Exercise-Induced Cardiac Troponin Elevations: From Underlying Mechanisms to Clinical Relevance

Serological assessment of cardiac troponins (cTn) is the gold standard to assess myocardial injury in clinical practice. A greater magnitude of acutely or chronically elevated cTn concentrations is associated with lower event-free survival in patients and the general population. Exercise training is known to improve cardiovascular function and promote longevity, but exercise can produce an acute rise in cTn concentrations, which may exceed the upper reference limit in a substantial number of individuals. Whether exercise-induced cTn elevations are attributable to a physiological or pathological response and if they are clinically relevant has been debated for decades. Thus far, exercise-induced cTn elevations have been viewed as the only benign form of cTn elevations. However, recent studies report intriguing findings that shed new light on the underlying mechanisms and clinical relevance of exercise-induced cTn elevations. We will review the biochemical characteristics of cTn assays, key factors determining the magnitude of postexercise cTn concentrations, the release kinetics, underlying mechanisms causing and contributing to exercise-induced cTn release, and the clinical relevance of exercise-induced cTn elevations. We will also explain the association with cardiac function, correlates with (subclinical) cardiovascular diseases and exercise-induced cTn elevations predictive value for future cardiovascular events. Last, we will provide recommendations for interpretation of these findings and provide direction for future research in this field.

Classification of maternal thyroid function in early pregnancy using repeated blood samples

Objective: The assessment of maternal thyroid function in early pregnancy is debated. It is well-established that pregnancy-specific reference ranges preferably should be used. We speculated if the use of repeated blood samples drawn in early pregnancy would influence the classification of maternal thyroid function. Design: Cohort study Methods: Pregnant women with repeated early pregnancy blood samples were identified in the North Denmark Region Pregnancy Cohort. Each sample was used for the measurement of TSH, free T4 (fT4), thyroid peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (Tg-Ab) (ADVIA Centaur XPT, Siemens Healthineers). Method- and pregnancy week-specific reference ranges were used for classification of maternal thyroid function. Results: Among 1,466 pregnancies included, 89 women had TSH above the upper reference limit in the first sample (median pregnancy week 8), and 44 (49.4%) of these similarly had high TSH in the second sample (median week 10). A total of 47 women had TSH below the lower reference limit in the first sample, and 19 (40.4 %) of these similarly had low TSH in the second sample. Regarding women classified with isolated changes in fT4 in the first sample, less than 20% were similarly classified as such in the second sample. The percentage agreement between the samples was dependent on the level of TSH in the first sample and the presence of TPO- and Tg-Ab. Conclusion: In a large cohort of pregnant women, the classification of maternal thyroid function varied considerably with the use of repeated blood samples. Results emphasize a focus on the severity of thyroid function abnormalities in pregnant women.

Revisited Upper Reference Limits for Highly Sensitive Cardiac Troponin T in Relation to Age, Sex, and Renal Function

(1) Background: Highly sensitive cardiac troponin T (hs-cTnT) plays an essential role in the diagnosis of myocardial injury. The upper reference limit of the respective assay is generally applied, irrespective of age, renal function, or sex. We aimed to identify age-adjusted and sex-adjusted upper reference limits in relation to renal function in a large population-based cohort without cardiac diseases. (2) Methods: We included 5428 subjects of the population-based LIFE-Adult cohort, free of diagnosed cardiac diseases. Sex-adjusted and age-adjusted 99th percentiles for hs-cTnT in subjects with preserved renal function were obtained. (3) Results: The hs-cTnT values were higher in men of all age groups. In both sexes, an increasing age positively correlated with higher hs-cTnT values. Hs-cTnT weakly correlated with serum creatinine. The three-dimensional analysis of age, creatinine, and hs-cTnT showed no relevant additional effect of creatinine on hs-cTnT. In men aged above 60 and women above 70, the calculated 99th percentiles clearly exceeded the commonly applied thresholds. (4) Conclusion: Age and sex have a major impact on the serum concentration of hs-cTnT, while renal function does not. We propose to consider age-adjusted and sex-adjusted reference values.

