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Markers of Myocardial Stress, Myocardial Injury, and Subclinical Inflammation and the Risk of Sudden Death.
Everett, BM, Moorthy, MV, Tikkanen, JT, Cook, NR, Albert, CM
Circulation. 2020;(12):1148-1158
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Abstract
BACKGROUND The majority of sudden cardiac deaths (SCDs) occur in low-risk populations often as the first manifestation of cardiovascular disease (CVD). Biomarkers are screening tools that may identify subclinical cardiovascular disease and those at elevated risk for SCD. We aimed to determine whether the total to high-density lipoprotein cholesterol ratio, high-sensitivity cardiac troponin I, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity C-reactive protein individually or in combination could identify individuals at higher SCD risk in large, free-living populations with and without cardiovascular disease. METHODS We performed a nested case-control study within 6 prospective cohort studies using 565 SCD cases matched to 1090 controls (1:2) by age, sex, ethnicity, smoking status, and presence of cardiovascular disease. RESULTS The median study follow-up time until SCD was 11.3 years. When examined as quartiles or continuous variables in conditional logistic regression models, each of the biomarkers was significantly and independently associated with SCD risk after mutually controlling for cardiac risk factors and other biomarkers. The mutually adjusted odds ratios for the top compared with the bottom quartile were 1.90 (95% CI, 1.30-2.76) for total to high-density lipoprotein cholesterol ratio, 2.59 (95% CI, 1.76-3.83) for high-sensitivity cardiac troponin I, 1.65 (95% CI, 1.12-2.44) for NT-proBNP, and 1.65 (95% CI, 1.13-2.41) for high-sensitivity C-reactive protein. A biomarker score that awarded 1 point when the concentration of any of those 4 biomarkers was in the top quartile (score range, 0-4) was strongly associated with SCD, with an adjusted odds ratio of 1.56 (95% CI, 1.37-1.77) per 1-unit increase in the score. CONCLUSIONS Widely available measures of lipids, subclinical myocardial injury, myocardial strain, and vascular inflammation show significant independent associations with SCD risk in apparently low-risk populations. In combination, these measures may have utility to identify individuals at risk for SCD.
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High-Sensitivity Troponin I and Coronary Computed Tomography in Symptomatic Outpatients With Suspected CAD: Insights From the PROMISE Trial.
Januzzi, JL, Suchindran, S, Coles, A, Ferencik, M, Patel, MR, Hoffmann, U, Ginsburg, GS, Douglas, PS, ,
JACC. Cardiovascular imaging. 2019;(6):1047-1055
Abstract
OBJECTIVES The goal of this study was to examine associations between concentrations of high-sensitivity troponin I (hsTnI) (measured by using a single-molecule counting method) and obstructive coronary artery disease (CAD) in 1,844 stable, symptomatic outpatients with suspected CAD randomized to undergo coronary computed tomography angiography (CTA) in the PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial. BACKGROUND Elevated concentrations of hsTnI are associated with CAD in patients with myocardial infarction. The meaning of hsTnI concentrations in stable symptomatic outpatients is not well understood. METHODS Clinical characteristics and CTA results (including coronary artery calcium [CAC] scores) were expressed across hsTnI quartiles. Determinants of hsTnI concentration were identified. Multivariable logistic regression identified independent predictors of obstructive CAD50 (≥50% stenosis in any vessel) and CAD70 (≥70% stenosis or ≥50% left main). RESULTS The median hsTnI concentration was 1.5 ng/l; nearly all (98.5%) subjects had measurable hsTnI, and 6.1% had concentrations ≥99th percentile concentration for this assay (6 ng/l). Higher CAC scores, as well as more prevalent and diffuse CAD, was seen in upper hsTnI quartiles (all p < 0.001). Independent predictors of hsTnI concentrations included age, sex, and CAC score (all p < 0.05). After adjusting for demographic and clinical characteristics, log-transformed hsTnI concentrations were associated with obstructive CAD50 (odds ratio: 1.15 per interquartile range; p = 0.02) and CAD70 (odds ratio: 1.25 per interquartile range; p = 0.001). CONCLUSIONS In stable symptomatic outpatients undergoing nonemergent coronary CTA for the diagnosis of suspected CAD, higher concentrations of hsTnI were associated with increasing presence and severity of coronary atherosclerosis. (Prospective Multicenter Imaging Study for Evaluation of Chest Pain [PROMISE]; NCT01174550).
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A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease.
