RESUMO
The 88thAnnual Scientific Meeting of the Japanese Circulation Society (JCS2024) was held from Friday, March 8thto Sunday, March 10thin Kobe, Japan. The main theme of this 3-day meeting was "The Future of Cardiology: Challenges in Overcoming Cardiovascular Disease". As COVID-19 has been finally conquered, with revision of its categorization under the Infectious Disease Control Law and relaxation of infection prevention measures, it was once again possible to have face-to-face presentations and lively discussion. JCS2024 was a major success, with 19,209 participants and attendees, thanks to the greatly appreciated cooperation and support from all affiliates.
RESUMO
Elevated circulating homocysteine (Hcy) is a well-known risk factor for cardiovascular diseases (CVDs), including coronary artery disease (CAD) and heart failure (HF). It remains unclear how Hcy and its derivatives relate to left ventricular (LV) diastolic function. The aim of the present study was to investigate the relationship between plasma Hcy-related metabolites and diastolic dysfunction (DD) in patients with heart disease (HD). A total of 62 HD patients with preserved LV ejection fraction (LVEF ≥ 50%) were enrolled. Plasma Hcy and its derivatives were measured by liquid chromatographyâmass spectrometry (LC-MS/MS). Spearman's correlation test and multiple linear regression models were used to analyze the associations between metabolite levels and LV diastolic function. The cystine/methionine (CySS/Met) ratio was positively correlated with LV diastolic function, which was defined from the ratio of mitral inflow E and mitral e' annular velocities (E/e') (Spearman's r = 0.43, p < 0.001). When the subjects were categorized into two groups by E/e', the high-E/e' group had a significantly higher CySS/Met ratio than the low-E/e' group (p = 0.002). Multiple linear regression models revealed that the CySS/Met ratio was independently associated with E/e' after adjustment for age, sex, body mass index (BMI), diabetes mellitus, hypertension, chronic kidney disease (CKD),ãhemoglobin, and lipid peroxide (LPO) {standardized ß (95% CI); 0.14 (0.04-0.23); p = 0.005}. Hcy, CySS, and Met did not show a significant association with E/e' in the same models. A high plasma CySS/Met ratio reflected DD in patients with HD.
Assuntos
Cistina , Disfunção Ventricular Esquerda , Humanos , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia , Metionina , Cromatografia Líquida , Espectrometria de Massas em Tandem , Função Ventricular Esquerda , Volume Sistólico , DiástoleRESUMO
Alterations in cardiac metabolism are strongly associated with the pathogenesis of heart failure (HF). We recently reported that glutamine-dependent anaplerosis, termed glutaminolysis, was activated by H2O2 stimulation in rat cardiomyocytes, which seemed to be an adaptive response by which cardiomyocytes survive acute stress. However, the molecular mechanisms and fundamental roles of glutaminolysis in the pathophysiology of the failing heart are still unknown. Here, we treated wild-type mice (C57BL/6J) and rat neonatal cardiomyocytes (RNCMs) and fibroblasts (RNCFs) with angiotensin II (ANG II) to induce pathological cardiac remodeling. Glutaminase 1 (GLS1), a rate-limiting glutaminolysis enzyme, was significantly increased in ANG II-induced mouse hearts, RNCMs and RNCFs. Unexpectedly, a GLS1 inhibitor attenuated ANG II-induced left ventricular hypertrophy and fibrosis in the mice, and gene knockdown and pharmacological perturbation of GLS1 suppressed hypertrophy and the proliferation of RNCMs and RNCFs, respectively. Using mass spectrometry (MS)-based stable isotope tracing with 13C-labeled glutamine, we observed glutamine metabolic flux in ANG II-treated RNCMs and RNCFs. The incorporation of 13C atoms into tricarboxylic acid (TCA) cycle intermediates and their derivatives was markedly enhanced in both cell types, indicating the activation of glutaminolysis in hypertrophied hearts. Notably, GLS1 inhibition reduced the production of glutamine-derived aspartate and citrate, which are required for the biosynthesis of nucleic acids and lipids, possibly contributing to the suppression of cardiac hypertrophy and fibrosis. The findings of the present study reveal that GLS1-mediated upregulation of glutaminolysis leads to maladaptive cardiac remodeling. Inhibition of this anaplerotic pathway could be a novel therapeutic approach for HF.NEW & NOTEWORTHY To our knowledge, this study is the first to demonstrate that increased GLS1 expression and subsequent activation of glutaminolysis are associated with exacerbation of cardiac hypertrophy and fibrosis. Inhibiting GLS1 antagonized the adverse cardiac remodeling in vitro and in vivo, partly due to reduction of glutamine-derived metabolites, which are necessary for cellular growth and proliferation. Increased glutamine utilization for anabolic reactions in cardiac cells may be related to the pathogenesis and development of HF.
