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SUPPLEMENTAL MATERIAL Supplemental Methods CDCS protocol This study (The Acute Coronary Syndrome, ACS) is registered with the Australian and New Zealand Clinical Trials Registry, ID ACTRN 12605000431628. Briefly, inclusion criteria at index admission were: ischaemic discomfort plus one or more of ECG changes (ST segment depression or elevation of at least 0.5mm, T-wave inversion of at least 3mm in at least 3 leads, or left bundle branch block), elevated levels of cardiac markers, a history of coronary disease, or age of at least 65 years in patients with diabetes or vascular disease. Patients were excluded in the presence of any severe co-morbidity limiting life expectancy to less than 3 years. Since numbers of suitable cases presenting each week exceeded the capacity to process, cases were randomly selected weekly from a list of eligible candidates, prior to obtaining informed consent. The overall aim of the CDCS was to assess candidate predictive markers in the subacute to chronic phase of CAD. CDCS intentionally recruited a “real life” post-ACS population with a broad spectrum of age, both genders and significant numbers of subjects in the three distinct sub-groups (NSTEMI, STEMI and UA) determined at the time of discharge As such, the CDCS represents the burden of expected important antecedent risk factors and disease processes such as previous myocardial infarction, heart failure, hypertension, diabetes and vascular disease (1-3). Establishing outcomes: All events (hospital admissions and mortality) were documented by scrutinising data obtained from i) outpatient attendance or phone calls with subjects, family member or primary care physician; ii) Hospital Patient Management System (PMS); iii) National Health Information Service records (case note examination) and iv) standardised questionnaires mailed to participants at year 2 and year 3 post index discharge. Echocardiography. Standard M-mode measurements of LV dimensions and wall thickness and LA dimensions were made according to the recommendations of the American Society of Echocardiography. LV volume was measured by the Simpson modified biplane method and LA area and volume were estimated by the biplane area-length method. LVEDV and LVESV were indexed to BSA to derive the indexed volumes (LVEDVi and LVESVi) and LV ejection fraction (LVEF). Mitral pulsed-wave Doppler velocities of early passive (E) and atrial (A) filling were obtained from the apical 4-chamber view with a 5-mm sample volume placed between the tips of the mitral leaflets. Tissue Doppler measurements of early diastolic myocardial relaxation (e′) was recorded from the lateral mitral annulus in the apical 4-chamber view with a 5-mm sample volume and with filters set to exclude high frequency signals and with gain minimized. Natriuretic Peptide assays. Samples were stored frozen at minus 80 C and assayed within 6 months of receipt. Circulating CNP (4), NT-proCNP (4), BNP (5), NT-proBNP (6), ANP and NT-proANP (7) were assayed as previously described. Intra- and inter assay coefficients of variations were as follows:- CNP (5.0% and 8.5% at 8.1 pmol/L); NTproCNP (6.6% and 8.1% at 45 pmol/L); 1 BNP (7.9% and 15.2% at 26 pmol/L); NT-proBNP (4.9% and 5.9% at 83 pmol/L); ANP (4.5% and 5.7% at 25.5 pmol/L); NT-proANP (6.4% and 8.8% at 440 pmol/L). Reference