Research Article

Laboratory Parameters Predicting Mortality in Heart Failure Patients treated with Implantable Cardioverter Defibrillator: Single Centre, Long-term Results

10.4274/atfm.galenos.2021.41033

  • Veysel Özgür Barış
  • Ahmet Büyük
  • Fatih Poyraz
  • Murat Can Güney
  • Sedat Sakallı

Received Date: 31.05.2020 Accepted Date: 08.02.2021 J Ankara Univ Fac Med 2021;74(1):83-89

Objectives:

Neutrophil/lymphocyte (NLR), Monocyte/HDL (MHR), lymphocyte/monocyte (LMR) and platelet/lymphocyte ratios (PLR) are inflammation markers with proven prognostic values in various cardiovascular diseases. However, a clinical study demonstrating the prognostic value of these markers in heart failure (HF) patients treated with an implantable cardioverter-defibrillator (ICD) is not yet available. It is aimed to demonstrate the relationship between NLR, MHR, LMR, PLR and mortality development in patients with HF with ICD.

Materials and Methods:

One hundred and ninety-four patients who underwent ICD implantation due to systolic HF between January 2015 and December 2019 were included in the study.

Results:

The mean age was 59.84±13.26 years. The female gender ratio was 25.3%. Death developed in 16 patients (8%) after a median follow-up of 27 months. While basal urea, uric acid, gamma-glutamyl transferase, C-reactive protein and neutrophil levels were found to be high, hemoglobin and lymphocyte levels were found to be low in the exitus developing group. While the rates of NLR, MHR and PLR were statistically significantly higher in the group with death during follow-up (p=0.001, p=0.049, p=0.020, respectively ), LMR was significantly lower (p<0.001). In ROC analyses, mortality was predicted with 81% sensitivity and 61% specificity (p=0.001 AUC=0.76) of values of NLR and above 3.06; 86% sensitivity and 61% specificity [p=0.046 Area under curve (AUC)=0.723] of values of MHR and above 0,0196; 81% sensitivity and 55% specificity (p<0.001 AUC=0.784) of values of LMR 3.22 and 113.59 and above of PLR with 75% sensitivity and 51% specificity (p=0.020 AUC=0.68). Multiple logistic regression analysis showed LMR was an independent factor for mortality (p=0.027).

Conclusion:

In our study, it has been shown that NLR, MHR, PLR and LMR, which are inflammation markers, can predict mortality in patients with ICD implanted HF. In the multivariate analysis, LMR value has been found to be significant. This is the first study demonstrating the predictive power of these parameters in this patient group.

Keywords: Heart Failure, Neutrophil Lymphocyte Ratio, Monocyte HDL Ratio, Platelet Lymphocyte Ratio, Lymphocyte Monocyte Ratio

Introduction

Heart failure is a clinical depiction with symptoms such as dyspnea, orthopnea, weakness in patients as a result of decreased cardiac output or increased intracardiac pressures due to structural or functional disorders developing in the cardiac muscle (1). Moreover; heart failure is defined as a clinical syndrome with inflammation at its center rather than being a disease above this classical definition (2). Even with the most recent treatments in this clinical syndrome, mortality is as high as 17% and many parameters are used to predict it (3-5).

Implantable cardioverter-defibrillator (ICD) is recommended in current guidelines for primary and secondary protection in patients with heart failure (6). Even in patients with heart failure who underwent ICD implantation, the mortality rate is around 22% (7).  Despite all current medications and drugs, such a high mortality ratio in patients with heart failure can be explained by the presence of inflammation in the center (2). Neutrophil lymphocyte ratio (NLR), monocyte HDL ratio (MHR), lymphocyte monocyte ratio (LMR), platelet lymphocyte ratio (PLR) are markers of the systemic inflammatory response and have prognostic values in many cardiovascular diseases (8-11). However, no study on the prognostic values of ICD implanted patients is yet available.

The aim of this study is to investigate and compare the predictive values of NLR, MHL, LMR, PLR ratios with proven prognostic values in many cardiovascular diseases due to all causes in patients with ICD implanted heart failure.