Assuntos
Glutaminase , Remodelação Ventricular , Animais , Glutaminase/genética , Glutaminase/metabolismo , Glutamina/metabolismo , Peróxido de Hidrogênio , Camundongos , Camundongos Endogâmicos C57BL , RatosRESUMO
BACKGROUND: Metabolic remodeling in cardiomyocytes is deeply associated with the pathogenesis of heart failure (HF). Glutaminolysis is an anaplerotic pathway that incorporates α-ketoglutarate (αKG) derived from glutamine into the tricarboxylic acid (TCA) cycle. It is well known that cancer cells depend on glutamine for their increased energy demand and proliferation; however, the physiological roles of glutamine metabolism in failing hearts remain unclear. OBJECTIVE: To investigate the regulatory mechanisms and biological effects of glutamine metabolism in oxidative stress-induced failing myocardium. METHODS AND RESULTS: The intracellular levels of glutamine, glutamate, and αKG were significantly decreased by H2O2 stimulation in rat neonatal cardiomyocytes (RNCMs). To better understand the metabolic flux in failing myocardium, we performed a stable isotope tracing study and found that glutaminolysis was upregulated in RNCMs under oxidative stress. Consistent with this, the enzymatic activity of glutaminase (Gls), which converts glutamine to glutamate, was augmented in RNCMs treated with H2O2. These findings suggest that glutamine anaplerosis is enhanced in cardiomyocytes under oxidative stress to compensate for the reduction of αKG. Furthermore, the inhibition of Gls reduced cardiac cell viability, ATP production, and glutathione (GSH) synthesis in RNCMs with H2O2 stimulation. Finally, we evaluated the effects of αKG on failing myocardium and observed that dimethyl α-ketoglutarate (DMKG) suppressed oxidative stress-induced cell death likely due to the enhancement of intracellular ATP and GSH levels. CONCLUSION: Our study demonstrates that under oxidative stress, glutaminolysis is upregulated to compensate for the loss of αKG and its replenishment into the TCA cycle, thereby exerting cardioprotective effects by maintaining ATP and GSH levels. Modulation of glutamine metabolism in failing hearts might provide a new therapeutic strategy for HF.
Assuntos
Glutamina/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Animais Recém-Nascidos , Sobrevivência Celular , Células Cultivadas , Ciclo do Ácido Cítrico , Metabolismo Energético , Ácido Glutâmico/metabolismo , Glutaminase/metabolismo , Insuficiência Cardíaca/metabolismo , Ácidos Cetoglutáricos/metabolismo , Redes e Vias Metabólicas , Miócitos Cardíacos/citologia , Estresse Oxidativo , RatosRESUMO
Assessment of frailty is important for risk stratification among the elderly with severe aortic stenosis (AS) when considering interventions such as surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). However, evidence of the impact of preoperative frailty on short-term postoperative outcomes or functional recovery is limited. This retrospective study included 234 consecutive patients with severe AS who underwent SAVR or TAVR at Kobe University Hospital between Dec 2013 and Dec 2019. Primary outcomes were postoperative complications, postoperative 6-min walking distance (6MWD), and home discharge rates. The mean age was 82 ± 6.6 years. There were 169 (SAVR: 80, TAVR: 89) and 65 (SAVR: 20, TAVR: 45) patients in the non-frail and frail groups, respectively (p = 0.02). The postoperative complication rates in the frail group were significantly higher than those in the non-frail group [30.8% (SAVR: 35.0%, TAVR: 28.9%) vs. 10.7% (SAVR: 15.0%, TAVR: 6.7%), p < 0.001]. The home discharge rate in the non-frail group was significantly higher than that in the frail group [85.2% (SAVR: 81.2%, TAVR: 88.8%) vs. 49.2% (SAVR: 55.0%, TAVR: 46.7%), p < 0.001]. The postoperative 6MWD in the non-frail group was significantly longer than that in the frail group [299.3 ± 87.8 m (SAVR: 321.9 ± 90.8 m, TAVR: 281.1 ± 81.3 m) vs. 141.9 ± 92.4 m (SAVR: 167.8 ± 92.5 m, TAVR: 131.6 ± 91.3 m), p < 0.001]. The TAVR group did not show a decrease in the 6MWD after intervention, regardless of frailty. We report for the first time that preoperative frailty was strongly associated with postoperative complications, 6MWD, and home discharge rates following both SAVR and TAVR. Preoperative frailty assessment may provide useful indications for planning better individualized therapeutic interventions and supporting comprehensive intensive care before and after interventions.
