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1.
Arterioscler Thromb Vasc Biol ; 42(2): e61-e73, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34809448

RESUMO

OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.


Assuntos
Proteínas de Ligação ao Cálcio/sangue , Proteínas da Matriz Extracelular/sangue , Insuficiência Cardíaca/sangue , Rigidez Vascular , Animais , Pressão Sanguínea , Proteínas de Ligação ao Cálcio/genética , Proteínas da Matriz Extracelular/genética , Feminino , Deleção de Genes , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Estudos Prospectivos , Volume Sistólico , Proteína de Matriz Gla
2.
Gut ; 71(2): 254-264, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-33597157

RESUMO

OBJECTIVE: Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D). DESIGN: Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m2, fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks. RESULTS: Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient. CONCLUSIONS: DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG. TRIAL REGISTRATION NUMBER: NCT02879383.


Assuntos
Ablação por Cateter , Diabetes Mellitus Tipo 2/terapia , Duodeno/cirurgia , Ressecção Endoscópica de Mucosa , Hipertermia Induzida , Mucosa Intestinal/cirurgia , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Med Care ; 57(12): 968-976, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31567860

RESUMO

IMPORTANCE: Hospitals that serve poorer populations have higher readmission rates. It is unknown whether these hospitals effectively lowered readmission rates in response to the Hospital Readmissions Reduction Program (HRRP). OBJECTIVE: To compare pre-post differences in readmission rates among hospitals with different proportion of dual-eligible patients both generally and among the most highly penalized (ie, low performing) hospitals. DESIGN: Retrospective cohort study using piecewise linear model with estimated hospital-level risk-standardized readmission rates (RSRRs) as the dependent variable and a change point at HRRP passage (2010). Economic burden was assessed by proportion of dual-eligibles served. SETTING: Acute care hospitals within the United States. PARTICIPANTS: Medicare fee-for-service beneficiaries aged 65 years or older discharged alive from January 1, 2003 to November 30, 2014 with a principal discharge diagnosis of acute myocardial infarction (AMI), congestive heart failure (CHF), and pneumonia. MAIN OUTCOME AND MEASURE: Decrease in hospital-level RSRRs in the post-law period, after controlling for the pre-law trend. RESULTS: For AMI, the pre-post difference between hospitals that service high and low proportion of dual-eligibles was not significant (-65 vs. -64 risk-standardized readmissions per 10000 discharges per year, P=0.0678). For CHF, RSRRs declined more at high than low dual-eligible hospitals (-79 vs. -75 risk-standardized readmissions per 10000 discharges per year, P=0.0006). For pneumonia, RSRRs declined less at high than low dual-eligible hospitals (-44 vs. -47 risk-standardized readmissions per 10000 discharges per year, P=0.0003). Among the 742 highest penalized hospitals and all conditions, the pre-post decline in rate of change of RSRRs was less for high dual-eligible hospitals than low dual-eligible hospitals (-68 vs. -74 risk-standardized readmissions per 10000 discharges per year for AMI, -88 vs. -97 for CHF, and -47 vs. -56 for pneumonia, P<0.0001 for all). CONCLUSIONS AND RELEVANCE: For all hospitals, differences in pre-post trends in RSRRs varied with disease conditions. However, for the highest-penalized hospitals, the pre-post decline in RSRRs was greater for low than high dual-eligible hospitals for all penalized conditions. These results suggest that high penalty, high dual-eligible hospitals may be less able to improve performance on readmission metrics.


Assuntos
Medicaid/estatística & dados numéricos , Medicare/legislação & jurisprudência , Readmissão do Paciente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Planos de Pagamento por Serviço Prestado , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/terapia , Humanos , Masculino , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/terapia , Propriedade , Pneumonia/epidemiologia , Pneumonia/terapia , Pobreza , Características de Residência , Estudos Retrospectivos , Estados Unidos
4.
J Nucl Cardiol ; 26(5): 1642-1646, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-29374373

RESUMO

BACKGROUND: The management of patients presenting to an emergency department with chest discomfort at low-risk for acute coronary syndrome represents a common clinical challenge. Such patients are often triaged to chest pain units for monitoring and cardiac stress testing for further risk stratification. METHODS: We conducted a retrospective study of 292 low-risk patients who presented to an emergency department with chest discomfort. We performed physician-adjudicated chart reviews of all patients with positive stress tests to assess downstream testing, subsequent coronary revascularization, and outcomes. RESULTS: Of the 292 patients, 33 (11.3%) had stress tests positive for ischemia, and 12 (4.1%) underwent diagnostic cardiac catheterization. Of the 292 patients, 4 (1.4%) underwent coronary revascularization that may have resulted in a mortality benefit. CONCLUSION: These data suggest a very low yield of detecting clinically significant coronary disease with stress testing low-risk patients with chest discomfort in emergency department chest pain units.


