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BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.
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Enfermedad de la Arteria Coronaria , Trombosis , Humanos , Inhibidores de Agregación Plaquetaria/farmacología , Ticagrelor/uso terapéutico , Fibrinolíticos/uso terapéutico , Enfermedad de la Arteria Coronaria/metabolismo , Aspirina , Agregación Plaquetaria , Plaquetas/metabolismoRESUMEN
BACKGROUND: Anthracycline-induced cardiotoxicity has a variable incidence, and the development of left ventricular dysfunction is preceded by elevations in cardiac troponin concentrations. Beta-adrenergic receptor blocker and renin-angiotensin system inhibitor therapies have been associated with modest cardioprotective effects in unselected patients receiving anthracycline chemotherapy. METHODS: In a multicenter, prospective, randomized, open-label, blinded end-point trial, patients with breast cancer and non-Hodgkin lymphoma receiving anthracycline chemotherapy underwent serial high-sensitivity cardiac troponin testing and cardiac magnetic resonance imaging before and 6 months after anthracycline treatment. Patients at high risk of cardiotoxicity (cardiac troponin I concentrations in the upper tertile during chemotherapy) were randomized to standard care plus cardioprotection (combination carvedilol and candesartan therapy) or standard care alone. The primary outcome was adjusted change in left ventricular ejection fraction at 6 months. In low-risk nonrandomized patients with cardiac troponin I concentrations in the lower 2 tertiles, we hypothesized the absence of a 6-month change in left ventricular ejection fraction and tested for equivalence of ±2%. RESULTS: Between October 2017 and June 2021, 175 patients (mean age, 53 years; 87% female; 71% with breast cancer) were recruited. Patients randomized to cardioprotection (n=29) or standard care (n=28) had left ventricular ejection fractions of 69.4±7.4% and 69.1±6.1% at baseline and 65.7±6.6% and 64.9±5.9% 6 months after completion of chemotherapy, respectively. After adjustment for age, pretreatment left ventricular ejection fraction, and planned anthracycline dose, the estimated mean difference in 6-month left ventricular ejection fraction between the cardioprotection and standard care groups was -0.37% (95% CI, -3.59% to 2.85%; P=0.82). In low-risk nonrandomized patients, baseline and 6-month left ventricular ejection fractions were 69.3±5.7% and 66.4±6.3%, respectively: estimated mean difference, 2.87% (95% CI, 1.63%-4.10%; P=0.92, not equivalent). CONCLUSIONS: Combination candesartan and carvedilol therapy had no demonstrable cardioprotective effect in patients receiving anthracycline-based chemotherapy with high-risk on-treatment cardiac troponin I concentrations. Low-risk nonrandomized patients had similar declines in left ventricular ejection fraction, bringing into question the utility of routine cardiac troponin monitoring. Furthermore, the modest declines in left ventricular ejection fraction suggest that the value and clinical impact of early cardioprotection therapy need to be better defined in patients receiving high-dose anthracycline. REGISTRATION: URL: https://doi.org; Unique identifier: 10.1186/ISRCTN24439460. URL: https://www.clinicaltrialsregister.eu/ctr-search/search; Unique identifier: 2017-000896-99.
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Antraciclinas , Neoplasias de la Mama , Humanos , Femenino , Persona de Mediana Edad , Masculino , Antraciclinas/efectos adversos , Troponina I , Volumen Sistólico , Carvedilol/uso terapéutico , Cardiotoxicidad/etiología , Función Ventricular Izquierda , Estudios Prospectivos , Antibióticos Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Antagonistas Adrenérgicos beta/uso terapéutico , Antagonistas Adrenérgicos beta/farmacologíaRESUMEN
BACKGROUND: Aortic valve replacement in asymptomatic severe aortic stenosis is controversial. The Early valve replacement in severe ASYmptomatic Aortic Stenosis (EASY-AS) trial aims to determine whether early aortic valve replacement improves clinical outcomes, quality of life and cost-effectiveness compared to a guideline recommended strategy of 'watchful waiting'. METHODS: In a pragmatic international, open parallel group randomized controlled trial (NCT04204915), 2844 patients with severe aortic stenosis will be randomized 1:1 to either a strategy of early (surgical or transcatheter) aortic valve replacement or aortic valve replacement only if symptoms or impaired left ventricular function develop, or other cardiac surgery becomes nessessary. Exclusion criteria include other severe valvular disease, planned cardiac surgery, ejection fraction <50%, previous aortic valve replacement or life expectancy <2 years. The primary outcome is a composite of cardiovascular mortality or heart failure hospitalization. The primary analysis will be undertaken when 663 primary events have accrued, providing 90% power to detect a reduction in the primary endpoint from 27.7% to 21.6% (hazard ratio 0.75). Secondary endpoints include disability-free survival, days alive and out of hospital, major adverse cardiovascular events and quality of life. RESULTS: Recruitment commenced in March 2020 and is open in the UK, Australia, New Zealand, and Serbia. Feasibility requirements were met in July 2022, and the main phase opened in October 2022, with additional international centers in set-up. CONCLUSIONS: The EASY-AS trial will establish whether a strategy of early aortic valve replacement in asymptomatic patients with severe aortic stenosis reduces cardiovascular mortality or heart failure hospitalization and improves other important outcomes.
