Has the role of troponin as a biomarker of cardiac complications after non-cardiac surgery been fully understood?

Myocardial injury after non-cardiac surgery is a major issue with a rate of almost 20%, as suggested by the literature. Guidelines recommend screening patients undergoing non-cardiac surgery who have at least one cardiovascular risk factor. Clinical trials are characterized by a high degree of heterogeneity. Myocardial injury definitions vary among studies, and multiple troponin assays with different cut-offs are utilized. Myocardial injury has a poorly understood pathophysiology. While some studies only include troponin elevations that are thought to be caused by ischemia, others do not. Troponin elevation can be a result of patient-related factors and comorbidities, including age, chronic renal failure, and inflammatory status. Currently, there is no effective strategy to prevent perioperative myocardial injury, and there are no therapeutic options that significantly improve the outcome of patients with myocardial injury. We have focused on this topic and on perioperative myocardial injury to highlight the areas of research that remain unexplored.

Efeitos cardiotóxicos da terapia com células CAR-T: uma meta-análise / Cardiotoxic effects of CAR-T cell therapy: a meta-analysis

INTRODUÇÃO: A terapia com células T receptoras de antígeno quimérico (CAR-T) mostrou-se promissora no tratamento de malignidades hematológicas, mas seus potenciais efeitos cardiotóxicos requerem investigação aprofundada. Esse trabalho tem como objetivo realizar uma meta-análise, examinando os efeitos cardiotóxicos da terapia CAR-T em adultos com malignidadeshematológicas. MÉTODOS: Como estratégia de busca, foram utilizadas as bases de dados PubMed, Embase e o Registro Cochrane Central de Ensaios Controlados para estudos que relataram desfechos cardiovasculares, como arritmias, insuficiência cardíaca e redução da fração de ejeção do ventrículo esquerdo (FEVE). RESULTADOS: Foi feita análise de 20 estudos envolvendo 4.789 pacientes, que revelou uma taxa de incidência de eventos cardiovasculares de 19,68%, sendo as arritmias (10,19%), insuficiência cardíaca (5,73%) e redução da FEVE (3,86%) as mais prevalentes. Elevação de troponina foi observada em 23,61% dos pacientes, enquanto a elevação de NT-Pro-BNP foi observada em 9,4%. Análises de subgrupos mostraram riscos maiores em pacientes com condições pré-existentes, como arritmia atrial (OR 3,12; p<0,001), hipertensão (OR 1,85; p=0,002), insuficiência cardíaca anterior (OR 3,38; p=0,003) e doença arterial coronariana (OR 2,80; p=0,003). CONCLUSÃO: A partir dos dados obtidos neste estudo, que analisou 20 artigos e envolveu 4.789 pacientes, conclui-se que há uma incidência significativa de eventos cardiovasculares entre os pacientes tratados com terapia CAR-T, particularmente aqueles com condições cardíacas pré-existentes. As arritmias, a insuficiência cardíaca e a redução da FEVE foram as complicações mais frequentes. Este achado ressalta a importância de um monitoramento cardiovascular rigoroso durante a terapia CAR-T, a fim de maximizar a segurança e eficácia do tratamento, especialmente para aqueles em maior risco devido a condições pré-existentes.

Calcium has a direct effect on thick filament activation in porcine myocardium.

Sarcomere activation in striated muscle requires both thin filament-based and thick filament-based activation mechanisms. Recent studies have shown that myosin heads on the thick filaments undergo OFF to ON structural transitions in response to calcium (Ca2+) in permeabilized porcine myocardium in the presence of a small molecule inhibitor that eliminated active force. The changes in X-ray diffraction signatures of OFF to ON transitions were interpreted as Ca2+ acting to activate the thick filaments. Alternatively, Ca2+ binding to troponin could initiate a Ca2+-dependent crosstalk from the thin filament to the thick filament via interfilament connections such as the myosin binding protein-C. Here, we exchanged native troponin in permeabilized porcine myocardium for troponin containing the cTnC D65A mutation, which disallows the activation of troponin through Ca2+ binding to determine if Ca2+-dependent thick filament activation persists in the absence of thin filament activation. After the exchange protocol, over 95% of the Ca2+-activated force was eliminated. Equatorial intensity ratio increased significantly in both WT and D65A exchanged myocardium with increasing Ca2+ concentration. The degree of helical ordering of the myosin heads decreased by the same amount in WT and D65A myocardium when Ca2+ concentration increased. These results are consistent with a direct effect of Ca2+ in activating the thick filament rather than an indirect effect due to Ca2+-mediated crosstalk between the thick and thin filaments.