Assuntos
Estenose da Valva Aórtica , Fragilidade , Implante de Prótese de Valva Cardíaca , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/diagnóstico , Estenose da Valva Aórtica/cirurgia , Tolerância ao Exercício , Fragilidade/complicações , Fragilidade/diagnóstico , Humanos , Alta do Paciente , Complicações Pós-Operatórias/epidemiologia , Estudos Retrospectivos , Substituição da Valva Aórtica Transcateter/efeitos adversosRESUMO
BACKGROUND: Postoperative delirium (POD) is a critical complication that is closely associated with mortality and major morbidity in elective cardiac surgery. The identification of patients at risk for POD is crucial but has not been fully explored. AIMS: The aim of this study was to determine the predictive value of the assessment of preoperative exercise capacity for POD. METHODS: We enrolled 313 consecutive patients (mean age, 68.6 ± 14.8 years) undergoing elective cardiac surgery. We measured physical functions such as the 6-minute walking distance (6MWD) and Timed Up-and-Go test (TUG) before surgery. The assessment of delirium was conducted every 8 h from the day of surgery to 5 days after surgery using the Intensive Care Delirium Screening Checklist. RESULTS: POD occurred in 46 patients (14.6%). Age, 6MWD, TUG, serum hemoglobin, estimated glomerular filtration rate, and length of intensive care unit stay were significantly different based on the presence or absence of POD (p < 0.05 for each). After multivariate analysis, 6MWD remained a statistically significant indicator for developing POD (OR 0.98; p = 0.02). The cut-off value of 6MWD for predicting POD was 345 m (AUC = 0.75; p = 0.001). CONCLUSIONS: Poor exercise capacity was found to be an independent predictor of POD following elective cardiac surgery. This finding suggests the importance of preoperative functional evaluation in the prevention and management of POD in cardiac surgery patients.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Delírio do Despertar/prevenção & controle , Teste de Esforço , Exercício Físico/fisiologia , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos , Procedimentos Cirúrgicos Eletivos/efeitos adversos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de RiscoRESUMO
We have reported that knockdown of Necl-4 decreases vascular endothelial growth factor (VEGF)-induced phosphorylation of extracellular signal-regulated kinase (ERK) without affecting phosphorylation of VEGF receptor 2 (VEGFR2) in sparsely cultured human umbilical vein endothelial cells (HUVECs). However, the underlying molecular mechanism is unknown. Compared with control HUVECs, VEGF-induced phosphorylation of phospholipase Cγ (PLCγ), c-Raf, mitogen-activated protein kinase/ERK kinase (MEK) and ERK were all inhibited in Necl-4-knockdown HUVECs. However, VEGF-induced internalization of VEGFR2 was not different between control and Necl-4-knockdown HUVECs. We have reported that protein-tyrosine phosphatase, non-receptor type 13 (PTPN13) and Rho-associated kinase (ROCK) are involved in the Necl-4-knockdown-induced inhibition of the VEGF-induced activation of Rac1. However, the effects of Necl-4-knockdown on VEGF-induced phosphorylation of VEGFR2 and ERK were not affected either by knockdown of PTPN13 or by ROCK inhibitors. These results suggest that Necl-4 enhances VEGF-induced activation of PLCγ-c-Raf-MEK-ERK pathway without affecting the phosphorylation and internalization of VEGFR2.
Assuntos
Moléculas de Adesão Celular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Imunoglobulinas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfolipase C gama/metabolismo , Proteínas Proto-Oncogênicas c-raf/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Células Cultivadas , HumanosRESUMO
N-glycosylation of proteins is important for protein folding and function. We have recently reported that FAM5C/BRINP3 contributes to the tumor necrosis factor-α-induced expression of leukocyte adhesion molecules in vascular endothelial cells (ECs). However, regulatory mechanism of the FAM5C biosynthesis is poorly understood. Co-immunoprecipitation assay revealed the interaction of FAM5C with UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1), a glycoprotein folding-sensor enzyme. FAM5C ectopically expressed in HEK293 cells was localized to the endoplasmic reticulum and co-localized with endogenously expressed UGGT1. Molecular size of FAM5C was reduced by treatment with N-glycosidase F and in FAM5C-expressing cells cultured in the presence of the N-glycosylation inhibitor tunicamycin. FAM5C was secreted by the cells and the secretion of FAM5C was blocked by tunicamycin. Among six potential N-glycosylation sites, the potential site at Asn168 was not N-glycosylated, and Asn337, Asn456, Asn562, Asn609, and Asn641 mutants were poorly secreted by the cells. These results demonstrated that FAM5C is an N-glycosylated protein and N-glycosylation is necessary for the secretion of FAM5C.
