RESUMEN
The process of valve formation is a complex process that involves intricate interplay between various pathways at precise times. Although we have not completely elucidated the molecular pathways that lead to normal valve formation, we have identified a few major players in this process. We are now able to implicate TGF-ß, BMP, and NOTCH as suspects in tricuspid atresia (TA), as well as their downstream targets: NKX2-5, TBX5, NFATC1, GATA4, and SOX9. We know that the TGF-ß and the BMP pathways converge on the SMAD4 molecule, and we believe that this molecule plays a very important role to tie both pathways to TA. Similarly, we look at the NOTCH pathway and identify the HEY2 as a potential link between this pathway and TA. Another transcription factor that has been implicated in TA is NFATC1. While several mouse models exist that include part of the TA abnormality as their phenotype, no true mouse model can be said to represent TA. Bridging this gap will surely shed light on this complex molecular pathway and allow for better understanding of the disease process.
Asunto(s)
Modelos Animales de Enfermedad , Transducción de Señal , Atresia Tricúspide , Animales , Atresia Tricúspide/genética , Atresia Tricúspide/metabolismo , Atresia Tricúspide/patología , Humanos , Ratones , Corazón Univentricular/genética , Corazón Univentricular/metabolismo , Corazón Univentricular/fisiopatología , Corazón Univentricular/patología , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/genética , Receptores Notch/metabolismo , Receptores Notch/genéticaRESUMEN
Despite advances in both medical and surgical therapies, individuals with single ventricle heart disease (SV) remain at high risk for the development of heart failure (HF). However, the molecular mechanisms underlying remodeling and eventual HF in patients with SV are poorly characterized. Cardiolipin (CL), an inner mitochondrial membrane phospholipid, is critical for proper mitochondrial function, and abnormalities in CL content and composition are known in various cardiovascular disease etiologies. The purpose of this study was to investigate myocardial CL content and composition in failing and nonfailing single right ventricle (RV) samples compared with normal control RV samples, to assess mRNA expression of CL biosynthetic and remodeling enzymes, and to quantitate relative mitochondrial copy number. A cross-sectional analysis of RV myocardial tissue from 22 failing SV (SVHF), 9 nonfailing SV (SVNF), and 10 biventricular control samples (BVNF) was performed. Expression of enzymes involved in CL biosynthesis and remodeling were analyzed using RT-qPCR and relative mitochondrial DNA copy number determined by qPCR. Normal phase high-pressure liquid chromatography coupled to electrospray ionization mass spectrometry was used to quantitate total and specific CL species. While mitochondrial copy number was not significantly different between groups, total CL content was significantly lower in SVHF myocardium compared with BVNF controls. Despite having lower total CL content however, the relative percentage of the major tetralinoleoyl CL species is preserved in SVHF samples relative to BVNF controls. Correspondingly, expression of enzymes involved in CL biosynthesis and remodeling were upregulated in SVHF samples when compared with both SVNF samples and BVNF controls.NEW & NOTEWORTHY The mechanisms underlying heart failure in the single ventricle (SV) congenital heart disease population are largely unknown. In this study we identify alterations in cardiac cardiolipin metabolism, composition, and content in children with SV heart disease. These findings suggest that cardiolipin could be a novel therapeutic target in this unique population of patients.
Asunto(s)
Cardiolipinas/biosíntesis , Corazón Univentricular/metabolismo , Cardiolipinas/genética , Niño , Preescolar , ADN Mitocondrial/genética , Femenino , Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/patología , Humanos , Masculino , Mitocondrias Cardíacas/enzimología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Corazón Univentricular/genética , Remodelación VentricularRESUMEN
Because of remarkable surgical and medical advances over the past several decades, there are growing numbers of infants and children living with single ventricle congenital heart disease (SV), where there is only one functional cardiac pumping chamber. Nevertheless, cardiac dysfunction (and ultimately heart failure) is a common complication in the SV population, and pharmacological heart failure therapies have largely been ineffective in mitigating the need for heart transplantation. Given that there are several inherent risk factors for ventricular dysfunction in the setting of SV in addition to probable differences in molecular adaptations to heart failure between children and adults, it is perhaps not surprising that extrapolated adult heart failure medications have had limited benefit in children with SV heart failure. Further investigations into the molecular mechanisms involved in pediatric SV heart failure may assist with risk stratification as well as development of targeted, efficacious therapies specific to this patient population. In this review, we present a brief overview of SV anatomy and physiology, with a focus on patients with a single morphological right ventricle requiring staged surgical palliation. Additionally, we discuss outcomes in the current era, risk factors associated with the progression to heart failure, present state of knowledge regarding molecular alterations in end-stage SV heart failure, and current therapeutic interventions. Potential avenues for improving SV outcomes, including identification of biomarkers of heart failure progression, implications of personalized medicine and stem cell-derived therapies, and applications of novel models of SV disease, are proposed as future directions.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Corazón Univentricular/fisiopatología , Procedimiento de Blalock-Taussing/efectos adversos , Procedimiento de Blalock-Taussing/métodos , Puente Cardíaco Derecho/efectos adversos , Puente Cardíaco Derecho/métodos , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/cirugía , Ventrículos Cardíacos/anomalías , Humanos , Modelación Específica para el Paciente , Corazón Univentricular/genética , Corazón Univentricular/metabolismo , Corazón Univentricular/cirugíaRESUMEN
BACKGROUND: We assess whether the lower exercise tolerance in children with univentricular heart (UVH) after Fontan operation is associated with altered peripheral muscular and cerebral tissue oxygenation. METHODS: 18 children with UVH and 20 healthy subjects performed an incremental ramp exercise test. Changes in the cerebral and muscular pattern of oxygenated (O2Hb) and deoxygenated hemoglobin (HHb) and local tissue oxygenation (TOI) were analyzed by means of Near Infrared Spectroscopy (NIRS). Correlations between arterial saturation during exercise and tissue oxygenation were evaluated. RESULTS: In UVH, maximal oxygen consumption (VO2peak/kg, 28.9⯱â¯7.9 vs. 46.3⯱â¯11.9â¯ml/min/kg, Pâ¯<â¯0.001), heart rate (HRpeak, 168⯱â¯13 vs. 193⯱â¯12â¯bpm, Pâ¯<â¯0.001) and load (Ppeak, 73⯱â¯19 vs. 133⯱â¯68â¯W, Pâ¯<â¯0.001) were lower, VE/VCO2 slope was higher (34.5⯱â¯5.9 vs. 27.1⯱â¯3.9, Pâ¯<â¯0.001). A faster and steeper course up to the same level of HHb and absent increase in O2Hb was seen at cerebral level in UVH; tissue oxygenation index (TOI) demonstrated a steady decrease from the start of exercise. At the muscular level, HHb curve has a similar pattern compared to controls, with an early cessation. O2Hb has a similar pattern, but with early discontinuation at a higher O2Hb-level. Muscular TOI has the same course throughout exercise, starting from a lower level. Lower arterial saturation and higher age correlated with lower VO2peak; higher amplitude of muscular TOI and lower amplitude cerebral TOI correlated with higher VO2peak. CONCLUSION: Children after Fontan procedure have different oxygenation mechanisms at muscular and cerebral level. This reflects a different balance between O2 supply to O2 demand which might contribute to the reduced exercise tolerance in this patient population.