The Role of Troponin Testing in Patients with Supraventricular Tachycardia, Systematic Review and Meta-Analysis.

BACKGROUND: Supraventricular tachycardia (SVT) is commonly evaluated in the emergency department (ED). While troponin has been shown to be elevated in SVT, its usefulness for predicting coronary artery disease and future adverse cardiovascular outcomes has not been shown. OBJECTIVES: We aimed to evaluate the prognostic utility of troponin measurement as part of SVT management in the ED. METHODS: We performed a literature search in the PubMed and Scopus databases from inception to August 30, 2023, including all studies reporting troponin measurements in adult patients (age > 18 years) presenting to the ED with supraventricular tachycardia. The primary outcome of interest for this study was the prevalence of elevated troponin in patients with SVT. Secondary outcomes included the prevalence of major adverse cardiac events (MACE) and additional cardiac testing with significant findings. RESULTS: We included 7 studies (500 patients) in our analysis. Six studies reported the number of patients with SVT and elevated troponin, with a pooled prevalence of 46% (95% CI 27-66%, I2 93%). The pooled prevalence of all MACE in our study was 6% (95% CI 1-25%), while the prevalence for MACE among patients with elevated serum troponin levels was 11% (95% CI 4-27%). CONCLUSIONS: Troponin levels are frequently ordered for ED patients with SVT and are often elevated. However, this review suggests that they have low prognostic value in predicting MACE.

Chest Pain in Primary Care: A Systematic Review of Risk Stratification Tools to Rule Out Acute Coronary Syndrome.

PURPOSE: Chest pain frequently poses a diagnostic challenge for general practitioners (GPs). Utilizing risk stratification tools might help GPs to rule out acute coronary syndrome (ACS) and make appropriate referral decisions. We conducted a systematic review of studies evaluating risk stratification tools for chest pain in primary care settings, both with and without troponin assays. Our aims were to assess the performance of tools for ruling out ACS and to provide a comprehensive review of the current evidence. METHODS: We searched PubMed and Embase for articles up to October 9, 2023 concerning adult patients with acute chest pain in primary care settings, for whom risk stratification tools (clinical decision rules [CDRs] and/or single biomarker tests) were used. To identify eligible studies, a combination of active learning and backward snowballing was applied. Screening, data extraction, and quality assessment (following the Quality Assessment of Diagnostic Accuracy Studies-2 tool) were performed independently by 2 researchers. RESULTS: Of the 1,204 studies screened, 14 were included in the final review. Nine studies validated 7 different CDRs without troponin. Sensitivities ranged from 75.0% to 97.0%, and negative predictive values (NPV) ranged from 82.4% to 99.7%. None of the CDRs outperformed the unaided judgment of GP's. Five studies reported on strategies using troponin measurements. Studies using high-sensitivity troponin showed highest diagnostic accuracy with sensitivity 83.3% to 100% and NPV 98.8% to 100%. CONCLUSION: Clinical decision rules without troponin and the use of conventional troponin showed insufficient sensitivity to rule out ACS in primary care and are not recommended as standalone tools. High-sensitivity troponin strategies are promising, but studies are limited. Further prospective validation in primary care is needed before implementation.

HEART vs EDACS Scores on Predicting Major Events Among Patients With Suspected Acute Coronary Syndrome at the Cardiac Emergency Department.

