Established Tumour Biomarkers Predict Cardiovascular Events and Mortality in the General Population

Introduction: Several lines of evidence reveal that cardiovascular disease (CVD) and cancer share similar common pathological milieus. The prevalence of the two diseases is growing as the population ages and the burden of shared risk factors increases. In this respect, we hypothesise that tumour biomarkers can be potential predictors of CVD outcomes in the general population. Methods: We measured six tumour biomarkers (AFP, CA125, CA15-3, CA19-9, CEA and CYFRA 21-1) and determined their predictive value for CVD in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study. A total of 8,592 subjects were enrolled in the study. Results: The levels of CEA significantly predicted CV morbidity and mortality, with hazard ratios (HRs) of HR 1.28 (95% CI 1.08–1.53), respectively. Two biomarkers (CA15-3 and CEA) showed statistical significance in predicting all-cause mortality, with HRs 1.58 (95% CI 1.18–2.12) and HR 1.60 (95% CI 1.30–1.96), when adjusted for shared risk factors and prevalent CVD. Furthermore, biomarkers seem to be sex specific. CYFRA 21-1 presented as an independent predictor of CV morbidity and mortality in female, but not in male gender, with HR 1.82 (95% CI 1.40–2.35). When it comes to all-cause mortality, both CYFRA and CEA show statistical significance in male gender, with HR 1.64 (95% CI 1.28–3.12) and HR 1.55 (95% CI 1.18–2.02), while only CEA showed statistical significance in female gender, with HR 1.64 (95% CI 1.20–2.24). Lastly, CA15-3 and CEA strongly predicted CV mortality with HR 3.01 (95% CI 1.70–5.32) and HR 1.82 (95% CI 1.30–2.56). On another hand, CA 15-3 also presented as an independent predictor of heart failure (HF) with HR 1.67 (95% CI 1.15–2.42). Conclusion: Several tumour biomarkers demonstrated independent prognostic value for CV events and all-cause mortality in a large cohort from the general population. These findings support the notion that CVD and cancer are associated with similar pathological milieus

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new‐onset or worsening heart failure (BIOSTAT‐CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT‐proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all‐cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT‐CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways

Prognostic value of mid-regional pro-adrenomedullin in patients with heart failure after an acute myocardial infarction

Objective To assess the cardiovascular prognostic value of mid-regional pro-adrenomedullin (MR-proADM) and compare this with B-type natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), on death or a composite end point in patients who developed heart failure after an acute myocardial infarction (AMI). Methods From a subset of 214 patients from the OPTIMAAL study, blood samples were obtained at a median of 3 days after AMI when patients had developed signs and/or symptoms of heart failure (HF) or a left ventricular ejection fraction <0.35%. End points were all-cause mortality and a composite end point, including death, myocardial reinfarction, stroke and/ or resuscitated cardiac arrest. Results Mean age of the patients was 68 +/- 10 years and mean follow-up was 918 +/- 311 days. During follow-up 31 patients died and 61 reached the composite end point. In multivariable Cox proportional hazard models adjusted for BNP, NT-proBNP and other covariates, a doubling of MR-proADM showed a 3.02 (95% CI 1.66 to 5.49) times increased risk of mortality (p <0.001) and a 1.77 (95% CI 1.13 to 2.78) times increased risk of reaching the composite end point (p=0.013). Receiver operating characteristic curves indicated that MR-proADM (area under the curve (AUC)=0.81) was a stronger predictor of mortality than BNP (AUC=0.66; p=0.0034 vs MR-proADM) and NT-proBNP (AUC=0.67; p <0.001 vs MR-proADM). Furthermore, MR-proADM enhanced significantly risk classification and integrated discrimination improvement in comparison with BNP and NT-proBNP. Finally, changes in MR-proADM over time significantly added prognostic information to the baseline value. Conclusion MR-proADM is a promising biomarker and has strong prognostic value for mortality and morbidity in patients with HF after an AMI. In this study, MR-proADM had stronger predictive value than BNP and NT-proBNP

Iron deficiency and health-related quality of life in chronic heart failure: Results from a multicenter European study