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INTRODUCTION: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. METHODS: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. RESULTS: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). CONCLUSION: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.
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INTRODUCTION: Non-invasive detection of pathological changes in thoracic aortic disease remains an unmet clinical need particularly for patients with congenital heart disease. Positron emission tomography combined with magnetic resonance imaging (PET-MRI) could provide a valuable low-radiation method of aortic surveillance in high-risk groups. Quantification of aortic microcalcification activity using sodium [18F]fluoride holds promise in the assessment of thoracic aortopathies. We sought to evaluate aortic sodium [18F]fluoride uptake in PET-MRI using three methods of attenuation correction compared to positron emission tomography computed tomography (PET-CT) in patients with bicuspid aortic valve, METHODS: Thirty asymptomatic patients under surveillance for bicuspid aortic valve disease underwent sodium [18F]fluoride PET-CT and PET-MRI of the ascending thoracic aorta during a single visit. PET-MRI data were reconstructed using three iterations of attenuation correction (Dixon, radial gradient recalled echo with two [RadialVIBE-2] or four [RadialVIBE-4] tissue segmentation). Images were qualitatively and quantitatively analysed for aortic sodium [18F]fluoride uptake on PET-CT and PET-MRI. RESULTS: Aortic sodium [18F]fluoride uptake on PET-MRI was visually comparable with PET-CT using each reconstruction and total aortic standardised uptake values on PET-CT strongly correlated with each PET-MRI attenuation correction method (Dixon R = 0.70; RadialVIBE-2 R = 0.63; RadialVIBE-4 R = 0.64; p < 0.001 for all). Breathing related artefact between soft tissue and lung were detected using Dixon and RadialVIBE-4 but not RadialVIBE-2 reconstructions, with the presence of this artefact adjacent to the atria leading to variations in blood pool activity estimates. Consequently, quantitative agreements between radiotracer activity on PET-CT and PET-MRI were most consistent with RadialVIBE-2. CONCLUSION: Ascending aortic microcalcification analysis in PET-MRI is feasible with comparable findings to PET-CT. RadialVIBE-2 tissue attenuation correction correlates best with the reference standard of PET-CT and is less susceptible to artefact. There remain challenges in segmenting tissue types in PET-MRI reconstructions, and improved attenuation correction methods are required.
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Aorta Torácica , Imagen por Resonancia Magnética , Imagen Multimodal , Humanos , Masculino , Femenino , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Imagen Multimodal/métodos , Aorta Torácica/diagnóstico por imagen , Adulto , Calcinosis/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Anciano , Válvula Aórtica/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
OBJECTIVES: Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. METHODS: A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. RESULTS: CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p < 0.001), likelihood ratio test 236.3, df: 1, p < 0.001, showing a higher net benefit across almost all threshold probabilities. CONCLUSION: Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. CLINICAL RELEVANCE STATEMENT: CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. KEY POINTS: ⢠The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). ⢠Diagnostic improvement was mostly seen in patients with non-diagnostic C. ⢠The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders.
