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Macrotroponin is a complex formed between endogenous cardiac troponin autoantibodies and circulating cardiac troponin (cTn). It is a recognised cause of discrepancy between current high sensitivity troponin (hs-cTn) assays; and immunoglobulin-bound (macrotroponin) and unbound cTn can coexist in varying proportions in the acute setting. Increasingly it is considered when laboratory cTn results do not match a patient's clinical picture. However, despite the better understanding of macrotroponin as an analytical interference, its clinical significance remains unclear. The aim of this study was to determine the potential impact of macrotroponin on the use of cTn as a long-term prognostic marker. We repeated cTnI testing after polyethylene glycol (PEG) precipitation on consecutive participants (n=159) with a first elevated cTn above 0.2 μg/L during their hospital admission episode. Because this paper is looking at outcomes in years, the initial data were generated at a time when non-hs-cTn assays were in use. We divided the cohort into two groups based on an exploratory PEG recovery cut-off of <34.6% to indicate the presence of possible macrotroponin and compared the overall and cardiovascular related mortality. The median follow-up time for the overall cohort was 8.35 years (8.32-8.40 interquartile range) with no difference between the two groups. The overall median survival was 8.1 years. Our findings indicate a hazard ratio of 0.54 (0.32-0.91 95% CI) for all-cause mortality and 0.48 (0.24-0.95) for cardiovascular mortality in patients with possible macrotroponin compared to those patients with troponin elevation without evidence of macrotroponin, after adjustment for common cardiovascular disease risk factors. Furthermore, an association was observed between PEG% recovery and all-cause mortality (p<0.05). This study showed that patients with macrotroponin have comparatively favourable long-term all-cause and cardiovascular mortality in a cohort of patients with elevated troponin. We illustrate the importance of recognising cTn results as being a summation of heterogeneous components, including those bound to antibodies, and the potential role of macrotroponin to further improve our interpretation and use of cTn as a biomarker., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Cardiac troponin levels can be elevated without myocardial injury in patients with renal impairment. However, the prognostic value of elevated troponin levels after cardiac surgery has not been well evaluated in patients with renal impairment. We evaluated the relationship between postoperative troponin levels and mortality following cardiac surgery according to preoperative renal function.Among 3661 patients underwent cardiac surgery between March 2005 and December 2015, 1909 patients were analyzed after excluding those with insufficient laboratory data, preoperative myocardial infarction, underwent Cox-Maze or redo surgery, or with a follow-up period <30 days. The primary outcome was risk of 30-day mortality according to elevated postoperative high-sensitivity cardiac troponin I (hs-cTnI) levels in varying degrees of renal function. Secondary outcomes included long-term cardiac-cause and all-cause mortality during the median follow-up of 52 months.After adjustment for risk factors, elevated peak postoperative hs-cTnI was associated with 30-day mortality [adjusted odds ratio 1.028, 95% confidence interval (CI) 1.013-1.043, P < .001], long-term cardiac-cause [adjusted hazard ratio (HR) 1.013, 95% CI 1.009-1.017, P < .001] and all-cause mortality (adjusted HR 1.013, 95% CI 1.009-1.016, P < .001), in patients with preoperative normal renal function [estimated glomerular filtration rate (eGFR) ≥60 ml/minute/1.73 m]. However, in patients with renal impairment (eGFR < 60 ml/minute/1.73 m), hs-cTnI levels were not associated with mortality following cardiac surgery.Elevated hs-cTnI levels following cardiac surgery did not predict short- and long-term mortality in patients with preoperative renal impairment.

Background: The adult mammalian heart has limited ability to repair itself after injury. Zebrafish, newts, and neonatal mice can regenerate cardiac tissue, largely by cardiac myocyte (CM) proliferation. It is unknown whether hearts of young large mammals can regenerate., Methods: We examined the regenerative capacity of the pig heart in neonatal animals (ages 2, 3, or 14 days postnatal) after myocardial infarction or sham procedure. Myocardial scar and left ventricular function were determined by cardiac magnetic resonance imaging and echocardiography. Bromodeoxyuridine pulse-chase labeling, histology, immunohistochemistry, and Western blotting were performed to study cell proliferation, sarcomere dynamics, and cytokinesis and to quantify myocardial fibrosis. RNA-sequencing was also performed., Results: After myocardial infarction, there was early and sustained recovery of cardiac function and wall thickness in the absence of fibrosis in 2-day-old pigs. In contrast, older animals developed full-thickness myocardial scarring, thinned walls, and did not recover function. Genome-wide analyses of the infarct zone revealed a strong transcriptional signature of fibrosis in 14-day-old animals that was absent in 2-day-old pigs, which instead had enrichment for cytokinesis genes. In regenerating hearts of the younger animals, up to 10% of CMs in the border zone of the myocardial infarction showed evidence of DNA replication that was associated with markers of myocyte division and sarcomere disassembly., Conclusions: Hearts of large mammals have regenerative capacity, likely driven by cardiac myocyte division, but this potential is lost immediately after birth.

