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. 2018 Nov 10;24(2):e12616. doi: 10.1111/anec.12616

Usefulness of platelet to lymphocyte ratio for predicting recurrence of atrial fibrillation after direct current cardioversion

Seçkin Dereli 1,✉, Adil Bayramoğlu 2, Osman Can Yontar 3
PMCID: PMC6931753  PMID: 30414335

Abstract

Objective

Atrial fibrillation (AF) is the most common cardiac rhythm disorder with the associated risks of stroke and mortality. The usefulness of platelet to lymphocyte ratio (PLR), a recently described inflammatory marker, in predicting adverse cardiovascular events has been demonstrated in several studies. In the current study, we investigated the role of PLR in predicting recurrence after successful electrical cardioversion (ECV) in patients with non‐valvular persistent AF.

Methods

A total of 287 patients with non‐valvular persistent AF achieving restoration of the sinus rhythm after successful ECV were included in this study. At study entry, complete blood count, routine biochemistry tests, and transthoracic echocardiography (TTE) were performed routinely in all subjects. Patients were followed up for 6 months following the procedure and comparisons were performed between patients who recurred and who maintained the sinus rhythm (SR).

Results

At 6 months of follow‐up, AF recurred in 108 patients, corresponding to a recurrence rate of 39%. Mean PLR values in the “AF recurrence group” (mean age 57.4 ± 12.0 years, 47.6% [n = 80] female) and in “SR maintenance” group (mean age 65.0 ± 9.4 years, 55.6% [n = 60] female) were 184.8 ± 44.2 and 103.3 ± 44.2, respectively, with a significant difference between the two groups (p < 0.001). In multiple regression analyses, PLR emerged as a risk factor associated with AF recurrence during the 6‐month follow‐up period after successful ECV (odds ratio [OR]: 3.029 (1.013–9.055 95% confidence interval [CI]), p = 0.047). When a cutoff value of 147 was used, the sensitivity and specificity of PLR for predicting AF recurrence were 83.3% and 84.5%, respectively.

Conclusion

Elevated PLR is a marker of increased inflammation and may serve as a practical and inexpensive predictor for recurrence during 6 months of follow‐up in patients with non‐valvular persistent AF who had restoration of the sinus rhythm after successful ECV.

Keywords: atrial fibrillation, electrical cardioversion, platelet to lymphocyte ratio, recurrence

1. INTRODUCTION

Atrial fibrillation (AF) is the most common cardiac rhythm disorder affecting approximately 2% of the general population (Camm et al., 2012), and is associated with increased stroke and mortality risk as well as reduced exercise capacity (Kirchhof et al., 2007). Previous studies have clearly established the association between inflammation and increased risk of arrhythmia. Reports of increased incidence of AF following pericarditis, myocarditis, or cardiac surgery suggest that inflammation may be particularly important for initiation of AF among cardiac rhythm disturbances (Bruins et al., 1997; Chung et al., 2001; Spodick, 1976). Studies with inflammatory markers such as C‐reactive protein (CRP), interleukin 6 (IL‐6), high‐sensitivity CRP (hs‐CRP) have provided supportive evidence for the link between AF and inflammation (Psychari et al., 2005; Sata et al., 2004; Watanabe, Arakawa, Uchiyama, Kodama, & Hishida, 2006). Although CRP is the most commonly used marker of inflammation, platelet to lymphocyte ratio (PLR) has also recently been shown to be a useful marker of inflammation in certain conditions (Thaulow, Erikssen, Sandvik, Stormorken, & Cohn, 1991).

Platelet to lymphocyte ratio can be readily calculated using routine complete blood counts (CBCs) and represents a novel prognostic marker in cardiovascular diseases (Iijima et al., 2007; Nikolsky et al., 2007; Zouridakis, Garcia‐Moll, & Kaski, 2000). While increased platelet counts reflect more marked inflammation, low lymphocyte counts suggest poor general health and physiological stress. PLR is a stronger indicator combining these two independent parameters (Gensini, 1983). Several studies have established the role of PLR as a systemic inflammatory marker (Balta, Demırkol, & Kucuk, 2013). Again, in a recent study increased PLR was found to be associated with the risk of developing AF following cardiac surgery (Gungor et al., 2017). On the other hand, to our knowledge, the predictive value of PLR for AF recurrence after cardioversion has never been studied before. Thus, in this study, we aimed at assessing the relationship between PLR and AF recurrences after successful cardioversion.

