RESUMO
OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.
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Insuficiência Hepática Crônica Agudizada , Microbioma Gastrointestinal , Cirrose Hepática , Humanos , Animais , Cirrose Hepática/complicações , Camundongos , Masculino , Microbioma Gastrointestinal/efeitos dos fármacos , Método Duplo-Cego , Ratos , Modelos Animais de Doenças , Feminino , Pessoa de Meia-Idade , Translocação Bacteriana/efeitos dos fármacos , Carbono/uso terapêutico , Carbono/farmacologiaRESUMO
PURPOSE: Computed tomography (CT)-based robotic system for total knee arthroplasty (TKA) has shown improved accuracy compared to conventional. This study was designed to (1) confirm the accuracy of the robotic system in achieving the plan and (2) establish the alignment and positioning deviation between final components and planning, by measuring the discrepancy between final implant alignment and the corresponding planned cut. METHODS: Ninety-six cementless robotic-arm assisted (RA) TKAs were assessed. Bone resections were performed using the haptically controlled robotic arm. Alignment in the coronal and sagittal plane and resection depth of the distal femoral and proximal tibial cuts were recorded with a navigation planar probe. After final components were impacted, the probe was positioned on each implant surface to determine its alignment and positioning. RESULTS: The mean tibial resections and implanted tibial component's positioning were 0.4 mm (standard deviation, SD: 0.6) and 0.9 mm (SD: 0.8), respectively, higher than planned (p < 0.01). The tibial sagittal cut had 19/96 cases (19.8%) of ±1° outliers from plan. In 40/96 cases (41.7%), the tibial component was more prominent than planned of more than 1 mm. The mean femoral resections and impacted femoral component's positioning was 0.1 mm (SD: 0.8) and 0.2 mm (SD: 0.7), respectively, higher than planned. In 23/96 cases (24.0%), the femoral sagittal cut and femoral component coronal alignment deviated more than ±1° from plan. CONCLUSIONS: The computed tomography-based robotic-assisted TKA system showed good accuracy regarding bone preparation and component's positioning relative to the planning. Cementless tibial component impaction resulted in the most deviation from plan, with a large proportion of cases resulting in being more prominent than planned. LEVEL OF EVIDENCE: Level III.
Assuntos
Artroplastia do Joelho , Procedimentos Cirúrgicos Robóticos , Tíbia , Tomografia Computadorizada por Raios X , Humanos , Artroplastia do Joelho/métodos , Artroplastia do Joelho/instrumentação , Procedimentos Cirúrgicos Robóticos/métodos , Feminino , Masculino , Idoso , Tíbia/cirurgia , Tíbia/diagnóstico por imagem , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Fêmur/cirurgia , Fêmur/diagnóstico por imagem , Prótese do JoelhoRESUMO
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is characterized by severe systemic inflammation, multi-organ failure and high mortality rates. Its treatment is an urgent unmet need. DIALIVE is a novel liver dialysis device that aims to exchange dysfunctional albumin and remove damage- and pathogen-associated molecular patterns. This first-in-man randomized-controlled trial was performed with the primary aim of assessing the safety of DIALIVE in patients with ACLF, with secondary aims of evaluating its clinical effects, device performance and effect on pathophysiologically relevant biomarkers. METHODS: Thirty-two patients with alcohol-related ACLF were included. Patients were treated with DIALIVE for up to 5 days and end points were assessed at Day 10. Safety was assessed in all patients (n = 32). The secondary aims were assessed in a pre-specified subgroup that had at least three treatment sessions with DIALIVE (n = 30). RESULTS: There were no significant differences in 28-day mortality or occurrence of serious adverse events between the groups. Significant reduction in the severity of endotoxemia and improvement in albumin function was observed in the DIALIVE group, which translated into a significant reduction in the CLIF-C (Chronic Liver Failure consortium) organ failure (p = 0.018) and CLIF-C ACLF scores (p = 0.042) at Day 10. Time to resolution of ACLF was significantly faster in DIALIVE group (p = 0.036). Biomarkers of systemic inflammation such as IL-8 (p = 0.006), cell death [cytokeratin-18: M30 (p = 0.005) and M65 (p = 0.029)], endothelial function [asymmetric dimethylarginine (p = 0.002)] and, ligands for Toll-like receptor 4 (p = 0.030) and inflammasome (p = 0.002) improved significantly in the DIALIVE group. CONCLUSIONS: These data indicate that DIALIVE appears to be safe and impacts positively on prognostic scores and pathophysiologically relevant biomarkers in patients with ACLF. Larger, adequately powered studies are warranted to further confirm its safety and efficacy. IMPACT AND IMPLICATIONS: This is the first-in-man clinical trial which tested DIALIVE, a novel liver dialysis device for the treatment of cirrhosis and acute-on-chronic liver failure, a condition associated with severe inflammation, organ failures and a high risk of death. The study met the primary endpoint, confirming the safety of the DIALIVE system. Additionally, DIALIVE reduced inflammation and improved clinical parameters. However, it did not reduce mortality in this small study and further larger clinical trials are required to re-confirm its safety and to evaluate efficacy. CLINICAL TRIAL NUMBER: NCT03065699.
