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BACKGROUND: The annual administration of the influenza vaccine is the most effective method for preventing influenza. We have evaluated the effectiveness of the inactivated influenza vaccine in children aged 6 months to 15 years across the seasons from 2013/2014 to 2022/2023. This study aims to investigate the effectiveness of the inactivated influenza vaccine in the 2023/2024 season, the first year following the easing of strict COVID-19 measures, and possibly the last season when only the inactivated vaccine is available on the market. METHODS: Adjusted vaccine effectiveness for the 2023/2024 season was assessed using a test-negative case-control design, with results based on polymerase chain reaction and rapid influenza diagnostic tests. Vaccine effectiveness was calculated by influenza type and patient hospitalization/outpatient status. RESULTS: A total of 1832 children were recruited. The inactivated influenza vaccine was effective in preventing both symptomatic influenza A and B in both inpatient and outpatient settings. Overall vaccine effectiveness for influenza A was 51% (95% confidence interval [CI], 23%-69%, n = 930) in inpatient settings and 54% (95%CI, 27%-71%, n = 559) in outpatient settings. For influenza B, effectiveness was 60% (95%CI, 22%-79%, n = 859) in inpatient settings and 56% (95%CI, 26%-74%, n = 558) in outpatient settings. Analysis suggested that administering two doses enhanced effectiveness specifically against influenza B. CONCLUSIONS: This is the first study to demonstrate influenza vaccine effectiveness in children after the relaxation of strict COVID-19 measures in Japan (2023/2024). We recommend the current inactivated vaccine for preventing both influenza A and B in children, with consideration for the potential use of two doses to enhance effectiveness against influenza B.
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COVID-19 , Vacunas contra la Influenza , Gripe Humana , Eficacia de las Vacunas , Vacunas de Productos Inactivados , Humanos , Vacunas contra la Influenza/inmunología , Vacunas contra la Influenza/administración & dosificación , Niño , Gripe Humana/prevención & control , Gripe Humana/inmunología , COVID-19/prevención & control , COVID-19/inmunología , COVID-19/epidemiología , Preescolar , Vacunas de Productos Inactivados/inmunología , Vacunas de Productos Inactivados/administración & dosificación , Masculino , Adolescente , Femenino , Lactante , Estudios de Casos y Controles , SARS-CoV-2/inmunología , Virus de la Influenza B/inmunología , Estaciones del Año , Hospitalización/estadística & datos numéricos , Vacunación/métodosRESUMEN
PURPOSE: The aim of this study was to investigate the utility of native T1 and T2 mapping in the bowel to evaluate disease activity in Crohn disease (CD) using endoscopy as the reference standard. METHODS: This was a prospective study. Magnetic resonance imaging was performed by using a 1.5-T Philips scanner. We used a modified look-locker inversion recovery and a multiecho gradient-spin-echo sequences for single breath-hold native T1 and T2 maps, respectively, for the short-axis image of the intestine, and the measurement at the most severe site was compared with partial Simple Endoscopic Score for Crohn's Disease (pSES-CD, assessed by an expert endoscopist). A pSES-CD ≥ 4 indicated active disease. Statistical analyses were performed using the Student t test, Spearman correlation, and receiver operating characteristic curve analysis. RESULTS: A total of 27 patients (mean age ± standard deviation, 37 ± 18 years; 20 men, 7 women) were included in this study. The native T1 value of active disease was significantly higher than that of inactive disease (1170.8 ± 100.5 milliseconds vs 924.5 ± 95.3 milliseconds; P = 0.018), but the T2 value was not significantly different between active and inactive disease (76.1 ± 7.8 milliseconds vs 69.3 ± 10.9 milliseconds; P = 0.424). A good correlation was found between native T1 value and pSES-CD (ρ = 0.71; P < 0.001) but not between T2 value and pSES-CD (ρ = 0.06; P = 0.790). The area under the receiver operating characteristic curve for differentiating the disease activity was 0.96 (95% confidence interval [CI]: 0.90-1.00) for T1 values and 0.68 (95% confidence interval: 0.41-0.96) for T2 values. CONCLUSIONS: Native T1 mapping could be potentially used as a noninvasive method to differentiate disease activity in patients with CD and may be superior to T2 mapping for this purpose.
