lymphocytes, monocytes, and platelets) and C-reactive protein (CRP) were obtained from the medical records on the same day. The neutrophil–to-lymphocyte ratio (NLR), platelet–to-lymphocyte ratio (PLR), and lymphocyte–to-monocyte ratio (LMR) were calculated based on the results of the CBC. The exclusion criteria were as follows: (1) Patients with mechanical valves or moderate-to-severe mitral stenosis; (2) patients with chronic kidney disease, malignancy, connective tissue diseases, or chronic systemic disease; and (3) patients with recent acute infectious or inflammatory disease, high body temperature > 38 ℃, and white blood cell count > 12 × 10⁹/L or < 4 × 10⁹/L.

TEE

TEE was performed using a PHILIPS EPIQ7C device (PHILIPS, Amsterdam, Netherlands). The gain was continuously adjusted until the best image was obtained. The presence or absence of LAA thrombus (LAAT) or SEC was determined by two experienced echocardiographers. A thrombus was defined as an echodense mass with uniform tissue different from that of the LA endocardial wall[11]. SEC was defined as an echogenic, swirling pattern of blood flow at the standard gain setting during the cardiac cycle and was graded according to the Fatkin classification[12]. An SEC grade of 3 or 4 was considered dense.

Statistical analysis

The study patients were divided into two groups according to the presence (study group) or absence (control group) of LAAT/dense SEC. Normally distributed continuous variables are expressed as the mean ± SD and were compared using the t test. Skewed continuous variables are expressed as medians (interquartile ranges) and were compared using the Mann-Witney U test. Categorical variables are expressed as n (%) and were compared using the χ² test or Fisher’s exact test where appropriate.

Univariate and multivariate logistic regression analyses were performed to explore the associations of potential variables with LAAT/dense SEC. The multivariate model included variables with a P value < 0.1 in the univariate model. Odds ratios [ORs] and 95% confidence intervals [CIs] were calculated. Receiver operating characteristic (ROC) curve analysis was performed to assess the ability of inflammatory indices to predict LAAT/dense SEC. The optimal cutoff value was determined, as was the area under the curve (AUC). Statistical analyses were performed with SPSS 19.0 (IBM, Armonk, NY, United States), and a P value < 0.05 (two-tailed) was considered to indicate statistical significance.

RESULTS

Baseline characteristics

A total of 416 patients with nonvalvular AF who underwent TEE were consecutively screened. We excluded 10 subjects because of systemic inflammatory conditions. Finally, 406 patients were included in the study. LAAT and dense SEC were detected in 11 (2.7%) and 42 (10.3%) patients, respectively. Thus, the study population was divided into a study group (n = 53) and a control group (n = 353) (Table 1). The percentage of patients with paroxysmal AF (34.6% vs 15.1%, P = 0.005) and diabetes mellitus (18.7% vs 7.5%, P = 0.045) was significantly higher in the control group than in the study group. The LA diameter (47.6 ± 6.6 mm vs 44.5 ± 7.4 mm, P = 0.004) in the study group was greater than that of the control group.

Table 1 Baseline characteristics of patients with or without left atrial appendage thrombus/dense spontaneous echo contrast.

Variable	Study group	Control group	P value
n	53	353	-
Age, years	69.0 ± 9.5	69.4 ± 8.7	0.731
Male	34 (64.2)	224 (63.5)	0.922
Body mass index, kg/m2	24.3 ± 3.5	24.4 ± 3.4	0.943
Paroxysmal AF	8 (15.1)	122 (34.6)	0.005
Hypertension	38 (71.7)	233 (66.0)	0.412
Diabetes mellitus	4 (7.5)	66 (18.7)	0.045
Congestive heart failure	9 (17.0)	43 (12.2)	0.330
Coronary heart disease	5 (9.4)	31 (8.8)	0.799
Prior TIA/stroke	34 (64.2)	256 (72.5)	0.208
CHA2DS2-VASc score	4.4 ± 1.7	4.6 ± 1.5	0.273
LA diameter, mm	47.6 ± 6.6	44.5 ± 7.4	0.004
LVEF, %	60.8 ±6.3	62.0 ± 6.7	0.231
LAA orifice diameter, mm	24.8 ± 4.4	24.7 ± 5.0	0.876
LAA depth, mm	30.5 ± 4.9	29.3 ± 5.8	0.151
Uric acid, μmol/L	374.1 ± 95.4	350.4 ± 91.2	0.081
eGFR, mL/min/1.73 m2	84.0 ± 24.7	85.2 ± 23.5	0.735

AF: Atrial fibrillation; TIA: Transient ischemic attack; OAC: Oral anticoagulation; LA: Left atrium; LVEF: Left ventricular ejection fraction; LAA: Left atrial appendage; eGFR: Estimated glomerular filtration rate.

