Study patients
This single-center study was performed at Boramae Medical Center (Seoul, Korea). Between January 2013 and December 2015, consecutive patients who underwent elective invasive coronary angiography (ICA) were prospectively recruited. Coronary angiography was performed for suspected CAD. A total of 466 paitents were initially screened, however, 78 patients with following conditions were exclued: 1) AMI, 2) ongoing chest pain, 3) unstable vital signs, 4) left ventricular ejection fraction < 50% or clinical heart failure syndrom, 5) the presence of regional wall motion abnormalies, 6) valvular dysfunction greater mild degree, and 7) the presence of pericardial effusion. Finally, a total of 388 patients were analyzed in this study. This study conforms to the ethical guidelines of the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board (IRB) of Boramae Medical Center (Seoul, Korea) (IRB number: 16-2015-161). All subjects provided written informed consent prior to their participation in the study.
Data collection
The height and weight were measured on the day of hospital admission by a nurse, and BMI was calculated using wieght and height (kg/m2). Hypertension, diabetes mellitus and dyslipidemia were diagnosed based on a previous history of diagnosis made by doctors or current medications controlling them. Current smokers were defined as those who regularly smoked in the last year. After overnight fasting for 12 hours, blood was collected from antecubital vein, and the blood levels following parameters were masured: total cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, and triglyceride and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the following the Modification of Diet in Renal Disease (MDRD) study formula: 175 × serum creatinine− 1.154 × age− 0.203 (× 0.742, if woman). Left ventricular ejection fraction was measured by Simpson’s biplane method using tranthoracic echocardiography. Concomitant cardiovascular medications taken at study entry including beta-blocker, renin-angiotensin system blocker, nitrate and statin were also reviewed.
ICA
Coronary angiography and percutaneous coronary intervention were performed in accordiance with current guidelines11. After ICA with or without revascularization, all patients received the standard medical treatment at the discretion of the attending physician. Luminal narowwing more than 50% of the major epicardial coronary artery or main branches with diameter ≥ 2 mm was considered significant coronary artery stenosis. CAD extent was classified as 1-, 2- or 3-vessel diseasebased on the number of coronary arteris with significant stenosis. Left main stenosis more than 50% was considered as 2-vessel disease. Cardiac catheterization was performed by a single experienced interventional cardiologist.
Blood tests
Before the day of ICA, patients were overnight fast for at least 12 hours. After insertion of arterial sheath to radial or femoral arteries, 20 mL of arterial blood was drawn from the sheath in the supine position just before ICA. The drawn arterial blood was immediately centrifuged at 3,000 rpm for 15 minutes, and the separated serum was stored at -70◦C until used for analysis. Using a commercially available kit (The Presage® ST2 Assay, Critical Diagnostics, San Diego, CA, USA), the serum levels of sST2 were measured. The minimum detectable concentration of sST2 was 3.1–200.0 ng/ml. The intra-assay and inter-assay coefficients of variations for sST2 were 5.1% and 5.2%, respectively.
Clinical events
After index hospitalization, patients were followed-up every 3 month. Composite events, termed major adverse cardiac events (MACE), including cardiac death, non-fatal AMI, coronary revascularization (PCI [percutaneous coronary intervention] or coronary bypass surgery), and ischemic stroke were assessed. All outcome data was evaluated by an expert physician who was blinded to sST2 concentration. Cardiac death was defined as a death from ventricular arrhythmia, acute coronary syndrome, heart failure and sudden death. AMI was defined based on patient’s symptom, electrocardiographic changes and elevated cardiac enzyme. In order to exclude, test-driven procedure, PCI or coronary bypass surgery 90 days after ICA was considered as MACE. Ischemic stroke was defined as an episode of neurological dysfunction caused by focal cerebral infarction, which was demonstrated by brain imaging study.
Statistical analysis
Continuous variables are presented as mean ± standard deviation (SD), and categorical variables are expressed as counts and percentages. Continuous variables were compared using Student’s t-test, and categorical variables are compared using The Fischer exact test or the χ2 test between groups with and without MACE. Receiver operating characteristic (ROC) curve analysis was used to get a cut-off value of sST2 predicting MACE. MACE free survival curves according to sST2 levels were generated using Kaplan-Meier survival estimates, and the differences in survival rates were compared using the log-rank test. Multivariable Cox proportional hazard model was used to analyze the effect of sST2 and several potential confounders on MACE, and hazard ratio and 95% confidence interval were reported. Confounders adjusted in multivariable model include age, sex, BMI, hypertension, diabetes mellitus, smoking and CAD severity. A P value of < 0.05 (2-tailed) was considered statistically significant. All statistical analyses were conducted using SPSS version 18.0 (IBM Co., Armonk, NY, USA).