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BACKGROUND: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke. METHODS AND RESULTS: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population. CONCLUSIONS: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.
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Estudo de Associação Genômica Ampla , Hiperaldosteronismo , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/epidemiologia , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/epidemiologia , Predisposição Genética para Doença , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/epidemiologia , Povo Asiático/genética , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etnologia , População Branca/genética , Medição de Risco , Fatores de RiscoRESUMO
Beige adipocytes are inducible thermogenic adipocytes used for anti-obesity treatment. Beige adipocytes rapidly lose their thermogenic capacity once external cues are removed. However, long-term administration of stimulants, such as PPARγ and ß-adrenergic receptor agonists, is unsuitable due to various side effects. Here, we reported that PPARα pharmacological activation was the preferred target for maintaining induced beige adipocytes. Pemafibrate used in clinical practice for dyslipidemia was developed as a selective PPARα modulator (SPPARMα). Pemafibrate administration regulated the thermogenic capacity of induced beige adipocytes, repressed body weight gain, and ameliorated impaired glucose tolerance in diet-induced obese mouse models. The transcriptome analysis revealed that the E-twenty-six transcription factor ELK1 acted as a cofactor of PPARα. ELK1 was mobilized to the Ucp1 transcription regulatory region with PPARα and modulated its expression by pemafibrate. These results suggest that selective activation of PPARα by pemafibrate is advantageous to maintain the function of beige adipocytes.
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BACKGROUND: Hypertension imposes substantial health and economic burden worldwide. Primary aldosteronism (PA) is one of the most common causes of secondary hypertension, causing cardiovascular events at higher risk compared with essential hypertension. However, the germline genetic contribution to the susceptibility of PA has not been well elucidated. METHOD: We conducted a genome-wide association analysis of PA in the Japanese population and a cross-ancestry meta-analysis combined with UK Biobank and FinnGen cohorts (816 PA cases and 425 239 controls) to identify genetic variants that contribute to PA susceptibility. We also performed a comparative analysis for the risk of 42 previously established blood pressure-associated variants between PA and hypertension with the adjustment of blood pressure. RESULTS: In the Japanese genome-wide association study, we identified 10 loci that presented suggestive evidence for the association with the PA risk (P<1.0×10-6). In the meta-analysis, we identified 5 genome-wide significant loci (1p13, 7p15, 11p15, 12q24, and 13q12; P<5.0×10-8), including 3 of the suggested loci in the Japanese genome-wide association study. The strongest association was observed at rs3790604 (1p13), an intronic variant of WNT2B (odds ratio, 1.50 [95% CI, 1.33-1.69]; P=5.2×10-11). We further identified 1 nearly genome-wide significant locus (8q24, CYP11B2), which presented a significant association in the gene-based test (P=7.2×10-7). Of interest, all of these loci were known to be associated with blood pressure in previous studies, presumably because of the prevalence of PA among individuals with hypertension. This assumption was supported by the observation that they had a significantly higher risk effect on PA than on hypertension. We also revealed that 66.7% of the previously established blood pressure-associated variants had a higher risk effect for PA than for hypertension. CONCLUSIONS: This study demonstrates the genome-wide evidence for a genetic predisposition to PA susceptibility in the cross-ancestry cohorts and its significant contribution to the genetic background of hypertension. The strongest association with the WNT2B variants reinforces the implication of the Wnt/ß-catenin pathway in the PA pathogenesis.