The role of advanced glycation end products (AGEs) and its C-terminal truncated receptor (soluble receptor for advanced glycation end products, sRAGE) in ST-segment elevation myocardial infarction (STEMI) patients with or without diabetes is unknown. We compared their levels in patients with and without STEMI, as well as with and without diabetes. A prospective observational study was performed between December 2014 and December 2015. Study group included STEMI patients with coronary artery disease; control group included patients without coronary artery disease. Levels of AGEs and sRAGE were tested on Days 0, 2, and 5 after STEMI. Levels of creatine kinase-MB (CK-MB), cardiac troponin I, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were tested on Days 0, 1, 2, and 3. Patient's diabetic status was determined by medical history or oral glucose tolerance test. Compared to patients in the control group, STEMI patients showed elevated levels of AGEs and sRAGE. In the STEMI group, diabetic patients had higher levels of AGEs and sRAGE compared to nondiabetic patients. The level of AGEs correlated with peak level of CK-MB in the overall population of patients with STEMI and with peak level of NT-proBNP in diabetic patients with STEMI. Levels of AGEs and sRAGE were elevated after STEMI, especially among patients with diabetes. These markers could serve to indicate the severity of myocardial injury and cardiac insufficiency, and play a potential role in predicting the prognosis of patients with STEMI.

Rationale: Bezold-Jarisch reflex (BJR) occurs when the cardioinhibitory receptors in the walls of ventricles are activated by various stimuli, with typical features of bradycardia, vasorelaxation, and hypotension. This reflex usually happens in parturient intrathecal anesthesia, as a result of decreased venous return by compression of inferior vena cava, but it is only rarely reported during general anesthesia., Patient Concerns: Severe bradycardia and hypotension, indicating BJR, occurred during the induction of general anesthesia in a 3-month-old female child with giant intra-abdominal teratoma., Diagnoses: A giant intra-abdominal teratoma was detected by computed tomography scanning. The decreased left ventricular ejection faction along with increased troponin I and N-terminal pro-B-type natriuretic peptide indicated a preoperative mild cardiac dysfunction. BJR was diagnosed on the basis of the severe bradycardia and hypotension observed during the induction of general anesthesia, INTERVENTIONS:: Atropine failed to increase heart rate. Cardiopulmonary resuscitation was initiated immediately and epinephrine was injected intravenously because of sudden circulatory collapse. Soon after the return of spontaneous circulation, a central venous line was placed and invasive blood pressure was monitored. Vital signs and homeostasis were kept stable during teratoma resection., Outcomes: The child was extubated after emergence from anesthesia in the operating room. Eleven days later, she had recovered without complications and was discharged., Lessons: General anesthesia should be induced with great care in patients with giant intra-abdominal masses, and the patient should be kept in the left-lateral table tilt position before induction.

Background: Myocyte necrosis as a result of elective percutaneous coronary intervention (PCI) occurs in approximately one third of cases and is associated with subsequent cardiovascular events. This study assessed the ability of remote ischemic preconditioning (IPC) to attenuate cardiac troponin I (cTnI) release after elective PCI., Methods and Results: Two hundred forty-two consecutive patients undergoing elective PCI with undetectable preprocedural cTnI were recruited. Subjects were randomized to receive remote IPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mm Hg around the upper arm, followed by 5-minute intervals of reperfusion) or control (an uninflated cuff around the arm) before arrival in the catheter laboratory. The primary outcome was cTnI at 24 hours after PCI. Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months. The median cTnI at 24 hours after PCI was lower in the remote IPC compared with the control group (0.06 versus 0.16 ng/mL; P=0.040). After remote IPC, cTnI was <0.04 ng/mL in 44 patients (42%) compared with 24 in the control group (24%; P=0.01). Subjects who received remote IPC experienced less chest discomfort (P=0.0006) and ECG ST-segment deviation (P=0.005) than control subjects. At 6 months, the major adverse cardiac and cerebral event rate was lower in the remote IPC group (4 versus 13 events; P=0.018)., Conclusions: Remote IPC reduces ischemic chest discomfort during PCI, attenuates procedure-related cTnI release, and appears to reduce subsequent cardiovascular events.

