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Stress Cardiac Biomarkers, Cardiovascular and Renal Outcomes, and Response to Canagliflozin.
Vaduganathan, M, Sattar, N, Xu, J, Butler, J, Mahaffey, KW, Neal, B, Shaw, W, Rosenthal, N, Pfeifer, M, Hansen, MK, et al
Journal of the American College of Cardiology. 2022;(5):432-444
Abstract
BACKGROUND Circulating biomarkers reflecting different mechanistic pathways may identify at-risk individuals with diabetes who may benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitors. OBJECTIVES The purpose of this study was to determine if high-sensitivity cardiac troponin T (hs-cTnT), soluble suppression of tumorigenesis-2 (sST2), and insulin-like growth factor binding protein 7 (IGFBP7) levels, either alone or in combination, may modify the treatment benefits of canagliflozin. METHODS In the CANVAS (CANagliflozin cardioVascular Assessment Study) biomarker substudy, we evaluated the prognostic significance of baseline biomarker measurements, the long-term trajectory of each, and response to canagliflozin on key cardiovascular and kidney outcomes. RESULTS Among the 4,330 study participants, baseline hs-cTnT, sST2, and IGFBP7 were available in 3,503 (81%), 3,084 (71%), and 3,577 (83%). In total, 39% had elevated hs-cTnT ≥14 pg/mL, 6% had sST2 >35 ng/mL, and 49% had IGFBP7 >96.5 ng/mL. Canagliflozin significantly slowed increases of hs-cTnT (P = 0.027) and sST2 (P = 0.033) through 6 years. Each biomarker was significantly associated with cardiovascular and kidney outcomes, independent of clinical covariates. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Patients with hs-cTnT ≥14 ng/L and those with sST2 >35 ng/mL derived greater relative benefit for major adverse cardiovascular events (MACE) (both Pinteraction ≤0.05). A panel of all 3 biomarkers predicted each cardiac and kidney outcome evaluated; participants with an increasing number of abnormal circulating biomarkers appeared to have greater relative reductions in MACE from canagliflozin treatment (Pinteraction trend = 0.005). CONCLUSIONS Canagliflozin delays longitudinal rise in hs-cTnT and sST2 compared with placebo out to 6 years. Canagliflozin reduced heart failure and kidney events regardless of baseline biomarker concentration. Elevated cardiovascular biomarkers, either alone or in combination, may identify individuals who may derive greater MACE benefit from SGLT2 inhibition. CANVAS (CANagliflozin cardioVascular Assessment Study; NCT01032629).
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Mutation location of HCM-causing troponin T mutations defines the degree of myofilament dysfunction in human cardiomyocytes.
Schuldt, M, Johnston, JR, He, H, Huurman, R, Pei, J, Harakalova, M, Poggesi, C, Michels, M, Kuster, DWD, Pinto, JR, et al
Journal of molecular and cellular cardiology. 2021;:77-90
Abstract
BACKGROUND The clinical outcome of hypertrophic cardiomyopathy patients is not only determined by the disease-causing mutation but influenced by a variety of disease modifiers. Here, we defined the role of the mutation location and the mutant protein dose of the troponin T mutations I79N, R94C and R278C. METHODS AND RESULTS We determined myofilament function after troponin exchange in permeabilized single human cardiomyocytes as well as in cardiac patient samples harboring the R278C mutation. Notably, we found that a small dose of mutant protein is sufficient for the maximal effect on myofilament Ca2+-sensitivity for the I79N and R94C mutation while the mutation location determines the magnitude of this effect. While incorporation of I79N and R94C increased myofilament Ca2+-sensitivity, incorporation of R278C increased Ca2+-sensitivity at low and intermediate dose, while it decreased Ca2+-sensitivity at high dose. All three cTnT mutants showed reduced thin filament binding affinity, which coincided with a relatively low maximal exchange (50.5 ± 5.2%) of mutant troponin complex in cardiomyocytes. In accordance, 32.2 ± 4.0% mutant R278C was found in two patient samples which showed 50.0 ± 3.7% mutant mRNA. In accordance with studies that showed clinical variability in patients with the exact same mutation, we observed variability on the functional single cell level in patients with the R278C mutation. These differences in myofilament properties could not be explained by differences in the amount of mutant protein. CONCLUSIONS Using troponin exchange in single human cardiomyocytes, we show that TNNT2 mutation-induced changes in myofilament Ca2+-sensitivity depend on mutation location, while all mutants show reduced thin filament binding affinity. The specific mutation-effect observed for R278C could not be translated to myofilament function of cardiomyocytes from patients, and is most likely explained by other (post)-translational troponin modifications. Overall, our studies illustrate that mutation location underlies variability in myofilament Ca2+-sensitivity, while only the R278C mutation shows a highly dose-dependent effect on myofilament function.