Assuntos
Asparagina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Glucosiltransferases/metabolismo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a DNA/genética , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Expressão Gênica , Glucosiltransferases/genética , Glicosilação/efeitos dos fármacos , Células HEK293 , Humanos , Mutação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Dobramento de Proteína , Tunicamicina/farmacologiaRESUMO
BACKGROUND: Preoperative nutritional status and physical function are important predictors of mortality and morbidity after cardiac surgery. However, the influence of nutritional status before cardiac surgery on physical function and the progress of postoperative rehabilitation requires clarification. AIMS: To determine the effect of preoperative nutritional status on preoperative physical function and progress of rehabilitation after elective cardiac surgery. METHODS: We enrolled 131 elderly patients with mean age of 73.7 ± 5.8 years undergoing cardiac surgery. We divided them into two groups by nutritional status as measured by the Geriatric Nutritional Risk Index (GNRI): high GNRI group (GNRI ≥ 92, n = 106) and low GNRI group (GNRI < 92, n = 25). Physical function was estimated by handgrip strength, knee extensor muscle strength (KEMS), the Short Physical Performance Battery (SPPB), and 6-minute walk test (6MWT). Progress of postoperative rehabilitation was evaluated by the number of days to independent walking after surgery, length of stay in the ICU, and length of hospital stay. RESULTS: After adjusting for potential confounding factors, preoperative handgrip strength (P = 0.034), KEMS (P = 0.009), SPPB (P < 0.0001), and 6MWT (P = 0.012) were all significantly better in the high GNRI group. Multiple regression analysis revealed that a low GNRI was an independent predictor of the retardation of postoperative rehabilitation. CONCLUSIONS: Preoperative nutritional status as assessed by the GNRI could reflect perioperative physical function. Preoperative poor nutritional status may be an independent predictor of the retardation of postoperative rehabilitation in patients undergoing elective cardiac surgery.
Assuntos
Envelhecimento/fisiologia , Procedimentos Cirúrgicos Cardíacos , Estado Nutricional/fisiologia , Idoso , Procedimentos Cirúrgicos Cardíacos/mortalidade , Procedimentos Cirúrgicos Cardíacos/reabilitação , Feminino , Avaliação Geriátrica/métodos , Humanos , Japão , Tempo de Internação/estatística & dados numéricos , Masculino , Força Muscular/fisiologia , Avaliação Nutricional , Cuidados Pré-Operatórios/métodos , Resultado do Tratamento , Teste de Caminhada/métodosRESUMO
Recent studies have shown that the ketone body ß-hydroxybutyrate (ßOHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). In this study, we investigated regulatory mechanism and pathophysiological role of ßOHB in HF. First, we revealed that ßOHB level was elevated in failing hearts, but not in blood, using pressure-overloaded mice. We also measured cellular ßOHB levels in both cardiomyocytes and non-cardiomyocytes stimulated with or without H2O2 and revealed that increased myocardial ßOHB was derived from cardiomyocytes but not non-cardiomyocytes under pathological states. Next, we sought to elucidate the mechanisms of myocardial ßOHB elevation and its implication under pathological states. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in failing hearts. In cardiomyocytes, H2O2 stimulation caused ßOHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial ßOHB occurs because of the decline in its utilization. Finally, we checked the effects of ßOHB on cardiomyocytes under oxidative stress. We found that ßOHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Consequently, ßOHB attenuated reactive oxygen species production and alleviated apoptosis induced by oxidative stress. It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of ßOHB also occurs as a compensatory response against oxidative stress in failing hearts.
Assuntos
Ácido 3-Hidroxibutírico/metabolismo , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo , Ácido 3-Hidroxibutírico/análise , Animais , Células Cultivadas , Coenzima A-Transferases/metabolismo , Peróxido de Hidrogênio/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , RatosRESUMO
BACKGROUND: Vascular calcification is an independent risk factor for cardiovascular disease. Diabetes mellitus increases the incidence of vascular calcification; however, detailed molecular mechanisms of vascular calcification in diabetes mellitus remain unknown. We recently reported that bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER) regulates osteoblast-like trans-differentiation of human coronary artery smooth muscle cells (HCASMCs). METHODS: We investigated the effect of a hydroxymethylglutaryl-coenzyme A reductase inhibitor (statin), commonly used in patients with atherosclerotic diseases and diabetes mellitus, on alkaline phosphatase (ALP) mRNA expression in aortas of streptozotocin-induced diabetic mice. We also investigated the effects of the statin, Rho-associated protein kinase (ROCK) inhibitors and BMPER knockdown on ALP mRNA expression and activity in HCASMCs cultured in high glucose-containing media. RESULTS: Alkaline phosphatase mRNA expression was increased in aortas of streptozotocin-induced diabetic mice, and the increase was inhibited by rosuvastatin. ALP mRNA expression and activity were increased in HCASMCs cultured in high glucose-containing media, and the increases were suppressed by rosuvastatin. This suppression was reversed by the addition of mevalonate or geranylgeranyl pyrophosphate, but not farnesyl pyrophosphate. High glucose-increased ALP mRNA expression and activity were suppressed by ROCK inhibitors. Moreover, BMPER mRNA expression was increased in diabetic mouse aortas and in HCASMCs cultured in high glucose-containing media, but was not inhibited by rosuvastatin or ROCK inhibitors. Knockdown of BMPER suppressed high glucose-increased ALP activity, but not ROCK activity in HCASMCs. CONCLUSIONS: There are at least two independent pathways in high glucose-induced ALP activation in HCASMCs: the Rho-ROCK signaling pathway and the BMPER-dependent pathway.