Assuntos
Síndrome Coronariana Aguda/diagnóstico por imagem , Serviço Hospitalar de Emergência , Teste de Esforço , Idoso , Dor no Peito , Doença da Artéria Coronariana/diagnóstico por imagem , Medicina de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Perfusão do Miocárdio , Estudos Prospectivos , Estudos Retrospectivos , Risco , Medição de Risco , Resultado do Tratamento
5.
J Interv Cardiol ; 31(2): 150-158, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29166703

RESUMO

OBJECTIVE: We aimed to analyze the association between morphine and in-hospital outcomes in invasively managed ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS) patients. BACKGROUND: Morphine is commonly used for analgesia in the setting of acute coronary syndromes (ACS); however, recently its utility in ACS has come under closer scrutiny. METHODS: We identified all STEMI and NSTE-ACS patients undergoing coronary angiogram +/- percutaneous intervention between January 2009 and July 2016 in our center and recorded patient characteristics and inpatient outcomes. RESULTS: Overall, 3027 patients were examined. Overall, STEMI patients who received morphine had no difference in in-hospital mortality [4.18% vs. 7.54%, odds ratio (OR): 0.36, P = 0.19], infarct size (mean troponin level 0.75 ng/mL vs. 1.29 ng/mL, P = 0.32) or length of hospital stay (P = 0.61). The NSTE-ACS patients who received morphine had a longer hospital stay (mean 6.58 days vs. 4.78 days, P < 0.0001) and larger infarct size (mean troponin 1.16 ng/mL vs. 0.90 ng/mL, P = 0.02). Comparing matched patients, the use of morphine was associated with larger infarct size (mean troponin 1.14 ± 1.92 ng/mL vs. 0.83 ± 1.49 ng/mL, P = 0.01), longer hospital stay (6.5 ± 6.82 days vs. 4.89 ± 5.36 days, P = 0.004) and a trend towards increased mortality (5% vs. 2%, OR: 2.55, P = 0.06) in NSTE-ACS patients but morphine did not affect outcomes in the propensity matched STEMI patients. CONCLUSION: In a large retrospective study, morphine was associated with larger infarct size, a longer hospital stay and a trend towards increased mortality in invasively managed NSTE-ACS patients even after adjustment for clinical characteristics.


Assuntos
Síndrome Coronariana Aguda , Morfina , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/mortalidade , Síndrome Coronariana Aguda/cirurgia , Idoso , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Feminino , Mortalidade Hospitalar , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/efeitos adversos , Razão de Chances , Avaliação de Processos e Resultados em Cuidados de Saúde , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Estudos Retrospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Estados Unidos/epidemiologia
6.
bioRxiv ; 2023 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-37292633

RESUMO

Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival.

7.
Diabetes Res Clin Pract ; 184: 109194, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35032562

RESUMO

AIMS: Duodenal mucosal resurfacing (DMR) is an endoscopic procedure developed to improve metabolic parameters and restore insulin sensitivity in patients with diabetes. Here we report long-term DMR safety and efficacy from the REVITA-1 study. MATERIALS AND METHODS: REVITA-1 was a prospective, single-arm, open-label, multicenter study of DMR feasibility, safety, and efficacy in patients with type 2 diabetes (hemoglobin A1c [HbA1c] of 7.5-10.0% (58-86 mmol/mol)) on oral medication. Safety and glycemic (HbA1c), hepatic (alanine aminotransferase [ALT]), and cardiovascular (HDL, triglyceride [TG]/HDL ratio) efficacy parameters were assessed (P values presented for LS mean change). RESULTS: Mean ± SD HbA1c levels reduced from 8.5 ± 0.7% (69.1 ± 7.1 mmol/mol) at baseline (N = 34) to 7.5 ± 0.8% (58.9 ± 8.8 mmol/mol) at 6 months (P < 0.001); and this reduction was sustained through 24 months post-DMR (7.5 ± 1.1% [59.0 ± 12.3 mmol/mol], P < 0.001) while in greater than 50% of patients, glucose-lowering therapy was reduced or unchanged. ALT decreased from 38.1 ± 21.1 U/L at baseline to 32.5 ± 22.1 U/L at 24 months (P = 0.048). HDL and TG/HDL improved during 24-months of follow-up. No device- or procedure-related serious adverse events, unanticipated device effects, or hypoglycemic events were noted between 12 and 24 months post-DMR. CONCLUSIONS: DMR is associated with durable improvements in insulin sensitivity and multiple downstream metabolic parameters through 24 months post-treatment in type 2 diabetes. Clinical trial reg. no. NCT02413567, clinicaltrials.gov.