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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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Change in cardiac troponin T level after intravitreal anti-vascular endothelial growth factor treatment: Prospective pilot study.
Rebeiz, AG, Mahfoud, Z, Abdul Fattah, M, Saad, A, Safar, A, Bashshur, ZF
European journal of ophthalmology. 2020;(3):563-569
Abstract
BACKGROUND Evaluate subclinical myocardial injury associated with intravitreal anti-vascular endothelial growth factor therapy by measuring serum high-sensitivity cardiac troponin T. METHODS This is a prospective pilot comparative study conducted at American University of Beirut Medical Center, Beirut, Lebanon. In total, 40 consecutive patients were randomized to receive either intravitreal bevacizumab or ranibizumab. Patients received three consecutive monthly injections of the assigned drug, then continued treatment as needed. Systemic concentrations of high-sensitivity cardiac troponin T and vascular endothelial growth factor were obtained at baseline, week 9, and week 24. Primary endpoint measure was change in high-sensitivity cardiac troponin T levels compared to baseline. Secondary endpoint measure was change in systemic vascular endothelial growth factor levels. RESULTS There was no significant difference in high-sensitivity cardiac troponin T levels over time (p = 0.227) within each treatment group and no significant difference between treatments at any time point (p = 0.276). There was a significant decrease in plasma vascular endothelial growth factor levels at week 9 (p = 0.001) and week 24 (p < 0.001) compared to baseline. In the ranibizumab group, vascular endothelial growth factor levels were not significantly different at weeks 9 and 24 compared to baseline (p = 0.708 and p = 0.117, respectively). There was a significant association between the number of bevacizumab injections from weeks 8 to 24 and the decrease in vascular endothelial growth factor levels at week 24 (R = -0.67, p = 0.032). This correlation was not observed in the ranibizumab group (R = -0.341, p = 0.141). CONCLUSION Repeated intravitreal bevacizumab or ranibizumab did not influence serum high-sensitivity cardiac troponin levels. Intravitreal bevacizumab but not ranibizumab lowered free-systemic vascular endothelial growth factor levels, which was observed in this study to be inversely related to the number of bevacizumab injections.
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Prognostic Value of Troponins in Patients With or Without Coronary Heart Disease: Is it Dependent on Structure and Biology?
Lippi, G, Cervellin, G, Sanchis-Gomar, F
Heart, lung & circulation. 2020;(3):324-330
Abstract
Convincing evidence has emerged that cardiac troponins (cTns) T and I are the biochemical gold standard for diagnosing cardiac injury, and may also be used as efficient screening and risk stratification tools, especially when measured with the new high-sensitivity (hs-) immunoassays. In this narrative review, we aim to explore and critically discuss the results of recent epidemiological studies that have attempted to characterise the prognostic value of cTns in patients with or without cardiovascular disease, and then interpret this information according to cTn biology. Overall, all recent studies agree that higher blood levels of cTns reflect the larger risk of cardiovascular events and/or death, both in the general population and in patients with cardiovascular disease. Additional evidence has shown that the clinical information provided by assessment of both cTns molecules is greater compared to that of either protein alone, and this is mostly due to differential metabolism and clearance of cTnI and cTnT after release in the bloodstream. Although it seems likely that the prognostic value of these biomarkers may be higher than that of other conventional cardiovascular risk factors such as cholesterol or C reactive protein, large and reliable cost-effectiveness investigations are needed to define whether cTns-based population screening may be biologically plausible, clinically effective and economically sustainable.
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Large increases in plasma fast skeletal muscle troponin I after whole-body eccentric exercises.
Chen, TC, Liu, HW, Russell, A, Barthel, BL, Tseng, KW, Huang, MJ, Chou, TY, Nosaka, K
Journal of science and medicine in sport. 2020;(8):776-781
Abstract
OBJECTIVES It has been reported that plasma fast skeletal muscle troponin I (fsTnI) but not slow skeletal muscle troponin I (ssTnI) increases after a bout of eccentric exercise of the elbow flexors. The present study compared the first and second bouts of whole-body eccentric exercises for changes in plasma fsTnI and ssTnI concentrations. DESIGN Observational study in an experimental group. METHODS Fifteen sedentary men (20-25 y) performed nine eccentric exercises targeting arm, leg and trunk muscles, and repeated them two weeks later. Blood samples were taken before and for five days following each bout, and plasma ssTnI and fsTnl concentrations were measured by enzyme-linked immunosorbent assays. Their changes were compared between bouts and their relationships to plasma CK activity and myoglobin concentrations were analysed. RESULTS Plasma fsTnI concentration increased after the first bout and peaked at 4 days post-exercise (2152-40,295 ng/mL), but no significant increases were evident after the second bout. Plasma ssTnI concentration did not change significantly from the baseline (<0.08 ng/mL) after either bout. Peak plasma fsTnI concentration was significantly (p < 0.005) correlated with peak plasma CK activity (peak: 23,238-207,304 IU/L, r = 0.727) and myoglobin concentration (1047-3936 μg/L, r = 0.625) after the first bout. CONCLUSIONS These results suggest that plasma TnI concentrations are more specific biomarker of muscle damage than plasma CK activity and myoglobin concentration. It seems that the whole-body eccentric exercises induced damage preferentially to fast-twitch muscle fibres, and increases in plasma CK activity and myoglobin concentration after eccentric exercise may reflect fast-twitch muscle fibre damage.