Assuntos
Fosfatase Alcalina/metabolismo , Proteínas de Transporte/metabolismo , Glucose/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Calcificação Vascular/enzimologia , Quinases Associadas a rho/metabolismo , Fosfatase Alcalina/genética , Animais , Proteínas de Transporte/genética , Células Cultivadas , Vasos Coronários/enzimologia , Vasos Coronários/patologia , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Técnicas de Silenciamento de Genes , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Inibidores de Proteínas Quinases/farmacologia , Interferência de RNA , RNA Mensageiro/metabolismo , Transdução de Sinais , Transfecção , Regulação para Cima , Calcificação Vascular/genética , Calcificação Vascular/patologia , Quinases Associadas a rho/antagonistas & inibidoresRESUMO
RATIONALE: Vascular endothelial growth factor (VEGF), a major proangiogenic agent, exerts its proangiogenic action by binding to VEGF receptor 2 (VEGFR2), the activity of which is regulated by direct interactions with other cell surface proteins, including integrin α(V)ß(3). However, how the interaction between VEGFR2 and integrin α(V)ß(3) is regulated is not clear. OBJECTIVE: To investigate whether Necl-5/poliovirus receptor, an immunoglobulin-like molecule that is known to bind integrin α(V)ß(3), regulates the interaction between VEGFR2 and integrin α(V)ß(3), and to clarify the role of Necl-5 in the VEGF-induced angiogenesis. METHODS AND RESULTS: Necl-5-knockout mice displayed no obvious defect in vascular development; however, recovery of blood flow after hindlimb ischemia and the VEGF-induced neovascularization in implanted Matrigel plugs were impaired in Necl-5-knockout mice. To clarify the mechanism of the regulation of angiogenesis by Necl-5, we investigated the roles of Necl-5 in the VEGF-induced angiogenic responses in vitro. Knockdown of Necl-5 by siRNAs in human umbilical vein endothelial cells (HUVECs) inhibited the VEGF-induced capillary-like network formation on Matrigel, migration, and proliferation, and conversely, enhanced apoptosis. Coimmunoprecipitation assays showed the interaction of Necl-5 with VEGFR2, and knockdown of Necl-5 prevented the VEGF-induced interaction of integrin α(V)ß(3) with VEGFR2. Knockdown of Necl-5 suppressed the VEGFR2-mediated activation of downstream proangiogenic and survival signals, including Rap1, Akt, and endothelial nitric oxide synthase. CONCLUSIONS: These results demonstrate the critical role of Necl-5 in angiogenesis and suggest that Necl-5 may regulate the VEGF-induced angiogenesis by controlling the interaction of VEGFR2 with integrin α(v)ß(3), and the VEGFR2-mediated Rap1-Akt signaling pathway.
Assuntos
Antígenos de Neoplasias/fisiologia , Moléculas de Adesão Celular/fisiologia , Endotélio Vascular/fisiologia , Proteínas de Neoplasias/fisiologia , Neovascularização Fisiológica/fisiologia , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Antígenos de Neoplasias/genética , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Humanos , Integrina alfaVbeta3/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Modelos Animais , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas c-akt/fisiologia , RNA Interferente Pequeno/farmacologia , Receptores Virais/efeitos dos fármacos , Receptores Virais/fisiologia , Transdução de Sinais/fisiologia , Proteínas rap1 de Ligação ao GTP/fisiologiaRESUMO
OBJECTIVE: Intimal thickening is considered to result from the dedifferentiation of medial smooth muscle cells (SMCs) from a contractile to a synthetic phenotype, and their subsequent migration and proliferation. It is unknown whether nectin-like molecule (Necl)-5, which is overexpressed in cancer cells, is involved in intimal thickening. APPROACH AND RESULTS: Necl-5 was upregulated in mouse carotid artery after ligation. Compared with wild-type mice, intimal thickening after carotid artery ligation was milder in Necl-5 knockout mice. In vitro, the expression levels of SMC differentiation markers were higher, whereas the expression level of an SMC dedifferentiation marker was lower, in Necl-5 knockout mouse aortic SMCs (MASMCs) compared with wild-type MASMCs. The migration, proliferation, and extracellular signal-regulated kinase activity in response to serum were decreased in Necl-5 knockout MASMCs compared with wild-type MASMCs. In wild-type MASMCs, inhibition of extracellular signal-regulated kinase activity increased the expression levels of SMC differentiation markers and decreased their migration and proliferation in response to serum. CONCLUSIONS: The present findings indicate that Necl-5 plays a role in the formation of intimal thickening after carotid artery ligation by regulating dedifferentiation, migration, and proliferation of SMCs in an extracellular signal-regulated kinase-dependent manner. Our results suggest that Necl-5 may represent a potential therapeutic target to limit intimal thickening after vascular injury.