Bodde, MC, Welsh, P, Bergheanu, SC, Lijfering, WM, Mertens, B, Liem, AH, van der Laarse, A, Sattar, N, Jukema, JW
Clinical pharmacology and therapeutics. 2018;(2):311-316
Abstract
Serum troponin within the normal range is an emerging predictor of cardiovascular mortality. We aimed to determine how rapidly high-sensitivity troponin-I (hs-cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease. In the RADAR substudy, patients were randomized to atorvastatin 20 mg/day (n = 39) or rosuvastatin 10 mg/day (n = 39) and up-titrated at 6-week intervals to 80 mg of atorvastatin or 40 mg of rosuvastatin. Hs-cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow-up. Statin treatment resulted in a mean change of serum hs-cTnI of -8.2% (P = 0.010) after 6 weeks and -12.3% (P = 0.001) after 18 weeks. After 18 weeks, hs-cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P = 0.001 and P = 0.133, respectively). During statin therapy, serum hs-cTnI levels decreased rapidly within weeks of treatment, suggesting an effect beyond long-term atherosclerosis regression. Mechanisms that mediate this effect require further study.
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B-Type Natriuretic Peptide and Cardiac Troponin I Are Associated With Adverse Outcomes in Stable Kidney Transplant Recipients.
Jarolim, P, Claggett, BL, Conrad, MJ, Carpenter, MA, Ivanova, A, Bostom, AG, Kusek, JW, Hunsicker, LG, Jacques, PF, Gravens-Mueller, L, et al
Transplantation. 2017;(1):182-190
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Abstract
BACKGROUND Approximately 200 000 kidney transplant recipients are living in the United States; they are at increased risk for cardiovascular and other adverse outcomes. Biomarkers predicting these outcomes are needed. Using specimens collected during the Folic Acid for Vascular Outcome Reduction in Transplantation trial, we determined whether plasma levels of B-type natriuretic peptide (BNP) and cardiac troponin I are associated with adverse outcomes in stable kidney transplant recipients. METHODS Five hundred ten subjects were selected randomly from the 4110 Folic Acid for Vascular Outcome Reduction in Transplantation participants. This cohort was then enriched for all additional subjects with adverse outcomes (death, dialysis-dependent kidney failure (DDKF), and cardiovascular outcomes) for a total of 1131 participants studied. Quartiles of BNP and high-sensitivity cardiac troponin I (hs-cTnI) were included in adjusted models. Combinations of normal and elevated hs-cTnI (>26.2 ng/L) and BNP (>100 pg/mL) were also studied. RESULTS Median concentrations (interquartile ranges) were 5.6 (3.3-10.5) ng/L for hs-cTnI and 39 (15, 94) pg/mL for BNP. Hazard ratios for each adverse outcome were higher with higher quartiles of BNP after adjustment and remained statistically significant after adding hs-cTnI to the model. The highest quartile hazard ratio for DDKF was 2.47 (95% confidence interval [95% CI], 1.21-5.05). Simultaneous elevations of BNP and hs-cTnI over clinical cutoffs were strongly associated with adverse outcomes with hazard ratios 8.8 (95% CI, 3.4-23.1) for DDKF and 6.3 (95% CI, 2.7-15.0) for cardiovascular outcomes. CONCLUSIONS Higher BNP is associated with mortality and cardiovascular and kidney outcomes in stable kidney transplant recipients. Elevated BNP and hs-cTnI identify candidates for targeted risk reduction.
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Effects of Canagliflozin on Cardiovascular Biomarkers in Older Adults With Type 2 Diabetes.
Januzzi, JL, Butler, J, Jarolim, P, Sattar, N, Vijapurkar, U, Desai, M, Davies, MJ
Journal of the American College of Cardiology. 2017;(6):704-712
Abstract
BACKGROUND Sodium glucose co-transporter 2 inhibitors may reduce cardiovascular and heart failure risk in patients with type 2 diabetes mellitus (T2DM). OBJECTIVES The goal of this study was to examine the effects of canagliflozin on cardiovascular biomarkers in older patients with T2DM. METHODS In 666 T2DM patients randomized to receive canagliflozin 100 or 300 mg or placebo, the study assessed the median percent change in serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin I (hsTnI), soluble (s)ST2, and galectin-3 from baseline to 26, 52, and 104 weeks. RESULTS Both serum NT-proBNP and serum hsTnI levels increased in placebo recipients, but they remained largely unchanged in those randomized to canagliflozin. Hodges-Lehmann estimates of the difference in median percent change between pooled canagliflozin and placebo were -15.0%, -16.1%, and -26.8% for NT-proBNP, and -8.3%, -11.9%, and -10.0% for hsTnI at weeks 26, 52, and 104, respectively (all p < 0.05). Serum sST2 was unchanged with canagliflozin and placebo over 104 weeks. Serum galectin-3 modestly increased from baseline with canagliflozin versus placebo, with significant differences observed at 26 and 52 weeks but not at 104 weeks. These results remained unchanged when only patients with complete samples were assessed. CONCLUSIONS Compared with placebo, treatment with canagliflozin delayed the rise in serum NT-proBNP and hsTnI for over 2 years in older T2DM patients. These cardiac biomarker data provide support for the beneficial cardiovascular effect of sodium glucose co-transporter 2 inhibitors in T2DM. (A Safety and Efficacy Study of Canagliflozin in Older Patients [55 to 80 Years of Age] With Type 2 Diabetes Mellitus; NCT01106651).
