Potential Biomarkers to Distinguish Type 1 Myocardial Infarction in Troponin-Elevated Diseases.

Classifying myocardial infarction by subtype is crucial for appropriate patient management. Although troponin is currently the most commonly used biomarker, it is not a specific marker for myocardial infarction and cannot distinguish subtypes. Furthermore, previous studies have confirmed that proteins known as myocardial infarction markers could function to distinguish the type of myocardial infarction. Therefore, we identify a marker that can distinguish type 1 myocardial infarction from other diseases with elevated troponin. We used mass spectrometry to compare type 1 myocardial infarction with other conditions characterized by troponin elevation and identified new candidate markers for disease classification. We then verified these markers, along with those already known to be associated with cardiovascular disease and plaque rupture. We identified α-1 acid glycoprotein 2, corticosteroid-binding globulin, and serotransferrin as potential distinguishing markers. The presence of these markers and other parameters, such as chest pain, electrocardiogram, and troponin levels from the complementary diagnostic processes, could provide valuable information to specifically diagnose type 1 myocardial infarction.

Outcomes in patients with chest pain in emergency departments using high-sensitivity versus conventional troponins.

Objectives. There is a paucity of data regarding the association between the use of high-sensitivity troponin (hs-cTn) compared with conventional troponin (cTn) and outcomes in chest pain patients in emergency departments (EDs). This study examined the impact of hs-cTnT on prognosis in chest pain patients in EDs. Design. In an observational cohort study, we included chest pain patients visiting the EDs of 14 hospitals in Sweden from 2011 to 2016. The study population was retrieved from each hospital, and information on characteristics and outcomes was collected from nationwide registries. Cox regression was used to estimate adjusted hazard ratios with 95% confidence intervals (HR, 95% CI) for (1) 1-year all-cause mortality, (2) missed acute coronary syndromes (ACSs), (3) use of coronary angiography, and (4) revascularizations within 30 days. Results. We included 170461 patients with chest pain where 62669 patients were tested with cTn while 107792 patients were tested with hs-cTnT. We found 4149 (4.6%) deaths in the cTn group and 6087 (3.7%) deaths in the hs-cTnT group. Patients in the hs-cTnT group had 9% lower mortality (0.91, 0.87-0.94), and were 14% more likely to undergo coronary angiography (1.14, 1.10-1.17), and 12% more likely to be revascularized (1.12, 1.08-1.17) than patients in the cTn group. Conclusions. Patients with chest pain visiting EDs using hs-cTnT had lower mortality and a higher likelihood of undergoing coronary angiographies and revascularizations than those using cTn. There may be a survival benefit of being tested with hs-cTnT compared with cTn in patients seeking medical attention for chest pain.

Cell-Specific Mechanisms in the Heart of COVID-19 Patients.

From the onset of the pandemic, evidence of cardiac involvement in acute COVID-19 abounded. Cardiac presentations ranged from arrhythmias to ischemia, myopericarditis/myocarditis, ventricular dysfunction to acute heart failure, and even cardiogenic shock. Elevated serum cardiac troponin levels were prevalent among hospitalized patients with COVID-19; the higher the magnitude of troponin elevation, the greater the COVID-19 illness severity and in-hospital death risk. Whether these consequences were due to direct SARS-CoV-2 infection of cardiac cells or secondary to inflammatory responses steered early cardiac autopsy studies. SARS-CoV-2 was reportedly detected in endothelial cells, cardiac myocytes, and within the extracellular space. However, findings were inconsistent and different methodologies had their limitations. Initial autopsy reports suggested that SARS-CoV-2 myocarditis was common, setting off studies to find and phenotype inflammatory infiltrates in the heart. Nonetheless, subsequent studies rarely detected myocarditis. Microthrombi, cardiomyocyte necrosis, and inflammatory infiltrates without cardiomyocyte damage were much more common. In vitro and ex vivo experimental platforms have assessed the cellular tropism of SARS-CoV-2 and elucidated mechanisms of viral entry into and replication within cardiac cells. Data point to pericytes as the primary target of SARS-CoV-2 in the heart. Infection of pericytes can account for the observed pericyte and endothelial cell death, innate immune response, and immunothrombosis commonly observed in COVID-19 hearts. These processes are bidirectional and synergistic, rendering a definitive order of events elusive. Single-cell/nucleus analyses of COVID-19 myocardial tissue and isolated cardiac cells have provided granular data about the cellular composition and cell type-specific transcriptomic signatures of COVID-19 and microthrombi-positive COVID-19 hearts. Still, much remains unknown and more in vivo studies are needed. This review seeks to provide an overview of the current understanding of COVID-19 cardiac pathophysiology. Cell type-specific mechanisms and the studies that provided such insights will be highlighted. Given the unprecedented pace of COVID-19 research, more mechanistic details are sure to emerge since the writing of this review. Importantly, our current knowledge offers significant clues about the cardiac pathophysiology of long COVID-19, the increased postrecovery risk of cardiac events, and thus, the future landscape of cardiovascular disease.

