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Factors associated with baseline and serial changes in circulating NT-proBNP and high-sensitivity cardiac troponin T in a population-based cohort (Dallas Heart Study).
Puleo, CW, Ayers, CR, Garg, S, Neeland, IJ, Lewis, AA, Pandey, A, Drazner, MH, de Lemos, JA
Biomarkers in medicine. 2021;(16):1487-1498
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Abstract
Aim: N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) associate with structural heart disease and heart failure risk in individuals without known cardiovascular disease (CVD). However, few data are available regarding whether factors influencing levels of these two biomarkers are similar or distinct. We performed serial measurement of NT-proBNP and hs-cTnT in a contemporary multiethnic cohort with extensive phenotyping, with the goal of identifying their respective biological determinants in a population without known or suspected CVD. Methods: We evaluated 1877 participants of the Dallas Heart Study who had NT-proBNP and hs-cTnT measured and were free from clinical CVD at the each of its two examinations (2000-2002 and 2007-2009). Variables collected included demographic and risk factors, high-sensitivity C-reactive protein, body composition via dual-energy x-ray absorptiometry, coronary artery calcium by computed tomography, and cardiac dimensions and function by cardiac MRI. Linear regression was used to identify associations of these factors with each biomarker at baseline and with changes in biomarkers over follow-up. Results: NT-proBNP and hs-cTnT were poorly correlated at baseline (Spearman rho 0.083, p = 0.015), with only moderate correlation between change values (rho 0.18, p < 0.001). hs-cTnT positively associated and NT-proBNP inversely associated with male gender and black race. At baseline, both NT-proBNP and hs-cTnT associated with left ventricular end-diastolic volume and wall thickness, but only NT-proBNP associated with left atrial size. Changes in cardiac dimensions between phases were more strongly associated with changes in NT-proBNP than hs-cTnT. NT-proBNP was more strongly associated with high-sensitivity C-reactive protein and measures of body composition than hs-cTnT. Conclusion: Among individuals without CVD in the general population, NT-proBNP and hs-cTnT are nonredundant biomarkers that are differentially associated with demographic and cardiac factors. These findings indicate that hs-cTnT and NT-proBNP may reflect different pathophysiological pathways.
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Familial Hypertrophic Cardiomyopathy - Identification of cause and risk stratification through exome sequencing.
Biswas, A, Das, S, Kapoor, M, Shamsudheen, KV, Jayarajan, R, Verma, A, Seth, S, Bhargava, B, Scaria, V, Sivasubbu, S, et al
Gene. 2018;:151-156
Abstract
BACKGROUND Hypertrophic Cardiomyopathy (HCM) with variable clinical presentations and heterogeneity is the common cause of sudden cardiac death. Genetic diagnosis is challenging in these complex diseases but exome sequencing as a genetic diagnostic tool provides explainable results. METHODS In a familial Hypertrophic Cardiomyopathy with multigenerational inheritance with apparent phenotype, had a history of sudden death and severe arrhythmia followed by implantation of Implantable cardioverter defibrillator (ICD). Exome sequencing (100×) trailed by effective filtering steps for exome variants on the basis of different parameters, segregated variants are prioritized for the disease and further clinical relevance are evaluated for the variants. RESULTS A rare causal variant in troponin-T gene (TNNT2, NM_000364.3;c.274C > T;p.Arg92Trp) is identified, shared by only affected members, absent in unaffected members and also in 200 unrelated control chromosomes. TNNT2 mutation act as a driver mutation but mutations in other disease-related genes, KCNMB1, LPL, APOE and other biochemical factors provides risk stratification within affected family members. CONCLUSION This study contributes to the role of "rare variants" in complex disease phenotypes and heterogeneity within family and the necessity of whole exome targeted approaches in complex cardiomyopathy, which are known to harbor private mutations.
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Ratio of high-sensitivity troponin to creatine kinase-MB in takotsubo syndrome.
