Additional burden of iron deficiency in heart failure patients beyond the cardio-renal anaemia syndrome: findings from the BIOSTAT-CHF study.

AIMS: Whereas the combination of anaemia and chronic kidney disease (CKD) has been extensively studied in patients with heart failure (HF), the contribution of iron deficiency (ID) to this dysfunctional interplay is unknown. We aimed to assess clinical associates and pathophysiological pathways related to ID in this multimorbid syndrome. METHODS AND RESULTS: We studied 2151 patients with HF from the BIOSTAT-CHF cohort. Patients were stratified based on ID (transferrin saturation <20%), anaemia (World Health Organization definition) and/or CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2 ). Patients were mainly men (73.3%), with a median age of 70.5 (interquartile range 61.4-78.1). ID was more prevalent than CKD and anaemia (63.3%, 47.2% and 35.6% respectively), with highest prevalence in those with concomitant CKD and anaemia (77.5% vs. 59.3%; p < 0.001). There was a considerable overlap in biomarkers and pathways between patients with isolated ID, anaemia or CKD, or in combination, with processes related to immunity, inflammation, cell survival and cancer amongst the common pathways. Key biomarkers shared between syndromes with ID included transferrin receptor, interleukin-6, fibroblast growth factor-23, and bone morphogenetic protein 6. Having ID, either alone or on top of anaemia and/or CKD, was associated with a lower overall summary Kansas City Cardiomyopathy Questionnaire score, an impaired 6-min walk test and increased incidence of hospitalizations and/or mortality in multivariable analyses (all p < 0.05). CONCLUSION: Iron deficiency, CKD and/or anaemia in patients with HF have great overlap in biomarker profiles, suggesting common pathways associated with these syndromes. ID either alone or on top of CKD and anaemia is associated with worse quality of life, exercise capacity and prognosis of patients with worsening HF.

The influence of atrial fibrillation on the levels of NT-proBNP versus GDF-15 in patients with heart failure.

BACKGROUND: In heart failure (HF), levels of NT-proBNP are influenced by the presence of concomitant atrial fibrillation (AF), making it difficult to distinguish between HF versus AF in patients with raised NT-proBNP. It is unknown whether levels of GDF-15 are also influenced by AF in patients with HF. In this study we compared the plasma levels of NT-proBNP versus GDF-15 in patients with HF in AF versus sinus rhythm (SR). METHODS: In a post hoc analysis of the index cohort of BIOSTAT-CHF (n = 2516), we studied patients with HF categorized into three groups: (1) AF at baseline (n = 733), (2) SR at baseline with a history of AF (n = 183), and (3) SR at baseline and no history of AF (n = 1025). The findings were validated in the validation cohort of BIOSTAT-CHF (n = 1738). RESULTS: Plasma NT-proBNP levels of patients who had AF at baseline were higher than those of patients in SR (both with and without a history of AF), even after multivariable adjustment (3417 [25th-75th percentile 1897-6486] versus 1788 [682-3870], adjusted p < 0.001, versus 2231 pg/mL [902-5270], adjusted p < 0.001). In contrast, after adjusting for clinical confounders, the levels of GDF-15 were comparable between the three groups (3179 [2062-5253] versus 2545 [1686-4337], adjusted p = 0.36, versus 2294 [1471-3855] pg/mL, adjusted p = 0.08). Similar patterns of both NT-proBNP and GDF-15 were found in the validation cohort. CONCLUSION: These data show that in patients with HF, NT-proBNP is significantly influenced by underlying AF at time of measurement and not by previous episodes of AF, whereas the levels of GDF-15 are not influenced by the presence of AF. Therefore, GDF-15 might have additive value combined with NT-proBNP in the assessment of patients with HF and concomitant AF.

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.

AIMS: Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort. METHODS AND RESULTS: We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007). CONCLUSION: Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

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.

Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients.

