Original article
Plasma cortisol and prognosis of patients with acute myocardial infarction Sandeep K. Jutlaa,b,, Matthew F. Yuyuna,b,, Paulene A. Quinna,b and Leong L. Nga,b Aims Cortisol is associated with increased cardiovascular morbidity and mortality in patients with chronic heart failure and in the general population. The negative predictive effect of cortisol on survival in non-diabetic patients who have suffered an acute myocardial infarction (AMI) has been shown. We aimed to determine the prognostic significance of cortisol in a general group of AMI patients, as this is not well known. Methods Plasma cortisol levels were measured in 955 consecutive patients admitted with AMI. We prospectively evaluated the relationship between cortisol and major adverse cardiovascular event (MACE), which was a composite of all-cause mortality, and combination all-cause mortality and re-hospitalization for heart failure, in post-AMI patients. Results During the 2-year follow-up, MACE occurred in 261 patients (27.3%). Patients with MACE had significantly higher median levels of cortisol than those without (609.4 versus 549.4 pmol/ml, P U 0.0073). Log cortisol was independently predictive of MACE after adjusting for covariates with hazard ratio (95% confidence interval) of 1.55 (1.05–2.27), P U 0.027. Patients in the highest quartile of cortisol had significantly more risk of MACE compared
Introduction Hormones acting on the mineralocorticoid receptor have been associated with increased cardiovascular disease (CVD) morbidity and mortality.1–4 Mineralocorticoid receptor blockade has been shown to significantly reduce negative CVD outcomes as part of a multiple biomarker strategy in two landmark trials.5,6 Cortisol is the final hormone product of the hypothalamic–pituitary–adrenal (HPA) axis, acting as ligand for intracellular glucocorticoid receptors found in almost all cells, as well as acting on mineralocorticoid receptors found on sodium transporting epithelia of the kidney nephrons, salivary glands, colon, sweat glands, vascular endothelium2,3 and nonepithelial tissues including vascular smooth muscle, myocardium and the brain.2,7–10 Mineralocorticoid receptors have equal affinity for cortisol and aldosterone.1,2,11 Cortisol levels measured in blood, urine or hair are associated with increased CVD risk factors,12,13 1558-2027 ß 2014 Italian Federation of Cardiology
with those in the lowest quartile, with an adjusted hazard ratio (95% confidence interval) of 1.91(1.16–3.15), P U 0.0120. Kaplan–Meier survival estimates for MACE were lower in patients with plasma cortisol levels in the highest quartile compared with those in the first three quartiles (Log rank test x2 for survival U 10.41, P U 0.0013). Conclusion This study has shown the prognostic significance of cortisol in 955 post-AMI patients from a single centre. J Cardiovasc Med 2014, 15:33–41 Keywords: cortisol, heart failure, mineralocorticoid receptor, mortality, myocardial infarction a Department of Cardiovascular Sciences, University of Leicester and bNIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
Correspondence to Professor Leong L. Ng, MBBChir, MD, FRCP, Department of Cardiovascular Sciences, NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK Tel: +44 116 250 2449; fax: +44 116 2523108; e-mail: [email protected]
Sandeep K. Jutla and Matthew F. Yuyun contributed equally to the writing of the article. Received 28 November 2012 Revised 4 March 2013 Accepted 20 April 2013
atherosclerosis,14–18 CVD mortality and all-cause mortality in the general population.19–22 Studies have correlated cortisol levels with an increase in myocardial infarct size,23,24 ventricular remodelling post-acute myocardial infarction (AMI)25 and increased mortality in chronic heart failure patients.26,27 Cortisol is also significantly raised in acute coronary syndromes,28–32 and correlates with the development of left ventricular failure, arrhythmias, shock and in-hospital mortality postAMI.33–35 The majority of smaller cross-sectional studies have shown increased morbidity and mortality risks with raised cortisol levels in patients with AMI,33–35 although others have found no association,36 and some have even found inverse associations.37 Apart from one study which showed a significantly negative effect of serum cortisol level on 5.5-year event-free survival in 231 non-diabetic patients who had suffered an AMI,38 no other long-term study has evaluated the prognostic significance of cortisol in post-AMI patients. Therefore, the overall aim of our DOI:10.2459/JCM.0b013e328364100b
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
34 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
study was to prospectively evaluate the prognostic significance of plasma cortisol in a larger cohort of 955 post-AMI patients in relation to major adverse cardiovascular events (MACEs), all-cause mortality and a combination of all-cause mortality and hospitalization for heart failure.