Intervals for Natriuretic Peptides Normal reference values ( 95% confidence interval for adults (age 40-80yr) are:- CNP 0.4 – 1.0 pmol/L; NT proCNP 11 – 28 pmol/L; BNP 3 – 12 pmol/L; NTproBNP 2 – 50 pmol/L; ANP 4 – 27 pmol/L; NTproANP 0.13 – 0.91 nmol/L. All NP measurements were performed in the same laboratory (Endolab, Christchurch, New Zealand). To convert NP concentrations to pg/ml, multiply pmol/L values by 2.20 (CNP), 4.98 (NT-proCNP), 3.46 (BNP), 8.47 (NTproBNP), 3.08 (ANP), 10.6 (NT-proANP). Supplemental Figure 1 LVEF <40% NT-proCNP Tertiles LVEF >40% NT-proCNP Tertiles 100 80 80 60 60 Cumulative Survival (%) 100 40 40 Low Middle High 20 20 0 0 0 2 4 6 8 0 LVEF <40% NT-proBNP Tertiles 100 80 80 60 60 40 40 20 20 Cumulative Survival (%) 4 6 8 LVEF >40% NT-proBNP Tertiles 100 0 2 0 0 2 4 6 8 0 2 Years 4 6 8 Years Tertile Numbers at risk NT-proCNP (pmol/L) <16.5 16.5 - 21.9 >21.9 38 50 114 34 45 80 23 35 52 16 18 21 4 7 9 608 585 506 589 562 458 435 430 323 205 227 162 62 70 69 NT-proBNP (pmol/L) <49 49 -126 >126 9 34 164 9 34 121 6 25 84 5 12 40 2 4 14 636 613 482 627 596 418 476 451 282 267 233 106 84 86 34 Figure 1. Kaplan-Meier curves as tertiles of NT-proCNP, NT-proBNP at baseline for allcause mortality across all subjects stratified by LVEF. 2 Supplemental Tables Table 1. Summary of data collection in subjects with ACS Baseline 5-56 days after onset of ACS 3-5 months 12-14 months X X 24-26 months 36-38 months Check eligibility/exclusion criteria X Obtain informed consent X Physical exam * X Medical history Family medical history Admission details † X X X Medications on admission X Medications at discharge X Current medications X X X X X Adverse Events X X X X X ECG X X X Echocardiograph X X X Neurohormonal blood samples ‡ X X X DNA blood sample X Questionnaire X X X NYHA, CCS Scores X X X X X * i.e, height, weight, girth, BP, pulse. † Killip score, TIMI Risk Scores for STEMI and UA/NSTEMI, All ECGs CXR reports, Angio reports, thrombolysis details, MUGA Scan report, serial biochemistry, haematology, lipids, cardiac enzymes reports. ‡ NTproBNP, BNP, ANP, NTproANP, CNP and NTproCNP. 3 Table 2. Spearman correlation coefficients showing the associations between clinical variables and baseline concentrations of C-type Natriuretic Peptides. Variable CNP NT-proCNP r r Age (n=2083) 0.31 † BMI (n=2055) -0.13 * 0.00 Waist hip ratio (males, n=1471) -0.03 0.07 * Waist hip ratio (females, n=575) 0.07 0.07 Height (males, n=1483) -0.18 † -0.15 † Height (females, n=576) -0.15 † -0.18 † 0.03 -0.02 -0.13 † -0.09 † Systolic BP (n=2040) Diastolic BP (n =2040) 0.23 † * P<0.01, † P<0.001 4 Table 3. Median plasma CNP and NT-proCNP (interquartile range) at baseline according to gender, comorbidity and drug use&. CNP (pmol/L) Variable Male Sex (n=1496) NT-proCNP (pmol/L) Presence Absence Presence Absence 0.54 (0.34 – 0.84) † 0.61 (39 – 0.93) 19.5 (16.1 – 24.9) * 17.2 (14.3 – 22.3) ‡ 18.7 (15.5 – 23.6) Diabetes (n=341) 0.61 (0.38 – 0.95) * 0.55 (0.35 – 0.85) 20.6 (15.8 – 28.0) HT (n=1074) 0.60 (0.38 – 0.91) ‡ 0.52 (0.33 – 0.80) 19.5 (15.8 -26.3) ‡ † 18.3 (15.2 – 18.3) H-Cholesterol (n=1108) 0.55 (0.35 – 0.85) 0.56 (0.36 – 0.88) 19.1 (15.7 – 25.2) PVD (n=185) 0.70 (0.48-1.04) ‡ 0.55 (0.35-0.85) 23.8 (17.3-33.5) ‡ Statin use (n=949) 0.55 (0.35 – 0.85) 0.57 (0.35 – 0.87) 18.7 (15.5 – 24.2) ‡ 19.1 (15.6 – 24.5) † 18.8 (15.5 – 