Heart Failure: Is There an Ideal Biomarker?

An always-rising prevalence of heart failure (HF), formerly classified as an emerging epidemic in 1997 and still representing a serious problem of public health, imposes on us to examine more in-depth the pathophysiological mechanisms it is based on. Over the last few years, several biomarkers have been chosen and used in the management of patients affected by HF. The research about biomarkers has broadened our knowledge by identifying some underlying pathophysiological mechanisms occurring in patients with both acute and chronic HF. This review aims to provide an overview of the role of biomarkers previously identified as responsible for the pathophysiological mechanisms subtending the disease and other emerging ones to conduct the treatment and identify possible prognostic implications that may allow the optimization of the therapy and/or influence a closer follow-up. Taking the high prevalence of HF-associated comorbidities into account, an integrated approach using various biomarkers has shown promising results in predicting mortality, a preferable risk stratification, and the decrease of rehospitalizations, reducing health care costs as well.

Higher troponin T serum concentrations in hospital patients without diagnosed cardiac diseases compared to a population-based cohort.

OBJECTIVES: Upper reference limits of high-sensitivity cardiac troponin T (hs-cTnT) are derived from healthy, population-based cohorts, and are frequently exceeded in hospitalized patients. In this study we aim to systematically examine the differences between in-hospital patients with no diagnosed cardiac diseases and a population-based cohort. METHODS: Retrospective analyses were performed in two independent cohorts. We included 5,652 participants of the prospective population-based LIFE cohort as well as 9,300 patients having been treated at our hospital between 2014 and 2021. In both cohorts, subjects with diagnosed or suspected cardiac diseases were excluded. We used Spearman's rank correlation for correlation analyses of hs-cTnT serum concentrations and age. Sex- and age-adjusted 99th percentiles for hs-cTnT in subjects with preserved renal function were obtained in both cohorts. RESULTS: In both cohorts, hs-cTnT serum concentrations positively correlated with age. Male sex was associated with higher hs-cTnT serum concentrations. Persons treated in hospital showed significantly higher hs-cTnT concentrations in females and males aged above 50. While in the population-based cohort only 99th percentile hs-cTnT results of females aged above 70 and males aged above 60 years exceeded the assay's upper reference limit, the 99th percentiles of in-hospital females over 40 years and males of all age groups exceeded this threshold. CONCLUSIONS: Besides age and sex, hospitalization per se is correlated with higher serum concentrations of hs-cTnT in most age groups. Our results indicate, that unconditionally applying current hs-cTnT cut-offs to inpatients might overestimate myocardial infarction and potentially lead to overdiagnosis.

A comparison of modelled serum cTnT and cTnI kinetics after 60 min swimming.

Post-exercise elevations of cardiac troponin T (cTnT) and I (cTnI) are often used in isolation but interpreted interchangeably. Research suggests, however, that post-exercise cTn kinetic might differ with each isoform. In this cross-sectional observational study, we collected blood samples before, immediately after (5 minutes), and at 1-, 3-, 6-, 12-, and 24-hour post-exercise in a mixed cohort of 56 participants after a distance-trial of 60 min continuous swimming (age range from 14 to 22, 57.1% female). Cardiac troponin kinetics were modelled using Bayesian mixed-effects models to estimate time to peak (TTP) and peak concentration (PC) for each isoform, while controlling for participants sex, tanner stage and average relative heart rate during the test. Exercise induced an elevation of cTnT and cTnI in 93% and 75% of the participants, respectively. Cardiac troponin T peaked earlier, at 2.9 h (CI: 2.6 - 3.2 h) post-exercise, whereas cTnI peaked later, at 4.5 h (CI: 4.2 - 4.9 h). Peak concentrations for cTnT and cTnI were 2.5 ng/L, CI: 0 - 11.2 ng/L and 2.16 ng/L, CI: 0 - 22.7 ng/L, respectively. Additionally, we did not observe a systematic effect of sex and maturational status mediating cTn responses.

