Arq Bras CardiolabcArquivos Brasileiros de CardiologiaArq. Bras. Cardiol.0066-782X1678-4170Sociedade Brasileira de Cardiologia - SBCSXCh9mVPRb6wYfcrnxwZNKjS0066-782X2015002500606S0066-782X201500505012610.5935/abc.20150126Original ArticlesNeutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio are Predictors of Heart FailureDurmusErdal1KivrakTarik2GerinFethullah3SunbulMurat4SariIbrahim4ErdoganOkan4Silifke State HospitalCardiology ClinicMersinTurkeySilifke State Hospital, Cardiology Clinic, Mersin, TurkeySivas Numune HospitalCardiology ClinicSivasTurkeySivas Numune Hospital, Cardiology Clinic, Sivas, TurkeyCentral Laboratory of Public HealthDepartment of Clinical BiochemistryIstanbulTurkeyCentral Laboratory of Public Health, Department of Clinical Biochemistry, Istanbul, TurkeyMarmara UniversityFaculty of MedicineDepartment of CardiologyIstanbulTurkeyMarmara University Faculty of Medicine, Department of Cardiology, Istanbul, TurkeyMarmara UniversityMailing Address: Murat Sunbul , Marmara Universitesi Eðitim ve Araþtýrma Hastanesi, Postal Code 34899, Pendik, Istanbul – Turkey. E-mail: drmuratsunbul@gmail.com; dresraaydin@yahoo.com
Author contributions
Conception and design of the research: Durmus E, Kivrak T, Gerin F, Sunbul M, Sari I, Erdogan O; Acquisition of data and Analysis and interpretation of the data: Durmus E, Kivrak T, Gerin F, Sunbul M, Erdogan O; Statistical analysis: Durmus E, Gerin F, Sunbul M, Sari I; Obtaining financing: Durmus E; Writing of the manuscript: Durmus E, Sunbul M, Sari I, Erdogan O; Critical revision of the manuscript for intellectual content: Sunbul M, Sari I, Erdogan O.
Potential Conflict of Interest
No potential conflict of interest relevant to this article was reported.
0311201512201510566066131303201527072015This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.AbstractBackground:
Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are inflammatory markers used as prognostic factors in various diseases. The aims of this study were to compare the PLR and the NLR of heart failure (HF) patients with those of age-sex matched controls, to evaluate the predictive value of those markers in detecting HF, and to demonstrate the effect of NLR and PLR on mortality in HF patients during follow-up.
Methods:
This study included 56 HF patients and 40 controls without HF. All subjects underwent transthoracic echocardiography to evaluate cardiac functions. The NLR and the PLR were calculated as the ratio of neutrophil count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively. All HF patients were followed after their discharge from the hospital to evaluate mortality, cerebrovascular events, and re-hospitalization.
Results:
The NLR and the PLR of HF patients were significantly higher compared to those of the controls (p < 0.01). There was an inverse correlation between the NLR and the left ventricular ejection fraction of the study population (r: -0.409, p < 0.001). The best cut-off value of NLR to predict HF was 3.0, with 86.3% sensitivity and 77.5% specificity, and the best cut-off value of PLR to predict HF was 137.3, with 70% sensitivity and 60% specificity. Only NLR was an independent predictor of mortality in HF patients. A cut-off value of 5.1 for NLR can predict death in HF patients with 75% sensitivity and 62% specificity during a 12.8-month follow-up period on average.
Conclusion:
NLR and PLR were higher in HF patients than in age-sex matched controls. However, NLR and PLR were not sufficient to establish a diagnosis of HF. NLR can be used to predict mortality during the follow-up of HF patients.
The prevalence of heart failure (HF) is increasing due to the aging of the population and the decreased cardiac mortality and morbidity related to modern treatment approaches worldwide. The prevalence of HF is approximately 10% in patients aged over 70 years1. Despite advanced treatment approaches, mortality rates are still high. Moreover, the need for long-term care of HF patients constitutes a difficult situation for caregivers and relatives of patients.
Previous studies have shown that inflammation plays an important role in the initiation and progression of cardiovascular diseases (CVD)2-5. Chronic inflammation is also more common in HF patients6. White blood cells (WBCs) and their subtypes are associated with increased cardiovascular risk factors7-9. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel inflammatory biomarkers used as prognostic factors in various diseases6,10,11. Previous studies have demonstrated that a higher NLR is associated with a higher mortality rate in those with coronary artery disease (CAD)5,6,10. A study carried out by Uthamalingam et al6 showed that a higher NLR is associated with higher mortality in HF patients. However, to the best of our knowledge, there is no data about the significance of the PLR in HF patients in the literature. Comparison of the PLR of HF patients with those of age-sex matched healthy controls has not been studied previously. Therefore, the first aim of this study was to compare the PLR and the NLR of HF patients with those of age-sex matched controls. The second aim was to evaluate the predictive value of NLR and PLR in detecting HF. The third aim was to demonstrate the effect of the PLR and the NLR on mortality in HF patients during follow-up.
MethodsStudy population
Between June 2012 and October 2013, 71 patients diagnosed with decompensated HF were evaluated for study enrollment. A decompensated HF diagnosis was made if the patients had one of the typical HF symptoms, such as dyspnea at rest, orthopnea, or paroxysmal nocturnal dyspnea, and one of the typical HF signs, such as bilateral rales, pretibial edema, jugular venous distension, or a n-terminal pro brain natriuretic peptide (NT-pro BNP) level more than two times the upper limit of normal values depending on age group and according to current HF recommendations1. If patients had no symptoms or signs of HF despite a reduced ejection fraction (EF), they were not diagnosed as having decompensated HF. The plasma level of NT-pro BNP was measured using an Elecsys 2010 (Roche) device and an electrochemiluminescence immunoassay method. Patients with renal failure, acute and chronic infection, acute coronary syndromes, or connective tissue disease were excluded from the study. After the exclusion criteria were applied, 56 decompensated HF patients were included in the study. Forty patients who were admitted to our cardiology clinic and who were proven to have no cardiac abnormality after a complete cardiac evaluation, including a physical examination, electrocardiography, and echocardiography, and who had not been previously hospitalized for HF were included in the study as a control group. The whole study population was evaluated for the presence of hypertension (HT), hyperlipidemia (HL), and diabetes mellitus (DM). Hypertension was defined as systolic and/or diastolic blood pressure ≥ 140 /90 mm Hg, previously diagnosed HT, or the use of any antihypertensive medication. Diabetes mellitus was defined as fasting plasma glucose levels > 126 mg/dL in ≥ 2 measurements, previously diagnosed DM, or the use of antidiabetic medications, such as oral antidiabetic agents or insulin. Hyperlipidemia was defined as serum total cholesterol ≥ 200 mg/dL, serum triglyceride ≥ 150 mg/dL, low-density lipoprotein cholesterol ≥ 130 mg/dL, previously diagnosed HL, or if a patient had to use lipid-lowering medication.
