RESUMO
Cardiomyopathy is the predominant defect in Barth syndrome (BTHS) and is caused by a mutation of the X-linked Tafazzin (TAZ) gene, which encodes an enzyme responsible for remodeling mitochondrial cardiolipin. Despite the known importance of mitochondrial dysfunction in BTHS, how specific TAZ mutations cause diverse BTHS heart phenotypes remains poorly understood. We generated a patient-tailored CRISPR/Cas9 knock-in mouse allele (TazPM) that phenocopies BTHS clinical traits. As TazPM males express a stable mutant protein, we assessed cardiac metabolic dysfunction and mitochondrial changes and identified temporally altered cardioprotective signaling effectors. Specifically, juvenile TazPM males exhibit mild left ventricular dilation in systole but have unaltered fatty acid/amino acid metabolism and normal adenosine triphosphate (ATP). This occurs in concert with a hyperactive p53 pathway, elevation of cardioprotective antioxidant pathways, and induced autophagy-mediated early senescence in juvenile TazPM hearts. However, adult TazPM males exhibit chronic heart failure with reduced growth and ejection fraction, cardiac fibrosis, reduced ATP, and suppressed fatty acid/amino acid metabolism. This biphasic changeover from a mild-to-severe heart phenotype coincides with p53 suppression, downregulation of cardioprotective antioxidant pathways, and the onset of terminal senescence in adult TazPM hearts. Herein, we report a BTHS genotype/phenotype correlation and reveal that absent Taz acyltransferase function is sufficient to drive progressive cardiomyopathy.
Assuntos
Aciltransferases , Síndrome de Barth , Cardiomiopatias , Síndrome de Barth/genética , Síndrome de Barth/metabolismo , Síndrome de Barth/patologia , Animais , Camundongos , Aciltransferases/genética , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Masculino , Humanos , Mutação Puntual , Modelos Animais de Doenças , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , FenótipoRESUMO
The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49 years, mean of 35.8 vs. mean 32.6 years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality.
Assuntos
Insuficiência Cardíaca , Transposição dos Grandes Vasos , Humanos , Masculino , Adulto , Transposição dos Grandes Vasos/cirurgia , Seguimentos , Biomarcadores , Coração , Insuficiência Cardíaca/etiologia , Arritmias Cardíacas/etiologia , Artérias , PrognósticoRESUMO
The Pediatric Heart Network's Fontan Udenafil Exercise Longitudinal (FUEL) Trial (Mezzion Pharma Co. Ltd., NCT02741115) demonstrated improvements in some measures of exercise capacity and in the myocardial performance index following 6 months of treatment with udenafil (87.5 mg twice daily). In this post hoc analysis, we evaluate whether subgroups within the population experienced a differential effect on exercise performance in response to treatment. The effect of udenafil on exercise was evaluated within subgroups defined by baseline characteristics, including peak oxygen consumption (VO2), serum brain-type natriuretic peptide level, weight, race, gender, and ventricular morphology. Differences among subgroups were evaluated using ANCOVA modeling with fixed factors for treatment arm and subgroup and the interaction between treatment arm and subgroup. Within-subgroup analyses demonstrated trends toward quantitative improvements in peak VO2, work rate at the ventilatory anaerobic threshold (VAT), VO2 at VAT, and ventilatory efficiency (VE/VCO2) for those randomized to udenafil compared to placebo in nearly all subgroups. There was no identified differential response to udenafil based on baseline peak VO2, baseline BNP level, weight, race and ethnicity, gender, or ventricular morphology, although participants in the lowest tertile of baseline peak VO2 trended toward larger improvements. The absence of a differential response across subgroups in response to treatment with udenafil suggests that the treatment benefit may not be restricted to specific sub-populations. Further work is warranted to confirm the potential benefit of udenafil and to evaluate the long-term tolerability and safety of treatment and to determine the impact of udenafil on the development of other morbidities related to the Fontan circulation.Trial Registration NCT0274115.