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Hiperaldosteronismo , Hipertensão , Humanos , Estudo de Associação Genômica Ampla , Hipertensão/epidemiologia , Hipertensão/genética , Pressão Sanguínea/genética , Fatores de Risco , Predisposição Genética para Doença , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiologia , Hiperaldosteronismo/genética , Polimorfismo de Nucleotídeo Único , Loci GênicosRESUMO
DNA methylation and demethylation regulate the transcription of genes. DNA methylation-associated gene expression of adrenal steroidogenic enzymes may regulate cortisol production in cortisol-producing adenoma (CPA). We aimed to determine the DNA methylation levels of all genes encoding steroidogenic enzymes involved in CPA. Additionally, the aims were to clarify the DNA methylation-associated gene expression and evaluate the difference of CPA genotype from others using DNA methylation data. Twenty-five adrenal CPA and six nonfunctioning adrenocortical adenoma (NFA) samples were analyzed. RNA sequencing and DNA methylation array were performed. The methylation levels at 118 methylation sites of the genes were investigated, and their methylation and mRNA levels were subsequently integrated. Among all the steroidogenic enzyme genes studied, CYP17A1 gene was mainly found to be hypomethylated in CPA compared to that in NFA, and the Benjamini-Hochberg procedure demonstrated that methylation levels at two sites in the CYP17A1 gene body were statistically significant. PRKACA mutant CPAs predominantly exhibited hypomethylation of CYP17A1 gene compared with the GNAS mutant CPAs. Inverse associations between CYP17A1 methylation in three regions of the gene body and its mRNA levels were observed in the NFAs and CPAs. In applying clustering analysis using CYP17A1 methylation and mRNA levels, CPAs with PRKACA mutation were differentiated from NFAs and CPAs with a GNAS mutation. We demonstrated that CPAs exhibited hypomethylation of the CYP17A1 gene body in CPA, especially in the PRKACA mutant CPAs. Methylation of CYP17A1 gene may influence its transcription levels.
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Adenoma , Neoplasias do Córtex Suprarrenal , Adenoma Adrenocortical , Adenoma/genética , Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Metilação de DNA , Humanos , Hidrocortisona/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
DNA methylation alteration is tissue-specific and play a pivotal role in regulating gene transcription during cell proliferation and survival. We aimed to detect genes regulated by DNA methylation, and then investigated whether the gene influenced cell proliferation or survival in adrenal cells. DNA methylation and qPCR analyses were performed in nonfunctioning adrenocortical adenoma (NFA, n = 12) and aldosterone-producing adenoma (APA, n = 35) samples. The VDR gene promoter was markedly hypomethylated in APA with ATP1A1 mutation, and the promoter methylation levels showed a significant inverse association with the transcripts in APA. ATP1A1 mutation led to VDR transcription in HAC15 cells, and VDR suppression abrogated ATP1A1 mutation-mediated cell proliferation in HAC15 cells. We demonstrated that APA with ATP1A1 mutation showed entire hypomethylation in the VDR promoter and abundant VDR mRNA and protein expression. VDR suppression abrogated ATP1A1 mutation-mediated cell proliferation in HAC15 cells. Abundant VDR expression would be essential for ATP1A1 mutation-mediated cell proliferation.
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Adenoma , Adenoma Adrenocortical , Hiperaldosteronismo , Receptores de Calcitriol , ATPase Trocadora de Sódio-Potássio , Adenoma/genética , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Metilação de DNA/genética , Humanos , Hiperaldosteronismo/genética , Mutação/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA.
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Adenoma/patologia , Aldosterona/metabolismo , Proliferação de Células , ATPase Trocadora de Sódio-Potássio/genética , Adenoma/metabolismo , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Humanos , Mutação , Ouabaína/farmacologia , Fosforilação/efeitos dos fármacos , Pontos de Checagem da Fase S do Ciclo Celular , ATPase Trocadora de Sódio-Potássio/metabolismo , Transcriptoma , Quinases da Família src/metabolismoRESUMO
The intracellular molecular mechanisms underlying the genotype of cortisol-producing adenoma (CPA) have not been fully determined. We analyzed gene expressions in CPA and the human adrenocortical cell line (HAC15 cells) with PRKACA mutation. Clustering analysis using a gene set associated with responses to cAMP revealed the possible differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. The levels of STAR, CYP11A1, CYP17A1, CYP21A2, and FDX1 transcripts and cortisol levels per unit area in PRKACA mutant CPAs were significantly higher than those in GNAS mutant CPAs. PRKACA mutations led to an increase in steroidogenic enzyme expression and cortisol production in HAC15 cells. Transcriptome analysis revealed differences between PRKACA mutant CPAs and GNAS and CTNNB1 mutant CPAs. Cortisol production in PRKACA mutant CPAs is increased by the cAMP-PKA signaling pathway-mediated upregulation of steroidogenic enzymes transcription. The intracellular molecular mechanisms underlying these processes would be notably important in PRKACA mutant CPAs.
