RESUMO
BACKGROUND: Women and men with heart failure (HF) and preserved ejection fraction may differ in their clinical characteristics and their response to therapy. The aim of this study was to evaluate the influence of sex on the effects of empagliflozin in patients with HF and preserved ejection fraction enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: The effects of empagliflozin on the primary outcome of cardiovascular death or hospitalization for HF and on secondary outcomes (including total HF hospitalization, cardiovascular and all-cause mortality, and Kansas City Cardiomyopathy Questionnaire scores) were compared in women and men in the overall cohort and in subgroups defined by left ventricular ejection fraction (41%-49%, 50%-59%, and ≥60%). The effects of empagliflozin on physiological measures, including changes in systolic blood pressure, uric acid, hemoglobin, body weight, and natriuretic peptide levels, were also assessed. RESULTS: Of the 5988 patients randomized, 2676 (44.7%) were women. In the placebo arm, women tended to have lower risk for adverse outcomes, including a lower risk of all-cause mortality (hazard ratio, 0.69 [95% CI, 0.56, 0.84]). Compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for HF to a similar degree in both sexes (hazard ratio, 0.81 [95% CI, 0.69, 0.96] for men; and hazard ratio, 0.75 [95% CI, 0.61, 0.92] for women; Pinteraction=0.54). Sex did not modify the relationship between empagliflozin and outcomes across ejection fraction groups. Similar results were seen for secondary outcomes and physiological measures. Compared with placebo, empagliflozin improved the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score to a similar extent in both sexes (1.38 for men versus 1.63 for women at 52 weeks; Pinteraction=0.77); the results were similar for Kansas City Cardiomyopathy Questionnaire overall summary score and total summary score. CONCLUSIONS: Empagliflozin produced similar benefits on outcomes and health status in women and men with HF and preserved ejection fraction. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03057951.
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Cardiomiopatias , Insuficiência Cardíaca , Compostos Benzidrílicos , Cardiomiopatias/complicações , Feminino , Glucosídeos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Volume Sistólico , Ácido Úrico/farmacologia , Ácido Úrico/uso terapêutico , Função Ventricular EsquerdaRESUMO
AIMS: The aim of this study was to generate a biomarker-driven prognostic tool for patients with chronic HFrEF. Circulating levels of N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) each have a marked positive relationship with adverse outcomes in heart failure with reduced ejection fraction (HFrEF). A risk model incorporating biomarkers and clinical variables has not been validated in contemporary heart failure (HF) trials. METHODS AND RESULTS: In EMPEROR-Reduced, 33 candidate variables were pre-selected. Multivariable Cox regression models were developed using stepwise selection for: (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, and (iii) cardiovascular mortality. A total of 3730 patients were followed up for a median of 16 months, 823 (22%) patients had a primary outcome and 515 (14%) patients died, of whom 389 (10%) died from a cardiovascular cause. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last HF hospitalization, longer time since HF diagnosis, lower systolic blood pressure, New York Heart Association (NYHA) Class III or IV, higher heart rate and peripheral oedema were key predictors (eight variables in total, all P < 0.001). The primary outcome risk score discriminated well (c-statistic = 0.73), with patients in the top 10th of risk having an event rate >9 times higher than those in the bottom 10th. Empagliflozin benefitted patients across risk levels for the primary outcome. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality, followed by NYHA Class III or IV and ischaemic aetiology (four variables in total, all P < 0.001). The mortality risk model presented good event discrimination for all-cause and cardiovascular mortality (c-statistic = 0.69 for both). These simple models were externally validated in the BIOSTAT-CHF study, achieving similar c-statistics. CONCLUSIONS: The combination of NT-proBNP and hs-cTnT with a small number of readily available clinical variables provides prognostic assessment for patients with HFrEF. This predictive tool kit can be easily implemented for routine clinical use.
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Insuficiência Cardíaca , Biomarcadores , Humanos , Morbidade , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Prognóstico , Volume Sistólico , Troponina TRESUMO
AIMS: We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. METHODS AND RESULTS: The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45-0.89), P = 0.009 and hazard ratio 0.77 (95% CI 0.66-0.90), P = 0.0008, respectively, interaction P = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P < 0.0001), interaction P = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated. CONCLUSION: The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits.
