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Aims: Genetic dilated cardiomyopathy (DCM) is a leading cause of heart failure. Despite significant progress in understanding the genetic aetiologies of DCM, the molecular mechanisms underlying the pathogenesis of familial DCM remain unknown, translating to a lack of disease-specific therapies. The discovery of novel targets for the treatment of DCM was sought using phenotypic sceening assays in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) that recapitulate the disease phenotypes in vitro., Methods and Results: Using patient-specific iPSCs carrying a pathogenic TNNT2 gene mutation (p.R183W) and CRISPR-based genome editing, a faithful DCM model in vitro was developed. An unbiased phenotypic screening in TNNT2 mutant iPSC-derived cardiomyocytes (iPSC-CMs) with small molecule kinase inhibitors (SMKIs) was performed to identify novel therapeutic targets. Two SMKIs, Gö 6976 and SB 203580, were discovered whose combinatorial treatment rescued contractile dysfunction in DCM iPSC-CMs carrying gene mutations of various ontologies (TNNT2, TTN, LMNA, PLN, TPM1, LAMA2). The combinatorial SMKI treatment upregulated the expression of genes that encode serine, glycine, and one-carbon metabolism enzymes and significantly increased the intracellular levels of glucose-derived serine and glycine in DCM iPSC-CMs. Furthermore, the treatment rescued the mitochondrial respiration defects and increased the levels of the tricarboxylic acid cycle metabolites and ATP in DCM iPSC-CMs. Finally, the rescue of the DCM phenotypes was mediated by the activating transcription factor 4 (ATF4) and its downstream effector genes, phosphoglycerate dehydrogenase (PHGDH), which encodes a critical enzyme of the serine biosynthesis pathway, and Tribbles 3 (TRIB3), a pseudokinase with pleiotropic cellular functions., Conclusions: A phenotypic screening platform using DCM iPSC-CMs was established for therapeutic target discovery. A combination of SMKIs ameliorated contractile and metabolic dysfunction in DCM iPSC-CMs mediated via the ATF4-dependent serine biosynthesis pathway. Together, these findings suggest that modulation of serine biosynthesis signalling may represent a novel genotype-agnostic therapeutic strategy for genetic DCM., Competing Interests: Conflict of interest: M.M. is a shareholder and an advisory board member of Vala Sciences. R.S. is a consultant of Vala Sciences. The other authors declare no competing interests., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging., Methods and Results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone., Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology)