Right atrium size in the general population

Echocardiography is the most common routine cardiac imaging method. Nevertheless, only few data about sex-specific reference limits for right atrium (RA) dimensions are available. Transthoracic echocardiographic RA measurements were studied in 9511 participants of the Gutenberg-Health-Study. A reference sample of 1942 cardiovascular healthy subjects without chronic obstructive pulmonary disease was defined. We assessed RA dimensions and sex-specific reference limits were defined using the 95th percentile of the reference sample. Results showed sex-specific differences with larger RA dimensions in men that were attenuated by standardization for body-height. RA-volume was 20.2 ml/m in women (5th–95th: 12.7–30.4 ml/m) and 26.1 ml/m in men (5th–95th: 16.0–40.5 ml/m). Multivariable regressions identified body-mass-index (BMI), coronary artery disease (CAD), chronic heart failure (CHF) and atrial fibrillation (AF) as independent key correlates of RA-volume in both sexes. All-cause mortality after median follow-up-period of 10.7 (9.81/11.6) years was higher in individuals who had RA volume/height outside the 95% reference limit (HR 1.70 [95%CI 1.29–2.23], P = 0.00014)). Based on a large community-based sample, we present sex-specific reference-values for RA dimensions normalized for height. RA-volume varies with BMI, CHF, CAD and AF in both sexes. Individuals with RA-volume outside the reference limit had a 1.7-fold higher mortality than those within reference limits.

Effects of short-term bisoprolol on perioperative myocardial injury in patients undergoing non-cardiac surgery: a randomized control study

The protective role of preoperative beta-blocker in patients undergoing non-cardiac surgery is unknown. We aimed to evaluate the effects of beta-blocker on perioperative myocardial injury in patients undergoing non-cardiac surgery. We consecutively enrolled 112 patients undergoing non-cardiac surgery. They were randomly allocated to receive bisoprolol or placebo given at least 2 days preoperatively and continued until 30 days after surgery. The primary outcome was incidence of perioperative myocardial injury defined by a rise of high-sensitive troponin-T (hs-TnT) more than 99th percentile of upper reference limit or a rise of hs-TnT more than 20% if baseline level is abnormal. Baseline characteristics were comparable between bisoprolol and placebo in randomized cohort Mean age was 62.5 ± 11.8 years and 76 (67.8%) of 112 patients were male. Among 112 patients, 49 (43.8%) underwent vascular surgery and 63 (56.2%) underwent thoracic surgery. The median duration of assigned treatment prior to surgery was 4 days (2–6 days). We did not demonstrate the significant difference in the incidence of perioperative myocardial injury [52.6% (30 of 57 patients) vs. 49.1% (27 of 55 patients), P = 0.706]. In addition, the incidence of intraoperative hypotension was higher in bisoprolol group than placebo group in patients undergoing non-cardiac surgery [70.2% (40 of 57 patients) vs. 47.3% (26 of 55 patients), P = 0.017]. We demonstrated that there was no statistically significant difference in perioperative myocardial injury observed between patients receiving bisoprolol and placebo who had undergone non-cardiac surgery.

Potential impact of a novel pathway for suspected myocardial infarction utilising a new high-sensitivity cardiac troponin I assay

BackgroundHigh-sensitivity cardiac troponin I (hs-cTnI) assays promise high diagnostic accuracy for myocardial infarction (MI). In an ED where conventional cTnI was in use, we evaluated an assessment pathway using the new Access hsTnI assay.MethodsThis retrospective analysis recruited ED patients with suspected MI between June and September 2019. All patients received routine care with a conventional cTnI assay (AccuTnI +3: limit of detection (LoD) 10 ng/L, 99th centile upper reference limit (URL) 40 ng/L, abnormal elevation cut-point 80 ng/L). Arrival, then 90-minute or 360-minute cTnI levels for low and non-low risk patients, respectively (ED Assessment of Chest pain score) guided diagnosis and disposition which was at treating physician discretion. The same patients had arrival and 90-minute or 180-minute samples drawn for hs-cTnI levels (Access hsTnI: LoD 2 ng/L, 99th centile URL 10 ng/L (females) and 20 ng/L (males); abnormal elevation above the URL and delta >30%). Treating physicians were blinded to the hs-cTnI results. Using the hs-cTnI values, investigators retrospectively assigned likely diagnosis, disposition and likelihood of a 30-day major adverse cardiac event (MACE). Admission was recommended for significantly rising hs-cTnI elevations. The primary objective was to demonstrate an acceptable unexpected 30-day post-discharge MACE rate of <1%. cTnI elevation rates, diagnostic outcomes and ED disposition were also compared between pathways.ResultsFor the 935 patients, unexpected 30-day post-discharge MACE rates were 0/935 (0%, 95% CI 0% to 0.4%) with the conventional or novel pathway. For the high-sensitivity and conventional assays, respectively, abnormal elevation rates were 29% (95% CI 26% to 32%) and 19% (95% CI 17% to 22%), for MI were 9% (95% CI 8% to 11%) and 8% (95% CI 6% to 10%), and for hospital admission were 42% (95% CI 39% to 45%) and 43% (95% CI 40% to 47%).ConclusionThe novel pathway using the Access hsTnI assay has an acceptably low 30-day MACE rate.

