ARTYKUŁ ORYGINALNY / ORYGINAL ARTICLE

The role of baseline indirect inflammatory markers in prediction of response to cardiac resynchronisation therapy

Kevser G. Balci, Mustafa M. Balci, Fatih Sen, Ugur Canpolat, Mehmet Kadri Akboga, Sefa Unal, Meryem Kara, Orhan Maden, Hatice Selcuk, Timur Selcuk

Turkiye Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey

Address for correspondence:
Kevser G. Balci, MD, Specialist of Cardiology, Turkiye Yuksek Ihtisas Research and Education Hospital, Park Flora Sitesi B blok No. 4 Yaşamkent Çayyolu, Ankara, Turkey, tel: +90 530 328 38 69, e-mail: kevs84@gmail.com
Received: 21.03.2015 Accepted: 29.06.2015 Available as AoP: 16.07.2015

Abstract Background: In many cardiovascular diseases (CVD), white blood cell counts with differentials are used to predict adverse events. Both platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) are studied in various CVDs. Aim: The role of inflammatory condition assessed using routine laboratory tests in cardiac resynchronisation therapy (CRT) response has not been investigated thoroughly. Therefore, we aimed to assess the association of NLR, PLR, and relative lymphocyte count (L%) with response to CRT. Methods: A total of 157 patients (76.4% male; mean age 58.7 ± 11.8 years) who underwent CRT implantation at our tertiary referral hospital were retrospectively analysed. Results: Among included patients, a total of 50 (31.8%) patients were defined as “non-responders”. Median NLR and PLR were significantly higher in the non-responder group (p < 0.001), and median L% was significantly lower in the non-responder group (p < 0.001). Also, median NLR was significantly higher in patients with New York heart Association (NYHA) class II–III when compared to patients with NYHA class I after six months of CRT implantation (p < 0.001, p = 0.004, respectively). Correlation analysis demonstrated a positive correlation between paced QRS duration and NLR (p = 0.031) and a negative correlation between paced QRS duration and L% (p = 0.002). In addition, both NLR and L% showed significant correlations with post-procedural NYHA functional classes (p < 0.001; p = 0.008, respectively). Patients with PLR > 173.09 had a 2.9-fold and NLR > 3.45 had a 12.2-fold increased risk of CRT nonresponse, respectively. Conclusions: In the current study non-responders to CRT had higher NLR and PLR and lower L%, which may support the deleterious effects of baseline inflammatory condition in advanced heart failure. Key words: cardiac resynchronisation therapy, heart failure, lymphocyte, platelet, neutrophil Kardiol Pol 2016; 74, 2: 119–126

INTRODUCTION

The clinical efficiency of cardiac resynchronisation therapy (CRT) in carefully selected heart failure (HF) patients when used with an optimal medical therapy has been well established in several large studies and meta-analyses [1]. However, recent knowledge has demonstrated that approximately 30% of CRT recipients, due to current indications, actually do not respond favorably [2]. Therefore, all efforts in the current practice guidelines aim to define patients in whom such an invasive and costly therapy is most likely to result in substantial benefit. Various predictors of CRT response, including clinical, electrocardiographic, laboratory, and imaging parameters, have been identified in previous studies [3–8]. Both neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are recently found parameters and have been shown to be associated with adverse cardiovascular events in several disease conditions [9–12]. However, the role of pre-implantation inflammatory condition assessed using routine laboratory tests has been rarely investigated [6–8]. Although the prognostic value of NLR has been investigated in CRT response [7], there was no study assessing the impact of baseline relative lymphocyte count (L%) and PLR on CRT response. Therefore, in this study we aimed to assess the association of NLR, PLR, and L% with response to CRT.

METHODS

Study population

We performed a retrospective analysis of prospectively collected data. Between January 2012 and January 2014 a total of 157 patients (76.4% male; mean age 58.7 ± 11.8 years) who underwent CRT implantation at our tertiary referral hospital were analysed. Inclusion criteria were severe symptomatic HF (New York Heart Association [NYHA] class III or ambulatory class IV) despite optimal medical therapy, left ventricular ejection fraction (LVEF) ≤ 35%, and left bundle branch block on 12-lead electrocardiography (ECG) with widened QRS duration (≥ 120 ms). Patients with mechanical tricuspid valve, recent myocardial infarction or coronary artery bypass graft surgery (≤ six months), decompensated HF, malignancies, chronic inflammatory disease, haematological disorders, renal or hepatic disorders, right bundle branch block morphology on ECG, right ventricular pacing only, pacemaker upgraded to CRT, left ventricular (LV) lead inserted into other than lateral or postero-lateral branches of coronary sinus, life expectancy of less than 12 months, and follow-up interval less than six months were excluded from the study. All patients included in the study with either sinus rhythm or atrial fibrillation provided biventricular pacing over 90%. The study protocol was approved by the local institutional Ethics Committee.

