RESUMO
Increasing sea levels associated with climate change threaten the survival of coastal forests, yet the mechanisms by which seawater exposure causes tree death remain poorly understood. Despite the potentially crucial role of nonstructural carbohydrate (NSC) reserves in tree survival, their dynamics in the process of death under seawater exposure are unknown. Here we monitored progressive tree mortality and associated NSC storage in Sitka-spruce (Picea sitchensis) trees dying under ecosystem-scale increases in seawater exposure in western Washington, USA. All trees exposed to seawater, because of monthly tidal intrusion, experienced declining crown foliage during the sampling period, and individuals with a lower percentage of live foliated crown (PLFC) died faster. Tree PLFC was strongly correlated with subsurface salinity and needle ion contents. Total NSC concentrations in trees declined remarkably with crown decline, and reached extremely low levels at tree death (2.4% and 1.6% in leaves and branches, respectively, and 0.4% in stems and roots). Starch in all tissues was almost completely consumed, while sugars remained at a homeostatic level in foliage. The decreasing NSC with closer proximity to death and near zero starch at death are evidences that carbon starvation occurred during Sitka-spruce mortality during seawater exposure. Our results highlight the importance of carbon storage as an indicator of tree mortality risks under seawater exposure.
Assuntos
Metabolismo dos Carboidratos , Carboidratos/análise , Picea/química , Picea/metabolismo , Folhas de Planta/química , Folhas de Planta/metabolismo , Estresse Salino , Água do Mar/efeitos adversos , Causas de Morte , Salinidade , WashingtonRESUMO
We determined the occurrence of aortic regurgitation (AR), AR progression and risk factors in patients followed up for up to three decades after closure of subarterial VSD. We reviewed the outcomes of 86 patients categorized into three groups: group I comprised 37 patients without AR and had VSD closure alone, group II comprised 40 patients with AR and had VSD closure without aortic valvoplasty, and group III comprised 9 patients with AR and required both VSD closure and aortic valvoplasty. Patients were followed up for 18.9 ± 7.3 years (median 19.5 years, range 3.5-36.6). At latest follow up, 54.7% (47/86) of patients had AR. The prevalence of progression of AR from any one grade to the next one higher was 37.2% (32/86). Freedom from AR progression was 75.6%, 52.1%, and 22.2% at 20 years of follow-up for groups I, II and III, respectively (p < 0.05). On the other hand, progression to moderate to severe AR occurred only in 4.7% (4/86). Group I and II patients were free from progression to significant AR, while only 33.3% of group III patients were free from progression on follow-up (p < 0.001). Multivariate Cox regression analysis showed that severity of preoperative AR was the significant risk factor for persistence and progression of postoperative AR after VSD closure. In conclusion, aortic regurgitation is common and may progress even after surgical repair of subarterial VSD. Severity of preoperative AR is the most significant predictor of persistence and progression of AR after surgical closure of subarterial VSD.
Assuntos
Insuficiência da Valva Aórtica/epidemiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Comunicação Interventricular/cirurgia , Adolescente , Insuficiência da Valva Aórtica/etiologia , Procedimentos Cirúrgicos Cardíacos/estatística & dados numéricos , Estudos de Casos e Controles , Criança , Pré-Escolar , Seguimentos , Humanos , Masculino , Período Pós-Operatório , Estudos Retrospectivos , Fatores de RiscoRESUMO
Aquaporin-1 (AQP1) dual water and ion channels enhance migration and invasion when upregulated in leading edges of certain classes of cancer cells. Work here identifies structurally related furan compounds as novel inhibitors of AQP1 ion channels. 5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, and three structurally related compounds, 5-nitro-2-furoic acid (5NFA), 5-acetoxymethyl-2-furaldehyde (5AMF), and methyl-5-nitro-2-furoate (M5NF), were analyzed for effects on water and ion channel activities of human AQP1 channels expressed in Xenopus oocytes. Two-electrode voltage clamp showed dose-dependent block of the AQP1 ion current by 5HMF (IC50 0.43 mM), 5NFA (IC50 1.2 mM), and 5AMF (IC50 â¼3 mM) but no inhibition by M5NF. In silico docking predicted the active ligands interacted with glycine 165, located in loop D gating domains surrounding the intracellular vestibule of the tetrameric central pore. Water fluxes through separate intrasubunit pores were unaltered by the furan compounds (at concentrations up to 5 mM). Effects on cell migration, invasion, and cytoskeletal organization in vitro were tested in high-AQP1-expressing cancer lines, colon cancer (HT29) and AQP1-expressing breast cancer (MDA), and low-AQP1-expressing SW480. 5HMF, 5NFA, and 5AMF selectively impaired cell motility in the AQP1-enriched cell lines. In contrast, M5NF immobilized all the cancer lines by disrupting actin cytoskeleton. No reduction in cell viability was observed at doses that were effective in blocking motility. These results define furans as a new class of AQP1 ion channel inhibitors for basic research and potential lead compounds for development of therapeutic agents targeting aquaporin channel activity. SIGNIFICANCE STATEMENT: 5-Hydroxymethyl-2-furfural (5HMF), a component of natural medicinal honeys, blocks the ion conductance but not the water flux through human Aquaporin-1 (AQP1) channels and impairs AQP1-dependent cell migration and invasiveness in cancer cell lines. Analyses of 5HMT and structural analogs demonstrate a structure-activity relationship for furan compounds, supported by in silico docking modeling. This work identifies new low-cost pharmacological antagonists for AQP1 available to researchers internationally. Furans merit consideration as a new class of therapeutic agents for controlling cancer metastasis.