Aims: Non-contrast T1-weighted imaging (T1WI) has emerged as a novel non-invasive imaging for vulnerable coronary plaque showing a high-intensity plaque (HIP). However, the association between HIP and percutaneous coronary intervention (PCI) has not been evaluated. We investigated the association between the presence of HIP and the incidence of myocardial injury after PCI., Methods and Results: A total of 77 patients with stable angina were imaged with non-contrast T1WI by using a 1.5 T magnetic resonance system (HIP and non-HIP group, N = 31 and 46 patients, respectively). We defined HIP as a coronary plaque to myocardium signal intensity ratio (PMR) of ≥1.4. High-sensitive cardiac troponin-T (hs-cTnT) was measured at baseline and 24 h after PCI. Percutaneous coronary intervention-related myocardial injury (PMI) was defined as an elevation of hs-cTnT >5× 99th percentile upper reference limit. High-intensity plaque was associated with the characteristics of ultrasound attenuation and positive remodelling on intravascular ultrasound. Although baseline hs-cTnT was similar between the groups, increase in hs-cTnT was significantly greater in the HIP vs. non-HIP group (0.065 [0.023-0.304] vs. 0.017 [0.005-0.026], P < 0.001). Percutaneous coronary intervention-related myocardial injury occurred more frequently in the HIP than non-HIP group (58.1 vs. 10.9%, P < 0.001), and the cut-off value of PMR found to be 1.44 for predicting PMI (sensitivity 78.3% and specificity 81.5%). In multivariate analysis, a PMR of ≥1.4 was a significant predictor of PMI (odds ratio 5.63, 95% confidence interval 1.28-24.7, P = 0.022)., Conclusion: High-intensity plaque on non-contrast T1WI was characterized as vulnerable coronary plaque on IVUS and was associated with higher incidence of PMI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Aims: This randomized controlled trial (RCT) evaluated whether a process with single combined testing of copeptin and troponin at admission in patients with low-to-intermediate risk and suspected acute coronary syndrome (ACS) does not lead to a higher proportion of major adverse cardiac events (MACE) than the current standard process (non-inferiority design)., Methods and Results: A total of 902 patients were randomly assigned to either standard care or the copeptin group where patients with negative troponin and copeptin values at admission were eligible for discharge after final clinical assessment. The proportion of MACE (death, survived sudden cardiac death, acute myocardial infarction (AMI), re-hospitalization for ACS, acute unplanned percutaneous coronary intervention, coronary artery bypass grafting, or documented life threatening arrhythmias) was assessed after 30 days. Intention to treat analysis showed a MACE proportion of 5.17% [95% confidence intervals (CI) 3.30-7.65%; 23/445] in the standard group and 5.19% (95% CI 3.32-7.69%; 23/443) in the copeptin group. In the per protocol analysis, the MACE proportion was 5.34% (95% CI 3.38-7.97%) in the standard group, and 3.01% (95% CI 1.51-5.33%) in the copeptin group. These results were also corroborated by sensitivity analyses. In the copeptin group, discharged copeptin negative patients had an event rate of 0.6% (2/362)., Conclusion: After clinical work-up and single combined testing of troponin and copeptin to rule-out AMI, early discharge of low- to intermediate risk patients with suspected ACS seems to be safe and has the potential to shorten length of stay in the ED. However, our results need to be confirmed in larger clinical trials or registries, before a clinical directive can be propagated., (© The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: It is unknown whether cardiac troponin (cTn) I or cTnT is the preferred biomarker in the early diagnosis of acute myocardial infarction without ST segment elevation (NSTEMI)., Methods and Results: In a prospective multicentre study, we measured cTnI and cTnT using clinically available high-sensitivity assays (hs-cTnI Abbott and hs-cTnT Roche) and compared their diagnostic and prognostic accuracies in consecutive patients presenting to the emergency department with acute chest pain. The final diagnosis was adjudicated by two independent cardiologists using all information pertaining to the individual patient. The mean follow-up was 24 months. Among 2226 consecutive patients, 18% had an adjudicated final diagnosis of NSTEMI. Diagnostic accuracy at presentation as quantified by the area under the receiver-operating-characteristics curve (AUC) for NSTEMI was very high and similar for hs-cTnI [AUC: 0.93, 95% confidence interval (CI) 0.92-0.94] and hs-cTnT (0.94, 95% CI: 0.92-0.94) P = 0.62. In early presenters (<3 h since chest pain onset) hs-cTnI showed a higher diagnostic accuracy (AUC: 0.92, 95% CI: 0.89-0.94) when compared with hs-cTnT AUC (0.89, 95% CI: 0.86-0.91) (P = 0.019), while hs-cTnT was superior in late presenters [AUC hs-cTnT 0.96 (95% CI: 0.94-0.96)  vs. hs-cTnI 0.94 (95% CI: 0.93-0.95); P = 0.007]. The prognostic accuracy for all-cause mortality, quantified by AUC, was significantly higher for hs-cTnT (AUC: 0.80; 95% CI: 0.78-0.82) when compared with hs-cTnI (AUC: 0.75; 95% CI: 0.73-0.77; P < 0.001)., Conclusion: Both hs-cTnI and hs-cTnT provided high diagnostic and prognostic accuracy. The direct comparison revealed small but potentially important differences that might help to further improve the clinical use of hs-cTn., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aim: Clinical cardiovascular disease is a major risk factor for cognitive impairment and dementia. However, less is known about the association of subclinical myocardial damage with cognition and dementia. We sought to examine the associations of high-sensitivity cardiac troponin T (hs-cTnT) with cognition and dementia., Methods and Results: Cross-sectional analysis of cognition (baseline 1996-98) and prospective analysis of dementia (follow-up through 2010) in 9472 participants in the Atherosclerosis Risk in Communities study. High-sensitivity cardiac troponin T was measured using a novel highly sensitive assay with a lower limit of the blank of 3 ng/L. Cognitive function was assessed by three tests: the delayed word recall test (DWRT), the digit symbol substitution test (DSST), and the word fluency test (WFT). Dementia was defined using ICD-9 codes. Linear regression and Cox models were adjusted for traditional cardiovascular risk factors. The mean age of participants was 63 years, 59% were female, 21% were black, and 66% had hs-cTnT ≥3 ng/L. In cross-sectional analyses, higher hs-cTnT was associated with lower scores on the DSST (P-trend < 0.001) and the WFT (P-trend = 0.002), but not on the DWRT (P-trend = 0.089). Over a median of 13 years, there were 455 incident dementia hospitalizations. In prospective analyses, higher baseline concentrations of hs-cTnT were associated with an increased risk for dementia hospitalizations overall (P-trend < 0.001) and for vascular dementia (P-trend = 0.029), but not for Alzheimer's dementia (P-trend = 0.212)., Conclusion: Elevations in baseline concentrations of hs-cTnT were associated with lower cognitive test scores at baseline and increased dementia hospitalization risk during the follow-up. Our results suggest that subclinical myocardial injury is associated with cognition and dementia., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Aims: We aimed to evaluate the incremental value of high-sensitive troponin T (hsTnT) for risk prediction prior to non-cardiac surgery in comparison with the established revised cardiac index., Methods and Results: In this prospective, international multicentre observational study, 979 patients prior to non-cardiac surgery were enrolled. The endpoints were in-hospital mortality, the combination of death, acute myocardial infarction, cardiac arrest, cardio-pulmonary resuscitation, and acute decompensated heart failure. Twenty-five patients (2.6%) deceased and 36 (3.7%) of the patients experienced the combined endpoint. Cardiac markers were elevated in those patients who died when compared with survivors (hsTnT: 21 ng/L vs. 7 ng/L; P < 0.001; NT-proBNP: 576 pg/mL vs. 166 pg/mL; P < 0.001). Applying a cut-off for hsTnT of 14 ng/L and for NT-proBNP of 300 pg/mL, those patients with elevated hsTnT had a mortality of 6.9 vs. 1.2% (P < 0.001) and with elevated NT-proBNP 4.8 vs. 1.4% (P = 0.002). The highest AUC of the ROC curve was found for hsTnT as a predictor for mortality of 0.809. In a multivariate Cox regression analyses, hsTnT was the strongest independent predictor for the combined endpoint [HR 2.6 (95% CI: 1.3-5.3); P = 0.01]., Conclusion: High-sensitive troponin T provides strong prognostic information in patients undergoing non-cardiac surgery incremental to the widely accepted revised cardiac index.