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Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Femenino , Humanos , Masculino , Calcio , Dolor en el Pecho/diagnóstico , Angiografía por Tomografía Computarizada/métodos , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Estenosis Coronaria/diagnóstico por imagen , Valor Predictivo de las Pruebas , Tomografía Computarizada por Rayos X/métodos , Persona de Mediana Edad , AncianoRESUMEN
BACKGROUND: Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography and radiomics-based precision coronary plaque phenotyping derived from coronary computed tomography angiography may enhance risk stratification in patients with coronary artery disease. We sought to investigate whether the prognostic information provided by these 2 approaches is complementary in the prediction of myocardial infarction. METHODS: Patients with known coronary artery disease underwent coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography on a hybrid positron emission tomography/computed tomography scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity. We performed quantitative plaque analysis of coronary computed tomography angiography datasets and extracted 1103 radiomic features for each plaque. Using weighted correlation network analysis, we derived latent morphological features of coronary lesions which were aggregated to patient-level radiomics nomograms to predict myocardial infarction. RESULTS: Among 260 patients with established coronary artery disease (age, 65±9 years; 83% men), 179 (69%) participants showed increased coronary 18F-NaF activity (coronary microcalcification activity>0). Over 53 (40-59) months of follow-up, 18 patients had a myocardial infarction. Using weighted correlation network analysis, we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns in an unsupervised fashion. Following adjustments for calcified, noncalcified, and low-density noncalcified plaque volumes and 18F-NaF coronary microcalcification activity, 4 radiomic features remained independent predictors of myocardial infarction (hazard ratio, 1.46 [95% CI, 1.03-2.08]; P=0.03; hazard ratio, 1.62 [95% CI, 1.04-2.54]; P=0.02; hazard ratio, 1.49 [95% CI, 1.07-2.06]; P=0.01; and hazard ratio, 1.50 (95% CI, 1.05-2.13); P=0.02). CONCLUSIONS: In patients with established coronary artery disease, latent coronary plaque morphological features, quantitative plaque volumes, and disease activity on 18F-sodium fluoride positron emission tomography are additive predictors of myocardial infarction.
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Calcinosis , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Placa Aterosclerótica , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Angiografía por Tomografía Computarizada , Fluoruro de Sodio , Radioisótopos de Flúor , Radiofármacos , Tomografía de Emisión de Positrones/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Infarto del Miocardio/diagnóstico por imagen , Infarto del Miocardio/etiología , Angiografía Coronaria/métodosRESUMEN
BACKGROUND: 18F-GP1 is a novel positron-emitting radiotracer that is highly specific for activated platelets and thrombus. In a proof-of-concept study, we aimed to determine its potential clinical application in establishing the role and origin of thrombus in ischemic stroke. METHODS: Eleven patients with recent ischemic stroke (n=9) or transient ischemic attack (n=2) underwent 18F-GP1 positron emission tomography and computed tomography angiography at a median of 11 (range, 2-21) days from symptom onset. 18F-GP1 uptake (maximum target-to-background ratio) was assessed in the carotid arteries and brain. RESULTS: 18F-GP1 uptake was identified in 10 of 11 patients: 4 in the carotid arteries only, 3 in the brain only, and 3 in both the brain and carotid arteries. In those with carotid uptake, 4 participants had >50% stenosis and 3 had nonstenotic disease. One case had bilateral stenotic disease (>70%), but only the culprit carotid artery demonstrated 18F-GP1 uptake. The average uptake was higher in the culprit (median maximum target-to-background ratio, 1.55 [interquartile range, 1.26-1.82]) compared with the contralateral nonculprit carotid artery (maximum target-to-background ratio, 1.22 [1.19-1.6]). In those with brain 18F-GP1 uptake (maximum target-to-background ratio, 6.45 [4.89-7.65]), areas of acute infarction on computed tomography correlated with brain 18F-GP1 uptake in 6 cases. Ex vivo autoradiography of postmortem infarcted brain tissue showed focal uptake corresponding to intraluminal thrombus within the culprit vessel and downstream microvasculature. There was also evidence of diffuse uptake within some of the infarcted brain tissue reflecting parenchymal petechial hemorrhage. CONCLUSIONS: 18F-GP1 positron emission tomography and computed tomography angiography is a novel noninvasive method of identifying in vivo cerebrovascular thrombosis, which holds major promise in understanding the role and origin of thrombosis in stroke. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03943966.
