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. 2022 Dec 15;17(12):e0276138. doi: 10.1371/journal.pone.0276138

Pre-operative systemic inflammatory response index influences long-term survival rate in off-pump surgical revascularization

Tomasz Urbanowicz 1,*, Anna Olasińska-Wiśniewska 1, Michał Michalak 2, Bartłomiej Perek 1, Ahmed Al-Imam 2,3, Michał Rodzki 1, Anna Witkowska 1, Ewa Straburzyńska-Migaj 4, Michał Bociański 1, Marcin Misterski 1, Maciej Lesiak 4, Marek Jemielity 1
Editor: Vipin Zamvar5
PMCID: PMC9754600  PMID: 36520919

Abstract

Coronary artery bypass revascularization is still the optimal treatment for complex coronary artery disease with good long-term results. The relation between inflammatory activation in the post-operative period and the long-term prognosis was already postulated. The possible predictive role of preoperative inflammatory indexes after the off-pump coronary artery bypass grafting technique on long term survival was the aim of the study. Study population included 171 patients with a median age of 64 years (59–64) operated on using off-pump technique between January and December 2014. Patients enrolled in the current study were followed-up for 8 years. We conducted a multivariable analysis of pre-operative and post-operative inflammatory markers based on analysis of the whole blood count. The overall survival rate was 80% for the total follow-up period, while 34 deaths were reported (30-days mortality rate of 1%). In the multivariable analysis, a pre-operative value of systemic inflammatory response index (SIRI) >1.27 (HR = 6.16, 95% CI 2.17–17.48, p = 0.012) revealed a prognostic value for long-term mortality assessment after off-pump surgery. Preoperative inflammatory activation evaluated by systemic inflammatory reaction index (SIRI) possess a prognostic value for patients with complex coronary artery disease. The SIRI value above 1.27 indicates a worse late prognosis after off-pump coronary artery bypass (AUC = 0.682, p<0.001).

Introduction

Diffuse atherosclerotic disease of the coronary arteries limits the daily activity and life span of patients due to insufficient blood supply of the myocardium. Concerning long-term results, coronary artery bypass revascularization is still the optimal treatment for complex coronary artery disease management [1]. The surgical revascularization allows for the complex provision of coronary blood supply to the heart due to multiple grafts utility [2]. The arterial grafts provide superior results to venous ones which are commonly applied in clinical practice [3].

Coronary artery disease evolves from a chronic inflammatory process that leads to atherosclerotic changes influencing the survival rate [4–6]. The atherosclerotic plaques initiation and progression depend on an imbalance between pro-inflammatory and anti-inflammatory changes in the endothelium after triggering the inflammation reaction chain [7, 8].

The surgical revascularization can be performed with the utility of cardiopulmonary bypass (CPB) or with the off-pump technique [9, 10]. The omittance of CBP results in diminishing of the systemic inflammatory reaction which is the critical factor for long-term mortality risk [11]. The relation between inflammatory activation in the peri-operative period and the long-term prognosis was already postulated [8, 12].

Researchers proved the significant role of inflammatory indices in clinical practice in the prediction of the post-operative morbidity and mortality [13, 14]. The postulated indices include systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate inflammatory systemic index (AISI). The clinical significance of post-operative indices in surgical coronary artery revascularization in mortality prediction has been already presented [15, 16]. Little is however known on the significance of the inflammatory indices on the long-term mortality after off-pump coronary bypass surgery.

We present the results of a single-center retrospective analysis of patients’ survival after surgical revascularizations with the off-pump technique. The study aimed to evaluate pre-operative inflammatory markers for long-term outcomes prediction.

Material and methods

The current study included 171 patients operated on in our Department between January and December 2014 as presented in Fig 1.

Fig 1. Inclusion criteria for the study.

Fig 1

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There were 71 (42%) patients with left main disease, 62 (36%) and 38 (22%) with diagnosis of three and two vessels disease, respectively. The indication for surgery was a chronic coronary syndrome. All patients were operated on by the experienced surgical team with the use the off-pump technique, and then followed up for a period of eight years. The exclusion criteria were concomitant procedures and haematological or oncological diseases. Moreover, patients with acute coronary syndromes were not taken into consideration.

