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BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronization therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life-, clinical-, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were non-significant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = .03; adjusted Pinteraction = .33) and diabetics (Pinteraction = .01; adjusted Pinteraction = .06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.
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Insuficiencia Cardíaca , Arteria Pulmonar , Calidad de Vida , Humanos , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/fisiopatología , Femenino , Masculino , Anciano , Persona de Mediana Edad , Arteria Pulmonar/fisiopatología , Enfermedad Crónica , Volumen Sistólico/fisiología , Terapia de Resincronización Cardíaca/métodos , Desfibriladores ImplantablesRESUMEN
PURPOSE: Splenectomy might be a risk factor for valvular heart disease (VHD) in adult Hodgkin lymphoma survivors. As this risk is still unclear for childhood cancer survivors (CCS), the aim of this study is to evaluate the association between treatments affecting splenic function (splenectomy and radiotherapy involving the spleen) and VHD in CCS. METHODS: CCS were enrolled from the DCCSS-LATER cohort, consisting of 6,165 five-year CCS diagnosed between 1963 and 2002. Symptomatic VHD, defined as symptoms combined with a diagnostic test indicating VHD, was assessed from questionnaires and validated using medical records. Differences in the cumulative incidence of VHD between CCS who received treatments affecting splenic function and CCS who did not were assessed using the Gray test. Risk factors were analyzed in a multivariable Cox proportional hazards model. RESULTS: The study population consisted of 5,286 CCS, with a median follow-up of 22 years (5-50 years), of whom 59 (1.1%) had a splenectomy and 489 (9.2%) radiotherapy involving the spleen. VHD was present in 21 CCS (0.4%). The cumulative incidence of VHD at the age of 40 years was significantly higher in CCS who received treatments affecting splenic function (2.7%, 95% confidence interval (CI) 0.4%-4.9%) compared with CCS without (0.4%, 95% CI 0.1%-0.7%) (Gray's test, p = 0.003). Splenectomy was significantly associated with VHD in a multivariable analysis (hazard ratio 8.6, 95% CI 3.1-24.1). CONCLUSIONS AND IMPLICATIONS: Splenectomy was associated with VHD. Future research is needed to determine if CCS who had a splenectomy as part of cancer treatment might benefit from screening for VHD.
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PURPOSE: The purpose of this study is to assess the available literature on the prevalence and risk factors of electrocardiographic (ECG) abnormalities after cardiotoxic treatment in childhood cancer survivors (CCS). METHODS: A literature search was performed within MEDLINE, EMBASE, and CENTRAL (1966-11/2020) and reference lists of relevant studies. Studies were eligible for inclusion if they reported ECG abnormalities ≥2 years after cancer diagnosis in ≥50 CCS treated with anthracyclines, RT involving the heart region and/or mitoxantrone. Information about population, treatment, outcome, and risk factors were extracted and risk of bias was assessed. RESULTS: Of 934 identified publications, 10 studies were included. Outcome definitions, treatment regimens, follow-up period, and risk of bias varied. These ECG abnormalities and prevalences were reported: major (5%-23%) and minor (12%) abnormalities according to the Minnesota Code, rhythm abnormalities (0%-12%), conduction abnormalities (0.3%-7.1%), depolarization abnormalities (0%), and repolarization abnormalities (0%-65%). The reported risk factors of ECG abnormalities (two studies) are male sex, anthracyclines, RT involving the heart region, and hypertension, although results were not univocal between studies and abnormalities. CONCLUSIONS: Multiple ECG abnormalities have been described in CCS ≥2 years from diagnosis, some of which can have important implications. Future research is needed to evaluate the exact long-term incidence and risk factors, and to investigate their clinical relevance and relation with cardiac dysfunction or future cardiac events. This could improve cardiac surveillance for CCS.