Assuntos
Diabetes Mellitus Tipo 2 , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/cirurgia , Duodeno/química , Duodeno/metabolismo , Duodeno/cirurgia , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Prospectivos , Resultado do Tratamento
8.
J Am Heart Assoc ; 9(5): e014195, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32079475

RESUMO

Background Experimental studies support a link between obesity and pulmonary hypertension (PH), yet clinical studies have been limited. This study sought to determine the association of obesity and pulmonary hemodynamic measures and mortality in PH. Methods and Results We examined patients undergoing right-sided heart catherization (2005-2016) in a hospital-based cohort. Multivariable regression models tested associations of body mass index and pulmonary vascular hemodynamics, with PH defined as mean pulmonary artery pressure >20 mm Hg, and further subclassified into precapillary, postcapillary, and mixed PH. Multivariable Cox models were used to examine the effect of PH and obesity on mortality. Among 8940 patients (mean age, 62 years; 40% women), 52% of nonobese and 69% of obese individuals had evidence of PH. Higher body mass index was independently associated with greater odds of overall PH (odds ratio, 1.34; 95% CI, 1.29-1.40; P<0.001 per 5-unit increase in body mass index) as well as each PH subtype (P<0.001 for all). Patients with PH had greater risk of mortality compared with individuals without PH regardless of subgroup (P<0.001 for all). We found that obesity was associated with 23% lower hazard of mortality among patients with PH (hazard ratio, 0.77; 95% CI, 0.69-0.85; P<0.001). The effect of obesity was greatest among those with precapillary PH (hazard ratio, 0.57; 95% CI, 0.46-0.70; P<0.001), where obesity modified the effect of PH on mortality (P for interaction=0.02). Conclusions Obesity is independently associated with PH. PH is associated with greater mortality; this is modified by obesity such that obese patients with precapillary PH have lower mortality compared with nonobese counterparts. Further studies are needed to elucidate mechanisms underlying obesity-related PH.


Assuntos
Hipertensão Pulmonar/mortalidade , Obesidade/mortalidade , Idoso , Pressão Arterial , Índice de Massa Corporal , Cateterismo Cardíaco , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/fisiopatologia , Prevalência , Prognóstico , Artéria Pulmonar/fisiopatologia , Circulação Pulmonar , Medição de Risco , Fatores de Risco
9.
Clin Pediatr (Phila) ; 58(5): 541-546, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30781998

RESUMO

Recently, several professional groups have recommended a change from chart-based to instrument-based screening for preschool-age children, but the effect of this change on health care utilization is unknown. We performed a secondary analysis of a site-randomized quality improvement project on transitioning from chart-based to instrument-based vision screening for 3- to 5-year-old children in primary care. We analyzed visit rates to ophthalmologists and optometrists and costs of such care before and after implementation of instrument-based vision screening with comparison to nonparticipating practices. The implementation of instrument-based vision screening resulted in a decrease in visits to eye care specialists from 83.1 visits per 1000 children per year to 55.0, a reduction of 33.8%; no comparable reduction was seen in nonparticipating practices. The cost of services by eye care specialists fell from $65 715 per 1000 children per year prior to $55 740, a decline of 15.2%; similar costs among control practices rose 13.4%.


Assuntos
Custos de Cuidados de Saúde/estatística & dados numéricos , Atenção Primária à Saúde/métodos , Encaminhamento e Consulta/estatística & dados numéricos , Seleção Visual/métodos , Pré-Escolar , Redução de Custos/estatística & dados numéricos , Humanos , Massachusetts , Oftalmologia/economia , Oftalmologia/organização & administração , Optometria/economia , Optometria/organização & administração , Atenção Primária à Saúde/economia , Atenção Primária à Saúde/normas , Melhoria de Qualidade , Encaminhamento e Consulta/economia , Encaminhamento e Consulta/normas , Seleção Visual/economia , Seleção Visual/instrumentação , Seleção Visual/normas
10.
J Am Coll Cardiol ; 74(6): 715-725, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31071413