Evaluation of the 0 h/1 h high-sensitivity cardiac troponin T algorithm in diagnosis of non-ST-segment elevation myocardial infarction (NSTEMI) in Han population.

OBJECTIVES: A rapid 0 h/1 h algorithm using high-sensitivity cardiac troponin T (hs-cTnT) for rule-out and rule-in of non-ST-segment elevation myocardial infarction (NSTEMI) is recommended by the European Society of Cardiology. We aim to prospectively evaluate the diagnostic performance of the algorithm in Chinese Han patients with suspected NSTEMI. METHODS: In this prospective diagnostic cohort study, 577 patients presenting to the emergency department with suspected NSTEMI and recent (<12 h) onset of symptoms were enrolled. The levels of serum hs-cTnT were measured on admission, 1 h later and 4-14 h later. All patients underwent the initial clinical assessment and were triaged into three groups (rule-out, rule-in and observe) according to the 0 h/1 h algorithm. The major cardiovascular events (MACE) were evaluated at the 7-day and 30-day follow-ups. RESULTS: Among 577 enrolled patients, NSTEMI was the final diagnosis for 106 (18.4%) patients. Based on the hs-cTnT 0 h/1 h algorithm, 148 patients (25.6%) were classified as rule-out, 278 patients (48.2%) as rule-in and 151 patients (26.2%) were assigned to the observe group. The rule-out approach resulted in a sensitivity of 100% and negative predictive value of 100%. The rule-in approach resulted in a specificity of 62.9% [95% CI (58.5-67.2%)] and positive predictive value of 37.1% [95%CI (31.3-42.8%)]. No MACE was observed in the rule-out group within 30-day follow-up. CONCLUSIONS: The hs-cTnT 0 h/1 h algorithm is a safe tool for early rule-out of NSTEMI, while probably not an effective strategy for accurate rule-in of NSTEMI in Chinese Han population.

Establishment of the reference interval for high-sensitivity cardiac troponin T in healthy children of Chongqing Nan'an district.

OBJECTIVE: To detect the concentration of high-sensitivity cardiac troponin T (hs-cTnT) in healthy children aged 0-14 years by electrochemiluminescence immunoassay (ECLIA), so as to explore the differences in different ages and genders. The aim of this study is to establish the reference interval for hs-cTnT in healthy children aged 0-14 years. METHODS: After screening, 3463 healthy children, including 1924 boys and 1539 girls, were selected from 4617 children aged 0-14 years. They were divided into nine groups: one day (umbilical cord blood; 'UCB'), one day (venous blood; 'VB'), 2-28 days, 29 days-<3 months, 3-<6 months, 6 months-<1 year old, 1-< 3 years old, 3-< 6 years old and 6-14 years old. A nonparametric test was used to detect the hs-cTnT concentration. The upper limit of the reference interval is the mean of the 99th percentile after bootstrap sampling. RESULTS: Hs-cTnT levels conformed to a non-Gaussian distribution. There was no significant difference in the concentration of hs-cTnT between boys and girls in the general data, but there were differences between boys and girls in the 3-<6 years old and 6-14 years old age groups. Except for UCB and 2-28 days, the concentration of hs-cTnT was significantly different in other age groups. The level of hs-cTnT in neonatal serum (2-28 days) was the highest. In other groups, it decreased gradually with age and dropped to the reference range of adults (0-14ng/L) at one-year old. The upper limit of reference interval of hs-cTnT concentration in each group was, respectively, 60.8, 78.8, 96.6, 58.6, 34.2, 16.2, 11.4, 8.0 (7.8 female), and 7.9 (7.3 female) ng/L. CONCLUSIONS: Referring to WS/T 402-2012 establishment of reference intervals for clinical laboratory testing projects and CLSI (Clinical and Laboratory Standards Institute) C28-A3 documents and the joint expert consensus of ESC (European Society of Cardiology) and ACC (American College of Cardiology) in 2007, we established the reference interval of hs-cTnT concentration in children aged 0-14 years in Chongqing Nan'an district of China which can provide certain reference value for clinical diagnosis and treatment of myocarditis and myocardial (micro) injury in children.