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Adenoma/genética , Cromograninas/genética , Síndrome de Cushing/genética , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Mutação , beta Catenina/genética , Adenoma/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Análise por Conglomerados , Síndrome de Cushing/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Hidrocortisona/metabolismo , Masculino , Pessoa de Meia-Idade , RNA-SeqRESUMO
BACKGROUND: Whether coronary plaque characteristics assessed in coronary computed tomography angiography (CCTA) in association with the coronary artery calcium score (CACS) have predictive value for coronary events is unclear. We aimed to examine the predictive value of the CACS and plaque characteristics for the occurrence of coronary events. METHODS: Among 2802 patients who were analyzed in the PREDICT registry, 2083 with suspected coronary artery disease (CAD) were studied using post hoc analysis. High-risk plaques were defined as having ≥2 adverse characteristics, such as low computed tomographic attenuation, positive remodeling, spotty calcification, and napkin-ring sign. An adjudicative composite of coronary events (cardiac death, nonfatal acute coronary syndrome, and coronary revascularization ≥3 months after indexed CCTA) were analyzed. RESULTS: Seventy-three (3.5%) patients had coronary events and 313 (15.0%) had high-risk plaques. Multivariate Cox proportional hazard analysis showed that high-risk plaques remained an independent predictor of coronary events (adjusted hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.13-3.34, P â= â0.0154), as well as the log-transformed CACS (adjusted HR 1.24, 95% CI 1.11-1.39, P â= â0.0002) and the presence of obstructive stenosis (adjusted HR 5.63, 95% CI 3.22-10.12, P 0.0001). In subgroup analyses, high-risk plaques were independently predictive only in the low CACS class (<100). CONCLUSION: This study shows that assessment of adverse features by coronary plaque imaging independently predicts coronary events in patients with suspected CAD and a low CACS. Our findings suggest that the clinical value of high-risk plaques to CACS and stenosis assessment appears marginal.
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Angiografia por Tomografia Computadorizada , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Estenose Coronária/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Placa Aterosclerótica , Calcificação Vascular/diagnóstico por imagem , Idoso , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/terapia , Estenose Coronária/mortalidade , Estenose Coronária/terapia , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Sistema de Registros , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Calcificação Vascular/mortalidade , Calcificação Vascular/terapiaRESUMO
Japanese Americans living in the United States are genetically identical to Japanese people, but have undergone a rapid and intense westernization of their lifestyle. This study investigated variability in glucagon secretion after glucose loading among Japanese Americans with normal glucose tolerance (NGT) according to obesity status. The 75-g oral glucose tolerance test (OGTT) was performed for 138 Japanese Americans (aged 40-75 years) living in Los Angeles. Plasma glucagon levels measured using the sandwich enzyme-linked immunosorbent assay were compared according to body mass index (BMI) categories among 119 individuals with NGT. The individuals were classified into three categories according to their BMI values: <22 kg/m2 (n = 37), 22-24.9 kg/m2 (n = 46), and ≥25 kg/m2 (n = 36). Fasting plasma glucagon levels and glucagon-area under the curve levels during the OGTT were the highest in the BMI ≥25 kg/m2 group. Fasting glucagon levels were correlated with BMI (r = 0.399, p < 0.001), fasting insulin levels (r = 0.275, p = 0.003) and the homeostasis model assessment-insulin resistance (r = 0.262, p = 0.004). In conclusion, our findings suggest that fasting hyperglucagonemia is associated with obesity and insulin resistance even during the NGT stage in the Japanese American population.
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Glucagon/sangue , Glucose/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Asiático , Glicemia/metabolismo , Índice de Massa Corporal , Feminino , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/etnologia , Resistência à Insulina/fisiologia , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/etnologia , Estados Unidos/epidemiologiaRESUMO
Pulmonary expression of angiotensin-converting enzyme 2, which is a receptor of severe acute respiratory syndrome coronavirus 2, is not regulated by angiotensin II or renin-angiotensin system inhibitors #COVID19 https://bit.ly/3fkopuO.