Assuntos
Aquaporina 1/genética , Aquaporina 1/metabolismo , Furaldeído/análogos & derivados , Furaldeído/farmacologia , Neoplasias/metabolismo , Animais , Aquaporina 1/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo , Feminino , Furaldeído/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HT29 , Humanos , Simulação de Acoplamento Molecular , Invasividade Neoplásica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Xenopus laevisRESUMO
BACKGROUND: The QRS-T angle has been associated with adverse cardiovascular events and sudden cardiac deaths. We determined frontal QRS-T angle in patients with complete transposition of the great arteries (TGA) after atrial switch operation and repaired tetralogy of Fallot (TOF) and explored its relationships with ventricular mechanics. METHODS: Thirty TGA patients aged 32.3 ± 4.4 years after atrial switch operation and 47 repaired TOF patients aged 28.7 ± 6.0 years were studied. The frontal planar QRS-T angle and QRS duration were measured from 12-lead electrocardiograms. Right (RV) and left ventricular (LV) strain parameters were determined using speckle tracking echocardiography. RESULTS: Compared with TOF patients, TGA patients after atrial switch operation had significantly greater frontal QRS-T angle (136.3° ± 43.5° vs 74.5° ± 59.6°, p < 0.001), greater prevalence of QRS-T angle ≥ 100° (83.3% vs 29.8%, p < 0.001), and showed progressive increase in QRS-T angle over a duration of 3.3 ± 1.0 years (p = 0.035). The QRS-T angle correlated positively with QRS duration in both the TGA (r = 0.61, p < 0.001) and TOF (r = 0.30, p < 0.043) groups. Among TGA patients, QRS-T angle was found to correlate negatively with systemic RV global longitudinal strain (r = - 0.49, p = 0.007), early diastolic strain rate (r = - 0.41, p = 0.026), and fractional area change (r = - 0.38, p = 0.045), but not subpulmonary LV strain indices. By contrast, among repaired TOF patients, there were no significant correlations between QRS-T angle and systemic and subpulmonary ventricular strain indices (all p > 0.05). CONCLUSION: Increased frontal QRS-T angle is prevalent in TGA patients after atrial switch operation and is related to worse systemic RV mechanics.
Assuntos
Potenciais de Ação , Transposição das Grandes Artérias , Técnica de Fontan , Frequência Cardíaca , Tetralogia de Fallot/cirurgia , Transposição dos Grandes Vasos/cirurgia , Disfunção Ventricular Direita/etiologia , Função Ventricular Esquerda , Função Ventricular Direita , Adulto , Transposição das Grandes Artérias/efeitos adversos , Ecocardiografia , Eletrocardiografia , Feminino , Técnica de Fontan/efeitos adversos , Humanos , Masculino , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/fisiopatologia , Fatores de Tempo , Transposição dos Grandes Vasos/diagnóstico por imagem , Transposição dos Grandes Vasos/fisiopatologia , Resultado do Tratamento , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/fisiopatologiaRESUMO
We determined the prevalence and factors associated with tricuspid regurgitation (TR) in adults with repair of right ventricular (RV) outflow obstruction. A total of 256 patients (128 males) were studied at 25.7 ± 7.2 years after surgery, of whom 179 had repaired tetralogy of Fallot (TOF), 31 had pulmonary atresia with intact ventricular septum (PAIVS), and 46 had pulmonary stenosis (PS). The mitral and tricuspid annulus diameters, maximum right atrial (RA) area, RV end-systolic and end-diastolic areas, and tricuspid and pulmonary regurgitation were assessed using echocardiography. The prevalence of moderate-to-severe TR was 20.7%. Subgroup analysis revealed that prevalence was greater in patients with repaired TOF (20.7%) and PAIVS (35.5%) than PS patients (10.9%). As a group, severity of TR was found to be correlated with RA area (r = 0.35, p < 0.001), RV end-diastolic (r = 0.28, p < 0.001) and end-systolic (r = 0.22, p = 0.001) areas, and tricuspid valve annulus diameter (r = 0.15, p = 0.022). Moderate-to-severe TR was associated with development of cardiac arrhythmias with an odds ratio of 2.9 (95% CI 1.1 to 8.1, p = 0.031). Multivariate analysis revealed maximum RA area (ß = 0.36, p = 0.016) as an independent determinant of severity of TR. Moderate-to-severe TR occurs in about one-fifth of adults with repaired TOF, PAVIS, and PS and is associated with RA dilation and risk of development of cardiac arrhythmias.