Complete blood cell counts, which included total WBCs, neutrophils, lymphocytes, and platelets, were obtained at the time of admission. The NLR and the PLR were calculated as the ratio of neutrophil count to lymphocyte count and as the ratio of platelet count to lymphocyte count, respectively.
All decompensated HF patients who clinically improved with treatment were followed up after discharge. The data about death, cerebrovascular events, and re-hospitalization were gathered via telephone. The study was approved by the local ethics committee, and written informed consent was obtained from all participants.
Assessment of standard transthoracic echocardiography
All patients underwent complete two-dimensional (2D) transthoracic echocardiography with a commercially available echocardiography device (Vivid 7, GE Vingmed Ultrasound AS, Horten, Norway) operated by a single experienced cardiologist. Data acquisition was performed with a 3.5-MHz transducer at a depth of 16 cm in the parasternal and apical views (standard parasternal short-axis view at the midventricular level, apical long-axis, two-chamber and four-chamber images), and a color Doppler frame scanning rate of 100-140 Hz was used for color time delay and integration (TDI) images. Echocardiographic parameters were measured according to the recent guidelines of the American Society of Echocardiography, and the left ventricular (LV) EF was calculated using the biplane Simpson method12.
Statistical analysis
For the statistical analysis, we used the Statistical Package for the Social Sciences (SPSS) 15.0 for Windows. Categorical variables were defined as a percentage, and comparisons were made using the chi-square test. Quantitative variables were expressed as mean ± standard deviation, and, for the comparison of variables between the two groups, Student t test (parametric distributed parameters) and Mann-Whitney U test (for the parameters showing the nonparametric distribution) were used. To compare more than two groups, a Kruskal-Wallis test (nonparametric distributed data) was used, and the results were assessed using post-hoc analysis. Correlation analyses were performed using a Spearman correlation test. Receiver operating characteristic (ROC) analysis was used to assess the ability of the NLR and the PLR to predict the presence of HF. For multivariate analysis to evaluate the effects of independent parameters on the presence of HF and mortality, we performed logistic regression analysis. A p value < 0.05 was accepted as statistically significant.
Results
The study population consisted of 56 patients with decompensated HF [40 with reduced EF (< 50%), 16 with preserved EF (> 50%)] and 40 age-sex matched controls without HF. The baseline characteristics and echocardiographic parameters of the HF patients and controls are shown in Table 1. There were no statistically significant differences in age and sex between the two groups (p = 0.20, p = 0.780, respectively). Atrial fibrillation (AF), DM, HT, and HL were observed to be more common in the HF group compared to the controls. Left ventricular diameters and left atrial area were significantly larger in HF patients, and the LVEF was significantly lower in HF patients compared to the controls. The medications of HF patients and controls are listed in Table 2.
Comparison of baseline characteristics and conventional echocardiographic parameters of study population
Patients (n = 56)
Controls (n = 40)
p
Age (years)
67.5 ± 12.6
64.6 ± 8.5
0.20**
Sex (male, n)
32
24
0.780*
AF (n)
33
0
< 0.001*
DM (n)
28
6
< 0.001*
HT (n)
49
19
< 0.001*
HL (n)
18
3
0.004*
EF (%)
40.8 ± 12.8
65.4 ± 4.9
< 0.001
LVEDD (mm)
55.0 ± 14.5
46.0 ± 3.2
< 0.001
LVESD (mm)
43.9 ± 15.4
29.0 ± 3.1
< 0.001
LAA (cm2)
25.6 ± 10.1
15.5 ± 2.2
< 0.001
Data are presented as mean ± standard deviation or number of patients. AF: Atrial fibrillation; DM: Diabetes Mellitus; HT: Hypertension; HL: Hyperlipidemia; EF: Ejection fraction; LVEDD: Left ventricle end-diastolic diameter; LVESD: Left ventricle end-systolic diameter; LAA: Left atrial area.
Chi-square test was used,
Student t test was used, others were evaluated with Mann-Whitney U test.
Current medications of heart failure patients and controls
Group of drugs
Patients
Controls
p
Diuretics (%)
40 (71.4)
0 (0)
< 0.001
ACEI-ARB (%)
32 (57.1)
19 (47.5)
0.351
Calcium channel blockers (%)
21 (37.5)
8(20)
0.66
Beta-blocker (%)
33 (58.9)
2(5)
< 0.001
Digoxin (%)
15 (26.8)
0 (0)
< 0.001
Nitrates (%)
5 (8.9)
(0)
< 0.001
Data are presented as number and percentage of patients. ACEI: Angiotensin-converting-enzyme inhibitors; ARB: Angiotensin receptor blockers.
A comparison of laboratory findings between the two groups is shown in Table 3. White blood cell counts were similar in both groups, whereas the NLR (5.5 ± 2.8 vs. 2.5 ± 1.7, p < 0.01) and the PLR (197 ± 103 vs. 140 ± 57, p < 0.01) of the HF patients were significantly higher than those of the controls (Figure 1). We also compared the NLR and the PLR of HF patients to check for the presence of cardiovascular risk factors including AF, DM, HT, and HL (Table 4). The NLR and the PLR of AF patients were higher than those of the patients without AF. A correlation analysis performed using a Spearman test revealed that there was an inverse correlation between the NLR and the LV EF in the study population (r: -0.409, p < 0.001) (Figure 2). The NLR also correlated positively with the left atrium area (r: 0.496, p < 0.001). After ROC analysis, the best cut-off value of the NLR to predict the presence of HF was 3.0 with 86.3% sensitivity and 77.5% specificity (AUC: 0.868, p < 0.001), and the best cut-off value of the PLR to predict HF was 137.3 with 70% sensitivity and 60% specificity (AUC: 0.689, p = 0.004) (Figure 3).
Comparison of laboratory findings between two groups
Patients (n = 56)
Controls (n = 40)
p
Hemoglobin (gr/dL)
11.7 ± 1.6
13.3 ± 1.8
< 0.001*
WBC (103/µL)
7.6 ± 2.2
7.2 ± 1.6
0.322**
Neutrophils (103/µL)
5.6 ± 1.8
4.3 ± 1.3
< 0.001**
Lymphocytes (103/µL)
1.2 ± 0.7
2.0 ± 0.7
< 0.001**
Platelets (103/µL)
203 ± 68
254 ± 63
< 0.001*
NLR
5.5 ± 2.8
2.5 ± 1.7
< 0.001**
PLR
197± 103
140 ± 57
0.001**
Data are presented as mean ± standard deviation. WBC: White blood cell; NLR: Neutrophil-to-lymphocyte ratio; PLR: Platelet-to-lymphocyte ratio. Parameters evaluated with
Student t test and
Mann-Whitney U test.
Comparison of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio between two groups.
