Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Agreement Between Spatiotemporal Gait Parameters Measured by a Markerless Motion Capture System and Two Reference Systems-a Treadmill-Based Photoelectric Cell and High-Speed Video Analyses: Comparative Study.

BACKGROUND: Markerless systems to capture body motion require no markers to be attached to the body, thereby improving clinical feasibility and testing time. However, the lack of markers might affect the accuracy of measurements. OBJECTIVE: This study aimed to determine the absolute reliability and concurrent validity of the Kinect system with MotionMetrix software for spatiotemporal variables during running at a comfortable velocity, by comparing data between the combination system and two widely used systems-OptoGait and high-speed video analysis at 1000 Hz. METHODS: In total, 25 runners followed a running protocol on a treadmill at a speed of 12 km/h. The Kinect+MotionMetrix combination measured spatiotemporal parameters during running (ie, contact time, flight time, step frequency, and step length), which were compared to those obtained from two reference systems. RESULTS: Regardless of the system, flight time had the highest coefficients of variation (OptoGait: 16.4%; video analysis: 17.3%; Kinect+MotionMetrix: 23.2%). The rest of the coefficients of variation reported were lower than 8.1%. Correlation analysis showed very high correlations (r>0.8; P<.001) and almost perfect associations (intraclass correlation coefficient>0.81) between systems for all the spatiotemporal parameters except contact time, which had lower values. Bland-Altman plots revealed smaller systematic biases and random errors for step frequency and step length and larger systematic biases and random errors for temporal parameters with the Kinect+MotionMetrix system as compared to OptoGait (difference: contact time +3.0%, flight time -7.9%) and high-speed video analysis at 1000 Hz (difference: contact time +4.2%, flight time -11.3%). Accordingly, heteroscedasticity was found between systems for temporal parameters (r2>0.1). CONCLUSIONS: The results indicate that the Kinect+MotionMetrix combination slightly overestimates contact time and strongly underestimates flight time as compared to the OptoGait system and high-speed video analysis at 1000 Hz. However, it is a valid tool for measuring step frequency and step length when compared to reference systems. Future studies should determine the reliability of this system for determining temporal parameters.

Exome array analysis identifies ETFB as a novel susceptibility gene for anthracycline-induced cardiotoxicity in cancer patients.

PURPOSE: Anthracyclines are widely used chemotherapeutic drugs that can cause progressive and irreversible cardiac damage and fatal heart failure. Several genetic variants associated with anthracycline-induced cardiotoxicity (AIC) have been identified, but they explain only a small proportion of the interindividual differences in AIC susceptibility. METHODS: In this study, we evaluated the association of low-frequency variants with risk of chronic AIC using the Illumina HumanExome BeadChip array in a discovery cohort of 61 anthracycline-treated breast cancer patients with replication in a second independent cohort of 83 anthracycline-treated pediatric cancer patients, using gene-based tests (SKAT-O). RESULTS: The most significant associated gene in the discovery cohort was ETFB (electron transfer flavoprotein beta subunit) involved in mitochondrial ß-oxidation and ATP production (P = 4.16 × 10-4) and this association was replicated in an independent set of anthracycline-treated cancer patients (P = 2.81 × 10-3). Within ETFB, we found that the missense variant rs79338777 (p.Pro52Leu; c.155C > T) made the greatest contribution to the observed gene association and it was associated with increased risk of chronic AIC in the two cohorts separately and when combined (OR 9.00, P = 1.95 × 10-4, 95% CI 2.83-28.6). CONCLUSIONS: We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset and related to anthracycline-mediated mitochondrial dysfunction. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC.

Exome array analysis identifies GPR35 as a novel susceptibility gene for anthracycline-induced cardiotoxicity in childhood cancer.

