2.1

Patient population

We enrolled 395 patients presenting with either stable angina (SA) or non ST-elevations acute coronary syndrome (NSTE-ACS) who underwent PCI from January 2009 to December 2010 at the Catholic University of Rome and for whom a pre-procedural blood sample was available. Overall, 481 patients were initially screened for the study. Exclusion criteria were: acute ST-elevation myocardial infarction ( n = 30), chronic systolic and/or diastolic heart failure ( n = 20), severe valvular disease ( n = 5), systemic inflammatory diseases ( n = 4), moderate–severe kidney disease ( n = 10), acute and chronic infections ( n = 3), autoimmune diseases ( n = 3), liver diseases ( n = 2), neoplasia ( n = 3), evidence of immunologic disorders ( n = 2), use of anti-inflammatory or immunosuppressive drugs ( n = 3), and recent (3 months) surgical procedures or trauma ( n = 1). Patients with in-stent restenosis of drug-eluting stent (DES) or bare-metal stent (BMS) were excluded as well as patients with stent implantation in the last 12 months before the start of the study in order to avoid potential effects of previously implanted stents. Biological measurements were available in all patients.

In all patients cardiovascular risk factors were carefully examined, including a family history of early CAD [first degree relative with a history of myocardial infarction (MI) < 60 years], hypercholesterolemia (total cholesterol > 200 mg/dL or treated hypercholesterolemia), smoking habit [current regular use (any amount) or cigarette withdrawal more than 2 months], hypertension (systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg or treated hypertension). History of CAD was defined as any previous diagnosis of SA or ACS.

Patients underwent mono-dimensional and bi-dimensional echocardiography and left ventricular ejection fraction (LVEF) was measured with 2D echo Simpson’s biplane.

The choice between BMS or DES was left at the operator discretion. All patients received the same DES if more than one lesion per patient was treated. Post-procedural therapies, including antiplatelet therapy, were prescribed according to current guidelines. All patients received aspirin and clopidogrel at least 2 hours before the procedure. Following PCI, aspirin was prescribed lifelong and clopidogrel for 12 months in NSTE-ACS patients. The duration of clopidogrel therapy in SA patients was based on the type of implanted stent (1 month for BMS and 1 year for DES).

A clinical follow-up was planned at 12, 24, 36 and 48 months after discharge, and data about the follow-up were available for all patients. The primary endpoint of the study was the occurrence of MACEs, defined as the composite of cardiovascular death, MI and clinically driven target lesion revascularization (c-TLR). A secondary endpoint was the occurrence of hard MACE, defined as the composite of cardiac death and MI. Cardiac death was ascertained by contacting the family doctor or the hospital where the patient died. MI was diagnosed by elevation of CK-MB levels above the 99th percentile upper reference limit associated with typical chest pain . C-TLR was carried out in the presence of a diameter stenosis > 50% within 5 mm proximal or distal to the previously implanted stent. C-TLR was clinically driven either due to recurrent angina or to evidence of ischemia by stress test.

This study complied with the Declaration of Helsinki. All patients provided informed written consent and the study was approved by the Ethics Committee of the Catholic University of Rome.

2.2

Coronary angiographic evaluation

An expert angiographer (M.C.), unaware of NP values, evaluated angiographic images both qualitatively and quantitatively. Lesion morphology was assessed by using the modified American College of Cardiology/American Heart Association grading system (type A, B1, B2, and C), whereas CAD severity by counting the number of coronary artery branches showing at least one critical stenosis (> 70% reduction in lumen diameter). Digital angiograms were quantitatively analyzed offline with the use of an automated edge-detection system (CMS; Medis Medical Imaging Systems, The Netherlands). All measurements were performed on images obtained after intracoronary nitrate administration. The following angiographic parameters were obtained: reference vessel diameter, minimal lumen diameter, percent of diameter stenosis, which were evaluated both at baseline and at the end of the procedure, lesion length, and total stent length. The procedure was considered successful if residual stenosis was < 30% with TIMI flow grade 3.

2.3

Blood sampling and NP levels assay

Blood samples were obtained just prior coronary angiography. Biochemical analyses (renal function parameters, glucose, total, HDL and HDL cholesterol, triglycerides, troponin T) were performed with specific biochemical methods on automatic analyzers (Thermo Scientific) of the clinical laboratory. For hormonal measurement, blood was firstly collected in ethylene-diamine-tetraacetic-acid (EDTA) vacutainer tubes, centrifuged at 3000 rpm at 4 °C; and plasma was stored at − 80 °C for blind batch analysis. Thereafter, assays of NT-proANP and NT-proBNP plasma levels were performed by commercially available Elisa kits (Gruppe Biomedica, Wien, Austria).