Clinical evaluation

An independent physician who was blinded to all other data performed the clinical evaluation, including assessment of NYHA class, in all of the patients. QRS duration was measured by surface ECG using the widest QRS complex from the II, V1, and V6 leads. All patients were evaluated in terms of age, gender, coronary artery disease history, diabetes mellitus, hyperlipidaemia, hypertension, and other concomitant diseases. Patients were classified as ischaemic if they had a known history of significant coronary artery disease and/or prior myocardial infarction. Patients were classified as nonischaemic if they had no history of myocardial infarction or revascularisation, with no evidence of coronary atherosclerotic lesions ≥ 50% in two or more epicardial vessels or left main or proximal left anterior descending artery. The patients underwent a detailed echocardiographic examination at baseline and six months after the CRT.

Echocardiography

Standard echocardiographic imaging was performed at rest in the left lateral decubitus position using a commercially available device (Vivid 7 Ultrasound System; GE, Horten, Norway) both before and six months after the CRT. The measurements were based on the criteria proposed by the American Society of Echocardiography. LVEF was calculated using modified Simpson’s method [13].

Blood sampling

Venous blood samples were obtained without venostasis by venipuncture of the large antecubital veins of the patients at least 24 h before CRT implantation and were immediately studied in the laboratory without any time delay. Blood samples were taken into standardised tubes containing dipotassium ethylene dinitro tetra acetic acid (EDTA) for complete blood count (CBC). Coulter Counter LH Series (Siemens ADVIA 2120i Hematology System, Siemens Healthcare, Malvern, PA) was used for CBC analysis. The L% was calculated as the ratio of the total number of lymphocytes to total leukocyte count × 100. The normal reference limits for the L% in our laboratory was between 21.1% and 52.8%. All other laboratory tests were performed by using commercially available kits.

Device implantation

All patients received a CRT device in combination with a cardioverter defibrillator. Implantation of whole CRT system including LV lead was performed transvenously by using left subclavian route. A coronary sinus venography was routinely obtained before the introduction of the LV lead. The LV lead was preferably inserted into the lateral or postero-lateral branches of the coronary sinus. The right atrial and right ventricular leads were implanted in the atrial appendage and at the apex, respectively. Optimisation of atrio-ventricular (interactive method) [14] and ventricular–ventricular interval was performed by an experienced cardiologist using Doppler echocardiographic measurements of transmitral flow.

Definition of CRT response

Left ventricular reverse remodelling was quantified as the percentage of improvement in the LVEF after CRT. An increase of ≥ 5% in LVEF at the six-month follow-up was defined as a positive echocardiographic response [15, 16]. Clinical response was defined as improvement ≥ 1 NYHA class and without HF hospitalisation.

Statistical analysis

Analyses were performed using with the Statistical Package for the Social Sciences (SPSS) software version 15.0 for Windows (SPSS Inc., Chicago, IL). The Kolmogorov-Smirnov test was used to test the normality of distribution of continous varibles. Continuous variables were defined as means ± standard deviation or median (minimum–maximum intervals). The independent sample t test or the Mann-Whitney U test was used for the comparison of continuous variables, and the χ2 test was used for the comparision of categorical variables. The mean differences between more than two independent groups were analysed by one-way ANOVA, and the Kruskal-Wallis test was applied for comparisons of the median values. When the p value from one-way ANOVA or Kruskal-Wallis test statistics were statistically significant post hoc Tukey HSD or Conover’s non-parametric multiple comparison test were used to know which groups differed from which others. Nominal data were analysed by Pearson’s χ2 or Fisher’s exact test, where applicable. Degrees of association between continuous variables were evaluated by Spearman’s rank correlation analyses. The optimal cut-off points for NLR, PLR, and L% in order to determine CRT response were evaluated by receiver operating characteristic (ROC) analysis. Variables associated with responders in univariate analysis were entered into a forward stepwise logistic regression model. Any variable whose univariable test had a p < 0.25 was accepted as a candidate for the multivariable model along with all variables of known clinical importance. Inter- and intra-observer agreements for LVEF were assessed with intra- and inter-class correlation coefficients and with the average difference between readings, corrected for their mean (variability). Statistical significance was defined as p < 0.05. For all multiple comparisons, Bonferroni adjustment was applied for controlling type I error.