Assuntos
Insuficiência da Valva Tricúspide/etiologia , Obstrução do Fluxo Ventricular Externo/cirurgia , Adolescente , Adulto , Arritmias Cardíacas/etiologia , Estudos Transversais , Ecocardiografia , Feminino , Átrios do Coração/patologia , Humanos , Masculino , Resultado do Tratamento , Obstrução do Fluxo Ventricular Externo/complicações , Adulto JovemRESUMO
BACKGROUND: Idiopathic systemic capillary leak syndrome (ISCLS) is rare, and there has been about 32 cases reported in children worldwide since this disorder was first described in 1960. Clinical guidelines on the management approach stemming from robust scientific evidence are lacking. This case report presents the first reported paediatric case of severe ISCLS with significant myocardial oedema and emphasizes this disease's impact on a child's cardiac function. CASE PRESENTATION: A Chinese boy had his first attack of severe hypovolaemic shock that responded to fluid resuscitation when he was 6 years of age. His second attack developed at 8 years of age. He was then transferred to our cardiac unit for refractory hypotensive shock. The patient's echocardiogram revealed ventricular wall thickening with significant cardiac dysfunction requiring extracorporeal membrane oxygenation support. Subsequently, he made a full recovery, including his myocardial wall thickness and function. The echocardiographic findings suggested myocardial oedema that was transient in nature. Clinical and laboratory investigation from both episodes were compatible with ISCLS. CONCLUSION: ISCLS is rare, and therefore there is only a limited understanding on the pathophysiology of this disorder. The current treatment approach is based on a few case reports and series. During the acute phase, optimal supportive management is paramount. Our case highlights the importance of early recognition and consideration for extracorporeal membrane oxygenation support in patients with a life-threatening presentation, as it was lifesaving for this child who suffered myocardial oedema and ventricular dysfunction.
Assuntos
Síndrome de Vazamento Capilar/complicações , Cardiomiopatias/etiologia , Edema/etiologia , Povo Asiático , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Criança , Edema/diagnóstico , Edema/terapia , Humanos , MasculinoRESUMO
There is paucity of long-term data on adult survivors after biventricular repair of pulmonary atresia with intact ventricular septum (PAIVS) and pulmonary stenosis (PS). This study aimed to determine the cardiac and non-cardiac outcomes of adult survivors after biventricular repair of PAIVS and PS. The cardiac, neurodevelopmental and liver problems of 111 adults, 40 with PAIVS and 71 with PS, were reviewed. The median follow-up duration of our patients was 26.5 years (range 14.8-55 years). The freedom from reintervention at 30 years was 17.4% and 73.3% for PAIVS and PS patients (p < 0.001), respectively. Compared with PS patients, PAIVS patients had significantly greater prevalence of right atrial and right ventricular (RV) dilatation, and moderate to severe tricuspid and pulmonary regurgitation (all p < 0.05), and cardiac arrhythmias (22.5% vs. 8.5%, p = 0.047). The freedom from development of cardiac arrhythmias at 30 years of 68.4% and 91.6%, respectively, in PAIVS and PS patients (p = 0.03). Cox proportional hazards model identified PAIVS as an independent risk factor for reintervention (HR 4.0, 95% CI 2.1-7.6, p < 0.001) and development of arrhythmias (HR 4.1, 95% CI 1.1-14.4, p = 0.03). Neurodevelopmental problems were found in 17.5% of PAIVS patients and 7.0% of PS patients (p = 0.11). Liver problems occurred in 2 (5%) PAIVS patients, both of whom required conversion to 1.5 ventricular repair. In conclusion, long-term problems, including the need for reinterventions, cardiac arrhythmias, RV dilation, pulmonary regurgitation, and neurodevelopmental and liver issues are more prevalent in adult PAIVS than PS survivors.
Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Cardiopatias Congênitas/cirurgia , Atresia Pulmonar/cirurgia , Estenose da Valva Pulmonar/cirurgia , Adulto , Arritmias Cardíacas/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ecocardiografia/métodos , Feminino , Seguimentos , Cardiopatias Congênitas/complicações , Ventrículos do Coração/cirurgia , Humanos , Masculino , Atresia Pulmonar/complicações , Estenose da Valva Pulmonar/complicações , Reoperação/estatística & dados numéricos , Fatores de Risco , Sobreviventes , Resultado do TratamentoRESUMO
Aquaporin (AQP) channels in the major intrinsic protein (MIP) family are known to facilitate transmembrane water fluxes in prokaryotes and eukaryotes. Some classes of AQPs also conduct ions, glycerol, urea, CO2 , nitric oxide, and other small solutes. Ion channel activity has been demonstrated for mammalian AQPs 0, 1, 6, Drosophila Big Brain (BIB), soybean nodulin 26, and rockcress AtPIP2;1. More classes are likely to be discovered. Newly identified blockers are providing essential tools for establishing physiological roles of some of the AQP dual water and ion channels. For example, the arylsulfonamide AqB011 which selectively blocks the central ion pore of mammalian AQP1 has been shown to impair migration of HT29 colon cancer cells. Traditional herbal medicines are sources of selective AQP1 inhibitors that also slow cancer cell migration. The finding that plant AtPIP2;1 expressed in root epidermal cells mediates an ion conductance regulated by calcium and protons provided insight into molecular mechanisms of environmental stress responses. Expression of lens MIP (AQP0) is essential for maintaining the structure, integrity and transparency of the lens, and Drosophila BIB contributes to neurogenic signalling pathways to control the developmental fate of fly neuroblast cells; however, the ion channel roles remain to be defined for MIP and BIB. A broader portfolio of pharmacological agents is needed to investigate diverse AQP ion channel functions in situ. Understanding the dual water and ion channel roles of AQPs could inform the development of novel agents for rational interventions in diverse challenges from agriculture to human health.
Assuntos
Aquaporinas/química , Aquaporinas/metabolismo , Sequência de Aminoácidos , Animais , Humanos , Especificidade da EspécieRESUMO
BACKGROUND: Emerging data suggest that heart-related microRNAs (miRs) may serve as circulating biomarkers of myocardial injury. We aimed to determine the circulating profile of miRs in patients with volume-overloaded right ventricles after repair of tetralogy (TOF). MATERIALS AND METHODS: A total of 104 TOF patients and 70 controls were recruited. The study was conducted in two phases: (1) determination of circulating heart-related miRs described in left heart diseases (miR-1, miR-133a, miR-208a, miR-208b and miR423-5p) by quantitative real-time PCR in 49 patients and 30 controls and followed by validation in an independent cohort of 55 patients and 40 controls; (2) expression profiling of serum samples from eight patients and eight controls, followed by validation. Alteration in circulating miRNA expression was related to cardiac functional indices as assessed by 2D speckle tracking and 3D echocardiography. RESULTS: No significant differences in serum levels of left heart-associated miRNAs were found between patients and controls. Of the candidate 19 miRNAs identified by profiling, upregulation of miR-99b and down-regulation of miR-766 were validated. However, no correlations were found between miRs levels and echo indices. CONCLUSION: In young adults with repaired TOF and volume-overloaded right ventricles, circulating levels of miR-99b and miR-766, but not left heart-associated miRNAs, were significantly altered.
Assuntos
MicroRNA Circulante/metabolismo , Tetralogia de Fallot/diagnóstico , Biomarcadores/metabolismo , Estudos de Casos e Controles , Regulação para Baixo/fisiologia , Ecocardiografia , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Tetralogia de Fallot/fisiopatologia , Regulação para Cima/fisiologia , Função Ventricular/fisiologia , Adulto JovemRESUMO
BACKGROUND: Cardiomyocyte apoptosis has been implicated in ventricular remodeling and initiation of cardiac failure. We sought to determine the severity of right ventricular (RV) cardiomyocyte apoptosis in cyanotic and acyanotic children with RV pressure overload. METHODS: Fourteen patients, seven with tetralogy of Fallot (group I) and seven with pulmonary stenosis and ventricular septal defect (group II), undergoing open-heart surgery were studied. Right ventricular biopsies were examined for cardiomyocyte apoptosis by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling. The magnitude of cardiomyocyte apoptosis was related to preoperative oxygen saturation and postoperative inotrope use and hospital stay. RESULTS: Compared with group I patients, group II patients were significantly older at operation (p = 0.002) and had a larger body size (p < 0.01) and higher preoperative oxygen saturation (p = 0.01). The prevalence of cardiomyocyte apoptosis in both group I and II patients as a whole was 0.24 ± 0.29% (range, 0% to 1.10%). The prevalence was similar between group I (median 0.30%, range 0% to 1.10%) and group II (median 0.20, range 0% to 0.40%, p = 0.65). The prevalence of cardiomyocyte apoptosis correlated positively with preoperative oxygen saturation on room air (r = -0.69, p < 0.005) and postoperative inotrope score (r = 0.67, p = 0.001). A higher postoperative inotrope score (r = 0.68, p = 0.001) was associated with a significant longer duration of postoperative stay in the hospital. CONCLUSIONS: The prevalence of cardiomyocyte apoptosis in the pressure-overloaded right ventricle is related to the severity of hypoxia and may have an impact on postoperative course in terms of early postoperative use of inotropes and duration of hospital stay.