Coronary risk scores, such as History, Electrocardiogram, Age, Risk Factors, and Troponin (HEART) and Emergency Department Assessment of Chest Pain Score (EDACS) scores, help nurses identify suspected acute coronary syndrome (ACS) patients who have a risk for major adverse cardiac events (MACE) within 30 days. AIM: To compare the accuracy of HEART and EDACS scores in predicting major events among patients suspected of ACS in the cardiac emergency department (ED). DESIGN AND METHODS: A prospective correlational observational study design was performed on cardiac ED patients who presented with suspected ACS. TOOLS: Three tools were utilized to collect data pertinent to the study: Tool I comprises patients' assessment (personal characteristics, risk factors for ACS, and chest pain assessment sheet); Tool II is the risk assessment tool that includes HEART and EDACS scores; and Tool III is MACE incidence among studied patients within 30 days. RESULTS: HEART score was significantly (P < .01) higher among patients for whom MACE was present than absent. However, EDACS score showed no significant difference (P > .05) among patients whose MACE was present or absent. HEART risk score >6 correctly predicted MACE cases with sensitivity and specificity of 77.46% and 48.28%, respectively. However, EDACS score >18 correctly predicted MACE cases with sensitivity and specificity of 42.25% and 75.86%, respectively. CONCLUSION: This study concludes that HEART score has better sensitivity than EDACS in predicting MACE among suspected ACS patients at the cardiac ED. The HEART score provides the nurses with a quicker and more reliable predictor of MACE shortly after the arrival of the suspected ACS patients at the cardiac ED than the EDACS score. The study recommended the implementation of a HEART score in the cardiac ED for predicting MACE in suspected ACS patients. Follow up closely for high-risk patients to MACE. An educational program should be made for nurses about the implementation of the heart score in the cardiac ED.

The cardiotoxic effects of CAR-T cell therapy: an updated systematic review and meta-analysis

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy has shown promise in treating hematologic malignancies, yet its potential cardiotoxic effects require thorough investigation. OBJECTIVES: We aim to conduct a systematic review and meta-analysis to examine the cardiotoxic effects of CAR-T therapy in adults with hematologic malignancies. METHODS: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for studies reporting cardiovascular outcomes, such as arrhythmias, heart failure, and reduced left ventricle ejection fraction (LVEF). RESULTS: Our analysis of 20 studies involving 4789 patients revealed a 19.68% incidence rate of cardiovascular events, with arrhythmias (7.70%), heart failure (5.73%), and reduced LVEF (3.86%) being the most prevalent. Troponin elevation was observed in 23.61% of patients, while NT-Pro-BNP elevation was observed in 9.4. Subgroup analysis showed higher risks in patients with pre-existing conditions, such as atrial arrhythmia (OR 3.12; p < .001), hypertension (OR 1.85; p = .002), previous heart failure (OR 3.38; p = .003), and coronary artery disease (OR 2.80; p = .003). CONCLUSION: Vigilant cardiovascular monitoring is crucial for patients undergoing CAR-T therapy to enhance safety and treatment efficacy.Novelty Statements.

In a Canine Model of Septic Shock, Cardiomyopathy Occurs Independent of Catecholamine Surges and Cardiac Microvascular Ischemia.

BACKGROUND: High levels of catecholamines are cardiotoxic and associated with stress-induced cardiomyopathies. Using a septic shock model that reproduces the reversible cardiomyopathy seen over 10 days associated with human septic shock, we investigated the effects of catecholamines on microcirculatory perfusion and cardiac dysfunction. METHODS AND RESULTS: Purpose-bred beagles received intrabronchial Staphylococcus aureus (n=30) or saline (n=6). The septic animals were than randomized to epinephrine (1 µg/kg per minute, n=15) or saline (n=15) infusions from 4 to 44 hours. Serial cardiac magnetic resonance imaging, catecholamine levels, and troponins were collected over 92 hours. Serial adenosine-stress perfusion cardiac magnetic resonance imaging was performed on septic animals randomized to receive saline (n=8 out of 15) or epinephrine (n=8 out of 15). High-dose sedation was given to suppress endogenous catecholamine release. Despite catecholamine levels largely remaining within the normal range throughout, by 48 hours, septic animals receiving saline versus nonseptic animals still developed significant worsening of left ventricular ejection fraction, circumferential strain, and ventricular-aortic coupling. In septic animals that received epinephrine versus saline infusions, plasma epinephrine levels increased 800-fold, but epinephrine produced no significant further worsening of left ventricular ejection fraction, circumferential strain, or ventricular-aortic coupling. Septic animals receiving saline had a significant increase in microcirculatory reserve without troponin elevations. Septic animals receiving epinephrine had decreased edema, blunted microcirculatory perfusion, and elevated troponin levels that persisted for hours after the epinephrine infusion stopped. CONCLUSIONS: Cardiac dysfunction during sepsis is not primarily due to elevated endogenous or exogenous catecholamines nor due to decreased microvascular perfusion-induced ischemia. However, epinephrine itself has potentially harmful long-lasting ischemic effects during sepsis including impaired cardiac microvascular perfusion that persists after stopping the infusion.

