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Effect of coronary atherosclerotic burden and inducible myocardial ischemia on circulating levels of high sensitivity cardiac troponin T (hs-cTnT) and N terminal probrain natriuretic peptide (NT-proBNP) in patients with stable angina: results from the EVINCI study.Cardiac biomarkers and stable angina. Chiara Caselli,a Concetta Prontera,b Rosetta Ragusa,c Riccardo Liga,d Michiel A. De Graaf,e Valentina Lorenzoni,c Silvia Del Ry,a Daniele Rovai,a Daniela Giannessi,a Oliver G?emperli,f Jeroen J. Bax,e Massimo Lombardi,b Rosa Sicari,a Jose’ Zamorano,g Arthur J. Scholte, e Philipp A. Kaufmann,f Juhani Knuuti,h S Richard Underwood,i Aldo Clerico, b,c Danilo Neglia, MD.a,ba CNR, Institute of Clinical Physiology, Pisa, Italy; b Fondazione Toscana G. Monasterio, Pisa, Italy;c Scuola Superiore Sant’Anna, Pisa, Italy; d Cardio-Thoracic and Vascular Department, University Hospital of Pisa, Pisa, Italy;e Leiden University Medical Center, Leiden, The Netherlands; f University Hospital Zurich, Zurich, Switzerland;g University Hospital Clinico San Carlos, Madrid, Spain;h University of Turku and Turku University Hospital, Turku, Finland;i Imperial College London, United KingdomThis work was supported by a grant from the European Union FP7-CP-FP506 2007 project (grant agreement no. 222915, EVINCI).The authors declare that they have no relationships relevant to the contents of this paper to disclose.Total word count: Address for correspondence: Chiara Caselli, PhDCNR Institute of Clinical PhysiologyArea della Ricerca – Via Moruzzi, 1 56100 PisaFax: 39 050 3152166Phone: 39 050 3152019e-mail: chiara.caselli@r.itAbstractBackground. Circulating levels of high sensitivity cardiac troponin T (hs-cTnT) and N terminal probrain natriuretic peptide (NT-proBNP) are predictors of coronary artery disease (CAD) and long term prognosis in patients with stable angina. Purpose. The aim of this study was to evaluate the effect of coronary atherosclerotic burden and inducible myocardial ischemia on cardiac release of hs-cTnT and NT-proBNP in a contemporary European population of patients with suspected CAD. Methods. Hs cTnT and NT-proBNP were measured in 378 patients (60.1 ±0.5 years, 229 males) with stable angina and unknown CAD enrolled in the Evaluation of INtegrated Cardiac Imaging (EVINCI) study. All patients underwent stress imaging, by myocardial perfusion or wall motion imaging, to detect inducible ischemia, and coronary computed tomography angiography (CTA) to assess the presence of CAD (>50% stenosis of at least one major coronary vessel). An individual CTA score, expressing the coronary atherosclerotic burden, was calculated combining extent, severity, composition, and location of plaques. Results. In the whole population the median (IQR) value of plasma hs-cTnT was 6.17 (4.2-9.1) ng/L and of NT-proBNP was 61.66 (31.2-132.6) ng/L. In a multivariate model, CTA score was an independent predictor of the plasma hs cTnT (coefficient 0.06, SE 0.02, p=0.0089), while ischemia was a predictors of NT-proBNP (coefficient 0.38, SE 0.12, p=0.0015). When patients were subdivided according to the absence/presence of CAD and ischemia, hs-cTnT concentrations were significantly increased in patients with CAD with or without inducible ischemia (p<0.005), while only patients with CAD and ischemia showed significantly higher levels of NT-proBNP compared with all the other groups (p<0.001).Conclusions. In patients with stable angina, the presence and extent of CAD is related with increased levels of hs-cTnT also in absence of ischemia. This suggest an ischemia-independent mechanisms of hs cTnT release linked with coronary atherosclerosis. NT-proBNP is a strong and independent predictor of obstructive CAD causing myocardial ischemia, thus identifying those subject at high risk of future events, probably requiring invasive procedure.Keywordshs cardiac Troponin T, NT-proBNP, stable angina, coronary artery disease, atherosclerotic burden, myocardial ischemia, cardiac imagingIntroductionThe stable coronary artery disease (CAD) population represents a heterogeneous group of patients for patho-physiologic substrate, clinical presentation and outcome (1). These patients may have different morphology, severity and extent of coronary atherosclerotic lesions and of inducible myocardial ischemia and these multiple aspects may have independent prognostic value (2-3). High-sensitivity cardiac troponins (hs-TnT) is commonly used in the diagnosis of acute coronary syndromes (4-7). Recently, it has been shown that episodes of minute troponin release, below the threshold for acute myocardial infarction, often occur in patients with stable CAD and this has been demonstrated to predict all cause mortality, cardiovascular mortality and heart failure (HF) (5-8). N-terminal pro brain natriuretic peptide (NT-proBNP) is a powerful prognostic indicator in patients with left ventricular (LV) dysfunction and HF. However, it is also a predictor of all cause and cardiovascular mortality in patients with stable CAD without HF (9-11), Hence both these biomarkers may be used as prognostic indicators in stable CAD (5-11). The aim of this study was to evaluate the effect of coronary atherosclerotic burden, assessed by CT angiography (CTA), or myocardial ischemia, assessed by stress imaging, on cardiac release of hs-cTnT and N-terminal pro B-type natriuretic peptide (NT-proBNP) in patients with stable CAD enrolled in the EValuation of INtegrated Cardiac Imaging (EVINCI) (12). In the subgroup of EVINCI patients in whom imaging fusion of CTA and myocardial perfusion imaging (MPI) was performed, the combined effects of coronary atherosclerosis and downstream inducible ischemia on circulating biomarkers was also evaluated. Materials and MethodsPopulation, diagnostic protocol and study designPatients with stable chest pain or equivalent symptoms and intermediate probability of CAD were studied. These patients were enrolled at 14 European centres in the EValuation of INtegrated Cardiac Imaging for the detection and characterization of ischemic heart disease (EVINCI) study (12). Patients with acute coronary syndrome, known CAD, left ventricular ejection fraction < 35%, significant heart valve disease, cardiomyopathy or contraindications to stress imaging were excluded. According to the EVINCI protocol, each patient underwent CTA, stress imaging (by MPI or WMI) and - if at least one non invasive tests was positive - invasive coronary angiography and measurement of FFR when indicated (12). Ethical approval was provided by each participating centre and all subjects provided written informed consent.The patients whose CTA images and plasma samples were available for core laboratory analyses were included in this study. Patients with also available MPI studies by SPECT or PET were included in a sub-analysis. Image fusion of MPI with CCTA datasets and hybrid analysis were performed by a dedicated core laboratory.Blood collection and analysisBlood samples were collected before non-invasive imaging in tubes with EDTA and then locally separated by centrifugation for 15 min at 1000 ×g. Plasma samples were provisionally stored in a local refrigerator at - 80°C and shipped to the bio-humoral core laboratory (CNR-Institute of Clinical Physiology, Pisa, Italy) for the final cryo-conservation in the EVINCI biological bank (13-14). Analyses of hs-cTnT and NT-proBNP were performed at the Laboratory of Fondazione Toscana G. Monasterio (Pisa, Italy) using standard clinical laboratory procedures on automatic analyzers, according to the recommendations made by the manufacturer (Roche Diagnostics International Ltd, Switzerland). Plasma concentrations of cTnT were measured using the hs-cTnT method on COBAS E411 with Elecsys Troponin T hs STAT by Roche Diagnostics, as previously described in detail (15 ). Measurement of NT pro-BNP was performed using the electrochemical luminescence immunoassay Elecsys proBNP II by Roche Diagnostics using monoclonal antibodies, as previously described in detail (16).In order to complete the clinical/biohumoral profile of study patients, additional traditional biomarkers were measured using standard methods (13-14).Image acquisition Image acquisition protocols were agreed on for each technique covering patient preparation, cardiovascular stress, administration of radiopharmaceutical or contrast medium, image acquisition and quality control. These procedures were based on best available clinical practice. Image analysis and reporting was performed at specific core laboratories dedicated to each technique by experienced observers blinded to clinical history and other imaging findings (12).Coronary CTA analysis and CTA risk scoreThe coronary CTAs were analyzed in a core laboratory (Leiden University Medical Center, Leiden, The Netherlands) by consensus of experienced observers blinded to any other clinical data or imaging test. First, each segment of the AHA 17-segment model was assessed for interpretability. Segments were defined as uninterpretable