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BACKGROUND: There is a paucity of data comparing the long-term outcomes after inferior vena cava (IVC) filters placement for patients with acute venous thromboembolism (VTE) between those with and without active cancer. METHODS: In the COMMAND VTE Registry, we evaluated the effects of IVC filter use on the long-term clinical outcomes stratified by the presence and absence of active cancer. RESULTS: Among 2,626 patients with acute symptomatic VTE, there were 604 patients with active cancer, and 2022 patients without active cancer. IVC filters were placed and not retrieved in 455 patients (17%) in the entire cohort, in 150 patients (24.8%) in the active cancer stratum, and in 305 patients (15.1%) in the non-cancer stratum. In the entire cohort, non-retrieved IVC filter placement was not associated with a lower adjusted risk for PE recurrence (HR 0.59, 95% CI 0.30-1.15, P = 0.122), but with an increased adjusted risk for DVT recurrence (HR 2.27, 95% CI 1.43-3.60, P<0.001). In the non-cancer stratum, the non-retrieved IVC filter placement was associated with a decreased risk for PE (HR 0.29, 95% CI 0.09-0.93, P = 0.037), but not with an increased risk for DVT (HR 1.73, 95% CI 0.89-3.38, P = 0.108), while in the active cancer stratum, it was associated with an increased risk for DVT (HR 2.47, 95% CI 1.24-4.91, P = 0.010), but not with a decreased risk for PE (HR 0.82, 95% CI 0.34--1.96, P = 0.650). CONCLUSIONS: There were some differences in the risk-benefit balance between VTE patients with and without active cancer.
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Neoplasias , Embolia Pulmonar , Filtros de Veia Cava , Tromboembolia Venosa , Humanos , Neoplasias/complicações , Embolia Pulmonar/epidemiologia , Recidiva , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Veia Cava Inferior , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/prevenção & controleRESUMO
Endovascular therapy (EVT) was performed in two cases with chronic total occlusion (CTO) of superficial femoral artery. In these cases, angioscopy was deployed in the backyard of the CTO lesion from popliteal artery retrogradely, then the guidewire was advanced from antegrade. When the wire crossed the distal of the CTO lesion, the wire penetration was clearly visualized by the retrograde-angioscopy. Therefore, wire crossing of CTO into the distal true lumen was certainly confirmed, and EVT was successful.
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The instantaneous wave-free ratio (iFR) is used for assessing the hemodynamic severity of a lesion, as an alternative to the fractional flow reserve (FFR). We evaluated the relationship between iFR and FFR in detail and the clinical significance of iFR in patients with mild to intermediate coronary artery stenosis. We recruited consecutive 323 patients (421 lesions) with lesions exhibiting 30% to 80% diameter stenosis on angiography in whom FFR and iFR were measured. In the total lesions, mean diameter stenosis was 48.6% ± 9.0%, and physiological significance, defined by FFR of 0.80 or less or by iFR of 0.92 or less, was observed in 32.5% or 33.5%, respectively. Mismatch between iFR and FFR was observed in 18.1% of the lesions. Clinical factors did not predict FFR value; however, gender, diabetes mellitus, aortic stenosis, anemia, high-sensitivity CRP value, and renal function predicted iFR value. In multivariate logistic analysis after adjustment for FFR value, gender (p < 0.001), diabetes mellitus (p = 0.005), aortic stenosis (p = 0.016), high-sensitivity CRP (p < 0.001), and renal function (p = 0.003) were all independent predictors of iFR value. In Kaplan-Meier analysis, the baseline iFR predicted the subsequent major cardiovascular events (MACE) (hazard ratio, 2.40; 95% CI, 1.16-4.93; p = 0.018) and the results of the iFR-guided strategy for predicting rates of MACE and myocardial infarction/revascularization were superior to those of the FFR-guided strategy. In conclusion, significant clinical factors predicted iFR value, which affected the prognostic capacity. The iFR-guided strategy may be superior in patients with mild to intermediate stenosis.