Materials and Methods

Patient Group

Patients with systolic heart failure (included ischemic and non-ischemic) and treated with maximal medical treatment and ICD implantation due to primary prevention were included this trail. Systolic heart failure and ICD indication for primary prevention defined as the patients with the left ventricular ejection fraction less than 30% with New York Heart Association (NYHA) 1 or the left ventricular ejection fraction less than 35% with NYHA 2 and 3. Maximal medical treatment defined as beta-blocker (aimed heart rate with 55-65 beat per minute), ACEI/ARB (controlled blood pressure) and spironolactone usage if creatinine and potassium levels were normal.

Exclusion criteria from the study are: 1) Performing ICD implantation for reasons other than systolic heart failure, 2) patient groups who could not receive maximal medical treatment before ICD implantation, 3) being under 18 years of age, 4) ischemic cardiomyopathy with residual ischemia 5) ICD indication other than systolic heart failure (hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia), 6) patient with active infection, hepatic or romatological diseases. The study protocol has been approved by the local ethics committee.

Information of the patients, hospitalized in Gaziantep Dr. Ersin Arslan Training and Research Hospital, has been accessed from the archive. Totally, 194 patients, that signed informed consent, between January 2015 and December 2019 have been included in the study.

Endpoint

The primary endpoint of the study was defined as all-cause mortality.

Laboratory Analysis

In the study, routine biochemistry and whole blood parameters taken from the patients before the procedure have been used. Urea, creatinine, gamma-glutamyl transferase (GGT), uric acid, cholesterol panel, C-reactive protein (CRP) levels from biochemical tests have been included in the study. Leukocyte, haemoglobin, platelet, neutrophil, monocyte, lymphocyte levels and mean platelet volume and red cell distribution width have been included in the study. NLR has been calculated by dividing neutrophil count into lymphocyte number, MHR by dividing monocyte number into HDL cholesterol level, LMR by dividing lymphocyte number into monocyte number and PLR by dividing platelet number into lymphocyte number.

Statistical Analysis

All statistical analyses have been performed using the SPSS program (Version 20.0 for Windows, SPSS Inc. Chicago, IL). The groups have been compared in terms of the obtained data. It has been predicted that the data of continuous variables matching the normal distribution should be given with mean ± standard deviation and the comparison should be made with the Student’s t-test. The comparison of continuous variables that do not conform to the normal distribution should be given with the median and 25th and 75th percentile (25%-75%) and the comparison should be made with the Mann-Whitney U test. The data of the categorical variables have been given as a percentage and compared with the chi-squared test. The value of p<0.05 has been considered statistically significant.

ROC curves have been drawn to demonstrate the sensitivity and specificity of NLR, MHL, LMR, PLR ratios in predicting mortality. Multiple logistic regression analysis has been performed to compare the effects of these parameters on showing death due to all causes.


Results

The mean age of the patients included in the study was 59.84±13.26. The female gender ratio was 25.3%. Seventy-six patients underwent single-chamber ICD (39.2%), 57 patients underwent double chamber ICD (29.4%) and 61 patients underwent biventricular ICD (31.4%) implantation. The patients were followed for a median of 27 months. Death developed in 16 patients (8%) after this follow-up. Age, female gender ratio, ejection fraction, basal creatinine, high-density lipoprotein, low-density lipoprotein and total cholesterol values have been found to be similar when the group with and without death has been compared (Table 1). Basal blood urea level, uric acid, GGT and CRT values of the developing death group have been found to be high. While the neutrophil count has been found to be high in the group developing death from complete blood parameters, haemoglobin and lymphocyte levels have been found to be low (Table 2).

NLR has been significantly higher in the group with death [2.6524 (1.80-3.83) vs. 6.18 (3.23-10.64), p<0.001] (Table 3). The NLR value above 3.06 in the drawn ROC curve predicted mortality with 81% sensitivity and 61% specificity (p=0.001 AUC: 0.76) in long-term follow-ups (Figure 1).

MHR has been significantly higher in the group developing death [0.0168 (0.012-0.026) vs. 0.0291 (0.024-0.033), p=0.049] (Table 3). The MHR value above 0.0196 in the drawn ROC curve predicted mortality with 86% sensitivity and 61% specificity (p: 0.046 AUC: 0.723) in long-term follow-ups (Figure 1).