Relationship of tissue dimensions and three captive bolt placements on cadaver heads from mature swine (Sus scrofa domesticus) > 200 kg body weight

Three penetrating captive bolt (PCB) placements were tested on cadaver heads from swine with estimated body weight (BW) &gt;200 kg (sows = 232.9 ± 4.1 kg; boars = 229.3 ± 2.6 kg). The objectives were to determine tissue depth, cross-sectional brain area, visible brain damage (BD), regions of BD, and bolt-brain contact; and determine relationships between external head dimensions and tissue depth at each placement. A Jarvis PAS – Type P 0.25R PCB with a Long Stunning Rod Nosepiece Assembly and 3.5 gr power loads was used at the following placements on heads from 111 sows and 46 boars after storage at 2-4° C for approximately 62 h before treatment: FRONTAL (F) – 3.5 cm superior to the optic orbits at midline, TEMPORAL (T) – at the depression posterior to the lateral canthus of the eye within the plane between the lateral canthus and the base of the ear, or BEHIND EAR (BE) – directly caudal to the pinna of the ear on the same plane as the eyes and targeting the middle of the opposite eye. For sows, the bolt path was in the plane of the brain for 42/42 (100%, 95% CI: 91.6-100.0%) F heads, 39/40 (97.5%, 95% CI: 86.8-99.9%) T heads, and 34/39 (87.5%, 95% CI: 72.6-95.7%) BE heads; for the heads that could reliably be assessed for BD damage was detected in 25/26 (96.2%, 95% CI: 80.4-99.9%) F heads, 24/35 (68.6%, 95% CI: 50.7-83.2%) T heads, and 5/40 (12.5%, 95% CI: 4.2-26.8%) BE heads. For boars, the bolt path was in the plane of the brain for 17/17 (100.0%, 95% CI: 80.5-100.0%) F heads, 18/18 (100.0%, 95% CI: 81.5-100.0%) T heads, and 14/14 (100.0%, 95% CI: 76.8-100.0%) BE heads; damage was detected in 11/12 (91.7%, 95% CI: 61.5-99.8%) F heads, 2/15 (13.3%, 95% CI: 1.7-40.5%) T heads, and 7/14 (50.0%, 95% CI: 23.0-77.0%) BE heads. Tissue depth was reported as mean ± standard error followed by 95% one-sided upper reference limit (URL). For sows, total tissue thickness was different (P &lt; 0.05) between placements (F: 52.7 ± 1.0 mm, URL: 64.1 mm; T: 69.8 ± 1.4 mm, URL: 83.9 mm; BE: 89.3 ± 1.5 mm, URL: 103.4 mm). In boars, total tissue thickness was different (P &lt; 0.05) between placements (F: 41.2 ± 2.1 mm, URL: 56.3 mm; T: 73.2 ± 1.5 mm, URL: 83.4 mm; BE: 90.9 ± 3.5 mm, URL: 113.5 mm). For swine &gt; 200 kg BW, F placement may be more effective than T or BE due to less soft tissue thickness, which may reduce concussive force. The brain was within the plane of bolt travel for 100% of F heads with brain damage for 96.2% and 91.7% of F sow and boar heads, respectively.

Evaluation of plasma N-terminal pro-B-type natriuretic peptide levels in healthy North American Salukis with normal echocardiographic measurements.