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Estenose Coronária/diagnóstico , Idoso , Angiografia Coronária , Estenose Coronária/fisiopatologia , Feminino , Reserva Fracionada de Fluxo Miocárdico , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
We sought here to induce the excision of a large intragenic segment within the intact dystrophin gene locus, with the ultimate goal to elucidate dystrophin protein function and stability in striated muscles in vivo. To this end, we implemented an inducible-gene excision methodology using a floxed allele approach, demarcated by dystrophin exons 2-79, in complementation with a cardiac and skeletal muscle directed gene deletion system for spatial-temporal control of dystrophin gene excision in vivo. Main findings of this study include evidence of significant intact dystrophin gene excision, ranging from ~ 25% in heart muscle to ~ 30-35% in skeletal muscles in vivo. Results show that despite evidence of significant dystrophin gene excision, no significant decrease in dystrophin protein content was evident by Western blot analysis, at three months post excision in skeletal muscles or by 6 months post gene excision in heart muscle. Challenges of in vivo dystrophin gene excision revealed acute deleterious effects of tamoxifen on striated muscles, including a transient down regulation in dystrophin gene transcription in the absence of dystrophin gene excision. In addition, technical limitations of incomplete dystrophin gene excision became apparent that, in turn, tempered interpretation. Collectively, these findings are in keeping with earlier studies suggesting the dystrophin protein to be long-lived in striated muscles in vivo; however, more rigorous quantitative analysis of dystrophin stability in vivo will require future works in which more complete gene excision can be demonstrated, and without significant off-target effects of the gene deletion experimental platform per se.
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Marcação de Genes/métodos , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Cardiomiopatias/induzido quimicamente , Distrofina/deficiência , Distrofina/genética , Feminino , Deleção de Genes , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes/métodos , Coração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/metabolismo , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/metabolismo , Estabilidade Proteica , Tamoxifeno/farmacologia , Tamoxifeno/toxicidadeRESUMO
A medical survey of Japanese Americans have been carried out since 1970; in particular, this survey was administered to the Japanese emigrants from Hiroshima (Japan) to Hawaii or Los Angeles (USA) and their offspring. Labeled the Hawaii-Los Angeles-Hiroshima Study, it constituted a long-term epidemiological study of Japanese Americans who are genetically identical to the native Japanese people, but have experienced rapid and intense Westernization in terms of their lifestyles. The authors have compared the medical survey data procured from two Japanese populations, evincing very disparate lifestyles; that is, the native Japanese inhabitants of Hiroshima (Japan) and Japanese Americans living in Hawaii or Los Angeles (USA). The focus was particularly on differences in the intake of nutrients, the frequency of obesity, the prevalence of metabolic syndrome and diabetes mellitus, and the progression of atherosclerosis. The authors believe that the health effects of the lifestyles of Japanese Americans can predict the imminent health prospects of native Japanese people who adopt Westernized lifestyles in Japan. This review thus summarized the major results accumulated from the Hawaii-Los Angeles-Hiroshima Study over the past 50 years.
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Aterosclerose/epidemiologia , Diabetes Mellitus/epidemiologia , Dieta Ocidental/efeitos adversos , Estilo de Vida , Síndrome Metabólica/epidemiologia , Obesidade/fisiopatologia , Asiático , Havaí/epidemiologia , Comportamentos Relacionados com a Saúde , Humanos , Japão/epidemiologia , Los Angeles/epidemiologia , Fatores de Tempo , OcidenteRESUMO
The endoplasmic reticulum (ER) plays a pivotal role in syntheses of proteins and steroid hormones and regulation of intracellular Ca2+ level. We aimed to investigate ER-associated genes in aldosterone-producing adenomas (APAs) and clarify their effect on aldosterone production. Microarray analysis targeting 288 ER-associated genes was conducted using nonfunctioning adrenocortical adenomas (n=5) and APAs (n=19). Immunohistochemistry and quantitative polymerase chain reaction analyses were performed with 13 nonfunctioning adrenocortical adenoma and 48 APA samples. Functional studies were performed with human adrenocortical carcinoma (HAC15) cells, some of which were genetically modified using lentiviruses. The ER chaperone calmegin (CLGN) was the most highly expressed ER-associated gene in APAs relative to nonfunctioning adrenocortical adenomas. Analysis with quantitative polymerase chain reaction revealed CLGN to be 9.5-fold upregulated in APAs relative to nonfunctioning adrenocortical adenomas. There were no differences among different APA genotypes affecting aldosterone production. Immunohistochemistry analysis revealed that CLGN was strongly expressed in APAs and aldosterone-producing cell clusters. Angiotensin II stimulation or KCNJ5 T158A overexpression in HAC15 cells did not affect CLGN mRNA levels. CLGN overexpression in HAC15 cells increased aldosterone levels but did not stimulate CYP11B2 mRNA levels. Pathway and gene ontology analyses using RNA sequencing results showed that tRNA aminoacyl metabolism was the most enriched pathway in CLGN-overexpressing cells. CYP11B2 (aldosterone synthase) and HSD3B2 (3 beta-hydroxysteroid dehydrogenase/delta 5->4-isomerase type 2) protein expression were more abundant in CLGN-overexpressing cells. CLGN knockdown using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9) method in HAC15 cells that carry the KCNJ5 mutation did not affect aldosterone production. To summarize, CLGN was upregulated and associated with aldosterone production via translational regulation of CYP11B2 in APAs.