OBJECTIVES: Pediatric cancer survivors are a steadily growing population; however, chronic anthracycline-induced cardiotoxicity (AIC) is a serious long-term complication leading to considerable morbidity. We aimed to identify new genes and low-frequency variants influencing the susceptibility to AIC for pediatric cancer patients. PATIENTS AND METHODS: We studied the association of variants on the Illumina HumanExome BeadChip array in 83 anthracycline-treated pediatric cancer patients. In addition to single-variant association tests, we carried out a gene-based analysis to investigate the combined effects of common and low-frequency variants to chronic AIC. RESULTS: Although no single-variant showed an association with chronic AIC that was statistically significant after correction for multiple testing, we identified a novel significant association for G protein-coupled receptor 35 (GPR35) by gene-based testing, a gene with potential roles in cardiac physiology and pathology (P=7.0×10), which remained statistically significant after correction for multiple testing (PFDR=0.03). The greatest contribution to this observed association was made by rs12468485, a missense variant (p.Thr253Met, c.758C>T, minor allele frequency=0.04), with the T allele associated with an increased risk of chronic AIC and more severe symptomatic cardiac manifestations at low anthracycline doses. CONCLUSION: Using exome array data, we identified GPR35 as a novel susceptibility gene associated with chronic AIC in pediatric cancer patients.

Usefulness of 64-detector computed tomography in the diagnosis and management of patients with congenital heart disease.

INTRODUCTION AND OBJECTIVES: Although congenital heart defects are the most common major congenital abnormalities, the associated mortality has been decreasing due to improvements in their diagnosis and treatment. We assessed the usefulness of 64-multidetector computed tomography in the diagnosis and management of these patients. METHODS: This 5-year observational, analytical, retrospective, cohort study included a total of 222 tomographic studies of patients with congenital heart disease. Computed tomography scans were read twice and medical records were reviewed. We assessed the complexity of the disease, patient, and radiological technique, and evaluated the contribution of new data in relation to clinical suspicion and diagnostic change. A confidence interval was set at 95% and a P value of<.05 was used as the cutoff for statistical significance. RESULTS: In 35.1% of patients, the treatment procedure was performed after computed tomography without other tests. Additional diagnostic catheterization was performed in 12.5% of patients. There were new findings in 77% of patients (82.9% with complex disease), which prompted a change in patient management in 35.6%. All unexpected reports described new findings. No significant differences were found by age, sex, study period, urgency of the test order, patient complexity, or difficulty of the technique. CONCLUSIONS: Use of 64-detector computed tomography yields good diagnostic performance in congenital heart disease, prompts changes in management in more than one-third of patients, and reveals new findings in relation to the presumed diagnosis in 77% of patients.

Utilidad de la tomografía computarizada de 64 detectores en el diagnóstico y el manejo de los pacientes con cardiopatías congénitas / Usefulness of 64-detector computed tomography in the diagnosis and management of patients with congenital heart disease

Introducción y objetivos Las cardiopatías congénitas son las malformaciones congénitas mayores más frecuentes, y su mortalidad ha ido disminuyendo con las mejoras en el diagnóstico y el tratamiento. Se ha valorado la utilidad de la tomografía computarizada de 64 detectores en el diagnóstico y el manejo de estos pacientes. Métodos Estudio observacional analítico sobre una cohorte retrospectiva (5 años). Se incluyeron 222 estudios de tomografía de pacientes con cardiopatías congénitas. Se realizó doble lectura de los casos y revisión de historias clínicas. Se determinó la complejidad de la cardiopatía, del paciente y de la técnica radiológica. Se valoró la aportación de datos nuevos sobre la sospecha clínica y el cambio de diagnóstico. Se fijó un intervalo de confianza del 95% y p < 0,05 como valor umbral de la significación estadística de las asociaciones. Resultados En el 35,1% de los casos, se realizó procedimiento terapéutico tras tomografía sin otras pruebas. Se realizó cateterismo diagnóstico complementario al 12,5%. Se observaron nuevos hallazgos en el 77% de los casos (el 82,9% con enfermedad compleja), que motivaron cambio de manejo del paciente en el 35,6%. Todos los diagnósticos no esperados resultaron nuevos hallazgos. No se detectaron diferencias significativas por edad, sexo, periodo de estudio, urgencia de la petición, dificultad de los pacientes o técnica empleada. Conclusiones La tomografía computarizada de 64 detectores tiene buena capacidad diagnóstica en cardiopatías congénitas, cambia su manejo en más de un tercio de los pacientes y pone de manifiesto hallazgos nuevos sobre la sospecha inicial en el 77% de los casos