Background: Strategies to limit adverse cardiac events after vascular surgery continue to evolve. Early recognition and treatment of myocardial ischemia may be a key to improving postoperative survival rates. Cardiac troponin I (cTnI) screening is an effective means of surveillance for postoperative myocardial ischemic injury and has long-term prognostic value., Methods: We designed a Markov-based decision analysis model to determine the cost-effectiveness of routine surveillance with cTnI on postoperative Days 0, 1, 2, and 3, with an aim to institute tight heart rate control (60-65 bpm) with close monitoring and coronary care in the intensive care unit for 5 days in patients with cTnI >1.5 ng/mL. The key input variables obtained from published literature were as follows: probability of myocardial infarction, 0.049; cost of cTnI surveillance, $357; cost and efficacy of interventions, $13,145 and 0.55, respectively. The time horizon was lifetime and the target population being individuals aged 65 yr (median) undergoing elective open abdominal aortic surgery. The perspective for analysis was third-party payer., Results: The incremental cost-effectiveness ratio for cTnI surveillance was $12,641 per quality-adjusted life year compared with standard care without cTnI surveillance. During one-way sensitivity analysis, probability of myocardial infarction and efficacy of interventions were found to influence the cost-effectiveness. Multivariate sensitivity analysis with second-order Monte Carlo simulation revealed that cTnI surveillance was favored in 90.75% of simulations at a commonly used threshold of $50,000 per quality-adjusted life year., Conclusions: In patients presenting for elective open abdominal aortic surgery, intensive surveillance with cTnI and early institution of aggressive beta-blockade is cost-effective.

The aim of this study was to evaluate the immunohistochemical differences between the muscular fiber types in the pars peripheralis and pars marginalis of human orbicularis oris muscle. Five upper lips of fresh human adult cadavers were used. Full thickness of the upper lip, 5 mm in width, was harvested vertically at a peak point of cupid's bow. Troponin I-SS and Troponin I-FS antibodies were used to determinate the slow and fast skeletal muscle fibers. The pars peripheralis is composed of slow fibers (22%) and fast fibers (73%). The pars marginalis is composed of slow fibers (30%) and fast fibers (66%). We assume that the pars peripheralis and pars marginalis should be repaired sortably because the muscle reaction and endurance are not the same.

Background: Abnormal Ca2+ handling may contribute to impaired atrial contractility and arrhythmogenesis in human chronic atrial fibrillation (cAF). Here, we assessed the phosphorylation levels of key proteins involved in altered Ca2+ handling and contractility in cAF patients., Methods and Results: Total and phosphorylation levels of Ca2+-handling and myofilament proteins were analyzed by Western blotting in right atrial appendages of 49 patients in sinus rhythm and 52 cAF patients. We found a higher total activity of type 1 (PP1) and type 2A phosphatases in cAF, which was associated with inhomogeneous changes of protein phosphorylation in the cellular compartments, ie, lower protein kinase A (PKA) phosphorylation of myosin binding protein-C (Ser-282 site) at the thick myofilaments but preserved PKA phosphorylation of troponin I at the thin myofilaments and enhanced PKA (Ser-16 site) and Ca2+-calmodulin protein kinase (Thr-17 site) phosphorylation of phospholamban. PP1 activity at sarcoplasmic reticulum is controlled by inhibitor-1 (I-1), which blocks PP1 in its PKA-phosphorylated form only. In cAF, the ratio of Thr-35-phosphorylated to total I-1 was 10-fold higher, which suggests that the enhanced phosphorylation of phospholamban may result from a stronger PP1 inhibition by PKA-hyperphosphorylated (activated) I-1., Conclusions: Altered Ca2+ handling in cAF is associated with impaired phosphorylation of myosin binding protein-C, which may contribute to the contractile dysfunction after cardioversion. The hyperphosphorylation of phospholamban probably results from enhanced inhibition of sarcoplasmic PP1 by hyperphosphorylated I-1 and may reinforce the leakiness of ryanodine channels in cAF. Restoration of sarcoplasmic reticulum-associated PP1 function may represent a new therapeutic option for treatment of atrial fibrillation.