2. METHODS

2.1. Study design and population

The study design is a prospective cohort study. A total of 287 non‐valvular persistent AF patients over 18 years of age with a minimum follow‐up duration of 6 months after successful elective ECV with restoration to sinus rhythm (SR) between July 2014 and June 2018 were prospectively included. Exclusion criteria were as follows: presence of thrombus in the left atrium and appendix, having undergone ablation for AF, left atrial (LA) diameter >50 mm, use of class I or III antiarrhythmic within the past 6 months, a diagnosis of paroxysmal or permanent AF, presence of permanent cardiac pacemaker, acute coronary syndrome, congenital cardiac disease, NYHA class IV heart failure, active inflammatory or infectious disease, moderate to severe kidney failure, severe hepatic failure, thyroid dysfunction, malignancy, alcohol use, and pregnancy. The study protocol was approved by the local ethics committee. Written consent and oral informed consent were obtained from each patient after information on AF and ECV as well as the need for the procedure was provided.

2.2. Clinical data and echocardiography

Age, gender, weight, height, body mass index (BMI, kg/m2), and cardiac apex beat per minute were recorded for each patient. History of congestive heart failure, hypertension, diabetes, thromboembolic events, thyroid conditions, smoking, and duration of AF were determined, followed by the estimation of CHA2DS2‐VASc score. Also, information on the use of rate‐limiting drugs, and particularly the use of antiarrhythmic agents that can affect the clinical course of AF and ECV was gathered. Prior to the procedure, blood samples were obtained after 12 hr of overnight fast for total cholesterol, low‐density lipoprotein (LDL) cholesterol, high‐density lipoprotein (HDL) cholesterol, triglycerides (TG), leukocytes, hemoglobin, platelet, creatinine, glucose, hemoglobin A1c (HbA1c), uric acid, high‐sensitivity C‐reactive protein (hs‐CRP) and thyroid‐stimulating hormone measurements. Glomerular filtration rate was determined. Before ECV, all patients underwent an echographic examination with a Philips Envisor CHD device (Philips Medical Systems, Andover, MA, USA). A 2–4 MHz (Philips S4‐2 Broadband Sector Array) transducer and a 4.8–6 MHz (S6‐2 MPT TEE) transducer were used for TTE and TEE, respectively. TEE was not planned for patients using new oral anticoagulant or warfarin who had an international normalized ratio (INR) value between 2.0 and 3.0 in the last month. The examinations were performed with the patient in left decubitus position. Assessments were based on the criteria proposed by the American Association of Echocardiography. Apical four‐chamber, two‐chamber, parasternal long axis, and short axis images were obtained (Quiñones, Otto, Stoddard, Waggoner, & Zoghbi, 2002). Ejection fraction (EF) was calculated in apical four‐chamber views using the Modified Simpson's method with measurements of the left ventricular end‐diastolic volumes and end‐systolic volumes. Left atrial diameter was measured using parasternal long axis views. TEE was performed after 12 hr of fasting under local anesthesia and mild sedation. Presence of thrombus in the left atrium and left atrial appendix was examined using TEE, and those with thrombus formation were excluded.

2.3. Cardioversion

Antiarrhythmic treatment with oral amiodarone was initiated 1 week prior to ECV procedure. Patients who did not use oral anticoagulant scheduled for elective ECV after the initial assessment received anticoagulation with heparin infusion, with a target activated partial thromboplastin time 1.5–2 fold higher than normal. Intravenous midazolam, morphine, and fentanyl were used for sedation. Transthoracic electrical cardioversion procedures were performed in the intensive care unit with a direct‐current ECV (Nihon Kohden Corporation, TEC‐5521K, Tokyo, Japan) device using biphasic direct current synchronized with the R waves in electrocardiography (ECG). The paddles were placed in the antero‐lateral position (right parasternal and left apical). Escalating energy protocol was applied. ECV was initiated with 100 biphasic joules (J), and were incremented to 150 and 200 J when 100 J failed. ECV was attempted up to four times maximum, with the last attempt being in antero‐posterior position at 200 J. Successful ECV was defined as the presence of sinus rhythm lasting 1 min after a shock (Van Gelder et al., 2002). Overall, SR was restored successfully in 287 patients, who were included in the study.