Normal high-sensitivity cardiac troponin for ruling-out inpatient mortality in acute COVID-19.

INTRODUCTION: Assessment of inpatient mortality risk in COVID-19 patients is important for guiding clinical decision-making. High sensitivity cardiac troponin T (hs-cTnT) is a biomarker of cardiac injury associated with a worse prognosis in COVID-19. We explored how hs-cTnT could potentially be used in clinical practice for ruling in and ruling out mortality in COVID-19. METHOD: We tested the diagnostic value of hs-cTnT in laboratory-confirmed COVID-19 patients (≥18 years old) admitted to the Royal Berkshire Hospital (UK) between 1st March and 10th May 2020. A normal hs-cTnT was defined as a value within the 99th percentile of healthy individuals (≤14 ng/L), and an elevated hs-cTnT was defined as >14 ng/L. Adverse clinical outcome was defined as inpatient mortality related to COVID-19. RESULTS: A total of 191 COVID-19 patients (62% male; age 66±16 years) had hs-cTnT measured on admission. Of these patients, 124 (65%) had elevated hs-cTnT and 67 (35%) had normal hs-cTnT. On a group level, patients with elevated hs-cTnT had worse inpatient survival (p = 0.0014; Kaplan-Meier analysis) and higher risk of inpatient mortality (HR 5.84 [95% CI 1.29-26.4]; p = 0.02; Cox multivariate regression) compared to patients with normal hs-cTnT. On a per-patient level, a normal hs-cTnT had a negative predictive value of 94% (95% CI: 85-98%) for ruling out mortality, whilst an elevated hs-cTnT had a low positive predictive value of 38% (95% CI: 39-47%) for ruling in mortality. CONCLUSIONS: In this study cohort of COVID-19 patients, the potential clinical utility of hs-cTnT appears to rest in ruling out inpatient mortality. This finding, if prospectively validated in a larger study, may allow hs-cTnT to become an important biomarker to facilitate admission-avoidance and early safe discharge.

Ischemic Preconditioning Is Present in Patients With Non-ST Elevation Myocardial Infarction Screened With Electrocardiogram-Derived Moderate Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with an increased risk of cardiovascular events, including acute coronary syndrome (ACS). There is conflicting evidence that suggests OSA has a cardioprotective effect (ie, lower troponin), via ischemic preconditioning, in patients with ACS. PURPOSE: This study had 2 aims: (1) compare peak troponin between non-ST elevation (NSTE) ACS patients with and without moderate OSA identified using a Holter-derived respiratory disturbance index (HDRDI) and (2) determine the frequency of transient myocardial ischemia (TMI) between NSTE-ACS patients with and without moderate HDRDI. METHOD: This was a secondary analysis. Obstructive sleep apnea events were identified from 12-lead electrocardiogram Holter recordings using QRSs, R-R intervals, and the myogram. Moderate OSA was defined as an HDRDI of greater than or equal to 15 events per hour. Transient myocardial ischemia was defined as greater than or equal to 1 mm of ST-segment ↑ or ↓, in 1 or more electrocardiogram lead, lasting at least 1 minute. RESULTS: In 110 patients with NSTE-ACS, 39% (n = 43) had moderate HDRDI. Peak troponin was lower in patients with moderate HDRDI (6.8 ng/mL yes vs 10.2 ng/mL no; P = .037). There was a trend for fewer TMI events, but there were no differences (16% yes vs 30% no; P = .081). CONCLUSIONS: Non-ST elevation ACS patients with moderate HDRDI have less cardiac injury than those without moderate HDRDI measured using a novel electrocardiogram-derived method. These findings corroborate previous studies suggesting a possible cardioprotective effect of OSA in patients with ACS via ischemic precondition. There was a trend for fewer TMI events in patients with moderate HDRDI, but there was no statistical difference. Future research should explore the underlying physiologic mechanisms of this finding.