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Estenosis Carotídea , Ataque Isquémico Transitorio , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Trombosis , Humanos , Arterias Carótidas , Ataque Isquémico Transitorio/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagenRESUMEN
BACKGROUND: Frailty is increasingly present in patients with acute myocardial infarction. The electronic Frailty Index (eFI) is a validated method of identifying vulnerable older patients in the community from routine primary care data. Our aim was to assess the relationship between the eFI and outcomes in older patients hospitalised with acute myocardial infarction. STUDY DESIGN AND SETTING: Retrospective cohort study using the DataLoch Heart Disease Registry comprising consecutive patients aged 65 years or over hospitalised with a myocardial infarction between October 2013 and March 2021. METHODS: Patients were classified as fit, mild, moderate, or severely frail based on their eFI score. Cox-regression analysis was used to determine the association between frailty category and all-cause mortality. RESULTS: In 4670 patients (median age 77 years [71-84], 43% female), 1865 (40%) were classified as fit, with 1699 (36%), 798 (17%) and 308 (7%) classified as mild, moderate and severely frail, respectively. In total, 1142 patients died within 12 months of which 248 (13%) and 147 (48%) were classified as fit and severely frail, respectively. After adjustment, any degree of frailty was associated with an increased risk of all-cause death with the risk greatest in the severely frail (reference = fit, adjusted hazard ratio 2.87 [95% confidence intervals 2.24 to 3.66]). CONCLUSION: The eFI identified patients at high risk of death following myocardial infarction. Automatic calculation within administrative data is feasible and could provide a low-cost method of identifying vulnerable older patients on hospital presentation.
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Anciano Frágil , Fragilidad , Evaluación Geriátrica , Infarto del Miocardio , Humanos , Femenino , Masculino , Anciano , Infarto del Miocardio/mortalidad , Infarto del Miocardio/diagnóstico , Anciano de 80 o más Años , Estudios Retrospectivos , Fragilidad/diagnóstico , Fragilidad/mortalidad , Fragilidad/epidemiología , Evaluación Geriátrica/métodos , Anciano Frágil/estadística & datos numéricos , Medición de Riesgo/métodos , Sistema de Registros , Factores de Riesgo , Hospitalización/estadística & datos numéricos , Causas de MuerteRESUMEN
AIMS: Whether a single cardiac troponin measurement can safely rule out myocardial infarction in patients presenting within a few hours of symptom onset is uncertain. The study aim was to assess the performance of troponin in early presenters. METHODS AND RESULTS: In patients with possible myocardial infarction, the diagnostic performance of a single measurement of high-sensitivity cardiac troponin I at presentation was evaluated and externally validated in those tested ≤3, 4-12, and >12 h from symptom onset. The limit-of-detection (2 ng/L), rule-out (5 ng/L), and sex-specific 99th centile (16 ng/L in women; 34 ng/L in men) thresholds were compared. In 41 103 consecutive patients [60 (17) years, 46% women], 12 595 (31%) presented within 3 h, and 3728 (9%) had myocardial infarction. In those presenting ≤3 h, a threshold of 2 ng/L had greater sensitivity and negative predictive value [99.4% (95% confidence interval 99.2%-99.5%) and 99.7% (99.6%-99.8%)] compared with 5 ng/L [96.5% (96.2%-96.8%) and 99.3% (99.1%-99.4%)]. In those presenting ≥3 h, the sensitivity and negative predictive value were similar for both thresholds. The sensitivity of the 99th centile was low in early and late presenters at 71.4% (70.6%-72.2%) and 92.5% (92.0%-93.0%), respectively. Findings were consistent in an external validation cohort of 7088 patients. CONCLUSION: In early presenters, a single measurement of high-sensitivity cardiac troponin I below the limit of detection may facilitate the safe rule out of myocardial infarction. The 99th centile should not be used to rule out myocardial infarction at presentation even in those presenting later following symptom onset.