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High-Sensitivity Cardiac Troponin, Statin Therapy, and Risk of Coronary Heart Disease.
Ford, I, Shah, AS, Zhang, R, McAllister, DA, Strachan, FE, Caslake, M, Newby, DE, Packard, CJ, Mills, NL
Journal of the American College of Cardiology. 2016;(25):2719-2728
Abstract
BACKGROUND Cardiac troponin is an independent predictor of cardiovascular mortality in individuals without symptoms or signs of cardiovascular disease. The mechanisms for this association are uncertain, and a role for troponin testing in the prevention of coronary heart disease has yet to be established. OBJECTIVES This study sought to determine whether troponin concentration could predict coronary events, be modified by statins, and reflect response to therapy in a primary prevention population. METHODS WOSCOPS (West of Scotland Coronary Prevention Study) randomized men with raised low-density lipoprotein cholesterol and no history of myocardial infarction to pravastatin 40 mg once daily or placebo for 5 years. Plasma cardiac troponin I concentration was measured with a high-sensitivity assay at baseline and at 1 year in 3,318 participants. RESULTS Baseline troponin was an independent predictor of myocardial infarction or death from coronary heart disease (hazard ratio [HR]: 2.3; 95% confidence interval [CI]: 1.4 to 3.7) for the highest (≥5.2 ng/l) versus lowest (≤3.1 ng/l) quarter of troponin (p < 0.001). There was a 5-fold greater reduction in coronary events when troponin concentrations decreased by more than a quarter, rather than increased by more than a quarter, for both placebo (HR: 0.29; 95% CI: 0.12 to 0.72 vs. HR: 1.95; 95% CI: 1.09 to 3.49; p < 0.001 for trend) and pravastatin (HR: 0.23; 95% CI: 0.10 to 0.53 vs. HR: 1.08; 95% CI: 0.53 to 2.21; p < 0.001 for trend). Pravastatin reduced troponin concentration by 13% (10% to 15%; placebo adjusted, p < 0.001) and doubled the number of men whose troponin fell more than a quarter (p < 0.001), which identified them as having the lowest risk for future coronary events (1.4% over 5 years). CONCLUSIONS Troponin concentration predicts coronary events, is reduced by statin therapy, and change at 1 year is associated with future coronary risk independent of cholesterol lowering. Serial troponin measurements have major potential to assess cardiovascular risk and monitor the impact of therapeutic interventions.
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hs-Troponin I Followed by CT Angiography Improves Acute Coronary Syndrome Risk Stratification Accuracy and Work-Up in Acute Chest Pain Patients: Results From ROMICAT II Trial.
Ferencik, M, Liu, T, Mayrhofer, T, Puchner, SB, Lu, MT, Maurovich-Horvat, P, Pope, JH, Truong, QA, Udelson, JE, Peacock, WF, et al
JACC. Cardiovascular imaging. 2015;(11):1272-1281
Abstract
OBJECTIVES This study compared diagnostic accuracy of conventional troponin/traditional coronary artery disease (CAD) assessment and highly sensitive troponin (hsTn) I/advanced CAD assessment for acute coronary syndrome (ACS) during the index hospitalization. BACKGROUND hsTnI and advanced assessment of CAD using coronary computed tomography angiography (CTA) are promising candidates to improve the accuracy of emergency department evaluation of patients with suspected ACS. METHODS We performed an observational cohort study in patients with suspected ACS enrolled in the ROMICAT II (Rule Out Myocardial Infarction/Ischemia using Computer Assisted Tomography) trial and randomized to coronary CTA who also had hsTnI measurement at the time of the emergency department presentation. We assessed coronary CTA for traditional (no CAD, nonobstructive CAD, ≥50% stenosis) and advanced features of CAD (≥50% stenosis, high-risk plaque features: positive remodeling, low <30-Hounsfield units plaque, napkin-ring sign, spotty calcium). RESULTS Of 160 patients (mean age: 53 ± 8 years, 40% women) 10.6% were diagnosed with ACS. The ACS rate in patients with hsTnI below the limit of detection (n = 9, 5.6%), intermediate (n = 139, 86.9%), and above the 99th percentile (n = 12, 7.5%) was 0%, 8.6%, and 58.3%, respectively. Absence of ≥50% stenosis and high-risk plaque ruled out ACS in patients with intermediate hsTnI (n = 87, 54.4%; ACS rate 0%), whereas patients with both ≥50% stenosis and high-risk plaque were at high risk (n = 13, 8.1%; ACS rate 69.2%) and patients with either ≥50% stenosis or high-risk plaque were at intermediate risk for ACS (n = 39, 24.4%; ACS rate 7.7%). hsTnI/advanced coronary CTA assessment significantly improved the diagnostic accuracy for ACS as compared to conventional troponin/traditional coronary CTA (area under the curve 0.84, 95% confidence interval [CI]: 0.80 to .88 vs. 0.74, 95% CI: 0.70 to 0.78; p < 0.001). CONCLUSIONS hsTnI at the time of presentation followed by early advanced coronary CTA assessment improves the risk stratification and diagnostic accuracy for ACS as compared to conventional troponin and traditional coronary CTA assessment. (Multicenter Study to Rule Out Myocardial Infarction/Ischemia by Cardiac Computed Tomography [ROMICAT-II]; NCT01084239).