RESULTS

Baseline clinical, echocardiographic, and laboratory parameters of the study population are shown in Table 1. There were no significant differences in baseline LVEF, mean age, sex, baseline QRS duration, and pre-procedural NYHA between responders and non-responders (p > 0.05). Ischaemic HF was significantly higher in the non-responder group than responders (p = 0.033). Among included patients, a total of 50 (31.8%) patients were defined as “non-responders”. In the non-responder group, paced QRS (pQRS) duration was significantly longer than in the responder group (p = 0.036). The intra- and inter-observer correlation coefficient and variability for LVEF were 0.942 and 1.8% and 0.896 and 2.2%, respectively.

Table 1. Baseline features of the study population according to the cardiac resynchronisation therapy response

Variables	Responders (n = 107)	Non-responders (n = 50)	P
Age	58.8 ± 11.9	58.9 ± 10.7	0.963
Gender:			0.930
Male	82 (76.6%)	38 (%76.0)
Female	25 (23.4%)	12 (24.0%)
Ejection fraction	25 (12–35)	25 (10–35)	0.867
Aetiology:			0.033
Ischaemic	49 (%45.8)	32 (64.0%)
Non-ischaemic	58 (%54.2)	18 (36.0%)
NYHA:			0.659
II	33 (31.1%)	17 (34.7%)
III	73 (68.9%)	32 (65.3%)
QRS duration	150 (120–200)	150 (125–180)	0.866
Paced QRS duration	120 (100–160)	120 (90–180)	0.036
PCI	42 (39.3%)	32 (64.0%)	0.004
Hypertension	73 (68.2%)	40 (80.0%)	0.126
Diabetes mellitus	40 (37.4%)	15 (70.0%)	0.366
Rhythm:			0.509
Sınus rhythm	94 (87.9%)	42 (84.0%)
Atrial fibrillation	13 (12.1%)	8 (16.0%)
ACEI/ARB	101 (94.4%)	48 (96.0%)	1.000
Statin	34 (31.8%)	23 (46.0%)	0.084
Beta-blocker	106 (99.1%)	49 (98.0%)	0.537
Amiodarone	20 (18.7%)	6 (12.0%)	0.293
ACEI — angiotensin-converting enzyme inhibitor; ARB — angiotensin receptor II blocker; NYHA — New York Heart Association; PCI — percutaneous coronary intervention

Median NLR and PLR were significantly higher in the non-responder group (p < 0.001), and median L% was significantly lower in the non-responder group (p < 0.001) (Figs. 1–3). Also, median NLR was significantly higher in patients with NYHA II–III when compared to patients with NYHA I after six months of CRT implantation (p < 0.001, p = 0.004, respectively). In non-responder patients with ischaemic aetiology, median L% was significantly lower as compared to responders (p < 0.001). However, there was a lack of significant difference between responders and non-responders regarding median L% among the non-ischaemic aetiology group (p = 0.054) (Table 2). When NLR, PLR, and L% were evaluated according to the HF aetiology among all patients, there were no significant differences between the ischaemic and non-ischaemic HF groups (median NLR 2.8 [0.99–26] vs. 2.9 [0.80–23], p = 0.346; median PLR 144.3 [49.6–432] vs. 125.5 [41.4–270], p = 0.081; median L% 22 [3.9–69] vs. 22.5 [6.9–50], p = 0.120, respectively).

Figure 1. Comparison of the neutrophil-to-lymphocyte ratio (NLR) between responders and non-responders. Responders’ median NLR 2.5 (0.8–8.8); non-responders’ median NLR 3.7 (1.5–26.0); p < 0.001

Figure 2. Comparison of the platelet-to-lymphocyte ratio (PLR) between responders and non-responders. Responders’ median PLR 125.4 (41.5–243.5); non-responders’ median PLR 161.5 (61.2–432.0); p < 0.001

Figure 3. Comparison of the relative lymphocyte count (L%) between responders and non-responders. Responders’ mean L% 24.7 ± 8.9; non-responders’ mean L% 18.6 ± 7.6; p < 0.001