24.1) Steroid use (n=218) 0.61 (0.37 – 0.92) 0.55 (0.35-0.86 19.4 (15.5 – 28.1) 18.5 (15.2 – 23.2) 18.6 (15.4-23.5) Variable states were compared using 2-way ANOVA with gender as a fixed factor. Abbreviations: HT, hypertension; H-cholesterol, hypercholesterolemia; PVD, peripheral vascular disease. & To convert NP concentrations to pg/ml, multiply pmol/L values by 2.20 (CNP), 4.98 (NT-proCNP). * P<0.05, † P<0.01, ‡ P<0.001 5 Table 4. Multivariate regression analysis – baseline data. Standardized Coefficients (Beta) t Significance (P) Age 0.19 7. 8 0.000 Height -0.05 -2.2 0.028 BMI -0.04 -1.9 0.054 E/e’ 0.23 10.1 0.000 Systolic blood pressure -0.06 -2.8 0.006 Creatinine 0.17 7.6 0.000 Gender 0.11 4.4 0.000 Age 0.12 6.2 0.000 Height -0.07 -2.9 0.004 BMI 0.04 2.1 0.038 Waist Hip ratio 0.04 1.8 0.079 E/e’ 0.08 4.2 0.000 Systolic blood pressure -0.05 -2.6 0.009 Creatinine 0.65 38.6 0.000 Model Dependent Variable: Log10 CNP Dependent Variable: Log10 NT-proCNP 6 Table 5. Temporal changes in Natriuretic Peptides. Values are medians (IQR)&. Baseline 4 Month visit 12 Month visit (n=1075) (n=1014) (n=954) ANP (pmol/L) 35.9 (22.7-56.8) 34.7 (22.2-54.3) 34.6 (21.7-53.4) 0.000 NT-proANP (nmol/L) 1.06 (0.68-1.82) 1.02 (0.64-1.70) 0.97 (0.64-1.63) 0.001 BNP (pmol/L) 16.6 (8.9-32.7) 13.4 (7.2-25.5) 12.1 (6.9-22.9) 0.000 NT-proBNP (pmol/L) 79.1 (35.9-172) 59.9 (26.0-142) 54.3 (24.9-125) 0.000 CNP (pmol/L) 0.53 (0.34-0.88) 0.49 (0.30-0.78) 0.47 (0.28-0.73) 0.000 NT-proCNP (pmol/L) 19.0 (15.5-25.4) 18.6 (15.5-24.8) 18.4 (15.3-24.0) 0.022 (n=479) (n=458) (n=447) ANP (pmol/L) 33.9 (22.5-53.1) 30.8 (19.8-48.0) 29.7 (18.6-46.7) 0.000 NT-proANP (nmol/L) 0.95 (0.62-1.52) 0.86 (0.57-1.44) 0.82 (0.52-1.33) 0.000 BNP (pmol/L) 20.4 (11.3-34.3) 12.0 (7.0-20.9) 10.3 (6.2-18.3) 0.000 NT-proBNP (pmol/L) 95.9 (49.7-170) 56.3 (26.2-118) 43.8 (21.4-97.9) 0.000 CNP (pmol/L) 0.62 (0.42-0.90) 0.50 (0.33-0.74) 0.47 (0.30-0.66) 0.000 NT-proCNP (pmol/L) 18.6 (15.5-22.9) 18.8 (15.6-23.4) 18.0 (15.2-23.1) 0.41 Unstable Angina (n=562) (n=522) (n=502) ANP (pmol/L) 33.8 (21.4-52.6) 33.9 (21.9-49.2) 36.0 (22.8-55.0) 0.018 NT-proANP (nmol/L) 1.03 (0.66-1.63) 1.04 (0.63-1.54) 1.04 (0.64-1.72) 0.026 BNP (pmol/L) 13.4 (7.5-24.3) 12.4 (7.0-21.2) 12.8 (7.2-21.9) 0.10 NT-proBNP (pmol/L) 63.7 (27.4-124) 59.6 (23.9-107) 55.8 (27.0-121) 0.008 CNP (pmol/L) 0.53 (0.32-0.80) 0.48 (0.32-0.73) 0.50 (0.31-0.75) 0.42 NT-proCNP (pmol/L) 19.0 (15.5-25.4) 18.6 (15.5-24.8) 18.4 (15.3-24.0) 0.51 NSTEMI STEMI P* * Analysis of the effect of time on NP by RM-ANOVA & To convert NP concentrations to pg/ml, multiply pmol/L values by 2.20 (CNP), 4.98 (NT-proCNP), 3.46 (BNP), 8.47 (NT-proBNP), 3.08 (ANP), 10.6 (NT-proANP). 7 Table 6. Spearman Correlation coefficients of cardiac and renal function indices with Natriuretic Peptides. ANP NT-proANP BNP NT-proBNP CNP NT-proCNP Baseline LA Area (n=1967) LVESVol (n=1578) E/e’ (n=2005) LVEF (n=1938) Creatinine (n=2053) 0.33 † 0.21 † 0.40 † -0.31 † 0.23 † 0.37 † 0.18 † 0.44 † -0.30 † 0.37 † 0.37 † 0.27 † 0.43 † -0.41 † 0.23 † 0.38 † 0.28 † 0.47 † -0.41 † 0.29 † 0.30 † 0.21 † 0.37 † -0.33 † 0.23 † 0.14 † 0.12 † 0.19 † -0.19 † 0.63 † 4 Month visit LA Area (n=1839) LVESVol (n=1505) E/e’ (n=2005) LVEF (n=1901) Creatinine (n=1952) 0.37 † 0.22 † 0.37 † -0.28 † 0.27 † 0.38 † 0.17 † 0.40 † -0.26 † -0.40 † 0.39 † 0.23 † 0.41 † -0.31 † 0.25 † 0.40 † 0.23 † 0.44 † -0.32 † 0.30 † 0.35 † 0.14 † 0.36 † -0.26 † -0.21 † 0.12 † 0.12 † 0.16 † -0.19 † 0.63 † 12 Month visit LA Area (n=1760) LVESVol (n=1433) E/e’ (n=1827) LVEF (n=1732) Creatinine (n=1857) 0.33 † 0.20 † 0.37 † -0.25 † 0.23 † 0.34 † 0.18 † 0.42 † -0.25 † 0.37 † 0.38 † 0.23 † 0.41 † -0.30 † 0.23 † 0.37 † 0.23 † 0.45 † -0.32 † 0.29 † 0.32 † 0.17 † 0.38 † -0.29 † 0.23 † 0.15 † 0.11 † 0.18 † -0.18 † 0.61 † † P<0.001 8 Table 7. Univariate hazard ratios, HR, (95% confidence intervals, CI) at baseline across brackets of E/e’ (<8, 8-15, >15) and across tertiles of creatinine, eGFR and natriuretic peptides for all-cause mortality over median 4 years follow up. HR (CI) E/e’ 3.22 (2.72 – 3.80) * Creatinine 1.78 (1.58 – 2.02) * eGFR 0.43 (0.38-0.49) * CNP 2.04 (1.80 – 2.32) * NT-proCNP 1.94 (1.71 – 2.20) * BNP 2.63 (2.30 – 3.02) * NT-proBNP 2.98 (2.58 – 3.43) * ANP 2.46 (2.16 – 2.81) * NT-proANP 3.31 (2.86 – 3.84) * * P <0.001 Table 8. Changes in aortic plasma CNP peptides after percutaneous coronary intervention (PCI) In 51 subjects with STEMI undergoing percutaneous intervention (8) paired aortic plasma samples were drawn just prior to and immediately after the successful PCI and measured for CNP and NTproCNP concentrations. Values (pmol/L) are mean (SE)&. CNP NTproCNP PRE POST Delta % CHANGE 1.14 (0.08) 23.7 (1.5) 1.27 (0.07) 31.3 ( 1.1) 15.8 (3.8)% * 46.8 (7.5)% * * P <0.001 & To convert NP concentrations to pg/ml, multiply pmol/L values by 2.20 (CNP), 4.98 (NT-proCNP). 9 Supplemental References 1. Palmer BR, Jarvis MD, Pilbrow AP, Ellis KL, Frampton CM, Skelton L, Yandle TG, Doughty RN, Whalley GA, Ellis CJ, Troughton RW, Richards AM, Cameron VA. Angiotensin-converting enzyme 2 A1075G polymorphism is associated with survival in an acute coronary syndromes cohort. Am Heart J 2008;156(4):752-8. 2. Palmer BR, Frampton CM, Skelton L, Yandle TG, Doughty RN, Whalley GA, Ellis CJ, Troughton RW, Richards AM, Cameron VA. KCNE5 polymorphism rs697829 is associated with QT interval and survival in acute coronary syndromes patients. Journal of cardiovascular electrophysiology 2012;23(3):319-24. 3. Earle NJ, Poppe KK, Pilbrow AP, Cameron VA, Troughton RW, Skinner JR, Love DR, Shelling AN, Whalley GA, Ellis CJ, Richards AM, Doughty RN. Genetic markers of repolarization and arrhythmic events after acute coronary syndromes. Am Heart J 2015;169(4):579-86 e3. 4. Olney RC, Permuy JW, Prickett TC, Han JC, Espiner EA. Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children. Clin Endocrinol (Oxf) 2012;77:416-422. 5. Palmer SC, Prickett TC, Espiner EA, Yandle TG, Richards AM. Regional Release and Clearance of C-Type Natriuretic Peptides in the Human Circulation and Relation to Cardiac Function. Hypertension 2009;54:612-618. 6. Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner EA. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clinical Endocrinology 1997;47(3):287-296. 7. Yandle TG, Espiner EA, Nicholls MG, Duff H. Radioimmunoassay and characterization of atrial natriuretic peptide in human plasma. Journal of Clinical Endocrinology & Metabolism 1986;63(1):72-9. 8. Marshall CJ, Nallaratnam M, Mocatta T, Smyth D, Richards M, Elliott JM, Blake J, Winterbourn CC, Kettle AJ, McClean DR. Factors influencing local and systemic levels of plasma myeloperoxidase in ST-segment elevation acute myocardial infarction. Am J Cardiol. 2010;106:316-22. 10