Soluble Transferrin Receptor as Iron Deficiency Biomarker: Impact on Exercise Capacity in Heart Failure Patients.

The soluble transferrin receptor (sTfR) is a marker of tissue iron status, which could indicate an increased iron demand at the tissue level. The impact of sTfR levels on functional capacity and quality of life (QoL) in non-anemic heart failure (HF) patients with otherwise normal systemic iron status has not been evaluated. We conducted an observational, prospective, cohort study of 1236 patients with chronic HF. We selected patients with normal hemoglobin levels and normal systemic iron status. Tissue iron deficiency (ID) was defined as levels of sTfR > 75th percentile (1.63 mg per L). The primary endpoints were the distance walked in the 6 min walking test (6MWT) and the overall summary score (OSS) of the Minnesota Living with Heart Failure Questionnaire (MLHFQ). The final study cohort consisted of 215 patients. Overall QoL was significantly worse (51 ± 27 vs. 39 ± 20, p-value = 0.006, respectively), and the 6 MWT distance was significantly worse in patients with tissue ID when compared to patients without tissue ID (206 ± 179 m vs. 314 ± 155, p-value < 0.0001, respectively). Higher sTfR levels, indicating increased iron demand, were associated with a shorter distance in the 6 MWT (standardized ß = -0.249, p < 0.001) and a higher MLHFQ OSS (standardized ß = 0.183, p-value = 0.008). In this study, we show that in patients with normal systemic iron parameters, higher levels of sTfR are strongly associated with an impaired submaximal exercise capacity and with worse QoL.

Population-based evaluation of the impact of socioeconomic status on clinical outcomes in patients with heart failure in integrated care settings.

INTRODUCTION AND OBJECTIVES: Low socioeconomic status (SES) is associated with poor outcomes in patients with heart failure (HF). We aimed to examine the influence of SES on health outcomes after a quality of care improvement intervention for the management of HF integrating hospital and primary care resources in a health care area of 209 255 inhabitants. METHODS: We conducted a population-based pragmatic evaluation of the implementation of an integrated HF program by conducting a natural experiment using health care data. We included all individuals consecutively admitted to hospital with at least one ICD-9-CM code for HF as the primary diagnosis and discharged alive in Catalonia between January 1, 2015 and December 31, 2019. We compared outcomes between patients exposed to the new HF program and those in the remaining health care areas, globally and stratified by SES. RESULTS: A total of 77 554 patients were included in the study. Death occurred in 37 469 (48.3%), clinically-related hospitalization in 41 709 (53.8%) and HF readmission in 29 755 (38.4%). On multivariate analysis, low or very low SES was associated with an increased risk of all-cause death and clinically-related hospitalization (all Ps <.05). The multivariate models showed a significant reduction in the risk of all-cause death (HR, 0.812; 95%CI, 0.723-0.912), clinically-related hospitalization (HR, 0.886; 95%CI, 0.805-0.976) and HF hospitalization (HR, 0.838; 95%CI, 0.745-0.944) in patients exposed to the new HF program compared with patients exposed to the remaining health care areas and this effect was independent of SES. CONCLUSIONS: An intensive transitional HF management program improved clinical outcomes, both overall and across SES strata.

Blood Differential Gene Expression in Patients with Chronic Heart Failure and Systemic Iron Deficiency: Pathways Involved in Pathophysiology and Impact on Clinical Outcomes.