Pirlet, C, Pierard, L, Legrand, V, Gach, O
International journal of cardiology. 2017;:300-305
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Abstract
BACKGROUND Takotsubo syndrome (TT) and myocardial infarction (MI) share numerous similarities in clinical presentation, ECG modifications and biomarker elevation. We sought to determine whether the ratio of high-sensitivity cardiac troponin T (hs-TnT) to the myocardial fraction of creatine kinase (CKMB) could be a potent discriminator between TT and MI patients. METHODS We separately present analysis of data from retrospective files and prospectively recruited patients presenting with TT (35 retrospective and 42 prospective), NSTEMI (48 retrospective and 75 prospective) and STEMI (20 retrospective and 39 prospective). We compared ratios of hs-TnT to CKMB on admission to the hospital between TT, NSTEMI and STEMI patients. Receiver operating characteristic (ROC) curves were analysed to determine optimal cut-off values. RESULTS On admission, hs-TnT/CKMB ratio was significantly higher in TT patients than in NSTEMI and STEMI patients in both the retrospective phase (median and interquartile range, TT 0.024 [0.018-0.047] vs NSTEMI 0.009 [0.006-0.022], p<0.0001; TT vs STEMI 0.011 [0.006-0.016], p=0.0002) and the prospective cohort (median and interquartile range, TT 0.032 [0.018-0.040] vs NSTEMI 0.009 [0.006-0.015], p<0.0001; TT vs STEMI 0.009 [0.005-0.017], p<0.0001). A cut-off hs-TnT/CKMB ratio of 0.015 distinguished TT from MI with a sensitivity of 85.7% and a specificity of 67.6% (AUC 0.796; 95%CI: 0.71-0.89) in the retrospective phase. In the prospective phase, a ratio of 0.017 distinguished TT from MI with a sensitivity of 83.3% and a specificity of 78.1% (AUC 0.88; 95%CI: 0.83-0.94). CONCLUSION hs-TnT/CKMB ratio is a novel, readily available parameter that could be used alongside clinical risk scores, other biomarkers and ECG findings to discriminate between TT and MI.
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Evaluation of Serial High Sensitivity Troponin T Levels in Individuals Without Overt Coronary Heart Disease Following Exercise Stress Testing.
Saad, YME, Idris, H, Shugman, IM, Kadappu, KK, Rajaratnam, R, Thomas, L, Mussap, C, Leung, DYC, Juergens, CP, French, JK
Heart, lung & circulation. 2017;(7):660-666
Abstract
BACKGROUND Detectable levels of high sensitivity (cardiac) troponin T (HsTnT), occur in the majority of patients with stable coronary heart disease (CHD), and often in 'healthy' individuals. Extreme physical activity may lead to marked elevations in creatine kinase MB and TnT levels. However, whether HsTnT elevations occur commonly after exercise stress testing (EST), and if so, whether this has clinical significance, needs clarification. METHODS To determine whether HsTnT levels become elevated after EST (Bruce protocol) to ≥95% of predicted maximum heart rate in presumed healthy subjects without overt CHD, we assayed HsTnT levels for ∼5h post-EST in 105 subjects (median age 37 years). RESULTS Pre-EST HsTnT levels <5 ng/L were present in 31/32 (97%) of females and 52/74 (70%) of males. Post-EST, 13 (12%) subjects developed HsTnT levels >14 ng/L, with troponin elevation occurring at least three hours post-EST. Additionally, a detectable ≥ 50% increase in HsTnT levels (4.9→9ng/L) occurred in 28 (27%) of subjects who during EST achieved ≥ 95% of their predicted target heart rate. The median age of the subjects with HsTnT elevations to > 14ng/L post-EST was higher than those without such elevation (42 and 36 years respectively; p=0.038). At a median follow-up of 13 months no adverse events were recorded. CONCLUSION The current study demonstrates that detectable elevations occur in HsTnT post-EST in 'healthy' subjects without overt CHD. Future studies should evaluate the clinical significance of detectable elevations in post-EST HsTnT with long-term follow-up for adverse cardiac events.
