Investigation into the effect of hyperbaric hyperoxia on serum cardiac Troponin T levels as a biomarker of cardiac injury.

Introduction: There is clinical equipoise as to whether hyperoxia is injurious to the myocardium, both in the setting of acute ischaemic insults and on the stable myocardium. This study examined the effect of extreme hyperoxia - in the form of hyperbaric oxygen treatment - on the myocardium through measurement of high-sensitivity cardiac troponin. Methods: Forty-eight individuals were enrolled to undergo a series of 30 exposures to hyperbaric oxygen for treatment of non-cardiac pathologies. High-sensitivity troponin T was measured before and after each session. Results: There was no clinically significant difference in troponin measurements following acute or recurrent sequential exposures to extreme hyperoxia, despite the studied patient population having a high rate of previous ischaemic heart disease or cardiovascular risk factors. Conclusions: This study demonstrates that profound hyperoxaemia does not induce any measurable cardiac injury at a biochemical level. Neither is there a reduction in cardiac troponin to suggest a cardioprotective effect of hyperbaric hyperoxia. This provides some reassurance as to the cardiac safety of the routine use of hyperbaric oxygen treatment in management of non-cardiac pathology.

Cardiac Myosin-Binding Protein C to Diagnose Acute Myocardial Infarction in the Pre-Hospital Setting.

Background Early triage is essential to improve outcomes in patients with suspected acute myocardial infarction (AMI). This study investigated whether cMyC (cardiac myosin-binding protein), a novel biomarker of myocardial necrosis, can aid early diagnosis of AMI and risk stratification. Methods and Results cMyC and high-sensitivity cardiac troponin T were retrospectively quantified in blood samples obtained by ambulance-based paramedics in a prospective, diagnostic cohort study. Patients with ongoing or prolonged periods of chest discomfort, acute dyspnoea in the absence of known pulmonary disease, or clinical suspicion of AMI were recruited. Discrimination power was evaluated by calculating the area under the receiver operating characteristics curve; diagnostic performance was assessed at predefined thresholds. Diagnostic nomograms were derived and validated using bootstrap resampling in logistic regression models. Seven hundred seventy-six patients with median age 68 [58;78] were recruited. AMI was the final adjudicated diagnosis in 22%. Median symptom to sampling time was 70 minutes. cMyC concentration in patients with AMI was significantly higher than with other diagnoses: 98 [43;855] versus 17 [9;42] ng/L. Discrimination power for AMI was better with cMyC than with high-sensitivity cardiac troponin T (area under the curve, 0.839 versus 0.813; P=0.005). At a previously published rule-out threshold (10 ng/L), cMyC reaches 100% sensitivity and negative predictive value in patients after 2 hours of symptoms. In logistic regression analysis, cMyC is superior to high-sensitivity cardiac troponin T and was used to derive diagnostic and prognostic nomograms to evaluate risk of AMI and death. Conclusions In patients undergoing blood draws very early after symptom onset, cMyC demonstrates improved diagnostic discrimination of AMI and could significantly improve the early triage of patients with suspected AMI.

Forecasting aortic aneurysm rupture: A systematic review of seasonal and atmospheric associations.

BACKGROUND: Abdominal aortic aneurysms (AAAs) represent a significant burden of disease worldwide, and their rupture, without treatment, has an invariably high mortality rate. Whereas some risk factors for ruptured AAAs (rAAAs) are well established, such as hypertension, smoking, and female sex, the impact of seasonal and meteorologic variables is less clear. We systematically reviewed the literature to determine whether these variables are associated with rAAA. METHODS: Review methods were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We calculated pooled proportions and incidence rate ratios (IRRs) for the different months and seasons. Funnel plots were constructed to assess for publication bias. Given the poor methodologic quality of included studies, a sensitivity analysis was performed on better-quality studies, which scored 6 and above of 9 in the author-modified Newcastle-Ottawa Scale. RESULTS: The pooled proportion of rAAA was highest in the autumn season (incidence rate, 26.6%; 95% confidence interval [CI], 25.6%-27.7%; I2 = 15.4%), followed by winter (incidence rate, 26.2%; 95% CI, 24.1%-28.2%; I2 = 72.4%), and lowest in summer (incidence rate, 21.1%; 95% CI, 19.3%-23.0%; I2 = 70.4%). The IRRs of rAAA were -6.9% (95% CI, -9.8% to -3.9%), -19.5% (95% CI, -22% to -16.8%), +10.5% (95% CI, 7.2%-13.9%), and +18.1% (95% CI, 15%-22%) in spring, summer, autumn, and winter compared with the remaining seasons, respectively (all P < .0001), thus affirming existence of seasonal variation. The pooled proportion of rAAA was highest in December (incidence rate, 8.9%; 95% CI, 7.1%-10.9%; I2 = 54.5%) but lowest in July (incidence rate, 5.7%; 95% CI, 4.2%-7.3%; I2 = 54.5%). The IRR was significantly the highest in January (IRR, 1.14; 95% CI, 1.01-1.29; P = .031) but lowest in July (IRR, 0.75; 95% CI, 0.65-0.87; P < .0001). There is also some evidence for a possible association with atmospheric pressure. Associations with temperature and daylight hours, however, are at best speculative. CONCLUSIONS: Autumn and winter are significantly associated with a higher incidence of rAAAs, and autumn is associated with the highest rupture incidence of all the seasons. However, the inability to appropriately control for other confounding factors known to increase the risk of AAA rupture precludes any additional recommendations to alter current provision of vascular services on the basis of these data.