BACKGROUND: Iron deficiency is a common disorder in patients with heart failure and is related with adverse outcomes and poor quality of life. Previous experimental studies have shown biological connections between iron homeostasis, mitochondrial metabolism, and myocardial function. However, the mechanisms involved in this crosstalk are yet to be unfolded. METHODS: The present research attempts to investigate the intrinsic biological mechanisms between heart failure and iron deficiency and to identify potential prognostic biomarkers by determining the gene expression pattern in the blood of heart failure patients, using whole transcriptome and targeted TaqMan® low-density array analyses. RESULTS: We performed a stepwise cross-sectional longitudinal study in a cohort of chronic heart failure patients with and without systemic iron deficiency. First, the full transcriptome was performed in a nested case-control exploratory cohort of 7 paired patients and underscored 1128 differentially expressed transcripts according to iron status (cohort1#). Later, we analyzed the messenger RNA levels of 22 genes selected by their statistical significance and pathophysiological relevance, in a validation cohort of 71 patients (cohort 2#). Patients with systemic iron deficiency presented lower mRNA levels of mitochondrial ferritin, sirtuin-7, small integral membrane protein 20, adrenomedullin and endothelin converting enzyme-1. An intermediate mitochondrial ferritin gene expression and an intermediate or low sirtuin7 and small integral membrane protein 20 mRNA levels were associated with an increased risk of all-cause mortality and heart failure admission ((HR 2.40, 95% CI 1.04-5.50, p-value = 0.039), (HR 5.49, 95% CI 1.78-16.92, p-value = 0.003), (HR 9.51, 95% CI 2.69-33.53, p-value < 0.001), respectively). CONCLUSIONS: Patients with chronic heart failure present different patterns of blood gene expression depending on systemic iron status that affect pivotal genes involved in iron regulation, mitochondrial metabolism, endothelial function and cardiovascular physiology, and correlate with adverse clinical outcomes.

Trombo en la aurícula derecha tras neumonía por COVID-19 / Thrombus in the right atrium after COVID-19 pneumonia

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Use of intravenous iron in patients with iron deficiency and chronic heart failure: Real-world evidence.

INTRODUCTION AND OBJECTIVES: Treatment with intravenous iron in patients with heart failure (HF) and iron deficiency (ID) improves symptoms, however its impact on survival and safety is unknown. We aimed to evaluate the management of ID and anemia with intravenous iron in patients with HF and long-term safety of intravenous iron. METHODS: We evaluated anemia and ID in patients with chronic HF at 3 university hospitals. Anemia was defined using the World Health Organization definition and ID was defined as ferritin <100 ug/L or a Transferrin Saturation <20% if ferritin between 100 and 299 ug/L. We assessed treatment with intravenous iron during follow-up and its association with mortality and HF hospitalizations using multivariate cox regression analysis. RESULTS: We included 2,114 patients, median age 72 years and 57% had reduced left ventricular ejection fraction. ID was present in 55% and ID and anemia in 29%. Treatment with intravenous iron was used in 24% of patients with ID and 34% of patients with ID and anemia. In patients with ID, after multivariate adjustment, treatment with intravenous iron was associated with lower all-cause mortality: HR = 0.38 (0.28-0.56), lower cardiovascular mortality: HR = 0.34 (0.20-0.57) and no differences in HF hospitalizations: HR = 1.15 (0.88-1.50). Similar outcomes were found for patients with anemia and ID. CONCLUSIONS: In a real-world cohort of patients with HF, treatment with intravenous iron was used in one third of patients with ID and anemia and appears safe in mid-term follow-up.

Importance of iron deficiency in patients with chronic heart failure as a predictor of mortality and hospitalizations: insights from an observational cohort study.