Materials and methods Study design and study population
In this prospective cohort study, 955 consecutive patients with AMI admitted to the University Hospitals of Leicester NHS Trust between 2003 and 2008 were recruited. Written informed consent was obtained from patients, and the study complied with the Declaration of Helsinki and was approved by the local ethics committee. AMI was diagnosed if a patient had a plasma cardiac troponin I level more than 0.1 ng/ml (Advia Centaur Troponin-I assay; Siemens, Erlangen, Germany) with at least one of the following: chest pain lasting more than 20 min or diagnostic serial ECG changes consisting of new pathological Q waves or ST segment and T wave changes. Exclusion criteria included malignancy or surgery in the previous month. Hypertension was defined as a blood pressure measurement of greater than 140/90 mmHg on two or more occasions or if the patient was on medication for hypertension. Hypercholesterolaemia was defined as total cholesterol of greater than 5.0 mmol/l, or treatment with a statin. Diabetes was defined as random plasma glucose of 11.1 mmol/l, fasting plasma glucose of 7 mmol/l, or a history of diabetes on treatment. Past medical history of ischaemic heart disease (angina or myocardial infarction), heart failure and smoking history (current or ex-smoking) were obtained directly from patients or from their medical records. Data on demographics, clinical including treatment, laboratory and echocardiography were obtained. The estimated glomerular filtration rate (eGFR) was calculated from the simplified formula derived from the Modification of Diet in Renal Disease study.39 All patients received standard secondary prevention therapy for ischaemic heart disease, and revascularization was at the discretion of the attending physician. Blood sampling
Blood samples were drawn during admission with AMI. Blood was taken from patients 15 min after bed rest. Ten millilitres of venous blood was taken from the antecubital vein into tubes containing EDTA (1 ml/10 ml blood) and aprotinin (500 international units/ml blood). The blood samples were centrifuged at 3000 rpm at 48C for 15 min. The plasma was aspirated and stored at 808C until assayed.
shaker for 2 h and then spun down using a centrifuge at 2000 rpm. Then, 0.1 ml of the dichloromethane layer was taken for cortisol extraction and dried down in a speed vacuum centrifuge. Cortisol immunoassay
Cortisol was measured using a competitive immunoluminometric assay. Each well of the microlite-2 plate was coated with 100 ml (50 ng per well) of antimouse IgG antibody (Sigma, Gillingham, Dorset, UK) and left overnight at room temperature. Plates were washed following which 200 ml of bovine serum albumin (BSA) was pipetted into each well of the plate and left for 2 h at room temperature. The plasma cortisol extracts were re-constituted in 285 ml immunoluminometric assay buffer (ILMA) and immersed in an ultrasonic bath for 15 min. Then, 50 ml of mouse monoclonal cortisol antibody (10 ng; Abcam, Cambridge, UK) was pipetted accurately into each well of the plate, followed by 100 ml of standards or sample; each sample was done in duplicate format. After this, 50 ml of cortisol-biotin tracer was pipetted into each well. The plates were left for incubation overnight at 48C, then washed to remove any unbound cortisol tracer and 100 ml of MAE (methylacridinium ester)-labelled streptavidin was pipetted accurately into each well and the plates were left in the dark at room temperature to incubate for 90 min. A standard curve was constructed using Rodbard’s quadratic equation (Biosoft, Cambridge, UK). The luminometer readings were plotted on the y-axis relative light units (RLUs) against cortisol concentration (pmol/ml) on the x-axis. The patient’s plasma cortisol concentration was calculated by interpolation of the standard curve. The RLU values for the samples were plotted on the standard curve and the corresponding concentration in pmol/ml was efficiently calculated. The reproducibility of the assay was assessed by calculating the coefficient of variation, which was 3.6%. N-terminal pro-B type natriuretic peptide assay
Plasma N-terminal pro-B type natriuretic peptide (NTproBNP) assay was measured using a non-competitive immunoluminometric assay as previously published.40 Samples or NT-proBNP standards (10 ml) were incubated in ELISA plate wells coated with mouse monoclonal IgG directed to the C-terminal end of NT-proBNP. Detection was with biotinylated rabbit N-terminal antibody followed by MAE-streptavidin on an MLX plate luminometer (Dynex Technologies, Worthing, West Sussex, UK). The lower limit of detection was 0.3 pmol/l. This highly specific assay shows no cross-reactivity with ANP (atrial natriuretic peptide), brain natriuretic peptide (BNP) or CNP (C-type natriuretic peptide).