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We have analyzed the inactivated vaccine effectiveness (VE)for preventing influenza hospitalization by test-negative design in the 2022/23 season. This is the first season of co-circulation of influenza and COVID-19, and a unique period because all inpatients received COVID-19 screening. Among 536 children hospitalized with fever, none were positive for both influenza and SARS-CoV-2. The adjusted VE for preventing influenza A for all children, the 6-12-year-old group, and those with underlying diseases was 34 % (95 ï¼ CI, -16 %-61 %, n = 474), 76 % (95 ï¼ CI, 21 %-92 %, n = 81), and 92 % (95 ï¼ CI, 30 %-99 %, n = 86), respectively. Only 1 out of 35 hospitalized cases with COVID-19, and 42 out of 429 controls, had been immunized with COVID-19 vaccine. This is the first report showing influenza VE by age group in children in this limited season. We still recommend the inactivated influenza vaccine for children based on the significant VE in subgroup analysis.
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COVID-19 , Vacunas contra la Influenza , Gripe Humana , Niño , Humanos , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Vacunas contra la COVID-19 , Niño Hospitalizado , Estaciones del Año , Japón/epidemiología , COVID-19/epidemiología , COVID-19/prevención & control , Estudios de Casos y Controles , SARS-CoV-2 , Vacunas de Productos Inactivados , Vacunación , Subtipo H3N2 del Virus de la Influenza ARESUMEN
We synthesized the 0.1, 0.5, 1.0, and 1.5% Ce-doped mullite single crystals by the floating zone method and evaluated their photoluminescence (PL) and thermally stimulated luminescence (TSL) properties. The single-phase orthorhombic structure was confirmed in all the samples from powder X-ray diffraction patterns. The transmittance spectra of all the samples showed the absorption related to the 4f-5d transitions of Ce3+ ions and optical band gap of mullite. The Ce-doped mullite single crystals had the PL attributed to the 5d-4f transitions of Ce3+ ions. In TSL properties, TSL glow curves had the glow peaks at 250 and 370 °C, and TSL spectra heated at 250 and 370 °C had the peak at around 390 nm owing to the Ce3+ ions. TSL dose response functions showed linear response from 0.01 mGy to 10 Gy for the 1.0% Ce-doped mullite single crystal and from 0.1 mGy to 10 Gy for the 0.1, 0.5, and 1.5% Ce-doped ones. The 1.0% Ce-doped mullite single crystal could be used multiple times for dosimetry. In addition, the TSL intensity of the 1.0% Ce-doped mullite single crystal after 7 days from X-ray irradiation was about 82.4% from immediately one after X-ray irradiation.
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OBJECTIVES: The incidence of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria has increased. This study aimed to clarify the risk factors and treatment strategies for febrile urinary tract infection (fUTI) caused by ESBL-producing bacteria in Japanese children. METHODS: A retrospective observational study was conducted in 21 hospitals among children aged <16 years diagnosed with an fUTI between 2008 and 2017. Clinical data of children with fUTI caused by ESBL-producing and non-ESBL-producing bacteria were compared. RESULTS: Of the 2049 cases of fUTI, 147 (7.2%) were caused by ESBL-producing bacteria. Children in the ESBL group were more likely to have a history of recent antibiotic use or prophylactic antibiotic use, and experience recurrent UTIs (P <0.001) compared with those in the non-ESBL group. Of the 124 cases of fUTI due to ESBL-producing bacteria that were reviewed, 20 and 100 had concordant and discordant antibiotic use, respectively, and four had unknown antibiotic susceptibility. The median time from the start of treatment to fever resolution was 24 hours and did not differ significantly by therapy group (P = 0.39). CONCLUSION: ESBL-producing bacteria should be considered in children with recurrent UTIs and recent antibiotic use. Most children with fUTI experience clinical improvement regardless of the choice of antibiotic.
