The impact of remote ischemic preconditioning on cardiac biomarker and functional response to endurance exercise.

Remote ischemic preconditioning (RIPC; repeated short reversible periods of ischemia) protects the heart against subsequent ischemic injury. We explored whether RIPC can attenuate post-exercise changes in cardiac troponin T (cTnT) and cardiac function in healthy individuals. In a randomized, crossover design, 14 participants completed 1-h cycling time trials (TT) on two separate visits; preceded by RIPC (arms/legs, 4 × 5-min 220 mmHg), or SHAM-RIPC (20 mmHg). Venous blood was sampled before and 0-, 1-, and 3-h post-exercise to assess high sensitivity (hs-)cTnT and brain natriuretic peptide (NT-proBNP). Echocardiograms were performed at the same time points to assess left and right ventricular systolic (ejection fraction; EF and right ventricular fractional area change; RVFAC, respectively) and diastolic (early transmitral flow velocities; E) function. Baseline hs-cTnT was not different between RIPC and SHAM. Post-exercise hs-cTnT levels were consistently lower following RIPC (18 ± 3 vs 21 ± 3; 19 ± 3 vs 23 ± 3; and 20 ± 2 vs 25 ± 2 ng/L at 0, 1 and 3-h post-exercise, respectively; P < 0.05). There was no main effect of time, trial, or interaction for NT-proBNP and left ventricular EF or RVFAC (all P < 0.05). A main effect of time was evident for E which transiently declined immediately after exercise to a similar level in both trials (0.85 ± 0.04 vs 0.74 ± 0.04 m/s, respectively; P < 0.05). In summary, RIPC was associated with lower hs-cTnT levels after exercise but there was no independent effect of RIPC for NT-proBNP or LV systolic and diastolic function. The lower hs-cTnT levels after RIPC suggests that further research should evaluate the role of ischemia in exercise-induced elevation in hs-cTnT.

The clinical and diagnostic performance characteristics of the high sensitivity Abbott cardiac troponin I assay.

OBJECTIVES: The aim of this study is to determine the imprecision profile, 99th percentile and diagnostic efficiency of a new high sensitivity cardiac troponin I (cTnI) assay. METHODS: Total imprecision was assessed by following CLSI protocol EP15-A.14. Serum pools prepared from sera of known high cardiac troponin concentrations were adjusted by dilution with serum considered to be troponin free. Determination of the 99th-percentile reference value examined a fully characterized population that had undergone non-invasive cardiac imaging. Diagnostic accuracy utilised samples from the point of care arm of the RATPAC trial (Randomised Assessment of Treatment using Panel Assay of Cardiac markers), set in the emergency departments of six hospitals. Blood samples were taken on admission and 90min from admission. Diagnosis was based on the universal definition of myocardial infarction utilising laboratory measurements of cardiac troponin performed at the participating sites together with measurements performed in a core laboratory and compared by construction of receiver operator characteristic curves. RESULTS: Total imprecision was 4%-12.1% with 10% CV of 7ng/L. cTnI was measureable in 99.5% of the samples. Troponin values were influenced by gender but not by age. The 99th percentile was 14.8ng/L (18.1 males, 8.6 females). Progressive filtering of the population reduced the 99th percentile. For the diagnosis of MI on admission the area under the curve was 0.92, statistically indistinguishable from four other assays studied (0.90-0.94). CONCLUSION: The analytical performance of the new assay meets the criteria for a high sensitivity troponin assay.

Randomised Assessment of Treatment using Panel Assay of Cardiac markers--Contemporary Biomarker Evaluation (RATPAC CBE).

