Inflammatory Conditions in Acute Coronary Syndrome Patients Treated with Percutaneous Coronary Intervention of Saphenous Vein Graft

Abstract

The study aimed to evaluate the inflammatory blood parameters in acute coronary syndrome (ACS) patients with a history of coronary artery bypass graft (CABG) and treated with percutaneous coronary intervention (PCI) of saphenous vein graft (SVG). A total of 347 patients who underwent urgent SVG PCI with the diagnosis of ACS were included in the study. After the application of exclusion criteria, 79 patients were allocated into two groups, namely, successful PCI ( n  = 59) and unsuccessful PCI ( n  = 20), and included in the statistical analysis. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) levels were significantly higher in patients with unsuccessful SVG PCI. In the logistic regression analysis, PLR, C-reactive protein, and diabetes mellitus emerged as independent factors associated with unsuccessful SVG PCI. The area under the curve for PLR was 0.70 (95% confidence interval: 0.55–0.85, p  = 0.006). The cut-off value of PLR (128.99) was associated with 70.0% sensitivity and 69.5% specificity. Elevated inflammatory status is associated with unsuccessful PCI of SVG in ACS patients. Increased PLR levels on admission is an independent predictor of this situation. This cheap and simple marker can help us to predict unsuccessful SVG PCI in ACS patients.

There have been significant improvements in the treatment of coronary artery disease (CAD) both in the percutaneous coronary intervention (PCI) and bypass surgery era in last decades. However, occlusive atherosclerotic vessel disease still remains a significant cause of morbidity and mortality worldwide. ¹ Coronary artery bypass graft (CABG) surgery is the main treatment option in patients suffering from three-vessel disease and/or left main CAD. Besides improving ischemia, chest pain and quality of life, CABG surgery also improves prognosis in some cases. ² Arterial grafts and saphenous vein grafts (SVGs) are usually used for bypassing the obstructed vessel. Although arterial grafts have higher patency rates compared with SVGs, SVGs are widely used during surgery due to their easy accessibility and availability. ^{1 2 3} It is known that 12% of SVGs are obstructed at 1 month as a result of acute thrombosis and approximately 40% of SVGs are obstructed at the 10th year of CABG surgery. This is a significant limitation hampering SVG use as a bypass conduit during surgery. ^{3 4} The main pathophysiological mechanism underlying SVG failure and atherosclerosis at all stages is increased inflammatory status and oxidative stress. ^{1 3 5 6 7}

Since the first cardiac biomarker, aspartate aminotransferase (AST) was defined in acute myocardial infarction (AMI) patients by Karmen and colleagues in 1954, ⁸ they have been widely investigated and used in the daily cardiology practice for diagnostic and prognostic purposes. ⁹ In addition, there has been a strong interest to hematological parameters as inflammatory biomarkers in cardiovascular diseases, especially in acute coronary syndrome (ACS) due to the fact that they provide information about diagnostic evaluation, risk stratification, their low cost, and easy availability in routine clinical practice. The most widely used hematological inflammatory parameters include neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). ¹⁰ In a similar manner, biochemical indices such as C-reactive protein (CRP), sedimentation rate, and fibrinogen have been extensively investigated and used in cardiology practice as inflammatory biomarkers. ^{11 12 13} This study aims to evaluate the hematological and biochemical inflammatory markers in ACS patients with a history of CABG surgery who were treated with PCI of SVG.

Methods

Patient Characteristics

Between 2009 and 2014, a total of 347 patients who presented to our hospital and underwent urgent SVG PCI with the diagnosis of ACS were included in the study retrospectively. Clinical data of patients were obtained from hospital records. ACS types were classified as ST-elevation myocardial infarction (STEMI) and non-ST-elevation-ACS (NSTE-ACS). Diagnosis of STEMI included patients with acute onset chest pain and persistent ST-segment elevation on electrocardiography (ECG). ¹⁴ Diagnosis of NSTE-ACS included patients with acute onset chest pain, no persistent ST-segment elevation on ECG and/or elevation of the cardiac troponin level greater than the upper limit of normal range. ¹⁵

Patients with active infection, older than 85 years of age, acute decompensated heart failure, active malignancy, moderate or significant valvular heart disease, autoimmune disease, liver disease, renal insufficiency, metabolic acidosis, and insufficient hospital records were excluded from analysis. Patients receiving steroid treatment or chemotherapy and patients whose time interval between bypass operation and index ACS less than 1 month were also excluded from the study. After the application of exclusion criteria, the remaining 79 patients were allocated into two groups, namely, successful PCI and unsuccessful PCI, and included in the statistical analysis. The local ethics committee of the hospital approved the study protocol and the study was conducted according to the Helsinki Declaration. The flow chart of the study including exclusion criteria is shown in Fig. 1 .