2.4

Statistical analysis

Data distribution for continuous variables was assessed according to the Kolmogorov–Smirnov test. Continous variables not following normal distribution were expressed as median and interquartile range, whereas other continuous variables were expressed as mean ± SD; categorical variables were expressed as proportions. Unpaired t-test or Mann Whitney U-test was used for comparisons of continuous variables between two groups; categorical variables were compared using the chi square test or the Fisher’s exact test, as appropriate. Correlations between continuous variables were analyzed using Pearson or Spearman test, as appropriate. In this study, there was only right censoring of the data, i.e. MACE did not occur in the remaining patients before the end of follow up and use of Cox proportional hazard ratio (HR) model is allowed with this type of data. Event-free survival was measured from the date of discharge to the occurrence of MACE or to the date of last known follow up evaluation. Thus, as primary analysis, we performed a simple Cox regression analysis using all variables on their original continuous scale in order to estimate the unadjusted HR of all variables. We also calculated the 95% confidence interval (CI) of the coefficient of the Cox regression. Adjusted HRs were calculated according to multivariable Cox regression analysis, including variables with p of significance ≤ 0.1 at univariate analysis. Survival curves using Kaplan–Meier methods were made for NT-proNPs according to the cut-off values derived from ROC curves analysis and compared by the log-rank test. In particular, cut-off values of 2.100 fmol/mL and 100 fmol/mL for NT-proANP and NT-proBNP, respectively, were used. Statistical significance was considered for p values < 0.05. All analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA).

2.1

Patient population

We enrolled 395 patients presenting with either stable angina (SA) or non ST-elevations acute coronary syndrome (NSTE-ACS) who underwent PCI from January 2009 to December 2010 at the Catholic University of Rome and for whom a pre-procedural blood sample was available. Overall, 481 patients were initially screened for the study. Exclusion criteria were: acute ST-elevation myocardial infarction ( n = 30), chronic systolic and/or diastolic heart failure ( n = 20), severe valvular disease ( n = 5), systemic inflammatory diseases ( n = 4), moderate–severe kidney disease ( n = 10), acute and chronic infections ( n = 3), autoimmune diseases ( n = 3), liver diseases ( n = 2), neoplasia ( n = 3), evidence of immunologic disorders ( n = 2), use of anti-inflammatory or immunosuppressive drugs ( n = 3), and recent (3 months) surgical procedures or trauma ( n = 1). Patients with in-stent restenosis of drug-eluting stent (DES) or bare-metal stent (BMS) were excluded as well as patients with stent implantation in the last 12 months before the start of the study in order to avoid potential effects of previously implanted stents. Biological measurements were available in all patients.

In all patients cardiovascular risk factors were carefully examined, including a family history of early CAD [first degree relative with a history of myocardial infarction (MI) < 60 years], hypercholesterolemia (total cholesterol > 200 mg/dL or treated hypercholesterolemia), smoking habit [current regular use (any amount) or cigarette withdrawal more than 2 months], hypertension (systolic blood pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg or treated hypertension). History of CAD was defined as any previous diagnosis of SA or ACS.

Patients underwent mono-dimensional and bi-dimensional echocardiography and left ventricular ejection fraction (LVEF) was measured with 2D echo Simpson’s biplane.

The choice between BMS or DES was left at the operator discretion. All patients received the same DES if more than one lesion per patient was treated. Post-procedural therapies, including antiplatelet therapy, were prescribed according to current guidelines. All patients received aspirin and clopidogrel at least 2 hours before the procedure. Following PCI, aspirin was prescribed lifelong and clopidogrel for 12 months in NSTE-ACS patients. The duration of clopidogrel therapy in SA patients was based on the type of implanted stent (1 month for BMS and 1 year for DES).