Comparison of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels according to presence of cardiovascular risk factors in patients with heart failure
NLR
p
PLR
p
Yes
No
Yes
No
AF
5.38 (2.80)
2.64 (2.55)
< 0.001
194.3 (123.7)
135.2 (77.4)
0.006
DM
4.27 (2.85)
3.15 (3.52)
0.188
151.1 (222.2)
153.3 (120)
0.957
HT
3.95 (3.22)
2.56 (3.10)
0.141
153.3 (105.4)
140.5 (102.1)
0.314
HL
4.54 (3.25)
3.50 (3.40)
0.154
134.2 (104.7)
154.8 (112.5)
0.349
Data are presented as median (interquartile range). AF: Atrial fibrillation; DM: Diabetes mellitus; HT: Hypertension; HL: Hyperlipidemia.
Correlation analysis of neutrophil-to-lymphocyte ratio with left ventricle ejection fraction.
Receiver Operating Characteristic (ROC) curve analysis of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to predict presence of heart failure.
After discharge from hospital, we acquired information about the HF patients via telephone. The average follow-up duration of HF patients was 12.8 ± 7.6 months (min-max: 1-26 months). The incidence of death, cerebrovascular events, and re-hospitalization of HF patients were 17.9%, 3.6%, and 32.1%, respectively. The cut-off value of 5.1 for the NLR can predict mortality in HF patients with 75% sensitivity and 62% specificity (AUC: 0.730, p = 0.045) during a 12.8-month follow-up period on average13. Based on multivariate logistic regression analysis, only the NLR was an independent predictor of mortality in HF patients (Table 5).
Multivariate logistic regression analysis to determine the independent predictors of mortality in heart failure
In this study, we demonstrated that the NLR and the PLR were higher in HF patients compared to age-sex matched controls. To the best of our knowledge, this is the first study to demonstrate that the PLR levels of HF patients are higher than those of controls. Moreover, the NLR was inversely correlated with the EF and is also an independent predictor of HF mortality. During the follow-up of HF patients, the NLR can be used to predict mortality.
Chronic inflammation is observed to be more common in chronic diseases, such as cancers, DM, HT, connective tissue disease, and chronic kidney disease14-18. Increased levels of inflammation are also associated with a poor prognosis in CAD4. Inflammatory reactions play a pivotal role in the development of HF19,20. White blood cells and their subtypes are remarkable inflammatory markers in CVD. As a result of inflammatory stimulus, leukocytes release many inflammatory cytokines, such as TNF-α , IL-6, and CRP, as well as some proteolytic enzymes. These pro-inflammatory cytokines have destructive effects on the myocardium, resulting in decreased LV function and HF21-24. Previous studies have shown that higher levels of pro-inflammatory cytokines may lead to myocardial remodeling and cardiac arrhythmia25,26. Lymphocytes play an important role in healing by modulating mononuclear cell phenotypes and inducing the tissue inhibitor of metalloproteinase-1 expression27. Lymphopenia is seen to be more common in stressful conditions such as HF due to the activation of the hypothalamic-pituitary-adrenal axis. The activation of this axis leads to cortisol secretion, and increased cortisol levels result in a decrease in the relative concentration of lymphocytes28,29. Lymphopenia is an independent prognostic factor and is also associated with decreased survival in patients with HF29,30.
Heart failure is a chronic disease with high mortality rates. The estimated one-year mortality rate is more than 20%6. The most powerful predictors of mortality are older age (more than 60), the presence of DM, and a lower LVEF13. Because of poor prognosis in HF, determining the prognostic factors is important for these patients. In a previous study of acute decompensated HF patients, higher NLR values were associated with a higher mortality rate, and the ability of the NLR to predict mortality was superior to that of the neutrophil count, the total WBC count, and a relative low lymphocyte count6. Therefore, an increased NLR in HF was associated with poor prognosis. In HF patients, despite similar total WBC counts compared to age-sex matched controls, the NLR was changing in favor of neutrophils. In this study, we proved that the NLR of HF patients was significantly higher than that of controls. The cut-off values of 3.0 and 5.1 can be used to predict the presence of HF and mortality, respectively. A study of HF patients demonstrated that after levosimendan infusion therapy, patients with higher NLRs had a higher mortality rate compared to patients with lower NLRs, and the 5.5 cut-off value of the NLR was determined as an effective cut-off point for predicting in-hospital mortality31. Previous studies have demonstrated that higher platelet and lower lymphocyte counts are associated with poor cardiovascular outcomes. High PLR is associated with a poorer prognosis in various disease states, such as several cancers and CAD32-34. However, there has been no available data about the PLR in HF patients until now. This is the first study to demonstrate that the PLR levels of HF patients are higher than those of controls. The cut-off value 137.3 can be used to predict the presence of HF.
Study limitations
Our study had some limitations. One was the small sample size. This might be why the power of the study was lower. We did not observe a significant correlation between the PLR and the LVEF for that reason. Due to the increased range of the PLR level and the small sample size, the sensitivity and specificity levels were too low to predict HF (70% and 60%, respectively). Therefore, the cut-off point value was close to the mean PLR level in the control group. We did not measure the level of inflammatory markers, such as TNF-α , IL-6, and CRP. Therefore, we did not compare the prognostic value of the NLR and those inflammatory factors. In addition, this was an observational and nonrandomized study; it can be accepted as a prototype of further prospective and randomized studies to compare the effect of the NLR on cardiovascular mortality.
Conclusions
The NLR and the PLR of HF patients were higher than those of the age-sex matched controls. However, the NLR and the PLR were not sufficient to establish a diagnosis of HF. The NLR may be used in the HF patient follow-up to predict mortality.
Sources of Funding
There were no external funding sources for this study.
Study Association
This study is not associated with any thesis or dissertation work.
