Material and Method: The study is a retrospective cohort study including 237 consecutive patients with ADHF admitted to cardiology. Clinical follow-up was performed by telephone interviews with the patient and/or relatives and by review of hospital medical records.

Results: These patients were divided into two groups: the deceased group (group 1), who died during hospitalization or the follow-up period, and the survival group (group 2). There was a significant difference in the mean percentage of monocytes and monocyte count between the two groups (p=0.003; p=0.006, respectively). ROC curve was drawn (AUC=0.618, 95% confidence interval: 0.544-0.693, p=0.003).

Conclusion: In summary monocyte-related cytokines play an important role in ADHF. Our study shows that monocytes can be used in patients with ADHF as a independent predictor of mortality; moreover it is inexpensive and easy to perform. Nonetheless, further larger-scale and multi-center studies needed to confirm these findings.

The inflammatory mechanisms play an important role in this complex syndrome involving acute and chronic heart failure process and atherosclerosis ^{3, 4}. Leukocytes and its subgroups play key roles in the presence of active inflammation. Monocytes are im-portant components of the immune system constituting 3-8% of peripheral blood leukocytes. It is also known that inflammatory process plays a role in the patho-physiology of HF and atherosclerosis ^5-7.

The objective of this study was to investigate the association of monocytes count with cardiovascular mortality in patients with ADHF.

Patients with New York Heart Association (NY-HA) class III or IV systolic heart failure were included in this study. Patients with acute myocardial injury, acute and/or chronic infection, leukemia, lymphoma, inflammatory bowel disease, connective tissue disease were excluded from the study.

Statistical Analysis
Parametric data were expressed as mean±standard de-viation, and categorical data as percentages. Data were processed using the Medcalc statistical software (v12.3.0, personallicence of MBY). Independent para-meters were compared via the independent samples t-test, and via the Mann-Whitney U-test if there was an abnormal distribution. Categorical data were evaluated by the chi-square test as appropriate for the prediction of mortality, Receiver operating characteristic (ROC) curve analysis was performed to identify the optimal cut-off of monocyte percentage. Area under the curve (AUC) was calculated as measure of the accuracy of the test and compared with the use of the z-test. Out-come curves were generated using the Kaplan–Meier analysis for patients having above and below the mo-nocyte percentage cut-off point and the groups were compared by the log-rank test. Patients were censored if alive at the end of the follow- up. A p value <0.05 was accepted as significant.

Their baseline clinical and laboratory data, length of stay in hospital, frequency of hospitalization, and follow-up time are presented in Table 1. The mean monocyte count of patients in groups 1 and 2 was 0.69±0.28 and 0.59±0.25, respectively. The mean per-centage of monocytes of patients in groups 1 and 2 was 7.90±2.18 and 7.18±2.68, respectively. There was a significant difference in the mean percentage of mo-nocytes and monocyte count between the two groups as shown in Table 2 (p=0.003; p=0.006, respectively).

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Table 1: The baseline demographic characteristics of the patients

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Table 2: Comparison of leukocyte and sub-groups of patients

ROC curve was constructed to evaluate the relati-onship mortality and monocyte count. ROC curve was drawn in figure 1 (AUC=0.618, 95% confidence inter-val: 0.544-0.693, p=0.003).

The results showed that monocyte percentage and count were not associated with follow-up time, length of stay in hospital, frequency of hospitalization. The cumulative mortality rates are presented in Figure 2.

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Figure 1: Evaluation by Roc analysis of monocytes in patients whit acute decompensated heart failure

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Figure 2: .

The activation of monocytes is caused by vent-ricular distension, hypoxia and ischemia of tissues, increasing systemic congestion, and bacterial trans-location. The activation of monocytes causes cytokine release such as interleukin (IL)-1b, IL-6, tumor nec-rosis factor (TNF) ¹⁰. However, myocardial injury al-so causes local cytokine release. Moreover, these cyto-kines create a positive feedback loop and reactivate the monocyte activation. Cytokines cause not only myocar-dial hypertrophy and fibrosis but also cardiac dysfunc-tion via its effect on signal conduction system ^{10, 11}.

