RESUMO
For healthspan and lifespan, ERK, AMPK and mTORC1 represent critical pathways and inflammation is a centrally important hallmark1-7. Here we examined whether IL-11, a pro-inflammatory cytokine of the IL-6 family, has a negative effect on age-associated disease and lifespan. As mice age, IL-11 is upregulated across cell types and tissues to regulate an ERK-AMPK-mTORC1 axis to modulate cellular, tissue- and organismal-level ageing pathologies. Deletion of Il11 or Il11ra1 protects against metabolic decline, multi-morbidity and frailty in old age. Administration of anti-IL-11 to 75-week-old mice for 25 weeks improves metabolism and muscle function, and reduces ageing biomarkers and frailty across sexes. In lifespan studies, genetic deletion of Il11 extended the lives of mice of both sexes, by 24.9% on average. Treatment with anti-IL-11 from 75 weeks of age until death extends the median lifespan of male mice by 22.5% and of female mice by 25%. Together, these results demonstrate a role for the pro-inflammatory factor IL-11 in mammalian healthspan and lifespan. We suggest that anti-IL-11 therapy, which is currently in early-stage clinical trials for fibrotic lung disease, may provide a translational opportunity to determine the effects of IL-11 inhibition on ageing pathologies in older people.
Assuntos
Envelhecimento , Interleucina-11 , Longevidade , Transdução de Sinais , Animais , Feminino , Masculino , Camundongos , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/metabolismo , Envelhecimento/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fragilidade/genética , Fragilidade/metabolismo , Fragilidade/prevenção & controle , Inflamação/metabolismo , Inflamação/tratamento farmacológico , Interleucina-11/antagonistas & inibidores , Interleucina-11/deficiência , Interleucina-11/genética , Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/metabolismo , Subunidade alfa de Receptor de Interleucina-11/deficiência , Longevidade/efeitos dos fármacos , Longevidade/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Humanos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiologiaRESUMO
Interleukin-11 (IL11) is important for fibroblast-to-myofibroblast transformations. Here, we examined the signalling and phenotypic effects of inhibiting IL11 signalling using neutralizing antibodies against IL11 or its cognate receptor (IL11RA) in a mouse model of acute and severe pressure overload. C57BL/6J mice underwent ascending aortic constriction (AAC) surgery and were randomized to anti-IL11, anti-IL11RA, or isotype control antibodies (20 mg/kg, bi-weekly for 2 weeks). AAC surgery induced the expression of IL11, IL11RA and extracellular matrix (ECM) genes that was associated with cardiac hypertrophy and aortic remodelling. Inhibition of IL11 signalling reduced AAC-induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy. STAT3 was phosphorylated in the hearts of AAC-treated mice but this was unrelated to IL11 activity, which we confirmed in mouse cardiac fibroblasts in vitro. These data highlight that blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway.
Assuntos
Cardiomegalia , Interleucina-11 , Animais , Fibrose , Camundongos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Although obesity is associated with alterations in left ventricular (LV) mass and volume which are of prognostic significance, widely differing patterns of remodelling have been attributed to adiposity. Our aim was to define the relationship between body composition and LV geometry using three-dimensional cardiovascular magnetic resonance. METHODS: In an observational study 1530 volunteers (55 % female, mean age 41.3 years) without known cardiovascular disease underwent investigation including breath-hold high spatial resolution 3D cines. Atlas-based segmentation and co-registration was used to create a statistical model of wall thickness (WT) and relative wall thickness (RWT) throughout the LV. The relationship between bio-impedence body composition and LV geometry was assessed using 3D regression models adjusted for age, systolic blood pressure (BP), gender, race and height, with correction to control the false discovery rate. RESULTS: LV mass was positively associated with fat mass in women but not in men (LV mass: women ß = 0.11, p < 0.0001; men ß = -0.01, p = 0.82). The 3D models revealed that in males fat mass was strongly associated with a concentric increase in relative wall thickness (RWT) throughout most of the LV (ß = 0.37, significant area = 96 %) and a reduced mid-ventricular cavity (ß = -0.22, significant area = 91 %). In women the regional concentric hypertrophic association was weaker, and the basal lateral wall showed an inverse relationship between RWT and fat mass (ß = -0.11, significant area = 4.8 %). CONCLUSIONS: In an adult population without known cardiovascular disease increasing body fat is predominately associated with asymmetric concentric hypertrophy independent of systolic BP, with women demonstrating greater cavity dilatation than men. Conventional mass and volume measurements underestimate the impact of body composition on LV structure due to anatomic variation in remodelling.