Cardiovascular outcomes of type 2 myocardial infarction among COVID-19 patients: a propensity matched national study.

BACKGROUND: Myocardial infarction Type II (T2MI) is a prevalent cause of troponin elevation secondary to a variety of conditions causing stress/demand mismatch. The impact of T2MI on outcomes in patients hospitalized with COVID-19 is not well studied. METHODS: The Nationwide Inpatient Sample database from the year 2020 was queried to identify COVID-19 patients with T2MI during the index hospitalization. Clinical Modification (ICD-10-CM) codes 'U07.1' and 'I21.A1' were used as disease identifiers for COVID-19 and T2MI respectively. Multivariate adjusted Odds ratio (aOR) and propensity score matching (PSM) was done to compare outcomes among COVID patients with and without T2MI. The primary outcome was in-hospital mortality. RESULTS: A total of 1,678,995 COVID-19-weighted hospitalizations were identified in the year 2020, of which 41,755 (2.48%) patients had T2MI compared to 1,637,165 (97.5%) without T2MI. Patients with T2MI had higher adjusted odds of in-hospital mortality (aOR 1.44, PSM 32.27%, 95% CI 1.34-1.54) sudden cardiac arrest (aOR 1.29, PSM 6.6%, 95% CI 1.17-1.43) and CS (aOR 2.16, PSM 2.73%, 95% CI 1.85-2.53) compared to patients without T2MI. The rate of coronary angiography (CA) in T2MI with COVID was 1.19%, with significant use of CA among patients with T2MI complicated by CS compared to those without CS (4% vs 1.1%, p < 0.001). Additionally, COVID-19 patients with T2MI had an increased prevalence of sepsis compared to COVID-19 without T2MI (48% vs 24.1%, p < 0.001). CONCLUSION: COVID-19 patients with T2MI had worse cardiovascular outcomes with significantly higher in-hospital mortality, SCA, and CS compared to those without T2MI. Long-term mortality and morbidity among COVID-19 patients who had T2MI will need to be clarified in future studies. [Figure: see text].

External validation of the Manchester Acute Coronary Syndromes ECG risk model within a pre-hospital setting.

OBJECTIVES: The Manchester Acute Coronary Syndromes ECG (MACS-ECG) prediction model calculates a score based on objective ECG measurements to give the probability of a non-ST elevation myocardial infarction (NSTEMI). The model showed good performance in the emergency department (ED), but its accuracy in the pre-hospital setting is unknown. We aimed to externally validate MACS-ECG in the pre-hospital environment. METHODS: We undertook a secondary analysis from the Pre-hospital Evaluation of Sensitive Troponin (PRESTO) study, a multi-centre prospective study to validate decision aids in the pre-hospital setting (26 February 2019 to 23 March 2020). Patients with chest pain where the treating paramedic suspected acute coronary syndrome were included. Paramedics collected demographic and historical data and interpreted ECGs contemporaneously (as 'normal' or 'abnormal'). After completing recruitment, we analysed ECGs to calculate the MACS-ECG score, using both a pre-defined threshold and a novel threshold that optimises sensitivity to differentiate AMI from non-AMI. This was compared with subjective ECG interpretation by paramedics. The diagnosis of AMI was adjudicated by two investigators based on serial troponin testing in hospital. RESULTS: Of 691 participants, 87 had type 1 AMI and 687 had complete data for paramedic ECG interpretation. The MACS-ECG model had a C-index of 0.68 (95% CI: 0.61 to 0.75). At the pre-determined cut-off, MACS-ECG had 2.3% (95% CI: 0.3% to 8.1%) sensitivity, 99.5% (95% CI: 98.6% to 99.9%) specificity, 40.0% (95% CI: 10.2% to 79.3%) positive predictive value (PPV) and 87.6% (87.3% to 88.0%) negative predictive value (NPV). At the optimal threshold for sensitivity, MACS-ECG had 50.6% sensitivity (39.6% to 61.5%), 83.1% specificity (79.9% to 86.0%), 30.1% PPV (24.7% to 36.2%) and 92.1% NPV (90.4% to 93.5%). In comparison, paramedics had a sensitivity of 71.3% (95% CI: 60.8% to 80.5%) with 53.8% (95% CI: 53.8% to 61.8%) specificity, 19.7% (17.2% to 22.45%) PPV and 93.3% (90.8% to 95.1%) NPV. CONCLUSION: Neither MACS-ECG nor paramedic ECG interpretation had a sufficiently high PPV or NPV to 'rule in' or 'rule out' NSTEMI alone.

