The importance of inflammation in atrial fibrillation recurrence in patients with atrial fibrillation treated with Cryo balloon ablation

Abstract

Aim/background

Although atrial fibrillation is the most common rhythm problem, the results of treatment to restore sinus rhythm are still not satisfactory. Nearly half of patients undergoing ablation relapse within one year. Therefore, triggered activities may not be the only cause. Inflammation is quite common in AF. In this study, we investigated the effect of PIV, an inflammatory marker, on recurrence.

Methods

A total of 157 patients who underwent ablation with cryo balloon were included in the study. One-year follow-up was evaluated for causes of recurrence.

Results

When the inflammatory parameters between the two groups are analyzed, CRP (5.9 [5.0–6.9] vs 9.7 [7.6–11.9], p < 0.001), NL ratio (2.8 [2.5–3.0] vs 6.4 [5.0–6.8], p < 0.001), SII2 (618.5 [557.1–679.9] vs 1798.9 [1305.8–2292.1], p < 0.001), PIV (355.9 [313.4–398.4] vs 1832 [1317.8–2347.1], p < 001) were significantly higher in the AF recurrence group. ROC analysis showed that PIV had the best sensitivity and specificity.

Conclusions

Inflammation has been found to be a cause of AF recurrence and PIV is one of the best markers for this.

1. Introductions

Atrial fibrillation (AF) is the most common cardiac rhythm problem and the most common cause of hemodynamic instability and thromboembolic events. In addition to worsening patient quality of life, AF is associated with stroke, heart failure, and increased mortality [1]. Of course, for these reasons, the importance of the rhythm of the sinus is obvious. Although it is not easy to achieve sinus rhythm in most patients, this can be attempted with two treatment methods. Medical treatment and catheter ablation are the most important treatments today. Although medical treatment is prioritized in current guidelines, catheter ablation has become a candidate for the first place due to the developing experience in catheter ablation with good results [2]. Despite such progress and the advancement of ablation techniques, recurrence still occurs between in 20 % and to 50 % in of case within 1 year [3].

Therefore, triggered activities may not be the only cause. Studies have shown that inflammation is quite common in AF [4]. Several studies have reported necrosis of adjacent myocyte cells and higher levels of inflammatory markers (such as CRP, IL-6 (interleukin), IL-8 and TNF (tumor necrosis factor)) and well as higher proportions of neutrophils and lymphocytes in patients with AF compared to patients in sinus rhythm [[5], [6], [7], [8]]. While looking for these markers requires specialized methods and specialized devices, more useful biomarkers have recently come to the fore. The neutrophil to lymphocyte ratio and systemic immune inflammatory index are the most important of these. Now a newer and more useful marker, the Pan-Immune-Inflammation Value (PIV), has proven valuable in showing inflammation. As a new marker, PIV was evaluated as a predictor of inflammation with the addition of monocytes, which are effective in inflammation, to concepts such as N/L and SII, which were previously effective in predicting inflammation. A new marker came to the agenda and was considered to be effective in previous studies.

Studies on Pan-Immune-Inflammation Value suggest that it may be more specific in inflammation Mortality and morbidity studies in coronary artery disease and cancer patients have come to the fore [9,10]. The association between PIV and AF recurrence has not yet been documented. Therefore, in this study, we investigated the association between PIV and recurrence in AF patients undergoing cryo balloon ablation.

2. Method

2.1. Study populations

The study was designed as a single-center cross-sectional retrospective study. It was performed on patients who underwent cryo balloon ablation for atrial fibrillation between 2019 and 2023 with a mean follow-up of 1 year. A total of 190 patients were included in the study. After applying the exclusion criteria and excluding patients who did not attend the follow-up periods, a total of 157 patients were included in the final analysis. Echocardiography and electrocardiography data were evaluated individually before the procedure. AF was diagnosed in patients with unequal R-R intervals longer than 30 s according to ECG (electro cardio grapy) evaluation in whom no P wave could be detected. Paroxysmal AF was included in the study. Monthly ECG follow-up was performed to monitor for recurrence. Exclusion criteria included an ejection fraction below 30 %, severe valvular pathology, inflammatory disease, left atrial diameter of 55 mm or more, chronic renal failure, allergy to contrast, allergy to antiarrhythmics and impaired liver function. The study was approved by the local ethics committee, and written informed consent was obtained from all patients.