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Supervivientes de Cáncer , Neoplasias , Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/uso terapéutico , Cardiotoxicidad/epidemiología , Cardiotoxicidad/etiología , Niño , Electrocardiografía , Femenino , Humanos , Masculino , Neoplasias/tratamiento farmacológico , Factores de Riesgo , SobrevivientesRESUMEN
BACKGROUND: Cardiotoxicity is a well-known side effect after anthracyclines and chest radiotherapy in childhood cancer survivors (CCS). The DCCSS LATER 2 CARD (cardiology) study includes evaluation of echocardiographic measurements for early identification of CCS at highest risk of developing heart failure. This paper describes the design, feasibility, and reproducibility of the echocardiography protocol. METHODS: Echocardiograms from CCS and sibling controls were prospectively obtained at the participating centers and centrally analyzed. We describe the image acquisition, measurement protocol, and software-specific considerations for myocardial strain analyses. We report the feasibility of the primary outcomes of systolic and diastolic function, as well as reproducibility analyses in 30 subjects. RESULTS: We obtained 1,679 echocardiograms. Biplane ejection fraction (LVEF) measurement was feasible in 91% and 96% of CCS and siblings, respectively, global longitudinal strain (GLS) in 80% and 91%, global circumferential strain (GCS) in 86% and 89%, and ≥2 diastolic function parameters in 99% and 100%, right ventricle free wall strain (RVFWS) in 57% and 65%, and left atrial reservoir strain (LASr) in 72% and 79%. Intra-class correlation coefficients for inter-observer variability were 0.85 for LVEF, 0.76 for GLS, 0.70 for GCS, 0.89 for RVFWS and 0.89 for LASr. Intra-class correlation coefficients for intra-observer variability were 0.87 for LVEF, 0.82 for GLS, 0.82 for GCS, 0.85 for RVFWS and 0.79 for LASr. CONCLUSION: The DCCSS LATER 2 CARD study includes a protocolized echocardiogram, with feasible and reproducible primary outcome measurements. This ensures high-quality outcome data for prevalence estimates and for reliable comparison of cardiac function parameters.
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Supervivientes de Cáncer , Cardiología , Neoplasias , Disfunción Ventricular Izquierda , Cardiotoxicidad , Niño , Detección Precoz del Cáncer , Ecocardiografía , Estudios de Factibilidad , Humanos , Estudios Multicéntricos como Asunto , Reproducibilidad de los Resultados , Disfunción Ventricular Izquierda/diagnóstico por imagen , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure. OBJECTIVE: To describe the methodology of the Dutch LATER cardiology study (LATER CARD). METHODS: The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings. CONCLUSIONS: The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure.
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Supervivientes de Cáncer , Diagnóstico Precoz , Cardiopatías/diagnóstico , Insuficiencia Cardíaca , Adolescente , Apoptosis , Biomarcadores/sangre , Niño , Preescolar , Estudios Transversales , Ecocardiografía , Electrocardiografía , Femenino , Cardiopatías/sangre , Humanos , Lactante , Recién Nacido , Inflamación , Masculino , Miocitos Cardíacos/fisiología , Neoplasias/terapia , Países Bajos , Estrés Oxidativo , Factores de Riesgo , Disfunción Ventricular Izquierda/sangre , Disfunción Ventricular Izquierda/diagnóstico , Remodelación VentricularRESUMEN
This corrects the article DOI: 10.1038/bjc.2017.85.
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Supervivientes de Cáncer/estadística & datos numéricos , Enfermedades Cardiovasculares/epidemiología , Enfermedad de Hodgkin/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Adulto , Enfermedades Cardiovasculares/mortalidad , Estudios de Cohortes , Femenino , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/mortalidad , Países Bajos/epidemiología , Adulto JovenRESUMEN
AIMS: Many heart failure (HF) patients do not receive optimal guideline-directed medical therapy (GDMT) despite clear benefit on morbidity and mortality outcomes. Digital consults (DCs) have the potential to improve efficiency on GDMT optimization to serve the growing HF population. The investigator-initiated ADMINISTER trial was designed as a pragmatic multicenter randomized controlled open-label trial to evaluate efficacy and safety of DC in patients on HF treatment. METHODS AND RESULTS: Patients (n = 150) diagnosed with HF with a reduced ejection fraction will be randomized to DC or standard care (1:1). The intervention group receives multifaceted DCs including (i) digital data sharing (e.g. exchange of pharmacotherapy use and home-measured vital signs), (ii) patient education via an e-learning, and (iii) digital guideline recommendations to treating clinicians. The consults are performed remotely unless there is an indication to perform the consult physically. The primary outcome is the GDMT prescription rate score, and secondary outcomes include time till full GDMT optimization, patient and clinician satisfaction, time spent on healthcare, and Kansas City Cardiomyopathy Questionnaire. Results will be reported in accordance to the CONSORT statement. CONCLUSIONS: The ADMINISTER trial will offer the first randomized controlled data on GDMT prescription rates, time till full GDMT optimization, time spent on healthcare, quality of life, and patient and clinician satisfaction of the multifaceted patient- and clinician-targeted DC for GDMT optimization.