References1 McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al; ESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2012;14(8):803-69. Erratum in: Eur J Heart Fail. 2013;15(3):361-2.McMurrayJJAdamopoulosSAnkerSDAuricchioABöhmMDicksteinKESC Committee for Practice Guidelines. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of CardiologyDeveloped in collaboration with the Heart Failure Association (HFA) of the ESCEur J Heart Fail2012148803869Erratum in: Eur J Heart Fail. 2013;15(3):361-2.2 Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med. 1999;340(2):115-26.RossRAtherosclerosis -an inflammatory diseaseN Engl J Med199934021151263 Libby P. What have we learned about the biology of atherosclerosis? The role of inflammation. Am J Cardiol. 2001;88(7B):3J-6J.LibbyPWhat have we learned about the biology of atherosclerosis? The role of inflammationAm J Cardiol2001887B3J6J4 Kruk M, Przyluski J, Kalinczuk L, Pregowski J, Deptuch T, Kadziela J, et al. Association of non-specific inflammatory activation with early mortality in patients with ST-elevation acute coronary syndrome treated with primary angioplasty. Circ J. 2008;72(2):205-11.KrukMPrzyluskiJKalinczukLPregowskiJDeptuchTKadzielaJAssociation of non-specific inflammatory activation with early mortality in patients with ST-elevation acute coronary syndrome treated with primary angioplastyCirc J20087222052115 Yildiz A, Kaya H, Ertas F, Oylumlu M, Bilik MZ, Yüksel M, et al. Association between neutrophil to lymphocyte ratio and pulmonary arterial hypertension. Turk Kardiyol Dern Ars. 2013;41(7):604-9.YildizAKayaHErtasFOylumluMBilikMZYükselMAssociation between neutrophil to lymphocyte ratio and pulmonary arterial hypertensionTurk Kardiyol Dern Ars20134176046096 Uthamalingam S, Patvardhan EA, Subramanian S, Ahmed W, Martin W, Daley M, et al. Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. Am J Cardiol. 2011;107(3):433-8.UthamalingamSPatvardhanEASubramanianSAhmedWMartinWDaleyMUtility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failureAm J Cardiol201110734334387 Guasti L, Dentali F, Castiglioni L, Maroni L, Marino F, Squizzato A, et al. Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularization: a systematic review on more than 34,000 subjects. Thromb Haemost. 2011;106(4):591-9.GuastiLDentaliFCastiglioniLMaroniLMarinoFSquizzatoANeutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularization: a systematic review on more than 34,000 subjectsThromb Haemost201110645915998 Tamhane UU, Aneja S, Montgomery D, Rogers EK, Eagle KA, Gurm HS. Association between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndrome. Am J Cardiol. 2008;102(6):653-7.TamhaneUUAnejaSMontgomeryDRogersEKEagleKAGurmHSAssociation between admission neutrophil to lymphocyte ratio and outcomes in patients with acute coronary syndromeAm J Cardiol200810266536579 Sunbul M, Gerin F, Durmus E, Kivrak T, Sari I, Tigen K, et al. Neutrophil to lymphocyte and platelet to lymphocyte ratio in patients with dipper versus non-dipper hypertension. Clin Exp Hypertens. 2014;36(4):217-21.SunbulMGerinFDurmusEKivrakTSariITigenKNeutrophil to lymphocyte and platelet to lymphocyte ratio in patients with dipper versus non-dipper hypertensionClin Exp Hypertens201436421722110 Park JJ, Jang HJ, Oh IY, Yoon CH, Suh JW, Cho YS, et al. Prognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Am J Cardiol. 2013;111(5):636-42.ParkJJJangHJOhIYYoonCHSuhJWChoYSPrognostic value of neutrophil to lymphocyte ratio in patients presenting with ST-elevation myocardial infarction undergoing primary percutaneous coronary interventionAm J Cardiol2013111563664211 Yildiz A, Yuksel M, Oylumlu M, Polat N, Akyuz A, Acet H, et al. The utility of the platelet-lymphocyte ratio for predicting no reflow in patients with ST-segment elevation myocardial infarction. Clin Appl Thromb Hemost. 2015;21(3):223-8.YildizAYukselMOylumluMPolatNAkyuzAAcetHThe utility of the platelet-lymphocyte ratio for predicting no reflow in patients with ST-segment elevation myocardial infarctionClin Appl Thromb Hemost201521322322812 Cheitlin MD, Armstrong WF, Aurigemma GP, Beller GA, Bierman FZ, Davis JL, et al. ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography). J Am Soc Echocardiogr. 2003;16(10):1091-110.CheitlinMDArmstrongWFAurigemmaGPBellerGABiermanFZDavisJLACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography)J Am Soc Echocardiogr200316101091111013 Pocock SJ, Wang D, Pfeffer MA, Yusuf S, McMurray JJ, Swedberg KB, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J. 2006;27(1):65-75.PocockSJWangDPfefferMAYusufSMcMurrayJJSwedbergKBPredictors of mortality and morbidity in patients with chronic heart failureEur Heart J2006271657514 Lee S, Choe JW, Kim HK, Sung J. High-sensitivity C-reactive protein and cancer. J Epidemiol. 2011;21(3):161-8.LeeSChoeJWKimHKSungJHigh-sensitivity C-reactive protein and cancerJ Epidemiol201121316116815 Pitsavos C, Tampourlou M, Panagiotakos DB, Skoumas Y, Chrysohoou C, Nomikos T, et al. Association between low-grade systemic inflammation and type 2 Diabetes Mellitus among men and women from the ATTICA study. Rev Diabet Stud. 2007;4(2):98-104.PitsavosCTampourlouMPanagiotakosDBSkoumasYChrysohoouCNomikosTAssociation between low-grade systemic inflammation and type 2 Diabetes Mellitus among men and women from the ATTICA studyRev Diabet Stud2007429810416 Okyay GU, Inal S, Oneç K, Er RE, Pasaoglu O, Pasaoglu H, et al. Neutrophil to lymphocyte ratio in evaluation of inflammation in patients with chronic kidney disease. Ren Fail. 2013;35(1):29-36.OkyayGUInalSOneçKErREPasaogluOPasaogluHNeutrophil to lymphocyte ratio in evaluation of inflammation in patients with chronic kidney diseaseRen Fail2013351293617 Rasouli M, Nesarhosseini V, Kiasari AM, Arab S, Shariati R, Kazemi D, et al. The multiplicative interactions of leukocyte counts with some other risk factors enhance the prognostic value for coronary artery disease. Cardiol J. 2011;18(3):246-53.RasouliMNesarhosseiniVKiasariAMArabSShariatiRKazemiDThe multiplicative interactions of leukocyte counts with some other risk factors enhance the prognostic value for coronary artery diseaseCardiol J201118324625318 Imtiaz F, Shafique K, Mirza SS, Ayoob Z, Vart P, Rao S. Neutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian population. Int Arch Med. 2012; 5(1): 2.ImtiazFShafiqueKMirzaSSAyoobZVartPRaoSNeutrophil lymphocyte ratio as a measure of systemic inflammation in prevalent chronic diseases in Asian populationInt Arch Med2012512219 Yndestad A, Damas JK, Oie E, Ueland T, Gullestad L, Aukrust P. Systemic inflammation in heart failure: the whys and wherefores. Heart Fail Rev. 2006;11(1):83-92.YndestadADamasJKOieEUelandTGullestadLAukrustPSystemic inflammation in heart failure: the whys and whereforesHeart Fail Rev2006111839220 Anker SD, von Haehling S. Inflammatory mediators in chronic heart failure: an overview. Heart. 2004;90(4):464-70.AnkerSDvon HaehlingSInflammatory mediators in chronic heart failure: an overviewHeart200490446447021 Mann DL, Young JB. Basic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokines. Chest. 