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Infarto del Miocardio , Troponina I , Masculino , Humanos , Femenino , Biomarcadores , Infarto del Miocardio/diagnóstico , Valor Predictivo de las Pruebas , Troponina T , Servicio de Urgencia en HospitalRESUMEN
BACKGROUND: The HEART score, the T-MACS model and the GRACE score support early decision-making for acute chest pain, which could be complemented by CT coronary angiography (CTCA). However, their performance has not been directly compared. METHODS: In this secondary analysis of a multicentre randomised controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, C-statistics and performance metrics (using the predefined cut-offs) of clinical decision aids and CTCA, alone and then in combination, for the index hospital diagnosis of acute coronary syndrome and for 30-day coronary revascularisation were assessed in those who underwent CTCA and had complete data. RESULTS: Among 699 patients, 358 (51%) had an index hospital diagnosis of acute coronary syndrome, for which the C-statistic was higher for CTCA (0.80), followed by the T-MACS model (0.78), the HEART score (0.74) and the GRACE score (0.60). The negative predictive value was higher for the absence of coronary artery disease on CTCA (0.90) or a T-MACS estimate of <0.05 (0.83) than a HEART score of <4 (0.81) and a GRACE score of <109 (0.55). For 30-day coronary revascularisation, CTCA had the greatest C-statistic (0.80) with a negative predictive value of 0.96 and 0.92 in the absence of coronary artery disease and obstructive coronary artery disease, respectively. The combination of the T-MACS estimates and the CTCA findings was most discriminative for the index hospital diagnosis of acute coronary syndrome (C-statistic, 0.88) and predictive of 30-day coronary revascularisation (C-statistic, 0.85). No patients with a T-MACS estimate of <0.05 and normal coronary arteries had acute coronary syndrome during index hospitalisation or underwent coronary revascularisation within 30 days. CONCLUSIONS: In intermediate-risk patients with suspected acute coronary syndrome, the T-MACS model combined with CTCA improved discrimination of the index hospital diagnosis of acute coronary syndrome and prediction of 30-day coronary revascularisation. TRIAL REGISTRATION NUMBER: NCT02284191.
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Síndrome Coronario Agudo , Angiografía por Tomografía Computarizada , Angiografía Coronaria , Técnicas de Apoyo para la Decisión , Humanos , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Angiografía Coronaria/métodos , Angiografía Coronaria/estadística & datos numéricos , Angiografía por Tomografía Computarizada/métodos , Anciano , Valor Predictivo de las Pruebas , Medición de Riesgo/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
Takotsubo syndrome is a condition characterized by acute transient left ventricular systolic dysfunction, which at presentation can be challenging to distinguish from acute myocardial infarction. Although previously thought to be a benign, self-limiting condition, recent studies have confirmed that patients with takotsubo syndrome have persistent subtle ongoing cardiac dysfunction, and many continue to have limiting symptoms despite restoration of left ventricular ejection fraction. Moreover, these patients have a substantial burden of morbidity and mortality, as well, with high rates of subsequent major adverse cardiovascular events that approach those of patients with acute coronary syndrome. The mechanisms behind this condition remain elusive. Despite substantial research, the medical community continues to have an incomplete understanding of its underlying pathogenesis and pathophysiology. Catecholamine-induced myocardial injury is the most established and well-known theory, but this does not explain all the clinical features and presentations of the condition, and numerous other pathways and abnormalities are emerging. Because of the poor understanding of its underlying pathophysiology, there is a lack of evidence-based interventions to treat the acute episode, to avoid recurrences, and to prevent major adverse cardiovascular events. This highlights the need for further research to gain a better understanding of the underlying pathophysiology to inform appropriate randomized controlled trials of interventions targeting the causative pathways. Only then can evidence-based management strategies be established to improve clinical outcomes of this potentially lethal condition.
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Infarto del Miocardio , Cardiomiopatía de Takotsubo , Catecolaminas , Humanos , Infarto del Miocardio/diagnóstico , Volumen Sistólico , Cardiomiopatía de Takotsubo/diagnóstico , Cardiomiopatía de Takotsubo/terapia , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Takotsubo syndrome is an acute cardiac emergency characterized by transient left ventricular systolic dysfunction typically following a stressful event. Despite its rapidly rising incidence, its pathophysiology remains poorly understood. Takotsubo syndrome may pass unrecognized, especially if timely diagnostic imaging is not performed. Defective myocardial calcium homeostasis is a central cause of contractile dysfunction and has not been explored in takotsubo syndrome. We aimed to investigate myocardial calcium handling using manganese-enhanced magnetic resonance imaging during the acute and recovery phases of takotsubo syndrome. METHODS: Twenty patients with takotsubo syndrome (63±12 years of age; 90% female) and 20 volunteers matched on age, sex, and cardiovascular risk factors (59±11 years of age; 70% female) were recruited from the Edinburgh Heart Centre between March 2020 and October 2021. Patients underwent gadolinium and manganese-enhanced magnetic resonance imaging during index hospitalization with repeat manganese-enhanced magnetic resonance imaging performed after at least 3 months. RESULTS: Compared with matched control volunteers, patients had a reduced left ventricular ejection fraction (51±11 versus 67±8%; P<0.001), increased left ventricular mass (86±11 versus 57±14 g/m2; P<0.001), and, in affected myocardial segments, elevated native T1 (1358±49 versus 1211±28 ms; P<0.001) and T2 (60±7 versus 38±3 ms; P<0.0001) values at their index presentation. During manganese-enhanced imaging, kinetic modeling demonstrated a substantial reduction in myocardial manganese uptake (5.1±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min], respectively; P<0.0001), consistent with markedly abnormal myocardial calcium handling. After recovery, left ejection fraction, left ventricular mass, and T2 values were comparable with those of matched control volunteers. Despite this, native and postmanganese T1 and myocardial manganese uptake remained abnormal compared with matched control volunteers (6.6±0.5 versus 8.2±1.1 mL/[100 g of tissue ·min]; P<0.0001). CONCLUSIONS: In patients with takotsubo syndrome, there is a profound perturbation of myocardial manganese uptake, which is most marked in the acute phase but persists for at least 3 months despite apparent restoration of normal left ventricular ejection fraction and resolution of myocardial edema, suggesting abnormal myocardial calcium handling may be implicated in the pathophysiology of takotsubo syndrome. Manganese-enhanced magnetic resonance imaging has major potential to assist in the diagnosis, characterization, and risk stratification of patients with takotsubo syndrome. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04623788.
