Análisis del papel de las pruebas de esfuerzo y el impacto de la rehabilitación cardiopulmonar sobre los pacientes pediátricos con cardiopatías congénitas

INTRODUCCIÓN Y OBJETIVOS El avance del conocimiento y las técnicas quirúrgicas en el campo de las cardiopatías congénitas ha producido un incremento significativo en la supervivencia en los niños con cardiopatías congénitas. Esto ha ocasionado un cambio de paradigma, superando el problema de la mortalidad y apuntando hacia mejorar la calidad de vida. Con este último propósito se han realizado múltiples trabajos encaminados conseguir los beneficios de la rehabilitación cardiaca, para los pacientes pediátricos con cardiopatías congénitas. El presente trabajo consta de dos partes. En la primera se pretende evaluar el papel que tienen las pruebas de esfuerzo en los pacientes con cardiopatías congénitas, estudiando las diferencias entre ellos y la población sana, y definiendo los valores de normalidad en población pediátrica. En la segunda parte se pretende estudiar el impacto de un programa de rehabilitación cardiopulmonar sobre la calidad de vida, capacidad aeróbica, fuerza muscular respiratoria y periférica, y perfil metabolómico en orina de los pacientes pediátricos con cardiopatías congénitas. MÉTODOS Se realizó un reclutamiento prospectivo de 364 pacientes pediátricos remitidos al laboratorio de esfuerzo pediátrico del H. La Fe entre 2017 y 2020, 107 sujetos sanos, 171 pacientes con cardiopatías congénitas, y 64 pacientes con otras patologías. Se realizó una comparación entre los sujetos sanos y las cardiopatías congénitas, y se modelizó el comportamiento de cada una de las variables de la prueba de esfuerzo en los sujetos sanos. Se seleccionaron 15 pacientes con cardiopatías congénitas y afectación de la capacidad aeróbica, incluyéndolos en un programa de rehabilitación cardiopulmonar integral. Se analizó el impacto de dicho programa sobre la calidad de vida medida mediante los cuestionarios PedsQL. Se evaluó el efecto sobre la capacidad aeróbica mediante pruebas de esfuerzo cardiopulmonar. Se estudió el impacto sobre la fuerza muscular medida con dinamometría. Por último se analizó el perfil metabolómico en orina mediante cromatografía líquida de alta resolución acoplada a espectrometría de masas y análisis metabolómico. RESULTADOS Los pacientes con cardiopatías congénitas presentaron una disminución significativa de la capacidad aeróbica y de ejercicio, así como de la capacidad pulmonar, con respecto a sus homólogos sanos. Se describieron las curvas percentiladas y ecuaciones predictivas de los valores de normalidad de las pruebas de esfuerzo en pacientes pediátricos sanos. Se observó, en los pacientes incluidos en el programa de rehabilitación, un incremento de la percepción de bienestar físico y psicológico informada por los padres, y un incremento de la percepción de salud y autoimagen en los pacientes. Asimismo, se evidenció un incremento en esfuerzo máximo del consumo de oxígeno, la ventilación minuto, y la carga máxima alcanzada. Se objetivó un incremento de la distancia recorrida en el test 6 minutos marcha, así como una mejoría de la percepción de fatiga muscular en esta prueba. Se observó un incremento de la fuerza muscular periférica de bíceps, tríceps sural, cuádriceps, y prensión manual. Se evidenció una asociación entre el entrenamiento y las variaciones del perfil metabolómico, destacando el aumento significativo de metabolitos relacionados con la síntesis de triptófano, aminoácido esencial para la síntesis de masa muscular, y relacionado con funciones neurocognitivas y motoras

Cardiopulmonary Rehabilitation Improves Respiratory Muscle Function and Functional Capacity in Children with Congenital Heart Disease : A Prospective Cohort Study

Critical surgical and medical advances have shifted the focus of congenital heart disease (CHD) patients from survival to achievement of a greater health-related quality of life (HRQoL). HRQoL is influenced, amongst other factors, by aerobic capacity and respiratory muscle strength, both of which are reduced in CHD patients. This study evaluates the influence of a cardiopulmonary rehabilitation program (CPRP) on respiratory muscle strength and functional capacity. Fifteen CHD patients, ages 12 to 16, with reduced aerobic capacity in cardiopulmonary exercise testing (CPET) were enrolled in a CPRP involving strength and aerobic training for three months. Measurements for comparison were obtained at the start, end, and six months after the CPRP. A significant improvement of inspiratory muscle strength was evidenced (maximum inspiratory pressure 21 cm H2O, 23%, p < 0.01). The six-minute walking test showed a statistically and clinically significant rise in walked distance (48 m, p < 0.01) and a reduction in muscle fatigue (1.7 out of 10 points, p = 0.017). These results suggest CPRP could potentially improve respiratory muscle function and functional capacity, with lasting results, in children with congenital heart disease, but additional clinical trials must be conducted to confirm this finding