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Infecciones Urinarias , beta-Lactamasas , Niño , Humanos , Japón/epidemiología , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/epidemiología , Infecciones Urinarias/microbiología , Enterobacteriaceae , Estudios Retrospectivos , Antibacterianos/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. METHODS: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. RESULTS: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. CONCLUSIONS: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.
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Bacteriuria/diagnóstico , Adolescente , Bacterias/aislamiento & purificación , Niño , Preescolar , Femenino , Fiebre , Humanos , Lactante , Japón , Masculino , Estudios RetrospectivosRESUMEN
Currently, cardiomyocyte (CM) differentiation methods require a purification step after CM induction to ensure the high purity of the cell population. Here we show an improved human CM differentiation protocol with which high-purity ventricular-type CMs can be obtained and maintained without any CM purification process. We induced and collected a mesodermal cell population (platelet-derived growth factor receptor-α (PDGFRα)-positive cells) that can respond to CM differentiation cues, and then stimulated CM differentiation by means of Wnt inhibition. This method reproducibly generated CMs with purities above 95% in several human pluripotent stem cell lines. Furthermore, these CM populations were maintained in culture at such high purity without any further CM purification step for over 200 days. The majority of these CMs (>95%) exhibited a ventricular-like phenotype with a tendency to structural and electrophysiological maturation, including T-tubule-like structure formation and the ability to respond to QT prolongation drugs. This is a simple and valuable method to stably generate CM populations suitable for cardiac toxicology testing, disease modeling and regenerative medicine.
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Diferenciación Celular/genética , Células Madre Pluripotentes Inducidas/citología , Mesodermo/crecimiento & desarrollo , Miocitos Cardíacos/citología , Técnicas de Cultivo de Célula/métodos , Linaje de la Célula/genética , Fenómenos Electrofisiológicos , Ventrículos Cardíacos/citología , Humanos , Mesodermo/citología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Proteínas Wnt/antagonistas & inhibidoresRESUMEN
PURPOSE: To examine whether MRCP using a combination of compressed sensing and sensitivity encoding with navigator-triggered and breath-hold techniques (NT C-SENSE and BH C-SENSE, respectively) have comparable image quality to that of navigator-triggered MRCP using only sensitivity encoding (NT SENSE) at 1.5-T. METHODS: Fifty-one participants were enrolled in this prospective study between July and October 2018 and underwent the three 3D MRCP sequences each. The acquisition time and relative duct-to-periductal contrast ratios (RC values) of each bile duct segment were obtained. Visualization of the bile and main pancreatic ducts, background suppression, artifacts, and overall image quality were scored on 5-point scales. Mean and median differences in RC values and qualitative scores of NT C-SENSE and BH C-SENSE relative to NT SENSE were calculated with 95% confidence intervals (CIs). RESULTS: Acquisition time of NT SENSE, NT C-SENSE, and BH C-SENSE were 348, 143 (mean for both), and 18 s (for all participants), respectively. The RC value of each bile duct segment was inferior, but the lower limits of the 95% CIs of the mean differences were ≥ - 0.10, for both NT C-SENSE and BH C-SENSE. The visualization score of the intrahepatic duct in BH C-SENSE was inferior to that in NT SENSE (lower 95% CI limit, - 1.5). In both NT C-SENSE and BH C-SENSE, the 95% CIs of the median differences in the other qualitative scores were from - 1.0 to 0.0. CONCLUSION: NT C-SENSE and BH C-SENSE have comparable image quality to NT SENSE at 1.5-T.