Assuntos
Estenose das Carótidas/patologia , Moléculas de Adesão Celular/genética , Músculo Liso Vascular/metabolismo , Túnica Íntima/patologia , Animais , Estenose das Carótidas/metabolismo , Moléculas de Adesão Celular/metabolismo , Movimento Celular/genética , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Músculo Liso Vascular/citologia , Nectinas , Distribuição Aleatória , Sensibilidade e Especificidade , Túnica Íntima/metabolismo , Regulação para CimaRESUMO
Objective: The incidence of postoperative complications, including dysphagia, increases as the population undergoing cardiovascular surgery ages. This study aimed to explore the potential of maximum phonation time (MPT) as a simple tool for predicting postextubation dysphagia (PED) and major adverse cardiac and cerebrovascular events (MACCEs). Methods: This retrospective study included 442 patients who underwent elective cardiac surgery at a university hospital. MPT was measured before surgery, and patients were stratified into 2 groups based on normal and abnormal MPTs. Postoperative complications, including PED and MACCEs, were also investigated. Swallowing status was assessed using the Food Intake Level Scale. Results: MPT predicted PED with prevalence of 11.0% and 18.0% in the normal and abnormal MPT groups, respectively (P = .01). During the follow-up period, MACCEs developed in 17.0% of patients. Frailty, European System for Cardiac Operative Risk Evaluation II score, PED, and MPT were markedly associated with MACCEs (adjusted hazard ratios: 2.25, 1.08, 1.96, and 0.96, respectively). Mediation analysis revealed that MPT positively influenced PED and MACCEs, whereas PED positively influenced MACCEs. The trend in restricted cubic spline analysis indicated that the hazard ratio for MACCEs increased sharply when MPT was <10 seconds. Conclusions: These findings underscore the potential of MPT as a valuable tool in the preoperative assessment and management of patients undergoing cardiac surgery. By incorporating MPT into routine preoperative evaluations, clinicians can identify patients at a higher risk of PED and MACCEs, allowing for targeted interventions and closer postoperative monitoring. This may improve patient outcomes and reduce the health care costs associated with these complications.
RESUMO
Differentiation of vascular smooth muscle cells (SMCs) into osteoblast-like cells is considered to be a mechanism of vascular calcification. However, regulators of osteoblast-like differentiation of vascular SMCs are not fully elucidated. Here, we investigated the expression of bone morphogenetic protein (BMP)-binding endothelial cell precursor-derived regulator (BMPER), a vertebrate homologue of Drosophila crossveinless-2, in vascular SMCs and the role and mode of action of BMPER in osteoblast-like differentiation of human coronary artery SMCs (HCASMCs). BMPER was expressed in cultured human vascular SMCs, including HCASMCs. Silencing of endogenous BMPER expression by an RNA interference technique inhibited osteoblast-like differentiation of HCASMCs, as evaluated by up-regulation of osteoblast markers such as alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2), by down-regulation of a SMC marker α-smooth muscle actin (αSMA), and by mineralization. Treatment with recombinant BMPER enhanced, whereas BMP-2 reduced osteoblast-like differentiation. BMPER antagonized BMP-2-induced phosphorylation of Smad 1/5/8, suggesting that the effect of BMPER was mediated by antagonizing the action of BMP. BMPER increased IκBα phosphorylation and NF-κB activity and specific NF-κB decoy oligonucleotides deteriorated osteoblast-like differentiation of HCASMCs by BMPER. In human coronary artery with atherosclerotic plaque containing calcification, the BMPER-positive signals were observed in the neointimal and medial SMCs in the vicinity of the plaque. These findings indicate that BMPER is a novel regulator of the osteoblast-like differentiation of HCASMCs.
