Patient population

Patients undergoing scheduled CAG for suspected stable CAD at the Tsuchiura Kyodo General Hospital between June 2014 and February 2016 were prospectively screened. Exclusion criteria included the presence of unstable symptoms (worsening angina or rest angina within a month), MI episode within 30 days before CAG, decompensated heart failure, scheduled myocardial biopsy, chronic kidney disease (CKD) with dialysis, missing patient or procedural data and unavailable informed consent. In addition, in order to define a minor elevation in hs-cTnI due to catheterization (described below), patients who had an elevated hs-cTnI level above the URL before catheterization were excluded from analysis. At our institution, elective diagnostic CAG and PCI are performed separately in the majority of patients with stable CAD; accordingly, no patient undergoing ad hoc PCI was included in this study. The institutional ethics committee approved this study protocol. All patient data and procedural details were obtained from medical records.

Hs-cTnI measurement and definitions of procedure-related myocardial necrosis

Cardiac troponin-I was assessed using a commercially available hs-cTnI assay (ARCHITECT i2000_SR STAT hs-cTnI assay, Abbott Laboratories, North Chicago, Illinois, USA) immediately before catheterization and 18–24 h after the measurement (pre-TnI and post-TnI, respectively). The 99th percentile cut-off values were defined as 32.7 ng/L for men and 17.9 ng/L for women; the limit for a blank was 0.6 ng/L; limit of detection was 1.5 ng/L; and coefficient of variation of 10% was 6 ng/L, as based on a previous community cohort study of Asian healthy individuals.8 Two different sex-specific definitions of PMN were used: minor PMN was defined as a post-TnI level greater than the URL that was at least a 20% increase from the pre-TnI level according to the diagnosis of acute MI in the current guideline; and major PMN was defined as a post-TnI level >5x the URL, according to the definition of type 4a MI in the same guideline.9 Patients were accordingly divided into the no PMN group, the any PMN group (patients with minor or major PMN) and the major PMN group. Ischaemic symptoms and ECG changes were not mandatory for the definitions of PMN in the present study.

Procedures

Diagnostic CAG was performed via a radial, brachial or femoral artery using a 5Fr sheath, depending on the operator’s discretion. An iodine containing contrast agent, iopamidol, was used throughout the study except for patients with a history of allergy to this contrast agent. All patients received a bolus intravenous injection of heparin (3000 IU) before the procedure, followed by a 2000 IU bolus infusion every hour.

Adjunctive and provisional procedures. LVG was performed following CAG if not contraindicated, and left ventricular end-diastolic pressure (LVEDP) was measured before the contrast agent infusion. Adjunctive catheter-based examinations including aortography, bypass graft angiography, RHC, OCT imaging and FFR measurement were performed depending on the physician’s discretion. OCT imaging was indicated for patients with prior PCI in whom the angiographical appearance of the stent deserved a detailed observation, or for those enrolled in prospective studies that required OCT examinations. For OCT imaging, a 5Fr guiding catheter (Heartrail, Terumo, Tokyo, Japan) was introduced into the vessel of interest; thereafter, a 0.014-inch guidewire was advanced to the distal area of the vessel. A frequency-domain OCT system (C8-XR™ OCT imaging catheter and ILUMIEN OCT Intravascular Imaging System, St. Jude Medical, St. Paul, Minnesota, USA) was used with a pull-back speed of 20 mm/s during continuous flushing of the contrast medium through a guiding catheter at a rate of 3.5–4.5 mL/s for 3–4 s. FFR measurement was indicated for patients with intermediate stenosis in epicardial coronary arteries (30% to 80% diameter stenosis). The institutional protocol for coronary physiological tests are described elsewhere.10 Briefly, a sensor-tipped coronary guidewire (Pressure Wire, St. Jude Medical, St. Paul, Minnesota, USA) was introduced into the coronary artery of interest after the pressure was zeroed and equalised to the catheter-tip pressure before crossing the lesion. Thereafter, the wire was positioned approximately 8–10 cm distal to the ostium of the artery across the index stenosis. Intravenous infusion of adenosine 5’-triphosphate was administered at 160 μg/kg/min to induce steady-state maximal hyperaemia. Simultaneous measurement of the mean aortic pressure (Pa) and mean distal coronary pressure (Pd) was performed in the hyperaemic state, and FFR was calculated as hyperaemic Pd/ hyperemic Pa.

Angiographic analysis

Coronary stenosis was visually estimated, and quantitative coronary angiography (QCA) was indicated for lesions with >30% diameter stenosis. QCA was performed using dedicated off-line so ftware (QAngio XA 7.3, Medis, Leiden, Netherlands); thereafter, coronary lesions with >50% diameter stenosis were considered significant and multivessel disease was defined as significant stenosis in ≥2 coronary arteries. In order to assess the complexity of coronary lesions, SYNTAX and GENSINI scores were determined in patients without prior coronary artery bypass grafting (CABG).11 SYNTAX score was calculated using the online version of SYNTAX score calculator (www.syntaxscore.com), while GENSINI score was manually calculated as the sum of all segment scores, which were the multiply of scores representing percent diameter stenosis and scores of each segment.11 The incidences of coronary interventions, including PCI and CABG, that were performed within 6 months after CAG, based on CAG results, were also assessed.

Clinical follow-up

Clinical follow-up data were collected via a review of the medical records and/or telephone interviews. MI was diagnosed based on the third Universal Definition of Myocardial Infarction.7 Remote revascularisation was defined as a revascularisation required >6 months after the index catheterization, which excluded those required based on the index diagnostic CAG. Major adverse cardiac events (MACE) were defined as a composite of death from any cause, non-fatal spontaneous MI (except those following catheter procedures), hospital admission due to congestive heart failure (CHF), and remote revascularisation.

Statistical analysis

Categorical data are expressed as frequencies and percentages, and were compared using the χ2 or Fisher’s exact test, as appropriate. Continuous variables with normal distribution are expressed as mean±SD and were compared using the Student’s t-test. Variables with a non-normal distribution are expressed as median values (25–75th percentiles) and were compared using Mann-Whitney U tests. Multivariate logistic regression analysis was performed to determine the predictors of PMN and included factors showing a p value <0.05 in univariate analyses, as well as log-transformed N-terminal pro-brain natriuretic peptide (NT-proBNP). The incidence of MACE in patients with/without PMN was assessed using a Kaplan-Meier curve and log-rank test. We constructed Cox proportional-hazards models to estimate the adjusted association between major PMN and the risk of MACE. All variables associated with adverse events obtaining a p value <0.05 in univariate analyses, as well as age, sex and log-transformed NT-proBNP, were then tested in a multivariate Cox proportional-hazards regression analysis. All statistical analyses were performed using SPSS V.19.0 (SPSS, Chicago, Illinois, USA). A two-sided p value < 0.05 was considered statistically significant.