Fig. 1.

Flow-chart diagram of the study. ACS, acute coronary syndrome; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; SVG, saphenous vein graft; TIMI, thrombolysis in myocardial infarction.

Definitions

Patients included in the study were examined for baseline clinical parameters and recorded on a study chart. Arterial hypertension was defined as patients with repeated blood pressure measurements ≥ 140/90 mm Hg or a previous diagnosis of hypertension with usage of antihypertensive drugs. Diabetes mellitus (DM) was defined as fasting plasma glucose levels more than 126 mg/dL in multiple measurements or glucose level over 200 mg/dL at any measurement or active use of antidiabetic medications. Smoking was defined as current smoking in the previous 6 months. The family history of CAD was defined as presence of a history of CAD or sudden cardiac death in a first degree relative before the age of 55 years for men and before the age of 65 years for women. Hypercholesterolemia was defined as a baseline cholesterol level of > 200 mg/dL and/or a low-density lipoprotein cholesterol level of > 130 mg/dL or previously diagnosed and treated hypercholesterolemia.

Laboratory Measurements

Peripheral blood samples were obtained from all patients within 10 minutes upon admission to hospital from antecubital vein. Total complete blood count (Coulter LH 780 Hematology Analyzer, Beckman Coulter Corp., Hileh, FL) and blood chemistry parameters were performed at the biochemistry laboratory of the hospital. Blood samples were taken into standardized EDTA containing tubes and to avoid the platelet swelling with time because of EDTA, measurements were done immediately after the blood sampling. Glucose, creatinine, blood urea nitrogen, lipid profile including total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglyceride were determined by standard methods. CRP, fibrinogen levels, and sedimentation rate were also measured.

Coronary Angiography Procedure and Medications

All patients were treated with 300-mg chewable acetylsalicylic acid, loading dose of any P2Y12 receptor antagonist (clopidogrel, prasugrel, and ticagrelor) according to their clinical status before the coronary angiography, and intravenously heparin at the dose of 70 U/kg during the intervention. Coronary angiography was performed with the standard Judkins technique through the femoral route (Siemens Axiom Artis zee 2011; Siemens Healthcare, Erlangen, Germany). During the procedure, the operator was free to the decision of revascularization, choice of stent type (bare metal or drug eluting stent), and administration of glycoprotein IIb/IIIa receptor antagonist. Perfusion in the SVG after PCI was determined according to the thrombolysis in myocardial infarction (TIMI) grade scoring system. ¹⁶ TIMI grade-3 coronary flow in the SVG with a residual stenosis <  30% was accepted as successful PCI. TIMI grade 0–2 coronary flows in the treated SVG were considered as unsuccessful PCI. After the intervention, continuing dose of P2Y12 receptor inhibitor was continued for at least 12 months and 100-mg acetylsalicylic acid was prescribed indefinitely. Transthoracic echocardiography (Vivid 3; GE Medical System, Horten, Norway) was performed to patients in the first 24 hours of coronary intensive care unit follow-up process. Left ventricular ejection fraction (LVEF) was measured using modified Simpson's method.

Statistical Analysis

Categorical variables were determined as counts and percentages and compared between the groups using the Chi-squared test. Continuous variables were expressed as mean value ± standard deviation for parametric variables or as median (interquartile range) for nonparametric variables. Kolmogorov–Smirnov test was applied for the assessment of normality. Differences between the means were compared by unpaired t -test when the continuous variables showed normal distribution or by the Mann–Whitney U -test when they did not. Receiver operating characteristic (ROC) curve analyzes were conducted to determine cut-off values of NLR and PLR for predicting unsuccessful SVG PCI. The area under the ROC curve (AUC) was reported with 95% confidence interval (CI), in addition to sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). The variables which were determined as p  < 0.25 for unsuccessful SVG PCI as a result of univariate analysis were included in multivariate logistic regression analysis. A two-tailed p  < 0.05 was considered as statistically significant. All statistical analyses were performed using SPSS for Windows 18.0 (version 18.0, SPSS, Chicago, IL).