in case of severe motion artefacts or low contrast resolution. Additionally, segments with a diameter ≤ 1.5 mm were excluded. Interpretable segments were evaluated for stenosis, which was then stratified into four different categories: normal if no atherosclerosis was present, non-obstructive if the stenosis severity was <50%, obstructive for lesions with 50-70% stenosis of the coronary artery lumen. If plaque was present, plaque composition was visually determined (calcified, mixed, non-calcified). One type of plaque composition was assigned per segment. In 297/376 patients, CT acquisitions for coronary artery calcium were available and the Agatston CAC score was computed according to standard methods. A previously established CTA risk score was derived in each patient integrating all data on the location, severity, and composition of CAD (17). In brief, the score consists of three weight factors for each segment of the coronary tree. A stenosis severity weight factor, a stenosis location weight factor, and a weight factor for plaque composition. All three weight factors are multiplied to calculate the segment score. The risk score for each patient is calculated by adding all segment scores. Non invasive stress imaging analysis MPI and WMI were defined as abnormal if there was either an inducible perfusion abnormality or myocardial scarring. Perfusion in each of 17 segments was classified as 0 = normal, 1 = mild reduction, 2 = moderate reduction, 3 = severe reduction or 4 = absent perfusion and the segmental scores were summed for the stress and rest images. For MPI, an inducible perfusion abnormality was defined as a summed segmental difference score between stress and rest images ≥ 2, either from a score ≥ 1 in at least two contiguous segments or ≥ 2 in at least one segment. Scarring was defined similarly from the summed segmental rest score. For WMI, segmental myocardial wall motion was scored at rest and during stress as normal (0), hypokinetic (1), akinetic (2) or dyskinetic (3). Inducible ischaemia was defined as an increase in segmental wall motion score ≥ 1 from rest to stress in at least two contiguous segments. Scarring was defined similarly from the resting wall motion score. Hybrid imagingIn the subgroup of 195 patients submitted to MPI by PET or SPECT with an excellent image quality, a hybrid imaging study was performed. Individual datasets from MPI and CTA were transferred to a dedicated hybrid core laboratory blinded to clinical history and imaging findings (University Hospital Zurich, Switzerland). Image fusion of MPI and CCTA datasets was performed on a dedicated workstation (Advantage Workstation 4.4, GE Healthcare) using the CardIQ Fusion software package (GE Healthcare) as previously described (18). In case of H215O-PET images, parametric myocardial blood flow (MBF) datasets, showing MBF on a segmental level, were first generated and quantitative analysis was performed using an in-house developed software, PMOD 3.6 software package (PMOD Technologies Ltd., Zurich, Switzerland). Then hybrid analysis was performed using an optimized alignment tool that allows projection of the MPI image on the left ventricular epicardial surface obtained from the CTA. The 3D volume rendered fusion images allow a panoramic view of the coronary artery tree projected onto the left ventricular myocardial perfusion territories. Images can be displayed in freely selectable angles and displayed in standard anterior, posterior, lateral, and apical view for standardized documentation and reporting. In all patients, the image fusion procedure (including image generation and reading) was performed.A patient’s CTA was considered abnormal if at least one coronary artery had a diameter stenosis >50%. According to an intention-to-diagnose strategy, any non-diagnostic segment was considered abnormal. Significant left main stem stenosis were assigned to both left anterior descending (LAD) and left circumflex (LCX) coronary arteries. A reversible perfusion defect (ischemia) was defined as a SDS ≥2, either from a score ≥ 1 in at least two contiguous segments or ≥ 2 in at least one segment. Myocardial scar was defined similarly as a SRS ≥2. Each perfusion defect was assigned to one or more coronary territories according to the standardized myocardial segmentation model proposed by Cerqueria et al. (19). All hybrid MPI/CCTA images were analysed with regard to the presence of hemodynamically significant coronary lesions. Specifically, each abnormal myocardial segment was assigned