2.2. Laboratory measurements

Blood samples were collected from all patients diagnosed with atrial fibrillation before cryo balloon ablations through antecubital venous access using EDTA (ethylenediaminetetraacetic acid)- based anticoagulant tubes. White blood cell counts (WBC), neutrophils, lymphocytes, hemoglobin, platelet counts, glucose levels, lipid profiles, creatinine (Cr), and routine biochemical tests were conducted using an automated analyzer (Roche Diagnostic Modular Systems, Rotkreuz, Switzerland). EDTA anticoagulated blood samples were obtained in the morning after 20 min of rest, stored at 4 °C, and analyzed by a Sysmex K-1000 autoanalyzer (Sysmex, Caribbean, Latin America) within 30 min of sampling. The calculation formula for each indicator was: NLR (neutrophil lymphocyte ratio) = neutrophil count (10ˆ9/L)/lymphocyte count (10ˆ9/L) SII (systemic immune inflammation index) = platelet count (10ˆ9/L) × neutrophil count/lymphocyte count (10ˆ9/L) PIV = neutrophil count (10ˆ9/L) × platelet count (10ˆ9/L) x monocyte count (10ˆ9/L)/lymphocyte count L (10ˆ9/L) [11,12].

2.3. Echocardiography

Transthoracic echocardiography examination was performed for all patients and control subjects using a Vivid 7 Dimension® (GE Vingmed Ultrasound AS N-3190 Horten, Norway) echocardiography device with a 2.5 MHz transducer. For all individuals, the echocardiographic examination was conducted in a left lateral lying position, in standard parasternal and apical views and with normal inspiration. Patients were examined in the left lateral decubitus position. All measurements were obtained based on the standards of the American Society of Echocardiography. The left ventricle end-diastolic and systolic diameters, the left atrium diameters, and the left ventricular ejection fraction (EF) were measured using standard M-mode echocardiography imaging with the parasternal long axis view. In the apical four chamber view, the Doppler sample volume was placed between the cusps of the mitral valve and at the center of the SV inflow path 1 cm below the mitral annulus level where the maximal flow rate was measured in early diastole. The left ventricular systolic functions, left ventricular wall movements, and the structures of the mitral, aortic, tricuspid and pulmonary valves along whit their insufficiencies were evaluated using the 2-D color Doppler examination.

2.4. Cryo balloon ablations

Before cryo balloon ablation, all patients underwent transesophageal echocardiography examination the day before the procedure to evaluate possible left atrial thrombus. The procedure was performed under local anesthesia. Before transseptal puncture, 2500 units of heparin were administered to keep activated clotting time levels elevated. The procedure was started with femoral vein puncture. Once localization was determined at the appropriate site, left atrial access was obtained through a single transseptal puncture. Images were obtained by accessing the pulmonary vein orifices with a steerable 12 F sheath (FlexCath Advance, Medtronic, MN, USA). Following this, an Arctic Front Advance Cryoablation Catheter (Medtronic, Minneapolis, MN, USA) was guided through the FlexCath sheath to the antrum of each pulmonary vein (PV) using the Achieve Mapping Catheter (Medtronic, Minneapolis, Minnesota). The recommended protocol for pulmonary vein isolation (PVI) was 240 s of cryo applications using the freeze-thaw technique. If pulmonary vein isolation was not achieved, the procedure was repeated. The sequence of upper left, lower left, lower right and upper right pulmonary vein isolation was applied during the procedure. To reduce the risk of phrenic nerve injury, the right phrenic nerve pacemaker was applied with an electrode catheter placed in the superior vena cava, and capture was confirmed by palpation and intermittent fluoroscopy. Pulmonary vein temperature recordings and electrode recordings were obtained. If the temperature was low or the potential persisted in the electrode recordings, the balloon localization was changed and corrected until appropriate recordings were obtained. All the recordings were data recorded.