Biomarkers assessment in patients with Chagas disease and systemic arterial hypertension.

Chagas disease (ChD) and systemic arterial hypertension (SAH) are two severe comorbidities that lead to mortality and a reduction in people's quality of life, with an impact on public health. The aim of this study was to quantify the biomarkers of cardiac injury in patients with ChD and SAH. Eighty patients were divided into four groups: 20 hypertensive patients, 20 ChD-hypertensive patients, 20 ChD patients, and 20 normotensive volunteers; all of them came from outpatient's public health services. Among the evaluated markers for cardiac lesions (creatine kinase, creatine kinase-MB isoform, myoglobin, high-sensitive cardiac troponin T[hs-cTnT], B-type natriuretic peptide [BNP], and C-reactive protein), hs-cTnT and BNP were the most appropriate. Importantly, our results showed that the cut off point for hs-cTnT could be < 0.007 ng/mL, which could lead to the early detection of myocardial lesions. The BNP and hs-cTnT levels were high only in the ChD and ChD-hypertensive patient groups, suggesting that Chagas' disease may play an important role in the increase of these biomarkers. ChD patients, hypertensive or not, with cardiac or cardiodigestive involvement presented significantly higher values of hs-cTnT (p < 0.001) and BNP (p = 0.001) than ChD patients with indeterminate and digestive forms, which strengthens the validation of these markers for the follow-up of clinical cardiac form of ChD. This study suggests that the BNP and hs-cTnT can be used as possible indirect biomarkers of cardiac damage. In addition, the reference values of these biomarkers in Chagas and hypertensive cardiomyopathies should be better understood with further studies.

Associations of Cardiac, Kidney, and Diabetes Biomarkers With Peripheral Neuropathy among Older Adults in the Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population. METHODS: We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro-B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, ß-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A1c [Hb A1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016-2017; age 71-94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors. RESULTS: In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44-3.22]; no diabetes: OR, 2.31 [95%CI, 1.76-3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08-1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22-1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A1c (OR, 1.76 [95% CI, 1.22-2.54]), fructosamine (OR, 1.71 [95% CI, 1.19-2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03-2.03]) with PN were significant only among participants with diabetes. CONCLUSIONS: Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Cancer Survivorship and Subclinical Myocardial Damage.

Cancer survivors might have an excess risk of cardiovascular disease (CVD) resulting from toxicities of cancer therapies and a high burden of CVD risk factors. We sought to evaluate the association of cancer survivorship with subclinical myocardial damage, as assessed by elevated high-sensitivity cardiac troponin T (hs-cTnT) test results. We included 3,512 participants of the Atherosclerosis Risk in Communities Study who attended visit 5 (2011-2013) and were free of CVD (coronary heart disease, heart failure, or stroke). We used multivariate logistic regression to evaluate the cross-sectional associations of survivorship from any, non-sex-related, and sex-related cancers (e.g., breast, prostate) with elevated hs-cTnT (≥14 ng/L). Of 3,512 participants (mean age, 76 years; 62% women; 21% black), 19% were cancer survivors. Cancer survivors had significantly higher odds of elevated hs-cTnT (OR = 1.26, 95% CI: 1.03, 1.53). Results were similar for survivors of non-sex-related and colorectal cancers, but there was no association between survivorship from breast and prostate cancers and elevated hs-cTnT. Results were similar after additional adjustments for CVD risk factors. Survivors of some cancers might be more likely to have elevated hs-cTnT than persons without prior cancer. The excess burden of subclinical myocardial damage in this population might not be fully explained by traditional CVD risk factors.

The clinical prognostic significance of hs-cTnT elevation in patients with acute ischemic stroke.