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Insuficiência Hepática Crônica Agudizada , Doença Hepática Terminal , Humanos , Insuficiência Hepática Crônica Agudizada/terapia , Insuficiência Hepática Crônica Agudizada/complicações , Padrão de Cuidado , Prognóstico , Diálise Renal/efeitos adversos , Cirrose Hepática/complicações , Biomarcadores , Inflamação/complicaçõesRESUMO
In randomized clinical trials, the androgen-receptor inhibitor enzalutamide has demonstrated efficacy and safety in metastatic castration-resistant prostate cancer (mCRPC). This study captured efficacy, safety and patient-reported outcomes (PROs) of enzalutamide in mCRPC patients in a real-world European setting. PREMISE (NCT0249574) was a European, long-term, prospective, observational study in mCRPC patients prescribed enzalutamide as part of standard clinical practice. Patients were categorized based on prior docetaxel and/or abiraterone use. The primary endpoint was time to treatment failure (TTF), defined as time from enzalutamide initiation to permanent treatment discontinuation for any reason. Secondary endpoints included prostate-specific antigen (PSA) response, time to PSA progression, time to disease progression and safety. PROs included EuroQol 5-Dimension, 5-Level questionnaire, Functional Assessment of Cancer Therapy-Prostate and Brief Pain Inventory-Short Form. Overall, 1732 men were enrolled. Median TTF with enzalutamide was 12.9 months in the chemotherapy- and abiraterone-naïve cohort (Cohort 1) and 8.4 months in the postchemotherapy and abiraterone-naïve cohort (Cohort 2). Clinical outcomes based on secondary endpoints also varied between cohorts. Cohorts 1 and 2 showed small improvements in health-related quality of life and pain status. The proportions of patients reporting treatment-emergent adverse events (TEAEs) were 51.0% and 62.2% in Cohorts 1 and 2, respectively; enzalutamide-related TEAEs were similar in both cohorts. The most frequent TEAE across cohorts was fatigue. These data from unselected mCRPC patients in European, real-world, clinical-practice settings confirmed the benefits of enzalutamide previously shown in clinical trial outcomes, with safety results consistent with enzalutamide's known safety profile.
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Benzamidas/uso terapêutico , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzamidas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Nitrilas/efeitos adversos , Feniltioidantoína/efeitos adversos , Estudos Prospectivos , Antígeno Prostático Específico/análise , Neoplasias de Próstata Resistentes à Castração/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/psicologia , Qualidade de VidaRESUMO
Acute respiratory distress syndrome (ARDS) after cardiac surgery is reported with a widely variable incidence (from 0.4%-8.1%). Cardiac surgery patients usually are affected by several comorbidities, and the development of ARDS significantly affects their prognosis. Herein, evidence regarding the current knowledge in the field of ARDS in cardiac surgery is summarized and is followed by a discussion on therapeutic strategies, with consideration of the peculiar aspects of ARDS after cardiac surgery. Prevention of lung injury during and after cardiac surgery remains pivotal. Blood product transfusions should be limited to minimize the risk, among others, of lung injury. Open lung ventilation strategy (ventilation during cardiopulmonary bypass, recruitment maneuvers, and the use of moderate positive end-expiratory pressure) has not shown clear benefits on clinical outcomes. Clinicians in the intraoperative and postoperative ventilatory settings carefully should consider the effect of mechanical ventilation on cardiac function (in particular the right ventricle). Driving pressure should be kept as low as possible, with low tidal volumes (on predicted body weight) and optimal positive end-expiratory pressure. Regarding the therapeutic options, management of ARDS after cardiac surgery challenges the common approach. For instance, prone positioning may not be easily applicable after cardiac surgery. In patients who develop ARDS after cardiac surgery, extracorporeal techniques may be a valid choice in experienced hands. The use of neuromuscular blockade and inhaled nitric oxide can be considered on a case-by-case basis, whereas the use of aggressive lung recruitment and oscillatory ventilation should be discouraged.