It is known that high level of cytokines is associa-ted with cardiac dysfunction in HF. Haugen et al. ⁵ showed that level of IL-1b, IL-6, IL-8, and TNF was higher in patients with HF than control group. Stumpf et al. ¹² showed that level of TNF was higher in patients with congestive HF than healthy participants.

ADHF is one of the most common causes of the reasons for hospitalization in patients older than 65 years ¹³. Common causes of ADHF include myo-cardial ischemia and/or infarction, arrhythmias, severe hypertension, worsening of renal function, infection, severe thyroid disease, severe anemia, medication nonadherence, medical treatment such as non-steroidal inflammatory drugs, glitazones, negative inotropic agents ^{14, 15}. There are several studies investigating relationship between cytokines and mortality and/or morbidity. Schulze et al. ¹⁶ showed that TNF level in patients with HF was higher than control group. They also showed that TNF level in patients with ADHF was higher than patients with compensated HF. Miettinen et al. found that the IL-6 level at 48 hours after admission in patient with ADHF was higher than patients with compensated HF. They also showed that high level of IL-6 and TNF were a independent predictor of 12-month mortality. Milani et al. ¹⁸ found that TNF level in patients with ADHF without cachexia was higher than healthy control group.

The activation of chemokines occurs in HF as a part of the inflammatory response. Chemokines, espe-cially Monocyte Chemotactic Protein-1 (MCP-1) are polypeptides inducing monocyte mobilization from the bone marrow ^19-21. Inflammatory cytokines contri-bute to activation of chemokines. Aukrust et al. ¹⁹ s-howed that chemokines were high in patients with NYHA class IV systolic heart failure. Also they found an inversely proportional relationship between left ventricular ejection fraction and chemokin level. Makarewicz-Wujek and Kozlowska-Wojciechowska ²⁰ found that MCP-1 level was higher in patients with HF than control group. Cappuzello et al. ²¹ showed that MCP-1 level was higher in patients NY-HA class II-IV heart failure than control group.

Monocytes play important roles in phagocytosis, antigen processing and presentation ²². Despite the important role of monocytes, there were few studies investigating prognostic role of monocytes in HF. Green et al. ²³ found the association of monocyte count with poor prognosis in patients with HF admitted to hospital. Shantsila et al. ²⁴ showed that high mo-nocyte count was a independent predictor of mortality in patients with HF with preserved ejection fraction.

Interaction among monocytes, chemokines, and cytokines cause a vicious circle in HF. Many studies focused on monocyte-related cytokines. The aim of this study was to investigate the association of monocytes count with cardiovascular mortality in patients with ADHF. The results showed that monocyte percentage and count were associated with cardiovascular morta-lity.

This study had some limitations. This was a retros-pective cohort and single-centered study. Another limitation to our study was the relatively small sample size.

In summary monocyte-related cytokines play an important role in ADHF. Our study shows that mono-cytes can be used in patients with ADHF as a indepen-dent predictor of mortality; moreover it is inexpensive and easy to perform. Nonetheless, further larger-scale and multi-center studies are needed to confirm these findings.

1) Dec GW. Management of acute decompensated heart failure. Curr Probl Cardiol 2007; 32: 321-66.

2) Summers RL, Sterling S. Early emergency mana-gement of acute decompensated heart failure. Curr Opin Crit Care 2012; 18: 301-7.

3) Onwuanyi A, Taylor M. Acute decompensated heart failure: pathophysiology and treatment. Am J Cardiol 2007 26; 99: 25-30.

4) Corrêa CR, Dias-Melicio LA, Calvi SA, Lastória S, Soares AM. Activation of monocytes and cyto-kine production in patients with peripheral athe-rosclerosis obliterans. J Inflamm 2011; 8: 23 doi:10.1186/1476-9255-8-23.

5) Haugen E, Gan LM, Isic A, Skommevik T, Fu M. Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients. Exp Clin Cardiol 2008; 13: 19-24.