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Impact of ultra-marathon and marathon on biomarkers of myocyte necrosis and cardiac congestion: a prospective observational study.
Wegberger, C, Tscharre, M, Haller, PM, Piackova, E, Vujasin, I, Gomiscek, A, Tentzeris, I, Freynhofer, MK, Jäger, B, Wojta, J, et al
Clinical research in cardiology : official journal of the German Cardiac Society. 2020;(11):1366-1373
Abstract
BACKGROUND An elevation of cardiac biomarkers is observed after intense or long-lasting physical activity. However, a recent meta-analysis has suggested that there might be an inverse relationship between duration of exercise and degree of biomarker elevation. The objective of this observational study was to investigate the impact of ultra-marathon (UM) vs. marathon (M) on biomarkers of myocyte necrosis and hemodynamic stress/congestion. METHODS Well-trained endurance athletes were recruited to participate in a 130-km UM and a M run. Troponin I (TnI), creatine kinase (CK), N-terminal pro-brain natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), and copeptin were measured after both events, respectively. RESULTS Fifteen athletes (14 males, one female) were included. There was no difference in exercise intensity according to the Borg scale (UM 16 [IQR 15-17], M 16 [IQR 14-17]; p = 0.424). Biomarkers of myocyte necrosis both differed significantly with higher levels of TnI (UM 0.056 ng/L [IQR 0.022-0.104), M 0.028 ng/L [IQR 0.022-0.049]; p = 0.016) and CK (UM 6992 U/l [IQR 2886-23038], M 425 U/l [IQR 327-681]; p = 0.001) after UM compared to M. Also, NT-proBNP (UM 723 ng/L [IQR 378-1152], M 132 ng/L [IQR 64-198]; p = 0.001) and MR-proADM (UM 1.012 nmol/L [IQR 0.753-0.975], M 0.877 nmol/L [IQR 0.550-0.985]; p = 0.023) as markers of myocardial congestion were significantly higher after UM. There was a tendency for elevated copeptin levels after M, but did not reach statistical significance (p = 0.078). CONCLUSION Ultra-marathon is associated with higher levels of biomarkers of myocyte necrosis and cardiac congestion compared to marathon, highlighting the impact of exercise duration on the cardiovascular system.
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The impact of high-intensity interval training on the cTnT response to acute exercise in sedentary obese young women.
Nie, J, Zhang, H, He, Y, Cao, W, Liu, Y, Kong, Z, George, K
Scandinavian journal of medicine & science in sports. 2019;(2):160-170
Abstract
AIMS: This study characterized (a) the cardiac troponin T (cTnT) response to three forms of acute high-intensity interval exercise (HIE), and (b) the impact of 12 weeks of HIE training on the cTnT response to acute exercise in sedentary obese young women. METHODS Thirty-six sedentary women were randomized to traditional HIE training (repeated 4-minute cycling at 90% V˙ O2max interspersed with 3-minute rest, 200 kJ/session), work-equivalent sprint interval exercise (SIE) training (repeated 1-minute cycling at 120% V˙ O2max interspersed with 1.5-minute rest) or repeated-sprint exercise (RSE) training (40 × 6-second all-out sprints interspersed with 9-second rest) group. cTnT was assessed using a high-sensitivity assay before and immediately, 3 and 4 hours after the 1st (PRE), 6th (EARLY), 20th (MID), and 44th (END) training session, respectively. RESULTS cTnT was elevated (P < 0.05) after all forms of acute interval exercise at the PRE and EARLY assessment with cTnT response higher (P < 0.05) after HIE (307%) and SIE (318%) than RSE (142%) at the PRE assessment. All forms of acute interval exercise at MID and END had no effect on the cohort cTnT concentration post-exercise (all P > 0.05). CONCLUSION For sedentary obese young women, both HIE and SIE, matched for total work, induced a similar elevation in cTnT after acute exercise with a smaller rise observed after RSE. By the 44th training session, almost no post-exercise cTnT elevation was observed in all three groups. Such information is relevant for clinicians as it could improve medical decisionmaking.