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Procedimentos Cirúrgicos Cardíacos , Síndrome do Desconforto Respiratório , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Humanos , Período Perioperatório , Respiração com Pressão Positiva/métodos , Prognóstico , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia , Volume de Ventilação PulmonarRESUMO
BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF (AD-ACLF), defined by organ failure(s). Herein, we aimed to analyze and characterize the precipitants leading to both of these AD phenotypes. METHODS: The multicenter, prospective, observational PREDICT study (NCT03056612) included 1,273 non-electively hospitalized patients with AD (No ACLF = 1,071; ACLF = 202). Medical history, clinical data and laboratory data were collected at enrolment and during 90-day follow-up, with particular attention given to the following characteristics of precipitants: induction of organ dysfunction or failure, systemic inflammation, chronology, intensity, and relationship to outcome. RESULTS: Among various clinical events, 4 distinct events were precipitants consistently related to AD: proven bacterial infections, severe alcoholic hepatitis, gastrointestinal bleeding with shock and toxic encephalopathy. Among patients with precipitants in the AD-No ACLF cohort and the AD-ACLF cohort (38% and 71%, respectively), almost all (96% and 97%, respectively) showed proven bacterial infection and severe alcoholic hepatitis, either alone or in combination with other events. Survival was similar in patients with proven bacterial infections or severe alcoholic hepatitis in both AD phenotypes. The number of precipitants was associated with significantly increased 90-day mortality and was paralleled by increasing levels of surrogates for systemic inflammation. Importantly, adequate first-line antibiotic treatment of proven bacterial infections was associated with a lower ACLF development rate and lower 90-day mortality. CONCLUSIONS: This study identified precipitants that are significantly associated with a distinct clinical course and prognosis in patients with AD. Specific preventive and therapeutic strategies targeting these events may improve outcomes in patients with decompensated cirrhosis. LAY SUMMARY: Acute decompensation (AD) of cirrhosis is characterized by a rapid deterioration in patient health. Herein, we aimed to analyze the precipitating events that cause AD in patients with cirrhosis. Proven bacterial infections and severe alcoholic hepatitis, either alone or in combination, accounted for almost all (96-97%) cases of AD and acute-on-chronic liver failure. Whilst the type of precipitant was not associated with mortality, the number of precipitant(s) was. This study identified precipitants that are significantly associated with a distinct clinical course and prognosis of patients with AD. Specific preventive and therapeutic strategies targeting these events may improve patient outcomes.
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Insuficiência Hepática Crônica Agudizada , Infecções Bacterianas , Hepatite Alcoólica , Cirrose Hepática , Serviços Preventivos de Saúde/métodos , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/etiologia , Insuficiência Hepática Crônica Agudizada/prevenção & controle , Infecções Bacterianas/complicações , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/tratamento farmacológico , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Hepatite Alcoólica/complicações , Hepatite Alcoólica/diagnóstico , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/fisiopatologia , Masculino , Anamnese/estatística & dados numéricos , Pessoa de Meia-Idade , Avaliação das Necessidades , Escores de Disfunção Orgânica , Fatores Desencadeantes , PrognósticoRESUMO
BACKGROUND AND AIM: Acute-on-chronic liver failure (ACLF) is a sinister prognosis, and there is a need for accurate biomarkers and scoring systems to better characterize ACLF patients and predict prognosis. Systemic inflammation and renal failure are hallmarks in ACLF disease development and progression. We hypothesized that the combination of specific inflammatory markers in combination with clinical scores are better predictors of survival than the originally developed CLIF-C acute decompensation (AD) and CLIF-C ACLF scores. METHODS: We reevaluated all previously measured inflammatory markers in 522 patients from the CANONIC study, 342 without and 180 with ACLF. We used the Harrell's C-index to determine the best marker alone or in combination with the original scores and calculated new scores for prediction of mortality in the original CANONIC cohort. RESULTS: The best markers to predict 90-day mortality in patients without ACLF were the plasma macrophage activation markers soluble (s)CD163 and mannose receptor (sMR). Urinary neutrophil gelatinase associated lipocalin (UNGAL) and sCD163 were predictors for 28-day mortality in patients with ACLF. The newly developed CLIF-C AD + sMR score in patients without ACLF improved 90-day mortality prediction compared with the original CLIF-C AD score (C-index 0.82 [0.78-0.86] vs 0.74 [0.70-0.78, P = 0.004]). Further, the new CLIF-C ACLF + sCD163 + UNGAL improved the original CLIF-C ACLF score for 28-day mortality (0.85 [0.79-0.91] vs 0.75 [0.70-0.80], P = 0.039). CONCLUSIONS: The capability of these inflammatory markers to improve the original prognostic scores in cirrhosis patients without and with ACLF points to a key role of macrophage activation and inflammation in the development and progression of AD and ACLF.