Demographic and clinical data were collected. Although we focused in our study on inflammatory parameters obtained from whole blood count, the analysis was performed including additional laboratory parameters (troponin-I serum level, serum creatinine concentration, LDL cholesterol serum fraction) to obtain broader spectrum and distinguish significant factors. The history of previous peripheral vascular disease and events (PVE), including stroke and peripheral arterial disease (PAD) was analysed.

Pre-operative and post-operative (24 hours) whole blood results were obtained, including neutrophils, lymphocytes and platelets counts. Troponin-I levels were recorded after 4, 24 and 48 hours after surgery. The analysed inflammatory indexes were calculated as follows—systemic inflammatory index (SII)—quotient of neutrophils and platelets divided over lymphocyte counts; systemic inflammatory response index (SIRI)—quotient of neutrophil and monocyte divided by lymphocyte counts, and aggregate inflammatory systemic index (AISI)—quotient of neutrophils, monocytes and platelets divided by lymphocytes count.

C-reactive protein was not routinely measured as patients with infection suspicion were ruled out from the study. Postoperatively, C- reactive protein was not performed routinely except of patients presenting infection symptoms.

Echocardiography was performed in all patients before and after the surgery, and at the discharge.

The surgical team operated on all patients under general anaesthesia with the off-pump technique through median sternotomy. The anastomoses were performed using intraluminal shunt application as the target coronary artery segment was stabilized by Octopus (Medtronic, USA). The anastomosis was performed with a single running 7–0 monofilament suture.

The mortality analysis was based on all-cause mortality, and the researchers confirmed the information concerning deaths in the National Healthcare Database.

The study was approved by the Institutional Ethics Committee (No 914/21 and date of approval: 24 November 2021) and respected the principles outlined in the Declaration of Helsinki.

Statistical analysis

All continuous data were presented as medians and interquartile ranges Me (Q1-Q3) for non-normal distribution. A non-parametric test (Mann-Whitney) was used to compare the continuous variables. A receiver characteristic curve analysis was performed to reveal potential predictors for mortality. A proportional hazard regression model was used to assess mortality risk factors. Both univariable and multivariable analyses (stepwise backward selection) were performed. The results were presented as hazard ratios (HR) and 95% confidence intervals (95% CI). The statistical analysis was performed using MedCalc statistical package; MedCalc® Statistical Software version 20.010 (MedCalc Software Ltd, Ostend, Belgium; https://www.medcalc.org; 2021). All tests were considered significant at p<0.05.

Results

The study group comprised 171 patients (152 (89%) males and 19 (11%) females) with a median age of 64 (59–64). The overall survival rate was 80% during the follow-up period, while 34 deaths were reported. The 30 days mortality rate was 1% (2 patients), and the mean hospitalization time was 11 +/- 2 days.

The study patients suffered from several co-morbidities, including arterial hypertension (152 (89%)), hypercholesterolemia (98 (57%)), diabetes mellitus (DM) (65 (38%)), peripheral arterial disease (PAD) (29 (17%)), history of stroke (19 (11%)) and chronic obstructive pulmonary disease (COPD) (16 (9%)). Preoperatively, the mean left ventricular diastolic diameter and left ventricular ejection fraction were 48mm (44–52) and 55% (50–60), respectively. There was no difference between the survivors and deaths group regarding the pre-operative clinical data except for hypercholesterolemia (p = 0.034) though the LDL cholesterol serum fraction was insignificant (p = 0.875), as presented in the Table 1.

Table 1. Characteristics of survivors and non-survivors’ groups.

Pre-operative parameters Survivors (n = 137) Non-survivors (n = 34) p-value
Clinical characteristics:
    1. Age (years) median(Q1-Q3) 63 (59–67) 66 (63–73) 0.020
    2. Gender (M (%)/F (%)) 121 (88%) / 16 (12%) 31(91%) / 3 (9%) 0.635
Co-morbidities:
    1. Arterial hypertension 120 (88%) 32 (94%) 0.278
    2. Hypercholesterolemia 84 (61%) 14 (41%) 0.034*
    3. COPD 10 (7%) 6 (18%) 0.637
    4. History of stroke 12 (9%) 7 (21%) 0.495
    5. Peripheral artery disease 20 (15%) 9 (27%) 0.099
    6. Diabetes mellitus 50 (37%) 15 (44%) 0.413
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Abbreviations: AISI- aggregate inflammatory systemic index, F–female, M–male, n–number, SII–systemic inflammatory index, SIRI–systemic inflammatory response index, Q-quartile, WBC–white blood cell count. *—statistical significance.