Aims: It has been suggested that troponins and natriuretic peptides can be falsely elevated in subjects with impaired kidney function because of decreased renal clearance. The value of these biomarkers in subjects with impaired kidney function has therefore been debated. We tested in a population-based cohort study, first, whether high-sensitive troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) levels are cross-sectionally associated with the estimated glomerular filtration rate (eGFR) and albuminuria, and secondly, whether these markers are associated with cardiovascular outcome, independent of eGFR, albuminuria and conventional cardiovascular risk factors., Methods and Results: We included 8121 subjects from the PREVEND study with both values of hsTnT and NT-pro-BNP available. High-sensitive troponin T >0.01 µg/L and NT-pro-BNP >125 ng/L were defined as elevated. We first performed linear regression analyses with hsTnT and NT-pro-BNP as dependent variables. Next, we performed Cox-regression analyses, studying the associations of hsTnT and NT-pro-BNP with incident cardiovascular events. Of our cohort, 6.7% had an elevated hsTnT and 12.2% an elevated NT-pro-BNP. Also, the estimated glomerular filtration rate, albuminuria, and ECG-assessed ischaemia and left ventricular hypertrophy were all significantly associated with hsTnT and NT-pro-BNP in the linear regression analyses. Both hsTnT and NT-pro-BNP appeared associated with cardiovascular events, and these associations remained significant after adjustment for eGFR, albuminuria, age, gender and conventional cardiovascular risk factors (P= 0.03 and P< 0.001, respectively). Only a few subjects with markedly reduced renal function were included. The results presented are therefore mainly valid for a population with mildly impaired renal function., Conclusion: These data indicate that a finding of an increased hsTnT or NT-pro-BNP in subjects with chronic kidney disease stages 1/3 should be taken seriously as a prognostic marker for a worse cardiovascular outcome and not be discarded as merely a reflection of decreased renal clearance.