Introduction and objectives Although congenital heart defects are the most common major congenital abnormalities, the associated mortality has been decreasing due to improvements in their diagnosis and treatment. We assessed the usefulness of 64-multidetector computed tomography in the diagnosis and management of these patients. Methods This 5-year observational, analytical, retrospective, cohort study included a total of 222 tomographic studies of patients with congenital heart disease. Computed tomography scans were read twice and medical records were reviewed. We assessed the complexity of the disease, patient, and radiological technique, and evaluated the contribution of new data in relation to clinical suspicion and diagnostic change. A confidence interval was set at 95% and a P value of < .05 was used as the cutoff for statistical significance. Results In 35.1% of patients, the treatment procedure was performed after computed tomography without other tests. Additional diagnostic catheterization was performed in 12.5% of patients. There were new findings in 77% of patients (82.9% with complex disease), which prompted a change in patient management in 35.6%. All unexpected reports described new findings. No significant differences were found by age, sex, study period, urgency of the test order, patient complexity, or difficulty of the technique. Conclusions: Use of 64-detector computed tomography yields good diagnostic performance in congenital heart disease, prompts changes in management in more than one-third of patients, and reveals new findings in relation to the presumed diagnosis in 77% of patients

Pulmonary hypertension in bronchopulmonary dysplasia: clinical findings, cardiovascular anomalies and outcomes.

OBJECTIVE: Pulmonary hypertension (PH) worsens the prognosis of bronchopulmonary dysplasia (BPD). The following items have not been fully established for PH in BPD: clinical characterization, incidence of cardiovascular anomalies (CVAs), response to PH treatment, and outcome. STUDY DESIGN: A review of clinical records, computed tomography (CT) images and catheterization data of 36 patients with PH-BPD referred to our PH Unit (March 2006 to December 2011) was performed. Twenty-nine patients without major congenital heart defects and with complete follow-up data were included. RESULTS: The diagnosis of PH was made at a median age of 4.5 months (IQR 2.4-7.8), with an echocardiography estimated median right ventricular pressure/systemic pressure ratio of 70% (IQR 60-80%). CT scanning was performed in 21 patients and catheterization in 14 patients. CVAs were found in 19 patients (65.5%): aortopulmonary collaterals (n = 9), pulmonary vein stenosis (n = 7), ASD (n = 4), and PDA (n = 9). Hemodynamic data: PVRI 4.3 UW m(2) (2.7-7); PVRI/SVRI 0.44 (0.32-0.8); and transpulmonary gradient 28 mmHg (19-40). At a median follow-up of 35 months (IQR 21-91), 6 patients had undergone shunts closure, 22 received specific PH drugs, 3 spontaneously improved of their PH, and 8 (26%) had died. CONCLUSION: PH in BPD is not always a transient condition; it can be diagnosed at later stages and can have a protracted course. The incidence of associated CVAs is high. Prompt diagnosis, detection, and treatment of CVAs, and specific drug therapy can improve the outcome in these patients, although the mortality rate remains high.

Determinación de valores normalizados del desplazamiento sistólico del plano del anillo tricuspídeo (TAPSE) en 405 niños y adolescentes españoles / Determination of normalized values of the tricuspid annular plane systolic excursion (TAPSE) in 405 spanish children and adolescents