OBJECTIVES: To test the diagnostic accuracy for detecting an acute myocardial infarction (AMI) using highly sensitive troponin assays and a range of new cardiac biomarkers of plaque destabilisation, myocardial ischaemia and necrosis; to test the prognostic accuracy for detecting adverse cardiac events using highly sensitive troponin assays and this range of new cardiac biomarkers; and to estimate the cost-effectiveness of using highly sensitive troponin assays or this range of new cardiac biomarkers instead of an admission and 10- to 12-hour troponin measurement. DESIGN: Substudy of the point-of-care arm of the RATPAC (Randomised Assessment of Treatment using Panel Assay of Cardiac markers) trial. SETTING: The emergency departments of six hospitals. PARTICIPANTS: Prospective admissions with chest pain and a non-diagnostic electrocardiogram randomised to point-of-care assessment or conventional management. INTERVENTIONS: Blood samples taken on admission and 90 minutes from admission for measurement of cardiac markers [cardiac troponin I (cTnI), myoglobin and creatine kinase MB isoenzyme (CK-MB)] by point-of-care testing. An additional blood sample was taken at admission and 90 minutes from admission for analysis of high-sensitivity cTnI (two methods) and cardiac troponin T (cTnT), myoglobin, heart-type fatty acid-binding protein (H-FABP), copeptin and B-type natriuretic peptide (NTproBNP). MAIN OUTCOME MEASURES: 1. Diagnostic accuracy compared with the universal definition of myocardial infarction utilising laboratory measurements of cardiac troponin performed at the participating sites together with measurements performed in a core laboratory. 2. Ability of biomarker measurements to predict major adverse cardiac events (death, non-fatal AMI, emergency revascularisation or hospitalisation for myocardial ischaemia) at 3 months' follow-up. 3. Comparison of incremental cost per quality-adjusted life-year (QALY) of different biomarker measurement strategies for the diagnosis of myocardial infarction. RESULTS: Samples were available from 850 out of 1132 patients enrolled in the study. Measurement of admission myoglobin [area under the curve (AUC) 0.76] and CK-MB (AUC 0.84) was diagnostically inferior and did not add to the diagnostic efficiency of cTnI (AUC 0.90-0.94) or cTnT (AUC 0.92) measurement on admission. Simultaneous measurement of H-FABP and cTnT or cTnI did improve admission diagnostic sensitivity to 0.78-0.92, but only to the same level as that achieved with troponin measured on admission and at 90 minutes from admission (0.78-0.95). Copeptin (AUC 0.62) and NTproBNP (AUC 0.85) measured on admission were not useful as diagnostic markers. As a prognostic marker, troponin measured on admission using a high-sensitivity assay (AUC 0.73-0.83) was equivalent to NTproBNP measurement (AUC 0.77) on admission, but superior to copeptin measurement (AUC 0.58). From modelling, 10-hour troponin measurement is likely to be cost-effective compared with rapid rule-out strategies only if a £30,000 per QALY threshold is used and patients can be discharged as soon as a negative result is available. CONCLUSIONS: The measurement of high-sensitivity cardiac troponin is the best single marker in patients presenting with chest pain. Additional measurements of myoglobin or CK-MB are not clinically effective or cost-effective. The optimal timing for measurement of cardiac troponin remains to be defined. Copeptin measurement is not recommended. H-FABP requires further investigation before it can be recommended for simultaneous measurement with high-sensitivity troponin in patients with acute chest pain. TRIAL REGISTRATION: ISRCTN37823923. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 17, No. 15. See the HTA programme website for further project information.

Cardiac electromechanical delay is increased during recovery from 40 km cycling but is not mediated by exercise intensity.

Cardiac electrical-mechanical delay (cEMD), left ventricular (LV) function, and cardiac troponin I (cTnI) were assessed after 40 km cycle time trials completed at high (HIGH) and moderate (MOD) intensities in 12 cyclists. Echocardiograms and blood samples were collected before, 10, and 60 min after cycling. cEMD as assessed by time from QRS onset to peak systolic (S') tissue velocity was lengthened after both bouts of cycling but was not mediated by cycling intensity (HIGH: 174 ± 52 vs 198 ± 26 ms; MOD: 151 ± 40 vs 178 ± 52 ms, P < 0.05). Global LV systolic function was unaltered by exercise. cEMD from QRS to peak early (E') diastolic tissue velocity was also increased post-exercise (HIGH: 524 ± 95 vs 664 ± 68 ms; MOD: 495 ± 62 vs 604 ± 91 ms, P < 0.05). Indices of LV diastolic function was reduced after cycling but were not mediated by exercise intensity. cTnI was elevated in two participants after HIGH trial (0.06 ug/L; 0.04 ug/L) and one participant after MOD trial (0.02 ug/L). While cEMD is lengthened and LV diastolic function was reduced post-cycling, altering time-trial intensity had little impact upon cEMD, LV function, and cTnI release.