Assuntos
Apoptose , Ventrículos do Coração/citologia , Ventrículos do Coração/patologia , Hipóxia/patologia , Miócitos Cardíacos/patologia , Disfunção Ventricular Direita/patologia , Disfunção Ventricular Direita/fisiopatologia , Pressão Ventricular , Cardiotônicos/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Tempo de Internação , Masculino , Cuidados Pós-Operatórios , Índice de Gravidade de Doença , Remodelação VentricularRESUMO
BACKGROUND: Data on the use of circulating microRNAs (miRNAs) as biomarkers of cardiovascular diseases are emerging. Little, however, is known on the expression profile of circulating of microRNAs in congenital heart malformations with a systemic right ventricle that is prone to functional impairment. We aimed to test the hypothesis that circulating miRNA profile is altered in patients late after atrial switch operation for complete transposition of the great arteries (TGA) and further explored possible relationships between alteration of circulating miRNAs and systemic ventricular contractility. METHODS: Circulating miRNA expression profiling of serum samples from 5 patients and 5 healthy controls was performed. The results were validated in 26 patients and 20 controls using real-time quantitative reverse-transcription polymerase chain reaction for candidate miRNAs with fold changes >3 by expression profiling. Systemic ventricular myocardial acceleration during isovolumic contraction (IVA) was determined by colour tissue Doppler echocardiography. RESULTS: Compared with controls, patients had significantly lower systemic ventricular IVA (p = 0.002). Of the 23 upregulated miRNAs identified by profiling, 11 were validated to be increased in patients compared with controls: miR-16, miR-106a, miR-144*, miR-18a, miR-25, miR-451, miR-486-3p, miR-486-5p, miR-505*, let-7e and miR-93. Among the validated 11 miRNAs, miR-18a (r = -0.45, p = 0.002) and miR-486-5p (r = -0.35, p = 0.018) correlated negatively with systemic ventricular IVA for the whole cohort. CONCLUSIONS: A distinct serum miRNA expression signature exists in adults with complete TGA after atrial switch operation, with serum miR-18a and miR-486-5p being associated with systemic ventricular contractility.
Assuntos
Perfilação da Expressão Gênica/métodos , MicroRNAs/sangue , Transposição dos Grandes Vasos/sangue , Transposição dos Grandes Vasos/cirurgia , Função Ventricular Direita/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Transposição dos Grandes Vasos/genética , Adulto JovemRESUMO
Background In nonsyndromic conotruncal cardiac defects, the use of next-generation sequencing for clinical diagnosis is increasingly adopted, but gene-disease associations in research are only partially translated to diagnostic panels, suggesting a need for evidence-based consensus. Methods and Results In an exome data set of 245 patients with conotruncal cardiac defects, we performed burden analysis on a high-confidence congenital heart disease gene list (n=132) with rare (<0.01%) and ultrarare (absent in the Genome Aggregation Database) protein-altering variants. Overall, we confirmed an excess of rare variants compared with ethnicity-matched controls and identified 2 known genes (GATA6, NOTCH1) and 4 candidate genes supported by the literature (ANKRD11, DOCK6, NPHP4, and STRA6). Ultrarare variant analysis was performed in combination with 3 other published studies (n=1451) and identified 3 genes (FLT4, NOTCH1, TBX1) to be significant, whereas a subgroup analysis involving 391 Chinese subjects identified only GATA6 as significant. Conclusions We suggest that these significant genes in our rare and ultrarare burden analyses warrant prioritization for clinical testing implied for rare inherited and de novo variants. Additionally, associations on ClinVar for these genes were predominantly variants of uncertain significance. Therefore, a more stringent assessment of gene-disease associations in a larger and ethnically diverse cohort is required to be prudent for future curation of conotruncal cardiac defect genes.