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Insuficiência Hepática Crônica Agudizada/diagnóstico , Insuficiência Hepática Crônica Agudizada/mortalidade , Mediadores da Inflamação/sangue , Escores de Disfunção Orgânica , Adulto , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Biomarcadores/sangue , Biomarcadores/urina , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Lectinas Tipo C/sangue , Lipocalina-2/urina , Ativação de Macrófagos , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/sangue , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Receptores de Superfície Celular/sangue , Fatores de TempoRESUMO
INTRODUCTION: Functional alignment (FA) in total knee arthroplasty (TKA) has been introduced to restore the native joint line obliquity, respect the joint line height and minimize the need of soft tissue releases. The purpose of this study was to assess the intraoperative joint line alignment and compare it with the preoperative epiphyseal orientation of the femur and tibia in patients undergoing robotic-arm-assisted (RA)-TKA using FA. MATERIALS AND METHODS: This retrospective study included a consecutive series of patients undergoing RA-TKA between February 2019 and February 2021. The joint line orientation of the femur and tibia in the three-dimensions was calculated and classified on preoperative CT-scans and compared with the intraoperative implant alignment. The tibial cut was performed according to the tibial preoperative anatomy. The femoral cuts were fine-tuned based on tensioned soft tissues, aiming for balanced medial and lateral gaps in flexion and extension. RESULTS: A total of 115 RA-TKAs were assessed. On average, the tibial component was placed at 1.8° varus (SD 1.3), while the femur was placed at 0.8° valgus (SD 2.2) and 0.6° external rotation (SD 2.6) relative to the surgical transepicondylar axis. Moderate to strong, statistically significant relationships were described between preoperative tibial coronal alignment and tibial cut orientation (r = 0.7, p < 0.0001), preoperative femoral orientation in the coronal and axial planes and intraoperative femoral cuts alignment (r = 0.7, p < 0.0001 and r = 0.5, p < 0.0001, respectively). One case (0.9%) of slight tibial component varus subsidence was reported 45-days post-operatively, but implant revision was not necessary. CONCLUSIONS: The proposed robotic-assisted functional technique for TKA alignment, with a restricted tibial component coronal alignment, based on the preoperative phenotype and femoral component positioning as dictated by the soft tissues, provided joint line respecting resections. Further studies are needed to assess long-term implant survivorship, patient satisfaction and alignment-related failures.
Assuntos
Artroplastia do Joelho , Prótese do Joelho , Procedimentos Cirúrgicos Robóticos , Braço , Fêmur/diagnóstico por imagem , Fêmur/cirurgia , Humanos , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/cirurgia , Estudos Retrospectivos , Tíbia/diagnóstico por imagem , Tíbia/cirurgiaRESUMO
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a newly described syndrome, which develops in patients with acute decompensation of cirrhosis, and is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. The profile of circulating lipid mediators, which are endogenous signaling molecules that play a major role in inflammation and immunity, is poorly characterized in ACLF. METHODS: In the current study, we assessed the profile of lipid mediators by liquid chromatography coupled to tandem mass spectrometry in plasma from patients with acute decompensation of cirrhosis, with (n = 119) and without (n = 127) ACLF, and from healthy controls (n = 18). Measurements were prospectively repeated in 191 patients with acute decompensation of cirrhosis during a 28-day follow-up period. RESULTS: Fifty-nine lipid mediators (out of 100) were detected in plasma from cirrhotic patients, of which 16 were significantly associated with disease status. Among these, 11 lipid mediators distinguished patients at any stage from healthy controls, whereas 2 lipid mediators (LTE4 and 12-HHT, both derived from arachidonic acid) shaped a minimal plasma fingerprint that discriminated patients with ACLF from those without. Levels of LTE4 distinguished ACLF grade 3 from ACLF grades 1 and 2, followed the clinical course of the disease (increased with worsening and decreased with improvement) and positively correlated with markers of inflammation and non-apoptotic cell death. Moreover, LTE4 together with LXA5 (derived from eicosapentaenoic acid) and EKODE (derived from linoleic acid) were associated with short-term mortality. LXA5 and EKODE formed a signature associated with coagulation and liver failures. CONCLUSION: Taken together, these findings uncover specific lipid mediator profiles associated with disease severity and prognosis in patients with acute decompensation of cirrhosis. LAY SUMMARY: Acute-on-chronic liver failure (ACLF) is characterized by intense systemic inflammation, multiple organ failures and high short-term mortality. In the current study, we assessed the plasma lipid profile of 100 bioactive lipid mediators in healthy controls, patients with decompensated cirrhosis, and those who had developed ACLF. We identified lipid mediator signatures associated with inflammation and non-apoptotic cell death that discriminate disease severity and evolution, short-term mortality and organ failures.