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Insuficiência Cardíaca , Neprilisina , Aminobutiratos/uso terapêutico , Antagonistas de Receptores de Angiotensina/uso terapêutico , Compostos Benzidrílicos , Combinação de Medicamentos , Glucosídeos , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Volume Sistólico , Tetrazóis/uso terapêuticoAssuntos
Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Doença Arterial Periférica , Humanos , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/complicações , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/complicações , Diabetes Mellitus Tipo 2/complicações , Volume SistólicoRESUMO
Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Colecistite Aguda/genética , Linfócitos/imunologia , Mutação , Neutrófilos/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/genética , Bexiga Urinária/imunologia , Urotélio/imunologia , Animais , Butilidroxibutilnitrosamina , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/metabolismo , Colecistite Aguda/induzido quimicamente , Colecistite Aguda/imunologia , Colecistite Aguda/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Feminino , Predisposição Genética para Doença , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Neutrófilos/patologia , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Fatores de Tempo , Microambiente Tumoral , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/metabolismo , Urotélio/metabolismo , Urotélio/patologiaRESUMO
Although somatic mutations and overexpression of the tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) are strongly associated with bladder cancer, evidence for their functional involvement in the pathogenesis remains elusive. Previously we showed that activation of Fgfr3 alone is not sufficient to initiate urothelial tumourigenesis in mice. Here we hypothesize that cooperating mutations are required for Fgfr3-dependent tumourigenesis in the urothelium and analyse a mouse model in which an inhibitor of Pi3k-Akt signalling, Pten, is deleted in concert with Fgfr3 activation (UroIICreFgfr3(+/) (K644E) Pten(flox) (/flox)). Two main phenotypical characteristics were observed in the urothelium: increased urothelial thickness and abnormal cellular histopathology, including vacuolization, condensed cellular appearance, enlargement of cells and nuclei, and loss of polarity. These changes were not observed when either mutation was present individually. Expression patterns of known urothelial proteins indicated the abnormal cellular differentiation. Furthermore, quantitative analysis showed that Fgfr3 and Pten mutations cooperatively caused cellular enlargement, while Pten contributed to increased cell proliferation. Finally, FGFR3 overexpression was analysed along the level of phosphorylated mTOR in 66 T1 urothelial tumours in tissue microarray, which supported the occurrence of functional association of these two signalling pathways in urothelial pathogenesis. Taken together, this study provides evidence supporting a functional role of FGFR3 in the process of pathogenesis in urothelial neoplasms. Given the wide availability of inhibitors specific to FGF signalling pathways, our model may open the avenue for FGFR3-targeted translation in urothelial disease.
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Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/metabolismo , PTEN Fosfo-Hidrolase/deficiência , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias da Bexiga Urinária/enzimologia , Bexiga Urinária/enzimologia , Urotélio/enzimologia , Animais , Biomarcadores Tumorais/metabolismo , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , PTEN Fosfo-Hidrolase/genética , Fenótipo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Urotélio/patologiaRESUMO
Background: Postpartum mental health care is a public health priority requiring interprofessional and interorganizational collaboration. Primary care physicians (PCPs) have the potential to play an essential role in facilitating access to health care and providing comprehensive and coordinated care for postpartum mental health problems. In Japan, however, there are no previous studies on the extent to which PCPs are involved in postpartum mental health care. Therefore, this study aimed to investigate the practices and experiences of Japanese PCPs in providing such care. Methods: This study presents a subset of the findings from a cross-sectional study using an online questionnaire on postpartum care among Japanese PCPs. We employed descriptive analysis to examine their practices and experiences in providing general and postpartum mental health care. Results: We received 339 valid responses from 5811 PCPs. The median proportion of the outpatients with mental health problems that PCPs regularly saw was 15%. Approximately two out of three PCPs (68.7%) reported routinely performing screening for depression and anxiety. Seventy-six percent of PCPs had the opportunity to provide care for postpartum women. Approximately one in two PCPs (47.8%) had managed cases of postpartum mental health problems and collaborated with various professionals and resources to provide care. Conclusions: The majority of Japanese PCP participants in the study provide mental health care and have managed cases of postpartum mental health problems, collaborating with various health professionals.