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Pancreatocolangiografía por Resonancia Magnética , Enfermedades Pancreáticas , Contencion de la Respiración , Humanos , Imagenología Tridimensional , Estudios ProspectivosAsunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas del Citoesqueleto/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Mutación , Síndromes Orofaciodigitales/diagnóstico , Síndromes Orofaciodigitales/genética , Fenotipo , Alelos , Sustitución de Aminoácidos , Biomarcadores , Preescolar , Genotipo , Humanos , Masculino , RadiografíaRESUMEN
Rationale: To detect pulmonary arterial hypertension (PAH) at any early stage is a promising approach to optimize the outcome. Objectives: To investigate the impact of school ECG-based screening on detecting idiopathic or heritable (I/H)-PAH in the general pediatric population. Methods: This was a nationwide survey of patients with I/H-PAH newly diagnosed at 3 months to 18 years of age in Japan during 2005-2012. Measurements and Main Results: Eighty-seven eligible patients (age range, 1-16 yr) were recruited. Among 68 (78%) patients diagnosed at greater than or equal to 6 years of age (the age of the first ECG-based screening), 28 (41%) were detected by the ECG-based screening (screening group) and 40 (59%) were recognized by their symptoms (n = 37) or coincidental occasions (n = 3; nonscreening group). In the screening group, the proportion of patients in World Health Organization functional class I/II at diagnosis was higher (96% vs. 60%; P < 0.001), plasma brain natriuretic peptide level was lower (149 ± 290 vs. 398 ± 559 pg/ml; P = 0.045), and 6-minute-walk distance was longer (420 ± 109 vs. 327 ± 104 m; P < 0.001) than the nonscreening group, despite similar values in mean pulmonary artery pressure (58 ± 17 vs. 61 ± 17 mm Hg; P = 0.42) and pulmonary vascular resistance index (18 ± 8 vs. 21 ± 11 Wood units â m2; P = 0.24) between groups. The proportion of patients on intravenous epoprostenol at the final visit was lower in the screening group than the nonscreening group (14% vs. 50; P = 0.004). Conclusions: These findings suggest that the ECG-based screening detects a unique subpopulation of pediatric patients with I/H-PAH that is associated with already established pulmonary hypertension but without obvious right heart failure and warrants investigating the prognostic significance of this system.
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Diagnóstico Precoz , Electrocardiografía/métodos , Hipertensión Pulmonar Primaria Familiar/diagnóstico , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Servicios de Salud Escolar/estadística & datos numéricos , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Japón , Masculino , Estudios RetrospectivosRESUMEN
Resting bradycardia is an important symptom for early diagnosis of anorexia nervosa (AN) during weight loss, and it improves with body-weight recovery. However, chronotropic incompetence (CI) in exercise is observed in some patients with AN despite amelioration of resting bradycardia in the recovery phase. We examined the relationship between CI in exercise and other parameters in patients with AN during the recovery phase. Ninety-two girls with AN (aged 13-20 years, median 15 years) performed cardiopulmonary exercise tolerance tests with a bicycle ergometer in the post-treatment recovery phase. Subjects with a peak-heart rate (HR) of < 160 beats/min (bpm) on subjective maximum loading were assigned to the CI+ group (n = 7), and those with a peak-HR of ≥ 160 bpm were assigned to the CI- group (n = 85). The peak-oxygen uptake (VO2) of both groups was below the normal range. Although there was no difference in peak-VO2 between these groups, both the resting-HR and ΔHR (peak-HR - resting-HR) were significantly lower in the CI+ group than in the CI- group (82 ± 8 vs. 93 ± 16 bpm, respectively; 72 ± 14 vs. 89 ± 13 bpm, respectively), suggesting lower exercise tolerance in patients with CI during the recovery phase of AN. Interestingly, the ΔVO2/ΔHR value was higher in the CI+ group than in the CI- group (0.31 ± 0.13 vs. 0.26 ± 0.06, respectively), suggesting excessive stroke volume for maintaining the cardiac output in patients with CI during their recovery phase. These data suggest that CI could be an index of insufficient recovery of AN and utilized for ideal exercise treatments of patients with AN during the recovery phase.