BACKGROUND: Cardiac autonomic dysfunction caused by ischemic stroke might lead to an adverse outcome. Elevated high sensitivity cardiac troponin (hs-cTnT) is a marker of cardiac disease, it can elevate in acute stroke patients. The aim of the present study was to investigate association between serum hs-cTnT with prognosis among patients with acute ischemic stroke. METHODS: Five hundred and sixteen patients (mean age 66.19 ± 10.11) with acute ischemic stroke underwent a comprehensive clinical investigation and serum hs-cTnT activity test. All patients were followed up for 3 months. The prognosis was death or major disability (modified Rankin Scale score ≥ 3) at 3 months after acute ischemic stroke. RESULTS: 22.87% (118/516) of patients had serum hs-cTnT elevation (≥14 ng/l). Compared with normal hs-TnT group, the incidence of insular stroke (adjusted odds ratio, 2.84; 95% confidence interval, 1.48-4.17; P = 0.001) were more likely in patients with hs-cTnT elevation. In fully adjusted models, there was an association between serum hs-cTnT elevation and death (adjusted odds ratio, 3.14; 95% confidence interval, 1.16-8.49; P = 0.02) and major disability(adjusted odds ratio, 2.07; 95% confidence interval, 1.04-4.51; P = 0.04), and composite outcome(adjusted odds ratio,2.22;95% confidence interval,1.10-4.48; P = 0.03). CONCLUSIONS: Higher levels of serum hs-cTnT were independently associated with increased risk of death or major disability after stroke onset, suggesting that serum hs-cTnT may have prognostic value in poor outcomes of ischemic stroke.

Determination of age- and sex-specific 99th percentiles for high-sensitive troponin T from patients: an analytical imprecision- and partitioning-based approach.

BACKGROUND: Detection of acute myocardial infarction (AMI) is mainly based on a rise of cardiac troponin with at least one value above the 99th percentile upper reference limit (99th URL). However, circulating high-sensitive cardiac troponin T (hs-cTnT) concentrations depend on age, sex and renal function. Using an analytical imprecision-based approach, we aimed to determine age- and sex-specific hs-cTnT 99th URLs for patients without chronic kidney disease (CKD). METHODS: A 3.8-year retrospective analysis of a hospital laboratory database allowed the selection of adult patients with concomitant plasma hs-cTnT (<300 ng/L) and creatinine concentrations, both assayed twice within 72 h with at least 3 h between measurements. Absence of AMI was assumed when the variation between serial hs-cTnT values was below the adjusted-analytical change limit calculated according to the inverse polynomial regression of analytical imprecision. Specific URLs were determined using Clinical and Laboratory Standards Institute (CLSI) methods, and partitioning was tested using the proportion method, after adjustment for unequal prevalences. RESULTS: After outlier removal (men: 8.7%; women: 6.6%), 1414 men and 1082 women with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 were assumed as non-AMI. Partitioning into age groups of 18-50, 51-70 and 71-98 years, the hs-cTnT 99th URLs adjusted on French prevalence were 18, 33, 66 and 16, 30, 84 ng/L for men and women, respectively. Age-partitioning was clearly required. However, sex-partitioning was not justified for subjects aged 18-50 and 51-70 years for whom a common hs-cTnT 99th URLs of about 17 and 31 ng/L could be used. CONCLUSIONS: Based on a laboratory approach, this study supports the need for age-specific hs-cTnT 99th URLs.

Effects of acute, intermittent exercise in hypoxic environments on the release of cardiac troponin.