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BACKGROUND: Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period. METHODS: We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks). RESULTS: The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52. CONCLUSIONS: Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up.
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Compostos Benzidrílicos , Fragilidade , Glucosídeos , Insuficiência Cardíaca , Humanos , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Fragilidade/epidemiologia , Qualidade de Vida , Volume SistólicoRESUMO
BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin's risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. METHODS: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. RESULTS: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. CONCLUSIONS: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.
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In this review, the evidence for a role of fibroblast growth factor receptor (FGFR) mediated signalling in carcinogenesis are considered and relevant underlying mechanisms highlighted. FGF signalling mediated by FGFR follows a classic receptor tyrosine kinase signalling pathway and its deregulation at various points of its cascade could result in malignancy. Here we review the accumulating reports that revealed the association of FGF/FGFRs to various types of cancer at a genetic level, along with in vitro and in vivo evidences available so far, which indicates the functional involvement of FGF signalling in tumour formation and progression. An increasing number of drugs against the FGF pathways is currently in clinical testing. We will discuss the strategies for future FGF research in cancer and translational approaches.
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Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Animais , Transformação Celular Neoplásica/genética , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de SinaisRESUMO
BACKGROUND: Patients with a recent heart failure (HF) hospitalization have a high risk of rehospitalization and mortality. Early treatment may have a substantial impact on patient outcomes. OBJECTIVES: This study sought to study the outcomes and effect of empagliflozin according to timing of prior HF hospitalization. METHODS: EMPEROR-Pooled (EMPEROR-Reduced [EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction] and EMPEROR-Preserved [EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction] combined) included 9,718 HF patients who were grouped according to the recency of HF hospitalization (none, <3 months, 3-6 months, 6-12 months, >12 months). The primary outcome was a composite of time to first of HF hospitalization or cardiovascular death, over a median follow-up of 21 months. RESULTS: The primary outcome event rates (per 100 person-years) in the placebo group were 26.7, 18.1, 13.7, and 2.8 for patients hospitalized within 3 months, 3-6 months, 6-12 months, and >12 months, respectively. The relative risk reduction of primary outcome events with empagliflozin was similar across HF hospitalization categories (P interaction = 0.67). The primary outcome absolute risk reduction was more pronounced among patients with a recent HF hospitalization but without statistical heterogeneity of treatment effect: -6.9, -5.5, -0.8, and -0.6 events prevented per 100 person-years for patients hospitalized within <3 months, 3-6 months, 6-12 months, and >12 months, respectively, and -2.4 events prevented per 100 person-years of follow-up in those without a prior HF hospitalization (P interaction = 0.64). Empagliflozin was safe irrespective of HF hospitalization recency. CONCLUSIONS: Patients with a recent HF hospitalization have a high risk of events. Empagliflozin reduced HF events regardless of HF hospitalization recency.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Hospitalização , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume SistólicoRESUMO
AIMS: Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF. METHODS AND RESULTS: In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66-0.93] vs. 0.78 [0.64-0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57-0.94] vs. 0.72 [0.54-0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m2 /year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF. CONCLUSIONS: In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.