1994;105(3):897-904.MannDLYoungJBBasic mechanisms in congestive heart failure: recognizing the role of proinflammatory cytokinesChest1994105389790422 Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996;27(5):1201-6.Torre-AmioneGKapadiaSBenedictCOralHYoungJBMannDLProinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD)J Am Coll Cardiol19962751201120623 Reichlin T, Socrates T, Egli P, Potocki M, Breidthardt T, Arenja N, et al. Use of myeloperoxidase for risk stratification in acute heart failure. Clin Chem. 2010;56(6):944-51.ReichlinTSocratesTEgliPPotockiMBreidthardtTArenjaNUse of myeloperoxidase for risk stratification in acute heart failureClin Chem201056694495124 Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T, et al. Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation. 2003;108(12):1440-5.BaldusSHeeschenCMeinertzTZeiherAMEiserichJPMunzelTMyeloperoxidase serum levels predict risk in patients with acute coronary syndromesCirculation2003108121440144525 Prabhu SD. Cytokine-induced modulation of cardiac function. Circ Res. 2004;95(2):1140-53.PrabhuSDCytokine-induced modulation of cardiac functionCirc Res20049521140115326 Korantzopoulos P, Kolettis T, Siogas K, Goudevenos J. Atrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stress. Med Sci Monit. 2003;9(9):RA225-9.KorantzopoulosPKolettisTSiogasKGoudevenosJAtrial fibrillation and electrical remodeling: the potential role of inflammation and oxidative stressMed Sci Monit200399RA225RA22927 Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53(1):31-47.FrangogiannisNGSmithCWEntmanMLThe inflammatory response in myocardial infarctionCardiovasc Res2002531314728 Maisel AS, Knowlton KU, Fowler P, Rearden A, Ziegler MG, Motulsky HJ, et al. Adrenergic control of circulating lymphocyte subpopulations: effects of congestive heart failure, dynamic exercise, and terbutaline treatment. J Clin Invest. 1990;85(2):462-7.MaiselASKnowltonKUFowlerPReardenAZieglerMGMotulskyHJAdrenergic control of circulating lymphocyte subpopulations: effects of congestive heart failure, dynamic exercise, and terbutaline treatmentJ Clin Invest199085246246729 Ommen SR, Hodge DO, Rodeheffer RJ, McGregor CG, Thomson SP, Gibbons RJ. Predictive power of the relative lymphocyte count in patients with advanced heart failure. Circulation. 1998;97(1):19-22.OmmenSRHodgeDORodehefferRJMcGregorCGThomsonSPGibbonsRJPredictive power of the relative lymphocyte count in patients with advanced heart failureCirculation1998971192230 Rudiger A, Burckhardt OA, Harpes P, Müller SA, Follath F. The relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failure. Am J Emerg Med. 2006;24(4):451-4.RudigerABurckhardtOAHarpesPMüllerSAFollathFThe relative lymphocyte count on hospital admission is a risk factor for long-term mortality in patients with acute heart failureAm J Emerg Med200624445145431 Tasal A, Erturk M, Uyarel H, Karakurt H, Bacaksiz A, Vatankulu MA, et al. Utility of the neutrophil to lymphocyte ratio for predicting in-hospital mortality after levosimendan infusion in patients with acute decompensated heart failure. J Cardiol. 2014;63(6):418-23.TasalAErturkMUyarelHKarakurtHBacaksizAVatankuluMAUtility of the neutrophil to lymphocyte ratio for predicting in-hospital mortality after levosimendan infusion in patients with acute decompensated heart failureJ Cardiol201463641842332 Azab B, Shah N, Akerman M, McGinn JT Jr. Value of platelet/lymphocyte ratio as a predictor of all-cause mortality after non-ST-elevation myocardial infarction. J Thromb Thrombolysis. 2012;34(3):326-34.AzabBShahNAkermanMMcGinnJTJrValue of platelet/lymphocyte ratio as a predictor of all-cause mortality after non-ST-elevation myocardial infarctionJ Thromb Thrombolysis201234332633433 Asher V, Lee J, Innamaa A, Bali A. Preoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancer. Clin Transl Oncol. 2011;13(7):499-503.AsherVLeeJInnamaaABaliAPreoperative platelet lymphocyte ratio as an independent prognostic marker in ovarian cancerClin Transl Oncol201113749950334 Bhatti I, Peacock O, Lloyd G, Larvin M, Hall RI. Preoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil-lymphocyte versus platelet-lymphocyte ratio. Am J Surg. 2010;200(2):197-203.BhattiIPeacockOLloydGLarvinMHallRIPreoperative hematologic markers as independent predictors of prognosis in resected pancreatic ductal adenocarcinoma: neutrophil-lymphocyte versus platelet-lymphocyte ratioAm J Surg20102002197203Relações Neutrófilo-Linfócito e Plaqueta-Linfócito Como Preditores de Insuficiência CardíacaDurmusErdal1KivrakTarik2GerinFethullah3SunbulMurat4SariIbrahim4ErdoganOkan4Silifke State HospitalCardiology ClinicMersinTurkeySilifke State Hospital, Cardiology Clinic, Mersin, TurkeySivas Numune HospitalCardiology ClinicSivasTurkeySivas Numune Hospital, Cardiology Clinic, Sivas, TurkeyCentral Laboratory of Public HealthDepartment of Clinical BiochemistryIstanbulTurkeyCentral Laboratory of Public Health, Department of Clinical Biochemistry, Istanbul, TurkeyMarmara UniversityFaculty of MedicineDepartment of CardiologyIstanbulTurkeyMarmara University Faculty of Medicine, Department of Cardiology, Istanbul, TurkeyMarmara UniversityCorrespondência: Murat Sunbul , Marmara Universitesi Eðitim ve Araþtýrma Hastanesi, CEP 34899, Pendik, Istanbul – Turquia. E-mail: drmuratsunbul@gmail.com; dresraaydin@yahoo.com
Contribuição dos autores
Concepção e desenho da pesquisa: Durmus E, Kivrak T, Gerin F, Sunbul M, Sari I, Erdogan O; Obtenção de dados e Análise e interpretação dos dados: Durmus E, Kivrak T, Gerin F, Sunbul M, Erdogan O; Análise estatística: Durmus E, Gerin F, Sunbul M, Sari I; Obtenção de financiamento: Durmus E; Redação do manuscrito: Durmus E, Sunbul M, Sari I, Erdogan O; Revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Sunbul M, Sari I, Erdogan O.
Potencial conflito de interesse
Declaro não haver conflito de interesses pertinentes.
ResumoFundamentos:
A obesidade mórbida está diretamente relacionada à deterioração da capacidade cardiorrespiratória, incluindo alterações na modulação autonômica cardiovascular.
Objetivo:
Este estudo teve por objetivo avaliar a função autonômica cardiovascular de obesos mórbidos.
Métodos:
Estudo transversal, incluindo dois grupos, Grupo I, composto por 50 obesos mórbidos, e Grupo II, por 30 indivíduos não obesos. A função autonômica foi avaliada pela variabilidade da frequência cardíaca no domínio do tempo [desvio padrão de todos os intervalos R-R normais (SDNN); desvio-padrão de todos os intervalos R-R normais (SDNN); raiz quadrada das médias quadráticas das diferenças dos intervalos R-R sucessivos (RMSSD); e o percentual de diferenças de intervalo intervalos R-R sucessivos maior que 50 milissegundos (pNN50)] em comparação ao adjacente, e no domínio da frequência (HF, do inglês, “high frequency”, e LF, do inglês, “low frequency”: integração da função da densidade espectral de potência para as bandas de alta e baixa frequência, respectivamente). Os grupos foram comparados pelo teste t de Student, considerando-se um nível de significância de 5%.