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Insuficiencia Cardíaca , Calidad de Vida , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/diagnóstico , Morbilidad , Ensayos Clínicos Pragmáticos como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors. METHODS: In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability. RESULTS: 16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well. CONCLUSION: A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.
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Supervivientes de Cáncer , Electrocardiografía , Volumen Sistólico , Humanos , Femenino , Masculino , Estudios Transversales , Adulto , Volumen Sistólico/fisiología , Neoplasias/complicaciones , Cardiomiopatías/fisiopatología , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Cardiomiopatías/epidemiología , Niño , Países Bajos/epidemiología , Ecocardiografía , Función Ventricular Izquierda/fisiología , Prevalencia , Adolescente , Adulto Joven , Preescolar , Valor Predictivo de las PruebasRESUMEN
Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested. Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors. Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics. Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%). Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).
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AIMS: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms. METHODS: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death. CONCLUSION: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively.
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Biomarcadores , Insuficiencia Cardíaca , Arteria Pulmonar , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/sangre , Biomarcadores/sangre , Pronóstico , Arteria Pulmonar/fisiopatología , Femenino , Masculino , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Presión Esfenoidal Pulmonar/fisiología , Enfermedad Crónica , Persona de Mediana EdadRESUMEN
BACKGROUND: Cardiac involvement in idiopathic inflammatory myopathy (IIM or "myositis") is associated with an approximate 4% mortality, but standardised screening strategies are lacking. OBJECTIVE: We explored a multimodality screening on potentially reversible cardiac involvement -i.e. active (peri)myocarditis -in newly diagnosed IIM. METHODS: We included adult IIM patients from 2017 to 2020. At time of diagnosis, patients underwent cardiac evaluation including laboratory biomarkers, electrocardiography, echocardiography, and cardiac magnetic resonance imaging (CMR). Based on 2019 consensus criteria for myocarditis, an adjudication committee made diagnoses of definite, probable, possible or no (peri)myocarditis. We explored diagnostic values of sequentially added diagnostic modalities by Constructing Classification and Regression Tree (CART) analysis in patients with definite/probable versus no (peri)myocarditis. RESULTS: We included 34 IIM patients, in whom diagnoses of definite (six, 18%), probable (two, 6%), possible (11, 32%), or no (peri)myocarditis (15, 44%) were adjudicated. CART-analysis showed high-sensitivity cardiac troponin T (cut-off valueâ<â2.3 times the upper limit of normal (xULN)) ruled out (peri)myocarditis with a sensitivity of 88%, while high-sensitivity troponin I (cut-off valueâ>â2.9 xULN for females andâ>â1.8 xULN for males) ruled in (peri)myocarditis with a specificity of 100%. Applying high-sensitivity cardiac troponins with these cut-off values in a diagnostic algorithm without and with a CMR to the total population of 34 patients demonstrated a diagnostic accuracy for a clear diagnosis of probable/definite or no (peri)myocarditis of 59% and 68%, respectively. CONCLUSIONS: A diagnostic algorithm for detection of (peri)myocarditis in adult IIM may consist of sequential testing with high-sensitivity cardiac troponins and CMR.
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Miocarditis , Miositis , Adulto , Masculino , Femenino , Humanos , Miocarditis/complicaciones , Estudios Transversales , Miositis/diagnóstico , Corazón , Troponina IRESUMEN
AIMS: Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF. METHODS AND RESULTS: The DoPING-HFpEF trial was a phase II single-centre, double-blind, placebo-controlled, randomized cross-over trial. Patients were randomized to trimetazidine treatment or placebo for 3 months and switched after a 2-week wash-out period. The primary endpoint was change in pulmonary capillary wedge pressure, measured with right heart catheterization at multiple stages of bicycling exercise. Secondary endpoint was change in myocardial phosphocreatine/adenosine triphosphate, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance spectroscopy. The study included 25 patients (10/15 males/females; mean (standard deviation) age, 66 (10) years; body mass index, 29.8 (4.5) kg/m2 ); with the diagnosis of HFpEF confirmed with (exercise) right heart catheterization either before or during the trial. There was no effect of trimetazidine on the primary outcome pulmonary capillary wedge pressure at multiple levels of exercise (mean change 0 [95% confidence interval, 95% CI -2, 2] mmHg over multiple levels of exercise, P = 0.60). Myocardial phosphocreatine/adenosine triphosphate in the trimetazidine arm was similar to placebo (1.08 [0.76, 1.76] vs. 1.30 [0.95, 1.86], P = 0.08). There was no change by trimetazidine compared with placebo in the exploratory parameters: 6-min walking distance (mean change of -6 [95% CI -18, 7] m vs. -5 [95% CI -22, 22] m, respectively, P = 0.93), N-terminal pro-B-type natriuretic peptide (5 (-156, 166) ng/L vs. -13 (-172, 147) ng/L, P = 0.70), overall quality-of-life (KCCQ and EQ-5D-5L, P = 0.78 and P = 0.51, respectively), parameters for diastolic function measured with echocardiography and cardiac magnetic resonance, or metabolic parameters. CONCLUSIONS: Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.