Patients affected by chronic heart failure (CHF) present significant impairment of health-related quality of life (HRQoL). Iron deficiency (ID) is a common comorbidity in CHF with negative impact in prognosis and functional capacity. The role of iron in energy metabolism could be the link between ID and HRQoL. There is little information about the role of ID on HRQoL in patients with CHF. We evaluate the impact of ID on HRQoL and the interaction with the anaemia status, iron status, clinical baseline information and HRQoL, measured with the Minnesota Living with Heart Failure questionnaire (MLHFQ) was obtained at baseline in an international cohort of 1278 patients with CHF. Baseline characteristics were median age 68 +/- 12, 882 (69%) were males, ejection fraction was 38% +/- 15 and NYHA class was I/II/III/IV (156/247/487/66). ID (defined as ferritin level b 100 mu g/L or serum ferritin 100-299 mu g/L in combination with a TSAT <20%) was present in 741 patients (58%). 449 (35%) patients were anaemic. Unadjusted global scores of MLHFQ (where higher scores reflect worse HRQoL) were worse in ID and anaemic patients (ID+: 42 +/- 25 vs. ID-: 37 +/- 25; p-value = 0.001 and A+: 46 +/- 25 vs. A-: 37 +/- 25; p-value b 0.001). The combined influence of ID and anaemia was explored with different multivariable regression models, showing that ID but not anaemia was associated with impaired HRQoL. ID has a negative impact on HRQoL in CHF patients, and this is independent of the presence of anaemia. (C) 2014 Elsevier Ireland Ltd. All rights reserved

Differences in Clinical Profile and Outcomes of Low Iron Storage vs Defective Iron Utilization in Patients With Heart Failure: Results From the DEFINE-HF and BIOSTAT-CHF Studies

Importance: Iron deficiency is present in half of patients with heart failure (HF) and is associated with increased morbidity and an impaired prognosis. Iron deficiency due to low iron storage (LIS) and defective iron utilization (DIU) are not entirely the same clinical problem, although they generally receive the same treatment. Objective: To define and describe similarities and differences between LIS and DIU in patients with HF. Design, Setting, and Participants: This analysis included data from 2 prospective observational studies: the Definition of Iron Deficiency in Chronic Heart Failure (DEFINE-HF) study, a single-center study conducted from 2013 to 2015 including 42 patients with a reduced left ventricular ejection fraction of 45% or less scheduled for coronary artery bypass graft surgery, and the A Systems Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study, a multinational study conducted from 2010 to 2014 including 2357 patients with worsening HF from 69 centers in 11 countries. The median (interquartile range) follow-up time was 1.8 (1.3-2.3) years. Data were analyzed from January 2018 to January 2019. Main Outcomes and Measures: The DEFINE-HF cohort was set up to derive a definition for different etiologies of iron deficiency using bone marrow iron staining as the criterion standard. This definition was applied to the BIOSTAT-CHF cohort to assess its association with clinical profile, biomarkers, and the primary composite end point of all-cause mortality or HF hospitalizations. Results: Among the 42 patients in the DEFINE-HF study, 10 (24%) were women, and the mean (SD) age was 68.0 (9.5) years. Low iron storage was defined as a bone marrow-validated combination of transferrin saturation less than 20% and a serum ferritin concentration of 128 ng/mL or less; DIU was defined as transferrin saturation less than 20% and a serum ferritin concentration greater than 128 ng/mL. These criteria were applied to 2356 patients with worsening HF in the BIOSTAT-CHF study; 1074 (45.6%) were women, and the mean (SD) age was 68.9 (12.0) years. A total of 1453 patients with worsening HF (61.6%) had iron deficiency, of whom 960 (66.1%) had LIS and 493 (33.9%) had DIU. Low iron storage was characterized by a higher proportion of anemia and a poorer quality of life, while DIU was characterized by higher levels of various inflammatory markers. Both LIS and DIU were associated with an impaired 6-minute walking test. Low iron storage was independently associated with the composite end point of all-cause mortality or HF hospitalizations (hazard ratio, 1.47; 95% CI, 1.26-1.71; P < .001), while DIU was not (hazard ratio, 1.05; 95% CI, 0.87-1.26; P = .64). Conclusions and Relevance: In this study, both LIS and DIU were prevalent in patients with HF and had a distinct clinical profile. Only LIS was independently associated with increased rates of morality and HF hospitalizations, while DIU was not