Extracellular Vesicles Secreted by Hypoxic AC10 Cardiomyocytes Modulate Fibroblast Cell Motility

Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM-EVs to cardiac remodeling after an ischemic insult

miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia

[EN] Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are an emerging alternative to cell-based therapies to treat many diseases. However, the complexity of producing homogeneous populations of EVs in sufficient amount hampers their clinical use. To address these limitations, we immortalized dental pulp-derived MSC using a human telomerase lentiviral vector and investigated the cardioprotective potential of a hypoxia-regulated EV-derived cargo microRNA, miR-4732-3p. We tested the compared the capacity of a synthetic miR-4732-3p mimic with EVs to confer protection to cardiomyocytes, fibroblasts and endothelial cells against oxygen-glucose deprivation (OGD). Results showed that OGD-induced cardiomyocytes treated with either EVs or miR-4732-3p showed prolonged spontaneous beating, lowered ROS levels, and less apoptosis. Transfection of the miR-4732-3p mimic was more effective than EVs in stimulating angiogenesis in vitro and in vivo and in reducing fibroblast differentiation upon transforming growth factor beta treatment. Finally, the miR-4732-3p mimic reduced scar tissue and preserved cardiac function when transplanted intramyocardially in infarcted nude rats. Overall, these results indicate that miR-4732-3p is regulated by hypoxia and exerts cardioprotective actions against ischemic insult, with potential application in cell-free-based therapeutic strategies.This work was supported in part by grants from the Instituto de Salud Carlos III PI19/0245, RD16/0011/0004, cofunded by FEDER Una manera de hacer Europa and INNCON-2020-6-CARVEMO from Agencia Valenciana de la Innovación. This work was also supported by predoctoral fellowships to RS-S, MG-F, IR, and MB grants ACIF/2017/318, ACIF/2018/254, ACIF2019/257, and ACIF2019/250 from the Conselleria de Sanitat Universal i Salut Pública and co-financed by the European Union through the Operational Programme European Regional Development Fund (FEDER) of the Valencian Community 2014 2020.Sánchez-Sánchez, R.; Gómez-Ferrer, M.; Reinal-Ferre, I.; Buigues, M.; Villanueva-Bádenas, E.; Ontoria-Oviedo, I.; Hernándiz, A.... (2021). miR-4732-3p in Extracellular Vesicles From Mesenchymal Stromal Cells Is Cardioprotective During Myocardial Ischemia. Frontiers in Cell and Developmental Biology. 9. https://doi.org/10.3389/fcell.2021.734143

Effects of Cardiopulmonary Rehabilitation on the Muscle Function of Children with Congenital Heart Disease : A Prospective Cohort Study

Critical medical and surgical advances have led to a shift in the care and management of children with congenital heart disease (CHD). These patients present with muscle deconditioning, which negatively influences their response to exercise, functional capacities, and quality of life. This study evaluates the influence of a cardiopulmonary rehabilitation program (CPRP) on the function of peripheral musculature of children with CHD. A single-center prospective cohort study was designed. Fifteen CHD subjects, between 12 and 16 years of age, with reduced aerobic capacity on a cardiopulmonary exercise test, were included in a three-month, 24-session CPRP. Measurements of the subjects' handgrip strength, biceps brachii and quadriceps femoris strength, and triceps surae fatigue process were collected at the beginning of the program, after completion, and six months after the end of the intervention. A substantial and statistically significant improvement was observed in the subjects' handgrip strength (kg) (p < 0.001), biceps brachii and quadriceps femoris strength (N) (p < 0.001), as well as triceps surae fatigue process (repetitions) (p = 0.018), with a maintenance of the results six months after the intervention. These results suggest that a CPRP could potentially improve the peripheral muscle function of children with CHD. Additional research is needed to confirm and expand on this hypothesis

Effects of Cardiopulmonary Rehabilitation on the Muscle Function of Children with Congenital Heart Disease: A Prospective Cohort Study