Assuntos
Consumo de Oxigênio , Sulfonamidas , Humanos , Criança , Sulfonamidas/uso terapêutico , Exercício Físico , Pirimidinas/uso terapêutico , Teste de Esforço , Tolerância ao ExercícioRESUMO
Friedreich Ataxia (FA) is a rare and often fatal autosomal recessive disease in which a mitochondrial protein, frataxin (FXN), is severely reduced in all tissues. With loss of FXN, mitochondrial metabolism is severely disrupted. Multiple therapeutic approaches are in development, but a key limitation is the lack of biomarkers reflecting the activity of FXN in a timely fashion. We predicted this dysregulated metabolism would present a unique metabolite profile in blood of FA patients versus Controls (Con). Plasma from 10 FA and 11 age and sex matched Con subjects was analyzed by targeted mass spectrometry and untargeted NMR. This combined approach yielded quantitative measurements for 540 metabolites and found 59 unique metabolites (55 from MS and 4 from NMR) that were significantly different between cohorts. Correlation-based network analysis revealed several clusters of pathway related metabolites including a cluster associated with onecarbon (1C) metabolism composed of formate, sarcosine, hypoxanthine, and homocysteine. Receiver operator characteristics analyses demonstrated an excellent ability to discriminate between Con and FA with AUC values >0.95. These results are the first reported metabolomic analyses of human patients with FA. The metabolic perturbations, especially those related to 1C metabolism, may serve as a valuable biomarker panel of disease progression and response to therapy. The identification of dysregulated 1C metabolism may also inform the search for new therapeutic targets related to this pathway.
Assuntos
Ataxia de Friedreich , Biomarcadores/metabolismo , Carbono/metabolismo , Carbono/uso terapêutico , Ataxia de Friedreich/tratamento farmacológico , Ataxia de Friedreich/metabolismo , Humanos , Metabolômica , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismoRESUMO
BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.
Assuntos
Cardiopatias/tratamento farmacológico , Inibidores da Fosfodiesterase 5/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Adolescente , Criança , Método Duplo-Cego , Esquema de Medicação , Exercício Físico , Feminino , Técnica de Fontan , Cardiopatias/congênito , Cardiopatias/cirurgia , Frequência Cardíaca , Humanos , Masculino , Peptídeo Natriurético Encefálico/sangue , Consumo de Oxigênio , Inibidores da Fosfodiesterase 5/efeitos adversos , Efeito Placebo , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Trombose/diagnóstico , Trombose/etiologia , Resultado do TratamentoRESUMO
BACKGROUND: Children and young adults with single ventricle (SV) heart disease frequently develop heart failure (HF) that is intractable and difficult to treat. Our understanding of the molecular and biochemical reasons underlying this is imperfect. Thus, there is an urgent need for biomarkers that predict outcome and provide a rational basis for treatment, and advance our understanding of the basis of HF. OBJECTIVE: We sought to determine if a metabolomic approach would provide biochemical signatures of HF in SV children and young adults. If significant, these analytes might serve as biomarkers to predict outcome and inform on the biological mechanism(s) of HF. METHODS: We applied a multi-platform metabolomics approach composed of mass spectrometry (MS) and nuclear magnetic resonance (NMR) which yielded 495 and 26 metabolite measurements respectively. The plasma samples came from a cross-sectional set of young SV subjects, ages 2-19 years with ten control (Con) subjects and 16 SV subjects. Of the SV subjects, nine were diagnosed as congestive HF (SVHF), and 7 were not in HF. Metabolomic data were correlated with clinical status to determine if there was a signature associated with HF. RESULTS: There were no differences in age, height, weight or sex between the 3 cohorts. However, statistical analysis of the metabolomic profiles using ANOVA revealed 44 metabolites with significant differences between cohorts including 41 profiled by MS and 3 by NMR. These metabolites included acylcarnitines, amino acids, and bile acids, which distinguished Con from all SV subjects. Furthermore, metabolite profiles could distinguish between SV and SVHF subjects. CONCLUSION: These are the first data to demonstrate a clear metabolomic signature associated with HF in children and young adults with SV. Larger studies are warranted to determine if these findings are predictive of progression to HF in time to provide intervention.