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Cardiomiopatía de Takotsubo , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Cardiomiopatía de Takotsubo/diagnóstico por imagen , Volumen Sistólico , Función Ventricular Izquierda/fisiología , Manganeso , Calcio , Imagen por Resonancia Magnética , Imagen por Resonancia Cinemagnética/métodosRESUMEN
BACKGROUND: The 99th centile of cardiac troponin, derived from a healthy reference population, is recommended as the diagnostic threshold for myocardial infarction, but troponin concentrations are strongly influenced by age. Our aim was to assess the diagnostic performance of cardiac troponin in older patients presenting with suspected myocardial infarction. METHODS: In a secondary analysis of a multicenter trial of consecutive patients with suspected myocardial infarction, we assessed the diagnostic accuracy of high-sensitivity cardiac troponin I at presentation for the diagnosis of type 1, type 2, or type 4b myocardial infarction across 3 age groups (<50, 50-74, and ≥75 years) using guideline-recommended sex-specific and age-adjusted 99th centile thresholds. RESULTS: In 46 435 consecutive patients aged 18 to 108 years (mean, 61±17 years), 5216 (11%) had a diagnosis of myocardial infarction. In patients <50 (n=12 379), 50 to 74 (n=22 380), and ≥75 (n=11 676) years, the sensitivity of the guideline-recommended threshold was similar at 79.2% (95% CI, 75.5-82.9), 80.6% (95% CI, 79.2-82.1), and 81.6% (95% CI, 79.8-83.2), respectively. The specificity decreased with advancing age from 98.3% (95% CI, 98.1-98.5) to 95.5% (95% CI, 95.2-95.8), and 82.6% (95% CI, 81.9-83.4). The use of age-adjusted 99th centile thresholds improved the specificity (91.3% [90.8%-91.9%] versus 82.6% [95% CI, 81.9%-83.4%]) and positive predictive value (59.3% [57.0%-61.5%] versus 51.5% [49.9%-53.3%]) for myocardial infarction in patients ≥75 years but failed to prevent the decrease in either parameter with increasing age and resulted in a marked reduction in sensitivity compared with the use of the guideline-recommended threshold (55.9% [53.6%-57.9%] versus 81.6% [79.8%-83.3%]. CONCLUSIONS: Age alters the diagnostic performance of cardiac troponin, with reduced specificity and positive predictive value in older patients when applying the guideline-recommended or age-adjusted 99th centiles. Individualized diagnostic approaches rather than the adjustment of binary thresholds are needed in an aging population.