6) Ali S, Shahbaz AU, Nelson MD, et al. Reduced relative lymphocyte count in African-Americans with decompensated heart failure. Am J Med Sci 2009; 337: 156-60.

7) Korkmaz L, Kul S, Korkmaz AA, et al. Increased leucocyte count could predict coronary artery cal-cification in patients free of clinically apparent cardiovascular disease. Arch Turk Soc Cardiol 2012; 40: 223-8.

8) Vaduganathan M, Greene SJ, Butler J, Sabbah HN et al. The immunological axis in heart failure: Im-portance of the leukocyte differential. Heart Fail Rev 2013; 18: 835-45.

9) Lepage S. Acute decompensated heart failure. Can J Cardiol 2008; 24: 8-10.

10) Vaduganathan M, Greene SJ, Butler J, et al. The immunological axis in heart failure: Importance of the leukocyte differential. Heart Fail Rev 2013; 18: 835-45.

11) Pfister R, Sharp SJ, Luben R, Wareham NJ, Khaw KT. Differential white blood cell count and inci-dent heart failure in men and women in the EPIC-Norfolk study. Eur Heart J 2012; 33: 523-30.

12) Stumpf C, Lehner C, Yilmaz A, Daniel WG, Gar-lichs CD. Decrease of serum levels of the anti-inflammatory cytokine interleukin-10 in patients with advanced chronic heart failure. Clin Sci (Lond) 2003; 105: 45-50.

13) Amin A. Hospitalized patients with acute decom-pensated heart failure: recognition, risk stra-tifica-tion, and treatment review. J Hosp Med 2008; 3: 16-24.

14) Varughese S. Management of acute decompen-sated heart failure. Crit Care Nurs Q 2008; 94-103.

15) Givertz MM, Teerlink JR, Albert NM, et al. Acute decompensated heart failure: Update on new and e-merging evidence and directions for future rese-arch. J Card Fail 2013; 19: 371-89.

16) Schulze PC, Biolo A, Gopal D, et al. Dynamics in insulin resistance and plasma levels of adipokines in patients with acute decompensated and chronic stable heart failure. J Card Fail 2011; 17: 1004-11.

17) Miettinen KH, Lassus J, Harjola V-P, et al. Prog-nostic role of pro- and anti-inflammatory cytokines and their polymorphisms in acute de-compensated heart failure. Eur J Heart Fail 2008; 10: 396-403.

18) Milani RV, Mehra MR, Endres S, et al. The cli-nical relevance of circulating tumor necrosis fac-tor-alpha in acute decompensated chronic heart fai-lure without cachexia. Chest 1996; 110: 992-5.

19) Aukrust P, Ueland T, Müller F, Andreassen AK, et al. Elevated circulating levels of C-C chemokines in patients with congestive heart failure. Circula-tion 1998; 97: 1136-43.

20) Makarewicz-Wujec M, Kozlowska-Wojciechow-ska M. Nutrient intake and serum level of gamma-glutamyltransferase, MCP-1 and homocysteine in early stages of heart failure. Clin Nutr 2011; 30: 73-8.

21) Cappuzzello C, Di Vito L, Melchionna R, et al. Increase of plasma IL-9 and decrease of plasma IL-5, IL-7, and IFN-γ in patients with chronic heart failure. J Transl Med 2011; 21; 9-28.

22) Amir O, Spivak I, Lavi I, Rahat MA. Changes in the monocytic subsets CD14dimCD16+ and CD14++CD16- in chronic systolic heart failure pa-tients. Mediators Inflamm 2012; 2012: 992-5.

23) Greene SJ, Harinstein ME, Vaduganathan M, et al. EVEREST Trial Investigators. Prognostic value of monocyte count in patients hospitalized for heart failure with reduced ejection fraction (from the EVEREST Trial). Am J Cardiol 2012; 110: 1657-62.

24) Shantsila E, Bialiuk N, Navitski D, et al. Blood leukocytes in heart failure with preserved ejection fraction: impact on prognosis. Int J Cardiol 2012; 155: 337-8.