Assuntos
Insuficiência Cardíaca , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Estudos Transversais , Insuficiência Cardíaca/diagnóstico , Humanos , Metaboloma , Metabolômica , Adulto JovemRESUMO
Children with Friedreich's ataxia (FA) are at risk of perioperative morbidity and mortality from severe unpredictable heart failure. There is currently no clear way of identifying patients at highest risk. We used myocardial perfusion reserve (MPR), an MRI technique used to assess the maximal myocardial blood flow above baseline, to help determine potential surgical risk in FA subjects. In total, seven children with genetically confirmed FA, ages 8-17 years, underwent MPR stress testing using regadenoson. Six of the seven demonstrated impaired endocardial perfusion during coronary hyperemia. The same six were also found to have evidence of ongoing myocardial damage as illustrated by cardiac troponin I leak (range 0.04-0.17 ng/mL, normal < 0.03 ng/mL). None of the patients had a reduced ejection fraction (range 59-74%) or elevated insulin level (range 2.46-14.23 mCU/mL). This retrospective study shows that children with FA develop MPR defects early in the disease process. It also suggests MPR may be a sensitive tool to evaluate underlying cardiac compromise and could be of use in directing surgical management decisions in children with FA.
Assuntos
Ataxia de Friedreich , Adolescente , Criança , Circulação Coronária , Humanos , Miocárdio , Perfusão , Estudos RetrospectivosRESUMO
Anticoagulation in children is problematic for multiple reasons. Currently used anticoagulants have significant disadvantages and may negatively affect quality of life (QOL). This manuscript describes the design, rationale, and methods of a prospective, randomized, open label phase II multi-national clinical trial of a direct oral anticoagulant (DOAC), apixaban, in children and infants with congenital and acquired heart disease. This trial is designed to gather preliminary safety and pharmacokinetics (PK) data, as well as generate data on QOL of individuals taking apixaban compared to the standard of care (SOC) anticoagulants vitamin K antagonists (VKA) or low molecular weight heparin (LMWH). A key issue this trial seeks to address is the practice of using therapeutics tested in adult trials in the pediatric population without robust pediatric safety or efficacy data. Pediatric heart diseases are not common, and specific diagnoses often meet the criteria of a rare disease; thus, statistical efficacy may be difficult to achieve. This trial will provide valuable PK and safety data intended to inform clinical practice for anticoagulation in pediatric heart diseases, a setting in which a fully powered phase III clinical trial is not feasible. A second consideration this trial addresses is that metrics besides efficacy, such as QOL, have not been traditionally used as endpoints in regulated anticoagulation studies yet may add substantial weight to the clinical decision for use of a DOAC in place of VKA or LMWH. This study examines QOL related to both heart disease and anticoagulation among children randomized to either SOC or apixaban. There are considerable strengths and benefits to conducting a clinical trial in pediatric rare disease populations via an industry-academic collaboration. The SAXOPHONE study represents a collaboration between Bristol-Myers Squibb (BMS)/Pfizer Alliance, and the National Heart, Lung, and Blood Institute's (NHLBI) Pediatric Heart Network (PHN) and may be an attractive model for future pediatric drug trials.