Resultados:
Quando comparados aos controles, os indivíduos obesos apresentaram valores menores de SDNN (40,0 ± 18,0 ms vs. 70,0 ± 27,8 ms; p = 0,0004), RMSSD (23,7 ± 13,0 ms vs. 40,3 ± 22,4 ms; p = 0,0030), pNN50 (14,8 ± 10,4 % vs. 25,9 ± 7,2%; p = 0,0061) e HF (30,0 ± 17,5 Hz vs. 51,7 ± 25,5 Hz; p = 0,0023). A relação LF/HF média foi maior no Grupo I (5,0 ± 2,8 vs. 1,0 ± 0,9; p = 0,0189), refletindo alteração no equilíbrio simpato-vagal. Não houve diferença estatística entre os grupos I e II com relação ao índice LF (50,1 ± 30,2 Hz vs. 40,9 ± 23,9 Hz; p = 0,9013).
Conclusão:
obesos mórbidos apresentam aumento de atividade simpática e redução da atividade parassimpática, caracterizando uma disfunção autonômica cardiovascular.
Palavras-chave:Obesidade MórbidaDoenças CardiovascularesFatores de Risco; Doença Cardiopulmonar / complicaçõesFrequência CardíacaIntrodução
A prevalência de insuficiência cardíaca (IC) cresce devido ao envelhecimento da população e à redução da morbimortalidade cardíaca relacionada às modernas abordagens de tratamento em todo o mundo. A prevalência de IC é de aproximadamente 10% nos pacientes com mais de 70 anos1. A despeito das avançadas abordagens de tratamento, as taxas de mortalidade ainda são altas. Além disso, a necessidade de cuidado a longo prazo dos pacientes com IC constitui uma dificuldade para cuidadores e familiares.
Estudos prévios mostraram o importante papel da inflamação no início e na progressão das doenças cardiovasculares (DCV)2-5. A inflamação crônica é ainda mais comum em pacientes com IC6. Os leucócitos e seus subtipos estão associados com aumento dos fatores de risco cardiovascular7-9. A relação neutrófilo-linfócito (RNL) e a relação plaqueta-linfócito (RPL) são novos biomarcadores inflamatórios usados como fatores prognósticos em várias doenças6,10,11. Estudos prévios mostraram que uma RNL mais alta associa-se com maior taxa de mortalidade nos pacientes com doença arterial coronariana (DAC)5,6,10. Uthamalingam e cols.6desenvolveram um estudo mostrando que uma maior RNL associa-se a maior mortalidade em pacientes com IC. No entanto, até onde se sabe, não há na literatura informação sobre o significado da RPL em pacientes com IC. Ainda não se comparou a RPL de pacientes com IC àquela de controles saudáveis pareados por idade e sexo. Portanto, o primeiro objetivo deste estudo foi comparar a RPL e a RNL de pacientes com IC àquelas de controles pareados por idade e sexo. O segundo objetivo foi avaliar o valor preditivo da RNL e da RPL na detecção de IC. O terceiro objetivo foi demonstrar o efeito da RPL e da RNL na mortalidade de pacientes com IC durante o seguimento.
MétodosPopulação do estudo
Entre junho de 2012 e outubro de 2013, 71 pacientes com diagnóstico de IC descompensada foram avaliados para recrutamento no estudo. Os pacientes foram diagnosticados com IC descompensada caso apresentassem um dos sintomas típicos de IC, como dispneia de repouso, ortopneia ou dispneia paroxística noturna, e um dos sinais típicos de IC, como estertores bilaterais, edema pré-tibial, turgência jugular ou nível de peptídeo natriurético cerebral n-terminal (NT-pro-BNP) duas vezes maior do que o limite superior da normalidade dependendo do grupo etário e conforme as atuais recomendações de IC1. Se os pacientes não apresentassem sintomas ou sinais de IC, ainda que tivessem reduzida fração de ejeção (FE), não eram diagnosticados com IC descompensada. O nível plasmático de NT-pro-BNP foi medido usando-se o dispositivo Elecsys 2010 (Roche) e um imunoensaio de eletroquimioluminescência. Pacientes com insuficiência renal, infecção aguda ou crônica, síndromes coronarianas agudas ou doença do tecido conjuntivo foram excluídos do estudo. Após a aplicação dos critérios de exclusão, 56 pacientes com IC descompensada foram incluídos no estudo. O grupo controle do estudo foi constituído por 40 pacientes da nossa clínica cardiológica, que comprovadamente não apresentaram qualquer anormalidade cardíaca em uma avaliação completa que incluiu exame físico, eletrocardiografia e ecocardiografia, e nem hospitalização prévia por IC. Toda a população do estudo foi avaliada quanto à presença de hipertensão (HT), hiperlipidemia (HL) e diabetes mellitus (DM). Definiu-se HT como uma pressão sistólica e/ou diastólica ≥ 140/90 mmHg, diagnóstico prévio de HT, ou uso de qualquer medicação hipotensora. Definiu-se DM como uma glicemia de jejum > 126 mg/dL em duas ou mais medidas, diagnóstico prévio de DM, ou uso de qualquer medicação hipoglicemiante, como hipoglicemiantes orais ou insulina. Definiu-se HL como colesterol sérico total ≥ 200 mg/dL, trigliceridemia ≥ 150 mg/dL, colesterol da lipoproteína de baixa densidade ≥ 130 mg/dL, diagnóstico prévio de HL, ou uso de medicação hipolipemiante.
Hemogramas completos, incluindo leucócitos totais, neutrófilos, linfócitos e plaquetas, foram realizados por ocasião da admissão. As RNL e RPL foram calculadas como as relações entre o número de neutrófilos e o de linfócitos, e entre o número de plaquetas e o de linfócitos, respectivamente.
Todos os pacientes com IC descompensada, que melhoraram clinicamente com o tratamento foram acompanhados após a alta. Informações sobre morte, eventos cerebrovasculares e re-hospitalização foram obtidas por telefone. Este estudo foi aprovado pelo comitê de ética local, tendo todos os participantes fornecido consentimento livre e informado.
Avaliação com ecocardiografia transtorácica padrão
Todos os pacientes foram submetidos a ecocardiografia transtorácica bidimensional (2D) completa com um ecocardiógrafo comercialmente disponível (Vivid 7, GE Vingmed Ultrasound AS, Horten, Noruega) operado por um único cardiologista experiente. A aquisição de dados foi realizada com um transdutor de 3,5 MHz na profundidade de 16 cm nos cortes paraesternal e apical (corte transversal paraesternal padrão ao nível médio-ventricular, longitudinal apical de duas e quatro câmaras), e Doppler colorido com velocidade de varredura de 100-140 Hz foi usado para imagens coloridas com retardo de tempo e integração (TDI). Os parâmetros ecocardiográficos foram usados conforme as diretrizes recentes da Sociedade Americana de Ecocardiografia, calculando-se a fração de ejeção do ventrículo esquerdo (FEVE) pelo método biplanar de Simpson12.