to the pertinent vascular territory by spatial coregistration according to patients’ individual coronary anatomy. A matched hybrid imaging finding was defined as a perfusion defect in a territory subtended by a stenotic coronary artery on CCTA. All other combinations of pathologic findings were classified as unmatched. Statistical analysisCategorical variables are presented as numbers (percentage), continuous variables as mean ± SD or median [25-75 percentile] depending on their distribution. Differences in continuous variables between two groups were tested using Student’s t test or Mann-Whitney test. Comparisons among groups were performed using ANOVA analysis and Kruskall-Wallis test, Bonferroni test or Mann-Whitney test using Bonferroni correction for P-value were used for post-hoc comparisons. Pearson’s chi-squared test was used to compare categorical data. Univariate and multivariate linear regression were used to estimate the effect of clinical variables as well as imaging results on hs-cTnT and NT-proBNP plasma levels. the. All models were developed considering variables with P value < 0.1 at univariate analysis and then using backward and forward stepwise selections to build up the final models. The logarithmic transformation of continuous variables was used in linear regression analysis. All analyses were performed using StataCorp. 2007. Stata Statistical Software: Release 10. College Station, TX: StataCorp LP. A 2-sided value of P <0.05 was considered statistically significant.Results Baseline clinical characteristics of study populationIn the whole population the median (interquartile range) value of plasma hs-cTnT was 6.17 (4.16-9.09) ng/L and of NT-proBNP was 61.66 (31.19-132.60) ng/L. Only 34 (9%) and 77 (20%) of patients had plasma levels of hs-cTnT and of NT-proBNP exceeding the upper limits of the normality ranges (14 pg/mL and 157 ng/L, respectively). The median values were used as cut-off points to divide patients into groups with low (< median) or high (≥ median) concentrations of hs-cTnT and NT-proBNP. Baseline characteristics of the patients are compared between groups in Table 1. Patients with high levels of hs-cTnT were older and had higher frequency of male sex, diabetes, hypertension, anti-diabetic and anti-hypertensive treatments than patients with low levels of hs-cTnT. Patients with high levels of NT-proBNP were also older than patients with low levels of NT-proBNP but showed a lower frequency of male sex and diabetes and a lower LV ejection fraction. The metabolic and inflammatory profile was altered in patients with high levels of hs-cTnT but not in those with high NT-proBNP levels. Coronary atherosclerosis and inducible myocardial ischemiaResults from CTA (coronary anatomy, plaque characterization and risk scores) and stress imaging (inducible myocardial ischemia) are compared between groups of patients with high or low hs-cTnT or NT-proBNP in Table 2. Biomarker levels were associated with the severity and the extent of CAD. Patients with high hs-cTnT as well as patients with high NT-proBNP showed a higher frequency of obstructive coronary lesions as compared with patients with low hs-cTnT and NT-proBNP who showed a higher frequency of normal coronary arteries. Figure 1 illustrates the increase of hs-cTnT and NT-proBNP plasma levels according to the presence of non obstructive or obstructive coronary lesions (Figure 1A) or with the number of any coronary lesion (either obstructive or non obstructive) (Figure 1B). The two biomarkers were differently associated with plaque types. Patients with high hs-cTnT, but not patients with high NT-proBNP, showed more frequently calcified or mixed plaques than patients with low hs-cTnT and had a higher number of mixed plaques. CTA risk score was significantly higher in patients with high hs-cTnT or high NT-proBNP while CAC score was significantly higher only in patients with high hs-cTnT (Table 2).Both patients with high hs-cTnT and high NT-proBNP had higher frequency and extent of inducible ischemia (Table 2) . Integrated effects of coronary atherosclerotic burden and inducible ischemia on circulating hs-cTnT and NT-proBNP levelsMultiple linear regression model was used to identify the independent predictors of elevated levels of hs-cTnT and NT-proBNP (Table 3). Age, male sex and CTA risk score were independent predictors of increased hs-cTnT levels. Age, female sex, lower LVEF and presence of ischemia were independent predictors of increased NT-proBNP levels.Patients were subdivided in groups