RESUMO
AIMS: Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is characterized by fibrofatty infiltration of the myocardium and ventricular arrhythmias that may lead to sudden cardiac death. It has been observed that male patients develop the disease earlier and present with more severe phenotypes as compared to females. Thus, we hypothesized that serum levels of sex hormones may contribute to major arrhythmic cardiovascular events (MACE) in patients with ARVC/D. METHODS AND RESULTS: The serum levels of five sex hormones, sex hormone-binding globulin, high sensitivity troponin T, pro-brain natriuretic peptide, cholesterol, triglycerides, insulin, and glucose were measured in 54 ARVC/D patients (72% male). Twenty-six patients (48%) experienced MACE. Total and free testosterone levels were significantly increased in males with MACE as compared to males with a favourable outcome, whereas estradiol was significantly lower in females with MACE as compared to females with a favourable outcome. Increased testosterone levels remained independently associated with MACE in males after adjusting for age, body mass index, Task Force criteria, ventricular function, and desmosomal mutation status. Furthermore, an induced pluripotent stem cell-derived ARVC/D cardiomyocyte model was used to investigate the effects of sex hormones. In this model, testosterone worsened and estradiol improved ARVC/D-related pathologies such as cardiomyocyte apoptosis and lipogenesis, strongly supporting our clinical findings. CONCLUSIONS: Elevated serum testosterone levels in males and decreased estradiol levels in females are independently associated with MACE in ARVC/D, and directly influence disease pathology. Therefore, determining the levels of sex hormones may be useful for risk stratification and may open a new window for preventive interventions.
Assuntos
Displasia Arritmogênica Ventricular Direita/etiologia , Hormônios Esteroides Gonadais/metabolismo , Caracteres Sexuais , Adulto , Análise de Variância , Displasia Arritmogênica Ventricular Direita/sangue , Biomarcadores/metabolismo , Morte Súbita Cardíaca/etiologia , Desmossomos/genética , Estradiol/metabolismo , Exercício Físico/fisiologia , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Miócitos Cardíacos/fisiologia , Prognóstico , Testosterona/metabolismoRESUMO
Cellular reprogramming of somatic cells to patient-specific induced pluripotent stem cells (iPSCs) enables in-vitro modeling of human cardiac disorders for pathogenic and therapeutic investigations. However, using iPSC-derived cardiomyocytes (iPSC-CMs) to model an adult-onset heart disease remains challenging because of the uncertainty regarding the ability of relatively immature iPSC-CMs to fully recapitulate adult disease phenotypes. Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited cardiomyopathy characterized by pathological fibrofatty infiltration and cardiomyocyte (CM) loss predominantly in the right ventricle (RV), leading to heart failure and lethal arrhythmias. Over 50% of affected individuals have desmosome gene mutations, most commonly inPKP2encoding plakophilin-2. Using Yamanaka's pluripotent factors, we generated iPSC lines from ARVD patients withPKP2mutations. We first developed a method to induce metabolic maturation of iPSC-CMs and showed that induction of adult-like metabolic energetics from an embryonic/glycolytic state is essential to model an adult-onset cardiac disease using patient-specific iPSCs. Furthermore, we showed that coactivation of normal peroxisome proliferator-activated receptor (PPAR)-α and abnormal PPARγ pathways in ARVD iPSC-CMs resulted in exaggerated CM lipogenesis, CM apoptosis, Na(+)channel downregulation and defective intracellular calcium handling, recapitulating the pathological signatures of ARVD. Using this model, we revealed novel pathogenic insights that metabolic derangement in an adult-like metabolic milieu underlies ARVD pathologies, enabling us to propose novel disease-modifying therapeutic strategies.