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Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , Proteínas de Ligação ao Cálcio/genética , Retículo Endoplasmático/metabolismo , Regulação Neoplásica da Expressão Gênica , Chaperonas Moleculares/genética , Neoplasias Experimentais , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/patologia , Animais , Proteínas de Ligação ao Cálcio/biossíntese , Masculino , Chaperonas Moleculares/biossíntese , RNA Neoplásico/genética , Ratos , Ratos Endogâmicos Dahl , Testículo , Regulação para CimaRESUMO
BACKGROUND: Late gadolinium enhancement imaging (LGE) of the left ventricle (LV) by cardiac magnetic resonance (CMR) has prognostic value for patients with cardiac sarcoidosis (CS). Right ventricle (RV) dysfunction is also associated with adverse outcomes in patients with heart failure. Therefore, we sought to determine if RV LGE and dysfunction predicted adverse events in patients with suspected CS. METHODS: In 103 consecutive patients with suspected CS who underwent CMR, functional and remodeling indexes of both the LV and RV were measured and the extent and localization of LGE were also analyzed. Major adverse cardiac events (MACE) were defined as cardiovascular mortality, severe ventricular tachyarrhythmia, hospitalization with heart failure, and advanced atrioventricular block. RESULTS: During a median follow-up of 20.6 months, Kaplan-Meier analysis showed that decreased RV ejection fraction (EF) was associated with MACE (P < 0.001) and receiver operating characteristics curve (ROC) analysis indicated good predictive performance of RV EF for MACE (area under the ROC = 0.834). RV EF operated independently of LV EF or LGE extent for predicting MACE. In addition, the presence of LGE in RV was independently associated with MACE (P = 0.011), and a combined analysis of RV EF and RV LGE showed better risk stratification for MACE (P < 0.001). CONCLUSIONS: Both RV EF and LGE were independently associated with MACE and enhanced risk stratification in patients with suspected CS. CMR may be a useful tool for detecting myocardial function and fibrosis in both the LV and RV.
Assuntos
Cardiomiopatias/diagnóstico , Ventrículos do Coração/fisiopatologia , Imagem Cinética por Ressonância Magnética/métodos , Medição de Risco , Sarcoidose/diagnóstico , Volume Sistólico/fisiologia , Função Ventricular Direita/fisiologia , Idoso , Cardiomiopatias/fisiopatologia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Prognóstico , Estudos Prospectivos , Fatores de Risco , Sarcoidose/fisiopatologiaRESUMO
BACKGROUND: Visual-functional mismatch between coronary angiography and fractional flow reserve (FFR) has been reported, and the underlying reason remains poorly understood. Therefore, the relationship between angiographic measurements and FFR was evaluated, and predictors for FFR in intermediate coronary artery stenosis were determined. METHODS: Consecutive 314 patients (405 lesions) with a lesion of 30-80% angiographic diameter stenosis who underwent invasive FFR were recruited. The myocardial area supplied by the coronary artery distal to the stenosis was evaluated using a modified version of the Bypass Angioplasty Revascularization Investigation (BARI) score. Participants underwent follow-up, and major cardiovascular events (MACE), including all-cause death, myocardial infarction (MI), and unplanned revascularization were recorded. RESULTS: Although % diameter stenosis was correlated with FFR (R = 0.279, P < 0.001), diameter stenosis-FFR mismatch was observed in 37.8% of the lesions. Although FFR values were not associated with clinical factors, such as age, sex, and comorbidities, it was correlated with minimal lumen diameter (MLD), diffuse lesion, presence of proximal lesion, and BARI score. In addition, the lesions in left anterior descending (LAD) coronary artery showed low FFR values compared with those in the left circumflex coronary artery or right coronary artery. In multivariate logistic analysis, MLD (ß coefficient = 0.330), diffuse lesion (ß coefficient = -0.266), proximal lesion (ß coefficient = -0.144), BARI score (ß coefficient = -0.219), and LAD lesion (ß coefficient = -0.293) were all independent predictors for FFR value. The estimated FFR value based on these factors showed smaller mismatch and higher sensitivity. No difference was observed in the event rates for MACE and MI or revascularization between the FFR-guided and estimated FFR-guided strategies. CONCLUSIONS: MLD, diffuse lesion, proximal lesion, BARI score, and lesion vessel were independent predictors for FFR in intermediate coronary stenosis. Not only the extent of local lesion stenosis but also the amount of myocardial supply and the lesion location may determine the physiological significance and explain the visual-functional mismatch. The estimation of FFR by these factors may be useful in clinical practice.