BACKGROUND: Iron deficiency (ID) in patients with chronic heart failure (CHF) is considered an adverse prognostic factor. We aimed to evaluate if ID in patients with CHF is associated with increased mortality and hospitalizations. METHODS: We evaluated ID in patients with CHF at 3 university hospitals. ID was defined as absolute (ferritin < 100 µg/L) or functional (transferrin Saturation index < 20% and ferritin between 100 and 299 µg/L). We excluded patients who received treatment with intravenous Iron or Erythropoietin during follow-up. We evaluated if ID was a predictor of death or hospitalization due to heart failure or any cause using univariate and multivariate cox regression analysis. RESULTS: We included 1684 patients, 65% males, 38% diabetics, median age of 72 years, 37% in functional class III-IV and 30% of patients with a left ventricular ejection fraction > 45%. Patients were well treated, with 87% and 88% of patients receiving renin-angiotensin inhibitors and beta-blockers, respectively. Median transferrin saturation index was 20%, median ferritin 155 ng/mL and median haemoglobin 13 g/dL. ID was present in 53% of patients; in 35% it was absolute and in 18% functional. Median follow-up was 20 months. ID was a predictor of death, hospitalization due to heart failure or to any cause in univariate analysis but not after multivariate analysis. No differences were found between absolute or functional ID regarding prognosis. CONCLUSION: In a real life population of patients with CHF and a high prevalence of heart failure with preserved ejection fraction, ID did not predict mortality or hospitalizations after adjustment for comorbidities, functional class and neurohormonal treatment.

Iron deficiency and red cell indices in patients with heart failure.

AIMS: To investigate the prevalence of iron deficiency (ID) in heart failure (HF) patients with normal vs. abnormal red cell indices (RCI), the associations between iron parameters and RCI, and prognostic consequences of ID independently of RCI. METHODS AND RESULTS: We analysed clinical data of 1821 patients with HF [mean age 66 ± 13 years; 71% men; New York Heart Association class I/II/III/IV (11%/39%/44%/6%); left ventricular ejection fraction >45%: 19%]. Iron deficiency (ferritin <100 µg/L or ferritin 100-299 µg/L with transferrin saturation <20%) was common irrespective of the presence of anaemia (haemoglobin <12 g/dL in women and <13 g/dL in men) or low RCI, from 75% in anaemic subjects with low mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), and MCH concentration (MCHC), to 36% in non-anaemic subjects with MCV, MCH, and MCHC above the lower limit of normal. After adjustment for clinical variables, iron parameters remained independently associated with haemoglobin, MCV, MCH, MCHC, mean reticulocyte haemoglobin content (CHR), and red cell distribution width (RDW). In multivariable Cox proportional hazard regression models there was a trend towards higher mortality in patients with vs. without ID when adjusted for relevant HF prognosticators and MCH or MCHC (but not haemoglobin, CHR or RDW). CONCLUSIONS: Patients with HF should be routinely screened for ID irrespective of the presence of anaemia or abnormal RCI. The detrimental impact of ID on long-term survival in HF is partially independent of RCI.

Limitaciones de la prueba de marcha de 6 minutos como instrumento de medida en pacientes con insuficiencia cardiaca crónica. Respuesta / The limitations of the 6-minute walk test as a measurement tool in chronic heart failure patients. Response

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Estado del hierro en la insuficiencia cardiaca crónica: impacto en síntomas, clase funcional y capacidad de ejercicio submáxima / Iron status in chronic heart failure: impact on symptoms, functional class and submaximal exercise capacity