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Insuficiência Hepática Crônica Agudizada/sangue , Metabolismo dos Lipídeos , Lipidômica/métodos , Lipídeos/sangue , Idoso , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND & AIMS: Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF. METHODS: A total of 1,071 patients with AD were enrolled. We collected detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed up for 3 months. Outcomes (liver transplantation and death) at 1 year were also recorded. RESULTS: Three groups of patients were identified. Pre-ACLF patients (n = 218) developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but did not develop ACLF and had mortality rates of 21.0% and 35.6%, respectively. Stable decompensated cirrhosis (SDC) patients (n = 620) were not readmitted, did not develop ACLF and had a 1-year mortality rate of only 9.5%. The 3 groups differed significantly regarding the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in SDC) and the prevalence of surrogates of severe portal hypertension throughout the study (high in UDC vs. low in pre-ACLF and SDC). CONCLUSIONS: Acute decompensation without ACLF is a heterogeneous condition with 3 different clinical courses and 2 major pathophysiological mechanisms: systemic inflammation and portal hypertension. Predicting the development of ACLF remains a major future challenge. CLINICALTRIALS. GOV NUMBER: NCT03056612. LAY SUMMARY: Herein, we describe, for the first time, 3 different clinical courses of acute decompensation (AD) of cirrhosis after hospital admission. The first clinical course includes patients who develop acute-on-chronic liver failure (ACLF) and have a high short-term risk of death - termed pre-ACLF. The second clinical course (unstable decompensated cirrhosis) includes patients requiring frequent hospitalizations unrelated to ACLF and is associated with a lower mortality risk than pre-ACLF. Finally, the third clinical course (stable decompensated cirrhosis), includes two-thirds of all patients admitted to hospital with AD - patients in this group rarely require hospital admission and have a much lower 1-year mortality risk.
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Insuficiência Hepática Crônica Agudizada/complicações , Hipertensão Portal/fisiopatologia , Cirrose Hepática/fisiopatologia , Insuficiência Hepática Crônica Agudizada/mortalidade , Insuficiência Hepática Crônica Agudizada/fisiopatologia , Europa (Continente)/epidemiologia , Feminino , Seguimentos , Humanos , Hipertensão Portal/etiologia , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Taxa de Sobrevida/tendênciasRESUMO
BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. Therefore, we aimed to analyze the blood metabolome in patients with cirrhosis, with and without ACLF. METHODS: We performed untargeted metabolomics using liquid chromatography coupled to high-resolution mass spectrometry in serum from 650 patients with AD (acute decompensation of cirrhosis, without ACLF), 181 with ACLF, 43 with compensated cirrhosis, and 29 healthy individuals. RESULTS: Of the 137 annotated metabolites identified, 100 were increased in patients with ACLF of any grade, relative to those with AD, and 38 comprised a distinctive blood metabolite fingerprint for ACLF. Among patients with ACLF, the intensity of the fingerprint increased across ACLF grades, and was similar in patients with kidney failure and in those without, indicating that the fingerprint reflected not only decreased kidney excretion but also altered cell metabolism. The higher the ACLF-associated fingerprint intensity, the higher the plasma levels of inflammatory markers, tumor necrosis factor α, soluble CD206, and soluble CD163. ACLF was characterized by intense proteolysis and lipolysis; amino acid catabolism; extra-mitochondrial glucose metabolism through glycolysis, pentose phosphate, and D-glucuronate pathways; depressed mitochondrial ATP-producing fatty acid ß-oxidation; and extra-mitochondrial amino acid metabolism giving rise to metabotoxins. CONCLUSIONS: In ACLF, intense systemic inflammation is associated with blood metabolite accumulation and profound alterations in major metabolic pathways, in particular inhibition of mitochondrial energy production, which may contribute to the development of organ failures. LAY SUMMARY: Acute-on-chronic liver failure (ACLF), which develops in patients with cirrhosis, is characterized by intense systemic inflammation and organ failure(s). Because systemic inflammation is energetically expensive, its metabolic costs may result in organ dysfunction/failure. We identified a 38-metabolite blood fingerprint specific for ACLF that revealed mitochondrial dysfunction in peripheral organs. This may contribute to organ failures.
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Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/complicações , Glicólise , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Metaboloma , Metabolômica/métodos , Mitocôndrias/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). METHODS: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. RESULTS: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). CONCLUSIONS: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279.
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Insuficiência Hepática Crônica Agudizada , Infecções Bacterianas , Peritonite , Albuminas , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/epidemiologia , Humanos , Cirrose Hepática/complicações , Peritonite/tratamento farmacológico , Peritonite/epidemiologiaRESUMO
BACKGROUND & AIMS: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections. METHODS: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study). RESULTS: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines. CONCLUSIONS: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.
