RESUMO
Consensus holds that hematopoietic stem cells (HSCs) give rise to multipotent progenitors (MPPs) of reduced self-renewal potential and that MPPs eventually produce lineage-committed progenitor cells in a stepwise manner. Using a single-cell transplantation system and marker mice, we unexpectedly found myeloid-restricted progenitors with long-term repopulating activity (MyRPs), which are lineage-committed to megakaryocytes, megakaryocyte-erythroid cells, or common myeloid cells (MkRPs, MERPs, or CMRPs, respectively) in the phenotypically defined HSC compartment together with HSCs. Paired daughter cell assays combined with transplantation revealed that HSCs can give rise to HSCs via symmetric division or directly differentiate into MyRPs via asymmetric division (yielding HSC-MkRP or HSC-CMRP pairs). These myeloid bypass pathways could be essential for fast responses to ablation stress. Our results show that loss of self-renewal and stepwise progression through specific differentiation stages are not essential for lineage commitment of HSCs and suggest a revised model of hematopoietic differentiation.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células Progenitoras Mieloides/citologia , Animais , Antígenos CD34 , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células Progenitoras Mieloides/metabolismoRESUMO
Checkpoints that limit stem cell self-renewal in response to DNA damage can contribute to cancer protection but may also promote tissue aging. Molecular components that control stem cell responses to DNA damage remain to be delineated. Using in vivo RNAi screens, we identified basic leucine zipper transcription factor, ATF-like (BATF) as a major component limiting self-renewal of hematopoietic stem cells (HSCs) in response to telomere dysfunction and γ-irradiation. DNA damage induces BATF in a G-CSF/STAT3-dependent manner resulting in lymphoid differentiation of HSCs. BATF deletion improves HSC self-renewal and function in response to γ-irradiation or telomere shortening but results in accumulation of DNA damage in HSCs. Analysis of bone marrow from patients with myelodysplastic syndrome supports the conclusion that DNA damage-dependent induction of BATF is conserved in human HSCs. Together, these results provide experimental evidence that a BATF-dependent differentiation checkpoint limits self-renewal of HSCs in response to DNA damage.
Assuntos
Pontos de Checagem do Ciclo Celular , Diferenciação Celular , Senescência Celular , Dano ao DNA , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Animais , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Organismos Livres de Patógenos Específicos , Encurtamento do TelômeroRESUMO
Although angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) play critical roles in the treatment of heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF; left-ventricular ejection fraction ≤ 50%), the ideal timing for initiation in patients with acute heart failure (AHF) is unclear. We sought to clarify the timing and safety of ACEi/ARB prescription relative to hemodynamic stabilization (pre or post) in patients hospitalized with acute HFrEF/HFmrEF. This was a retrospective, observational analysis of electronic data of patients hospitalized for AHF at 17 Japanese hospitals. Among 9107 patients hospitalized with AHF, 2648 had HFrEF/HFmrEF, and 83.0% met the hemodynamic stabilization criteria within 10 days of admission. During hospitalization, 63.5% of patients with HFrEF/HFmrEF were prescribed an ACEi/ARB, 79.4% of which were prescribed pre-stabilization. In a multivariable analysis, patients treated with an ACEi/ARB pre-stabilization were more likely to have comorbid hypertension, diabetes mellitus, or ischemic heart disease. ACEi/ARB prescription timing was not associated with adverse events, including hypotension and renal impairment, and early prescription was associated with a lower incidence of subsequent worsening of HF. In clinical practice, more hospitalized patients with AHF received an ACEi/ARB before compared with after hemodynamic stabilization, and no safety concerns were observed. Moreover, early prescription may be associated with a lower incidence of worsening HF.
Assuntos
Inibidores da Enzima Conversora de Angiotensina , Insuficiência Cardíaca , Humanos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudos Retrospectivos , Antagonistas de Receptores de Angiotensina/uso terapêutico , Volume Sistólico , Função Ventricular EsquerdaRESUMO
OBJECTIVES: Factors that affect the change of first-line antimicrobial agents were investigated to further promote their appropriate use. METHODS: This descriptive study used an electronic medical records database. Total 16,353 of the 199,896 patients enrolled between 1996 and 2019 met the inclusion criteria and formed the overall pediatric acute otitis media (AOM) cohort. The factors leading to the change in first-line antimicrobial agents within 14 days were analyzed using classification and regression trees (CART) analysis. RESULTS: This antimicrobial treatment cohort, involved 4860 cases of AOM alone and 9567 cases of AOM with other diseases. The size of the medical facility based on number of beds and historical duration of patient registration impacted on antimicrobial changes. CONCLUSIONS: The current results show that hospital-wide or nation-wide antimicrobial stewardship promotion could be the most influencing factor for antimicrobial changes. Particularly in cases of AOM where other diseases coexist, a more accurate diagnosis and definition of treatment failure of first-line drug are suggested to be important while establishing future treatment strategies. The current study is important to promote appropriate antimicrobial use for AOM treatment.