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Diurnal Rhythm of Cardiac Troponin: Consequences for the Diagnosis of Acute Myocardial Infarction.
Klinkenberg, LJ, Wildi, K, van der Linden, N, Kouw, IW, Niens, M, Twerenbold, R, Rubini Gimenez, M, Puelacher, C, Daniel Neuhaus, J, Hillinger, P, et al
Clinical chemistry. 2016;(12):1602-1611
Abstract
BACKGROUND Interpretation of serial high-sensitivity cardiac troponin (hs-cTn) measurements for the diagnosis of acute myocardial infarction (AMI) assumes random fluctuation of hs-cTn around an individual's homeostatic set point. The aim of this study was to challenge this diagnostic concept. METHODS Study 1 examined the presence of a diurnal hs-cTn rhythm by hourly blood sampling, day and night, in 24 individuals without a recent history of AMI. Study 2 assessed morning vs evening diagnostic accuracy of hs-cTnT and hs-cTnI in a prospective multicenter diagnostic study of 2782 unselected patients, presenting to the emergency department with acute chest pain. RESULTS In study 1, hs-cTnT, but not hs-cTnI, exhibited a diurnal rhythm, characterized by gradually decreasing concentrations throughout daytime, rising concentrations during nighttime, to peak concentrations in the morning (mean 16.2 ng/L at 8:30 AM and 12.1 ng/L at 7:30 PM). In study 2, the hs-cTnT rhythm was confirmed by higher hs-cTnT concentrations in early-morning presenters compared to evening presenters with an adjudicated diagnosis of noncardiac disease. The diagnostic accuracy [area under the receiver-operation characteristics curve (AUC)] of hs-cTnT at presentation, 1 h, and for the combination of absolute changes with presenting concentration, were very high and comparable among patients presenting early morning as compared to evening (all AUC >0.93). hs-cTnI exhibited no diurnal rhythm with no differences in AUC among early-morning and evening presenters. CONCLUSIONS Rhythmic diurnal variation of hs-cTnT is a general phenomenon that is not seen with hs-cTnI. While the diurnal hs-cTnT rhythm does not seem to affect the diagnostic accuracy of hs-cTnT for AMI, it should be considered when using hs-cTnT for screening purposes. CLINICAL TRIAL REGISTRATION 1. Circadian Variation of Cardiac Troponin, NCT02091427, www.clinicaltrials.gov/ct2/show/NCT02091427. 2. Advantageous Predictors of Acute Coronary Syndrome Evaluation (APACE) Study, NCT00470587, www.clinicaltrials.gov/ct2/show/NCT00470587.
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The effect of exercise training on the course of cardiac troponin T and I levels: three independent training studies.
van der Linden, N, Klinkenberg, LJ, Leenders, M, Tieland, M, Verdijk, LB, Niens, M, van Suijlen, JD, de Groot, LC, Bekers, O, van Loon, LJ, et al
Scientific reports. 2015;:18320
Abstract
With the introduction of high-sensitive assays, cardiac troponins became potential biomarkers for risk stratification and prognostic medicine. Observational studies have reported an inverse association between physical activity and basal cardiac troponin levels. However, causality has never been demonstrated. This study investigated whether basal cardiac troponin concentrations are receptive to lifestyle interventions such as exercise training. Basal high-sensitive cardiac troponin T (cTnT ) and I (cTnI) were monitored in two resistance-type exercise training programs (12-week (study 1) and 24-week (study 2)) in older adults (≥65 years). In addition, a retrospective analysis for high sensitive troponin I in a 24-week exercise controlled trial in (pre)frail older adults was performed (study 3). In total, 91 subjects were included in the final data analyses. There were no significant changes in cardiac troponin levels over time in study 1 and 2 (study 1: cTnT -0.13 (-0.33-+0.08) ng/L/12-weeks, cTnI -0.10 (-0.33-+0.12) ng/L/12-weeks; study 2: cTnT -1.99 (-4.79-+0.81) ng/L/24-weeks, cTnI -1.59 (-5.70-+2.51) ng/L/24-weeks). Neither was there a significant interaction between training and the course of cardiac troponin in study 3 (p = 0.27). In conclusion, this study provides no evidence that prolonged resistance-type exercise training can modulate basal cardiac troponin levels.