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Fibrilação Atrial , Insuficiência Cardíaca , Humanos , Fibrilação Atrial/complicações , Fibrilação Atrial/tratamento farmacológico , Volume Sistólico , Função Ventricular EsquerdaRESUMO
BACKGROUND: Empagliflozin reduces the risk of major heart failure outcomes in heart failure with reduced or preserved ejection fraction. OBJECTIVES: The goal of this study was to evaluate the effect of empagliflozin across the spectrum of chronic kidney disease in a pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced or Preserved Ejection Fraction, respectively). METHODS: A total of 9,718 patients were grouped into Kidney Disease Improving Global Outcomes (KDIGO) categories based on estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio into low-, moderate-, high-, and very-high-risk categories, comprising 32.0%, 29.1%, 21.9%, and 17.0% of the participants, respectively. RESULTS: In the placebo arm, when compared with lower risk categories, patients at higher risk experienced a slower rate of decline in eGFR, but a higher risk of a composite kidney event. Empagliflozin reduced the risk of cardiovascular death or heart failure hospitalizations similarly in all KDIGO categories (HR: 0.81; 95% CI: 0.66-1.01 for low-; HR: 0.63; 95% CI: 0.52-0.76 for moderate-; HR: 0.82; 95% CI: 0.68-0.98 for high-; and HR: 0.84; 95% CI: 0.71-1.01 for very-high-risk groups; P trend = 0.30). Empagliflozin reduced the rate of decline in eGFR whether it was estimated by chronic slope, total slope, or unconfounded slope. When compared with the unconfounded slope, the magnitude of the effect on chronic slope was larger, and the effect on total slope was smaller. In EMPEROR-Reduced, patients at lowest risk experienced the largest effect of empagliflozin on eGFR slope; this pattern was not observed in EMPEROR-Preserved. CONCLUSIONS: The benefit of empagliflozin on major heart failure events was not influenced by KDIGO categories. The magnitude of the renal effects of the drug depended on the approach used to calculate eGFR slopes.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Insuficiência Renal Crônica , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/induzido quimicamente , Rim , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/epidemiologia , Volume SistólicoRESUMO
AIMS: There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. METHODS AND RESULTS: In the EMPEROR-Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5-point increase in KCCQ-CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). CONCLUSION: Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients.
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Anemia , Fibrilação Atrial , Diabetes Mellitus , Insuficiência Cardíaca , Insuficiência Renal Crônica , Humanos , Feminino , Idoso , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/diagnóstico , Qualidade de Vida , Volume Sistólico , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/epidemiologia , Nível de SaúdeRESUMO
The mitogen-activated protein kinase (MAPK) pathway is frequently activated in human cancers, leading to malignant phenotypes such as autonomous cellular proliferation. Here, we demonstrate a novel role of the activated MAPK pathway in immune evasion by melanoma cells with the mutation of BRAF, which encodes a MAPKKs, (BRAF(V600E)). MEK inhibitor U0126 or RNA interference (RNAi) for BRAF(V600E) decreased production of the immunosuppressive soluble factors interleukin (IL)-10, VEGF, or IL-6 from melanoma cells to levels comparable to those after signal transducer and activator of transcription (STAT)3 inactivation. The suppressive activity of the culture supernatants from the melanoma cells on the production of inflammatory cytokines IL-12 and tumor necrosis factor alpha by dendritic cells upon lipopolysaccharide stimulation was markedly reduced after transduction with BRAF(V600E) RNAi, comparable to the effects observed with STAT3 RNAi transduction. No additive or synergistic effects were observed by the simultaneous transduction of RNAi for both BRAF(V600E) and STAT3. Furthermore, specific DNA binding and transcriptional activity of STAT3 were not affected by down-regulation of the MAPK signaling with the BRAF RNAi. These results indicate that the MAPK signal, along with the STAT3 signal, is essential for immune evasion by human melanomas that have constitutively active MAPK signaling and is a potential molecular target for overcoming melanoma cell evasion of the immune system.
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Tolerância Imunológica , Sistema de Sinalização das MAP Quinases/imunologia , Melanoma/enzimologia , Melanoma/imunologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Proteínas Proto-Oncogênicas B-raf/fisiologia , Linhagem Celular Tumoral , Humanos , Melanoma/genética , Melanoma/prevenção & controle , Proteínas Proto-Oncogênicas B-raf/genética , Fator de Transcrição STAT3/fisiologiaRESUMO
The fibroblast growth factor receptor 3 (Fgfr3) is expressed in a rostral(low) to caudal(high) gradient in the developing cerebral cortex. Therefore, we hypothesized that Fgfr3 contributes to the correct morphology and connectivity of the caudal cortex. Overall, the forebrain structures appeared normal in Fgfr3(-/-) mice. However, cortical and hippocampal volumes were reduced by 26.7% and 16.3%, respectively. Hypoplasia was particularly evident in the caudo-ventral region of the telencephalon where proliferation was mildly decreased at embryonic day 18.5. Dysplasia of GABAergic neurons in the amygdala and piriform cortex was seen following GAD67 immunohistochemistry. Dye-tracing studies and diffusion magnetic resonance imaging and tractography detected a subtle thalamocortical tract deficit, and significant decreases in the stria terminalis and lateral arms of the anterior commissure. These results indicate the subtle role of Fgfr3 in formation of caudal regions of the telencephalon affecting some brain projections.