Assuntos
Calcinose/metabolismo , Proteínas de Transporte/metabolismo , Diferenciação Celular , Vasos Coronários/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteoblastos/metabolismo , Placa Aterosclerótica/metabolismo , Actinas/genética , Actinas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Calcinose/genética , Calcinose/patologia , Proteínas de Transporte/genética , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Vasos Coronários/patologia , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Masculino , Pessoa de Meia-Idade , Miócitos de Músculo Liso/patologia , NF-kappa B/genética , NF-kappa B/metabolismo , Técnicas de Cultura de Órgãos , Osteoblastos/patologia , Fosforilação/genética , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologiaRESUMO
Background: Although cardiac involvement is relatively common in mixed connective tissue disease (MCTD), few reports on MCTD-associated fulminant myocarditis are available. Case summary: A 22-year-old woman diagnosed with MCTD was admitted to our institution for cold-like symptoms and chest pain. Echocardiography revealed that the left ventricular ejection fraction (LVEF) had rapidly decreased from 50 to 20%. Because endomyocardial biopsy revealed no significant lymphocytic infiltration, immunosuppressant drugs were not started initially; however, steroid pulse therapy (methylprednisolone, one1000â mg/day) was initiated due to prolonged symptoms and unimproved haemodynamics. Despite strong immunosuppressant therapy, the LVEF did not improve, and severe mitral regurgitation appeared. Three days after steroid pulse therapy initiation, she experienced a sudden cardiac arrest; thus, venoarterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pumping (IABP) were initiated. Subsequent immunosuppressant therapy was continued with prednisolone (100â mg/day) and intravenous cyclophosphamide (1000â mg). Six days after steroid therapy initiation, the LVEF improved to 40% and then recovered to near-normal levels. After successful weaning off of VA-ECMO and IABP, she was discharged. Thereafter, a detailed histopathological examination revealed multi-focal signs of ischaemic micro-circulatory injury and diffuse HLA-DR in the vascular endothelium, suggesting an autoimmune inflammatory response. Discussion: We report a rare case of fulminant myocarditis in a patient with MCTD who recovered with immunosuppressive treatment. Despite the absence of significant lymphocytic infiltration findings on histopathological examination, patients with MCTD may experience a dramatic clinical course. Although it is unclear whether myocarditis is triggered by viral infections, certain autoimmune mechanisms may lead to its development.
RESUMO
AIMS: Post-extubation dysphagia (PED), an often overlooked problem, is a common and serious complication associated with mortality and major morbidity after cardiovascular surgery. Dysphagia is considered an age-related disease, and evaluating its long-term effects is a pressing issue with rapidly progressing ageing worldwide. Therefore, we examined the effect of PED on functional status and long-term cardiovascular events in patients undergoing cardiovascular surgery. METHODS AND RESULTS: This single-centre, retrospective cohort study included 712 patients who underwent elective cardiovascular surgery and met the inclusion criteria. Patients were divided into PED and non-PED groups based on their post-operative swallowing status. The swallowing status was assessed using the Food Intake Level Scale. Functional status was evaluated as hospital-associated disability (HAD), defined as a decrease in activities of daily living after hospital discharge compared with preoperative values. The patients were subsequently followed up to detect major adverse cardiac and cerebrovascular events (MACCEs). Post-extubation dysphagia was present in 23% of the 712 patients and was independently associated with HAD (adjusted odds ratio, 2.70). Over a 3.5-year median follow-up period, MACCE occurred in 14.1% of patients. Multivariate Cox proportional hazard analysis revealed HAD to be independently associated with an increased risk of MACCE (adjusted hazard ratio, 1.85), although PED was not significantly associated with MACCE. CONCLUSION: Post-extubation dysphagia was an independent HAD predictor, with the odds of HAD occurrence being increased by 2.7-fold due to PED. Hospital-associated disability accompanied by PED is a powerful predictor of poor prognosis. Perioperative evaluation and management of the swallowing status, and appropriate therapeutic interventions, are warranted.
Assuntos
Atividades Cotidianas , Transtornos de Deglutição , Humanos , Estudos Retrospectivos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/diagnóstico , Fatores de Risco , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , PrognósticoRESUMO
RATIONALE: Angiogenesis contributes to physiological and pathological conditions, including atherosclerosis. The Rap1 small G protein regulates vascular integrity and angiogenesis. However, little is known about the effectors of Rap1 involved in angiogenesis. It is not known whether afadin, an adherens junction protein that connects immunoglobulin-like adhesion molecule nectins to the actin cytoskeleton and binds activated Rap1, plays a role in angiogenesis. OBJECTIVE: We investigated the role of endothelial afadin in angiogenesis and attempted to clarify the underlying molecular mechanism. METHODS AND RESULTS: Treatment of human umbilical vein endothelial cells (HUVECs) with vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) induced the activation of Rap1. Activated Rap1 regulated intracellular localization of afadin. Knockdown of Rap1 or afadin by small interfering RNA inhibited the VEGF- and S1P-induced capillary-like network formation, migration, and proliferation, and increased the serum deprivation-induced apoptosis of HUVECs. Knockdown of Rap1 or afadin decreased the accumulation of adherens and tight junction proteins to the cell-cell contact sites. Rap1 regulated the interaction between afadin and phosphatidylinositol 3-kinase (PI3K), recruitment of the afadin-PI3K complex to the leading edge, and the activation of Akt, indicating the involvement of Rap1 and afadin in the PI3K-Akt signaling pathway. Binding of afadin to Rap1 regulated the activity of Rap1 in a positive-feedback manner. In vivo, conditional deletion of afadin in mouse vascular endothelium using a Cre-loxP system impaired the VEGF- and S1P-induced angiogenesis. CONCLUSIONS: These results demonstrate a novel molecular mechanism by which Rap1 and afadin regulate the VEGF- and S1P-induced angiogenesis.