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Síndrome Coronario Agudo , Infarto del Miocardio , Síndrome Coronario Agudo/diagnóstico , Anciano , Biomarcadores , Femenino , Humanos , Masculino , Infarto del Miocardio/diagnóstico , Medición de Riesgo , Troponina IRESUMEN
Coronary artery disease (CAD) remains the leading cause of adult mortality globally. Targeting known modifiable risk factors has had substantial benefit, but there remains a need for new approaches. Improvements in invasive and noninvasive imaging techniques have enabled an increasing recognition of distinct quantitative phenotypes of coronary atherosclerosis that are prognostically relevant. There are marked differences in plaque phenotype, from the high-risk, lipid-rich, thin-capped atheroma to the low-risk, quiescent, eccentric, nonobstructive calcified plaque. Such distinct phenotypes reflect different pathophysiologic pathways and are associated with different risks for acute ischemic events. Noninvasive coronary imaging techniques, such as computed tomography, positron emission tomography, and coronary magnetic resonance imaging, have major potential to accelerate cardiovascular drug development, which has been affected by the high costs and protracted timelines of cardiovascular outcome trials. This may be achieved through enrichment of high-risk phenotypes with higher event rates or as primary end points of drug efficacy, at least in phase 2 trials, in a manner historically performed through intravascular coronary imaging studies. Herein, we provide a comprehensive review of the current technology available and its application in clinical trials, including implications for sample size requirements, as well as potential limitations. In its effort to accelerate drug development, the US Food and Drug Administration has approved surrogate end points for 120 conditions, but not for CAD. There are robust data showing the beneficial effects of drugs, including statins, on CAD progression and plaque stabilization in a manner that correlates with established clinical end points of mortality and major adverse cardiovascular events. This, together with a clear mechanistic rationale for using imaging as a surrogate CAD end point, makes it timely for CAD imaging end points to be considered. We discuss the importance of global consensus on these imaging end points and protocols and partnership with regulatory bodies to build a more informed, sustainable staged pathway for novel therapies.
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Fármacos Cardiovasculares , Enfermedad de la Arteria Coronaria , Placa Aterosclerótica , Estados Unidos , Humanos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Corazón , Desarrollo de MedicamentosRESUMEN
BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.
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Infarto de la Pared Anterior del Miocardio , Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Disfunción Ventricular Izquierda , Anciano , Medios de Contraste , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Femenino , Gadolinio , Humanos , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Estudios Prospectivos , Troponina I , Disfunción Ventricular Izquierda/complicacionesRESUMEN
Background In the Scottish Computed Tomography of the Heart (SCOT-HEART) trial in individuals with stable chest pain, a treatment strategy based on coronary CT angiography (CTA) led to improved outcomes. Purpose To assess 5-year cumulative radiation doses of participants undergoing investigation for suspected angina due to coronary artery disease with or without coronary CTA. Materials and Methods This secondary analysis of the SCOT-HEART trial included data from six of 12 recruiting sites and two of three imaging sites. Participants were recruited between November 18, 2010, and September 24, 2014, with follow-up through January 31, 2018. Study participants had been randomized (at a one-to-one ratio) to standard care with CT (n = 1466) or standard care alone (n = 1428). Imaging was performed on a 64-detector (n = 223) or 320-detector row scanner (n = 1466). Radiation dose from CT (dose-length product), SPECT (injected activity), and invasive coronary angiography (ICA; kerma-area product) was assessed for 5 years after enrollment. Effective dose was calculated using conversion factors appropriate for the imaging modality and body region imaged (using 0.026 mSv/mGy · cm for cardiac CT). Results Cumulative radiation dose was assessed in 2894 participants. Median effective dose was 3.0 mSv (IQR, 2.6-3.3 mSv) for coronary calcium scoring, 4.1 mSv (IQR, 2.6-6.1 mSv) for coronary CTA, 7.4 mSv (IQR, 6.2-8.5 mSv) for SPECT, and 4.1 mSv (IQR, 2.5-6.8 mSv) for ICA. After 5 years, total per-participant cumulative dose was higher in the CT group (median, 8.1 mSv; IQR, 5.5-12.4 mSv) compared with standard-care group (median, 0 mSv; IQR, 0-4.5 mSv; P < .001). In participants who underwent any imaging, cumulative radiation exposure was higher in the CT group (n = 1345; median, 8.6 mSv; IQR, 6.1-13.3 mSv) compared with standard-care group (n = 549; median, 6.4 mSv; IQR, 3.4-9.2 mSv; P < .001). Conclusion In the SCOT-HEART trial, the 5-year cumulative radiation dose from cardiac imaging was higher in the coronary CT angiography group compared with the standard-care group, largely because of the radiation exposure from CT. Clinical trial registration no. NCT01149590 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Dodd and Bosserdt in this issue.