Análise estatística
Utilizou-se o programa Statistical Package for the Social Sciences (SPSS), versão 15.0 para Windows, para a análise estatística. As variáveis categóricas foram definidas como porcentagem, sendo as comparações realizadas com o teste do qui-quadrado. As variáveis quantitativas foram expressas como média ± desvio padrão, sendo os testes t de Student (parâmetros com distribuição paramétrica) e U de Mann-Whitney (parâmetros sem distribuição paramétrica) usados para comparar as variáveis entre os dois grupos. O teste de Kruskal-Wallis (dados com distribuição não paramétrica) foi utilizado para comparar mais de dois grupos, sendo os resultados avaliados com análise post-hoc. As correlações foram analisadas com o teste de correlação de Spearman. Usou-se análise da curva ROC (Receiver Operating Characteristic) para avaliar a capacidade da RNL e da RPL para predizer a presença de IC. Regressão logística foi realizada para verificar os efeitos de parâmetros independentes na presença de IC e mortalidade. Adotou-se o valor de p < 0,05 para significado estatístico.
Resultados
A população do estudo consistiu em 56 pacientes com IC descompensada [40 com FE reduzida (< 50%) e 16 com FE preservada (> 50%)] e 40 controles pareados por idade e sexo sem IC. A Tabela 1 mostra as características basais e os parâmetros ecocardiográficos dos pacientes com IC e dos controles. Não houve diferença estatisticamente significativa quanto a idade e sexo entre os dois grupos (p = 0,20 e p = 0,780, respectivamente). Fibrilação atrial (FA), DM, HT e HL foram mais comuns no grupo com IC do que nos controles. O diâmetro ventricular esquerdo e a área do átrio esquerdo foram significativamente maiores nos pacientes com IC, e a FEVE significativamente menor nos pacientes com IC em comparação aos controles. A Tabela 2 mostra os medicamentos dos pacientes com IC e dos controles.
Comparação das características basais e dos parâmetros ecocardiográficos convencionais da população do estudo
Pacientes (n = 56)
Controles (n = 40)
p
Idade (anos)
67,5 ± 12,6
64,6 ± 8,5
0,20**
Sexo (masculino, n)
32
24
0,780*
FA (n)
33
0
< 0,001*
DM (n)
28
6
< 0,001*
HT (n)
49
19
< 0,001*
HL (n)
18
3
0,004*
FE (%)
40,8 ± 12,8
65,4 ± 4,9
< 0,001
DDFVE (mm)
55,0 ± 14,5
46,0 ± 3,2
< 0,001
DSFVE (mm)
43,9 ± 15,4
29,0 ± 3,1
< 0,001
AAE (cm2)
25,6 ± 10,1
15,5 ± 2,2
< 0,001
Dados apresentados como média ± desvio padrão ou número de pacientes. FA: Fibrilação atrial; DM: Diabetes mellitus; HT: Hipertensão; HL: Hiperlipidemia; FE: Fração de ejeção; DDFVE: Diâmetro diastólico final ventricular esquerdo; DSFVE: Diâmetro sistólico final ventricular esquerdo; AAE: Área do átrio esquerdo.
Usou-se o teste do qui-quadrado.
Usou-se o teste t de Student, outros avaliados com o teste U de Mann-Whitney.
Medicações usados pelos pacientes com insuficiência cardíaca e controles
Grupo de medicamentos
Pacientes
Controles
p
Diuréticos (%)
40 (71,4)
0 (0)
< 0,001
IECA-BRA (%)
32 (57,1)
19 (47,5)
0,351
Bloqueadores dos canais de cálcio (%)
21 (37,5)
8 (20)
0,66
Betabloqueador (%)
33 (58,9)
2 (5)
< 0,001
Digoxina (%)
15 (26,8)
0 (0)
< 0,001
Nitratos (%)
5(8,9)
(0)
< 0,001
Dados apresentados como número e porcentagem de pacientes. IECA: Inibidores da enzima conversora da angiotensina; BRA: Bloqueadores dos receptores de angiotensina.
A Tabela 3 compara os achados laboratoriais dos dois grupos. A leucometria foi semelhante nos dois grupos de pacientes, enquanto a RNL (5,5 ± 2,8 vs. 2,5 ± 1,7, p < 0,01) e a RPL (197 ± 103 vs. 140 ± 57, p < 0,01) dos pacientes com IC foram significativamente maiores do que as dos controles (Figura 1). Comparamos ainda a RNL e a RPL dos pacientes com IC para verificar a presença de fatores de risco cardiovascular, como FA, DM, HT e HL (Tabela 4). A RNL e a RPL dos pacientes com FA foram mais altas do que aquelas de pacientes sem FA. O teste de Spearman revelou uma correlação inversa entre a RNL e a FEVE na população do estudo (r: -0,409; p < 0,001) (Figura 2). A RNL também se correlacionou positivamente com a área do átrio esquerdo (r: 0,496; p < 0,001). Após a análise da curva ROC, o melhor ponto de corte da RNL para prever a presença de IC foi 3,0, com 86,3% de sensibilidade e 77,5% de especificidade [área sob a curva (AUC): 0,868; p < 0,001], e o melhor ponto de corte da RPL para prever a presença de IC foi 137,3, com 70% de sensibilidade e 60% de especificidade (AUC: 0,689; p = 0,004) (Figura 3).
Comparação dos achados laboratoriais entre os dois grupos
Pacientes (n = 56)
Controles (n = 40)
p
Hemoglobina (gr/dL)
11,7 ± 1,6
13,3 ± 1,8
< 0,001*
Leucócitos (103/µL)
7,6 ± 2,2
7,2 ± 1,6
0,322**
Neutrófilos (103/µL)
5,6 ± 1,8
4,3 ± 1,3
< 0,001**
Linfócitos (103/µL)
1,2 ± 0,7
2,0 ± 0,7
< 0,001**
Plaquetas (103/µL)
203 ± 68
254 ± 63
< 0,001*
RNL
5,5 ± 2,8
2,5 ± 1,7
< 0,001**
RPL
197±103
140 ± 57
0,001**
Dados apresentados como média ± desvio padrão. RNL: Relação neutrófilo-linfócito; RPL: Relação plaqueta-linfócito.
Parâmetros avaliados com o teste t de Student *
e teste U de Mann-Whitney**.
Comparison of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio between two groups.
Comparação das relações neutrófMo-linfócito (RNL) e plaqueta-linfócito (RPL) de acordo com a presença de fatores de risco cardiovascular em pacientes com insuficiência cardíaca
RNL
p
RPL
p
Sim
Não
Sim
Não
FA
5,38 (2,80)
2,64 (2,55)
< 0,001
194,3 (123,7)
135,2 (77,4)
0,006
DM
4,27 (2,85)
3,15 (3,52)
0,188
151,1 (222,2)
153,3 (120)
0,957
HT
3,95 (3,22)
2,56 (3,10)
0,141
153,3 (105,4)
140,5 (102,1)
0,314
HL
4,54 (3,25)
3,50 (3,40)
0,154
134,2 (104,7)
154,8 (112,5)
0,349
Dados apresentados como mediana (variação interquartil). FA: Fibrilação atrial; DM: Diabetes mellitus; HT: Hipertensão; HL: Hiperlipidemia.