RESUMO

BACKGROUND: Patients with isolated tricuspid regurgitation (TR) in the absence of left-sided valvular dysfunction are often managed nonoperatively. OBJECTIVES: The purpose of this study was to assess the impact of surgery for isolated TR, comparing survival for isolated severe TR patients who underwent surgery with those who did not. METHODS: A longitudinal echocardiography database was used to perform a retrospective analysis of 3,276 adult patients with isolated severe TR from November 2001 to March 2016. All-cause mortality for patients who underwent surgery versus those who did not was analyzed in the entire cohort and in a propensity-matched sample. To assess the possibility of immortal time bias, the analysis was performed considering time from diagnosis to surgery as a time-dependent covariate. RESULTS: Of 3,276 patients with isolated severe TR, 171 (5%) underwent tricuspid valve surgery, including 143 (84%) repairs and 28 (16%) replacements. The remaining 3,105 (95%) patients were medically managed. When considering surgery as a time-dependent covariate in a propensity-matched sample, there was no difference in overall survival between patients who received medical versus surgical therapy (hazard ratio: 1.34; 95% confidence interval: 0.78 to 2.30; p = 0.288). In the subgroup that underwent surgery, there was no difference in survival between tricuspid repair versus replacement (hazard ratio: 1.53; 95% confidence interval: 0.74 to 3.17; p = 0.254). CONCLUSIONS: In patients with isolated severe TR, surgery is not associated with improved long-term survival compared to medical management alone after accounting for immortal time bias.


Assuntos
Procedimentos Cirúrgicos Cardíacos/métodos , Tratamento Conservador/métodos , Pontuação de Propensão , Insuficiência da Valva Tricúspide/terapia , Valva Tricúspide/cirurgia , Idoso , Causas de Morte/tendências , Ecocardiografia Doppler , Feminino , Seguimentos , Humanos , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida/tendências , Valva Tricúspide/diagnóstico por imagem , Insuficiência da Valva Tricúspide/diagnóstico , Insuficiência da Valva Tricúspide/mortalidade
11.
J Am Coll Cardiol ; 74(12): 1543-1553, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31537263

RESUMO

BACKGROUND: Differences in proteomic profiles between men and women may provide insights into the biological pathways that contribute to known sex differences in cardiovascular disease (CVD). OBJECTIVES: This study sought to investigate sex differences in circulating biomarkers representative of biological pathways implicated in the development of CVD among Framingham Heart Study participants. METHODS: The authors measured 71 circulating CVD protein biomarkers in 7,184 participants (54% women, mean age 49 years). Multivariable models were used to evaluate the associations of sex, menopause, and hormone status with biomarkers. Cox models were used to examine whether sex modified the association of biomarkers with incident CVD. RESULTS: Of 71 biomarkers examined, 61 (86%) differed significantly between men and women, of which 37 were higher in women (including adipokines and inflammatory markers such as leptin and C-reactive protein), and 24 were higher in men (including fibrosis and platelet markers such as MMP-8 (matrix metalloproteinase-8) and TIMP-1 (tissue inhibitor of metalloproteinases 1); false discovery rate q < 0.05 for all). Sex differences in biomarker profiles were most pronounced between pre-menopausal women versus men, with attenuated sex differences among post-menopausal women not taking hormone replacement therapy. Sex modified the association of specific biomarkers with incident CVD, including CD14 and apolipoprotein B (pinteraction <0.05 for all). CONCLUSIONS: In a predominantly Caucasian population, the authors identified widespread sex differences in circulating biomarkers that reflect distinct pathways implicated in CVD, including inflammation, adiposity, fibrosis, and platelet homeostasis. Menopause and hormone status accounted for some, but not all, of the observed sex differences. Further investigation into factors underlying sex-based differences may provide mechanistic insight into CVD development.