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Cardiomyocyte injury induced by hemodynamic cardiac stress: Differential release of cardiac biomarkers.
Irfan, A, Reichlin, T, Twerenbold, R, Fischer, C, Ballarino, P, Nelles, B, Wildi, K, Zellweger, C, Rubini Gimenez, M, Mueller, M, et al
Clinical biochemistry. 2015;(18):1225-9
Abstract
OBJECTIVE We explored whether hemodynamic cardiac stress leads to a differential release of cardiomyocyte injury biomarkers, used in the diagnosis of acute myocardial infarction (AMI). METHODS In an observational international multicenter study, we enrolled 831 unselected patients presenting with symptoms suggestive of AMI to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. Hemodynamic cardiac stress was quantified by levels of B-type natriuretic peptide (BNP). Spearman's rho correlation was used to analyze the correlations between BNP and high-sensitivity cardiac troponin T (hs-cTnT), Siemens cTnI-Ultra (cTnI-ultra), CK-MB and Myoglobin. Patients were categorized according to the extent of hemodynamic cardiac stress as quantified by BNP tertiles. RESULTS Among all patients, the positive pair-wise correlation with BNP was strongest with hs-cTnT and cTnI-ultra (r=0.58 and 0.50, respectively), moderate for Myoglobin (r=0.43), and weakest with CK-MB (r=0.25; p<0.001 for each). Similar pattern of correlations was also observed among AMI patients. Among patients diagnosed with non-cardiac cause of chest pain (n=385, 46%) and cardiac but non-coronary (n=109, 13%), BNP had significant positive correlations with hs-cTnT, cTnI-ultra and Myoglobin (p<0.05), but not with CK-MB (p=NS). A similar pattern of stronger correlation between BNP and hs-cTnT, cTnI-ultra and Myoglobin as compared to that with CK-MB was also observed within the higher BNP tertile range. There was no correlation between BNP and other biomarkers within the 1st BNP tertile group. CONCLUSION Hemodynamic cardiac stress, as quantified by BNP, as a likely cause of cardiomyocyte injury, is more closely reflected by concentrations of hs-cTnT, cTnI-ultra and Myoglobin than CK-MB.
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Randomised Assessment of Treatment using Panel Assay of Cardiac markers--Contemporary Biomarker Evaluation (RATPAC CBE).