Steroid extraction
Plasma samples were defrosted at room temperature. One hundred microlitres of patient plasma was mixed with 1 ml dichloromethane. The mixture was left on a
Endpoints
Patients were reviewed 24 months after their initial admission with AMI, giving a censoring time of 730 days.
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
Plasma cortisol and acute myocardial infarction Jutla et al. 35
The primary endpoint was MACE, which was a composite of all-cause mortality, myocardial re-infarction and re-hospitalization for heart failure. There were two secondary endpoints: all-cause mortality and a combination of all-cause mortality and hospitalization for heart failure. Deaths were validated by reviewing the hospital record management systems and the Office of National Statistics Registry. Hospitalization for heart failure was defined as a hospital admission for which heart failure was the primary reason, requiring treatment with high-dose diuretics, inotropes or intravenous nitrate with echocardiographic evidence of heart failure. New myocardial infarction and heart failure endpoints were ascertained using computerized hospital patients’ records for University Hospitals of Leicester and validated by contacting each patient. Patients were contacted about re-hospitalizations that occurred at hospitals other than the University Hospitals of Leicester.
mortality and combination of all-cause mortality and rehospitalization for heart failure rate across ordered quartiles of plasma cortisol. Curves of Kaplan–Meier survival estimates were obtained and the Log rank test was used to compare survival rates between patients whose cortisol levels were above the median value and those below the median. Univariate and multivariate hazard ratios for the predictive impact of baseline serum cortisol on MACE, death and combination of death and heart failure were estimated by the Cox proportional hazard model. Because cortisol distribution was skewed to the right, levels were log-transformed to base 10 before the Cox regression analyses were carried out. The likelihood ratio x2 test was used to test for statistical significance of each variable in the Cox regression model.