Introducción y objetivos. El desplazamiento sistólico del plano del anillo tricuspídeo (siglas en inglés, TAPSE) es una medida ecocardiográfica que permite evaluar adecuadamente la función sistólica del ventrículo derecho y se emplea habitualmente en adultos. No obstante, hay poca información sobre los valores de referencia de TAPSE en niños. Nuestro objetivo fue determinar valores de referencia de TAPSE en niños españoles y evaluar su relación con la edad y la superficie corporal. Métodos. Incluimos prospectivamente a 405 sujetos (neonatos hasta 18 años, el 53% varones) remitidos para evaluación de soplo cardiaco. Excluimos a los sujetos con cardiopatía o cualquier otra enfermedad. Recogimos la medida por modo M de TAPSE y variables antropométricas. Analizamos la reproducibilidad intraobservador e interobservadores de las mediciones. Resultados. El TAPSE medio fue 17,09±5,09cm, sin diferencias significativas entre sexos. Se demostró adecuado un modelo de regresión curvilínea, con valores incrementales proporcionales a los estratos de edad, talla, peso, índice de masa corporal y superficie corporal. La superficie corporal presentó una importante correlación positiva con los valores de TAPSE (r=0,81), mientras que la frecuencia mantuvo una correlación negativa (r=−0,74). El análisis multivariable confirmó estas correlaciones, así como las interacciones entre variables (edad, talla, peso, superficie corporal). Aportamos gráficas con las estimaciones poblacionales normales para TAPSE ajustadas por edad y superficie corporal. Conclusiones. Presentamos valores de referencia de TAPSE para población pediátrica española. La medida del TAPSE fue reproducible y se relacionó directamente con la edad y la superficie corporal. Estos valores de referencia podrían guiar la toma clínica de decisiones (AU)

Introduction and objectives. Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measure that allows us to assess right ventricular systolic function. TAPSE measurement is common in adults but reference values for children are scarce. Our objective was to establish reference values for TAPSE in Spanish children and to determine the relationship of these values with age and body surface. Methods. This prospective study included 405 patients (from newborn to age 18 years, 53% male) referred for assessment of cardiac murmurs. Patients with confirmed cardiac or any other disease were excluded. We collected TAPSE measurements by M-mode echocardiography and recorded anthropometric variables. We analyzed the intra- and interobserver reproducibility of these measurements. Results. Mean TAPSE values were 17.09±5.09cm with nonsignificant differences between sexes. A curvilinear regression model proved appropriate, with values increasing in proportion to age group, height, weight, body mass index, and body surface. Body surface showed a strong positive correlation with TAPSE values (r=0.81), whereas frequency had a negative correlation (r=–0.74). Multivariate analysis confirmed these correlations and the interactions between variables (age, height, weight, body surface). Graphs of estimated normal population-based TAPSE values adjusted by age and body surface are provided. Conclusions. We present reference values for TAPSE in Spanish children and adolescents. The TAPSE measurement was reproducible and associated directly with age and body surface. These reference values could guide decision making in daily clinical practice (AU)

Determination of normalized values of the tricuspid annular plane systolic excursion (TAPSE) in 405 Spanish children and adolescents.

INTRODUCTION AND OBJECTIVES: Tricuspid annular plane systolic excursion (TAPSE) is an echocardiographic measure that allows us to assess right ventricular systolic function. TAPSE measurement is common in adults but reference values for children are scarce. Our objective was to establish reference values for TAPSE in Spanish children and to determine the relationship of these values with age and body surface. METHODS: This prospective study included 405 patients (from newborn to age 18 years, 53% male) referred for assessment of cardiac murmurs. Patients with confirmed cardiac or any other disease were excluded. We collected TAPSE measurements by M-mode echocardiography and recorded anthropometric variables. We analyzed the intra- and interobserver reproducibility of these measurements. RESULTS: Mean TAPSE values were 17.09 ± 5.09 cm with nonsignificant differences between sexes. A curvilinear regression model proved appropriate, with values increasing in proportion to age group, height, weight, body mass index, and body surface. Body surface showed a strong positive correlation with TAPSE values (r = 0.81), whereas frequency had a negative correlation (r = -0.74). Multivariate analysis confirmed these correlations and the interactions between variables (age, height, weight, body surface). Graphs of estimated normal population-based TAPSE values adjusted by age and body surface are provided. CONCLUSIONS: We present reference values for TAPSE in Spanish children and adolescents. The TAPSE measurement was reproducible and associated directly with age and body surface. These reference values could guide decision making in daily clinical practice.