Collinson, PO, Gaze, DC, Thokala, P, Goodacre, S
Health technology assessment (Winchester, England). 2013;(15):v-vi, 1-122
Abstract
OBJECTIVES To test the diagnostic accuracy for detecting an acute myocardial infarction (AMI) using highly sensitive troponin assays and a range of new cardiac biomarkers of plaque destabilisation, myocardial ischaemia and necrosis; to test the prognostic accuracy for detecting adverse cardiac events using highly sensitive troponin assays and this range of new cardiac biomarkers; and to estimate the cost-effectiveness of using highly sensitive troponin assays or this range of new cardiac biomarkers instead of an admission and 10- to 12-hour troponin measurement. DESIGN Substudy of the point-of-care arm of the RATPAC (Randomised Assessment of Treatment using Panel Assay of Cardiac markers) trial. SETTING The emergency departments of six hospitals. PARTICIPANTS Prospective admissions with chest pain and a non-diagnostic electrocardiogram randomised to point-of-care assessment or conventional management. INTERVENTIONS Blood samples taken on admission and 90 minutes from admission for measurement of cardiac markers [cardiac troponin I (cTnI), myoglobin and creatine kinase MB isoenzyme (CK-MB)] by point-of-care testing. An additional blood sample was taken at admission and 90 minutes from admission for analysis of high-sensitivity cTnI (two methods) and cardiac troponin T (cTnT), myoglobin, heart-type fatty acid-binding protein (H-FABP), copeptin and B-type natriuretic peptide (NTproBNP). MAIN OUTCOME MEASURES 1. Diagnostic accuracy compared with the universal definition of myocardial infarction utilising laboratory measurements of cardiac troponin performed at the participating sites together with measurements performed in a core laboratory. 2. Ability of biomarker measurements to predict major adverse cardiac events (death, non-fatal AMI, emergency revascularisation or hospitalisation for myocardial ischaemia) at 3 months' follow-up. 3. Comparison of incremental cost per quality-adjusted life-year (QALY) of different biomarker measurement strategies for the diagnosis of myocardial infarction. RESULTS Samples were available from 850 out of 1132 patients enrolled in the study. Measurement of admission myoglobin [area under the curve (AUC) 0.76] and CK-MB (AUC 0.84) was diagnostically inferior and did not add to the diagnostic efficiency of cTnI (AUC 0.90-0.94) or cTnT (AUC 0.92) measurement on admission. Simultaneous measurement of H-FABP and cTnT or cTnI did improve admission diagnostic sensitivity to 0.78-0.92, but only to the same level as that achieved with troponin measured on admission and at 90 minutes from admission (0.78-0.95). Copeptin (AUC 0.62) and NTproBNP (AUC 0.85) measured on admission were not useful as diagnostic markers. As a prognostic marker, troponin measured on admission using a high-sensitivity assay (AUC 0.73-0.83) was equivalent to NTproBNP measurement (AUC 0.77) on admission, but superior to copeptin measurement (AUC 0.58). From modelling, 10-hour troponin measurement is likely to be cost-effective compared with rapid rule-out strategies only if a £30,000 per QALY threshold is used and patients can be discharged as soon as a negative result is available. CONCLUSIONS The measurement of high-sensitivity cardiac troponin is the best single marker in patients presenting with chest pain. Additional measurements of myoglobin or CK-MB are not clinically effective or cost-effective. The optimal timing for measurement of cardiac troponin remains to be defined. Copeptin measurement is not recommended. H-FABP requires further investigation before it can be recommended for simultaneous measurement with high-sensitivity troponin in patients with acute chest pain. TRIAL REGISTRATION ISRCTN37823923. FUNDING This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 15. See the HTA programme website for further project information.
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Very early diagnosis of chest pain by point-of-care testing: comparison of the diagnostic efficiency of a panel of cardiac biomarkers compared with troponin measurement alone in the RATPAC trial.
Collinson, P, Goodacre, S, Gaze, D, Gray, A, ,
Heart (British Cardiac Society). 2012;(4):312-8
Abstract
OBJECTIVE To assess the impact of triple marker testing on patient management and the diagnostic efficiencies of different biomarker strategies examined. DESIGN A prospective randomised trial of triple marker testing by point-of-care testing (POCT); the Randomised Assessment of Panel Assay of Cardiac markers (RATPAC) study. SETTING Six emergency departments. PATIENTS Low-risk patients presenting with chest pain to diagnostic assessment with a cardiac panel measured by POCT or to diagnosis when biomarker measurement was based on central laboratory testing. Interventions 1125 patients were randomly assigned to POCT measurement of the triple marker panel of cardiac troponin I (cTnI), myoglobin and the MB isoenzyme of creatine kinase (CK-MB) on admission and 90 min from admission. MAIN OUTCOME MEASURES Myocardial infarction (MI) was defined by the universal definition of MI. The following diagnostic strategies were compared by receiver operator characteristic (ROC) curve analysis and comparison of area under the curve (AUC): individual marker values, change (Δ) in CK-MB and myoglobin and the combination of presentation or 90 min value plus Δ value. RESULTS Admission sample measurement of cTnI was the most diagnostically efficient AUC 0.96 (0.93-0.98) with areas under the ROC curve statistically significantly greater than CK-MB 0.85 (0.80-0.90) and myoglobin 0.75 (0.68-0.81). At 90 min cTnI measurement had the highest AUC 0.95 (0.87-1.00) but was statistically significantly different only from Δmyoglobin and ΔCK-MB. CONCLUSION Measurement of cTnI alone is sufficient for diagnosis. Measurement of a marker panel does not facilitate diagnosis.