High sensitivity troponins and mortality in the population with metabolic dysfunction-associated steatotic liver disease.

Given the global high prevalence of MASLD and its poor CVD prognosis, it is essential to perform risk stratification for MASLD patients. The specific impact of High Sensitivity Troponins (hs-cTn ) on mortality in MASLD patients remains unexplored.  The NHANES databases from 1999 to 2004, which include data on high-sensitivity cardiac troponin (hs-cTn) levels and comorbidities, were linked with the most recent mortality dataset. Myocardial injury was determined using the 99th upper reference limits (URL) for hs-cTn.  Our study included 3460 MASLD patients. The mean follow-up duration was 192 months, during which 1074 (23%) MASLD participants died from all-cause mortality, and 363 (7.3%) died from CVD mortality. Our findings indicate that MASLD patients with elevated levels of hs-cTnT (> 99th URL) exhibit increased risks of all-cause mortality [adjusted hazard ratio (aHR) = 1.93] and CVD mortality (aHR = 2.4). Similar results were observed for hs-cTnI, where the aHRs for all-cause mortality and CVD mortality were 2.03 and 2.97, respectively. Furthermore, we identified a nonlinear dose-response relationship between hs-cTn levels and the risk of mortality (P for nonlinearity < 0.001).  Our findings suggest that hs-cTn can predict mortality risk in MASLD, aiding clinicians in risk-stratifying this population. Therefore, we recommend considering hs-cTn detection in individuals with MASLD to effectively assess their future mortality risk.

COVID-19 and myocardial injury: Targeting elevated biomarkers for potential novel therapies.

BACKGROUND: The prevalence of COVID-19 as the primary diagnosis among hospitalized patients with myocardial injury has increased during the pandemic and targeting elevated oxidant stress and inflammatory biomarkers may offer a potential role for novel therapies to improve outcomes. METHODS: At a single VA Medical Center from January 1 through December 31, 2021, troponin assays from patients being evaluated in the Emergency Room for consideration of admission were analyzed and peak levels from each patient were considered abnormal if exceeding the Upper Reference Limit (URL). Among admitted patients with an elevated troponin level, ICD-10 diagnoses were categorized, biomarker elevations were recorded, and independent predictors of death in patients with COVID-19 were determined at a median of 6-months following admission. RESULTS: Of 998 patients, 399 (40 %) had a negative troponin and were not included in the analysis. Additional patients with an elevated troponin were also excluded, either because they were not admitted (n = 68) or had a final diagnosis of Type 1 MI (n = 117). Of the remaining 414 patients with an elevated peak troponin, COVID-19 was the primary diagnosis in 43 patients (10 %) and was the 4th most common diagnosis of patients admitted with myocardial injury behind congestive heart failure, sepsis, and COPD or pneumonia. At a median of 6-months following admission, 18 (42 %) of the COVID-19 patients had died and independent predictors of death (Odd Ratio: Confidence Intervals) were age (1.18: 1.06‒1.37), Troponin level (Log 10 transformed) (16.54: 2.30‒266.65) and C-Reactive Protein (CRP) (1.30: 1.10‒1.65). CONCLUSIONS: Newly diagnosed COVID-19 during the pandemic was a common cause of elevated troponin in hospitalized patients without a Type 1 MI. Age, peak troponin level and peak CRP level were independent predictors of poor outcomes and suggest a need to target these cardiac biomarkers, potentially with novel antioxidant or anti-inflammatory therapies.

Visualising myocardial injury after noncardiac surgery: a case series using postoperative cardiovascular MRI.

Myocardial injury after noncardiac surgery (MINS) and perioperative myocardial injury are associated with increased morbidity and mortality. Both are diagnosed by a perioperative increase in troponin, yet there is controversy if MINS is a genuine myocardial insult. We applied postoperative cardiovascular magnetic resonance T2 mapping techniques to visualise acute myocardial injury (i.e. oedema) in six patients with multiple cardiovascular risk factors who underwent aortic surgery. The burden of myocardial oedema was substantially higher in four patients with elevated troponin qualifying for MINS, compared with patients without MINS. The data and images suggest that MINS represents genuine myocardial injury.