Background: Cardiac troponin I (cTnI), a standard for detection of myocardial damage, has recently been reported to predict acute myocardial infarction or death in patients with unstable coronary heart disease (CHD). Cardiac TnI concentrations increase with age in subjects free from clinical signs of CHD, suggesting silent myocardial damage. We investigated the association between cTnI and future CHD and mortality in a community-based cohort of men., Methods and Results: A community-based study was conducted from August 1991 to May 1995 among 1203 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10.4 years with the use of registry data (National Board of Health and Welfare, Sweden). CHD was defined with the use of data taken from the Cause of Death Registry or from first-time hospitalization for CHD as recorded in the Hospital Discharge Registry. Cardiac TnI concentrations were measured blinded for outcome, in frozen baseline plasma samples, with the use of the AccuTnI from Beckman Coulter, Inc. Hazard ratios (HRs) from Cox proportional hazards are presented with 95% confidence intervals (CIs) for a 1-SD increase. In men free from cardiovascular disease (CVD), cTnI predicted death (HR, 1.26; 95% CI, 1.08 to 1.46; P=0.003) or first CHD event (HR, 1.31; 95% CI, 1.11 to 1.54; P=0.001) after adjustment for conventional risk factors: total and HDL cholesterol, plasma glucose, body mass index, smoking, and systolic blood pressure., Conclusions: In this first longitudinal report, cTnI was shown to predict death and first CHD event in men free from CVD at baseline, indicating the importance of silent cardiac damage in the development of CHD and mortality.

Background: Aggressive platelet inhibition is crucial to reduce myocardial injury and early cardiac events after coronary intervention. Although observational data have suggested that pretreatment with a high loading dose of clopidogrel may be more effective than a conventional dose, this hypothesis has never been tested in a randomized trial., Methods and Results: A total of 255 patients scheduled to undergo percutaneous coronary intervention were randomized to a 600-mg (n=126) or 300-mg (n=129) loading regimen of clopidogrel given 4 to 8 hours before the procedure. Creatine kinase MB, troponin I, and myoglobin levels were measured at baseline and at 8 and 24 hours after intervention. The primary end point was the 30-day occurrence of death, myocardial infarction (MI), or target vessel revascularization. The primary end point occurred in 4% of patients in the high loading dose versus 12% of those in the conventional loading dose group (P=0.041) and was due entirely to periprocedural MI. Peak values of all markers were significantly lower in patients treated with the 600-mg regimen (P< or =0.038). Safety end points were similar in the 2 arms. At multivariable analysis, the high loading regimen was associated with a 50% risk reduction of MI (OR 0.48, 95% CI 0.15 to 0.97, P=0.044). An incremental benefit was observed in patients randomized to the 600-mg dose who were receiving statins, with an 80% risk reduction., Conclusions: Pretreatment with a 600-mg loading dose of clopidogrel 4 to 8 hours before the procedure is safe and, as compared with the conventional 300-mg dose, significantly reduced periprocedural MI in patients undergoing percutaneous coronary intervention. These results may influence practice patterns with regard to antiplatelet therapy before percutaneous revascularization.

Background: The incidence and significance of troponin I release and its mechanism are unknown in severe trauma patients. The characteristics of this release were prospectively studied in such patients and correlated with presence of shock, existence of myocardial contusion, and outcome., Methods: During a 24-month period, serial electrocardiogram recordings and troponin I measurements were performed in all trauma patients admitted at a surgical intensive care unit. The diagnosis of a significant myocardial contusion was made on electrocardiographic criteria. According to the time course of troponin I, three groups of patients were defined a priori: very transient (/= 2 microg/l), and sustained (> 36 h) and significant release (troponin I > 2 microg/l). In the last group, coronary artery angiography was performed., Results: The incidence of troponin I release was 12% (95% confidence interval [CI], 9.6-14.4%) in 728 patients. A significant myocardial contusion was found in 35 patients (5%; 95% CI, 3.4-6.6%) and may occur in the absence of chest trauma and without troponin I release. Sensitivity, specificity, and positive and negative predictive values of troponin I for the diagnosis of myocardial contusion were 63, 98, 40, and 98%, respectively. Troponin I release was observed in 54 early (> 48 h) survivors (7%; 95% CI, 5.6-9.6%) without preexisting coronary artery disease. A sustained and significant release of troponin I (17 patients) was frequently associated with chest trauma (82%) and constantly with electrocardiographic abnormalities. A coronary artery injury was found in 7 patients (2 major and 5 minor vascular injuries) (1% of the whole group; 95% CI, 0.4-2.0%). Mortality was similar in early survivors with (15%; 95% CI, 7-27%) or without (12%; 95% CI, 9-14%) troponin I release. The odds ratio for late mortality was 1.32 (95% CI, 0.61-2.85) in patients with troponin I release., Conclusions: Serial electrocardiogram recordings and troponin I assessments may be proposed for initial screening in high-risk trauma patients to detect anatomical cardiac injuries through the time course of circulating protein. Troponin I release does not have a prognosis value in trauma patients.