2.4. Discharge and follow‐up

Patients with restoration of the sinus rhythm after ECV received anticoagulation (warfarin) for at least 4 weeks to achieve an INR. Patients who were using oral anticoagulant treatment prior to ECV continued to present anticoagulant treatment after the procedure. Also, subjects with a failure to restore SR after unsuccessful ECV received oral anticoagulant therapy at discharge if CHA2DS2‐VASc was ≥1. Four weeks after ECV procedure, antiarrhythmic treatment was continued with oral amiodarone. In order to detect possible recurrences, patients were instructed to seek immediate medical attention if they felt palpitations or irregular heartbeats. During the follow‐up, patients were examined on four separate occasions (weeks 2 and 4, and months 3 and 6), unless they had palpitations. In subjects with palpitations, in addition to periodic follow‐up controls, a 12‐lead electrocardiography followed by 3‐day Holter ECG monitoring was performed. During the follow‐up period, identification of a paroxysmal AF episode lasting more than 30 s in the 12‐lead ECG or 3‐day Holter recordings was considered to indicate recurrence (Van Gelder et al., 2002). After 6 months of follow‐up, no patients had embolic or hemorrhagic complications. Eleven patients were lost to follow‐up and were therefore excluded from the study. Thus, a total of 276 patients completed the study.

2.5. Endpoints

The primary outcome was the proportion of patients with sustained SR after ECV during 6 months of follow‐up. Arrhythmia lasting for more than 30 s in 12‐lead ECG or Holter recordings during the follow‐up period was considered as the primary endpoint.

2.6. Statistical assessments

The data analysis was conducted using SPSS (version 20.0, SPSS Inc., Chicago, IL, USA), and Continuous variables were expressed as the mean ± standard deviation. Categorical variables were compared using chi‐square or Fisher's exact tests and summarized as percentages. Kolmogorov–Smirnov test was used to evaluate the distribution of the continuous variables. Age, BMI, GFR, diabetes, hypertension, CHA2DS2‐VASc score, PLR, left atrial diameter (mm), and left ventricular end‐diastolic diameter (mm) were included in the univariate analysis. Parameters with p value of <0.05 were included in the multiple logistic analysis.

3. RESULTS

After 6 months of follow‐up, no patients had embolic or hemorrhagic complications. A total of 11 patients were lost to follow‐up and were therefore excluded from the study. Thus, a total of 276 patients completed the study.

About 276 patients who had restoration of SR following elective ECV were included, and 108 patients had recurrence of AF during 6 months of follow‐up corresponding to a recurrence rate of 39%.

Patients were divided into two groups at the completion of the study period as those who sustained SR and those who continued to have AF. Tables 1 and 2 show the clinical and laboratory characteristics of the patients, respectively.

Table 1.