Assuntos
Albuminas/administração & dosagem , Infecções Bacterianas/imunologia , Citocinas/imunologia , Hipertensão Portal/fisiopatologia , Hipoalbuminemia/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Albumina Sérica/metabolismo , Infecções Bacterianas/complicações , Infecções Bacterianas/fisiopatologia , Estudos de Casos e Controles , Feminino , Hemodinâmica , Humanos , Hipertensão Portal/etiologia , Hipoalbuminemia/etiologia , Hipoalbuminemia/imunologia , Hipoalbuminemia/fisiopatologia , Inflamação , Circulação Hepática , Cirrose Hepática/complicações , Cirrose Hepática/imunologia , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Pressão na Veia Porta , Sistema Porta , Estudos Prospectivos , Renina/sangueRESUMO
Systemic inflammation (SI) is involved in the pathogenesis of acute decompensation (AD) and acute-on-chronic liver failure (ACLF) in cirrhosis. In other diseases, SI activates tryptophan (Trp) degradation through the kynurenine pathway (KP), giving rise to metabolites that contribute to multiorgan/system damage and immunosuppression. In the current study, we aimed to characterize the KP in patients with cirrhosis, in whom this pathway is poorly known. The serum levels of Trp, key KP metabolites (kynurenine and kynurenic and quinolinic acids), and cytokines (SI markers) were measured at enrollment in 40 healthy subjects, 39 patients with compensated cirrhosis, 342 with AD (no ACLF) and 180 with ACLF, and repeated in 258 patients during the 28-day follow-up. Urine KP metabolites were measured in 50 patients with ACLF. Serum KP activity was normal in compensated cirrhosis, increased in AD and further increased in ACLF, in parallel with SI; it was remarkably higher in ACLF with kidney failure than in ACLF without kidney failure in the absence of differences in urine KP activity and fractional excretion of KP metabolites. The short-term course of AD and ACLF (worsening, improvement, stable) correlated closely with follow-up changes in serum KP activity. Among patients with AD at enrollment, those with the highest baseline KP activity developed ACLF during follow-up. Among patients who had ACLF at enrollment, those with immune suppression and the highest KP activity, both at baseline, developed nosocomial infections during follow-up. Finally, higher baseline KP activity independently predicted mortality in patients with AD and ACLF. Conclusion: Features of KP activation appear in patients with AD, culminate in patients with ACLF, and may be involved in the pathogenesis of ACLF, clinical course, and mortality.
Assuntos
Insuficiência Hepática Crônica Agudizada/etiologia , Cinurenina/sangue , Cirrose Hepática/complicações , Triptofano/sangue , Insuficiência Hepática Crônica Agudizada/sangue , Idoso , Infecções Bacterianas/sangue , Infecções Bacterianas/complicações , Estudos de Casos e Controles , Europa (Continente)/epidemiologia , Feminino , Encefalopatia Hepática/sangue , Encefalopatia Hepática/complicações , Humanos , Inflamação/sangue , Inflamação/complicações , Cirrose Hepática/sangue , Cirrose Hepática/mortalidade , Cirrose Hepática/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal/sangue , Insuficiência Renal/complicaçõesRESUMO
The World Health Organization (WHO) has declared coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a pandemic. Global health care now faces unprecedented challenges with widespread and rapid human-to-human transmission of SARS-CoV-2 and high morbidity and mortality with COVID-19 worldwide. Across the world, medical care is hampered by a critical shortage of not only hand sanitizers, personal protective equipment, ventilators, and hospital beds, but also impediments to the blood supply. Blood donation centers in many areas around the globe have mostly closed. Donors, practicing social distancing, some either with illness or undergoing self-quarantine, are quickly diminishing. Drastic public health initiatives have focused on containment and "flattening the curve" while invaluable resources are being depleted. In some countries, the point has been reached at which the demand for such resources, including donor blood, outstrips the supply. Questions as to the safety of blood persist. Although it does not appear very likely that the virus can be transmitted through allogeneic blood transfusion, this still remains to be fully determined. As options dwindle, we must enact regional and national shortage plans worldwide and more vitally disseminate the knowledge of and immediately implement patient blood management (PBM). PBM is an evidence-based bundle of care to optimize medical and surgical patient outcomes by clinically managing and preserving a patient's own blood. This multinational and diverse group of authors issue this "Call to Action" underscoring "The Essential Role of Patient Blood Management in the Management of Pandemics" and urging all stakeholders and providers to implement the practical and commonsense principles of PBM and its multiprofessional and multimodality approaches.