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Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/fisiologia , Telencéfalo/embriologia , Animais , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Regulação para Baixo , Desenvolvimento Embrionário/genética , Desenvolvimento Embrionário/fisiologia , Hipocampo/embriologia , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Neurogênese/genética , Neurogênese/fisiologia , Tamanho do Órgão/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Telencéfalo/metabolismoRESUMO
AIMS: Anaemia is frequent among patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with poor outcomes. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) increase haematocrit and may correct anaemia. This study aims to investigate the impact of empagliflozin on haematocrit and anaemia, and whether anaemia influenced the effect of empagliflozin in EMPEROR-Reduced. METHODS AND RESULTS: Mixed-effects models and survival analysis. A total of 3726 patients (out of 3730) had baseline haematocrit values, 3013 (81%) had no anaemia and 713 (19%) had anaemia. Patients with anaemia were older (70.4 vs. 66.0 years), had lower body mass index (26.6 vs. 28.2 kg/m2 ), lower estimated glomerular filtration rate (54.2 vs. 63.9 ml/min/1.73 m2 ), and higher N-terminal pro-B-type natriuretic peptide (2362 vs. 1800 pg/ml). Compared to patients without anaemia, those with anaemia had 1.5 to 2.5-fold higher rates of cardiovascular and all-cause mortality, total HF hospitalizations, and kidney composite outcomes. The effect of empagliflozin to reduce the primary composite outcome of cardiovascular death or HF hospitalizations, total HF hospitalizations, and kidney composite outcome was not modified by baseline anaemia status (interaction p > 0.1 for all). Compared to placebo, empagliflozin rapidly (as early as week 4) increased haematocrit and haemoglobin and reduced the rates of new-onset anaemia throughout the follow-up (22.6% in placebo vs. 12.3% in empagliflozin; hazard ratio 0.49, 95% confidence interval 0.41-0.59; p < 0.001). CONCLUSIONS: Anaemia was associated with poor outcomes. Empagliflozin reduced new-onset anaemia throughout the follow-up and improved HF and kidney outcomes irrespective of anaemia status at baseline.
Assuntos
Anemia , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Anemia/tratamento farmacológico , Anemia/etiologia , Compostos Benzidrílicos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Volume SistólicoRESUMO
AIMS: Empagliflozin improves cardiovascular and renal outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF), but its efficacy and safety across patient's age is not well established. METHODS AND RESULTS: We assessed the effects of empagliflozin (10 mg daily) versus placebo, on top of standard HF therapy, in symptomatic HFrEF patients with a left ventricular ejection fraction ≤40% and increased natriuretic peptides stratified by age (<65, 65-74, ≥75 years). The primary endpoint was a composite of cardiovascular death or HF hospitalization. Key secondary endpoints included first and recurrent HF hospitalizations and slope of change in estimated glomerular filtration rate (eGFR); the latter was supported by an analysis of a renal composite endpoint (chronic dialysis or renal transplantation or profound and sustained reduction in eGFR). Of 3730 patients, 38% were <65 years, 35% were 65-74 years and 27% were ≥75 years. Compared with placebo, empagliflozin reduced the primary endpoint consistently across the three age groups (hazard ratio 0.71 [95% confidence interval 0.57-0.89] for <65 years, 0.72 [0.57-0.93] for 65-74 years, 0.86 [0.67-1.10] for ≥75 years, interaction p-trend test = 0.24). The effects of empagliflozin were also consistent across age groups for key secondary endpoints of first and recurrent HF hospitalization (p-trend = 0.30), the rate of decline in eGFR (p-trend = 0.78) and the renal composite (p-trend = 0.94). Adverse events (AEs), serious AEs and AEs leading to drug discontinuation increased with age in both treatment arms, but empagliflozin did not increase their incidence over placebo within each age group. CONCLUSION: The efficacy and safety of empagliflozin in improving cardiovascular and renal outcomes in HFrEF was consistent across the spectrum of age, including older patients (aged ≥75).