Assuntos
Proteínas Sanguíneas/análise , Doenças Cardiovasculares/sangue , Adulto , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Sexuais
12.
Nat Med ; 25(11): 1739-1747, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700183

RESUMO

Type 2 diabetes is characterized by insulin resistance and a gradual loss of pancreatic beta cell mass and function1,2. Currently, there are no therapies proven to prevent beta cell loss and some, namely insulin secretagogues, have been linked to accelerated beta cell failure, thereby limiting their use in type 2 diabetes3,4. The adipokine adipsin/complement factor D controls the alternative complement pathway and generation of complement component C3a, which acts to augment beta cell insulin secretion5. In contrast to other insulin secretagogues, we show that chronic replenishment of adipsin in diabetic db/db mice ameliorates hyperglycemia and increases insulin levels while preserving beta cells by blocking dedifferentiation and death. Mechanistically, we find that adipsin/C3a decreases the phosphatase Dusp26; forced expression of Dusp26 in beta cells decreases expression of core beta cell identity genes and sensitizes to cell death. In contrast, pharmacological inhibition of DUSP26 improves hyperglycemia in diabetic mice and protects human islet cells from cell death. Pertaining to human health, we show that higher concentrations of circulating adipsin are associated with a significantly lower risk of developing future diabetes among middle-aged adults after adjusting for body mass index (BMI). Collectively, these data suggest that adipsin/C3a and DUSP26-directed therapies may represent a novel approach to achieve beta cell health to treat and prevent type 2 diabetes.


Assuntos
Complemento C3a/genética , Fator D do Complemento/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fosfatases de Especificidade Dupla/genética , Células Secretoras de Insulina/efeitos dos fármacos , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Animais , Índice de Massa Corporal , Desdiferenciação Celular/efeitos dos fármacos , Fator D do Complemento/genética , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Glucose/metabolismo , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/genética , Hiperglicemia/patologia , Insulina/genética , Resistência à Insulina/genética , Células Secretoras de Insulina/patologia , Camundongos , Camundongos Endogâmicos NOD
13.
J Am Heart Assoc ; 7(16): e009339, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30369306

RESUMO

Background Medicare's Hospital Readmissions Reduction Program assesses financial penalties to hospitals based on risk-standardized readmission rates after specific episodes of care, including acute myocardial infarction. Detailed information about the type of patients included in the penalty is unknown. Methods and Results Starting with administrative data from Medicare, we conducted physician-adjudicated chart reviews of all patients considered 30-day readmissions after acute myocardial infarction from July 2012 to June 2015. Of 197 readmissions, 68 (34.5%) received percutaneous coronary intervention and 18 (9.1%) underwent coronary artery bypass grafting on index hospitalization. The remaining 111 patients did not receive any intervention. Of the 197 patients, 56 patients (28.4%) were considered too high risk for invasive management, 23 (11.7%) had nonobstructive coronary artery disease on diagnostic catheterization and therefore no indication for revascularization, 19 patients had a type II myocardial infarction (9.6%) for which noninvasive, outpatient workup was recommended, and 13 (6.6%) declined further care. The most common readmission diagnoses were cardiac causes and noncardiac chest discomfort, infection, and gastrointestinal bleeding. Conclusions Our results demonstrate that more than a quarter of the patients included in the penalty do not receive revascularization either because of provider assessment of risk or patient preference, and nearly one tenth have type II myocardial infarction. As such, administrative codes for prohibitive procedural risk, patient-initiated "do not resuscitate" status, or type II myocardial infarction may improve the risk-adjustment of the metric. Furthermore, provider organizations seeking to reduce readmission rates should focus resources on the needs of these patients, such as care coordination, hospice services when requested by patients, and treatment of noncardiac conditions.


Assuntos
Infarto do Miocárdio/terapia , Readmissão do Paciente/estatística & dados numéricos , Risco Ajustado/métodos , Idoso , Idoso de 80 Anos ou mais , Codificação Clínica , Ponte de Artéria Coronária , Feminino , Hospitais , Humanos , Masculino , Medicare , Infarto do Miocárdio/fisiopatologia , Preferência do Paciente , Intervenção Coronária Percutânea , Medição de Risco , Índice de Gravidade de Doença , Estados Unidos
14.
J Am Coll Cardiol ; 72(25): 3246-3254, 2018 12 25.
Artigo em Inglês | MEDLINE | ID: mdl-30573026