Background: Myocardial contusion during blunt chest trauma is common and may lead to potentially fatal cardiac complications. Therefore, it is useful to identify a serum marker reflecting the myocardial damage that can predict risk for cardiac complications. In this study, the authors determined the strength of the association between cardiac troponin I (cTnI) levels and the risk of arrhythmia or the development of left ventricular dysfunction in a cohort of patients with blunt chest trauma., Methods and Results: In 187 multiply injured patients with blunt chest trauma, serial measurements of cTnI, total creatine kinase (CK), and isoenzyme of creatine kinase with muscle and brain subunits (CK-MB) were combined with sequential electrocardigraphic and echocardiographic recordings. The results showed that 63 patients (34%) had myocardial contusion, as defined by positive cTnI levels, of which 47 (25%) were symptomatic and 16 (9%) showed no abnormalities. The remaining 124 patients (66%) displaying negative CTnI levels were asymptomatic during the entire study. Severity of arrhythmia correlated directly with increase in cTnI levels. The levels of cTnI in the symptomatic group remained elevated significantly longer than the levels in the asymptomatic group. The depression of left ventricular ejection fraction was inversely correlated with the increase in cTn levels. The patients whose cTnI levels were below 1.05 microg/L at admission and during the first 6 hours afterward showed no cardiac abnormalities throughout the entire study period, Conclusions: Levels of cTnI below 1.05 microg/L in asymptomatic patients at admission and within the first 6 hours after admission rule out myocardial injury, whereas positive cTn levels above 1.05 microg/L mandate further cardiologic workup for the detection and management of myocardial injury. Furthermore, the dynamics and peak levels of pathologic cTnI levels allow estimation of arrhythmia risk and left ventricular dysfunction in trauma patients with myocardial contusion.

Human embryonic stem (hES) cells can differentiate in vitro, forming embryoid bodies (EBs) composed of derivatives of all three embryonic germ layers. Spontaneously contracting outgrowths from these EBs contain cardiomyocytes (CMs); however, the types of human CMs and their functional properties are unknown. This study characterizes the contractions and action potentials (APs) from beating EB outgrowths cultured for 40 to 95 days. Spontaneous and electrical field-stimulated contractions were measured with video edge-detection microscopy. beta-Adrenergic stimulation with 1.0 micromol/L isoproterenol resulted in a significant increase in contraction magnitude. Intracellular electrical recordings using sharp KCl microelectrodes in beating EB outgrowths revealed three distinct classes of APs: nodal-like, embryonic atrial-like, and embryonic ventricular-like. The APs were described as embryonic based on the relatively depolarized resting membrane potential and slow AP upstroke. Repeated impalements of an individual beating outgrowth revealed a reproducible AP morphology recorded from different cells, suggesting that each outgrowth is composed of a predominant cell type. Complex functional properties typical of cardiac muscle were observed in the hES cell-derived CMs including rate adaptation of AP duration and provoked early and delayed afterdepolarizations. Repolarization of the AP showed a significant role for IKr based on E-4031 induced prolongation of AP duration as anticipated for human CMs. In conclusion, hES cells can differentiate into multiple types of CMs displaying functional properties characteristic of embryonic human cardiac muscle. Thus, hES provide a renewable source of distinct types of human cardiac myocytes for basic research, pharmacological testing, and potentially therapeutic applications.

Background: This study investigates the efficacy of pinacidil, an adenosine triphosphate-sensitive potassium (KATP) channel opening agent, added to custadiol solution on myocardial protection during deep hypothermia and prolonged global ischemia on isolated rat hearts., Methods: After 20 minutes of stabilization, 24 rats were divided into two groups. In group I (n=12), hearts were arrested with cold (4 degrees C) custadiol solution containing 50 micromol/L of pinacidil and subsequently dipped into the same solution for 120 minutes at 4 degrees C. Group I hearts were perfused with low-flow pinacidil-custadiol (PC) solution during the ischemic period. Group II (n=12) hearts, after the stabilization period, were arrested with cold custadiol solution only, then subsequently dipped and perfused with the same solution for 120 minutes at 4 degrees C. All hearts were reperfused with Krebb's-Henseleit solution at 37 degrees C for 60 minutes. Hemodynamic parameters (peak systolic pressure, end diastolic pressure, maximum rate of increase of left ventricular pressure [+dP/dt], ischemic contracture, and coronary sinus flow) were recorded at the end of the stabilization period and at 10-minute intervals during the reperfusion period. Biochemical data (creatine kinase [CK-MB] washout and troponin I [cTnI] levels) were compared between the two groups., Results: There was no significant difference in any hemodynamic or biochemical parameters between the two groups during the stabilization period. The peak systolic pressure, +dP/dt, ischemic contraction amplitude, and coronary flow values were significantly higher in group I ( P<0.05) compared with group II during reperfusion. End diastolic pressures as well as CK-MB and cTnI levels were lower in the pinacidil-treated group, which is consistent with improved functional recovery during the reperfusion period., Conclusion: The addition of pinacidil to the preservation solution, custadiol, improves myocardial recovery after deep hypothermia and prolongs ischemia.