according to the absence or the presence of coronary atherosclerosis (CAD) and ischemia, either alone or combined. Patients with CAD with/without ischemia showed significantly higher levels of hs-cTnT than patients without CAD, while only patients with CAD plus ischemia had significantly higher levels of NT-proBNP as compared with all the other groups (Figure 2A). Similar results were obtained by hybrid imaging analysis. Patients with a perfusion defect in a territory subtended by a stenotic coronary artery on CTA (macthed) were compared with patients with all other combinations of pathologic findings (unmatched) and with normals. As compared with normals, NT-proBNP levels were significantly increased only in patients with matched findings while hs-cTnT levels were significantly elevated in both patients with matched and mismatched findings. (Figure 2B).LVEF and NT-proBNP were linearly correlated in the whole population (p = 0.002). Interestingly, only patients with coronary atherosclerosis and inducible myocardial ischemia had significantly decreased LVEF values as compared with all the other patient groups (Figure 3).DiscussionThe present study examines the relative effects of coronary atherosclerotic burden and inducible myocardial ischemia on circulating levels of hs-cTnT and NT-proBNP in patients with stable CAD . The main findings of the present study can be summarized as follows: circulating levels of hs-cTnT are related with presence and extent of coronary lesions as well as coronary plaque composition; in addition the global coronary atherosclerotic burden, as assessed by CTA risk score, is a predictor of hs-cTnT plasma levels independently of inducible myocardial ischemia; circulating levels of NT-proBNP are mainly related with the presence of functionally relevant coronary disease causing myocardial ischemia. Cardiac troponins are the marker of choice for the detection of myocardial injury and the diagnosis of myocardial infarction, as recommended by the most recent guidelines (20-21). Over the past 10 years cTn assays have been improved in analytical sensitivity and precision thereby allowing the measurement of cTn in nearly all healthy subjects (22-23) and patients with stable CAD (5-6). In stable CADrelease of cTnT has been linked to the extent of coronary atherosclerosis (4-6) while the relationship with transient inducible myocardial ischemia is debated (24-29). In this study, an association of plasma hs-cTnT with several features of coronary atherosclerosis as well as the presence of myocardial ischemia was observed. However, only the global atherosclerotic burden, as assessed by CTA risk score, and not myocardial ischemia, was an independent predictor of hs-cTnT levels at multivariate analysis. Patients with coronary atherosclerosis showed significantly higher levels of hs-cTnT compared with patients without, independently of the presence of inducible myocardial ischemia (Figure 3). The mechanisms of hs-cTnT elevation in patients with stable CAD, who had no occurrence of acute events with myocyte necrosis, are not fully understood. Consistently with the present findings, it has been hypothesized that at the site of atherosclerotic lesions, dislodging and erosion processes could cause micro-embolization of atherosclerotic and thrombotic material into the microcirculation (4, 30-31). Plaques more prone to erosion have a different composition than more stable plaques. It has been very recently reported that chronic clinically silent rupture of non-calcified plaque with subsequent microembolisation may be a potential source of troponin elevation (32). These findings are in line with results from this study, in which patients with higher coronary atherosclerotic burden and mixed plaques showed higher levels of hs-cTnT than patients without.The phenomenon of microembolization can cause myocardial damage and troponin release. Mechanisms of progressive myocardial damage involve tumor necrosis factor alpha (TNF-alpha) and nitric oxide (NO) (33-35) . It has been observed in an animal model of coronary microembolization that an increase in TNF-alpha is associated with modification of myofibrillar proteins, such as tropomyosin (36). TNF-alpha binds to its receptors to activate a cascade of caspases leading to apoptosis (37-38). Microembolization also causes excessive NO and oxidation (34). Excessive NO may also trigger apoptotic pathways of cardiomyocytes (38). Importantly, in vitro studies have demonstrated that, during the apoptotic process, caspase-3 