Assuntos
Bancos de Sangue/organização & administração , Transfusão de Sangue , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Doadores de Sangue , COVID-19 , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Medicina Baseada em Evidências , Humanos , Pneumonia Viral/terapia , Pneumonia Viral/transmissãoRESUMO
BACKGROUND & AIMS: Antibiotic resistance has been increasingly reported in patients with decompensated cirrhosis in single-center studies. Prospective investigations reporting broad epidemiological data are scarce. We aimed to analyze epidemiological changes in bacterial infections in patients with decompensated cirrhosis. METHODS: This was a prospective evaluation of 2 series of patients hospitalized with decompensated cirrhosis. The Canonic series included 1,146 patients from Northern, Southern and Western Europe in 2011. Data on epidemiology, clinical characteristics of bacterial infections, microbiology and empirical antibiotic schedules were assessed. A second series of 883 patients from Eastern, Southern and Western Europe was investigated between 2017-2018. RESULTS: A total of 455 patients developed 520 infections (39.7%) in the first series, with spontaneous bacterial peritonitis, urinary tract infections and pneumonia the most frequent infections. Nosocomial episodes predominated in this series. Nearly half of the infections were culture-positive, of which 29.2% were caused by multidrug-resistant organisms (MDROs). MDR strains were more frequently isolated in Northern and Western Europe. Extended-spectrum beta-lactamase-producing Enterobacteriaceae were the most frequent MDROs isolated in this series, although prevalence and type differed markedly among countries and centers. Antibiotic resistance was associated with poor prognosis and failure of antibiotic strategies, based on third-generation cephalosporins or quinolones. Nosocomial infection (odds ratio [OR] 2.74; pâ¯<â¯0.001), intensive care unit admission (OR 2.09; pâ¯=â¯0.02), and recent hospitalization (OR 1.93; pâ¯=â¯0.04) were identified as independent predictors of MDR infection. The prevalence of MDROs in the second series (392 infections/284 patients) was 23%; 38% in culture-positive infections. A mild increase in the rate of carbapenem-resistant Enterobacteriaceae was observed in this series. CONCLUSIONS: MDR bacterial infections constitute a prevalent, growing and complex healthcare problem in patients with decompensated cirrhosis and acute-on-chronic liver failure across Europe, negatively impacting on prognosis. Strategies aimed at preventing the spread of antibiotic resistance in cirrhosis should be urgently evaluated. LAY SUMMARY: Infections caused by bacteria resistant to the main antibiotic families are prevalent in patients with cirrhosis. This study demonstrates that this healthcare problem is increasing and extends through all European regions. Infections caused by these difficult to treat bacteria resolve less frequently and often cause the death of the patient. The type of resistant bacteria varies markedly among different hospitals.
Assuntos
Insuficiência Hepática Crônica Agudizada , Antibacterianos/farmacologia , Bactérias , Infecções Bacterianas , Farmacorresistência Bacteriana Múltipla , Cirrose Hepática , Insuficiência Hepática Crônica Agudizada/epidemiologia , Insuficiência Hepática Crônica Agudizada/terapia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/isolamento & purificação , Infecções Bacterianas/classificação , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/microbiologia , Infecção Hospitalar/epidemiologia , Progressão da Doença , Europa (Continente)/epidemiologia , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Cirrose Hepática/fisiopatologia , Cirrose Hepática/terapia , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Prevalência , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Data on the outcome of adverse events (AEs) and the risk of developing acute-on-chronic liver failure (ACLF) after ERCP in patients with cirrhosis are unknown. We examined the incidence and risk factors of post-ERCP AEs in patients with cirrhosis and the appearance of ACLF after ERCP. METHODS: In this multicenter, retrospective, matched-cohort study, we evaluated ERCPs performed from January 2002 to 2015. A group of patients with cirrhosis with non-ERCP interventions and one without interventions was also analyzed for the development of ACLF. RESULTS: A total of 441 ERCPs were analyzed; 158 in patients with cirrhosis (cases) and 283 in patients without cirrhosis (controls). The overall rate of AEs after all ERCPs was significantly higher in cases compared to controls (17% vs 9.5, p = 0.02). Cholangitis developed more in cases compared to controls (6.3% vs 1.8%; p = 0.01). In a subanalysis of those with sphincterotomy, the rate of bleeding was higher in those with cirrhosis (9.4% vs 3.4%; p = 0.03). Logistic regression identified cirrhosis (OR, 2.48; 95% CI, 1.36-4.53; p = 0.003) and sphincterotomy (OR, 2.66; 95% CI, 1.23-5.72; p = 0.01) as risk factors of AEs. A total of 18/158 (11.4%) cases developed ACLF after ERCP. ACLF occurred in 7/27 cases with post-ERCP AEs and in 11/131 without post-ERCP AEs (25.9% vs 8.3%; p = 0.01). A total of 3.2% (13/406) patients without interventions developed ACLF compared to 17.5% (102/580) who developed ACLF after non-ERCP interventions. Patients with decompensated cirrhosis at ERCP had a higher risk of developing ACLF (17% vs 6.8%; p = 0.04). Patients with a MELD score ≥ 15 were 3.1 times more likely (95% CI: 1.14-8.6; p = 0.027) to develop ACLF after ERCP. CONCLUSIONS: The rate of AEs after ERCP is higher in patients with cirrhosis compared to the non-cirrhotic population. The incidence of ACLF is higher in those with AEs after ERCP compared to those without AEs, especially cholangitis. The development of ACLF is common after ERCP and other invasive procedures. ACLF can be precipitated by numerous factors which include preceding events before the procedure, including manipulation of the bile duct, and AEs after an ERCP.