The mean number of performed grafts was 2.2 +/- 0.1 and 2.2 +/- 0.2 in survivors and deaths groups, respectively.

Maximum post-operative Troponin-I were 1.97 (0.68–3.97) ng/ml in survivors vs 1.86 (0.46–4.92) in deaths subgroups (p = 0.667), respectively. We retrieved the complete blood count test results before surgery and 24 hours after (Table 2) and presented the significant preoperative parameters in Fig 2.

Table 2. Comparison of pre-operative and post-operative results between survivors and non-survivors groups.

Pre-operative parameters Survivors (n = 137) Non-survivors (n = 34) p-value
Clinical characteristics:
    1. Age (years) median(Q1-Q3) 63 (59–67) 66 (63–73) 0.020
    2. Gender M/F (%) 121 (88%) / 16 (12%) 31(91%) / 3 (9%) 0.635
Preoperative laboratory results:
    1. WBC x109/l (median(Q1-Q3)) 7.47 (6.51–8.33) 7.94 (7.55–9.88) 0.058
    2. Lymphocytes x109/l (median(Q1-Q3)) 1.83 (1.47–2.27) 1.83 (1.57–2.05) 0.976
    3. Neutrophils x109/l (median(Q1-Q3)) 4.66 (4.02–5.73) 5.45 (4.40–6.99) 0.009*
    4. Hemoglobin mmol/l (median(Q1-Q3)) 8.90 (8.20–9.45) 8.55 (8.00–9.10) 0.133
    5. Platelets x103/l (median(Q1-Q3)) 213 (188–259) 220 (180–272) 0.843
    6. Monocytes x109/l (median(Q1-Q3)) 0.42 (0.35–0.53) 0.48 (0.40–0.63) 0.021
    7. SIRI (median(Q1-Q3)) 1.11 (0.78–1.47) 1.39 (1.18–2.01) <0.001*
    8. SII (median(Q1-Q3)) 562 (409–792) 618 (498–1017) 0.106
    9. AISI (median(Q1-Q3)) 235 (162–369) 305 (213–500) 0.031*
    10. Serum creatinine umol/L (median(Q1-Q3)) 97 (81–121) 99 (79–124) 0.745
    11. Troponin–I ng/mL (median(Q1-Q3)) 0.02 (0.01–0.03) 0.02 (0.01–0.03) 0.901
    12. LDL serum level mg/dL (median(Q1-Q3)) 58 (51–66) 60 (52–69) 0.875
Number of grafts 2.2 +/- 0.1 2.2 +/- 0.2 0.897
Postoperative laboratory results:
    1. WBC x109/l (median(Q1-Q3)) 8.51 (7.125–10.01) 8.51 (7.13–10.01) 0.955
    2. Lymphocytes x109/l (median(Q1-Q3)) 1.85 (1.53–2.34) 1.77 (1.33–2.23) 0.151
    3. Neutrophils x109/l (median(Q1-Q3)) 5.53 (4.03–6.55) 5.53 (4.13–7.08) 0.447
    4. Hemoglobin mmol/l (median(Q1-Q3)) 7.06 (6.6–7.55) 6.75 (6.50–7.40) 0.233
    5. Platelets x103/l (median(Q1-Q3)) 309 (244–355) 255 (199–317) 0.041*
    6. Monocytes x109/l (median(Q1-Q3)) 1.02 (0.73–1.17) 0.88 (0.64–1.18) 0.446
    7. SIRI (median(Q1-Q3)) 2.46 (1.62–3.55) 2.60 (1.73–5.51) 0.329
    8. SII (median(Q1-Q3)) 764 (512–1109) 864 (597–1059) 0.633
    9. AISI (median(Q1-Q3)) 692 (424–1232) 651 (484–1425) 0.998
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Abbreviations: AISI—aggregate inflammatory systemic index, F–female, M–male, n–number, SII–systemic inflammatory index, SIRI–systemic inflammatory response index, Q-quartile, WBC–white blood cell count. *—statistical significance.