BACKGROUND: The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100-300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition. METHODS AND RESULTS: Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively (P<0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction ≤45%). In these patients, TSAT ≤19.8% and serum iron ≤13 µmol/L, and not ferritin, were independently associated with mortality. CONCLUSIONS: A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin.

Potassium and the use of renin-angiotensin-aldosterone system inhibitors in heart failure with reduced ejection fraction: data from BIOSTAT-CHF.

BACKGROUND: Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome. METHODS AND RESULTS: Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P < 0.001). Baseline potassium was an independent predictor of lower ACEi/ARB dosage achieved [odds ratio 0.70; 95% confidence interval (CI) 0.51-0.98]. An increase in potassium was not associated with adverse outcomes (hazard ratio 1.15; 95% CI 0.86-1.53). No interaction on outcome was found between baseline potassium, potassium increase during uptitration, or potassium at 9 months and increased dosage of ACEi/ARB (Pinteraction > 0.5 for all). CONCLUSION: Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.

Comorbidities in Heart Failure.

Comorbidities frequently accompany chronic heart failure (HF), contributing to increased morbidity and mortality, and an impaired quality of life. We describe the prevalence of several high-impact comorbidities in chronic HF patients and their impact on morbidity and mortality. Furthermore, we try to explain the underlying pathophysiological processes and the complex interaction between chronic HF and specific comorbidities. Although common risk factors are likely to contribute, it is reasonable to believe that factors associated with HF might cause other comorbidities and vice versa. Potential factors are inflammation, neurohormonal activation, and hemodynamic changes.

Dynamics of cerebral blood flow in patients with mild non-ischaemic heart failure.

AIMS: Heart failure (HF) is associated with tissue hypoperfusion and congestion leading to organ dysfunction. Although cerebral blood flow (CBF) is preserved over a wide range of perfusion pressures in healthy subjects, it is impaired in end-stage HF. We aimed to compare CBF, autoregulation, and cognitive function in patients with mild non-ischaemic HF with healthy controls. METHODS AND RESULTS: Fifteen patients with mild idiopathic dilated cardiomyopathy and 15 matched healthy controls were studied. Co-existing cerebrovascular disease was excluded. All subjects, except five patients with an implantable cardioverter defibrillator, underwent magnetic resonance imaging for measurements of both CBF by arterial spin labelling and quantitative volume flow entering the brain. Cardiocerebral vascular function was assessed with Doppler techniques testing cerebral dynamic autoregulation and vasomotor reactivity. Cognitive analysis was performed by neuropsychological testing. Global and regional CBF did not differ between HF patients (44.3 mL/100 g.min) and controls (42.1 mL/100 g.min). Basilar but not carotid artery inflow was reduced in patients (1.95 mL/s vs. 2.51 mL/s, P = 0.009). Testing autoregulation revealed fewer dampened blood flow fluctuations in HF patients vs. controls (0.96% vs. 0.67%, P < 0.001). Vasomotor reactivity in HF patients showed a reduced CBF velocity (48.4% vs. 61.0%, P = 0.05) and regional cerebral oxygen saturation (18.3% vs. 23.8%, P = 0.02). Cognitive function overall was not affected. CONCLUSION: Although global CBF was unaffected in patients with mild HF, significant changes in basilar inflow volume, cerebral autoregulation and vasomotor reactivity were observed. We describe a model of dynamic cerebral mechanisms required to compensate for the impaired haemodynamics in early-stage HF.

Pharmacotherapy for comorbidities in chronic heart failure: a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia.

INTRODUCTION: Chronic heart failure (HF) is frequently accompanied by one or more comorbidities. The presence of comorbidities in chronic HF is strongly correlated to HF severity and impaired outcome. AREAS COVERED: This review will address several comorbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these comorbidities will be discussed. For this review, a MEDLINE search was performed. EXPERT OPINION: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of comorbidities. Although several comorbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these comorbidities will improve patient outcome in chronic HF.

High serum erythropoietin levels are related to heart failure development in subjects from the general population with albuminuria: data from PREVEND.