Do the effects of high intensity 40 km cycling upon left ventricular function and cardiac biomarker during recovery vary with time of day?

Twelve healthy participants performed two identical high-intensity 40 km cycling trials (morning and evening) under controlled laboratory conditions. Echocardiograms and venous blood samples were collected before and after each exercise bout. Cardiac electro-mechanical-delay (cEMD) was measured as QRS-complex onset to peak systolic (S') and early diastolic (E') tissue velocities. Myocardial strain and strain rates were assessed in longitudinal, circumferential and radial planes at the left ventricular apex and base. Cardiac troponin I (cTnI) and N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) were assessed as biomarkers of cardiomyocyte damage and wall stress. cEMD was lengthened after both morning (S': 160 ± 30 vs. 193 ± 27; E': 478 ± 60 vs. 620 ± 87, P < 0.05) and evening (S': 155 ± 29 vs. 195 ± 31; E': 488 ± 42 vs. 614 ± 61, P < 0.05) trials. A reduction in peak S' (morning: 6.96 ± 1.12 vs. 6.66 ± 0.89; evening: 7.09 ± 0.94 vs. 7.02 ± 0.76) was correlated with cEMD (r = -0.335, P < 0.05). Peak longitudinal strain was reduced, atrial strain rates were sporadically increased in both trials post-cycling. cTnI was elevated in only two participants (0.04 µg · L(-1), 0.03 µg · L(-1)), whilst NT-proBNP was below the clinical cut-off point in all participants. Prolonged-cycling resulted in a lengthening of cEMD, small changes in aspects of left ventricular deformation and sporadic increases in cardiac biomarkers. None of these effects were moderated by time-of-day.

Post-exercise cardiac troponin release is related to exercise training history.

Marathon running can increase circulating cardiac troponin above the diagnostic criteria for myocardial infarction. We determined whether prior-exercise experience (training history) might be related to the magnitude of immediate post-race troponin release following completion of the London Marathon in a group of non-elite runners. Using a prospective study design, 52 runners were recruited into either HIGH T-E (trained-experience) (n=27) or LOW T-E (n=25) groups. Cardiac troponin I (cTnI) release following race completion was compared between these 2 groups. To examine relationships between cTnI release and participant demographic and indices of prior training experience an additional 52 runners who did not meet the criteria for either the HIGH T-E or LOW T-E groups were also recruited. The combined data from all 104 runners was analysed using multivariate linear regression analysis. The results revealed a significant difference in post marathon circulating cTnI between LOW T-E runners (median: 0.11 µg/L; interquartile range [IQR]: 0.03-0.18 µg/L) and HIGH T-E runners (median: 0.03 µg/L; IQR 0.02-0.057 µg/L) (p<0.05). Average miles run per week in the last 3 years, a marker of total training experience, encompassing training volume and duration, was negatively associated with post-marathon cTnI release (p<0.001).In conclusion, exercise-induced cTnI release is strongly related to previous training experience.

The perils, pitfalls and opportunities of using high sensitivity cardiac troponin.

Cardiac troponins (cTn) are considered to be the 'gold standard' biomarker for the diagnosis of acute coronary syndrome (ACS); a pathological spectrum which includes cardiac ischemia, angina, myocardial infarction and ultimately cardiac failure. The growing evidence base for the diagnostic and prognostic use of cTn in ACS has resulted in a universal redefinition of acute myocardial infarction (AMI). Recently a number of immunoassays with claims of superior sensitivity have been produced. The analytical and clinical performance of these assays require appropriate evaluation. Sensitive assays can be used for diagnosis in the first few hours after an ischemic episode. Early elevations in cTn are prognostic. A single time point for cTn testing may be useful for rule out, however such a strategy does not detect the rising and falling pattern required for diagnosis as suggested in the universal definition of AMI. The newer assays demonstrate low level cTn positivity in apparently healthy people. In addition, the sensitive assays detect more cTn positive patients who do not have a final diagnosis of ACS. It is unknown if such mild elevations in cTn detected by sensitive assays are of clinical concern. What is certain is that AMI remains a clinical not a biochemical diagnosis and interpretation of cTn concentrations should be made according to the clinical context. This review highlights the development of the sensitive assays, documents their analytical and clinical performance and reviews the usefulness of cTn elevation in non-ACS conditions.