Aims: Systolic dysfunction in septic shock is well recognized and, paradoxically, predicts better outcome. In contrast, diastolic dysfunction is often ignored and its role in determining early mortality from sepsis has not been adequately investigated., Methods and Results: A cohort of 262 intensive care unit patients with severe sepsis or septic shock underwent two echocardiography examinations early in the course of their disease. All clinical, laboratory, and survival data were prospectively collected. Ninety-five (36%) patients died in the hospital. Reduced mitral annular e'-wave was the strongest predictor of mortality, even after adjusting for the APACHE-II score, low urine output, low left ventricular stroke volume index, and lowest oxygen saturation, the other independent predictors of mortality (Cox's proportional hazards: Wald = 21.5, 16.3, 9.91, 7.0 and 6.6, P< 0.0001, <0.0001, 0.002, 0.008, and 0.010, respectively). Patients with systolic dysfunction only (left ventricular ejection fraction ≤50%), diastolic dysfunction only (e'-wave <8 cm/s), or combined systolic and diastolic dysfunction (9.1, 40.4, and 14.1% of the patients, respectively) had higher mortality than those with no diastolic or systolic dysfunction (hazard ratio = 2.9, 6.0, 6.2, P= 0.035, <0.0001, <0.0001, respectively) and had significantly higher serum levels of high-sensitivity troponin-T and N-terminal pro-B-type natriuretic peptide (NT-proBNP). High-sensitivity troponin-T was only minimally elevated, whereas serum levels of NT-proBNP were markedly elevated [median (inter-quartile range): 0.07 (0.02-0.17) ng/mL and 5762 (1001-15 962) pg/mL, respectively], though both predicted mortality even after adjusting for highest creatinine levels (Wald = 5.8, 21.4 and 2.3, P= 0.015, <0.001 and 0.13)., Conclusion: Diastolic dysfunction is common and is a major predictor of mortality in severe sepsis and septic shock.

Cardiac troponin (cTn) I and T are structural proteins unique to the heart. Detection of cTn in peripheral blood indicates cardiomyocyte damage. As acute myocardial infarction (AMI) is the most important cause of cardiomyocyte damage, cTns have become an integral part in the diagnosis of AMI. For this indication, cTns are superior to all other biomarkers and therefore are the preferred marker for the diagnosis of AMI. However, cTn indicates and provides an estimate of cardiomyocyte damage irrespective of its cause. The major limitation of contemporary cTn assays is that they are often not elevated during the initial hours of AMI. Recent advances in assay technology have led to more sensitive and precise cTn assays that will have a profound impact on clinical practice. High-sensitive cTn (hs-cTn) assays have two differentiating features from contemporary cTn assays: (i) detection of cTn in a majority of healthy persons and (ii) precise definition of what is 'normal' (=the 99th percentile). Recent multicentre studies have shown that hs-cTn assays improve the early diagnosis of patients with suspected AMI, particularly the early rule-out. To achieve best clinical use, cTn has to be interpreted as a quantitative variable. Rising and/or falling levels differentiate acute from chronic cardiomyocyte damage. The terms 'troponin-positive' and 'troponin negative' should therefore be avoided. 'Detectable' levels will become the norm and will have to be differentiated from 'elevated' levels. The differential diagnosis of a small amount of cardiomyocyte damage and therefore minor elevations of cTn is broad and includes acute and chronic cardiac disorders. The differential diagnosis of larger amount of injury and therefore more substantial elevations of cTn is largely restricted to AMI, myocarditis, and a rare patient with tako-tsubo cardiomyopathy.