LMR has been significantly lower in the group developing death [3.36 (2.41-4.38) vs. 1.80 (1.30-2.70) p=<0.001] (Table 3). The LMR value of 3.22 and below in the drawn ROC curve predicted mortality with 81% sensitivity and 55% specificity (p<0.001 AUC: 0.784) in long-term follow-ups (Figure 1).

The PLR has been significantly higher in the group developing death [113.04 (77,03-150,64) vs. 180.97 (112,78-245,84) p=0, 0.020] (Table 3). LMR value above 113.59 in the drawn ROC curve predicted mortality with 75% sensitivity and 51% specificity (p=0.020 AUC: 0.68) in long-term follow-ups (Figure 1). In the multivariate logistic regression analysis in which NLR, MHR, LMR, and PLR have been incorporated, the LMR value has been statistically significant (p=0.027) (Table 3).


Discussion

In this study, the predictive power of NLR, MHR, PLR, LMR ratios, which have been shown to play a role in predicting cardiovascular events in many previous studies, due to all causes in patients with ICD implanted heart failure has been investigated, and when the groups with and without death are compared, these four ratios have been found statistically significant. Death due to all causes has been predicted with 81% sensitivity and 61% specificity (p=0.001 AUC: 0.76) of values of NLR and above; 86% sensitivity and 61% specificity (p=0.046 AUC: 0.723) of values of MHR and above; 81% sensitivity and 55% specificity (p<0.001 AUC: 0.784) of values of PLR and above with 75% sensitivity and 51% specificity (p=0.020 AUC: 0.68). In the multiple logistic regression analysis in which these rates have been incorporated, the LMR value has been statistically significant (p=0.027). To the best of our knowledge for the first time in the literature, we investigated the predictive value of NLR, MHR, PLR, LMR ratios for the development of mortality after ICD implantation in patients with heart failure.

Heart failure progresses with high mortality and morbidity despite all improved drug and device treatments (1). The mortality ratio has been around 17% even with the angiotensin receptor blocker and neprilysin inhibitor that is the newest treatment option recommended in the guidelines and the mortality ratio in previous ICD studies not involving this treatment option has been around 22% (3,7). In this syndrome where mortality ratios are so high, predicting mortality can bring great benefit to the doctor and health system in terms of availability and timing of treatment (1). There are many markers and models that predict death in patients with heart failure (12,13). In addition to the markers predicting mortality such as low sodium, high BNP levels, markers showing systemic inflammatory response are also mentioned in the guidelines (1). NLR, MHL, LMR, PLR (8-11) have been shown to have prognostic values in many cardiovascular diseases as systemic inflammatory responses in previous studies.

Beyond several mechanical or functional disorders that exist in the definition of heart failure, it is now seen as a clinical syndrome with underlying inflammation. As with all other inflammations, white blood cells are known to play a role in this syndrome (2). Due to inflammation in heart failure, many inflammatory cytokine releases such as tumour necrosis factor alpha, interleukin-6 and C-reactive protein from white blood cells are increased (14). Ventricular dysfunction progresses with the direct effect of these cytokines on the myocardium (15). Hence, increased leukocyte levels have been found to be associated with long-term death and increased hospitalization in patients with heart failure (16,17).

In addition to the cumulative effect, neutrophil, monocyte, lymphocyte, and platelets, whose main function is haemostasis, play separate roles in inflammation cascade and should be investigated. Cytokines that cause tissue destruction such as myeloperoxidase, acid phosphatase, and elastase are released from neutrophils activated by inflammation on the basis of heart failure (18-20). Myeloperoxidase levels have been found to be high, especially in patients with heart failure and it is thought to be at the center of the inflammation seen in these patients (21). Myeloperoxidase released from neutrophils may lead to progression of heart failure by increasing myocyte destruction and fibrosis (21). Monocytes are other white blood cells that play a role in the inflammatory response (22) and the first step of atherosclerosis response (23,24). In addition to being the main source of circulating tumour necrosis alpha and interleukin-6, procoagulant effect by tissue factor release and pro-oxidant effects by oxidation of LDL are also present. HDL cholesterol has been shown to reduce these effects of monocytes (25). Lymphocyte’ apoptosis and low lymphocyte levels are observed due to increased neurohumoral activation in patients with heart failure (26,27). In systemic inflammatory conditions such as heart failure, platelets act as an inflammatory cell due to their interaction with leukocytes and endothelial cells and start producing cytokines and lead to adhesion and transmigration of monocytes. Platelets act as bridges between inflammation and coagulation in this respect (28,29).