A single centre prospective cohort study addressing the effect of a rule-in/rule-out troponin algorithm on routine clinical practice.

AIMS: In 2015, the European Society of Cardiology introduced new guidelines for the diagnosis of acute coronary syndromes in patients presenting without persistent ST-segment elevation. These guidelines included the use of high-sensitivity troponin assays for 'rule-in' and 'rule-out' of acute myocardial injury at presentation (using a '0 hour' blood test). Whilst these algorithms have been extensively validated in prospective diagnostic studies, the outcome of their implementation in routine clinical practice has not been described. The present study describes the change in the patient journey resulting from implementation of such an algorithm in a busy innercity Emergency Department. METHODS AND RESULTS: Data were prospectively collected from electronic records at a large Central London hospital over seven months spanning the periods before, during and after the introduction of a new high-sensitivity troponin rapid diagnostic algorithm modelled on the European Society of Cardiology guideline. Over 213 days, 4644 patients had high-sensitivity troponin T measured in the Emergency Department. Of these patients, 40.4% could be 'ruled-out' based on the high-sensitivity troponin T concentration at presentation, whilst 7.6% could be 'ruled-in'. Adoption of the algorithm into clinical practice was associated with a 37.5% increase of repeat high-sensitivity troponin T measurements within 1.5 h for those patients classified as 'intermediate risk' on presentation. CONCLUSIONS: Introduction of a 0 hour 'rule-in' and 'rule-out' algorithm in routine clinical practice enables rapid triage of 48% of patients, and is associated with more rapid repeat testing in intermediate risk patients.

Direct Comparison of Cardiac Myosin-Binding Protein C With Cardiac Troponins for the Early Diagnosis of Acute Myocardial Infarction.

BACKGROUND: Cardiac myosin-binding protein C (cMyC) is a cardiac-restricted protein that is more abundant than cardiac troponins (cTn) and is released more rapidly after acute myocardial infarction (AMI). We evaluated cMyC as an adjunct or alternative to cTn in the early diagnosis of AMI. METHODS: Unselected patients (N=1954) presenting to the emergency department with symptoms suggestive of AMI, concentrations of cMyC, and high-sensitivity (hs) and standard-sensitivity cTn were measured at presentation. The final diagnosis of AMI was independently adjudicated using all available clinical and biochemical information without knowledge of cMyC. The prognostic end point was long-term mortality. RESULTS: Final diagnosis was AMI in 340 patients (17%). Concentrations of cMyC at presentation were significantly higher in those with versus without AMI (median, 237 ng/L versus 13 ng/L, P<0.001). Discriminatory power for AMI, as quantified by the area under the receiver-operating characteristic curve (AUC), was comparable for cMyC (AUC, 0.924), hs-cTnT (AUC, 0.927), and hs-cTnI (AUC, 0.922) and superior to cTnI measured by a contemporary sensitivity assay (AUC, 0.909). The combination of cMyC with hs-cTnT or standard-sensitivity cTnI (but not hs-cTnI) led to an increase in AUC to 0.931 (P<0.0001) and 0.926 (P=0.003), respectively. Use of cMyC more accurately classified patients with a single blood test into rule-out or rule-in categories: Net Reclassification Improvement +0.149 versus hs-cTnT, +0.235 versus hs-cTnI (P<0.001). In early presenters (chest pain <3 h), the improvement in rule-in/rule-out classification with cMyC was larger compared with hs-cTnT (Net Reclassification Improvement +0.256) and hs-cTnI (Net Reclassification Improvement +0.308; both P<0.001). Comparing the C statistics, cMyC was superior to hs-cTnI and standard sensitivity cTnI (P<0.05 for both) and similar to hs-cTnT at predicting death at 3 years. CONCLUSIONS: cMyC at presentation provides discriminatory power comparable to hs-cTnT and hs-cTnI in the diagnosis of AMI and may perform favorably in patients presenting early after symptom onset. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00470587.