Results

Baseline demographic characteristics and clinical features of the study patients are presented in Table 1 . There was no difference between the groups with respect to age, smoking status, and hypercholesterolemia. Female gender (30 and 10%, respectively, p  = 0.04), hypertension (100 and 80%, respectively, p  = 0.005), and DM (95 and 42%, respectively, p  < 0.01) were more frequent in patients with unsuccessful SVG PCI compared with patients with successful SVG PCI. When it comes to CABG characteristics, time interval between CABG surgery to index ACS event was shorter in terms of years in unsuccessful SVG PCI group compared with successful PCI group (7.4 ± 4.9 and 10.4 ± 6.1, respectively, p  = 0.03). There was no difference between the groups in terms of number of SVGs and localization of culprit saphenous vein. Additionally, clinical presentation and LVEF was comparable between the groups.

Table 1. Baseline demographics and clinical characteristics of the study population.

Variable	Saphenous vein graft PCI		p -Value
	TIMI 0–2 grade flows (unsuccessful) ( n  = 20)	TIMI 3 grade flow (successful) ( n  = 59)
Age (y)	62 ± 10	63 ± 9	0.52
Women	6 (30%)	6 (10%)	0.04
Hypertension	20 (100%)	47 (80%)	0.005
Diabetes mellitus	19 (95%)	25 (42%)	<0.01
Current smoker	9 (45%)	29 (49%)	0.74
Hypercholesterolemia	16 (80%)	35 (59%)	0.08
Time interval after by pass (y)	7.4 ± 4.9	10.4 ± 6.1	0.03
Number of saphenous vein grafts	2.3 ± 0.7	1.9 ± 0.6	0.05
Localization of culprit saphenous vein 0.15
Left anterior descending artery	2 (10%)	12 (20%)
Circumflex artery	6 (30%)	26 (44%)
Right coronary artery	12 (60%)	21 (36%)
Clinical presentation 0.14
ST-elevation myocardial infarction	9 (36%)	16 (64%)
Non-ST-elevation acute coronary syndrome	11 (20%)	43 (80%)
Left ventricular ejection fraction (%)	46.5 ± 7.9	46.3 ± 10.7	0.93

Abbreviations: PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Note: values are expressed as mean ± standard deviation or n (%).

Laboratory parameters of the study groups are given in Table 2 . There was no difference between the groups regarding platelet counts, mean platelet volume (MPV), mean corpuscular volume, and red cell distribution width. White blood cell (WBC) count (10.5 ± 3.3 and 8.8 ± 2.7, respectively, p  = 0.04) and neutrophil count (7.9 ± 3.0 and 5.9 ± 2.2, respectively, p  = 0.01) was higher in unsuccessful SVG PCI group compared with successful SVG PCI group. In contrast, lymphocyte count was lower in unsuccessful SVG PCI group than successful SVG PCI group (1.58 ± 0.6 and 2.0 ± 0.6, respectively, p  = 0.02). NLR levels were significantly higher in patients with unsuccessful SVG PCI compared with patients with successful SVG PCI (6.1 ± 4.3 and 3.2 ± 1.6, respectively, p  = 0.009). PLR levels were also significantly higher in patients with unsuccessful SVG PCI compared with patient group with successful SVG PCI (154.2 ± 60.7 and 113.1 ± 38.3, respectively, p  = 0.009). The AUC for the NLR was 0.77 (95% CI: 0.64–0.89, p  < 0.001). The cut-off value of the NLR (3.45) was associated with 80.0% sensitivity, 69.0% specificity, 47% PPV, and 91% NPV ( Fig. 2A ). The AUC for the PLR was 0.70 (95% CI: 0.55–0.85, p  = 0.0060. The cut-off value of the PLR (128.99) was associated with 70.0% sensitivity, 69.5% specificity, 44% PPV, and 87% NPV ( Fig. 2B ). Biochemical parameters, such as glucose, creatinine, AST, alanine aminotransferase, gamma glutamyl transferase, albumin, and lipid levels, were similar between the groups, whereas lactate dehydrogenase level was significantly higher in unsuccessful SVG PCI group ( p  = 0.001). CRP levels and sedimentation rate were also significantly higher in unsuccessful SVG PCI group than successful PCI group ( p  < 0.001, 0.01, respectively).