Assuntos
Adiposidade , Ventrículos do Coração/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Imagem Cinética por Ressonância Magnética/métodos , Obesidade/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Suspensão da Respiração , Estudos Transversais , Impedância Elétrica , Feminino , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores Sexuais , Função Ventricular Esquerda , Remodelação Ventricular , Adulto JovemRESUMO
BACKGROUND: Detection of intracardiac shunts using CT Coronary Angiography (CTCA) is currently based on anatomical demonstration of defects. We assessed a novel technique using a standard CTCA test bolus in detecting shunts independent of anatomical assessment and to provide an estimate of Qp/Qs. METHODS: We retrospectively reviewed 51 CTCAs: twenty-one from patients with known simple left to right intracardiac shunts with contemporaneous functional assessment (using CMR) within 6 months, 20 controls with structurally normal hearts, and 10 patients with shunt repairs. From the dynamic acquisition of a test bolus, we measured mean Hounsfield Units (HU) in various anatomical structures. We created time/density curves from the test bolus data, and calculated disappearance time (DT) from the ascending aorta (deriving a Qp/Qs), peak ascending aortic HU, and mean coefficient of variation of the arterial curves, and compared these with the Qp/Qs from the respective CMR. RESULTS: Patients with intracardiac shunts had significantly higher test bolus derived Qp/Qs compared with both the controls, and the repaired shunt comparator group. There was a very strong agreement between the test bolus derived Qp/Qs, and Qp/Qs as measured by CMR (Intraclass correlation 0.89). Mean bias was 0.032 â± â0.341 (95% limits of agreement -0.64 to 0.70). Interobserver, and intraobserver agreement of the disappearance time was excellent (0.99, 0.99 (reader 1) and 1.00 (reader 2) respectively). CONCLUSION: In this proof-of-concept study, we demonstrate a novel technique to detect, and to estimate severity of left to right intracardiac shunts on routine Cardiac CT.
Assuntos
Coração , Tomografia Computadorizada por Raios X , Humanos , Angiografia Coronária , Estudos Retrospectivos , Valor Preditivo dos Testes , Circulação PulmonarRESUMO
BACKGROUND: Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSPtv cardiomyopathy. METHODS: Individuals with DSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSPtv performed. RESULTS: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSPtv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P<0.0001). CONCLUSIONS: In the largest series of individuals with DSPtv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.
Assuntos
Displasia Arritmogênica Ventricular Direita , Cardiomiopatias , Desmoplaquinas , Feminino , Humanos , Masculino , Arritmias Cardíacas/genética , Displasia Arritmogênica Ventricular Direita/diagnóstico , Cardiomiopatias/genética , Desmoplaquinas/genética , Fatores de RiscoRESUMO
There are currently no specific treatments for cardiac fibrosis. We tested the efficacy of a neutralising anti-IL11 antibody (X203) to reduce cardiac fibrosis in two preclinical models: transverse aortic constriction (TAC) and chronic angiotensin II infusion (AngII). In the first model, male C57BL/6J mice were subjected to TAC for 2 weeks. In the second model, mice received continuous angiotensin II for 4 weeks via subcutaneous pump. In both models, mice received either 20 mg/kg of X203 or isotype-control antibody twice-weekly, starting 24 h after surgery. Cardiac fibrosis and extracellular matrix gene expression were assessed by RT-qPCR, Western blot, histology and collagen (hydroxyproline) assays. In both models, X203 significantly reduced pro-fibrotic gene expression and myocardial fibrosis (TAC: 51% reduction in total collagen, P < 0.001, 39% in perivascular fibrosis, P < 0.001; AngII: 17% reduction in total collagen, P = 0.04, 83% in perivascular fibrosis, P < 0.001). Pharmacological targeting of IL11 reduces cardiac fibrosis in preclinical models. Figa Graphical Abstract.