Quantifying the Release of Biomarkers of Myocardial Necrosis from Cardiac Myocytes and Intact Myocardium.

BACKGROUND: Myocardial infarction is diagnosed when biomarkers of cardiac necrosis exceed the 99th centile, although guidelines advocate even lower concentrations for early rule-out. We examined how many myocytes and how much myocardium these concentrations represent. We also examined if dietary troponin can confound the rule-out algorithm. METHODS: Individual rat cardiac myocytes, rat myocardium, ovine myocardium, or human myocardium were spiked into 400-µL aliquots of human serum. Blood was drawn from a volunteer after ingestion of ovine myocardium. High-sensitivity assays were used to measure cardiac troponin T (cTnT; Roche, Elecsys), cTnI (Abbott, Architect), and cardiac myosin-binding protein C (cMyC; EMD Millipore, Erenna®). RESULTS: The cMyC assay could only detect the human protein. For each rat cardiac myocyte added to 400 µL of human serum, cTnT and cTnI increased by 19.0 ng/L (95% CI, 16.8-21.2) and 18.9 ng/L (95% CI, 14.7-23.1), respectively. Under identical conditions cTnT, cTnI, and cMyC increased by 3.9 ng/L (95% CI, 3.6-4.3), 4.3 ng/L (95% CI, 3.8-4.7), and 41.0 ng/L (95% CI, 38.0-44.0) per µg of human myocardium. There was no detectable change in cTnI or cTnT concentration after ingestion of sufficient ovine myocardium to increase cTnT and cTnI to approximately 1 × 108 times their lower limits of quantification. CONCLUSIONS: Based on pragmatic assumptions regarding cTn and cMyC release efficiency, circulating species, and volume of distribution, 99th centile concentrations may be exceeded by necrosis of 40 mg of myocardium. This volume is much too small to detect by noninvasive imaging.

The development and application of a high-sensitivity immunoassay for cardiac myosin-binding protein C.

Cardiac troponins (cTns) are released and cleared slowly after myocardial injury. Cardiac myosin-binding protein C (cMyC) is a similar cardiac-restricted protein that has more rapid release and clearance kinetics. Direct comparisons are hampered by the lack of an assay for cMyC that matches the sensitivity of the contemporary assays for cTnI and cTnT. Using a novel pair of monoclonal antibodies, we generated a sensitive assay for MyC on the Erenna platform (Singulex) and compared serum concentrations with those of cTnI (Abbott) and cTnT (Roche) in stable ambulatory cardiac patients without evidence of acute cardiac injury or significant coronary artery stenoses. The assay for cMyC had a lower limit of detection of 0.4 ng/L, a lower limit of quantification (LLoQ) of 1.2 ng/L (LLoQ at 20% coefficient of variation [CV]) and reasonable recovery (107.1 ± 3.7%; mean ± standard deviation), dilutional linearity (101.0 ± 7.7%), and intraseries precision (CV, 11 ± 3%) and interseries precision (CV, 13 ± 3%). In 360 stable patients, cMyC was quantifiable in 359 patients and compared with cTnT and cTnI measured using contemporary high-sensitivity assays. cMyC concentration (median, 12.2 ng/L; interquartile range [IQR], 7.9-21.2 ng/L) was linearly correlated with those for cTnT (median, <3.0 ng/L; IQR, <3.0-4.9 ng/L; R = 0.56, P < 0.01) and cTnI (median, 2.10 ng/L; IQR, 1.3-4.2 ng/L; R = 0.77, P < 0.01) and showed similar dependencies on age, renal function, and left ventricular function. We have developed a high-sensitivity assay for cMyC. Concentrations of cMyC in clinically stable patients are highly correlated with those of cTnT and cTnI. This high correlation may enable ratiometric comparisons between biomarkers to distinguish clinical instability.