[Cardiac biomarkers and their clinical relevance]. / Kardiale Biomarker und ihre klinische Bedeutung.

Cardiac biomarkers are an integral, guideline-recommended part of the diagnosis and follow-up of heart diseases. High sensitivity tests for troponin I or T allow for the early diagnosis of myocardial infarction. Rule-in and rule-out algorithms based on the dynamic of plasma concentrations in the first hour after admission improve safe, evidence-based decision making for patients with acute chest pain. Low concentrations of brain natriuretic peptides (BNP or NT-proBNP) reliably exclude heart failure. Elevated BNP/NT-proBNP concentrations are part of the definition of all types of heart failure but require additional tests to diagnose heart failure. Chronic elevations of troponins and BNP/NT-proBNP identify subpopulations at increased risk of cardiovascular events even in the absence of manifest cardiac disease. Whether and how this risk can be reduced requires further evaluation. Several novel biomarkers were recently discovered and characterised. Their place in cardiovascular medicine has yet to be defined.

Advances in rapid diagnostic tests for myocardial infarction patients.

INTRODUCTION: A rapid diagnosis of myocardial infarction (MI) is of utmost importance in order to provide adequate therapy for patients that suffer from acute ischemic cardiac injury. Cardiac troponin has evolved as the most significant biomarker in the diagnostic assessment of MI, but its evaluation and management can be challenging. Different troponin-based diagnostic protocols have been suggested for the diagnosis of MI and they have been validated and further developed over the years. AREAS COVERED: This review highlights the advances, characteristics, and challenges of rapid diagnostic protocols for MI and summarizes recent findings of investigations in the field. EXPERT OPINION: Although high-sensitivity troponin assays and rapid diagnostic protocols have revolutionized the assessment of suspected MI, we are still facing challenges that must be overcome in order to improve the outcome of patients with MI.

Clinical Features and Blood Indicators for Severity and Prognosis in COVID-19 Patients.

BACKGROUND: This study aimed to analyze the clinical manifestations and blood indicators to deepen the understanding of Coronavirus disease 2019 (COVID-19). METHODS: COVID-19 patients admitted to C10 West Ward, Tongji Hospital in Wuhan City ("West Ward") between January 31 and March 28, 2020, were retrospectively analyzed. RESULTS: A total of 61 COVID-19 patients were hospitalized, wherein the non-critical Group had 30 cases, while the critical group had 31 (including 14 survivors and 17 deaths). Age, the proportion of fever cases, white blood cell (WBC), basophils, red blood cell (RBC), hemoglobin, lactate dehydrogenase (LDH), C-reactive protein (CRP), high-sensitivity troponin, pro-BNP (brain natriuretic peptide), prothrombin time (PT), and D-dimer were higher in the critical group while lymphocytes, eosinophils, albumin were lower compared with those of the non-critical group (all p < 0.05). WBC (p = 0.008), basophils (p = 0.034), and LDH (p = 0.005) of the death subgroup climbed remarkably in comparison with those of the survival subgroup. CONCLUSIONS: Advanced age, high fever, increases in indicators such as WBC, basophils, CRP, LDH, high-sensitivity troponin, pro-BNP, and D-dimer, and decreases in indicators, including lymphocytes, eosinophils, and albumin, might forebode a critical condition.