Assuntos
Cardiopatias Congênitas , Humanos , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Fatores de Transcrição/genética , Povo Asiático , EtnicidadeRESUMO
BACKGROUND: Circulating carboxy-terminal propeptide of type I procollagen (PICP) and amino-terminal propeptide of type III procollagen (PIIINP) are biomarkers of collagen synthesis. We tested the hypothesis that circulating PICP and PIIINP are altered and may correlate with ventricular volume load and function in patients with repaired tetralogy of Fallot (TOF). METHODS AND RESULTS: Serum PICP and plasma PIIINP levels were determined in 39 patients with repaired TOF aged 17.7 ± 4.1 years and 25 healthy controls and correlated with right ventricular (RV) and left ventricular (LV) volumes, functional indices, and mechanical dyssynchrony as assessed by 3-dimensional and tissue Doppler echocardiography. Compared with controls, patients had significantly higher circulating PICP (P = .016) and PIIINP (P = .008) levels, worse RV function with intra-RV mechanical delay (all P < .001), impaired LV systolic functional indices (all P < .05), and greater LV systolic dyssynchrony index (SDI) (P < .001). For the whole cohort, circulating PICP and PIIINP levels correlated with age (P = .001 and P < .001, respectively), body mass index (P = .033 and P = .012, respectively), LV eccentricity (P = .035 and P = .046, respectively), RV end-diastolic volume (P = .029 and P = .047, respectively), and LV SDI (both P < .001). In addition, PICP levels correlated negatively with RV and LV isovolumic acceleration and RV ejection fraction. Multiple linear regression analysis identified LV SDI as a significant independent correlate of circulating levels of PICP (ß = .31, P = .045) and PIIINP (ß = .37, P = .004). CONCLUSION: Circulating levels of PICP and PIIINP correlate positively with LV mechanical dyssynchrony in patients after TOF repair, implicating a possible role of increased collagen synthesis in its pathogenesis.
Assuntos
Colágeno/biossíntese , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Volume Sistólico/fisiologia , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Esquerda/sangue , Função Ventricular/fisiologia , Adolescente , Biomarcadores/sangue , Procedimentos Cirúrgicos Cardíacos/métodos , Progressão da Doença , Ecocardiografia Doppler em Cores , Ecocardiografia Tridimensional , Feminino , Seguimentos , Humanos , Imunoensaio , Masculino , Período Pós-Operatório , Prognóstico , Tetralogia de Fallot/complicações , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
AIMS: This study determined the associations between right atrial (RA) and right ventricular (RV) mechanics and liver stiffness in adults with repaired tetralogy of Fallot (TOF), pulmonary atresia with intact ventricular septum (PAVIS), and pulmonary stenosis (PS). METHODS AND RESULTS: Ninety subjects including 26 repaired TOF, 24 PAIVS, and 20 PS patients and 20 controls were studied. Hepatic shear wave velocity and tissue elasticity (E), measures of liver stiffness, were assessed by two-dimensional shear wave elastography, while RA and RV mechanics were assessed by speckle tracking echocardiography. Deformation analyses revealed worse RV systolic strain and strain rate, and RA peak positive and total strain, and strain rates at ventricular systole and at early diastole in all of the patient groups compared with controls (all P < 0.05). Compared with controls, all of the patient groups had significantly greater shear wave velocity and hepatic E-value (all P < 0.05). Shear wave velocity and hepatic E-value correlated negatively with RV systolic strain rate, and RA positive strain, total strain, and strain rate at ventricular systole and at early diastole (all P < 0.05). Multivariate analyses revealed RA strain rate at early diastole (P = 0.015, P < 0.001), maximum RA size (P < 0.001, P < 0.001), and severity of pulmonary regurgitation (P = 0.05, Pp = 0.014) as significant correlates of shear wave velocity and hepatic E-value. CONCLUSION: In adults with repaired TOF, PAIVS, and PS, RA dysfunction and pulmonary regurgitation are associated with liver stiffness.