The influence of a half-marathon race upon cardiac troponin T release in adolescent runners.

OBJECTIVES: Post-exercise cardiac troponin T (cTnT) release has been widely reported in adult athletes but limited data is available for adolescents. The aim of this study was to determine the incidence and magnitude of cTnT appearance in a large group of adolescent runners, and to determine any association between cTnT release and personal characteristics of adolescents. METHODS: We recruited 63 adolescent runners (mean±SD: age 16.4±1.5 years; 10 females) who all completed a simulated half-marathon race (an all-out 21-km run) during routine training. Personal data collected included age, training history, 21-km run performance as well as pre-post exercise serum cTnT levels. Serum cTnT was assayed using a 3rd generation assay. RESULTS: At pre-exercise, cTnT concentrations were below the 0.01 µg/L cTnT detection limit of assay in 58/63 runners. The post-exercise cTnT level (range: <0.01-1.36 µg/L) was significantly (p<0.001) greater than that of the pre-exercise (range: <0.01-0.02 µg/L). After the exercise, 57 (90%) and 44 (70%) subjects had cTnT concentrations above the detection: 0.01, and clinical thresholds: 0.05 µg/L, respectively. Post-exercise cTnT was inversely correlated with training years (r=-0.25, p<0.05) and age (r=-0.31, p<0.05). Compared with runners who had trained for ≥ 3 years, runners with less training experience demonstrated increased post-race cTnT levels (p<0.01). CONCLUSION: cTnT increases are virtually universal among adolescent runners following a 21-km run during routine training and can reach levels typically diagnostic for acute myocardial infarction potentially initiating diagnostic dilemmas. Adolescents with less training experience had higher post-exercise cTnT.

A unique case series of novel biomarkers of cardiac damage in cyclists completing the 4800 km Race Across America (RAAM).

Prolonged strenuous exercise is associated with the appearance of biomarkers of cardiac cell damage and a decline in cardiac function during recovery. Few studies have assessed repeated bouts of prolonged exercise and whether this results in further biomarker accumulation and greater dysfunction. Further, it may be useful to describe the changes in a range of biomarkers that may provide additional insight into the clinical significance of cardiac biomarker release. Four highly trained cyclists completed the 4800 km Race Across America (RAAM) in 7 days. Venous blood samples and echocardiograms were taken prior to, every 24 hours during and immediately after the RAAM. Venous blood was analysed for cardiac troponin I (cTnI), creatine kinase MB (CK-MB), fatty acid binding protein (HFABP), glycogen phosphorylase BB (GPBB) and N-Terminal Brain Natriuretic Peptide (NTproBNP). Echocardiograms allowed analysis of septal, left ventricular free wall and right ventricular free wall tissue velocities during systole and diastole. Before the RAAM cTnI levels were below the assay detection level (0.02 ng.ml⁻¹). In three riders cTnI peaked on day one (0.03 ng.ml⁻¹) and returned below detection levels post race. In the 4th rider cTnI peaked on day 5 (0.08 ng.ml⁻¹) and was still elevated post-race. Both CK-MB and H-FABP were increased during the RAAM in all 4 cyclists. In three riders H-FABP peaked on day one (3.49 to 5.09 ng.ml⁻¹) and declined over the rest of the RAAM. In the final rider H-FABP peaked on day two (5.90 ng.ml⁻¹) and then dropped back to baseline by the post-RAAM assessment. Interestingly, changes in H-FABP mirrored, temporally, changes in CK-MB in places and this may reflect an association with skeletal muscle damage. Data for GPBB value to (2.9 - 149.6 ng.ml⁻¹) and NTproBNP value to (27.3 - 310.0 ng.L⁻¹) were variable but again was elevated in all riders during the course of the RAAM. Changes in ventricular wall tissue velocities were minor and not cumulative. Peak atrial diastolic tissue velocity in the left ventricular free wall increased (P < 0.05) from 11 to 18 cm.s⁻¹ over the last two race days but this did not significantly impact the ratio of early to late diastolic wall motion. Cardiac biomarkers were elevated during the completion of the RAAM in all 4 cyclist but changes were not cumulative which suggest that the hearts of the cyclists coped well with the extreme cardiac work demanded by this ultra-endurance exercise challenge.