Baseline characteristics of the two study groups

SR

N:168

AF

N:108

 p
Age (years) 57.4 ± 12.0 65.0 ± 9.4 <0.001
Sex (%female) 80 (47.6%) 60 (55.6%) 0.360
Body mass index (kg/m2) 27.4 ± 3.7 29.6 ± 3.7 0.001
Heart rate (bpm) 100 ± 40 103 ± 44 0.790
AF duration, months 5.9 ± 1.2 6.3 ± 2.4 0.400
Smokers, n (%) %39.3 %37.7 0.790
Diabetes, n (%) 18 (10.7%) 54 (50%) <0.001
Hypertension, n (%) 92 (54.8%) 90 (83.3%) 0.001
Coronary artery disease, n (%) 58 (34.5%) 66 (61.1%) 0.002
Congestive heart failure, n (%) 30 (18%) 16 (15%) 0.450
Previous ischemic stroke, n (%) 6 (3.6%) 10 (9.4%) 0.260
Dyslipidemia, n (%) 18 (10.7%) 38 (35.2%) <0.001
CHA2‐DS2‐VASc score 1.7 ± 1.3 3.4 ± 1.5 <0.001
Oral anticoagulant, n (%) 33 (21%) 35 (32%) 0.001
Calcium channel blockers, n (%) 74 (44%) 54 (50.0%) 0.490
Beta‐blockers, n (%) 82 (48.8%) 72 (66.7%) 0.390
Digoxin, n (%) 20 (11.9%) 10 (9.4%) 0.650
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AF, atrial fibrillation; SR, sinus rhythm.

Table 2.

Echocardiographic findings and biomarkers

SR

N:168

AF

N:108

 p
Glomerular filtration rate (GFR) (ml/min/1.73 m2) 100.44 ± 37.2 88.10 ± 27.5 0.038
Hemoglobin, mg/dl 13.3 ± 1.5 12.8 ± 1.6 0.118
White blood cell 103/μl 8.45 ± 2.9 8.56 ± 3.4 0.846
Platelet, 103/μl 226.7 ± 48.6 341.5 ± 67.4 <0.001
Platelet to lymphocyte ratio 103.3 ± 44.2 184.8 ± 44.2 <0.001
Uric acid, (μmol/L) 5.1 ± 1.76 5.8 ± 1.61 0.574
High‐sensitivity C‐reactive protein, mg/L 3.4 ± 2.1 5.1 ± 1.9 <0.001
Low‐density lipoprotein cholesterol, mg/dl 125.2 ± 36.6 126.3 ± 36.8 0.862
High‐density lipoprotein cholesterol, mg/dl 43.4 ± 12.6 40.9 ± 9.8 0.193
Ejection fraction (%) 58.1 ± 7.4 54.1 ± 6.0 0.001
left ventricular end‐diastolic, diameter (mm) 45.9 ± 3.9 46.7 ± 3.6 0.667
left ventricular end‐systolic, diameter (mm) 30.0 ± 3.8 30.7 ± 3.2 0.317
Left atrial diameter (mm) 39.3 ± 4.4 45.9 ± 7.0 <0.001
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AF, atrial fibrillation; SR, sinus rhythm.

There were no significant differences between the groups with regard to duration of AF, gender, heart rate, smoking status, history of stroke, and biochemical parameters other than the platelet count. However, the two groups were significantly different in terms of age (p < 0.001), BMI (p = 0.001), diabetes (p < 0.001), hypertension (p = 0.001), coronary artery disease (p = 0.002), CHA2‐DS2‐VASc score (p < 0.001), platelet count (p < 0.001), EF (p = 0.001), left atrial end‐diastolic diameter (p < 0.001), left ventricular end‐diastolic diameter, and hs‐CRP (p < 0.001).PLR among patients with recurrent AF and sustained SR was 184.8 ± 44.2 and 103.3 ± 44.2, respectively, the difference being statistically significant (p < 0.001).

The results of the multiple regression analysis are shown in Table 3. Accordingly, PLR was found to be a risk factor associated with long‐term AF recurrence after successful ECV (OR: 3,029 [95% CI 1,013%–9,055], p = 0.01). Furthermore, in a receiver operating characteristic analysis using a cutoff value of 147, the sensitivity and specificity of PLR in predicting AF recurrence were 83.3% and 84.5%, respectively (area under ROC curve = 0.645, p < 0.001; Figure 1).

Table 3.