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Enfermedad de la Arteria Coronaria , Exposición a la Radiación , Humanos , Dolor en el Pecho/diagnóstico por imagen , Dolor en el Pecho/etiología , Angiografía por Tomografía Computarizada , Angiografía Coronaria/métodos , Enfermedad de la Arteria Coronaria/complicaciones , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Dosis de Radiación , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Computed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome. METHODS: In this secondary analysis of a multicenter randomized controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin-angiotensin system blocker, and beta-blocker therapies from randomization to discharge were compared within then between those randomized to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined. RESULTS: In 1,743 patients (874 randomized to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapies increased more in the early CTCA group (between-group difference: 4.6% [95% confidence interval, 0.3-8.9], 4.5% [95% confidence interval, 0.2-8.7], and 4.3% [95% confidence interval, 0.2-8.5], respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Among patients randomized to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries. CONCLUSIONS: Prescription patterns of preventative treatment varied during index hospitalization in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualization of these therapies based on the extent of coronary artery disease.
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Síndrome Coronario Agudo , Enfermedad de la Arteria Coronaria , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Humanos , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/prevención & control , Enfermedad de la Arteria Coronaria/complicaciones , Angiografía Coronaria/métodos , Síndrome Coronario Agudo/diagnóstico por imagen , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/prevención & control , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Tomografía Computarizada por Rayos X/métodos , Angiografía por Tomografía ComputarizadaRESUMEN
Manganese-based contrast media were the first in vivo paramagnetic agents to be used in magnetic resonance imaging (MRI). The uniqueness of manganese lies in its biological function as a calcium channel analog, thus behaving as an intracellular contrast agent. Manganese ions are taken up by voltage-gated calcium channels in viable tissues, such as the liver, pancreas, kidneys, and heart, in response to active calcium-dependent cellular processes. Manganese-enhanced magnetic resonance imaging (MEMRI) has therefore been used as a surrogate marker for cellular calcium handling and interest in its potential clinical applications has recently re-emerged, especially in relation to assessing cellular viability and myocardial function. Calcium homeostasis is central to myocardial contraction and dysfunction of myocardial calcium handling is present in various cardiac pathologies. Recent studies have demonstrated that MEMRI can detect the presence of abnormal myocardial calcium handling in patients with myocardial infarction, providing clear demarcation between the infarcted and viable myocardium. Furthermore, it can provide more subtle assessments of abnormal myocardial calcium handling in patients with cardiomyopathies and being excluded from areas of nonviable cardiomyocytes and severe fibrosis. As such, MEMRI offers exciting potential to improve cardiac diagnoses and provide a noninvasive measure of myocardial function and contractility. This could be an invaluable tool for the assessment of both ischemic and nonischemic cardiomyopathies as well as providing a measure of functional myocardial recovery, an accurate prediction of disease progression and a method of monitoring treatment response. EVIDENCE LEVEL: 5: TECHNICAL EFFICACY: STAGE 5.
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Cardiomiopatías , Manganeso , Humanos , Calcio , Imagen por Resonancia Magnética/métodos , Medios de Contraste , Miocitos CardíacosRESUMEN
AIMS: To investigate whether manganese-enhanced magnetic resonance imaging can assess functional pancreatic beta-cell mass in people with type 1 diabetes mellitus. METHODS: In a prospective case-control study, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. RESULTS: Mean pancreatic manganese uptake was 31 ± 6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23 ± 4 and 13 ± 5 mL/100 g of tissue/min (p ≤ 0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma C-peptide concentrations respectively. Pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r = 0.73, p < 0.001) but not in healthy volunteers (r = -0.054, p = 0.880). There were no statistically significant correlations between manganese uptake and age, body-mass index, or glycated haemoglobin. There was strong intra-observer (mean difference: 0.31 (limits of agreement -1.42 to 2.05) mL/100 g of tissue/min; intra-class correlation, ICC = 0.99), inter-observer (-1.23 (-5.74 to 3.27) mL/100 g of tissue/min; ICC = 0.85) and scan-rescan (-0.72 (-2.9 to 1.6) mL/100 g of tissue/min; ICC = 0.96) agreement for pancreatic manganese uptake. CONCLUSIONS: Manganese-enhanced magnetic resonance imaging provides a potential reproducible non-invasive measure of functional beta-cell mass in people with type 1 diabetes mellitus. This holds major promise for investigating type 1 diabetes, monitoring disease progression and assessing novel immunomodulatory interventions.