Comparison of inflammatory indices between groups

The CBC test parameters and inflammatory indices are displayed in Table 2. The neutrophil, monocyte, and platelet counts were greater, while the lymphocyte count was lower in the study group than in the control group. In addition, the CRP level was greater in the study group. The NLR (3.8 ± 1.9 vs 2.6 ± 1.2, P < 0.001) and PLR (164.8 ± 58.5 vs 134.1 ± 53.4, P < 0.001) were greater, while the LMR (1.8 ± 1.2 vs 2.9 ± 1.3, P < 0.001) was lower in the study group than in the control group.

Table 2 Inflammatory indices of patients with or without left atrial appendage thrombus /dense spontaneous echo contrast.

Variable	Study group	Control group	P value
n	53	353	-
Neutrophil count, × 109/L	4.5 ± 1.8	3.7 ± 1.3	0.004
Lymphocyte count, × 109/L	1.3 ± 0.3	1.6 ± 0.5	< 0.001
Monocyte count, × 109/L	0.7 (0.5-1.4)	0.6 (0.5-0.6)	< 0.001
Platelet count, × 109/L	197.2 ± 62.7	193.3 ± 60.0	< 0.001
CRP, mg/L	1.1 (0.5-3.1)	0.5 (0.4-1.2)	< 0.001
NLR	3.8 ± 1.9	2.6 ± 1.2	< 0.001
LMR	1.8 ± 1.2	2.9 ± 1.3	< 0.001
PLR	164.8 ± 58.5	134.1 ± 53.4	< 0.001

CRP: C-reactive protein; NLR: Neutrophil-lymphocyte ratio; LMR: Lymphocyte-monocyte ratio; PLR: Platelet-to-lymphocyte ratio.

NLR and LMR are associated with LAAT/dense SEC

The effects of multiple variables on LAAT/dense SEC were analyzed using univariate and multivariate logistic regression analyses (Table 3). Nonparoxysmal AF, larger LA diameter, increased CRP level, greater NLR and PLR, and lower LMR were associated with a greater incidence of LAAT/SEC in the univariate model. According to the multivariate analysis, high NLR (OR = 1.48, 95%CI: 1.11-1.98, P = 0.007) and low LMR (OR = 0.59, 95%CI: 0.41-0.83, P = 0.003) were found to be independent risk factors for the presence of LAAT/dense SEC in patients with nonvalvular AF.

Table 3 Predictors of left atrial appendage thrombus/spontaneous echo contrast according to univariate and multivariate logistic analyses.

Variable	Univariable analysis		Multivariable analysis
	OR (95%CI)	P value	OR (95%CI)	P value
Nonparoxysmal AF	2.97 (1.36-6.50)	0.006	1.67 (0.71-3.95)	0.243
Diabetes mellitus	0.36 (0.12-1.02)	0.054	0.37 (0.12-1.18)	0.093
LA diameter, per 1 mm increase	1.06 (1.02-1.10)	0.005	1.04 (0.99-1.09)	0.121
Uric acid, per 10 μmol/L increase	1.03 (0.99-1.06)	0.082	1.03 (0.99-1.06)	0.113
CRP, per 1 mg/L increase	1.06 (1.01-1.11)	0.012	1.04 (0.98-1.09)	0.171
NLR, per 1 unit increase	1.75 (1.41-2.18)	< 0.001	1.48 (1.11-1.98)	0.007
LMR, per 1 unit increase	0.43 (0.31-0.59)	< 0.001	0.59 (0.41-0.83)	0.003
PLR, per 10 units increase	1.10 (1.04-1.15)	< 0.001	1.00 (0.93-1.07)	0.893

AF: Atrial fibrillation; LA: Left atrium; CRP: C-reactive protein; NLR: Neutrophil-lymphocyte ratio; LMR: Lymphocyte-monocyte ratio; PLR: Platelet-to-lymphocyte ratio.

The ROC analysis for the NLR as a predictor of LAAT/dense SEC showed an AUC of 0.73 (95%CI: 0.66-0.80, P < 0.001). A cutoff value of 2.8 for the NLR was associated with a sensitivity of 69.8% and specificity of 64.0% for predicting LAAT/dense SEC (Figure 1A). The AUC for the LMR was 0.73 (95%CI: 0.65-0.81, P < 0.001). The cutoff value of the LMR was 2.4, yielding a sensitivity and specificity of 71.7% and 60.6%, respectively (Figure 1B).