Table 2. Relation between neutrophil/lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), relative lymphocyte count (L%), and heart failure aetiology according to response to cardiac resynchronisation therapy

	Responders	Non-responders	P†
NLR
Ischaemic	2.5 (1.0–8.8)	3.8 (1.5–26.0)	< 0.001
Non-ischaemic	2.7 (0.8–8.1)	3.6 (1.5–23.0)	0.014
P‡	0.883	0.642
PLR
Ischaemic	136.4 (49.6–228.8)	172.3 (61.2–432.0)	0.018
Non-ischaemic	115.6 (41.5–243.5)	135.5 (76.8–270.0)	0.019
P‡	0.245	0.558
L%
Ischaemic	24.3 ± 9.3	17.5 ± 7.8	< 0.001
Non-ischaemic	25.0 ± 8.5	20.6 ± 7.0	0.054
P‡	0.724	0.166
†‡According to Bonferroni adjustment, a value of p < 0.025 was accepted as significant.

Correlation analysis demonstrated a low but significant positive correlation between pQRS duration and NLR (r = 0.270, p = 0.031) and a moderate negative correlation between pQRS duration and L% (r = –0.413, p = 0.002). However, there was no significant correlation between PLR and pQRS duration (p = 0.344). In addition, both NLR and L% showed a low but significant correlation with post-procedural NYHA functional classes (r = 0.307, p < 0.001; r = –0.225, p = 0.008, respectively) (Table 3).

Table 3. Correlation analysis of neutrophil/lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), relative lymphocyte count (L%), and other clinical variables

	r value/p-value
	NLR	PLR	L%
Paced QRS duration	0.270/0.031	0.120/0.344	–0.413/0.002
Pre-EF	–0.154/0.054	–0.138/0.084	0.228/0.004
Post-EF	–0.140/0.120	–0.019/0.835	0.126/0.163
Pre-NYHA	0.145/0.071	0.048/0.552	–0.097/0.229
Post-NYHA	0.307/< 0.001	0.156/0.065	–0.225/0.008
EF — ejection fraction; NYHA — New York Heart Association

In multivariate logistic regression analysis both pre-implantation PLR and NLR independently predicted the CRT nonresponse (p = 0.005; p < 0.021, respectively). Patients with PLR > 173.09 had a 2.9-fold and NLR > 3.45 had a 12.2-fold increased risk of CRT nonresponse, respectively (Table 4). The ROC curve was plotted to determine the relation between NLR, PLR, L%, and nonresponse to CRT (Table 5). The pre-implantation NLR predicted CRT nonresponse with a sensitivity of 64% and a specificity of 74.8% (p < 0.001). Also, the pre-implantation PLR predicted CRT response with a sensitivity of 44% and a specificity of 83.28% (p < 0.001). Furthermore, L% < 19.75 predicted nonresponse to CRT with a specificity of 72.0% and a sensitivity of 58.0% (p < 0.001).

Table 4. Multivariate analysis of relevant variables concerning non-response to cardiac resynchronisation therapy

Variables	Odds ratio	95% confidence interval		Wald	P
		Lower	Upper
Ischaemic aetiology	0.919	0.201	4.210	0.012	0.913
PCI	2.519	0.266	23.860	0.648	0.421
Hypertension	1.168	0.439	3.111	0.097	0.756
Statin	1.307	0.500	3.413	0.298	0.585
NLR > 3.45	12.216	2.161	69.052	8.021	0.005
PLR > 173.09	2.891	1.178	7.097	5.368	0.021
L% < 19.75	0.264	0.045	1.542	2.186	0.139
L% — relative lymphocyte count; NLR — neutrophil/lymphocyte ratio; PCI — percutaneous coronary intervention; PLR — platelet lymphocyte ratio

Table 5. Receiver operating characteristics analysis indicating the best cut-off value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and relative lymphocyte count (L%) for predicting non-response to cardiac resynchronisation therapy

	NLR	PLR	L%
Area under the curve	0.718	0.667	0.691
95% confidence interval	0.633–0.803	0.574–0.759	0.604–0.779
P-value	< 0.001	< 0.001	< 0.001
Cut-off	> 3.45	> 173.09	< 19.75
Number of patients	157	157	157
Sensitivity	32/50 (64.0%)	22/50 (44.0%)	29/50 (58.0%)
Specificity	80/107 (74.8%)	89/107 (83.2%)	77/107 (72.0%)
Pegative predictive value	32/59 (54.2%)	22/40 (55.0%)	29/59 (49.2%)
Positive predictive value	80/98 (81.6%)	89/117 (76.1%)	77/98 (78.6%)

DISCUSSION

The major findings of our study were as follows: (1) baseline indirect inflammatory markers including NLR and PLR levels were significantly higher and L% was significantly lower in the non-responder group; (2) a cut-off value of PLR > 173.09, NLR > 3.45, and L% < 19.75 predicted nonresponse to CRT well; (3) both NLR and L% showed a significant correlation with NYHA functional classes during follow-up and pQRS duration.