Univariate and multivariate logistic regression analyses

Univariate analysis Multivariate analysis
OR (95%CI) p OR 95%CI p
Age 1.064 (1.012–1.119) 0.001
Body mass index 1.242 (1.080–1.427) 0.001
Diabetes 0.111 (0.026–0.479) 0.001
Hypertension 0.155 (0.032–0.745) 0.011
Coronary artery disease 5.833 (1.904–17.868) 0.001
CHA2‐DS2‐VASc score 2.196 (1.382–3.491) 0.001
hs‐CRP 1.11 (0.99–1.25) 0.06
Platelet to lymphocyte ratio 3.614 (1.972–6.622) 0.001 3.029 1.013–9.055 0.047
Left atrial diameter 1.126 (0.975–1.301) 0.001 1.320 1.023–1.703 0.032
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hs‐CRP, high‐sensitivity CRP.

Figure 1.

Figure 1

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The receiver operating characteristic (ROC) curve analysis of platelet‐to‐lymphocyte ratio for predicting atrial fibrillation recurrence

4. DISCUSSION

Our results have shown that PLR is a risk factor associated with long‐term AF recurrence after successful ECV in non‐valvular persistent AF patients.

The role of chronic inflammation in cardiovascular diseases has been well established. Similarly, development of AF exhibits a close association with the inflammatory processes in the body in conjunction with the medical condition of the patient. A link between occurrence of AF after cardiac surgery and IL‐8, IL‐6, and leukocyte count has also been shown (Abdelhadi, Gurm, Van Wagoner, & Chung, 2004; Ucar et al., 2007; Wu et al., 2008). In a recent study by Rienstra et al., (2012 examining 936 participants in the original Framingham Heart Study, an association between elevated leukocyte count and new onset of AF during 5 years of follow‐up. In several studies investigating the success rates with pharmacological or DC cardioversion and maintenance of sinus rhythm, an adverse effect due to an increase in inflammatory markers such as IL‐6, IL‐2, and hs‐CRP has been shown to occur (Fujiki, Sakamoto, Nishida, Mizumaki, & Inoue, 2007; Malouf et al., 2005; Ozaydin et al., 2011; Rizos et al., 2007). In a study by Celebi et al. (2011, elevated hs‐CRP levels were found to be associated with AF recurrence during 12 months of follow‐up after ECV, suggesting that an association between AF and inflammation exists based on the electrical and structural remodeling (Nakamura et al., 2003).

PLR is calculated as the ratio between the number of platelets and lymphocytes, and represents a new reproducible and practical biological marker of systemic inflammation. It combines the prognostic value of the number of both platelets and lymphocytes in cardiovascular disorders. Number of lymphocytes is a rational early marker of physiological and systemic inflammation. Reduced numbers of lymphocytes in PLR ratio are indicative of physiological stress and poor general health, and provide more detailed information as compared to leukocyte numbers alone (Hotchkiss & Karl, 2003; Onsrud & Thorsby, 1981). Platelets release pro‐inflammatory mediators such as chemokines and cytokines (Demirtas et al., 2014). Adults with elevated numbers of platelets also carry an increased risk of thrombotic complications. Circulatory platelets may contribute to the formation of atheromatous plaques and may trigger complications (Thaulow et al., 1991).

Previously, high circulatory platelets and low lymphocytes have been proposed to be indicative of worse cardiovascular risk (Iijima et al., 2007; Nikolsky et al., 2007; Ommen et al., 1998; Thaulow et al., 1991; Thomson et al., 1995; Zouridakis et al., 2000).

Platelet distribution width, erythrocyte distribution width, and mean platelet volume are among the components of CBC, which may serve as inflammatory markers, when one considers previous studies that have clearly indicated the presence of a relationship between these parameters and various cardiovascular conditions. On the other hand, since PLR is a ratio, it is relatively more stable than the above‐mentioned parameters that may be influenced by a number of factors (e.g., dehydration, excessive water intake, or treatment with blood products). Thus, from a practical viewpoint, PLR potentially represents a superior measure than other CBC parameters such as the simple leukocyte or platelet count.