Assuntos
Antibacterianos , Gestão de Antimicrobianos , Otite Média , Humanos , Otite Média/tratamento farmacológico , Otite Média/microbiologia , Estudos Retrospectivos , Japão , Gestão de Antimicrobianos/métodos , Feminino , Masculino , Pré-Escolar , Lactente , Antibacterianos/uso terapêutico , Doença Aguda , Criança , Anti-Infecciosos/uso terapêutico , Análise de Regressão , Registros Eletrônicos de Saúde/estatística & dados numéricosRESUMO
Aging and carcinogenesis coincide with the accumulation of DNA damage and mutations in stem and progenitor cells. Molecular mechanisms that influence responses of stem and progenitor cells to DNA damage remain to be delineated. Here, we show that niche positioning and Wnt signaling activity modulate the sensitivity of intestinal stem and progenitor cells (ISPCs) to DNA damage. ISPCs at the crypt bottom with high Wnt/ß-catenin activity are more sensitive to DNA damage compared to ISPCs in position 4 with low Wnt activity. These differences are not induced by differences in cell cycle activity but relate to DNA damage-dependent activation of Wnt signaling, which in turn amplifies DNA damage checkpoint activation. The study shows that instructed enhancement of Wnt signaling increases radio-sensitivity of ISPCs, while inhibition of Wnt signaling decreases it. These results provide a proof of concept that cell intrinsic levels of Wnt signaling modulate the sensitivity of ISPCs to DNA damage and heterogeneity in Wnt activation in the stem cell niche contributes to the selection of ISPCs in the context of DNA damage.
Assuntos
Dano ao DNA/fisiologia , Intestinos/citologia , Tolerância a Radiação/fisiologia , Células-Tronco/metabolismo , Via de Sinalização Wnt/fisiologia , Animais , Western Blotting , Citometria de Fluxo , Imunofluorescência , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise em Microsséries , Reação em Cadeia da Polimerase em Tempo Real , Estatísticas não ParamétricasRESUMO
The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.
Assuntos
Aneuploidia , Telomerase/metabolismo , Telômero/metabolismo , Animais , Senescência Celular/genética , Senescência Celular/fisiologia , Replicação do DNA/genética , Replicação do DNA/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Telomerase/genética , Telômero/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
The peripheral maturation of human CD1d-restricted natural killer T (NKT) cells has not been well described. In this study, we identified four major subsets of NKT cells in adults, distinguished by the expression of CD4, CD8 and CCR5. Phenotypic analysis suggested a hierarchical pattern of differentiation, whereby immature CD4+ CD8- CCR5- cells progressed to an intermediate CD4+ CD8- CCR5+ stage, which remained less differentiated than the CD4- CD8- and CD4- CD8+ subsets, both of which expressed CCR5. This interpretation was supported by functional data, including clonogenic potential and cytokine secretion profiles, as well as T-cell receptor (TCR) excision circle analysis. Moreover, conventional and high-throughput sequencing of the corresponding TCR repertoires demonstrated significant clonotypic overlap within individuals, especially between the more differentiated CD4- CD8- and CD4- CD8+ subsets. Collectively, these results mapped a linear differentiation pathway across the post-thymic landscape of human CD1d-restricted NKT cells.
Assuntos
Subpopulações de Linfócitos/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/genética , Antígenos CD1d/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Diferenciação Celular , Células Cultivadas , Células Clonais , Citocinas/metabolismo , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Receptores CCR5/metabolismoRESUMO
The regenerative capacity of most tissues declines dramatically after embryonic development and during post-natal life. The underlying mechanisms of this phenomenon are incompletely understood. In a recent issue of Cell, Shyh-Chang and colleagues provide experimental evidence that Lin28 prolongs youthful regenerative capacity by increasing oxidative glucose metabolism (Shyh-Chang et al, 2013).