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Insuficiencia Cardíaca , Trimetazidina , Humanos , Masculino , Femenino , Anciano , Trimetazidina/uso terapéutico , Trimetazidina/farmacología , Fosfocreatina/farmacología , Fosfocreatina/uso terapéutico , Estudios Cruzados , Volumen Sistólico , Adenosina Trifosfato/farmacología , Adenosina Trifosfato/uso terapéuticoRESUMEN
Background: Childhood cancer survivors (CCS) are at risk for cardiotoxicity. Objectives: We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors. Methods: This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 ≥5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression. Results: CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as <52% in men, <54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors. Conclusions: Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-term CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481).
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BACKGROUND: The use of waterpipe in shisha lounges is popular among young people, but it has a risk of carbon monoxide poisoning and can lead to serious cardiac problems. CASE DESCRIPTION: A 26-year-old man presented to the emergency department with chest pain, dyspnea and syncope after working in a shisha lounge. Blood gas analysis showed carbon monoxide intoxication and an increased lactate level. Troponin-I measurement was normal. Ventricular arrhythmias on the monitor were the impetus for further cardiac analysis. Echocardiography showed a reduced left ventricular ejection fraction (27%). The acute treatment consisted of high dose oxygen, followed by normalization of carboxyhemoglobin and lactate levels. The ventricular extrasystoles were reduced with beta-blockers. There was improvement of the left ventricular ejection fraction (42%) within a week, but PVC-induced cardiomyopathy remained a possible underlying condition. CONCLUSION: The use of waterpipe can cause carbon monoxide intoxication, which may be accompanied by arrhythmias and cardiomyopathy.
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Intoxicación por Monóxido de Carbono , Cardiomiopatías , Pipas de Agua , Adolescente , Adulto , Arritmias Cardíacas , Monóxido de Carbono , Intoxicación por Monóxido de Carbono/complicaciones , Intoxicación por Monóxido de Carbono/diagnóstico , Humanos , Lactatos , Masculino , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
PURPOSE: Echocardiographic surveillance for asymptomatic left ventricular systolic dysfunction (ALVSD) is advised in childhood cancer survivors (CCS), because of their risk of heart failure after anthracycline treatment. ALVSD can be assessed with different echocardiographic parameters. We systematically reviewed the prevalence and risk factors of late ALVSD, as defined by contemporary and more traditional echocardiographic parameters. METHODS: We searched databases from 2001 to 2020 for studies on ≥ 100 asymptomatic 5-year CCS treated with anthracyclines, with or without radiotherapy involving the heart region. Outcomes of interest were prevalence of ALVSD-measured with volumetric methods (ejection fraction; LVEF), myocardial strain, or linear methods (fractional shortening; FS)-and its risk factors from multivariable analyses. RESULTS: Eleven included studies represented 3840 CCS. All studies had methodological limitations. An LVEF < 50% was observed in three studies in 1-6% of CCS, and reduced global longitudinal strain (GLS) was reported in three studies in 9-30% of CCS, both after a median follow-up of 9 to 23 years. GLS was abnormal in 20-28% of subjects with normal LVEF. Abnormal FS was reported in six studies in 0.3-30% of CCS, defined with various cut-off values (< 25 to < 30%), at a median follow-up of 10 to 18 years. Across echocardiographic parameters, reported risk factors were cumulative anthracycline dose and radiotherapy involving the heart region, with no 'safe' dose for ALVSD. CONCLUSIONS: GLS identifies higher prevalence of ALVSD in anthracycline-treated CCS, than LVEF. IMPLICATIONS FOR CANCER SURVIVORS: The diagnostic and prognostic value of GLS should be evaluated within large cohorts. PROTOCOL REGISTRATION: PROSPERO CRD42019126588.