AIMS: In patients with heart failure (HF), serum erythropoietin (EPO) levels are elevated and associated with disease severity and outcome. Whether endogenous EPO levels are prospectively associated with the development of HF or cardiovascular events in the general population is unknown. METHODS AND RESULTS: Serum EPO levels were measured at baseline in 6686 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Mean age (±SD) was 53 ± 12 years, 49.8% were male, and the median (interquartile range) EPO level was 7.7 (5.9-10.2) IU/L. During a median follow-up of 8.3 (7.7-8.8) years, 209 (3.1%) subjects were newly diagnosed with HF, 97 (1.5%) died of a cardiovascular cause, and 386 (6.0%) subjects had a non-fatal cardiovascular event (277 cardiac events and 93 strokes). Each doubling of EPO level was multivariably associated with new-onset HF [hazard ratio (HR) 1.32, 95% confidence interval (CI) 1.03-1.69, P = 0.031]. EPO levels showed interaction with urinary albumin excretion (P = 0.006) and were only associated with HF in subjects with albuminuria (HR 1.51, 95% CI 1.13-2.03, P = 0.005). There was an independent association of EPO levels with stroke in women (HR 1.82, 95% CI 1.24-2.65, P = 0.002), but not in men. No association was observed for EPO levels with other cardiovascular events or cardiovascular mortality. CONCLUSION: High serum EPO levels are independently associated with an increased risk of new-onset HF in subjects with albuminuria. More research into the pathophysiological mechanisms linking EPO levels to HF is needed to understand this association.

Validity and Predictive Value of a Portable Two-Channel Sleep-Screening Tool in the Identification of Sleep Apnea in Patients With Heart Failure.

BACKGROUND: Sleep apnea is an important comorbidity in heart failure (HF) and is associated with an adverse outcome. Diagnosing sleep apnea is difficult, and polysomnography, considered to be the criterion standard, is not widely available. We assessed the validity of a portable 2-channel sleep-screening tool for the identification of sleep apnea in patients with HF. METHODS AND RESULTS: One hundred patients with stable HF had simultaneous recordings of home-based polysomnography and the screening tool (Apnealink). To compare the apnea-hypopnea index of the screening tool with polysomnography, intraclass correlation (ICC), sensitivity, and specificity were calculated, and a Bland-Altman plot and receiver operating characteristic (ROC) curves were constructed. Ninety valid measurements with the screening tool were obtained (mean age 65.5 ± 11.0 y, 72% male, mean left ventricular ejection fraction 34.6 ± 11.0%). Agreement between the screening tool and polysomnography was high (ICC 0.85). The optimal cutoff value was apnea-hypopnea index ≥15/h (area under the ROC curve 0.94). Sensitivity and specificity were 92.9% and 91.9%, respectively. CONCLUSIONS: The screening tool is useful in excluding the presence of sleep apnea in HF patients to refer only high-risk patients for more extensive polysomnography. This method may potentially reduce the need for the more expensive polysomnography.

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/1.73m²) 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.

Vitamin B12 and folate deficiency in chronic heart failure.

OBJECTIVE: To determine the prevalence, clinical correlates and the effects on outcome of vitamin B12 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 B12 deficiency (serum level <200 pg/mL), folate deficiency (serum level <4.0 ng/mL) and iron deficiency (serum ferritin level <100 µg/L, or 100-299 µg/L with a transferrin saturation <20%) were present in 5%, 4% and 58% of the patients, respectively. No significant correlation between mean corpuscular volume and vitamin B12, folic acid or ferritin levels was observed. Lower folate levels were associated with an impaired health-related quality of life (p=0.029). During a median follow-up of 2.10 years (1.31-3.60 years), 254 subjects died. In multivariable proportional hazard models, vitamin B12 and folic acid levels were not associated with prognosis. CONCLUSIONS: Vitamin B12 and folate deficiency are relatively rare in patients with chronic HF. Since no significant association was observed between mean corpuscular volume and neither vitamin B12 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 B12 and folic acid levels were not related to prognosis.