Assuntos
Anticorpos Neutralizantes/farmacologia , Aorta/cirurgia , Cardiomiopatias/prevenção & controle , Interleucina-11/antagonistas & inibidores , Miocárdio/metabolismo , Angiotensina II , Animais , Aorta/fisiopatologia , Pressão Arterial , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Colágeno/genética , Colágeno/metabolismo , Constrição , Modelos Animais de Doenças , Fibronectinas/genética , Fibronectinas/metabolismo , Fibrose , Hidroxiprolina/metabolismo , Interleucina-11/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Transdução de SinaisRESUMO
Background: Hypertrophic cardiomyopathy (HCM) is defined as left ventricular end-diastolic maximal wall thickness (WTMax) ≥15.0 mm, without accounting for ethnicity, sex, and body size. It is well-established that Asians have smaller hearts than do Caucasians. Objectives: This study aims to examine the implications of this single absolute WTMax threshold on the diagnosis of HCM in Asians. Methods: The study consisted of 360 healthy volunteers (male: n = 174; age: 50 ± 12 years) and 114 genetically characterized patients with HCM (male: n = 83; age: 52 ± 13 years; genotype-positive, n = 39). All participants underwent cardiovascular magnetic resonance. WTMax was measured semiautomatically at end-diastole according to the standard 16 myocardial segments. Results: Healthy male volunteers had increased WTMax compared with that of female volunteers (8.4 ± 1.2 mm vs 6.6 ± 1.1 mm, respectively; P < 0.001). Conversely, WTMax was similar between male and female patients with HCM (15.2 ± 3.4 mm vs 14.7 ± 3.0 mm, respectively; P = 0.484) and between those with and without a pathogenic gene variant (P = 0.828). Using the recommended diagnostic threshold of 15.0 mm, 56 patients with HCM had WTMax <15.0 mm and no healthy volunteers had WTMax >15.0 mm (specificity of 100% and sensitivity of 51%). Lowering WTMax thresholds to 10.0 mm in female patients and 12.0 mm in male patients did not affect specificity (100%) but significantly improved sensitivity (84%). Despite lower left ventricular mass, female patients with HCM demonstrated more features of adverse cardiac remodeling than did male patients: increased myocardial fibrosis, higher asymmetric ratio, and disproportionately worse myocardial strain. Conclusions: The study highlights cautious application of guideline-recommended WTMax to diagnose HCM in Asians. Lowering WTMax to account for ethnicity and sex improves diagnostic sensitivity without compromising specificity.
RESUMO
OBJECTIVES: This study sought to investigate whether shape-based late gadolinium enhancement (LGE) metrics and simulations of re-entrant electrical activity are associated with arrhythmic events in patients with nonischemic dilated cardiomyopathy (NIDCM). BACKGROUND: The presence of LGE predicts life-threatening ventricular arrhythmias in NIDCM; however, risk stratification remains imprecise. LGE shape and simulations of electrical activity may be able to provide additional prognostic information. METHODS: Cardiac magnetic resonance (CMR)-LGE shape metrics were computed for a cohort of 156 patients with NIDCM and visible LGE and tested retrospectively for an association with an arrhythmic composite endpoint of sudden cardiac death and ventricular tachycardia. Computational models were created from images and used in conjunction with simulated stimulation protocols to assess the potential for re-entry induction in each patient's scar morphology. A mechanistic analysis of the simulations was carried out to explain the associations. RESULTS: During a median follow-up of 1,611 (interquartile range: 881 to 2,341) days, 16 patients (10.3%) met the primary endpoint. In an inverse probability weighted Cox regression, the LGE-myocardial interface area (hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.24 to 2.47; p = 0.001), number of simulated re-entries (HR: 1.40; 95% CI: 1.23 to 1.59; p < 0.01) and LGE volume (HR: 1.44; 95% CI: 1.07 to 1.94; p = 0.02) were associated with arrhythmic events. Computational modeling revealed repolarization heterogeneity and rate-dependent block of electrical wavefronts at the LGE-myocardial interface as putative arrhythmogenic mechanisms directly related to the LGE interface area. CONCLUSIONS: The area of interface between scar and surviving myocardium, as well as simulated re-entrant activity, are associated with an elevated risk of major arrhythmic events in patients with NIDCM and LGE and represent novel risk predictors.