Aims: Chronic heart failure following myocardial infarction (MI) is characterized by progressive left ventricular remodelling (LVR). Despite significant improvements in MI management, LVR remains a frequent complication. Although several risk factors have been identified, such as infarct size, LVR is difficult to predict in clinical practice., Methods and Results: Using a rat model of MI and phosphoproteomic technology, we discovered that remodelling is associated with decreased levels of myocardial and plasma serine(208)-phosphorylated troponin T (TnT). To confirm the association in human plasma, we developed new specific polyclonal antibodies against human/rat serine(207/208)-phosphorylated TnT and tested plasma obtained in the first week after MI from patients with low, intermediate, and high remodelling a year later. We observed a significant decrease of serine(207)-phosphorylated TnT and of the serine(207)-phosphorylated TnT/total TnT ratio in those with intermediate or high LVR. These differences remained statistically significant when adjusted for other determinants of LVR. In contrast, baseline B-type natriuretic peptide levels were not associated with LVR., Conclusion: The level of circulating phosphorylated TnT could be a new biomarker of LVR.

Aims: To assess the role of cardiac troponin T (cTnT) levels on admission using a new, highly sensitive assay (hsTnT) in the risk assessment of normotensive patients with acute pulmonary embolism (PE)., Methods and Results: We prospectively studied 156 consecutive normotensive patients with confirmed PE. The prognostic value of hsTnT at baseline was compared with the conventional cTnT troponin assay and with N-terminal pro-brain natriuretic peptide concentrations. Long-term follow-up was available for 153 patients (98.1%). Highly sensitive troponin T values ranged from 0.001 to 357.2 pg/mL [median 27.2 (25th-75th percentile 9.4-69.4) pg/mL]. Overall, 100 patients (64%) had hsTnT > or =14 pg/mL. Baseline hsTnT was higher in patients with an adverse 30-day outcome (> or =1: death, need for catecholamines, endotracheal intubation, or cardiopulmonary resuscitation) compared with an uncomplicated course [71.7 (35.5-117.9) vs. 26.4 (9.2-68.2) pg/mL; P = 0.027]. The cut-off value of 14 pg/mL showed an excellent prognostic sensitivity and negative predictive value (both 100%). In comparison, as many as 50% of the patients with an adverse early outcome would have been misclassified as low risk by cTnT (cut-off 0.03 ng/mL). Logistic regression indicated a two-fold increase in the risk of an adverse outcome for each increase of hsTnT by 1SD of the natural logarithm (P = 0.037). Patients with elevated hsTnT levels had a reduced probability of long-term survival (P = 0.029 by log-rank); by Cox's regression analysis, hsTnT was the only laboratory biomarker predicting an elevated risk of death over the long term., Conclusion: Highly sensitive troponin T assays may be capable of improving risk stratification of non-high-risk PE.

Aims: To determine independent predictors of left ventricular (LV) dyssynchrony after non-ST elevation myocardial infarction (NSTEMI) and prognostic value of combining dyssynchrony parameters for long-term LV dysfunction., Methods and Results: Left ventricular dyssynchrony assessments were performed in 100 NSTEMI patients followed-up for 1 year using a composite dyssynchrony score. Early LV dyssynchrony was independently predicted by the presence of significant proximal left circumflex artery (LCx) stenosis and global systolic dysfunction. Left ventricular end-diastolic volume index decreased with time and was independently determined by a lower number of diseased vessels and the absence of early dyssynchrony. Left ventricular end-systolic volume index decreased with time and was independently determined by the absence of early dyssynchrony, lower number of diseased vessels, and revascularization. Left ventricular ejection fraction increased with time and was independently determined by the absence of early dyssynchrony, lower number of diseased vessels, and revascularization. The composite dyssynchrony score was an independent determinant of a persistently dilated LV and low LVEF at follow-up., Conclusion: After NSTEMI, proximal LCx stenosis and impaired LV function independently predicted LV dyssynchrony. The composite dyssynchrony score had prognostic value and identified patients with persistently dilated and impaired LV on follow-up.