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The homozygous K280N troponin T mutation alters cross-bridge kinetics and energetics in human HCM.
Piroddi, N, Witjas-Paalberends, ER, Ferrara, C, Ferrantini, C, Vitale, G, Scellini, B, Wijnker, PJM, Sequiera, V, Dooijes, D, Dos Remedios, C, et al
The Journal of general physiology. 2019;(1):18-29
Abstract
Hypertrophic cardiomyopathy (HCM) is a genetic form of left ventricular hypertrophy, primarily caused by mutations in sarcomere proteins. The cardiac remodeling that occurs as the disease develops can mask the pathogenic impact of the mutation. Here, to discriminate between mutation-induced and disease-related changes in myofilament function, we investigate the pathogenic mechanisms underlying HCM in a patient carrying a homozygous mutation (K280N) in the cardiac troponin T gene (TNNT2), which results in 100% mutant cardiac troponin T. We examine sarcomere mechanics and energetics in K280N-isolated myofibrils and demembranated muscle strips, before and after replacement of the endogenous troponin. We also compare these data to those of control preparations from donor hearts, aortic stenosis patients (LVHao), and HCM patients negative for sarcomeric protein mutations (HCMsmn). The rate constant of tension generation following maximal Ca2+ activation (k ACT) and the rate constant of isometric relaxation (slow k REL) are markedly faster in K280N myofibrils than in all control groups. Simultaneous measurements of maximal isometric ATPase activity and Ca2+-activated tension in demembranated muscle strips also demonstrate that the energy cost of tension generation is higher in the K280N than in all controls. Replacement of mutant protein by exchange with wild-type troponin in the K280N preparations reduces k ACT, slow k REL, and tension cost close to control values. In donor myofibrils and HCMsmn demembranated strips, replacement of endogenous troponin with troponin containing the K280N mutant increases k ACT, slow k REL, and tension cost. The K280N TNNT2 mutation directly alters the apparent cross-bridge kinetics and impairs sarcomere energetics. This result supports the hypothesis that inefficient ATP utilization by myofilaments plays a central role in the pathogenesis of the disease.
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Impact of high-intensity interval training and moderate-intensity continuous training on resting and postexercise cardiac troponin T concentration.
Nie, J, Zhang, H, Kong, Z, George, K, Little, JP, Tong, TK, Li, F, Shi, Q
Experimental physiology. 2018;(3):370-380
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Abstract
NEW FINDINGS What is the central question of this study? Does exercise training impact resting and postexercise cardiac troponin T (cTnT) concentration? What is the main finding and its importance? This randomized controlled intervention study demonstrated that 12 weeks of either high-intensity interval training or moderate-intensity continuous training largely abolished the exercise-induced elevation in cTnT when exercise was performed at the same absolute intensity. There was no impact of training on resting cTnT or postexercise appearance of cTnT when exercise was performed at the same relative intensity. These findings provide new information that might help clinicians with decision-making in relationship to basal and postexercise values of cTnT in individuals with different training status. ABSTRACT We evaluated the influence of 12 weeks of high-intensity interval training [HIIT; repeated 4 min cycling at 90% of maximal oxygen uptake (V̇O2max) interspersed with 3 min rest, 200-300 kJ per session, 3 or 4 days each week] and work-equivalent moderate-intensity continuous training (MICT; continuous cycling at 60% V̇O2max) on resting cardiac troponin T (cTnT) and the appearance of exercise-induced cTnT. Forty-eight sedentary obese young women were randomly assigned to HIIT, MICT or a control group. The V̇O2max and body composition were measured before and after training. At baseline, cTnT was assessed using a high-sensitivity assay at rest and immediately, 2 and 4 h after 45 min cycling at 60% V̇O2max. After a 12 week training period, cTnT was assessed before and after 45 min cycling at the same relative and absolute intensities as before training. Training led to higher V̇O2max and lower fat mass in both HIIT and MICT groups (all P < 0.05). Before training, cTnT was significantly elevated in all three groups (by 35-118%, all P < 0.05) with acute exercise. After training, both resting and postexercise cTnT concentrations (same relative intensity) were similar to pretraining values. In contrast, postexercise cTnT (same absolute intensity, which represented a smaller exercise stimulus) was not elevated from rest in both HIIT and MICT groups. In conclusion, 12 weeks of either HIIT or MICT largely abolished the postexercise elevation of cTnT concentration when exercise was performed at the same absolute intensity. There was, however, no impact of training on resting cTnT or postexercise appearance of cTnT for exercise performed at the same relative intensity.