RESUMO

BACKGROUND: Galectin-3 (Gal-3) has been associated with heart failure (HF) and poor cardiovascular outcomes. However, the effect of longitudinal changes in Gal-3 on clinical outcomes remains unclear. OBJECTIVES: The authors sought to study clinical determinants of change in Gal-3 among community-dwelling individuals. Further, they sought to examine the role of serial Gal-3 measurements in predicting risk of future HF, cardiovascular disease (CVD), and mortality. METHODS: A total of 2,477 participants in the Framingham Heart Study Offspring cohort underwent measurement of plasma Gal-3 levels at 2 examinations (1995 to 1998 and 2005 to 2008). Linear regression models were used to examine clinical correlates of change in Gal-3. Proportional hazards models were used to relate future clinical outcomes with change in Gal-3. RESULTS: The following clinical correlates were associated with greater longitudinal increases in Gal-3 levels: age, female sex, hypertension, diabetes, body mass index, interim development of chronic kidney disease, and HF (p < 0.0001 for all in multivariable model). Change in Gal-3 was associated with future HF (hazard ratio [HR]: 1.39 per 1-SD increase; 95% confidence interval [CI]: 1.13 to 1.71), CVD (HR: 1.29; 95% CI: 1.11 to 1.51), and all-cause mortality (HR: 1.30; 95% CI: 1.17 to 1.46). Change in Gal-3 was associated with both HF with preserved as well as reduced ejection fraction (p < 0.05 for both). CONCLUSIONS: Longitudinal changes in Gal-3 are associated with traditional cardiovascular risk factors and renal disease. In turn, change in Gal-3 predicts future HF, CVD, and mortality in the community. Future studies are needed to determine whether serial Gal-3 measures may be useful in disease prevention.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Galectina 3/sangue , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas , Doenças Cardiovasculares/diagnóstico , Estudos de Coortes , Feminino , Galectinas , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos
15.
Heart ; 104(10): 835-840, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29092919

RESUMO

OBJECTIVES: Although guidelines support aortic valve replacement (AVR) in patients with severe aortic regurgitation (AR) and left ventricular ejection fraction (LVEF) <50%, severe left ventricular dysfunction (LVEF <35%) is thought to confer high surgical risk. We sought to determine if a survival benefit exists with AVR compared with medical management in this high-risk, relatively rare population. METHODS: A large institutional echocardiography database was queried to identify patients with severe AR and LVEF <35%. Manual chart review was performed. Due to small sample size and population heterogeneity, corrected group prognosis method was applied, which calculates the adjusted survival curve for each individual using fitted Cox proportional hazard model. Average survival adjusted for comorbidities and age was then calculated using the weighted average of the individual survival curves. RESULTS: Initially, 2 54 614 echocardiograms were considered, representing 1 45 785 unique patients, of which 40 patients met inclusion criteria. Of those, 18 (45.0%) underwent AVR and 22 (55.0%) were managed medically. Absolute mortality was 27.8% in the AVR group and 91.2% in the medical management group. After multivariate adjustment, end-stage renal disease (HR=17.633, p=0.0335) and peripheral arterial disease (HR=6.050, p=0.0180) were associated with higher mortality. AVR was associated with lower mortality (HR=0.143, p=0.0490). Mean follow-up time of the study cohort was 6.58 years, and mean survival for patients undergoing AVR was 6.31 years. CONCLUSIONS: Even after adjustment for clinical characteristics and patient age, AVR is associated with higher survival for patients with low LVEF and severe AR. Although treatment selection bias cannot be completely eliminated by this analysis, these results provide some evidence that surgery may be associated with prolonged survival in this high-risk patient group.


Assuntos
Valva Aórtica , Ecocardiografia/métodos , Próteses Valvulares Cardíacas , Volume Sistólico , Disfunção Ventricular Esquerda , Idoso , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/fisiopatologia , Insuficiência da Valva Aórtica/diagnóstico , Insuficiência da Valva Aórtica/mortalidade , Insuficiência da Valva Aórtica/cirurgia , Estudos de Coortes , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/epidemiologia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Estados Unidos/epidemiologia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/etiologia
16.
JACC Heart Fail ; 6(8): 701-709, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30007554