Introducción y objetivos: Evaluar el efecto del déficit de hierro y la anemia en la capacidad de esfuerzo submáxima de pacientes con insuficiencia cardiaca crónica. Métodos: Se llevó a cabo un estudio transversal unicéntrico en un grupo de pacientes estables con insuficiencia cardiaca crónica. En el momento de incluirlos en el estudio, los pacientes aportaron información basal y realizaron una prueba de marcha de 6 minutos para evaluar la capacidad de ejercicio submáxima y los síntomas desencadenados por el esfuerzo. Al mismo tiempo, se obtuvieron muestras de sangre para la evaluación serológica. El déficit de hierro se definió como un valor de ferritina < 100 ng/ml o una saturación de transferrina < 20% cuando la ferritina era < 800 ng/ml. Se efectuaron también determinaciones de otros marcadores del estado del hierro. Resultados: Se consideró aptos para la inclusión en el estudio a 538 pacientes con insuficiencia cardiaca. La media de edad era 71 años y el 33% se encontraba en las clases III/IV de la New York Heart Association. La distancia media recorrida en la prueba de marcha de 6 minutos por los pacientes con alteración del estado del hierro fue 285 ± 101 m, en comparación con los 322 ± 113 m del otro grupo (p = 0,002). Los síntomas durante la prueba fueron más frecuentes en los pacientes con déficit de hierro (el 35 frente al 27%; p = 0,028) y el síntoma registrado con más frecuencia fue la fatiga. Los análisis de regresión logística multivariables mostraron que el aumento de la concentración de receptor de transferrina soluble, que indica un estado anormal del hierro, se asociaba de manera independiente con una clase avanzada de la New York Heart Association (p < 0,05). En el análisis multivariable realizado empleando modelos aditivos generalizados, el receptor de transferrina soluble y el índice de ferritina, biomarcadores que miden el estado del hierro, mostraron una asociación lineal, significativa e independiente con la capacidad de ejercicio submáxima (p = 0,03 en ambos casos). En cambio, en el análisis multivariable los valores de hemoglobina no mostraron una asociación significativa con la distancia recorrida en la prueba de marcha de 6 minutos. Conclusiones: En los pacientes con insuficiencia cardiaca crónica, el déficit de hierro, pero no así la anemia, se asoció con deterioro de la capacidad de ejercicio submáxima y limitación funcional sintomática (AU)

Introduction and objectives: To evaluate the effect of iron deficiency and anemia on submaximal exercise capacity in patients with chronic heart failure. Methods: We undertook a single-center cross-sectional study in a group of stable patients with chronic heart failure. At recruitment, patients provided baseline information and completed a 6-minute walk test to evaluate submaximal exercise capacity and exercise-induced symptoms. At the same time, blood samples were taken for serological evaluation. Iron deficiency was defined as ferritin < 100 ng/mL or transferrin saturation < 20% when ferritin is < 800 ng/mL. Additional markers of iron status were also measured. Results: A total of 538 heart failure patients were eligible for inclusion, with an average age of 71 years and 33% were in New York Heart Association class III/IV. The mean distance walked in the test was 285 ± 101 meters among those with impaired iron status, vs 322 ± 113 meters (P = .002). Symptoms during the test were more frequent in iron deficiency patients (35% vs 27%; P = .028) and the most common symptom reported was fatigue. Multivariate logistic regression analyses showed that increased levels of soluble transferrin receptor indicating abnormal iron status were independently associated with advanced New York Heart Association class (P < .05). Multivariable analysis using generalized additive models, soluble transferrin receptor and ferritin index, both biomarkers measuring iron status, showed a significant, independent and linear association with submaximal exercise capacity (P = .03 for both). In contrast, hemoglobin levels were not significantly associated with 6-minute walk test distance in the multivariable analysis. Conclusions: In patients with chronic heart failure, iron deficiency but not anemia was associated with impaired submaximal exercise capacity and symptomatic functional limitation (AU)

Impact on clinical events and healthcare costs of adding telemedicine to multidisciplinary disease management programmes for heart failure: Results of a randomized controlled trial.

BACKGROUND: The role of telemedicine in the management of patients with chronic heart failure (HF) has not been fully elucidated. We hypothesized that multidisciplinary comprehensive HF care could achieve better results when it is delivered using telemedicine. METHODS AND RESULTS: In this study, 178 eligible patients with HF were randomized to either structured follow-up on the basis of face-to-face encounters (control group, 97 patients) or delivering health care using telemedicine (81 patients). Telemedicine included daily signs and symptoms based on telemonitoring and structured follow-up by means of video or audio-conference. The primary end-point was non-fatal HF events after six months of follow-up. The median age of the patients was 77 years, 41% were female, and 25% were frail patients. The hazard ratio for the primary end-point was 0.35 (95% confidence interval (CI), 0.20-0.59; p-value < 0.001) in favour of telemedicine. HF readmission (hazard ratio 0.39 (0.19-0.77); p-value=0.007) and cardiovascular readmission (hazard ratio 0.43 (0.23-0.80); p-value=0.008) were also reduced in the telemedicine group. Mortality was similar in both groups (telemedicine: 6.2% vs control: 12.4%, p-value > 0.05). The telemedicine group experienced a significant mean net reduction in direct hospital costs of €3546 per patient per six months of follow-up. CONCLUSIONS: Among patients managed in the setting of a comprehensive HF programme, the addition of telemedicine may result in better outcomes and reduction of costs.