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Supervivientes de Cáncer , Neoplasias , Disfunción Ventricular Izquierda , Antraciclinas/efectos adversos , Niño , Ecocardiografía , Humanos , Neoplasias/tratamiento farmacológico , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiologíaRESUMEN
Background Plasma biomarkers may aid in the detection of anthracycline-related cardiomyopathy (ACMP). However, the currently available biomarkers have limited diagnostic value in long-term childhood cancer survivors. This study sought to identify diagnostic plasma biomarkers for ACMP in childhood cancer survivors. Methods and Results We measured 275 plasma proteins in 28 ACMP cases with left ventricular ejection fraction <45%, 29 anthracycline-treated controls with left ventricular ejection fraction ≥53% matched on sex, time after cancer, and anthracycline dose, and 29 patients with genetically determined dilated cardiomyopathy with left ventricular ejection fraction <45%. Multivariable linear regression was used to identify differentially expressed proteins. Elastic net model, including clinical characteristics, was used to assess discrimination of proteins diagnostic for ACMP. NT-proBNP (N-terminal pro-B-type natriuretic peptide) and the inflammatory markers CCL19 (C-C motif chemokine ligands 19) and CCL20, PSPD (pulmonary surfactant protein-D), and PTN (pleiotrophin) were significantly upregulated in ACMP compared with controls. An elastic net model selected 45 proteins, including NT-proBNP, CCL19, CCL20 and PSPD, but not PTN, that discriminated ACMP cases from controls with an area under the receiver operating characteristic curve (AUC) of 0.78. This model was not superior to a model including NT-proBNP and clinical characteristics (AUC=0.75; P=0.766). However, when excluding 8 ACMP cases with heart failure, the full model was superior to that including only NT-proBNP and clinical characteristics (AUC=0.75 versus AUC=0.50; P=0.022). The same 45 proteins also showed good discrimination between dilated cardiomyopathy and controls (AUC=0.89), underscoring their association with cardiomyopathy. Conclusions We identified 3 specific inflammatory proteins as candidate plasma biomarkers for ACMP in long-term childhood cancer survivors and demonstrated protein overlap with dilated cardiomyopathy.
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Supervivientes de Cáncer , Cardiomiopatías , Cardiomiopatía Dilatada , Neoplasias , Antraciclinas/efectos adversos , Antibióticos Antineoplásicos/efectos adversos , Biomarcadores , Cardiomiopatías/inducido químicamente , Cardiomiopatías/diagnóstico , Estudios de Casos y Controles , Niño , Humanos , Péptido Natriurético Encefálico , Neoplasias/inducido químicamente , Neoplasias/tratamiento farmacológico , Fragmentos de Péptidos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: Anthracyclines and radiotherapy involving the heart region are cardiotoxic, but the potential cardiotoxicity of vincristine remains unknown. We assessed cardiac function in vincristine-treated >5-year childhood cancer survivors (CCS). METHODS AND RESULTS: We cross-sectionally compared echocardiograms of 101 vincristine-treated CCS (median age 35 years [range: 17-53], median vincristine dose 63 mg/m2) from the national Dutch Childhood Cancer Survivor Study, LATER cohort, to 101 age- and sex-matched controls. CCS treated with anthracyclines, radiotherapy involving the heart region, cyclophosphamide or ifosfamide were excluded. Twelve CCS (14%) versus four controls (4%; p 0.034) had a decreased left ventricular ejection fraction (LVEF; men <52%, women <54%). Mean LVEF was 58.4% versus 59.7% (p 0.050). Global longitudinal strain (GLS) was abnormal in nineteen (24%) CCS versus eight controls (9%; p 0.011). Mean GLS was 19.0% versus 20.1% (p 0.001). No ≥grade 2 diastolic dysfunction was detected. In multivariable logistic regression analysis CCS had higher risk of abnormal GLS (OR 3.55, p 0.012), but not abnormal LVEF (OR 3.07, p 0.065), than controls. Blood pressure and smoking history contributed to variation in LVEF, whereas obesity and diastolic blood pressure contributed to variation in GLS. Cumulative vincristine dose was not associated with either abnormal LVEF or abnormal GLS in multivariable models corrected for age and sex (OR per 50 mg/m2: 0.88, p 0.85 and 1.14, p 0.82, respectively). CONCLUSIONS: Vincristine-treated long-term CCS showed an abnormal GLS more frequently than controls. Their risk for future clinical cardiac events and the role of risk factor modification should be further elucidated.