Background: Matrix metalloproteinases are best recognized for their ability to degrade the extracellular matrix in both physiological and pathological conditions. However, recent findings indicate that some of them are also involved in mediating acute processes such as platelet aggregation and vascular tone. The acute contractile defect of the heart after ischemia-reperfusion may involve the proteolytic degradation of the thin filament protein troponin I; however, the protease responsible for this remains obscure., Methods and Results: Here we report that matrix metalloproteinase-2 is colocalized with troponin I within the thin myofilaments of cardiomyocytes in ischemic-reperfused hearts and that troponin I is a novel intracellular target for proteolytic cleavage by matrix metalloproteinase-2. Inhibition of matrix metalloproteinase-2 activity prevented ischemia-reperfusion-induced troponin I degradation and improved the recovery of mechanical function of the heart., Conclusions: These data reveal for the first time a novel molecular mechanism by which matrix metalloproteinase-2 causes acute myocardial dysfunction after ischemia-reperfusion-injury and that matrix metalloproteinase-2 has a biological action within the cell.

Background: In patients with acute coronary syndromes (ACS), troponin I (TnI), C-reactive protein (CRP), and B-type natriuretic peptide (BNP) each predict adverse cardiac events. Little is known, however, about the utility of these biomarkers in combination., Methods and Results: Baseline measurements of TnI, CRP, and BNP were performed in 450 patients in OPUS-TIMI 16. Elevations in TnI, CRP, and BNP each were independent predictors of the composite of death, myocardial infarction (MI), or congestive heart failure (CHF). When patients were categorized on the basis of the number of elevated biomarkers at presentation, there was a near doubling of the mortality risk for each additional biomarker that was elevated (P=0.01). Similar relationships existed for the endpoints of MI, CHF, and the composite, both at 30 days and through 10 months. In a validation cohort of 1635 patients in TACTICS-TIMI 18, the number of elevated biomarkers remained a significant predictor of the composite endpoint after adjustment for known clinical predictors: patients with one, two, and three elevated biomarkers had a 2.1- (P=0.006), 3.1- (P<0.001), and 3.7- (P=0.001) fold increase in the risk of death, MI, or CHF by 6 months., Conclusions: Troponin, CRP, and BNP each provide unique prognostic information in patients with ACS. A simple multimarker strategy that categorizes patients based on the number of elevated biomarkers at presentation allows risk stratification over a broad range of short- and long-term major cardiac events.

Objective: To study the value of assaying cardiac troponin I (cTnI) for the early diagnosis of perioperative myocardial infarction (PMI) and various complications of cardiac surgery., Design: A prospective observational clinical study., Setting: Biochemical laboratory, anesthesia, and cardiac surgery department of Hôpital Broussais., Patients: Two hundred and sixty consecutive patients undergoing cardiac surgery., Interventions: All patients underwent coronary artery bypass grafting and/or valvular surgery under extracorporeal circulation. Per-operative and postoperative follow-up consisted of electrocardiogram, echocardiography (mainly by the transesophageal approach), and serial determinations of biochemical markers such as creatinine kinase-MB isoenzyme (CK-MB) and cTnI. PMI, new ST segment changes, and ventricular arrhythmias were considered postoperative adverse cardiac outcome., Measurements and Main Results: CTnI was measured before cardiopulmonary bypass (T0) and 12 and 24 hrs after (T12, T24). CK-MB was measured on arrival in the intensive care unit and on the first postoperative day (D1). Patients were divided into three groups according to the type of surgery: coronary artery bypass graft (CABG), valvular surgery (VS), or both procedures. The plasma CK-MB and cTnI concentrations were high in all patients after extracorporeal circulation because of aortic clamping or cardioplegia. The CK-MB and cTnI values were higher in the VS group than in the CABG group. Values peaked at T12 and fell by T24, except when PMI occurred. Eight patients developed a PMI. Patients with PMI had significantly higher cTnI levels at T12 and T24, and higher CK-MB values at D1 than patients without PMI. Cutoff values of cTnI for diagnosing PMI were >19 microg/L at T12 with 100% sensitivity and 73% specificity, and >36 microg/L at T24, with 100% sensitivity and 93% specificity. Lower cTnI values were highly suggestive of the absence of PMI after CABG and/or VS. Other complications such as ST segment changes, ventricular arrhythmias and cardiac failure were indicated by high cTnI levels at T12 and T24. Myocardial protective measures were associated with a nonsignificant increase in cTnI values., Conclusions: CTnI is more sensitive and specific than CK-MB for diagnosing PMI and other forms of heart failure after cardiac surgery.