The purpose of this study was to examine the effects of acute, intermittent exercise performed in hypoxic environments on the release of cardiac troponin (cTn). Ten well-trained, male marathon runners (22.1 ± 2.6 years, 64.0 ± 4.9 kg and 177.3 ± 3.9 cm) completed three intermittent exercise protocols under normoxic (trial N) and hypoxic (trial AH and RH) conditions. In trial N, the fraction of inspiration oxygen (FIO2 ) was 21.0% and exercise intensity was 90% and 50% normoxic velocity of VO2max (vVO2max). In trial AH, FIO2 was 14.4% (simulated altitude of 3000 m) and exercise intensity was 90% and 50% normoxic vVO2max. In trial RH, FIO2 was 14.4% and exercise intensity was 90% and 50% hypoxic vVO2max. High-sensitivity cardiac troponin T (hs-cTnT) and cardiac troponin I (cTnI) were measured pre- and 0, 2, 4, and 24 h post-exercise. Hs-cTnT was elevated in all three trials, peaking at 2 to 4 h and returning to the baseline 24 h post-exercise. CTnI increased in trial AH, peaking at 2 to 4 h and returning below the detection limit 24 h post-exercise. It is concluded that the stimulus of hypoxia did not in and of itself induce more cTn to be released, but exercise intensity could affect this response in hypoxic environments.

Assessed value of high-sensitivity cardiac troponin T for cardiovascular disease among CKD patients.

Objective To analyze the relationship between serum high-sensitivity cardiac troponin T (hs-cTnT) and cardiovascular disease (CVD) among non-dialysis chronic kidney disease (CKD) patients, and to further explore its value of evaluating and predicting CVD in this population. Methods Five hundred and fifty-seven non-dialysis CKD patients were involved in this cross-sectional study. The relationship between serum hs-cTnT and CVD was analyzed using comparison between groups and regression analysis, and its value on assessing cardiac structure and function was evaluated by ROC curves. Results Median level of hs-cTnT was 13 (7-29) ng/L, with 1.7% undetectable, 46.4% greater than 99th percentile of the general population. Multivariate analysis suggested that compared with the lowest quartile of hs-cTnT, the highest quartile was approximately six times as likely to develop into LVH (OR, 6.515; 95% CI, 3.478-12.206, p < 0.05) and 18 times as likely to progress to left ventricular diastolic dysfunction(OR, 18.741; 95% CI, 2.422-145.017, p < 0.05). And Ln cTnT level had a more modest association with LVEF (OR, -1.117; 95% CI, -5.839 to -0.594; p < 0.05). When evaluated as a screening test, the area under the curve of ROC curves for hs-cTnT was 0.718, 0.788 and 0.736, respectively (p < 0.05). With a specificity of 90% as a diagnostic criterion, the value of hs-cTnT to evaluate LVH, LVEF < 50%, left ventricular diastolic dysfunction increased across CKD stages, from CKD 1 stage to CKD 5 stage. Conclusions In CKD non-dialysis population, hs-cTnT and NT-proBNP were valuable for evaluating LVH, left ventricular systolic dysfunction and left ventricular diastolic dysfunction.

Association of high-sensitivity cardiac troponin T and natriuretic peptide with incident ESRD: the Atherosclerosis Risk in Communities (ARIC) study.