Assuntos
Cardiomiopatia Dilatada , Gadolínio , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/diagnóstico por imagem , Meios de Contraste , Humanos , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Cardiac fibrosis is central to the pathology of heart failure, particularly heart failure with preserved ejection fraction (HFpEF). Irrespective of the underlying profibrotic condition (e.g. ageing, diabetes, hypertension), maladaptive cardiac fibrosis is defined by the transformation of resident fibroblasts to matrix-secreting myofibroblasts. Numerous profibrotic factors have been identified at the molecular level (e.g. TGFß, IL11, AngII), which activate gene expression programs for myofibroblast activation. A number of existing HF therapies indirectly target fibrotic pathways; however, despite multiple clinical trials in HFpEF, a specific clinically effective antifibrotic therapy remains elusive. Therapeutic inhibition of TGFß, the master-regulator of fibrosis, has unfortunately proven toxic and ineffective in clinical trials to date, and new approaches are needed. In this review, we discuss the pathophysiology and clinical implications of interstitial fibrosis in HFpEF. We provide an overview of trials targeting fibrosis in HFpEF to date and discuss the promise of potential new therapeutic approaches and targets in the context of underlying molecular mechanisms.
Assuntos
Insuficiência Cardíaca , Hipertensão , Fibrose , Humanos , Miofibroblastos , Volume SistólicoRESUMO
Transforming growth factor beta-1 (TGFß1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFß1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFß1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFß1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.
Assuntos
Aorta/patologia , Interleucina-11/fisiologia , Modelos Animais , Músculo Liso Vascular/patologia , Fenótipo , Remodelação Vascular/fisiologia , Animais , Anticorpos Neutralizantes/imunologia , Aorta/fisiopatologia , Fibrose , Interleucina-11/imunologia , Camundongos , Receptores de Interleucina-11/genética , Receptores de Interleucina-11/imunologia , Fator de Crescimento Transformador beta1/fisiologiaRESUMO
Importance: There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM. Objective: To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices. Design, Setting, and Participants: This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017. Main Outcome and Measures: The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation. Results: Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P < .001). This association was independent of all covariates, including midwall fibrosis measured by late gadolinium enhancement on cardiac magnetic resonance images (adjusted HR, 8.3; 95% CI, 1.8-37.6; P = .006). Having a TTNtv was also associated with the risk of receiving a shock (HR, 3.6; 95% CI, 1.1-11.6; P = .03). Individuals with a TTNtv and fibrosis had a greater rate of receiving appropriate device therapy than those with neither (HR, 16.6; 95% CI, 3.5-79.3; P < .001). Having a TTNtv was also a risk factor for developing new persistent atrial fibrillation (HR, 3.9; 95% CI, 1.3-12.0; P = .01). Conclusions and Relevance: Having a TTNtv was an important risk factor for clinically significant arrhythmia in patients with DCM and ICD or CRT-D devices. Having a TTNtv, especially in combination with midwall fibrosis confirmed with cardiovascular magnetic resonance imaging, may provide a risk stratification approach for evaluating the need for ICD therapy in patients with DCM. This hypothesis should be tested in larger studies.
Assuntos
Arritmias Cardíacas/genética , Cardiomiopatia Dilatada/genética , Conectina/genética , Adulto , Idoso , Arritmias Cardíacas/fisiopatologia , Cardiomiopatia Dilatada/fisiopatologia , Desfibriladores Implantáveis , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos RetrospectivosRESUMO
We combined eye-tracking technology with a test of facial affect recognition and a measure of self-reported social anxiety in order to explore the aetiology of social-perceptual deficits in Asperger's syndrome (AS). Compared to controls matched for age, IQ and visual-perceptual ability, we found a group of AS adults was impaired in their recognition of fearful and sad expressions and spent significantly less time fixating the eye region of all faces. For AS subjects, but not controls, the extent of the failure to fixate the eyes predicted the degree of impairment at recognising fearful expressions. In addition, poor fear recognition and reduced fixation of the eyes were independently associated with greater levels of social anxiety in AS individuals. These findings support the hypothesis that avoidance of emotionally arousing stimuli, such as eyes, contributes to social-perceptual impairment in AS. Furthermore, our findings are consistent with theories implicating amygdala-mediated over-arousal and anxiety in the development of these social-perceptual deficits.
Assuntos
Afeto/fisiologia , Síndrome de Asperger/complicações , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/etiologia , Transtornos da Personalidade/etiologia , Percepção Social , Adulto , Análise de Variância , Estudos de Casos e Controles , Movimentos Oculares/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estimulação Luminosa , Valor Preditivo dos Testes , Tempo de Reação/fisiologiaRESUMO
Using an attentional blink paradigm, we show that the typical enhancement of perception for emotionally arousing events is significantly reduced in Asperger's syndrome (AS) at short inter-target intervals. Control experiments demonstrate that this finding cannot be attributed to differences in the perceived arousal of the stimuli, or to a global impairment affecting any type of modulation of perceptual encoding. Because a functioning amygdala is critical for emotional modulation of the attentional blink, the findings support a role for the amygdala in the pathophysiology of AS. More specifically, they suggest there is a fundamental failure of the amygdala to modulate processing in cortex, a concept at the heart of some recent theories of amygdala involvement in the aetiology of autistic-spectrum disorders.