Assuntos
Ensaios Clínicos Fase I como Assunto , Inibidores do Fator Xa/efeitos adversos , Cardiopatias/tratamento farmacológico , Pirazóis/efeitos adversos , Piridonas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Adolescente , Anticoagulantes/uso terapêutico , Criança , Pré-Escolar , Inibidores do Fator Xa/farmacocinética , Feminino , Cardiopatias Congênitas/tratamento farmacológico , Cardiopatias/metabolismo , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Lactente , Masculino , Estudos Multicêntricos como Assunto , Estudos Prospectivos , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Piridonas/administração & dosagem , Piridonas/farmacocinética , Tamanho da Amostra , Vitamina K/antagonistas & inibidoresRESUMO
The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.
Assuntos
Terapia por Exercício/métodos , Exercício Físico/fisiologia , Técnica de Fontan , Cardiopatias Congênitas/terapia , Cuidados Pós-Operatórios/métodos , Pirimidinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Sulfonamidas/uso terapêutico , Humanos , Estudos Longitudinais , Inibidores da Fosfodiesterase 5/uso terapêuticoRESUMO
BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.
Assuntos
Débito Cardíaco/efeitos dos fármacos , Técnica de Fontan , Cardiopatias Congênitas/terapia , Ventrículos do Coração/fisiopatologia , Cuidados Pós-Operatórios/métodos , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Resistência Vascular/efeitos dos fármacos , Adolescente , Relação Dose-Resposta a Droga , Esquema de Medicação , Ecocardiografia , Feminino , Seguimentos , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/anormalidades , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Inibidores da Fosfodiesterase 5/administração & dosagem , Inibidores da Fosfodiesterase 5/farmacocinética , Circulação Pulmonar/efeitos dos fármacos , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Fatores de Tempo , Resultado do TratamentoRESUMO
There is an intimate interplay between cellular metabolism and the pathophysiology of disease. Mitochondria are essential to maintaining and regulating metabolic function of cells and organs. Mitochondrial dysfunction is implicated in diverse diseases, such as cardiovascular disease, diabetes and metabolic syndrome, neurodegeneration, cancer, and aging. Multiple reversible post-translational protein modifications are located in the mitochondria that are responsive to nutrient availability and redox conditions, and which can act in protein-protein interactions to modify diverse mitochondrial functions. Included in this are physiologic redox signaling via reactive oxygen and nitrogen species, phosphorylation, O-GlcNAcylation, acetylation, and succinylation, among others. With the advent of mass proteomic screening techniques, there has been a vast increase in the array of known mitochondrial post-translational modifications and their protein targets. The functional significance of these processes in disease etiology, and the pathologic response to their disruption, are still under investigation. However, many of these reversible modifications act as regulatory mechanisms in mitochondria and show promise for mitochondrial-targeted therapeutic strategies. This review addresses the current knowledge of post-translational processing and signaling mechanisms in mitochondria, and their implications in health and disease.
Assuntos
Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Animais , Humanos , Lisina/metabolismo , OxirreduçãoRESUMO
Alterations in mitochondrial protein acetylation are implicated in the pathophysiology of diabetes, the metabolic syndrome, mitochondrial disorders, and cancer. However, a viable mechanism responsible for the widespread acetylation in mitochondria remains unknown. Here, we demonstrate that the physiologic pH and acyl-CoA concentrations of the mitochondrial matrix are sufficient to cause dose- and time-dependent, but enzyme-independent acetylation and succinylation of mitochondrial and nonmitochondrial proteins in vitro. These data suggest that protein acylation in mitochondria may be a chemical event facilitated by the alkaline pH and high concentrations of reactive acyl-CoAs present in the mitochondrial matrix. Although these results do not exclude the possibility of enzyme-mediated protein acylation in mitochondria, they demonstrate that such a mechanism may not be required in its unique chemical environment. These findings may have implications for the evolutionary roles that the mitochondria-localized SIRT3 deacetylase and SIRT5 desuccinylase have in the maintenance of metabolic health.