A clinical follow-up was planned at 12, 24, 36 and 48 months after discharge, and data about the follow-up were available for all patients. The primary endpoint of the study was the occurrence of MACEs, defined as the composite of cardiovascular death, MI and clinically driven target lesion revascularization (c-TLR). A secondary endpoint was the occurrence of hard MACE, defined as the composite of cardiac death and MI. Cardiac death was ascertained by contacting the family doctor or the hospital where the patient died. MI was diagnosed by elevation of CK-MB levels above the 99th percentile upper reference limit associated with typical chest pain . C-TLR was carried out in the presence of a diameter stenosis > 50% within 5 mm proximal or distal to the previously implanted stent. C-TLR was clinically driven either due to recurrent angina or to evidence of ischemia by stress test.

This study complied with the Declaration of Helsinki. All patients provided informed written consent and the study was approved by the Ethics Committee of the Catholic University of Rome.

2.2

Coronary angiographic evaluation

An expert angiographer (M.C.), unaware of NP values, evaluated angiographic images both qualitatively and quantitatively. Lesion morphology was assessed by using the modified American College of Cardiology/American Heart Association grading system (type A, B1, B2, and C), whereas CAD severity by counting the number of coronary artery branches showing at least one critical stenosis (> 70% reduction in lumen diameter). Digital angiograms were quantitatively analyzed offline with the use of an automated edge-detection system (CMS; Medis Medical Imaging Systems, The Netherlands). All measurements were performed on images obtained after intracoronary nitrate administration. The following angiographic parameters were obtained: reference vessel diameter, minimal lumen diameter, percent of diameter stenosis, which were evaluated both at baseline and at the end of the procedure, lesion length, and total stent length. The procedure was considered successful if residual stenosis was < 30% with TIMI flow grade 3.

2.3

Blood sampling and NP levels assay

Blood samples were obtained just prior coronary angiography. Biochemical analyses (renal function parameters, glucose, total, HDL and HDL cholesterol, triglycerides, troponin T) were performed with specific biochemical methods on automatic analyzers (Thermo Scientific) of the clinical laboratory. For hormonal measurement, blood was firstly collected in ethylene-diamine-tetraacetic-acid (EDTA) vacutainer tubes, centrifuged at 3000 rpm at 4 °C; and plasma was stored at − 80 °C for blind batch analysis. Thereafter, assays of NT-proANP and NT-proBNP plasma levels were performed by commercially available Elisa kits (Gruppe Biomedica, Wien, Austria).

2.4

Statistical analysis

Data distribution for continuous variables was assessed according to the Kolmogorov–Smirnov test. Continous variables not following normal distribution were expressed as median and interquartile range, whereas other continuous variables were expressed as mean ± SD; categorical variables were expressed as proportions. Unpaired t-test or Mann Whitney U-test was used for comparisons of continuous variables between two groups; categorical variables were compared using the chi square test or the Fisher’s exact test, as appropriate. Correlations between continuous variables were analyzed using Pearson or Spearman test, as appropriate. In this study, there was only right censoring of the data, i.e. MACE did not occur in the remaining patients before the end of follow up and use of Cox proportional hazard ratio (HR) model is allowed with this type of data. Event-free survival was measured from the date of discharge to the occurrence of MACE or to the date of last known follow up evaluation. Thus, as primary analysis, we performed a simple Cox regression analysis using all variables on their original continuous scale in order to estimate the unadjusted HR of all variables. We also calculated the 95% confidence interval (CI) of the coefficient of the Cox regression. Adjusted HRs were calculated according to multivariable Cox regression analysis, including variables with p of significance ≤ 0.1 at univariate analysis. Survival curves using Kaplan–Meier methods were made for NT-proNPs according to the cut-off values derived from ROC curves analysis and compared by the log-rank test. In particular, cut-off values of 2.100 fmol/mL and 100 fmol/mL for NT-proANP and NT-proBNP, respectively, were used. Statistical significance was considered for p values < 0.05. All analyses were performed using SPSS version 20 (SPSS Inc., Chicago, IL, USA).

3.1

Main features and clinical outcomes of the study population

We included 303 patients (76.7%) with NSTE-ACS and 92 patients (23.3%) with SA. Follow up mean time was 48.53 ± 14.69 months. Baseline clinical, angiographic and procedural data of the study population are shown in Table 1 .

Table 1

Baseline clinical, laboratory, angiographic and procedural characteristics in the overall patient population and according to the clinical presentation.