Assuntos
Atresia Pulmonar , Tetralogia de Fallot , Disfunção Ventricular Direita , Adulto , Função do Átrio Direito , Ventrículos do Coração/diagnóstico por imagem , Humanos , Fígado/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/etiologia , Função Ventricular DireitaRESUMO
In sickle cell disease (SCD), the pathological shift of red blood cells (RBCs) into distorted morphologies under hypoxic conditions follows activation of a cationic leak current (Psickle) and cell dehydration. Prior work showed sickling was reduced by 5-hydroxylmethyl-2-furfural (5-HMF), which stabilized mutant hemoglobin and also blocked the Psickle current in RBCs, though the molecular basis of this 5-HMF-sensitive cation current remained a mystery. Work here is the first to test the hypothesis that Aquaporin-1 (AQP1) cation channels contribute to the monovalent component of Psickle. Human AQP1 channels expressed in Xenopus oocytes were evaluated for sensitivity to 5-HMF and four derivatives known to have differential efficacies in preventing RBC sickling. Ion conductances were measured by two-electrode voltage clamp, and osmotic water permeability by optical swelling assays. Compounds tested were: 5-HMF; 5-PMFC (5-(phenoxymethyl)furan-2-carbaldehyde); 5-CMFC (5-(4-chlorophenoxymethyl)furan-2-carbaldehyde); 5-NMFC (5-(2-nitrophenoxymethyl)-furan-2-carbaldehyde); and VZHE006 (tert-butyl (5-formylfuran-2-yl)methyl carbonate). The most effective anti-sickling agent, 5-PMFC, was the most potent inhibitor of the AQP1 ion conductance (98% block at 100 µM). The order of sensitivity of the AQP1 conductance to inhibition was 5-PMFC > VZHE006 > 5-CMFC ≥ 5-NMFC, which corresponded with effectiveness in protecting RBCs from sickling. None of the compounds altered AQP1 water channel activity. Combined application of a selective AQP1 ion channel blocker AqB011 (80 µM) with a selective hemoglobin modifying agent 5-NMFC (2.5 mM) increased anti-sickling effectiveness in red blood cells from human SCD patients. Another non-selective cation channel known to be expressed in RBCs, Piezo1, was unaffected by 2 mM 5-HMF. Results suggest that inhibition of AQP1 ion channels and capacity to modify hemoglobin are combined features of the most effective anti-sickling agents. Future therapeutics aimed at both targets could hold promise for improved treatments for SCD.
RESUMO
Chlamydia trachomatis is an obligate intracellular Gram-negative pathogen affecting over 600 million people worldwide with 92 million new cases occurring globally each year. C. trachomatis enter the cells and replicate to infect different tissues/organs, giving rise to a spectrum of pathological conditions; however, the exact mechanism or receptor(s) for their entry is not well understood. Here we report that CFTR (cystic fibrosis transmembrane conductance regulator), an apical epithelial anion channel, is required for cellular entry and internalization of C. trachomatis. Human epithelial cell lines expressing functional CFTR internalized more C. trachomatis than the cells expressing mutant Delta508 CFTR. The in vitro cellular uptake of C. trachomatis can be blocked by CFTR inhibitors or antibody, and the in vivo cellular uptake of C. trachomatis in CFTR mutant (CFTR(-/-)) mice was significantly less compared with that in the wild-type. Direct interaction between CFTR and C. trachomatis LPS (lipopolysaccharide) is demonstrated by their immune-co-localization and co-immunoprecipitation. Despite an increase in CFTR expression observed upon C. trachomatis LPS challenge, a reduction in its ion channel activity is observed, consistent with the notion that CFTR functions as a receptor for cellular entry and internationization of C. trachomatis, with compromised ion-channel function. These findings, for the first time, demonstrate that CFTR functions as a cell-surface receptor for epithelial cell entry, and internalization of C. trachomatis and these findings may lead to the development of new treatment strategies to curtail the spread of chlamydial infections.
Assuntos
Infecções por Chlamydia/microbiologia , Chlamydia trachomatis/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/fisiologia , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular , Infecções por Chlamydia/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/deficiência , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/ultraestrutura , Células HeLa , Humanos , Imunoprecipitação , Lipopolissacarídeos/metabolismo , Camundongos , Camundongos Knockout , MutaçãoRESUMO
Aquaporin (AQP) channels enable regulated transport of water and solutes essential for fluid homeostasis, but they are gaining attention as targets for anticancer therapies. Patterns of AQP expression and survival rates for patients were evaluated by systematic review (PubMed and Embase) and transcriptomic analyses of RNAseq data (Human Protein Atlas database). Meta-analyses confirmed predominantly negative associations between AQP protein and RNA expression levels and patient survival times, most notably for AQP1 in lung, breast and prostate cancers; AQP3 in esophageal, liver and breast cancers; and AQP9 in liver cancer. Patterns of AQP expression were clustered for groups of cancers and associated with risk of death. A quantitative transcriptomic analysis of AQP1-10 in human cancer biopsies similarly showed that increased transcript levels of AQPs 1, 3, 5 and 9 were most frequently associated with poor survival. Unexpectedly, increased AQP7 and AQP8 levels were associated with better survival times in glioma, ovarian and endometrial cancers, and increased AQP11 with better survival in colorectal and breast cancers. Although molecular mechanisms of aquaporins in pathology or protection remain to be fully defined, results here support the hypothesis that overexpression of selected classes of AQPs differentially augments cancer progression. Beyond fluid homeostasis, potential roles for AQPs in cancers (suggested from an expanding appreciation of their functions in normal tissues) include cell motility, membrane process extension, transport of signaling molecules, control of proliferation and apoptosis, increased mechanical compliance, and gas exchange. AQP expression also has been linked to differences in sensitivity to chemotherapy treatments, suggesting possible roles as biomarkers for personalized treatments. Development of AQP pharmacological modulators, administered in cancer-specific combinations, might inspire new interventions for controlling malignant carcinomas.