Assuntos
Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Succinatos/metabolismo , Acetilação , Sequência de Aminoácidos , Animais , Catálise , Coenzima A/metabolismo , Biologia Computacional , Concentração de Íons de Hidrogênio , Hidróxidos/metabolismo , Cinética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/química , Dados de Sequência Molecular , Sirtuína 3/metabolismoRESUMO
Friedreich's ataxia (FRDA) is the most common inherited human ataxia and is caused by a deficiency in the mitochondrial protein frataxin. Clinically, patients suffer from progressive spinocerebellar degeneration, diabetes and a fatal cardiomyopathy, associated with mitochondrial respiratory chain defects. Recent findings have shown that lysine acetylation regulates mitochondrial function and intermediary metabolism. However, little is known about lysine acetylation in the setting of pathologic energy stress and mitochondrial dysfunction. We tested the hypothesis that the respiratory chain defects in frataxin deficiency alter mitochondrial protein acetylation. Using two conditional mouse models of FRDA, we demonstrate marked hyperacetylation of numerous cardiac mitochondrial proteins. Importantly, this biochemical phenotype develops concurrently with cardiac hypertrophy and is caused by inhibition of the NAD(+)-dependent SIRT3 deacetylase. This inhibition is caused by an 85-fold decrease in mitochondrial NAD(+)/NADH and direct carbonyl group modification of SIRT3, and is reversed with excess SIRT3 and NAD(+) in vitro. We further demonstrate that protein hyperacetylation may be a common feature of mitochondrial disorders caused by respiratory chain defects, notably, cytochrome oxidase I (COI) deficiency. These findings suggest that SIRT3 inhibition and consequent protein hyperacetylation represents a negative feedback mechanism limiting mitochondrial oxidative pathways when respiratory metabolism is compromised, and thus, may contribute to the lethal cardiomyopathy in FRDA.
Assuntos
Ataxia de Friedreich/metabolismo , Proteínas de Ligação ao Ferro/metabolismo , Mitocôndrias Cardíacas/metabolismo , Sirtuína 3/metabolismo , Acetilação , Animais , Western Blotting , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Retroalimentação Fisiológica , Feminino , Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Humanos , Proteínas de Ligação ao Ferro/genética , Masculino , Camundongos , Camundongos Knockout , Proteínas Mitocondriais/metabolismo , Modelos Biológicos , Miocárdio/metabolismo , NAD/metabolismo , Estresse Oxidativo , FrataxinaRESUMO
Friedreich's ataxia (FRDA) is the most common inherited human ataxia and results from a deficiency of the mitochondrial protein, frataxin (FXN), which is encoded in the nucleus. This deficiency is associated with an iron-sulfur (Fe-S) cluster enzyme deficit leading to progressive ataxia and a frequently fatal cardiomyopathy. There is no cure. To determine whether exogenous replacement of the missing FXN protein in mitochondria would repair the defect, we used the transactivator of transcription (TAT) protein transduction domain to deliver human FXN protein to mitochondria in both cultured patient cells and a severe mouse model of FRDA. A TAT-FXN fusion protein bound iron in vitro, transduced into mitochondria of FRDA deficient fibroblasts and reduced caspase-3 activation in response to an exogenous iron-oxidant stress. Injection of TAT-FXN protein into mice with a conditional loss of FXN increased their growth velocity and mean lifespan by 53% increased their mean heart rate and cardiac output, increased activity of aconitase and reversed abnormal mitochondrial proliferation and ultrastructure in heart. These results show that a cell-penetrant peptide is capable of delivering a functional mitochondrial protein in vivo to rescue a very severe disease phenotype, and present the possibility of TAT-FXN as a protein replacement therapy.