Utility of serial troponin testing for emergency department patients with syncope.

BACKGROUND: For emergency department (ED) patients with syncope, cardiac troponin can identify acute coronary syndrome (ACS) and prognosticate for 30-day serious adverse events. However, it is unclear if serial testing improves diagnostic yield and prognostication. METHODS: This was a secondary analysis of data from two prospective studies conducted to develop the Canadian Syncope Risk Score. Adults (age ≥ 16 years) with syncope were enrolled, and patient characteristics, vital signs, physician diagnostic impression, electrocardiogram and troponin results, and adjudicated 30-day serious adverse event were collected. The primary outcome was the detection of a serious adverse event within 30 days of ED disposition. The secondary outcome was comparison of ED length of stay among patients with single versus serial troponin measurements. RESULTS: 4996 patients [mean age 64.5 (SD 18.8) years, 52.2% male] were included: 4397 (89.8%) with single troponin [232 (5.3%) with serious adverse event in the ED and 203 (4.6%) after ED disposition]; 499 (10.2%) patients with > 1 troponin measurement [39 (7.8%) with serious adverse event in ED and 60 (12.0%) after ED disposition]. Among those with serial measurements, 10 patients (2.0%) had a rise from below to above the 99th percentile threshold, of whom 4 patients (0.8%) suffered serious adverse event: two with arrhythmias diagnosed on electrocardiogram, one with ACS and one suffered respiratory failure. Nine patients (1.8%) had Canadian Syncope Risk Score risk reclassification based on serial measurement, and none suffered 30-day serious adverse event. Median ED length of stay was significantly longer for patients with serial testing (5.6 vs. 3.8 h, p < 0.001). CONCLUSIONS: The initial troponin measurement was sufficient for serious adverse event detection and in-ED risk stratification. Serial troponin testing does not improve the diagnostic yield or prognostication and should be reserved for patients with ongoing symptoms or electrocardiogram findings suggestive of cardiac ischemia.

ABSTRAIT: CONTEXTE: Pour les patients du service des urgences (DE) atteints de syncope, la troponine cardiaque peut identifier le syndrome coronarien aigu (SCA) et le pronostic pour les événements indésirables graves de 30 jours. Cependant, il n'est pas clair si les tests en série améliorent le rendement diagnostique et le pronostic. MéTHODES: Il s'agissait d'une analyse secondaire des données de deux études prospectives menées pour élaborer le Canadian Syncope Risk Score. Des adultes (âgés de 16 ans) atteints de syncope ont été recrutés, et les caractéristiques du patient, les signes vitaux, l'empreinte diagnostique du médecin, les résultats de l'électrocardiogramme et de la troponine, ainsi que les événements indésirables graves évalués à 30 jours ont été recueillis. Le critère de jugement principal était la détection d'un événement indésirable grave dans les 30 jours suivant la décision de l'urgence. Le critère de jugement secondaire était la comparaison de la durée de séjour à l'urgence chez les patients ayant une seule mesure de troponine par rapport à la mesure en série. RéSULTATS: 4 996 patients [âge moyen 64,5 (ET 18,8) ans, 52,2 % d'hommes] ont été inclus : 4 397 (89,8 %) avec une seule troponine [232 (5,3 %) avec un événement indésirable grave à l'urgence et 203 (4,6 %) après l'urgence]; 499 (10,2 %) patients avec > 1 mesure de la troponine [39 (7,8 %) avec événement indésirable grave à l'urgence et 60 (12,0 %) après la décision à l'urgence]. Parmi les patients ayant fait l'objet de mesures en série, 10 (2,0 %) présentaient une augmentation du seuil inférieur à supérieur au seuil du 99e percentile, dont 4 (0,8 %) ont subi un événement indésirable grave : deux avec arythmies diagnostiquées par électrocardiogramme, un avec SCA et un avec insuffisance respiratoire. Neuf patients (1,8 %) ont présenté une reclassification du risque selon le score canadien de risque de syncope en fonction de la mesure en série, et aucun n'a subi d'événement indésirable grave de 30 jours. La durée médiane de séjour aux urgences était significativement plus longue pour les patients ayant subi des tests en série (5,6 vs. 3,8 heures, p < 0,001). CONCLUSIONS: La mesure initiale de la troponine était suffisante pour la détection des effets indésirables graves et la stratification des risques aux urgences. Les tests de troponine en série n'améliorent pas le rendement diagnostique ou le pronostic et doivent être réservés aux patients présentant des symptômes continus ou des résultats d'électrocardiogramme suggérant une ischémie cardiaque.