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Anorexia Nerviosa/fisiopatología , Sistema Nervioso Autónomo/fisiopatología , Bradicardia/fisiopatología , Ritmo Circadiano/fisiología , Terapia por Ejercicio/métodos , Tolerancia al Ejercicio/fisiología , Frecuencia Cardíaca/fisiología , Adolescente , Adulto , Anorexia Nerviosa/complicaciones , Anorexia Nerviosa/rehabilitación , Peso Corporal , Bradicardia/etiología , Bradicardia/rehabilitación , Niño , Electrocardiografía , Prueba de Esfuerzo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Estudios Retrospectivos , Volumen Sistólico/fisiología , Adulto JovenRESUMEN
Pediatric pulmonary hypertension after surgery for congenital heart disease is a significant complication. We present a case of living-donor lung transplantation for a 12-year-old girl with pulmonary hypertension after surgical repair of transposition of great arteries. Despite repairing the transposition of great arteries, her growth was severely restricted because of progressive pulmonary hypertension; thus, lung transplantation was discussed. Standard bilateral lobar transplantation seemed unfeasible due to oversized grafts, so we performed a single lobar transplantation. Unexpectedly, she developed complications and died 3 months postoperatively despite another emergent lobar transplantation. We discussed the challenges and potential solutions regarding lobar size mismatching.
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Hipertensión Pulmonar/cirugía , Trasplante de Pulmón , Transposición de los Grandes Vasos/cirugía , Niño , Resultado Fatal , Femenino , Trastornos del Crecimiento/etiología , Humanos , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/fisiopatología , Donadores Vivos , Trasplante de Pulmón/efectos adversos , Complicaciones Posoperatorias/etiología , Transposición de los Grandes Vasos/complicacionesRESUMEN
Here, we find that human-induced pluripotent stem cell (hiPSC)-derived cardiomyocyte (CM)-fated progenitors (CFPs) that express a tetraspanin family glycoprotein, CD82, almost exclusively differentiate into CMs both in vitro and in vivo. CD82 is transiently expressed in late-stage mesoderm cells during hiPSC differentiation. Purified CD82+ cells gave rise to CMs under nonspecific in vitro culture conditions with serum, as well as in vivo after transplantation to the subrenal space or injured hearts in mice, indicating that CD82 successfully marks CFPs. CD82 overexpression in mesoderm cells as well as in undifferentiated hiPSCs increased the secretion of exosomes containing ß-catenin and reduced nuclear ß-catenin protein, suggesting that CD82 is involved in fated restriction to CMs through Wnt signaling inhibition. This study may contribute to the understanding of CM differentiation mechanisms and to cardiac regeneration strategies.
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Células Madre Pluripotentes Inducidas/metabolismo , Proteína Kangai-1/genética , Miocitos Cardíacos/metabolismo , Diferenciación Celular , HumanosRESUMEN
Torsade de Pointes (TdP) is a lethal arrhythmia that is often drug-induced, thus there is an urgent need for development of models to test or predict the drug sensitivity of human cardiac tissue. Here, we present an in vitro TdP model using 3D cardiac tissue sheets (CTSs) that contain a mixture of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and non-myocytes. We simultaneously monitor the extracellular field potential (EFP) and the contractile movement of the CTSs. Upon treatment with IKr channel blockers, CTSs exhibit tachyarrhythmias with characteristics of TdP, including both a typical polymorphic EFP and meandering spiral wave re-entry. The TdP-like waveform is predominantly observed in CTSs with the cell mixture, indicating that cellular heterogeneity and the multi-layered 3D structure are both essential factors for reproducing TdP-like arrhythmias in vitro. This 3D model could provide the mechanistic detail underlying TdP generation and means for drug discovery and safety tests.
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Arritmias Cardíacas/fisiopatología , Células Madre Pluripotentes Inducidas/citología , Torsades de Pointes/fisiopatología , Células Cultivadas , Humanos , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Taquicardia/fisiopatologíaRESUMEN
BACKGROUND: Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however. METHODS AND RESULTS: We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log-transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc-transferase (GALNT) 1 and 2 mediated the glycosylation-regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)-30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts. CONCLUSIONS: We have elucidated a novel miR-30-GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.