RESUMO

OBJECTIVES: This study evaluated the associations of obesity and cardiometabolic traits with incident heart failure with preserved versus reduced ejection fraction (HFpEF vs. HFrEF). Given known sex differences in HF subtype, we examined men and women separately. BACKGROUND: Recent studies suggest that obesity confers greater risk of HFpEF versus HFrEF. Contributions of associated metabolic traits to HFpEF are less clear. METHODS: We studied 22,681 participants from 4 community-based cohorts followed for incident HFpEF versus HFrEF (ejection fraction ≥50% vs. <50%). We evaluated the association of body mass index (BMI) and cardiometabolic traits with incident HF subtype using Cox models. RESULTS: The mean age was 60 ± 13 years, and 53% were women. Over a median follow-up of 12 years, 628 developed incident HFpEF and 835 HFrEF. Greater BMI portended higher risk of HFpEF compared with HFrEF (hazard ratio [HR]: 1.34 per 1-SD increase in BMI; 95% confidence interval [CI]: 1.24 to 1.45 vs. HR: 1.18; 95% CI: 1.10 to 1.27). Similarly, insulin resistance (homeostatic model assessment of insulin resistance) was associated with HFpEF (HR: 1.20 per 1-SD; 95% CI: 1.05 to 1.37), but not HFrEF (HR: 0.99; 95% CI: 0.88 to 1.11; p < 0.05 for difference HFpEF vs. HFrEF). We found that the differential association of BMI with HFpEF versus HFrEF was more pronounced among women (p for difference HFpEF vs. HFrEF = 0.01) when compared with men (p = 0.34). CONCLUSIONS: Obesity and related cardiometabolic traits including insulin resistance are more strongly associated with risk of future HFpEF versus HFrEF. The differential risk of HFpEF with obesity seems particularly pronounced among women and may underlie sex differences in HF subtypes.


Assuntos
Insuficiência Cardíaca/epidemiologia , Síndrome Metabólica/epidemiologia , Obesidade/epidemiologia , Volume Sistólico , Adulto , Idoso , Glicemia/metabolismo , Índice de Massa Corporal , Colesterol/sangue , HDL-Colesterol/sangue , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Incidência , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Fatores Sexuais , Triglicerídeos/sangue
17.
Eur J Heart Fail ; 20(4): 651-659, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29226491

RESUMO

AIMS: While heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community. METHODS AND RESULTS: We pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78). CONCLUSIONS: We found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.


Assuntos
Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Medição de Risco , Volume Sistólico/fisiologia , Idoso , Causas de Morte/tendências , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia
18.
JAMA Cardiol ; 3(3): 215-224, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29322198

RESUMO

Importance: Nearly half of all patients with heart failure have preserved ejection fraction (HFpEF) as opposed to reduced ejection fraction (HFrEF), yet associations of biomarkers with future heart failure subtype are incompletely understood. Objective: To evaluate the associations of 12 cardiovascular biomarkers with incident HFpEF vs HFrEF among adults from the general population. Design, Setting, and Participants: This study included 4 longitudinal community-based cohorts: the Cardiovascular Health Study (1989-1990; 1992-1993 for supplemental African-American cohort), the Framingham Heart Study (1995-1998), the Multi-Ethnic Study of Atherosclerosis (2000-2002), and the Prevention of Renal and Vascular End-stage Disease study (1997-1998). Each cohort had prospective ascertainment of incident HFpEF and HFrEF. Data analysis was performed from June 25, 2015, to November 9, 2017. Exposures: The following biomarkers were examined: N-terminal pro B-type natriuretic peptide or brain natriuretic peptide, high-sensitivity troponin T or I, C-reactive protein (CRP), urinary albumin to creatinine ratio (UACR), renin to aldosterone ratio, D-dimer, fibrinogen, soluble suppressor of tumorigenicity, galectin-3, cystatin C, plasminogen activator inhibitor 1, and interleukin 6. Main Outcomes and Measures: Development of incident HFpEF and incident HFrEF. Results: Among the 22 756 participants in these 4 cohorts (12 087 women and 10 669 men; mean [SD] age, 60 [13] years) in the study, during a median follow-up of 12 years, 633 participants developed incident HFpEF, and 841 developed HFrEF. In models adjusted for clinical risk factors of heart failure, 2 biomarkers were significantly associated with incident HFpEF: UACR (hazard ratio [HR], 1.33; 95% CI, 1.20-1.48; P < .001) and natriuretic peptides (HR, 1.27; 95% CI, 1.16-1.40; P < .001), with suggestive associations for high-sensitivity troponin (HR, 1.11; 95% CI, 1.03-1.19; P = .008), plasminogen activator inhibitor 1 (HR, 1.22; 95% CI, 1.03-1.45; P = .02), and fibrinogen (HR, 1.12; 95% CI, 1.03-1.22; P = .01). By contrast, 6 biomarkers were associated with incident HFrEF: natriuretic peptides (HR, 1.54; 95% CI, 1.41-1.68; P < .001), UACR (HR, 1.21; 95% CI, 1.11-1.32; P < .001), high-sensitivity troponin (HR, 1.37; 95% CI, 1.29-1.46; P < .001), cystatin C (HR, 1.19; 95% CI, 1.11-1.27; P < .001), D-dimer (HR, 1.22; 95% CI, 1.11-1.35; P < .001), and CRP (HR, 1.19; 95% CI, 1.11-1.28; P < .001). When directly compared, natriuretic peptides, high-sensitivity troponin, and CRP were more strongly associated with HFrEF compared with HFpEF. Conclusions and Relevance: Biomarkers of renal dysfunction, endothelial dysfunction, and inflammation were associated with incident HFrEF. By contrast, only natriuretic peptides and UACR were associated with HFpEF. These findings highlight the need for future studies focused on identifying novel biomarkers of the risk of HFpEF.