Iron Status in Chronic Heart Failure: Impact on Symptoms, Functional Class and Submaximal Exercise Capacity.

INTRODUCTION AND OBJECTIVES: To evaluate the effect of iron deficiency and anemia on submaximal exercise capacity in patients with chronic heart failure. METHODS: We undertook a single-center cross-sectional study in a group of stable patients with chronic heart failure. At recruitment, patients provided baseline information and completed a 6-minute walk test to evaluate submaximal exercise capacity and exercise-induced symptoms. At the same time, blood samples were taken for serological evaluation. Iron deficiency was defined as ferritin < 100 ng/mL or transferrin saturation < 20% when ferritin is < 800 ng/mL. Additional markers of iron status were also measured. RESULTS: A total of 538 heart failure patients were eligible for inclusion, with an average age of 71 years and 33% were in New York Heart Association class III/IV. The mean distance walked in the test was 285 ± 101 meters among those with impaired iron status, vs 322 ± 113 meters (P=.002). Symptoms during the test were more frequent in iron deficiency patients (35% vs 27%; P=.028) and the most common symptom reported was fatigue. Multivariate logistic regression analyses showed that increased levels of soluble transferrin receptor indicating abnormal iron status were independently associated with advanced New York Heart Association class (P < .05). Multivariable analysis using generalized additive models, soluble transferrin receptor and ferritin index, both biomarkers measuring iron status, showed a significant, independent and linear association with submaximal exercise capacity (P=.03 for both). In contrast, hemoglobin levels were not significantly associated with 6-minute walk test distance in the multivariable analysis. CONCLUSIONS: In patients with chronic heart failure, iron deficiency but not anemia was associated with impaired submaximal exercise capacity and symptomatic functional limitation.

Invasive mechanical ventilation in acute coronary syndromes in the era of percutaneous coronary intervention.

BACKGROUND: Percutaneous coronary intervention (PCI) improves prognosis in patients with acute coronary syndromes (ACS) reducing ischaemic complications and the development of heart failure, thus potentially changing invasive mechanical ventilation (IMV) requirements. Little information exists about patients with ACS requiring IMV in the current era. We aimed to analyze IMV requirements and characteristics of ACS patients treated under current recommendations (including a high rate of PCI). METHODS: Baseline characteristics, indications for IMV, management and in-hospital and mid-term clinical course were analyzed prospectively in a consecutive series of patients with ACS admitted to a tertiary care hospital. RESULTS: We included 1821 patients, of which 106 (5.8%) required IMV. Mean follow-up was 347 days. PCI was performed in 84% of cases. Patients with IMV had more comorbidities, worse left ventricular function and more unstable hemodynamic parameters on admission. In-hospital mortality in patients requiring IMV was 29%. These patients also had higher mid-term mortality (hazard ratio (HR) 6.58; 95% confidence interval (CI) 4.49-9.64; p 0.001). The most common indication for IMV was cardiopulmonary arrest (CA) (65; 61%), followed by pulmonary oedema (27; 26%) and shock (14; 13.2%). Patients with CA were younger, with better hemodynamic parameters at admission, more favourable coronary anatomy and higher rates of PCI. There were no significant differences in overall mortality between the three groups. The main cause of death in CA patients was persistent vegetative state. CONCLUSIONS: Mortality in patients with ACS requiring IMV remained high despite a high rate of PCI. Baseline characteristics, management and clinical course were different according to the reason for IMV. The most common cause for IMV requirement was CA.