The aim of this study was to test the hypothesis that novel biomarkers may predict cardiac events in diabetic patients with stable coronary artery disease (CAD). Serum levels of highly sensitive troponin T (hs-TnT), B-type natriuretic peptide, highly sensitive C-reactive protein (hs-CRP), galectin-3, and soluble suppressor of tumorigenicity-2 (sST2) were analyzed in 1,137 patients with CAD and with type 2 diabetes, impaired glucose tolerance, or fasting glycaemia (diabetic group) and in 649 patients with normal glucose state. Cardiac death or hospitalization for congestive heart failure was the major end point during the follow-up of 2 years. Forty patients in the diabetic group (3.5%) and 9 patients in the nondiabetic group (1.4%) reached the primary end point. High hs-TnT level (≥14 ng/l) was the strongest predictor of the primary end point with hazard ratio of 24.5 (95% confidence interval 8.7 to 69.0; p <0.001) and remained so when adjusted for clinical variables, ejection fraction, renal, lipid, and glycemic status and other biomarkers (hazard ratio 9.9, 95% confidence interval 3.2 to 30.8; p <0.001). In the multivariate model, hs-CRP, B-type natriuretic peptide, and sST2 also predicted the primary end point in the diabetic group (p <0.01 for all). Only sST2 (p <0.001) and hs-CRP (p = 0.02) predicted the primary end point in nondiabetic group. The inclusion of hs-TnT in the model significantly improved discrimination (integrated discrimination improvement 0.050) and reclassification of the patients (net reclassification index 0.21). In conclusion, hs-TnT is a strong predictor of cardiac death or hospitalization for heart failure independently from traditional risk markers or other biomarkers in diabetic patients with stable CAD.
Several biomarkers have been shown to predict all-cause mortality or combination of major cardiovascular events in general population or in patients with acute coronary syndromes or congestive heart failure. Better prognostic tools are still needed to recognize the patients with stable coronary artery disease (CAD) with greater risk of cardiac death or congestive heart failure. Novel biomarkers of myocardial injury or stress have been introduced during the past years, such as highly sensitive troponin, which can detect very low levels of troponin T and troponin I, which cannot be seen using traditional assays. They have been shown to have some predictive value of death and incidence of congestive heart failure but controversial association with future myocardial infarcts. Biomarkers of inflammation, fibrosis, and increased myocardial stress such as highly sensitive C-reactive protein (hs-CRP) soluble suppressor of tumorigenicity-2 (sST2), galectin-3, and B-type natriuretic peptide (BNP) have also been associated with poorer outcome in cohort studies and especially in patients with heart failure. The objective of this study was to evaluate the prognostic value of these novel biomarkers in patients with stable CAD and abnormal glucose metabolism: type 2 diabetes (T2D), impaired glucose tolerance, or impaired fasting glycaemia, who have a worse outcome and more adverse cardiac events than the patients without diabetes.
Methods
The study population consisted of 1,243 patients with glucose metabolism disorder (diabetic group) and a matched (gender, age, history of myocardial infarction, treatment strategy) control group of 649 patients with normal glucose metabolism from the Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection (ARTEMIS) study database. ARTEMIS study is conducted in the Division of Cardiology of the Oulu University Hospital (Oulu, Finland) and has been registered at ClinicalTrials.gov (Identifier NCT01426685 ). The goal of ARTEMIS study was to study the prognostic value of several traditional and novel cardiovascular risk markers in patients with stable CAD. The end point of the main ARTEMIS study is sudden cardiac death during the 5-year follow-up. The patients were recruited from a consecutive series of patients who had undergone coronary angiography in the Division of Cardiology of the Oulu University Hospital (Oulu, Finland) from 3 to 6 months before inclusion in the assessment of their risk profile. Most patients had undergone also coronary intervention, either percutaneous coronary angioplasty or coronary artery bypass during or right after the index procedure. Almost half the patients had experienced an acute coronary event >3 months before the enrollment into the risk profile study. Patients with age <18 years or >85 years, New York Heart Association or Canadian Cardiovascular Society class IV, significant valvular disease, permanent pacemaker or permanent or planned implantable cardioverter defibrillator implantation, or end-stage renal failure needing dialysis; who had life expectancy <1 year; or who were psychologically or physically (due to any other illness) unfit for participation in the study were excluded from this study. The study was performed according to the Declaration of Helsinki, and the local committee of research ethics of the Northern Ostrobothnia Hospital District approved the protocol; all the subjects gave written informed consent.