Results Baseline characteristics
Table 1 shows baseline characteristics of the study participants in the total study population and stratified by MACE outcomes. Post-AMI patients who developed MACE were significantly older, and had significantly greater median levels of baseline serum cortisol. They were more likely to be women when compared with men, had more prevalence of classical risk factors of coronary artery disease (CAD) and were more likely to have experienced previous myocardial infarction or angina. Patients who subsequently registered a MACE also had lower glomerular filtration rates, significantly higher levels of N-terminal pro-B type natriuretic peptide, had higher rates of clinical evidence of heart failure postmyocardial necrosis as demonstrated by a Killip class of greater than 1 and were more likely to have been prescribed a diuretic for their heart failure. Patients who
Statistical analyses
Statistical analyses were done using STATA 11. The twosample t-test was used to test for any statistically significant difference between the means of normally distributed continuous variables across the binary outcomes (presence or absence of MACE, death and combination of death and heart failure). The median and interquartile range were used for plasma cortisol levels because their distribution was positively skewed and for other skewed variables. The two-sample Wilcoxon rank-sum test was used to test for any significant difference in the medians of continuous variables, which were not normally distributed, across the binary outcomes. The Pearson x2 test was used to compare categorical variables. The x2 test for trend was used to test the trend of MACE, all-cause Table 1
Baseline characteristics
Variables Number Cortisol (pmol/ml)a Age Male Female Hypertension Diabetes Previous CAD Smoking history STEMI eGFR (ml/min/1.73m2) Killip class >1 Heart failure NT-proBNP(pmol/l)a ACEI or ARB b-Blockers Diuretics Statins Aspirin GRACE score
Total
557.4 66.5 667 288 512 244 356 410 398 66.2 376 41 768.4 766 757 244 811 803 151.2
955 (301.9–828.9) (12.8) (69.8%) (30.2%) (53.6%) (25.6%) (37.3%) (43.0%) (41.7%) (19.9) (39.6%) (4.3%) (255.2–2259.9) (80.2%) (79.3%) (25.6%) (84.9%) (84.0%) (39.8)
MACE absent 694 549.4 64.3 510 184 344 159 230 318 285 69.4 225 28 591.2 576 574 141 614 601 143.6
(72.7) (285.5–790.1) (12.4) (73.5%) (26.5%) (49.6%) (22.9%) (33.1%) (45.9%) (41.1%) (18.8) (32.7%) (4.0%) (182.2–1591.1) (83.0%) (82.7%) (20.3%) (88.5%) (86.6%) (36.6)
MACE present 261 609.4 72.3 157 104 168 85 126 92 113 57.6 151 13 2036.1 190 183 103 197 202 171.9
(27.3) (349.0–914.2) (11.7) (60.2%) (39.9%) (64.4%) (32.6%) (48.3%) (35.4%) (43.3%) (20.6) (58.1%) (5.0%%) (568.8–3908.4) (72.8%) (70.1%) (39.7%) (75.5%) (77.4%) (41.1)
P value
0.0073
Plasma cortisol and prognosis of patients with acute myocardial infarction Sandeep K. Jutlaa,b,, Matthew F. Yuyuna,b,, Paulene A. Quinna,b and Leong L. Nga,b Aims Cortisol is associated with increased cardiovascular morbidity and mortality in patients with chronic heart failure and in the general population. The negative predictive effect of cortisol on survival in non-diabetic patients who have suffered an acute myocardial infarction (AMI) has been shown. We aimed to determine the prognostic significance of cortisol in a general group of AMI patients, as this is not well known. Methods Plasma cortisol levels were measured in 955 consecutive patients admitted with AMI. We prospectively evaluated the relationship between cortisol and major adverse cardiovascular event (MACE), which was a composite of all-cause mortality, and combination all-cause mortality and re-hospitalization for heart failure, in post-AMI patients. Results During the 2-year follow-up, MACE occurred in 261 patients (27.3%). Patients with MACE had significantly higher median levels of cortisol than those without (609.4 versus 549.4 pmol/ml, P U 0.0073). Log cortisol was independently predictive of MACE after adjusting for covariates with hazard ratio (95% confidence interval) of 1.55 (1.05–2.27), P U 0.027. Patients in the highest quartile of cortisol had significantly more risk of MACE compared
Introduction Hormones acting on the mineralocorticoid receptor have been associated with increased cardiovascular disease (CVD) morbidity and mortality.1–4 Mineralocorticoid receptor blockade has been shown to significantly reduce negative CVD outcomes as part of a multiple biomarker strategy in two landmark trials.5,6 Cortisol is the final hormone product of the hypothalamic–pituitary–adrenal (HPA) axis, acting as ligand for intracellular glucocorticoid receptors found in almost all cells, as well as acting on mineralocorticoid receptors found on sodium transporting epithelia of the kidney nephrons, salivary glands, colon, sweat glands, vascular endothelium2,3 and nonepithelial tissues including vascular smooth muscle, myocardium and the brain.2,7–10 Mineralocorticoid receptors have equal affinity for cortisol and aldosterone.1,2,11 Cortisol levels measured in blood, urine or hair are associated with increased CVD risk factors,12,13 1558-2027 ß 2014 Italian Federation of Cardiology