It was known that the immune system and inflammation play an important role in the pathogenesis of HF [17]. However, the immunological axis represents a potentially unknown feature in HF prognostication. The mechanistic basis for interplay between leukocyte differentials and HF is sophisticated. It has been proposed that systemic release of cytokines potentially causing lymphocyte apoptosis and activation of hypothalamic–pituitary–adrenal axis, particularly due to physical stress, result in a reduced relative lymphocyte count [18, 19]. Previous studies have shown that relative lymphocyte count was significantly associated with incident HF, hospitalisations due to HF, and mortality [20–22]. Neutrophils play a major role in the inflammatory process, by producing myeloperoxidase that promotes phagocytic function. Elevated levels of this enzyme also cause an excess production of free radicals that have deleterious effects on the myocardium, resulting in tissue injury and decreased ventricular function [23]. In a study conducted by Avcı et al. [24] among idiopathic dilated cardiomyopathy patients, a significant negative correlation between NLR and LVEF was observed. They observed worse functional classes with higher levels of NLR and concluded that higher NLR was useful to assess the severity of HF. Yıldız et al. [25] reported higher NLR levels and reduced functional capacity without significant difference in LVEF according to the exercise capacity in HF patients. In addition, Agacdiken et al. [7] observed an increment in baseline NLR among non-responders to CRT, and they found that baseline NLR was the only predictor of response to CRT. In our study, NYHA functional classes did not vary according to the CRT response, but we observed higher baseline NLR levels with worse post-procedural functional capacity. Also, we observed that both NLR and L% correlated significantly with post-procedural NYHA functional classes. Although we did not find any significant correlation between NLR and LVEF, NLR was significantly higher in the non-responder group, which may support the hypothesis that NLR might be related to advanced HF and consequent non-response to CRT.

The platelet lymphocyte ratio has been investigated as an easily available inflammatory marker that joins the predictive risk of platelet and lymphocyte counts into a single risk factor [26]. The relation between elevated PLR and HF has not been studied. We showed that PLR was significantly higher in non-responders to CRT and PLR levels were useful in predicting CRT response. HF is a state of chronic immune activation [27], thus higher PLR together with higher NLR may indicate inflammation and also the severity of the underlying disease. Large randomised clinical trials and clinical experience have suggested that irreversibly advanced HF patients will not respond to CRT. There is no certain limit for LVEF to determine patients who will respond to CRT or any simple parameter that identifies patients who may not have a chance for LV reverse remodel via CRT due to advanced disease [28]. Notably, we observed that L% showed a significant correlation with pre-LVEF, post-NYHA, and pQRS duration. The present study supports the previous data showing that decreased L% in non-responders may show LV dysfunction that is too far advanced to reverse remodel and consequently non-response to CRT. We can conclude that simple baseline inflammation markers like NLR, PLR, and L% may be useful in estimating the severity of HF and the assessing whether candidates have a chance to respond to CRT.

Limitations of the study

This study has some limitations. First, this retrospective study was conducted in a single centre with a small sample size. Second, additional inflammation markers were not assessed to address the other confounding factors. Third, CRT response was evaluated only with improvement in the LVEF due to the absence of LV end-systolic dimension data. Finally, the follow-up duration is relatively short, and our centre is a tertiary referral hospital, so our study cohort may not represent all patient characteristics.

CONCLUSIONS

Higher NLR and PLR are related to higher rates of nonresponse to CRT, which may support the deleterious effects of baseline inflammatory condition in advanced HF. Complete blood count is an easily available test that is commonly ordered in HF, and its ability to predict CRT response is attractive.

Conflict of interest: none declared

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Cite this article as: Balci KG, Balcı MM, Sen F et al. The role of baseline indirect inflammatory markers in prediction of response to cardiac resynchronisation therapy. Kardiol Pol, 2016; 74: 119–126. doi: 10.5603/KP.a2015.0142.