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Aortic dilation has been increasingly recognized in congenital heart diseases, and aortic dissection is one of the important complications. We report a case of aortic dissection in a patient 31 years after repair of tetralogy of Fallot (TOF) and review reported cases. While aortic dissection is uncommon, aortic dilation is common among patients with repaired TOF and it appeared progressive in some patients. Based on the reported cases, progressive aortic dilation appeared as the pre-requisite for aortic dissection, although other factors might be involved. Regular surveillance and monitoring for aortic complications should be incorporated into clinical practice.
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BACKGROUND: This study aimed to assess diffuse myocardial fibrosis of the systemic right ventricle and subpulmonary left ventricle in patients after Senning or Mustard operation for complete transposition of the great artery (TGA) using cardiac magnetic resonance (CMR) T1 mapping. METHODS: Thirty-one adult TGA patients after Senning (n = 24) or Mustard (n = 7) operation were studied at the age of 33.3 ± 4.0 years. Systemic right ventricular (RV) and subpulmonary left ventricular (LV) volumes, ejection fraction, and myocardial T1 values and extracellular volume fraction (ECV) were determined using CMR. RESULTS: The RV and LV ejection fractions were 47.0 ± 10.9% and 61.3 ± 7.4%, respectively. Compared to published normative values, patients had significantly greater RV and LV native T1 and ECV values (all p < 0.001). For each of the basal, mid, and apical segments, the LV native T1 and ECV values were significantly greater in the left than the right ventricle (all p < 0.05). There is a significant trend on progressive increase in ECV value from the basal towards the apical segments in both the right (p = 0.002) and the left (p < 0.001) ventricle. Modestly strong correlations were found between RV and LV native T1 (r = 0.60, p < 0.001) and ECV (r = 0.49, p = 0.005) values but not with ejection fractions of the respective ventricles. CONCLUSIONS: Differential myocardial fibrosis, with greater involvement of the subpulmonary left ventricle than the systemic right ventricle, is present in patients with TGA after atrial switch operation. Associations between the magnitude of RV and LV fibrosis suggests adverse ventricular-ventricular interaction at the cardiac extracellular matrix level.
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BACKGROUND: Human heterotaxy is a group of congenital disorders characterized by misplacement of one or more organs according to the left-right axis. The genetic causes of human heterotaxy are highly heterogeneous. METHODS: We performed exome sequencing in a cohort of 26 probands with heterotaxy followed by gene burden analysis for the enrichment of novel rare damaging mutations. Transcription activator-like effector nuclease was used to generate somatic loss-of-function mutants in a zebrafish model. Ciliary defects were examined by whole-mount immunostaining of acetylated α-tubulin. RESULTS: We identified a significant enrichment of novel rare damaging mutations in the CC2D1A gene. Seven occurrences of CC2D1A mutations were found to affect 4 highly conserved amino acid residues of the protein. Functional analyses in the transcription activator-like effector nuclease-mediated zebrafish knockout models were performed, and heterotaxy phenotypes of the cardiovascular and gastrointestinal systems in both somatic and germline mutants were observed. Defective cilia were demonstrated by whole-mount immunostaining of acetylated α-tubulin. These abnormalities were rescued by wild-type cc2d1a mRNA but not cc2d1a mutant mRNA, strongly suggesting a loss-of-function mechanism. On the other hand, overexpression of cc2d1a orthologous mutations cc2d1a P559L and cc2d1a G808V (orthologous to human CC2D1A P532L and CC2D1A G781V) did not affect embryonic development. CONCLUSIONS: Using a zebrafish model, we were able to establish a novel association of CC2D1A with heterotaxy and ciliary dysfunction in the F2 generation via a loss-of-function mechanism. Future mechanistic studies are needed for a better understanding of the role of CC2D1A in left-right patterning and ciliary dysfunction.