Fig 2. Box-plot 1.

Fig 2

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Preoperative significant parameters.

The receiver-operating characteristic (ROC) curve analysis confirmed a significant effect of the pre-operative SIRI (AUC = 0.682, p<0.001) with a sensitivity of 73.53% and specificity of 63.5%, and a cut-off value above 1.27, as presented in Fig 3.

Fig 3. The receiver-operating characteristic curve for the pre-operative value of systemic inflammatory response index.

Fig 3

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Univariable analysis

According to the univariate Cox regression analysis (Table 3), significant preoperative factors included PVE (summed stroke and peripheral artery disease) (HR = 2.70, 95% CI 1.17–6.26, p = 0.020), left ventricle diastolic diameter above 45mm (HR = 6.09, 95% CI 1.46–25.48, p = 0.013) and left ventricle ejection fraction below 50% (HR = 2.72, 95% CI 1.36–5.22, p = 0.005).

Table 3. Univariable analysis results.

Parameters HR 95% CI p-value
Stroke 2.70 1.17–6.26 0.020*
Pre-operative echocardiographic results:
1. LVd 1.07 1.02–1.12 0.009*
2. LVd > 45 mm 6.09 1.46–25.48 0.013*
3. LVEF 0.95 0.92–0.98 0.001*
4. LVEF < 50% 2.72 1.36–5.44 0.005*
Pre-operative laboratory results:
1. Neutrophils above 5.2 2.59 1.29–5.22 0.007*
2. Monocytes > 0.44 2.83 2.31–6.13 0.008*
3. SIRI > 1.27 1.39 1.72–7.69 0.001*
4. AISI >362 2.28 1.13–4.76 0.020*
Postoperative echocardiographic results:
1. LVd > 48 mm 4.06 1.67–9.85 0.002*
2. LVEF < 50% 2.56 1.28–5.13 0.008*
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Abbreviations: AISI—aggregate inflammatory systemic index, LVd–left ventricle diameter, LVEF–left ventricle ejection fraction, SIRI–systemic inflammatory response index.

Significant preoperative laboratory markers for long-term prognosis prediction included—the neutrophils count above 5.2 (HR = 2.59, 95% CI 1.29–5.22, p = 0.007), monocytes count above 0.44 (HR = 2.83, 95% CI 6.13–11.39, p = 0.008), SIRI above 1.27 (HR = 1.39, 95% CI 1.72–7.69, p = 0.001) and AISI > 362 (HR = 2.28, 95% CI 1.13–4.76, p = 0.020). The postoperative echocardiographic results significant for mortality prediction included the left ventricle diastolic diameter above 48 mm (HR = 4.06, 95% CI 1.67–9.85, p = 0.002) and ejection fraction below 50% (HR = 2.56, 95% CI 1.28–5.13, p = 0.008).

Multivariable analysis

We deployed multivariate analysis for parameters presenting as significant in univariable analysis, and novel data emerged concerning the significance concerning age (HR = 1.09, 95% CI 1.03–1.16, p = 0.005), COPD (HR = 5.24, 95% CI 1.84–14.91, p = 0.002), stroke (HR = 3.29, 95% CI 1.31–8.29, p = 0.012), and the preoperative left ventricle ejection fraction (HR = 3.28, 95% CI 1.50–7.16, p = 0.003). Significant pre-operative laboratory markers obtained from whole blood count included SIRI above 1.27 (HR = 6.16, 95% CI 2.17–17.48, p = 0.001) as presented in Table 4.

Table 4. Multivariable analysis results.

Parameters HZ 95% CI p-value
Clinical:
1. Age 1.09 1.03–1.16 0.005*
Co-morbidities:
1. COPD 5.24 1.84–14.91 0.002*
2. PVE 3.29 1.31–8.29 0.012*
Preoperative echocardiography:
1. LVEF below 50% 3.28 1.50–7.16 0.003*
Pre-operative laboratory parameters:
1. SIRI on admission > 1.27 6.16 2.17–17.48 0.012*
Postoperative laboratory parameters:
1. Platelets count 0.99 0.98–0.99 0.002*
2. Lymphocytes count 0.35 0.13–0.92 0.034*
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Abbreviations: COPD- chronic pulmonary obstructive disease, PVE–peripheral vascular events in history, LVEF-left ventricle ejection fraction, SIRI–systemic inflammatory response index.