Variables	All patients ( N = 395)	ACS 303 (76.7%)	SA 92 (23.3%)	p
Clinical variables
Age, years, mean ± SD	70 ± 11	68 ± 12	74 ± 15	0.83
Male, n (%)	278 (70.4)	211 (69.6)	67 (72.8)	0.6
Hypertension, n (%)	301 (76.2)	228 (75.2)	73 (19)	0.48
Smoking, n (%)	141 (35.7)	106 (35.0)	35 (38)	0.62
Dyslipidaemia, n (%)	230 (58.2)	175 (57.8)	55 (59.8)	0.80
Diabetes, n (%)	103 (26.1)	75 (24.8)	28 (30.4)	0.28
Family history of CAD, n (%)	104 (26.3)	75 (24.8)	29 (31.5)	0.22
Previous CAD, n (%)	106 (26.8)	85 (28.1)	21 (22.8)	0.35
Previous PCI, n (%)	96 (24.3)	75 (24.8)	21 (22.8)	0.78
Previous CABG, n (%)	31 (7.8)	27 (8.9)	4 (4.3)	0.18
Multivessel disease, n (%)	207 (52.4)	165 (54.5)	42 (45.7)	0.15
LEVF, %, median (range)	60 (55–65)	61 (57–64)	58 (54–63)	0.94
TIMI risk score	–	2.2 ± 1.9	–	–
Laboratory assays
Creatinine, mg/dL, mean (range)	0.9 (0.81–1.20)	0.85 (0.75–1.11)	0.89 (0.79–1.17)	0.75
NT-proANP, fmol/mL, median (range)	2376 (1383–4130)	2174 (1431–3949)	2098 (1432–4049)	0.83
NT-proBNP, fmol/mL, median (range)	523 (276–1036)	413 (243–1143)	476 (313–1094)	0.78
Total cholesterol, mg/dL, mean ± SD	187 ± 50.9	174 ± 53	179 ± 46	0.55
HDL, mg/dL, mean ± SD	44 ± 11.8	39 ± 19	43 ± 11	0.63
LDL, mg/dL, mean ± SD	112 ± 42	104 ± 37	109 ± 41	0.45
Triglycerides, mg/dL, mean ± SD	143 ± 67.1	137 ± 57	144 ± 71	0.62
Hemoglobin, mg/dL, mean ± SD	14 ± 1.6	13.5 ± 1.8	13.9 ± 1.9	0.74
Glycaemia, mg/dL, median (range)	106 (92–139)	101 (99–125)	104 (94–137)	0.96
Troponin T, ng/mL, median (range)	9.432 (1.257–16.306)	13.322 (7.431–19.436)	0.000 (0.000–0.000)	< 0.001
Medical therapy at discharge
Βeta-blockers, n (%)	252 (67.2)	198 (65.3)	54 (58.7)	0.26
ACE-I/ARB, n (%)	258 (68.8)	202 (66.7)	56 (60.9)	0.32
Statin, n (%)	272 (72.7)	212 (70.0)	60 (65.2)	0.44
Antiplatelet drugs, n (%)	371 (98.9)	283 (93.4)	88 (95.7)	0.62
Angiographic and procedural data
Number of stent for patients, mean ± SD	1.3 ± 0.4	1.2 ± 0.4	1.3 ± 0.5	0.95
Stent type				0.62
BMS, n (%)	120 (30.4)	95 (31.4)	25 (27.2)
Stenosis length, mm, median (range)	17.9 (12.8–25.4)	16.4 (11.9–24.9)	17.4 (12.3–23.9)	0.39
RVD pre, mm, median (range)	2.63 (2.2–3.1)	2.49 (2.21–2.95)	2.34 (2.19–3.23)	0.56
MLD pre, mm, mean ± SD	0.86 ± 0.5	0.79 ± 0.80	0.93 ± 0.96	0.56
DS % pre, mean ± SD	69.5 ± 16.8	72.3 ± 17.6	69.4 ± 15.6	0.21
MLD post, mm, mean ± SD	2.7 ± 0.5	2.3 ± 0.4	2.5 ± 0.6	0.96
Pre-dilatation, n (%)	320 (81.0)	210 (69.3)	65 (70.7)	0.28
Post-dilatation, n (%)	255 (64.6)	250 (82.5)	70 (76.1)	0.17
Stent length, mm, median (range)	22.5 (18–33)	23.4 (17.5–32.6)	24.3 (19.6–34.7)	0.69
Stent diameter, mm, mean ± SD	3.1 ± 0.5	2.8 ± 0.8	3.2 ± 0.9	0.87
Acute gain, mm, mean ± SD	1.8 ± 0.6	1.7 ± 0.7	1.9 ± 0.8	0.63

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