Assuntos
Células Endoteliais/metabolismo , Isquemia/metabolismo , Lisofosfolipídeos/metabolismo , Proteínas dos Microfilamentos/metabolismo , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Neovascularização Retiniana/metabolismo , Esfingosina/análogos & derivados , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Movimento Celular , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Membro Posterior , Humanos , Junções Intercelulares/metabolismo , Isquemia/genética , Isquemia/patologia , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas dos Microfilamentos/deficiência , Proteínas dos Microfilamentos/genética , Fosfatidilinositol 3-Quinases/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos , Proteínas Recombinantes de Fusão/metabolismo , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Neovascularização Retiniana/fisiopatologia , Transdução de Sinais , Esfingosina/metabolismo , Fatores de Tempo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteínas rap1 de Ligação ao GTP/metabolismoRESUMO
Background: Postextubation dysphagia (PED) is a serious postoperative complication following cardiovascular surgery that can lead to a worse prognosis. On the other hand, frailty is a prognostic factor in patients who undergo cardiac surgery. Objectives: This study investigated the effect of frailty status on PED and impact of PED on postoperative complications. Methods: This single-center retrospective cohort study included 644 consecutive patients who underwent elective cardiovascular surgery between May 1, 2014, and December 31, 2020; they were assigned to the PED or non-PED group based on postoperative swallowing status, and postoperative complications were investigated. Frailty status and physical functions, including walking speed, grip strength, Short Physical Performance Battery, and 6-minute walking distance, were preoperatively assessed; the frailty-status cutoff for predicting PED was determined from the receiver-operating characteristic curve. Results: In this study cohort (mean age 67.7 years), the overall PED prevalence was 14.8%; preoperative frailty had a significantly higher prevalence in the PED group (50.0%) than in the non-PED group (20.3%; P < 0.001). PED correlated with a higher incidence of postoperative pneumonia and prolonged intensive care unit or hospital stay (P < 0.05 for all). After adjustment for confounders, multiple regression analysis revealed that preoperative frailty was independently associated with PED (P < 0.001). Conclusions: PED occurred commonly after cardiovascular surgery and increased the risk of postoperative complications. Preoperative frailty was independently associated with PED. The 6-minute walking distance was the most powerful predictor of PED. Evaluation of preoperative frailty status is important for risk stratification and prevention of postoperative morbidity in patients undergoing surgery.
RESUMO
Aim: The aim of this study was to investigate the mental health status of healthcare workers and medical students during the early phase of the COVID-19 pandemic. Methods: An online questionnaire was administered to 637 students and 3189 healthcare workers from May to July, 2020. The patient healthcare questionnaire-9 (PHQ-9) and state anxiety (A-State) of the state-trait anxiety inventory-form (STAI) were used to assess depression and anxiety symptoms, respectively. Individuals were categorized into severe (15 or higher) depression and severe (50-51 or higher) anxiety groups. Results: Healthcare workers and those taking care of COVID-19 patients had a higher risk of severe depression (PHQ-9 scores >15) than other comparison groups. Students and men also had a higher risk of severe anxiety (STAI > 50-51). Multivariable logistic regression analysis showed that healthcare workers had a fivefold higher risk of developing severe depression symptoms (adjusted odds ratio [OR] = 4.99, confidence interval [CI] 2.24-5.97, P-value < 0.001) and those taking care of COVID-19 patients had 2.8-fold higher risk of developing severe depression symptoms (OR 2.75, CI 1.36-5.53, P-value = 0.005). Conclusion: Both medical students and healthcare workers have been experiencing depression and anxiety symptoms during the first wave of the pandemic. Our findings showed a high rate of severe anxiety symptoms in medical students and a high rate of severe depression symptoms in healthcare workers. Those who treated COVID-19 patients were at greater risk of developing major depressive disorder than those who treated non-COVID-19 patients.