Assuntos
Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Disfunção Ventricular Esquerda , Humanos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Volume Sistólico , Disfunção Ventricular Esquerda/complicações , Função Ventricular EsquerdaRESUMO
BACKGROUND: Empagliflozin reduces cardiovascular death (CVD) or heart failure (HF) hospitalization (HFH) in patients with HF and preserved ejection fraction. Treatment effects and safety in relation to age have not been studied. OBJECTIVES: The purpose of this study was to evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction). METHODS: We grouped patients (n = 5,988) according to their baseline age (<65 years [n = 1,199], 65-74 years [n = 2,214], 75-79 years [n = 1,276], ≥80 years [n = 1,299]). We explored the influence of age on empagliflozin effects on CVD or HFH (primary outcome), total HFH, rate of decline in estimated glomerular filtration rate, health-related quality of life with the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score, and frequency of adverse events. RESULTS: Considering only patients on placebo, the incidence of primary outcomes (P trend = 0.02) and CVD (P trend = 0.003) increased with age. Empagliflozin reduced primary outcomes (P trend = 0.33), first HFH (P trend = 0.22), and first and recurrent HFH (P trend = 0.11) across all age groups with an effect being similar at ≥75 years (P interaction = 0.22) or >80 years (P interaction = 0.51). Empagliflozin improved Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at week 52 and attenuated the decline of estimated glomerular filtration rate without age interaction (P = 0.48 and P = 0.32, respectively). There were no clinically relevant differences in adverse events between empagliflozin and placebo across the age groups. CONCLUSIONS: Empagliflozin reduced primary outcomes and first and recurrent HFH and improved symptoms across a broad age spectrum. High age was not associated with reduced efficacy or meaningful intolerability. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction [EMPEROR-Preserved]; NCT0305951).
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Compostos Benzidrílicos , Glucosídeos , Insuficiência Cardíaca , Idoso , Idoso de 80 Anos ou mais , Compostos Benzidrílicos/uso terapêutico , Doença Crônica , Glucosídeos/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Humanos , Pessoa de Meia-Idade , Volume Sistólico/fisiologia , Resultado do TratamentoRESUMO
AIMS: Biomarker-driven prognostic models incorporating N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in heart failure (HF) with preserved ejection fraction (HFpEF) are lacking. We aimed to generate a biomarker-driven prognostic tool for patients with chronic HFpEF enrolled in EMPEROR-Preserved. METHODS AND RESULTS: Multivariable Cox regression models were created for (i) the primary composite outcome of HF hospitalization or cardiovascular death, (ii) all-cause death, (iii) cardiovascular death, and (iv) HF hospitalization. PARAGON-HF was used as a validation cohort. NT-proBNP and hs-cTnT were the dominant predictors of the primary outcome, and in addition, a shorter time since last hospitalization, New York Heart Association (NYHA) class III or IV, history of chronic obstructive pulmonary disease (COPD), insulin-treated diabetes, low haemoglobin, and a longer time since HF diagnosis were key predictors (eight variables, all p < 0.001). The consequent primary outcome risk score discriminated well (c-statistic = 0.75) with patients in the top 10th of risk having an event rate >22× higher than those in the bottom 10th. A model for HF hospitalization alone had even better discrimination (c = 0.79). Empagliflozin reduced the risk of cardiovascular death or hospitalization for HF in patients across all risk levels. NT-proBNP and hs-cTnT were also the dominant predictors of all-cause and cardiovascular mortality followed by history of COPD, low albumin, older age, left ventricular ejection fraction ≥50%, NYHA class III or IV and insulin-treated diabetes (eight variables, all p < 0.001). The mortality risk model had similar discrimination for all-cause and cardiovascular mortality (c-statistic = 0.72 for both). External validation provided c-statistics of 0.71, 0.71, 0.72, and 0.72 for the primary outcome, HF hospitalization alone, all-cause death, and cardiovascular death, respectively. CONCLUSIONS: The combination of NT-proBNP and hs-cTnT along with a few readily available clinical variables provides effective risk discrimination both for morbidity and mortality in patients with HFpEF. A predictive tool-kit facilitates the ready implementation of these risk models in routine clinical practice.