Background: Selective proteolysis of cardiac troponin I (cTnI) is a proposed mechanism of contractile dysfunction in stunned myocardium, and the presence of cTnI degradation products in serum may reflect the functional state of the remaining viable myocardium. However, recent swine and canine studies have not demonstrated stunning-dependent cTnI degradation., Methods and Results: To address the universality of cTnI modification, myocardial biopsy samples were obtained from coronary artery bypass patients (n=37) before and 10 minutes after removal of cross-clamp. Analysis of biopsy samples for cTnI by Western blotting revealed a spectrum of modified cTnI products in myocardium both before and after cross-clamp, including degradation products (7 products resulting from differential N- and C-terminal processing) and covalent complexes (3 products). In particular, a 22-kDa cTnI degradation product with C-terminal proteolysis was identified, which may represent an initial ischemia-dependent cTnI modification, similar to cTnI(1-193) observed in stunned rat myocardium. Although no systematic change in amount of modified cTnI was observed, subgroups of patients displayed an increase (n=10, 85+/-5% of cTnI remaining intact before cross-clamp versus 75+/-5% after) or a decrease (n=12, 67+/-5% before versus 78+/-5% after). Electron microscopy demonstrated normal ultrastructure in biopsy samples, which suggests no necrosis was present. In addition, cTnI modification products were observed in serum through a modified SDS-PAGE methodology., Conclusions: cTnI modification, in particular proteolysis, occurs in myocardium of bypass patients and may play a key role in stunning in some bypass patients.

Background: Patients with cardiac contusion have a high risk of cardiac complications during emergency anesthesia. Despite the progress in cardiac imaging, a biologic marker of myocardial damage such as cardiac troponin I remains useful and has been proposed in clinical practice. The relationship among histologic injury, left-ventricular function, and release of cardiac enzymes and cardiac troponin I has been investigated after a controlled myocardial contusion in a rabbit model., Methods: A global trauma (two levels of energy: 250 and 350 mJ) was produced on an isolated preparation of rabbit's heart, of which the temperature, perfusion flow, beating rate, and left-ventricular volume were kept constant. Left-ventricular pressure and its first derivative as a function of time were measured during a 60-min period after the blow; a timed collection of the effluent was made to assess creatine kinase, lactate dehydrogenase, and cardiac troponin I. At the end of the period, an anatomic score of the contusion was calculated by histologic examination of the hearts., Results: Compared with a control group, the two levels of cardiac trauma resulted in a proportional anatomic injury significantly correlated with left-ventricular dysfunction (Delta%dP/dtmax = -16 +/- 12 and -36 +/- 20% at 3 min, mean +/- SD). Transient releases in cardiac markers after the lesser amount of trauma contrasted with a prolonged and biphasic release of cardiac troponin I after the greater amount. Peak cardiac troponin I level was correlated with anatomic injury (rho = 0.596, P= 0.001) and negatively correlated with left-ventricular dysfunction (r = -0.375, P= 0.04)., Conclusion: Cardiac troponin I is a marker of anatomic and functional consequences of experimental cardiac trauma and may be a predictive indicator of early posttraumatic cardiac complications during the postoperative period.