Paediatric heart failure - understanding the pathophysiology and the current role of cardiac biomarkers in clinical practice.

INTRODUCTION: Paediatric heart failure is a common clinical syndrome that may be experienced by children with congenital heart disease (CHD) and/or cardiomyopathy. It is characterised by clinical signs/symptoms which reflect the underlying pathophysiology based on one of three main clinical states: Pulmonary over-circulation, pressure overload, and ventricular failure. Current diagnosis relies on clinical assessment and echocardiogram imaging as cardiac biomarkers has been predominantly scientific to date. This review provides a comprehensive overview of paediatric heart failure pathophysiology and considers the available evidence for cardiac biomarkers in this setting. METHODS: A literature review was completed using MEDLINE ALL, EMBASE, and PubMed on 10th November, 2022. Search terms included biomarkers, heart failure, heart defects, congenital heart disease, fontan circulation, single ventricle circulation, cardiomyopathy, and child. This allowed the identification of individual cardiac biomarkers which are the focus of this review. These included NT-proBNP, MR-proANP, MR-proADM, troponin, sST2, galectin 3, and growth differentiation factor-15. RESULTS: Paediatric studies have established reference ranges for NT-proBNP and troponin for children with structurally normal hearts. Of all the biomarkers reviewed, NT-proBNP appears to correlate most closely with symptoms of heart failure and ventricular dysfunction on echocardiogram. However, there remains limited longitudinal data for NT-proBNP, and no validated reference ranges for patients with CHD and/or cardiomyopathy. None of the other biomarkers reviewed were consistently superior to NT-proBNP. CONCLUSION: Further large paediatric studies of patients with heart failure are needed to validate NT-proBNP in CHD and to evaluate the role of novel biomarkers in specific types of CHD, e.g. single ventricle physiology.

Effect of selected cardiovascular factors on mortality in patients with ST-segment elevation myocardial infarction treated with primary coronary intervention.

OBJECTIVE: This work was aimed at analyzing in-hospital, 30-day and 1-year mortality rates, impact of selected cardiovascular factors on mortality of patients with ST-segment elevation myocardial infarction (STEMI) manifested on electrocardiogram (ECG) and treated by the percutaneous coronary intervention (PCI) at our cardiac center, comparing the subgroup of non-shock (survivors and deceased) patients after STEMI and evaluating how these patients differ from each other. METHODS: In total, 270 patients with STEMI manifested on ECG and treated by PCI were enrolled between April 1, 2018, and March 31, 2019, at our cardiologic center. Our study sought to determine the risk of death after acute myocardial infarction with carefully selected factors and parameters such as the presence of cardiogenic shock, ischemic time, left ventricular ejection fraction (LVEF), post­PCI TIMI (thrombolysis in myocardial infarction) flow and serum levels of cardio­specific markers, namely troponin T, creatine kinase and N-terminal pro-brain natriuretic peptide (NT-proBNP). Further evaluation included in-hospital, 30-day and 1-year mortality rates in shock and non-shock patients and determination of factors that influence the survival separately in each subgroup. The follow-up was carried out for 12 months after the myocardial infarction in form of outpatient examinations. After 12 months of follow-up, the collected data were statistically evaluated. RESULTS: Shock and non-shock patients differed in mortality and several other parameters including NT-proBNP values, ischemic time, TIMI flow defect and LVEF. In all outcomes (in-hospital, 30-day and 1-year mortality rates) the shock patients did worse than non-shock patients (p < 0.001). In addition, age, gender, LVEF, NT-proBNP and post­PCI TIMI flow less than 3 were found to be important factors influencing the overall survival. In shock patients, the survival was associated with age, LVEF and TIMI flow, while in non-shock patients, the factors predicting survival were age, LVEF, level of NT-proBNP and troponin levels. CONCLUSION: Shock patients differed in terms of mortality in post-PCI TIMI flow, while non-shock patients varied in troponin and NT-proBNP levels. Despite early intervention, certain risk factors might affect the clinical outcome and prognosis of patients with STEMI treated by PCI (Tab. 5, Fig. 1, Ref. 30). Text in PDF www.elis.sk Keywords: myocardial infarction, primary coronary intervention, shock, mortality, cardio­specific markers.