with those in the lowest quartile, with an adjusted hazard ratio (95% confidence interval) of 1.91(1.16–3.15), P U 0.0120. Kaplan–Meier survival estimates for MACE were lower in patients with plasma cortisol levels in the highest quartile compared with those in the first three quartiles (Log rank test x2 for survival U 10.41, P U 0.0013). Conclusion This study has shown the prognostic significance of cortisol in 955 post-AMI patients from a single centre. J Cardiovasc Med 2014, 15:33–41 Keywords: cortisol, heart failure, mineralocorticoid receptor, mortality, myocardial infarction a Department of Cardiovascular Sciences, University of Leicester and bNIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
Correspondence to Professor Leong L. Ng, MBBChir, MD, FRCP, Department of Cardiovascular Sciences, NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester LE3 9QP, UK Tel: +44 116 250 2449; fax: +44 116 2523108; e-mail: [email protected]
Sandeep K. Jutla and Matthew F. Yuyun contributed equally to the writing of the article. Received 28 November 2012 Revised 4 March 2013 Accepted 20 April 2013
atherosclerosis,14–18 CVD mortality and all-cause mortality in the general population.19–22 Studies have correlated cortisol levels with an increase in myocardial infarct size,23,24 ventricular remodelling post-acute myocardial infarction (AMI)25 and increased mortality in chronic heart failure patients.26,27 Cortisol is also significantly raised in acute coronary syndromes,28–32 and correlates with the development of left ventricular failure, arrhythmias, shock and in-hospital mortality postAMI.33–35 The majority of smaller cross-sectional studies have shown increased morbidity and mortality risks with raised cortisol levels in patients with AMI,33–35 although others have found no association,36 and some have even found inverse associations.37 Apart from one study which showed a significantly negative effect of serum cortisol level on 5.5-year event-free survival in 231 non-diabetic patients who had suffered an AMI,38 no other long-term study has evaluated the prognostic significance of cortisol in post-AMI patients. Therefore, the overall aim of our DOI:10.2459/JCM.0b013e328364100b
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
34 Journal of Cardiovascular Medicine 2014, Vol 15 No 1
study was to prospectively evaluate the prognostic significance of plasma cortisol in a larger cohort of 955 post-AMI patients in relation to major adverse cardiovascular events (MACEs), all-cause mortality and a combination of all-cause mortality and hospitalization for heart failure.
Materials and methods Study design and study population
In this prospective cohort study, 955 consecutive patients with AMI admitted to the University Hospitals of Leicester NHS Trust between 2003 and 2008 were recruited. Written informed consent was obtained from patients, and the study complied with the Declaration of Helsinki and was approved by the local ethics committee. AMI was diagnosed if a patient had a plasma cardiac troponin I level more than 0.1 ng/ml (Advia Centaur Troponin-I assay; Siemens, Erlangen, Germany) with at least one of the following: chest pain lasting more than 20 min or diagnostic serial ECG changes consisting of new pathological Q waves or ST segment and T wave changes. Exclusion criteria included malignancy or surgery in the previous month. Hypertension was defined as a blood pressure measurement of greater than 140/90 mmHg on two or more occasions or if the patient was on medication for hypertension. Hypercholesterolaemia was defined as total cholesterol of greater than 5.0 mmol/l, or treatment with a statin. Diabetes was defined as random plasma glucose of 11.1 mmol/l, fasting plasma glucose of 7 mmol/l, or a history of diabetes on treatment. Past medical history of ischaemic heart disease (angina or myocardial infarction), heart failure and smoking history (current or ex-smoking) were obtained directly from patients or from their medical records. Data on demographics, clinical including treatment, laboratory and echocardiography were obtained. The estimated glomerular filtration rate (eGFR) was calculated from the simplified formula derived from the Modification of Diet in Renal Disease study.39 All patients received standard secondary prevention therapy for ischaemic heart disease, and revascularization was at the discretion of the attending physician. Blood sampling
Blood samples were drawn during admission with AMI. Blood was taken from patients 15 min after bed rest. Ten millilitres of venous blood was taken from the antecubital vein into tubes containing EDTA (1 ml/10 ml blood) and aprotinin (500 international units/ml blood). The blood samples were centrifuged at 3000 rpm at 48C for 15 min. The plasma was aspirated and stored at 808C until assayed.