activation results in cleavage of cTn and subsequent release (4, 38-39). It remains to be established how cardiomyocytes could release cTnT. Potential mechanisms beyond rupture of plasma membrane have been suggested such as increased cellular wall permeability due to myocardial stretch or ischemia and formation and active secretion of membranous blebs from cardiac cells (24). Taking into account all these data, it is possible to hypothesize that elevated hs-cTnT levels observed in patients with stable CAD may be the result of microembolization activating the apoptotic program within cardiac myocytes. This could explain why hs-cTnT levels are associated with the extent and composition of atherosclerotic plaques in the present study. Whether this could be also the basis of the association of hs-cTnT with cardiovascular mortality in patients with stable CAD (5-6) remains to be demonstrated.In patients with HF, elevation of NT-proBNP is proportional to the extent of ventricular dysfunction (40). However elevation of this biomarker may be found in patients without HF and without overt LV dysfunction. There are a few data demonstrating the association of NT-proBNP circulating levels with coronary atherosclerosis and myocardial ischemia in patients with stable CAD (41-43). It has been found that NT-proBNP plasma levels were elevated in patients with obstructive coronary artery lesions (defined as a diameter stenosis >70%) and proportional to the number of affected vessels. Most importantly, experimental (44-45) studies have provided evidence that myocardial ischemia may cause per se an increased expression and secretion of natriuretic peptides by ventricular myocytes, triggering the release and induction of de novo synthesis of BNP. In clinical studies (41, 43, 46-48) measurement of plasma levels of NT-proBNP and BNP can distinguish patients with and without inducible ischemia with a high degree of accuracy even after adjustment for LV function (43). In this study, both coronary atherosclerotic burden and presence of inducible myocardial ischemia were predictors of higher NT-proBNP plasma levels in patients with stable CAD. However, at variance with hs-cTnT, only the presence of inducible myocardial ischemia was an independent predictor of higher NT-proBNP. Patients with obstructive coronary lesions and inducible ischemia had significantly higher values of NT-proBNP than all the other patients (Figure 2). Moreover, NT-proBNP levels were not associated with the characteristics of coronary plaques.Therefore, it is conceivable that the elevation of NT-proBNP in this study reflects the chronic and cumulative effects of repetitive myocardial ischemia due to obstructive CAD. As a matter of fact, despite patients were enrolled after exclusion of subject with LV systolic dysfunction (LVEF < 45%), LVEF and NT-proBNP were linearly correlated in the whole population and lower LVEF was an independent predictor of higher NT-proBNP values. Interestingly, only patients with obstructive coronary disease and inducible myocardial ischemia had both significantly increased NT-proBNP and signicantly decreased LVEF values as compared with all the other patient groups (Figure 3). Increased release of BNP from the cardiac myocytes may be consequent to the direct effects of repetitive ischemia on the cardiac myocytes resulting in an increased gene expression (44-45) as well as a consequence of subclinical ventricular dysfunction and mechanical myocardial stretching secondary to myocardial stunning (49). Whichever the mechanism, our results underline the relevance of circulating NT-proBNP as a marker of chronic ischemic coronary disease and are in agreement with the known prognostic role of this biomarker in patients with stable CAD (9-10).A schematic representation of the proposed mechanisms explaining the increased levels of hs-cTnT and NT-proBNP in patients with stable CAD is reported in Figure 4. ConclusionsThe present study provides evidence that circulating hs-cTnT and NT-proBNP levels, even if in the normal range, may provide different and complementary information on the presence and severity of CAD in patients with stable angina. Relative increase in circulating hs-cTnT is a marker of the coronary atherosclerotic process being related with the global atherosclerotic burden and with the type of atherosclerotic plaques. On the other hand, relative increase in circulating NT-proBNP is mainly associated with inducible myocardial ischemia due to more severe coronary lesions and expresses a