Assuntos
Displasia Arritmogênica Ventricular Direita/metabolismo , Displasia Arritmogênica Ventricular Direita/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Cardiovasculares , Adulto , Displasia Arritmogênica Ventricular Direita/genética , Diferenciação Celular , Células Cultivadas , Reprogramação Celular , Desmossomos/genética , Humanos , Mutação , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , PPAR alfa/metabolismo , PPAR gama/metabolismo , Placofilinas/genéticaRESUMO
BACKGROUND: Patient financial burden with chronic disease poses significant health risks, yet it remains outside the scope of clinical visits. Little is known about how physicians perceive their patients' health-related financial burden in the context of primary care. The purpose of this study was to describe physician experiences with patients' financial burden while managing chronic disease and the communication of these issues. METHODS: In November 2013, four focus groups were conducted in an academic medical center. A convenience sample of 29 internal and family medicine resident physicians was used in this study. A semi-structured interview protocol was employed by trained facilitators. Coded transcripts were analyzed for themes regarding physicians' experiences with identifying, managing, and communicating financial burden with their patients in the context of primary care. RESULTS: Major themes identified were 1) patient financial burden with chronic care is visible to physicians, 2) patient's financial burden with chronic care and discussing these issues is important to physicians, 3) ability to identify patients who perceive financial burden is imperfect, 4) communication of financial burden with patients is complex and difficult to navigate, 5) strategies utilized to address concerns are not always generalizable, and 6) physicians have ideas for widespread change to make these conversations easier for them. CONCLUSION: Awareness of physician perspectives in identifying and addressing their patients' disease-related financial burden may better equip researchers and medical educators to develop interventions that aid care teams in better understanding these patient concerns to promote compliance with treatment recommendations.
Assuntos
Doença Crônica/economia , Comunicação , Financiamento Pessoal , Conhecimentos, Atitudes e Prática em Saúde , Relações Médico-Paciente , Médicos/psicologia , Adulto , Doença Crônica/terapia , Feminino , Grupos Focais , Humanos , Masculino , Cooperação do Paciente , Atenção Primária à Saúde , Pesquisa QualitativaRESUMO
BACKGROUND: Little uniformity exists in the clinical and histologic variables reported with primary Merkel cell carcinoma (MCC). OBJECTIVE: To provide a rigorous descriptive analysis of a contemporary cohort and promote the prospective collection of detailed data on MCC for future outcome studies. METHODS AND MATERIALS: A detailed descriptive analysis was performed for clinical and histologic features of 147 patients with 150 primary MCC tumors in a prospectively collected database from 2006 to 2010. RESULTS: The majority (73.5%) of patients were at American Joint Committee on Cancer clinical stage I or II at presentation, 20.4% at stage III, and 6.1% at stage IV. Detailed descriptive clinical and histologic findings are presented. CONCLUSION: Clinical and histologic profiling of primary MCC in the literature is variable and limited. Systematic prospective collection of MCC data is needed for future outcome studies and the ability to compare and share data from multiple sources for this relatively rare tumor.
Assuntos
Carcinoma de Célula de Merkel/patologia , Neoplasias Cutâneas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Extremidades/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/epidemiologia , PrognósticoRESUMO
OBJECTIVE: To determine whether differentially methylated CpGs in synovium-derived fibroblast-like synoviocytes (FLS) of patients with rheumatoid arthritis (RA) were also differentially methylated in RA peripheral blood (PB) samples. METHODS: For this study, 371 genome-wide DNA methylation profiles were measured using Illumina HumanMethylation450 BeadChips in PB samples from 63 patients with RA and 31 unaffected control subjects, specifically in the cell subsets of CD14+ monocytes, CD19+ B cells, CD4+ memory T cells, and CD4+ naive T cells. RESULTS: Of 5,532 hypermethylated FLS candidate CpGs, 1,056 were hypermethylated in CD4+ naive T cells from RA PB compared to control PB. In analyses of a second set of CpG candidates based on single-nucleotide polymorphisms from a genome-wide association study of RA, 1 significantly hypermethylated CpG in CD4+ memory T cells and 18 significant CpGs (6 hypomethylated, 12 hypermethylated) in CD4+ naive T cells were found. A prediction score based on the hypermethylated FLS candidates had an area under the curve of 0.73 for association with RA case status, which compared favorably to the association of RA with the HLA-DRB1 shared epitope risk allele and with a validated RA genetic risk score. CONCLUSION: FLS-representative DNA methylation signatures derived from the PB may prove to be valuable biomarkers for the risk of RA or for disease status.