Asunto(s)
Supervivientes de Cáncer , Neoplasias , Disfunción Ventricular Izquierda , Adulto , Antraciclinas/uso terapéutico , Antibióticos Antineoplásicos , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/epidemiología , Cardiotoxicidad/etiología , Niño , Ecocardiografía/métodos , Femenino , Humanos , Ifosfamida/farmacología , Ifosfamida/uso terapéutico , Masculino , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Volumen Sistólico/fisiología , Disfunción Ventricular Izquierda/inducido químicamente , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiología , Función Ventricular Izquierda/fisiología , Vincristina/efectos adversosRESUMEN
As in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1-8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function.
Asunto(s)
Antraciclinas , Cardiomiopatías/patología , Matriz Extracelular/patología , Miocardio/patología , Función Ventricular Izquierda , Remodelación Ventricular , Animales , Apoptosis , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Cardiomiopatías/fisiopatología , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Proteínas de la Matriz Extracelular/genética , Proteínas de la Matriz Extracelular/metabolismo , Fibrosis , Regulación de la Expresión Génica , Miocardio/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
BACKGROUND: In childhood cancer survivors (CCS) at risk for heart failure, echocardiographic surveillance recommendations are currently based on anthracyclines and chest-directed radiotherapy dose. Whether the ejection fraction (EF) measured at an initial surveillance echocardiogram can refine these recommendations is unknown. OBJECTIVES: The purpose of this study was to assess the added predictive value of EF at >5 years after cancer diagnosis to anthracyclines and chest-directed radiotherapy dose in CCS, for the development of left ventricular dysfunction with an ejection fraction <40% (LVD40). METHODS: Echocardiographic surveillance was performed in 299 CCS from the Emma Children's Hospital in the Netherlands. Cox regression models were built including cardiotoxic cancer treatment exposures with and without EF to estimate the probability of LVD40 at 10-year follow-up. Calibration, discrimination, and reclassification were assessed. Results were externally validated in 218 CCS. RESULTS: Cumulative incidences of LVD40 at 10-year follow-up were 3.7% and 3.6% in the derivation and validation cohort, respectively. The addition of EF resulted in an integrated area under the curve increase from 0.74 to 0.87 in the derivation cohort and from 0.72 to 0.86 in the validation cohort (likelihood ratio p < 0.001). Reclassification of CCS without LVD40 improved significantly (noncase continuous net reclassification improvement 0.50; 95% confidence interval [CI]: 0.40 to 0.60). A predicted LVD40 probability ≤3%, representing 75% of the CCS, had a negative predictive value of 99% (95% CI: 98% to 100%) for LVD40 within 10 years. However, patients with midrange EF (40% to 49%) at initial screening had an incidence of LVD40 of 11% and a 7.81-fold (95% CI: 2.07- to 29.50-fold) increased risk of LV40 at follow-up. CONCLUSIONS: In CCS, an initial surveillance EF, in addition to anthracyclines and chest-directed radiotherapy dose, improves the 10-year prediction for LVD40. Through this strategy, both the identification of low-risk survivors in whom the surveillance frequency may be reduced and a group of survivors at increased risk of LVD40 could be identified.
RESUMEN
BACKGROUND: Phospholamban (PLN) p.Arg14del mutation carriers are known to develop dilated and/or arrhythmogenic cardiomyopathy, and typical electrocardiographic (ECG) features have been identified for diagnosis. Machine learning is a powerful tool used in ECG analysis and has shown to outperform cardiologists. OBJECTIVES: We aimed to develop machine learning and deep learning models to diagnose PLN p.Arg14del cardiomyopathy using ECGs and evaluate their accuracy compared to an expert cardiologist. METHODS: We included 155 adult PLN mutation carriers and 155 age- and sex-matched control subjects. Twenty-one PLN mutation carriers (13.4%) were classified as symptomatic (symptoms of heart failure or malignant ventricular arrhythmias). The data set was split into training and testing sets using 4-fold cross-validation. Multiple models were developed to discriminate between PLN mutation carriers and control subjects. For comparison, expert cardiologists classified the same data set. The best performing models were validated using an external PLN p.Arg14del mutation carrier data set from Murcia, Spain (n = 50). We applied occlusion maps to visualize the most contributing ECG regions. RESULTS: In terms of specificity, expert cardiologists (0.99) outperformed all models (range 0.53-0.81). In terms of accuracy and sensitivity, experts (0.28 and 0.64) were outperformed by all models (sensitivity range 0.65-0.81). T-wave morphology was most important for classification of PLN p.Arg14del carriers. External validation showed comparable results, with the best model outperforming experts. CONCLUSION: This study shows that machine learning can outperform experienced cardiologists in the diagnosis of PLN p.Arg14del cardiomyopathy and suggests that the shape of the T wave is of added importance to this diagnosis.