Maternal cardiac function in early pregnancies with high uterine artery resistance.

OBJECTIVE: To compare the maternal cardiac function and serum concentration of cardiac troponin T (cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in first-trimester patients, according to uterine artery Doppler velocimetry (UADV). METHODS: This cross-sectional study included singleton pregnancies with normal UADV (n=17) and abnormal UADV (n=19). Maternal echocardiography was performed and blood samples were taken at 11-14 weeks. Echocardiographic parameters included: (a) left ventricular (LV) long axis velocities; (b) atrial size; (c) LV filling pressure; (d) the ratio of peak mitral flow velocity in early diastole and early mitral annular diastolic velocity (E/Ea ratio); and (e) the E/flow propagation velocity ratio. The maternal serum concentrations of cTnT and NT-proBNP were determined by sensitive and specific immunoassays. RESULTS: Patients with abnormal UADV had higher estimated left ventricular filling pressure (P=0.004), higher E/Ea ratio (P=0.03), higher E/flow propagation ratio (P=0.02), and lower LV long axis velocity (P=0.02) than those with normal UADV. There were no significant differences in the maternal serum concentration of cTnT or NT-proBNP. CONCLUSIONS: Patients with abnormal UADV in the first trimester have higher left ventricular filling pressure and may have left ventricular systolic dysfunction.

Diagnostic and prognostic role of cardiac troponin I (cTnI) measured on the DPC Immulite.

OBJECTIVE: To evaluate the diagnostic and prognostic role of the Immulite cTnI assay for the detection of acute coronary syndromes (ACS). POPULATION: 150 males and 63 females with a median age of 63 years, range 28 to 88, and an interquartile range of 18 years were admitted within 24 h of chest pain and non-ST segment elevation ACS were studied. The median onset of symptoms was 3 h (range 0-23). METHODS: Venous samples were taken on admission (t = 0) and at 24 h (t = 24). The serum samples were assayed for CK, CK-MB and cTnT on an Elecsys 1010 (Roche Diagnostics, Lewes, UK). The cTnT assay CV was 5.5% at 0.32 microg/l and 5.4% at 6.0 microg/l, and the detection limit was 0.01 microg/l with an upper limit of 25 microg/l. For cTnI using the Immulite (DPC, Gwynedd, Wales), the detection limit was 0.1 microg/l, and the upper limit was 180 microg/l. Final diagnostic categorization was performed by both WHO and European Society of Cardiology criteria using cTnT as the diagnostic cardiac biomarker. Patients were followed for the major adverse cardiac events (MACE), endpoints cardiac death, AMI or need for urgent revascularization. ROC curves were constructed using final diagnosis. Outcome prediction was assessed by ROC curves and Kaplan-Meier survival curves. RESULTS: Both methods had equivalent diagnostic efficiency using WHO criteria for AMI. When ESC criteria were used the AUC for admission and 24 h cTnT and cTnI values were 0.945 vs. 0.910, P = 0.20 and 0.998 vs. 0.937, P = 0.005, respectively. Both methods predicted outcome as either death or MI or MACE and were not significantly different. CONCLUSION: The Immulite cTnI assay can be used for diagnosis and risk stratification in patients admitted with non-ST segment elevation acute coronary syndromes.

Utility of admission cardiac troponin and "Ischemia Modified Albumin" measurements for rapid evaluation and rule out of suspected acute myocardial infarction in the emergency department.