Assuntos
Nível de Alerta , Síndrome de Asperger/psicologia , Intermitência na Atenção Visual , Emoções , Expressão Facial , Reconhecimento Visual de Modelos , Semântica , Adulto , Tonsila do Cerebelo/fisiopatologia , Nível de Alerta/fisiologia , Síndrome de Asperger/diagnóstico , Síndrome de Asperger/fisiopatologia , Intermitência na Atenção Visual/fisiologia , Emoções/fisiologia , Medo , Feminino , Resposta Galvânica da Pele/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Reconhecimento Visual de Modelos/fisiologia , LeituraRESUMO
Individuals with autism are impaired in the recognition of fear, which may be due to their reduced tendency to look at the eyes. Here we investigated another potential perceptual and social consequence of reduced eye fixation. The eye region of the face is critical for identifying genuine, or sincere, smiles. We therefore investigated this ability in adults with autism. We used eye-tracking to measure gaze behaviour to faces displaying posed and genuine smiles. Adults with autism were impaired on the posed/genuine smile task and looked at the eyes significantly less than did controls. Also, within the autism group, task performance correlated with social interaction ability. We conclude that reduced eye contact in autism leads to reduced ability to discriminate genuine from posed smiles with downstream effects on social interaction.
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Transtorno Autístico/psicologia , Conscientização , Semântica , Sorriso , Adulto , Criança , Cognição , Expressão Facial , Feminino , Fixação Ocular , Humanos , Masculino , Percepção SocialRESUMO
BACKGROUND: Cardiac mass and volumes are often elevated in athletes, but it is not known whether moderate physical activity is also associated with cardiac dilatation and hypertrophy in a healthy adult population. METHODS AND RESULTS: In total, 1096 adults (54% female, median age 39 years) without cardiovascular disease or cardiomyopathy-associated genetic variants underwent cardiac magnetic resonance imaging to determine biventricular volumes and function. Physical activity was assessed using a validated activity questionnaire. The relationship between cardiac parameters and activity was assessed using multiple linear regression adjusting for age, sex, race, and systolic blood pressure. Logistic regression was performed to determine the effect of activity on the likelihood of subjects having cardiac dilatation or hypertrophy according to standard cardiac magnetic resonance normal ranges. Increasing physical activity was associated with greater left ventricular (LV) mass (ß=0.23; P<0.0001) and elevated LV and right ventricular volumes (LV: ß=0.26, P<0.0001; right ventricular: ß=0.26, P<0.0001). Physical activity had a larger effect on cardiac parameters than systolic blood pressure (0.06≤ß≤0.21) and a similar effect to age (-0.20≤ß≤-0.31). Increasing physical activity was a risk factor for meeting imaging criteria for LV hypertrophy (adjusted odds ratio 2.1; P<0.0001), LV dilatation (adjusted odds ratio 2.2; P<0.0001), and right ventricular dilatation (adjusted odds ratio 2.2; P<0.0001). CONCLUSIONS: Exercise-related cardiac remodeling is not confined to athletes, and there is a risk of overdiagnosing cardiac dilatation or hypertrophy in a proportion of active, healthy adults.
Assuntos
Cardiomegalia Induzida por Exercícios , Exercício Físico , Função Ventricular Esquerda , Função Ventricular Direita , Remodelação Ventricular , Adaptação Fisiológica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cardiomegalia/diagnóstico por imagem , Erros de Diagnóstico , Feminino , Voluntários Saudáveis , Humanos , Modelos Lineares , Modelos Logísticos , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Valor Preditivo dos Testes , Estudos Prospectivos , Volume Sistólico , Inquéritos e Questionários , Reino Unido , Adulto JovemRESUMO
Obesity is a major risk factor for cardiometabolic disease, but the effect of body composition on vascular aging and arterial stiffness remains uncertain. We investigated relationships among body composition, blood pressure, age, and aortic pulse wave velocity in healthy individuals. Pulse wave velocity in the thoracic aorta, an indicator of central arterial stiffness, was measured in 221 volunteers (range, 18-72 years; mean, 40.3±13 years) who had no history of cardiovascular disease using cardiovascular MRI. In univariate analyses, age (r=0.78; P<0.001) and blood pressure (r=0.41; P<0.001) showed a strong positive association with pulse wave velocity. In multivariate analysis, after adjustment for age, sex, and mean arterial blood pressure, elevated body fat% was associated with reduced aortic stiffness until the age of 50 years, thereafter adiposity had an increasingly positive association with aortic stiffness (ß=0.16; P<0.001). Body fat% was positively associated with cardiac output when age, sex, height, and absolute lean mass were adjusted for (ß=0.23; P=0.002). These findings suggest that the cardiovascular system of young adults may be capable of adapting to the state of obesity and that an adverse association between body fat and aortic stiffness is only apparent in later life.