Figure 1 Receiver operating characteristic curves of the neutrophil-lymphocyte ratio and lymphocyte-monocyte ratio in predicting left atrial appendage thrombus/dense spontaneous echo contrast. A: Neutrophil-lymphocyte ratio; B: Lymphocyte-monocyte ratio. AUC: Area under the curve.

DISCUSSION

The presence of LAAT in patients with AF is significantly and independently associated with thromboembolic events. The SEC observed via TEE is considered a known precursor to thrombus formation and thromboembolic events[13-15]. A previous investigation showed that a dense LA SEC was related to late stroke even after catheter ablation[16]. Therefore, the prediction of LAAT/dense SEC has become important for identifying appropriate thromboprophylaxis in AF patients. Various factors, either biomarkers or echocardiographic parameters, are associated with LAAT/dense SEC[17-19].

Chronic inflammation may cause both arterial and venous thrombosis[20]. Some inflammatory factors are related to atrial thrombus formation in AF patients[8,9]. However, testing for these markers is expensive, and the equipment needed to test these markers is not accessible in routine clinical practice. A previous study indicated that the CRP level was significantly correlated with the presence of SEC and thrombus[21]. However, the CRP level is also elevated in some noninflammatory diseases, such as rheumatoid systemic diseases and acute coronary syndrome. Inflammation-related CBC parameters can be classified into two groups: Upregulated variables during disease progression (neutrophils, platelets, and monocytes) and downregulated variables during disease progression (lymphocytes). The combination of the two can be used as an inflammation-related marker. Recently, several indices derived from the CBC test have been proposed as reliable systemic inflammatory markers and are associated with a worse prognosis in patients with various forms of cardiovascular disease (CVD)[22].

Current evidence suggests that high NLR may increase the risk of AF. A meta-analysis showed that high NLR, whether at baseline or after surgery/procedure, was associated with an increased risk of AF recurrence/occurrence[23]. Yalcin et al[24] included 309 patients with nonvalvular AF, and LA thrombi were detected in 32 patients via TEE. Multivariate analysis demonstrated that the NLR was independently associated with the presence of LA thrombus (OR = 1.59). However, dense SECs were not included in that investigation. This retrospective study included 183 paroxysmal AF patients, and LA SEC was detected in 30 individuals. Multivariate logistic analysis revealed that the NLR was significantly associated with LA SEC (OR = 1.86)[25]. However, the study sample was relatively small, and only paroxysmal AF patients were included. The present study included a relatively large sample, including both LAAT and SEC patients, and the results were concordant with those of previous investigations.

The LMR has recently been reported to be a prognostic factor in many diseases, especially in various malignancies[26]. Previous studies have shown that the LMR is a prognostic factor for some CVDs, e.g., myocardial infarction[27] and heart failure[28]. To our knowledge, there have been no investigations regarding LMR and LAAT/dense SEC in AF patients. We found that the LMR was an independent predictor of LAAT/dense SEC. A cutoff value of 2.4 yielded a moderate sensitivity and specificity.

Since the LAA is a common site of thrombus formation, the association of the NLR and LMR with LAAT/dense SEC has the potential to be a useful finding. In our previous study, we found that the LAA voltage was lower in patients with LAAT/SEC[15]. These findings suggested that fibrotic remodeling of the LAA substrate may be more significant in this subset of AF patients. Aguiar et al[29] reported that atrial fibrosis was correlated with the NLR. Therefore, the NLR is not only an inflammation marker but also a fibrosis marker. Patients with an elevated NLR and/or a reduced LMR should undergo TEE to evaluate the presence of LAAT or dense SEC. Moreover, LA/LAA function (e.g., strain or fibrosis) should be adequately evaluated. Finally, the treatment strategy (anticoagulation, catheter ablation, or LAA closure) should be determined based on the findings from the examinations.

This study has several limitations. First, this was a single-center, retrospective investigation. The relatively small proportion of patients with detected LAAT/dense SEC may influence the power of logistic regression. Second, although a relationship between inflammatory indices and LAAT/dense SEC was observed, data on LAA flow velocity, LAA anatomy, other specific inflammatory markers (e.g. interleukin-6 and procalcitonin), and so on were not available for all patients. Therefore, such data were not included in the current study. Finally, the impact of potential confounders, such as underlying inflammation or other comorbidities, should be explored further.

CONCLUSION

Inflammatory indices derived from the CBC test are widely available and reproducible. Elevated NLR and reduced LMR may be used to predict LAAT/dense SEC in patients with nonvalvular AF. Prospective studies with large sample sizes may clarify the exact predictive role of these parameters in daily clinical practice.

ACKNOWLEDGEMENTS

We would like to acknowledge all the patients included in this study.