Assuntos
Modelos Animais de Doenças , Ataxia de Friedreich/prevenção & controle , Produtos do Gene tat/fisiologia , Coração/fisiologia , Proteínas de Ligação ao Ferro/fisiologia , Longevidade/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Aconitato Hidratase/metabolismo , Animais , Caspase 3/metabolismo , Células Cultivadas , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Ataxia de Friedreich/mortalidade , Ataxia de Friedreich/patologia , Humanos , Integrases/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Camundongos Knockout , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Estresse Oxidativo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Taxa de Sobrevida , Transativadores/genética , FrataxinaRESUMO
BACKGROUND: Fontan-associated liver disease (FALD) refers to structural and functional changes of the liver caused by the physiology of the Fontan palliation. Currently, liver biopsy is the gold standard to assess liver fibrosis of FALD. AIM: Investigate biomarkers correlating with severity of liver biopsy fibrosis in FALD. METHODS: A retrospective study of post-Fontan patients ≥ 10 years of age who underwent liver biopsy was conducted. Advanced liver disease (ALD) was defined as bridging fibrosis and/or cirrhosis on liver biopsy. AST-to-platelet ratio index (APRI), Fibrosis-4 (FIB-4) and Liver Stiffness Measurement (LSM) from FibroScan were used as non-invasive fibrosis scores. RESULTS: Sixty-six patients (26/47; 55.3% adults and 13/19 children; 68.4%) had ALD on biopsy. ALD was associated with lower platelet count (151 vs. 198 K/uL, p = 0.003), higher APRI (0.64 vs. 0.32, p = 0.01), higher FIB-4 (0.64 vs. 0.32, p = 0.02). Liver fibrosis score correlated with APRI (0.34, p = 0.02) and FIB-4 (0.47, p = 0.001) in adults. LSM had a high sensitivity at 81.3% with 45.5% specificity at a cut-off 18.5 kPa. CONCLUSIONS: APRI and FIB-4 had modest discrimination to identify adults with advanced liver disease, but not children, indicating that these values may be followed as a marker of FALD progression in older patients.
Assuntos
Biomarcadores , Técnicas de Imagem por Elasticidade , Técnica de Fontan , Hipertensão Portal , Cirrose Hepática , Fígado , Humanos , Masculino , Hipertensão Portal/etiologia , Hipertensão Portal/sangue , Feminino , Estudos Retrospectivos , Cirrose Hepática/etiologia , Cirrose Hepática/sangue , Cirrose Hepática/patologia , Adulto , Biomarcadores/sangue , Criança , Técnica de Fontan/efeitos adversos , Adolescente , Contagem de Plaquetas , Adulto Jovem , Fígado/patologia , Fígado/diagnóstico por imagem , Biópsia , Índice de Gravidade de Doença , Aspartato Aminotransferases/sangue , Pessoa de Meia-IdadeRESUMO
To reduce study start-up time, increase data sharing, and assist investigators conducting clinical studies, the National Institute of Neurological Disorders and Stroke embarked on an initiative to create common data elements for neuroscience clinical research. The Common Data Element Team developed general common data elements, which are commonly collected in clinical studies regardless of therapeutic area, such as demographics. In the present project, we applied such approaches to data collection in Friedreich's ataxia (FRDA), a neurological disorder that involves multiple organ systems. To develop FRDA common data elements, FRDA experts formed a working group and subgroups to define elements in the following: ataxia and performance measures; biomarkers; cardiac and other clinical outcomes; and demographics, laboratory tests, and medical history. The basic development process included identification of international experts in FRDA clinical research, meeting by teleconference to develop a draft of standardized common data elements recommendations, vetting of recommendations across the subgroups, and dissemination of recommendations to the research community for public comment. The full recommendations were published online in September 2011 at http://www.commondataelements.ninds.nih.gov/FA.aspx. The subgroups' recommendations are classified as core, supplemental, or exploratory. Template case report forms were created for many of the core tests. The present set of data elements should ideally lead to decreased initiation time for clinical research studies and greater ability to compare and analyze data across studies. Their incorporation into new, ongoing studies will be assessed in an ongoing fashion to define their utility in FRDA.