Assuntos
Biomarcadores/metabolismo , Insuficiência Cardíaca/diagnóstico , Adulto , Idoso , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Volume Sistólico/fisiologia
19.
PLoS One ; 12(10): e0185051, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28968415

RESUMO

IMPORTANCE: In the U.S. presidential election of 2016, substantial shift in voting patterns occurred relative to previous elections. Although this shift has been associated with both education and race, the extent to which this shift was related to public health status is unclear. OBJECTIVE: To determine the extent to which county community health was associated with changes in voting between the presidential elections of 2016 and 2012. DESIGN: Ecological study with principal component analysis (PCA) using principal axis method to extract the components, then generalized linear regression. SETTING: General community. PARTICIPANTS: All counties in the United States. EXPOSURES: Physically unhealthy days, mentally unhealthy days, percent food insecure, teen birth rate, primary care physician visit rate, age-adjusted mortality rate, violent crime rate, average health care costs, percent diabetic, and percent overweight or obese. MAIN OUTCOME: The percentage of Donald Trump votes in 2016 minus percentage of Mitt Romney votes in 2012 ("net voting shift"). RESULTS: Complete public health data was available for 3,009 counties which were included in the analysis. The mean net voting shift was 5.4% (+/- 5.8%). Of these 3,009 counties, 2,641 (87.8%) had positive net voting shift (shifted towards Trump) and 368 counties (12.2%) had negative net voting shift (shifted away from Trump). The first principal component ("unhealthy score") accounted for 68% of the total variance in the data. The unhealthy score included all health variables except primary care physician rate, violent crime rate, and health care costs. The mean unhealthy score for counties was 0.39 (SD 0.16). Higher normalized unhealthy score was associated with positive net voting shift (22.1% shift per unit unhealthy, p < 0.0001). This association was stronger in states that switched Electoral College votes from 2012 to 2016 than in other states (5.9% per unit unhealthy, p <0.0001). CONCLUSIONS AND RELEVANCE: Substantial association exists between a shift toward voting for Donald Trump in 2016 relative to Mitt Romney in 2012 and measures of poor public health. Although these results do not demonstrate causality, these results suggest a possible role for health status in political choices.


Assuntos
Política , Saúde Pública , Análise de Componente Principal , Análise de Regressão , Estados Unidos
20.
Pediatrics ; 140(1)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28637654

RESUMO

BACKGROUND: Vision screening is an essential element of well-child care for young children. Recently, several professional groups have recommended the use of instrument-based screening; however, studies demonstrating the effectiveness of this technique in pediatric primary care settings are lacking. METHODS: We designed a cluster randomized quality improvement project to test the implementation of instrument-based vision screening for 3- to 5-year-old children within a pediatric primary care network. The program consisted of 12 pediatric practices randomized into phase 1 and phase 2 groups. We evaluated the effect of the intervention on completed vision screening at well-child visits, family satisfaction, and referrals to eye care specialists. RESULTS: Instrument-based vision screening increased completed screening among 3- to 5-year-old children from 54% to 89% in the phase 1 group and from 65% to 92% in the phase 2 group. Improvement was most marked among 3-year-old children, with completed screening increasing from 39% with chart-based screening to 87% with instrument screening. Family satisfaction was higher with instrument screening. In addition, instrument screening was associated with a 15% reduction in referrals to eye care specialists. CONCLUSIONS: Instrument-based vision screening for preschool-aged children can be effectively implemented into primary care practice, results in substantially improved rates of completed vision screening at well-child visits, and may result in a reduction in unnecessary referrals to eye care specialists. Additional research is needed regarding how best to overcome barriers to the widespread use of this technology in pediatric primary care settings, as well as its longer-term effect on referrals and the prevalence of amblyopia.


Assuntos
Atenção Primária à Saúde/métodos , Melhoria de Qualidade , Transtornos da Visão/diagnóstico , Seleção Visual/métodos , Pré-Escolar , Feminino , Humanos , Masculino , Encaminhamento e Consulta
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