Prognostic Role of Tissue Iron Deficiency Measured by sTfR Levels in Heart Failure Patients without Systemic Iron Deficiency or Anemia.

Background. Iron deficiency (ID) is a significant, high-prevalence comorbidity in chronic heart failure (HF) that represents an independent predictor of a worse prognosis. However, a clear-cut diagnosis of ID in HF patients is not assured. The soluble transferrin receptor (sTfR) is a marker that reflects tissue-level iron demand and may be an early marker of ID. However, the impact of sTfR levels on clinical outcomes in non-anemic HF patients with a normal systemic iron status has never been evaluated. Methods. This is a post hoc analysis of an observational, prospective cohort study of 1236 patients with chronic HF of which only those with normal hemoglobin levels and a normal systemic iron status were studied. The final cohort consisted of 215 patients. Tissue ID was defined as levels of sTfR > 75th percentile (1.65 mg/L). Our aim was to describe the association between sTfR and clinical outcomes (all-cause death and HF hospitalization) and to explore its association with a wide array of serum biomarkers. Results. The sTfR level (HR 1.48, 95% CI 1.13-1.96, p = 0.005) and tissue ID (HR 2.14, 95% CI 1.22-3.75, p = 0.008) was associated with all-cause death. However, we found no association between sTfR levels and the risk of HF hospitalization. Furthermore, high sTfR levels were associated with a worse biomarker profile indicating myocardial damage (troponin and NT-proBNP), systemic inflammation (CRP and albumin), and impaired erythropoiesis (erythropoietin). Conclusions. In this cohort, the presence of tissue ID defined by sTfR levels is an independent factor for all-cause death in patients with normal systemic iron parameters.

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.