Assuntos
Pesquisa Biomédica/estatística & dados numéricos , Interpretação Estatística de Dados , Ataxia de Friedreich/terapia , National Institute of Neurological Disorders and Stroke (USA) , Centros Médicos Acadêmicos , Biomarcadores , Coleta de Dados , Bases de Dados Factuais , Demografia , Ataxia de Friedreich/classificação , Ataxia de Friedreich/diagnóstico , Cardiopatias/etiologia , Humanos , Cooperação Internacional , National Institutes of Health (U.S.) , Exame Neurológico , Neurologia/estatística & dados numéricos , Desempenho Psicomotor/fisiologia , Padrões de Referência , Telecomunicações , Terminologia como Assunto , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages. OBJECTIVES: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease. METHODS: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis. PRIMARY ENDPOINT: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy. RESULTS: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels. CONCLUSIONS: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472).
Assuntos
Fibrinolíticos , Cardiopatias , Tromboembolia Venosa , Criança , Humanos , Recém-Nascido , Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Cardiopatias/complicações , Hemorragia/induzido quimicamente , Heparina de Baixo Peso Molecular , Piridonas/uso terapêutico , Qualidade de Vida , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Vitamina KRESUMO
Importance: Data are limited regarding adverse reactions after COVID-19 vaccination in patients with a history of multisystem inflammatory syndrome in children (MIS-C). The lack of vaccine safety data in this unique population may cause hesitancy and concern for many families and health care professionals. Objective: To describe adverse reactions following COVID-19 vaccination in patients with a history of MIS-C. Design, Setting, and Participants: In this multicenter cross-sectional study including 22 North American centers participating in a National Heart, Lung, and Blood Institute, National Institutes of Health-sponsored study, Long-Term Outcomes After the Multisystem Inflammatory Syndrome in Children (MUSIC), patients with a prior diagnosis of MIS-C who were eligible for COVID-19 vaccination (age ≥5 years; ≥90 days after MIS-C diagnosis) were surveyed between December 13, 2021, and February 18, 2022, regarding COVID-19 vaccination status and adverse reactions. Exposures: COVID-19 vaccination after MIS-C diagnosis. Main Outcomes and Measures: The main outcome was adverse reactions following COVID-19 vaccination. Comparisons were made using the Wilcoxon rank sum test for continuous variables and the χ2 or Fisher exact test for categorical variables. Results: Of 385 vaccine-eligible patients who were surveyed, 185 (48.1%) received at least 1 vaccine dose; 136 of the vaccinated patients (73.5%) were male, and the median age was 12.2 years (IQR, 9.5-14.7 years). Among vaccinated patients, 1 (0.5%) identified as American Indian/Alaska Native, non-Hispanic; 9 (4.9%) as Asian, non-Hispanic; 45 (24.3%) as Black, non-Hispanic; 59 (31.9%) as Hispanic or Latino; 53 (28.6%) as White, non-Hispanic; 2 (1.1%) as multiracial, non-Hispanic; and 2 (1.1%) as other, non-Hispanic; 14 (7.6%) had unknown or undeclared race and ethnicity. The median time from MIS-C diagnosis to first vaccine dose was 9.0 months (IQR, 5.1-11.9 months); 31 patients (16.8%) received 1 dose, 142 (76.8%) received 2 doses, and 12 (6.5%) received 3 doses. Almost all patients received the BNT162b2 vaccine (347 of 351 vaccine doses [98.9%]). Minor adverse reactions were observed in 90 patients (48.6%) and were most often arm soreness (62 patients [33.5%]) and/or fatigue (32 [17.3%]). In 32 patients (17.3%), adverse reactions were treated with medications, most commonly acetaminophen (21 patients [11.4%]) or ibuprofen (11 [5.9%]). Four patients (2.2%) sought medical evaluation, but none required testing or hospitalization. There were no patients with any serious adverse events, including myocarditis or recurrence of MIS-C. Conclusions and Relevance: In this cross-sectional study of patients with a history of MIS-C, no serious adverse events were reported after COVID-19 vaccination. These findings suggest that the safety profile of COVID-19 vaccination administered at least 90 days following MIS-C diagnosis appears to be similar to that in the general population.