Table 2. Laboratory parameters of the study population.

Variable	Saphenous vein graft PCI		p -Value
	TIMI 0–2 grade flow (unsuccessful) ( n  = 20)	TIMI 3 grade flow (successful) ( n  = 59)
White blood cell count (× 10 9 /L)	10.5 ± 3.3	8.8 ± 2.7	0.04
Neutrophil count (× 10 9 /L)	7.9 ± 3.0	5.9 ± 2.2	0.01
Lymphocyte count (× 10 9 /L)	1.58 ± 0.6	2.0 ± 0.6	0.02
Platelet count (× 10 9 /L)	215.9 ± 53.6	210.4 ± 54.1	0.69
Mean platelet volume (fL)	8.87 ± 0.86	9.09 ± 2.05	0.64
Mean corpuscular volume (fL)	86.4 ± 8.1	87.4 ± 11.8	0.67
Red cell distribution width	14.4 ± 1.1	14.6 ± 1.4	0.62
Neutrophil-to-lymphocyte ratio	6.1 ± 4.3	3.2 ± 1.6	0.009
Platelet-to-lymphocyte ratio	154.2 ± 60.7	113.1 ± 38.3	0.009
Glucose (mg/dL)	153 ± 64	130 ± 52	0.17
Creatinine (mg/dL)	0.9 ± 0.2	1.01 ± 0.2	0.49
Aspartate aminotransferase	26.5 (19.2–45.7)	30 (19–57)	0.80
Alanine aminotransferase	31.9 ± 18.0	26.3 ± 17.6	0.22
Gamma glutamyl transferase	24 (16.5–44.7)	31 (15–43)	0.73
Lactate dehydrogenase	674.0 ± 363.2	460.8 ± 197.2	0.001
Albumin (mg/dL)	3.95 ± 0.62	4.09 ± 0.41	0.28
Fibrinogen (mg/dL)	3.67 ± 1.02	3.42 ± 0.72	0.25
Total cholesterol	178.89 ± 43.24	179.45 ± 46.18	0.96
High density lipoprotein (mg/dL)	40.9 ± 13.2	36.7 ± 9.1	0.20
Low density lipoprotein (mg/dL)	109.3 ± 32.9	111.4 ± 39.5	0.81
Triglyceride (mg/dL)	124 (93–199)	144 (97–146)	0.60
C-reactive protein (mg/L)	13.8 ± 12.4	5.8 ± 4.1	<0.001
Sedimentation rate	13 (11–35)	11 (6–16)	0.01

Abbreviations: PCI, percutaneous coronary intervention; TIMI, thrombolysis in myocardial infarction.

Note: values are expressed as mean ± standard deviation, or odds ratio (95% confidence interval), or n (%).

Fig. 2.

The receiver-operating characteristic (ROC) curve analysis for the neutrophil-to-lymphocyte ratio ( A ) and platelet-to-lymphocyte ratio ( B ) for predicting unsuccessful saphenous vein graft PCI. PCI, percutaneous coronary intervention.

Logistic regression analysis results are presented in Table 3 . Gender, WBC count, NLR, PLR, CRP, and DM were determined as significant factors associated with unsuccessful SVG PCI in univariate analysis and these parameters were included in multivariate logistic regression analysis. PLR (Odds ratio [OR] = 1.02, 95% CI: 1.00–1.04, p  = 0.04), CRP (OR = 1.07, 95% CI: 1.00–1.15, p  = 0.03), and DM (OR = 0.04, 95% CI: 0.00–0.53, p  = 0.04) emerged as significant and independent predictors of unsuccessful SVG PCI, whereas gender, WBC, and NLR (OR = 0.93, 95% CI: 0.60–1.43, p  = 0.11) did not reach statistical significance in multivariate analysis.