BACKGROUND: Epidemiologic data for cardiac abnormality predating decreased kidney function are sparse. We investigated the associations of high-sensitivity cardiac troponin T (hs-cTnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) with end-stage renal disease (ESRD) risk in a community-based cohort. STUDY DESIGN: A prospective cohort study. SETTING & PARTICIPANTS: 10,749 white and black participants at the fourth visit (1996-1998) of the Atherosclerosis Risk in Communities (ARIC) Study with follow-up through 2010. PREDICTOR: hs-cTnT (3, 6, 9, and 14ng/L) and NT-proBNP (41.6, 81.0, 142.5, and 272.5pg/mL) levels were divided into 5 categories at the same percentiles (32th, 57th, 77th, and 91th; corresponding to ordinary thresholds of hs-cTnT), with the lowest category as a reference. OUTCOMES: Incident ESRD defined as initiation of dialysis therapy, transplantation, or death due to kidney disease. MEASUREMENTS: Relative risk and risk prediction of ESRD according to hs-cTnT and NT-proBNP levels based on Cox proportional hazards models. RESULTS: During a median follow-up of 13.1 years, 235 participants developed ESRD (1.8 cases/1,000 person-years). hs-cTnT and NT-proBNP levels were associated with ESRD risk independently of each other and of potential confounders, including kidney function and albuminuria (adjusted HRs for highest category, 4.43 [95% CI, 2.43-8.09] and 2.28 [95% CI, 1.44-3.60], respectively). For hs-cTnT level, the association was significant even at the third category (HR for 6-8ng/L of hs-cTnT, 2.74 [95% CI, 1.54-4.88]). Their associations were largely consistent even among persons without decreased kidney function or history of cardiovascular disease. hs-cTnT and NT-proBNP levels both significantly improved ESRD prediction (C statistic differences of 0.0084 [95% CI, 0.0005-0.0164] and 0.0045 [95% CI, 0.0004-0.0087], respectively, from 0.884 with conventional risk factors). LIMITATIONS: Relatively small number of ESRD cases and single measurement of hs-cTnT and NT-proBNP. CONCLUSIONS: hs-cTnT and NT-proBNP levels independently predicted ESRD risk in the general population, with more evident results for hs-cTnT. These results suggest the involvement of cardiac abnormality, particularly cardiac injury, in the progression of reduced kidney function and/or may reflect the useful property of hs-cTnT as an end-organ damage marker.

Individual variability of high-sensitivity cardiac troponin levels after aerobic exercise is not mediated by exercise mode.

We compared the response of high-sensitivity cardiac troponin T (hs-cTnT) after 60 min of swimming, running and cycling in well-trained triathletes. The maximal increase in hs-cTnT was similar in all exercise bouts (swimming 453%, cycling 349% and running 471%) although there was substantial individual variability in peak hs-cTnT. The post-exercise kinetics for hs-cTnT was consistent. The change in hs-cTnT was correlated between trials. In all trials, hs-cTnT had largely returned to baseline levels 24 h post-exercise. In summary, an increase in hs-cTnT was apparent in all triathletes independent of exercise mode and despite variable peak data the consistent kinetics over 24 h post-exercise would suggest this represents a physiological phenomenon.

Timing of Dynamic NT-proBNP and hs-cTnT Response to Exercise Challenge in Asymptomatic Children with Moderate Aortic Valve Regurgitation or Moderate Aortic Valve Stenosis.

Patients with congenital aortic valve stenosis (AVS) can remain asymptomatic but may develop progressive and often underestimated exercise intolerance. The risk of increased left ventricular (LV) wall stress, irreversible myocardial fibrosis and sudden death in untreated patients warrants earlier intervention. The timing for curative therapy for severe AVS is clear, but optimal timing for moderate stenosis (modAS) is unknown. AVS often coexists with aortic regurgitation, which adds a volume overload to an already pressure-overloaded LV, adding an additional challenge to the estimation of disease severity. We investigated the possible value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) upon treadmill exercise challenge in children with asymptomatic modAS versus moderate regurgitation (modAR). The aim was to determine optimal timing of peak biochemical response. Blood samples were obtained at rest, and then at 20, 40 and 60 min after peak exercise comparing modAS and modAR to healthy controls. Exercise performance was equivalent in all groups, with no difference for biomarker levels at rest. The increase in NT-proBNP was significant in modAR at 40 min (99.2 ± 48.6 ng/L; p = 0.04) and 60 min into recovery (100.0 ± 53.7 ng/L; p = 0.01), but not in modAS. The increase in hs-cTnT was significant only at 60 min into recovery for modAS and modAR. NT-proBNP and hs-cTnT following exercise challenge are possible discriminant biomarkers of modAR from modAS and controls at 60 min into recovery despite comparable exercise performance. This offers a promising avenue for future stratification of aortic valve disease and optimal timing of intervention.