Assuntos
COVID-19 , Doenças do Tecido Conjuntivo , Estados Unidos/epidemiologia , Criança , Humanos , Masculino , Pré-Escolar , Feminino , Vacinas contra COVID-19/efeitos adversos , Vacina BNT162 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Estudos Transversais , Vacinação/efeitos adversosRESUMO
Bone morphogenetic protein 10 (BMP10) belongs to the TGFß-superfamily. Previously, we had demonstrated that BMP10 is a key regulator for ventricular chamber formation, growth, and maturation. Ablation of BMP10 leads to hypoplastic ventricular wall formation, and elevated levels of BMP10 are associated with abnormal ventricular trabeculation/compaction and wall maturation. However, the molecular mechanism(s) by which BMP10 regulates ventricle wall growth and maturation is still largely unknown. In this study, we sought to identify the specific transcriptional network that is potentially mediated by BMP10. We analyzed and compared the gene expression profiles between α-myosin heavy chain (αMHC)-BMP10 transgenic hearts and nontransgenic littermate controls using Affymetrix mouse exon arrays. T-box 20 (Tbx20), a cardiac transcription factor, was significantly up-regulated in αMHC-BMP10 transgenic hearts, which was validated by quantitative RT-PCR and in situ hybridization. Ablation of BMP10 reduced Tbx20 expression specifically in the BMP10-expressing region of the developing ventricle. In vitro promoter analysis demonstrated that BMP10 was able to induce Tbx20 promoter activity through a conserved Smad binding site in the Tbx20 promoter proximal region. Furthermore, overexpression of Tbx20 in myocardium led to dilated cardiomyopathy that exhibited ventricular hypertrabeculation and an abnormal muscular septum, which phenocopied genetically modified mice with elevated BMP10 levels. Taken together, our findings demonstrate that the BMP10-Tbx20 signaling cascade is important for ventricular wall development and maturation.
Assuntos
Proteínas Morfogenéticas Ósseas/biossíntese , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Ventrículos do Coração/embriologia , Transdução de Sinais/fisiologia , Proteínas com Domínio T/metabolismo , Animais , Proteínas Morfogenéticas Ósseas/genética , Cardiomiopatia Dilatada/embriologia , Cardiomiopatia Dilatada/genética , Cardiomiopatia Dilatada/patologia , Comunicação Interventricular/embriologia , Comunicação Interventricular/genética , Comunicação Interventricular/patologia , Ventrículos do Coração/patologia , Camundongos , Camundongos Transgênicos , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Elementos de Resposta/fisiologia , Proteínas com Domínio T/genética , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo , Septo Interventricular/embriologia , Septo Interventricular/patologiaRESUMO
Friedreich Ataxia (FRDA) is an autosomal recessive disease in which a mitochondrial protein, frataxin, is severely decreased in its expression. In addition to progressive ataxia, patients with FRDA often develop a cardiomyopathy that can be hypertrophic. This cardiomyopathy is unlike the sarcomeric hypertrophic cardiomyopathies in that the hypertrophy is associated with massive mitochondrial proliferation within the cardiomyocyte rather than contractile protein overexpression. This is associated with atrial arrhythmias, apoptosis, and fibrosis over time, and patients often develop heart failure leading to premature death. The differences between this mitochondrial cardiomyopathy and the more common contractile protein hypertrophic cardiomyopathies can be a source of misunderstanding in the management of these patients. Although imaging studies have revealed much about the structure and function of the heart in this disease, we still lack an understanding of many important clinical and fundamental molecular events that determine outcome of the heart in FRDA. This review will describe the current basic and clinical understanding of the FRDA heart, and most importantly, identify major gaps in our knowledge that represent new directions and opportunities for research.