Table 3. Logistic regression analysis of parameters associated with unsuccessful PCI.

Variable	p -Value	Odds ratio	95% confidence interval
Gender	0.36	2.33	0.37–14.43
White blood cell count	0.15	1.23	0.92–1.65
Neutrophil-to-lymphocyte ratio	0.11	0.93	0.60–1.43
Platelet-to-lymphocyte ratio	0.04	1.02	1.00–1.04
C-reactive protein	0.03	1.07	1.00–1.15
Diabetes mellitus	0.04	0.04	0.00–0.53

Abbreviation: PCI, percutaneous coronary intervention.

Discussion

The main findings of this study include that (1) there is more severe inflammatory condition in ACS patients treated with unsuccessful SVG PCI compared with patients with successful SVG PCI, and (2) PLR is a significant and independent predictor of unsuccessful SVG PCI. To the best of our knowledge, this is the first study assessing the inflammatory status and hematological and biochemical markers in ACS patients treated with PCI of SVG.

SVG disease is associated with various situations including coronary anatomy, coronary physiology, graft age, surgical technique, race, and clinical risk factors such as smoking, gender, hyperlipidemia, hypertension, and DM. From a pathophysiological point of view, three mechanisms play role during this course: thrombosis, intimal hyperplasia, and atherosclerosis. The contribution of these mechanisms to SVG disease development may vary according to individualized risk factors. ^{1 3} Inflammation plays significant roles on all these mechanisms and constitutes the cornerstone in the pathophysiology of atherosclerosis. Various inflammatory system cells including lymphocytes, neutrophils, monocytes, and macrophages take part during this course. ^{5 17} Neutrophils are activated at various stages of atherosclerosis from initiation to progression of the atherosclerotic plaque. They also promote vascular inflammation, plaque erosion, and atherothrombosis. ¹⁸ Lymphocyte cells play role in the deposition of lipid particles into the atherosclerotic plaque. ⁵ Besides, platelet cell activation is a significant contributor of the thrombotic and inflammatory processes in the cardiovascular system. Chemokines, cytokines, and diverse inflammatory system mediators are secreted by activated platelets. ¹⁹ These platelet secreted mediators link inflammation, thrombosis, and atherogenesis to each other, which are pathophysiological processes of CAD development. ²⁰ In addition, inflammation develops at the vascular wall as a result of the interaction between platelets, immune system cells, and endothelial cells. This interaction leads to migration of leukocytes into the vascular wall. ²¹ These chronic inflammatory processes induced by platelet activation finally results with atherosclerosis development. Platelet-secreted mediators are also related with formation and development of arterial thrombus during the atherosclerotic process. ²²

DM, a well-demonstrated risk factor for atherosclerosis, is also associated with SVG disease and calcification through the phenotypic change of vascular smooth muscle cells to osteoblast like cells and their excessive proliferation. ^{23 24} Advanced glycation end products (AGEs), the products of nonenzymatic glycation/oxidation of proteins and lipids after glucose exposure, are mostly prevalent in diabetic vasculature and contribute to the development of atherosclerosis and plaque instability. They are also closely linked to inflammatory status and oxidative stress in various diseases. ²⁵ A recent study demonstrated that AGEs impair the functions of smooth muscle cells obtained from saphenous vein but not internal thoracic artery through mitogen activated protein kinase pathway and AGEs receptor activation in diabetic patients. ²³ In our study, we found that presence of DM is independently associated with unsuccessful SVG PCI in ACS patients suggesting a more advanced atherosclerosis in SVG of diabetic patients. It can be speculated that AGEs and oxidative stress–related reactive oxygen species might have a role in this situation; however, this hypothesis needs to be tested in future studies.