Aims: This study assessed the relationship between inflammatory mediators and indices of infarct size and left-ventricular (LV) remodelling following successful primary percutaneous coronary intervention (PCI) in patients with first time ST elevation myocardial infarction (MI)., Methods and Results: Forty-two patients admitted with an occluded single vessel were recruited consecutively. Cardiac magnetic resonance was used for serial assessment (2 days, 1 week, 2 months) of infarct size, microvascular obstruction (MO), and LV remodelling. Inflammatory mediators were analysed before and after PCI. Our major findings were: (1) Following PCI, there was a marked increase in plasma levels of C-reactive protein, closely correlated with an increase in interleukin-6 and terminal complement complex, reaching maximum 2 days after PCI; (2) C-reactive protein 2 days after PCI was significantly correlated with infarct size and parameters of LV remodelling 2 months after PCI; (3) Patients with persistent MO had significantly higher C-reactive protein levels 2 days following PCI., Conclusion: We suggest that the rapid increase in C-reactive protein levels in this model of successful revascularization of a single, totally occluded vessel reflects the degree of inflammation within the infarcted area. Our findings support a role for C-reactive protein-mediated complement activation as both a marker and mediator of myocardial damage following MI. Clinical study no.: NCT 00465868.

Aims: To evaluate the role of novel biomarkers in early detection of acute myocardial infarction (MI) in patients admitted with acute chest pain., Methods and Results: A prospective study of 664 patients presenting to two coronary care units with chest pain was conducted over 3 years from 2003. Patients were assessed on admission: clinical characteristics, ECG (electrocardiogram), renal function, cardiac troponin T (cTnT), heart fatty acid binding protein (H-FABP), glycogen phosphorylase-BB, NT-pro-brain natriuretic peptide, D-dimer, hsCRP (high sensitivity C-reactive protein), myeloperoxidase, matrix metalloproteinase-9, pregnancy associated plasma protein-A, soluble CD40 ligand. A > or = 12 h cTnT sample was also obtained. MI was defined as cTnT > or = 0.03 microg/L. In patients presenting <4 h of symptom onset, sensitivity of H-FABP for MI was significantly higher than admission cTnT (73 vs. 55%; P = 0.043). Specificity of H-FABP was 71%. None of the other biomarkers challenged cTnT. Combined use of H-FABP and cTnT (either one elevated initially) significantly improved the sensitivities of H-FABP or cTnT (85%; P < or = 0.004). This combined approach also improved the negative predictive value, negative likelihood ratio, and the risk ratio., Conclusion: Assessment of H-FABP within the first 4 h of symptoms is superior to cTnT for detection of MI, and is a useful additional biomarker for patients with acute chest pain.

Aims: Comprehensive evaluation of major depressive disorder (MDD), anxiety disorder, and MDD in conjunction with anxiety disorder in stable coronary heart disease (CHD) patients, including cardiac biomarkers such as C-reactive protein (CRP), troponin T (TnT), and amino-terminal pro-B-type brain natriuretic peptide (NT-proBNP)., Methods and Results: Cross-sectional study of a consecutive series of 120 stable CHD outpatients (n = 30 with MDD, n = 30 with anxiety disorder, n = 30 with MDD and anxiety disorder, n = 30 with no psychiatric disorder). Psychiatric diagnoses were established by using the structured clinical interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-IV). Binomial logistic regression analyses using cut-off scores of biomarkers as dependent variables showed associations between CRP and generalized anxiety disorder (GAD) (P = 0.04), and education (P = 0.004), whereas MDD, and MDD and anxiety disorder did not reach the significance level. TnT showed relationships with hyperlipidaemia (P = 0.009), history of obesity or overweight (P = 0.04), and education (P = 0.04). NT-proBNP was associated with type II diabetes (P = 0.005)., Conclusion: After adjusting for relevant demographic, medical, and psychiatric co-variables, CRP was associated with GAD.