2.5. Follow-up and recurrence decision

All patients underwent ECG at one week, one month and three months follow-up. Patients with symptoms and no AF detected on ECG had a 24-h rhythm holter monitor to determine whether they had AF or not. Atrial fibrillation lasting over 30 s was considered a recurrence.

2.6. Statistical analysis

Statistical analyses were performed using SPSS Statistics Package version 21.0 (SPSS Inc, Chicago, IL, USA) for Windows. Continuous variables showing normal distribution were analyzed using the Shapiro - Wilk test. The data means and standard deviations of continuous data were evaluated and recorded. The distribution of continuous variables among the groups was assessed using the Student's t-test or Mann-Whitney U test. Variability between groups was analyzed using t-test. The chi-square test was used for categorical variables and was calculated as a percentage. The relationship between the variables was analyzed using Pearson correlation analysis. A p-value of less than 0.05 was considered significant. Additionally, we used logistic regression analyses to observe the association between atrial fibrillation recurrence and the impact of the primary variable as well as other variables that may have acted as confounders (age in years, hypertension, neutrophils/lymphocytes ratio, Pan-Immune-Inflammation Value, systemic immune inflammatory index, CRP and left atrial diameter). The predictive values of the neutrophils/lymphocytes ratio, Pan-Immune-Inflammation Value, systemic immune inflammatory index, and CRP were estimated by the areas under the receiver operating characteristic (ROC) curve. All factors with a significance of p < 0.05 were entered into a stepwise multivariate logistic regression analysis.

3. Result

A total of 157 patients were included in the study. Of these, 101 were in the non-recurrence group and 56 in the recurrence (AF recurrence) group. There was a statistically significant age difference between the non-recurrence and recurrence groups (52.2 ± 17.4 vs 61.1 ± 9.8 years; p = 0.002). Other demographic features were similar between the two groups. Additionally, the two groups had no statistically significant differences in body mass index, diabetes mellitus, hypertension glomerular filtration rate, and gender (p > 0.05).

Laboratory data for both groups in our study are summarized in Table 1. WBC (white blood count) count (7.6 ± 2.1 vs 12.1 ± 5.0 × 10³/μL, p < 0.001), platelet count (232.1 ± 67.9 vs 270.4 ± 60.9 × 10³/μL, p < 0.001), monocyte count (0.6 ± 0.1 vs 1.3 ± 0.2 × 10³/μL, p < 0.001), and neutrophil count (4.9 ± 1.7 vs 9.3 ± 5.0, p < 0 0.001) were significantly higher in the AF recurrence group. Lymphocyte, triglyceride, LDL (low density lipoprotein), HDL (high density lipoprotein), total cholesterol, hemoglobin and glucose levels were similar between the two groups.

Table 1.

Baseline characteristics and operation-related data of patients with and without recurrence after AF ablation.