Age-specific 99th percentile cutoff of high-sensitivity cardiac troponin T for early prediction of non-ST-segment elevation myocardial infarction (NSTEMI) in middle-aged patients.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) assay is used in the diagnosis and risk assessment of patients with symptoms of myocardial infarction. This study was undertaken to establish an age-specific 99th percentile cutoff value for hs-cTnT in Chinese population, and to evaluate its potential for early prediction of non-ST-segment elevation myocardial infarction (NSTEMI) in middle-aged patients. METHODS: Troponin T levels in blood obtained from healthy Chinese adults were assayed using hs-cTnT. The distribution was plotted and 99th percentiles were determined by nonparametric statistics. Prediction performance at the conventional cutoff (14 ng/L) recommended by the Roche company was compared with the age-specific cutoff for NSTEMI in 100 middle-aged patients (40-60 years of age) with acute chest pain. RESULTS: The 99th percentile for hs-cTnT was 14 ng/L for patients ≥60 years of age and 11 ng/L for those <60. Fifty of the 100 patients were finally diagnosed with NSTEMI. The age-specific 99th percentile cutoff value of 11 ng/L identified a higher number of patients with NSTEMI than the conventional 14 ng/L cutoff (46 vs. 40 patients), although the difference was not statistically significant (P = 0.084). In addition, the sensitivity of hs-cTnT increased from 80 to 92% and the negative predictive values increased from 82.4 to 91.8%. CONCLUSION: Using 11 ng/L as a decision-making cutoff point for hs-cTnT facilitated earlier prediction of NSTEMI in middle-aged patients than the conventional 14 ng/L cutoff. Further studies are needed to confirm this finding in larger group of patients.

Heart Failure Risk Assessment Using Biomarkers in Patients With Atrial Fibrillation: Analysis From COMBINE-AF.

BACKGROUND: Heart failure (HF) is common among patients with atrial fibrillation (AF), and accurate risk assessment is clinically important. OBJECTIVES: The goal of this study was to investigate the incremental prognostic performance of N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), and growth differentiation factor (GDF)-15 for HF risk stratification in patients with AF. METHODS: Individual patient data from 3 large randomized trials comparing direct oral anticoagulants (DOACs) with warfarin (ARISTOTLE [Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation], ENGAGE AF-TIMI 48 [Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis In Myocardial Infarction 48], and RE-LY [Randomized Evaluation of Long-Term Anticoagulation Therapy]) from the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) cohort were pooled; all patients with available biomarkers at baseline were included. The composite endpoint was hospitalization for HF (HHF) or cardiovascular death (CVD), and secondary endpoints were HHF and HF-related death. Cox regression was used, adjusting for clinical factors, and interbiomarker correlation was addressed using weighted quantile sum regression analysis. RESULTS: In 32,041 patients, higher biomarker values were associated with a graded increase in absolute risk for CVD/HHF, HHF, and HF-related death. Adjusting for clinical variables and all biomarkers, NT-proBNP (HR per 1 SD: 1.68; 95% CI: 1.59-1.77), hs-cTnT (HR: 1.39; 95% CI: 1.33-1.44), and GDF-15 (HR: 1.20; 95% CI: 1.15-1.25) were significantly associated with CVD/HHF. The discrimination of the clinical model improved significantly upon addition of the biomarkers (c-index: 0.70 [95% CI: 0.69-0.71] to 0.77 [95% CI: 0.76-0.78]; likelihood ratio test, P < 0.001). Using weighted quantile sum regression analysis, the contribution to risk assessment was similar for NT-proBNP and hs-cTnT for CVD/HHF (38% and 41%, respectively); GDF-15 provided a statistically significant but lesser contribution to risk assessment. Results were similar for HHF and HF-related death, individually, and across key subgroups of patients based on a history of HF, AF pattern, and reduced or preserved left ventricular ejection fraction. CONCLUSIONS: NT-proBNP, hs-cTnT, and GDF-15 contributed significantly and independently to the risk stratification for HF endpoints in patients with AF, with hs-cTnT being as important as NT-proBNP for HF risk stratification. Our findings support a possible future use of these biomarkers to distinguish patients with AF at low or high risk for HF.