Assuntos
Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Idoso , Causas de Morte , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/epidemiologia , Índice de Gravidade de DoençaRESUMO
The aim of this study was to investigate possible associations of nutrient intake on glaucoma in subjects of Japanese descent living in Los Angeles, CA.In this cross-sectional study, 581 Japanese American participants in Los Angeles underwent an interview, fundus photography, comprehensive physical, and blood examinations, along with determining the body mass index status and any confounding factors. CDSketch was used to measure the cup-disc ratio and rim width of each fundus in the retinal photographs. A multivariate logistic regression test with adjustment for confounding factors was used to assess the association between glaucoma and nutrient intake.A total of 61 of 581 participants were diagnosed with glaucoma in this study. Multivariate logistic regression analysis showed that a high intake of iron (odds ratio [OR]: 1.303, Pâ=â.004), low intake of vitamin A (OR: 0.365, Pâ=â.019), and vegetable fat (OR: 0.957, Pâ=â.004) were associated with an increased risk of glaucoma.Current findings showed that high iron intake and low vitamin A and vegetable fat intake appeared to be associated with an increased risk of glaucoma in subjects of Japanese descent living in the Los Angeles populations.
Assuntos
Asiático , Glaucoma/etnologia , Glaucoma/epidemiologia , Estado Nutricional , Estudos Transversais , Ingestão de Energia , Feminino , Humanos , Ferro da Dieta/administração & dosagem , Japão/etnologia , Los Angeles/epidemiologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Verduras , Deficiência de Vitamina A/epidemiologiaRESUMO
AIMS/INTRODUCTION: The severity of insulin resistance is higher in Japanese-American people with American lifestyles than in native Japanese people with Japanese lifestyles. Recently, the role of gut microbiota in the control of host metabolic homeostasis and organ physiology has been recognized. In addition, gut microbiota alterations have been suggested to contribute to pathogenesis of insulin resistance. The principle aim of the present study was to evaluate the impact of a Westernized lifestyle on the gut microbiota of Japanese-Americans versus native Japanese, and its correlation with insulin resistance. MATERIALS AND METHODS: A total of 14 native Japanese men living in Hiroshima, Japan, and 14 Japanese-American men living in Los Angeles, USA, were included. A 75-g oral glucose tolerance test was carried out for all participants to assess their glucose tolerance, and normal glucose tolerance was observed. We compared the insulin response with oral glucose load, the Matsuda Index, and the composition of the gut microbiota between the native Japanese and Japanese-American men. RESULTS: Japanese-American men showed higher area under the curve values for serum insulin concentrations during the oral glucose tolerance test and lower Matsuda Index than native Japanese men. Gut microbiota composition of the Japanese-American men was different; in particular, they showed a relatively lower abundance of Odoribacter than native Japanese men. The ratio between relative abundance of Odoribacter and Matsuda Index was positively correlated between the two groups. CONCLUSIONS: Our findings suggest that Westernized lifestyles alter gut microbiota, and its alteration might induce insulin resistance in non-diabetic Japanese men.