	No recurrence Group	Recurrence Group	p value
	n = 106	n = 51
Age (year)	52.2 ± 17.4	61.1 ± 9.8	0.002
Male	45 (42 %)	29 (52 %)	0.064
Hypertension	32 (30 %)	21 (38 %)	0.119
DM	24 (22 %)	9 (18 %)	0.309
CAD	28 (26 %)	12 (23 %)	0.428
Smokers	8(7 %)	4 (8 %)	0.812
BMI (kg/m2)	23.4 ± 2.6	24.9 ± 2.5	0.373
GFR ml/min/1.73 m2	94.2 ± 11.5	93.1 ± 10.5	0.756
Albumine	4.3 ± 0.3	4.4 ± 0.3	0.270
Triglyceride (mg/dl)	150.6 ± 80.9	141.2 ± 52.6	0.484
LDL (mg/dl)	105.6 ± 37.1	108.6 ± 36.9	0.676
HDL (mg/dl)	48.3 ± 9.6	47.4 ± 10.1	0.645
Total Cholesterol (mg/dl)	184.1 ± 47.2	184.2 ± 42.3	0.988
Serum Glucose (mg/dl)	135.4 ± 89.6	133.6 ± 62.0	0.301
Hemoglobin (g/dl)	12.9 ± 2.2	13.9 ± 1.5	0.050
Platelet (103/μL)	232.1 ± 67.9	270.4 ± 60.9	0.001
WBC (103/μL)	7.6 ± 2.1	12.1 ± 5.0	0.001
Neutrophil (103/μL)	4.9 ± 1.7	9.3 ± 5.0	0.001
Lymphocyte (103/μL)	2.1 ± 1.1	1.7 ± 0.7	0.056
CRP (mg/L)	5.9 (5.0–6.9)	9.7 (7.6–11.9)	0.001
Pulmonary vein ablation grades (-Co all patient)
Left superior pulmonary vein	−45 ± 3	−46 ± 2	0.722
Left inferior pulmonary vein	−45 ± 6	−44 ± 7	0.643
Right superior pulmonary vein	−50 ± 2	−49 ± 4	0.534
Right inferior pulmonary vein	−47 ± 2	−48 ± 4	0.256
Echocardiographic findings
LVEF (%)	59.0 ± 4.6	57.6 ± 4.1	0.081
LA diameter (mm)	4,0 ± 0.4	4.0 ± 0.6	0.316

Data are expressed as mean ± standard deviation for normally distributed data and percentage (%) for categorical variables. DM: Diabetes Mellitus, CAD: Coronary arterial disease, BMI: Body mass index, GFR: Glomerular filtration rate, LVEF: Left ventricular ejection fraction, LA: Left atrium, LDL: Low density lypoprotein, HDL: High density lypoprotein, WBC: white blood cell.

When echocardiography findings were analyzed, no significant difference was found between the two groups in terms of left ventricular ejection fraction and left atrial diameter (p > 0.05).

Since this technique is based on heat change in pulmonary vein isolation and cell death as a result of this change, when the heat changes in pulmonary vein isolation are analyzed in Table 1, no difference was observed between the two groups in terms of heat change (p > 0.005).

When the inflammatory parameters between the two groups are analyzed in Table 2, CRP (5.9 [5.0–6.9] vs 9.7 [7.6–11.9], p < 0.001), NL ratio (2.8 [2.5–3.0] vs 6.4 [5.0–6.8], p < 0.001), SII (618.5 [557.1–679.9] vs 1798.9 [1305.8–2292.1], p < 0.001), PIV (355.9 [313.4–398.4] vs 1832 [1317.8–2347.1], p < 001) was significantly higher in the AF recurrence group.

Table 2.

Inflammatory marker relationships between groups.

	No recurrence Group	Recurrrence Group	p value
	n = 106	n = 51
WBC	7.6 ± 2.1	12.1 ± 5.0	0.001
CRP	5.9 (5.0–6.9)	9.7 (7.6–11.9)	0.001
NL ratio	2.8 (2.5–3.0)	6.4(5.0–6.8)	0.001
SII	618.5 (557.1–679.9)	1798.9(1305.8–2292.1)	0.001
PIV	355.9 (313.4–398.4)	1832.4 (1317.8–2347.1)	0.001

WBC: white blood cell, NL: Neutrophil Lymphocyte, SII: Sytemic immune inflammatory index, PIV: Pan immune inflamaory index.