Luteinizing hormone is independently associated with high-sensitive cardiac troponin T elevation in postmenopausal T2DM patients: A cross-sectional study.

BACKGROUND: It is known that the risk of ischemic heart disease increases in patients with type 2 diabetes mellitus (T2DM). For female patients, the incidence of heart disease can be even greater after menopause, accompanied by dramatic changes in sex hormones. We investigated the correlations between sex hormones and markers of ischemic heart diseases in postmenopausal females with T2DM patients. METHODS: This cross-sectional study collected data from 324 hospitalized postmenopausal females with T2DM. Multiple linear regression analyses were conducted to determine the correlations between sex hormones and cardiac markers including high-sensitive cardiac troponin T (hs-cTnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels. RESULTS: Multiple linear regression analyses revealed that luteinizing hormone (LH) was positively and independently associated with hs-cTnT concentrations in postmenopausal females with T2DM (ß = 0.189, p = 0.002). Postmenopausal females with T2DM and subclinical myocardial injury had higher LH levels than those without subclinical myocardial injury (29.67 vs. 25.08 mIU/mL, p < 0.001). A multivariate logistic regression analysis confirmed an independent and significant association between elevated LH and subclinical myocardial injury in postmenopausal females with T2DM (adjusted odds ratio [OR] = 1.077, 95% confidence interval [CI], 1.033-1.124; p < 0.001). As another gonadotropin, the follicle-stimulating hormone did not show independent correlations with hs-cTnT or NT-proBNP (p > 0.05). Neither estrogen nor testosterone was correlated with cardiac markers. CONCLUSIONS: Elevated LH levels were positively and independently associated with increased hs-cTnT levels in postmenopausal women with T2DM. Our findings suggest that LH could serve as a potential marker for assessing the risk of subclinical myocardial injury in postmenopausal females with T2DM.

EASIX (endothelial activation and stress index) predicts mortality in patients with coronary artery disease.

BACKGROUND: Coronary interventions reduce morbidity and mortality in patients with acute coronary syndrome. However, the risk of mortality for patients with coronary artery disease (CAD) additionally depends on their systemic endothelial health status. The 'Endothelial Activation and Stress Index' (EASIX) predicts endothelial complications and survival in diverse clinical settings. OBJECTIVE: We hypothesized that EASIX may predict mortality in patients with CAD. METHODS: In 1283 patients undergoing coronary catheterization (CC) and having a diagnosis of CAD, EASIX was measured within 52 days (range - 1 year to - 14 days) before CC and correlated with overall survival. In an independent validation cohort of 1934 patients, EASIXval was measured within 174 days (+ 28 days to + 11 years) after CC. RESULTS: EASIX predicted the risk of mortality after CC (per log2: hazard ratio (HR) 1.29, 95% confidence interval: [1.18-1.41], p < 0.001) in multivariable Cox regression analyses adjusting for age, sex, a high-grade coronary stenosis ≥ 90%, left ventricular ejection fraction, arterial hypertension and diabetes. In the independent cohort, EASIX correlated with EASIXval with rho = 0.7. The long-term predictive value of EASIXval was confirmed (per log2: HR 1.53, [1.42-1.64], p < 0.001) and could be validated by integrated Brier score and concordance index. Pre-established cut-offs (0.88-2.32) associated with increased mortality (cut-off 0.88: HR training: 1.63; HR validation: 1.67, p < 0.0001 and cut-off 2.32: HR training: 3.57; HR validation: 4.65, p < 0.0001). CONCLUSIONS: We validated EASIX as a potential biomarker to predict death of CAD patients, irrespective of the timing either before or after catheterization.