Increased neutrophil, monocyte, platelet and decreased lymphocyte and HDL levels with these basic inflammatory mechanisms and their effectiveness in showing prognosis in cardiac events have been investigated in many clinical studies. Uthamalingam et al. (8) found that increased neutrophil/lymphocyte ratio (NLR) was associated with long-term mortality in patients with acute heart failure. Yucel et al. (30) found that increased NLR levels in patients with heart failure who underwent ICD implantation were associated with appropriate shock. In our study, we demonstrated that increased NLR levels were associated with death in a similar patient group.

Prevention of procoagulant and proinflammatory effects caused by monocytes by HDL cholesterol suggested that increased MHR rate may predict poor prognosis in cardiovascular diseases (31). This assumption has been proven by many clinical trials. Increased MHR has been shown to be associated with high MACE rates in patients with the acute coronary syndrome, no-reflow and death in ST-elevation myocardial infarction patients and stent restenosis (32-35). However, there is no study showing that increased MHR can predict death in patients with heart failure. In this study, we have shown that increased MHR levels are associated with increased mortality ratios in patients with ICD implanted heart failure.

Low lymphocyte and high monocyte levels have also been believed to be associated with poor prognosis in cardiovascular diseases. The LMR ratio formed by the ratio of these two values is accepted as a marker of poor prognosis in many non-cardiac chronic diseases (36). In cardiac diseases, LMR has been found to be associated with the degree of rheumatic mitral stenosis, short-term mortality in acute pulmonary embolism and acute heart failure (9,11,37). In this study, it has been shown that low LMR levels are associated with increased mortality ratios in patients with ICD implanted heart failure, and multivariate analysis has shown that it is the strongest predictor independently of other ratios.

High PLR levels as a result of increased inflation, coagulation and neurohumoral activity have been found to be associated with the severity and complexity of stenosis in acute coronary syndromes and increased cardiovascular poor outcome in peripheral artery patients and short-term mortality in patients with acute heart failure (38-40). In our study, long-term mortality has also been demonstrated in patients with chronic heart failure implanted with ICD.


Conclusion

High NLR, MHR, PLR and low LMR ratios have been found to be associated with increased mortality in patients with heart failure in which inflammation plays a role and prognoses in its course, despite all medical treatment options including ICD. The use of cytokines such as myeloperoxidase, TNF alpha, which is a direct indicator of inflammation in this patient group, may be both costly and impossible due to the insufficiency of local facilities. However, as shown in our study, these parameters, which can only be obtained with a complete blood count, can predict death with high sensitivity and specificity in this patient group.

Restrictions

There are some limitations to our study. Firstly, in this study investigating the indirect relationship between inflammation and heart failure, markers such as myeloperoxidase and TNF that can directly demonstrate systemic inflammation could not be used. The fact that the study is a retrospective registry study is the second restriction. Finally, the fact that echocardiographic examinations are not elaborated and do not include mortality related conditions such as TAPSE, right ventriculitis parameters can be shown as a restriction.

Compliance with Ethical Standards

The study was not funded. Authors declare no conflicts of interest. The present study was approved by the local ethic committee.

Ethics

Ethics Committee Approval: The study protocol has been approved by the local ethics committee.

Informed Consent: Totally, 194 patients, that signed informed consent, between January 2015 and December 2019 have been included in the study.

Peer-review: Externally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: S.S., F.P., M.C.G., Concept: V.Ö.B., Design: V.Ö.B., Data Collection or Processing: V.Ö.B., Analysis or Interpretation: V.Ö.B., Literature Search: V.Ö.B., Writing: V.Ö.B., A.B.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.


Images

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