Assuntos
Doença Hepática Terminal/epidemiologia , Cirrose Hepática/cirurgia , Idoso , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Estudos de Coortes , Doença Hepática Terminal/etiologia , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Espanha/epidemiologiaRESUMO
Decompensated cirrhosis is characterized by exuberant systemic inflammation. Although the inducers of this feature remain unknown, the presence of circulating forms of oxidized albumin, namely human nonmercaptalbumin 1 (HNA1) and HNA2, is a common finding in cirrhosis. The aim of this study was to explore the ability of these oxidized albumin forms to induce systemic inflammation by triggering the activation of peripheral leukocytes. We observed significantly higher plasma levels of HNA1 and HNA2 in patients with cirrhosis (n = 256) compared to healthy volunteers (n = 48), which gradually increased during the course from compensated to decompensated to acute-on-chronic liver failure. Plasma HNA1 and HNA2 levels significantly correlated with inflammatory markers (i.e., interleukin-6 [IL-6], IL-1ß, tumor necrosis factor-alpha [TNF-α] and IL-8) in patients with cirrhosis. To directly test the inflammatory effects of HNA1 and HNA2 on leukocytes, these oxidized albumin forms were prepared ex vivo and their posttranslational modifications monitored by liquid chromatography (LC)-quadrupole time-of-flight/mass spectrometry (MS). HNA1, but not HNA2, increased IL-1ß, IL-6, and TNF-α mRNA and protein expression in leukocytes from both healthy volunteers and patients with cirrhosis. Moreover, HNA1 up-regulated the expression of eicosanoid-generating enzymes (i.e., cyclooxygenase-2 [COX-2] and microsomal prostaglandin E [PGE] synthase 1) and the production of inflammatory eicosanoids (PGE2 , PGF2α , thromboxane B2 , and leukotriene B4 ), as determined by LC-electrospray ionization-MS/MS. The inflammatory response to HNA1 was more pronounced in peripheral blood mononuclear cells (PBMCs) and marginal in polymorphonuclear neutrophils. Kinome analysis of PBMCs revealed that HNA1 induced the phosphorylation of p38 mitogen-activated protein kinase, the inhibition of which blocked HNA1-induced cytokine and COX-2 induction. Conclusion: HNA1 triggers an inflammatory response in PBMCs, providing a rationale for its removal and replacement by reduced albumin in the prevention of systemic inflammation in patients with advanced liver disease.
Assuntos
Citocinas/metabolismo , Inflamação/metabolismo , Leucócitos/metabolismo , Cirrose Hepática/metabolismo , Albumina Sérica Humana/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Western Blotting , Cromatografia Líquida , Feminino , Humanos , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/complicações , Falência Hepática/etiologia , Falência Hepática/metabolismo , Masculino , Pessoa de Meia-Idade , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Espectrometria de Massas em TandemRESUMO
The aims of this study were to determine the role of cell death in patients with cirrhosis and acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC (CLIF Acute-on-Chronic Liver Failure in Cirrhosis) study (N = 337; AD, 258; ACLF, 79); additional cohorts included healthy volunteers, stable patients with cirrhosis, and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death, respectively, and cK18:K18 ratio (apoptotic index) were measured in plasma by enzyme-linked immunosorbent assay. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (P < 0.001, respectively). Alcohol etiology, no previous decompensation, and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine aminotransferase, and bilirubin, but not with markers of extrahepatic organ injury. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (P < 0.05). CONCLUSION: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Nonapoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury, and type of organ failure. (Hepatology 2018;67:989-1002).
Assuntos
Insuficiência Hepática Crônica Agudizada/fisiopatologia , Biomarcadores/sangue , Morte Celular , Queratina-18/sangue , Cirrose Hepática/fisiopatologia , Insuficiência Hepática Crônica Agudizada/sangue , Insuficiência Hepática Crônica Agudizada/complicações , Adulto , Idoso , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
Anemia is one of the most frequent comorbidities found in patients with coronary artery disease and chronic heart failure (CHF) who are being followed in cardiac rehabilitation facilities. The more frequent type of anemia is caused by iron deficiency (IDA, iron-deficiency anemia): this review summarizes the state of the art of this topic. First of all, the mechanisms of IDA will be analyzed. Subsequently, a description of the main conditions where IDA can unfavorably affect the clinical course, and of its more frequent complications, will be presented (percutaneous interventions, heart surgery, CHF). Special attention will be paid in the description of anemia in the setting of CHF. To this regard, in recent years a relevant amount of research has been carried out, to determine whether treating anemia (either by directly stimulating erythropoiesis or by correcting iron deficiency by oral or intravenous route) is of any clinical and prognostic relevance in patients with CHF. The results of this research will, therefore, be summarized and critically discussed. Finally, we will outline the promising role of cardiac rehabilitation facilities and of its network of experts in the diagnosis, prognostic stratification, and treatment of anemia and iron deficiency.