subclinical LV dysfunction possibly consequent to the chronic ischemic process. According to these results, the two biomarkers may have a relevant clinical role in the screening process of patients with stable angina. Further studies are needed to define whether these biomarkers can improve the accuracy of clinical and bio-humoral models used to predict the presence, severity of CAD and outcome in patients with stable angina. In particular, the combined use of hs-cTnT and NT-proBNP may be a powerful tool to stratify these subjects prior to further clinical investigation and to target personalized treatment. As a future perspective, more information should be obtained to extend our present understanding of patho-physiological mechanisms explaining the effects of the different patterns of atherosclerotic disease on cardiac structure and endocrine function. Methodological improvements could help in this direction by providing more specific methods to distinguish intact non-degraded protein chain or proteolytic troponin degradation products (50) as well as different active peptide BNP forms instead of inactive peptide NT-proBNP (51). AcknowledgementsRoche Diagnostics International Ltd (Switzerland) kindly supplied all reagents and calibrators used in the study for the measurement of hs-cTnT and NT-proBNP plasma levels in the EVINCI population.References Valgimigli M, Biscaglia S. Stable angina pectoris. Curr Atheroscler Rep. 2014 Jul;16(7):422. Task Force Members. 2013 ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.American College of Cardiology Foundation Appropriate Use Criteria Task Force. 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Myocardial ischemia induced by rapid atrial pacing causes troponin T release detectable by a highly sensitive assay: insights from a coronary sinus sampling study. J Am Coll Cardiol. 2011 Jun 14;57(24):2398-405. Sabatine MS, Morrow DA, de Lemos JA, Jarolim P, Braunwald E. Detection of acute changes in circulating troponin in the setting of transient stress test-induced myocardial ischaemia using an ultrasensitive assay: results from TIMI 35. Eur Heart J. 2009 Jan;30(2):162-9. Kurz K, Giannitsis E, Zehelein J, Katus HA. Highly sensitive cardiac troponin T values remain constant after brief exercise- or pharmacologic-induced reversible myocardial ischemia. Clin Chem. 2008 Jul;54(7):1234-8.R?ysland R, Kravdal G, H?iseth AD, Nyg?rd S, Badr P, Hagve TA, Omland T, R?sj? H. Cardiac troponin T levels and exercise stress testing in patients with suspected coronary artery disease: the Akershus Cardiac Examination (ACE) 1 study. Clin Sci (Lond). 2012 Jun;122(12):599-606. 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Cardiac biomarker testing in the clinical laboratory: where do we stand? General overview of the methodology with special emphasis on natriuretic peptides. Clin Chim Acta. 2015 Mar 30;443:17-24.Figure Legends Figure 1.? Relation of hs-cTnT and NT-proBNP with extent and severity of CAD.Box plots represent hs-cTnT and NT-proBNP levels stratified per CAD severity (A) and number of plaques (B). Figure 2.?Effect of coronary atherosclerosis and inducible myocardial ischemia on hs-cTnT and NT-proBNP plasma levels.Circulating levels of hs-cTnT and NT-proBNP in patients subdivided according to: A) the absence of both CAD and ischemia (“Normals” group), the presence of only CAD (CAD), of only ischemia (Ischemia), and of both of them (CAD plus Ischemia) (A); B) the presence of a perfusion defect in a territory subtended by a stenotic coronary artery on CTA (matched), of all other combinations of pathologic findings (unmatched) at hybrid imaging analysis.Figure 3.?Effect of coronary atherosclerosis and inducible myocardial ischemia on LV function.Figure 4.?Schematic model illustrating the suggested mechanisms of hs-cTnT and NT-proBNP increasing plasma levels in patients with stable angina. At the site of the atherosclerotic lesions, dislodging and erosion processes could cause micro-embolization of atherosclerotic and thrombotic material into the microcirculation. This phenomenon can cause myocardial damage triggering the apoptotic process with consequently release of hs-cTnT from cardiac myocytes into peripheral circulation. Vice versa, increase in circulating NT-proBNP is mainly associated with inducible myocardial ischemia due to more severe coronary lesions and expresses a subclinical LV dysfunction possibly consequent to the chronic ischemic process. These mechanisms could be the basis of the association of hs-cTnT and