Magnitude of troponin elevation in patients with biomarker evidence of myocardial injury: relative frequency and outcomes in a cohort study across a large healthcare system.

BACKGROUND: Serum troponin levels correlate with the extent of myocyte necrosis in acute myocardial infarction (AMI) and predict adverse outcomes. However, thresholds of cardiac troponin elevation that could portend to poor outcomes have not been established. METHODS: In this cohort study, we characterized all cardiac troponin elevations > 0.04 ng/mL (upper limit of normal [ULN]) from patients hospitalized with an ICD-9/10 diagnosis of AMI across our health system from 2012-2019. We grouped events into exponential categories of peak cardiac troponin and evaluated the association of these troponin categories with all-cause mortality, heart transplants, or durable left ventricular assist devices (LVAD). Patients with cardiac troponin > 10,000 × ULN were manually chart reviewed and described. RESULTS: There were 18,194 AMI hospitalizations with elevated cardiac troponin. Peak troponin was 1-10 × ULN in 21.1%, 10-100 × ULN in 34.8%, 100-1,000 × ULN in 30.1%, 1,000-10,000 × ULN in 13.1%, and > 10,000 × ULN in 0.9% of patients. One-year mortality was 17-21% across groups, except in > 10,000 × ULN group where it was 33% (adjusted hazard ratio (99%CI) for > 10,000 × ULN group compared to all others: 1.86 (1.21, 2.86)). Hazards of one-year transplant and MCS were also significantly elevated in the > 10,000 × ULN group. CONCLUSIONS: Elevation in cardiac troponin levels post AMI that are > 10,000 × ULN was rare but identified patients at particularly high risk of adverse events. These patients may benefit from clarification of goals of care and early referral for advanced heart failure therapies. These data have implications for conversion to newer high-sensitivity cardiac troponin assays whose maximum assay limit is often lower than traditional assays.

Molecular Mechanisms of Deregulation of Muscle Contractility Caused by the R168H Mutation in TPM3 and Its Attenuation by Therapeutic Agents.

The substitution for Arg168His (R168H) in γ-tropomyosin (TPM3 gene, Tpm3.12 isoform) is associated with congenital muscle fiber type disproportion (CFTD) and muscle weakness. It is still unclear what molecular mechanisms underlie the muscle dysfunction seen in CFTD. The aim of this work was to study the effect of the R168H mutation in Tpm3.12 on the critical conformational changes that myosin, actin, troponin, and tropomyosin undergo during the ATPase cycle. We used polarized fluorescence microscopy and ghost muscle fibers containing regulated thin filaments and myosin heads (myosin subfragment-1) modified with the 1,5-IAEDANS fluorescent probe. Analysis of the data obtained revealed that a sequential interdependent conformational-functional rearrangement of tropomyosin, actin and myosin heads takes place when modeling the ATPase cycle in the presence of wild-type tropomyosin. A multistep shift of the tropomyosin strands from the outer to the inner domain of actin occurs during the transition from weak to strong binding of myosin to actin. Each tropomyosin position determines the corresponding balance between switched-on and switched-off actin monomers and between the strongly and weakly bound myosin heads. At low Ca2+, the R168H mutation was shown to switch some extra actin monomers on and increase the persistence length of tropomyosin, demonstrating the freezing of the R168HTpm strands close to the open position and disruption of the regulatory function of troponin. Instead of reducing the formation of strong bonds between myosin heads and F-actin, troponin activated it. However, at high Ca2+, troponin decreased the amount of strongly bound myosin heads instead of promoting their formation. Abnormally high sensitivity of thin filaments to Ca2+, inhibition of muscle fiber relaxation due to the appearance of the myosin heads strongly associated with F-actin, and distinct activation of the contractile system at submaximal concentrations of Ca2+ can lead to muscle inefficiency and weakness. Modulators of troponin (tirasemtiv and epigallocatechin-3-gallate) and myosin (omecamtiv mecarbil and 2,3-butanedione monoxime) have been shown to more or less attenuate the negative effects of the tropomyosin R168H mutant. Tirasemtiv and epigallocatechin-3-gallate may be used to prevent muscle dysfunction.