Aims: To evaluate the innocuousness of intense and prolonged exercise training above the threshold for myocardial ischaemia (1 mm ST-segment depression)., Methods and Results: Twenty-two patients with ischaemic heart disease (IHD) were randomized to exercise training either at a target intensity that induced myocardial ischaemia (ischaemic group) or that adhered to current guidelines (control group). Training was progressively increased to 60 min under continuous electrocardiographic (ECG) monitoring. Cardiac troponin T (cTnT) was measured at various intervals. Ambulatory ECG monitoring was performed before and after 6 weeks of training and left ventricular function was evaluated in the ischaemic group after at least 6 weeks of training. The ischaemic group had myocardial ischaemia during the first 20, 40, and 60 min exercise sessions for 12.3 +/- 6.8, 29.0 +/- 12.9, and 49.8 +/- 2.2 min, respectively, with ST-segment depression ranging from 1.0 to 2.1 mm. No patient in either group demonstrated significant arrhythmias or increased cTnT. The ischaemic group had preserved left ventricular function., Conclusion: In patients with IHD, prolonged and repeated ischaemic training sessions up to 60 min can be well tolerated without evidence of myocardial injury, significant arrhythmias, or left ventricular dysfunction.

Aims: The adverse prognostic significance of biomarker elevations after percutaneous coronary intervention (PCI) is well established. However, often baseline troponin values are not included in the analysis or sensitive criteria are not employed. Accordingly, we assessed the timing and magnitude of post-PCI troponin T (cTnT) levels and their relationships to outcomes in patients with and without pre-PCI baseline cTnT elevations using a sensitive assay and sensitive cut-off values., Methods and Results: cTnT was measured at baseline (pre-PCI), 8 and 16 h post-PCI in 2352 patients. A cTnT elevation was defined as > or =0.03 ng/mL. No baseline cTnT elevations were detected in 1619 patients undergoing mostly (97%) non-urgent procedures (cTnT = 0.01 +/- 0.002 ng/mL; mean +/- SD). 733 patients had baseline cTnT elevations. Only the baseline troponin value had prognostic importance. Patients with elevated cTnT baseline levels had a higher overall cumulative 12-month death/MI rate of 11.1% compared with those without elevated baseline levels of 4.7% (P < 0.05). Neither the timing nor the magnitude of the post-procedure cTnT elevations was predictive of long-term death/MI rates when baseline elevations were included in the analysis. Similar findings were observed for baseline creatine kinase-MB (CK-MB) levels. Late increases in cTnT levels (16 h post-PCI) presaged in-hospital events only., Conclusion: Long-term prognosis is most often related to the baseline pre-PCI troponin value and not the biomarker response to the PCI. These results support a re-evaluation of the use of biomarker data in relation to PCI.

Aims: Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events., Methods and Results: Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab., Conclusion: Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.

Although assays for cardiac troponin T (cTnT) and cardiac troponin I (cTnI) exhibit similar clinical performance in patients with acute coronary syndromes for diagnosis and risk stratification, there are differences in the release and clearance of these proteins from damaged myocytes. There are also differences in the percentages of patients with chronic renal failure and skeletal muscle myopathies that have abnormal results. A review of the biochemistry of these proteins may provide insights as to the nature of these differences. Cardiac troponin T has a higher overall tissue concentration and free cytoplasmic concentrations than cTnI, and appears in blood of patients with acute myocardial infarction as a mixture of complexed (cTnT-I-C) and free cTnT. Cardiac troponin I is more hydrophobic and appears in blood predominately in the binary complex (I-C) form, with smaller amounts of the ternary (T-I-C) complex. Degradation of the complex will lead to faster clearance of the protein. There are also differences in standardization and availability of commercial troponin kits. Cardiac troponin T assays are available from only one manufacturer and are standardized to a single material, whereas cTnI is available from multiple vendors. While there is some degree of correlation between assays, there are significant proportional biases between results which can be problematical when different tests are made on the same patient.