Assuntos
Proteínas de Ligação a RNA/metabolismo , Cicatrização , Animais , HumanosRESUMO
Reduced capacity of genome maintenance represents a problem for any organism, potentially causing premature death, carcinogenesis, or accelerated ageing. Strikingly though, loss of certain genome stability factors can be beneficial, especially for the maintenance of tissue stem cells of the intestine and the haematopoietic system. We therefore screened for genome stability factors negatively impacting maintenance of haematopoietic stem cells (HSC) in the context of ionising radiation (IR). We found that in vivo knock down of Xeroderma pigmentosum, complementation group G (Xpg) causes elevation of HSC numbers after IR treatment, while numbers of haematopoietic progenitors are elevated to a lesser extent. IR rapidly induces Xpg both on mRNA and on protein level. Prevention of this induction does not influence activation of the checkpoint cascade, yet attenuates late checkpoint steps such as induction of p21 and Noxa. This causes a leaky cell cycle arrest and lower levels of apoptosis, both contributing to increased colony formation and transformation rates. Xpg thus helps to adequately induce DNA damage responses after IR, thereby keeping the expansion of damaged cells under control. This represents a new function of Xpg in the response to IR, in addition to its well-characterized role in nucleotide excision repair.
Assuntos
Carcinogênese/efeitos da radiação , Reparo do DNA/genética , Proteínas de Ligação a DNA/biossíntese , Endonucleases/biossíntese , Instabilidade Genômica/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos da radiação , Proteínas Nucleares/biossíntese , Fatores de Transcrição/biossíntese , Apoptose/efeitos da radiação , Pontos de Checagem do Ciclo Celular/efeitos da radiação , Dano ao DNA/efeitos da radiação , Proteínas de Ligação a DNA/genética , Endonucleases/genética , Regulação da Expressão Gênica/efeitos da radiação , Técnicas de Silenciamento de Genes , Instabilidade Genômica/efeitos da radiação , Humanos , Proteínas Nucleares/genética , RNA Mensageiro/biossíntese , Radiação Ionizante , Fatores de Transcrição/genética , Xeroderma Pigmentoso/genéticaRESUMO
The transplantation of blood tissues from bone marrow into a lethally irradiated animal is an experimental procedure that is used to study how the blood system is reconstituted by haematopoietic stem cells (HSC). In a competitive repopulation experiment, a lethally irradiated mouse was transplanted with a single HSC as a test cell together with a number of bone marrow cells as competitor cells, and the fraction of the test cell progeny (percentage of chimerism) was traced over time. In this paper, we studied the stem cell kinetics in this experimental procedure. The balance between symmetric self-renewal and differentiation divisions in HSC determined the number of cells which HSC produce and the length of time for which HSC live after transplantation. The percentage of chimerism depended on the type of test cell (long-, intermediate-, or short-term HSC), as well as the type and number of HSC included in competitor cells. We next examined two alternative HSC differentiation models, one-step and multi-step differentiation models. Although these models differed in blood cell production, the percentage of chimerism appeared very similar. We also estimated the numbers of different types of HSC in competitor cells. Based on these results, we concluded that the experimental results inevitably include stochasticity with regard to the number and the type of HSC in competitor cells, and that, in order to detect different types of HSC, an appropriate number of competitor cells needs to be used in transplantation experiments.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Animais , Diferenciação Celular , Proliferação de Células , Simulação por Computador , Camundongos , Modelos BiológicosRESUMO
Throughout life, one's blood supply depends on sustained division of hematopoietic stem cells (HSCs) for self-renewal and differentiation. Within the bone marrow microenvironment, an adhesion-dependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-ß3 signaling contributes to HSC maintenance. Specific ligation of ß3-integrin on HSCs using an antibody or extracellular matrix protein prevented loss of long-term repopulating (LTR) activity during ex vivo culture. The actions required activation of αvß3-integrin "inside-out" signaling, which is dependent on thrombopoietin (TPO), an essential cytokine for activation of dormant HSCs. Subsequent "outside-in" signaling via phosphorylation of Tyr747 in the ß3-subunit cytoplasmic domain was indispensable for TPO-dependent, but not stem cell factor-dependent, LTR activity in HSCs in vivo. This was accompanied with enhanced expression of Vps72, Mll1, and Runx1, 3 factors known to be critical for maintaining HSC activity. Thus, our findings demonstrate a mechanistic link between ß3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture.
Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Integrina alfaVbeta3/fisiologia , Transdução de Sinais , Trombopoetina/farmacologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores/metabolismo , Western Blotting , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Comunicação Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de OligonucleotídeosRESUMO
HSC fate decisions are regulated by cell-intrinsic and cell-extrinsic cues. The latter cues are derived from the BM niche. Membrane-type 1 matrix metalloproteinase (MT1-MMP), which is best known for its proteolytic role in pericellular matrix remodeling, is highly expressed in HSCs and stromal/niche cells. We found that, in MT1-MMP(-/-) mice, in addition to a stem cell defect, the transcription and release of kit ligand (KitL), stromal cell-derived factor-1 (SDF-1/CXCL12), erythropoietin (Epo), and IL-7 was impaired, resulting in a trilineage hematopoietic differentiation block, while addition of exogenous KitL and SDF-1 restored hematopoiesis. Further mechanistic studies revealed that MT1-MMP activates the hypoxia-inducible factor-1 (HIF-1) pathway via factor inhibiting HIF-1 (FIH-1) within niche cells, thereby inducing the transcription of HIF-responsive genes, which induce terminal hematopoietic differentiation. Thus, MT1-MMP in niche cells regulates postnatal hematopoiesis, by modulating hematopoietic HIF-dependent niche factors that are critical for terminal differentiation and migration.
Assuntos
Citocinas/genética , Hematopoese , Células-Tronco Hematopoéticas/citologia , Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Ativação Transcricional , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Linhagem Celular , Células Cultivadas , Quimiocina CXCL12/metabolismo , Quimiocinas/genética , Células Eritroides/citologia , Células Eritroides/metabolismo , Deleção de Genes , Células-Tronco Hematopoéticas/metabolismo , Humanos , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Fator de Células-Tronco/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
BACKGROUND: Cancer patients not admissible for adjuvant chemotherapy are generally at high risk of considerably inferior prognosis. The aim of this retrospective study was to evaluate poorer survival without administration of oral adjuvant chemotherapy of stage III colon cancer patients in clinical settings. METHODS: Between April 2007 and September 2011, 259 patients with stage III colon cancer who underwent curative surgery were retrospectively assigned to the adjuvant chemotherapy group of 171 patients (66%) and the surgery alone group of 88 patients. Oral fluorouracil (5-FU) derivatives used in adjuvant chemotherapy, such as oral uracil and tegafur plus leucovorin (UFT/LV) or capecitabine, were the most commonly used. RESULTS: The 3-year relapse-free survival (RFS) rates were 74.9% for all cases, 58.3% for the surgery alone group, and 83.4% for the adjuvant chemotherapy group (P=0.0001). The chemotherapy group was associated with a dramatic improvement in survival for stage IIIB (surgery alone 57.7% versus adjuvant chemotherapy 83.9%; P=0.0001) and stage IIIC (surgery alone 18.2% versus adjuvant chemotherapy 57.3%; P=0.006) patients. There was a significant difference in the overall recurrence rate between groups (surgery alone 35.2% versus adjuvant chemotherapy 18.1%; P=0.002). Multivariate analysis identified adjuvant therapy as an independent predictive factor of reduced recurrence (hazard ratio (HR): 3.231; P=0.004) and improved RFS (HR: 2.653; P=0.001). CONCLUSION: In clinical settings, adjuvant therapy was the only significant prognostic factor of survival. Since many patients prefer not to receive chemotherapy, it is critical to inform stage III colon cancer patients that chemotherapy raises their chances of survival by three-fold compared with curative surgery alone.
Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colectomia/mortalidade , Neoplasias do Colo/terapia , Recidiva Local de Neoplasia/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Seguimentos , Humanos , Leucovorina/administração & dosagem , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tegafur/administração & dosagem , Uracila/administração & dosagem , Adulto JovemRESUMO
Fluorescent-protein transgenic mice are useful for obtaining marked somatic cells to study kinetics of development or differentiation. Fluorescence-marked hematopoietic stem cells in particular are commonly used for studying hematopoiesis. However, as far as we know, no transgenic mouse line is described in which a fluorescent protein is stably and constitutively expressed in all hematopoietic cells, including erythrocytes and platelets. Using the random segregation of provirus (RSP) method, we generated from retrovirally transduced mouse embryonic stem cells a transgenic mouse line expressing a red/orange fluorescent protein, Kusabira Orange (KuO). KuO transgenic mouse line cells carry only one proviral integration site and stably express KuO in all hematopoietic-lineage elements, including erythrocytes and platelets. Moreover, bone-marrow transplantation in KuO transgenic mice demonstrated normal hematopoieisis. KuO transgenic mice likely will prove useful for study of hematopoiesis that includes erythropoiesis and megakaryopoiesis.