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Aorta Torácica/metabolismo , Regulación de la Expresión Génica , Insuficiencia Cardíaca/genética , MicroARNs/genética , Miocardio/metabolismo , N-Acetilgalactosaminiltransferasas/genética , Péptido Natriurético Encefálico/sangre , Fragmentos de Péptidos/sangre , Anciano , Animales , Animales Recién Nacidos , Biomarcadores/sangre , Western Blotting , Células Cultivadas , Cromatografía en Gel , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Ecocardiografía , Femenino , Estudios de Seguimiento , Glicosilación , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/metabolismo , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/metabolismo , Ventrículos Cardíacos/fisiopatología , Humanos , Masculino , MicroARNs/biosíntesis , Persona de Mediana Edad , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , N-Acetilgalactosaminiltransferasas/biosíntesis , Precursores de Proteínas , Ratas , Ratas Endogámicas Dahl , Reacción en Cadena en Tiempo Real de la Polimerasa , Estudios Retrospectivos , Transducción de Señal , Polipéptido N-AcetilgalactosaminiltransferasaRESUMEN
A 16-year-old boy with long QT syndrome type 3 (LQT3) was admitted for decompensated heart failure resulting from dilated cardiomyopathy (DCM). His brother was also diagnosed with LQT3 and DCM. A comprehensive genetic analysis identified a novel SCN5A missense mutation-p.Q371E-in these 2 affected living family members. It might be important to suspect the coexistence of DCM and LQT3 (which is rare according to previous articles) in cases with this novel SCN5A missense mutation.
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ADN/genética , Síndrome de QT Prolongado/genética , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.5/genética , Disfunción Ventricular Izquierda/etiología , Adolescente , Análisis Mutacional de ADN , Ecocardiografía , Electrocardiografía , Pruebas Genéticas , Humanos , Síndrome de QT Prolongado/complicaciones , Masculino , Canal de Sodio Activado por Voltaje NAV1.5/metabolismo , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Sístole , Disfunción Ventricular Izquierda/diagnóstico , Disfunción Ventricular Izquierda/fisiopatología , Función Ventricular IzquierdaRESUMEN
A cardioprotective response that alters ventricular contractility or promotes cardiomyocyte enlargement occurs with increased workload in conditions such as hypertension. When that response is excessive, pathological cardiac remodelling occurs, which can progress to heart failure, a leading cause of death worldwide. Mechanisms underlying this response are not fully understood. Here, we report that expression of angiopoietin-like protein 2 (ANGPTL2) increases in pathologically-remodeled hearts of mice and humans, while decreased cardiac ANGPTL2 expression occurs in physiological cardiac remodelling induced by endurance training in mice. Mice overexpressing ANGPTL2 in heart show cardiac dysfunction caused by both inactivation of AKT and sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA)2a signalling and decreased myocardial energy metabolism. Conversely, Angptl2 knockout mice exhibit increased left ventricular contractility and upregulated AKT-SERCA2a signalling and energy metabolism. Finally, ANGPTL2-knockdown in mice subjected to pressure overload ameliorates cardiac dysfunction. Overall, these studies suggest that therapeutic ANGPTL2 suppression could antagonize development of heart failure.
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Moyamoya disease is characterized by diffuse distal intracranial stenosis. Recently, RNF213 has been identified as a susceptibility gene in the development of this condition. Pulmonary hypertension is a rare progressive vasculopathy with an unknown etiology. The co-occurrence of pulmonary hypertension and Moyamoya disease has been described in four patients; however, whether this co-occurrence represents a chance association or a common vascular pathology has remained unknown. Here, we report two unrelated male patients who presented during their childhood with dyspnea on exertion. Systemic vascular imaging studies revealed the presence of pulmonary hypertension and Moyamoya disease in both patients. Medical exome sequencing revealed that both patients had a homozygous mutation for p.Arg4810Lys in RNF213. We suggest that homozygosity in RNF213 may lead to a novel entity involving the brain and lung. Interestingly, when present in a heterozygous state, this mutation causes a classic cerebral vascular disease, Moyamoya disease. In the homozygous state, the exact same mutation led to Moyamoya disease with extracranial systemic vasculopathy in at least two patients. From a clinical standpoint, cerebrovascular or pulmonary vascular investigations may be warranted in patients with pulmonary hypertension or Moyamoya disease, respectively. © 2016 Wiley Periodicals, Inc.