Measurement of N‐terminal pro‐B‐type natriuretic peptide (NT-proBNP) levels has been shown to have clinical significance for diagnosis and management of heart disease in dogs. Evaluation of current reference limits for specific breeds is necessary to ensure the test can accurately distinguish between healthy and diseased animals. The objective of this study is to evaluate the adequacy of currently established NT-proBNP reference limits for clinical use in healthy Salukis. Cardiac health of 33 clinically healthy Salukis was evaluated via echocardiography using available breed standards. Plasma concentrations of NT-proBNP were measured using a commercially available assay. A one-sided 97.5% upper reference limit for the NT-proBNP concentrations was calculated using non-parametric percentile method. The 97.5% upper reference limit was 769 pmol/L (90% CI, 547-1214 pmol/L) for the study dogs. This upper reference limit was within the currently established non-breed specific NT-proBNP upper reference limit of 900 pmol/L. No relationship between sex, age, or body weight on plasma levels of NT-proBNP was noted. Results of this study supports the use of currently available non-breed specific NT-proBNP cut-off values for clinical evaluation of healthy Salukis.

Distribution and specificity of high-sensitivity cardiac troponin T in older adults without acute cardiac conditions: cross-sectional results from the population-based AugUR study

ObjectiveEuropean guidelines recommended a uniform upper reference limit of high-sensitivity cardiac troponin T (hsTnT) to rule out non-ST segment elevation myocardial infarction. Our study aimed to provide a hsTnT reference distribution and to assess the specificity of the 14 ng/L cut-off value in the mobile population ≥70 years of age.DesignA cross-sectional analysis was performed in the German AugUR study (Altersbezogene Untersuchungen zur Gesundheit der University of Regensburg).SettingStudy population was the mobile population aged 70+ years living in the city and county of Regensburg, Germany.ParticipantsA random sample was derived from the local population registries of residence. Of the 5644 individuals invited, 1133 participated (response ratio=20.1%). All participants came to the study centre and were mentally and physically mobile to conduct the protocol (face-to-face interview, blood draw and standardised transthoracic echocardiography). None of the participants was in an acute state of myocardial infarction.ResultsAmong the 1129 individuals with hsTnT measurements (overall median=10.0 ng/L(25th, 75th percentile)=(7.0, 15.0 ng/L)), hsTnT was higher among the older individuals and higher among men (men 70–74 years median=9.6 ng/L (7.2, 13.1 ng/L); men 90–95 years median=21.2 ng/L (14.6, 26.0 ng/L); women 70–74 years median=6.3 ng/L (4.7, 8.7 ng/L); and women 90–95 years median=18.0 ng/L (11.0, 21.0 ng/L)). In participants with impaired kidney function (eGFRcrea <60 mL/min/1.73 m2), hsTnT was elevated (median=13.6 ng/L (9.4, 20.6 ng/L)).Specificity of recommended upper reference limit, 14 ng/L, is 68%. Most false positives were among men aged >79 years (specificity=34%). In a healthy subgroup (n=96, none of the following: overt heart disease, impaired renal function, blood pressure >160/100 mm Hg, left ventricular hypertrophy and diastolic/systolic dysfunction), specificity was 90%.ConclusionIn the elderly population without acute myocardial infarction, hsTnT further increases with age showing different levels for men and women. The specificity of the 14 ng/L cut-off is considerably lower than 99%, even in healthy subjects.

Postprocedural Troponin Elevation and Mortality After Transcatheter Aortic Valve Implantation

Background This study sought to investigate the role of postprocedural troponin elevations in mortality prediction after transcatheter aortic valve implantation and to define the threshold at which clinically relevant postprocedure myocardial injury determines mortality. Methods and Results A total of 1333 consecutive patients with transcatheter aortic valve implantation with available postprocedural high‐sensitivity cardiac troponin T measurements were included in the analysis. The threshold at which postprocedure myocardial injury determines long‐term mortality was identified using restricted cubic spline analysis. A >18.3‐fold increase of troponin above the upper reference limit was identified as threshold for relevant postprocedure myocardial injury. Associations remained significant in a landmark analysis between 30 days and 2 years (hazard ratio [HR], 1.61, [95% CI, 1.13–2.28]; P =0.01), after adjusting for known confounders (adjusted HR, 1.90 [95% CI, 1.40–2.57]; P <0001), and in subgroups of patients with coronary artery disease (adjusted HR, 2.17 [95% CI, 1.44–3.29]; P <0.001), renal dysfunction (adjusted HR, 1.88 [95% CI, 1.35–2.62]; P <0.001), and intermediate/high surgical risk (adjusted HR, 2.70 [95% CI, 1.40–5.22]; P =0.003). Conclusions This study determined a troponin threshold for the identification of patients at increased mortality risk after transcatheter aortic valve implantation. The proposed definition of postprocedure myocardial injury advances risk stratification in patients with transcatheter aortic valve implantation and may assist in postprocedural patient management.