All laboratory measurements were obtained after 12-hour overnight fast using standardized methods. Subjects without known diabetes were given a 75-g glucose load. Both 1-hour plasma and 2-hour capillary glucose were determined. T2D, impaired glucose tolerance, and impaired fasting glycaemia were verified according to current criteria of World Health Organization. Patients who had a fasting plasma glucose level ≥7.0 mmol/l (126 mg/ml) and/or a 2-hour postload capillary value in the oral glucose tolerance test ≥12.2 mmol/l (219.6 mg/ml) or were on antidiabetic medication based on previous diagnosis of diabetes were classified as having T2D. Patients who had fasting plasma glucose <7 mmol/l (126 mg/ml) and a 2-hour capillary value 8.9 to 12.1 mmol/l (160.2 to 217.8 mg/ml) were classified as having impaired glucose tolerance, and patients with fasting plasma glucose 6.1 to 6.9 mmol/l (109.8 to 124.2 mg/ml) and normal glucose tolerance were classified as having impaired fasting glycaemia. Blood samples and urine samples were obtained for the analysis of renal function (albumin–creatinine ratio), inflammation markers (hs-CRP), lipids, glycated hemoglobin (HbA1c), and cardiac markers (BNP and highly sensitive troponin T [hs-TnT]), and they were analyzed by hospital laboratory. The concentrations of BNP and hs-TnT were determined from plasma samples (ADVIA Centaur XP, Siemens Healthcare Diagnostics and MODULAR ANALYTICS, Roche Diagnostics, respectively). The concentrations of hs-CRP, galectin-3, and sST2 were determined from serum samples (BN Prospec System, Siemens Healthcare Diagnostics; Human ST2/IL-1 R4 Quantikine ELISA, R&D Systems Inc., Minneapolis, Minnesota; BG Medicine, Waltham, Massachusetts, respectively).
Two-dimensional and M-mode echocardiography were performed according to the American Society of Echocardiography guidelines. Left ventricular (LV) mass was calculated using the formula recommended by the American Society of Echocardiography (LV mass = 0.8 × [1.04 {(LVIDd + PWTd + SWTd) 3 – (LVIDd) 3 }] + 0.6 g). LV mass index was calculated by dividing LV mass with body surface area.
SYNTAX Score was calculated by 3 experienced interventional cardiologists using the Web-based calculator version 2.11 on SYNTAX Score Web site ( http://www.syntaxscore.com ).
The primary end point of this ARTEMIS substudy was defined as the composite of cardiac death and hospitalization for congestive heart failure during the 2-year follow-up. The secondary end point was hospitalization due to acute coronary syndrome. The follow-up information was collected from the patients by mailed questionnaire, telephone contact, and/or revisit at 2 years, after the enrollment into the study. The hospitalizations were collected and analyzed form the electronic patients records, and the cause of death was verified from the death certificates and autopsy reports, if available. One hundred five patients did not reach the 2-year follow-up period, experienced noncardiac death, or could not be contacted. Additionally, 1 patient was excluded because of missing hs-TnT value. Therefore, 1,137 patients were included in the analysis of T2D or prediabetic patients and 649 of the nondiabetic patients ( Table 1 ). None of the excluded patients met the primary endpoint.
