Developing Cardio-Oncology Programs in the New Era: Beyond Ventricular Dysfunction Due to Cancer Treatments.

Cardiovascular disease is a common problem in cancer patients that is becoming more widely recognized. This may be a consequence of prior cardiovascular risk factors but could also be secondary to the anticancer treatments. With the goal of offering a multidisciplinary approach to guaranteeing optimal cancer therapy and the early detection of related cardiac diseases, and in light of the recent ESC Cardio-Oncology Guideline recommendations, we developed a Cardio-Oncology unit devoted to the prevention and management of these specific complications. This document brings together important aspects to consider for the development and organization of a Cardio-Oncology program through our own experience and the current evidence.

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.

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.

Iron Deficiency: Impact on Functional Capacity and Quality of Life in Heart Failure with Preserved Ejection Fraction.

The effects of iron deficiency (ID) have been widely studied in heart failure (HF) with reduced ejection fraction. On the other hand, studies in HF with preserved ejection fraction (HFpEF) are few and have included small numbers of participants. The aim of this study was to assess the role that ID plays in functional capacity and quality of life (QoL) in HFpEF while comparing several iron-related biomarkers to be used as potential predictors. ID was defined as ferritin <100 ng/mL or transferrin saturation <20%. Submaximal exercise capacity, measured by the 6-min walking test (6MWT), and QoL, assessed by the Minnesotta Living with Heart Failure Questionnaire (MLHFQ), were compared between iron deficient patients and patients with normal iron status. A total of 447 HFpEF patients were included in the present cross-sectional study, and ID prevalence was 73%. Patients with ID performed worse in the 6MWT compared to patients with normal iron status (ID 271 ± 94 m vs. non-ID 310 ± 108 m, p < 0.01). They also scored higher in the MLHFQ, denoting worse QoL (ID 49 ± 22 vs. non-ID 43 ± 23, p = 0.01). Regarding iron metabolism biomarkers, serum soluble transferrin receptor (sTfR) was the strongest independent predictor of functional capacity (ß = -63, p < 0.0001, R2 0.39) and QoL (ß = 7.95, p < 0.0001, R2 0.14) in multivariate models. This study postulates that ID is associated with worse functional capacity and QoL in HFpEF as well, and that sTfR is the best iron-related biomarker to predict both. Our study also suggests that the effects of ID could differ among HFpEF patients by left ventricular ejection fraction.

Association Between Norepinephrine Levels and Abnormal Iron Status in Patients With Chronic Heart Failure: Is Iron Deficiency More Than a Comorbidity?

Background Mechanisms underlying iron homeostasis dysregulation in patients with chronic heart failure remain unsettled. In cardiomyocyte models, norepinephrine may lead to intracellular iron depletion, but the potential association between catecholamines (sympathetic activation markers) and iron metabolism biomarkers in chronic heart failure is unknown. Methods and Results In this cross-sectional analysis, we studied the association between plasma norepinephrine levels and serum iron status biomarkers indicating iron storage (ferritin), iron transport (transferrin saturation), and iron demand (soluble transferrin receptor) in a prospective cohort of 742 chronic heart failure patients (mean age, 72±11 years; 56% male). Impaired iron status was defined as ferritin <100 µg/L or transferrin saturation <20%. Impaired iron status was observed in 69% of patients. In multivariate models, greater norepinephrine levels were associated with impaired iron transport (transferrin saturation <20%, odds ratio=2.28; 95% CI [1.19-4.35]; P=0.013), but not with impaired iron storage (ferritin <100 µg/L, odds ratio=1.25; 95% CI [0.73-2.16]; P=0.415). Norepinephrine was a significant predictor of increased iron demand (soluble transferrin receptor, standardized ß-coefficient=0.12; P=0.006) and low transferrin saturation (standardized ß-coefficient=-0.12; P=0.003). However, norepinephrine levels were not associated with iron or ferritin levels ( P>0.05). Adjusted norepinephrine marginal means were significantly higher in patients with impaired iron status compared with those with normal iron status (528 pg/mL [505-551] versus 482 pg/mL [448-518], respectively; P=0.038). Conclusions In chronic heart failure patients, increased sympathetic activation estimated with norepinephrine levels is associated with impaired iron status and, particularly, dysregulation of biomarkers suggesting impaired iron transport and increased iron demand. Whether the relationship between norepinephrine and iron metabolism is bidirectional and entails causality need to be elucidated in future research.