Assuntos
Adiposidade/fisiologia , Envelhecimento/fisiologia , Aorta Torácica/fisiopatologia , Pressão Arterial/fisiologia , Doenças Cardiovasculares/fisiopatologia , Obesidade/complicações , Rigidez Vascular/fisiologia , Tecido Adiposo , Adolescente , Adulto , Fatores Etários , Idoso , Aorta Torácica/patologia , Velocidade do Fluxo Sanguíneo , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Imageamento Tridimensional , Incidência , Imagem Cinética por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Obesidade/fisiopatologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Reino Unido/epidemiologia , Adulto JovemRESUMO
By testing the facial fear-recognition ability of 341 men in the general population, we show that 8.8% have deficits akin to those seen with acquired amygdala damage. Using psychological tests and functional magnetic resonance imaging (fMRI) we tested the hypothesis that poor fear recognition would predict deficits in other domains of social cognition and, in response to socially relevant stimuli, abnormal activation in brain regions that putatively reflect engagement of the "social brain." On tests of "theory of mind" ability, 25 "low fear scorers" (LFS) performed significantly worse than 25 age- and IQ-matched "normal (good) fear scorers" (NFS). In fMRI, we compared evoked activity during a gender judgement task to neutral faces portraying different head and eye gaze orientations in 12 NFS and 12 LFS subjects. Despite identical between-group accuracy in gender discrimination, LFS demonstrated significantly reduced activation in amygdala, fusiform gyrus, and anterior superior temporal cortices when viewing faces with direct versus averted gaze. In a functional connectivity analysis, NFS show enhanced connectivity between the amygdala and anterior temporal cortex in the context of direct gaze; this enhanced coupling is absent in LFS. We suggest that important individual differences in social cognitive skills are expressed within the healthy male population, which appear to have a basis in a compromised neural system that underpins social information processing.
Assuntos
Mapeamento Encefálico , Emoções Manifestas/fisiologia , Medo , Reconhecimento Psicológico/fisiologia , Adulto , Tonsila do Cerebelo/irrigação sanguínea , Tonsila do Cerebelo/patologia , Tonsila do Cerebelo/fisiopatologia , Lesões Encefálicas/patologia , Lesões Encefálicas/fisiopatologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Julgamento/fisiologia , Imageamento por Ressonância Magnética/métodos , Masculino , Testes Neuropsicológicos/estatística & dados numéricos , Oxigênio/sangue , Valor Preditivo dos Testes , Lobo Temporal/irrigação sanguínea , Lobo Temporal/fisiologiaRESUMO
Turner syndrome (TS) is a chromosomal disorder of X-monosomy in females. A minority have impaired social responsiveness, poor discrimination of facial emotions (especially fear), and abnormal amygdala-cortical connectivity. We tested the hypothesis that abnormal gaze fixation, especially with the eye region of faces, would be associated with these features, in a similar pattern to that seen in subjects with autism. Furthermore, since these features tend to be more striking in TS women whose X chromosome is maternal in origin, we also predicted that there may be a difference within the Turner's group according to parental origin of the single X. Adults with 45,X karyotype and age and IQ matched 46,XX women were recruited and tested. Facial fear recognition was significantly worse in 45,X females than controls, but there were no group differences according to parental origin of their single X chromosome. Subsequently, we tested 45,X and 46,XX women using a remote eye-tracking device, as they viewed photographs of emotional human faces. Striking differences in scanpaths were found between the TS and controls, and within the TS group, but not according to parental origin of the X chromosome. These findings provide novel evidence for abnormal face processing in some women with TS, and indicate a potential neural mechanism underlying the difficulties in some key aspects of social cognition.