Discussion

The main finding of our study is the predictive value of pre-operative inflammatory activity characterized by systemic inflammatory reaction index (SIRI) for long-term mortality assessment. We present the results of the multivariable analysis of clinical and laboratory pre-operative factors in patients undergoing surgical revascularization due to complex coronary disease, suggesting that inflammatory reactivity possesses a high predictive significance for long-term results. Patients requiring surgical revascularization have an individual propensity for inflammatory activation that influences their post-operative survival [17, 18]. According to our analysis those patients with more advanced inflammatory status before surgery, have higher risk of death. Therefore, we believe that this particular group of patients should undergo more scrutinous follow-up controls to improve long-term survival. Potentially, pharmacological treatment which may diminish the inflammatory activation in the atherosclerotic plaque, would be beneficial in this group of patients. Currently, statins have proved anti-inflammatory effect on the formation of atherosclerotic changes [19, 20].

Inflammatory processes activate atherosclerosis, or more accurately, its development and progression characterized by inflammatory markers and indices [21, 22]. Several previous studies [8, 23, 24] proved the relationship between inflammation, inflammatory cells activation and coronary artery disease occurrence. The degree of atherosclerotic changes in coronary arteries may be evaluated with the use of currently available diagnostic tools including coronary angiography, optical coherence tomography or cardiac magnetic resonance [25]. The measurement of inflammatory intensity influencing the atherosclerosis progression would be also beneficial. The inflammation reaction can be characterized by simple parameters obtained from the whole blood count [17, 18, 26, 27]. Those parameters, including the neutrophil to lymphocyte ratio (NLR) or monocyte to lymphocyte ratio (MLR), have predictive values for long-term mortality in off-pump patients after the surgical procedure [8]. The significance of our retrospective analysis is proposing SIRI as the pre-operative factor to predict worse late survival. We believe that searching for pre-operative factors which can reveal subgroups of patients prone to diminished long-term results is crucial. Our most valuable finding is the fact that easily available index (SIRI) may reflect higher mortality risk and therefore it is worth to include in daily practice in patients with coronary artery disease qualified for cardiac surgery.

The significance of inflammatory reactions as a possible trigger in broad spectrum of cardiovascular diseases is currently strongly underlined. The inflammatory activation presented by indexes in our study point out those patients who are more prone for complex artery disease development with secondary higher risk for worse outcomes. Previous studies revealed the relationship between inflammation and other cardiovascular risk factors and events. Szczepaniak et al. [28] presented the inflammatory link between hypertension and periodontitis. Inflammatory reaction related to nosocomial infection was described as a possible risk factor for worse presentation and outcomes after acute coronary syndrome [29]. Moreover, Fan et al. [30] identified a series of key genes closely related with inflammatory response and atrial fibrillation. The dietary intake influencing the inflammatory reactions in men that possess long-term results in increased risk for acute coronary syndromes was presented in Sut et al. [31] study. The relation between chronic inflammatory activation and a risk for left ventricular dysfunction was found in Kloch et al. [32] analysis.

The SIRI components as neutrophils, monocytes and lymphocytes play a significant role in atherosclerotic plaques formation and destabilization [33]. The initial destruction of endothelium cause monocytes adhesion and influx into intimal lawyer of the vascular wall with secondary secretion of cytokines and proteolytic enzymes [34]. The relation between hyperlipidaemia and neutrophilia [35] and monocytes activation [36] was presented in previous studies. The further modulation of monocytes/macrophages and foam cells at the site of lipids accumulation and regulated by neutrophils as these groups of cells interact in atherosclerotic plaques development [37].

The atherosclerotic plaque destabilization is of significant importance related to inflammatory cells activations. The role of innative inflammatory cells like monocytes [38] or indexes as possible markers as neutrophil to lymphocyte ratio [39] is postulated in plaques instability prediction.