OBJECTIVE: To assess if the combination of cardiac troponin (cTn) and Ischemia Modified Albumin (IMA) can be used for early exclusion of acute myocardial infarction (AMI). METHODS: Prospective consecutive admissions to the emergency department (ED) with undifferentiated chest pain were assessed clinically and by electrocardiography. A total of 539 patients (335 men, 204 women; median age 51.9 years) considered at low risk of AMI had blood drawn on admission. If the first sample was less than 12 hours from onset of chest pain, a second sample was drawn two hours later, at least six hours from onset of chest pain. Creatine kinase MB isoenzyme (CKMB) mass was measured on the first sample and CKMB mass and cTnT on the second sample. An aliquot from the first available sample was frozen and subsequently analysed for IMA. If cTnT had not been measured on the original sample cTnI was measured (n = 189). RESULTS: Complete data were available for 538/539 patients. IMA or cTn was elevated in the admission sample of all patients with a final diagnosis of AMI (n = 37) with IMA alone elevated in 2/37, cTn alone in 19/37, and both in 16/37. In 173/501 patients in whom AMI was excluded both tests were negative. In the non-AMI group 22 patients had elevation of both IMA and cTn in the initial sample, suggesting ischaemic disease. CONCLUSION: Admission measurement of cardiac troponin plus IMA can be used for early classification of patients presenting to the ED to assist in patient triage.

Cardiac structural and functional abnormalities in end stage renal disease patients with elevated cardiac troponin T.

OBJECTIVES: To identify in a prospective observational study the cardiac structural and functional abnormalities and mortality in patients with end stage renal disease (ESRD) with a raised cardiac troponin T (cTnT) concentration. METHODS: 126 renal transplant candidates were studied over a two year period. Clinical, biochemical, echocardiographic, coronary angiographic, and dobutamine stress echocardiographic (DSE) data were examined in comparison with cTnT concentrations dichotomised at cut off concentrations of < 0.04 microg/l and < 0.10 microg/l. RESULTS: Left ventricular (LV) size and filling pressure were significantly raised and LV systolic and diastolic function parameters significantly impaired in patients with raised cTnT, irrespective of the cut off concentration. The proportions of patients with diabetes and on dialysis were higher in both groups with raised cTnT. With a cut off cTnT concentration of 0.04 microg/l but not 0.10 microg/l, significantly more patients had severe coronary artery disease and a positive DSE result. The total ischaemic burden during DSE was similar in cTnT positive and negative patients, irrespective of the cut off concentration used. LV end systolic diameter index and E:Ea ratio were independent predictors of cTnT rises > or = 0.04 microg/l and > or = 0.10 microg/l, respectively. Diabetes was independently associated with cTnT at both cut off concentrations. Mortality was higher in all patients with raised cTnT. CONCLUSIONS: Patients with ESRD with raised cTnT concentrations have increased mortality. Raised concentrations are strongly associated with diabetes, LV dilatation, and impaired LV systolic and diastolic function, but not with severe coronary artery disease.

The efficacy of ice massage in the treatment of exercise-induced muscle damage.

The purpose of this investigation was to, firstly, examine the effects of repeated applications of ice massage on the indirect markers associated with muscle damage using a within-subjects cross-over design and secondly, to examine how ice massage affects muscle function in both static and dynamic contractions following unaccustomed eccentric exercise. Twelve males performed damaging exercise on two separate occasions. The protocol consisted of three sets of 10 maximal eccentric repetitions of the elbow flexors using isokinetic dynamometry. Subjects were randomly assigned to an ice massage group or placebo group and received treatments immediately post-exercise, 24 and 48 h post-exercise. Muscle function (maximal isometric, slow and fast isokinetic contractions), creatine kinase, myoglobin, muscle soreness, limb girth and range of motion were measured pre, immediately post, 24, 48, 72 and 96 h post-exercise. Significant time effects were observed for all dependent variables (P<0.05). There were no significant differences between treatments. Ice massage is ineffective in reducing the indirect markers associated with exercise-induced muscle damage and enhancing recovery of muscle function in male exercisers unaccustomed to eccentric biased exercise.