In a study by Gary et al., (2013, PLR was found to be correlated with fibrinogen, which may impair the blood viscosity and thus tissue oxygen supply; also, these authors reported that higher platelet volumes may alter the blood viscosity and worsen inflammation. Frustaci et al., (1997 examining biopsy samples obtained from patients found that subjects with AF had higher levels of inflammatory infiltration, fibrosis, and myocyte necrosis as compared to those without AF. Gungor et al. (2013 identified poor coronary collateral circulation as a potent predictor of AF following coronary bypass surgery. A good collateral circulation may have an impact on AF occurring after CABG surgery by reducing atrial and myocardial ischemia, oxidative injury, inflammation, fibrosis, lipid accumulation, and dilatation. Therefore, it has been suggested that an elevation in PLR, which shows increased platelet volume and low lymphocyte count, may actually trigger a worsened inflammation through blood viscosity and increase the risk of AF due to myocardial tissue ischemia. In a recent study by Gungor et al., (2017, PLR was found to be a newly identified risk factor for AF developing after bypass surgery, in corroboration with our results.

Amiodarone is an effective multichannel blocker, which reduces ventricular rate and is safe in patients with heart failure (Roy et al., 2008; Singh, Tang, Reda, & Singh, 2009). Pretreatment with amiodarone can increase the effectiveness of electrical cardioversion (Channer et al., 2004; Singh et al., 2009). Clinically successful antiarrhythmic drug therapy can reduce the recurrence of AF more than it eliminates. Antiarrhythmic drug treatment doubles the sinus rhythm treatment compared to almost no treatment (Lafuente‐Lafuente, Mouly, Longás‐Tejero, Mahé, & Bergmann, 2006). A shorter period of antiarrhythmic medication is required to reduce the risk of adverse effects (Lafuente‐Lafuente et al., 2006; Nabauer et al., 2009). For these reasons, we chose amiodarone as a antiarrhythmic agents in our study. In addition, patients with severe heart failure or significant valvular heart disease (aortic stenosis) were present in the study population, so we were unable to use alternative antiarrhythmic agents to amiodarone. We used short‐term antiarrhythmic treatment for 1 week before and 4 weeks after ECV procedure.

Many factors may affect the maintenance and recurrence of sinus rhythm following successful ECV, and a better understanding of such factors may help develop better therapeutic strategies. Number of studies showing an association between AF recurrence and different novel indices such as echocardiographically determined left atrial volume index and atrial emptying fraction, and biomarkers including cardiotroponin‐1 and N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) are increasing (Altun et al., 2015; Andersson, Rosenqvist, Tornvall, & Boman, 2015; Luong et al., 2016; Toufan, Kazemi, & Molazadeh, 2017). These predictors may serve as a valuable tool when determining the rhythm control in clinical practice and when planning ECV; however, less expensive and more practical measures are required to predict recurrences. In this regard, PLR is a practical and widely utilized parameter requiring no additional costs that may be used for risk estimations prior to ECV.

4.1. Study limitations

The limitations of our study include the short duration of follow‐up, small sample size, and use of ECG for detection of recurrences. Routine use of 72‐hr holter monitoring could have provided more accurate results with regard to AF screening. However, this could not be routinely performed due to cost‐related issues, potentially leading to overlooking of paroxysmal AF recurrences in some asymptomatic patients. Absence of measurement of other established inflammatory markers such as CRP, interleukin‐6, and tumor necrosis factor may also be considered a potential limitation. Also, our results do not provide evidence for a causal relationship between PLR and AF. Although we identified a significant correlation, further prospective studies with larger sample size are warranted to better delineate this relationship. Despite these limitations, to the best of our knowledge, this is one of the first studies to examine the association between PLR at baseline and AF recurrence after ECV.

5. CONCLUSION

Our results have shown that PLR is an independent parameter for predicting recurrence of AF after successful ECV in non‐valvular persistent AF patients. PLR is an inexpensive and practical parameter that can be used to help clinical decisions regarding rhythm control in patients with AF. Prospective studies with larger populations in different clinical settings are needed to examine the role of this practical and inexpensive parameter in predicting the development and recurrence of AF.

Dereli S, Bayramoğlu A, Yontar OC. Usefulness of platelet to lymphocyte ratio for predicting recurrence of atrial fibrillation after direct current cardioversion. Ann Noninvasive Electrocardiol. 2019;24:e12616 10.1111/anec.12616

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