Biomarker Profiles in Heart Failure Patients With Preserved and Reduced Ejection Fraction

Background-Biomarkers may help us to unravel differences in the underlying pathophysiology between heart failure (HF) patients with a reduced ejection fraction (HFrEF) and a preserved ejection fraction (HFpEF). Therefore, we compared biomarker profiles to characterize pathophysiological differences between patients with HFrEF and HFpEF. Methods and Results-We retrospectively analyzed 33 biomarkers from different pathophysiological domains (inflammation, oxidative stress, remodeling, cardiac stretch, angiogenesis, arteriosclerosis, and renal function) in 460 HF patients (21% HFpEF, left ventricular ejection fraction amp;gt;= 45%) measured at discharge after hospitalization for acute HF. The association between these markers and the occurrence of all-cause mortality and/or HF-related rehospitalizations at 18 months was compared between patients with HFrEF and HFpEF. Patients were 70.6 +/- 11.4 years old and 37.4% were female. Patients with HFpEF were older, more often female, and had a higher systolic blood pressure. Levels of high-sensitive C-reactive protein were significantly higher in HFpEF, while levels of pro-atrial-type natriuretic peptide and N-terminal pro-brain natriuretic peptide were higher in HFrEF. Linear regression followed by network analyses revealed prominent inflammation and angiogenesis-associated interactions in HFpEF and mainly cardiac stretch-associated interactions in HrEF. The angiogenesis-specific marker, neuropilin and the remodeling-specific marker, osteopontin were predictive for all-cause mortality and/or HF-related rehospitalizations at 18 months in HFpEF, but not in HFrEF (P for interaction amp;lt;0.05). Conclusions-In HFpEF, inflammation and angiogenesis- mediated interactions are predominantly observed, while stretch-mediated interactions are found in HFrEF. The remodeling marker osteopontin and the angiogenesis marker neuropilin predicted outcome in HFpEF, but not in HFrEF.Funding Agencies|Netherlands Heart Foundation [2000Z003]; Biosite France SAS, Jouy-en-Josas, France; Roche Diagnostics Nederland BV, Venlo, the Netherlands; Novartis PharmaBV, Arnhem, the Netherlands; BG Medicine Inc, Waltham, MA</p

Erythropoietin in the General Population: Reference Ranges and Clinical, Biochemical and Genetic Correlates

Background Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population. Methods We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants. Results Mean age (+/- SD) was 53 +/- 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8-9.9) IU/L in men and 7.9 (6.0-10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P <0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR <60 mL/min/1.73m(2)) this relation was linear (men) or absent (women) (P <0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P <9x10(-21)), more significantly than other erythrocyte parameters. Conclusion We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin

Serum ferritin and risk for new-onset heart failure and cardiovascular events in the community

Aims Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population. Methods and results In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 +/- 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P <0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex. Conclusions Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community

Vitamin B-12 and folate deficiency in chronic heart failure

Objective To determine the prevalence, clinical correlates and the effects on outcome of vitamin B-12 and folic acid levels in patients with chronic heart failure (HF). Methods We studied an international pooled cohort comprising 610 patients with chronic HF. The main outcome measure was all-cause mortality. Results Mean age of the patients was 68 +/- 12 years and median serum N-terminal prohormone brain natriuretic peptide level was 1801 pg/mL (IQR 705-4335). Thirteen per cent of the patients had an LVEF >45%. Vitamin B-12 deficiency (serum level Conclusions Vitamin B-12 and folate deficiency are relatively rare in patients with chronic HF. Since no significant association was observed between mean corpuscular volume and neither vitamin B-12 nor folic acid levels, this cellular index should be used with caution in the differential diagnosis of anaemia in patients with chronic HF. In contrast to iron deficiency, vitamin B-12 and folic acid levels were not related to prognosis