shaker for 2 h and then spun down using a centrifuge at 2000 rpm. Then, 0.1 ml of the dichloromethane layer was taken for cortisol extraction and dried down in a speed vacuum centrifuge. Cortisol immunoassay
Cortisol was measured using a competitive immunoluminometric assay. Each well of the microlite-2 plate was coated with 100 ml (50 ng per well) of antimouse IgG antibody (Sigma, Gillingham, Dorset, UK) and left overnight at room temperature. Plates were washed following which 200 ml of bovine serum albumin (BSA) was pipetted into each well of the plate and left for 2 h at room temperature. The plasma cortisol extracts were re-constituted in 285 ml immunoluminometric assay buffer (ILMA) and immersed in an ultrasonic bath for 15 min. Then, 50 ml of mouse monoclonal cortisol antibody (10 ng; Abcam, Cambridge, UK) was pipetted accurately into each well of the plate, followed by 100 ml of standards or sample; each sample was done in duplicate format. After this, 50 ml of cortisol-biotin tracer was pipetted into each well. The plates were left for incubation overnight at 48C, then washed to remove any unbound cortisol tracer and 100 ml of MAE (methylacridinium ester)-labelled streptavidin was pipetted accurately into each well and the plates were left in the dark at room temperature to incubate for 90 min. A standard curve was constructed using Rodbard’s quadratic equation (Biosoft, Cambridge, UK). The luminometer readings were plotted on the y-axis relative light units (RLUs) against cortisol concentration (pmol/ml) on the x-axis. The patient’s plasma cortisol concentration was calculated by interpolation of the standard curve. The RLU values for the samples were plotted on the standard curve and the corresponding concentration in pmol/ml was efficiently calculated. The reproducibility of the assay was assessed by calculating the coefficient of variation, which was 3.6%. N-terminal pro-B type natriuretic peptide assay
Plasma N-terminal pro-B type natriuretic peptide (NTproBNP) assay was measured using a non-competitive immunoluminometric assay as previously published.40 Samples or NT-proBNP standards (10 ml) were incubated in ELISA plate wells coated with mouse monoclonal IgG directed to the C-terminal end of NT-proBNP. Detection was with biotinylated rabbit N-terminal antibody followed by MAE-streptavidin on an MLX plate luminometer (Dynex Technologies, Worthing, West Sussex, UK). The lower limit of detection was 0.3 pmol/l. This highly specific assay shows no cross-reactivity with ANP (atrial natriuretic peptide), brain natriuretic peptide (BNP) or CNP (C-type natriuretic peptide).
Steroid extraction
Plasma samples were defrosted at room temperature. One hundred microlitres of patient plasma was mixed with 1 ml dichloromethane. The mixture was left on a
Endpoints
Patients were reviewed 24 months after their initial admission with AMI, giving a censoring time of 730 days.
Copyright © Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.