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Cardiomyocyte injury induced by hemodynamic cardiac stress: Differential release of cardiac biomarkers.
Irfan, A, Reichlin, T, Twerenbold, R, Fischer, C, Ballarino, P, Nelles, B, Wildi, K, Zellweger, C, Rubini Gimenez, M, Mueller, M, et al
Clinical biochemistry. 2015;(18):1225-9
Abstract
OBJECTIVE We explored whether hemodynamic cardiac stress leads to a differential release of cardiomyocyte injury biomarkers, used in the diagnosis of acute myocardial infarction (AMI). METHODS In an observational international multicenter study, we enrolled 831 unselected patients presenting with symptoms suggestive of AMI to the emergency department. The final diagnosis was adjudicated by two independent cardiologists. Hemodynamic cardiac stress was quantified by levels of B-type natriuretic peptide (BNP). Spearman's rho correlation was used to analyze the correlations between BNP and high-sensitivity cardiac troponin T (hs-cTnT), Siemens cTnI-Ultra (cTnI-ultra), CK-MB and Myoglobin. Patients were categorized according to the extent of hemodynamic cardiac stress as quantified by BNP tertiles. RESULTS Among all patients, the positive pair-wise correlation with BNP was strongest with hs-cTnT and cTnI-ultra (r=0.58 and 0.50, respectively), moderate for Myoglobin (r=0.43), and weakest with CK-MB (r=0.25; p<0.001 for each). Similar pattern of correlations was also observed among AMI patients. Among patients diagnosed with non-cardiac cause of chest pain (n=385, 46%) and cardiac but non-coronary (n=109, 13%), BNP had significant positive correlations with hs-cTnT, cTnI-ultra and Myoglobin (p<0.05), but not with CK-MB (p=NS). A similar pattern of stronger correlation between BNP and hs-cTnT, cTnI-ultra and Myoglobin as compared to that with CK-MB was also observed within the higher BNP tertile range. There was no correlation between BNP and other biomarkers within the 1st BNP tertile group. CONCLUSION Hemodynamic cardiac stress, as quantified by BNP, as a likely cause of cardiomyocyte injury, is more closely reflected by concentrations of hs-cTnT, cTnI-ultra and Myoglobin than CK-MB.
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Cardiac troponin T (TNNT2) mutations in chinese dilated cardiomyopathy patients.
Li, X, Luo, R, Gu, H, Deng, Y, Xu, X, Wu, X, Hua, W
BioMed research international. 2014;:907360
Abstract
BACKGROUND Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure with high morbidity and mortality. Although more than 40 genes have been reported to cause DCM, the role of genetic testing in clinical practice is not well defined. Mutations in the troponin T (TNNT2) gene represent an important subset of known disease-causing mutations associated with DCM. Therefore, the aim of the present study was to determine the genetic variations in TNNT2 and the associations of those variations with DCM in Chinese patients. METHODS An approximately 4 kb fragment of the TNNT2 gene was isolated from 103 DCM patients and 192 healthy controls and was analyzed by DNA sequence analysis for genetic variations. RESULTS A total of 6 TNNT2 mutations were identified in 99 patients, including a G321T missense mutation (Leu84Phe) and 5 novel intronic mutations. Alleles of two novel SNPs (c.192 + 353 C>A, OR = 0.095, 95% CI: 0.013-0.714, P = 0.022; c.192 + 463 G>A, OR = 0.090, 95% CI: 0.012-0.675, P = 0.019) and SNP rs3729843 (OR = 1.889, 95% CI: 1.252-2.852; P = 0.002) were significantly correlated with DCM. CONCLUSIONS These results suggest that the missense mutation (Leu84Phe) and two novel SNPs (c.192 + 353 C>A, c.192 + 463 G>A) in TNNT2 gene might be associated with DCM in the Chinese population.