The process of biomarker investigations in cardiovascular diseases has substantially increased in recent years, especially focusing on circulating inflammatory markers. ²⁶ NLR and PLR, which can be calculated easily from a complete blood count test, are inexpensive, easy to obtain, widely available markers of inflammation and they can be used for diagnostic evaluation, and/or risk stratification in patients with various cardiovascular conditions. ^{27 28} For example, in a meta-analysis study, NLR was demonstrated to be a predictor of hospitalization and long-term prognosis in patients with STEMI after PCI. ²⁹ Preprocedural PLR levels were shown to be an independent predictor of slow flow and no reflow after primary PCI in STEMI patients. ³⁰ Likewise, admission PLR levels were shown to be strong and independent predictor of no-reflow phenomenon and long-term prognosis following primary PCI in STEMI patients. ³¹

These inflammatory markers have also been investigated in patients with CABG and/or SVG disease. In a retrospective study published by Doğan et al, it was demonstrated that NLR is an independent predictor of SVG disease. ³² Increased preoperative NLR levels were also shown to be independent predictor of adverse outcomes after CABG surgery. ³³ In a previous study published by Yayla and colleagues, PLR and MPV levels were independent predictors of SVG disease. ³⁴ Similarly, higher PLR levels were found to be independent predictor of SVG disease in patients presenting with stabile angina pectoris. ³⁵ In a recently published paper, it was demonstrated that elevated PLR and NLR levels are independent predictors of early postoperative acute kidney injury following isolated CABG surgery. ³⁶ In our retrospectively designed study, we hypothesized that there might be a difference between ACS patients treated with the PCI of SVG successfully or unsuccessfully in terms of inflammatory conditions. Our results indicated that WBC, neutrophil, CRP, NLR, and PLR levels are significantly higher and lymphocyte levels are significantly lower in patients with unsuccessful PCI suggesting an increased inflammatory status in these patients. However, from the biomarker perspective NLR did not reach statistical significance in logistic regression analysis, whereas PLR and CRP were independent predictors of unsuccessful PCI in our patient group. According to these results, PLR and CRP levels may be used to predict success rate of SVG PCI in ACS patients.

Elevated inflammatory cells are as important as lipids in the pathogenesis of CAD and currently underexamined and undertreated according to a previously published study. ³⁷ CRP is the most investigated biomarker due to the fact that it is closely related with systemic inflammation and a strong predictor of adverse outcomes in cardiovascular events. ³⁸ In addition, increased number of WBC was also shown to be related with atherosclerotic cardiovascular events. ³⁹ Activated WBCs penetrate to vascular endothelium, subsequently increasing capillary leukostasis and vascular resistance. Various hydrolytic enzymes, cytokines, and growth factors released from activated WBCs also increase vascular damage through the endothelium. ⁴⁰ In our study, CRP levels and WBC counts were significantly higher in unsuccessful SVG PCI group. Furthermore, CRP levels but not WBC counts reached statistical significance in multivariate regression analysis. PLR is a hematological inflammatory biomarker that is linked with both thrombocyte aggregation and inflammation. Besides, it was shown to be superior to NLR for predicting mortality and inflammation in end-stage renal disease patients. ^{41 42} Similarly, although NLR and PLR levels were both significantly higher, only PLR remained as independent predictor of unsuccessful SVG PCI in our ACS patient population. However, it should be noted that there was no difference between the groups in terms of platelet counts and MPV levels. Therefore, it can be speculated that decreased lymphocyte counts may be more important than platelet counts for the prediction of unsuccessful SVG PCI in ACS patients. It is known from a previous study that decreased lymphocyte count is associated with poor prognosis and complication development after AMI. ⁴³

Limitations

Our study has some limitations. This was a single-center retrospective study including a small number of ACS patients. In addition, due to its retrospective design, some recordings including blood parameters, clinical, and angiographical characteristics were missing, which resulted with exclusion of a significant number of patients from the study. Besides, we only assessed the admission blood parameters of the patients and it would be nice if we had evaluated the follow-up levels of these inflammatory markers.

Conclusion

In conclusion, elevated inflammatory status is associated with unsuccessful PCI of SVG in ACS patients. Besides, increased PLR levels on admission is an independent predictor of this situation in this patient group. This cheap and simple marker can help us to predict unsuccessful SVG PCI in ACS patients. Further studies with prospective design including larger patient populations are needed to substantiate these findings.

Funding Statement

Funding The authors received no financial support for the research, authorship, and/or publication of this article.