Several risk factors for AF recurrence were evaluated using multivariate analysis. This included age body mass index (BMI), gender, left ventricular ejection fractions, left atrial diameters, WBC count, CRP, SII, and PIV and was correlated with univariate analysis. In univariate analyses, PIV (odds ratio [OR]:1.004, 95 % confidence interval [CI]: 1.003–1.006, p < 0 0.001), SII (OR:1.003, 95 % CI:1.002–1.004, p < 0.001), CRP (OR:1.105, 95 % CI:1.043–1.171, p < 0.001), age (OR:1.048, 95 % CI:1.022–1.074, p < 0.001),and WBC count (OR: 1,456, 95 % CI:1.269–1.671, p < 0.001) were significant as predictors of AF recurrence. Multivariate logistic regression analysis showed that higher PIV was an independent predictor of AF recurrence development (OR: 1.011, 95 % CI:1.005–1.017, p = 0.001). However, SII (OR: 0.998, 95 % CI: 0.996–1.002, p = 0.045), and CRP (OR: 1.273, 95 % CI: 1.125–1.441, p = 0.001), were independent predictors of AF recurrence in patients (Table 3).

Table 3.

Univariate and multivariate regression analyses of multiple variables on recurrence after cryoablation.

Variables	Unadjusted OR	95 % CI	P value	Adjusted OR∗	95 % CI	P value
Age	1.048	1.022–1.074	0.001	1.053	0.992–1.118	0.089
BMI	0.937	0.867–1.014	0.373
Male	0.641	0.401–1.027	0.064
LV EF	0.924	0.845–1.011	0.085
WBC	1.456	1.269–1.671	0.001	0.614	0.370–1.019	0.059
SII	1.003	1.002–1.004	0.001	0.998	0.996–1.002	0.045
PIV	1.004	1.003–1.006	0.001	1.011	1.005–1.017	0.001
CRP	1.105	1.043–1.171	0.001	1.273	1.125–1.441	0.001
LA diameters on admission	1.432	0.712–2.881	0.314

BMI: Body mass index, LA: Left atrium, WBC: white blood cell, NL: Neutrophil Lymphocyte, SII: Sytemic immune inflammatory index, PIV: Pan immune inflamaory index LV EF: Left ventricular ejections fractions.

The PIV ROC analysis cut-off value for predicting AF recurrence in patients was 473.3 with a sensitivity of 84 % and specificity of 79 % (area under the ROC curve 0.89 [95 % CI: 0.83–0.94], P < 0.001). The cut-off value for SII was 692.1 with a sensitivity of 80 % and specificity of 72 % (area under the ROC curve 0.84 [95 % CI: 0.77–0.90], P < 0.001). The cut-off value for NLR was 2.6 with 78 % sensitivity and 60 % specificity (area under the ROC curve 0.76 [95 % CI: 0.68–0.84], P < 0.001), and cut-off value for CRP was 5.9 with 64 % sensitivity and 61 % specificity (area under the ROC curve 0.63 [95 % CI: 0.53–0.74], P < 0.001) (Fig. 1) (see Fig. 2).

Fig. 1.

Effect of Pan-Immune-Inflammation Value (PIV), systemic immune inflammation index (SII), CRP, and neutrophil-lymphocyte ratio (NLR) values on AF recurrence on ROC analysis.

Fig. 2.

Study populations and study design.

4. Discussion

In our study, PIV, which is evidence of inflammation, was examined in patients with recurrent atrial fibrillation and the results showed that the PIV levels were high in recurrent cases. Not only PIV but also CRP, neutrophil/lymphocyte ratio and SII, which are other inflammatory markers, were found to be elevated.

Atrial fibrillation is the most common cardiac rhythm disorder. It can affect cardiac function and quality of life and, together with additional risk factors, poses an increased risk of stroke [13]. In the treatment of AF are either rhythm control, which involves restoring and maintaining sinus rhythm, or reliance on rate control without any effort to restore sinus rhythm [14]. Even if the treatment of atrial fibrillation improves, there is still a high chance of recurrence. Studies have reported one-year recurrence rates of 30–50 % after ablation [3]. In our study, this rate was found to be 45 % on average. Since our study involved a selected group, the numbers are slightly higher.