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Combined use of the novel biomarkers high-sensitivity troponin T and ST2 for heart failure risk stratification vs conventional assessment.
Lupón, J, de Antonio, M, Galán, A, Vila, J, Zamora, E, Urrutia, A, Bayes-Genis, A
Mayo Clinic proceedings. 2013;(3):234-43
Abstract
OBJECTIVE To assess an innovative multimarker strategy for risk stratification of death in a real-life ambulatory heart failure (HF) cohort. PATIENTS AND METHODS The study included 876 consecutive outpatients (median age, 70.3 years; left ventricular ejection fraction, 34%) between May 22, 2006, and July 7, 2010, prospectively followed up in a structured HF unit. A combination of biomarkers reflecting myocardial stretch (N-terminal pro-B-type natriuretic peptide [NT-proBNP]), myocyte injury (high-sensitivity cardiac troponin T [hs-cTnT]), and ventricular fibrosis and remodeling (high-sensitivity ST2 [hs-ST2]) were added to an assessment based on established mortality risk factors (age, sex, left ventricular ejection fraction, New York Heart Association functional class, diabetes mellitus, estimated glomerular filtration rate, ischemic etiology, sodium level, hemoglobin level, and pharmacologic treatment). RESULTS During median follow-up of 41.4 months, 311 patients died. The combined addition of hs-cTnT and hs-ST2 to the model yielded good measurements of performance (C statistic, 0.789; Bayesian information criterion, 3611; integrated discrimination improvement, 4.1 [95% CI, 2.5-5.6]; and net reclassification index, 13.9% [95% CI, 6.2-21.6]). Reclassification did not significantly benefit after NT-proBNP addition into the full model; some indices even worsened with all 3 biomarkers. Separate addition of NT-proBNP provided prognostic discrimination only in the subgroup of patients with either hs-cTnT or hs-ST2 levels below the cutoff points (hazard ratio, 2.97; 95% CI, 2.24-9.39; P<.001). CONCLUSION A multimarker strategy seems useful for stratifying risk in chronic HF. However, NT-proBNP in addition to the new-generation biomarkers hs-cTnT and hs-ST2 had a limited effect on risk stratification.
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Use of cardiac markers for monitoring of doxorubixin-induced cardiotoxicity in children with cancer.
Pongprot, Y, Sittiwangkul, R, Charoenkwan, P, Silvilairat, S
Journal of pediatric hematology/oncology. 2012;(8):589-95
Abstract
The aim of this study was to evaluate N-terminal probrain natriuretic peptides (NT-pro-BNP), cardiac troponin T, and creatinine kinase, MB isoenzyme (CK-MB) in the determination of subclinical left ventricular (LV) dysfunction by echocardiography in patients treated with doxorubicin. We performed a cross-sectional case study of systolic, diastolic function and tissue Doppler imaging by echocardiography in children with cancer who received a certain cumulative dose of doxorubicin. Blood levels for NT-pro-BNP, cardiac troponin T, and CK-MB were analyzed within 6 hours of the cardiac study. Of 30 patients, 5 (16.7%) had LV dysfunction with an abnormally high NT-pro-BNP level of 363 ± 78 pg/mL, whereas patients with normal LV function had an NT-pro-BNP level of 148 ± 173 pg/mL (P = 0.012). The NT-pro-BNP level not only inversely correlated with fractional shortening (r = -0.43, P = 0.017) and ejection fraction (r = - 0.45, P = 0.013) but also correlated with mitral deceleration time ( r = 0.41, P = 0.021) and a cumulative dose of doxorubicin (r = 0.44, P = 0.014). For tissue Doppler imaging, NT-pro-BNP correlated with a peak systolic velocity at the myocardial segment (Sm) (r = -0.40, P = 0.027). NT-pro-BNP is a sensitive test and has a moderate relationship with the LV systolic and diastolic function, thus making it a useful cardiac marker for the monitoring of early anthracycline cardiotoxicity.