| Variable | Glucose Metabolism Disorder | |||||||
|---|---|---|---|---|---|---|---|---|
| Yes | No | |||||||
| No event (n=1025) | Primary Endpoint (n=40) | Secondary Endpoint (n=72) | Main effect p-value | No event (n=591) | Primary Endpoint (n=9) | Secondary Endpoint (n=49) | Main effect p-value | |
| Age (years) | 67.6 ± 8.2 | 68.2 ± 7.4 | 67.6 ± 8.3 | 0.94 | 66.4 ± 8.7 | 68.1 ± 9.6 | 64.8 ± 9.3 | 0.37 |
| Men | 692 (68%) | 34 (85%) ∗ | 44 (61%) † | 0.031 | 414 (70%) | 8 (89%) | 30 (61%) | 0.20 |
| Body Mass Index (kg/m 2 ) | 29.2 ± 4.8 | 31.5 ± 6.7 ∗ | 28.8 ± 4.1 † | 0.022 | 26.6 ± 3.6 | 28.3 ± 3.1 | 27.2 ± 3.7 | 0.033 |
| Systolic Blood Pressure (mmHg) | 147 ± 23 | 140 ± 26 | 147 ± 23 | 0.15 | 146 ± 25 | 137 ± 14 | 144 ± 24 | 0.41 |
| Diastolic Blood Pressure (mmHg) | 78 ± 11 | 77 ± 11 | 78 ± 11 | 0.62 | 80 ± 11 | 79 ± 10 | 80 ± 11 | 0.90 |
| Smokers | 85 (8%) | 4 (10%) | 6 (8%) | 0.93 | 53 (9%) | 3 (33%) ∗ | 5 (10%) | 0.045 |
| Prior Acute Myocardial Infarction | 464 (45%) | 23 (58%) | 39 (54%) | 0.12 | 259 (44%) | 6 (67%) | 25 (51%) | 0.26 |
| Prior PCI/CABG | 800 (79%) | 34 (85%) | 64 (89%) | 0.073 | 466 (79%) | 8 (89%) | 42 (86%) | 0.41 |
| Canadian Cardiovascular Society grading of angina pectoris | <0.001 | <0.001 | ||||||
| 1 | 542 (54%) | 10 (25%) | 33 (48%) | 394 (68%) | 4 (45%) | 26 (53%) | ||
| 2 | 376 (37%) | 17 (44%) | 27 (39%) | 170 (29%) | 3 (33%) | 19 (39%) | ||
| 3 | 90 (9%) | 12 (31%) | 9 (13%) | 18 (3%) | 2 (22%) | 4 (8%) | ||
| Syntax score | 4.5 ± 7.4 | 4.8 ± 6.1 | 7.7 ± 13.4 | 0.78 | 3.4 ± 6.1 | 5.7 ± 7.3 | 4.5 ± 5.0 | 0.037 |
| Type of Glucose Metabolism Disorder | 0.015 | – | ||||||
| Impaired Glucose Tolerance | 266 (26%) | 5 (13%) | 10 (14%) | – | – | – | ||
| Impaired Fasting Glucose | 89 (9%) | 1 (2%) | 3 (7%) | – | – | – | ||
| Diabetes Mellitus | 670 (65%) | 34 (85%) | 57 (79%) | – | – | – | ||
| Duration of Diabetes (months) | 98 ± 101 | 141 ± 118 | 122 ± 103 | 0.026 | – | – | – | |
| Medication (n) | ||||||||
| β-blocker | 921 (90%) | 37 (93%) | 72 (93%) | 0.61 | 493 (83%) | 8 (89%) | 44 (90%) | 0.47 |
| Angiotensin Converting Enzyme Inhibitor / Angiotensin II Receptor Blocker | 702 (69%) | 27 (68%) | 55 (76%) | 0.37 | 337 (57%) | 9 (100%) ∗ | 27 (55%) † | 0.033 |
| Calcium Channel Blocker | 291 (28%) | 9 (23%) | 22 (31%) | 0.65 | 100 (17%) | 2 (22%) | 9 (18%) | 0.89 |
| Diuretics | 420 (41%) | 29 (73%) ∗ | 32 (44%) † | <0.001 | 132 (22%) | 4 (44%) | 9 (18%) | 0.23 |