Mortality After Procedural or Spontaneous Myocardial Infarction.

BACKGROUND: It remains unclear whether procedural myocardial infarction (pMI) and spontaneous myocardial infarction (spMI) have a similar impact on prognosis. OBJECTIVES: The aim of this study was to assess mortality after pMI and spMI. METHODS: Patients with chronic coronary syndrome (CCS) and baseline troponin ≤1× the upper reference level (URL) or with acute spMI who underwent percutaneous coronary intervention (PCI) were included. PMI was defined as post-PCI troponin increase >1× URL in patients with CCS. SpMI comprised any acute coronary syndrome with elevated troponin. The 1-year risk of all-cause death was assessed after pMI and spMI across 3 strata of troponin elevation (>1-5×, >5-35×, and >35× URL), with CCS patients having post-PCI troponin ≤1× URL as a reference group. Conventional troponin I was measured using the Architect methodology (Abbott). RESULTS: Among 10,707 patients undergoing PCI from 2012 to 2020, 8,515 patients presented with CCS and 2,192 with spMI. Among CCS patients, 913 (10.7%) had pMI. Troponin peaks >1-5×, >5-35×, and >35× URL were observed in 53%, 41%, and 6% of patients with pMI, and in 24%, 38%, and 37% of patients with spMI, respectively. Mortality at 1 year was higher after pMI (7.7%; adjusted HR: 4.40; 95% CI: 1.59-12.2), and spMI (8.5%; adjusted HR: 7.57; 95% CI: 5.44-10.5) with troponin peak >35× URL compared with no-MI (1.4%). Mortality was also increased after spMI with troponin peak >1-5× or >5-35× URL. CONCLUSIONS: Mortality at 1 year was significantly increased after pMI and spMI with troponin peak >35× URL, whereas for troponin levels ≤35× only spMI had a relevant impact on mortality.

Symptoms and coronary risk factors predictive of adverse cardiac events in chest pain patients in an Asian emergency department: the need for a local prediction score.

INTRODUCTION: Clinical assessment is pivotal in diagnosing acute coronary syndrome. Our study aimed to identify clinical characteristics predictive of major adverse cardiac events (MACE) in an Asian population and to derive a risk score for MACE. METHODS: Patients presenting to the emergency department (ED) with chest pain and non-diagnostic 12-lead electrocardiograms were recruited. Clinical history was recorded in a predesigned template. Random glucose and direct low-density lipoprotein measurements were taken, in addition to serial troponin. We derived the age, coronary risk factors (CRF), sex and symptoms (ACSS) risk score based on multivariate analysis results, considering age, CRF, sex and symptoms and classifying patients into very low, low, moderate and high risk for MACE. Comparison was made with the ED Assessment of Chest Pain Score (EDACS) and the history, electrocardiogram, age, risk factors, troponin (HEART) score. We also modified the HEART score with the CRF that we had identified. The outcomes were 30-day and 1-year MACE. RESULTS: There were a total of 1689 patients, with 172 (10.2%) and 200 (11.8%) having 30-day and 1-year MACE, respectively. Symptoms predictive of MACE included central chest pain, radiation to the jaw/neck, associated diaphoresis, and symptoms aggravated by exertion and relieved by glyceryl trinitrate. The ACSS score had an area under the curve of 0.769 (95% confidence interval [CI]: 0.735-0.803) and 0.760 (95% CI: 0.727-0.793) for 30-day and 1-year MACE, respectively, outperforming EDACS. Those in the very-low-risk and low-risk groups had <1% risk of 30-day MACE. CONCLUSION: The ACSS risk score shows potential for use in the local ED or primary care setting, potentially reducing unnecessary cardiac investigations and admission.