Undoubtfully, both, on-pump and off-pump methods might cause an inflammatory response. The off-pump method of surgical procedures described in our analysis allowed us to minimalize the influence of post-operative inflammatory response on our results. Several studies confirmed that the off-pump surgical revascularization technique omits the risk for inflammatory activation secondary to CBP administration [40–43]. In the Mirhafez et al. [41] study serum cytokines levels in off-pump coronary surgery were lower compared with on-pump method. Despite some disadvantages, the off-pump technique still possesses a profound protective value in high-risk patients [44, 45]. The main advantage of surgical revascularization is the time-related long-term survival rate [46]. Despite its invasive nature, the surgery gives superior results and places the surgical procedure as the optimal treatment for complex coronary artery disease [47–49] especially with ulitity of arterial grafts [50, 51].

Our analysis focused on pre-operative factors that may interfere with long-term prognosis. In multivariable analysis, the diminished left ventricle ejection fraction, combined with co-morbidities such as COPD and stroke, were presented significant which is consistent with the previous reports [52, 53]. Importantly, results from previous research focused on post-operative prognostic parameters [17]. To our best knowledge, our study is the first to reveal pre-operative inflammatory activation as patients’ dependent characteristics that may interfere with post-operative results.

We noticed higher percentage of hypercholesterolemia in the survivor group. The serum LDL cholesterol fraction levels was insignificant, presenting effective therapy. However, this phenomenon was not statistically significant neither in the uni- nor in multivariable analysis. We shall point out that all patients referred for surgery reported long-lasting statin therapy, and the obtained results depended on the individual response to prescribed medication. Moreover, the results obtained for analysis were found irrelevant to hypercholesterolemia, as the target LDL serum levels were achieved suggesting more aggressive therapy in hypercholesterolemia group.

The long-term results following the off-pump coronary artery bypass grafting procedure depend on pre-operative, intraoperative, and post-operative factors [18]. Our analysis points out that among patients referred for off-pump coronary surgery, a subgroup is characterized by excessive inflammatory activity that interferes with post-operative results and long-term survival.

The present study has several limitations. It is a retrospective, single-centre study limited to less than 200 cases. However, we included all consecutive patients who met the inclusion criteria, thus we showed the real-life cohort of patients. There is a gender discrepancy in presented population, but the consecutive patients were enrolled into the analysis and the same inequality is present in clinical practise. Moreover, we only analysed patients with stable complex coronary disease. We aimed to form the most homogenic study group, therefore, acute coronary syndrome was an exclusion criterium. Patients with concomitant diseases requiring surgical intervention were not included due to already proved worse results of combined procedures [54]. We believe the broader cohort of patients, preferably including multicentre research is necessary for further investigation.

Conclusions

The systemic inflammatory response index is a prognostic factor for worse long-term outcomes after off-pump coronary artery bypass grafting in patients with chronic coronary syndrome. A pre-operative value of SIRI above 1.27 indicates patients with higher long-term mortality risk.

Acknowledgments

Dr Ahmed Al-Imam is a participant of STER Internationalisation of Doctoral Schools Programme from NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/00014/DEC/02.

Data Availability

Data are available from transplantologia@skpp.edu.pl for researchers who meet the criteria for access to confidential data.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Antonino Salvatore Rubino

19 May 2022

PONE-D-22-08151Pre-operative systemic inflammatory response index influences long-term survival rate in off-pump surgical revascularization.PLOS ONE

Dear Dr. Urbanowicz,

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Reviewer #1: Partly

**********

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Reviewer #1: Yes

**********

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Reviewer #1: Yes

**********

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Reviewer #1: No

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Reviewer #1: PONE-D-22-08151

Reviewer comment - The present manuscript aim to explore the possible predictive role of preoperative inflammatory indexes after the off-pump coronary artery bypass grafting technique on long-term survival. The study indicate that preoperative inflammatory activation, evaluated by systemic inflammatory reaction index (SIRI) possesses a prognostic value for complex coronary artery disease patients. A SIRI value above 1.27 indicates a worse late prognosis after off-pump coronary artery bypass.

The authors took up an interesting topic of research, but I have some comments to address them:

1. Materials and methods. A) The authors stated to include additional laboratory parameters other than blood count. Which ones?