Plasma cortisol and acute myocardial infarction Jutla et al. 35
The primary endpoint was MACE, which was a composite of all-cause mortality, myocardial re-infarction and re-hospitalization for heart failure. There were two secondary endpoints: all-cause mortality and a combination of all-cause mortality and hospitalization for heart failure. Deaths were validated by reviewing the hospital record management systems and the Office of National Statistics Registry. Hospitalization for heart failure was defined as a hospital admission for which heart failure was the primary reason, requiring treatment with high-dose diuretics, inotropes or intravenous nitrate with echocardiographic evidence of heart failure. New myocardial infarction and heart failure endpoints were ascertained using computerized hospital patients’ records for University Hospitals of Leicester and validated by contacting each patient. Patients were contacted about re-hospitalizations that occurred at hospitals other than the University Hospitals of Leicester.
mortality and combination of all-cause mortality and rehospitalization for heart failure rate across ordered quartiles of plasma cortisol. Curves of Kaplan–Meier survival estimates were obtained and the Log rank test was used to compare survival rates between patients whose cortisol levels were above the median value and those below the median. Univariate and multivariate hazard ratios for the predictive impact of baseline serum cortisol on MACE, death and combination of death and heart failure were estimated by the Cox proportional hazard model. Because cortisol distribution was skewed to the right, levels were log-transformed to base 10 before the Cox regression analyses were carried out. The likelihood ratio x2 test was used to test for statistical significance of each variable in the Cox regression model.
Results Baseline characteristics
Table 1 shows baseline characteristics of the study participants in the total study population and stratified by MACE outcomes. Post-AMI patients who developed MACE were significantly older, and had significantly greater median levels of baseline serum cortisol. They were more likely to be women when compared with men, had more prevalence of classical risk factors of coronary artery disease (CAD) and were more likely to have experienced previous myocardial infarction or angina. Patients who subsequently registered a MACE also had lower glomerular filtration rates, significantly higher levels of N-terminal pro-B type natriuretic peptide, had higher rates of clinical evidence of heart failure postmyocardial necrosis as demonstrated by a Killip class of greater than 1 and were more likely to have been prescribed a diuretic for their heart failure. Patients who
Statistical analyses
Statistical analyses were done using STATA 11. The twosample t-test was used to test for any statistically significant difference between the means of normally distributed continuous variables across the binary outcomes (presence or absence of MACE, death and combination of death and heart failure). The median and interquartile range were used for plasma cortisol levels because their distribution was positively skewed and for other skewed variables. The two-sample Wilcoxon rank-sum test was used to test for any significant difference in the medians of continuous variables, which were not normally distributed, across the binary outcomes. The Pearson x2 test was used to compare categorical variables. The x2 test for trend was used to test the trend of MACE, all-cause Table 1
Baseline characteristics
Variables Number Cortisol (pmol/ml)a Age Male Female Hypertension Diabetes Previous CAD Smoking history STEMI eGFR (ml/min/1.73m2) Killip class >1 Heart failure NT-proBNP(pmol/l)a ACEI or ARB b-Blockers Diuretics Statins Aspirin GRACE score
Total
557.4 66.5 667 288 512 244 356 410 398 66.2 376 41 768.4 766 757 244 811 803 151.2
955 (301.9–828.9) (12.8) (69.8%) (30.2%) (53.6%) (25.6%) (37.3%) (43.0%) (41.7%) (19.9) (39.6%) (4.3%) (255.2–2259.9) (80.2%) (79.3%) (25.6%) (84.9%) (84.0%) (39.8)
MACE absent 694 549.4 64.3 510 184 344 159 230 318 285 69.4 225 28 591.2 576 574 141 614 601 143.6
(72.7) (285.5–790.1) (12.4) (73.5%) (26.5%) (49.6%) (22.9%) (33.1%) (45.9%) (41.1%) (18.8) (32.7%) (4.0%) (182.2–1591.1) (83.0%) (82.7%) (20.3%) (88.5%) (86.6%) (36.6)
MACE present 261 609.4 72.3 157 104 168 85 126 92 113 57.6 151 13 2036.1 190 183 103 197 202 171.9
(27.3) (349.0–914.2) (11.7) (60.2%) (39.9%) (64.4%) (32.6%) (48.3%) (35.4%) (43.3%) (20.6) (58.1%) (5.0%%) (568.8–3908.4) (72.8%) (70.1%) (39.7%) (75.5%) (77.4%) (41.1)
P value
0.0073