| Lipid Lowering Medication | 941 (92%) | 34 (85%) | 65 (90%) | 0.28 | 534 (90%) | 9 (100%) | 47 (96%) | 0.27 |
| Echogardiography | ||||||||
| Left Ventricle Ejection Fraction (%) | 64 ± 10 | 56 ± 19 ∗ | 64 ± 10 † | 0.010 | 65 ± 8 | 59 ± 17 | 63 ± 9 | 0.23 |
| Left Ventricle End Diastolic Dimension (mm) | 50 ± 6 | 54 ± 11 ∗ | 49 ± 6 † | 0.016 | 50 ± 6 | 53 ± 10 | 51 ± 6 | 0.51 |
| Left Ventricle Mass Index (g/m2) | 107 ± 28 | 121 ± 42 | 107 ± 24 | 0.10 | 105 ± 25 | 133 ± 32 ∗ | 104 ± 22 † | 0.019 |
| Laboratory analyses | ||||||||
| Glycosylated Hemoglobin, Type A1C (HbA 1c) (%) | 6.6 ± 1.1 | 7.9 ± 2.3 ∗ | 6.7 ± 1.2 † | <0.001 | 5.8 ± 0.4 | 6.0 ± 0.4 | 5.9 ± 0.4 | 0.19 |
| (mmol/mol) | 49 ± 12 | 63 ± 25.1 | 50 ± 13.1 | 40 ± 4.4 | 42 ± 4.4 | 41 ± 4.4 | ||
| Total cholesterol (mmol/L) | 3.9 ± 0.9 | 4.0 ± 1.0 | 3.9 ± 0.7 | 0.99 | 4.1 ± 0.8 | 3.7 ± 0.8 | 4.2 ± 0.9 | 0.26 |
| (mg/dL) | 152 ± 34 | 154 ± 39 | 152 ± 29 | 157 ± 33 | 145 ± 30 | 161 ± 36 | ||
| HDL cholesterol (mmol/L) | 1.2 ± 0.3 | 1.1 ± 0.4 | 1.2 ± 0.2 | 0.021 | 1.4 ± 0.3 | 1.2 ± 0.3 | 1.3 ± 0.4 | 0.31 |
| (mg/dL) | 48 ± 12 | 44 ± 16 | 46 ± 9 | 52 ± 13 | 46 ± 12 | 51 ± 14 | ||
| LDL cholesterol (mmol/L) | 2.3 ± 0.7 | 2.2 ± 0.7 | 2.3 ± 0.7 | 0.74 | 2.3 ± 0.8 | 2.2 ± 0.8 | 2.5 ± 0.9 | 0.53 |
| (mg/dL) | 87 ± 29 | 86 ± 29 | 88 ± 25 | 90 ± 30 | 84 ± 29 | 96 ± 36 | ||
| Triglycerides (mmol/L) | 1.5 ± 0.8 | 1.9 ± 1.6 | 1.6 ± 0.8 | 0.18 | 1.2 ± 0.6 | 1.2 ± 0.7 | 1.3 ± 0.5 ∗ | 0.035 |
| (mg/dL) | 131 ± 68 | 167 ± 143 | 138 ± 71 | 104 ± 50 | 107 ± 58 | 119 ± 49 | ||
| Highly Sensitive C-reactive Protein (mg/L) | 2.3 ± 4.2 | 8.1 ± 13.0 ∗ | 3.4 ± 11.5 † | <0.001 | 1.5 ± 3.0 | 3.9 ± 6.6 | 2.1 ± 4.1 | 0.29 |
| Highly Sensitive Troponin T (ng/L) | 11.6 ± 9.0 | 31.4 ± 22.4 ∗ | 10.7 ± 6.1 † | <0.001 | 9.5 ± 7.9 | 14.8 ± 6.9 ∗ | 11.2 ± 7.3 | 0.009 |
| B-type Natriuretic Peptide (ng/L) | 73 ± 82 | 214 ± 254 ∗ | 74 ± 64 † | <0.001 | 69 ± 70 | 336 ± 438 ∗ | 76 ± 85 | 0.039 |
| Soluble Suppressor of Tumorigenity 2 Protein (ng/mL) | 19.7 ± 8.7 | 30.5 ± 16.7 ∗ | 19.6 ± 4.9 † | <0.001 | 15.3 ± 6.0 | 29.1 ± 19.0 ∗ | 15.9 ± 6.7 † | 0.003 |
| Galectin-3 (ng/mL) | 12.6 ± 6.4 | 17.0 ± 8.4 ∗ | 12.5 ± 4.9 † | <0.001 | 12.1 ± 6.7 | 14.0 ± 5.3 | 11.8 ± 2.8 | 0.208 |
| Creatinine Clearance (mL/min) | 96 ± 38 | 93 ± 36 | 93 ± 31 | 0.79 | 87 ± 26 | 88 ± 28 | 93 ± 29 | 0.39 |
| U-Alb/Crea | 2.3 ± 10.3 | 4.8 ± 7.8 ∗ | 2.9 ± 10.4 † | 0.001 | 1.1 ± 1.3 | 8.7 ± 16.9 | 1.4 ± 3.0 | 0.16 |
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