Assuntos
Eritrócitos/metabolismo , Engenharia Genética/métodos , Proteínas Luminescentes/metabolismo , Camundongos Transgênicos/metabolismo , Camundongos Transgênicos/virologia , Provírus/genética , Transfecção/métodos , Animais , Proteínas Luminescentes/genética , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Especificidade de Órgãos , Distribuição Tecidual , Proteína Vermelha FluorescenteRESUMO
A 37-year-old man was transported by ambulance to our hospital due to abrupt chest pain. The pain began when he was practicing a combative-type sport. He denied any impact or blunt trauma. A chest radiograph revealed massive left pleural effusion with a mediastinal shift. Thoracentesis revealed a hemothorax;therefore, we performed an emergency thoracotomy. The intraoperative findings revealed a rupture of a posterior mediastinal tumor itself located between the descending aorta and the thoracic vertebra. After we identified the artery of Adamkiewicz that originates away from the tumor and evaluated the degree of tumor extension into the inter-vertebral foramen, we safely performed an elective tumor resection 1 month after the initial emergency operation. In patients with a hemothorax caused by rupture of the tumor itself, an elective tumor resection after detailed investigation should be considered if hemostasis can be achieved in the emergency thoracotomy.
Assuntos
Hemotórax/etiologia , Neoplasias do Mediastino/patologia , Tumores Fibrosos Solitários/patologia , Adulto , Humanos , Masculino , Ruptura EspontâneaRESUMO
A 36-year-old woman visited our hospital with a chief complaint of bleeding during defecation. Colonoscopy revealed a 20-mm pedunculated polyp in the sigmoid colon, which was en bloc resected under endoscopy. The histopathological diagnosis was adenoma cancer with a depth of invasion indicating mucosal cancer, no lymphovascular invasion, and negative at the resection margin. The poorly differentiated adenocarcinoma component comprised approximately 5% of the tumor. Although there were no recurrence signs in the computed tomography scans obtained 4 months post polypectomy, the patient experienced aggressive lower back pain at 6 months post polypectomy. Local recurrence, peritoneal dissemination, and liver metastasis were confirmed. Finally, the patient died following a rapid and aggressive deterioration of her general condition. Histological examination of the local recurrence revealed a poorly differentiated adenocarcinoma (por2), with immunostaining revealing a high Ki67 positivity rate of 95%. Moreover, the poorly differentiated adenocarcinoma region of the resected polyp had a Ki67 positivity rate of 90%, which suggested that they were the same tumors. These findings suggested that the recurrence could have occurred through implantation.
RESUMO
Background: Triple combination therapy with a renin-angiotensin system modulator, a ß-blocker, and a mineralocorticoid receptor antagonist is currently recommended for patients with heart failure (HF) with reduced ejection fraction. However, there is limited evidence on the extent to which triple combination therapy is currently prescribed to patients at the time of discharge from hospital in Japan. MethodsâandâResults: Japanese patients hospitalized for HF (n=3,582) were evaluated in subgroups defined by left ventricular ejection fraction (LVEF) using anonymized claims and electronic health record data. At discharge, triple combination therapy prescription rates were low (40.4%, 30.0%, 20.8%, 14.0%, and 12.5% for patients with LVEF <30%, 30-<40%, 40-<50%, 50-<60%, and ≥60%, respectively). Advanced age, lower levels of B-type natriuretic peptide, and renal impairment were all significantly associated with lower rates of triple combination therapy use in the overall population. There were no significant differences in rehospitalization rates between LVEF subgroups; however, triple combination therapy use was associated with a significantly reduced risk of rehospitalization for HF in patients with LVEF <30%, 30-<40%, and 40-<50%. Conclusions: The use of triple combination therapy was significantly associated with a lower risk of rehospitalization for HF within 1 year of discharge in patients with LVEF <30%, 30-<40%, and 40-<50%. However, patients were undertreated with triple combination therapy.