AF shows an increasing prevalence and incidence with advancing age and in addition is the strongest risk factor worldwide among gender, smoking, alcohol consumption, body mass index, hypertension, left ventricular hypertrophy, prominent heart murmur, heart failure and myocardial infarction [15]. Increasing evidence supporting the role of inflammation in the pathophysiology of AF suggests that the inflammatory process is a potential therapeutic target. Among the main pathophysiological mechanisms contributing to AF development and progression are both electrical and structural remodeling of the atria. Moreover, AF itself can cause inflammation during atrial remodeling, which perpetuates arrhythmia [16,17].

Atrial dilatation is an important mechanism. Inflammation is thought to be critical in atrial remodeling [18]. TNF has also been reported to have a direct effect on cardiomyocytes by altering their electrophysiological properties. Overexpression of TNF in cardiomyocyte-specific mutant mice has been observed in atrial arrhythmias, including AF [19]. These include CRP, albumin, neutrophil/lymphocyte ratio, SII and the recently introduced Pan Immune Inflammatory Value (PIV).

CRP is still a valuable finding as one of the best indicators of infection and inflammation. Some studies have also investigated the relationship between AF and CRP. In one study, elevated CRP levels were associated with AF burden and patients with permanent AF had higher CRP levels compared to those with paroxysmal AF. In this study, higher CRP levels were found in both persistent and paroxysmal AF groups compared to controls [20]. In our study, similar to this study, CRP levels were higher in patients with AF recurrence, indicating both excess inflammation and excess AF burden. We also found CRP to be an independent predictor of AF recurrence in our study. In addition, Ozkan et al. showed that not only CRP but also the CAR (CRP/albumin) ratio is high in AF recurrence and is independent [4].

SII, which has recently come to the agenda and started to be used quite frequently, has also been shown to be an indicator of inflammation and an independent variable factor in recurrence after cardioversion in AF patients [21]. In addition, a study showed that SII was predictive of AF recurrence after crio balloon [22]. Our study was similar to these studies and SII' values were found to be quite high in AF recurrence. This value was also found to be an independent predictive factor. As is known, the systemic inflammatory index is a combination of several parameters. The question of whether so many parameters are sufficient has been raised and monocyte values, which are a part of inflammation, have also come to the fore.

PIV was more useful than SII in predicting the development of no-reflow in patients undergoing percutan coronary intervention (PCI) for ST elevation myocardial infarctus (STEMI), with the results showing better sensitivity and specificity with increasing data [23]. In our study, in contrast to other data, PIV was more sensitive and specific as well as having a higher independent predictive value in determining AF recurrence. There may be several explanations for this. The main one is the addition of monocytes by increasing one more parameter in addition to platelets, neutrophils and lymphocytes. Monocytes are an important parameter for the cardiovascular system. Cardiovascular mortality and morbidity studies have suggested that a high monocyte count is a predictor of cardiovascular events, and in another study involving patients undergoing PCI for STEMI, monocyte count was significantly higher in the group that developed CIN [24,25] These data show how effective monocytes are on cardiovascular events.

While the mechanisms of AF formation have not been fully clarified, this study tried to bring the inflammation hypothesis to the agenda once again. In the light of these data, if studies that clarify inflammation pathways are planned, treatment options will increase. It may also cause ablation treatments in AF to be more effective for a longer period of time. This study may shed light on future studies on inflammation and recurrence at the cellular level and develop new treatment strategies.

In conclusion, while AF recurrence remains a major problem, it should be addressed not only by ablation but also by other methods. The most important indicator of this is inflammation and PIV, which provides new evidence of inflammation, is quite high in these patients.

Our study had some limitations. It included a relatively small number of patients and was a single-center retrospective study, which might affect the representativeness of the chosen population. Another limitation was that the PIV value was calculated from the blood sample taken at hospital admission.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Deniz Elcik reports was provided by Erciyes University School of Medicine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.