Did they evaluated other inflammatory mediators such as C-reactive protein?

B) the definition of PVE and PAD is a bit confusing both in the test and in the tables. Sometimes the authors speak of PVE and others of stroke… Sometimes they use the abbreviations other the full name (Table 1. Point 4 and 5).

2. Results section: data is not well presented. I believe it is necessary to show a table with all the preoperative demographic and clinical characteristics of the study population.

The laboratory parameters, significantly different between the surviving and non-surviving groups, can be presented as box-plot images, instead of Table 2. Furthermore, the univariate table (Table 3) must contain all the variables that have been analyzed to better understand which enter the multivariable model.

I also would like to ask the authors to explain why they think hypercholesterolemia is higher in survivors than in non-survivors.

Did they also consider the different drug treatments?

**********

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Reviewer #1: No

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PLoS One. 2022 Dec 15;17(12):e0276138. doi: 10.1371/journal.pone.0276138.r002

Author response to Decision Letter 0

8 Jun 2022

Poznań, 7.6.2022

Dear Reviewer,

I would like to thank you for your valuable comments.

The answers are presented below.

If you have further suggestions, I would be more than happy to answer.

Kind regards

Tomasz Urbanowicz

On behalf of all co-authors

Reviewer #1: PONE-D-22-08151

Reviewer comment - The present manuscript aim to explore the possible predictive role of preoperative inflammatory indexes after the off-pump coronary artery bypass grafting technique on long-term survival. The study indicate that preoperative inflammatory activation, evaluated by systemic inflammatory reaction index (SIRI) possesses a prognostic value for complex coronary artery disease patients. A SIRI value above 1.27 indicates a worse late prognosis after off-pump coronary artery bypass.

The authors took up an interesting topic of research, but I have some comments to address them:

1. Materials and methods. A) The authors stated to include additional laboratory parameters other than blood count. Which ones?

� We included troponin level. The information is included in the Methods section

Did they evaluated other inflammatory mediators such as C-reactive protein?

� Pre-procedural CRP was not routinely measured except from patients with signs of infection – those subjects were however excluded from the study group. We did not evaluated CRP levels postoperatively and did not correlated them with other markers as this marker was not routinely collected after surgery.

B) the definition of PVE and PAD is a bit confusing both in the test and in the tables. Sometimes the authors speak of PVE and others of stroke… Sometimes they use the abbreviations other the full name (Table 1. Point 4 and 5).

Thank you for this valuable comment – we unified the definitions.

2. Results section: data is not well presented. I believe it is necessary to show a table with all the preoperative demographic and clinical characteristics of the study population.

Table 1 presents pre-operative characteristics of the study group

The laboratory parameters, significantly different between the surviving and non-surviving groups, can be presented as box-plot images, instead of Table 2.

Thank you for this valuable comments – we added box-plot images.

Furthermore, the univariate table (Table 3) must contain all the variables that have been analyzed to better understand which enter the multivariable model.

Thank you for this valuable comments – we added all variables in the univariate table .

I also would like to ask the authors to explain why they think hypercholesterolemia is higher in survivors than in non-survivors.

Did they also consider the different drug treatments?

We noticed higher percentage of hypercholesterolemia in the survivor group. However, this phenomenon was not statistically significant neither in the uni- nor in multivariable analysis. We shall point out that all patients referred for surgery reported long-lasting statin therapy, and the obtained results depended on the individual response to prescribed medication. We did not evaluated target serum levels of cholesterol’ fraction. Moreover, the results obtained for analysis were relevant for the time of surgery and the initial lipid profile characteristics was not available for the analysis. Therefore, the cholesterol level changes, and achievement of treatment goals were not evaluated and, in our opinion, should not be treated as a prognostic factor.

Attachment

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Decision Letter 1

Vipin Zamvar

29 Sep 2022

Pre-operative systemic inflammatory response index influences long-term survival rate in off-pump surgical revascularization.

PONE-D-22-08151R1

Dear Dr. Urbanowicz,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Vipin Zamvar

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors adequately answered to all points.

I wolud suggest them to check again the text.

There are still some word repetitions that prevent the flow and the readabilityof the manuscipt (e.g line 171 "concerning").

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

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