NT-proBNP with cardiovascular mortality in patients with stable CAD.Table 1. Baseline clinical and biohumoral characteristics.Clinical variablesLowhs cTnT(n=188)Highhs cTnT(n=188)PvalueLowNT-proBNP(n=188)HighNT-proBNP(n=188)PvalueDemographicsAge, yr 57.7 ± 0.662.5 ± 0.6<0.000157.4 ± 0.762.8 ± 0.6<0.0001Male sex95 (42)131 (58)0.0001128 (56.6)98 (43.4)0.0016CV risk factorsFamily history of CAD70 (45.3)58 (54.7)ns70 (54.7)58 (45.3)nsDiabetes mellitus30 (33.7)59 (66.3)0.000453 (59.5)36 (40.5)0.0392Hypertension101 (45.9)124 (55.1)0.0155107 (47.6)118 (52.4)nsHypercholesterolemia116 (53)103 (47)ns111 (50.7)108 (49.3)nsObesity35 (44.9)43 (55.1)ns38 (48.7)40 (51.3)nsSmoking 48 (55.3)42 (46.7)ns49 (54.4)41 (45.6)nsLV FunctionLVEF, %60 [55-67]60 [55-65]ns62 [58.5-67]60 [50-65]<0.0001MedicationsBeta-blockers74 (49.3)76 (50.7)ns51 (34)99 (66)<0.0001Calcium antagonists17 (38.6)27 (61.4)ns19 (43.2)25 (56.8)nsARBs/ACE Inhibitors60 (37.7)99 (62.3)<0.000172 (42.3)87 (54.7)nsDiuretics25 (39)39 (61)ns 31 (48.4)33 (51.6)nsNitrates16 (43.2)21 (56.8)ns16 (43.2)21 (50.8)nsAnti-thrombotics104 (46.4)120 (53.6)ns100 (44.6)124 (55.4)0.0117Oral antidiabetics/Insulin23 (31.5)50 (68.5)0.000440 (54.8)33 (45.2)ns Statins99 (50.3)98 (49.7)ns93 (44.7)104 (55.3)nsBio-humoral variables Creatinine, mg/dL 0.82 [0.68-0.97]0.86 [0.75-1.02]0.01130.85 [0.72-1.00]0.83 [0.73-0.98]ns Glucose, mg/dL 101 [90.8-114]105.0 [93-126]0.0033104 [102-120]102 [92-115.3]nsTotal cholesterol, mg/dL 183 [147.3-220]177[142.3-209.5]ns185[1473.3-216]171[142-214.8]nsLDL cholesterol, mg/dL 103 [78-136]99 [75-128]ns107 [78-131.5]96 [75-128.2]nsHDL cholesterol, mg/dL 52 [41-65]47 [39.3-58]0.008749 [41-59]50 [40-63]nsTriglycerides, mg/dL 98 [70.3-147.5]109 [77.3-156]0.0440113 [77.3-163]98 [71.3-128.5]0.0048hs-CRP, mg/dL 0.13 [0.07-0.30]0.19 [0.09-0.38]0.04270.14 [0.07-0.36]0.18 [0.09-0.34]nsCK-MB, mg/dL 1.4 [1.0-2.1]1.9 [1.3-2.9]<0.00011.5 [1.0-2.4]1.7 [1.2-2.5]nshs-cTnT, ng/L4.2 [3.0-5.2]9.09 [7.3-12.6]<0.00015.67 [4.0-8.3]6.75 [4.5-9.6]0.0122NT-proBNP, ng/L55.3[28.05-106.3]68.0 [36.5-168.3]<0.000131.2 [16.1-49.1]132.6[87.2-206.4]<0.0001Continuous variables are presented as mean ± standard error or median [25-75 percentile], categorical variables as absolute N and (%). ARB = Angiotensin Receptor Blockers; ACE = Angiotensin Converting Enzyme.Table 2. Coronary imaging and inducible ischemia.Lowhs cTnT (n=188)Highhs cTnT (n=188)PvalueLowNT-proBNP (n=188)HighNT-proBNP (n=188)PvalueCoronary anatomy Normals80 (71.4%)32 (28.6%)<0.000167 (59.8%)45 (40.2%)0.0004 Patients with non-obstructive CAD (<50%)65 (46.1%)76 (53.9%)77 (54.6%)64 (45.4%) Patients with obstructive CAD (≥50%)43 (35%)80 (65%)44 (35.8%)79 (64.2%)Coronary plaques Patients with calcified plaque57 (41.9%)79 (58.1%)0.018266 (49.1%)70 (50.1%)nsPatients with mixed plaque87 (39.2%)135 (60.8%)<0.0001103 (46.4%)119 (53.6%)nsPatients with non-calcified plaque47 (44.3%)59 (55.7%)ns52 (49.1%)54 (50.9%)nsN. of calcified plaques0.7 ± 0.121 ± 0.13ns0.9 ± 0.10.8 ± 0.1nsN. of mixed plaques1.7 ± 0.193.3 ± 0.25<0.00012.2 ± 0.222.8 ± 0.25nsN. of non-calcified plaques0.4 ± 0.060.5 ± 0.07ns0.4 ± 0.060.5 ± 0.07nsRisk scoresCTA risk score4.0 [0.0-15.0]12.9 [5.6-23.1]<0.00017.2 [0.0-16.6]11.8 [1.7-22.3]0.0084CAC score (n= 297)6 [0-127]78 [6-423]<0.000131 [0-202]46 [0-273]nsMyocardial ischemiaPatients with inducible ischemia(any modality)37 (37.7%)61 (62.3%)0.004634 (34.7%)64 (65.3%)0.0004Patients with inducible ischemia (MPI, n=298)33 (37.1%)56 (62.9%)0.020929 (32.6%)60 (67.4%)0.0003SDS at MPI (n=298)2.76 ± 0.574.10 ± 0.650.02741.79 ± 0.395.06 ± 0.74<0.0001Continuous variables are presented as mean ± standard error or median [25-75 percentile], categorical variables as absolute N and (%).Table 3. Predictive factors of hs cTnT and NT-proBNP plasma levels at multivariate analyses.Variableshs cTnT *NT-proBNP **Coefficient (SE)PCoefficient (SE)PAge0.011 (0.003)0.00160.036 (0.007)<0.0001Sex0.278 (0.057)<0.0001- 0.391 (0.109)0.0004LVEF------- 0.993 (0.349)0.0047CTA Risk Score0.060 (0.023)0.0089------Presence of Ischemia------0.384 (0.120)0.0015* adjusted for medications significantly associated with hs cTnT at univariate analysis, including ACE inhibitors/ARBs and insulin/oral anti-diabetics.** adjusted for medications significantly associated with NT-proBNP at univariate analysis, including beta-blockers, ACE inhibitors/ARBs, anti-thrombotics, and statins. ARB = Angiotensin Receptor Blockers; ACE = Angiotensin Converting Enzyme. ................
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