Correlation analysis of neutrophil-to-lymphocyte ratio with left ventricle ejection fraction.
Comparação das relações neutrófilo-linfócito e plaqueta-linfócito entre os dois grupos.
Após alta hospitalar, a informação sobre os pacientes com IC foi obtida por telefone. A duração média do seguimento dos pacientes com IC foi de 12,8 ± 7,6 meses (min-máx: 1-26 meses). As incidências de morte, eventos cerebrovasculares e re-hospitalização dos pacientes com IC foram 17,9%, 3,6% e 32,1%, respectivamente. O ponto de corte de 5,1 para RNL pode predizer mortalidade nos pacientes com IC com sensibilidade de 75% e especificidade de 62% (AUC: 0,730; p = 0,045) durante o seguimento médio de 12,8 meses13. Com base na regressão logística multivariada, apenas a RNL foi preditor independente de mortalidade nos pacientes com IC (Tabela 5).
Regressão logística multivariada para determinar os preditores independentes de mortalidade em insuficiência cardíaca
Razão de chance
Intervalo de confiança 95%
p
Idade (anos)
1,027
0,928 - 1,136
0,608
Sexo (masculino)
2,772
0,386 - 19,895
0,311
FE (%)
0,944
0,867 - 1,027
0,179
RNL
1,680
1,013 - 2,786
0,045
RPL
0,993
0,976 - 1,010
0,407
RNL: Relação neutrófilo-linfócito; RPL: Relação plaqueta-linfócito; FE: Fração de ejeção.
Discussão
Este estudo demonstrou que a RNL e a RPL foram maiores nos pacientes com IC em comparação às dos controles pareados por idade e sexo. Até onde sabemos, trata-se do primeiro estudo a demonstrar que os níveis de RPL dos pacientes com IC são mais altos do que aqueles dos controles. Além disso, a RNL correlacionou-se inversamente com a FE, sendo um preditor independente de mortalidade por IC. Durante o seguimento dos pacientes com IC, a RNL pode ser usada para predizer mortalidade.
Inflamação crônica foi mais comumente observada nas doenças crônicas, como câncer, DM, HT, doença do tecido conjuntivo e doença renal crônica14-18. Níveis elevados de inflamação também se associaram a um mau prognóstico em DAC4. As reações inflamatórias desempenham papel fundamental no desenvolvimento de IC19,20. Os leucócitos e seus subtipos são importantes marcadores de inflamação nas DCV. Como resultado do estímulo inflamatório, os leucócitos liberam citocinas inflamatórias, como TNF-α , IL-6 e proteína C reativa (PCR), assim como algumas enzimas proteolíticas. Essas citocinas pró-inflamatórias têm efeitos destrutivos no miocárdio, resultando em redução da função ventricular esquerda e IC21-24. Estudos prévios mostraram que níveis mais altos de citocinas pró-inflamatórias podem levar a remodelamento miocárdico e arritmia cardíaca25,26. Os linfócitos têm um importante papel na cicatrização através da modulação dos fenótipos de células mononucleares e indução do inibidor tecidual da expressão de metaloproteinase-127. A linfopenia é mais comum em condições de estresse, como a IC, devido à ativação do eixo hipotálamo-hipófise-adrenal. A ativação desse eixo leva à secreção de cortisol, e os níveis elevados de cortisol resultam em redução da concentração relativa de linfócitos28,29. Linfopenia é um fator prognóstico independente, estando associada à diminuição da sobrevida em pacientes com IC29,30.
A IC é uma doença crônica com alta taxa de mortalidade, que estimada em um ano é superior a 20%6. Os principais preditores de mortalidade são idade avançada (mais de 60 anos), presença de DM e uma baixa FEVE13. Devido ao mau prognóstico da IC, é importante a determinação dos fatores prognósticos para tais pacientes. Em um estudo prévio de pacientes com IC aguda descompensada, níveis mais altos de RNL associaram-se a uma maior taxa de mortalidade, sendo a capacidade de a RNL predizer mortalidade superior àquela da contagem de neutrófilos, da contagem total de leucócitos e da contagem relativa baixa de linfócitos6. Portanto, uma RNL elevada em IC foi associada com mau prognóstico. Em pacientes com IC, a despeito de uma contagem total de leucócitos semelhante à de controles pareados por idade e sexo, a RNL mudou, favorecendo os neutrófilos. O presente estudo provou que a RNL de pacientes com IC foi significativamente maior do que a de controles. Os valores de ponto de corte de 3,0 e 5,1 podem ser usados para predizer a presença de IC e mortalidade, respectivamente. Um estudo de pacientes com IC demonstrou que após a infusão de levosimendana, pacientes com RNL mais alta apresentaram maior taxa de mortalidade do que aqueles com uma RNL mais baixa, tendo-se determinado o ponto de corte de 5,5 para a RNL como eficaz para predizer mortalidade hospitalar31. Estudos prévios demonstraram que contagens mais altas de plaquetas e mais baixas de linfócitos associam-se a maus desfechos cardiovasculares. Uma alta RPL associa-se com um pior prognóstico em várias doenças, como câncer e DAC32-34. Entretanto, não havia até o momento informação sobre a RPL em pacientes com IC. Este é o primeiro estudo a demonstrar que os níveis da RPL de pacientes com IC são mais altos do que os de controles. O ponto de corte de 137,3 pode ser usado para predizer a presença de IC.
Limitações do estudo
Este estudo tem limitações, sendo uma delas o pequeno tamanho da amostra. Isso talvez explique o baixo poder deste estudo, não tendo sido observada uma significativa correlação entre a RPL e a FEVE por essa razão. Devido à elevada variação da RPL e ao pequeno tamanho da amostra, a sensibilidade e a especificidade foram demasiado baixas para predizer IC (70% e 60%, respectivamente). Logo, o ponto de corte aproximou-se do nível médio da RPL no grupo controle. Não medimos os níveis dos marcadores inflamatórios, como TNF-α , IL-6 e PCR. Portanto, não comparamos o valor prognóstico da RNL e daqueles fatores inflamatórios. Além disso, este é um estudo observacional não randomizado, que pode ser considerado um protótipo para futuros estudos prospectivos e randomizados para comparar o efeito da RNL na mortalidade cardiovascular.
Conclusões
A RNL e a RPL de pacientes com IC foram mais altas que aquelas de controles pareados por idade e sexo. Entretanto, a RNL e a RPL não foram suficientes para estabelecer o diagnóstico de IC. A RNL pode ser usada no seguimento de pacientes com IC para predizer mortalidade.
Fontes de financiamento
O presente estudo não teve fontes de financiamento externas.
Vinculação acadêmica
Não há vinculação deste estudo a programas de pós-graduação.