Critical medical and surgical advances have led to a shift in the care and management of children with congenital heart disease (CHD). These patients present with muscle deconditioning, which negatively influences their response to exercise, functional capacities, and quality of life. This study evaluates the influence of a cardiopulmonary rehabilitation program (CPRP) on the function of peripheral musculature of children with CHD. A single-center prospective cohort study was designed. Fifteen CHD subjects, between 12 and 16 years of age, with reduced aerobic capacity on a cardiopulmonary exercise test, were included in a three-month, 24-session CPRP. Measurements of the subjects’ handgrip strength, biceps brachii and quadriceps femoris strength, and triceps surae fatigue process were collected at the beginning of the program, after completion, and six months after the end of the intervention. A substantial and statistically significant improvement was observed in the subjects’ handgrip strength (kg) (p &lt; 0.001), biceps brachii and quadriceps femoris strength (N) (p &lt; 0.001), as well as triceps surae fatigue process (repetitions) (p = 0.018), with a maintenance of the results six months after the intervention. These results suggest that a CPRP could potentially improve the peripheral muscle function of children with CHD. Additional research is needed to confirm and expand on this hypothesis

Extracellular Vesicles Secreted by Hypoxic AC10 Cardiomyocytes Modulate Fibroblast Cell Motility

[EN] Extracellular vesicles (EVs) are small membrane vesicles secreted by most cell types with important roles in cell-to-cell communication. To assess their relevance in the context of heart ischemia, EVs isolated from the AC10 ventricular cardiomyocyte cell line (CM-EVs), exposed to normoxia (Nx) or hypoxia (Hx), were incubated with fibroblasts (Fb) and endothelial cells (EC). CM-EVs were studied using electron microscopy, nanoparticle tracking analysis (NTA), western blotting and proteomic analysis. Results showed that EVs had a strong preference to be internalized by EC over fibroblasts, suggesting an active exosome-based communication mechanism between CM and EC in the heart. In Matrigel tube-formation assays, Hx CM-EVs were inferior to Nx CM-EVs in angiogenesis. By contrast, in a wound-healing assay, wound closure was faster in fibroblasts treated with Hx CM-EVs than with Nx CM-EVs, supporting a pro-fibrotic effect of Hx CM-EVs. Overall, these observations were consistent with the different protein cargoes detected by proteomic analysis under Nx and Hx conditions and the biological pathways identified. The paracrine crosstalk between CM-EVs, Fb, and EC in different physiological conditions could account for the contribution of CM-EVs to cardiac remodeling after an ischemic insult.This work was supported by grants PI16/0107 and RETICS Program (RD16/0011/0004) from Instituto de Salud Carlos III cofunded by the European Regional Development Fund ERDF una manera de hacer Europa. The proteomic studies were carried out in the University of Valencia Proteomics Unit, a member of the ISCIII ProteoRed Proteomics Platform. The bioinformatics analysis was performed in the Bioinformatic and Biostatistics Unit of the Principe Felipe Research Center using the computational infrastructure supported by ERDF.Ontoria-Oviedo, I.; Dorronsoro, A.; Sánchez, R.; Ciria, M.; Gómez-Ferrer, M.; Buiges, M.; Grueso, E.... (2018). Extracellular Vesicles Secreted by Hypoxic AC10 Cardiomyocytes Modulate Fibroblast Cell Motility. Frontiers in Cardiovascular Medicine. 5. https://doi.org/10.3389/fcvm.2018.00152

MicroRNA-4732-3p Is Dysregulated in Breast Cancer Patients with Cardiotoxicity, and Its Therapeutic Delivery Protects the Heart from Doxorubicin-Induced Oxidative Stress in Rats

Anthracycline-induced cardiotoxicity is the most severe collateral effect of chemotherapy originated by an excess of oxidative stress in cardiomyocytes that leads to cardiac dysfunction. We assessed clinical data from patients with breast cancer receiving anthracyclines and searched for discriminating microRNAs between patients that developed cardiotoxicity (cases) and those that did not (controls), using RNA sequencing and regression analysis. Serum levels of 25 microRNAs were differentially expressed in cases versus controls within the first year after anthracycline treatment, as assessed by three different regression models (elastic net, Robinson and Smyth exact negative binomial test and random forest). MiR-4732-3p was the only microRNA identified in all regression models and was downregulated in patients that experienced cardiotoxicity. MiR-4732-3p was also present in neonatal rat cardiomyocytes and cardiac fibroblasts and was modulated by anthracycline treatment. A miR-4732-3p mimic was cardioprotective in cardiac and fibroblast cultures, following doxorubicin challenge, in terms of cell viability and ROS levels. Notably, administration of the miR-4732-3p mimic in doxorubicin-treated rats preserved cardiac function, normalized weight loss, induced angiogenesis, and decreased apoptosis, interstitial fibrosis and cardiac myofibroblasts. At the molecular level, miR-4732-3p regulated genes of TGFβ and Hippo signaling pathways. Overall, the results indicate that miR-4732-3p is a novel biomarker of cardiotoxicity that has therapeutic potential against anthracycline-induced heart damage

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589