Pathologists frequently examine victims of sudden cardiac death. In some cases, a firm diagnosis of cardiac-related death can be made based on conclusive gross and histologic findings. In many other cases, we find evidence supportive of, but not diagnostic of, cardiac death (e.g., atherosclerotic coronary artery disease, cardiomegaly, myocardial scarring). A final cohort consists of cases of sudden death with minimal to mild cardiac disease, no other significant pathology, and negative toxicologic studies. This prospective study compared 38 cardiac-related deaths with 52 control cases with respect to concentrations of pericardial cardiac troponin I (cTnI), heart weight, evidence of old and/or recent myocardial injury, and presence of significant coronary artery disease. The influence of documented chest trauma and/or perimortem cardiopulmonary resuscitation (CPR) on levels of cTnI was also analyzed. Even though median cTnI levels were significantly higher in cardiac deaths than in controls (p = .003), cTnI was not found to be a significant predictor of cardiac deaths, as determined by discriminant analysis (p = .52). Heart weight >500 g, evidence of old and recent myocardial injury, and significant coronary artery disease were seen statistically more often in cardiac deaths than in controls (p < or = .005 in each case), and median age was significantly higher in cardiac deaths than in controls (p = .001). Based on a stepwise logistic regression model, significant coronary artery disease, old and recent myocardial injury, and heart weight >500 g were found to contribute significantly to the prediction of cardiac death. Finally, neither chest injury nor CPR significantly affected concentrations of cTnI in pericardial fluid. These data confirm that the presence of acute and remote myocardial injury, significant coronary artery disease, and cardiomegaly (heart weight >500 g) strongly supports the diagnosis of a cardiac-related death. In contrast to a recently published report, we do not find that elevated concentrations of cTnI in pericardial fluid are strong indicators of cardiac-related deaths using our methodology.

Unlabelled: Pericardial fluid can reflect the composition of cardiac interstitium in myocardial ischemia. This study investigated the hypothesis that pericardial cardiac troponin I (CTnI) measurements could be a more accurate marker of perioperative myocardial infarction (MI) than serum CTnI after coronary artery bypass grafting (CABG). Postoperative arterial and pericardial blood samples were taken in 102 subjects undergoing elective CABG allocated to one of three groups according to the 12-lead electrocardiogram (ECG) abnormalities observed during the first postoperative 24 h: Group 1 = normal ECG; Group 2 = nonspecific ECG abnormalities; and Group 3 = perioperative Q-wave MI. Peak pericardial CTnI concentrations were much higher than peak serum concentrations in all subjects and significantly greater in Group 3 than in Groups 1 and 2 (1,318 +/- 1,810 ng/mL vs 367 +/- 339 ng/mL and 558 +/- 608 ng/mL, respectively; P < 0.01). However, no significant difference between groups occurred at any time for pericardial/serum CTnI ratios, indicating that time courses of CTnI were not different in pericardial fluid and serum. A significant correlation was found between serum and pericardial CTnI concentrations (R = 0.70, P < 0.001). Pericardial CTnI was not more accurate than serum CTnI in predicting Q-wave MI as shown by the low value of the area under the receiver-operator characteristic curve (= 0.71). Peak and early pericardial CTnI were also not accurate in predicting an increase of serum CTnI greater than a cutoff value of 19 ng/mL. Thus, pericardial CTnI measurements were less useful than serum CTnI measurements in the diagnosis of perioperative MI after CABG., Implications: Although cardiac troponin I concentrations were much higher in pericardial fluid than in serum and significantly increased in subjects who experienced perioperative Q-wave myocardial infarction, pericardial cardiac troponin I measurements were of less value than serum cardiac troponin I measurements for the diagnosis of perioperative myocardial infarction after coronary artery bypass grafting and cannot be recommended in routine clinical practice.

Background: The cardiac isoform of troponin I (cTnI) is a myofibrillar protein highly specific for myocardial injury. We used a recently developed new-generation immunoassay with high analytical sensitivity to measure cTnI in patients diagnosed with hematologic malignancies, before chemotherapy and after an intermediate cumulative dose of anthracyclines. We hypothesized that measurement of cTnI with this sensitive method would provide evidence of myocardial injury in these patients., Methods: Sera from 115 individuals (60 healthy controls, 25 anthracycline-naive patients and 30 patients treated with intermediate cumulative doses of anthracyclines) were assessed for cTnI, creatine kinase MB (CKMB) mass and myoglobin. Radionuclide left ventricular ejection fraction (LVEF) was also determined., Results: Using this sensitive assay, detectable concentrations of cTnl were measured in the healthy population [mean, 19.5 pg/ml, 95% confidence interval (CI) 13.5-25.5 pg/ml]. Anthracycline-naive patients had cTnI mean values (36.5 pg/ml, 95% CI 25.1-47.9 pg/ml) that were significantly (P < 0.01) greater than those in the control group. cTnI was significantly (P < 0.00001) increased in anthracycline-treated patients (76.4 pg/ml, 95% CI 67.0-85.8 pg/ml) compared with both the anthracycline-naive patients and the controls. CKMB, myoglobin and LVEF were within the normal range in all patients., Conclusions: These data provide evidence for cardiac involvement in patients with hematological malignancies before and during the course of anthracycline chemotherapy. They suggest that detection of myocardial injury may be facilitated by measurement of cTnI with a highly sensitive assay.